FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Ochocinska, MJ Munoz, EM Veleri, S Weller, JL Coon, SL Pozdeyev, N Iuvone, PM Goebbels, S Furukawa, T Klein, DC AF Ochocinska, Margaret J. Munoz, Estela M. Veleri, Shobi Weller, Joan L. Coon, Steven L. Pozdeyev, Nikita Iuvone, P. Michael Goebbels, Sandra Furukawa, Takahisa Klein, David C. TI NeuroD1 is required for survival of photoreceptors but not pinealocytes: Results from targeted gene deletion studies SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE gene expression; microarray; NeuroD1; pineal gland; retina; transcriptome profiling ID LEBER CONGENITAL AMAUROSIS; TRANSCRIPTION FACTOR; RETINAL PHOTORECEPTOR; MEKA PHOSDUCIN; NUCLEAR IMPORT; MOUSE MODEL; S-ANTIGEN; CELL FATE; EXPRESSION; GLAND AB NeuroD1 encodes a basic helix-loop-helix transcription factor involved in the development of neural and endocrine structures, including the retina and pineal gland. To determine the effect of NeuroD1 knockout in these tissues, a Cre/loxP recombination strategy was used to target a NeuroD1 floxed gene and generate NeuroD1 conditional knockout (cKO) mice. Tissue specificity was conferred using Cre recombinase expressed under the control of the promoter of Crx, which is selectively expressed in the pineal gland and retina. At 2 months of age, NeuroD1 cKO retinas have a dramatic reduction in rod- and cone-driven electroretinograms and contain shortened and disorganized outer segments; by 4 months, NeuroD1 cKO retinas are devoid of photoreceptors. In contrast, the NeuroD1 cKO pineal gland appears histologically normal. Microarray analysis of 2-month-old NeuroD1 cKO retina and pineal gland identified a subset of genes that were affected 2100-fold; in addition, a small group of genes exhibit altered differential night/day expression. Included in the down-regulated genes are Aipl1, which is necessary to prevent retinal degeneration, and Ankrd33, whose protein product is selectively expressed in the outer segments. These findings suggest that NeuroD1 may act through Aipl1 and other genes to maintain photoreceptor homeostasis. C1 [Ochocinska, Margaret J.; Weller, Joan L.; Coon, Steven L.; Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Munoz, Estela M.] Natl Univ Cuyo, Inst Histol & Embryol, Natl Council Res Sci & Technol CONICET, Sch Med,ANPCyT, Mendoza, Argentina. [Veleri, Shobi] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Pozdeyev, Nikita; Iuvone, P. Michael] Emory Univ, Sch Med, Dept Ophthalmol & Pharmacol, Atlanta, GA USA. [Goebbels, Sandra] Max Planck Inst Expt Med, Dept Neurogenet, D-3400 Gottingen, Germany. [Furukawa, Takahisa] Osaka Univ, Inst Prot Res, Osaka, Japan. [Furukawa, Takahisa] Osaka Univ, CREST JST, Osaka, Japan. RP Klein, DC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, 49 Convent Dr,Room 6A82, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov OI Munoz, Estela/0000-0002-6701-1535 FU National Institute of Child Health and Human Development, NIH [R01EY004864, P30EY006360]; Research to Prevent Blindness, Inc. (RPB); RPB FX This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH grants R01EY004864 and P30EY006360, and an unrestricted departmental grant from Research to Prevent Blindness, Inc. (RPB). PMI is a recipient of a Senior Scientific Investigator Award from RPB. We would like to thank members of the Klein laboratory, Dr. Morten Moller and Dr. James Russell for many helpful discussions, Dr. Cheryl Craft for the gift of S-opsin and M-opsin antisera, Dr. Robert Molday for the gift of the Rho (Rho 4D2) antiserum, Dr. David J. Erle for the gift of Agr2+/) mice, Chip Dye (NICHD Microscopy and Imaging Core) for his help with transmission electron microscopy, Dr. Anand Swaroop and members of the Neurobiology-Neurodegeneration and Repair Laboratory, and Dr. Haohua Qian in the NEI Visual Function Core for assistance with electroretinography, and Daniel Abebe for his veterinary support. NR 52 TC 11 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2012 VL 123 IS 1 BP 44 EP 59 DI 10.1111/j.1471-4159.2012.07870.x PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 003SO UT WOS:000308631800005 PM 22784109 ER PT J AU Qin, C Zhou, M Callaghan, WM Posner, SF Zhang, J Berg, CJ Zhao, GL AF Qin, Cheng Zhou, Min Callaghan, William M. Posner, Samuel F. Zhang, Jun Berg, Cynthia J. Zhao, Gengli TI Clinical Indications and Determinants of the Rise of Cesarean Section in Three Hospitals in Rural China SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Cesarean delivery rate; Cesarean indication; Rural China ID PREGNANCY OUTCOMES; DELIVERY; WOMEN AB This study investigated changes in cesarean delivery rate and cesarean indications in 3 county-level hospitals in rural China. Hospital delivery records in 1997 and 2003 were used to examine the reasons behind the changes. In Chengde County Hospital, the cesarean delivery rate increased from 28% in 1997 to 54% in 2003. The rate increased from 43% in 1997 to 65% in 2003 in Anxian County Hospital and Anxian Maternal and Child Health Hospital. The dramatic increase in cesarean delivery in the study hospitals was associated with a shift from more severe to mild or no clinical indications. The ratio of mild to moderate to severe hypertension increased substantially. More than half of the cephalopelvic disproportion cases were diagnosed prior to labor. The majority of nuchal cord cases were diagnosed without fetal distress. Maternal/family request was the number one cesarean indication in Anxian County Hospital and Anxian MCH Hospital in 2003. Ultrasound evidence of nuchal cord moved from the ninth ranked indication in 1997 to the second in 2003 in Chengde County Hospital. C1 [Qin, Cheng; Callaghan, William M.; Berg, Cynthia J.] Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Zhou, Min; Zhao, Gengli] Peking Univ, Womens & Childrens Hlth Ctr, Beijing 100871, Peoples R China. [Zhang, Jun] NICHHD, NIH, Rockville, MD USA. RP Qin, C (reprint author), Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway,NE MS K-23, Atlanta, GA 30341 USA. EM caq9@cdc.gov OI Posner, Samuel/0000-0003-1574-585X NR 21 TC 9 Z9 11 U1 1 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD OCT PY 2012 VL 16 IS 7 BP 1484 EP 1490 DI 10.1007/s10995-011-0913-7 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 006LT UT WOS:000308821400015 PM 22160744 ER PT J AU Miller, PE Snyder, DC AF Miller, Paige E. Snyder, Denise C. TI Phytochemicals and Cancer Risk: A Review of the Epidemiological Evidence SO NUTRITION IN CLINICAL PRACTICE LA English DT Review DE neoplasms; carotenoids; phytoestrogens; phytosterols; isothiocyanates; chlorophyll; epidemiology ID NESTED CASE-CONTROL; SINGAPORE CHINESE HEALTH; S-TRANSFERASE POLYMORPHISMS; EPITHELIAL OVARIAN-CANCER; DIETARY FLAVONOID INTAKE; RENAL-CELL CANCER; BREAST-CANCER; PROSTATE-CANCER; COLORECTAL-CANCER; LUNG-CANCER AB A number of epidemiological studies have investigated associations between various phytochemicals and cancer risk. Phytoestrogens and carotenoids are the two most commonly studied classes of phytochemicals; phytosterols, isothiocyanates, and chlorophyll also have been investigated, although to a much lesser extent. Because there have been no systematic reviews of the literature on all phytochemicals and cancer risk to date, this article systematically reviews 96 published epidemiological studies that examined associations between phytochemicals and cancer risk. Most studies found null associations between individual phytochemicals and cancer risk at various sites. In addition, results from past studies have been largely inconsistent, and observed associations have been of relatively modest magnitude. The most consistent protective effects were observed for higher levels-dietary intake, serum, plasma, or urinary metabolites-of beta-carotene and renal cell cancer, beta-cryptoxanthin and lung cancer, isothiocyanates and lung cancer, isothiocyanates and gastrointestinal cancer, lignans and postmenopausal breast cancer, and flavonoids and lung cancer. Although elevated risk of certain cancers with higher levels of certain phytochemicals was observed, an insufficient pool of studies examining the same associations or inconsistent findings across studies limit the ability to conclude that any one phytochemical increases cancer risk. Additional research is needed to support previously identified associations in cases where only one study has examined a particular relationship. Importantly, continued research efforts are needed to evaluate the cumulative and interactive effects of numerous phytochemicals and phytochemical-rich foods on cancer risk. (Nutr Clin Pract. 2012;27:599-612) C1 [Miller, Paige E.] NCI, Rockville, MD 20852 USA. [Snyder, Denise C.] Duke Univ, Sch Med, Durham, NC USA. RP Miller, PE (reprint author), NCI, 6130 Execut Blvd,EPN 4081, Rockville, MD 20852 USA. EM paige.miller@nih.gov NR 119 TC 45 Z9 46 U1 1 U2 54 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0884-5336 J9 NUTR CLIN PRACT JI Nutr. Clin. Pract. PD OCT PY 2012 VL 27 IS 5 BP 599 EP 612 DI 10.1177/0884533612456043 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 000UC UT WOS:000308413300005 PM 22878362 ER PT J AU Martin, KR Shreffler, J Schoster, B Callahan, LF AF Martin, Kathryn Remmes Shreffler, Jack Schoster, Britta Callahan, Leigh F. TI Coping with Prescription Medication Costs: a Cross-sectional Look at Strategies Used and Associations with the Physical and Psychosocial Health of Individuals with Arthritis SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Medication cost; Medication underuse; Coping strategies; Health status outcomes; Arthritis ID QUALITY-OF-LIFE; RHEUMATOLOGY ATTITUDES INDEX; CONCEPTUALLY BASED APPROACH; CHRONICALLY ILL PATIENTS; UNITED-STATES; OLDER-ADULTS; ASSESSMENT QUESTIONNAIRE; TREATMENT ADHERENCE; HELPLESSNESS INDEX; CHRONIC ILLNESSES AB Prescription medication costs increase financial burden, often leading individuals to engage in intentional nonadherence. Little is known about what specific medication cost-coping strategies individuals with arthritis employ. The purposes of this study are (1) to identify characteristics of individuals with arthritis who self-report prescription medication cost-coping strategies and (2) to examine the association between medication cost-coping strategies and health status. Seven hundred twenty-nine people self-reporting arthritis and prescription medication use completed a telephone survey. Adjusted regression models examined medication cost-coping strategies and five health status outcomes. Participants reported engaging in cost-coping strategies due to medication costs. Those borrowing money had worse psychosocial health and greater disability; those with increasing credit card debt reported worse physical functioning, self-rated health, and greater helplessness. Medication underuse was associated with worse psychosocial health, greater disability, and depressive symptoms. Individuals with arthritis use multiple strategies to cope with medication costs, and these strategies are associated with adverse physical and psychosocial health status. C1 [Martin, Kathryn Remmes] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Martin, Kathryn Remmes; Shreffler, Jack; Schoster, Britta; Callahan, Leigh F.] Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC 27599 USA. RP Martin, KR (reprint author), NIA, Lab Epidemiol Demog & Biometry, Gateway Bldg,Suite 3C-309,7201 Wisconsin Ave,MSC, Bethesda, MD 20892 USA. EM kathryn.martin@nih.gov FU Intramural NIH HHS [Z99 AG999999]; NIAMS NIH HHS [T32 AR007416, P60 AR049465, P60-AR049465-05, 5T32-AR007416] NR 73 TC 1 Z9 1 U1 6 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD OCT PY 2012 VL 44 IS 2 BP 236 EP 247 DI 10.1007/s12160-012-9380-7 PG 12 WC Psychology, Multidisciplinary SC Psychology GA 006MI UT WOS:000308822900013 PM 22740363 ER PT J AU Shinar, Y Obici, L Aksentijevich, I Bennetts, B Austrup, F Ceccherini, I Costa, JM De Leener, A Gattorno, M Kania, U Kone-Paut, I Lezer, S Livneh, A Moix, I Nishikomori, R Ozen, S Phylactou, L Risom, L Rowczenio, D Sarkisian, T van Gijn, ME Witsch-Baumgartner, M Morris, M Hoffman, HM Touitou, I AF Shinar, Y. Obici, L. Aksentijevich, I. Bennetts, B. Austrup, F. Ceccherini, I. Costa, J. M. De Leener, A. Gattorno, M. Kania, U. Kone-Paut, I. Lezer, S. Livneh, A. Moix, I. Nishikomori, R. Ozen, S. Phylactou, L. Risom, L. Rowczenio, D. Sarkisian, T. van Gijn, M. E. Witsch-Baumgartner, M. Morris, M. Hoffman, H. M. Touitou, I. TI Guidelines for the genetic diagnosis of hereditary recurrent fevers SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Review ID FAMILIAL-MEDITERRANEAN-FEVER; AUTOINFLAMMATORY SYNDROMES; PERIODIC FEVER; MUTATION; INFEVERS; REGISTRY; EXPERIENCE; DISORDERS; FREQUENCY; SPECTRUM AB Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance. C1 [Touitou, I.] Univ UM1, Unite Med Malad Autoinflammatoires, CHRU Montpellier, INSERM,U844, Montpellier, France. [Shinar, Y.] Chaim Sheba Med Ctr, Heller Inst Med Res, IL-52621 Tel Hashomer, Israel. [Obici, L.] Policlin San Matteo, Fdn IRCCS, Biotechnol Res Labs, Amyloid Ctr, I-27100 Pavia, Italy. [Aksentijevich, I.] NHGRI, Bethesda, MD 20892 USA. [Bennetts, B.] Childrens Hosp Westmead, Dept Mol Genet, Sydney, NSW, Australia. [Ceccherini, I.] Ist Giannina Gaslini, Genet Mol Lab, I-16148 Genoa, Italy. [Costa, J. M.] Lab Cerba, Dept Mol Genet, Cergy Pontoise, France. [De Leener, A.] Univ Libre Brussels, Hop Erasme, Dept Human Genet ULB, B-1070 Brussels, Belgium. [Gattorno, M.] Ist Giannina Gaslini, UO Pediat Reumatol 2, Genoa, Italy. [Kania, U.] Jagiellonian Univ, Coll Med, Polish Amer Childrens Hosp, Dept Pediat, PL-31007 Krakow, Poland. [Kone-Paut, I.] Univ Paris 11, Kremlin Bicetre Hosp, APHP, Dept Paediat & Paediat Rheumatol,Reference Ctr Au, Paris, France. [Lezer, S.] Pronto Diagnost, Tel Aviv, Israel. [Livneh, A.] Tel Aviv Univ, Sheba Med Ctr, Heller Inst Med Res, IL-69978 Tel Aviv, Israel. [Moix, I.; Morris, M.] Univ Hosp Geneva, Serv Med Genet, Mol Diagnost Lab, Geneva, Switzerland. [Nishikomori, R.] Kyoto Univ, Grad Sch Med, Dept Pediat, Kyoto, Japan. [Ozen, S.] Hacettepe Univ, Dept Pediat Rheumatol & Nephrol, Ankara, Turkey. [Phylactou, L.] Cyprus Inst Neurol & Genet, Dept Mol Genet Funct & Therapy, Nicosia, Cyprus. [Risom, L.] Copenhagen Univ Hosp, Dept Clin Genet, Copenhagen, Denmark. [Rowczenio, D.] UCL Med Sch, Natl Amyloidosis Ctr, London, England. [Sarkisian, T.] Ctr Med Genet & Primary Hlth Care, Yerevan, Armenia. [van Gijn, M. E.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Witsch-Baumgartner, M.] Med Univ Innsbruck, Sekt Humangenet, Innsbruck, Austria. [Hoffman, H. M.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. RP Touitou, I (reprint author), Univ UM1, Unite Med Malad Autoinflammatoires, CHRU Montpellier, INSERM,U844, Montpellier, France. EM isabelle.touitou@inserm.fr FU EU projects EuroGentest [FP6-512148]; Eurotraps (coordination theme 1 (health) of the European Community's FP7) [HEALTH-F2-2008-200923]; Eurotraps (la Region Languedoc-Roussillon); Eurofever (EAHC) [2007332]; French Ministry of Health FX This study was supported and performed within the framework of the EU projects EuroGentest (FP6-512148), Eurotraps (coordination theme 1 (health) of the European Community's FP7, grant agreement number HEALTH-F2-2008-200923 and la Region Languedoc-Roussillon) and Eurofever (EAHC, Project No2007332). It was also supported by the French Ministry of Health. The authors are indebted to Drs Catherine Dode, Laurence Cuisset and Isabelle Jeru from the GenMAI network for the elaboration of the clinical questionnaire for the genetic diagnosis of HRFs. The authors thank Dr Robert Elles for reviewing the paper and Outi Kamarainen and Simon Patton for overseeing the HRF EQA scheme of EMQN and for the logistic support of the meeting. NR 28 TC 38 Z9 45 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD OCT PY 2012 VL 71 IS 10 BP 1599 EP 1605 DI 10.1136/annrheumdis-2011-201271 PG 7 WC Rheumatology SC Rheumatology GA 005JY UT WOS:000308747900003 PM 22661645 ER PT J AU Fujita, M Hines, CS Zoghbi, SS Mallinger, AG Dickstein, LP Liow, JS Zhang, Y Pike, VW Drevets, WC Innis, RB Zarate, CA AF Fujita, Masahiro Hines, Christina S. Zoghbi, Sami S. Mallinger, Alan G. Dickstein, Leah P. Liow, Jeih-San Zhang, Yi Pike, Victor W. Drevets, Wayne C. Innis, Robert B. Zarate, Carlos A., Jr. TI Downregulation of Brain Phosphodiesterase Type IV Measured with C-11-(R)-Rolipram Positron Emission Tomography in Major Depressive Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE cAMP; compartmental analysis; in vivo imaging; second messenger; unipolar depression; unmedicated ID SUICIDE VICTIMS; ANTIDEPRESSANT TREATMENT; TEMPORAL CORTEX; RAT-BRAIN; BINDING; ROLIPRAM; PDE4; EXPRESSION; INHIBITOR; PET AB Background: Phosphodiesterase type IV (PDE4), an important component of the cyclic adenosine monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to the inactive monophosphate. Basic studies suggest that PDE4 mediates the effects of several antidepressants. This study sought to quantify the binding of C-11-(R)-rolipram, a PDE4 inhibitor, as an indirect measure of this enzyme's activity in the brain of individuals with major depressive disorder (MDD) compared with healthy control subjects. Methods: C-11-(R)-Rolipram brain positron emission tomography scans were performed in 28 unmedicated MDD subjects and 25 age-and gender-matched healthy control subjects. Patients were moderately depressed and about one half were treatment-naive. C-11-(R)-Rolipram binding in the brain was measured using arterial C-11-(R)-rolipram levels to correct for the influence of cerebral blood flow. Results: Major depressive disorder subjects showed a widespread, approximately 20% reduction in C-11-(R)-rolipram binding (p = .002), which was not caused by different volumes of gray matter. Decreased rolipram binding of similar magnitudes was observed in most brain areas. Rolipram binding did not correlate with the severity of depressive or anxiety symptoms. Conclusions: This study is the first to demonstrate that brain levels of PDE4, a critical enzyme that regulates cAMP, are decreased in unmedicated individuals with MDD in vivo. These results are in line with human postmortem and rodent studies demonstrating downregulation of the cAMP cascade in MDD and support the hypothesis that agents such as PDE4 inhibitors, which increase activity within the cAMP cascade, may have antidepressant effects. C1 [Fujita, Masahiro; Hines, Christina S.; Zoghbi, Sami S.; Dickstein, Leah P.; Liow, Jeih-San; Zhang, Yi; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Mallinger, Alan G.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Drevets, Wayne C.] Univ Oklahoma, Laureate Inst Brain Res, Coll Med, Tulsa, OK USA. [Drevets, Wayne C.] Univ Oklahoma, Dept Psychiat, Coll Med, Tulsa, OK USA. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B1D43,10 Ctr Dr,MSC 1026, Bethesda, MD 20892 USA. EM fujitam@mail.nih.gov OI Dickstein, Leah/0000-0002-4779-4122 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. NR 29 TC 28 Z9 29 U1 4 U2 10 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 OCT 1 PY 2012 VL 72 IS 7 BP 548 EP 554 DI 10.1016/j.biopsych.2012.04.030 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 004XE UT WOS:000308714000008 PM 22677471 ER PT J AU Cornwell, BR Salvadore, G Furey, M Marquardt, CA Brutsche, NE Grillon, C Zarate, CA AF Cornwell, Brian R. Salvadore, Giacomo Furey, Maura Marquardt, Craig A. Brutsche, Nancy E. Grillon, Christian Zarate, Carlos A., Jr. TI Synaptic Potentiation Is Critical for Rapid Antidepressant Response to Ketamine in Treatment-Resistant Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cortical excitability; gamma oscillation; ketamine; magnetoencephalography; major depression; NMDA antagonist ID NMDA RECEPTOR HYPOFUNCTION; D-ASPARTATE ANTAGONIST; MOOD DISORDERS; PREFRONTAL CORTEX; AMPA RECEPTOR; RILUZOLE; NEURONS; TRIAL; LOCALIZATION; INTERNEURONS AB Background: Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous gamma oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine. Methods: Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Asberg Depression Rating Scale scores. Results: Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical gamma-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders. Conclusions: These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine. C1 [Cornwell, Brian R.; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Salvadore, Giacomo; Furey, Maura; Marquardt, Craig A.; Brutsche, Nancy E.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Salvadore, Giacomo] Johnson & Johnson, Pharmaceut Res & Dev, Titusville, NJ USA. RP Cornwell, BR (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, NIH, 15K North Dr,Room 200,MSC 2670, Bethesda, MD 20892 USA. EM cornwellb@mail.nih.gov RI Furey, Maura/H-5273-2013 FU National Institute of Mental Health; National Alliance for Research on Schizophrenia and Depression FX This research was supported by the intramural research program of the National Institute of Mental Health and National Alliance for Research on Schizophrenia and Depression awards to CAZ and GS. NR 57 TC 51 Z9 52 U1 1 U2 22 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 OCT 1 PY 2012 VL 72 IS 7 BP 555 EP 561 DI 10.1016/j.biopsych.2012.03.029 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 004XE UT WOS:000308714000009 PM 22521148 ER PT J AU Sinthuvanich, C Haines-Butterick, LA Nagy, KJ Schneider, JP AF Sinthuvanich, Chomdao Haines-Butterick, Lisa A. Nagy, Katelyn J. Schneider, Joel P. TI Iterative design of peptide-based hydrogels and the effect of network electrostatics on primary chondrocyte behavior SO BIOMATERIALS LA English DT Article DE Peptide; Hydrogel; Cell delivery; Self-assembly; Chondrocyte; Tissue engineering ID CELL-PROLIFERATION; CARTILAGE TISSUE; ADHESION; PROTEIN; ASSAY; DNA; HYDROXYPROLINE; ELASTICITY; STRATEGIES; SURFACES AB Iterative peptide design was used to generate two peptide-based hydrogels to study the effect of network electrostatics on primary chondrocyte behavior. MAX8 and HLT2 peptides have formal charge states of +7 and +5 per monomer, respectively. These peptides undergo triggered folding and self-assembly to afford hydrogel networks having similar theological behavior and local network morphologies, yet different electrostatic character. Each gel can be used to directly encapsulate and syringe-deliver cells. The influence of network electrostatics on cell viability after encapsulation and delivery, extracellular matrix deposition, gene expression, and the bulk mechanical properties of the gel-cell constructs as a function of culture time was assessed. The less electropositive HLT2 gel provides a microenvironment more conducive to chondrocyte encapsulation, delivery, and phenotype maintenance. Cell viability was higher for this gel and although a moderate number of cells dedifferentiated to a fibroblast-like phenotype, many retained their chondrocytic behavior. As a result, gel-cell constructs prepared with HLT2, cultured under static in vitro conditions, contained more GAG and type II collagen resulting in mechanically superior constructs. Chondrocytes delivered in the more electropositive MAX8 gel experienced a greater degree of cell death during encapsulation and delivery and the remaining viable cells were less prone to maintain their phenotype. As a result, MAX8 gel-cell constructs had fewer cells, of which a limited number were capable of laying down cartilage-specific ECM. Published by Elsevier Ltd. C1 [Sinthuvanich, Chomdao; Nagy, Katelyn J.; Schneider, Joel P.] NCI, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Sinthuvanich, Chomdao; Haines-Butterick, Lisa A.; Nagy, Katelyn J.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. RP Schneider, JP (reprint author), NCI, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM Joel.Schneider@nih.gov RI Schneider, Joel/N-2610-2014 FU Office of the Higher Education Commission, Ministry of Education, Thailand; National Cancer Institute, National Institutes of Health FX We thank Dr. Weidong Yang and Dr. Sonia D'Souza for technical assistance. We also thank Dr. Mary C. Farach-Carson for fruitful discussion. This work is partially supported by a graduate fellowship awarded to Chomdao Sinthuvanich through the Strategic Scholarship for Frontier Research Network (SFR) from the Office of the Higher Education Commission, Ministry of Education, Thailand. Research funding was provided by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 36 TC 17 Z9 17 U1 2 U2 61 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD OCT PY 2012 VL 33 IS 30 BP 7478 EP 7488 DI 10.1016/j.biomaterials.2012.06.097 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 002HZ UT WOS:000308524000017 PM 22841922 ER PT J AU Kubben, N Adriaens, M Meuleman, W Voncken, JW van Steensel, B Misteli, T AF Kubben, Nard Adriaens, Michiel Meuleman, Wouter Voncken, Jan Willem van Steensel, Bas Misteli, Tom TI Mapping of lamin A- and progerin-interacting genome regions SO CHROMOSOMA LA English DT Article ID DEPENDENT SPATIAL ARRANGEMENTS; NUCLEAR LAMINA; TRANSCRIPTION FACTOR; TAIL DOMAIN; CHROMATIN; ORGANIZATION; EXPRESSION; DEFECTS; CELLS; DIFFERENTIATION AB Mutations in the A-type lamins A and C, two major components of the nuclear lamina, cause a large group of phenotypically diverse diseases collectively referred to as laminopathies. These conditions often involve defects in chromatin organization. However, it is unclear whether A-type lamins interact with chromatin in vivo and whether aberrant chromatin-lamin interactions contribute to disease. Here, we have used an unbiased approach to comparatively map genome-wide interactions of gene promoters with lamin A and progerin, the mutated lamin A isoform responsible for the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) in mouse cardiac myoytes and embryonic fibroblasts. We find that lamin A-associated genes are predominantly transcriptionally silent and that loss of lamin association leads to the relocation of peripherally localized genes, but not necessarily to their activation. We demonstrate that progerin induces global changes in chromatin organization by enhancing interactions with a specific subset of genes in addition to the identified lamin A-associated genes. These observations demonstrate disease-related changes in higher order genome organization in HGPS and provide novel insights into the role of lamin-chromatin interactions in chromatin organization. C1 [Kubben, Nard; Misteli, Tom] NCI, Genome Cell Biol Grp, NIH, Bethesda, MD 20892 USA. [Adriaens, Michiel] AMC Med Res, Dept Expt Cardiol, NL-1100 DD Amsterdam, Netherlands. [Meuleman, Wouter; van Steensel, Bas] Netherlands Canc Inst, Div Gene Regulat, Amsterdam, Netherlands. [Voncken, Jan Willem] Maastricht Univ, Dept Mol Genet, NL-6229 ER Maastricht, Netherlands. RP Misteli, T (reprint author), NCI, Genome Cell Biol Grp, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Meuleman, Wouter/0000-0002-1196-5401; Adriaens, Michiel/0000-0002-4472-7119 FU Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research; Dutch Heart Foundation; ZonMW; EU FX We thank K. Meaburn, T. Karpova, O. Hakim, E. Olson, L. de Windt, A. van Erk, L. Eijssen, R. van Leeuwen, L. van Opstal, and C. Calis for help with experiments and reagents. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research; the Dutch Heart Foundation; ZonMW; and the EU-KP7 grant "Inheritance". NR 39 TC 43 Z9 46 U1 1 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-5915 J9 CHROMOSOMA JI Chromosoma PD OCT PY 2012 VL 121 IS 5 BP 447 EP 464 DI 10.1007/s00412-012-0376-7 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 006LB UT WOS:000308819600002 PM 22610065 ER PT J AU Cadenhead, K Addington, J Cannon, T Cornblatt, B Mathlan, D McGlashan, T Perkins, D Seidman, L Tsuang, M Woods, S Heinssen, R AF Cadenhead, Kristin Addington, Jean Cannon, Tyrone Cornblatt, Barbara Mathlan, Daniel McGlashan, Thomas Perkins, Diana Seidman, Larry Tsuang, Ming Woods, Scott Heinssen, Robert CA NAPLS Consortium TI Startle reactivity and prepulse inhibition are reliable across sites: Findings from the North American Prodromal Longitudinal Studies (NAPLS) consortium traveling subjects study SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Meeting Abstract C1 [Cadenhead, Kristin; Tsuang, Ming] Univ Calif San Diego, La Jolla, CA 92093 USA. [Addington, Jean] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Cannon, Tyrone] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Mathlan, Daniel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Cannon, Tyrone; McGlashan, Thomas; Woods, Scott] Yale Univ, New Haven, CT 06520 USA. [Perkins, Diana] Univ N Carolina, Chapel Hill, NC 27515 USA. [Seidman, Larry] Harvard Univ, Cambridge, MA 02138 USA. [Heinssen, Robert] NIMH, Bethesda, MD 20892 USA. [Cadenhead, Kristin; NAPLS Consortium] San Diego VA Med Ctr, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-7885 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD OCT PY 2012 VL 6 SU 1 SI SI BP 38 EP 38 PG 1 WC Psychiatry SC Psychiatry GA 003AI UT WOS:000308580100138 ER PT J AU Tarbox, SI Addington, J Cadenhead, KS Cannon, TD Cornblatt, BA Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Heinssen, R McGlashan, TH Woods, SW AF Tarbox, Sarah I. Addington, Jean Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Heinssen, Robert McGlashan, Thomas H. Woods, Scott W. TI Effect of prodromal symptoms on the association between premorbid social functioning and conversion to psychosis in clinical high-risk youth SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Meeting Abstract C1 [Tarbox, Sarah I.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Addington, Jean] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, San Diego, CA 92103 USA. [Cannon, Tyrone D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, New York, NY USA. [Cornblatt, Barbara A.] Albert Einstein Coll Med, Bronx, NY USA. [Perkins, Diana O.] Univ N Carolina, Chapel Hill, NC USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Tsuang, Ming T.] Harvard Inst Psychiat Epidemiol & Genet, Boston, MA USA. [Walker, Elaine F.] Emory Univ, Atlanta, GA 30322 USA. [Heinssen, Robert] NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-7885 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD OCT PY 2012 VL 6 SU 1 SI SI BP 122 EP 122 PG 1 WC Psychiatry SC Psychiatry GA 003AI UT WOS:000308580100465 ER PT J AU Winter, L Kellman, P Renz, W Grassl, A Hezel, F Thalhammer, C von Knobelsdorff-Brenkenhoff, F Tkachenko, V Schulz-Menger, J Niendorf, T AF Winter, Lukas Kellman, Peter Renz, Wolfgang Grassl, Andreas Hezel, Fabian Thalhammer, Christof von Knobelsdorff-Brenkenhoff, Florian Tkachenko, Valeriy Schulz-Menger, Jeanette Niendorf, Thoralf TI Comparison of three multichannel transmit/receive radiofrequency coil configurations for anatomic and functional cardiac MRI at 7.0T: implications for clinical imaging SO EUROPEAN RADIOLOGY LA English DT Article DE Ultra-high field MRI; Cardiovascular MRI; Transceiver array; Parallel imaging; Cardiac chamber quantification ID CARDIOVASCULAR MAGNETIC-RESONANCE; 7 TESLA; SYNCHRONIZATION; FEASIBILITY; ANGIOGRAPHY AB To implement, examine, and compare three multichannel transmit/receive coil configurations for cardiovascular MR (CMR) at 7T. Three radiofrequency transmit-receive (TX/RX) coils with 4-, 8-, and 16-coil elements were used. Ten healthy volunteers (seven males, age 28 +/- 4 years) underwent CMR at 7T. For all three RX/TX coils, 2D CINE FLASH images of the heart were acquired. Cardiac chamber quantification, signal-to-noise ratio (SNR) analysis, parallel imaging performance assessment, and image quality scoring were performed. Mean total examination time was 29 +/- 5 min. All images obtained with the 8- and 16-channel coils were diagnostic. No significant difference in ejection fraction (EF) (P > 0.09) or left ventricular mass (LVM) (P > 0.31) was observed between the coils. The 8- and 16-channel arrays yielded a higher mean SNR in the septum versus the 4-channel coil. The lowest geometry factors were found for the 16-channel coil (mean +/- SD 2.3 +/- 0.5 for R = 4). Image quality was rated significantly higher (P < 0.04) for the 16-channel coil versus the 8- and 4-channel coils. All three coil configurations are suitable for CMR at 7.0T under routine circumstances. A larger number of coil elements enhances image quality and parallel imaging performance but does not impact the accuracy of cardiac chamber quantification. aEuro cent Cardiac chamber quantification using 7.0T magnetic resonance imaging is feasible. aEuro cent Examination times for cardiac chamber quantification at 7.0T match current clinical practice. aEuro cent Multichannel transceiver RF technology facilitates improved image quality and parallel imaging performance. aEuro cent Increasing the number of RF channels does not influence cardiac chamber quantification. C1 [Winter, Lukas; Renz, Wolfgang; Grassl, Andreas; Hezel, Fabian; Thalhammer, Christof; von Knobelsdorff-Brenkenhoff, Florian; Schulz-Menger, Jeanette; Niendorf, Thoralf] Max Delbruck Ctr Mol Med, Berlin Ultrahigh Field Facil, D-13125 Berlin, Germany. [von Knobelsdorff-Brenkenhoff, Florian; Schulz-Menger, Jeanette] HELIOS Klinikum Berlin Buch, Dept Cardiol & Nephrol, Berlin, Germany. [von Knobelsdorff-Brenkenhoff, Florian; Tkachenko, Valeriy; Schulz-Menger, Jeanette; Niendorf, Thoralf] Expt & Clin Res Ctr, Berlin, Germany. [Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Renz, Wolfgang] Siemens Healthcare, Erlangen, Germany. RP Niendorf, T (reprint author), Max Delbruck Ctr Mol Med, Berlin Ultrahigh Field Facil, Robert Roessle Str 10, D-13125 Berlin, Germany. EM Thoralf.Niendorf@mdc-berlin.de RI Niendorf, Thoralf/H-7738-2013; OI Niendorf, Thoralf/0000-0001-7584-6527; Winter, Lukas/0000-0002-4381-275X NR 22 TC 31 Z9 31 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD OCT PY 2012 VL 22 IS 10 BP 2211 EP 2220 DI 10.1007/s00330-012-2487-1 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 998KM UT WOS:000308237500020 PM 22653280 ER PT J AU Aschard, H Lutz, S Maus, B Duell, EJ Fingerlin, TE Chatterjee, N Kraft, P Van Steen, K AF Aschard, Hugues Lutz, Sharon Maus, Barbel Duell, Eric J. Fingerlin, Tasha E. Chatterjee, Nilanjan Kraft, Peter Van Steen, Kristel TI Challenges and opportunities in genome-wide environmental interaction (GWEI) studies SO HUMAN GENETICS LA English DT Review ID GENE-GENE INTERACTIONS; MULTIFACTOR-DIMENSIONALITY REDUCTION; DETECTING EPISTATIC INTERACTIONS; FAMILY-BASED ASSOCIATION; CASE-PARENT TRIADS; SEMIPARAMETRIC BAYESIAN-ANALYSIS; COMMON SNPS EXPLAIN; CASE-ONLY DESIGN; COMPLEX DISEASES; QUANTITATIVE TRAITS AB The interest in performing gene-environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate the role of environmental factors in disease risk and hence to investigate their role as genetic effect modifiers. The understanding that genetics is important in the uptake and metabolism of toxic substances is an example of how genetic profiles can modify important environmental risk factors to disease. Several rationales exist to set up gene-environment interaction studies and the technical challenges related to these studies-when the number of environmental or genetic risk factors is relatively small-has been described before. In the post-genomic era, it is now possible to study thousands of genes and their interaction with the environment. This brings along a whole range of new challenges and opportunities. Despite a continuing effort in developing efficient methods and optimal bioinformatics infrastructures to deal with the available wealth of data, the challenge remains how to best present and analyze genome-wide environmental interaction (GWEI) studies involving multiple genetic and environmental factors. Since GWEIs are performed at the intersection of statistical genetics, bioinformatics and epidemiology, usually similar problems need to be dealt with as for genome-wide association gene-gene interaction studies. However, additional complexities need to be considered which are typical for large-scale epidemiological studies, but are also related to "joining" two heterogeneous types of data in explaining complex disease trait variation or for prediction purposes. C1 [Aschard, Hugues; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lutz, Sharon; Fingerlin, Tasha E.] Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol & Biostat, Aurora, CO USA. [Lutz, Sharon; Fingerlin, Tasha E.] Univ Colorado, Colorado Sch Publ Hlth, Dept Informat, Aurora, CO USA. [Maus, Barbel; Van Steen, Kristel] Univ Liege, Inst Montefiore, Syst & Modeling Unit, B-4000 Liege, Belgium. [Maus, Barbel; Van Steen, Kristel] Univ Liege, GIGA R, B-4000 Liege, Belgium. [Duell, Eric J.] Bellvitge Biomed Res Inst IDIBELL, Unit Nutr Environm & Canc, Epidemiol Res Program, Catalan Inst Oncol ICO, Barcelona, Spain. [Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Aschard, H (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM haschard@hsph.harvard.edu OI Duell, Eric J/0000-0001-5256-0163 FU Interuniversity Attraction Poles Program (Phase VI/4); Belgian State, Science Policy Office; IST Program of the European Community under the PASCAL2 Network of Excellence (Pattern Analysis, Statistical Modeling and Computational Learning) [IST-2007-216886]; Spanish Ministry of Health [ISCIII RETICC RD06/0020]; [NIH/NIDDK-R21 DK084529] FX H. Aschard and P. Kraft were supported by grant NIH/NIDDK-R21 DK084529. B. Maus and K. Van Steen acknowledge research opportunities offered by the Belgian Network BioMAGNet (Bioinformatics and Modeling: from Genomes to Networks), funded by the Interuniversity Attraction Poles Program (Phase VI/4), initiated by the Belgian State, Science Policy Office. Their work was also supported in part by the IST Program of the European Community, under the PASCAL2 Network of Excellence (Pattern Analysis, Statistical Modeling and Computational Learning), IST-2007-216886. E.J. Duell was supported by the Spanish Ministry of Health (ISCIII RETICC RD06/0020). The scientific responsibility for this work rests with its authors. NR 195 TC 49 Z9 49 U1 1 U2 31 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD OCT PY 2012 VL 131 IS 10 SI SI BP 1591 EP 1613 DI 10.1007/s00439-012-1192-0 PG 23 WC Genetics & Heredity SC Genetics & Heredity GA 998OH UT WOS:000308249300006 PM 22760307 ER PT J AU Johnson, MD Schlett, CD Grandits, GA Mende, K Whitman, TJ Tribble, DR Hospenthal, DR Murray, PR AF Johnson, Mark D. Schlett, Carey D. Grandits, Greg A. Mende, Katrin Whitman, Timothy J. Tribble, David R. Hospenthal, Duane R. Murray, Patrick R. TI Chlorhexidine Does Not Select for Resistance in Staphylococcus aureus Isolates in a Community Setting SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Letter ID DOUBLE-BLIND; INFECTION; MUPIROCIN; TRIAL C1 [Whitman, Timothy J.] Walter Reed Natl Mil Med Ctr, Dept Infect Dis, Div Infect Dis, Bethesda, MD 20889 USA. [Johnson, Mark D.] USN, Med Ctr, Div Infect Dis, San Diego, CA 92152 USA. [Schlett, Carey D.; Mende, Katrin; Tribble, David R.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Grandits, Greg A.] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Mende, Katrin; Hospenthal, Duane R.] Brooke Army Med Ctr, Infect Dis Serv, Ft Sam Houston, TX 78234 USA. [Murray, Patrick R.] NIH, Bethesda, MD 20892 USA. RP Whitman, TJ (reprint author), Walter Reed Natl Mil Med Ctr, Dept Infect Dis, Div Infect Dis, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM timothy.whitman@med.navy.mil FU NIAID NIH HHS [Y1-AI-5072] NR 10 TC 3 Z9 3 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD OCT PY 2012 VL 33 IS 10 BP 1061 EP 1063 DI 10.1086/667744 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 004RR UT WOS:000308699300019 PM 22961032 ER PT J AU Morris, SM Petibone, DM Lin, WJ Chen, JJ Vitiello, B Witt, KL Mattison, DR AF Morris, Suzanne M. Petibone, Dayton M. Lin, Wei-Jiun Chen, James J. Vitiello, Benedetto Witt, Kristine L. Mattison, Donald R. TI The genetic toxicity of methylphenidate: a review of the current literature SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Review DE methylphenidate; ADHD; chromosome damage; mutation ID ATTENTION DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; OXIDATIVE DNA-DAMAGE; IN-VIVO; CHROMOSOMAL-ABERRATIONS; RAT-BRAIN; CHILDREN; HYDROCHLORIDE; CANCER; RISK AB Attention deficit/hyperactivity disorder (ADHD), a common children's behavioral disorder, is characterized by inattention, hyperactivity and impulsivity. The disorder is thought to stem from abnormalities in the catecholamine pathway and the symptoms of the disorder have been successfully treated with methylphenidate (MPH) since the FDA approved the drug in the 1950s. MPH underwent the appropriate safety testing as part of the FDA approval process; however, a publication in 2005 that reported significant increases in cytogenetic damage in the lymphocytes of MPH-treated pediatric patients caused concern for patients and their families, the pharmaceutical industry and regulatory agencies. This communication will review the many studies that were subsequently initiated worldwide to address the genetic safety of MPH in both animal models and human subjects. Animal experiments broadened the study protocols used in the 2005 investigation to include a wider dose-range, a longer treatment period and automated scoring of biological endpoints, where possible, to reduce observer bias. The human subject studies replicated the experimental design used in the 2005 study, but increased the treatment periods and the sizes of the study populations. Neither the laboratory animal nor human subject studies found an increase in any of the measures of genetic damage that were evaluated. Taken together, these new studies are consistent with the original safety evaluation of the FDA and do not support the hypothesis that MPH treatment increases the risk of genetic damage in ADHD patients. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 [Morris, Suzanne M.; Petibone, Dayton M.] US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lin, Wei-Jiun; Chen, James J.] US FDA, Div Personalized Nutr & Med, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Vitiello, Benedetto] NIMH, Child & Adolescent Treatment & Prevent Branch, NIH, Bethesda, MD 20892 USA. [Witt, Kristine L.] NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. RP Morris, SM (reprint author), US FDA, Div Genet & Mol Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM suzanne.morris@fda.hhs.gov RI Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 47 TC 3 Z9 3 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X J9 J APPL TOXICOL JI J. Appl. Toxicol. PD OCT PY 2012 VL 32 IS 10 BP 756 EP 764 DI 10.1002/jat.2721 PG 9 WC Toxicology SC Toxicology GA 996JU UT WOS:000308082800002 PM 22337063 ER PT J AU Jesus, AA Fujihira, E Watase, M Terreri, MT Hilario, MO Carneiro-Sampaio, M Len, CA Oliveira, SK Rodrigues, MC Pereira, RM Bica, B Silva, NA Cavalcanti, A Marini, R Sztajnbok, F Quintero, MV Ferriani, VP Moraes-Vasconcelos, D Silva, CA Oliveira, JB AF Jesus, Adriana A. Fujihira, Erika Watase, Mariana Terreri, Maria T. Hilario, Maria O. Carneiro-Sampaio, Magda Len, Claudio A. Oliveira, Sheila K. Rodrigues, Marta C. Pereira, Rosa M. Bica, Blanca Silva, Nilzio A. Cavalcanti, Andre Marini, Roberto Sztajnbok, Flavio Quintero, Maria V. Ferriani, Virginia P. Moraes-Vasconcelos, Dewton Silva, Clovis A. Oliveira, Joao B. TI Hereditary Autoinflammatory Syndromes: A Brazilian Multicenter Study SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Autoinflammatory syndromes; genetics; familial mediterranean fever; mevalonate kinase deficiency; TRAPS; NLRP3; cryopyrin; MVK; MEFV; TNFRSF1A ID FAMILIAL MEDITERRANEAN FEVER; GENOTYPE-PHENOTYPE CORRELATION; MEVALONATE KINASE-DEFICIENCY; MUCKLE-WELLS-SYNDROME; PERIODIC FEVER; CIAS1 MUTATIONS; HYPERIMMUNOGLOBULINEMIA D; GENETIC-HETEROGENEITY; MISSENSE MUTATIONS; AA AMYLOIDOSIS AB To evaluate the prevalence of genetic defects in clinically suspected autoinflammatory syndromes (AIS) in a Brazilian multicenter study. The study included 102 patients with a clinical diagnosis of Cryopyrin Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD) and Pediatric Granulomatous Arthritis (PGA). One of the five AIS-related genes (NLRP3, TNFRSF1A, MEFV, MVK and NOD2) was evaluated in each patient by direct DNA sequencing, based on the most probable clinical suspect. Clinical diagnoses of the 102 patients were: CAPS (n = 28), TRAPS (n = 31), FMF (n = 17), MKD (n = 17) and PGA (n = 9). Of them, 27/102 (26 %) had a confirmed genetic diagnosis: 6/28 (21 %) CAPS patients, 7/31 (23 %) TRAPS, 3/17 (18 %) FMF, 3/17 (18 %) MKD and 8/9 (89 %) PGA. We have found that approximately one third of the Brazilian patients with a clinical suspicion of AIS have a confirmed genetic diagnosis. C1 [Silva, Clovis A.] Univ Sao Paulo, Inst Crianca, Fac Med, HC, BR-05403000 Sao Paulo, Brazil. [Oliveira, Joao B.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20814 USA. [Ferriani, Virginia P.] FMUSP Ribeirao Preto, Ribeirao Preto, SP, Brazil. [Sztajnbok, Flavio] Univ Estado Rio De Janeiro, Rio De Janeiro, RJ, Brazil. [Marini, Roberto] Univ Estadual Campinas, Campinas, SP, Brazil. [Cavalcanti, Andre] Univ Fed Pernambuco, Recife, PE, Brazil. [Silva, Nilzio A.] Univ Fed Goias, Fac Med, Serv Reumatol, Goiania, Go, Brazil. [Bica, Blanca] Univ Fed Rio de Janeiro, Disciplina Reumatol, Rio de Janeiro, RJ, Brazil. [Pereira, Rosa M.] FMUSP, Disciplina Reumatol, Sao Paulo, Brazil. [Jesus, Adriana A.; Carneiro-Sampaio, Magda] FMUSP, Inst Crianca, Sao Paulo, Brazil. [Fujihira, Erika; Watase, Mariana; Moraes-Vasconcelos, Dewton] FMUSP, LIM 56, Sao Paulo, Brazil. [Fujihira, Erika] FMUSP, LIM 53, Sao Paulo, Brazil. [Terreri, Maria T.; Hilario, Maria O.; Len, Claudio A.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Oliveira, Sheila K.; Rodrigues, Marta C.] Univ Fed Rio de Janeiro, IPPMG, Rio de Janeiro, RJ, Brazil. [Quintero, Maria V.] Santa Casa de Misericordia Belo Horizonte, Belo Horizonte, MG, Brazil. RP Silva, CA (reprint author), Univ Sao Paulo, Inst Crianca, Fac Med, HC, Av Dr Eneas Carvalho de Aguiar 647, BR-05403000 Sao Paulo, Brazil. EM adriaj@uol.com.br; clovis.silva@icr.usp.br; oliveirajb@cc.nih.gov RI Pereira, Rosa /C-5192-2012; Ferriani, Virginia/E-2209-2012; Marini, Roberto/D-3279-2013; Oliveira, Sheila/F-5213-2016; OI Oliveira, Sheila/0000-0002-2426-716X; Oliveira, Joao/0000-0001-9388-8173; Cavalcanti, Andre/0000-0002-9105-3153 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP [2008/58866-5, 2009/12334-5]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPQ [300248/2008-3]; Federico Foundation FX This study was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP (grants 2008/58866-5 and 2009/12334-5), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPQ (grant 300248/2008-3 to CAS) and Federico Foundation Grant to CAS. We thank the following pediatric rheumatologists and pediatricians and their respective services for sample referral: Nadyesda D. Brandao (Universidade Federal de Santa Catarina), Ana Paula Vecchi (Hospital Materno-Infantil de Goiania), Maria Custodia M. Ribeiro and Fabio Tadeu M. Oliveira (Universidade de Brasilia), Erica N. Naka and Izaias P. Costa (Universidade Federal do Mato Grosso do Sul), Katia Lino (Universidade Federal Fluminense), Maria Virginia Andrade (Hospital das Clinicas da Faculdade de Medicina de Marilia), Silvana B. Sacchetti (Irmandade da Santa Casa de Misericordia de Sao Paulo), Simone Lotufo (Hospital Municipal Menino Jesus), Ana Julia P. Moraes (Universidade Federal do Para), Tereza C Robazzi (Universidade Federal da Bahia), Claudia Saad-Magalhaes (Universidade Estadual de Sao Paulo-Botucatu) and Mayra B. Dorna (Instituto da Crianca da FMUSP). We also thank Paolo Zanotto (Laboratorio de Evolucao Molecular e Bioinformatica, ICBII, USP, Jose Eduardo Krieger (Laboratorio de Genetica e Cardiologia Molecular, FMUSP), Claudio Panutti (Laboratorio de Virologia, FMUSP), Silvia Figueiredo Costa (Laboatorio de Bacteriologia, FMUSP) and Suzane Ono-Nita (Laboratorio de Gastroenterologia Clinica e Experimental) for the use of equipments. NR 44 TC 6 Z9 6 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD OCT PY 2012 VL 32 IS 5 BP 922 EP 932 DI 10.1007/s10875-012-9688-x PG 11 WC Immunology SC Immunology GA 006OM UT WOS:000308828500003 PM 22566169 ER PT J AU Sugui, JA Peterson, SW Clark, LP Nardone, G Folio, L Riedlinger, G Zerbe, CS Shea, Y Henderson, CM Zelazny, AM Holland, SM Kwon-Chung, KJ AF Sugui, Janyce A. Peterson, Stephen W. Clark, Lily P. Nardone, Glenn Folio, Les Riedlinger, Gregory Zerbe, Christa S. Shea, Yvonne Henderson, Christina M. Zelazny, Adrian M. Holland, Steven M. Kwon-Chung, Kyung J. TI Aspergillus tanneri sp nov., a New Pathogen That Causes Invasive Disease Refractory to Antifungal Therapy SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; TRANSCRIBED SPACER REGIONS; OCHRACEUS GROUP; OCHRATOXIN PRODUCTION; PHYLOGENETIC ANALYSIS; SECTION CIRCUMDATI; DNA-SEQUENCES; FUMIGATUS; NIDULANS; IDENTIFICATION AB The most common cause of invasive aspergillosis (IA) in patients with chronic granulomatous disease (CGD) is Aspergillus fumigatus followed by A. nidulans; other aspergilli rarely cause the disease. Here we review two clinical cases of fatal IA in CGD patients and describe a new etiologic agent of IA refractory to antifungal therapy. Unlike typical IA caused by A. fumigatus, the disease caused by the new species was chronic and spread from the lung to multiple adjacent organs. Mycological characteristics and the phylogenetic relationship with other aspergilli based on the sequence analysis of Mcm7, RPB2, and Tsr1 indicated that the new species, which we named as A. tanneri, belongs to Aspergillus section Circumdati. The species has a higher amphotericin B, voriconazole, and itraconazole MIC and causes more chronic infection in CGD mice than A. fumigatus. This is the first report documenting IA in CGD patients caused by a species belonging to the Aspergillus section Circumdati that is inherently resistant to azoles and amphotericin B. Unlike the results seen with many members of Aspergillus section Circumdati, ochratoxin was not detected in filtrates of cultures grown in various media. Our phenotypic and genetic characterization of the new species and the case reports will assist future diagnosis of infection caused by A. tanneri and lead to more appropriate patient management. C1 [Sugui, Janyce A.; Clark, Lily P.; Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Peterson, Stephen W.] USDA, Natl Ctr Agr Utilizat Res, Peoria, IL USA. [Nardone, Glenn] NIH, Res Technol Branch, Rockville, MD USA. [Riedlinger, Gregory] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zerbe, Christa S.; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Shea, Yvonne; Henderson, Christina M.; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 42 TC 14 Z9 15 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2012 VL 50 IS 10 BP 3309 EP 3317 DI 10.1128/JCM.01509-12 PG 9 WC Microbiology SC Microbiology GA 007DY UT WOS:000308870200025 PM 22855513 ER PT J AU Pilotto, A D'Onofrio, G Panza, F Copetti, M Cascavilla, L Paris, F Pellegrini, F Seripa, D Ferrucci, L AF Pilotto, Alberto D'Onofrio, Grazia Panza, Francesco Copetti, Massimiliano Cascavilla, Leandro Paris, Francesco Pellegrini, Fabio Seripa, Davide Ferrucci, Luigi TI Treatment of Late-Life Major Depressive Disorder With Selective Serotonin Reuptake Inhibitors Improves the Multidimensional Prognostic Index SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Letter ID COMPREHENSIVE GERIATRIC ASSESSMENT; HOSPITALIZED OLDER PATIENTS; LONG-TERM MORTALITY; ELDERLY-PATIENTS; RATING-SCALE; PRIMARY-CARE; VALIDATION; DEMENTIA; STATE C1 [Pilotto, Alberto] S Antonio Hosp, Geriatr Unit, Azienda ULSS Padova 16, Padua, Italy. [D'Onofrio, Grazia; Panza, Francesco; Seripa, Davide] IRCCS Casa Sollievo Sofferenza San Giovanni Roton, Lab Gerontol & Geriatr, Dept Med Sci, Foggia, Italy. [D'Onofrio, Grazia; Panza, Francesco; Cascavilla, Leandro; Paris, Francesco; Seripa, Davide] IRCCS Casa Sollievo Sofferenza San Giovanni Roton, Geriatr Unit, Foggia, Italy. [Copetti, Massimiliano; Paris, Francesco] IRCCS Casa Sollievo Sofferenza San Giovanni Roton, Unit Biostat, Foggia, Italy. [Pellegrini, Fabio] Consorzio Mario Negri Sud, Dept Clin Pharmacol & Epidemiol, Chieti, Italy. [Ferrucci, Luigi] NIA, Harbor Hosp Ctr, Baltimore, MD 21224 USA. RP Pilotto, A (reprint author), S Antonio Hosp, Geriatr Unit, Azienda ULSS Padova 16, Padua, Italy. EM alberto.pilotto@sanita.padova.it RI Copetti, Massimiliano/K-3186-2016; D'Onofrio, Grazia/K-9740-2016; OI Copetti, Massimiliano/0000-0002-7960-5947; D'Onofrio, Grazia/0000-0002-5905-6063; Panza, Francesco/0000-0002-7220-0656 FU Intramural NIH HHS NR 18 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2012 VL 32 IS 5 BP 726 EP 729 DI 10.1097/JCP.0b013e31826866bd PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 004HI UT WOS:000308671800029 PM 22926617 ER PT J AU Kottgen, A Albrecht, E Teumer, A Vitart, V Krumsiek, J Ciullo, M Fox, C Caulfield, M Bochud, M Geiger, C AF Kottgen, A. Albrecht, E. Teumer, A. Vitart, V. Krumsiek, J. Ciullo, M. Fox, C. Caulfield, M. Bochud, M. Geiger, C. TI Common gene variants associate with uric acid concentrations and gout but not with blood pressure or cardiovascular disease SO JOURNAL OF HUMAN HYPERTENSION LA English DT Meeting Abstract C1 [Kottgen, A.] Univ Frieburg, Freiburg, Germany. [Teumer, A.] Ernst Moritz Arndt Univ Greifswald, D-17487 Greifswald, Germany. [Vitart, V.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Ciullo, M.] Inst Genet & Biophys, Milan, Italy. [Fox, C.] NHLBI Framingham, Bethesda, MD USA. [Caulfield, M.] Barts & London Queen Marys Sch Med & Dent, London, England. [Bochud, M.] Univ Lausanne, Lausanne, Switzerland. RI Bochud, Murielle/A-3981-2010 OI Bochud, Murielle/0000-0002-5727-0218 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9240 J9 J HUM HYPERTENS JI J. Hum. Hypertens. PD OCT PY 2012 VL 26 IS 10 BP 626 EP 626 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 004NP UT WOS:000308688700027 ER PT J AU Castro, FA Quint, W Gonzalez, P Katki, HA Herrero, R van Doorn, LJ Schiffman, M Struijk, L Rodriguez, AC DelVecchio, C Lowy, DR Porras, C Jimenez, S Schiller, J Solomon, D Wacholder, S Hildesheim, A Kreimer, AR AF Castro, Felipe A. Quint, Wim Gonzalez, Paula Katki, Hormuzd A. Herrero, Rolando van Doorn, Leen-Jan Schiffman, Mark Struijk, Linda Rodriguez, Ana Cecilia DelVecchio, Corey Lowy, Douglas R. Porras, Carolina Jimenez, Silvia Schiller, John Solomon, Diane Wacholder, Sholom Hildesheim, Allan Kreimer, Aimee R. CA Costa Rica Vaccine Trial Grp TI Prevalence of and Risk Factors for Anal Human Papillomavirus Infection Among Young Healthy Women in Costa Rica SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HPV-RELATED CANCERS; INTRAEPITHELIAL LESIONS; BROAD-SPECTRUM; PCR; MEN; NEOPLASIA; CARCINOMA; VACCINE; TRENDS; TRIAL AB Methods. A total of 2017 sexually active women in the control arm of an HPV-16/18 vaccine trial had a single anal specimen collected by a clinician at the 4-year study visit. Samples were tested for HPV by SPF10 PCR/DEIA/LiPA(25), version 1. Results. A total of 4% of women had HPV-16, 22% had oncogenic HPV, and 31% had any HPV detected in an anal specimen. The prevalence of anal HPV was higher among women who reported anal intercourse, compared with those who did not (43.4% vs 28.4%; P < .001). Among women who reported anal intercourse, cervical HPV (adjusted odds ratio [aOR], 5.3 [95% confidence interval {CI}, 3.4-8.2]), number of sex partners (aOR, 2.2 [95% CI, 1.1-4.6] for >= 4 partners), and number of anal intercourse partners (aOR, 1.9 [95% CI, 1.1-3.3] for >= 2 partners) were independent risk factors for anal HPV detection. Among women who reported no anal intercourse, cervical HPV (aOR, 4.7 [95% CI, 3.7-5.9]), number of sex partners (aOR, 2.4 [95% CI, 1.7-3.4] for >= 4 partners), and report of anal fissures (aOR, 2.3 [95% CI, 1.1-4.8]) were associated with an increased odds of anal HPV detection. Conclusion. Anal HPV is common among young women, even those who report no anal sex, and was associated with cervical HPV infection. Anal fissures in women who report never having had anal intercourse may facilitate HPV exposure. Clinical Trials Registration. NCT00128661. C1 [Castro, Felipe A.; Katki, Hormuzd A.; Schiffman, Mark; Wacholder, Sholom; Hildesheim, Allan; Kreimer, Aimee R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lowy, Douglas R.; Schiller, John] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rodriguez, Ana Cecilia; Solomon, Diane] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Quint, Wim; van Doorn, Leen-Jan; Struijk, Linda] DDL Diagnost Lab, Voorburg, Netherlands. [Herrero, Rolando] Int Agcy Res Canc, Early Detect & Prevent Sect, F-69372 Lyon, France. RP Castro, FA (reprint author), 6120 Execut Blvd,EPS 7057, Rockville, MD 20852 USA. EM felipe.castro@nih.gov RI Kreimer, Aimee/H-1687-2015; Castro, Felipe/N-4241-2013; Katki, Hormuzd/B-4003-2015; Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI [N01-CP-11005]; National Institutes of Health Office of Research on Women's Health FX The Costa Rica HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the NCI. The trial is sponsored and funded by the NCI (contract N01-CP-11005), with funding support from the National Institutes of Health Office of Research on Women's Health, and is conducted with support from the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GSK Biologicals, under a clinical trials agreement with the NCI. GSK Biologicals also provided support for aspects of the trial associated with regulatory submission needs of the company, under FDA BB-IND 7920. Drs Schiller and Lowy report that they are named inventors on US government-owned HPV vaccine patents that are licensed to GSK Biologicals and Merck and for which the NCI receives licensing fees. Drs Schiller and Lowy are entitled to limited royalties as specified by federal law. The NCI and Costa Rica investigators are responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. The NCI and Costa Rica investigators make final editorial decisions on this and subsequent publications; GSK Biologicals has the right to review and comment. NR 25 TC 12 Z9 13 U1 0 U2 5 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 OCT 1 PY 2012 VL 206 IS 7 BP 1103 EP 1110 DI 10.1093/infdis/jis458 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 002JW UT WOS:000308529200015 PM 22850119 ER PT J AU Laughlin, CA Morens, DM Cassetti, MC Denis, ACS San Martin, JL Whitehead, SS Fauci, AS AF Laughlin, Catherine A. Morens, David M. Cassetti, M. Cristina Denis, Adriana Costero-Saint San Martin, Jose-Luis Whitehead, Stephen S. Fauci, Anthony S. TI Dengue Research Opportunities in the Americas SO JOURNAL OF INFECTIOUS DISEASES LA English DT Review ID ANTIBODY-DEPENDENT ENHANCEMENT; MOSQUITO AEDES-AEGYPTI; VIRUS-INFECTION; CLINICAL-EVALUATION; HEMORRHAGIC-FEVER; DISEASE SEVERITY; HOST FACTORS; VACCINE; PATHOGENESIS; GENOME AB Dengue is a systemic arthropod-borne viral disease of major global public health importance. At least 2.5 billion people who live in areas of the world where dengue occurs are at risk of developing dengue fever (DF) and its severe complications, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Repeated reemergences of dengue in sudden explosive epidemics often cause public alarm and seriously stress healthcare systems. The control of dengue is further challenged by the lack of effective therapies, vaccines, and point-of-care diagnostics. Despite years of study, even its pathogenic mechanisms are poorly understood. This article discusses recent advances in dengue research and identifies challenging gaps in research on dengue clinical evaluation, diagnostics, epidemiology, immunology, therapeutics, vaccinology/clinical trials research, vector biology, and vector ecology. Although dengue is a major global tropical pathogen, epidemiologic and disease control considerations in this article emphasize dengue in the Americas. C1 [Laughlin, Catherine A.; Cassetti, M. Cristina] NIAID, Virol Branch, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Morens, David M.; Fauci, Anthony S.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. [Denis, Adriana Costero-Saint] NIAID, Parasitol & Int Programs Branch, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [San Martin, Jose-Luis] Pan Amer Hlth Org, Reg Advisor Dengue, San Jose, Costa Rica. [Whitehead, Stephen S.] NIAID, Infect Dis Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Laughlin, CA (reprint author), NIAID, Virol Branch, Div Microbiol & Infect Dis, NIH, 6610 Rockledge Dr,MSC 6603, Bethesda, MD 20892 USA. EM claughlin@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX S. S. W. was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. There was no specific funding for preparation of this review. NR 50 TC 27 Z9 30 U1 0 U2 19 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 OCT 1 PY 2012 VL 206 IS 7 BP 1121 EP 1127 DI 10.1093/infdis/jis351 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 002JW UT WOS:000308529200017 PM 22782946 ER PT J AU Decker, M Adamska, M Cronin, A Di Giallonardo, F Burgener, J Marowsky, A Falck, JR Morisseau, C Hammock, BD Gruzdev, A Zeldin, DC Arand, M AF Decker, Martina Adamska, Magdalena Cronin, Annette Di Giallonardo, Francesca Burgener, Julia Marowsky, Anne Falck, John R. Morisseau, Christophe Hammock, Bruce D. Gruzdev, Artiom Zeldin, Darryl C. Arand, Michael TI EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides SO JOURNAL OF LIPID RESEARCH LA English DT Article DE epoxyeicosatrienoic acid; blood pressure; pain; diabetes type II ID EPOXYEICOSATRIENOIC ACIDS; CATALYTIC MECHANISM; IDENTIFICATION; METHYLATION; TARGET; VISUALIZATION; INTERMEDIATE; INFLAMMATION; ANGIOGENESIS; ATTENUATION AB Epoxide hydrolases are a small superfamily of enzymes important for the detoxification of chemically reactive xenobiotic epoxides and for the processing of endogenous epoxides that act as signaling molecules. Here, we report the identification of two human epoxide hydrolases: EH3 and EH4. They share 45% sequence identity, thus representing a new family of mammalian epoxide hydrolases. Quantitative RT-PCR from mouse tissue indicates strongest EH3 expression in lung, skin, and upper gastrointestinal tract. The recombinant enzyme shows a high turnover number with 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid (EET), as well as 9,10-epoxyoctadec-11-enoic acid (leukotoxin). It is inhibited by a subclass of N,N'-disubstituted urea derivatives, including 12-(3-adamantan-1-yl-ureido)-dodecanoic acid, 1-cyclohexyl-3-dodecylurea, and 1-(1-acetylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, compounds so far believed to be selective inhibitors of mammalian soluble epoxide hydrolase (sEH). Its sensitivity to this subset of sEH inhibitors may have implications on the pharmacologic profile of these compounds. This is particularly relevant because sEH is a potential drug target, and clinical trials are under way exploring the value of sEH inhibitors in the treatment of hypertension and diabetes type II.-Decker, M., M. Adamska, A. Cronin, F. Di Giallonardo, J. Burgener, A. Marowsky, J. R. Falck, C. Morisseau, B. D. Hammock, A. Gruzdev, D. C. Zeldin, and M. Arand. EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides. J. Lipid Res. 2012. 53: 2038-2045. C1 [Decker, Martina; Adamska, Magdalena; Cronin, Annette; Di Giallonardo, Francesca; Burgener, Julia; Marowsky, Anne; Arand, Michael] Univ Zurich, Inst Pharmacol & Toxicol, CH-8057 Zurich, Switzerland. [Falck, John R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Morisseau, Christophe; Hammock, Bruce D.] Univ Calif Davis, Entomol & Comprehens Canc Res Ctr, Davis, CA 95616 USA. [Gruzdev, Artiom; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Arand, M (reprint author), Univ Zurich, Inst Pharmacol & Toxicol, CH-8057 Zurich, Switzerland. EM arand@pharma.uzh.ch RI Arand, Michael/J-3926-2014; OI Arand, Michael/0000-0003-2413-3177; Falck, John/0000-0002-9219-7845 FU Swiss National Funds [31-108326]; National Institutes of Health [GM-31278, R01-ES-002710, R01-HL-059699]; Robert Welch Foundation FX This work was supported by Swiss National Funds Grant 31-108326 (M. A.); National Institutes of Health Grants GM-31278 (J.R.F.), R01-ES-002710 (C. M. and B. D. H.), and R01-HL-059699 (C. M. and B. D. H.); and the Robert Welch Foundation (J.R.F.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 46 TC 14 Z9 14 U1 2 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2012 VL 53 IS 10 BP 2038 EP 2045 DI 10.1194/jlr.M024448 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 004QQ UT WOS:000308696600004 PM 22798687 ER PT J AU Camargos, S Lees, AJ Singleton, A Cardoso, F AF Camargos, Sarah Lees, Andrew J. Singleton, Andrew Cardoso, Francisco TI DYT16: the original cases SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID DEPENDENT PROTEIN-KINASE; DYSTONIA; DISEASE; APOPTOSIS; MUTATION; PRKRA; PKR AB Objective DYT16 is an autosomal recessive dystonia-parkinsonism due to putative mutations at PRKRA gene. The aim of this study was to describe clinical features providing video documentation of patients with DYT16 dystonia. Methods We examined and videotaped all homozygous carriers of the DYT16 gene. Results We identified two phenotypes, generalised dystonia and dystonia-parkinsonism non-responsive to levo-dopa, with three patients belonging to each of the groups. There was inter-individual and intra-family phenotypic heterogeneity. Conclusions DYT16 is a rare autosomal recessive dystonia characterised by generalised dystonia or dystonia-parkinsonism. Patients are refractory to pharmacological therapy. C1 [Camargos, Sarah; Cardoso, Francisco] Univ Fed Minas Gerais, Movement Disorders Clin, Hosp Clin, Dept Clin Med,Fac Med, Belo Horizonte, MG, Brazil. [Lees, Andrew J.] UCL, Reta Lila Weston Inst Neurol Studies, London, England. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cardoso, F (reprint author), Ave Pasteur Av 89-1107, BR-30150290 Belo Horizonte, MG, Brazil. EM cardosofe@terra.com.br RI Lees, Andrew/A-6605-2009; Cardoso, Francisco/A-2285-2014; CAMARGOS, SARAH/O-4670-2014; Singleton, Andrew/C-3010-2009 OI Cardoso, Francisco/0000-0003-0808-0116; CAMARGOS, SARAH/0000-0001-9829-6783; FU FAPEMIG FX FC has received honoraria from Boehringer-Ingelheim, Novartis and Roche; and a research grant from FAPEMIG. SC has received honoraria from Boehringer-Ingelheim and Roche. NR 9 TC 6 Z9 6 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD OCT PY 2012 VL 83 IS 10 BP 1012 EP 1014 DI 10.1136/jnnp-2012-302841 PG 3 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 004SS UT WOS:000308702000054 PM 22842711 ER PT J AU Manger, WM Manger, LS Minno, AM Killmeyer, M Holzman, RS Schullinger, JN Roccella, EJ AF Manger, William M. Manger, Lynn S. Minno, Alexander M. Killmeyer, Mike Holzman, Robert S. Schullinger, John N. Roccella, Edward J. TI Obesity Prevention in Young Schoolchildren: Results of a Pilot Study SO JOURNAL OF SCHOOL HEALTH LA English DT Article DE young schoolchildren; overweight and obesity; healthy nutrition and physical activity; school intervention program ID RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR RISK-FACTORS; UNITED-STATES; BLOOD-PRESSURE; CHILDHOOD OBESITY; CHILDREN; ADOLESCENTS; OVERWEIGHT; SCHOOL; HEALTH AB BACKGROUND: Overweight and obesity occur in 17% of children in the United States. Complications of excess weight in Americans cause 216,000 to 300,000 deaths yearly and cost $147 billion. METHODS: A convenience sample of 14 intervention and 15 control schools in the Catholic Diocese of Pittsburgh was used. A program to improve lifestyle (Values Initiative Teaching About Lifestyle [VITAL (R)]), was implemented in young children to encourage healthy eating and appropriate physical activity. Students had annual evaluations of height and weight over a 2-year period, and teachers participating in VITAL completed questionnaires regarding the program. Changes in age- and sex-adjusted body mass index (BMI) percentiles in control and intervention groups were compared using linear mixed models regression. RESULTS: VITAL was highly rated by teachers and was popular with children. Over the 2-year period, adjusted mean BMI percentiles declined from 66.1 to 65.0 in control children and from 62.8 to 58.9 in intervention children. The rates of change in the 2 groups were significantly different (p = .015). CONCLUSION: VITAL improves lifestyle of young schoolchildren, is inexpensive, easy to implement, and should be expanded to improve health and reduce healthcare's financial burden. C1 [Manger, William M.; Manger, Lynn S.; Minno, Alexander M.; Roccella, Edward J.] Natl Hypertens Assoc, New York, NY 10016 USA. [Manger, William M.] NYU, Langone Med Ctr, New York, NY 10016 USA. [Killmeyer, Mike] Catholic Diocese Pittsburgh, Pittsburgh, PA 15222 USA. [Holzman, Robert S.] NYU, Sch Med, New York, NY 10016 USA. [Schullinger, John N.] Columbia Univ, Ctr Med, Woodstock, VT 05091 USA. [Roccella, Edward J.] NIH, Educ Program, Vienna, VA 22180 USA. [Roccella, Edward J.] Natl Hypertens Assoc, Vienna, VA 22180 USA. RP Manger, WM (reprint author), Natl Hypertens Assoc, New York, NY 10016 USA. EM nathypertension@aol.com; lsm81012@aol.com; mkillmeyer@diopitt.org; robert.holzman@med.nyu.edu; nschull@gmail.com; edroccella@cox.net FU Hilda Willis Foundation; I.S. Cooper Foundation; Hearst Foundation; Weezie Foundation; National Hypertension Association FX We express gratitude to the Hilda Willis Foundation, the I.S. Cooper Foundation, the Hearst Foundation, The Weezie Foundation, and the National Hypertension Association for support of the VITAL program to prevent and combat childhood obesity in schoolchildren reported in this study. We express deep gratitude to Ms. Alla Krayko for expert secretarial assistance. NR 41 TC 4 Z9 4 U1 3 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4391 J9 J SCHOOL HEALTH JI J. Sch. Health PD OCT PY 2012 VL 82 IS 10 BP 462 EP 468 DI 10.1111/j.1746-1561.2012.00723.x PG 7 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA 002MY UT WOS:000308537500003 PM 22954165 ER PT J AU Turkbey, B Mani, H Aras, O Rastinehad, AR Shah, V Bernardo, M Pohida, T Daar, D Benjamin, C McKinney, YL Linehan, WM Wood, BJ Merino, MJ Choyke, PL Pinto, PA AF Turkbey, Baris Mani, Haresh Aras, Omer Rastinehad, Ardeshir R. Shah, Vijay Bernardo, Marcelino Pohida, Thomas Daar, Dagane Benjamin, Compton McKinney, Yolanda L. Linehan, W. Marston Wood, Bradford J. Merino, Maria J. Choyke, Peter L. Pinto, Peter A. TI Correlation of Magnetic Resonance Imaging Tumor Volume with Histopathology SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; magnetic resonance imaging; tumor burden ID RADICAL PROSTATECTOMY SPECIMENS; ENDORECTAL MR; FOCAL THERAPY; CANCER; QUALITY; MEN AB Purpose: The biology of prostate cancer may be influenced by the index lesion. The definition of index lesion volume is important for appropriate decision making, especially for image guided focal treatment. We determined the accuracy of magnetic resonance imaging for determining index tumor volume compared with volumes derived from histopathology. Materials and Methods: We evaluated 135 patients (mean age 59.3 years) with a mean prostate specific antigen of 6.74 ng/dl who underwent multiparametric 3T endorectal coil magnetic resonance imaging of the prostate and subsequent radical prostatectomy. Index tumor volume was determined prospectively and independently by magnetic resonance imaging and histopathology. The ellipsoid formula was applied to determine histopathology tumor volume, whereas manual tumor segmentation was used to determine magnetic resonance tumor volume. Histopathology tumor volume was correlated with age and prostate specific antigen whereas magnetic resonance tumor volume involved Pearson correlation and linear regression methods. In addition, the predictive power of magnetic resonance tumor volume, prostate specific antigen and age for estimating histopathology tumor volume (greater than 0.5 cm(3)) was assessed by ROC analysis. The same analysis was also conducted for the 1.15 shrinkage factor corrected histopathology data set. Results: There was a positive correlation between histopathology tumor volume and magnetic resonance tumor volume (Pearson coefficient 0.633, p <0.0001), but a weak correlation between prostate specific antigen and histopathology tumor volume (Pearson coefficient 0.237, p = 0.003). On linear regression analysis histopathology tumor volume and magnetic resonance tumor volume were correlated (r(2) = 0.401, p <0.00001). On ROC analysis AUC values for magnetic resonance tumor volume, prostate specific antigen and age in estimating tumors larger than 0.5 cm(3) at histopathology were 0.949 (p <0.0000001), 0.685 (p = 0.001) and 0.627 (p = 0.02), respectively. Similar results were found in the analysis with shrinkage factor corrected tumor volumes at histopathology. Conclusions: Magnetic resonance imaging can accurately estimate index tumor volume as determined by histology. Magnetic resonance imaging has better accuracy in predicting histopathology tumor volume in tumors larger than 0.5 cm(3) than prostate specific antigen and age. Index tumor volume as determined by magnetic resonance imaging may be helpful in planning treatment, specifically in identifying tumor margins for image guided focal therapy and possibly selecting better active surveillance candidates. C1 [Rastinehad, Ardeshir R.; Benjamin, Compton; Linehan, W. Marston; Pinto, Peter A.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Turkbey, Baris; Aras, Omer; Bernardo, Marcelino; Daar, Dagane; McKinney, Yolanda L.; Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Mani, Haresh; Merino, Maria J.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Pohida, Thomas] NCI, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Bernardo, Marcelino] NCI, Ctr Clin, NIH, SAIC Frederick, Frederick, MD 21701 USA. [Shah, Vijay] VirtualScopics, Rochester, NY USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr,MSC 1210,Bldg 10,Room 2-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov RI Shah, Vijay/D-4083-2014 OI Shah, Vijay/0000-0003-3856-156X FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. NR 27 TC 82 Z9 83 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD OCT PY 2012 VL 188 IS 4 BP 1157 EP 1163 DI 10.1016/j.juro.2012.06.011 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 005IZ UT WOS:000308745400025 PM 22901591 ER PT J AU Tribouillard-Tanvier, D Race, B Striebel, JF Carroll, JA Phillips, K Chesebro, B AF Tribouillard-Tanvier, Deborah Race, Brent Striebel, James F. Carroll, James A. Phillips, Katie Chesebro, Bruce TI Early Cytokine Elevation, PrPres Deposition, and Gliosis in Mouse Scrapie: No Effect on Disease by Deletion of Cytokine Genes IL-12p40 and IL-12p35 SO JOURNAL OF VIROLOGY LA English DT Article ID PRION DISEASE; NERVOUS-SYSTEM; MICROGLIA; BRAIN; MICE; ACCUMULATION; ACTIVATION; EXPRESSION; STIMULATION; MACROPHAGES AB Neurodegenerative diseases are typically associated with an activation of glia and an increased level of cytokines. In our previous studies of prion disease, the cytokine response in the brains of clinically sick scrapie-infected mice was restricted to a small group of cytokines, of which IL-12p40, CCL2, and CXCL10 were present at the highest levels. The goal of our current research was to determine the relationship between cytokine responses, gliosis, and neuropathology during prion disease. Here, in time course studies of C57BL/10 mice intracerebrally inoculated with 22L scrapie, abnormal protease-resistant prion protein (PrPres), astrogliosis, and microgliosis were first detected at 40 days after intracerebral scrapie inoculation. In cytokine studies, IL-12p40 was first elevated by 60 days; CCL3, IL-1 beta, and CXCL1 were elevated by 80 days; and CCL2 and CCL5 were elevated by 115 days. IL-12p40 showed the most extensive increase throughout disease and was 30-fold above control levels at the terminal stage. Because of the early onset and dramatic elevation of IL-12p40 during scrapie, we investigated whether IL-12p40 contributed to the development of prion disease neuropathogenesis by using three different scrapie strains (22L, RML, 79A) to infect knockout mice in which the gene encoding IL-12p40 was deleted. We also studied knockout mice lacking IL-12p35, which combines with IL-12p40 to form active IL-12 heterodimers. In all instances, knockout mice did not differ from control mice in survival time, clinical tempo, or levels of spongiosis, gliosis, or PrPres in the brain. Thus, neither IL-12p40 nor IL-12p35 molecules were required for prion disease-associated neurodegeneration or neuroinflammation. C1 [Tribouillard-Tanvier, Deborah; Race, Brent; Striebel, James F.; Carroll, James A.; Phillips, Katie; Chesebro, Bruce] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM bchesebro@nih.gov FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research FX This work was supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research. NR 35 TC 12 Z9 12 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2012 VL 86 IS 19 BP 10377 EP 10383 DI 10.1128/JVI.01340-12 PG 7 WC Virology SC Virology GA 005HE UT WOS:000308740700013 PM 22787236 ER PT J AU Zhang, JF Markus, J Bies, J Paul, T Wolff, L AF Zhang, Junfang Markus, Jan Bies, Juraj Paul, Thomas Wolff, Linda TI Three Murine Leukemia Virus Integration Regions within 100 Kilobases Upstream of c-myb Are Proximal to the 5 ' Regulatory Region of the Gene through DNA Looping SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN GENOME; CHROMOSOME CONFORMATION; HISTONE MODIFICATIONS; SITE SELECTION; CHROMATIN LOOP; CANCER-CELLS; BALB/C MICE; EXPRESSION; TUMORS; DIFFERENTIATION AB Retroviruses integrated into genomic DNA participate in long-range gene activation from as far away as several hundred kilobases. Hypotheses have been put forth to account for these phenomena, but data have not been provided to support a physical mechanism that explains long-range activation. In murine leukemia virus-induced myeloid leukemia in mice, integrated proviruses have been found upstream of c-myb in three regions, named Mml1, Mml2, and Mml3 (25, 50, and 70 kb upstream, respectively). The transcription factor c-Myb is an oncogene whose dysregulation and/or mutation can lead to human leukemia. We hypothesized that the murine c-myb upstream region contains regulatory elements accessed by the retrovirus. To identify regulatory sites in the murine c-myb upstream region, we looked by chromatin immunoprecipitation with microarray technology (ChIP-on-chip) for histone modifications implicating gene activation in normal cells. H3K4me3, H3K4me1, and H3K9/14ac were enriched at Mml1 and/or Mml2 in the myeloblastic cell line M1, which expresses c-myb. The enrichment of all of these histone marks decreased with differentiation-induced downregulation of the gene in M1 cells but increased and spread in tumor cells containing integrated provirus. Importantly, using chromosome conformation capture (3C)-quantitative PCR assays, interactions between the 5' region, including the promoter and all Mml sites (Mml1, Mml2, and Mml3), were detected due to DNA looping in M1 cells and tumor cells with provirus in Mml1, Mml2, or Mml3. Therefore, our study provides a new mechanism of retrovirus insertional mutagenesis whereby spatial chromatin organization allows distally located provirus, with its own enhancer elements, to access the 5' regulatory region of the gene. C1 [Zhang, Junfang; Markus, Jan; Bies, Juraj; Paul, Thomas; Wolff, Linda] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wolff, L (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM wolffl@mail.nih.gov FU National Cancer Institute, Center for Cancer Research; Slovak Grant Agency VEGA [2/0135/09] FX The work was supported by the Intramural Program at the National Cancer Institute, Center for Cancer Research. J.M. was partially supported by grant 2/0135/09 from the Slovak Grant Agency VEGA. NR 41 TC 12 Z9 13 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2012 VL 86 IS 19 BP 10524 EP 10532 DI 10.1128/JVI.01077-12 PG 9 WC Virology SC Virology GA 005HE UT WOS:000308740700027 PM 22811527 ER PT J AU Hu, LY Chow, DC Patton, JT Palzkill, T Estes, MK Prasad, BVV AF Hu, Liya Chow, Dar-Chone Patton, John T. Palzkill, Timothy Estes, Mary K. Prasad, B. V. Venkataram TI Crystallographic Analysis of Rotavirus NSP2-RNA Complex Reveals Specific Recognition of 5 ' GG Sequence for RTPase Activity SO JOURNAL OF VIROLOGY LA English DT Article ID NONSTRUCTURAL PROTEIN NSP2; GENOME REPLICATION; POLYMERASE VP1; MESSENGER-RNA; RIG-I; SYSTEM; VISUALIZATION; MULTIMERS; PROLINE; CELLS AB Rotavirus nonstructural protein NSP2, a functional octamer, is critical for the formation of viroplasms, which are exclusive sites for replication and packaging of the segmented double-stranded RNA (dsRNA) rotavirus genome. As a component of replication intermediates, NSP2 is also implicated in various replication-related activities. In addition to sequence-independent single-stranded RNA-binding and helix-destabilizing activities, NSP2 exhibits monomer-associated nucleoside and 5' RNA triphosphatase (NTPase/RTPase) activities that are mediated by a conserved H225 residue within a narrow enzymatic cleft. Lack of a 5' gamma-phosphate is a common feature of the negative-strand RNA [(-)RNA] of the packaged dsRNA segments in rotavirus. Strikingly, all (-)RNAs (of group A rotaviruses) have a 5' GG dinucleotide sequence. As the only rotavirus protein with 5' RTPase activity, NSP2 is implicated in the removal of the gamma-phosphate from the rotavirus (-)RNA. To understand how NSP2, despite its sequence-independent RNA-binding property, recognizes (-) RNA to hydrolyze the gamma-phosphate within the catalytic cleft, we determined a crystal structure of NSP2 in complex with the 5' consensus sequence of minus-strand rotavirus RNA. Our studies show that the 5' GG of the bound oligoribonucleotide interacts extensively with highly conserved residues in the NSP2 enzymatic cleft. Although these residues provide GG-specific interactions, surface plasmon resonance studies suggest that the C-terminal helix and other basic residues outside the enzymatic cleft account for sequence-independent RNA binding of NSP2. A novel observation from our studies, which may have implications in viroplasm formation, is that the C-terminal helix of NSP2 exhibits two distinct conformations and engages in domain-swapping interactions, which result in the formation of NSP2 octamer chains. C1 [Hu, Liya; Prasad, B. V. Venkataram] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Chow, Dar-Chone; Palzkill, Timothy] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Palzkill, Timothy; Estes, Mary K.; Prasad, B. V. Venkataram] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Patton, John T.] NIAID, NIH, Bethesda, MD 20892 USA. RP Prasad, BVV (reprint author), Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. EM vprasad@bcm.edu RI Patton, John/P-1390-2014 FU National Institutes of Health (NIH) [AI36040, AI080656, P30 DK56338]; Robert Welch Foundation [Q1279]; National Institute of Allergy and Infectious Disease, NIH; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We acknowledge the support from National Institutes of Health (NIH) grants AI36040 (B.V.V.P.) and AI080656 and P30 DK56338 (M.K.E.) and of the Robert Welch Foundation (Q1279) to B.V.V. P.J.T.P. was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, NIH. SBC-CAT 19ID at Advanced Photon Source is supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. NR 41 TC 6 Z9 6 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2012 VL 86 IS 19 BP 10547 EP 10557 DI 10.1128/JVI.01201-12 PG 11 WC Virology SC Virology GA 005HE UT WOS:000308740700030 PM 22811529 ER PT J AU Lou, S Luo, Y Cheng, F Huang, QF Shen, WR Kleiboeker, S Tisdale, JF Liu, ZW Qiu, JM AF Lou, Sai Luo, Yong Cheng, Fang Huang, Qinfeng Shen, Weiran Kleiboeker, Steve Tisdale, John F. Liu, Zhengwen Qiu, Jianming TI Human Parvovirus B19 DNA Replication Induces a DNA Damage Response That Is Dispensable for Cell Cycle Arrest at Phase G(2)/M SO JOURNAL OF VIROLOGY LA English DT Article ID ERYTHROID PROGENITOR CELLS; HEMATOPOIETIC STEM-CELLS; HUMAN-BONE MARROW; NONSTRUCTURAL PROTEIN; VIRUS-REPLICATION; NS1 PROTEIN; INDUCED PHOSPHORYLATION; TRANSCRIPTION FACTORS; GENOME INTEGRITY; GENE-EXPRESSION AB Human parvovirus B19 (B19V) infection is highly restricted to human erythroid progenitor cells, in which it induces a DNA damage response (DDR). The DDR signaling is mainly mediated by the ATR (ataxia telangiectasia-mutated and Rad3-related) pathway, which promotes replication of the viral genome; however, the exact mechanisms employed by B19V to take advantage of the DDR for virus replication remain unclear. In this study, we focused on the initiators of the DDR and the role of the DDR in cell cycle arrest during B19V infection. We examined the role of individual viral proteins, which were delivered by lentiviruses, in triggering a DDR in ex vivo-expanded primary human erythroid progenitor cells and the role of DNA replication of the B19V double-stranded DNA (dsDNA) genome in a human megakaryoblastoid cell line, UT7/Epo-S1 (S1). All the cells were cultured under hypoxic conditions. The results showed that none of the viral proteins induced phosphorylation of H2AX or replication protein A32 (RPA32), both hallmarks of a DDR. However, replication of the B19V dsDNA genome was capable of inducing the DDR. Moreover, the DDR per se did not arrest the cell cycle at the G(2)/M phase in cells with replicating B19V dsDNA genomes. Instead, the B19V nonstructural 1 (NS1) protein was the key factor in disrupting the cell cycle via a putative transactivation domain operating through a p53-independent pathway. Taken together, the results suggest that the replication of the B19V genome is largely responsible for triggering a DDR, which does not perturb cell cycle progression at G(2)/M significantly, during B19V infection. C1 [Lou, Sai; Luo, Yong; Cheng, Fang; Huang, Qinfeng; Shen, Weiran; Qiu, Jianming] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66103 USA. [Lou, Sai; Liu, Zhengwen] Xi An Jiao Tong Univ, Sch Med, Affiliated Hosp 1, Dept Infect Dis, Xian 710049, Peoples R China. [Kleiboeker, Steve] ViraCor IBT Labs, Lees Summit, MO USA. [Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, Bethesda, MD 20892 USA. RP Qiu, JM (reprint author), Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66103 USA. EM liuzhengwen2011@gmail.com; jqiu@kumc.edu FU PHS from the NIAID [R01 AI070723]; NHLBI [R21 HL106299] FX This work was supported in full by PHS grant R01 AI070723 from the NIAID and grant R21 HL106299 from the NHLBI to J.Q. NR 75 TC 15 Z9 15 U1 0 U2 19 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 OCT PY 2012 VL 86 IS 19 BP 10748 EP 10758 DI 10.1128/JVI.01007-12 PG 11 WC Virology SC Virology GA 005HE UT WOS:000308740700050 PM 22837195 ER PT J AU Li, YY Ndjango, JB Learn, GH Ramirez, MA Keele, BF Bibollet-Ruche, F Liu, WM Easlick, JL Decker, JM Rudicell, RS Inogwabini, BI Ahuka-Mundeke, S Leendertz, FH Reynolds, V Muller, MN Chancellor, RL Rundus, AS Simmons, N Worobey, M Shaw, GM Peeters, M Sharp, PM Hahn, BH AF Li, Yingying Ndjango, Jean-Bosco Learn, Gerald H. Ramirez, Miguel A. Keele, Brandon F. Bibollet-Ruche, Frederic Liu, Weimin Easlick, Juliet L. Decker, Julie M. Rudicell, Rebecca S. Inogwabini, Bila-Isia Ahuka-Mundeke, Steve Leendertz, Fabian H. Reynolds, Vernon Muller, Martin N. Chancellor, Rebecca L. Rundus, Aaron S. Simmons, Nicole Worobey, Michael Shaw, George M. Peeters, Martine Sharp, Paul M. Hahn, Beatrice H. TI Eastern Chimpanzees, but Not Bonobos, Represent a Simian Immunodeficiency Virus Reservoir SO JOURNAL OF VIROLOGY LA English DT Article ID PAN-TROGLODYTES-SCHWEINFURTHII; WILD-CAPTURED CHIMPANZEE; HIV-1 VPU; GROUP O; PRIMATE LENTIVIRUSES; DOWN-MODULATION; SIV INFECTION; NATIONAL-PARK; CELL-SURFACE; BETA-TRCP AB Chimpanzees in west central Africa (Pan troglodytes troglodytes) are endemically infected with simian immunodeficiency viruses (SIVcpzPtt) that have crossed the species barrier to humans and gorillas on at least five occasions, generating pandemic and nonpandemic forms of human immunodeficiency virus type 1 (HIV-1) as well as gorilla SIV (SIVgor). Chimpanzees in east Africa (Pan troglodytes schweinfurthii) are also infected with SIVcpz; however, their viruses (SIVcpzPts) have never been found in humans. To examine whether this is due to a paucity of natural infections, we used noninvasive methods to screen wild-living eastern chimpanzees in the Democratic Republic of the Congo (DRC), Uganda, and Rwanda. We also screened bonobos (Pan paniscus) in the DRC, a species not previously tested for SIV in the wild. Fecal samples (n = 3,108) were collected at 50 field sites, tested for species and subspecies origin, and screened for SIVcpz antibodies and nucleic acids. Of 2,565 samples from eastern chimpanzees, 323 were antibody positive and 92 contained viral RNA. The antibody-positive samples represented 76 individuals from 19 field sites, all sampled north of the Congo River in an area spanning 250,000 km(2). In this region, SIVcpzPts was common and widespread, with seven field sites exhibiting infection rates of 30% or greater. The overall prevalence of SIVcpzPts infection was 13.4% (95% confidence interval, 10.7% to 16.5%). In contrast, none of the 543 bonobo samples from six sites was antibody positive. All newly identified SIVcpzPts strains clustered in strict accordance to their subspecies origin; however, they exhibited considerable genetic diversity, especially in protein domains known to be under strong host selection pressure. Thus, the absence of SIVcpzPts zoonoses cannot be explained by an insufficient primate reservoir. Instead, greater adaptive hurdles may have prevented the successful colonization of humans by P. t. schweinfurthii viruses. C1 [Li, Yingying; Learn, Gerald H.; Ramirez, Miguel A.; Bibollet-Ruche, Frederic; Liu, Weimin; Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Ndjango, Jean-Bosco] Univ Kisangani, Fac Sci, Dept Ecol & Management Plant & Anim Resources, Kisangani, Zaire. [Keele, Brandon F.] Sci Applicats Int Cooperat Frederick Inc, AIDS & Canc Virus Program, Natl Canc Inst Frederick, Frederick, MD USA. [Easlick, Juliet L.; Decker, Julie M.; Rudicell, Rebecca S.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Inogwabini, Bila-Isia] World Wildlife Fund, Lac Tumba Project, Kinshasa, Zaire. [Inogwabini, Bila-Isia] Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, Uppsala, Sweden. [Ahuka-Mundeke, Steve] Inst Natl Rech Biomed, Kinshasa, Zaire. [Ahuka-Mundeke, Steve] IRD, UM1 233, Montpellier, France. [Ahuka-Mundeke, Steve; Peeters, Martine] Univ Montpellier I, Montpellier, France. [Leendertz, Fabian H.] Robert Koch Inst, Res Grp Emerging Zoonoses, Berlin, Germany. [Reynolds, Vernon] Univ Oxford, Sch Anthropol, Oxford, England. [Reynolds, Vernon] Budongo Conservat Field Stn, Masindi, Uganda. [Muller, Martin N.] Univ New Mexico, Dept Anthropol, Albuquerque, NM 87131 USA. [Chancellor, Rebecca L.; Rundus, Aaron S.] W Chester Univ, Dept Psychol, W Chester, PA 19380 USA. [Chancellor, Rebecca L.; Rundus, Aaron S.] Great Ape Trust, Gishwati Area Conservat Program, Gisenyi, Rwanda. [Simmons, Nicole] Makerere Univ, Dept Zool, Kampala, Uganda. [Simmons, Nicole] Univ Arizona, Dept Ecol & Evolut Biol, Tucson, AZ 85721 USA. [Sharp, Paul M.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Sharp, Paul M.] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. RP Hahn, BH (reprint author), Univ Penn, Dept Med, Philadelphia, PA 19104 USA. EM bhahn@upenn.edu RI Sharp, Paul/F-5783-2010 OI Sharp, Paul/0000-0001-9771-543X FU National Institutes of Health [R01 AI50529, R01 AI58715, P30 AI 27767]; Agence Nationale de Recherches sur le SIDA [ANRS 12255]; Great Ape Trust; Howard Hughes Medical Institute; Infectiopole Sud, France FX This work was supported in part by grants from the National Institutes of Health (R01 AI50529, R01 AI58715, and P30 AI 27767), the Agence Nationale de Recherches sur le SIDA (ANRS 12255), and the Great Ape Trust. R. S. R. was funded by a Howard Hughes Medical Institute Med-into-Grad Fellowship, and S.A.-M. was funded by a grant from Infectiopole Sud, France. NR 85 TC 33 Z9 33 U1 1 U2 36 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 OCT PY 2012 VL 86 IS 19 BP 10776 EP 10791 DI 10.1128/JVI.01498-12 PG 16 WC Virology SC Virology GA 005HE UT WOS:000308740700053 PM 22837215 ER PT J AU Luongo, C Winter, CC Collins, PL Buchholz, UJ AF Luongo, Cindy Winter, Christine C. Collins, Peter L. Buchholz, Ursula J. TI Increased Genetic and Phenotypic Stability of a Promising Live-Attenuated Respiratory Syncytial Virus Vaccine Candidate by Reverse Genetics SO JOURNAL OF VIROLOGY LA English DT Article ID TEMPERATURE-SENSITIVE MUTANTS; SERONEGATIVE CHIMPANZEES; SH GENE; RSV; INFANTS; MUTATIONS; IMMUNIZATION; CHILDREN; NS2; IMMUNOGENICITY AB Human respiratory syncytial virus (RSV) is the most important viral cause of serious pediatric respiratory illness worldwide. Currently, the most promising live-attenuated vaccine candidate is a temperature-sensitive (ts) cDNA-derived virus named rA2cp248/404/1030 Delta SH, in reference to its set of attenuating mutations. In a previous clinical study, more than one-third of postvaccination nasal wash isolates exhibited partial loss of the ts phenotype. Most of this instability appeared to be due to reversion at a missense point mutation called 1030. This 1030 mutation is a single-nucleotide tyrosine-to-asparagine substitution at position 1321 (Y1321N) of the polymerase L protein that contributes to the ts and attenuation phenotypes of the vaccine candidate. The goals of the present study were to identify a reversion-resistant codon at position 1321 conferring a comparable level of attenuation and to use this to develop a genetically stable version of the vaccine virus. We modified wild-type (wt) RSV to insert each of the 20 possible amino acids at position 1321; 19 viruses were recoverable. We also investigated small deletions at or near this position, but these viruses were not recoverable. Phenotypic analysis identified alternative attenuating amino acids for position 1321. Several of these amino acids were predicted, based on the genetic code, to be refractory to deattenuation. Classical genetics, using temperature stress tests in vitro combined with nucleotide sequencing, confirmed this stability but identified a second site with a compensatory mutation at position 1313. It was possible to stabilize the 1313 site as well, providing a stable 1030 mutation. Further stress tests identified additional incidental mutations, but these did not reverse the ts/attenuation phenotype. An improved version of the vaccine candidate virus was constructed and validated in vitro by temperature stress tests and in vivo by evaluation of attenuation in seronegative chimpanzees. In addition to developing an improved version of this promising live-attenuated RSV vaccine candidate, this study demonstrated the propensity of an RNA virus to escape from attenuation but also showed that, through systematic analysis, genetics can be used to cut off the routes of escape. C1 [Luongo, Cindy; Winter, Christine C.; Collins, Peter L.; Buchholz, Ursula J.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Buchholz, UJ (reprint author), NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases; NIH; MedImmune, LLC FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. This research was also supported in part by a Cooperative Research and Development Agreement (CRADA) between NIH and MedImmune, LLC, for the development of RSV vaccines. NR 37 TC 29 Z9 29 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 OCT PY 2012 VL 86 IS 19 BP 10792 EP 10804 DI 10.1128/JVI.01227-12 PG 13 WC Virology SC Virology GA 005HE UT WOS:000308740700054 PM 22837193 ER PT J AU Naruto, T Gatanaga, H Nelson, G Sakai, K Carrington, M Oka, S Takiguchi, M AF Naruto, Takuya Gatanaga, Hiroyuki Nelson, George Sakai, Keiko Carrington, Mary Oka, Shinichi Takiguchi, Masafumi TI HLA Class I-Mediated Control of HIV-1 in the Japanese Population, in Which the Protective HLA-B(star)57 and HLA-B(star)27 Alleles Are Absent SO JOURNAL OF VIROLOGY LA English DT Article ID DISEASE PROGRESSION; INFECTION; AIDS; ADVANTAGE; SUPERTYPE AB We investigated the effect of HLA class I alleles on clinical parameters for HIV-1 disease progression in the Japanese population, where two strongly protective alleles, HLA-B(star)57 and HLA-B(star)27, are virtually nonexistent. HLA-B alleles showed a dominant role, primarily through HLA-B(star)67:01 and the HLA-B(star)52:01-C(star)12:02 haplotype. Neither a rare-allele nor a heterozygote advantage was found, suggesting that the effect of HLA alleles in the Japanese population is either different from those observed in Africans and Caucasians or undetectable due to limited power. C1 [Naruto, Takuya; Gatanaga, Hiroyuki; Sakai, Keiko; Oka, Shinichi; Takiguchi, Masafumi] Kumamoto Univ, Ctr AIDS Res, Kumamoto, Japan. [Gatanaga, Hiroyuki; Oka, Shinichi] Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo, Japan. [Nelson, George] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Ctr Canc Res Genet Core, Basic Sci Program, Frederick, MD USA. [Carrington, Mary] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA USA. RP Takiguchi, M (reprint author), Kumamoto Univ, Ctr AIDS Res, Kumamoto, Japan. EM masafumi@kumamoto-u.ac.jp RI Takiguchi, Masafumi/E-7468-2013; sakai, Keiko/F-5807-2013; Kumamoto University, CAIDS/G-8446-2013; Publications, Remarkable/I-1756-2013 FU Global COE program "Global Education and Research Center Aiming at the Control of AIDS"; Ministry of Health, Japan [H21-AIDS-010, H24-AIDS-007]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Global COE program "Global Education and Research Center Aiming at the Control of AIDS," launched as a project commissioned by the Ministry of Education, Science, Sports, and Culture, Japan, and by a grant-in-aid for scientific research from the Ministry of Health (no. H21-AIDS-010 and H24-AIDS-007), Japan. This project was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 13 TC 14 Z9 15 U1 0 U2 5 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 OCT PY 2012 VL 86 IS 19 BP 10870 EP 10872 DI 10.1128/JVI.00689-12 PG 3 WC Virology SC Virology GA 005HE UT WOS:000308740700063 PM 22811530 ER PT J AU Bukreyev, A Yang, LJ Collins, PL AF Bukreyev, Alexander Yang, Lijuan Collins, Peter L. TI The Secreted G Protein of Human Respiratory Syncytial Virus Antagonizes Antibody-Mediated Restriction of Replication Involving Macrophages and Complement SO JOURNAL OF VIROLOGY LA English DT Article ID ALVEOLAR MACROPHAGES; G GLYCOPROTEIN; NEUTROPHILS; INFECTION; CELLS; DISEASE; IMMUNITY; FORM AB The respiratory syncytial virus (RSV) G and F glycoproteins are the neutralization antigens, and G also is expressed in a soluble form (sG). Previously, sG was demonstrated to reduce the efficiency of RSV antibody-mediated neutralization by serving as an antigen decoy and to inhibit the antibody-mediated antiviral effects of Fc receptor-bearing leukocytes. The present study demonstrated that effective antibody-mediated restriction in vivo, and the evasion of this restriction by sG, involves pulmonary macrophages and complement, but not neutrophils. C1 [Bukreyev, Alexander; Yang, Lijuan; Collins, Peter L.] NIAID, RNA Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bukreyev, A (reprint author), Univ Texas Med Branch Galveston, Dept Pathol, Galveston Natl Lab, Galveston, TX USA. EM alexander.bukreyev@utmb.edu FU NIAID FX The study was funded by the NIAID Intramural Research Program. NR 19 TC 10 Z9 10 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2012 VL 86 IS 19 BP 10880 EP 10884 DI 10.1128/JVI.01162-12 PG 5 WC Virology SC Virology GA 005HE UT WOS:000308740700065 PM 22837211 ER PT J AU Buck, CB Phan, GQ Raiji, MT Murphy, PM McDermott, DH McBride, AA AF Buck, Christopher B. Phan, Giao Q. Raiji, Manish T. Murphy, Philip M. McDermott, David H. McBride, Alison A. TI Complete Genome Sequence of a Tenth Human Polyomavirus SO JOURNAL OF VIROLOGY LA English DT Article AB Nine polyomavirus (PyV) species are known to productively infect humans. The circular DNA genomes of PyVs are readily detectable using rolling circle amplification (RCA). RCA-based analysis of condyloma specimens from a patient with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome demonstrated the presence of a tenth apparently human-tropic polyomavirus species, which we name HPyV10. C1 [Buck, Christopher B.; Phan, Giao Q.; Raiji, Manish T.] NCI, Bethesda, MD 20892 USA. [Murphy, Philip M.; McDermott, David H.; McBride, Alison A.] NIAID, Bethesda, MD 20892 USA. RP Buck, CB (reprint author), NCI, Bethesda, MD 20892 USA. EM buckc@mail.nih.gov OI McDermott, David/0000-0001-6978-0867; Buck, Christopher/0000-0003-3165-8094; McBride, Alison/0000-0001-5607-5157 FU NIH; Center for Cancer Research; NIAID FX This work was funded by the NIH Intramural Research Program, with support from the Center for Cancer Research and NIAID. NR 4 TC 60 Z9 61 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2012 VL 86 IS 19 BP 10887 EP 10887 DI 10.1128/JVI.01690-12 PG 1 WC Virology SC Virology GA 005HE UT WOS:000308740700067 PM 22966183 ER PT J AU Keim, SA Daniels, JL Siega-Riz, AM Herring, AH Dole, N Scheidt, PC AF Keim, Sarah A. Daniels, Julie L. Siega-Riz, Anna Maria Herring, Amy H. Dole, Nancy Scheidt, Peter C. TI Breastfeeding and long-chain polyunsaturated fatty acid intake in the first 4 post-natal months and infant cognitive development: an observational study SO MATERNAL AND CHILD NUTRITION LA English DT Article DE arachidonic acid; breast milk; docosahexaenoic acid; infant feeding; polyunsaturated fatty acids; breastfeeding ID RANDOMIZED CONTROLLED-TRIAL; DOCOSAHEXAENOIC ACID; PRETERM INFANTS; TERM INFANTS; ARACHIDONIC-ACID; FISH-OIL; RECOGNITION MEMORY; NEURAL INDEXES; VISUAL-ACUITY; DOUBLE-BLIND AB The aim of this study was to examine infant feeding and the long-chain polyunsaturated fatty acid (LCPUFA) concentration of breast milk and formulas in relation to infant development. The prospective Pregnancy, Infection and Nutrition Study (n = 358) collected data on breastfeeding, breast milk samples and the formulas fed through 4 months post-partum. At 12 months of age, infants' development was assessed (Mullen Scales of Early Learning). Linear regression was used to examine development in relation to breastfeeding, breast milk docosahexaenoic acid (DHA) and arachidonic acid (AA) concentration, and DHA and AA concentration from the combination of breast milk and formula. The median breast milk DHA concentration was 0.20% of total fatty acids [interquartile range (IQR) = 0.14, 0.34]; median AA concentration was 0.52% (IQR = 0.44, 0.63). Upon adjustment for preterm birth, sex, smoking, race and ethnicity and education, breastfeeding exclusivity was unrelated to development. Among infants exclusively breastfed, breast milk LCPUFA concentration was not associated with development (Mullen composite, DHA: adjusted beta = -1.3, 95% confidence interval: -10.3, 7.7). Variables combining DHA and AA concentrations from breast milk and formula, weighted by their contribution to diet, were unassociated with development. We found no evidence of enhanced infant development related to the LCPUFA content of breast milk or formula consumed during the first four post-natal months. C1 [Keim, Sarah A.; Daniels, Julie L.; Siega-Riz, Anna Maria; Herring, Amy H.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Daniels, Julie L.] Univ N Carolina, Dept Maternal & Child Hlth, Chapel Hill, NC USA. [Siega-Riz, Anna Maria; Herring, Amy H.; Dole, Nancy] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Siega-Riz, Anna Maria] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Keim, Sarah A.; Scheidt, Peter C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Keim, SA (reprint author), Nationwide Childrens Hosp, Ctr Biobehav Hlth, 700 Childrens Dr, Columbus, OH 43205 USA. EM sarah.keim@nationwidechildrens.org RI Keim, Sarah/F-8929-2013; OI Keim, Sarah/0000-0003-3490-3649; Dole, Nancy/0000-0002-2113-7984 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD37584, HD39373]; National Institute of Diabetes and Digestive and Kidney Diseases [DK61981, DK56350]; National Institute of Environmental Health Sciences of the National Institutes of Health [P30ES10126]; Carolina Population Center FX This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD37584, HD39373), the National Institute of Diabetes and Digestive and Kidney Diseases (DK61981, DK56350) and the National Institute of Environmental Health Sciences (P30ES10126) of the National Institutes of Health, the Carolina Population Center, and as part of the salary-supported activities of extramural staff of the NICHD. NR 36 TC 12 Z9 16 U1 2 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1740-8695 EI 1740-8709 J9 MATERN CHILD NUTR JI Matern. Child Nutr. PD OCT PY 2012 VL 8 IS 4 BP 471 EP 482 DI 10.1111/j.1740-8709.2011.00326.x PG 12 WC Nutrition & Dietetics; Pediatrics SC Nutrition & Dietetics; Pediatrics GA 999CT UT WOS:000308287400006 PM 21615865 ER PT J AU Arime, Y Kasahara, Y Hall, FS Uhl, GR Sora, I AF Arime, Yosefu Kasahara, Yoshiyuki Hall, F. Scott Uhl, George R. Sora, Ichiro TI Cortico-Subcortical Neuromodulation Involved in the Amelioration of Prepulse Inhibition Deficits in Dopamine Transporter Knockout Mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE prepulse inhibition; norepinephrine reuptake inhibitor; medial prefrontal cortex; neural circuits; mouse ID MEDIAL PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; NOREPINEPHRINE TRANSPORTER; EXTRACELLULAR DOPAMINE; C-FOS; ANTIPSYCHOTIC MEDICATIONS; SCHIZOPHRENIA; RAT; EXPRESSION; STARTLE AB Prepulse inhibition (PPI) deficits are among the most reproducible phenotypic markers found in schizophrenic patients. We recently reported that nisoxetine, a selective norepinephrine transporter (NET) inhibitor, reversed the PPI deficits that have been identified in dopamine transporter (DAT) knockout (KO) mice. However, the mechanisms underlying nisoxetine-induced PPI recovery in DAT KO mice were unclear in previous experiments. To clarify these mechanisms, PPI was tested after microinjections of nisoxetine into the medial prefrontal cortex (mPFc) or nucleus accumbens (NAc) in wildtype (WT) and DAT KO mice. c-Fos immunohistochemistry provided an indicator of neural activation. Multiple-fluorescent-labeling procedures and the retrograde tracer fluorogold were employed to identify nisoxetine-activated neurons and circuits. Systemic nisoxetine activated the mPFc, the NAc shell, the basolateral amygdala, and the subiculum. Infusions of nisoxetine into the mPFc reversed PPI deficits in DAT KO mice, but produced no changes in WT mice, while infusion of nisoxetine into the NAc had no effect on PPI in both WT and DAT KO mice. Experiments using multiple-fluorescent labeling/fluorogold revealed that nisoxetine activates presumed glutamatergic pyramidal cells that project from the mPFc to the NAc. Activated glutamatergic projections from the mPFc to the NAc appear to have substantial roles in the ability of a NET inhibitor to normalize PPI deficits in DAT KO. Thus, this data suggest that selective NET inhibitors such as nisoxetine might improve information processing deficits in schizophrenia via regulation of cortico-subcortical neuromodulation. Neuropsychopharmacology (2012) 37, 2522-2530; doi:10.1038/npp.2012.114; published online 11 July 2012 C1 [Arime, Yosefu; Kasahara, Yoshiyuki; Sora, Ichiro] Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 9808574, Japan. [Arime, Yosefu] Dokkyo Med Univ, Sch Med, Dept Biol Psychiat & Neurosci, Mibu, Tochigi, Japan. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Div Intramural Res, NIH,DHSS, Baltimore, MD USA. RP Sora, I (reprint author), Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan. EM sora@med.tohoku.ac.jp RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Scientific Research on Priority Areas-System study on higher-order brain functions and Research on Pathomechanisms of Brain Disorders; Ministry of Education, Culture, Sports, Science and Technology of Japan; Global COE Program (Basic and Translational Research Center for Global Brain Science), MEXT, Japan; Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS, USA FX We thank Dr Takeshi Kaneko for the gift of PAG monoclonal antibody, Nozomi Okayasu for technical assistance, and Dr Taku Sato and Dr Shiho Miyazawa for assistance with statistical analysis. This work was supported in part by Scientific Research on Priority Areas-System study on higher-order brain functions and Research on Pathomechanisms of Brain Disorders, Core Research for Evolutional Science and Technology (CREST) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Global COE Program (Basic and Translational Research Center for Global Brain Science), MEXT, Japan, and through funding from the Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS, USA (GRU and FSH). NR 46 TC 12 Z9 13 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2012 VL 37 IS 11 BP 2522 EP 2530 DI 10.1038/npp.2012.114 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 004NL UT WOS:000308688300018 PM 22781838 ER PT J AU Eliav, U Komlosh, M Basser, PJ Navon, G AF Eliav, Uzi Komlosh, Michal Basser, Peter J. Navon, Gil TI Characterization and mapping of dipolar interactions within macromolecules in tissues using a combination of DQF, MT and UTE MRI SO NMR IN BIOMEDICINE LA English DT Article DE DQF; MT; UTE; dipolar interaction; rat tail; tendons; annulus pulposus; intervertebral disc; short T2 ID MAGNETIC-RESONANCE; TENDON; WATER; COLLAGEN AB This study shows that by combining a double-quantum filtered magnetization transfer (DQF-MT) with an ultra-short TE (UTE) MRI that it is possible to obtain contrast between tissue compartments based on the following characteristics: (a) the residual dipolar coupling interaction within the biomacromolecules, which depends on their structure, (b) residual dipolar interactions within water molecules, and (c) the magnetization exchange rate between biomacromolecules and water. The technique is demonstrated in rat-tail specimens, where the collagenous tissue such as tendons and the annulus pulposus of the disc are highlighted in these images, and their macromolecular properties along with those of bones and muscles can be characterized. DQF-MT UTE MRI also holds promise because collagenous tissues that are typically invisible in conventional MRI experiments produce significant signal intensities using this approach. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Eliav, Uzi; Navon, Gil] Tel Aviv Univ, Sch Chem, IL-69978 Tel Aviv, Israel. [Komlosh, Michal; Basser, Peter J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, STBB, NIH, Bethesda, MD USA. [Komlosh, Michal] Ctr Neuroregenerat Med CNRM, Bethesda, MD USA. [Komlosh, Michal] Henry Jackson Fdn, Bethesda, MD USA. RP Navon, G (reprint author), Tel Aviv Univ, Sch Chem, Levanon St, IL-69978 Tel Aviv, Israel. EM navon@post.tau.ac.il RI Basser, Peter/H-5477-2011 FU US-Israel Binational Science Foundation [2007157]; European PF7 program ENCITE; Israel Ministry of Science and Technology [3-6446]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Center for Neuroregenerative Medicine (CNRM); Henry Jackson Foundation (HJF) FX GN and UE were supported by grants from the US-Israel Binational Science Foundation no. 2007157, the European PF7 program ENCITE and the Israel Ministry of Science and Technology No. 3-6446. PJB was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. MK was supported by the Center for Neuroregenerative Medicine (CNRM) and the Henry Jackson Foundation (HJF). We gratefully acknowledge Daryl DesPres and Danielle Donahue of the Mouse Imaging Facility (MIF), NIH, for preparing and skinning the rat tails. All 14 T MRI experiments were performed at the MIF, NIH. NR 18 TC 4 Z9 4 U1 0 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD OCT PY 2012 VL 25 IS 10 BP 1152 EP 1159 DI 10.1002/nbm.2784 PG 8 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 004VW UT WOS:000308710400008 PM 22362643 ER PT J AU Lamers, F Rhebergen, D Merikangas, KR de Jonge, P Beekman, ATF Penninx, BWJH AF Lamers, F. Rhebergen, D. Merikangas, K. R. de Jonge, P. Beekman, A. T. F. Penninx, B. W. J. H. TI Stability and transitions of depressive subtypes over a 2-year follow-up SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Latent transition analysis; major depressive disorder; stability; subtypes ID LATENT CLASS ANALYSIS; NATIONAL COMORBIDITY SURVEY; MAJOR DEPRESSION; PSYCHOMETRIC PROPERTIES; ANXIETY NESDA; ATYPICAL DEPRESSION; ENDOGENOUS SUBTYPE; SYMPTOMS; NETHERLANDS; DISORDER AB Background. Identifying depressive subtypes is an important tool in reducing the heterogeneity of major depressive disorder. However, few studies have examined the stability of putative subtypes of depression over time. Method. The sample included 488 persons from the Netherlands Study of Depression and Anxiety (NESDA) who had major depressive disorder at baseline and at the 2-year follow-up assessment. A latent transition analysis (LTA) was applied to examine the stability of depressive subtypes across time-points. Differences in demographic, clinical, psychosocial and health correlates between subtypes were evaluated in a subsample of persons with stable subtypes. Results. Three subtypes were identified at each time-point: a moderate subtype (prevalence T0 39%, T1 42%), a severe typical subtype (T0 30%, T1 25%), and a severe atypical subtype (T0 31%, T1 34%). The LTA showed 76% stability across the 2-year follow-up, with the greatest stability in the severe atypical class (79%). Analyses of correlates in the stable subtypes showed a predominance of women and more overweight and obesity in the severe atypical subtype, and a greater number of negative life events and higher neuroticism and functioning scores in the severe typical subtype. Conclusions. Subtypes of major depressive disorder were found to be stable across a 2-year follow-up and to have distinct determinants, supporting the notion that the identified subtypes are clinically meaningful. C1 [Lamers, F.; Merikangas, K. R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Rhebergen, D.; Penninx, B. W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat EMGO, Inst Hlth & Care Res, Amsterdam, Netherlands. [de Jonge, P.; Penninx, B. W. J. H.] Univ Groningen, Univ Med Ctr Groningen, ICPE, Dept Psychiat, NL-9700 AB Groningen, Netherlands. [de Jonge, P.; Penninx, B. W. J. H.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 AB Groningen, Netherlands. [Penninx, B. W. J. H.] Leiden Univ, Med Ctr, Dept Psychiat, NL-2300 RA Leiden, Netherlands. RP Lamers, F (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, 35 Convent Dr,Room 1A108,MSC 3720, Bethesda, MD 20892 USA. EM lamersf@mail.nih.gov RI Lamers, Femke/G-5161-2012; de Jonge, peter/L-6395-2013 OI de Jonge, peter/0000-0002-0866-6929 FU Netherlands Organization for Health Research and Development (Zon-Mw) [10-000-1002]; VU University Medical Center; GGZ inGeest; Arkin; Leiden University Medical Center; GGZ Rivierduinen; University Medical Center Groningen; Lentis; GGZ Friesland; GGZ Drenthe; Scientific Institute for Quality of Healthcare (IQ healthcare); Netherlands Institute for Health Services Research (NIVEL); Netherlands Institute of Mental Health and Addiction (Trimbos); Netherlands Organization for Scientific Research (NWO) FX The infrastructure for the NESDA (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (Zon-Mw, grant no. 10-000-1002) and is supported by participating universities and mental health care organizations: VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), the Netherlands Institute for Health Services Research (NIVEL) and the Netherlands Institute of Mental Health and Addiction (Trimbos). Dr Lamers is supported by a Rubicon fellowship from the Netherlands Organization for Scientific Research (NWO). NR 53 TC 17 Z9 17 U1 2 U2 24 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD OCT PY 2012 VL 42 IS 10 BP 2083 EP 2093 DI 10.1017/S0033291712000141 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 006UR UT WOS:000308845200007 PM 22340131 ER PT J AU Fondell, E O'Reilly, EJ Fitzgerald, KC Falcone, GJ McCullough, ML Thun, MJ Park, Y Kolonel, LN Ascherio, A AF Fondell, Elinor O'Reilly, Eilis J. Fitzgerald, Kathryn C. Falcone, Guido J. McCullough, Marjorie L. Thun, Michael J. Park, Yikyung Kolonel, Laurence N. Ascherio, Alberto TI Non-steroidal anti-inflammatory drugs and amyotrophic lateral sclerosis: Results from five prospective cohort studies SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article DE ALS; NSAID; cohort; epidemiology ID TRANSGENIC MOUSE MODEL; BASE-LINE CHARACTERISTICS; ANALGESIC USE; CYCLOOXYGENASE-2 INHIBITORS; PARKINSON-DISEASE; RISK-FACTORS; IBUPROFEN; ALS; WOMEN; NEUROINFLAMMATION AB Animal and pathological studies suggest that inflammation may contribute to amyotrophic lateral sclerosis (ALS) pathology and that non-steroidal anti-inflammatory drugs (NSAIDs) might be protective. However, there are no prospective data on the relation between NSAID use and ALS risk in humans. The relation between NSAID use and ALS risk was explored in five large prospective cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health - AARP Diet and Health Study). Detailed NSAID information was sought from 780,000 participants, 708 of whom developed ALS during follow-up. Cox proportional hazards models were used within each cohort and cohort-specific estimates were pooled with random effects models. Results showed that neither non-aspirin NSAID use, nor aspirin use was associated with ALS risk overall. The multivariable, pooled relative risk was 0.96 (95% CI 0.76-1.22) among non-aspirin NSAID users compared with non-users. Duration of NSAID use in years and frequency of NSAID use were not associated with ALS risk overall. In conclusion, the results do not support an overall effect of NSAIDs on ALS risk, but because NSAIDs have heterogeneous effects, a role of individual compounds cannot be excluded. C1 [Fondell, Elinor; O'Reilly, Eilis J.; Fitzgerald, Kathryn C.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Falcone, Guido J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McCullough, Marjorie L.; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Park, Yikyung; Kolonel, Laurence N.] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Fondell, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM efondell@hsph.harvard.edu RI Falcone, Guido/L-2287-2016; OI Falcone, Guido/0000-0002-6407-0302; Park, Yikyung/0000-0002-6281-489X FU National Institute of Neurological Diseases and Stroke; National Cancer Institute; Blanceflor Foundation, Stockholm, Sweden FX This work was supported by a grant from the National Institute of Neurological Diseases and Stroke, and by grants from the National Cancer Institute. E. Fondell is supported by a grant from the Blanceflor Foundation, Stockholm, Sweden. NR 40 TC 7 Z9 7 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1748-2968 J9 AMYOTROPH LATERAL SC JI Amyotroph. Lateral. Scler. PD OCT PY 2012 VL 13 IS 6 BP 573 EP 579 DI 10.3109/17482968.2012.703209 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 000XJ UT WOS:000308423800016 PM 22871075 ER PT J AU Cuddy, M Papps, BJ Thambisetty, M Leigh, PN Goldstein, LH AF Cuddy, Marion Papps, Benjamin J. Thambisetty, Madhav Leigh, P. Nigel Goldstein, Laura H. TI Processing and memory for emotional and neutral material in amyotrophic lateral sclerosis SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article DE Amyotrophic lateral sclerosis; emotional processing; memory; depression ID MOTOR-NEURON DISEASE; COGNITIVE IMPAIRMENT; TEMPORAL LOBECTOMY; HOSPITAL ANXIETY; DEPRESSION SCALE; AMYGDALA DAMAGE; ALS; PREVALENCE; PERCEPTION; DIAGNOSIS AB Several studies have reported changes in emotional memory and processing in people with ALS (pwALS). In this study, we sought to analyse differences in emotional processing and memory between pwALS and healthy controls and to investigate the relationship between emotional memory and self-reported depression. Nineteen pwALS and 19 healthy controls were assessed on measures of emotional processing, emotional memory, verbal memory and depression. Although pwALS and controls did not differ significantly on measures of emotional memory, a subgroup of patients performed poorly on an emotional recognition task. With regard to emotional processing, pwALS gave significantly stronger ratings of emotional valence to positive words than to negative words. Higher ratings of emotional words were associated with better recall in controls but not pwALS. Self-reported depression and emotional processing or memory variables were not associated in either group. In conclusion, the results from this small study suggest that a subgroup of pwALS may show weakened 'emotional enhancement', although in the current sample this may reflect general memory impairment rather than specific changes in emotional memory. Nonetheless, different patterns of processing of emotionally-salient material by pwALS may have care and management-related implications. C1 [Cuddy, Marion; Goldstein, Laura H.] Kings Coll London, KHP Ctr Neurodegenerat Res, Dept Psychol, Inst Psychiat, London WC2R 2LS, England. [Papps, Benjamin J.] Northwick Pk Hosp & Clin Res Ctr, Reg Rehabil Unit, Harrow HA1 3UJ, Middx, England. [Thambisetty, Madhav] NIA, Biomed Res Ctr, Baltimore, MD 21224 USA. [Leigh, P. Nigel] Univ Sussex, Brighton & Sussex Med Sch, Trafford Ctr Biomed Res, Falmer, Sussex, England. RP Goldstein, LH (reprint author), Inst Psychiat, Dept Psychol PO77, De Crespigny Pk, London SE5 8AF, England. EM laura.goldstein@kcl.ac.uk RI Goldstein, Laura/E-7817-2010 OI Goldstein, Laura/0000-0001-9387-3035 FU Sanofi Aventis; GlaxoSmithKline (GSK); Acceleron; Cytokinetics; Neuyronova; Motor Neurone Disease Association; Wellcome Trust UK; National Institute for Health Research (NIHR); Dementia Biomedical Research Unit at South London; Maudsley NHS Foundation Trust; King's College London; Department of Health/National Institute for Health Research (NIHR) UK; Motor Neurone Disease Association UK; Epilepsy Research UK; Institute of Social Psychiatry FX P.N. Leigh has received honoraria or consultancy fees and travel expenses from Sanofi Aventis, GlaxoSmithKline (GSK), Acceleron, Cytokinetics, Neuyronova, and is/or has been a member of advisory boards for GSK, Acceleron, Cytokinetics, Neuronova, TauPx. He has received research support from the Motor Neurone Disease Association and the Wellcome Trust UK. L. H. Goldstein receives salary support from the National Institute for Health Research (NIHR), Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. She serves on the Scientific Awards Panel for Epilepsy Action (UK); has received travel expenses and honoraria for speaking and educational activities not funded by industry; receives royalties from the publication of Clinical Neuropsychology (Wiley, 2004) and The Clinical Psychologist's Handbook of Epilepsy (Routledge, 1997); and receives research support from Department of Health/National Institute for Health Research (NIHR) UK and the Motor Neurone Disease Association UK. She has also received research support from Epilepsy Research UK, the Institute of Social Psychiatry and the Wellcome Trust UK. NR 33 TC 5 Z9 6 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1748-2968 J9 AMYOTROPH LATERAL SC JI Amyotroph. Lateral. Scler. PD OCT PY 2012 VL 13 IS 6 BP 592 EP 598 DI 10.3109/17482968.2012.708936 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 000XJ UT WOS:000308423800020 PM 22873560 ER PT J AU Cho, HY van Houten, B Wang, XT Miller-DeGraff, L Fostel, J Gladwell, W Perrow, L Panduri, V Kobzik, L Yamamoto, M Bell, DA Kleeberger, SR AF Cho, Hye-Youn van Houten, Bennett Wang, Xuting Miller-DeGraff, Laura Fostel, Jennifer Gladwell, Wesley Perrow, Ligon Panduri, Vijayalakshmi Kobzik, Lester Yamamoto, Masayuki Bell, Douglas A. Kleeberger, Steven R. TI Targeted Deletion of Nrf2 Impairs Lung Development and Oxidant Injury in Neonatal Mice SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID ANTIOXIDANT RESPONSE ELEMENTS; GUINEA-PIG LUNG; BRONCHOPULMONARY DYSPLASIA; ENHANCES SUSCEPTIBILITY; INCREASES SURVIVAL; GENE-EXPRESSION; GROWTH-FACTOR; HYPEROXIA; PROTECTION; RATS AB Aims: Nrf2 is an essential transcription factor for protection against oxidant disorders. However, its role in organ development and neonatal disease has received little attention. Therapeutically administered oxygen has been considered to contribute to bronchopulmonary dysplasia (BPD) in prematurity. The current study was performed to determine Nrf2-mediated molecular events during saccular-to-alveolar lung maturation, and the role of Nrf2 in the pathogenesis of hyperoxic lung injury using newborn Nrf2-deficient (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice. Results: Pulmonary basal expression of cell cycle, redox balance, and lipid/carbohydrate metabolism genes was lower while lymphocyte immunity genes were more highly expressed in Nrf(2-/-) neonates than in Nrf2(+/+) neonates. Hyperoxia-induced phenotypes, including mortality, arrest of saccular-to-alveolar transition, and lung edema, and inflammation accompanying DNA damage and tissue oxidation were significantly more severe in Nrf2(-/-) neonates than in Nrf2(+/+) neonates. During lung injury pathogenesis, Nrf2 orchestrated expression of lung genes involved in organ injury and morphology, cellular growth/proliferation, vasculature development, immune response, and cell-cell interaction. Bioinformatic identification of Nrf2 binding motifs and augmented hyperoxia-induced inflammation in genetically deficient neonates supported Gpx2 and Marco as Nrf2 effectors. Innovation: This investigation used lung transcriptomics and gene targeted mice to identify novel molecular events during saccular-to-alveolar stage transition and to elucidate Nrf2 downstream mechanisms in protection from hyperoxia-induced injury in neonate mouse lungs. Conclusion: Nrf2 deficiency augmented lung injury and arrest of alveolarization caused by hyperoxia during the newborn period. Results suggest a therapeutic potential of specific Nrf2 activators for oxidative stress-associated neonatal disorders including BPD. Antioxid. Redox Signal. 17, 1066-1082. C1 [Cho, Hye-Youn; Miller-DeGraff, Laura; Fostel, Jennifer; Gladwell, Wesley; Perrow, Ligon; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [van Houten, Bennett] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [van Houten, Bennett] Hillman Canc Ctr, Pittsburgh, PA USA. [Wang, Xuting; Panduri, Vijayalakshmi; Bell, Douglas A.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kobzik, Lester] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Yamamoto, Masayuki] Tohoku Univ, Grad Sch Med, Sendai, Miyagi 980, Japan. RP Cho, HY (reprint author), NIEHS, Lab Resp Biol, NIH, 111 TW Alexander Dr,Bldg 101,MD D-201, Res Triangle Pk, NC 27709 USA. EM cho2@niehs.nih.gov RI Yamamoto, Masayuki/A-4873-2010; OI Wang, Xuting/0000-0001-6781-8008 FU Intramural Research Program; Director's Challenge Program of the NIEHS, National Institutes of Health (NIH), Department of Health and Human Services FX This research was supported by the Intramural Research Program and Director's Challenge Program of the NIEHS, National Institutes of Health (NIH), Department of Health and Human Services. Hyperoxia exposures were conducted at the NIEHS. The authors thank Dr. Mary Grant and Mr. Norman Gage for installation of hyperoxia exposure chamber apparatus. The authors also thank Dr. Sue Edelstein of Image Associates for the professional artwork. We thank NIEHS Microarray Core personnel (Dr. Kevin Gerrish and Ms. Laura Wharey), and Ms. Laura Hall in the National Toxicology Program for submitting array data to GEO and NIEHS CEBS. Histopathologic evaluation of neonatal lung was performed by the pathologist Dr. Arlin Rogers (ILS, Inc., Research Triangle Park, NC) with support by Ms. Julie Foley of NIEHS Cellular and Molecular Pathology Branch. Drs. Pierre Buschel and Rick Paules of the NIEHS provided excellent critical review of the article. NR 50 TC 28 Z9 28 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2012 VL 17 IS 8 BP 1066 EP 1082 DI 10.1089/ars.2011.4288 PG 17 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 996JA UT WOS:000308079800003 PM 22400915 ER PT J AU Huff, J AF Huff, James TI Long-term toxicology and carcinogenicity of 2,4,6-trichlorophenol SO CHEMOSPHERE LA English DT Article DE Bone marrow hyperplasia; Carcinogenesis bioassay; Fischer 344 rats and B6C3F1 mice; Leukemia/lymphoma; Leukocytosis/monocytosis; Liver tumor ID SOFT-TISSUE SARCOMA; PRIMARY PREVENTION; BODY-WEIGHT; RODENT CARCINOGENICITY; ENVIRONMENTAL CANCER; TUMOR TRENDS; RISK; PENTACHLOROPHENOL; EXPOSURE; RATS AB Carcinogenesis bioassays were conducted by giving 2,4,6-trichlorophenol [2,4,6-TCP] in feed to groups of 50 male and female Fischer rats and male B6C3F1 mice for two years. Dietary concentrations were 0 [20/group], 5000 [0.5%], or 10,000 [1%] ppm. Female mice began with 10,000 and 20,000 ppm but after 38 weeks were lowered due to reduced body weights to 2500 and 5000 ppm for 67 weeks: exposures averaged 5200 and 10,400 ppm. Adverse effects at two years were leukocytosis and monocytosis of peripheral blood and hyperplasia of bone marrow in both sexes of rats. In mice, liver toxicity, including individual liver cell abnormalities, focal areas of cellular alteration, and focal and nodular areas of hyperplasia were commonly present. Regarding carcinogenic activity, TCP caused leukemias/lymphomas in male rats, and possibly in female rats and female mice as well, and induced liver tumors in male and female mice. Using NTP categories of evidence indicates 'clear evidence of carcinogenicity' for male rats [hematopoietic system tumors]; 'equivocal evidence of carcinogenicity' for female rats [hematopoietic system tumors]; 'clear evidence of carcinogenicity' for male and female mice [liver tumors]. Published by Elsevier Ltd. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institutes of Health FX National Institute of Environmental Health Sciences, National Institutes of Health. NR 49 TC 7 Z9 8 U1 1 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 J9 CHEMOSPHERE JI Chemosphere PD OCT PY 2012 VL 89 IS 5 BP 521 EP 525 DI 10.1016/j.chemosphere.2012.05.015 PG 5 WC Environmental Sciences SC Environmental Sciences & Ecology GA 996AH UT WOS:000308055900005 PM 22748215 ER PT J AU Mackowick, KM Lynch, MJ Weinberger, AH George, TP AF Mackowick, Kristen M. Lynch, Marie-Josee Weinberger, Andrea H. George, Tony P. TI Treatment of Tobacco Dependence in People With Mental Health and Addictive Disorders SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Mental health and addictive disorders; Nicotine dependence; Tobacco; Treatment; Smoking cessation; Psychiatric disorders; Schizophrenia; Anxiety disorders; Mood disorders; Substance use disorders; Alcoholism; Comorbidities; Pharmacotherapy; Integrated care ID POSTTRAUMATIC-STRESS-DISORDER; BUPROPION SUSTAINED-RELEASE; RANDOMIZED CONTROLLED-TRIAL; SMOKING-CESSATION TREATMENT; PLACEBO-CONTROLLED TRIAL; NICOTINE-PATCH THERAPY; ALCOHOL DEPENDENCE; CIGARETTE-SMOKING; MAJOR DEPRESSION; DOUBLE-BLIND AB People with mental health and addictive disorders (MHADs) have higher rates of cigarette smoking, and less success in quitting smoking compared with the general population. Moreover, tobacco-related medical illness may be the leading cause of death in the MHAD population. We discuss the scope of this comorbidity, and approaches to the treatment of tobacco dependence in people with MHAD, including schizophrenia, mood disorders, anxiety disorders, and alcohol and substance use disorders. Finally, at the level of health systems, we emphasize the importance of integrated treatment of tobacco dependence in MHADs. C1 [Lynch, Marie-Josee; George, Tony P.] CAMH, Schizophrenia Program, Toronto, ON M5T 1R8, Canada. [Mackowick, Kristen M.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Mackowick, Kristen M.] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada. [Lynch, Marie-Josee; George, Tony P.] Univ Toronto, Dept Psychiat, Div Brain & Therapeut, Toronto, ON, Canada. [Weinberger, Andrea H.; George, Tony P.] Yale Univ, Sch Med, Dept Psychiat, Div Subst Abuse, New Haven, CT USA. [Weinberger, Andrea H.] Yale Canc Ctr, Canc Prevent & Control Res Program, New Haven, CT USA. RP George, TP (reprint author), CAMH, Schizophrenia Program, Toronto, ON M5T 1R8, Canada. EM tony.george@camh.ca FU National Institute on Drug Abuse (NIDA) [2U01-DA-020830-07, R03-DA027052]; Canadian Institutes of Health Research (CIHR) [115145]; Ontario Mental Health Foundation; Pfizer; AstraZeneca; Janssen-Ortho; Taylor Francis FX This work was supported in part by the Chair in Addiction Psychiatry at the University of Toronto (to T. P. George), and grant support from the National Institute on Drug Abuse (NIDA; 2U01-DA-020830-07, to Caryn Lerman, Rachel Tyndale, and T. P. George; R03-DA027052, to A. H. Weinberger), the Canadian Institutes of Health Research (CIHR; MOP#115145, to T. P. George), and the Ontario Mental Health Foundation (to T. P. George).; K. M. Mackowick: none; M.-J. Lynch: none; A. H. Weinberger: funding from NIDA (R03-DA027052); T. P. George: member of Novartis Data Monitoring Committee; consultant to Janssen-Ortho and Pfizer; payment for serving on speakers bureaus for Pfizer, AstraZeneca, and Janssen-Ortho; grants from National Institute on Drug Abuse, Canadian Institutes of Health Research, Ontario Mental Health Foundation, and Pfizer; royalties from Taylor & Francis. NR 76 TC 20 Z9 20 U1 3 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD OCT PY 2012 VL 14 IS 5 BP 478 EP 485 DI 10.1007/s11920-012-0299-2 PG 8 WC Psychiatry SC Psychiatry GA 999XK UT WOS:000308348800006 PM 22821177 ER PT J AU Dilmanian, FA Rusek, A Fois, GR Olschowka, J Desnoyers, NR Park, JY Dioszegi, I Dane, B Wang, RL Tomasi, D Lee, H Hurley, SD Coyle, PK Meek, AG O'Banion, MK AF Dilmanian, F. Avraham Rusek, Adam Fois, Giovanna R. Olschowka, John Desnoyers, Nicolle R. Park, Jane Y. Dioszegi, Istvan Dane, Bari Wang, Ruiliang Tomasi, Dardo Lee, Hedok Hurley, Sean D. Coyle, Patricia K. Meek, Allen G. O'Banion, M. Kerry TI Interleaved Carbon Minibeams: An Experimental Radiosurgery Method With Clinical Potential SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Carbon therapy; Carbon minibeams; Tissue-sparing effect; High RBE radiation; Radiosurgery ID MICROBEAM RADIATION-THERAPY; X-RAYS; SYNCHROTRON-WIGGLER; DOSE DISTRIBUTIONS; MICROPLANAR BEAMS; MOUSE-BRAIN; IRRADIATION AB Purpose: To evaluate the efficacy of "interleaved carbon minibeams" for ablating a 6.5-mm target in a rabbit brain with little damage to the surrounding brain. The method is based on the well-established tissue-sparing effect of arrays of thin planes of radiation. Methods and Materials: Broad carbon beams from the National Aeronautics and Space Agency Space Radiation Facility at Brookhaven National Laboratory were segmented into arrays of parallel, horizontal, 0.3-mm-thick planar beams (minibeams). The minibeams' gradual broadening in tissues resulted in 0.525-mm beam thickness at the target's proximal side in the spread-out Bragg peak. Interleaving was therefore implemented by choosing a 1.05 mm beam spacing on-center. The anesthetized rabbit, positioned vertically on a stage capable of rotating about a vertical axis, was exposed to arrays from four 90 degrees angles, with the stage moving up by 0.525 mm in between. This produced a solid radiation field at the target while exposing the non-targeted tissues to single minibeam arrays. The target "physical" absorbed dose was 40.2 Gy. Results: The rabbit behaved normally during the 6-month observation period. Contrast magnetic resonance imaging and hematoxylin and eosin histology at 6 months showed substantial focal target damage with little damage to the surrounding brain. Conclusion: We plan to evaluate the method's therapeutic efficacy by comparing it with broad-beam carbon therapy in animal models. The method's merits would combine those of carbon therapy (i.e., tight target dose because of the carbon's Bragg-peak, sharp dose falloff, and high relative biological effectiveness at the target), together with the method's low impact on the nontargeted tissues. The method's smaller impact on the nontargeted brain might allow carbon therapy at higher target doses and/or lower normal tissue impact, thus leading to a more effective treatment of radioresistant tumors. It should also make the method more amenable to administration in either a single dose fraction or in a small number of fractions. (C) 2012 Elsevier Inc. C1 [Dilmanian, F. Avraham; Fois, Giovanna R.; Desnoyers, Nicolle R.; Park, Jane Y.; Dane, Bari; Wang, Ruiliang; Tomasi, Dardo; Lee, Hedok] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Rusek, Adam] Brookhaven Natl Lab, NASA Space Radiat Lab, Upton, NY 11973 USA. [Dioszegi, Istvan] Brookhaven Natl Lab, Nonproliferat & Natl Secur Dept, Upton, NY 11973 USA. [Dilmanian, F. Avraham; Meek, Allen G.] SUNY Stony Brook, Dept Radiat Oncol, Med Ctr, Stony Brook, NY USA. [Dilmanian, F. Avraham; Coyle, Patricia K.] SUNY Stony Brook, Dept Neurol, Med Ctr, Stony Brook, NY USA. [Fois, Giovanna R.] Univ Cagliari, Dept Phys, Sardinia, Italy. [Olschowka, John; Hurley, Sean D.; O'Banion, M. Kerry] Univ Rochester, Dept Neurobiol & Anat, Rochester, NY USA. [Tomasi, Dardo] NIAAA, Bethesda, MD USA. [Desnoyers, Nicolle R.] Ross Univ, Sch Vet Med, Basseterre, St Kitts, W Ind Assoc St. [Park, Jane Y.] Cornell Univ, Coll Vet Med, Ithaca, NY 14853 USA. RP Dilmanian, FA (reprint author), Brookhaven Natl Lab, Dept Med, 30 Bell Ave, Upton, NY 11973 USA. EM dilmanian@bnl.gov RI Tomasi, Dardo/J-2127-2015; OI Dane, Bari/0000-0003-2205-3309 FU Musella Brain Tumor Foundation; Brain Tumor Foundation of "Lauren's First and Goal"; Brain Tumor Foundation of Have a Chance; Voices against Brain Cancer; Stony Brook Foundation; Stony Brook's School of Medicine; Office of Vice President for Research, Stony Brook's Targeted Research Opportunities program; Concerned Women of the Grove FX Research was supported by grants from the Musella Brain Tumor Foundation, Brain Tumor Foundations of "Lauren's First and Goal" and "Have a Chance", Voices against Brain Cancer, Stony Brook Foundation (Allen G. Meek MD, PI), Stony Brook's School of Medicine and the Office of Vice President for Research, Stony Brook's Targeted Research Opportunities program, and Concerned Women of the Grove. NR 20 TC 3 Z9 3 U1 2 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2012 VL 84 IS 2 BP 514 EP 519 DI 10.1016/j.ijrobp.2011.12.025 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 996CW UT WOS:000308062700061 PM 22342299 ER PT J AU Leopold, DA Maier, A AF Leopold, David A. Maier, Alexander TI Ongoing physiological processes in the cerebral cortex SO NEUROIMAGE LA English DT Review ID MONKEY VISUAL-CORTEX; INTRINSIC FUNCTIONAL ARCHITECTURE; BOLD SIGNAL FLUCTUATIONS; STATE BRAIN NETWORKS; SENSORY CORTEX; GLOBAL SIGNAL; BASE-LINE; CONNECTIVITY; FMRI; SLEEP AB Functional magnetic resonance imaging (fMRI) has revealed that the human brain undergoes prominent, regional hemodynamic fluctuations when a subject is at rest. These ongoing fluctuations exhibit distinct patterns of spatiotemporal synchronization that have been dubbed "resting state functional connectivity", and which currently serve as a principal tool to investigate neural networks in the normal and pathological human brain. Despite the wide application of this approach in human neuroscience, the neural mechanisms that give rise to spontaneous fMRI correlations are largely unknown. Here we review results of recent electrophysiological studies in the cerebral cortex of humans and nonhuman primates that link neural activity to ongoing fMRI fluctuations. We begin by describing results obtained with simultaneous fMRI and electrophysiological measurements that allow for the identification of direct neural correlates of resting state functional connectivity. We next highlight experiments that investigate the correlational structure of spontaneous neural signals, including the spatial variation of signal coherence over the cortical surface, across cortical laminae, and between the two hemispheres. In the final section we speculate on the origins and potential consequences of ongoing signals for normal brain function, and point out inherent limitations of the fMRI correlation approach. Published by Elsevier Inc. C1 [Leopold, David A.; Maier, Alexander] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Leopold, David A.] Natl Inst Neurol Disorders & Stroke, Neurophysiol Imaging Facil, NIMH, Bethesda, MD 20892 USA. [Leopold, David A.] NEI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Maier, Alexander] Vanderbilt Univ, Dept Psychol, Coll Arts & Sci, Nashville, TN 37240 USA. RP Leopold, DA (reprint author), NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH,Dept Hlth & Human Serv, 49 Convent Dr,1E-21,MSC 4400, Bethesda, MD 20892 USA. EM leopoldd@mail.nih.gov RI Maier, Alexander/B-7489-2009; OI Maier, Alexander/0000-0002-7250-502X; Leopold, David/0000-0002-1345-6360 FU NIMH; NINDS; NEI FX We thank Drs. Jeff Duyn and Biyu He for comments on an earlier version of the manuscript. This research was supported by the Intramural Research Programs of the NIMH, NINDS, and NEI. NR 84 TC 50 Z9 51 U1 2 U2 27 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2012 VL 62 IS 4 SI SI BP 2190 EP 2200 DI 10.1016/j.neuroimage.2011.10.059 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 998UF UT WOS:000308265200003 PM 22040739 ER PT J AU Sutherland, MT McHugh, MJ Pariyadath, V Stein, EA AF Sutherland, Matthew T. McHugh, Meredith J. Pariyadath, Vani Stein, Elliot A. TI Resting state functional connectivity in addiction: Lessons learned and a road ahead SO NEUROIMAGE LA English DT Review DE fMRI; Connectivity; Drug abuse; Nicotine; Insula; Default mode; Attention ID ANTERIOR CINGULATE CORTEX; DEFAULT-MODE NETWORK; MEDIAL FRONTAL-CORTEX; HEROIN-DEPENDENT INDIVIDUALS; ANTI-CORRELATED NETWORKS; SCALE BRAIN NETWORKS; PREFRONTAL CORTEX; DRUG-ADDICTION; STRUCTURAL CONNECTIVITY; ALZHEIMERS-DISEASE AB Despite intensive scientific investigation and public health imperatives, drug addiction treatment outcomes have not significantly improved in more than 50 years. Non-invasive brain imaging has, over the past several decades, contributed important new insights into the neuroplastic adaptations that result from chronic drug intake, but additional experimental approaches and neurobiological hypotheses are needed to better capture the totality of the motivational, affective, cognitive, genetic and pharmacological complexities of the disease. Recent advances in assessing network dynamics through resting-state functional connectivity (rsFC) may allow for such systems-level assessments. In this review, we first summarize the nascent addiction-related rsFC literature and suggest that in using this tool, circuit connectivity may inform specific neurobiological substrates underlying psychological dysfunctions associated with reward, affective and cognitive processing often observed in drug addicts. Using nicotine addiction as an exemplar, we subsequently provide a heuristic framework to guide future research by linking recent findings from intrinsic network connectivity studies with those interrogating nicotine's neuropharmacological actions. Emerging evidence supports a critical role for the insula in nicotine addiction. Likewise, the anterior insula, potentially together with the anterior cingulate cortex, appears to pivotally influence the dynamics between large-scale brain networks subserving internal (default-mode network) and external (executive control network) information processing. We suggest that a better understanding of how the insula modulates the interaction between these networks is critical for elucidating both the cognitive impairments often associated with withdrawal and the performance-enhancing effects of nicotine administration. Such an understanding may be usefully applied in the design and development of novel smoking cessation treatments. Published by Elsevier Inc. C1 [Sutherland, Matthew T.; McHugh, Meredith J.; Pariyadath, Vani; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH DHHS, Baltimore, MD 21224 USA. RP Stein, EA (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH DHHS, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM estein@mail.nih.gov OI Pariyadath, Vani/0000-0001-6340-0771 FU National Institute on Drug Abuse, Intramural Research Program, NIH/DHHS FX This work was supported by the National Institute on Drug Abuse, Intramural Research Program, NIH/DHHS. NR 181 TC 112 Z9 114 U1 5 U2 60 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2012 VL 62 IS 4 SI SI BP 2281 EP 2295 DI 10.1016/j.neuroimage.2012.01.117 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 998UF UT WOS:000308265200012 PM 22326834 ER PT J AU Laeyendecker, O Brookmeyer, R Mullis, CE Donnell, D Lingappa, J Celum, C Baeten, JM Campbell, MS Essex, M de Bruyn, G Farquhar, C Quinn, TC Eshleman, SH AF Laeyendecker, Oliver Brookmeyer, Ron Mullis, Caroline E. Donnell, Deborah Lingappa, Jairam Celum, Connie Baeten, Jared M. Campbell, Mary S. Essex, Max de Bruyn, Guy Farquhar, Carey Quinn, Thomas C. Eshleman, Susan H. CA Partners Prevention HSV HIV Transm TI Specificity of Four Laboratory Approaches for Cross-Sectional HIV Incidence Determination: Analysis of Samples from Adults with Known Nonrecent HIV Infection from Five African Countries SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CAPTURE ENZYME-IMMUNOASSAY; ASSAY; SEROCONVERSION; TRANSMISSION; CHALLENGES AB Assays to determine cross-sectional HIV incidence misclassify some individuals with nonrecent HIV infection as recently infected, overestimating HIV incidence. We analyzed factors associated with false-recent misclassification in five African countries. Samples from 2197 adults from Botswana, Kenya, South Africa, Tanzania, and Uganda who were HIV infected > 12 months were tested using the (1) BED capture enzyme immunoassay (BED), (2) avidity assay, (3) BED and avidity assays with higher assay cutoffs (BED + avidity screen), and (4) multiassay algorithm (MAA) that includes the BED + avidity screen, CD4 cell count, and HIV viral load. Logistic regression identified factors associated with misclassification. False-recent misclassification rates and 95% confidence intervals were BED alone: 7.6% (6.6, 8.8); avidity assay alone: 3.5% (2.7, 4.3); BED + avidity screen: 2.2% (1.7, 2.9); and MAA: 1.2% (0.8, 1.8). The misclassification rate for the MAA was significantly lower than the rates for the other three methods (each p < 0.05). Misclassification rates were lower when the analysis was limited to subtype C-endemic countries, with the lowest rate obtained for the MAA [0.8% (0.2, 1.9)]. Factors associated with misclassification were for BED alone: country of origin, antiretroviral treatment (ART), viral load, and CD4 cell count; for avidity assay alone: country of origin; for BED + avidity screen: country of origin and ART. No factors were associated with misclassification using the MAA. In a multivariate model, these associations remained significant with one exception: the association of ART with misclassification was completely attenuated. A MAA that included CD4 cell count and viral load had lower false-recent misclassification than the BED or avidity assays (alone or in combination). Studies are underway to compare the sensitivity of these methods for detection of recent HIV infection. C1 [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Mullis, Caroline E.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Brookmeyer, Ron] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Donnell, Deborah; Lingappa, Jairam; Celum, Connie; Baeten, Jared M.; Farquhar, Carey] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Donnell, Deborah] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Lingappa, Jairam] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Lingappa, Jairam; Celum, Connie; Baeten, Jared M.; Campbell, Mary S.; Farquhar, Carey] Univ Washington, Dept Med, Seattle, WA USA. [Celum, Connie; Farquhar, Carey] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Essex, Max] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [de Bruyn, Guy] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Laeyendecker, O (reprint author), NIAID, LIR, NIH, 855 N Wolfe St,Room 538A, Baltimore, MD 21205 USA. EM olaeyen1@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760; Donnell, Deborah/0000-0002-0587-7480 FU HIV Prevention Trials Network (HPTN); National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Mental Health (NIMH); National Institute on Drug Abuse (NIDA); Office of AIDS Research, of the National Institutes of Health (NIH); Department of Health and Human Services (DHHS) [U01-AI46745, U01-AI48054, U01-AI068613, UM1-AI068613]; International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network [U01-AI068632]; Division of Intramural Research, NIAID; NIAID [1R01-AI095068]; Bill and Melinda Gates Foundation [26469] FX This work was supported by (1) the HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), Office of AIDS Research, of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS) (Grants U01-AI46745, U01-AI48054, U01-AI068613, and UM1-AI068613), and the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network (U01-AI068632), (2) the Division of Intramural Research, NIAID, (3) the NIAID (Grant 1R01-AI095068), and (4) the Bill and Melinda Gates Foundation (Grant 26469). NR 23 TC 21 Z9 21 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2012 VL 28 IS 10 BP 1177 EP 1183 DI 10.1089/aid.2011.0341 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 013TV UT WOS:000309329700003 PM 22283149 ER PT J AU Bagi, P Arora, M Heimall, J Trivedi, A Henderson, C Quezado, M Kleiner, D Venkatesan, A Holland, S Freeman, A Heller, T AF Bagi, Preet Arora, Manish Heimall, Jeniffer Trivedi, Apurva Henderson, Carolyn Quezado, Martha Kleiner, David Venkatesan, Aradhana Holland, Steven Freeman, Alexandra Heller, Theo TI Esophageal and Other GI Manifestations of Autosomal Dominant Hyper IgE Syndrome: The First Reported Disease Causing Secondary Eosinophilic Esophagitis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract C1 [Bagi, Preet; Arora, Manish; Trivedi, Apurva; Heller, Theo] NIDDK, NIH, Bethesda, MD 20892 USA. [Henderson, Carolyn; Holland, Steven; Freeman, Alexandra] NIAID, NIH, Bethesda, MD 20892 USA. [Heimall, Jeniffer] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Quezado, Martha; Kleiner, David] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Venkatesan, Aradhana] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2012 VL 107 SU 1 MA 77 BP S34 EP S34 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V30UA UT WOS:000208839700078 ER PT J AU Chalasani, N Watkins, P Fontana, R Gu, JZ Lee, W Bonkovsky, H Talwalkar, J Stolz, A Navarro, V Reddy, R Serrano, J AF Chalasani, Naga Watkins, Paul Fontana, Robert Gu, Jiezhun Lee, William Bonkovsky, Herbert Talwalkar, Jayant Stolz, Andrew Navarro, Victor Reddy, Rajender Serrano, Jose TI Causative Agents, Clinical Features, and Outcomes of Idiosyncratic Drug Induced Liver Injury (DILI) in the Elderly: Results From the DILIN Prospective Study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract C1 [Chalasani, Naga] Indiana Univ, Indianapolis, IN 46204 USA. [Watkins, Paul] Hamner Inst, Chapel Hill, NC USA. [Fontana, Robert] Univ Michigan, Ann Arbor, MI 48109 USA. [Gu, Jiezhun] Duke Univ, Durham, NC USA. [Lee, William] Ohio State Univ, Columbus, OH 43210 USA. [Bonkovsky, Herbert] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Talwalkar, Jayant] Mayo Clin, Rochester, MN USA. [Stolz, Andrew] Univ So Calif, Los Angeles, CA USA. [Navarro, Victor] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Reddy, Rajender] U Penn, Philadelphia, PA USA. [Serrano, Jose] NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2012 VL 107 SU 1 MA 370 BP S157 EP S158 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V30UA UT WOS:000208839700371 ER PT J AU Kohli, D Majithia, R Sherker, A AF Kohli, Divyanshoo Majithia, Raj Sherker, Averell TI Primary Gastric Diff use B Cell Lymphoma in Association with Chronic Hepatitis C SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract C1 [Kohli, Divyanshoo; Majithia, Raj] Washington Hosp Ctr, Washington, DC 20010 USA. [Sherker, Averell] NIDDKD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2012 VL 107 SU 1 MA 1046 BP S423 EP S424 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V30UA UT WOS:000208839701483 ER PT J AU Arcaroli, J Quackenbush, K Dasari, A Powell, R McManus, M Tan, AC Foster, NR Picus, J Wright, J Nallapareddy, S Erlichman, C Hidalgo, M Messersmith, WA AF Arcaroli, John Quackenbush, Kevin Dasari, Arvind Powell, Rebecca McManus, Martine Tan, Aik-Choon Foster, Nathan R. Picus, Joel Wright, John Nallapareddy, Sujatha Erlichman, Charles Hidalgo, Manuel Messersmith, Wells A. TI Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer SO CANCER MEDICINE LA English DT Article DE Biomarker; clinical trial; pancreas cancer; Src AB Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] "top scoring pairs" polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3' untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible. C1 [Arcaroli, John; Quackenbush, Kevin; Powell, Rebecca; McManus, Martine; Tan, Aik-Choon; Nallapareddy, Sujatha; Messersmith, Wells A.] Univ Colorado, Ctr Canc, Denver, CO 80262 USA. [Dasari, Arvind] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Foster, Nathan R.; Erlichman, Charles] Mayo Clin, Ctr Canc, Rochester, MN USA. [Picus, Joel] Washington Univ, Sch Med, St Louis, MO USA. [Wright, John] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Hidalgo, Manuel] Ctr Nacl Invest Oncol, Madrid, Spain. RP Messersmith, WA (reprint author), 12801 E 17th Ave,MS 8117, Aurora, CO 80045 USA. EM Wells.Messersmith@ucdenver.edu RI Tan, Aik Choon/A-3135-2011; HIDALGO, MANUEL/I-4995-2015; OI HIDALGO, MANUEL/0000-0002-3765-3318; Tan, Aik Choon/0000-0003-2955-8369 FU NCI/CTEP [7602]; P2C grant [N01-CM62205]; [1R21CA135622-01] FX Supported by NCI/CTEP (Protocol #7602), P2C grant (N01-CM62205, PI, Erlichman), 1R21CA135622-01 (PI, Messersmith). NR 39 TC 6 Z9 6 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD OCT PY 2012 VL 1 IS 2 BP 207 EP 217 DI 10.1002/cam4.27 PG 11 WC Oncology SC Oncology GA V36KF UT WOS:000209210300010 PM 23342270 ER PT J AU Nogueira, LM Lavigne, JA Chandramouli, GVR Lui, HT Barrett, JC Hursting, SD AF Nogueira, Leticia M. Lavigne, Jackie A. Chandramouli, Gadisetti V. R. Lui, Huaitian Barrett, J. Carl Hursting, Stephen D. TI Dose-dependent effects of calorie restriction on gene expression, metabolism, and tumor progression are partially mediated by insulin-like growth factor-1 SO CANCER MEDICINE LA English DT Article DE Cancer biology; cancer prevention; carcinogenesis; nutrition AB The prevalence of obesity, an established risk and progression factor for breast and many other cancer types, remains very high in the United States and throughout the world. Calorie restriction (CR), a reduced-calorie dietary regimen typically involving a 20-40% reduction in calorie consumption, prevents or reverses obesity, and inhibits mammary and other types of cancer in multiple tumor model systems. Unfortunately, the mechanisms underlying the tumor inhibitory effects of CR are poorly understood, and a better understanding of these mechanisms may lead to new intervention targets and strategies for preventing or controlling cancer. We have previously shown that the anticancer effects of CR are associated with decreased systemic levels of insulin-like growth factor-1 (IGF-1), the primary source of which is liver. We have also reported that CR strongly suppresses tumor development and growth in multiple mammary cancer models. To identify CR-responsive genes and pathways, and to further characterize the role of IGF-1 as a mediator of the anticancer effects of CR, we assessed hepatic and mammary gland gene expression, hormone levels and growth of orthotopically transplanted mammary tumors in control and CR mice with and without exogenous IGF-1. C57BL/6 mice were fed either control AIN-76A diet ad libitum (AL), subjected to 20%, 30%, or 40% CR plus placebo timed-release pellets, or subjected to 30% or 40% CR plus timed-release pellets delivering murine IGF-1 (mIGF-1, 20 mu g/day). Compared with AL-fed controls, body weights were decreased 14.3% in the 20% CR group, 18.5% in the 30% CR group, and 38% in the 40% CR group; IGF-1 infusion had no effect on body weight. Hepatic transcriptome analyses indicated that compared with 20% CR, 30% CR significantly modulated more than twice the number of genes and 40% CR more than seven times the number of genes. Many of the genes specific to the 40% CR regimen were hepatic stress-related and/or DNA damage-related genes. Exogenous IGF-1 rescued the hepatic expression of several metabolic genes and pathways affected by CR. Exogenous IGF-1 also rescued the expression of several metabolism-and cancer-related genes affected by CR in the mammary gland. Furthermore, exogenous IGF-1 partially reversed the mammary tumor inhibitory effects of 30% CR. We conclude that several genes and pathways, particularly those associated with macronutrient and steroid hormone metabolism, are associated with the anticancer effects of CR, and that reduced IGF-1 levels can account, at least in part, for many of the effects of CR on gene expression and mammary tumor burden. C1 [Nogueira, Leticia M.; Lavigne, Jackie A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Chandramouli, Gadisetti V. R.] NCI, Ctr Bioinformat, Sci Applicat Int Corp, Rockville, MD USA. [Lui, Huaitian] Sci Applicat Int Corp, Rockville, MD USA. [Barrett, J. Carl] AstraZeneca Pharmaceut Inc, Translat Sci Oncol Innovat Med, Waltham, MA USA. [Hursting, Stephen D.] Univ Texas Austin, Dept Nutr Sci, Smithville, TX USA. [Hursting, Stephen D.] UT MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Smithville, TX USA. RP Hursting, SD (reprint author), Univ Texas Austin, Dept Nutr Sci, Smithville, TX USA. EM shursting@austin.utexas.edu FU Breast Cancer Research Foundation FX Funding for this work was provided by a grant from the Breast Cancer Research Foundation to S. D. Hursting. NR 51 TC 14 Z9 14 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD OCT PY 2012 VL 1 IS 2 BP 275 EP 288 DI 10.1002/cam4.23 PG 14 WC Oncology SC Oncology GA V36KF UT WOS:000209210300016 PM 23342276 ER PT J AU Alexander, PG McCarron, JA Levine, MJ Melvin, GM Murray, PJ Manner, PA Tuan, RS AF Alexander, Peter G. McCarron, Jesse A. Levine, Matthew J. Melvin, Gary M. Murray, Patrick J. Manner, Paul A. Tuan, Rocky S. TI An In Vivo Lapine Model for Impact-Induced Injury and Osteoarthritic Degeneration of Articular Cartilage SO CARTILAGE LA English DT Article DE articular cartilage; mechanical impact; trauma; cartilage degeneration; osteoarthritis; in vivo model AB Objective: In this study, we applied a spring-loaded impactor to deliver traumatic forces to articular cartilage in vivo. Based on our recent finding that a 0.28-J impact induces maximal catabolic response in adult bovine articular cartilage in vitro using this device, we hypothesize that this impact will induce the formation of a focal osteoarthritic defect in vivo. Design: The femoral condyle of New Zealand White rabbits was exposed and one of the following procedures performed: 0.28 J impact, anterior cruciate ligament transection, articular surface grooving, or no joint or cartilage destruction (control). After 24 hours, 4 weeks, or 12 weeks (n = 3 for each time point), wounds were localized with India ink, and tissue samples were collected and characterized histomorphometrically with Safranin O/Fast green staining and Hoechst 33342 nuclear staining for cell vitality. Results: The spring-loaded device delivered reproducible impacts with the following characteristics: impact area of 1.39 +/- 0.11 mm(2), calculated load of 326 +/- 47.3 MPa, time-to-peak of 0.32 +/- 0.03 ms, and an estimated maximal displacement of 25.1% +/- 4.5% at the tip apex. The impact resulted in immediate cartilage fissuring and cell loss in the surface and intermediate zones, and it induced the formation of a focal lesion at 12 weeks. The degeneration was defined and appeared more slowly than after anterior cruciate ligament transection, and more pronounced and characteristic than after grooving. Conclusion: A single traumatic 0.28 J impact delivered with this spring-loaded impactor induces focal cartilage degeneration characteristic of osteoarthritis. C1 [Alexander, Peter G.; Tuan, Rocky S.] Univ Pittsburgh, Dept Orthopaed Surg, Pittsburgh, PA 15219 USA. [McCarron, Jesse A.; Levine, Matthew J.; Murray, Patrick J.; Manner, Paul A.] George Washington Univ, Dept Orthopaed Surg, Washington, DC USA. [Melvin, Gary M.] NIAMSD, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU National Institute of Arthritis, and Musculoskeletal and Skin Diseases, NIH [AR Z01 41131]; Commonwealth of Pennsylvania Department of Health [SAP 4100050913]; U.S. Department of Defense [W81XWH-10-1-0850]; National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health [AR Z01 41131] FX We thank Dr. John Bacher for veterinary assistance, and Dr. Wesley M. Jackson and Dr. Juan Taboas for their technical advice. Funding sources of the study include the following: Intramural Research Program of the National Institute of Arthritis, and Musculoskeletal and Skin Diseases, NIH (AR Z01 41131); Commonwealth of Pennsylvania Department of Health (SAP 4100050913); and the U.S. Department of Defense (W81XWH-10-1-0850). This research was supported by the Intramural Research Program of the National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health (AR Z01 41131); Commonwealth of Pennsylvania Department of Health (SAP 4100050913); and the U.S. Department of Defense (W81XWH-10-1-0850). NR 52 TC 4 Z9 4 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1947-6035 EI 1947-6043 J9 CARTILAGE JI Cartilage PD OCT PY 2012 VL 3 IS 4 BP 323 EP 333 DI 10.1177/1947603512447301 PG 11 WC Orthopedics SC Orthopedics GA V36NH UT WOS:000209218000004 PM 26069642 ER PT J AU Trehanpati, N Shrivastav, S Shivakumar, B Khosla, R Bhardwaj, S Chaturvedi, J Sukriti Kumar, B Bose, S Tripathi, DM Das, T Sakhuja, P Rastogi, A Bhihari, C Singh, S Gupta, S Kottilil, S Sarin, SK AF Trehanpati, Nirupama Shrivastav, Shikha Shivakumar, Bhavana Khosla, Ritu Bhardwaj, Suvercha Chaturvedi, Jaya Sukriti Kumar, Binayak Bose, Sujoy Tripathi, Dinesh Mani Das, Trinath Sakhuja, Puja Rastogi, Archana Bhihari, Chagan Singh, Shivender Gupta, Subhash Kottilil, Shyam Sarin, Shiv Kumar TI Analysis of Notch and TGF-beta Signaling Expression in Different Stages of Disease Progression During Hepatitis B Virus Infection SO CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY LA English DT Article AB OBJECTIVES: CD4+ regulatory T cells (Tregs) seem to have a key role in persistence of hepatitis B virus (HBV) infection. Notch and transforming growth factor (TGF-beta) signaling independently help in the differentiation and regulation of CD4+T cells, including T-helper (T-H) 1, T(H)2, and Tregs. Whether, the two pathways have modulatory role on different stages of HBV infection and severity of liver disease is not clear. We investigated Notch and TGF-beta families' gene expression in peripheral blood and intrahepatic lymphocytes in patients with different stages of chronic HBV (CHB) infection. METHODS: Peripheral blood mononuclear cells (PBMCs), CD4(+), and CD8(+) T cells were isolated from patients with acute HBV (AVH-B, n = 15), CHB (n = 16), and controls (HC, n = 10). In addition to PBMCs, intrahepatic lymphocytes were obtained from liver biopsies from CHB (n = 12), cirrhosis (n = 12), hepatocellular carcinoma (HCC, n = 5), and healthy livers (n = 5). Notch family (Notch1-4, Hes1, Jag1, and NF-k beta) and TGF-beta family gene expressions were studied by real-time PCR, flow cytometry, and immunohistochemistry. RESULTS: Relative expression of Notch signaling target genes, Hes1 and NF-k beta, was higher in the total PBMCs of AVH-B and CHB patients than that in HC patients (Log relative quantification (RQ); 1.1 AVH-B vs. 0.3 HC, 1.3 CHB vs. 0.3 HC; P = 0.02). CD8(+) T cells showed upregulated expression of Hes1 and Notch1 (P = 0.02 and 0.01, respectively) in AVH-B than in CHB patients. Also, in AVH-B patients, HBV-specific CD8(+) T-cell proliferation (5.74% vs. 2.7%) and TGF-beta signaling activity were higher. All Notch receptors and ligands were upregulated in the PBMCs in CHB infection (CHB vs. cirrhosis, P = 0.001; CHB vs. HCC, P = 0.023; and cirrhosis vs. HCC, P = NS). Intrahepatic expression of Notch1 and FoxP3 were significantly higher in cirrhotics and HCCs, and further blockage of Notch signaling reduced the FoxP3 expression. Array data of TGF-beta family showed increased TGF-beta 3, TGF-alpha, SMAD3, SMAD4, SMAD6, and GDF9 expression on intrahepatic lymphocytes in cirrhotic and HCC patients compared with CHB. CONCLUSIONS: Our findings suggest that there is a complementary association between Notch1 and Hes1 in CD8(+)T cells during AVH-B infection. On development of CHB infection, repression of the Notch receptors mediates the regulation of immune response in patients, who progress to cirrhosis and HCC. Finally, HBV infection drives increased Notch1, TGF-beta, and FoxP3 expression on intrahepatic T cells in cirrhosis, resulting in fibrogenesis and disease progression. C1 [Trehanpati, Nirupama; Shrivastav, Shikha; Khosla, Ritu; Bhardwaj, Suvercha; Chaturvedi, Jaya; Sukriti; Kumar, Binayak; Bose, Sujoy; Tripathi, Dinesh Mani; Rastogi, Archana; Bhihari, Chagan; Singh, Shivender; Sarin, Shiv Kumar] ILBS, D-1 Vasant Kunj, New Delhi 110070, India. [Shivakumar, Bhavana; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Das, Trinath] Jawaharlal Nehru Univ, Mol Biol Lab, Sch Biotechnol, New Delhi 110067, India. [Sakhuja, Puja] GB Pant Hosp, Dept Pathol, New Delhi, India. [Gupta, Subhash] Indraprastha Apollo Hosp, Dept Liver Transplant, New Delhi, India. RP Sarin, SK (reprint author), ILBS, D-1 Vasant Kunj, New Delhi 110070, India. EM trehanpati@gmail.com; shivsarin@gmail.com RI Tripathi, Dinesh Mani/E-6236-2016 OI Tripathi, Dinesh Mani/0000-0003-0897-6959 FU Department of Biotechnology, Government of India, New Delhi, India [BT/PR12759/MED/29/135/2009] FX This study was in part supported by grant no. BT/PR12759/MED/29/135/2009 received from the Department of Biotechnology, Government of India, New Delhi, India. NR 33 TC 10 Z9 10 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2155-384X J9 CLIN TRANSL GASTROEN JI Clin. Transl. Gastroenterol. PD OCT PY 2012 VL 3 AR e23 DI 10.1038/ctg.2012.17 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V42RK UT WOS:000209630700001 PM 23238065 ER PT J AU An, Y Gregg, E Zhang, P Wang, J Gong, Q Engelgau, M Roglic, G Bennett, PH Li, G AF An, Y. Gregg, E. Zhang, P. Wang, J. Gong, Q. Engelgau, M. Roglic, G. Bennett, P. H. Li, G. TI Long-duration diabetes reduces physical function in Chinese adults: Da Qing IGT and diabetes study SO DIABETOLOGIA LA English DT Meeting Abstract C1 [An, Y.; Gong, Q.] Fuwai Hosipital, Endocrine Dept, Beijing, Peoples R China. [Gregg, E.; Zhang, P.; Engelgau, M.] CDC, Atlanta, GA 30333 USA. [Wang, J.] DaQing First Hosp, Daqing, Peoples R China. [Roglic, G.] WHO, CH-1211 Geneva, Switzerland. [Bennett, P. H.] NIDDK, Phoenix, AZ USA. [Li, G.] China Japan Friendship Hosp, Beijing, Peoples R China. 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 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2012 VL 55 SU 1 MA 1204 BP S489 EP S489 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V30OY UT WOS:000208826502519 ER PT J AU Ehlers, MR Gottlieb, PA Herold, K Rigby, MR Willi, SM Aggarwal, S Phippard, D Gelmont, DM Jepson, B McNamara, J Strom, T Weir, GC AF Ehlers, M. R. Gottlieb, P. A. Herold, K. Rigby, M. R. Willi, S. M. Aggarwal, S. Phippard, D. Gelmont, D. M. Jepson, B. McNamara, J. Strom, T. Weir, G. C. CA RETAIN Study Team TI Alpha-1 antitrypsin therapy in new-onset type 1 diabetes: interim results from Part I of the RETAIN study SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Ehlers, M. R.] Immune Tolerance Network, Clin Trials Grp, San Francisco, CA USA. [Gottlieb, P. A.] Barbara Davis Ctr, Aurora, CO USA. [Herold, K.] Yale Univ, New Haven, CT USA. [Rigby, M. R.] Indiana Univ, Indianapolis, IN 46204 USA. [Willi, S. M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Aggarwal, S.; Phippard, D.] Immune Tolerance Network, Bethesda, MD USA. [Jepson, B.] RhoFed Inc, Biostat, Chapel Hill, NC USA. [McNamara, J.] NIAID, DAIT, Bethesda, MD 20892 USA. [Strom, T.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Weir, G. C.] Joslin Diabet Ctr, Boston, MA 02215 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 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2012 VL 55 SU 1 MA 147 BP S67 EP S67 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V30OY UT WOS:000208826500148 ER PT J AU Gitelman, SE Fisher, LK Gottlieb, PA Gottschalk, M Moore, WV Moran, A Rigby, MR Willi, SM Keyes-Elstein, L Pinckney, A Ding, L Ehlers, MR AF Gitelman, S. E. Fisher, L. K. Gottlieb, P. A. Gottschalk, M. Moore, W. V. Moran, A. Rigby, M. R. Willi, S. M. Keyes-Elstein, L. Pinckney, A. Ding, L. Ehlers, M. R. CA START Study Team TI Effect of anti-thymocyte globulin (ATG) on preserving beta cell function in new-onset type 1 diabetes SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Gitelman, S. E.] Univ Calif San Francisco, Pediat Diabet Program, San Francisco, CA 94143 USA. [Fisher, L. K.] Childrens Hosp Los Angeles, Los Angeles, CA USA. [Gottlieb, P. A.] Barbara Davis Ctr, Aurora, CO USA. [Gottschalk, M.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Moore, W. V.] Childrens Mercy Hosp, Kansas City, KS USA. [Moran, A.] Univ Minnesota, Minneapolis, MN USA. [Rigby, M. R.] Indiana Univ, Indianapolis, IN 46204 USA. [Willi, S. M.] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Keyes-Elstein, L.; Pinckney, A.] RhoFed Inc, Chapel Hill, NC USA. [Ding, L.] NIAID, DAIT, Bethesda, MD 20892 USA. [Ehlers, M. R.] Immune Tolerance Network, Clin Trials Grp, San Francisco, CA USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2012 VL 55 SU 1 MA 454 BP S191 EP S192 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V30OY UT WOS:000208826501201 ER PT J AU Herold, KC Ehlers, M Boyle, K McNamara, J Gitelman, S Gottlieb, P Greenbaum, C Hagopian, W Bluestone, JA AF Herold, K. C. Ehlers, M. Boyle, K. McNamara, J. Gitelman, S. Gottlieb, P. Greenbaum, C. Hagopian, W. Bluestone, J. A. TI Metabolic parameters at baseline identify clinical responders to teplizumab 2 years after diagnosis of type 1 diabetes SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Herold, K. C.] Yale Univ, New Haven, CT USA. [Ehlers, M.] Immune Tolerance Network, San Francisco, CA USA. [Boyle, K.] Rho Inc, Chapel Hill, NC USA. [McNamara, J.] NIAID, Bethesda, MD 20892 USA. [Gitelman, S.; Bluestone, J. A.] UCSF, San Francisco, CA USA. [Gottlieb, P.] Univ Colorado, Aurora, CO USA. [Greenbaum, C.] Benaroya Res Inst, Seattle, WA USA. [Hagopian, W.] Pacific Northwest Res Inst, Seattle, WA 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 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2012 VL 55 SU 1 MA 452 BP S191 EP S191 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V30OY UT WOS:000208826501199 ER PT J AU Moreno-Villegas, Z Ramos-Alvarez, I Sanz, R Jensen, R Gonzalez, N AF Moreno-Villegas, Z. Ramos-Alvarez, I. Sanz, R. Jensen, R. Gonzalez, N. TI Role of bombesin receptor subtype-3 and its agonist [D-Phe(6)-beta-Ala(11),Phe(13),Nle(14)]bombesin(6-14) in lipid metabolism SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Moreno-Villegas, Z.; Sanz, R.] IIS Fdn Jimenez Diaz, Madrid, Spain. [Ramos-Alvarez, I.; Gonzalez, N.] CIBERDEM, IIS Fdn Jimenez Diaz, Madrid, Spain. [Jensen, R.] NIH, Bethesda, MD 20892 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 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2012 VL 55 SU 1 MA 634 BP S261 EP S261 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V30OY UT WOS:000208826501381 ER PT J AU Raimondo, A Rees, MG Wang, J Barrett, A Collins, FS Hegele, RA Gloyn, AL AF Raimondo, A. Rees, M. G. Wang, J. Barrett, A. Collins, F. S. Hegele, R. A. Gloyn, A. L. TI Functional analysis of GCKR mutations identified in subjects with hypertriglyceridaemia demonstrates the inherent challenges in clinical interpretation of rare variants SO DIABETOLOGIA LA English DT Meeting Abstract C1 [Raimondo, A.; Rees, M. G.; Barrett, A.; Gloyn, A. L.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [Rees, M. G.; Collins, F. S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Wang, J.; Hegele, R. A.] Univ Western Ontario, Robarts Res Inst, London, ON, Canada. [Gloyn, A. L.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Cambridge, 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 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2012 VL 55 SU 1 MA 174 BP S78 EP S78 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V30OY UT WOS:000208826500175 ER PT J AU Hong, J Alvarez, LM Shah, NJ Cho, Y Kim, BS Griffith, LG Char, K Hammond, PT AF Hong, Jinkee Alvarez, Luis M. Shah, Nisarg J. Cho, Younghyun Kim, Byeong-Su Griffith, Linda G. Char, Kookheon Hammond, Paula T. TI Multilayer thin-film coatings capable of extended programmable drug release: application to human mesenchymal stem cell differentiation SO DRUG DELIVERY AND TRANSLATIONAL RESEARCH LA English DT Article DE Layer-by-layer; Multilayer; Controlled release; Human mesenchymal stem cells; Differentiation; Dexamethasone AB The promise of cellular therapy lies in healing damaged tissues and organs in vivo as well as generating tissue constructs in vitro for subsequent transplantation. Postnatal stem cells are ideally suited for cellular therapies due to their pluripotency and the ease with which they can be cultured on functionalized substrates. Creating environments to control and successfully drive their differentiation toward a lineage of choice is one of the most important challenges of current cell-based engineering strategies. In recent years, a variety of biomaterials platforms have been prepared for stem cell cultures, primarily to provide efficient delivery of growth or survival factors to cells and a conductive microenvironment for their growth. Here, we demonstrate that repeating tetralayer structures composed of biocompatible poly(methacrylic acid), poly(acrylamide), and poly(ethylene oxide)-block-poly(epsilon-caprolactone) micelles arrayed in layer-by-layer films can serve as a payload region for dexamethasone delivery to human mesenchymal stem cells (MSCs). This architecture can induce MSC differentiation into osteoblasts in a dose-dependent manner. The amount of Dex loaded in the films is controlled by varying the deposition conditions and the film thickness. Release of Dex is tuned by changing the amount of covalent cross-linking of multilayers via thermal treatments. The multilayer architecture including payload and cell-adhesion region introduced here are well suited for extended cell culture thus affording the important and protective effect of both Dex release and immobilization. These films may find applications in the local delivery of immobilized therapeutics for biomedical applications, as they can be deposited on a wide range of substrates with different shapes, sizes, and composition. C1 [Hong, Jinkee; Shah, Nisarg J.; Kim, Byeong-Su; Hammond, Paula T.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Hong, Jinkee; Shah, Nisarg J.; Hammond, Paula T.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Alvarez, Luis M.; Griffith, Linda G.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Alvarez, Luis M.] Frederick Natl Lab Canc Res, Canc & Dev Biol Lab, Frederick, MD 21702 USA. [Hong, Jinkee; Cho, Younghyun; Char, Kookheon] Seoul Natl Univ, Natl Creat Res Initiat Ctr Intelligent Hybrids, WCU Program Chem Convergence Energy & Environm, Sch Chem & Biol Engn, Seoul 151744, South Korea. RP Hammond, PT (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM khchar@plaza.snu.ac.kr; hammond@mit.edu FU Singapore-MIT Alliance for Research and Technology (SMART) at the Massachusetts Institute of Technology (MIT); National Research Foundation of Korea (NRF); Korean Ministry of Education, Science and Technology (MEST) through The National Creative Research Initiative Program for "Intelligent Hybrids Research Center" [2010-0018290]; WCU Program of Chemical Convergence for Energy and Environment [R31-10013]; Brain Korea 21 Program in Chemical Engineering of Seoul National University; NIH [R01DE19523]; Hertz Foundation (Livermore, CA) FX This research was funded by the Singapore-MIT Alliance for Research and Technology (SMART) at the Massachusetts Institute of Technology (MIT). Additionally, this work was financially supported by the National Research Foundation of Korea (NRF) funded by the Korean Ministry of Education, Science and Technology (MEST) through The National Creative Research Initiative Program for "Intelligent Hybrids Research Center" (No. 2010-0018290), the WCU Program of Chemical Convergence for Energy and Environment (R31-10013), and the Brain Korea 21 Program in Chemical Engineering of Seoul National University and NIH R01DE19523. Additionally, LMA acknowledges support from the Hertz Foundation (Livermore, CA). NR 47 TC 7 Z9 7 U1 2 U2 8 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2190-393X EI 2190-3948 J9 DRUG DELIV TRANSL RE JI Drug Deliv. Transl. Res. PD OCT PY 2012 VL 2 IS 5 BP 375 EP 383 DI 10.1007/s13346-012-0093-z PG 9 WC Instruments & Instrumentation; Medicine, Research & Experimental; Pharmacology & Pharmacy SC Instruments & Instrumentation; Research & Experimental Medicine; Pharmacology & Pharmacy GA V39PY UT WOS:000209424100008 PM 25485185 ER PT J AU Nielsen, ACY Gyhrs, ML Holmes, EC Cui, J AF Nielsen, Alex Christian Yde Gyhrs, Mette Louise Holmes, Edward C. Cui, Jie TI Co-Circulation and Persistence of Genetically Distinct Saffold Viruses, Denmark SO EMERGING INFECTIOUS DISEASES LA English DT Letter ID CHILDREN; CARDIOVIRUSES; INFECTIONS C1 [Nielsen, Alex Christian Yde] Statens Serum Inst, DK-2300 Copenhagen, Denmark. [Nielsen, Alex Christian Yde] Odense Univ Hosp, DK-5000 Odense, Denmark. [Holmes, Edward C.; Cui, Jie] Penn State Univ, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Bethesda, MD 20892 USA. RP Cui, J (reprint author), Penn State Univ, Dept Biol, Millennium Sci Complex, University Pk, PA 16802 USA. EM jiecui@yahoo.com OI Cui, Jie/0000-0001-8176-9951; Holmes, Edward/0000-0001-9596-3552 NR 10 TC 5 Z9 5 U1 1 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD OCT PY 2012 VL 18 IS 10 BP 1694 EP 1696 DI 10.3201/eid1810.120793 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 268LP UT WOS:000328172500031 PM 23017727 ER PT J AU Raoult, D Koonin, EV AF Raoult, Didier Koonin, Eugene V. TI Microbial genomics challenge Darwin SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Editorial Material C1 [Raoult, Didier] Aix Marseille Univ, CNRS UMR 6236, IRD 198, Fac Med,Unite Rech Malad Infect & Trop Emergentes, Marseille, France. [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Raoult, D (reprint author), Aix Marseille Univ, CNRS UMR 6236, IRD 198, Fac Med,Unite Rech Malad Infect & Trop Emergentes, Marseille, France. EM didier.raoult@gmail.com NR 24 TC 4 Z9 5 U1 1 U2 11 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD OCT PY 2012 VL 2 AR UNSP 127 DI 10.3389/fcimb.2012.00127 PG 2 WC Immunology; Microbiology SC Immunology; Microbiology GA 221BS UT WOS:000324632900006 PM 23091803 ER PT J AU Karahalil, B Bohr, VA Wilson, DM AF Karahalil, B. Bohr, V. A. Wilson, D. M., III TI Impact of DNA polymorphisms in key DNA base excision repair proteins on cancer risk SO HUMAN & EXPERIMENTAL TOXICOLOGY LA English DT Article DE OGG1; XRCC1; APE1; cancer; gene polymorphism; DNA repair; DNA damage ID HOGG1 SER326CYS POLYMORPHISM; SQUAMOUS-CELL CARCINOMA; GENE XRCC1 POLYMORPHISMS; SINGLE-NUCLEOTIDE POLYMORPHISMS; LUNG-CANCER; COLORECTAL-CANCER; GASTRIC-CANCER; OGG1 SER326CYS; BREAST-CANCER; CHINESE POPULATION AB Genetic variation in DNA repair genes can modulate DNA repair capacity and may be related to cancer risk. However, study findings have been inconsistent. Inheritance of variant DNA repair genes is believed to influence individual susceptibility to the development of environmental cancer. Reliable knowledge on which the base excision repair (BER) sequence variants are associated with cancer risk would help elucidate the mechanism of cancer. Given that most of the previous studies had inadequate statistical power, we have conducted a systematic review on sequence variants in three important BER proteins. Here, we review published studies on the association between polymorphism in candidate BER genes and cancer risk. We focused on three key BER genes: 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease (APE1/APEX1) and x-ray repair cross-complementing group 1 (XRCC1). These specific DNA repair genes were selected because of their critical role in maintaining genome integrity and, based on previous studies, suggesting that single-nucleotide polymorphisms (SNPs) in these genes have protective or deleterious effects on cancer risk. A total of 136 articles in the December 13, 2010 MEDLINE database (National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov/pubmed/) reporting polymorphism in OGG1, XRCC1 or APE1 genes were analyzed. Many of the reported SNPs had diverse association with specific human cancers. For example, there was a positive association between the OGG1 Ser326Cys variant and gastric and lung cancer, while the XRCC1Arg399Gln variant was associated with reduced cancer risk. Gene-environment interactions have been noted and may be important for colorectal and lung cancer risk and possibly other human cancers. C1 [Karahalil, B.] Gazi Univ, Fac Pharm, Dept Toxicol, TR-06330 Ankara, Turkey. [Bohr, V. A.; Wilson, D. M., III] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Karahalil, B (reprint author), Gazi Univ, Fac Pharm, Dept Toxicol, TR-06330 Ankara, Turkey. EM bensu@gazi.edu.tr FU Intramural NIH HHS [ZIA AG000727-20] NR 107 TC 51 Z9 54 U1 2 U2 16 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0960-3271 EI 1477-0903 J9 HUM EXP TOXICOL JI Hum. Exp. Toxicol. PD OCT PY 2012 VL 31 IS 10 BP 981 EP 1005 DI 10.1177/0960327112444476 PG 25 WC Toxicology SC Toxicology GA 019BW UT WOS:000309712900002 PM 23023028 ER PT J AU Zanella, A Rezoagli, E Cressoni, M Ferlicca, D Berra, L Kolobow, T AF Zanella, A. Rezoagli, E. Cressoni, M. Ferlicca, D. Berra, L. Kolobow, T. TI DEVELOPMENT OF POST EXTUBATION PNEUMONIA: ROLE OF 24 HOURS OF ENDOTRACHEAL INTUBATION AND MECHANICAL VENTILATION. AN EXPERIMENTAL STUDY SO INTENSIVE CARE MEDICINE LA English DT Meeting Abstract C1 [Zanella, A.; Rezoagli, E.; Ferlicca, D.] Univ Milano Bicocca, Osped San Gerardo Nuovo Tintori, Monza, Italy. [Cressoni, M.] Univ Milan, Milan, Italy. [Berra, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kolobow, T.] NIH, Bethesda, MD 20892 USA. RI Cressoni, Massimo/B-7315-2017 NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD OCT PY 2012 VL 38 SU 1 MA 0748 BP S204 EP S204 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA V34JP UT WOS:000209083001064 ER PT J AU Luk, JW Wang, J Simons-Morton, BG AF Luk, Jeremy W. Wang, Jing Simons-Morton, Bruce G. TI The co-occurrence of substance use and bullying behaviors among US adolescents: Understanding demographic characteristics and social influences SO JOURNAL OF ADOLESCENCE LA English DT Article DE Substance use; Bullying; Parental knowledge; Peer influence; Latent class analysis ID MULTIPLE PROBLEM BEHAVIORS; HIGH-SCHOOL DROPOUT; INDIRECT AGGRESSION; GRADE-LEVEL; ALCOHOL-USE; PREVALENCE; PEER; GENDER; ABUSE; YOUTH AB This study examined the co-occurrence of subtypes of substance use and bullying behaviors using latent class analysis and evaluated latent class differences in demographic characteristics, peer and parental influences. Self-reported questionnaire data were collected from a nationally representative sample (N = 7508) of 6-10th grade adolescents in the United States. Four latent classes were identified: the non-involved (57.7%), substance users (19.4%), bullies (17.5%), and substance-using bullies (5.4%). Older and Hispanic adolescents were more likely to be substance users and substance-using bullies, whereas younger and African American adolescents were more likely to be bullies. Females were more likely to be substance users, whereas males were more likely to be bullies and substance-using bullies. Spending more evenings with peers posed greater risks for substance use, bullying, and the co-occurrence of both problem behaviors. Paternal knowledge exerted protective effects over-and-above the effects of maternal knowledge. Implications for prevention and intervention efforts are discussed. (C) 2012 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved. C1 [Luk, Jeremy W.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Wang, Jing; Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Bethesda, MD USA. [Wang, Jing] Glotech Inc, Norfolk, VA USA. RP Luk, JW (reprint author), Univ Washington, Dept Psychol, Box 351525, Seattle, WA 98195 USA. EM jwluk@uw.edu; wangji2@mail.nih.gov; mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [ZIA HD002525-15]; NIAAA NIH HHS [F31 AA020700] NR 64 TC 16 Z9 16 U1 5 U2 17 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0140-1971 EI 1095-9254 J9 J ADOLESCENCE JI J. Adolesc. PD OCT PY 2012 VL 35 IS 5 BP 1351 EP 1360 DI 10.1016/j.adolescence.2012.05.003 PG 10 WC Psychology, Developmental SC Psychology GA 233WK UT WOS:000325600000023 PM 22698675 ER PT J AU Kitanaka, J Kitanaka, N Hall, FC Uhl, GR Tanaka, KI Nishiyama, N Takemura, M AF Kitanaka, J. Kitanaka, N. Hall, F. C. Uhl, G. R. Tanaka, K. -I. Nishiyama, N. Takemura, M. TI Hypothalamic histamine levels are negatively correlated with expression frequency of methamphetamine-induced stereotypical biting in mice SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract C1 [Kitanaka, J.; Kitanaka, N.; Takemura, M.] Hyogo Coll Med, Dept Pharmacol, Nishinomiya, Hyogo, Japan. [Hall, F. C.; Uhl, G. R.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Tanaka, K. -I.; Nishiyama, N.] Hyogo Univ Hlth Sci, Sch Pharm, Dept Pharm, Div Pharmacol, Kobe, Hyogo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2012 VL 123 SU 1 SI SI BP 79 EP 79 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA V31EE UT WOS:000208866100214 ER PT J AU Futatsugi, A Utreras, E Rudrabhatla, P Jaffe, H Pant, HC Kulkarni, AB AF Futatsugi, A. Utreras, E. Rudrabhatla, P. Jaffe, H. Pant, H. C. Kulkarni, A. B. TI Cyclin dependent kinase 5 regulates E2F transcription factor through phosphorylation of Rb protein in neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract C1 [Futatsugi, A.] Kobe City Coll Nursing, Dept Basic Med Sci, Kobe, Hyogo, Japan. [Futatsugi, A.; Utreras, E.; Kulkarni, A. B.] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Rudrabhatla, P.; Pant, H. C.] NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Jaffe, H.] NINDS, Prot & Peptide Facil, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2012 VL 123 SU 1 SI SI BP 114 EP 114 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA V31EE UT WOS:000208866100324 ER PT J AU Stamler, J Neaton, JD Cohen, JD Cutler, J Eberly, L Grandits, G Kuller, LH Ockene, J Prineas, R AF Stamler, Jeremiah Neaton, James D. Cohen, Jerome D. Cutler, Jeffrey Eberly, Lynn Grandits, Gregory Kuller, Lewis H. Ockene, Judith Prineas, Ronald CA MRFIT Res Grp TI Multiple Risk Factor Intervention Trial Revisited: A New Perspective Based on Nonfatal and Fatal Composite Endpoints, Coronary and Cardiovascular, During the Trial SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE clinical trials; primary prevention; risk factors ID HYPERTENSIVE PARTICIPANTS; BLOOD-PRESSURE; MRFIT; MORTALITY; OUTCOMES AB Background-The Multiple Risk Factor Intervention Trial evaluated a multifactor intervention on coronary heart disease (CHD) in 12 866 men. A priori defined endpoints (CHD death, CHD death or nonfatal myocardial infarction, cardiovascular disease [CVD] death, and all-cause death) did not differ significantly between the special intervention (SI) and usual care (UC) groups over an average follow-up period of 7 years. Event rates were lower than anticipated, reducing power. Other nonfatal CVD outcomes were prespecified but not considered in composite outcomes comparing SI with UC. Methods and Results-Post-trial CVD mortality risks associated with nonfatal CVD events occurring during the trial were determined with Cox regression. Nonfatal outcomes associated with >2-fold risk of CVD death over the subsequent 20 years were combined with during-trial deaths to create 2 new composite outcomes. SI/UC hazard ratios and 95% confidence intervals were estimated for each composite outcome. Of 10 during-trial nonfatal events, 6 were associated (P<0.001) with >2-fold risk of CVD death. A CHD composite outcome (CHD death, myocardial infarction [clinical or serial ECG change], CHF, or coronary artery surgery) was experienced by 520 SI and 602 UC men (SI/UC hazard ratio = 0.86; 95% confidence interval, 0.76-0.97; P=0.01). A CVD composite outcome (CHD [as above], other CVD deaths, stroke, or renal impairment) was experienced by 581 SI and 652 UC men (hazard ratio = 0.89; 95% confidence interval, 0.79-0.99; P=0.04). Conclusions-In post hoc analyses, composite fatal/nonfatal CHD and CVD rates over 7 years were significantly lower for SI than for UC. These findings reinforce recommendations for improved dietary/lifestyle practices, with pharmacological therapy as needed, to prevent and control major CVD risk factors. C1 [Stamler, Jeremiah] Northwestern Univ, Sch Med, Chicago, IL USA. [Neaton, James D.; Eberly, Lynn; Grandits, Gregory] Univ Minnesota, Minneapolis, MN 55414 USA. [Cohen, Jerome D.] St Louis Univ, Sch Med, St Louis, MO USA. [Cutler, Jeffrey] NHLBI, NIH, Bethesda, MD 20892 USA. [Kuller, Lewis H.] Univ Pittsburgh, Pittsburgh, PA USA. [Ockene, Judith] Univ Massachusetts, Sch Med, Worcester, MA USA. [Prineas, Ronald] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Neaton, JD (reprint author), Univ Minnesota, Div Biostat, 2221 Univ Ave SE,Suite 200, Minneapolis, MN 55414 USA. EM jim@ccbr.umn.edu OI Eberly, Lynn/0000-0003-4763-330X FU NIH/NHLBI [R01-HL-43232, R01-HL-68140] FX The Multiple Risk Factor Intervention Trial was contracted by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD. Follow-up after the end of the trial was supported with NIH/NHLBI grants R01-HL-43232 and R01-HL-68140. NR 20 TC 9 Z9 9 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD OCT PY 2012 VL 1 IS 5 AR UNSP e003640 DI 10.1161/JAHA.112.003640 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 243RU UT WOS:000326335500025 PM 23316301 ER PT J AU Maggi, P Sati, P Macri, S Leibovitch, E Absinta, M Massacesi, L Westmoreland, S Jacobson, S Silva, A Reich, DS AF Maggi, P. Sati, P. Macri, S. Leibovitch, E. Absinta, M. Massacesi, L. Westmoreland, S. Jacobson, S. Silva, A. Reich, D. S. TI Biological origin of MR phase contrast in white matter lesions at 7T SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 28th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis CY OCT 10-13, 2012 CL Lyon, FRANCE SP European Comm Treatment & Res Multiple Sclerosis C1 NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. New England Primate Res Ctr, Boston, MA USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2012 VL 18 SU 4 BP 150 EP 150 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 275UC UT WOS:000328702200293 ER PT J AU Kane, R Ikonomidou, V Ohayon, J Cantor, F Stern, S Gallo, A Pellegrini, S Ehrmantraut, M Bagnato, F AF Kane, R. Ikonomidou, V. Ohayon, J. Cantor, F. Stern, S. Gallo, A. Pellegrini, S. Ehrmantraut, M. Bagnato, F. TI Is the development of T2 hypointensity a global process? SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 28th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis CY OCT 10-13, 2012 CL Lyon, FRANCE SP European Comm Treatment & Res Multiple Sclerosis C1 Univ Maryland, Washington, DC USA. George Mason Univ, Fairfax, VA 22030 USA. NIH, Washington, DC USA. Georgia State Univ, Atlanta, GA 30303 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2012 VL 18 SU 4 BP 346 EP 346 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 275UC UT WOS:000328702202138 ER PT J AU Harrison, D Oh, J Seigo, M Aquino, J Jones, C van Zijl, P Reich, D Calabresi, P AF Harrison, D. Oh, J. Seigo, M. Aquino, J. Jones, C. van Zijl, P. Reich, D. Calabresi, P. TI Thalamic lesion analysis on 7-Tesla MRI as a surrogate for cortical demyelination SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 28th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis CY OCT 10-13, 2012 CL Lyon, FRANCE SP European Comm Treatment & Res Multiple Sclerosis C1 Johns Hopkins Sch Med, Baltimore, MD USA. Kennedy Krieger Inst, Baltimore, MD USA. NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2012 VL 18 SU 4 BP 347 EP 347 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 275UC UT WOS:000328702202139 ER PT J AU Hametner, S Yao, B van Gelderen, P Merkle, H Lassmann, H Cantor, FK Chen, C Duyn, J Bagnato, F AF Hametner, S. Yao, B. van Gelderen, P. Merkle, H. Lassmann, H. Cantor, F. K. Chen, C. Duyn, J. Bagnato, F. TI Imaging cortical lesions in multiple sclerosis brains - a combined post-mortem 7 Tesla MRI and histopathological study SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 28th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis CY OCT 10-13, 2012 CL Lyon, FRANCE SP European Comm Treatment & Res Multiple Sclerosis C1 Med Univ Vienna, Vienna, Austria. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2012 VL 18 SU 4 BP 349 EP 349 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 275UC UT WOS:000328702202143 ER PT J AU Leibovitch, E Maggi, P Macri, SC Brunetto, G Motanic, K Wohler, J Westmoreland, S Silva, A Reich, D Jacobson, S AF Leibovitch, E. Maggi, P. Macri, S. Cummings Brunetto, G. Motanic, K. Wohler, J. Westmoreland, S. Silva, A. Reich, D. Jacobson, S. TI Intranasal HHV-6A infection accelerates EAE in the common marmoset SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 28th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis CY OCT 10-13, 2012 CL Lyon, FRANCE SP European Comm Treatment & Res Multiple Sclerosis C1 NIH, Bethesda, MD 20892 USA. New England Reg Primate Res Ctr, Southborough, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2012 VL 18 SU 4 BP 353 EP 353 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 275UC UT WOS:000328702202151 ER PT J AU Mitchell, SA Dueck, AC Velikova, G Lalla, D Basch, E AF Mitchell, Sandra A. Dueck, Amylou C. Velikova, Galina Lalla, Deepa Basch, Ethan TI Patient-centered approach to adverse event reporting: the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE; HHSN261201000043C and HHSN261201000063C) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Bethesda, MD 20892 USA. [Dueck, Amylou C.] Mayo Clin, Scottsdale, AZ USA. [Velikova, Galina] Univ Leeds, St James Inst Oncol, Leeds, W Yorkshire, England. [Lalla, Deepa] Genentech Inc, Hlth Outcomes, San Francisco, CA 94080 USA. [Basch, Ethan] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2012 VL 21 SU 1 MA 4 BP 2 EP 2 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QW UT WOS:000209358900005 ER PT J AU Atkinson, T Dueck, AC Li, YL Mitchell, SA Rogak, L Sit, L Bennett, AV Mendoza, TR Clauser, SB Basch, E AF Atkinson, Thomas Dueck, Amylou C. Li, Yuelin Mitchell, Sandra A. Rogak, Lauren Sit, Laura Bennett, Antonia V. Mendoza, Tito R. Clauser, Steven B. Basch, Ethan TI Symptom frequency, severity and interference represent non-overlapping attributes of symptomatic treatment toxicity in patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Atkinson, Thomas; Li, Yuelin; Rogak, Lauren; Bennett, Antonia V.; Basch, Ethan] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Dueck, Amylou C.] Mayo Clin, Rochester, MN USA. [Mitchell, Sandra A.; Clauser, Steven B.] NCI, Bethesda, MD 20892 USA. [Sit, Laura] George Mason Univ, Fairfax, VA 22030 USA. [Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2012 VL 21 SU 1 MA 109.4 BP 16 EP 17 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QW UT WOS:000209358900043 ER PT J AU Holch, P Warrington, L Ziegler, L Hector, C Keding, A Bamforth, L Harley, C Mitchell, SA Basch, E Velikova, G AF Holch, Patricia Warrington, Lorraine Ziegler, Lucy Hector, Ceri Keding, Ada Bamforth, Leon Harley, Clare Mitchell, Sandra A. Basch, Ethan Velikova, Galina TI Asking the right questions to get the right answers: using cognitive interviews to review the acceptability, comprehension and clinical meaningfulness of patient self-report adverse event items in oncology patients SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Holch, Patricia; Warrington, Lorraine; Ziegler, Lucy; Hector, Ceri; Keding, Ada; Bamforth, Leon; Harley, Clare; Velikova, Galina] Univ Leeds, Leeds LS2 9JT, W Yorkshire, England. [Mitchell, Sandra A.] NCI, Bethesda, MD 20892 USA. [Basch, Ethan] Mem Sloan Kettering Canc Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2012 VL 21 SU 1 MA 109.2 BP 16 EP 16 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QW UT WOS:000209358900041 ER PT J AU Stover, AM Reeve, BB Piper, B Alfano, CM Smith, AW Mitchell, SA Bernstein, L Baumgartner, KB McTiernan, A Ballard-Barbash, R AF Stover, Angela M. Reeve, Bryce B. Piper, Barbara Alfano, Catherine M. Smith, Ashley Wilder Mitchell, Sandra A. Bernstein, Leslie Baumgartner, Katherine B. McTiernan, Anne Ballard-Barbash, Rachel TI Assessing the Association of Cancer-Related Fatigue Thresholds on the Piper Fatigue Scale-12 with sexual functioning in a population-based cohort of breast cancer survivors: a HEAL study SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Stover, Angela M.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Reeve, Bryce B.] Univ N Carolina, Chapel Hill, NC USA. [Piper, Barbara] Univ Arizona, Tucson, AZ 85721 USA. [Alfano, Catherine M.; Smith, Ashley Wilder; Mitchell, Sandra A.; Ballard-Barbash, Rachel] NCI, Bethesda, MD 20892 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Duarte, CA USA. [Baumgartner, Katherine B.] Univ Louisville, Louisville, KY 40292 USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2012 VL 21 SU 1 MA 305.4 BP 37 EP 37 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QW UT WOS:000209358900099 ER PT J AU Mendoza, TR Dueck, AC Rogak, LJ Sit, L Li, YL Bennett, A Atkinson, T Clauser, SB Mitchell, SA Basch, E AF Mendoza, Tito R. Dueck, Amylou C. Rogak, Lauren J. Sit, Laura Li, Yuelin Bennett, Antonia Atkinson, Thomas Clauser, Steven B. Mitchell, Sandra A. Basch, Ethan TI Evaluation of severity and frequency levels that optimally differentiate between levels of interference for symptoms in the National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Mendoza, Tito R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Dueck, Amylou C.] Mayo Clin, Scottsdale, AZ USA. [Rogak, Lauren J.; Li, Yuelin; Bennett, Antonia; Atkinson, Thomas; Basch, Ethan] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sit, Laura] George Mason Univ, Fairfax, VA 22030 USA. [Clauser, Steven B.; Mitchell, Sandra A.] NCI, Outcomes Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2012 VL 21 SU 1 MA 3090 BP 132 EP 132 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V38QW UT WOS:000209358900377 ER PT J AU de Serres, FJ Blanco, I AF de Serres, Frederick J. Blanco, Ignacio TI Prevalence of a1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review SO THERAPEUTIC ADVANCES IN RESPIRATORY DISEASE LA English DT Review DE alpha 1-antitrypsin deficiency; PI subtypes; PI phenotypes; genetic epidemiology; SERPINA1 AB Genetic epidemiological studies on the prevalence and numbers of individuals with alpha 1-antitrypsin deficiency in each of 97 countries worldwide were used to estimate the numbers in each of the five following phenotypic classes: PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ. These 97 countries were then grouped into 10 major geographic regions to make it possible to compare the numbers in each of these five phenotypic classes in immediately adjacent countries. Such groupings also make it possible to review the spread of the PI*S and PI*Z alleles from one major geographic grouping to another in the world as well as the spread of these two deficiency alleles within a major geographic region. The data in the 10 tables on the numbers in each of the five phenotypic classes in the countries in the same geographic region as well as the prevalence of the PI*S and PI*Z alleles in countries in the same geographic region provide a novel database for the identification of large numbers of individuals in a given phenotypic class. The database also provides useful information for the identification of countries with high numbers of PI*ZZ individuals for augmentation therapy within a given geographic region. C1 [de Serres, Frederick J.] NIEHS, Ctr Evaluat Risks Human Reprod, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Blanco, Ignacio] Biomed Res Off OIB FICYT, Oviedo, Spain. RP de Serres, FJ (reprint author), NIEHS, Ctr Evaluat Risks Human Reprod, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. EM deserres@bellsouth.net NR 28 TC 34 Z9 35 U1 3 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-4658 EI 1753-4666 J9 THER ADV RESPIR DIS JI Ther. Adv. Respir. Dis. PD OCT PY 2012 VL 6 IS 5 BP 277 EP 295 DI 10.1177/1753465812457113 PG 19 WC Respiratory System SC Respiratory System GA V32DA UT WOS:000208930700003 PM 22933512 ER PT J AU Wang, QQ Zhu, JY Gleisner, R Kuster, TA Baxa, U McNeil, SE AF Wang, Q. Q. Zhu, J. Y. Gleisner, R. Kuster, T. A. Baxa, U. McNeil, S. E. TI Morphological development of cellulose fibrils of a bleached eucalyptus pulp by mechanical fibrillation SO CELLULOSE LA English DT Article DE Cellulose nanofibrils (CNF); Morphology; Mechanical fibrillation/grinding; Fiber/fibril network; TEM imaging; Nanowhisker ID HOMOGENIZATION; NANOCOMPOSITES; FIBERS AB This study reports the production of cellulose nanofibrils (CNF) from a bleached eucalyptus pulp using a commercial stone grinder. Scanning electronic microscopy and transmission electronic microscopy imaging were used to reveal morphological development of CNF at micro and nano scales, respectively. Two major structures were identified: (1) highly kinked, naturally helical, and untwisted fibrils that serve as backbones of CNF networks, and (2) entangled, less distinctively kinked (or curled) and twisted "soft looking" nanofibrils. These two major structures appeared in different features of CNF network such as "trees", "net", "flower", single fibril, etc. Prolonged fibrillation can break the nanofibrils into nanowhiskers from the untwisted fibrils with high crystallinity. Energy input for mechanical fibrillation is on the order of 5-30 kWh/kg. The gradual reduction in network size of CNF with time may be used to fractionate CNF. C1 [Zhu, J. Y.; Gleisner, R.; Kuster, T. A.] US Forest Serv, Forest Prod Lab, USDA, Madison, WI 53705 USA. [Wang, Q. Q.] S China Univ Technol, State Key Lab Pulp & Paper Engn, Guangzhou, Guangdong, Peoples R China. [Baxa, U.] NCI, Electron Microscopy Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [McNeil, S. E.] NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Zhu, JY (reprint author), US Forest Serv, Forest Prod Lab, USDA, 1 Gifford Pinchot Dr, Madison, WI 53705 USA. EM jzhu@fs.fed.us RI Nanotechnology Characterization Lab, NCL/K-8454-2012; Wang, Qianqian/G-1915-2012 OI Wang, Qianqian/0000-0003-3514-455X FU USDA Agriculture and Food Research Initiative (AFRI) Competitive Grant [2011-67009-20056]; Chinese Scholarship Council (CSC); National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We acknowledge the financial supports by a USDA Agriculture and Food Research Initiative (AFRI) Competitive Grant (No. 2011-67009-20056) and Chinese Scholarship Council (CSC). The funding from these two programs made the visiting appointment of Wang at the USDA Forest Products Laboratory (FPL) possible. We also acknowledge Ann Masco of FPLL Paper Test Lab for FQA analysis. The authors also wish to thank Anne Kamata, SAIC-Frederick, Inc. for electron microscopy imaging. TEM imaging work was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 29 TC 56 Z9 61 U1 7 U2 60 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-0239 J9 CELLULOSE JI Cellulose PD OCT PY 2012 VL 19 IS 5 BP 1631 EP 1643 DI 10.1007/s10570-012-9745-x PG 13 WC Materials Science, Paper & Wood; Materials Science, Textiles; Polymer Science SC Materials Science; Polymer Science GA 992IF UT WOS:000307768100015 ER PT J AU Xu, Z Lefevre, GM Felsenfeld, G AF Xu, Z. Lefevre, G. M. Felsenfeld, G. TI Chromatin structure, epigenetic mechanisms and long-range interactions in the human insulin locus SO DIABETES OBESITY & METABOLISM LA English DT Review DE chromatin conformation capture (3C); histones; synaptotagmin 8 (SYT8) ID BECKWITH-WIEDEMANN-SYNDROME; NEONATAL DIABETES-MELLITUS; NONCODING RNAS; CHROMOSOME CONFORMATION; INTERACTIONS REVEALS; CONTROL REGION; HUMAN GENOME; H19 GENE; CTCF; EXPRESSION AB Regulation of gene expression in eukaryotes is largely dependent on variations in chromatin structure. More recently, it has become clear that this may involve not only local chromatin organization but also distant regulatory elements that participate in large-scale chromatin architecture within the nucleus. We describe recent methods that make possible the detection of such structures and apply them to analysis of the human insulin (INS) locus in pancreatic islets. We show that the INS gene is part of an extended open chromatin domain that includes adjacent genes as well. We also find that in islets, the INS promoter is in physical contact with distant sites on the same human chromosome and notably, with the SYT8 gene, located nearly 300 kb away. The strength of the contact between INS and SYT8 is increased by glucose, and this results in stimulation of SYT8 expression. Inhibition of INS transcription decreases SYT8 expression. Furthermore, downregulation of SYT8 results in decreased secretion of insulin. Our results thus establish the existence of a regulatory network between the INS gene and other distant genes through long-range physical interactions, and suggest that such networks may have general importance for insulin biology and diabetes. C1 [Xu, Z.; Lefevre, G. M.; Felsenfeld, G.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 64 TC 7 Z9 7 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-8902 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD OCT PY 2012 VL 14 SU 3 BP 1 EP 11 DI 10.1111/j.1463-1326.2012.01645.x PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 995UJ UT WOS:000308038300002 PM 22928559 ER PT J AU Kaess, BM Pedley, A Massaro, JM Murabito, J Hoffmann, U Fox, CS AF Kaess, B. M. Pedley, A. Massaro, J. M. Murabito, J. Hoffmann, U. Fox, C. S. TI The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk SO DIABETOLOGIA LA English DT Article DE Body fat distribution; Obesity; Risk factors; Subcutaneous fat; Visceral fat ID TYPE-2 DIABETIC-PATIENTS; ADIPOSE-TISSUE; INSULIN-RESISTANCE; HEART; DISEASE; OBESITY; ASSOCIATION; METABOLISM; LIPODYSTROPHY; ACCUMULATION AB The anatomic location of excess body fat has an impact on associated cardiometabolic morbidity, and visceral adipose tissue (VAT) is more pathogenic than subcutaneous adipose tissue (SAT). However, VAT or SAT alone provides little information regarding the relative distribution of body fat. We hypothesised that the propensity to store energy in VAT relative to SAT depots may be a correlate of cardiometabolic risk, and tested this hypothesis using the VAT/SAT ratio as a metric of fat distribution. We investigated associations of the VAT/SAT ratio with cardiometabolic traits in 3,223 participants (48% women) from the Framingham Heart Study. Fat depots were quantified by multidetector computed tomography (CT) scanning. In women and men, higher VAT/SAT ratio was associated (p < 0.05) with most assessed cardiovascular risk factors reflecting blood pressure, dyslipidaemia and insulin resistance. Additional adjustment for BMI did not materially change the findings in women, and generally strengthened associations in men. Further adjustment for VAT attenuated some associations in women, but those with lower HDL-cholesterol, higher triacylglycerol (both p < 0.0001) and higher prevalence of hypertension (p = 0.02), diabetes (p = 0.01) and the metabolic syndrome (p = 0.005) remained significant. Similarly, in men, associations with higher systolic (p = 0.006) and diastolic blood pressure (p = 0.03), higher fasting glucose (p = 0.0005), lower HDL-cholesterol and higher triacylglycerol (both p < 0.0001) and higher prevalence of diabetes (p = 0.006) remained significant. VAT/SAT ratio is a correlate of cardiometabolic risk, above and beyond BMI and VAT. The propensity to store fat viscerally versus subcutaneously may be a unique risk factor independent of absolute fat volumes. C1 [Kaess, B. M.; Pedley, A.; Fox, C. S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Kaess, B. M.] Univ Regensburg, Klin Poliklin Innere Med 2, Regensburg, Germany. [Massaro, J. M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murabito, J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hoffmann, U.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Fox, C. S.] Brigham & Womens Div Endocrinol Hypertens & Metab, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Murabito, Joanne/0000-0002-0192-7516; Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung and Blood Institute's (Bethesda, MD, USA) Framingham Heart Study [N01-HC-25195] FX This work was supported by the National Heart, Lung and Blood Institute's (Bethesda, MD, USA) Framingham Heart Study (N01-HC-25195). NR 32 TC 69 Z9 70 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2012 VL 55 IS 10 BP 2622 EP 2630 DI 10.1007/s00125-012-2639-5 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 999ZH UT WOS:000308354600010 PM 22898763 ER PT J AU Koch, KR Zhang, CO Kaczmarek, P Barchi, J Guo, L Shahjee, HM Keay, S AF Koch, Kristopher R. Zhang, Chen-Ou Kaczmarek, Piotr Barchi, Joseph, Jr. Guo, Li Shahjee, Hanief M. Keay, Susan TI The effect of a novel frizzled 8-related antiproliferative factor on in vitro carcinoma and melanoma cell proliferation and invasion SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Antiproliferative factor; MMP2; HB-EGF; Invasion; Carcinoma; Melanoma ID EPITHELIAL-MESENCHYMAL TRANSITION; INTERSTITIAL CYSTITIS PATIENTS; BLADDER-CANCER; LUNG-CANCER; E-CADHERIN; MATRIX METALLOPROTEINASE-2; BREAST-CANCER; GROWTH-FACTOR; PROGNOSTIC-SIGNIFICANCE; TUMOR MICROENVIRONMENT AB Antiproliferative factor (APF) is a potent frizzled protein 8-related sialoglycopeptide inhibitor of bladder epithelial cell proliferation that mediates its activity by binding to cytoskeletal associated protein 4 in the cell membrane. Synthetic asialylated APF (as-APF) (Gal beta 1-3GalNAc alpha-O-TVPAAVVVA) was previously shown to inhibit both normal bladder epithelial as well as T24 bladder carcinoma cell proliferation and heparin-binding epidermal growth factor-like growth factor (HB-EGF) production at low nanomolar concentrations, and an L-pipecolic acid derivative (Gal beta 1-3GalNAc alpha-O-TV-pipecolic acid-AAVVVA) was also shown to inhibit normal bladder epithelial cell proliferation. To better determine their spectrum of activity, we measured the effects of these APF derivatives on the proliferation of cells derived from additional urologic carcinomas (bladder and kidney), non-urologic carcinomas (ovary, lung, colon, pancreas, and breast), and melanomas using a H-3-thymidine incorporation assay. We also measured the effects of as-APF on cell HB-EGF and matrix metalloproteinase (MMP2) secretion plus cell invasion, using qRT-PCR, Western blot and an in vitro invasion assay. L-pipecolic acid as-APF and/or as-APF significantly inhibited proliferation of each cell line in a dose-dependent manner with IC50's in the nanomolar range, regardless of tissue origin, cell type (carcinoma vs. melanoma), or p53 or ras mutation status. as-APF also inhibited HB-EGF and MMP2 production plus in vitro invasion of tested bladder, kidney, breast, lung, and melanoma tumor cell lines, in a dose-dependent manner (IC50 = 1-100 nM). Synthetic APF derivatives are potent inhibitors of urologic and non-urologic carcinoma plus melanoma cell proliferation, MMP2 production, and invasion, and may be useful for development as adjunctive antitumor therapy(ies). C1 [Keay, Susan] VA Med Ctr, Baltimore, MD 21201 USA. [Koch, Kristopher R.; Guo, Li; Shahjee, Hanief M.; Keay, Susan] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Zhang, Chen-Ou] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Kaczmarek, Piotr; Barchi, Joseph, Jr.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Keay, Susan] Vet Adm Maryland Hlth Care Syst, Baltimore, MD 21201 USA. RP Keay, S (reprint author), VA Med Ctr, Room 3B 184,10 N Greene St, Baltimore, MD 21201 USA. EM krkoch@hotmail.com; chen-ou.zhang@va.gov; pkacz@mit.edu; barchi@helix.nih.gov; guoxli@yahoo.com; hanief_shahjee@urmc.rochester.edu; skeay@medicine.umaryland.edu RI Barchi Jr., Joseph/N-3784-2014 FU Office of Research and Development (Medical Research Service), Department of Veterans Affairs; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors thank Stewart Martin, Greenebaum Cancer Center and the University of Maryland School of Medicine, for providing some of the breast carcinoma cell lines, and Eunice Katz for assistance with the preparation of this manuscript. This material is based upon work supported by the Office of Research and Development (Medical Research Service), Department of Veterans Affairs, as well as funding from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We also gratefully acknowledge the assistance of the Biophysics Resource in the Structural Biophysics Laboratory, at the Center for Cancer Research, National Cancer Institute. NR 80 TC 3 Z9 3 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD OCT PY 2012 VL 30 IS 5 BP 1849 EP 1864 DI 10.1007/s10637-011-9746-x PG 16 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 999OU UT WOS:000308324400005 PM 21931970 ER PT J AU Hurley, RK Drummond, JL Viana, GC Galang, MT AF Hurley, Ryan K. Drummond, James L. Viana, Grace C. Galang, Maria T. TI The effects of environment and cyclic fatigue on the mechanical properties of an indirect composite SO JOURNAL OF DENTISTRY LA English DT Article DE Indirect composite; Cyclic loading; Ageing ID DENTAL RESIN COMPOSITE; RESTORATIVE MATERIALS; CLINICAL-EVALUATION; FRACTOGRAPHY; DEGRADATION; STRENGTH; FAILURE; LIMITS; WEAR AB Objectives: The purpose of this study was to examine the flexure strength (sigma) and fracture toughness (K-IC) of three indirect dental composites (dentin, body, and incisal) with respect to loading (static and cyclic), testing environments (air and water) and ageing (0 (controls) and 6 months in air and water). Methods: The specimens were 3 mm x 3 mm x 25 mm bars with the fracture toughness specimens having a 0.75 mm notch machined in the midspan. Static testing utilized 15 bars and cyclic testing 25 bars for each testing variable. All bars were tested using three-point loading and the cyclic testing was for 1000 cycles using a staircase approach. Results: For flexure strength and fracture toughness, all specimen groups showed a decrease in mean values when exposed to cyclic loading as compared to the static loading mean and when exposed to ageing compared to the control specimens. ANOVA analysis demonstrated that dentin specimens had higher flexure strength and fracture toughness means than incisal and body specimens and that control and water specimens had higher flexure strength and fracture toughness means than aged and air specimens. Conclusions: Degradation of these materials, as a result of cyclic loading and ageing in an aqueous environment, appears to be influenced by more than just the processing of the composite. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Hurley, Ryan K.] Private Orthodont Practice, Schaumburg, IL 60914 USA. [Drummond, James L.] Natl Inst Dent & Craniofacial Res, Dent Mat & Biomat Program, Biol & Infect Dis Branch, NIH, Bethesda, MD USA. [Viana, Grace C.; Galang, Maria T.] Univ Illinois, Coll Dent, Dept Orthodont, Chicago, IL USA. RP Hurley, RK (reprint author), 1443 W Schaumburg Rd,Suite 200, Schaumburg, IL 60914 USA. EM ryan.hvortho@gmail.com NR 25 TC 2 Z9 4 U1 2 U2 18 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0300-5712 J9 J DENT JI J. Dent. PD OCT PY 2012 VL 40 IS 10 BP 787 EP 792 DI 10.1016/j.jdent.2012.05.012 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 997PP UT WOS:000308178400001 PM 22722058 ER PT J AU Ragupathy, V Casado, C Jacob, SM Samuel, NM Lopez-Galindez, C AF Ragupathy, Viswanath Casado, Concepcion Jacob, Saramma Mini Samuel, Narasappa Mathew Lopez-Galindez, C. TI Circulation of HIV-1 subtype A within the subtype C HIV-1 epidemic in Tamil Nadu, India SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HIV; subtype; diversity; India; risk group ID IMMUNODEFICIENCY-VIRUS TYPE-1; PHYLOGENETIC ANALYSIS; IDENTIFICATION; SEQUENCES; VARIANTS; CALCUTTA; MUMBAI AB The HIV-1 epidemic in India is caused mainly by subtype C viruses that are transmitted sexually and by injecting drug use. The state of Tamil Nadu in Southern India has an HIV-1 median prevalence of 16.8% among injecting drug users, 6.6% in men who have sex with men, and 4.6% in female sex workers. In the rural district of Namakkal, a prevalence >3% was detected among antenatal women. The goal of this study was to determine the HIV-1 molecular epidemiology in Tamil Nadu. Blood samples were collected from 40 high-risk HIV-seropositive individuals from Chennai and Namakkal. HIV-1 subtype was determined by envelope nucleotide sequencing. Among the samples studied, 85% were subtype C, however, a cluster of subtype A samples (12.5%) and one subtype E recombinant form CRF01_AE (close to the Thailand strains) were detected. The average genetic distance of subtype C samples from Chennai and Namakkal were 9.44?+/-?0.77% and 11.8?+/-?0.7%, respectively indicating an evolved epidemic. This pilot study confirmed that subtype C was predominant in these regions but an outbreak of subtype A was detected in Namakkal. These results stress the importance of periodic monitoring of circulating HIV-1 subtypes in South India. J. Med. Virol. 84:15071513, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Ragupathy, Viswanath; Jacob, Saramma Mini; Samuel, Narasappa Mathew] Tamil Nadu Dr MGR Med Univ, Dept Expt Med, Madras, Tamil Nadu, India. [Casado, Concepcion; Lopez-Galindez, C.] Inst Salud Carlos III, CNM, Madrid 28220, Spain. RP Ragupathy, V (reprint author), FDA-CBER 8800,Rockville Pike NIH Campus,Bldg 29B,, Bethesda, MD 20892 USA. EM ragupathy.viswanath@fda.hhs.gov; clopez@isciii.es RI Lopez-Galindez, Cecilio/A-3603-2008; Casado, Concepcion/F-3060-2016 OI Lopez-Galindez, Cecilio/0000-0002-2324-9584; FU Fundacion para la Investigacion Prevencion del SIDA en Espana (FIPSE) [36558/06, 36641/07, 36779/08, 360766/09]; Red Tematica Cooperativa de Investigacion en SIDA of the Fondo de Investigaciones Sanitarias de la Seguridad Social (FISss); [SAF 2007-61036]; [2010-17226] FX Work in CNM is supported by grant SAF 2007-61036 and 2010-17226, by Fundacion para la Investigacion Prevencion del SIDA en Espana (FIPSE) grants 36558/06, 36641/07, 36779/08, 360766/09 and in part by the Red Tematica Cooperativa de Investigacion en SIDA (Red de grupos 173) of the Fondo de Investigaciones Sanitarias de la Seguridad Social (FISss). NR 20 TC 0 Z9 0 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD OCT PY 2012 VL 84 IS 10 BP 1507 EP 1513 DI 10.1002/jmv.23383 PG 7 WC Virology SC Virology GA 996QF UT WOS:000308106500001 PM 22930495 ER PT J AU Osinusi, A Chary, A Winters, MA Naggie, S Masur, H Polis, MA Kottilil, S Holodniy, M AF Osinusi, Anu Chary, Aarthi Winters, Mark A. Naggie, Susanna Masur, Henry Polis, Michael A. Kottilil, Shyam Holodniy, Mark TI IL28B polymorphism is not associated with HCV protease diversity in patients co-infected with HIV and HCV treated with pegylated interferon and ribavirin SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HIV; HCV; IL28B; HCV protease diversity; genomics ID HUMAN-IMMUNODEFICIENCY-VIRUS; GENOTYPE 1 INFECTION; CHRONIC HEPATITIS-C; QUASI-SPECIES DIVERSITY; COINFECTED PATIENTS; THERAPY; PEGINTERFERON; BOCEPREVIR; TELAPREVIR; CLEARANCE AB Recent studies have demonstrated that IL28B polymorphisms predict therapeutic responses in chronic hepatitis C virus (HCV)-treated patients; however, the effect on HCV viral diversity, particularly on the HCV protease gene, is not clear. This study sought to evaluate the effect of IL28B polymorphisms on HCV diversity at NS3/4 protease region, which may influence therapeutic response to an HCV protease inhibitor based regimen. Twenty-two patients co-infected with HIV and HCV genotype 1, treatment-naive on stable HIV antiretroviral therapy initiating interferon-based treatment were evaluated. Plasma HCV NS3 gene diversity was analyzed by clonal analysis at baseline and end of treatment. IL28B (rs12979860) genotypes were tested for associations with virologic outcomes and diversity parameters. There was similar baseline NS3 diversity in patients with CC (favorable) genotype compared to those with CT/TT (unfavorable) genotypes. There was no significant association between IL28B genotype and baseline NS3 nucleotide p-distance, dS-dN, amino acid p-distance, or nucleotide changes. Among patients without a sustained virologic response, between baseline and follow-up there was a significant trend towards decreased diversity after treatment among patients with favorable genotype, which was not observed in unfavorable genotypes. In patients treated with peginterferon/ribavirin therapy, IL28B polymorphism was not associated with enhanced NS3 diversity at baseline. Among non-SVR patients with the less favorable genotype, there was no change in diversity after treatment. This suggests that IL28B genotype is unlikely to have a negative impact on subsequent HCV PI efficacy in patients co-infected with HIV and HCV patients who have previously failed HCV therapy. J. Med. Virol. 84:15221527, 2012. (c) Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Osinusi, Anu] NCI, CMRP, SAIC Frederick Inc, Frederick, MD 21701 USA. [Osinusi, Anu; Polis, Michael A.; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Chary, Aarthi; Winters, Mark A.; Holodniy, Mark] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Chary, Aarthi; Winters, Mark A.; Holodniy, Mark] Stanford Univ, Stanford, CA 94305 USA. [Naggie, Susanna] Duke Clin Res Inst, Durham, NC USA. [Masur, Henry] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Osinusi, A (reprint author), Bldg10,Rm 6A-33A,10 Ctr Dr, Bethesda, MD 20892 USA. EM osinusia@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU Department of Veterans Affairs; Intramural Research Program of the NIH [National Institute of Allergy and Infectious Diseases and NIH Clinical Center]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Grant sponsor: Department of Veterans Affairs and by the Intramural Research Program of the NIH [National Institute of Allergy and Infectious Diseases and NIH Clinical Center] (partial support); Grant sponsor: National Cancer Institute, National Institutes of Health (in whole or in part with federal funds); Grant number: HHSN261200800001E. NR 33 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD OCT PY 2012 VL 84 IS 10 BP 1522 EP 1527 DI 10.1002/jmv.23376 PG 6 WC Virology SC Virology GA 996QF UT WOS:000308106500003 PM 22930497 ER PT J AU Qiu, G Spangler, EL Wan, RQ Miller, M Mattson, MP So, KF de Cabo, R Zou, SG Ingram, DK AF Qiu, Guang Spangler, Edward L. Wan, Ruiqian Miller, Marshall Mattson, Mark P. So, Kwok-Fai de Cabo, Rafael Zou, Sige Ingram, Donald K. TI Neuroprotection provided by dietary restriction in rats is further enhanced by reducing glucocortocoids SO NEUROBIOLOGY OF AGING LA English DT Article ID ELEMENT-BINDING PROTEIN; LONG-TERM POTENTIATION; NF-KAPPA-B; CALORIC RESTRICTION; NEURODEGENERATIVE DISORDERS; NEURONAL PLASTICITY; NEUROTROPHIC FACTOR; COGNITIVE FUNCTION; SPATIAL MEMORY; ENERGY-INTAKE AB Glucocorticoids (GC)-corticosterone (CORT) in rodents and cortisol in primates-are stress-induced hormones secreted by adrenal glands that interact with the hypothalamic pituitary axis. High levels of cortisol in humans are observed in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in diabetes, post-traumatic stress syndrome, and major depression. Experimental models of diabetes in rats and mice have demonstrated that reduction of CORT reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (ADX-DR) followed by central administration of the neurotoxin, kainic acid (KA), significantly attenuates learning deficits in a 14-unit T-maze task. The performance of the ADX-DR KA group did not differ from a control group (CON) that did not receive KA and was fed ad libitum (AL). By contrast, the sham-operated DR (SHAM-DR KA) group, SHAM-AL KA group, and ADX-ALKAgroup demonstrated poorer learning behavior in this task compared to the CON group. Stereological analysis revealed equivalent DR-induced neuroprotection in the SH-DR KA and ADX-DR KA groups, as measured by cell loss in the CA2/CA3 region of the hippocampus, while substantial cell loss was observed in SH-AL and ADX-AL rats. A separate set of experiments was conducted with similar dietary and surgical treatment conditions but without KA administration to examine markers of neurotrophic activity, brain-derived neurotrophic factor (BDNF), transcriptions factors (pCREB), and chaperone proteins (HSP-70). Under these conditions, we noted elevations in both BDNF and pCREB in ADX DR rats compared to the other groups; whereas, HSP-70, was equivalently elevated in ADX-DR and SH-DR groups and was higher than observed in both SH-AL and ADX-AL groups. These results support findings that DR protects hippocampal neurons against KA-induced cellular insult. However, this neuroprotective effect was further enhanced in rats with a lower-than control level of CORT resulting from ADX and maintained by exogenous CORT supplementation. Our results then suggest that DR-induced physiological elevation of GC may have negative functional consequences to DR-induced beneficial effects. These negative effects, however, can be compensated by other DR-produced cellular and molecular protective mechanisms. (C) 2012 Elsevier Inc. All rights reserved. C1 [Qiu, Guang] Nanfang Med Univ, Nanfang Hosp, Dept Neurol, Nanfang 510515, Guangdong, Peoples R China. [Spangler, Edward L.; Miller, Marshall; de Cabo, Rafael; Zou, Sige] NIA, Lab Expt Gerontol, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Wan, Ruiqian; Mattson, Mark P.] NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. [So, Kwok-Fai] Univ Hong Kong, Dept Anat, Pokfulam, Hong Kong, Peoples R China. [So, Kwok-Fai] Univ Hong Kong, State Key Lab Brain & Cognit Sci, Pokfulam, Hong Kong, Peoples R China. [Ingram, Donald K.] Louisiana State Univ Syst, Nutr Neurosci & Aging Lab, Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Ingram, DK (reprint author), Louisiana State Univ Syst, Nutr Neurosci & Aging Lab, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA USA. EM Donald.Ingram@pbrc.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural Research Program (IRP of the National Institute on Aging) FX This research was supported in part by the Intramural Research Program (IRP of the National Institute on Aging). This research was conducted under animal protocols approved by the IRP Institutional Care and Use committee at NIA, and in compliance with the National Institute of Health Guidelines for Animal Experimentation. NR 64 TC 9 Z9 9 U1 1 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2012 VL 33 IS 10 BP 2398 EP 2410 DI 10.1016/j.neurobiolaging.2011.11.025 PG 13 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 996LG UT WOS:000308088500016 PM 22226488 ER PT J AU Pistell, PJ Spangler, EL Kelly-Bell, B Miller, MG de Cabo, R Ingram, DK AF Pistell, Paul J. Spangler, Edward L. Kelly-Bell, Bennett Miller, Marshall G. de Cabo, Rafael Ingram, Donald K. TI Age-associated learning and memory deficits in two mouse versions of the stone T-maze SO NEUROBIOLOGY OF AGING LA English DT Article DE Aging; Mice; Learning; Memory; Maze ID ALZHEIMERS-DISEASE; TRANSGENIC MICE; RETENTION PERFORMANCE; COGNITIVE ENHANCEMENT; WATER MAZE; RATS; ACQUISITION; IMPAIRMENT; LESIONS; CORTEX AB We have previously reported that a modified Stone T-maze (STM), using escape from water as motivation, was effective in evaluating learning and memory ability in young C57/BL6 mice. Here we report on the effectiveness and sensitivity of the STM in the assessment of age-related learning and memory deficits in mice using either escape from foot shock or water as the motivational manipulations. C57BL/6Nia mice 7-, 12-, 20- and 24-months old received 15 massed trials in the escape from foot shock motivated STM while C57BL/6Nia mice 5-, 12-, and 25-months old were tested in the escape from water STM. Analysis of errors, the main performance variable, revealed similar results in both versions of the task with younger mice making fewer errors. Notably, mice of all ages in the water-motivated version moved quickly through the maze, while all ages of mice in the shock-motivated version tended to wait for shock to be initiated to move forward. Overall, both versions of the STM appear to be sensitive to age-related changes in learning and memory and provide an alternative to other testing paradigms such as the Morris water maze which are susceptible to performance confounds which can lead to uninterpretable results. (C) 2012 Elsevier Inc. All rights reserved. C1 [Pistell, Paul J.; Ingram, Donald K.] Louisiana State Univ Syst, Nutr Neurosci & Aging Lab, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Spangler, Edward L.; Kelly-Bell, Bennett; Miller, Marshall G.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Pistell, Paul J.] Towson Univ, Dept Psychol, Towson, MD 21252 USA. RP Pistell, PJ (reprint author), Louisiana State Univ Syst, Nutr Neurosci & Aging Lab, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM ppistell@towson.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU National Institute on Aging; Animal Phenotyping Core supported through NORC Center [1P30 DK072476]; NIDDK FX Special thanks to Richard Zichos in the instrument shop at the National Institute on Aging (NIA) intramural program for construction of the mazes. This research was supported, in part, by the Intramural Research Program at the National Institute on Aging. Partial support was provided through the Animal Phenotyping Core supported through NORC Center grant no. 1P30 DK072476 entitled "Nutritional Programming: Environmental and Molecular Interactions" sponsored by NIDDK. NR 35 TC 8 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2012 VL 33 IS 10 BP 2431 EP 2439 DI 10.1016/j.neurobiolaging.2011.12.004 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 996LG UT WOS:000308088500019 PM 22217418 ER PT J AU Gao, JJ Nalls, MA Shi, M Joubert, BR Hernandez, DG Huang, XM Hollenbeck, A Singleton, AB Chen, HL AF Gao, Jianjun Nalls, Michael A. Shi, Min Joubert, Bonnie R. Hernandez, Dena G. Huang, Xuemei Hollenbeck, Albert Singleton, Andrew B. Chen, Honglei TI An exploratory analysis on gene-environment interactions for Parkinson disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Parkinson disease (PD); Gene-environment interactions; Genome-wide association study ID GENOME-WIDE ASSOCIATION; RISK; VARIANTS AB Little is known about gene-environment interactions in Parkinson disease (PD). We examined potential interactions of smoking and caffeine intake with 10 genome-wide association studies single nucleotide polymorphisms (SNPs) at or near the SNCA, MAPT, LRRK2, and HLA loci among 584 PD patients and 1571 controls. The main effects of these SNPs and environmental exposures were consistent with previous reports. Family history of PD was associated with PD risk (odds ratio = 2.71, 95% confidence interval, 1.97-3.74), which was little affected by further adjustment for these SNPs and environmental exposures. Overall, we did not find significant interactions of either smoking or caffeine intake with these SNPs. However, with a combined smoking and caffeine intake exposure, we found a significant interaction with rs2896905 at SLC2A13, near LRRK2 (p uncorrected = 0.0008). Each A allele was associated with a 35% higher PD risk among never smokers with low caffeine intake, but with a 32% lower risk among smokers with high caffeine intake. This study provides preliminary evidence of a potential gene-environment interaction for PD, which should be investigated in future studies. Published by Elsevier Inc. C1 [Gao, Jianjun; Joubert, Bonnie R.; Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Nalls, Michael A.; Hernandez, Dena G.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Shi, Min] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Hollenbeck, Albert] Amer Assoc Retired Persons, Washington, DC USA. RP Chen, HL (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov RI Singleton, Andrew/C-3010-2009; OI Chen, Honglei/0000-0003-3446-7779 FU National Institute of Environmental Health Sciences, National Cancer Institute; National Institute on Aging, National Institute of Neurological Disorders and Stroke; National Human Genome Research Institute of the National Institutes of Health [Z01-ES-101986, Z01 CP010196-02, Z01-AG000949-02, 2003-077]; US Department of Defense [W81XWH-09-2-0128]; National Institutes of Health [NS057105, RR024992]; NIH [R01-NS060722] FX The authors are grateful to the continuous contribution of the NIH-AARP Diet and Health Study participants. This study was supported by the intramural research program of the National Institute of Environmental Health Sciences, National Cancer Institute, National Institute on Aging, National Institute of Neurological Disorders and Stroke, the National Human Genome Research Institute of the National Institutes of Health (Z01-ES-101986, Z01 CP010196-02, Z01-AG000949-02, NIA human subjects protocol 2003-077). This work was also supported by the US Department of Defense (award no. W81XWH-09-2-0128); National Institutes of Health (grants NS057105 and RR024992) and a NIH extramural grant (R01-NS060722) to Dr. Huang. NR 19 TC 3 Z9 3 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2012 VL 33 IS 10 AR 2528.e1 DI 10.1016/j.neurobiolaging.2012.06.007 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 996LG UT WOS:000308088500030 PM 22763023 ER PT J AU Majounie, E Abramzon, Y Renton, AE Keller, MF Traynor, BJ Singleton, AB AF Majounie, Elisa Abramzon, Yevgeniya Renton, Alan E. Keller, Margaux F. Traynor, Bryan J. Singleton, Andrew B. TI Large C9orf72 repeat expansions are not a common cause of Parkinson's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Parkinson's disease; C9orf72 AB The concept of a pathological overlap between neurodegenerative disorders is gaining momentum. We sought to determine the contribution of C9orf72 repeat expansions, recently discovered as a cause of frontotemporal dementia and amyotrophic lateral sclerosis, in a large number of Parkinson's disease patients. No large expansions were identified in our cohort. (C) 2012 Published by Elsevier Inc. C1 [Majounie, Elisa; Keller, Margaux F.; Singleton, Andrew B.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Abramzon, Yevgeniya; Renton, Alan E.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Keller, Margaux F.] Temple Univ, Dept Biol Anthropol, Philadelphia, PA 19122 USA. [Traynor, Bryan J.] Johns Hopkins Univ Hosp, Dept Neurol, Brain Sci Inst, Baltimore, MD 21287 USA. RP Majounie, E (reprint author), NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM Elisa.Majounie@nih.gov RI Traynor, Bryan/G-5690-2010; Singleton, Andrew/C-3010-2009 FU Intramural NIH HHS [Z01 AG000949-02]; NIA NIH HHS [Z01 AG000957] NR 0 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2012 VL 33 IS 10 AR 2527.e1 DI 10.1016/j.neurobiolaging.2012.05.007 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 996LG UT WOS:000308088500028 PM 22721568 ER PT J AU Forsythe, L Helzlsouer, K MacDonald, R Gallicchio, L AF Forsythe, Laura P. Helzlsouer, Kathy J. MacDonald, Ryan Gallicchio, Lisa TI Daytime sleepiness and sleep duration in long-term cancer survivors and non-cancer controls: results from a registry-based survey study SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Cancer; Survivorship; Sleep; Daytime sleepiness; Survey ID QUALITY-OF-LIFE; BREAST-CANCER; OLDER-ADULTS; FUNCTIONAL OUTCOMES; WAKE DISTURBANCES; MORTALITY; INSOMNIA; HEALTH; SCALE; POPULATION AB Sleep-related complaints are common in cancer survivors. Although daytime sleepiness and sleep duration are associated with poor functional status, quality of life, and mortality in the general population, little is known about these issues in long-term cancer survivors. This study examined differences in daytime sleepiness and sleep duration between long-term cancer survivors and non-cancer controls. Survey data were analyzed from individuals diagnosed with cancer a parts per thousand yen2 years in the past (n = 1,171, mean age = 64.30, 80.8% white, 22.8% male) and spouse/friends controls (n = 250, mean age = 60.78, 88.0% white, 64.8% male). Daytime sleepiness was assessed using the Epworth Sleepiness Scale. Associations between sleep-related variables and history of cancer were estimated with multivariable logistic regression, adjusting for potential confounders. Stratified analyses were conducted to identify subgroups of survivors most at risk for sleep problems. Cancer survivors were more likely than controls to report excessive daytime sleepiness (OR = 1.64, 95% CI: 1.07, 2.50). A cancer diagnosis was associated with longer sleep duration among males (OR = 1.25, 95% CI: 1.02, 1.53), but not in females (OR = 0.87, 95% CI: 0.37, 1.05). All other associations were similar regardless of cancer site, histology, time since diagnosis, treatment history, and history of multiple cancers. Disturbances in daytime sleepiness and sleep duration persist among long-term cancer survivors and should be monitored in routine survivorship care. More research is needed to identify cancer survivors who are at increased risk for daytime sleepiness and disturbed sleep duration, as well as to identify causal mechanisms for, and interventions to mitigate, persistent differences. C1 [Forsythe, Laura P.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Forsythe, Laura P.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, Bethesda, MD 20892 USA. [Forsythe, Laura P.; Helzlsouer, Kathy J.; Gallicchio, Lisa] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Helzlsouer, Kathy J.; MacDonald, Ryan; Gallicchio, Lisa] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. RP Forsythe, L (reprint author), NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, 6116 Execut Blvd,Suite 404,MSC 8336, Bethesda, MD 20892 USA. EM Laura.Forsythe@nih.gov NR 45 TC 10 Z9 10 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD OCT PY 2012 VL 20 IS 10 BP 2425 EP 2432 DI 10.1007/s00520-011-1358-7 PG 8 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 997UX UT WOS:000308193500023 PM 22218738 ER PT J AU Curtis, E Hsu, LL Noguchi, AC Geary, L Shiva, S AF Curtis, Erin Hsu, Lewis L. Noguchi, Audrey C. Geary, Lisa Shiva, Sruti TI Oxygen Regulates Tissue Nitrite Metabolism SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; DIETARY INORGANIC NITRATE; XANTHINE OXIDOREDUCTASE; REDUCTASE-ACTIVITY; SODIUM-NITRITE; MITOCHONDRIAL RESPIRATION; CYTOCHROME-OXIDASE; ELECTRON-TRANSFER; HEMOGLOBIN; NO AB Aims: Once dismissed as an inert byproduct of nitric oxide (NO) auto-oxidation, nitrite (NO2-) is now accepted as an endocrine reservoir of NO that elicits biological responses in major organs. While it is known that tissue nitrite is derived from NO oxidation and the diet, little is known about how nitrite is metabolized by tissue, particularly at intermediate oxygen tensions. We investigated the rates and mechanisms of tissue nitrite metabolism over a range of oxygen concentrations. Results: We show that the rate of nitrite consumption differs in each organ. Further, oxygen regulates the rate and products of nitrite metabolism. In anoxia, nitrite is reduced to NO, with significant formation of iron-nitrosyl proteins and S-nitrosothiols. This hypoxic nitrite metabolism is mediated by different nitrite reductases in each tissue. In contrast, low concentrations (similar to 3.5 mu M) of oxygen increase the rate of nitrite consumption by shifting nitrite metabolism to oxidative pathways, yielding nitrate. While cytochrome P-450 and myoglobin contribute in the liver and heart, respectively, mitochondrial cytochrome c oxidase plays a significant role in nitrite oxidation, which is inhibited by cyanide. Using cyanide to prevent artifactual nitrite decay, we measure metabolism of oral and intraperitoneally administered nitrite in mice. Innovation: These data provide insight into the fate of nitrite in tissue, the enzymes involved in nitrite metabolism, and the role of oxygen in regulating these processes. Conclusion: We demonstrate that even at low concentrations, oxygen is a potent regulator of the rate and products of tissue nitrite metabolism. Antioxid. Redox Signal. 17, 951-961. C1 [Shiva, Sruti] Univ Pittsburgh, Vasc Med Inst, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA. [Noguchi, Audrey C.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Shiva, S (reprint author), Univ Pittsburgh, Vasc Med Inst, Dept Pharmacol & Chem Biol, BST3,10051, Pittsburgh, PA 15261 USA. EM sss43@pitt.edu FU Institute of Transfusion Medicine; Hemophilia Center of Western Pennsylvania; NIH [NIH (1R01HL096973]; AHA [09SDG2150066] FX We thank Dr. Mark Gladwin for helpful discussion. This work was supported by the Institute of Transfusion Medicine and the Hemophilia Center of Western Pennsylvania, the NIH (1R01HL096973), and by the AHA (09SDG2150066). NR 51 TC 25 Z9 25 U1 2 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2012 VL 17 IS 7 BP 951 EP 961 DI 10.1089/ars.2011.4242 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 984ZD UT WOS:000307231600004 PM 22098300 ER PT J AU Gandini, NA Fermento, ME Salomon, DG Blasco, J Patel, V Gutkind, JS Molinolo, AA Facchinetti, MM Curino, AC AF Gandini, Norberto A. Fermento, Maria E. Salomon, Debora G. Blasco, Jorge Patel, Vyomesh Gutkind, J. Silvio Molinolo, Alfredo A. Facchinetti, Maria M. Curino, Alejandro C. TI Nuclear localization of heme oxygenase-1 is associated with tumor progression of head and neck squamous cell carcinomas SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE Heme oxygenase-1; Head and neck cancer; Tissue microarray ID LYMPH-NODE METASTASIS; CANCER STATISTICS; UP-REGULATION; NITRIC-OXIDE; EXPRESSION; CONVERSION; INDUCTION; GENE; PAPILLOMAS; BILIRUBIN AB The expression of heme oxygenase-1 (HO-1) was shown to be increased in multiple tumors compared with their surrounding healthy tissues and was also observed to be up-regulated in oral squamous cell carcinomas (OSCC). However, conflicting results were obtained and little information is available regarding HO-1 significance in head and neck squamous cell carcinoma (HNSCC). Therefore, the aim of the present study was to perform a wide screening of HO-1 expression in a large collection of human primary HNSCCs and to correlate the results with clinical and pathological parameters. For this purpose, we investigated the expression of this protein by immunohistochemistry (IHC) in tissue microarrays (TMAs) of HNSCC and in an independent cohort of paraffin-embedded tumor specimens. HO-1 expression was further validated by real-time qPCR performed on selected laser capture-microdissected (LCM) oral tissue samples. Both the number of HO-1-positive samples and HO-1 immunoreactivity in the cancerous tissues were significantly higher than those in the non-tumor tissues. These results were confirmed at the mRNA level. Interestingly. HO-1 localization was observed in the nucleus, and the rate of nuclear HO-1 in HNSCC was higher than that in nonmalignant tissues. Nuclear HO-1 was observed in HNSCC cell lines and increased even further following hemin treatment. Analysis of HO-1 expression and sub-cellular localization in a mouse model of squamous cell carcinoma (SCC) and in human HNSCC revealed that nuclear HO-1 increases with tumor progression. Taken together, these results demonstrate that HO-1 is up-regulated in HNSCC and that nuclear localization of HO-1 is associated with malignant progression in this tumor type. (C) 2012 Elsevier Inc. All rights reserved. C1 [Gandini, Norberto A.; Fermento, Maria E.; Salomon, Debora G.; Facchinetti, Maria M.; Curino, Alejandro C.] Ctr Cient Tecnol Bahia Blanca, Lab Biol Canc, Inst Invest Bioquim Bahia Blanca INIBIBB CONICET, RA-8000 Bahia Blanca, Buenos Aires, Argentina. [Blasco, Jorge] Hosp Interzonal Agudos Dr Jose Penna, Serv Patol, RA-8000 Bahia Blanca, Buenos Aires, Argentina. [Patel, Vyomesh; Gutkind, J. Silvio; Molinolo, Alfredo A.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Curino, AC (reprint author), Ctr Cient Tecnol Bahia Blanca, Lab Biol Canc, Inst Invest Bioquim Bahia Blanca INIBIBB CONICET, Camino La Carrindanga Km 7,CC 857, RA-8000 Bahia Blanca, Buenos Aires, Argentina. EM acurino@criba.edu.ar FU Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT); Comision Nacional de Investigaciones Cientificas y Tecnicas (CONICET); Universidad Nacional del Sur, Bahia Blanca, Buenos Aires, Argentina; Comision de Investigaciones Cientificas de la Provincia de Buenos Aires (CIC); National Institute of Dental and Craniofacial Research, NIH FX This work was supported by the Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT), the Comision Nacional de Investigaciones Cientificas y Tecnicas (CONICET) and by the Universidad Nacional del Sur, Bahia Blanca, Buenos Aires, Argentina. Norberto A. Gandini is a recipient of a fellowship from CONICET and Maria E. Fermento is a recipient of a fellowship from Comision de Investigaciones Cientificas de la Provincia de Buenos Aires (CIC). We wish to acknowledge Dr Stuart Yuspa for providing the samples of the mouse model of SCC. Drs. Patel, Gutkind and Molinolo are supported by the Intramural Research Programme of the National Institute of Dental and Craniofacial Research, NIH. NR 37 TC 31 Z9 31 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD OCT PY 2012 VL 93 IS 2 BP 237 EP 245 DI 10.1016/j.yexmp.2012.05.001 PG 9 WC Pathology SC Pathology GA 990DL UT WOS:000307611100009 PM 22580187 ER PT J AU Batra, V Maris, JM Kang, MH Reynolds, CP Houghton, PJ Alexander, D Kolb, EA Gorlick, R Keir, ST Carol, H Lock, R Billups, CA Smith, MA AF Batra, Vandana Maris, John M. Kang, Min H. Reynolds, C. Patrick Houghton, Peter J. Alexander, Denise Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Carol, Hernan Lock, Richard Billups, Catherine A. Smith, Malcolm A. TI Initial testing (stage 1) of SGI-1776, a PIM1 kinase inhibitor, by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; kinase inhibitors; preclinical testing ID TRANSGENIC MICE; N-MYC; C-MYC; CELL; LYMPHOMAGENESIS; ONCOGENE; MODELS; TARGET; TUMORS AB The PIM kinase inhibitor, SGI-1776, was tested against the PPTP in vitro (1.0?nM10?mu M) and in vivo panels (148?mg/kg daily?x?5 days for 3 weeks). SGI-1776 exhibited cytotoxic activity in vitro with a median relative IC50 of 3.1?mu M. SGI-1776 induced significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. SGI-1776 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induced complete responses of subcutaneous MV4;11 (B myeloid leukemia). Pediatr Blood Cancer 2012;59:749752. (c) 2011 Wiley Periodicals, Inc. C1 [Batra, Vandana; Maris, John M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Maris, John M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Houghton, Peter J.; Alexander, Denise] Nationwide Childrens Hosp, Columbus, OH USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Carol, Hernan; Lock, Richard] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Billups, Catherine A.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Maris, JM (reprint author), Childrens Hosp Philadelphia, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM maris@chop.edu RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786]; SuperGen [SGI-1776] FX This work was supported by NO1-CM-42216, CA21765, and CA108786 from the National Cancer Institute, and SGI-1776 was provided by SuperGen. In addition to the authors represents work contributed by the following: Sherry Ansher, Lili T Belcastro, Edward Favours, Henry S. Friedman, Debbie Payne-Turner, Charles Stopford, Mayamin Tajbakhsh, Chandra Tucker, Amy Wozniak, Joe Zeidner, Ellen Zhang, and Jian Zhang. Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital. NR 20 TC 9 Z9 10 U1 0 U2 5 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2012 VL 59 IS 4 BP 749 EP 752 DI 10.1002/pbc.23364 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 986ZN UT WOS:000307386300031 PM 22052829 ER PT J AU Smith, MA Kang, MH Reynolds, CP Kurmasheva, RT Alexander, D Billups, CA Toretsky, JA Houghton, PJ AF Smith, Malcolm A. Kang, Min H. Reynolds, C. Patrick Kurmasheva, Raushan T. Alexander, Denise Billups, Catherine A. Toretsky, Jeffrey A. Houghton, Peter J. TI Evaluation of arsenic trioxide by the pediatric preclinical testing program with a focus on Ewing sarcoma SO PEDIATRIC BLOOD & CANCER LA English DT Article DE arsenic trioxide; developmental therapeutics; Ewing sarcoma; preclinical testing ID ACUTE PROMYELOCYTIC LEUKEMIA; PHASE-II TRIAL; PML-RAR-ALPHA; RETINOIC ACID; IN-VITRO; CELLS; ONCOPROTEIN; CARCINOMA; PATHWAY; MODELS AB Arsenic trioxide was tested against the PPTP in vitro panel (1.0?nM to 10?mu M) and against the PPTP Ewing sarcoma in vivo panel administered intraperitoneally at a dose of 2.5?mg/kg daily?x?5 per week for a planned treatment duration of 3 weeks. Arsenic trioxide showed a median relative IC50 value of 0.9?mu M, with Ewing sarcoma cell lines having IC50 values similar to those of the remaining PPTP cell lines. Arsenic trioxide did not induce significant differences in EFS distribution compared to control in any of the Ewing sarcoma xenografts studied, and no objective responses were observed. Pediatr Blood Cancer 2012;59:753755. (c) 2012 Wiley Periodicals, Inc. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Kurmasheva, Raushan T.; Alexander, Denise; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Toretsky, Jeffrey A.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, 6130 Execut Blvd,Room 7025, Bethesda, MD 20892 USA. EM smithm@ctep.nci.nih.gov RI Houghton, Peter/E-3265-2011; OI Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765. NR 20 TC 6 Z9 6 U1 0 U2 2 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2012 VL 59 IS 4 BP 753 EP 755 DI 10.1002/pbc.23391 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 986ZN UT WOS:000307386300032 PM 22315235 ER PT J AU Sherenco, KD Weed, JL Tustin, GW Lambeth, SP Williams, LE AF Sherenco, K. D. Weed, J. L. Tustin, G. W. Lambeth, S. P. Williams, L. E. TI PAIR FORMATIONS AND MANAGEMENT WITHIN A CAPTIVE BREEDING AOTUS COLONY OVER A TEN YEAR TIME PERIOD SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 35th Meeting of the American-Society-of-Primatologists (ASP) CY JUN 20-23, 2012 CL Sacramento, CA SP Amer Soc Primatol (ASP), Calilf Natl Primate Res Ctr C1 [Sherenco, K. D.; Tustin, G. W.; Lambeth, S. P.; Williams, L. E.] Univ Texas MD Anderson Canc Ctr, Dept Vet Sci, Michale E Keeling Ctr Comparat Med & Res, Bastrop, TX 78602 USA. [Weed, J. L.] NIH, Vet Resources 1Div, Off Res Serv, DHHS1, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD OCT PY 2012 VL 74 SU 1 MA 60 BP 44 EP 44 PG 1 WC Zoology SC Zoology GA 991UT UT WOS:000307728700060 ER PT J AU Simmons, TC Aldous, IT Espinel, WF Chaffin, AC Schwandt, ML Barr, CS Suomi, SJ Higley, JD AF Simmons, T. C. Aldous, I. T. Espinel, W. F. Chaffin, A. C. Schwandt, M. L. Barr, C. S. Suomi, S. J. Higley, J. D. TI MU OPIOID GENOTYPE X REARING X SEX EFFECTS ON AGGRESSION AND ANTISOCIAL BEHAVIOR DURING SOCIAL CHALLENGE IN RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 35th Meeting of the American-Society-of-Primatologists (ASP) CY JUN 20-23, 2012 CL Sacramento, CA SP Amer Soc Primatol (ASP), Calilf Natl Primate Res Ctr C1 [Simmons, T. C.; Aldous, I. T.; Espinel, W. F.; Chaffin, A. C.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Schwandt, M. L.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Barr, C. S.] NIAAA, Sect Comparat Behav Genom, NIH, LNG, Bethesda, MD 20892 USA. [Suomi, S. J.] NICHHD, NIH, Anim Ctr, LCE, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD OCT PY 2012 VL 74 SU 1 MA 66 BP 46 EP 46 PG 1 WC Zoology SC Zoology GA 991UT UT WOS:000307728700066 ER PT J AU Dettmer, AM Paukner, A Novak, MA Meyer, JS Ferrari, PF Suomi, SJ AF Dettmer, A. M. Paukner, A. Novak, M. A. Meyer, J. S. Ferrari, P. F. Suomi, S. J. TI EMOTIONAL AND SOCIAL TRAJECTORIES OF RHESUS MACAQUE IMITATORS AND NON-IMITATORS (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 35th Meeting of the American-Society-of-Primatologists (ASP) CY JUN 20-23, 2012 CL Sacramento, CA SP Amer Soc Primatol (ASP), Calilf Natl Primate Res Ctr C1 [Dettmer, A. M.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15239 USA. [Paukner, A.; Suomi, S. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, NIH, Anim Ctr, Poolesville, MD 20837 USA. [Novak, M. A.; Meyer, J. S.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Ferrari, P. F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD OCT PY 2012 VL 74 SU 1 MA 70 BP 47 EP 47 PG 1 WC Zoology SC Zoology GA 991UT UT WOS:000307728700070 ER PT J AU Page, HE Tuft, HR Jackson, J Espinel, WF Sorenson, AN Schwandt, ML Barr, CS Suomi, SJ Higley, JD AF Page, H. E. Tuft, H. R. Jackson, J. Espinel, W. F. Sorenson, A. N. Schwandt, M. L. Barr, C. S. Suomi, S. J. Higley, J. D. TI A GXE ANALYSIS OF THE EFFECT OF THE SEROTONIN TRANSPORTER GENOTYPE, PARITY, AND SEPARATION CONDITION ON INFANT AGGRESSION FOLLOWING THE STRESS OF MOTHER-INFANT REUNIONS IN RHESUS MACAQUES (MACACA MULATTA) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 35th Meeting of the American-Society-of-Primatologists (ASP) CY JUN 20-23, 2012 CL Sacramento, CA SP Amer Soc Primatol (ASP), Calilf Natl Primate Res Ctr C1 [Page, H. E.; Tuft, H. R.; Jackson, J.; Espinel, W. F.; Sorenson, A. N.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Schwandt, M. L.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Barr, C. S.] NIAAA, Sect Comparat Behav Genom, LNG, NIH, Bethesda, MD 20892 USA. [Suomi, S. J.] NICHHD, NIH, Anim Ctr, LCE Poolesville, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD OCT PY 2012 VL 74 SU 1 MA 68 BP 47 EP 47 PG 1 WC Zoology SC Zoology GA 991UT UT WOS:000307728700068 ER PT J AU Espinel, WF Sorenson, AN Schwandt, ML Lindell, SG Fairbanks, LA Barr, CS Suomi, SJ Higley, JD AF Espinel, W. F. Sorenson, A. N. Schwandt, M. L. Lindell, S. G. Fairbanks, L. A. Barr, C. S. Suomi, S. J. Higley, J. D. TI A LONGITUDINAL STUDY OF THE EFFECT OF ADOPTION ON ANXIETY AND ALCOHOL INTAKE: A NONHUMAN PRIMATE MODEL SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 35th Meeting of the American-Society-of-Primatologists (ASP) CY JUN 20-23, 2012 CL Sacramento, CA SP Amer Soc Primatol (ASP), Calilf Natl Primate Res Ctr C1 [Espinel, W. F.; Sorenson, A. N.; Higley, J. D.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Schwandt, M. L.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Lindell, S. G.; Barr, C. S.] NIAAA, Sect Comparat Behav Genom, LNG, NIH, Bethesda, MD 20892 USA. [Fairbanks, L. A.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Semel Inst, Los Angeles, CA 90024 USA. [Suomi, S. J.] NICHHD, NIH, Anim Ctr, LCE, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD OCT PY 2012 VL 74 SU 1 MA 74 BP 49 EP 49 PG 1 WC Zoology SC Zoology GA 991UT UT WOS:000307728700074 ER PT J AU Paukner, A Simpson, E Bower, SB Suomi, SJ AF Paukner, A. Simpson, E. Bower, S. B. Suomi, S. J. TI INVESTIGATING FACIAL PROCESSING IN INFANT RHESUS MACAQUES USING EYE TRACKING TECHNOLOGY SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 35th Meeting of the American-Society-of-Primatologists (ASP) CY JUN 20-23, 2012 CL Sacramento, CA SP Amer Soc Primatol (ASP), Calilf Natl Primate Res Ctr C1 [Paukner, A.; Simpson, E.; Bower, S. B.; Suomi, S. J.] NIH Anim Ctr, Comparat Ethol Lab, Poolesville, MD 20837 USA. [Simpson, E.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD OCT PY 2012 VL 74 SU 1 MA 103 BP 58 EP 58 PG 1 WC Zoology SC Zoology GA 991UT UT WOS:000307728700101 ER PT J AU Weed, JL Williams, LE Thomas, ML Mandel, M AF Weed, J. L. Williams, L. E. Thomas, M. L. Mandel, M. TI HAIR CORTISOL TITER AS A MEASURE OF STRESS IN CAPTIVE OWL MONKEYS (AOTUS NANCYMAAE) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract CT 35th Meeting of the American-Society-of-Primatologists (ASP) CY JUN 20-23, 2012 CL Sacramento, CA SP Amer Soc Primatol (ASP), Calilf Natl Primate Res Ctr C1 [Weed, J. L.; Thomas, M. L.; Mandel, M.] NIH, Div Vet Resources, Off Res Serv, US Dept HHS, Bethesda, MD 20892 USA. [Williams, L. E.] UT MD Anderson Canc Ctr, Keeling Ctr Comparat Med, Bastrop, TX 78602 USA. NR 0 TC 0 Z9 0 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD OCT PY 2012 VL 74 SU 1 MA 157 BP 76 EP 76 PG 1 WC Zoology SC Zoology GA 991UT UT WOS:000307728700155 ER PT J AU Yang, J Cao, Z Xu, X Chen, G AF Yang, J. Cao, Z. Xu, X. Chen, G. TI The amygdala is involved in affective priming effect for fearful faces SO BRAIN AND COGNITION LA English DT Article DE Amygdala; Unconscious; Emotional memory; Affective priming ID FACIAL EXPRESSIONS; COGNITIVE NEUROSCIENCE; EMOTIONAL MEMORY; REPETITION; AWARENESS; RESPONSES; DISCRIMINATION; STIMULI; SYSTEMS; MODELS AB The object of this study was to investigate whether the amygdala is involved in affective priming effect after stimuli are encoded unconsciously and consciously. During the encoding phase, each masked face (fearful or neutral) was presented to participants six times for 17 ms each, using a backward masking paradigm. During the retrieval phase, participants made a fearful/neutral judgment for each face. Half of the faces had the same valence as that seen during encoding (congruent condition) and the other half did not (incongruent condition). Participants were divided into unaware and aware groups based on their subjective and objective awareness assessments. The fMRI results showed that during encoding, the amygdala elicited stronger activation for fearful faces than neutral faces but differed in the hemisphere according to the awareness level. During retrieval, the amygdala showed a significant repetition priming effect, with the congruent faces producing less activation than the incongruent faces, especially for fearful faces. These data suggest that the amygdala is important in unconscious retrieving of memories for emotional faces whether they are encoded consciously or unconsciously. (C) 2012 Elsevier Inc. All rights reserved. C1 [Yang, J.; Cao, Z.; Xu, X.] Peking Univ, Dept Psychol, Beijing 100871, Peoples R China. [Chen, G.] NIMH, Sci & Stat Comp Core, NIH, DHHS, Bethesda, MD 20892 USA. RP Yang, J (reprint author), Peking Univ, Dept Psychol, Beijing 100871, Peoples R China. EM yangjj@pku.edu.cn FU Global Research Initiative Program, National Institutes of Health, USA [R01TW007897]; National Science Foundation of China [31171078] FX This research was supported by grants from the Global Research Initiative Program, National Institutes of Health, USA (R01TW007897, J. Yang, 2008), and the National Science Foundation of China (31171078, J. Yang, 2012). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 6 Z9 7 U1 3 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD OCT PY 2012 VL 80 IS 1 BP 15 EP 22 DI 10.1016/j.bandc.2012.04.005 PG 8 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 986TH UT WOS:000307368000003 PM 22626918 ER PT J AU Rao, MS Malik, N AF Rao, Mahendra S. Malik, Nasir TI Assessing iPSC reprogramming methods for their suitability in translational medicine SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE INDUCED PLURIPOTENT STEM CELLS; REPROGRAMMING METHODS; TRANSLATIONAL MEDICINE ID PLURIPOTENT STEM-CELLS; HUMAN SOMATIC-CELLS; HUMAN FIBROBLASTS; DEFINED FACTORS; SENDAI-VIRUS; BLOOD-CELLS; GENERATION; INDUCTION; VECTOR; EXPRESSION AB The discovery of the ability to induce somatic cells to a pluripotent state through the overexpression of specific transcription factors has the potential to transform the ways in which pharmaceutical agents and cellular transplantation therapies are developed. Proper utilization of the technology to generate induced pluripotent stem cells (iPSCs) requires that researchers select the appropriate reprogramming method for generating iPSCs so that the resulting iPSCs can be transitioned towards clinical applications effectively. This article reviews all of the currently available reprogramming techniques with a focus on critiquing them on the basis of their utility in translational medicine. J. Cell. Biochem. 113: 3061-3068, 2012. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Rao, Mahendra S.; Malik, Nasir] NIAMSD, NIH, Lab Stem Cell Biol, Bethesda, MD 20892 USA. [Rao, Mahendra S.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Rao, MS (reprint author), NIAMSD, NIH, Lab Stem Cell Biol, Bethesda, MD 20892 USA. EM raomah@mail.nih.gov FU Intramural NIH HHS [ZIA AR041193-02] NR 45 TC 24 Z9 25 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT PY 2012 VL 113 IS 10 BP 3061 EP 3068 DI 10.1002/jcb.24183 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 986MD UT WOS:000307344800003 PM 22573568 ER PT J AU Kouprina, N Lee, NCO Pavlicek, A Samoshkin, A Kim, JH Lee, HS Varma, S Reinhold, WC Otstot, J Solomon, G Davis, S Meltzer, PS Schleutker, J Larionov, V AF Kouprina, Natalay Lee, Nicholas C. O. Pavlicek, Adam Samoshkin, Alexander Kim, Jung-Hyun Lee, Hee-Sheung Varma, Sudhir Reinhold, William C. Otstot, John Solomon, Greg Davis, Sean Meltzer, Paul S. Schleutker, Johanna Larionov, Vladimir TI Exclusion of the 750-kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy in HPCX1-linked families SO GENES CHROMOSOMES & CANCER LA English DT Article ID CANCER SUSCEPTIBILITY LOCUS; MULTIPLE SEQUENCE ALIGNMENT; GENOME-WIDE SCAN; CEREBELLAR DEGENERATION; LINKAGE ANALYSIS; STRUCTURAL VARIATION; MICRORNA EXPRESSION; HUMAN SPERMATOZOA; NONCODING RNAS; X-CHROMOSOME AB Several linkage studies provided evidence for the presence of the hereditary prostate cancer locus, HPCX1, at Xq27-q28. The strongest linkage peak of prostate cancer overlies a variable region of 750 kb at Xq27 enriched by segmental duplications (SDs), suggesting that the predisposition to prostate cancer may be a genomic disorder caused by recombinational interaction between SDs. The large size of SDs and their sequence similarity make it difficult to examine this region for possible rearrangements using standard methods. To overcome this problem, direct isolation of a set of genomic segments by in vivo recombination in yeast (a TAR cloning technique) was used to perform a mutational analysis of the 750 kb region in X-linked families. We did not detect disease-specific rearrangements within this region. In addition, transcriptome and computational analyses were performed to search for nonannotated genes within the Xq27 region, which may be associated with genetic predisposition to prostate cancer. Two candidate genes were identified, one of which is a novel gene termed SPANXL that represents a highly diverged member of the SPANX gene family, and the previously described CDR1 gene that is expressed at a high level in both normal and malignant prostate cells, and mapped 210 kb of upstream the SPANX gene cluster. No disease-specific alterations were identified in these genes. Our results exclude the 750-kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy. Adjacent regions appear to be the most likely candidates to identify the elusive HPCX1 locus. (c) 2012 Wiley Periodicals, Inc. C1 [Kouprina, Natalay; Lee, Nicholas C. O.; Samoshkin, Alexander; Kim, Jung-Hyun; Lee, Hee-Sheung; Varma, Sudhir; Reinhold, William C.; Larionov, Vladimir] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Pavlicek, Adam] Pfizer Global Res & Dev, Oncol Res Unit, Computat Biol, La Jolla, CA USA. [Otstot, John; Solomon, Greg] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Davis, Sean; Meltzer, Paul S.] NCI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, SF-20500 Turku, Finland. [Schleutker, Johanna] Fimlab Labs, Tampere, Finland. [Schleutker, Johanna] Univ Tampere, Inst Biomed Technol BioMediTech, FIN-33101 Tampere, Finland. RP Kouprina, N (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM kouprinn@mail.nih.gov RI Varma, Sudhir/N-8763-2014; Lee, Nicholas/F-3668-2015; OI Varma, Sudhir/0000-0002-4096-4782; lee, nicholas/0000-0003-2628-6599; Davis, Sean/0000-0002-8991-6458 FU NIH NCI Center for Cancer Research FX Supported by: Intramural Research Program of the NIH NCI Center for Cancer Research. NR 73 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD OCT PY 2012 VL 51 IS 10 BP 933 EP 948 DI 10.1002/gcc.21977 PG 16 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 982NM UT WOS:000307052000004 PM 22733720 ER PT J AU Li, Q Chuang, SC Eluf-Neto, J Menezes, A Matos, E Koifman, S Wunsch, V Fernandez, L Daudt, AW Curado, MP Winn, DM Franceschi, S Herrero, R Castellsague, X Morgenstern, H Zhang, ZF Lazarus, P Muscat, J McClean, M Kelsey, KT Hayes, RB Purdue, MP Schwartz, SM Chen, C Benhamou, S Olshan, AF Yu, GP Schantz, S Ferro, G Brennan, P Boffetta, P Hashibe, M AF Li, Qian Chuang, Shu-Chun Eluf-Neto, Jose Menezes, Ana Matos, Elena Koifman, Sergio Wuensch-Filho, Victor Fernandez, Leticia Daudt, Alexander W. Curado, Maria Paula Winn, Deborah M. Franceschi, Silvia Herrero, Rolando Castellsague, Xavier Morgenstern, Hal Zhang, Zuo-Feng Lazarus, Philip Muscat, Joshua McClean, Michael Kelsey, Karl T. Hayes, Richard B. Purdue, Mark P. Schwartz, Stephen M. Chen, Chu Benhamou, Simone Olshan, Andrew F. Yu, Guopei Schantz, Stimson Ferro, Gilles Brennan, Paul Boffetta, Paolo Hashibe, Mia TI Vitamin or mineral supplement intake and the risk of head and neck cancer: pooled analysis in the INHANCE consortium SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE vitamin supplement; mineral supplement; head and neck cancer ID BETA-CAROTENE SUPPLEMENTATION; UPPER AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMA; PHARYNGEAL CANCER; RANDOMIZED-TRIAL; ORAL-CANCER; ANTIOXIDANT SUPPLEMENTS; METAANALYSIS; POLYMORPHISMS; PREVENTION AB To investigate the potential role of vitamin or mineral supplementation on the risk of head and neck cancer (HNC), we analyzed individual-level pooled data from 12 casecontrol studies (7,002 HNC cases and 8,383 controls) participating in the International Head and Neck Cancer Epidemiology consortium. There were a total of 2,028 oral cavity cancer, 2,465 pharyngeal cancer, 874 unspecified oral/pharynx cancer, 1,329 laryngeal cancer and 306 overlapping HNC cases. Odds ratios (OR) and 95% confidence intervals (CIs) for self reported ever use of any vitamins, multivitamins, vitamin A, vitamin C, vitamin E, and calcium, beta-carotene, iron, selenium and zinc supplements were assessed. We further examined frequency, duration and cumulative exposure of each vitamin or mineral when possible and stratified by smoking and drinking status. All ORs were adjusted for age, sex, race/ethnicity, study center, education level, pack-years of smoking, frequency of alcohol drinking and fruit/vegetable intake. A decreased risk of HNC was observed with ever use of vitamin C (OR = 0.76, 95% CI = 0.590.96) and with ever use of calcium supplement (OR = 0.64, 95% CI = 0.420.97). The inverse association with HNC risk was also observed for 10 or more years of vitamin C use (OR = 0.72, 95% CI = 0.540.97) and more than 365 tablets of cumulative calcium intake (OR = 0.36, 95% CI = 0.160.83), but linear trends were not observed for the frequency or duration of any supplement intake. We did not observe any strong associations between vitamin or mineral supplement intake and the risk of HNC. C1 [Li, Qian] Chinese Acad Med Sci, Natl Off Canc Prevent & Control, Canc Inst Hosp, Beijing 100730, Peoples R China. [Chuang, Shu-Chun] Imperial Coll London, London, England. [Eluf-Neto, Jose; Wuensch-Filho, Victor] Univ Sao Paulo, Sao Paulo, Brazil. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Matos, Elena] Univ Buenos Aires, Inst Oncol Angel H Roffo, RA-1053 Buenos Aires, DF, Argentina. [Koifman, Sergio] Fundacao Oswaldo Cruz, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. [Fernandez, Leticia] Inst Oncol & Radiobiol, Havana, Cuba. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Curado, Maria Paula; Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Winn, Deborah M.; Purdue, Mark P.] NCI, Bethesda, MD 20892 USA. [Franceschi, Silvia; Herrero, Rolando] Int Agcy Res Canc, Prevent & Implementat Grp, F-69372 Lyon, France. [Castellsague, Xavier] CIBER ESP, ICO, IDIBELL, Lhospitalet De Llobregat, Spain. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Lazarus, Philip; Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [McClean, Michael] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Kelsey, Karl T.] Brown Univ, Providence, RI 02912 USA. [Hayes, Richard B.] NYU, Sch Med, New York, NY USA. [Schwartz, Stephen M.; Chen, Chu] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Schantz, Stimson] Natl Inst Hlth & Med Res, Paris, France. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Yu, Guopei; Schantz, Stimson] New York Eye & Ear Infirm, New York, NY 10003 USA. [Boffetta, Paolo] Mt Sinai Sch Med, New York, NY USA. RP Hashibe, M (reprint author), Univ Utah, Sch Med, Div Publ Hlth, Dept Family & Prevent Med,Huntsman Canc Inst, 375 Chipeta Way,Suite A, Salt Lake City, UT 84108 USA. EM mia.hashibe@utah.edu RI Epidemiologicas, Centro de pesquisas /D-4561-2013; Chuang, Shu-Chun/N-3358-2013; Menezes, Ana/G-7266-2012; Kelsey, Karl/I-1252-2014; McClean, Michael/J-2934-2015; Castellsague Pique, Xavier/N-5795-2014; Purdue, Mark/C-9228-2016; Eluf-Neto, Jose/B-2522-2009; Benhamou, Simone/K-6554-2015; Curado, Maria Paula/M-6200-2013 OI Hayes, Richard/0000-0002-0918-661X; Schwartz, Stephen/0000-0001-7499-8502; Castellsague Pique, Xavier/0000-0002-0802-3595; Purdue, Mark/0000-0003-1177-3108; Eluf-Neto, Jose/0000-0001-7504-2115; Curado, Maria Paula/0000-0001-8172-2483 FU NIH, NCI [R03CA113157]; NIDCR [R03 DE016611]; Swiss League against Cancer [KFS1069-09-2000]; Fribourg League gainst Cancer [FOR381.88]; Swiss Cancer Research [AKT 617]; Gustave-Roussy Institute [88D28]; National Institutes of Health (NIH) US [P01CA068384, K07CA104231, R01CA048896, R01DE012609, R01CA61188, R01DE13158, P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667, R01CA078609, R01CA100679]; National Institute of Environmental Health Sciences [P30ES010126]; UCLA Jonsson Comprehensive Cancer Center, IARC; National Institutes of Health (NCI) US; NIDCR; Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina; IMIM (Barcelona); Fundacao de Amparo a Pesquisa no Estado de Sao Paulo (FAPESP) [01/01768-2]; European Commission [IC18-CT97-0222]; Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government [FIS 97/0024, FIS 97/0662, BAE 01/5013]; International Union Against Cancer (UICC); Yamagiwa-Yoshida Memorial International Cancer Study Grant; National Cancer Institute, National Institutes of Health, USA; NIH [R01CA51845]; IARC FX Grant sponsors: NIH, NCI; Grant number: R03CA113157; Grant sponsor: NIDCR; Grant number: R03 DE016611; Grant sponsor: Swiss League against Cancer; Grant number: KFS1069-09-2000; Grant sponsor: Fribourg League gainst Cancer; Grant number: FOR381.88; Grant sponsor: Swiss Cancer Research; Grant number: AKT 617; Grant sponsor: Gustave-Roussy Institute; Grant number: 88D28; Grant sponsor: National Institutes of Health (NIH) US; Grant numbers: P01CA068384, K07CA104231; Grant sponsor: National Institutes of Health (NIH) US; Grant numbers: R01CA048896, R01DE012609; Grant sponsor: National Institutes of Health (NIH) US; Grant number: R01CA61188; Grant sponsor: National Institute of Environmental Health Sciences; Grant number: P30ES010126; Grant sponsor: National Institutes of Health (NIH) US; Grant numbers: P01CA068384, K07CA104231, R01DE13158; Grant sponsor: National Institute of Health (NIH) US; Grant numbers: P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667; Grant sponsor: Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center, IARC; Grant sponsors: National Institutes of Health (NCI) US and NIDCR intramural programs; Grant sponsors: Fondo para la Investigacion Cientifica y Tecnologica (FONCYT) Argentina, IMIM (Barcelona), Fundacao de Amparo a Pesquisa no Estado de Sao Paulo (FAPESP); Grant number: No 01/01768-2; Grant sponsor: European Commission; Grant number: IC18-CT97-0222; Grant sponsor: Fondo de Investigaciones Sanitarias (FIS) of the Spanish Government; Grant numbers: FIS 97/0024, FIS 97/0662, BAE 01/5013; Grant sponsors: International Union Against Cancer (UICC) and Yamagiwa-Yoshida Memorial International Cancer Study Grant; Grant sponsor: National Institutes of Health (NIH) US; Grant numbers: R01CA078609, R01CA100679; Grant sponsor: The Intramural Program of the National Cancer Institute, National Institutes of Health, USA; Grant sponsor: NIH; Grant number: R01CA51845; The work reported in this article was undertaken during the tenure of a Postdoctoral Fellowship awarded by the IARC (postdoctoral fellowship, Q. Li). NR 49 TC 10 Z9 10 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2012 VL 131 IS 7 BP 1686 EP 1699 DI 10.1002/ijc.27405 PG 14 WC Oncology SC Oncology GA 980TJ UT WOS:000306915700036 PM 22173631 ER PT J AU Koenigsberg, HW Yuan, PX Diaz, GA Guerreri, S Dorantes, C Mayson, S Zamfirescu, C New, AS Goodman, M Manji, HK Siever, LJ AF Koenigsberg, Harold W. Yuan, Peixiong Diaz, George A. Guerreri, Stephanie Dorantes, Christine Mayson, Sarahjo Zamfirescu, Constantin New, Antonia S. Goodman, Marianne Manji, Husseini K. Siever, Larry J. TI Platelet protein kinase C and brain-derived neurotrophic factor levels in borderline personality disorder patients SO PSYCHIATRY RESEARCH LA English DT Article; Proceedings Paper CT 66th Annual Meeting of the Society-of-Biological-Psychiatry CY MAY 12-14, 2011 CL San Francisco, CA SP Soc Biol Psychiat DE PKC; BDNF; Neurotrophic factors; Second messengers; Personality disorders; Borderline personality disorder ID BIPOLAR AFFECTIVE-DISORDER; TEENAGE SUICIDE VICTIMS; POSTMORTEM BRAIN; DEPRESSED-PATIENTS; MAJOR DEPRESSION; MOOD DISORDERS; EXPRESSION; TRANSLOCATION; TRANSDUCTION; COMORBIDITY AB Borderline personality disorder (BPD) is a prevalent and difficult to treat psychiatric condition characterized by abrupt mood swings, intense anger and depression, unstable interpersonal relationships, impulsive self-destructive behavior and a suicide rate of approximately 10%. Possible underlying molecular dysregulations in BPD have not been well explored. Protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) have both been implicated in affective disorders, but their role in BPD has not been examined. Platelets were isolated from blood obtained from 24 medication-free BPD patients and 18 healthy control subjects. PKC-alpha, phosphorylated-PKC-alpha (p-PKC alpha), PKC-beta II, and BDNF were measured in platelet homogenates by immunoblotting. In the males, platelet BDNF and PKC-alpha levels were lower in patients than controls. p-PKC-alpha and PKC-beta II were lower at trend levels. In the entire sample, platelet p-PKC alpha and PKC-alpha activity were lower, at a trend level, in patients compared to controls. This is the first report to our knowledge of PKC and BDNF activity in BPD and calls for replication. These findings are consistent with altered PKC and BDNF activity in a range of neuropsychiatric conditions including bipolar disorder, depression and suicide. Published by Elsevier Ireland Ltd. C1 [Koenigsberg, Harold W.; Diaz, George A.; Guerreri, Stephanie; Dorantes, Christine; Mayson, Sarahjo; Zamfirescu, Constantin; New, Antonia S.; Goodman, Marianne; Siever, Larry J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Koenigsberg, Harold W.; New, Antonia S.; Goodman, Marianne; Siever, Larry J.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Yuan, Peixiong] NIMH, Bethesda, MD 20892 USA. [Manji, Husseini K.] Johnson & Johnson Pharmaceut, New Brunswick, NJ USA. RP Koenigsberg, HW (reprint author), Mental Hlth Patient Care Ctr, James J Peters VA Med Ctr, Mt Sinai Sch Med, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM HWarrenK@nyc.rr.com FU Intramural NIH HHS; NCRR NIH HHS [M01 RR000071, 5MO1RR00071] NR 41 TC 7 Z9 7 U1 2 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD SEP 30 PY 2012 VL 199 IS 2 BP 92 EP 97 DI 10.1016/j.psychres.2012.04.026 PG 6 WC Psychiatry SC Psychiatry GA 056SC UT WOS:000312510700003 PM 22633012 ER PT J AU Horiuchi, M Wakayama, K Itoh, A Kawai, K Pleasure, D Ozato, K Itoh, T AF Horiuchi, Makoto Wakayama, Kouji Itoh, Aki Kawai, Kumi Pleasure, David Ozato, Keiko Itoh, Takayuki TI Interferon regulatory factor 8/interferon consensus sequence binding protein is a critical transcription factor for the physiological phenotype of microglia SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Microglia; Interferon regulatory factor; Phagocytosis; Cytokine; Cuprizone-induced demyelination ID COLONY-STIMULATING FACTOR; OLIGODENDROGLIAL PROGENITOR CELLS; CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; RAT FACIAL NUCLEUS; IN-VIVO; MYELOID CELLS; FACTOR FAMILY; IFN-GAMMA; TARGETED DISRUPTION AB Background: Recent fate-mapping studies establish that microglia, the resident mononuclear phagocytes of the CNS, are distinct in origin from the bone marrow-derived myeloid lineage. Interferon regulatory factor 8 (IRF8, also known as interferon consensus sequence binding protein) plays essential roles in development and function of the bone marrow-derived myeloid lineage. However, little is known about its roles in microglia. Methods: The CNS tissues of IRF8-deficient mice were immunohistochemically analyzed. Pure microglia isolated from wild-type and IRF8-deficient mice were studied in vitro by proliferation, immunocytochemical and phagocytosis assays. Microglial response in vivo was compared between wild-type and IRF8-deficient mice in the cuprizon-induced demyelination model. Results: Our analysis of IRF8-deficient mice revealed that, in contrast to compromised development of IRF8-deficient bone marrow myeloid lineage cells, development and colonization of microglia are not obviously affected by loss of IRF8. However, IRF8-deficient microglia demonstrate several defective phenotypes. In vivo, IRF8-deficient microglia have fewer elaborated processes with reduced expression of IBA1/AIF1 compared with wild-type microglia, suggesting a defective phenotype. IRF8-deficient microglia are significantly less proliferative in mixed glial cultures than wild-type microglia. Unlike IRF8-deficient bone marrow myeloid progenitors, exogenous macrophage colony stimulating factor (colony stimulating factor 1) (M-CSF (CSF1)) restores their proliferation in mixed glial cultures. In addition, IRF8-deficient microglia exhibit an exaggerated growth response to exogenous granulocyte-macrophage colony stimulating factor (colony stimulating factor 2) (GM-CSF (CSF2)) in the presence of other glial cells. IRF8-deficient microglia also demonstrate altered cytokine expressions in response to interferon-gamma and lipopolysaccharide in vitro. Moreover, the maximum phagocytic capacity of IRF8-deficient microglia is reduced, although their engulfment of zymosan particles is not overtly impaired. Defective scavenging activity of IRF8-deficient microglia was further confirmed in vivo in the cuprizone-induced demyelination model in mice. Conclusions: This study is the first to demonstrate the essential contribution of IRF8-mediated transcription to a broad range of microglial phenotype. Microglia are distinct from the bone marrow myeloid lineage with respect to their dependence on IRF8-mediated transcription. C1 [Horiuchi, Makoto; Itoh, Aki; Pleasure, David; Itoh, Takayuki] Univ Calif Davis, Sch Med, Dept Neurol, Sacramento, CA 95817 USA. [Horiuchi, Makoto; Itoh, Aki; Pleasure, David; Itoh, Takayuki] 601A Shriners Hosp Children No Calif, Inst Pediat Regenerat Med, Sacramento, CA 95817 USA. [Wakayama, Kouji] Univ Tokyo, Grad Sch Med, Dept Adv Clin Sci & Therapeut, Bunkyo Ku, Tokyo 1138655, Japan. [Kawai, Kumi] Nagoya Univ, Grad Sch Med, Dept Med Technol, Higashi Ku, Nagoya, Aichi 4618673, Japan. [Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Itoh, T (reprint author), Univ Calif Davis, Sch Med, Dept Neurol, 4860 Y St, Sacramento, CA 95817 USA. EM takito@ucdavis.edu RI Horiuchi, Makoto/M-5344-2014; Kumi, Kawai/I-6275-2014 OI Kumi, Kawai/0000-0002-7772-2605 FU Research Grant of Shriners Hospitals for Children [85400]; US National Institute of Health grant [NS025044] FX This work was supported by Research Grant of Shriners Hospitals for Children 85400 (to TI) and by US National Institute of Health grant NS025044 (to DP and TI). The authors thank Maksim Gusev for his technical assistance. NR 68 TC 25 Z9 25 U1 1 U2 7 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 SEP 28 PY 2012 VL 9 AR 227 DI 10.1186/1742-2094-9-227 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 087GW UT WOS:000314750500001 PM 23020843 ER PT J AU Jallow, M Casals-Pascual, C Ackerman, H Walther, B Walther, M Pinder, M Sisay-Joof, F Usen, S Jallow, M Abubakar, I Olaosebikan, R Jobarteh, A Conway, DJ Bojang, K Kwiatkowski, D AF Jallow, Muminatou Casals-Pascual, Climent Ackerman, Hans Walther, Brigitte Walther, Michael Pinder, Margaret Sisay-Joof, Fatou Usen, Stanley Jallow, Mariatou Abubakar, Ismaela Olaosebikan, Rasaq Jobarteh, Aminata Conway, David J. Bojang, Kalifa Kwiatkowski, Dominic TI Clinical Features of Severe Malaria Associated with Death: A 13-Year Observational Study in The Gambia SO PLOS ONE LA English DT Article ID SEVERE FALCIPARUM-MALARIA; AFRICAN CHILDREN; CEREBRAL MALARIA; RANDOMIZED-TRIAL; TRANSMISSION; INDICATORS; MORBIDITY AB Background: Severe malaria (SM) is a major cause of death in sub-Saharan Africa. Identification of both specific and sensitive clinical features to predict death is needed to improve clinical management. Methods: A 13-year observational study was conducted from 1997 through 2009 of 2,901 children with SM enrolled at the Royal Victoria Teaching Hospital in The Gambia to identify sensitive and specific predictors of poor outcome in Gambian children with severe malaria between the ages 4 months to 14 years. We have measured the sensitivity and specificity of clinical features that predict death or development of neurological sequelae. Findings: Impaired consciousness (odds ratio {OR} 4.4 [95% confidence interval {CI}, 2.7-7.3]), respiratory distress (OR 2.4 [95% CI, 1.7-3.2]), hypoglycemia (OR 1.7 [95%CI, 1.2-2.3]), jaundice (OR 1.9 [95%CI, 1.2-2.9]) and renal failure (OR 11.1 [95%CI, 3.3-36.5]) were independently associated with death in children with SM. The clinical features that showed the highest sensitivity and specificity to predict death were respiratory distress (area under the curve 0.63 [95% CI, 0.60-0.65]) and impaired consciousness (AUC 0.61[95% CI, 0.59-0.63]), which were comparable to the ability of hyperlactatemia (blood lactate>5 mM) to predict death (AUC 0.64 [95% CI, 0.55-0.72]). A Blantyre coma score (BCS) of 2 or less had a sensitivity of 74% and specificity of 67% to predict death (AUC 0.70 [95% C.I. 0.68-0.72]), and sensitivity and specificity of 74% and 69%, respectively to predict development of neurological sequelae (AUC 0.72 [95% CI, 0.67-0.76]). The specificity of this BCS threshold to identify children at risk of dying improved in children less than 3 years of age (AUC 0.74, [95% C.I 0.71-0.76]). Conclusion: The BCS is a quantitative predictor of death. A BCS of 2 or less is the most sensitive and specific clinical feature to predict death or development of neurological sequelae in children with SM. C1 [Casals-Pascual, Climent; Kwiatkowski, Dominic] Wellcome Trust Ctr Human Genet, Oxford, England. [Jallow, Muminatou; Walther, Brigitte; Pinder, Margaret; Sisay-Joof, Fatou; Usen, Stanley; Abubakar, Ismaela; Olaosebikan, Rasaq; Jobarteh, Aminata; Bojang, Kalifa] MRC Labs, Malaria Programme, Banjul, Gambia. [Ackerman, Hans; Walther, Michael] NIAID, Lab Malaria & Vector Res, Rockville, MD USA. [Conway, David J.] London Sch Hyg & Trop Med, London WC1, England. [Jallow, Muminatou; Jallow, Mariatou] Royal Victoria Teaching Hosp, Banjul, Gambia. RP Casals-Pascual, C (reprint author), Wellcome Trust Ctr Human Genet, Oxford, England. EM ccasals@well.ox.ac.uk OI Conway, David/0000-0002-8711-3037; Kwiatkowski, Dominic/0000-0002-5023-0176 FU Wellcome Trust [077383/Z/05/Z, 075491/Z/04]; Bill & Melinda Gates Foundation through the Foundation for the National Institutes of Health as part of the Grand Challenges in Global Health initiative [566]; Medical Research Council [G0701885]; Division of Intramural Research, National Institutes of Allergy and Infectious Diseases FX This work was supported by the Wellcome Trust [grant number 077383/Z/05/Z] [grant number 075491/Z/04] and by the Bill & Melinda Gates Foundation, through the Foundation for the National Institutes of Health (grant number 566) as part of the Grand Challenges in Global Health initiative. CC-P is supported by the Medical Research Council (Clinician Scientist Fellowship: G0701885). HA is supported by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 15 Z9 15 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 28 PY 2012 VL 7 IS 9 AR e45645 DI 10.1371/journal.pone.0045645 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022PZ UT WOS:000309973900049 PM 23029157 ER PT J AU Ramasamy, A Kuokkanen, M Vedantam, S Gajdos, ZK Alves, AC Lyon, HN Ferreira, MAR Strachan, DP Zhao, JH Abramson, MJ Brown, MA Coin, L Dharmage, SC Duffy, DL Haahtela, T Heath, AC Janson, C Kahonen, M Khaw, KT Laitinen, J Le Souef, P Lehtimaki, T Madden, PAF Marks, GB Martin, NG Matheson, MC Palmer, CD Palotie, A Pouta, A Robertson, CF Viikari, J Widen, E Wjst, M Jarvis, DL Montgomery, GW Thompson, PJ Wareham, N Eriksson, J Jousilahti, P Laitinen, T Pekkanen, J Raitakari, OT O'Connor, GT Salomaa, V Jarvelin, MR Hirschhorn, JN AF Ramasamy, Adaikalavan Kuokkanen, Mikko Vedantam, Sailaja Gajdos, Zofia K. Alves, Alexessander Couto Lyon, Helen N. Ferreira, Manuel A. R. Strachan, David P. Zhao, Jing Hua Abramson, Michael J. Brown, Matthew A. Coin, Lachlan Dharmage, Shyamali C. Duffy, David L. Haahtela, Tari Heath, Andrew C. Janson, Christer Kahonen, Mika Khaw, Kay-Tee Laitinen, Jaana Le Souef, Peter Lehtimaki, Terho Madden, Pamela A. F. Marks, Guy B. Martin, Nicholas G. Matheson, Melanie C. Palmer, Cameron D. Palotie, Aarno Pouta, Anneli Robertson, Colin F. Viikari, Jorma Widen, Elisabeth Wjst, Matthias Jarvis, Deborah L. Montgomery, Grant W. Thompson, Philip J. Wareham, Nick Eriksson, Johan Jousilahti, Pekka Laitinen, Tarja Pekkanen, Juha Raitakari, Olli T. O'Connor, George T. Salomaa, Veikko Jarvelin, Marjo-Riitta Hirschhorn, Joel N. CA Australian Asthma Genetics TI Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA SO PLOS ONE LA English DT Article ID CARDIOVASCULAR RISK; ROR-ALPHA; VARIANTS; GENETICS; HEALTH; LUNG; SUSCEPTIBILITY; METAANALYSIS; DISEASES; ALLERGY AB Rationale: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P < 5x10(-8)) and three variants reported as suggestive (P < 5 x 10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4x10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma. C1 [Kuokkanen, Mikko; Jousilahti, Pekka; Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Ramasamy, Adaikalavan; Alves, Alexessander Couto; Coin, Lachlan; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Ramasamy, Adaikalavan] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England. [Vedantam, Sailaja; Gajdos, Zofia K.; Lyon, Helen N.; Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Vedantam, Sailaja; Gajdos, Zofia K.; Lyon, Helen N.; Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Vedantam, Sailaja; Gajdos, Zofia K.; Lyon, Helen N.; Palmer, Cameron D.; Hirschhorn, Joel N.] Broad Inst, Cambridge, MA USA. [Strachan, David P.] Univ London, Div Community Hlth Sci, London, England. [Ferreira, Manuel A. R.; Duffy, David L.; Martin, Nicholas G.; Montgomery, Grant W.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Zhao, Jing Hua; Wareham, Nick] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Abramson, Michael J.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Brown, Matthew A.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia. [Dharmage, Shyamali C.; Matheson, Melanie C.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Heath, Andrew C.; Madden, Pamela A. F.] Washington Univ, Sch Med, St Louis, MO USA. [Haahtela, Tari] Helsinki Univ Hosp, Skin & Allergy Hosp, Helsinki, Finland. [Janson, Christer] Uppsala Univ, Dept Med Sci Resp Med & Allergol, Uppsala, Sweden. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Khaw, Kay-Tee] Addenbrookes Hosp, Clin Gerontol Unit, Cambridge, England. [Laitinen, Jaana] Finnish Inst Occupat Hlth, Oulu, Finland. [Le Souef, Peter] Princess Margaret Hosp Children, Sch Paediat & Child Hlth, Perth, WA, Australia. [Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, FIN-33101 Tampere, Finland. [Marks, Guy B.] Univ Sydney, Woolcock Inst Med Res, Sydney, NSW 2006, Australia. [Palotie, Aarno] Wellcome Trust Sanger Inst, Hinxton, England. [Palotie, Aarno; Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Palotie, Aarno] Broad Inst MIT & Harvard, Cambridge, MA USA. [Palotie, Aarno] Univ Cent Hosp, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Pouta, Anneli] Natl Inst Hlth & Welf, Dept Children Young People & Families, Helsinki, Finland. [Pouta, Anneli] Univ Oulu, Inst Clin Med Obstet & Gynecol, Oulu, Finland. [Robertson, Colin F.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Viikari, Jorma] Univ Turku, Dept Med, Turku, Finland. [Wjst, Matthias] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Munich, Germany. [Jarvis, Deborah L.; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Ctr Environm & Hlth, MRC Hlth Protect Agcy HPA, London, England. [Thompson, Philip J.] Univ Western Australia, Ctr Asthma Allergy & Resp Res, Perth, WA 6009, Australia. [Thompson, Philip J.] Univ Western Australia, Lung Inst Western Australia, Perth, WA 6009, Australia. [Eriksson, Johan] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Laitinen, Tarja] Turku Univ Hosp, Dept Pulm Dis & Clin Allergol, FIN-20520 Turku, Finland. [Eriksson, Johan] Folkhalsan Res Ctr, Helsinki, Finland. [Pekkanen, Juha] Natl Inst Hlth & Welf THL, Dept Environm Hlth, Kuopio, Finland. [Pekkanen, Juha] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Med, Turku, Finland. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol, FIN-20520 Turku, Finland. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Salomaa, V (reprint author), Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. EM veikko.salomaa@thl.fi; m.jarvelin@imperial.ac.uk; joelh@broadinstitute.org RI Ramasamy, Adaikalavan/G-2632-2010; Ferreira, Manuel/D-3609-2013; Jarvis, Deborah/E-6494-2011; Montgomery, Grant/B-7148-2008; Matheson, Melanie/O-4721-2015; Duffy, David/B-7392-2013; Kuokkanen, Mikko/M-8247-2016; Coin, Lachlan/A-9001-2014; OI Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Eriksson, Johan/0000-0002-2516-2060; Dharmage, Shyamali/0000-0001-6063-1937; Martin, Nicholas/0000-0003-4069-8020; Ramasamy, Adaikalavan/0000-0002-7598-2892; Abramson, Michael/0000-0002-9954-0538; O'Connor, George/0000-0002-6476-3926; Montgomery, Grant/0000-0002-4140-8139; Matheson, Melanie/0000-0002-5822-3499; Duffy, David/0000-0001-7227-632X; Kuokkanen, Mikko/0000-0003-4375-9327; Coin, Lachlan/0000-0002-4300-455X; Alves, Alex/0000-0001-8519-7356 FU European Commission [018996, LSH-2004-1.2.5-1, 223367]; Department of Health, UK; National Health and Medical Research Council, Australia (NHMRC) [613627, 455836]; Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]; Wellcome Trust [089062]; European Community; ENGAGE Consortium [201413]; Academy of Finland [129287, 134839, 129494, 139635]; Samfundet Folkhalsan; Finnish Diabetes Research Foundation; Finska Lakaresallskapet; Finnish Foundation for Cardiovascular Research; Yrjo Jahnsson Foundation; Foundation Liv och Halsa; Foundation of the Finnish Anti-Tuberculosis Association; Foundation of the Allergy Association; Biocenter Oulu, University of Oulu; National Heart Lung and Blood Institute (NHLBI) - National Institutes of Health [5R01HL087679-02, 1RL1MH083268-01]; American Asthma Foundation FX Please see Supplementary Methods S1 for the details of the many charities, governmental bodies and scientific funding organisations that supported the study recruitment, phenotyping, DNA collection and genotyping for the studies involved in the discovery stage (Stage1) and replication stage (Stage2). The personal research funding supports are listed as follows: AR was supported through the European Commission (through project GABRIEL - contract #018996 under the Integrated Program LSH-2004-1.2.5-1) and the Department of Health, UK. ACA was funded by the European Commission, Framework 7 (grant #223367). The National Health and Medical Research Council, Australia (NHMRC) supported MARF through a project grant (#613627), MAB via a Principal Research Fellowship (#455836) and SCD, DLD, NGM, MCM and GWM via a fellowship scheme. AP acknowledges funding from The Academy of Finland Center of Excellence in Complex Disease Genetics (#213506 and 129680), the Wellcome Trust (#089062), the European Community's Framework 7 Programme and the ENGAGE Consortium (#201413). The Academy of Finland supported EW (#129287, #134839) and VS (#129494, #139635). JE was supported through Academy of Finland, Samfundet Folkhalsan, Finnish Diabetes Research Foundation, Finska Lakaresallskapet, Finnish Foundation for Cardiovascular Research; Yrjo Jahnsson Foundation and Foundation Liv och Halsa. TL was supported by Foundation of the Finnish Anti-Tuberculosis and Allergy Associations. M-RJ has received financial support from the Academy of Finland, Biocenter Oulu, University of Oulu and National Heart Lung and Blood Institute (NHLBI) - National Institutes of Health (#5R01HL087679-02 through the STAMPEED program 1RL1MH083268-01). JNH was supported by a grant from the American Asthma Foundation for analysis of Framingham SHARe data for association with asthma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 39 Z9 40 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 28 PY 2012 VL 7 IS 9 AR e44008 DI 10.1371/journal.pone.0044008 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022PZ UT WOS:000309973900004 PM 23028483 ER PT J AU Ma, JC Tang, WK Esser, L Pastan, I Xia, D AF Ma, Jichun Tang, Wai Kwan Esser, Lothar Pastan, Ira Xia, Di TI Recognition of Mesothelin by the Therapeutic Antibody MORAb-009 STRUCTURAL AND MECHANISTIC INSIGHTS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OVARIAN-CANCER; MOLECULAR-REPLACEMENT; MONOCLONAL-ANTIBODY; EXPRESSION; ADENOCARCINOMAS; PANCREAS; AFFINITY; BINDING; CLONING AB Mesothelin is a tumor differentiation antigen that is highly expressed in many epithelial cancers, with limited expression in normal human tissues. Binding of mesothelin on normal mesothelial cells lining the pleura or peritoneum to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. This binding can be prevented by MORAb-009, a humanized monoclonal antibody against mesothelin currently under clinical trials. Weshow here that MORAb-009 recognizes a non-linear epitope that is contained in the first 64-residue fragment of the mesothelin. We further demonstrate that the recognition is independent of glycosylation state of the protein but sensitive to the loss of a disulfide bond linking residues Cys-7 and Cys-31. The crystal structure of the complex between the mesothelin N-terminal fragment and Fab of MORAb-009 at 2.6 angstrom resolution reveals an epitope encompassing multiple secondary structural elements of the mesothelin, including residues from helix alpha 1, the loops linking helices alpha 1 and alpha 2, and between helices alpha 4 and alpha 5. The mesothelin fragment has a compact, right-handed superhelix structure consisting of five short helices and connecting loops. A residue essential for complex formation has been identified as Phe-22, which projects its side chain into a hydrophobic niche formed on the antibody recognition surface upon antigen-antibody contact. The overlapping binding footprints of both the monoclonal antibody and the cancer antigen CA-125 explains the therapeutic effect and provides a basis for further antibody improvement. C1 [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Xia, D (reprint author), 37 Convent Dr,Bldg 37,Rm 2122C, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research; Cooperative Research and Development Agreement CRADA with Morphotek FX This work was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This work was also supported by a Cooperative Research and Development Agreement CRADA with Morphotek. NR 33 TC 6 Z9 7 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 28 PY 2012 VL 287 IS 40 BP 33123 EP 33131 DI 10.1074/jbc.M112.381756 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 017PG UT WOS:000309602100004 PM 22787150 ER PT J AU Shi, CS Huang, NN Kehrl, JH AF Shi, Chong-Shan Huang, Ning-Na Kehrl, John H. TI Regulator of G-Protein Signaling 3 Isoform 1 (PDZ-RGS3) Enhances Canonical Wnt Signaling and Promotes Epithelial Mesenchymal Transition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-CATENIN; NEGATIVE REGULATOR; WNT/BETA-CATENIN; IMMUNE FUNCTION; RGS PROTEINS; PATHWAY; CELLS; AXIN; TRANSCRIPTION; CANCER AB The Wnt beta-catenin pathway controls numerous cellular processes including cell differentiation and cell-fate decisions. Wnt ligands engage Frizzled receptors and the low-density-lipoprotein-related protein 5/6 (LRP5/6) receptor complex leading to the recruitment of Dishevelled (Dvl) and Axin1 to the plasma membrane. Axin1 has a regulator of G-protein signaling (RGS) domain that binds adenomatous polyposis coli and G alpha subunits, thereby providing a mechanism by which G alpha subunits can affect beta-catenin levels. Here we show that Wnt signaling enhances the expression of another RGS domain-containing protein, PDZRGS3. Reducing PDZ-RGS3 levels impaired Wnt3a-induced activation of the canonical pathway. PDZ-RGS3 bound GSK3 beta and decreased its catalytic activity toward beta-catenin. PDZRGS3 overexpression enhanced Snail1 and led to morphological and biochemical changes reminiscent of epithelial mesenchymal transition (EMT). These results indicate that PDZ-RGS3 can enhance signals generated by the Wnt canonical pathway and that plays a pivotal role in EMT. C1 [Shi, Chong-Shan; Huang, Ning-Na; Kehrl, John H.] NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, 10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X FU intramural research program of the NIAID; National Institutes of Health FX This work was supported, in whole or in part, by the intramural research program of the NIAID, National Institutes of Health. NR 31 TC 7 Z9 7 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 SEP 28 PY 2012 VL 287 IS 40 BP 33480 EP 33487 DI 10.1074/jbc.M112.361873 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 017PG UT WOS:000309602100034 PM 22859293 ER PT J AU Nie, ZQ Hu, GQ Wei, G Cui, KR Yamane, A Resch, W Wang, RN Green, DR Tessarollo, L Casellas, R Zhao, KJ Levens, D AF Nie, Zuqin Hu, Gangqing Wei, Gang Cui, Kairong Yamane, Arito Resch, Wolfgang Wang, Ruoning Green, Douglas R. Tessarollo, Lino Casellas, Rafael Zhao, Keji Levens, David TI c-Myc Is a Universal Amplifier of Expressed Genes in Lymphocytes and Embryonic Stem Cells SO CELL LA English DT Article ID GRAPHICAL USER-INTERFACE; TRANSCRIPTION FACTOR MYC; LYMPHOMA CELLS; RNA-POLYMERASE; ACTIVATION; MOUSE; FIBROBLASTS; ONCOGENES; REVEALS; GENOME AB The c-Myc HLH-bZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism, and differentiation at the cellular, tissue, or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc's targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II, and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a nonlinear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature. C1 [Hu, Gangqing; Wei, Gang; Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. [Nie, Zuqin; Levens, David] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Yamane, Arito; Resch, Wolfgang; Casellas, Rafael] NIAMS, Genom & Immun Sect, Bethesda, MD 20892 USA. [Wang, Ruoning; Green, Douglas R.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Tessarollo, Lino] NCI, Neural Dev Sect, FNL, Frederick, MD 21702 USA. RP Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov; levens@helix.nih.gov RI HU, GANGQING/K-5849-2012; Yamane, Arito/A-2959-2013; Wang, Ruoning/C-1683-2014; Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU NIH, National Cancer Institute, Center for Cancer Research; NHLBI; NIAMS FX We thank our colleagues, especially Eric Batchelor and Dan Larson for insight and valuable discussions. D.L. thanks Dirk Eick for insightful discussion. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, of NHLBI and of NIAMS. We thank the DNA Sequencing Core Facility of NHLBI for sequencing some of the ChIP-Seq libraries. NR 58 TC 369 Z9 372 U1 9 U2 46 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD SEP 28 PY 2012 VL 151 IS 1 BP 68 EP 79 DI 10.1016/j.cell.2012.08.033 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 016UE UT WOS:000309544200011 PM 23021216 ER PT J AU Gao, WD Murray, CI Tian, Y Zhong, X DuMond, JF Shen, XX Stanley, BA Foster, DB Wink, DA King, SB Van Eyk, JE Paolocci, N AF Gao, Wei Dong Murray, Christopher I. Tian, Ye Zhong, Xin DuMond, Jenna F. Shen, Xiaoxu Stanley, Brian A. Foster, D. Brian Wink, David A. King, S. Bruce Van Eyk, Jennifer E. Paolocci, Nazareno TI Nitroxyl-Mediated Disulfide Bond Formation Between Cardiac Myofilament Cysteines Enhances Contractile Function SO CIRCULATION RESEARCH LA English DT Article DE calcium; contractility; nitroxyl; oxidation; oxidant signaling; redox; redox switch ID MUSCLE THIN-FILAMENTS; TRUNCATED TROPONIN-I; HEART-FAILURE; MYOSIN SUBFRAGMENT-1; ALPHA-TROPOMYOSIN; STRUCTURAL BASIS; STRIATED-MUSCLE; NITRIC-OXIDE; ACTIVATION; CALCIUM AB Rationale: In the myocardium, redox/cysteine modification of proteins regulating Ca2+ cycling can affect contraction and may have therapeutic value. Nitroxyl (HNO), the one-electron-reduced form of nitric oxide, enhances cardiac function in a manner that suggests reversible cysteine modifications of the contractile machinery. Objective: To determine the effects of HNO modification in cardiac myofilament proteins. Methods and Results: The HNO-donor, 1-nitrosocyclohexyl acetate, was found to act directly on the myofilament proteins, increasing maximum force (F-max) and reducing the concentration of Ca2+ for 50% activation (Ca-50) in intact and skinned cardiac muscles. The effects of 1-nitrosocyclohexyl acetate are reversible by reducing agents and distinct from those of another HNO donor, Angeli salt, which was previously reported to increase F-max without affecting Ca-50. Using a new mass spectrometry capture technique based on the biotin switch assay, we identified and characterized the formation by HNO of a disulfide-linked actin-tropomyosin and myosin heavy chain-myosin light chain 1. Comparison of the 1-nitrosocyclohexyl acetate and Angeli salt effects with the modifications induced by each donor indicated the actin-tropomyosin and myosin heavy chain-myosin light chain 1 interactions independently correlated with increased Ca2+ sensitivity and force generation, respectively. Conclusions: HNO exerts a direct effect on cardiac myofilament proteins increasing myofilament Ca2+ responsiveness by promoting disulfide bond formation between critical cysteine residues. These findings indicate a novel, redox-based modulation of the contractile apparatus, which positively impacts myocardial function, providing further mechanistic insight for HNO as a therapeutic agent. (Circ Res. 2012;111:1002-1011.) C1 [Gao, Wei Dong; Tian, Ye; Zhong, Xin; Shen, Xiaoxu] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Murray, Christopher I.; Van Eyk, Jennifer E.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Tian, Ye; Zhong, Xin] Harbin Med Univ, Dept Pathophysiol, Harbin, Peoples R China. [DuMond, Jenna F.; King, S. Bruce] Wake Forest Univ, Dept Chem, Winston Salem, NC 27109 USA. [Stanley, Brian A.; Foster, D. Brian; Van Eyk, Jennifer E.; Paolocci, Nazareno] Johns Hopkins Sch Med, Div Cardiol, Dept Med, Baltimore, MD USA. [Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Paolocci, Nazareno] Univ Perugia, Dept Clin Med, I-06100 Perugia, Italy. RP Gao, WD (reprint author), Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Zayed Tower 6208,1800 Orleans St, Baltimore, MD 21205 USA. EM wgao3@jhmi.edu; npaoloc1@jhmi.edu RI Foster, D. Brian/C-6350-2009; OI Foster, D. Brian/0000-0002-9290-9590; Paolocci, Nazareno/0000-0001-7011-997X FU American Heart Association [0815145E, AHA0855439E, 0855242E]; National Institutes of Health [HL62198, P01 HL77180-0, N01-HV-28180, P50 HL 084946-01, R01HL075265, R01 HL091923] FX This work was supported by the American Heart Association (Pre-Doctoral Fellowship grant 0815145E to C. I. M., grant-in-aid AHA0855439E to W. G., and grant-in-aid 0855242E to N.P.), and by National Institutes of Health (HL62198 to S. B. K.; P01 HL77180-0, N01-HV-28180, and P50 HL 084946-01 to J.V.E.; and R01HL075265 and R01 HL091923 to N.P.). NR 63 TC 35 Z9 35 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD SEP 28 PY 2012 VL 111 IS 8 BP 1002 EP + DI 10.1161/CIRCRESAHA.112.270827 PG 24 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 016HG UT WOS:000309507800014 PM 22851540 ER PT J AU Webb, CT Selkrig, J Perry, AJ Noinaj, N Buchanan, SK Lithgow, T AF Webb, Chaille T. Selkrig, Joel Perry, Andrew J. Noinaj, Nicholas Buchanan, Susan K. Lithgow, Trevor TI Dynamic Association of BAM Complex Modules Includes Surface Exposure of the Lipoprotein BamC SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE beta-barrel proteins; Omp85; outer membrane biogenesis; protein transport ID OUTER-MEMBRANE BIOGENESIS; BARREL ASSEMBLY MACHINE; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; YAET COMPLEX; PROTEIN; COMPONENT; DOMAIN; MITOCHONDRIA; SECRETION AB The beta-barrel assembly machinery (BAM) complex drives the assembly of beta-barrel proteins into the outer membrane of gram-negative bacteria. It is composed of five subunits: BamA, BamB, BamC, BamD, and BamE. We find that the BAM complex isolated from the outer membrane of Escherichia coli consists of a core complex of BamA:B:C:D:E and, in addition, a BamA:B module and a BamC:D module. In the absence of BamC, these modules are destabilized, resulting in increased protease susceptibility of BamD and BamB. While the N-terminus of BamC carries a highly conserved region crucial for stable interaction with BamD, immunofluorescence, immunoprecipitation, and protease-sensitivity assays show that the C-terminal domain of BamC, composed of two helix-grip motifs, is exposed on the surface of E. coli. This unexpected topology of a bacterial lipoprotein is reminiscent of the analogous protein subunits from the mitochondrial beta-barrel insertion machinery, the SAM complex. The modular arrangement and topological features provide new insight into the architecture of the BAM complex, towards a better understanding of the mechanism driving beta-barrel membrane protein assembly. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Webb, Chaille T.; Selkrig, Joel; Perry, Andrew J.; Lithgow, Trevor] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3800, Australia. [Noinaj, Nicholas; Buchanan, Susan K.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lithgow, T (reprint author), Monash Univ, Bldg 76, Clayton, Vic 3800, Australia. EM trevor.lithgow@monash.edu RI Perry, Andrew/E-5607-2010 OI Perry, Andrew/0000-0001-9256-6068 FU National Health and Medical Research Council (NHMRC) of Australia through an NHMRC [606788]; NHMRC Postgraduate Research Scholarship; Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Yue Qu for expert advice on immunofluorescence microscopy. This work was supported by the National Health and Medical Research Council (NHMRC) of Australia through an NHMRC Program Grant (606788). T.L. is an Australian Research Council Federation Fellow, C.T.W. and A.J.P. are NHMRC Biomedical Fellows, and J.S. is supported by an NHMRC Postgraduate Research Scholarship. S.K.B. and N.N. are supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 44 TC 26 Z9 27 U1 0 U2 9 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 SEP 28 PY 2012 VL 422 IS 4 BP 545 EP 555 DI 10.1016/j.jmb.2012.05.035 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 017CR UT WOS:000309568200010 PM 22683355 ER PT J AU De Lay, N Gottesman, S AF De Lay, Nicholas Gottesman, Susan TI RNase E Finds Some sRNAs Stimulating SO MOLECULAR CELL LA English DT Editorial Material ID ESCHERICHIA-COLI AB In this issue of Molecular Cell, Bandyra et al. (2012) describe how a bacterial sRNA can lead to degradation of an mRNA by pairing within the coding region of the mRNA; the 5' monophosphate end of the sRNA activates RNase E, leading to rapid cleavage of the paired mRNA. C1 [De Lay, Nicholas; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM gottesms@helix.nih.gov FU Intramural NIH HHS [ZIA BC008714-33] NR 8 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 28 PY 2012 VL 47 IS 6 BP 825 EP 826 DI 10.1016/j.molcel.2012.09.007 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 013NU UT WOS:000309312900002 PM 23020853 ER PT J AU Sparks, JL Chon, H Cerritelli, SM Kunkel, TA Johansson, E Crouch, RJ Burgers, PM AF Sparks, Justin L. Chon, Hyongi Cerritelli, Susana M. Kunkel, Thomas A. Johansson, Erik Crouch, Robert J. Burgers, Peter M. TI RNase H2-Initiated Ribonucleotide Excision Repair SO MOLECULAR CELL LA English DT Article ID YEAST REPLICATIVE POLYMERASES; CELL NUCLEAR ANTIGEN; DNA-REPLICATION; SACCHAROMYCES-CEREVISIAE; TOPOISOMERASE-I; MECHANISM; SUBSTRATE; PCNA; RECOMBINATION; INSTABILITY AB Ribonucleotides are incorporated into DNA by the replicative DNA polymerases at frequencies of about 2 per kb, which makes them by far the most abundant form of potential DNA damage in the cell. Their removal is essential for restoring a stable intact chromosome. Here, we present a complete biochemical reconstitution of the ribonucleotide excision repair (RER) pathway with enzymes purified from Saccharomyces cerevisiae. RER is most efficient when the ribonucleotide is incised by RNase H2, and further excised by the flap endonuclease FEN1 with strand displacement synthesis carried out by DNA polymerase delta, the PCNA clamp, its loader RFC, and completed by DNA ligase I. We observed partial redundancy for several of the enzymes in this pathway. Exo1 substitutes for FEN1 and Pol epsilon for Pol delta with reasonable efficiency. However, RNase H1 fails to substitute for RNase H2 in the incision step of RER. C1 [Sparks, Justin L.; Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Chon, Hyongi; Cerritelli, Susana M.; Crouch, Robert J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. [Kunkel, Thomas A.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Kunkel, Thomas A.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Johansson, Erik] Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. RP Burgers, PM (reprint author), Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. EM burgers@biochem.wustl.edu FU National Institutes of Health [GM032431]; Swedish research council and Cancerfonden; Division of Intramural Research of the National Institutes of Health, National Institute on Environmental Health Sciences [Z01 ES065089]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX The authors thank Carrie Stith and Else-Britt Lundstrom for protein purification and Bonnie Yoder for strain construction. This work was supported in part by Grant GM032431 from the National Institutes of Health to P.M.B.; the Swedish research council and Cancerfonden to E.J.; by Project Z01 ES065089 from the Division of Intramural Research of the National Institutes of Health, National Institute on Environmental Health Sciences, to T.A.K.; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH to R.J.C. and T.A.K. NR 33 TC 98 Z9 98 U1 2 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 28 PY 2012 VL 47 IS 6 BP 980 EP 986 DI 10.1016/j.molcel.2012.06.035 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 013NU UT WOS:000309312900016 PM 22864116 ER PT J AU Pfeiffer, RM Forzani, L Bura, E AF Pfeiffer, Ruth M. Forzani, Liliana Bura, Efstathia TI Sufficient dimension reduction for longitudinally measured predictors SO STATISTICS IN MEDICINE LA English DT Article DE discrimination; AUC; Kronecker product; sliced inverse regression (SIR) ID SLICED INVERSE REGRESSION AB We propose a method to combine several predictors (markers) that are measured repeatedly over time into a composite marker score without assuming a model and only requiring a mild condition on the predictor distribution. Assuming that the first and second moments of the predictors can be decomposed into a time and a marker component via a Kronecker product structure that accommodates the longitudinal nature of the predictors, we develop first-moment sufficient dimension reduction techniques to replace the original markers with linear transformations that contain sufficient information for the regression of the predictors on the outcome. These linear combinations can then be combined into a score that has better predictive performance than a score built under a general model that ignores the longitudinal structure of the data. Our methods can be applied to either continuous or categorical outcome measures. In simulations, we focus on binary outcomes and show that our method outperforms existing alternatives by using the AUC, the area under the receiveroperator characteristics (ROC) curve, as a summary measure of the discriminatory ability of a single continuous diagnostic marker for binary disease outcomes. Published 2011. This article is a US Government work and is in the public domain in the USA. C1 [Pfeiffer, Ruth M.] NCI, Biostat Branch, Bethesda, MD 20892 USA. [Forzani, Liliana] Consejo Nacl Invest Cient & Tecn, Inst Matemat Aplicada Litoral, RA-3000 Santa Fe, Argentina. [Forzani, Liliana] UNL, Fac Ingn Quim, RA-3000 Santa Fe, Argentina. [Bura, Efstathia] George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Pfeiffer, RM (reprint author), NCI, Biostat Branch, Bethesda, MD 20892 USA. EM pfeiffer@mail.nih.gov NR 26 TC 5 Z9 5 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2414 EP 2427 DI 10.1002/sim.4437 PG 14 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 003UK UT WOS:000308636700003 PM 22161635 ER PT J AU Roy, A Danaher, M Mumford, SL Chen, Z AF Roy, Anindya Danaher, Michelle Mumford, Sunni L. Chen, Zhen TI A Bayesian order-restricted model for hormonal dynamics during menstrual cycles of healthy women SO STATISTICS IN MEDICINE LA English DT Article DE Gibbs sampling; parameter constraints; quadratic programming; reproductive hormones; oxidative stress ID OXIDATIVE STRESS; LIPID-PEROXIDATION; ESTROGENS; CANCER; RISK AB We propose a Bayesian framework for analyzing multivariate linear mixed effect models with linear constraints on the fixed effect parameters. The procedure can incorporate both firm and soft restrictions on the parameters and Bayesian model selection for the random effects. The framework is used to analyze data from the BioCycle study. One of the main objectives of the BioCycle study is to investigate the association between markers of oxidative stress and hormone levels during menstrual cycles of healthy women. Contrary to the popular belief that ovarian hormones are negatively associated with level of F 2-isoprostanes, a known marker for oxidative stress, our analysis finds a positive association between ovarian hormone levels and isoprostane levels. The positive association corroborates the findings from a previous analysis of the BioCycle data. Copyright (c) 2011 John Wiley & Sons, Ltd. C1 [Roy, Anindya; Danaher, Michelle] Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. [Danaher, Michelle; Mumford, Sunni L.; Chen, Zhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Roy, A (reprint author), Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. EM anindya@umbc.edu FU Long-Range Research Initiative of the American Chemistry Council; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX The Long-Range Research Initiative of the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health partially supported this research. NR 24 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2428 EP 2440 DI 10.1002/sim.4419 PG 13 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 003UK UT WOS:000308636700004 PM 22147446 ER PT J AU Schildcrout, JS Mumford, SL Chen, Z Heagerty, PJ Rathouz, PJ AF Schildcrout, Jonathan S. Mumford, Sunni L. Chen, Zhen Heagerty, Patrick J. Rathouz, Paul J. TI Outcome-dependent sampling for longitudinal binary response data based on a time-varying auxiliary variable SO STATISTICS IN MEDICINE LA English DT Article DE outcome-dependent sampling; bias sampling; study design; generalized estimating equations; longitudinal data analysis; binary data ID CASE-COHORT DESIGN; MARGINALIZED MODELS; REGRESSION-ANALYSIS; MENSTRUAL-CYCLE; MISSING DATA; DISEASE; INFERENCE; BIOCYCLE; BIAS AB Outcome-dependent sampling (ODS) study designs are commonly implemented with rare diseases or when prospective studies are infeasible. In longitudinal data settings, when a repeatedly measured binary response is rare, an ODS design can be highly efficient for maximizing statistical information subject to resource limitations that prohibit covariate ascertainment of all observations. This manuscript details an ODS design where individual observations are sampled with probabilities determined by an inexpensive, time-varying auxiliary variable that is related but is not equal to the response. With the goal of validly estimating marginal model parameters based on the resulting biased sample, we propose a semi-parametric, sequential offsetted logistic regressions (SOLR) approach. The SOLR strategy first estimates the relationship between the auxiliary variable and the response and covariate data by using an offsetted logistic regression analysis where the offset is used to adjust for the biased design. Results from the auxiliary variable model are then combined with the known or estimated sampling probabilities to formulate a second offset that is used to correct for the biased design in the ultimate target model relating the longitudinal binary response to covariates. Because the target model offset is estimated with SOLR, we detail asymptotic standard error estimates that account for uncertainty associated with the auxiliary variable model. Motivated by an analysis of the BioCycle Study (Gaskins et al., Effect of daily fiber intake on reproductive function: the BioCycle Study. American Journal of Clinical Nutrition 2009; 90(4): 10611069) that aims to describe the relationship between reproductive health (determined by luteinizing hormone levels) and fiber consumption, we examine properties of SOLR estimators and compare them with other common approaches. Copyright (c) 2011 John Wiley & Sons, Ltd. C1 [Schildcrout, Jonathan S.] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37232 USA. [Mumford, Sunni L.; Chen, Zhen] NICHHD, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Bethesda, MD 20892 USA. [Heagerty, Patrick J.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rathouz, Paul J.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. RP Schildcrout, JS (reprint author), Vanderbilt Univ, Sch Med, Dept Biostat, 1161 21st Ave S,S-2323 Med Ctr N, Nashville, TN 37232 USA. EM jonathan.schildcrout@vanderbilt.edu FU NIH from the National Heart, Lung, and Blood Institute [R01 HL094786]; Long-Range Research Initiative of the American Chemistry Council; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This project was partially funded by the NIH grant R01 HL094786 from the National Heart, Lung, and Blood Institute, the Long-Range Research Initiative of the American Chemistry Council, and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 38 TC 3 Z9 3 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2441 EP 2456 DI 10.1002/sim.4359 PG 16 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 003UK UT WOS:000308636700005 PM 22086716 ER PT J AU Albert, PS Schisterman, EF AF Albert, Paul S. Schisterman, Enrique F. TI Novel statistical methodology for analyzing longitudinal biomarker data SO STATISTICS IN MEDICINE LA English DT Article ID MIXED MODELS; SURVIVAL; PROFILES; WOMEN C1 [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B05, Bethesda, MD 20892 USA. EM albertp@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, MA, USA 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, MA, USA. NR 19 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2457 EP 2460 DI 10.1002/sim.5500 PG 4 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 003UK UT WOS:000308636700006 PM 22969022 ER PT J AU Whitcomb, BW Perkins, NJ Zhang, ZW Ye, AJ Lyles, RH AF Whitcomb, Brian W. Perkins, Neil J. Zhang, Zhiwei Ye, Aijun Lyles, Robert H. TI Assessment of skewed exposure in case-control studies with pooling SO STATISTICS IN MEDICINE LA English DT Article DE pooling; biomarkers; case-control studies; logistic regression; gamma distribution ID DOSE-RESPONSE RELATIONSHIPS; BLOOD LEAD CONCENTRATIONS; ROC CURVE ANALYSIS; BIOSPECIMENS; MISCARRIAGE; BIOMARKERS; EFFICIENCY; PREGNANCY; SUBJECT; HORMONE AB Pooling-based strategies that combine samples from multiple participants for laboratory assays have been proposed for epidemiologic investigations of biomarkers to address issues including cost, efficiency, detection, and when minimal sample volume is available. A modification of the standard logistic regression model has been previously described to allow use with pooled data; however, this model makes assumptions regarding exposure distribution and logit-linearity of risk (i.e., constant odds ratio) that can be violated in practice. We were motivated by a nested case-control study of miscarriage and inflammatory factors with highly skewed distributions to develop a more flexible model for analysis of pooled data. Using characteristics of the gamma distribution and the relation between models of binary outcome conditional on exposure and of exposure conditional on outcome, we use a modified logistic regression to accommodate nonlinearity because of unequal shape parameters in gamma distributed exposure for cases and controls. Using simulations, we compare our approach with existing methods for logistic regression for pooled data considering: (1) constant and dose-dependent effects; (2) gamma and log-normal distributed exposure; (3) effect size; and (4) the proportions of biospecimens pooled. We show that our approach allows estimation of odds ratios that vary with exposure level, yet has minimal loss of efficiency compared with existing approaches when exposure effects are dose-invariant. Our model performed similarly to a maximum likelihood estimation approach in terms of bias and efficiency, and provides an easily implemented approach for estimation with pooled biomarker data when effects may not be constant across exposure. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Whitcomb, Brian W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Perkins, Neil J.; Zhang, Zhiwei; Ye, Aijun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH DHHS, Rockville, MD USA. [Lyles, Robert H.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. RP Whitcomb, BW (reprint author), Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. EM bwhitcomb@schoolph.umass.edu OI Perkins, Neil/0000-0002-6802-4733 FU Long-Range Research Initiative of the American Chemistry Council; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was partially supported by the Long-Range Research Initiative of the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 27 TC 9 Z9 9 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2461 EP 2472 DI 10.1002/sim.5351 PG 12 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 003UK UT WOS:000308636700007 PM 22437722 ER PT J AU Zhang, Z Liu, A Lyles, RH Mukherjee, B AF Zhang, Z. Liu, A. Lyles, R. H. Mukherjee, B. TI Logistic regression analysis of biomarker data subject to pooling and dichotomization SO STATISTICS IN MEDICINE LA English DT Article DE case-control; cohort; cost efficiency; group testing; measurement error; missing covariate ID LIGASE CHAIN-REACTION; ROC CURVE ANALYSIS; MAXIMUM-LIKELIHOOD; POOLED ASSESSMENTS; COLORECTAL-CANCER; DISEASE INCIDENCE; URINE SAMPLES; PREVALENCE; MODELS; VIRUS AB There is growing interest in pooling specimens across subjects in epidemiologic studies, especially those involving biomarkers. This paper is concerned with regression analysis of epidemiologic data where a binary exposure is subject to pooling and the pooled measurement is dichotomized to indicate either that no subjects in the pool are exposed or that some are exposed, without revealing further information about the exposed subjects in the latter case. The pooling process may be stratified on the disease status (a binary outcome) and possibly other variables but is otherwise assumed random. We propose methods for estimating parameters in a prospective logistic regression model and illustrate these with data from a population-based case-control study of colorectal cancer. Simulation results show that the proposed methods perform reasonably well in realistic settings and that pooling can lead to sizable gains in cost efficiency. We make recommendations with regard to the choice of design for pooled epidemiologic studies. Copyright (c) 2011 John Wiley & Sons, Ltd. C1 [Zhang, Z.; Liu, A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Lyles, R. H.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Mukherjee, B.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. RP Zhang, Z (reprint author), BBB DESPR NICHD, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM zhiwei.zhang@nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development; Long-Range Research Initiative of the American Chemistry Council; National Institute of Environmental Health Sciences [5R01ES012458-07]; NIH [R01 CA81488] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development, and by the Long-Range Research Initiative of the American Chemistry Council. Dr. Lyles' research was partially supported by an R01 grant from the National Institute of Environmental Health Sciences (5R01ES012458-07). The computation was facilitated by the Biowulf cluster computer system made available by the Center for Information Technology at the NIH. We thank Drs. Enrique Schisterman and Paul Albert for helpful discussions and Drs. Stephen B. Gruber and Gad Rennert for sharing the genotype/covariate data from the Molecular Epidemiology of Colorectal Cancer Study supported by NIH grant R01 CA81488. NR 33 TC 3 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2473 EP 2484 DI 10.1002/sim.4367 PG 12 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 003UK UT WOS:000308636700008 PM 21953741 ER PT J AU Lyles, RH Tang, L Lin, J Zhang, ZW Mukherjee, B AF Lyles, Robert H. Tang, Li Lin, Ji Zhang, Zhiwei Mukherjee, Bhramar TI Likelihood-based methods for regression analysis with binary exposure status assessed by pooling SO STATISTICS IN MEDICINE LA English DT Article DE cross-sectional study; case-control study; efficiency; logistic regression; pooling; repeated measures; single nucleotide polymorphism ID COLORECTAL-CANCER; DISEASE INCIDENCE; BIOMARKERS; MODELS; BIOSPECIMENS; PREVALENCE; SUBJECT AB The need for resource-intensive laboratory assays to assess exposures in many epidemiologic studies provides ample motivation to consider study designs that incorporate pooled samples. In this paper, we consider the case in which specimens are combined for the purpose of determining the presence or absence of a pool-wise exposure, in lieu of assessing the actual binary exposure status for each member of the pool. We presume a primary logistic regression model for an observed binary outcome, together with a secondary regression model for exposure. We facilitate maximum likelihood analysis by complete enumeration of the possible implications of a positive pool, and we discuss the applicability of this approach under both cross-sectional and case-control sampling. We also provide a maximum likelihood approach for longitudinal or repeated measures studies where the binary outcome and exposure are assessed on multiple occasions and within-subject pooling is conducted for exposure assessment. Simulation studies illustrate the performance of the proposed approaches along with their computational feasibility using widely available software. We apply the methods to investigate genedisease association in a population-based case-control study of colorectal cancer. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Lyles, Robert H.; Tang, Li; Lin, Ji] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Zhang, Zhiwei] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Mukherjee, Bhramar] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. RP Lyles, RH (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM rlyles@sph.emory.edu FU Long-Range Research Initiative of the American Chemistry Council (ACC); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health; National Institute of Nursing Research [1RC4NR012527-01]; National Institute of Environmental Health Sciences [5R01ES012458-07]; National Cancer Institute in support of the MECC Study [1R01CA81488]; National Institutes of Health, Center for Research Resources [UL 1 RR025008]; NICHD/ACC FX This research was partially supported by the Long-Range Research Initiative of the American Chemistry Council (ACC) and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health. Other sources of support include an RC4 grant through the National Institute of Nursing Research (1RC4NR012527-01), an R01 from the National Institute of Environmental Health Sciences (5R01ES012458-07), an RO1 from the National Cancer Institute in support of the MECC Study (1R01CA81488), and a PHS grant (UL 1 RR025008) from the Clinical and Translational Science Award Program, National Institutes of Health, Center for Research Resources. Views expressed are those of the authors and not necessarily of the funding sponsors. The authors gratefully acknowledge the MECC principal investigators Gad Rennert and Stephen B. Gruber and all MECC participants for providing the data resource. We thank each member of the NICHD/ACC-sponsored Methods Development for Biomarkers Working Group, and particularly its organizers (Drs. Enrique Schisterman and Paul Albert). NR 23 TC 7 Z9 7 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2485 EP 2497 DI 10.1002/sim.4426 PG 13 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 003UK UT WOS:000308636700009 PM 22415630 ER PT J AU Vexler, A Tsai, WM Malinovsky, Y AF Vexler, Albert Tsai, Wan-Min Malinovsky, Yaakov TI Estimation and testing based on data subject to measurement errors: from parametric to non-parametric likelihood methods SO STATISTICS IN MEDICINE LA English DT Article DE cost-efficient sampling; empirical likelihood; hybrid design; likelihood; measurement error; pooling design; repeated measures ID ROC CURVE ANALYSIS; EMPIRICAL LIKELIHOOD; POOLED ASSESSMENTS; DIAGNOSTIC-ACCURACY; REGRESSION-MODELS; INCOMPLETE DATA; BIOMARKERS; BIOSPECIMENS; PNEUMONIA; DESIGN AB Measurement error (ME) problems can cause bias or inconsistency of statistical inferences. When investigators are unable to obtain correct measurements of biological assays, special techniques to quantify MEs need to be applied. Sampling based on repeated measurements is a common strategy to allow for ME. This method has been well addressed in the literature under parametric assumptions. The approach with repeated measures data may not be applicable when the replications are complicated because of cost and/or time concerns. Pooling designs have been proposed as cost-efficient sampling procedures that can assist to provide correct statistical operations based on data subject to ME. We demonstrate that a mixture of both pooled and unpooled data (a hybrid pooledunpooled design) can support very efficient estimation and testing in the presence of ME. Nonparametric techniques have not been well investigated to analyze repeated measures data or pooled data subject to ME. We propose and examine both the parametric and empirical likelihood methodologies for data subject to ME. We conclude that the likelihood methods based on the hybrid samples are very efficient and powerful. The results of an extensive Monte Carlo study support our conclusions. Real data examples demonstrate the efficiency of the proposed methods in practice. Copyright (c) 2011 John Wiley & Sons, Ltd. C1 [Vexler, Albert; Tsai, Wan-Min] SUNY Buffalo, Dept Biostat, Buffalo, NY 14214 USA. [Malinovsky, Yaakov] NICHHD, Div Epidemiol Stat & Prevent Res, NIH DHHS, Bethesda, MD 20892 USA. RP Vexler, A (reprint author), SUNY Buffalo, Dept Biostat, Buffalo, NY 14214 USA. EM avexler@buffalo.edu FU Long-Range Research Initiative of the American Chemistry Council; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX The authors thank Dr. Enrique F. Schisterman who inspired and motivated us to write this article and gave his valuable suggestions. This research was partially supported by the Long-Range Research Initiative of the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 33 TC 7 Z9 7 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2498 EP 2512 DI 10.1002/sim.4304 PG 15 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 003UK UT WOS:000308636700010 PM 21805485 ER PT J AU Schisterman, EF Albert, PS AF Schisterman, Enrique F. Albert, Paul S. TI The biomarker revolution SO STATISTICS IN MEDICINE LA English DT Article ID ROC CURVE ANALYSIS C1 [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [Z99 HD999999, ZIA HD008761-11] NR 11 TC 1 Z9 1 U1 0 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 SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2513 EP 2515 DI 10.1002/sim.5499 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 003UK UT WOS:000308636700011 PM 22969023 ER PT J AU Chen, JB Kang, GL VanderWeele, T Zhang, CL Mukherjee, B AF Chen, Jinbo Kang, Guolian VanderWeele, Tyler Zhang, Cuilin Mukherjee, Bhramar TI Efficient designs of gene-environment interaction studies: implications of Hardy-Weinberg equilibrium and gene-environment independence SO STATISTICS IN MEDICINE LA English DT Article DE gene-environment interaction; gene-environment independence; Hardy-Weinberg equilibrium; retrospective maximum likelihood; two-stage design ID ASSOCIATIONS; EXPOSURE; MODELS AB It is important to investigate whether genetic susceptibility variants exercise the same effects in populations that are differentially exposed to environmental risk factors. Here, we assess the power of four two-stage case-control design strategies for assessing multiplicative geneenvironment (GE) interactions or for assessing genetic or environmental effects in the presence of GE interactions. We considered a di-allelic single nucleotide polymorphism G and a binary environmental variable E under the constraints of GE independence and HardyWeinberg equilibrium and used the Wald statistic for all tests. We concluded that (i) for testing GE interactions or genetic effects in the presence of GE interactions when data for E are fully available, it is preferable to ascertain data for G in a subsample of cases with similar numbers of exposed and unexposed and a random subsample of controls; and (ii) for testing GE interactions or environmental effects in the presence of GE interactions when data for G are fully available, it is preferable to ascertain data for E in a subsample of cases that has similar numbers for each genotype and a random subsample of controls. In addition, supplementing external control data to an existing case-control sample leads to improved power for assessing effects of G or E in the presence of GE interactions. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Chen, Jinbo; Kang, Guolian] Univ Penn, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. [VanderWeele, Tyler] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02115 USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Mukherjee, Bhramar] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Chen, JB (reprint author), Univ Penn, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. EM jinboche@mail.med.upenn.edu FU Long-Range Research Initiative of the American Chemistry Council [ES016626, CA128071]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by ES016626 and CA128071 the Long-Range Research Initiative of the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 12 TC 8 Z9 8 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2516 EP 2530 DI 10.1002/sim.4460 PG 15 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 003UK UT WOS:000308636700012 PM 22362617 ER PT J AU Fan, RZ Albert, PS Schisterman, EF AF Fan, Ruzong Albert, Paul S. Schisterman, Enrique F. TI A discussion of gene-gene and gene-environment interactions and longitudinal genetic analysis of complex traits SO STATISTICS IN MEDICINE LA English DT Article ID MULTIFACTOR-DIMENSIONALITY REDUCTION; RHEUMATOID-ARTHRITIS; VARIANCE-COMPONENTS; MATHEMATICAL-THEORY; LINKAGE ANALYSIS; TEMPORAL TRENDS; BLOOD-PRESSURE; EPISTASIS; DISEASES; SUSCEPTIBILITY C1 [Fan, Ruzong; Albert, Paul S.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent, NIH, Rockville, MD 20852 USA. RP Fan, RZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent, NIH, 6100 Execut Blvd,Room 7B05,MSC 7510, Rockville, MD 20852 USA. EM fanr@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Long-Range Research Initiative of the American Chemistry Council FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and by the Long-Range Research Initiative of the American Chemistry Council. NR 28 TC 2 Z9 2 U1 0 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 SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2565 EP 2568 DI 10.1002/sim.5495 PG 4 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 003UK UT WOS:000308636700015 PM 22969024 ER PT J AU Louis, GMB Sundaram, R AF Louis, Germaine M. Buck Sundaram, Rajeshwari TI Exposome: time for transformative research SO STATISTICS IN MEDICINE LA English DT Article ID DYSGENESIS SYNDROME; PROSPECTIVE COHORT; LIFE; DISEASE; EXPOSURE; HEALTH; CANCER; EPIDEMIOLOGY; ENVIRONMENT; CHALLENGES C1 [Louis, Germaine M. Buck; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 NR 38 TC 24 Z9 24 U1 3 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD SEP 28 PY 2012 VL 31 IS 22 SI SI BP 2569 EP 2575 DI 10.1002/sim.5496 PG 7 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 003UK UT WOS:000308636700016 ER PT J AU Brock, KE Ke, L Gridley, G Chiu, BCH Ershow, AG Lynch, CF Graubard, BI Cantor, KP AF Brock, Kaye E. Ke, Liang Gridley, Gloria Chiu, Brian C. -H. Ershow, Abby G. Lynch, Charles F. Graubard, Barry I. Cantor, Kenneth P. TI Fruit, vegetables, fibre and micronutrients and risk of US renal cell carcinoma SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Renal cell carcinoma; Vegetable fibre intake; beta-Cryptoxanthin; Cruciferous vegetables; Fruit; Non-smokers; Elderly ID CANCER-RISK; KIDNEY CANCER; UNITED-STATES; LIPID-PEROXIDATION; POOLED ANALYSIS; CENTRAL-EUROPE; SWEDISH WOMEN; ENERGY INTAKE; DIETARY-FAT; OBESITY AB The association between renal cell cancer (RCC) and intake of fruit, vegetables and nutrients was examined in a population-based case-control study of 323 cases and 1827 controls; dietary intake was obtained using a mailed questionnaire. Cancer risks were estimated by OR and 95% CI, adjusting for age, sex, smoking, obesity, hypertension, proxy status, alcohol consumption and dietary fat intake and energy. Intake of vegetables was associated with a decreased risk of RCC (OR 0.5; 95% CI 0.3, 0.7; P-trend = 0.002), (top compared to the bottom quartile of intake). When intake of individual nutrients was investigated, vegetable fibre intake was associated with decreased risks (OR 0.4; 95% CI 0.2, 0.6; P<0.001), but this was not the case with fruit fibre (OR 0.7; 95% CI 0.4, 1.1) or grain fibre (OR 1.0; 95% CI 0.6, 1.5). beta-Cryptoxanthin and lycopene were also associated with decreased risks, but when both were included in a mutually adjusted backwards stepwise regression model, only beta-cryptoxanthin remained significant (OR 0.5; 95% CI 0.3, 0.8). When other micronutrients and types of fibre were investigated together, only vegetable fibre and beta-cryptoxanthin had significant trends (P<0. 01) (OR 0.6; 95% CI 0.3, 0.9) (OR 0.5; 95% CI 0.3, 0.9), respectively. These findings were stronger in those aged over 65 years (P-interaction = 0.001). Among non-smokers, low intake of cruciferous vegetables and fruit fibre was also associated with increased risk of RCC (P-interaction = 0.03); similar inverse associations were found for beta-cryptoxanthin, lycopene and vitamin C. When nutrients were mutually adjusted by backwards regression in these subgroups, only beta-cryptoxanthin remained associated with lower RCC risk. These findings deserve further investigation in ongoing prospective studies when sample size becomes sufficient. C1 [Brock, Kaye E.; Ke, Liang] Univ Sydney, Fac Hlth Sci, Dept Behav & Social Sci, Sydney, NSW 2006, Australia. [Gridley, Gloria; Graubard, Barry I.; Cantor, Kenneth P.] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Chiu, Brian C. -H.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ershow, Abby G.] NHLBI, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Cantor, Kenneth P.] KP Cantor Environm LLC, Silver Spring, MD USA. RP Brock, KE (reprint author), Univ Sydney, Fac Hlth Sci, Dept Behav & Social Sci, Sydney, NSW 2006, Australia. EM kaye.brock@sydney.edu.au FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Sydney University, NSW, Australia FX The present research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and Sydney University, NSW, Australia Sabbatical Program for K. E. B. In addition, we acknowledge the invaluable support of David Check, research assistant, Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. Contributions of the co-authors were as follows: K. P. C. and C. F. L. designed the study and had overall responsibility for the project; A. G. E. designed the collection of dietary information; C. F. L. was responsible for overseeing the subject selection and data collection; G. G., L. K., B. I. G., K. E. B. and B. C.-H. C. conducted the data analysis; K. E. B., L. K. and B. I. G. drafted the paper; and all authors contributed to the final completion of the manuscript. None of the authors had any conflicts of interest (personal, commercial, political, academic or financial). NR 59 TC 13 Z9 13 U1 0 U2 5 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD SEP 28 PY 2012 VL 108 IS 6 BP 1077 EP 1085 DI 10.1017/S0007114511006489 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 003BO UT WOS:000308583400016 PM 22186835 ER PT J AU Na, HJ Hamilton, RG Klion, AD Bochner, BS AF Na, Ho Jeong Hamilton, Robert G. Klion, Amy D. Bochner, Bruce S. TI Biomarkers of eosinophil involvement in allergic and eosinophilic diseases: Review of phenotypic and serum markers including a novel assay to quantify levels of soluble Siglec-8 SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Eosinophil; Granule proteins; ELISA; Soluble Siglec-8 ID ANTI-IL-5 MEPOLIZUMAB THERAPY; ALTERNATIVELY ACTIVATED MACROPHAGES; CHURG-STRAUSS-SYNDROME; BLOOD EOSINOPHILS; HYPEREOSINOPHILIC SYNDROME; CATIONIC PROTEIN; MAST-CELLS; BETA(1)-INTEGRIN ACTIVATION; SURFACE EXPRESSION; ATOPIC ASTHMATICS AB There remains considerable controversy in the management of eosinophilic disorders, mainly due to a paucity of information regarding the clinical interpretation of total blood eosinophil counts versus surface activation markers versus eosinophil-derived or eosinophil-influencing mediator levels. Regrettably, few tests have been validated that define a unique clinical or prognostic phenotype that is more useful than simply monitoring total blood eosinophil counts. In this manuscript, phenotypic (cell surface) markers, along with serum and tissue-based markers that have been examined in the context of disease activity, are reviewed. We also report the development of a novel assay for detecting soluble Siglec-8 (sSiglec-8), a protein likely derived largely from eosinophils, as a potential serum biomarker. The assay consists of a competitive ELISA using a recombinant Siglec-8-Fc fusion protein. The goal of this preliminary study was to determine if sSiglec-8 is a useful biomarker that differentiates among patients with various eosinophil-associated diseases. In the final analysis, it is fair to say that further research is sorely needed to fully understand and validate the utility of various biomarkers, including sSiglec-8, before their use in clinical practice can be recommended with confidence. (C) 2012 Elsevier B.V. All rights reserved. C1 [Na, Ho Jeong; Hamilton, Robert G.; Bochner, Bruce S.] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA. [Hamilton, Robert G.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bochner, BS (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA. EM bbochner@jhmi.edu OI Klion, Amy/0000-0002-4986-5326 FU National Institutes of Health [AI72265]; Johns Hopkins University; Division of Intramural Research, NIAID, NIH FX We thank Sherry Hudson for technical assistance. This work was supported by grant AI72265 from the National Institutes of Health. Dr. Bochner received support as a Cosner Scholar in Translational Research from Johns Hopkins University. This work was also funded in part by the Division of Intramural Research, NIAID, NIH. NR 74 TC 10 Z9 10 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD SEP 28 PY 2012 VL 383 IS 1-2 SI SI BP 39 EP 46 DI 10.1016/j.jim.2012.05.017 PG 8 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 996BU UT WOS:000308059800005 PM 22683541 ER PT J AU Jacobsohn, DA Kurland, BF Pidala, J Inamoto, Y Chai, X Palmer, JM Arai, S Arora, M Jagasia, M Cutler, C Weisdorf, D Martin, PJ Pavletic, SZ Vogelsang, G Lee, SJ Flowers, MED AF Jacobsohn, David A. Kurland, Brenda F. Pidala, Joseph Inamoto, Yoshihiro Chai, Xiaoyu Palmer, Jeanne M. Arai, Sally Arora, Mukta Jagasia, Madan Cutler, Corey Weisdorf, Daniel Martin, Paul J. Pavletic, Steven Z. Vogelsang, Georgia Lee, Stephanie J. Flowers, Mary E. D. TI Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; MARROW-TRANSPLANTATION; THERAPEUTIC RESPONSE; CLINICAL-TRIALS; BONE-MARROW; VALIDATION; CRITERIA; RELAPSE AB There are no validated criteria to measure skin response in chronic GVHD. In a prospectively assembled, multicenter cohort of patients with chronic GVHD (N = 458), we looked for correlation of change in several different scales recommended by the National Institutes of Health (NIH) Consensus with clinician and patient perception of change and overall survival. Of the clinician scales, the NIH composite 0-3 skin score was the only one that correlated with both clinician and patient perception of improvement or worsening. Of the patient-reported scales, the skin subscale of the Lee Symptom Scale was the only one that correlated with both clinician and patient perception of improvement or worsening. At study entry, NIH skin score 3 and Lee skin symptom score > 15 were both associated with worse overall survival. Worsening of NIH skin score at 6 months was associated with worse overall survival. Improvement in the Lee skin symptom score at 6 months was associated with improved overall survival. Our findings support the use of the NIH composite 0-3 skin score and the Lee skin symptom score as simple and sensitive measures to evaluate skin involvement in clinical trials as well as in the clinical monitoring of patients with cutaneous chronic GVHD. (Blood. 2012; 120(13):2545-2552) C1 [Kurland, Brenda F.; Inamoto, Yoshihiro; Chai, Xiaoyu; Martin, Paul J.; Lee, Stephanie J.; Flowers, Mary E. D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Jacobsohn, David A.] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Palmer, Jeanne M.] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Arai, Sally] Stanford Univ, Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Arora, Mukta; Weisdorf, Daniel] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pavletic, Steven Z.] NCI, NIH, Bethesda, MD 20892 USA. [Vogelsang, Georgia] Johns Hopkins Univ Hosp, Dept Oncol, Baltimore, MD 21287 USA. RP Flowers, MED (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-290, Seattle, WA 98109 USA. EM mflowers@fhcrc.org OI Kurland, Brenda/0000-0002-5669-0595 FU National Institutes of Health, Department of Health and Human Services [CA118953, CA163438]; National Cancer Institute FX This work was supported by grants CA118953 and CA163438 from the National Institutes of Health, Department of Health and Human Services and the National Cancer Institute. NR 22 TC 36 Z9 37 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 SEP 27 PY 2012 VL 120 IS 13 BP 2545 EP 2552 DI 10.1182/blood-2012-04-424135 PG 8 WC Hematology SC Hematology GA 044JP UT WOS:000311615800008 PM 22773386 ER PT J AU Cimbro, R Vassena, L Arthos, J Cicala, C Kehrl, JH Park, C Sereti, I Lederman, MM Fauci, AS Lusso, P AF Cimbro, Raffaello Vassena, Lia Arthos, James Cicala, Claudia Kehrl, John H. Park, Chung Sereti, Irini Lederman, Michael M. Fauci, Anthony S. Lusso, Paolo TI IL-7 induces expression and activation of integrin alpha 4 beta 7 promoting naive T-cell homing to the intestinal mucosa SO BLOOD LA English DT Article ID RHESUS MACAQUES; RETINOIC ACID; IN-VIVO; MEMORY; HOMEOSTASIS; EXPANSION; INTERLEUKIN-7; PROLIFERATION; CD4(+); CD8(+) AB Interleukin-7 (IL-7) is a nonredundant cytokine that plays a critical role in T-cell homeostasis and promotes immunologic reconstitution in lymphopenic hosts. Here, we show that IL-7, at doses that reflect suprahomeostatic concentrations achieved in lymphopenic hosts, is a potent and selective inducer of the guthoming integrin alpha 4 beta 7 in human T cells, as documented both ex vivo and in vivo in patients enrolled in a clinical trial of IL-7 treatment. Induction of alpha 4 beta 7 by IL-7 occurs primarily in naive T cells and is associated with functional activation of the integrin, as indicated by increased binding activity for the specific alpha 4 beta 7 ligand, MAdCAM-1. The physiologic relevance of these findings was validated by the preferential homing of IL-7-treated naive human T cells to the intestinal compartment in humanized NOD/SCID/IL-2 receptor-gamma(null) (NSG) mice. We also show that IL-7 triggers a peculiar activation program in naive T cells, characterized by the acquisition of memory-like phenotypic features and proliferation uncoupled from expression of classic T-cell activation markers. These findings provide a mechanism for the transient in vivo depletion of circulating T cells after IL-7 administration and suggest that intestinal homing and memory-like conversion of naive T cells are critical steps in the IL-7-driven immunologic reconstitution of lymphopenic hosts. (Blood. 2012; 120(13):2610-2619) C1 [Cimbro, Raffaello; Vassena, Lia; Arthos, James; Cicala, Claudia; Kehrl, John H.; Park, Chung; Sereti, Irini; Fauci, Anthony S.; Lusso, Paolo] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Lederman, Michael M.] Case Western Reserve Univ, Ctr AIDS Res, Univ Hosp Cleveland, Cleveland, OH 44106 USA. RP Lusso, P (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 6A11, Bethesda, MD 20892 USA. EM plusso@niaid.nih.gov OI Cimbro, Raffaello/0000-0002-6251-5160 FU National Institute of Allergy and Infectious Diseases, NIH; AIDS Clinical Trials Group [ACTG5214]; NIH [AI 068636, AI-069501] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. The clinical trial ACTG5214 was sponsored by the AIDS Clinical Trials Group and funded by the NIH (grants AI 068636 and AI-069501). NR 36 TC 25 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 SEP 27 PY 2012 VL 120 IS 13 BP 2610 EP 2619 DI 10.1182/blood-2012-06-434779 PG 10 WC Hematology SC Hematology GA 044JP UT WOS:000311615800015 PM 22896005 ER PT J AU Lingwood, D McTamney, PM Yassine, HM Whittle, JRR Guo, XT Boyington, JC Wei, CJ Nabel, GJ AF Lingwood, Daniel McTamney, Patrick M. Yassine, Hadi M. Whittle, James R. R. Guo, Xiaoti Boyington, Jeffrey C. Wei, Chih-Jen Nabel, Gary J. TI Structural and genetic basis for development of broadly neutralizing influenza antibodies SO NATURE LA English DT Article ID CELL ANTIGEN RECEPTOR; VIRUS; SPECIFICITY; VACCINATION; ACTIVATION; INDUCTION; LYMPHOMAS; IMMUNITY; DENSITY; HIV-1 AB Influenza viruses take a yearly toll on human life despite efforts to contain them with seasonal vaccines. These viruses evade human immunity through the evolution of variants that resist neutralization. The identification of antibodies that recognize invariant structures on the influenza haemagglutinin (HA) protein have invigorated efforts to develop universal influenza vaccines. Specifically, antibodies to the highly conserved stem region of HA neutralize diverse viral subtypes. These antibodies largely derive from a specific antibody gene, heavy-chain variable region IGHV1-69, after limited affinity maturation from their germline ancestors(1,2), but how HA stimulates naive B cells to mature and induce protective immunity is unknown. To address this question, we analysed the structural and genetic basis for their engagement and maturation into broadly neutralizing antibodies. Here we show that the germline-encoded precursors of these antibodies act as functional B-cell antigen receptors (BCRs) that initiate subsequent affinity maturation. Neither the germline precursor of a prototypic antibody, CR6261 (ref. 3), nor those of two other natural human IGHV1-69 antibodies, bound HA as soluble immunoglobulin-G(IgG). However, all three IGHV1-69 precursors engaged HA when the antibody was expressed as cell surface IgM. HA triggered BCR-associated tyrosine kinase signalling by germline transmembrane IgM. Recognition and virus neutralization was dependent solely on the heavy chain, and affinity maturation of CR6261 required only seven amino acids in the complementarity-determining region (CDR) H1 and framework region 3 (FR3) to restore full activity. These findings provide insight into the initial events that lead to the generation of broadly neutralizing antibodies to influenza, informing the rational design of vaccines to elicit such antibodies and providing a model relevant to other infectious diseases, including human immunodeficiency virus/AIDS. The data further suggest that selected immunoglobulin genes recognize specific protein structural 'patterns' that provide a substrate for further affinity maturation. C1 [Lingwood, Daniel; McTamney, Patrick M.; Yassine, Hadi M.; Whittle, James R. R.; Guo, Xiaoti; Boyington, Jeffrey C.; Wei, Chih-Jen; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gnabel@nih.gov RI Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health FX We thank N. Longo for help with JOINSOLVER analysis, Z.-Y. Yang for the design of membrane-bound IgM antibody, and X. Chen for technical support. We also thank A. Tislerics for manuscript preparation, B. Hartman and J. Farrar for preparation of figures, members of the G. J. N. laboratory and P. Kwong for advice and discussions. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health. NR 31 TC 86 Z9 87 U1 3 U2 48 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 27 PY 2012 VL 489 IS 7417 BP 566 EP + DI 10.1038/nature11371 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 046RG UT WOS:000311781500004 PM 22932267 ER PT J AU Beck, ET He, J Nelson, MI Bose, ME Fan, J Kumar, S Henrickson, KJ AF Beck, Eric T. He, Jie Nelson, Martha I. Bose, Michael E. Fan, Jiang Kumar, Swati Henrickson, Kelly J. TI Genome Sequencing and Phylogenetic Analysis of 39 Human Parainfluenza Virus Type 1 Strains Isolated from 1997-2010 SO PLOS ONE LA English DT Article ID HEMAGGLUTININ-NEURAMINIDASE GLYCOPROTEIN; RESPIRATORY SYNCYTIAL VIRUS; POLYMERASE-CHAIN-REACTION; NEWCASTLE-DISEASE VIRUS; SENDAI-VIRUS; RECOMBINANT SEQUENCES; MOLECULAR EVOLUTION; YOUNG-CHILDREN; GENE; IDENTIFICATION AB Thirty-nine human parainfluenza type 1 (HPIV-1) genomes were sequenced from samples collected in Milwaukee, Wisconsin from 1997-2010. Following sequencing, phylogenetic analyses of these sequences plus any publicly available HPIV-1 sequences (from GenBank) were performed. Phylogenetic analysis of the whole genomes, as well as individual genes, revealed that the current HPIV-1 viruses group into three different clades. Previous evolutionary studies of HPIV-1 in Milwaukee revealed that there were two genotypes of HPIV-1 co-circulating in 1991 (previously described as HPIV-1 genotypes C and D). The current study reveals that there are still two different HPIV-1 viruses co-circulating in Milwaukee; however, both groups of HPIV-1 viruses are derived from genotype C indicating that genotype D may no longer be in circulation in Milwaukee. Analyses of genetic diversity indicate that while most of the genome is under purifying selection some regions of the genome are more tolerant of mutation. In the 40 HPIV-1 genomes sequenced in this study, the nucleotide sequence of the L gene is the most conserved while the sequence of the P gene is the most variable. Over the entire protein coding region of the genome, 81 variable amino acid residues were observed and as with nucleotide diversity, the P protein seemed to be the most tolerant of mutation (and contains the greatest proportion of non-synonymous to synonymous substitutions) while the M protein appears to be the least tolerant of amino acid substitution. C1 [Beck, Eric T.; He, Jie; Bose, Michael E.; Fan, Jiang; Kumar, Swati; Henrickson, Kelly J.] Med Coll Wisconsin, Dept Pediat, Midwest Resp Virus Program, Milwaukee, WI 53226 USA. [Beck, Eric T.; He, Jie; Bose, Michael E.; Fan, Jiang; Kumar, Swati; Henrickson, Kelly J.] Childrens Hosp Wisconsin, Childrens Res Inst, Milwaukee, WI 53201 USA. [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Henrickson, KJ (reprint author), Med Coll Wisconsin, Dept Pediat, Midwest Resp Virus Program, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM Khenrick@mcw.edu FU National Institutes of Health [NIAID U01-AI077988, NIAID U01-AI070428]; Midwest Respiratory Virus Program; Department of Pediatrics; Medical College of Wisconsin FX This work was supported in part by grants from the National Institutes of Health (NIAID U01-AI077988 and NIAID U01-AI070428) with additional funding provided by the Midwest Respiratory Virus Program; Department of Pediatrics; Medical College of Wisconsin. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 7 Z9 7 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 27 PY 2012 VL 7 IS 9 AR e46048 DI 10.1371/journal.pone.0046048 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KQ UT WOS:000309517500058 PM 23029382 ER PT J AU Bliss, LA Sams, MR Deep-Soboslay, A Ren-Patterson, R Jaffe, AE Chenoweth, JG Jaishankar, A Kleinman, JE Hyde, TM AF Bliss, Lindsay A. Sams, Malik R. Deep-Soboslay, Amy Ren-Patterson, Renee Jaffe, Andrew E. Chenoweth, Josh G. Jaishankar, Amritha Kleinman, Joel E. Hyde, Thomas M. TI Use of Postmortem Human Dura Mater and Scalp for Deriving Human Fibroblast Cultures SO PLOS ONE LA English DT Article ID PLURIPOTENT STEM-CELLS; IN-VITRO; IPS CELLS; EXPRESSION; DISORDERS; INDUCTION; TIME AB Fibroblasts can be collected from deceased individuals, grown in culture, reprogrammed into induced pluripotent stem cells (iPSCs), and then differentiated into a multitude of cell types, including neurons. Past studies have generated iPSCs from somatic cell biopsies from either animal or human subjects. Previously, fibroblasts have only been successfully cultured from postmortem human skin in two studies. Here we present data on fibroblast cell cultures generated from 146 scalp and/or 53 dura mater samples from 146 postmortem human brain donors. In our overall sample, the odds of successful dural culture was almost two-fold compared with scalp (OR = 1.95, 95% CI: [1.01, 3.9], p = 0.047). Using a paired design within subjects for whom both tissues were available for culture (n = 53), the odds of success for culture in dura was 16-fold as compared to scalp (OR = 16.0, 95% CI: [2.1-120.6], p = 0.0007). Unattended death, tissue donation source, longer postmortem interval (PMI), and higher body mass index (BMI) were associated with unsuccessful culture in scalp (all p, 0.05), but not in dura. While scalp cells proliferated more and grew more rapidly than dura cells [F (1, 46) = 12.94, p, 0.008], both tissues could be generated and maintained as fibroblast cell lines. Using a random sample of four cases, we found that both postmortem scalp and dura could be successfully reprogrammed into iPSC lines. Our study demonstrates that postmortem dura mater, and to a lesser extent, scalp, are viable sources of living fibroblasts for culture that can be used to generate iPSCs. These tissues may be accessible through existing brain tissue collections, which is critical for studying disorders such as neuropsychiatric diseases. C1 [Jaffe, Andrew E.; Chenoweth, Josh G.; Jaishankar, Amritha; Hyde, Thomas M.] Lieber Inst Brain Dev, Baltimore, MD USA. [Bliss, Lindsay A.; Sams, Malik R.; Deep-Soboslay, Amy; Ren-Patterson, Renee; Kleinman, Joel E.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Div Intramural Res Programs,NIH, Bethesda, MD 20892 USA. RP Hyde, TM (reprint author), Lieber Inst Brain Dev, Johns Hopkins Med Campus, Baltimore, MD USA. EM hydetm@aol.com RI Jaffe, Andrew/L-3089-2016 OI Jaffe, Andrew/0000-0001-6886-1454 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health FX This work was supported by the Intramural Research Program at the National Institute of Mental Health, 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 15 TC 7 Z9 7 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 27 PY 2012 VL 7 IS 9 AR e45282 DI 10.1371/journal.pone.0045282 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KQ UT WOS:000309517500025 PM 23028905 ER PT J AU Yan, L Gao, Y Zhang, Y Tildesley, M Liu, LQ Zhang, Y Wen, LY Wang, W Li, XD Hu, Y Bai, T Wang, M Zeng, YH Wang, DM Wang, XJ Lan, Y Wang, SW Shu, YL AF Yan, Lei Gao, Yan Zhang, Yong Tildesley, Michael Liu, Liqi Zhang, Ye Wen, Leying Wang, Wei Li, Xiaodan Hu, Ying Bai, Tian Wang, Min Zeng, Yuhong Wang, Dingming Wang, Xianjun Lan, Yu Wang, Shiwen Shu, Yuelong TI Epidemiological and Virological Characteristics of Pandemic Influenza A (H1N1) School Outbreaks in China in 2009 SO PLOS ONE LA English DT Article ID INFECTION; VIRUS; CALIFORNIA; ENGLAND; ADULT; DEATH AB Background: During the 2009 pandemic influenza H1N1 (2009) virus (pH1N1) outbreak, school students were at an increased risk of infection by the pH1N1 virus. However, the estimation of the attack rate showed significant variability. Methods: Two school outbreaks were investigated in this study. A questionnaire was designed to collect information by interview. Throat samples were collected from all the subjects in this study 6 times and sero samples 3 times to confirm the infection and to determine viral shedding. Data analysis was performed using the software STATA 9.0. Findings: The attack rate of the pH1N1 outbreak was 58.3% for the primary school, and 52.9% for the middle school. The asymptomatic infection rates of the two schools were 35.8% and 37.6% respectively. Peak virus shedding occurred on the day of ARI symptoms onset, followed by a steady decrease over subsequent days (p = 0.026). No difference was found either in viral shedding or HI titer between the symptomatic and the asymptomatic infectious groups. Conclusions: School children were found to be at a high risk of infection by the novel virus. This may be because of a heightened risk of transmission owing to increased mixing at boarding school, or a lack of immunity owing to socioeconomic status. We conclude that asymptomatically infectious cases may play an important role in transmission of the pH1N1 virus. C1 [Yan, Lei; Gao, Yan; Liu, Liqi; Zhang, Ye; Wen, Leying; Wang, Wei; Li, Xiaodan; Hu, Ying; Bai, Tian; Wang, Min; Zeng, Yuhong; Lan, Yu; Wang, Shiwen; Shu, Yuelong] Chinese Ctr Dis Control & Prevent, State Key Lab Mol Virol & Genet Engn, Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China. [Zhang, Yong] Beijing Normal Univ, Sch Math Sci, Beijing 100875, Peoples R China. [Tildesley, Michael] Univ Warwick, Ctr Complex Sci, Coventry CV4 7AL, W Midlands, England. [Tildesley, Michael] US Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD USA. [Wang, Dingming] Ctr Dis Control & Prevent Guizhou Prov, Guiyang, Peoples R China. [Wang, Xianjun] Ctr Dis Control & Prevent Shandong Prov, Jinan, Peoples R China. RP Wang, SW (reprint author), Chinese Ctr Dis Control & Prevent, State Key Lab Mol Virol & Genet Engn, Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China. EM wangshiwencdc@163.com; yshu@cnic.org.cn FU National Institutes of Health (NIH) Fund for the Special Program for Prevention and Control of Infectious Diseases [2008ZX10004-012]; NIH/NIAID [5-U54-AI-057157-08]; Wellcome Trust; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This study was supported by National Institutes of Health (NIH) Fund for the Special Program for Prevention and Control of Infectious Diseases (Grant No. 2008ZX10004-012), and NIH/NIAID Grant 5-U54-AI-057157-08 (Epidemiology and Molecular Mechanism of Highly Pathogenic Avian Influenza H5N1 and Pandemic Influenza H1N1). MT is supported by the Wellcome Trust, the RAPIDD program of the Science and 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 29 TC 2 Z9 2 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 27 PY 2012 VL 7 IS 9 AR e45898 DI 10.1371/journal.pone.0045898 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KQ UT WOS:000309517500045 PM 23029300 ER PT J AU Wein, AN Williams, BN Liu, SH Ermolinsky, B Provenzano, D Abagyan, R Orry, A Leppla, SH Peredelchuk, M AF Wein, Alexander N. Williams, Brian N. Liu, Shihui Ermolinsky, Boris Provenzano, Daniele Abagyan, Ruben Orry, Andrew Leppla, Stephen H. Peredelchuk, Michael TI Small Molecule Inhibitors of Bacillus anthracis Protective Antigen Proteolytic Activation and Oligomerization SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CAPILLARY MORPHOGENESIS PROTEIN-2; LETHAL FACTOR; EDEMA FACTOR; MONOCLONAL-ANTIBODIES; FURIN INHIBITORS; TOXIN INHIBITOR; N-TERMINUS; IN-VIVO; RECEPTOR; BINDING AB Protective antigen (PA), lethal factor, and edema factor, the protein toxins of Bacillus anthracis, are among its most important virulence factors and play a key role in infection. We performed a virtual ligand screen of a library of 10000 members to identify compounds predicted to bind to PA and prevent its oligomerization. Four of these compounds slowed PA association in a FRET-based oligomerization assay, and two of those protected cells from intoxication at concentrations of 1-10 mu M. Exploration of the protective mechanism by Western blot showed decreased SDS-resistant PA oligomer on cells and, surprisingly, decreased amounts of activated PA. In vitro assays showed that one of the inhibitors blocked furin-mediated cleavage of PA, apparently through its binding to the PA substrate. Thus, we have identified inhibitors that can independently block both PA's cleavage by furin and its subsequent oligomerization. Lead optimization on these two backbones may yield compounds with high activity and specificity for the anthrax toxins. C1 [Orry, Andrew] MolSoft LLC, San Diego, CA 92121 USA. [Wein, Alexander N.; Williams, Brian N.; Liu, Shihui; Leppla, Stephen H.] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Ermolinsky, Boris; Provenzano, Daniele; Peredelchuk, Michael] Univ Texas Brownsville, Dept Biomed Sci, Brownsville, TX 78520 USA. [Abagyan, Ruben] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. RP Orry, A (reprint author), MolSoft LLC, 11199 Sorrento Valley Rd S209, San Diego, CA 92121 USA. EM andy@molsoft.com; sleppla@niaid.nih.gov; mperedel@gmail.com FU National Institutes of Health, National Institute of Allergy and Infectious Diseases; NIH [MD001091-01] FX Portions of this research were supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. M.P. and D.P. were supported, in part, by NIH grant MD001091-01. We thank Dr. Rodney Tweten for providing the pET vector encoding PA N645C, Rasem Fattah for protein purification, Dr. Iris Lindberg for the gift of furin, Dr. David Fitzgerald for TGF alpha-PE38, and Dr. Clinton E. Leysath for thoughtful discussions. NR 70 TC 6 Z9 6 U1 1 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 SEP 27 PY 2012 VL 55 IS 18 BP 7998 EP 8006 DI 10.1021/jm300804e PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 011GQ UT WOS:000309153500006 PM 22954387 ER PT J AU Tosh, DK Paoletta, S Deflorian, F Phan, K Moss, SM Gao, ZG Jiang, X Jacobson, KA AF Tosh, Dilip K. Paoletta, Silvia Deflorian, Francesca Phan, Khai Moss, Steven M. Gao, Zhan-Guo Jiang, Xiaohui Jacobson, Kenneth A. TI Structural Sweet Spot for A(1) Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PARTIAL EPILEPSY; AGONISTS; DERIVATIVES; LIGANDS; BRAIN; ANTAGONISTS; DISCOVERY; EFFICACY; DRUGS; MODEL AB A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N-6-cycloalkylmethyl 4'-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N-6-dicyclopropylmethyl, K-i = 47.9 nM) as a moderately A(1)AR-selective full agonist. Two stereochemically defined N-6-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A(1)AR selectivity. Nucleoside docking to A(1)AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger "A" forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), and carbon chains of glutamates (EL2) and the smaller subpocket "B" forming contacts between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A(1)AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A(1)AR agonists. Thus, we identified highly restricted regions for substitution around N-6 suitable for an A(1)AR agonist with anticonvulsant activity. C1 [Tosh, Dilip K.; Paoletta, Silvia; Deflorian, Francesca; Phan, Khai; Moss, Steven M.; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Jiang, Xiaohui] NINDS, Anticonvulsant Screening Program, Off Translat Res, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH, NIDDK; NINDS, NIH [HHSN271201100029C] FX We thank Prof. Ray Stevens and Dr. Vsevolod Katrich (Scripps Res. Inst., La Jolla, CA) for helpful discussions, Dr. Noel Whittaker (NIDDK) for mass spectral determinations, and Intramural Research Program of the NIH, NIDDK for support. The in vivo antiseizure studies conducted at the University of Utah were supported by NINDS, NIH Contract No. HHSN271201100029C. NR 63 TC 21 Z9 21 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD SEP 27 PY 2012 VL 55 IS 18 BP 8075 EP 8090 DI 10.1021/jm300965a PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 011GQ UT WOS:000309153500013 PM 22921089 ER PT J AU Hammerman, PS Lawrence, MS Voet, D Jing, R Cibulskis, K Sivachenko, A Stojanov, P McKenna, A Lander, ES Gabriel, S Getz, G Sougnez, C Imielinski, M Helman, E Hernandez, B Pho, NH Meyerson, M Chu, A Chun, HJE Mungall, AJ Pleasance, E Robertson, AG Sipahimalani, P Stoll, D Balasundaram, M Birol, I Butterfield, YSN Chuah, E Coope, RJN Corbett, R Dhalla, N Guin, R Hirst, AC Hirst, M Holt, RA Lee, D Li, HI Mayo, M Moore, RA Mungall, K Nip, KM Olshen, A Schein, JE Slobodan, JR Tam, A Thiessen, N Varhol, R Zeng, T Zhao, Y Jones, SJM Marra, MA Saksena, G Cherniack, AD Schumacher, SE Tabak, B Carter, SL Pho, NH Nguyen, H Onofrio, RC Crenshaw, A Ardlie, K Beroukhim, R Winckler, W Hammerman, PS Getz, G Meyerson, M Protopopov, A Zhang, JH Hadjipanayis, A Lee, S Xi, RB Yang, LX Ren, XJ Zhang, HL Shukla, S Chen, PC Haseley, P Lee, E Chin, L Park, PJ Kucherlapati, R Socci, ND Liang, YP Schultz, N Borsu, L Lash, AE Viale, A Sander, C Ladanyi, M Auman, JT Hoadley, KA Wilkerson, MD Shi, Y Liquori, C Meng, SW Li, L Turman, YJ Topal, MD Tan, DH Waring, S Buda, E Walsh, J Jones, CD Mieczkowski, PA Singh, D Wu, J Gulabani, A Dolina, P Bodenheimer, T Hoyle, AP Simons, JV Soloway, MG Mose, LE Jefferys, SR Balu, S O'Connor, BD Prins, JF Liu, J Chiang, DY Hayes, DN Perou, CM Cope, L Danilova, L Weisenberger, DJ Maglinte, DT Pan, F den Berg, DJ Triche, T Herman, JG Baylin, SB Laird, PW Getz, G Noble, M Voet, D Saksena, G Gehlenborg, N DiCara, D Zhang, JH Zhang, HL Wu, CJ Liu, SY Lawrence, MS Zou, LH Sivachenko, A Lin, P Stojanov, P Jing, R Cho, J Nazaire, MD Robinson, J Thorvaldsdottir, H Mesirov, J Park, PJ Chin, L Schultz, N Sinha, R Ciriello, G Cerami, E Gross, B Jacobsen, A Gao, J Aksoy, BA Weinhold, N Ramirez, R Taylor, BS Antipin, Y Reva, B Shen, RL Mo, Q Seshan, V Paik, PK Ladanyi, M Sander, C Akbani, R Zhang, NX Broom, BM Casasent, T Unruh, A Wakefield, C Cason, RC Baggerly, KA Weinstein, JN Haussler, D Benz, CC Stuart, JM Zhu, JC Szeto, C Scott, GK Yau, C Ng, S Goldstein, T Waltman, P Sokolov, A Ellrott, K Collisson, EA Zerbino, D Wilks, C Ma, S Craft, B Wilkerson, MD Auman, JT Hoadley, KA Du, Y Cabanski, C Walter, V Singh, D Wu, JY Gulabani, A Bodenheimer, T Hoyle, AP Simons, JV Soloway, MG Mose, LE Jefferys, SR Balu, S Marron, JS Liu, Y Wang, K Liu, J Prins, JF Hayes, DN Perou, CM Creighton, CJ Zhang, YQ Travis, WD Rekhtman, N Yi, J Aubry, MC Cheney, R Dacic, S Flieder, D Funkhouser, W Illei, P Myers, J Tsao, MS Penny, R Mallery, D Shelton, T Hatfield, M Morris, S Yena, P Shelton, C Sherman, M Paulauskis, J Meyerson, M Baylin, SB Govindan, R Akbani, R Azodo, I Beer, D Bose, R Byers, LA Carbone, D Chang, LW Chiang, D Chu, A Chun, E Collisson, E Cope, L Creighton, CJ Danilova, L Ding, L Getz, G Hammerman, PS Hayes, DN Hernandez, B Herman, JG Heymach, J Ida, C Imielinski, M Johnson, B Jurisica, I Kaufman, J Kosari, F Kucherlapati, R Kwiatkowski, D Ladanyi, M Lawrence, MS Maher, CA Mungall, A Ng, S Pao, W Peifer, M Penny, R Robertson, G Rusch, V Sander, C Schultz, N Shen, RL Siegfried, J Sinha, R Sivachenko, A Sougnez, C Stoll, D Stuart, J Thomas, RK Tomaszek, S Tsao, MS Travis, WD Vaske, C Weinstein, JN Weisenberger, D Wheeler, D Wigle, DA Wilkerson, MD Wilks, C Yang, P Zhang, JJ Jensen, MA Sfeir, R Kahn, AB Chu, AL Kothiyal, P Wang, Z Snyder, EE Pontius, J Pihl, TD Ayala, B Backus, M Walton, J Baboud, J Berton, DL Nicholls, MC Srinivasan, D Raman, R Girshik, S Kigonya, PA Alonso, S Sanbhadti, RN Barletta, SP Greene, JM Pot, DA Tsao, MS Bandarchi-Chamkhaleh, B Boyd, J Weaver, J Wigle, DA Azodo, IA Tomaszek, SC Aubry, MC Ida, CM Yang, P Kosari, F Brock, MV Rogers, K Rutledge, M Brown, T Lee, B Shin, J Trusty, D Dhir, R Siegfried, JM Potapova, O Fedosenko, KV Nemirovich-Danchenko, E Rusch, V Zakowski, M Iacocca, MV Brown, J Rabeno, B Czerwinski, C Petrelli, N Fan, Z Todaro, N Eckman, J Myers, J Rathmell, WK Thorne, LB Huang, M Boice, L Hill, A Penny, R Mallery, D Curley, E Shelton, C Yena, P Morrison, C Gaudioso, C Bartlett, JS Kodeeswaran, S Zanke, B Sekhon, H David, K Juhl, H Van Le, X Kohl, B Thorp, R Tien, NV Van Bang, N Sussman, H Phu, BD Hajek, R PhiHung, N Khan, KZ Muley, T Shaw, KRM Sheth, M Yang, L Buetow, K Davidsen, T Demchok, JA Eley, G Ferguson, M Dillon, LAL Schaefer, C Guyer, MS Ozenberger, BA Palchik, JD Peterson, J Sofia, HJ Thomson, E Meyerson, M AF Hammerman, Peter S. Lawrence, Michael S. Voet, Douglas Jing, Rui Cibulskis, Kristian Sivachenko, Andrey Stojanov, Petar McKenna, Aaron Lander, Eric S. Gabriel, Stacey Getz, Gad Sougnez, Carrie Imielinski, Marcin Helman, Elena Hernandez, Bryan Pho, Nam H. Meyerson, Matthew Chu, Andy Chun, Hye-Jung E. Mungall, Andrew J. Pleasance, Erin Robertson, A. Gordon Sipahimalani, Payal Stoll, Dominik Balasundaram, Miruna Birol, Inanc Butterfield, Yaron S. N. Chuah, Eric Coope, Robin J. N. Corbett, Richard Dhalla, Noreen Guin, Ranabir Hirst, Anhe Carrie Hirst, Martin Holt, Robert A. Lee, Darlene Li, Haiyan I. Mayo, Michael Moore, Richard A. Mungall, Karen Nip, Ka Ming Olshen, Adam Schein, Jacqueline E. Slobodan, Jared R. Tam, Angela Thiessen, Nina Varhol, Richard Zeng, Thomas Zhao, Yongjun Jones, Steven J. M. Marra, Marco A. Saksena, Gordon Cherniack, Andrew D. Schumacher, Stephen E. Tabak, Barbara Carter, Scott L. Pho, Nam H. Nguyen, Huy Onofrio, Robert C. Crenshaw, Andrew Ardlie, Kristin Beroukhim, Rameen Winckler, Wendy Hammerman, Peter S. Getz, Gad Meyerson, Matthew Protopopov, Alexei Zhang, Jianhua Hadjipanayis, Angela Lee, Semin Xi, Ruibin Yang, Lixing Ren, Xiaojia Zhang, Hailei Shukla, Sachet Chen, Peng-Chieh Haseley, Psalm Lee, Eunjung Chin, Lynda Park, Peter J. Kucherlapati, Raju Socci, Nicholas D. Liang, Yupu Schultz, Nikolaus Borsu, Laetitia Lash, Alex E. Viale, Agnes Sander, Chris Ladanyi, Marc Auman, J. Todd Hoadley, Katherine A. Wilkerson, Matthew D. Shi, Yan Liquori, Christina Meng, Shaowu Li, Ling Turman, Yidi J. Topal, Michael D. Tan, Donghui Waring, Scot Buda, Elizabeth Walsh, Jesse Jones, Corbin D. Mieczkowski, Piotr A. Singh, Darshan Wu, Junyuan Gulabani, Anisha Dolina, Peter Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, Matthew G. Mose, Lisle E. Jefferys, Stuart R. Balu, Saianand O'Connor, Brian D. Prins, Jan F. Liu, Jinze Chiang, Derek Y. Hayes, D. Neil Perou, Charles M. Cope, Leslie Danilova, Ludmila Weisenberger, Daniel J. Maglinte, Dennis T. Pan, Fei Van den Berg, David J. Triche, Timothy Herman, James G. Baylin, Stephen B. Laird, Peter W. Getz, Gad Noble, Michael Voet, Doug Saksena, Gordon Gehlenborg, Nils DiCara, Daniel Zhang, Jinhua Zhang, Hailei Wu, Chang-Jiun Liu, Spring Yingchun Lawrence, Michael S. Zou, Lihua Sivachenko, Andrey Lin, Pei Stojanov, Petar Jing, Rui Cho, Juok Nazaire, Marc-Danie Robinson, Jim Thorvaldsdottir, Helga Mesirov, Jill Park, Peter J. Chin, Lynda Schultz, Nikolaus Sinha, Rileen Ciriello, Giovanni Cerami, Ethan Gross, Benjamin Jacobsen, Anders Gao, Jianjiong Aksoy, B. Arman Weinhold, Nils Ramirez, Ricardo Taylor, Barry S. Antipin, Yevgeniy Reva, Boris Shen, Ronglai Mo, Qianxing Seshan, Venkatraman Paik, Paul K. Ladanyi, Marc Sander, Chris Akbani, Rehan Zhang, Nianxiang Broom, Bradley M. Casasent, Tod Unruh, Anna Wakefield, Chris Cason, R. Craig Baggerly, Keith A. Weinstein, John N. Haussler, David Benz, Christopher C. Stuart, Joshua M. Zhu, Jingchun Szeto, Christopher Scott, Gary K. Yau, Christina Ng, Sam Goldstein, Ted Waltman, Peter Sokolov, Artem Ellrott, Kyle Collisson, Eric A. Zerbino, Daniel Wilks, Christopher Ma, Singer Craft, Brian Wilkerson, Matthew D. Auman, J. Todd Hoadley, Katherine A. Du, Ying Cabanski, Christopher Walter, Vonn Singh, Darshan Wu, Junyuan Gulabani, Anisha Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, Matthew G. Mose, Lisle E. Jefferys, Stuart R. Balu, Saianand Marron, J. S. Liu, Yufeng Wang, Kai Liu, Jinze Prins, Jan F. Hayes, D. Neil Perou, Charles M. Creighton, Chad J. Zhang, Yiqun Travis, William D. Rekhtman, Natasha Yi, Joanne Aubry, Marie C. Cheney, Richard Dacic, Sanja Flieder, Douglas Funkhouser, William Illei, Peter Myers, Jerome Tsao, Ming-Sound Penny, Robert Mallery, David Shelton, Troy Hatfield, Martha Morris, Scott Yena, Peggy Shelton, Candace Sherman, Mark Paulauskis, Joseph Meyerson, Matthew Baylin, Stephen B. Govindan, Ramaswamy Akbani, Rehan Azodo, Ijeoma Beer, David Bose, Ron Byers, Lauren A. Carbone, David Chang, Li-Wei Chiang, Derek Chu, Andy Chun, Elizabeth Collisson, Eric Cope, Leslie Creighton, Chad J. Danilova, Ludmila Ding, Li Getz, Gad Hammerman, Peter S. Hayes, D. Neil Hernandez, Bryan Herman, James G. Heymach, John Ida, Cristiane Imielinski, Marcin Johnson, Bruce Jurisica, Igor Kaufman, Jacob Kosari, Farhad Kucherlapati, Raju Kwiatkowski, David Ladanyi, Marc Lawrence, Michael S. Maher, Christopher A. Mungall, Andy Ng, Sam Pao, William Peifer, Martin Penny, Robert Robertson, Gordon Rusch, Valerie Sander, Chris Schultz, Nikolaus Shen, Ronglai Siegfried, Jill Sinha, Rileen Sivachenko, Andrey Sougnez, Carrie Stoll, Dominik Stuart, Joshua Thomas, Roman K. Tomaszek, Sandra Tsao, Ming-Sound Travis, William D. Vaske, Charles Weinstein, John N. Weisenberger, Daniel Wheeler, David Wigle, Dennis A. Wilkerson, Matthew D. Wilks, Christopher Yang, Ping Zhang, Jianjua John Jensen, Mark A. Sfeir, Robert Kahn, Ari B. Chu, Anna L. Kothiyal, Prachi Wang, Zhining Snyder, Eric E. Pontius, Joan Pihl, Todd D. Ayala, Brenda Backus, Mark Walton, Jessica Baboud, Julien Berton, Dominique L. Nicholls, Matthew C. Srinivasan, Deepak Raman, Rohini Girshik, Stanley Kigonya, Peter A. Alonso, Shelley Sanbhadti, Rashmi N. Barletta, Sean P. Greene, John M. Pot, David A. Tsao, Ming-Sound Bandarchi-Chamkhaleh, Bizhan Boyd, Jeff Weaver, JoEllen Wigle, Dennis A. Azodo, Ijeoma A. Tomaszek, Sandra C. Aubry, Marie Christine Ida, Christiane M. Yang, Ping Kosari, Farhad Brock, Malcolm V. Rogers, Kristen Rutledge, Marian Brown, Travis Lee, Beverly Shin, James Trusty, Dante Dhir, Rajiv Siegfried, Jill M. Potapova, Olga Fedosenko, Konstantin V. Nemirovich-Danchenko, Elena Rusch, Valerie Zakowski, Maureen Iacocca, Mary V. Brown, Jennifer Rabeno, Brenda Czerwinski, Christine Petrelli, Nicholas Fan, Zhen Todaro, Nicole Eckman, John Myers, Jerome Rathmell, W. Kimryn Thorne, Leigh B. Huang, Mei Boice, Lori Hill, Ashley Penny, Robert Mallery, David Curley, Erin Shelton, Candace Yena, Peggy Morrison, Carl Gaudioso, Carmelo Bartlett, Johnm. S. Kodeeswaran, Sugy Zanke, Brent Sekhon, Harman David, Kerstin Juhl, Hartmut Van Le, Xuan Kohl, Bernard Thorp, Richard Tien, Nguyen Viet Van Bang, Nguyen Sussman, Howard Phu, Bui Duc Hajek, Richard PhiHung, Nguyen Khan, Khurram Z. Muley, Thomas Shaw, Kenna R. Mills Sheth, Margi Yang, Liming Buetow, Ken Davidsen, Tanja Demchok, John A. Eley, Greg Ferguson, Martin Dillon, Laura A. L. Schaefer, Carl Guyer, Mark S. Ozenberger, Bradley A. Palchik, Jacqueline D. Peterson, Jane Sofia, Heidi J. Thomson, Elizabeth Meyerson, Matthew CA Canc Genome Atlas Res Network TI Comprehensive genomic characterization of squamous cell lung cancers SO NATURE LA English DT Article ID COPY-NUMBER ALTERATION; THERAPEUTIC TARGET; MUTATIONS; CARCINOMA; GENE; GEFITINIB; PATHWAY; FUSION; ADENOCARCINOMA; AMPLIFICATION AB Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers. C1 [Sivachenko, Andrey; McKenna, Aaron; Cherniack, Andrew D.; Crenshaw, Andrew; Hadjipanayis, Angela; Chen, Peng-Chieh; Kucherlapati, Raju] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Hammerman, Peter S.; Meyerson, Matthew; Beroukhim, Rameen; Hammerman, Peter S.; Meyerson, Matthew; Johnson, Bruce] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Lander, Eric S.; Sougnez, Carrie] Harvard Univ, Dept Syst Biol, Boston, MA 02115 USA. [Gabriel, Stacey; Getz, Gad; Sougnez, Carrie; Onofrio, Robert C.; Ardlie, Kristin] Harvard Univ, Genet Anal Platform, Cambridge, MA 02142 USA. [Imielinski, Marcin; Meyerson, Matthew; Meyerson, Matthew; Imielinski, Marcin] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Chu, Andy; Chun, Hye-Jung E.; Mungall, Andrew J.; Pleasance, Erin; Robertson, A. Gordon; Sipahimalani, Payal; Stoll, Dominik; Balasundaram, Miruna; Birol, Inanc; Chuah, Eric; Guin, Ranabir; Hirst, Anhe Carrie; Hirst, Martin; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Mungall, Karen; Nip, Ka Ming; Schein, Jacqueline E.; Slobodan, Jared R.; Thiessen, Nina; Marra, Marco A.; Chun, Elizabeth; Mungall, Andy; Robertson, Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z, Canada. [Olshen, Adam] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. 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[Haussler, David; Stuart, Joshua M.; Zhu, Jingchun; Szeto, Christopher; Ng, Sam; Waltman, Peter; Sokolov, Artem; Ellrott, Kyle; Stuart, Joshua; Vaske, Charles] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Haussler, David; Stuart, Joshua M.; Zhu, Jingchun; Szeto, Christopher; Goldstein, Ted; Waltman, Peter; Sokolov, Artem; Ellrott, Kyle; Stuart, Joshua; Vaske, Charles] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Benz, Christopher C.; Scott, Gary K.; Yau, Christina] Buck Inst Age Res, Novato, CA 94945 USA. [Collisson, Eric] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94143 USA. [Marron, J. S.] Univ N Carolina, Dept Stat & Operat Res, Chapel Hill, NC 27599 USA. [Creighton, Chad J.; Zhang, Yiqun] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Zhang, Yiqun] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA. [Travis, William D.; Rekhtman, Natasha] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Yi, Joanne; Aubry, Marie C.; Ida, Cristiane] Mayo Clin, Dept Pathol, Rochester, MN 55905 USA. [Cheney, Richard; Shelton, Candace; Yena, Peggy; Morrison, Carl; Gaudioso, Carmelo] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA. [Dacic, Sanja] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Flieder, Douglas; Boyd, Jeff; Weaver, JoEllen] Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA. [Funkhouser, William] Univ N Carolina, Dept Pathol, Med Ctr, Chapel Hill, NC 27599 USA. [Illei, Peter] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. [Myers, Jerome] Penrose St Francis Hlth Syst, Dept Pathol, Colorado Springs, CO 80907 USA. [Tsao, Ming-Sound; Bandarchi-Chamkhaleh, Bizhan] Ontario Canc Inst, Dept Pathol & Med Biophys, Toronto, ON M5G 2MY, Canada. [Tsao, Ming-Sound; Bandarchi-Chamkhaleh, Bizhan] Princess Margaret Hosp, Toronto, ON M5G 2MY, Canada. [Penny, Robert; Mallery, David; Shelton, Troy; Hatfield, Martha; Morris, Scott; Yena, Peggy; Shelton, Candace; Sherman, Mark; Paulauskis, Joseph; Hill, Ashley; Curley, Erin] Int Genom Consortium, Phoenix, AZ 85004 USA. [Govindan, Ramaswamy; Bose, Ron; Chang, Li-Wei; Ding, Li; Maher, Christopher A.] Washington Univ, Dept Med, Div Oncol, Sch Med, St Louis, MO 63110 USA. [Beer, David] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Carbone, David; Kaufman, Jacob; Pao, William] Vanderbilt Univ, Dept Hematol, Nashville, TN 37232 USA. [Jurisica, Igor; Brock, Malcolm V.] IBM Life Sci Discovery Ctr, Ontario Canc Inst, Toronto, ON M5G 1L7, Canada. [Peifer, Martin; Thomas, Roman K.] Univ Cologne, Dept Translat Genom, D-50931 Cologne, Germany. [Rusch, Valerie] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Siegfried, Jill; Siegfried, Jill M.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Med Ctr, Pittsburgh, PA 15232 USA. [Thomas, Roman K.] Univ Cologne, Dept Translat Canc Genom, Ctr Integrated Oncol, D-50924 Cologne, Germany. [Wheeler, David] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Ida, Christiane M.] Mayo Clin, Dept Lab Med, Rochester, MN 55905 USA. [Yang, Ping] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Rogers, Kristen; Brown, Travis] Johns Hopkins Sch Med, Dept Surg, Baltimore, MD 21287 USA. [Rutledge, Marian; Lee, Beverly] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD 21287 USA. [Shin, James; Trusty, Dante] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Dhir, Rajiv] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Potapova, Olga; Nemirovich-Danchenko, Elena] Cureline, San Francisco, CA 94080 USA. [Fedosenko, Konstantin V.] City Clin Oncol Dispensary, St Petersburg 197022, Russia. [Zakowski, Maureen] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Iacocca, Mary V.; Brown, Jennifer; Rabeno, Brenda; Czerwinski, Christine; Petrelli, Nicholas] Helen F Graham Canc Ctr, Newark, DE 19713 USA. [Fan, Zhen; Todaro, Nicole; Huang, Mei] St Joseph Med Ctr, Towson, MD 21204 USA. [Thorne, Leigh B.] UNC Lineberger Canc Ctr, UNC Tissue Procurement Facil, Dept Pathol, Chapel Hill, NC 27599 USA. [Kodeeswaran, Sugy; Zanke, Brent] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [David, Kerstin] Indivumed GmbH, D-20251 Hamburg, Germany. [Juhl, Hartmut] Indivumed Inc, Kensington, MD 20895 USA. [Van Le, Xuan; Kohl, Bernard; Thorp, Richard] ILSBio LLC, Chestertown, MD 21620 USA. [Tien, Nguyen Viet] Minist Hlth, Hanoi, Vietnam. [Van Bang, Nguyen] Hue Cent Hosp, Hue City, Vietnam. [Sussman, Howard] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Hajek, Richard] Univ Texas MD Anderson Canc Ctr, Ctr Minor Hlth Res, Houston, TX 77030 USA. [Phu, Bui Duc; PhiHung, Nguyen] Natl Canc Inst, Hanoi, Vietnam. [Khan, Khurram Z.] ILSBio LLC, Chestertown, MD 21620 USA. [Muley, Thomas] Univ Heidelberg Hosp, ThoraxKlin, D-69126 Heidelberg, Germany. [Shaw, Kenna R. Mills; Sheth, Margi; Yang, Liming; Demchok, John A.; Dillon, Laura A. L.] NCI, Canc Genome Atlas Program Off, Bethesda, MD 20892 USA. [Buetow, Ken; Davidsen, Tanja; Eley, Greg; Schaefer, Carl] NCI, CBIIT, NIH, Rockville, MD 20852 USA. [Guyer, Mark S.; Ozenberger, Bradley A.; Palchik, Jacqueline D.; Peterson, Jane; Sofia, Heidi J.; Thomson, Elizabeth] NHGRI, NIH, Bethesda, MD 20892 USA. RP Meyerson, M (reprint author), MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. EM matthew_meyerson@dfci.harvard.edu RI Birol, Inanc/G-5440-2011; Holt, Robert/C-3303-2009; Laird, Peter/G-8683-2012; Jacobsen, Anders/K-1081-2013; Schein, Jacquie/G-3674-2015; Vaske, Charles/D-6018-2013; Schumacher, Steven/E-9821-2013; Gao, Jianjiong/B-5673-2016; Hirst, Martin/B-7684-2016; Jones, Steven/C-3621-2009; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Reva, Boris/B-6436-2014; Tang, Macy/B-9798-2014 OI Gehlenborg, Nils/0000-0003-0327-8297; Birol, Inanc/0000-0003-0950-7839; Schultz, Nikolaus/0000-0002-0131-4904; Triche, Tim/0000-0001-5665-946X; Hayes, D. Neil/0000-0001-6203-7771; Lash, Alex/0000-0003-3787-1590; Pot, David/0000-0002-1480-9826; Sinha, Rileen/0000-0001-5497-5055; Casasent, Anna/0000-0002-7857-179X; Zerbino, Daniel/0000-0001-5350-3056; Jacobsen, Anders/0000-0001-6847-4980; Vaske, Charles/0000-0001-8151-6612; Schumacher, Steven/0000-0002-6819-5647; Gao, Jianjiong/0000-0002-5739-1781; Lee, Semin/0000-0002-9015-6046; Reva, Boris/0000-0002-8805-389X; FU NIH [U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866, U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079, U54 HG003273] FX This study was supported by NIH grants U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866, U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079 and U54 HG003273. NR 46 TC 1116 Z9 1128 U1 31 U2 207 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 SEP 27 PY 2012 VL 489 IS 7417 BP 519 EP 525 DI 10.1038/nature11404 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 011LT UT WOS:000309167100041 ER PT J AU Fradkin, JE Roberts, BT Rodgers, GP AF Fradkin, Judith E. Roberts, B. Tibor Rodgers, Griffin P. TI What's Preventing Us from Preventing Type 2 Diabetes? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID LIFE-STYLE INTERVENTION; METFORMIN C1 [Fradkin, Judith E.] NIDDKD, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Roberts, B. Tibor] NIDDKD, Off Sci Program & Policy Anal, NIH, Bethesda, MD 20892 USA. [Rodgers, Griffin P.] NIDDKD, Off Director, NIH, Bethesda, MD 20892 USA. RP Fradkin, JE (reprint author), NIDDKD, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. NR 5 TC 23 Z9 23 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 27 PY 2012 VL 367 IS 13 BP 1177 EP 1179 DI 10.1056/NEJMp1208169 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 011JO UT WOS:000309161100001 PM 23013070 ER PT J AU Hoofnagle, JH Nelson, KE Purcell, RH AF Hoofnagle, Jay H. Nelson, Kenrad E. Purcell, Robert H. TI CURRENT CONCEPTS Hepatitis E SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID NON-B HEPATITIS; E VIRUS-INFECTION; UNITED-STATES; NON-A; IGG SEROPREVALENCE; RISK-FACTORS; PATIENT; DISEASE; FOOD; EPIDEMIOLOGY C1 [Hoofnagle, Jay H.] NIDDKD, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. [Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Nelson, Kenrad E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Hoofnagle, JH (reprint author), NIDDKD, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Rm 9A27,31 Ctr Dr, Bethesda, MD 20892 USA. EM hoofnaglej@extra.niddk.nih.gov NR 55 TC 143 Z9 151 U1 2 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 27 PY 2012 VL 367 IS 13 BP 1237 EP 1244 DI 10.1056/NEJMra1204512 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 011JO UT WOS:000309161100010 PM 23013075 ER PT J AU Mehta, NN AF Mehta, Nehal N. TI Introducing the Cardiovascular, metabolic and lipoprotein translation section of journal of translational medicine SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material AB Introducing the Cardiovascular, metabolic and lipoprotein translation section of journal of translational medicine. C1 NHLBI, Lab Inflammat & Cardiometabol Dis, Bethesda, MD 20892 USA. RP Mehta, NN (reprint author), NHLBI, Lab Inflammat & Cardiometabol Dis, Bldg 10, Bethesda, MD 20892 USA. EM nehal.mehta@nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 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 SEP 26 PY 2012 VL 10 AR 203 DI 10.1186/1479-587610-203 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 063LP UT WOS:000313000700002 PM 23013515 ER PT J AU Asthagiri, AR Vasquez, RA Butman, JA Wu, TX Morgan, K Brewer, CC King, K Zalewski, C Kim, HJ Lonser, RR AF Asthagiri, Ashok R. Vasquez, Raul A. Butman, John A. Wu, Tianxia Morgan, Keaton Brewer, Carmen C. King, Kelly Zalewski, Chris Kim, H. Jeffrey Lonser, Russell R. TI Mechanisms of Hearing Loss in Neurofibromatosis Type 2 SO PLOS ONE LA English DT Article ID HIPPEL-LINDAU-DISEASE; VESTIBULAR-SCHWANNOMA; ACOUSTIC NEUROMAS; NATURAL-HISTORY; FLUID; DETERIORATION; BEVACIZUMAB; PERILYMPH; PROTEINS; GROWTH AB Introduction: Patients with neurofibromatosis type 2 (NF2) develop bilateral cochleovestibular schwannomas (CVSs) that cause binaural deafness in most individuals. Hearing loss occurs in an unpredictable manner and the underlying mechanisms are not known. To gain insight into the pathophysiologic basis for hearing loss in NF2, we performed a prospective cross-sectional study of untreated ears in NF2 patients. Methods: One hundred consecutive NF2 patients in a prospective natural history study were included. Clinical and audiometric data were analyzed for treatment naive ears. In addition to standard MR-imaging sequences, alterations in intralabyrinthine protein content were determined utilizing high resolution FLAIR, the presence of cochlear aperture obstruction was determined by examining 3D T2 sequences, and endolymphatic hydrops was identified on delayed post-contrast FLAIR sequences. Results: Eighty-nine ears harboring 84 untreated CVSs in 56 consecutive NF2 patients (age 30 +/- 16 years) were analyzed. Thirty-four (38%) ears had varying degrees of hearing loss. Elevated intralabyrinthine protein was identified in 70 (75%) ears by FLAIR MR-imaging and was strongly associated with the presence of hearing loss (32/34 hearing loss ears; 94%)(Fisher's exact test; P = .005). Elevated intralabyrinthine protein was associated with the presence of CVS-associated cochlear aperture obstruction (64 of 67 ears with elevated protein; 96%)(Fisher's exact test; P<0.0001) in both normal and hearing loss ears. Elevated intralabyrinthine protein was not identified in ears without CVS (5 ears). While larger tumor size was associated with hearing loss (P = 0.006), 16 hearing loss ears (47%) harbored CVSs less than 0.5 cm(3), including 14 ears (88%) with block of the cochlear aperture and elevated protein. Discussion: These findings are consistent with a model in which hearing loss develops as a result of cochlear aperture obstruction and accumulation of intralabyrinthine protein. MRI based identification of elevated intralabyrinthine protein may help identify the ear at-risk for developing hearing loss. C1 [Asthagiri, Ashok R.; Vasquez, Raul A.; Morgan, Keaton; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Vasquez, Raul A.] Univ Florida, Dept Neurol Surg, Gainesville, FL USA. [Butman, John A.] NIH, Ctr Clin, Bethesda, MD USA. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. [Brewer, Carmen C.; King, Kelly; Zalewski, Chris] Natl Inst Deafness & Other Commun Disorders, Audiol Unit, Otolaryngol Branch, NIH, Bethesda, MD USA. [Kim, H. Jeffrey] Natl Inst Deafness & Other Commun Disorders, Off Clin Director, NIH, Bethesda, MD USA. RP Asthagiri, AR (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM asthagiria@ninds.nih.gov RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU National Institute of Neurologic Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; Clinical Center at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Neurologic Disorders and Stroke, National Institute on Deafness and Other Communication Disorders and the Clinical Center at the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 12 Z9 13 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 26 PY 2012 VL 7 IS 9 AR e46132 DI 10.1371/journal.pone.0046132 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KP UT WOS:000309517300088 PM 23049959 ER PT J AU Clay, JR Forger, DB Paydarfar, D AF Clay, John R. Forger, Daniel B. Paydarfar, David TI Ionic Mechanism Underlying Optimal Stimuli for Neuronal Excitation: Role of Na+ Channel Inactivation SO PLOS ONE LA English DT Article ID LACUNOSUM-MOLECULARE INTERNEURONS; HIPPOCAMPAL CA1-REGION; EXCITABILITY; SPIKING; MODELS; INPUTS; AXONS AB The ionic mechanism underlying optimal stimulus shapes that induce a neuron to fire an action potential, or spike, is relevant to understanding optimal information transmission and therapeutic stimulation in the nervous system. Here we analyze for the first time the ionic basis for stimulus optimality in the Hodgkin and Huxley model and for eliciting a spike in squid giant axons, the preparation for which the model was devised. The experimentally determined stimulus is a smoothly varying biphasic current waveform having a relatively long and shallow hyperpolarizing phase followed by a depolarizing phase of briefer duration. The hyperpolarizing phase removes a small degree of the resting level of Na+ channel inactivation. This result together with the subsequent depolarizing phase provides a signal that is energetically more efficient for eliciting spikes than rectangular current pulses. Sodium channel inactivation is the only variable that is changed during the stimulus waveform, other than the membrane potential, V. The activation variables for Na+ and K+ channels are unchanged throughout the stimulus. This result demonstrates how an optimal stimulus waveform relates to ionic dynamics and may have implications for energy efficiency of neural excitation in many systems including the mammalian brain. C1 [Clay, John R.] NINDS, NIH, Bethesda, MD 20892 USA. [Forger, Daniel B.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [Forger, Daniel B.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Paydarfar, David] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Paydarfar, David] Univ Massachusetts, Sch Med, Dept Physiol, Worcester, MA USA. [Paydarfar, David] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. RP Clay, JR (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM jrclay@ninds.nih.gov; forger@umich.edu; david.paydarfar@umassmed.edu RI Forger, Daniel/C-5552-2015 OI Forger, Daniel/0000-0001-7581-4031 FU National Institute of Neurological Disorders and Stroke, United States National Institutes of Health FX Funding was provided by the National Institute of Neurological Disorders and Stroke, United States 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 27 TC 7 Z9 7 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 26 PY 2012 VL 7 IS 9 AR e45983 DI 10.1371/journal.pone.0045983 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KP UT WOS:000309517300071 PM 23049913 ER PT J AU Gaskins, AJ Mumford, SL Chavarro, JE Zhang, CL Pollack, AZ Wactawski-Wende, J Perkins, NJ Schisterman, EF AF Gaskins, Audrey J. Mumford, Sunni L. Chavarro, Jorge E. Zhang, Cuilin Pollack, Anna Z. Wactawski-Wende, Jean Perkins, Neil J. Schisterman, Enrique F. TI The Impact of Dietary Folate Intake on Reproductive Function in Premenopausal Women: A Prospective Cohort Study SO PLOS ONE LA English DT Article ID NEURAL-TUBE DEFECTS; MARGINAL STRUCTURAL MODELS; MENSTRUAL-CYCLE; FOLIC-ACID; FOOD FORTIFICATION; PREVENTION; FERTILITY; SUPPLEMENTATION; BIOAVAILABILITY; BIOCYCLE AB Background: Folic acid is recommended to reproductive-aged women to prevent birth defects, though little is known about the effects of dietary intake on other reproductive outcomes. Improved pregnancy rates have been documented after folic acid supplement use, suggesting a possible link with ovulation, however research is limited. Our objective was to evaluate the association between dietary folate intake, hormone levels, and sporadic anovulation in healthy, regularly menstruating women. Methodology/Principal Findings: The BioCycle study (2005-2007) prospectively followed 259 healthy women aged 18-44 years from the western New York region for up to 2 menstrual cycles. Total folate and specific sources of folate were assessed up to 4 times per cycle by 24-hour recall. Estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured in serum up to 8 times per cycle, timed using fertility monitors. Anovulation was defined as a cycle with peak progesterone concentration <= 5 ng/mL and no LH peak in the mid/late luteal phase. Higher intake of dietary folate (in dietary equivalents) across tertiles had a marginally significant association with greater luteal progesterone levels (P trend 0.08). Higher intake of synthetic folate was significantly associated with higher luteal progesterone levels (P trend 0.05). Specifically, women in the 3rd tertile of synthetic folate intake had, on average, 16.0% (95% CI, 0.5-33.8%) higher luteal progesterone levels compared to women in the 1st tertile. Moreover, consumption of synthetic folate was significantly and inversely associated with anovulation such that women in the 3rd tertile had a 64% (95% CI, 8-86%) decreased odds of anovulation compared to the women in the 1st tertile (P trend 0.03). Conclusions/Significance: These findings suggest that a diet high in synthetic folate may be associated with increased progesterone levels and lower risk of sporadic anovulation. Further study of the effect of dietary folate and folic acid supplement use on reproductive health is warranted. C1 [Gaskins, Audrey J.; Mumford, Sunni L.; Zhang, Cuilin; Pollack, Anna Z.; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Gaskins, Audrey J.; Chavarro, Jorge E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chavarro, Jorge E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chavarro, Jorge E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Chavarro, Jorge E.] Harvard Univ, Sch Med, Boston, MA USA. [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, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Pollack, Anna/0000-0002-4313-3298; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Harvard Nutrition Department NIH [T32DK007703-16] FX The BioCycle Study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. Audrey J. Gaskins is funded by the Harvard Nutrition Department NIH Training Grant T32DK007703-16. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 8 Z9 8 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 26 PY 2012 VL 7 IS 9 AR e46276 DI 10.1371/journal.pone.0046276 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KP UT WOS:000309517300103 PM 23050004 ER PT J AU Hurtado, MD Acosta, A Riveros, PP Baum, BJ Ukhanov, K Brown, AR Dotson, CD Herzog, H Zolotukhin, S AF Hurtado, Maria D. Acosta, Andres Riveros, Paola P. Baum, Bruce J. Ukhanov, Kirill Brown, Alicia R. Dotson, Cedrick D. Herzog, Herbert Zolotukhin, Sergei TI Distribution of Y-Receptors in Murine Lingual Epithelia SO PLOS ONE LA English DT Article ID NEUROPEPTIDE YY1 RECEPTOR; PANCREATIC-POLYPEPTIDE; PROTEIN EXPRESSION; MICE LACKING; PEPTIDE YY; RAT-BRAIN; CELLS; PROLIFERATION; INTERNALIZATION; MIGRATION AB Peptide hormones and their cognate receptors belonging to neuropeptide Y (NPY) family mediate diverse biological functions in a number of tissues. Recently, we discovered the presence of the gut satiation peptide YY (PYY) in saliva of mice and humans and defined its role in the regulation of food intake and body weight maintenance. Here we report the systematic analysis of expression patterns of all NPY receptors (Rs), Y1R, Y2R, Y4R, and Y5R in lingual epithelia in mice. Using four independent assays, immunohistochemistry, in situ hybridization, immunocytochemistry and RT PCR, we show that the morphologically different layers of the keratinized stratified epithelium of the dorsal layer of the tongue express Y receptors in a very distinctive yet overlapping pattern. In particular, the monolayer of basal progenitor cells expresses both Y1 and Y2 receptors. Y1Rs are present in the parabasal prickle cell layer and the granular layer, while differentiated keratinocytes display abundant Y5Rs. Y4Rs are expressed substantially in the neuronal fibers innervating the lamina propria and mechanoreceptors. Basal epithelial cells positive for Y2Rs respond robustly to PYY3-36 by increasing intracellular Ca2+ suggesting their possible functional interaction with salivary PYY. In taste buds of the circumvallate papillae, some taste receptor cells (TRCs) express YRs localized primarily at the apical domain, indicative of their potential role in taste perception. Some of the YR-positive TRCs are co-localized with neuronal cell adhesion molecule (NCAM), suggesting that these TRCs may have synaptic contacts with nerve terminals. In summary, we show that all YRs are abundantly expressed in multiple lingual cell types, including epithelial progenitors, keratinocytes, neuronal dendrites and TRCs. These results suggest that these receptors may be involved in the mediation of a wide variety of functions, including proliferation, differentiation, motility, taste perception and satiation. C1 [Hurtado, Maria D.; Zolotukhin, Sergei] Univ Florida, Dept Pediat, Gainesville, FL 32611 USA. [Acosta, Andres] Univ Florida, Dept Med, Gainesville, FL USA. [Riveros, Paola P.; Baum, Bruce J.] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Ukhanov, Kirill; Brown, Alicia R.; Dotson, Cedrick D.] Univ Florida, Dept Neurosci, Ctr Smell & Taste, Gainesville, FL 32610 USA. [Ukhanov, Kirill; Brown, Alicia R.; Dotson, Cedrick D.] Univ Florida, Dept Psychiat, Ctr Smell & Taste, Gainesville, FL 32610 USA. [Herzog, Herbert] Garvan Inst Med Res, Neurosci Program, Sydney, NSW, Australia. RP Zolotukhin, S (reprint author), Univ Florida, Dept Pediat, Gainesville, FL 32611 USA. EM szlt@ufl.edu FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK62302-01]; Division of Intramural Research of the National Institute of Dental and Craniofacial Research; NHMRC of Australia FX This work was supported by 1R01DK62302-01 (National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases) to SZ; the Division of Intramural Research of the National Institute of Dental and Craniofacial Research in part supported this research (BB). HH is funded by an NHMRC of Australia Senior Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 14 Z9 16 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 26 PY 2012 VL 7 IS 9 AR e46358 DI 10.1371/journal.pone.0046358 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KP UT WOS:000309517300110 PM 23050020 ER PT J AU Maxwell, E Tan, Y Tan, YX Hu, H Benson, G Aizikov, K Conley, S Staples, GO Slysz, GW Smith, RD Zaia, J AF Maxwell, Evan Tan, Yan Tan, Yuxiang Hu, Han Benson, Gary Aizikov, Konstantin Conley, Shannon Staples, Gregory O. Slysz, Gordon W. Smith, Richard D. Zaia, Joseph TI GlycReSoft: A Software Package for Automated Recognition of Glycans from LC/MS Data SO PLOS ONE LA English DT Article ID TANDEM MASS-SPECTROMETRY; CHROMATOGRAPHY/MASS SPECTROMETRY; NONREDUCING END; OLIGOSACCHARIDES; PROTEOME; HEPARIN; IDENTIFICATIONS; DATABASES; SPECTRA; CHIP AB Glycosylation modifies the physicochemical properties and protein binding functions of glycoconjugates. These modifications are biosynthesized in the endoplasmic reticulum and Golgi apparatus by a series of enzymatic transformations that are under complex control. As a result, mature glycans on a given site are heterogeneous mixtures of glycoforms. This gives rise to a spectrum of adhesive properties that strongly influences interactions with binding partners and resultant biological effects. In order to understand the roles glycosylation plays in normal and disease processes, efficient structural analysis tools are necessary. In the field of glycomics, liquid chromatography/mass spectrometry (LC/MS) is used to profile the glycans present in a given sample. This technology enables comparison of glycan compositions and abundances among different biological samples, i.e. normal versus disease, normal versus mutant, etc. Manual analysis of the glycan profiling LC/MS data is extremely time-consuming and efficient software tools are needed to eliminate this bottleneck. In this work, we have developed a tool to computationally model LC/MS data to enable efficient profiling of glycans. Using LC/MS data deconvoluted by Decon2LS/DeconTools, we built a list of unique neutral masses corresponding to candidate glycan compositions summarized over their various charge states, adducts and range of elution times. Our work aims to provide confident identification of true compounds in complex data sets that are not amenable to manual interpretation. This capability is an essential part of glycomics work flows. We demonstrate this tool, GlycReSoft, using an LC/MS dataset on tissue derived heparan sulfate oligosaccharides. The software, code and a test data set are publically archived under an open source license. C1 [Maxwell, Evan; Tan, Yan; Tan, Yuxiang; Hu, Han; Benson, Gary; Zaia, Joseph] Boston Univ, Ctr Biomed Mass Spectrometry, Bioinformat Program, Boston, MA 02215 USA. [Maxwell, Evan] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Slysz, Gordon W.; Smith, Richard D.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Slysz, Gordon W.; Smith, Richard D.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Tan, Yan] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. RP Zaia, J (reprint author), Boston Univ, Ctr Biomed Mass Spectrometry, Bioinformat Program, Boston, MA 02215 USA. EM jzaia@bu.edu RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Zaia, Joseph/0000-0001-9497-8701 FU NIH [P41RR10888, P41GM104603, R01HL098950]; NSF (National Science Foundation); NIH National Center for Research Resources [RR018522]; W.R. Wiley Environmental Molecular Science Laboratory; US Department of Energy's Office of Biological and Environmental Research; National Institute of Allergy and Infectious Diseases (NIH/DHHS) [Y1-AI-4894-01]; US Department of Energy [DE-AC05-76RL0 1830] FX This work was supported by NIH grants P41RR10888, P41GM104603, and R01HL098950 and by an NSF (National Science Foundation) Integrative Graduate Education and Research Traineeship. This research utilized the Decon2LS and DeconTools software developed by the Pacific Northwest National Laboratory, supported by the NIH National Center for Research Resources (Grant RR018522), the W.R. Wiley Environmental Molecular Science Laboratory (a national scientific user facility sponsored by the US Department of Energy's Office of Biological and Environmental Research and located at PNNL), and the National Institute of Allergy and Infectious Diseases (NIH/DHHS through interagency agreement Y1-AI-4894-01). PNNL is operated by Battelle Memorial Institute for the US Department of Energy under contract DE-AC05-76RL0 1830. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 34 Z9 34 U1 1 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 26 PY 2012 VL 7 IS 9 AR e45474 DI 10.1371/journal.pone.0045474 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KP UT WOS:000309517300027 PM 23049804 ER PT J AU Ratto-Kim, S Currier, JR Cox, JH Excler, JL Valencia-Micolta, A Thelian, D Lo, V Sayeed, E Polonis, VR Earl, PL Moss, B Robb, ML Michael, NL Kim, JH Marovich, MA AF Ratto-Kim, Silvia Currier, Jeffrey R. Cox, Josephine H. Excler, Jean-Louis Valencia-Micolta, Anais Thelian, Doris Lo, Vicky Sayeed, Eddy Polonis, Victoria R. Earl, Patricia L. Moss, Bernard Robb, Merlin L. Michael, Nelson L. Kim, Jerome H. Marovich, Mary A. TI Heterologous Prime-Boost Regimens Using rAd35 and rMVA Vectors Elicit Stronger Cellular Immune Responses to HIV Proteins Than Homologous Regimens SO PLOS ONE LA English DT Article ID VACCINIA VIRUS ANKARA; RHESUS-MONKEYS; IMMUNOGENICITY; DNA; PROTECTION; HUMANS; MICE; SIV AB We characterized prime-boost vaccine regimens using heterologous and homologous vector and gene inserts. Heterologous regimens offer a promising approach that focuses the cell-mediated immune response on the insert and away from vector-dominated responses. Ad35-GRIN/ENV (Ad35-GE) vaccine is comprised of two vectors containing sequences from HIV-1 subtype A gag, rt, int, nef (Ad35-GRIN) and env (Ad35-ENV). MVA-CMDR (MVA-C), MVA-KEA (MVA-K) and MVA-TZC (MVA-T) vaccines contain gag, env and pol genes from HIV-1 subtypes CRF01_AE, A and C, respectively. Balb/c mice were immunized with different heterologous and homologous vector and insert prime-boost combinations. HIV and vector-specific immune responses were quantified post-boost vaccination. Gag-specific IFN-gamma ELISPOT, intracellular cytokine staining (ICS) (CD107 alpha, IFN-alpha, TNF-alpha and IL-2), pentamer staining and T-cell phenotyping were used to differentiate responses to inserts and vectors. Ad35-GE prime followed by boost with any of the recombinant MVA constructs (rMVA) induced CD8+ Gag-specific responses superior to Ad35-GE-Ad35-GE or rMVA-rMVA prime-boost combinations. Notably, there was a shift toward insert-focus responses using heterologous vector prime-boost regimens. Gag-specific central and effector memory T cells were generated more rapidly and in greater numbers in the heterologous compared to the homologous prime-boost regimens. These results suggest that heterologous prime-boost vaccination regimens enhance immunity by increasing the magnitude, onset and multifunctionality of the insert-specific cell-mediated immune response compared to homologous vaccination regimens. This study supports the rationale for testing heterologous prime-boost regimens in humans. C1 [Ratto-Kim, Silvia; Currier, Jeffrey R.; Valencia-Micolta, Anais; Thelian, Doris; Lo, Vicky; Polonis, Victoria R.; Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.; Marovich, Mary A.] Walter Reed Army Inst Res, US Mil HIV Res Program, Rockville, MD USA. [Cox, Josephine H.; Excler, Jean-Louis; Sayeed, Eddy] Int AIDS Vaccine Initiat, New York, NY USA. [Earl, Patricia L.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Ratto-Kim, S (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, Rockville, MD USA. EM sratto-kim@hivresearch.org FU United States Army Medical Research and Materiel Command [Y1-AI-2642-12]; National Institute of Allergy and Infectious Diseases; Henry M. Jackson Foundation for the Advancement of Military Medicine [W81XWH-07-2-6700-P00001]; United States Department of Defense; International AIDS Vaccine Initiative; American people through the United States Agency for International Development (USAID) [GPO-A-00-06-00006-00] FX This work was supported in part by an Interagency Agreement (Y1-AI-2642-12) between the United States Army Medical Research and Materiel Command and the National Institute of Allergy and Infectious Diseases and by a cooperative agreement (W81XWH-07-2-6700-P00001) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the United States Department of Defense. This study was also partially funded by the International AIDS Vaccine Initiative and its donors, including the generous support of the American people through the United States Agency for International Development (USAID; USAID Cooperative Agreement number GPO-A-00-06-00006-00). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 21 Z9 21 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 26 PY 2012 VL 7 IS 9 AR e45840 DI 10.1371/journal.pone.0045840 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016KP UT WOS:000309517300058 PM 23049876 ER PT J AU Rahimi, Z Nourozi-Rad, R Rahimi, Z Parsian, A AF Rahimi, Zohreh Nourozi-Rad, Reza Rahimi, Ziba Parsian, Abbas TI Strong interaction between T allele of endothelial nitric oxide synthase with B1 allele of cholesteryl ester transfer protein TaqIB highly elevates the risk of coronary artery disease and type 2 diabetes mellitus SO HUMAN GENOMICS LA English DT Article DE NOS3 G894T; CETP TaqIB; CAD; T2DM; Western Iran ID MYOCARDIAL-INFARCTION; GENE POLYMORPHISMS; JAPANESE PATIENTS; HEART-DISEASE; WESTERN IRAN; ASSOCIATION; POPULATION; VARIANT; METAANALYSIS; NEPHROPATHY AB Background: The present study was conducted to investigate the possible outcome of interaction between endothelial nitric oxide (NOS3) G894T and cholesteryl ester transfer TaqIB variants on the risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). The sample included a total of 207 CAD patients (102 CAD patients with T2DM and 105 CAD patients without T2DM). There were also 101 patients with T2DM and 92 age-and sex-matched healthy individuals as controls. All study participants were from Western Iran. The sample was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results: The presence of NOS3 T allele was not associated with the risk of CAD or T2DM, and the CETP B1 allele was only significantly associated with the increased risk of CAD in total CAD patients (odds ratio (OR) = 5.1, p = 0.019). However, the concomitant presence of both CETP B1 and NOS3 T alleles significantly increased the risk of CAD in total CAD patients (OR = 18.1, p < 0.001), in CAD patients without T2DM (OR = 27.1, p = 0.03), and in CAD patients with T2DM (OR = 13.5, p = 0.002). Also, the presence of both alleles increased the risk of T2DM (OR = 12, p = 0.004). Conclusions: Our findings, for the first time, indicate that NOS3 T allele strongly interacts with CETP B1 allele to augment the risk of CAD and T2DM in the population of Western Iran. C1 [Rahimi, Zohreh; Rahimi, Ziba] Kermanshah Univ Med Sci, Sch Med, Med Biol Res Ctr, Kermanshah, Iran. [Rahimi, Zohreh] Kermanshah Univ Med Sci, Sch Med, Dept Biochem, Kermanshah, Iran. [Nourozi-Rad, Reza] Dezful Univ Med Sci, Sch Med, Dept Biochem, Dezful, Iran. [Parsian, Abbas] NIAAA, Div Neurosci & Behav, NIH, Rockville, MD 20852 USA. RP Rahimi, Z (reprint author), Kermanshah Univ Med Sci, Sch Med, Med Biol Res Ctr, Daneshgah Ave,POB 67148-69914, Kermanshah, Iran. EM zrahimi@kums.ac.ir RI Norouzirad, Reza/L-7475-2015; OI Norouzirad, Reza/0000-0002-5046-057X; Rahimi, Zohreh/0000-0001-7589-3307 FU Kermanshah University of Medical Sciences office of Vice Chancellor for Research, Kermanshah, Iran FX This work was performed in partial fulfillment of the Master of Science requirements of RNR in Kermanshah University of Medical Sciences and was financially supported by a grant from Kermanshah University of Medical Sciences office of Vice Chancellor for Research, Kermanshah, Iran. We would like to thank Dr. Mansour Rezaei for his statistical comments. NR 30 TC 5 Z9 6 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 J9 HUM GENOMICS JI Hum. Genomics PD SEP 25 PY 2012 VL 6 AR 20 DI 10.1186/1479-7364-6-20 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 121DW UT WOS:000317224100002 PM 23157875 ER PT J AU Zhu, J Wang, YY Duan, JC Bai, H Wang, ZJ Wei, L Zhao, J Zhuo, ML Wang, SH Yang, L An, TT Wu, MN Wang, J AF Zhu, Jian Wang, Yuyan Duan, Jianchun Bai, Hua Wang, Zhijie Wei, Lai Zhao, Jun Zhuo, Minglei Wang, Shuhang Yang, Lu An, Tongtong Wu, Meina Wang, Jie TI DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH LA English DT Article DE DNA methylation; EGFR-TKI; Wnt antagonists; Non-small cell lung cancer ID GROWTH-FACTOR RECEPTOR; ACUTE MYELOID-LEUKEMIA; PROMOTER HYPERMETHYLATION; SIGNALING PATHWAY; EPIGENETIC INACTIVATION; GEFITINIB; MUTATIONS; GENE; CHEMOTHERAPY; EXPRESSION AB Background: It is well known that genetic alternation of epidermal growth factor receptor (EGFR) plays critical roles in tumorgenesis of lung cancer and can predict outcome of non-small-cell lung cancer treatment, especially the EGFR tyrosine-kinase inhibitors (EGFR-TKIs) therapy. However, it is unclear whether epigenetic changes such as DNA methylation involve in the response to the EGFR-TKI therapy. Methods: Tumor samples from 155 patients with stages IIIB to IV NSCLC who received EGFR-TKI therapy were analyzed for DNA methylation status of Wnt antagonist genes, including SFRP1, SFRP2, SFRP5, DKK3, WIF1, and APC, using methylation specific PCR (MSP) method. EGFR mutations detections were performed in the same tissues samples using Denaturing High Performance Liquid Chromatography (DHPLC). Results: We found that Wnt antagonists tend to methylate simultaneously. Methylation of sFRP1 and sFRP5 are reversely correlated with EGFR mutation (P = 0.005, P = 0.011). However, no correlations of methylations of other Wnt antagonist genes with EGFR mutation were found. The patients with methylated SFRP5 have a significant shorter progression free survival than those with unmethylated SFRP5 in response to EGFR-TKI treatment (P = 0.002), which is independent of EGFR genotype. Conclusions: Patients with unmethylated SFRP5 are more likely to benefit from EGFR-TKI therapy. C1 [Zhu, Jian; Wang, Yuyan; Duan, Jianchun; Bai, Hua; Wang, Zhijie; Zhao, Jun; Zhuo, Minglei; Wang, Shuhang; Yang, Lu; An, Tongtong; Wu, Meina; Wang, Jie] Peking Univ, Sch Oncol, Beijing Canc Hosp & Inst, Dept Thorac Med Oncol, Beijing 100036, Peoples R China. [Wei, Lai] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, J (reprint author), Peking Univ, Sch Oncol, Beijing Canc Hosp & Inst, Dept Thorac Med Oncol, Beijing 100036, Peoples R China. EM wangjie_cc@yahoo.com FU National Natural Sciences Foundation Distinguished Young Scholars [81025012]; National Natural Sciences Foundation General Program [81172235]; Beijing Health Systems Academic Leader [2011-2-22] FX Supported by grants from National Natural Sciences Foundation Distinguished Young Scholars (81025012), National Natural Sciences Foundation General Program (81172235), Beijing Health Systems Academic Leader (2011-2-22). NR 36 TC 14 Z9 16 U1 0 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-9966 J9 J EXP CLIN CANC RES JI J. Exp. Clin. Cancer Res. PD SEP 25 PY 2012 VL 31 AR 80 DI 10.1186/1756-9966-31-80 PG 9 WC Oncology SC Oncology GA 057XV UT WOS:000312598700001 PM 23009178 ER PT J AU Lodola, F Laforenza, U Bonetti, E Lim, D Dragoni, S Bottino, C Ong, HL Guerra, G Ganini, C Massa, M Manzoni, M Ambudkar, IS Genazzani, AA Rosti, V Pedrazzoli, P Tanzi, F Moccia, F Porta, C AF Lodola, Francesco Laforenza, Umberto Bonetti, Elisa Lim, Dmitry Dragoni, Silvia Bottino, Cinzia Ong, Hwei Ling Guerra, Germano Ganini, Carlo Massa, Margherita Manzoni, Mariangela Ambudkar, Indu S. Genazzani, Armando A. Rosti, Vittorio Pedrazzoli, Paolo Tanzi, Franco Moccia, Francesco Porta, Camillo TI Store-Operated Ca2+ Entry Is Remodelled and Controls In Vitro Angiogenesis in Endothelial Progenitor Cells Isolated from Tumoral Patients SO PLOS ONE LA English DT Article ID STROMAL INTERACTION MOLECULE-1; CAPACITATIVE CALCIUM-ENTRY; SIGNALING PATHWAYS; TUBE FORMATION; STIM PROTEINS; STEM-CELLS; PROLIFERATION; CHANNELS; CARCINOMA; GROWTH AB Background: Endothelial progenitor cells (EPCs) may be recruited from bone marrow to sustain tumor vascularisation and promote the metastatic switch. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis could outline novel targets for alternative anti-angiogenic treatments. Store-operated Ca2+ entry (SOCE), which is activated by a depletion of the intracellular Ca2+ pool, regulates the growth of human EPCs, where is mediated by the interaction between the endoplasmic reticulum Ca2+-sensor, Stim1, and the plasmalemmal Ca2+ channel, Orai1. As oncogenesis may be associated to the capability of tumor cells to grow independently on Ca2+ influx, it is important to assess whether SOCE regulates EPC-dependent angiogenesis also in tumor patients. Methodology/Principal Findings: The present study employed Ca2+ imaging, recombinant sub-membranal and mitochondrial aequorin, real-time polymerase chain reaction, gene silencing techniques and western blot analysis to investigate the expression and the role of SOCE in EPCs isolated from peripheral blood of patients affected by renal cellular carcinoma (RCC; RCC-EPCs) as compared to control EPCs (N-EPCs). SOCE, activated by either pharmacological (i.e. cyclopiazonic acid) or physiological (i.e. ATP) stimulation, was significantly higher in RCC-EPCs and was selectively sensitive to BTP-2, and to the trivalent cations, La3+ and Gd3+. Furthermore, 2-APB enhanced thapsigargin-evoked SOCE at low concentrations, whereas higher doses caused SOCE inhibition. Conversely, the anti-angiogenic drug, carboxyamidotriazole (CAI), blocked both SOCE and the intracellular Ca2+ release. SOCE was associated to the over-expression of Orai1, Stim1, and transient receptor potential channel 1 (TRPC1) at both mRNA and protein level The intracellular Ca2+ buffer, BAPTA, BTP-2, and CAI inhibited RCC-EPC proliferation and tubulogenesis. The genetic suppression of Stim1, Orai1, and TRPC1 blocked CPA-evoked SOCE in RCC-EPCs. Conclusions: SOCE is remodelled in EPCs from RCC patients and stands out as a novel molecular target to interfere with RCC vascularisation due to its ability to control proliferation and tubulogenesis. C1 [Lodola, Francesco; Dragoni, Silvia; Tanzi, Franco; Moccia, Francesco] Univ Pavia, Dept Biol & Biotechnol Lazzaro Spallanzani, I-27100 Pavia, Italy. [Laforenza, Umberto; Bottino, Cinzia] Univ Pavia, Sect Human Physiol, Dept Mol Med, I-27100 Pavia, Italy. [Bonetti, Elisa; Rosti, Vittorio] Clin Epidemiol Lab Fdn IRCCS Policlin San Matteo, Pavia, Italy. [Lim, Dmitry; Genazzani, Armando A.] Univ Eastern Piedmont Amedeo Avogadro, Dept Pharmaceut Sci, Novara, Italy. [Ong, Hwei Ling; Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Guerra, Germano] Univ Molise, Dept Hlth Sci, Campobasso, Italy. [Ganini, Carlo; Manzoni, Mariangela; Pedrazzoli, Paolo; Porta, Camillo] Med Oncol IRCCS Policlin San Matteo, Pavia, Italy. [Massa, Margherita] Fdn IRCCS Policlin San Matteo, Biotechnol Lab, Pavia, Italy. RP Moccia, F (reprint author), Univ Pavia, Dept Biol & Biotechnol Lazzaro Spallanzani, Via Palestro 3, I-27100 Pavia, Italy. EM francesco.moccia@unipv.it RI Lim, Dmitry/H-9101-2012; Bonetti, Elisa/D-4478-2016; OI Moccia, Francesco/0000-0003-0010-0098; Bonetti, Elisa/0000-0002-8406-5252; Ganini, Carlo/0000-0002-5839-3965; Genazzani, Armando/0000-0003-1923-7430; Rosti, Vittorio/0000-0003-4195-2289; Porta, Camillo/0000-0003-2412-1563 FU Ricerca Corrente, IRCCS Policlinico San Matteo Foundation, Pavia [674] FX This work was supported by a grant from Ricerca Corrente, #674, IRCCS Policlinico San Matteo Foundation, Pavia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 99 TC 63 Z9 63 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 25 PY 2012 VL 7 IS 9 AR e42541 DI 10.1371/journal.pone.0042541 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016YP UT WOS:000309556100003 PM 23049731 ER PT J AU Ribeiro, JMC Assumpcao, TCF Ma, DY Alvarenga, PH Pham, VM Andersen, JF Francischetti, IMB Macaluso, KR AF Ribeiro, Jose M. C. Assumpcao, Teresa C. F. Ma, Dongying Alvarenga, Patricia H. Pham, Van M. Andersen, John F. Francischetti, Ivo M. B. Macaluso, Kevin R. TI An Insight into the Sialotranscriptome of the Cat Flea, Ctenocephalides felis SO PLOS ONE LA English DT Article ID SALIVARY ADENOSINE-DEAMINASE; LUTZOMYIA-LONGIPALPIS; SEQUENCE ALIGNMENT; APYRASE ACTIVITY; ORAL SECRETION; BLACK FLY; DATABASE; IDENTIFICATION; SIALOME; PROTEIN AB Background: Saliva of hematophagous arthropods contains a diverse mixture of compounds that counteracts host hemostasis. Immunomodulatory and antiinflammatory components are also found in these organisms' saliva. Blood feeding evolved at least ten times within arthropods, providing a scenario of convergent evolution for the solution of the salivary potion. Perhaps because of immune pressure from hosts, the salivary proteins of related organisms have considerable divergence, and new protein families are often found within different genera of the same family or even among subgenera. Fleas radiated with their vertebrate hosts, including within the mammal expansion initiated 65 million years ago. Currently, only one flea species-the rat flea Xenopsylla cheopis-has been investigated by means of salivary transcriptome analysis to reveal salivary constituents, or sialome. We present the analysis of the sialome of cat flea Ctenocephaides felis. Methodology and Critical Findings: A salivary gland cDNA library from adult fleas was randomly sequenced, assembled, and annotated. Sialomes of cat and rat fleas have in common the enzyme families of phosphatases (inactive), CD-39-type apyrase, adenosine deaminases, and esterases. Antigen-5 members are also common to both sialomes, as are defensins. FS-I/Cys7 and the 8-Cys families of peptides are also shared by both fleas and are unique to these organisms. The Gly-His-rich peptide similar to holotricin was found only in the cat flea, as were the abundantly expressed Cys-less peptide and a novel short peptide family. Conclusions/Significance: Fleas, in contrast to bloodsucking Nematocera (mosquitoes, sand flies, and black flies), appear to concentrate a good portion of their sialome in small polypeptides, none of which have a known function but could act as inhibitors of hemostasis or inflammation. They are also unique in expansion of a phosphatase family that appears to be deficient of enzyme activity and has an unknown function. C1 [Ribeiro, Jose M. C.; Assumpcao, Teresa C. F.; Ma, Dongying; Pham, Van M.; Andersen, John F.; Francischetti, Ivo M. B.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, Rockville, MD USA. [Alvarenga, Patricia H.] Univ Fed Rio de Janeiro, Inst Bioquim Med, Lab Bioquim Resposta Estresse, Rio De Janeiro, Brazil. [Alvarenga, Patricia H.] INCT EM, Rio De Janeiro, Brazil. [Macaluso, Kevin R.] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Baton Rouge, LA 70803 USA. RP Ribeiro, JMC (reprint author), NIAID, Vector Biol Sect, Lab Malaria & Vector Res, Rockville, MD USA. EM jribeiro@niaid.nih.gov RI ma, dongying/D-8623-2012; Ribeiro, Jose/J-7011-2015; OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health; NIAID grant [AI077784]; Fundacao de Amparo a Pesquisa do Rio de Janeiro Carlos Chagas Filho (FAPERJ) FX This work was partly supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health, by NIAID grant (AI077784 KRM) to Dr. Macaluso, and by Fundacao de Amparo a Pesquisa do Rio de Janeiro Carlos Chagas Filho (FAPERJ) to Dr. Alvarenga. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 7 Z9 9 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 25 PY 2012 VL 7 IS 9 AR e44612 DI 10.1371/journal.pone.0044612 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016YP UT WOS:000309556100017 PM 23049752 ER PT J AU Trabert, B Wentzensen, N Yang, HP Sherman, ME Hollenbeck, A Danforth, KN Park, Y Brinton, LA AF Trabert, B. Wentzensen, N. Yang, H. P. Sherman, M. E. Hollenbeck, A. Danforth, K. N. Park, Y. Brinton, L. A. TI Ovarian cancer and menopausal hormone therapy in the NIH-AARP diet and health study SO BRITISH JOURNAL OF CANCER LA English DT Article DE ovarian cancer; menopausal hormone therapy; cohort ID ESTROGEN PLUS PROGESTIN; REPLACEMENT THERAPY; NATIONAL INSTITUTES; RISK; COHORT; WOMEN; TRIAL AB BACKGROUND: Women using unopposed estrogens during menopause are at increased risk of ovarian cancer. It is uncertain whether oestrogen plus progestin therapy exerts similar effects. METHODS: We evaluated menopausal hormone use and incident ovarian cancer (n = 426) in 92 601 post-menopausal women enrolled in the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study. Participants were administered questionnaires in 1996-1997 and followed through 2006. Hazard rate ratios (RR) and 95% confidence intervals (CIs) were estimated using Cox regression. RESULTS: Increased risks were associated with long duration (10 + years) use of unopposed oestrogen (RR 2.15, 95% CI: 1.30-3.57 among women with a hysterectomy) and oestrogen plus progestin (RR 1.68, 95% CI: 1.13-2.49 among women with intact uteri) therapy. Similar risks were associated with progestins that were used sequentially (< 15 days progestin per month) (RR 1.60, 95% CI: 1.10-2.33) or continuously (> 25 days progestin per month) (RR 1.43, 95% CI: 1.032-2.01; P-value for heterogeneity = 0.63). CONCLUSION: Our findings suggest that long duration use of both unopposed estrogens and oestrogen plus progestins are associated with increased risks of ovarian cancer, and that risk associated with oestrogen plus progestin use does not vary by regimen (sequential or continuous). British Journal of Cancer (2012) 107, 1181-1187. doi:10.1038/bjc.2012.397 www.bjcancer.com Published online 28 August 2012 (c) 2012 Cancer Research UK C1 [Trabert, B.; Wentzensen, N.; Yang, H. P.; Sherman, M. E.; Brinton, L. A.] NCI, Dept Hlth & Human Serv, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet,NIH, Rockville, MD 20852 USA. [Hollenbeck, A.] AARP, Washington, DC 20049 USA. [Danforth, K. N.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91188 USA. [Park, Y.] NCI, Dept Hlth & Human Serv, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet,NIH, Rockville, MD 20852 USA. RP Trabert, B (reprint author), NCI, Dept Hlth & Human Serv, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet,NIH, 6120 Execut Blvd,Suite 550, Rockville, MD 20852 USA. EM britton.trabert@nih.gov RI Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015; OI Brinton, Louise/0000-0003-3853-8562; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Programme of the NIH, National Cancer Institute; Florida Department of Health (FDOH) FX We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. This research was supported (in part) by the Intramural Research Programme of the NIH, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Programme, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumour Registry, Louisiana State University Medical Centre in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Centre for Health Data and Research, Bureau of Health Planning and Statistics, State Health Division, State of Nevada Department of Health and Human Services. NR 25 TC 10 Z9 10 U1 0 U2 6 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 SEP 25 PY 2012 VL 107 IS 7 BP 1181 EP 1187 DI 10.1038/bjc.2012.397 PG 7 WC Oncology SC Oncology GA 016SW UT WOS:000309540800026 PM 22929888 ER PT J AU Kuzmichev, AN Kim, SK D'Alessio, AC Chenoweth, JG Wittko, IM Campanati, L McKay, RD AF Kuzmichev, Andrey N. Kim, Suel-Kee D'Alessio, Ana C. Chenoweth, Josh G. Wittko, Ina M. Campanati, Loraine McKay, Ronald D. TI Sox2 Acts through Sox21 to Regulate Transcription in Pluripotent and Differentiated Cells SO CURRENT BIOLOGY LA English DT Article ID INTESTINAL STEM-CELLS; VERTEBRATE NEUROGENESIS; ORGAN FORMATION; EXPRESSION; GENE; CDX2; ENDODERM; MARKS; MAINTENANCE; PROGENITORS AB Sox2 is an important transcriptional regulator in embryonic and adult stem cells [1-4]. Recently, Sox2 was identified as an oncogene in many endodermal cancers, including colon cancer [5-8]. There is great interest in how Sox2 cooperates with other transcription factors to regulate stem cell renewal, differentiation, and reprogramming [9]. However, we still lack a general understanding of Sox2 transcriptional action. To determine transcriptional partners of Sox2 in adult cells, we generated mice where gene expression could be induced by an externally applied stimulus. We analyzed the consequences in the intestine where cell turnover is rapid. Sox2 expression, but not Oct4, specifically increased the numbers of stem cells and repressed Cdx2, a master regulator of endodermal identity. In vivo studies demonstrated that Sox21, another member of the SoxB gene family, was a specific, immediate, and cell-autonomous target of Sox2 in intestinal stem cells. In vitro experiments showed that Sox21 was sufficient to repress Cdx2 in colon cancer cells and in pluripotent stem cells. Sox21 was also specifically induced by Sox2 in fibroblasts and inhibition of Sox21 blocked reprogramming to the pluripotent state. These results show that transcriptional induction of Sox21 is a rapid and general mediator of the effects of Sox2 on cell identity in a wide range of cell types. C1 [Kuzmichev, Andrey N.; Kim, Suel-Kee; Chenoweth, Josh G.; Wittko, Ina M.; Campanati, Loraine; McKay, Ronald D.] NINDS, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. [Kuzmichev, Andrey N.; Kim, Suel-Kee; D'Alessio, Ana C.; Chenoweth, Josh G.; Campanati, Loraine; McKay, Ronald D.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP McKay, RD (reprint author), NINDS, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. EM ronald.mckay@libd.org RI Neurociencia, Inct/I-1011-2013 NR 45 TC 25 Z9 26 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD SEP 25 PY 2012 VL 22 IS 18 BP 1705 EP 1710 DI 10.1016/j.cub.2012.07.013 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 013TJ UT WOS:000309328500027 PM 22902753 ER PT J AU Je, HS Yang, F Ji, YY Nagappan, G Hempstead, BL Lu, B AF Je, H. Shawn Yang, Feng Ji, Yuanyuan Nagappan, Guhan Hempstead, Barbara L. Lu, Bai TI Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neuromuscular junction; pro-neurotrophin; synapse competition ID MATRIX METALLOPROTEINASES MMP-2; SYNAPTIC BASAL LAMINA; LONG-TERM DEPRESSION; RAT SOLEUS MUSCLE; CORTICAL CIRCUITS; P75(NTR); RECEPTOR; ELIMINATION; MODULATION; ACTIVATION AB Formation of specific neuronal connections often involves competition between adjacent axons, leading to stabilization of the active terminal, while retraction of the less active ones. The underlying molecular mechanisms remain unknown. We show that activity-dependent conversion of pro-brain-derived neurotrophic factor (proBDNF) to mature (m) BDNF mediates synaptic competition. Stimulation of motoneurons triggers proteolytic conversion of proBDNF to mBDNF at nerve terminals. In Xenopus nerve-muscle cocultures, in which two motoneurons innervate one myocyte, proBDNF-p75(NTR) signaling promotes retraction of the less active terminal, whereas mBDNF-tyrosine-related kinase B (TrkB) p75NTR (p75 neurotrophin receptor) facilitates stabilization of the active one. Thus, proBDNF and mBDNF may serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, and activity-dependent conversion of proBDNF to mBDNF may regulate synapse elimination. C1 [Je, H. Shawn; Yang, Feng; Ji, Yuanyuan; Nagappan, Guhan; Lu, Bai] NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. [Je, H. Shawn; Yang, Feng; Lu, Bai] NIMH, Genes Cognit & Psychosis Program GCAP, Bethesda, MD 20892 USA. [Je, H. Shawn] Duke Natl Univ Singapore Duke NUS, Grad Sch Med, Program Neurosci & Behav Disorders, Singapore 169857, Singapore. [Yang, Feng] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Ji, Yuanyuan; Nagappan, Guhan; Lu, Bai] GlaxoSmithKline, R&D China, Shanghai 201203, Peoples R China. [Hempstead, Barbara L.] Cornell Univ, Weill Med Coll, Dept Med, Div Hematol, New York, NY 10021 USA. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plast, Bethesda, MD 20892 USA. EM bai.b.lu@gsk.com OI Je, hyunsoo/0000-0002-2924-5621 FU National Institute of Mental Health (NIMH); National Institute of Child Health and Human Development (NICHD) intramural research programs; NIH; Muscular Dystrophy Association (MDA) FX We thank Drs. Phillip Nelson, Eugene Zaitsev, Keri Martinowitch, Jay Chang, and Newton Woo for thoughtful comments and suggestions and Regeneron Pharmaceuticals for providing recombinant BDNF. We also thank Drs. Bruce Carter, Mark Bothwell, Moses Chao, and Phil Barker for antibodies to p75NTR and Louis Reichardt and Moses Chao for antibodies to TrkB. Microscopy imaging was performed at the Porter Neuroscience Center Light Imaging Facility with the assistance of Dr. Carolyn Smith (NIH). This work was supported by the National Institute of Mental Health (NIMH) and National Institute of Child Health and Human Development (NICHD) intramural research programs (B. L.) and grants from the NIH and Muscular Dystrophy Association (MDA) (to B.H.). NR 53 TC 33 Z9 38 U1 1 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 25 PY 2012 VL 109 IS 39 BP 15924 EP 15929 DI 10.1073/pnas.1207767109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017QD UT WOS:000309604500079 PM 23019376 ER PT J AU Cannon, RE Peart, JC Hawkins, BT Campos, CR Miller, DS AF Cannon, Ronald E. Peart, John C. Hawkins, Brian T. Campos, Christopher R. Miller, David S. TI Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ABC transporters; chemotherapy; brain endothelium; ABCB1; breast cancer related protein; multidrug resistance-associated protein ID NECROSIS-FACTOR-ALPHA; PLATELET-ACTIVATING-FACTOR; XENOBIOTIC EFFLUX TRANSPORTERS; MEDIATED UP-REGULATION; MULTIPLE-SCLEROSIS; ENDOTHELIAL-CELLS; IN-VIVO; SPHINGOSINE 1-PHOSPHATE; SOLID TUMORS; MODULATION AB P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory-(TNF-alpha) and sphingolipid-based signaling. Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, H-3-verapamil (threefold increase), H-3-loperamide (fivefold increase), and H-3-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain C-14-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain. C1 [Cannon, Ronald E.; Peart, John C.; Campos, Christopher R.; Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Peart, John C.] N Carolina State Univ, Dept Biol, Raleigh, NC 27695 USA. [Hawkins, Brian T.] Univ Washington, Sch Med, Div Hematol, Seattle, WA 98104 USA. RP Cannon, RE (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM cannon1@niehs.nih.gov OI Hawkins, Brian/0000-0001-6719-5402 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences FX We thank Destiny Sykes for excellent technical support and Dr. Lindsay Smith for careful reading of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 44 TC 35 Z9 36 U1 2 U2 19 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 SEP 25 PY 2012 VL 109 IS 39 BP 15930 EP 15935 DI 10.1073/pnas.1203534109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 017QD UT WOS:000309604500080 PM 22949658 ER PT J AU Huang, P Lin, J Wang, XS Wang, Z Zhang, CL He, M Wang, K Chen, F Li, ZM Shen, GX Cui, DX Chen, XY AF Huang, Peng Lin, Jing Wang, Xiansong Wang, Zhe Zhang, Chunlei He, Meng Wang, Kan Chen, Feng Li, Zhiming Shen, Guangxia Cui, Daxiang Chen, Xiaoyuan TI Light-Triggered Theranostics Based on Photosensitizer-Conjugated Carbon Dots for Simultaneous Enhanced-Fluorescence Imaging and Photodynamic Therapy SO ADVANCED MATERIALS LA English DT Article DE theranostics; carbon dots; chlorin e6; fluorescence imaging; photodynamic therapy ID SEMICONDUCTOR QUANTUM DOTS; NEAR-INFRARED LIGHT; MODIFIED GOLD NANORODS; IN-VIVO; PHOTOTHERMAL THERAPY; MULTIFUNCTIONAL NANOPARTICLES; POLYMERIC MICELLES; ENERGY-TRANSFER; CANCER; DELIVERY C1 [Huang, Peng; Lin, Jing; Wang, Xiansong; Zhang, Chunlei; He, Meng; Wang, Kan; Chen, Feng; Li, Zhiming; Shen, Guangxia; Cui, Daxiang] Shanghai Jiao Tong Univ, Inst Micronano Sci & Technol, Shanghai 200240, Peoples R China. [Huang, Peng; Wang, Zhe; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Chen, Xiaoyuan] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Shen, GX (reprint author), Shanghai Jiao Tong Univ, Inst Micronano Sci & Technol, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. EM gxshen@sjtu.edu.cn; dxcui@sjtu.edu.cn; shawn.chen@nih.gov RI Chen, Feng/D-6406-2012; Huang, Peng/H-9985-2013; 1203, Feng/E-4310-2016; Huang, Peng/R-2480-2016 OI Chen, Feng/0000-0002-1162-1684; 1203, Feng/0000-0002-1162-1684; Huang, Peng/0000-0003-3651-7813 FU National Key Basic Research Program (973 Project) [2010CB933901, 2011CB933100]; National Natural Scientific Fund [51102258, 20803040, 81028009, 31170961]; New Century Excellent Talent of Ministry of Education of China [NCET-08-0350]; Shanghai Science and Technology Fund [1052nm04100]; Ministry of Education FX This work is supported by National Key Basic Research Program (973 Project) (No. 2010CB933901 and 2011CB933100), National Natural Scientific Fund (No. 51102258, 20803040, 81028009, 31170961), New Century Excellent Talent of Ministry of Education of China (NCET-08-0350), Shanghai Science and Technology Fund (No. 1052nm04100) and Scholarship Award for Excellent Doctoral Student granted by Ministry of Education. NR 77 TC 218 Z9 224 U1 60 U2 413 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0935-9648 J9 ADV MATER JI Adv. Mater. PD SEP 25 PY 2012 VL 24 IS 37 BP 5104 EP 5110 DI 10.1002/adma.201200650 PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 007JF UT WOS:000308883900010 PM 22718562 ER PT J AU Rossouw, JE Prentice, RL Manson, JE Aragaki, AK Hsia, J Martin, LW Kuller, L Johnson, KC Eaton, C Jackson, R Trevisan, M Allison, M Hoogeveen, RC AF Rossouw, Jacques E. Prentice, Ross L. Manson, JoAnn E. Aragaki, Aaron K. Hsia, Judith Martin, Lisa W. Kuller, Lewis Johnson, Karen C. Eaton, Charles Jackson, Rebecca Trevisan, Maurizio Allison, Matthew Hoogeveen, Ron C. TI Relationships of Coronary Heart Disease With 27-Hydroxycholesterol, Low-Density Lipoprotein Cholesterol, and Menopausal Hormone Therapy SO CIRCULATION LA English DT Article DE acute coronary syndrome; atherosclerosis; cholesterol, LDL; estrogens; pathophysiology ID ESTROGEN PLUS PROGESTIN; RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; STEROL 27-HYDROXYLASE; RISK; ATHEROSCLEROSIS; REPLACEMENT; OXYSTEROLS; PREVENTION AB Background-Menopausal hormone therapy (MHT) increases the risk of coronary heart disease (CHD) in older women with elevated low-density lipoprotein (LDLC) levels. The endogenous estrogen receptor antagonist 27-hydroxycholesterol (27OHC) is correlated with LDLC levels and may block the beneficial effects of estrogen on the cardiovascular system. Methods and Results-We conducted a nested case-control study in the Women's Health Initiative trials of 350 CHD cases and 813 matched controls to explore potential mediation by 27OHC of the dependence of the CHD risk elevation with MHT on LDLC. Baseline levels of 27OHC were not associated with CHD risk when LDLC was included in the multivariable models. The odds ratio for CHD associated with increased LDLC was 1.15 (95% confidence interval, 1.08-1.23) and was unchanged at 1.14 (95% confidence interval, 1.07-1.22) when 27OHC was added to the model. Baseline 27OHC did not interact with MHT on CHD risk (P=0.81). In contrast, LDLC levels modified the effect of MHT on CHD risk (P for interaction=0.02), and adding 27OHC did not affect this result. With the use of log scales, the effect of MHT on CHD increased linearly with increasing level of baseline LDLC, with a transition from no risk to increased risk at approximate to 3.36 mmol/L (130 mg/dL). Conclusions-This study found that 27OHC does not independently increase the risk of CHD, does not modify the increased risk of CHD resulting from MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation. C1 [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. [Prentice, Ross L.; Aragaki, Aaron K.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hsia, Judith] AstraZeneca LP, Wilmington, DE USA. [Martin, Lisa W.] George Washington Univ, Washington, DC USA. [Kuller, Lewis] Univ Pittsburgh, Pittsburgh, PA USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Eaton, Charles] Brown Univ, Mem Hosp Rhode Isl, Pawtucket, RI 02860 USA. [Jackson, Rebecca] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Trevisan, Maurizio] CUNY City Coll, New York, NY USA. [Allison, Matthew] Univ Calif San Diego, San Diego, CA 92103 USA. [Hoogeveen, Ron C.] Baylor Coll Med, Houston, TX 77030 USA. RP Rossouw, JE (reprint author), NHLBI, Rockledge 2 Bldg,Room 9192, Bethesda, MD 20892 USA. EM rossouwj@nih.gov OI Martin, Lisa Warsinger/0000-0003-4352-0914; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Study drugs were provided by Wyeth Research (St. Davids, PA). The National Institutes of Health had input into the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. Wyeth did not participate in any of the aforementioned aspects of the study. NR 33 TC 8 Z9 8 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 25 PY 2012 VL 126 IS 13 BP 1577 EP 1586 DI 10.1161/CIRCULATIONAHA.112.103218 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 012TX UT WOS:000309260600013 PM 22932256 ER PT J AU Wang, TJ Wollert, KC Larson, MG Coglianese, E McCabe, EL Cheng, SS Ho, JE Fradley, MG Ghorbani, A Xanthakis, V Kempf, T Benjamin, EJ Levy, D Vasan, RS Januzzi, JL AF Wang, Thomas J. Wollert, Kai C. Larson, Martin G. Coglianese, Erin McCabe, Elizabeth L. Cheng, Susan Ho, Jennifer E. Fradley, Michael G. Ghorbani, Anahita Xanthakis, Vanessa Kempf, Tibor Benjamin, Emelia J. Levy, Daniel Vasan, Ramachandran S. Januzzi, James L. TI Prognostic Utility of Novel Biomarkers of Cardiovascular Stress The Framingham Heart Study SO CIRCULATION LA English DT Article DE biological markers; growth differentiation factor-15; high-sensitivity troponin; risk; risk assessment; soluble ST2 ID GROWTH-DIFFERENTIATION FACTOR-15; ELEVATION MYOCARDIAL-INFARCTION; RECEPTOR FAMILY-MEMBER; HIGHLY SENSITIVE ASSAY; CARDIAC TROPONIN; NATRIURETIC PEPTIDE; INHIBITORY CYTOKINE-1; RISK STRATIFICATION; GENE-EXPRESSION; MORTALITY RISK AB Background-Biomarkers for predicting cardiovascular events in community-based populations have not consistently added information to standard risk factors. A limitation of many previously studied biomarkers is their lack of cardiovascular specificity. Methods and Results-To determine the prognostic value of 3 novel biomarkers induced by cardiovascular stress, we measured soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I in 3428 participants (mean age, 59 years; 53% women) in the Framingham Heart Study. We performed multivariable-adjusted proportional hazards models to assess the individual and combined ability of the biomarkers to predict adverse outcomes. We also constructed a "multimarker" score composed of the 3 biomarkers in addition to B-type natriuretic peptide and high-sensitivity C-reactive protein. During a mean follow-up of 11.3 years, there were 488 deaths, 336 major cardiovascular events, 162 heart failure events, and 142 coronary events. In multivariable-adjusted models, the 3 new biomarkers were associated with each end point (P<0.001) except coronary events. Individuals with multimarker scores in the highest quartile had a 3-fold risk of death (adjusted hazard ratio, 3.2; 95% confidence interval, 2.2-4.7; P<0.001), 6-fold risk of heart failure (6.2; 95% confidence interval, 2.6-14.8; P<0.001), and 2-fold risk of cardiovascular events (1.9; 95% confidence interval, 1.3-2.7; P=0.001). Addition of the multimarker score to clinical variables led to significant increases in the c statistic (P=0.005 or lower) and net reclassification improvement (P=0.001 or lower). Conclusion-Multiple biomarkers of cardiovascular stress are detectable in ambulatory individuals and add prognostic value to standard risk factors for predicting death, overall cardiovascular events, and heart failure. (Circulation. 2012;126:1596-1604.) C1 [Wang, Thomas J.; Coglianese, Erin; McCabe, Elizabeth L.; Ho, Jennifer E.; Fradley, Michael G.; Ghorbani, Anahita; Januzzi, James L.] Harvard Univ, Div Cardiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Wang, Thomas J.; Larson, Martin G.; Cheng, Susan; Ho, Jennifer E.; Benjamin, Emelia J.; Levy, Daniel; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Wollert, Kai C.; Kempf, Tibor] Hannover Med Sch, Dept Cardiol & Angiol, Div Mol & Translat Cardiol, D-3000 Hannover, Germany. [Larson, Martin G.] Boston Univ, Sch Med, Dept Math & Stat, Boston, MA 02118 USA. [Benjamin, Emelia J.; Levy, Daniel; Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Cardiol, Boston, MA 02118 USA. [Xanthakis, Vanessa; Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Prevent Med, Boston, MA 02118 USA. [Coglianese, Erin] Loyola Univ, Div Cardiol, Chicago, IL 60611 USA. [Cheng, Susan] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp,Div Cardiovasc Med, Boston, MA 02114 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Wang, TJ (reprint author), Harvard Univ, Div Cardiol, Massachusetts Gen Hosp, Sch Med, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org OI Larson, Martin/0000-0002-9631-1254; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute; Boston University [N01-HC-25195]; National Institutes of Health [R01-HL-08675]; German Ministry of Education and Research (BioChancePlus); Ellison Foundation; Roche Diagnostics; Siemens Diagnostics; Critical Diagnostics FX The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (contract N01-HC-25195). This manuscript was reviewed by the Framingham Heart Study for scientific content and consistency of data interpretation with previous Framingham Heart Study publications. Additional support was provided by National Institutes of Health grant R01-HL-08675. Dr Wollert was supported by the German Ministry of Education and Research (BioChancePlus). Dr Cheng is supported by a grant from the Ellison Foundation. Assays for sST2 were provided by Critical Diagnostics. Assays for hsTnI were provided by Singulex, Inc. GDF-15 assays were provided by Roche Diagnostics, Inc. These companies did not have access to study data and had no input into the data analyses, data interpretation, or preparation of the manuscript for submission. Dr Wang had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.; Dr Wang has received research or assay support from Diasorin, Brahms, LabCorp, and Siemens Diagnostics, as well as honoraria from Roche, Diasorin, and Quest Diagnostics. Drs Wang, Larson, and Vasan are named as coinventors on patent applications relating to the use of metabolomic or neurohormonal biomarkers in risk prediction. Dr Januzzi has received research grant funding from Roche Diagnostics, Siemens Diagnostics, and Critical Diagnostics. Drs Wollert and Kempf are named as coinventors on a patent for the use of GDF-15 for cardiovascular applications and have a contract with Roche Diagnostics for the development of a GDF-15 assay. Dr Wollert has received research grant funding from Roche Diagnostics. The other authors report no conflicts. NR 62 TC 144 Z9 146 U1 1 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 SEP 25 PY 2012 VL 126 IS 13 BP 1596 EP + DI 10.1161/CIRCULATIONAHA.112.129437 PG 18 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 012TX UT WOS:000309260600015 PM 22907935 ER PT J AU Fuster, V Bhatt, DL Califf, RM Michelson, AD Sabatine, MS Angiolillo, DJ Bates, ER Cohen, DJ Coller, BS Furie, B Hulot, JS Mann, KG Mega, JL Musunuru, K O'Donnell, CJ Price, MJ Schneider, DJ Simon, DI Weitz, JI Williams, MS Hoots, WK Rosenberg, YD Hasan, AAK AF Fuster, Valentin Bhatt, Deepak L. Califf, Robert M. Michelson, Alan D. Sabatine, Marc S. Angiolillo, Dominick J. Bates, Eric R. Cohen, David J. Coller, Barry S. Furie, Bruce Hulot, Jean-Sebastien Mann, Kenneth G. Mega, Jessica L. Musunuru, Kiran O'Donnell, Christopher J. Price, Matthew J. Schneider, David J. Simon, Daniel I. Weitz, Jeffrey I. Williams, Marlene S. Hoots, W. Keith Rosenberg, Yves D. Hasan, Ahmed A. K. TI Guided Antithrombotic Therapy: Current Status and Future Research Direction Report on a National Heart, Lung and Blood Institute Working Group SO CIRCULATION LA English DT Article DE anticoagulants; antiplatelet agents; antithrombotics; atrial fibrillation; coronary artery disease; myocardial infarction; platelet aggregation; stroke ID ACUTE CORONARY SYNDROMES; RESIDUAL PLATELET REACTIVITY; RECEPTOR GAMMA-CHAIN; TIMI 38 TRIAL; ATRIAL-FIBRILLATION; VENOUS THROMBOEMBOLISM; CARDIOVASCULAR EVENTS; ANTIPLATELET THERAPY; THROMBUS FORMATION; CLINICAL-OUTCOMES C1 [Fuster, Valentin; Hulot, Jean-Sebastien] Mt Sinai Sch Med, New York, NY USA. [Fuster, Valentin] CNIC, Madrid, Spain. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.; Michelson, Alan D.; Sabatine, Marc S.; Mega, Jessica L.; Musunuru, Kiran] Brigham & Womens Hosp, Boston, MA 02115 USA. [Califf, Robert M.] Duke Univ, Med Ctr, Durham, NC USA. [Michelson, Alan D.] Boston Childrens Hosp, Boston, MA USA. [Michelson, Alan D.; Sabatine, Marc S.; Furie, Bruce; Mega, Jessica L.; Musunuru, Kiran] Harvard Univ, Sch Med, Boston, MA USA. [Angiolillo, Dominick J.] Univ Florida, Coll Med, Jacksonville, FL USA. [Bates, Eric R.] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Cohen, David J.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Coller, Barry S.] Rockefeller Univ, New York, NY 10021 USA. [Furie, Bruce] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Mann, Kenneth G.; Schneider, David J.] Univ Vermont, Burlington, VA USA. [O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Bethesda, MD USA. [O'Donnell, Christopher J.; Hoots, W. Keith; Rosenberg, Yves D.; Hasan, Ahmed A. K.] NHLBI, NIH, Bethesda, MD 20892 USA. [Price, Matthew J.] Scripps Clin, La Jolla, CA 92037 USA. [Price, Matthew J.] Scripps Translat Sci Inst, La Jolla, CA USA. [Simon, Daniel I.] Univ Hosp Cleveland, Case Med Ctr, Cleveland, OH 44106 USA. [Weitz, Jeffrey I.] McMaster Univ, Hamilton, ON, Canada. [Williams, Marlene S.] Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. RP Fuster, V (reprint author), Mt Sinai Med Ctr, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM Valentin.Fuster@mssm.edu RI Hulot, Jean-Sebastien/A-2278-2016; Fuster, Valentin/H-4319-2015 OI Hulot, Jean-Sebastien/0000-0001-5463-6117; Fuster, Valentin/0000-0002-9043-9986 FU National Institutes of Health [HL57506]; Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc.; Medicines Company; Portola; Novartis; Medicure; Accumetrics; Arena Pharmaceuticals; Abbott Vascular; Astra Zeneca; Merck; Evolva; GlaxoSmithKline; Otsuka; Schering-Plough; Astra-Zeneca; Eisai; Amarin; Ethicon; Medtronic; Sanofi Aventis; Amylin; Johnson & Johnson (Scios); Novartis Pharma; Schering Plough; Bristol-Myers Squibb Foundation; Aterovax; Bayer; Roche; Lilly; Duke Clinical Research Institute; Eli Lilly; Daiichi-Sanko; Edwards Lifesciences; Boston Scientific; Pfizer; Biotronik; Medco Research Institute; NIH [PO1-HL046703]; Brigham and Women's Hospital from Eli Lilly; Daiichi Sankyo; Johnson Johnson; Bristol-Myers Squibb/Sanofi-Aventis; GLSynthesis; Takeda; Quest Diagnostics; Brigham; Women's Hospital from Abbott; Amgen; AstraZeneca; Bristol-Myers Squibb; Daiichi-Sankyo; Nanosphere; Bayer Pharmaceuticals; [HL 19278]; [CTSA UL1 TR000043] FX This work was supported in part by National Institutes of Health HL57506 MERIT Award to Dr Simon. Dr Coller is supported by grants HL 19278 and CTSA UL1 TR000043.; Dr Angiolillo received honoraria for lectures/speakers bureau from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc; Abbott Vascular; Astra Zeneca; consulting fees from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc.; The Medicines Company; Portola; Novartis; Medicure; Accumetrics; Arena Pharmaceuticals; Abbott Vascular; Astra Zeneca; Merck; Evolva; research grants (paid to Institution) from Bristol Myers Squibb; Sanofi-Aventis; GlaxoSmithKline; Otsuka; Eli Lilly Co; Daiichi Sankyo, Inc., The Medicines Company; Portola; Accumetrics; Schering-Plough; Astra-Zeneca; Eisai. Dr Bates serves as consultant for AstraZeneca, Eli Lilly, and Sanofi-Aventis. Dr Bhatt reports Advisory Board: Medscape Cardiology; Board of Directors: Boston VA Research Institute, Society of Chest Pain Centers; Chair: American Heart Association Get With The Guidelines Science Subcommittee; Honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; Unfunded Research: PLx Pharma, Takeda. Dr Califf reports receiving research grants that partially support his salary from Amylin, Johnson & Johnson (Scios), Merck, Novartis Pharma, Schering Plough, Bristol-Myers Squibb Foundation, Aterovax, Bayer, Roche, and Lilly; all grants are paid to Duke University. Dr Califf also consults for TheHeart. org, Johnson & Johnson (Scios), Kowa Research Institute, Nile, Parkview, Orexigen Therapeutics, Pozen, Servier International, WebMD, Bristol-Myers Squibb Foundation, AstraZeneca, Bayer-OrthoMcNeil, BMS, Boerhinger Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Li Ka Shing Knowledge Institute, Medtronic, Merck, Novartis, sanofi-aventis, XOMA, and the University of Florida; all income from these consultancies is donated to nonprofit organizations, with the majority going to the clinical research fellowship fund of the Duke Clinical Research Institute. Dr Califf holds equity in Nitrox LLC. Financial disclosure information for Dr Califf is also publicly available at https://www.dcri.org/about-us/conflict-of-interest. Dr Cohen has received research grants from Eli Lilly, Astra-Zeneca, Daiichi-Sanko, Medtronic, Edwards Lifesciences, Abbott Vascular, and Boston Scientific, and honoraria from Eli Lilly, Medtronic, and St. Jude. Dr Coller has royalty interests in abciximab (Centocor) and the VerifyNow Assays (Accumetrics) and currently serves as an unpaid advisor to Pfizer and Merck. As a result, Dr Coller's roles in the workshop and in writing this review were confined to providing scientific comments, without offering any specific diagnostic or therapeutic recommendations. Dr Furie has been the principal investigator on a research grant to the Marine Biological Laboratory from Pfizer and a consultant to Eleven Biotherapeutics. Drs Hasan and Hoots have no disclosures. Dr Hulot receives research grants (significant) from Biotronik and Medco Research Institute, and honoraria (significant) from Biotronik and Medco Health Solutions. Dr Mann serves as a consultant to Daiichi-Sankyo, Merck, Baxter, GTI, Alnylam and T2 Biosystems. He has a current NIH PO1-HL046703 and a prior grant and consultant with Johnson & Johnson. He is the Chairman of the Board of Hematologic Technologies, Inc.; Dr Mega receives research grants (significant) through Brigham and Women's Hospital from Eli Lilly, Daiichi Sankyo, Johnson & Johnson, Bayer, and Bristol-Myers Squibb/Sanofi-Aventis; honoraria from AstraZeneca, Merck, Bayer Healthcare, Bristol-Myers Squibb, and Sanofi-Aventis; and research supplies from Accumetrics and Nanosphere. Dr Michelson has been the principal investigator or coinvestigator on research grants to Boston Children's Hospital from GLSynthesis, Lilly and Takeda and on advisory boards for Lilly and Sanofi-Aventis. Drs Musunuru and O'Donnell have no disclosures. Dr Price receives research grants (significant) from Bristol-Myers Squibb/Sanofi-Aventis, Quest Diagnostics, and Accumetrics, and honoraria (significant) from Daiichi-Sankyo/Eli Lilly & Co., AstraZeneca, Accumetrics, W. L. Gore, and (moderate) from Boston Scientific, Johnson & Johnson, Bristol-Myers Squibb/Sanofi-Aventis, St. Jude Medical, Medicure, and Medtronic. Dr Rosenberg has no disclosure. Dr Sabatine receives research grants (significant) through Brigham and Women's Hospital from Abbott, Accumetrics, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Merck, Nanosphere, Roche, Sanofi-Aventis, and Takeda, honoraria from Amgen, Merck, Sanofi-Aventis (significant) and Bristol-Myers Squibb/Sanofi-Aventis. Dr Schneider has received research grants from Johnson & Johnson, Bayer Pharmaceuticals, Bristol-Myers Squibb, Sanofi Aventis, and The Medicines Company and honoraria from Johnson & Johnson, Sanofi Aventis, Bristol Myers Squibb, The Medicines Company, Astra Zeneca, and Regado Bioscience. Dr Simon has served on the scientific advisory board and/or consulting for Cordis/Johnson & Johnson (significant), Daiichi-Sankyo, Medtronic Vascular, Merck, and Portola. Dr Weitz receives honoraria (significant) from Boehringer-Ingelheim, Merck, Bayer Pharmaceuticals, Janssen Pharmaceuticals, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. Dr Williams reports no conflict. NR 128 TC 12 Z9 12 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 25 PY 2012 VL 126 IS 13 BP 1645 EP 1662 DI 10.1161/CIRCULATIONAHA.112.105908 PG 18 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 012TX UT WOS:000309260600021 PM 23008471 ER PT J AU Huang, CCJ Liu, C Yao, HHC AF Huang, Chen-Che Jeff Liu, Chang Yao, Humphrey Hung-Chang TI Investigating the role of adrenal cortex in organization and differentiation of the adrenal medulla in mice SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Adrenal cortex; Adrenal medulla; beta-Catenin; Sonic hedgehog; Dicer1 ID STEROIDOGENIC FACTOR-I; TARGETED DISRUPTION; BETA-CATENIN; CHROMAFFIN CELLS; SONIC HEDGEHOG; GENE; RECEPTOR; TRANSCRIPTION; AGENESIS; LINEAGE AB Functions of adrenal medulla, particularly synthesis of catecholamine, are under the control of glucocorticoids produced by the cortex. To further investigate whether development/differentiation of the adrenal medulla is associated with proper organization of the adrenal cortex, we examined development of the medulla in four different mouse models with various defects in the adrenal cortex. By using the Sf1/Cre mouse line that inactivates/activates genes in Steroidogenic factor 1 (SF1)-positive cells of the fetal adrenal cortex, we produced mice that exhibit either (1) cortex hypoplasia, (2) progressive degeneration of fetal adrenal cortex, (3) cortex dysgenesis, or (4) cortex-medulla disorganization. The formation of phenylethanolamine N-methyltransferase (PNMT)-positive medulla in all models indicates that differentiation of adrenal medulla is independent of the growth of adrenal cortex. However, the misplaced/dysgenic medulla in embryos where beta-catenin expression is altered, suggests that the beta-catenin pathway in the adrenal cortical cells plays an indirect role in controlling proper organization of the adrenal medulla. Published by Elsevier Ireland Ltd. C1 [Huang, Chen-Che Jeff; Liu, Chang; Yao, Humphrey Hung-Chang] Univ Illinois, Dept Comparat Biosci, Urbana, IL USA. [Liu, Chang; Yao, Humphrey Hung-Chang] NIEHS, Dev Reprod Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC USA. RP Yao, HHC (reprint author), Univ Illinois, Dept Comparat Biosci, Urbana, IL USA. EM humphrey.yao@nih.gov RI HUANG, CHEN-CHE JEFF/D-6502-2011; Yao, Humphrey Hung-Chang/B-4795-2010; OI HUANG, CHEN-CHE JEFF/0000-0003-0376-4682; Yao, Humphrey Hung-Chang/0000-0003-2944-8469; Liu, Chang/0000-0002-8723-7363 FU Intramural NIH HHS [ZIA ES102965-01] NR 35 TC 5 Z9 6 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD SEP 25 PY 2012 VL 361 IS 1-2 BP 165 EP 171 DI 10.1016/j.mce.2012.04.004 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 991HN UT WOS:000307692200017 PM 22580128 ER PT J AU Gartner, JJ Davis, S Wei, XM Lin, JC Trivedi, NS Teer, JK Meltzer, PS Rosenberg, SA Samuels, Y AF Gartner, Jared J. Davis, Sean Wei, Xiaomu Lin, Jimmy C. Trivedi, Niraj S. Teer, Jamie K. Meltzer, Paul S. Rosenberg, Steven A. Samuels, Yardena CA NISC Comparative Sequencing Progra TI Comparative exome sequencing of metastatic lesions provides insights into the mutational progression of melanoma SO BMC GENOMICS LA English DT Article AB Background: Metastasis is characterized by spreading of neoplastic cells to an organ other than where they originated and is the predominant cause of death among cancer patients. This holds true for melanoma, whose incidence is increasing more rapidly than any other cancer and once disseminated has few therapeutic options. Here we performed whole exome sequencing of two sets of matched normal and metastatic tumor DNAs. Results: Using stringent criteria, we evaluated the similarities and differences between the lesions. We find that in both cases, 96% of the single nucleotide variants are shared between the two metastases indicating that clonal populations gave rise to the distant metastases. Analysis of copy number variation patterns of both metastatic sets revealed a trend similar to that seen with our single nucleotide variants. Analysis of pathway enrichment on tumor sets shows commonly mutated pathways enriched between individual sets of metastases and all metastases combined. Conclusions: These data provide a proof-of-concept suggesting that individual metastases may have sufficient similarity for successful targeting of driver mutations. C1 [Gartner, Jared J.; Wei, Xiaomu; Samuels, Yardena] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Davis, Sean; Meltzer, Paul S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Lin, Jimmy C.] Washington Univ, Sch Med, Dept Pathol & Immunol, Dis Lab & Genom Med, St Louis, MO USA. [Teer, Jamie K.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Trivedi, Niraj S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Samuels, Y (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM samuelsy@mail.nih.gov OI Davis, Sean/0000-0002-8991-6458 FU National Human Genome Research Institute; National Cancer Institute, National Institutes of Health, USA; National Cancer Institute; Eli Lilly and Company FX We thank P. Cruz for the exome analyses of these data generated by NISC. This work supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute, National Institutes of Health, USA and Company. This work is supported by a public-private partnership between the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute, and Eli Lilly and Company coordinated by the Foundation for the National Institutes of Health. NR 0 TC 12 Z9 12 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD SEP 24 PY 2012 VL 13 AR 505 DI 10.1186/1471-2164-13-505 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 040XC UT WOS:000311358600001 PM 23006843 ER PT J AU Kiddle, SJ Thambisetty, M Simmons, A Riddoch-Contreras, J Hye, A Westman, E Pike, I Ward, M Johnston, C Lupton, MK Lunnon, K Soininen, H Kloszewska, I Tsolaki, M Vellas, B Mecocci, P Lovestone, S Newhouse, S Dobson, R AF Kiddle, Steven John Thambisetty, Madhav Simmons, Andrew Riddoch-Contreras, Joanna Hye, Abdul Westman, Eric Pike, Ian Ward, Malcolm Johnston, Caroline Lupton, Michelle Katharine Lunnon, Katie Soininen, Hilkka Kloszewska, Iwona Tsolaki, Magda Vellas, Bruno Mecocci, Patrizia Lovestone, Simon Newhouse, Stephen Dobson, Richard CA Alzheimers Dis Neuroimaging Initia TI Plasma Based Markers of [C-11] PiB-PET Brain Amyloid Burden SO PLOS ONE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; EARLY ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; CLUSTERIN CONCENTRATION; BIOMARKERS; MRI; CLASSIFICATION; PROGRESSION; PREDICTION; DEPOSITION AB Changes in brain amyloid burden have been shown to relate to Alzheimer's disease pathology, and are believed to precede the development of cognitive decline. There is thus a need for inexpensive and non-invasive screening methods that are able to accurately estimate brain amyloid burden as a marker of Alzheimer's disease. One potential method would involve using demographic information and measurements on plasma samples to establish biomarkers of brain amyloid burden; in this study data from the Alzheimer's Disease Neuroimaging Initiative was used to explore this possibility. Sixteen of the analytes on the Rules Based Medicine Human Discovery Multi-Analyte Profile 1.0 panel were found to associate with [C-11]-PiB PET measurements. Some of these markers of brain amyloid burden were also found to associate with other AD related phenotypes. Thirteen of these markers of brain amyloid burden - c-peptide, fibrinogen, alpha-1-antitrypsin, pancreatic polypeptide, complement C3, vitronectin, cortisol, AXL receptor kinase, interleukin-3, interleukin-13, matrix metalloproteinase-9 total, apolipoprotein E and immunoglobulin E - were used along with co-variates in multiple linear regression, and were shown by cross-validation to explain > 30% of the variance of brain amyloid burden. When a threshold was used to classify subjects as PiB positive, the regression model was found to predict actual PiB positive individuals with a sensitivity of 0.918 and a specificity of 0.545. The number of APOE epsilon 4 alleles and plasma apolipoprotein E level were found to contribute most to this model, and the relationship between these variables and brain amyloid burden was explored. C1 [Kiddle, Steven John; Simmons, Andrew; Westman, Eric; Johnston, Caroline; Lovestone, Simon; Newhouse, Stephen; Dobson, Richard] S London & Maudsley Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res, Biomed Res Ctr Mental Hlth, London, England. [Kiddle, Steven John; Simmons, Andrew; Riddoch-Contreras, Joanna; Hye, Abdul; Westman, Eric; Johnston, Caroline; Lupton, Michelle Katharine; Lunnon, Katie; Lovestone, Simon; Newhouse, Stephen; Dobson, Richard] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Thambisetty, Madhav] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Pike, Ian; Ward, Malcolm] Proteome Sci Plc, Surrey, England. [Soininen, Hilkka] Univ Eastern Finland, Sch Neurol, Kuopio, Finland. [Soininen, Hilkka] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Kloszewska, Iwona] Med Univ Lodz, Dept Old Age Psychiat & Psychot Disorders, Lodz, Poland. [Tsolaki, Magda] Aristotle Univ Thessaloniki, G Papanicolaou Hosp, Dept Neurol 3, GR-54006 Thessaloniki, Greece. [Vellas, Bruno] Toulouse Univ Hosp, Dept Geriatr Med, Grontople Toulouse, Toulouse, France. [Mecocci, Patrizia] Univ Perugia, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. RP Kiddle, SJ (reprint author), S London & Maudsley Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res, Biomed Res Ctr Mental Hlth, London, England. EM steven.kiddle@kcl.ac.uk; richard.j.dobson@kcl.ac.uk RI Westman, Eric/H-5771-2011; Kiddle, Steven/H-3463-2012; Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Simmons, Andrew/B-8848-2008; Saykin, Andrew/A-1318-2007; Dobson, Richard/C-9269-2011; Lunnon, Katie/C-4638-2012; Newhouse, Stephen/C-9330-2011 OI Kiddle, Steven/0000-0003-4350-7437; Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Simmons, Andrew/0000-0003-2306-5811; Saykin, Andrew/0000-0002-1376-8532; Dobson, Richard/0000-0003-4224-9245; Lunnon, Katie/0000-0001-7570-6065; Newhouse, Stephen/0000-0002-1843-9842 FU ADNI (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; Northern California Institute for Research and Education; National Institutes of Health [P30 AG010129, K01 AG030514]; InnoMed (Innovative Medicines in Europe); European Union; National Institutes for Health Research Biomedical Research Centre for Mental Health at the South London; Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King's College London; Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd; Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; Takeda Pharmaceutical Company FX Alzheimer's Disease Neuroimaging Initiative (ADNI) data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by National Institutes of Health grants P30 AG010129 and K01 AG030514. This study was supported by InnoMed (Innovative Medicines in Europe www.imi.europa.eu/) an Integrated Project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5, Life Sciences, Genomics and Biotechnology for Health. This study was also supported by funds from the National Institutes for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King's College London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Intellectual property has been registered on the use of plasma proteins for use as biomarkers for AD by King's College London and Proteome Sciences, with SL and M. Thambisetty named as inventors. IP and MW were full-time employees of Proteome Sciences, London, United Kingdom, at the time of their contribution to the work described in this manuscript. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. Patent Title Methods and Compositions Relating to Alzheimer's Disease Subject Covers utility of around 30 proteins, specifically listing 16 in the Dependent claims for diagnosis of Alzheimer's disease Filing Proteome Sciences with King's Business United Kingdom Priority GB0421639.6 dated 29/09/2004 PCT Application PCT/GB2005/003756 dated 29/09/2005 Application in Europe, Japan, United States, Australia, and Canada, dated 15/03/2007 to 16/10/2007. In addition Alzheimer's Disease Neuroimaging Initiative recieved funding from: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 53 TC 30 Z9 30 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 24 PY 2012 VL 7 IS 9 AR e44260 DI 10.1371/journal.pone.0044260 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016YB UT WOS:000309554700010 PM 23028511 ER PT J AU Pan, ST Thompson, RCA Grigg, ME Sundar, N Smith, A Lymbery, AJ AF Pan, Shuting Thompson, R. C. Andrew Grigg, Michael E. Sundar, Natarajan Smith, Andrew Lymbery, Alan J. TI Western Australian Marsupials Are Multiply Infected with Genetically Diverse Strains of Toxoplasma gondii SO PLOS ONE LA English DT Article ID SEXUAL RECOMBINATION; POPULATION-STRUCTURE; SEROPREVALENCE; TRANSMISSION; EXPANSION; PARASITES; GENOTYPE; SWEEPS; DRIVEN AB Five different organs from 16 asymptomatic free-ranging marsupial macropods (Macropus rufus, M. fuliginosus, and M. robustus) from inland Western Australia were tested for infection with Toxoplasma gondii by multi-locus PCR-DNA sequencing. All macropods were infected with T. gondii, and 13 had parasite DNA in at least 2 organs. In total, 45 distinct T. gondii genotypes were detected. Fourteen of the 16 macropods were multiply infected with genetically distinct T. gondii genotypes that often partitioned between different organs. The presence of multiple T. gondii infections in macropods suggests that native mammals have the potential to promote regular cycles of sexual reproduction in the definitive felid host in this environment. C1 [Lymbery, Alan J.] Murdoch Univ, Sch Vet & Biomed Sci, Fish Hlth Unit, Perth, WA, Australia. [Grigg, Michael E.; Sundar, Natarajan] NIAID, Mol Parasitol Unit, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Lymbery, AJ (reprint author), Murdoch Univ, Sch Vet & Biomed Sci, Fish Hlth Unit, Perth, WA, Australia. EM a.lymbery@murdoch.edu.au OI Lymbery, Alan/0000-0002-0542-3446 FU Australian Research Council; Murdoch University FX This work was supported by the Australian Research Council and Murdoch University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 12 Z9 15 U1 2 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 24 PY 2012 VL 7 IS 9 AR e45147 DI 10.1371/journal.pone.0045147 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 016YB UT WOS:000309554700025 PM 23028812 ER PT J AU Hwang, S Song, KD Lesourne, R Lee, J Pinkhasov, J Li, LQ El-Khoury, D Love, PE AF Hwang, SuJin Song, Ki-Duk Lesourne, Renaud Lee, Jan Pinkhasov, Julia Li, LiQi El-Khoury, Dalal Love, Paul E. TI Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID REGULATORY T-CELLS; FOXP3 EXPRESSION; EPITHELIAL-CELLS; AUTOREACTIVE THYMOCYTES; ACTIVATION MOTIFS; THYMIC EXPRESSION; SELF-ANTIGEN; MICE LACKING; TOLERANCE; AIRE AB Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR zeta chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous zeta regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability. C1 [Hwang, SuJin; Song, Ki-Duk; Lesourne, Renaud; Lee, Jan; Pinkhasov, Julia; Li, LiQi; El-Khoury, Dalal; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Love, PE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM lovep@mail.nih.gov RI Lesourne, Renaud/M-1855-2014 FU intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was funded by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 59 TC 14 Z9 14 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 SEP 24 PY 2012 VL 209 IS 10 BP 1781 EP 1795 DI 10.1084/jem.20120058 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 012EX UT WOS:000309219400007 PM 22945921 ER PT J AU Mateen, FJ Nath, A AF Mateen, Farrah J. Nath, Avindra TI Central nervous system-immune reconstitution inflammatory syndrome in resource-limited settings: current burden and future needs SO AIDS LA English DT Article DE cryptococcal meningitis; Cryptococcus; epidemiology; HIV; immune reconstitution inflammatory syndrome; immune system; progressive multifocal leukoencephalopathy ID STARTING ANTIRETROVIRAL THERAPY; CRYPTOCOCCAL MENINGITIS; HIV-INFECTION; AIDS PATIENTS; MANIFESTATIONS; MORTALITY; HIV/AIDS; AFRICA; IRIS; PML C1 [Mateen, Farrah J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21218 USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Mateen, Farrah J.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Mateen, FJ (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Room E8527,615 N Wolfe St, Baltimore, MD 21218 USA. EM fmateen@jhsph.edu FU American Brain Foundation FX F.J.M. is supported by the 2010-2012 American Brain Foundation Practice Research Fellowship Grant. NR 28 TC 4 Z9 4 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 24 PY 2012 VL 26 IS 15 BP 1851 EP 1855 DI 10.1097/QAD.0b013e3283574e1a PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 012GN UT WOS:000309224100001 PM 22781220 ER PT J AU Tomescu, C Duh, FM Hoh, R Viviani, A Harvill, K Martin, MP Carrington, M Deeks, SG Montaner, LJ AF Tomescu, Costin Duh, Fuh-Mei Hoh, Rebecca Viviani, Anne Harvill, Kara Martin, Maureen P. Carrington, Mary Deeks, Steven G. Montaner, Luis J. TI Impact of protective killer inhibitory receptor/human leukocyte antigen genotypes on natural killer cell and T-cell function in HIV-1-infected controllers SO AIDS LA English DT Article DE AIDS; elite controllers; HIV-1; human leukocyte antigen; killer inhibitory receptor; natural killer cells; T cells ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMACYTOID DENDRITIC CELLS; LONG-TERM NONPROGRESSORS; ELITE CONTROLLERS; INFECTED FIBROBLASTS; ACCESSORY CELLS; HIV-1 INFECTION; HLA-B; REPLICATION CAPACITY; NK-CELLS AB Objective: Both protective T-cell genotypes and natural killer (NK) cell genotypes have been associated with delayed progression to AIDS and shown to be co-inherited in HIV-1-infected individuals who limit viral replication in absence of antiretroviral therapy ('controllers'). However, a comparative analysis of the genotype and function of the innate and adaptive immune compartments in HIV-1-infected controller individuals has been understudied to date. Design: Here, we simultaneously tested NK and T-cell function in controllers to investigate the mechanism(s) thatmight account for host immune control over viral replication. Methods: We measured CD8 T-cell responses against HIV-1 utilizing overlapping 15-mer peptides spanning the HIV-1 consensus clade B Gag protein and tested NK cell degranulation and cytokine secretion against tumor target cells following interferon-alpha (IFN alpha) stimulation. Results: Among a cohort of 37 controllers, the presence of protective major histocompatibility complex class I human leukocyte antigen (HLA) alleles (such as HLA-B*57) was not correlated with HIV-specific CD8 responses. In contrast, the inheritance of a protective killer inhibitory receptor KIR3DL1*h/*y receptor genotype along with the corresponding HLA-Bw4*80I ligand was associated with significantly heightened target cell-induced NK degranulation and cytokine secretion following IFN alpha stimulation (P = 0.0201, n = 13). Interestingly, we observed a significant inverse association between the IFN alpha stimulated NK response to K562 cells and the HIV-specific CD8 T-cell response to Gag among elite controllers (rho = -0.8321, P = 0.0010, n = 12). Conclusion: Together, these results suggest that heightened NK responses can be evidenced independently of HIV-specific T-cell responses in HIV-1-infected elite controllers. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Tomescu, Costin; Montaner, Luis J.] Wistar Inst Anat & Biol, HIV Immunopathogenesis Lab, Philadelphia, PA 19104 USA. [Duh, Fuh-Mei; Martin, Maureen P.; Carrington, Mary] NCI Frederick, SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Duh, Fuh-Mei; Martin, Maureen P.; Carrington, Mary] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. [Hoh, Rebecca; Viviani, Anne; Harvill, Kara; Deeks, Steven G.] Univ Calif San Francisco, Posit Hlth AIDS Study, San Francisco, CA 94143 USA. RP Montaner, LJ (reprint author), Wistar Inst Anat & Biol, HIV Immunopathogenesis Lab, 3601 Spruce St,Room 480, Philadelphia, PA 19104 USA. EM montaner@wistar.org FU National Institutes of Health [R21 AI078870, NIDA R01 DA028775, R01 AI073219, RO1 AI065279, P30 CA10815]; Philadelphia Foundation; Pennsylvania Commonwealth Universal Research Enhancement Program; Centers for AIDS Research at UCSF [PO AI27763]; CFAR Network of Integrated Systems [R24 AI067039]; UCSF CTSI [UL1 RR024131]; NIAID [RO1 AI087145, K24AI069994, AI 76174]; amfAR; Ragon Institute; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This study was supported by grants from the National Institutes of Health (R21 AI078870, NIDA R01 DA028775, R01 AI073219, RO1 AI065279, Core grant P30 CA10815), the Philadelphia Foundation and funds from the Pennsylvania Commonwealth Universal Research Enhancement Program. The UCSF-based SCOPE cohort of controllers was supported in part by the Centers for AIDS Research at UCSF (PO AI27763), CFAR Network of Integrated Systems (R24 AI067039), the UCSF CTSI (UL1 RR024131), NIAID (RO1 AI087145, K24AI069994, AI 76174), amfAR, and the Ragon Institute. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U. S. Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 48 TC 26 Z9 27 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 24 PY 2012 VL 26 IS 15 BP 1869 EP 1878 DI 10.1097/QAD.0b013e32835861b0 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 012GN UT WOS:000309224100003 PM 22874514 ER PT J AU Bild, DE AF Bild, Diane E. TI Thriving of the Fittest SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Bild, DE (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Mail Stop Code 7938, Bethesda, MD 20892 USA. EM bildd@nhlbi.nih.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 24 PY 2012 VL 172 IS 17 BP 1340 EP 1341 DI 10.1001/archinternmed.2012.3406 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 010FE UT WOS:000309079300011 PM 22928179 ER PT J AU Adeyemo, A Bentley, AR Meilleur, KG Doumatey, AP Chen, GJ Zhou, J Shriner, D Huang, HX Herbert, A Gerry, NP Christman, MF Rotimi, CN AF Adeyemo, Adebowale Bentley, Amy R. Meilleur, Katherine G. Doumatey, Ayo P. Chen, Guanjie Zhou, Jie Shriner, Daniel Huang, Hanxia Herbert, Alan Gerry, Norman P. Christman, Michael F. Rotimi, Charles N. TI Transferability and Fine Mapping of genome-wide associated loci for lipids in African Americans SO BMC MEDICAL GENETICS LA English DT Article DE Lipids; Genetics; African Americans; Genome-wide association study; Ethnicity ID LINKAGE DISEQUILIBRIUM; NATIONAL-HEALTH; POPULATION; RISK; CHOLESTEROL; TRAITS; ADULTS; SET AB Background: A recent, large genome-wide association study (GWAS) of European ancestry individuals has identified multiple genetic variants influencing serum lipids. Studies of the transferability of these associations to African Americans remain few, an important limitation given interethnic differences in serum lipids and the disproportionate burden of lipid-associated metabolic diseases among African Americans. Methods: We attempted to evaluate the transferability of 95 lipid-associated loci recently identified in European ancestry individuals to 887 non-diabetic, unrelated African Americans from a population-based sample in the Washington, DC area. Additionally, we took advantage of the generally reduced linkage disequilibrium among African ancestry populations in comparison to European ancestry populations to fine-map replicated GWAS signals. Results: We successfully replicated reported associations for 10 loci (CILP2/SF4, STARD3, LPL, CYP7A1, DOCK7/ANGPTL3, APOE, SORT1, IRS1, CETP, and UBASH3B). Through trans-ethnic fine-mapping, we were able to reduce associated regions around 75% of the loci that replicated. Conclusions: Between this study and previous work in African Americans, 40 of the 95 loci reported in a large GWAS of European ancestry individuals also influence lipid levels in African Americans. While there is now evidence that the lipid-influencing role of a number of genetic variants is observed in both European and African ancestry populations, the still considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of these traits. C1 [Adeyemo, Adebowale; Bentley, Amy R.; Doumatey, Ayo P.; Chen, Guanjie; Zhou, Jie; Shriner, Daniel; Huang, Hanxia; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Meilleur, Katherine G.] NINDS, NIH, Bethesda, MD 20892 USA. [Herbert, Alan] Boston Univ, Dept Genet & Genom, Boston, MA 02215 USA. [Gerry, Norman P.; Christman, Michael F.] Coriell Inst Med Res, Camden, NJ USA. RP Adeyemo, A (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM adeyemoa@mail.nih.gov; rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health [S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Coriell Institute for Medical Research; Office of the Director at the National Institutes of Health [Z01HG200362] FX The Howard University Family Study was supported by National Institutes of Health grants S06GM008016-320107 to CNR and S06GM008016-380111 to AA. We thank the participants of the study, for which enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). Genotyping support was provided by the Coriell Institute for Medical Research. NR 27 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 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD SEP 21 PY 2012 VL 13 AR 88 DI 10.1186/1471-2350-13-88 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 092WO UT WOS:000315153900001 PM 22994408 ER PT J AU Lebovitz, EE Keller, JM Kominsky, H Kaszas, K Maric, D Iadarola, MJ AF Lebovitz, Evan E. Keller, Jason M. Kominsky, Hal Kaszas, Krisztian Maric, Dragan Iadarola, Michael J. TI Positive allosteric modulation of TRPV1 as a novel analgesic mechanism SO MOLECULAR PAIN LA English DT Article DE TRPV1; Pain; Capsaicin; Vanilloid; Nociception; Resiniferatoxin; ATF3; Dorsal root ganglion; MRS1477; Adelta fiber ID CONCENTRATION CAPSAICIN PATCH; PRIMARY AFFERENT NEURONS; SENSORY NERVE-TERMINALS; PERIPHERAL AXOTOMY; INFLAMMATORY MEDIATORS; SPINAL-CORD; VANILLOID RECEPTOR-1; NEUROPATHIC PAIN; UNITED-STATES; SCIATIC-NERVE AB Background: The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C-and lightly-myelinated Ad-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment. Results: Withdrawal responses of the capsaicin-only or MRS1477-only treated paws were not significantly different from the untreated, contralateral paws. However, rats treated with the combination of capsaicin and MRS1477 exhibited increased withdrawal latency and decreased response intensity consistent with agonist potentiation and inactivation or lesion of TRPV1-containing nerve terminals. The loss of nerve endings was manifested by an increase in levels of axotomy markers assessed by qRT-PCR and colocalization of ATF3 in TRPV1(+) cells visualized via immunohistochemistry. Conclusions: The present observations suggest a novel, non-narcotic, selective, long-lasting TRPV1-based approach for analgesia that may be effective in acute, persistent, or chronic pain disorders. C1 [Lebovitz, Evan E.; Keller, Jason M.; Kominsky, Hal; Kaszas, Krisztian; Iadarola, Michael J.] NIDCR, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Iadarola, MJ (reprint author), NIDCR, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bldg 49,Rm 1C2049,Convent Dr, Bethesda, MD 20892 USA. EM miadarola@dir.nidcr.nih.gov FU Howard Hughes Medical Institute as an HHMI-NIH Research Scholar; Division of Intramural Research NIDCR, NIH; NIH [R03MH089480] FX EEL received funding from the Howard Hughes Medical Institute as an HHMI-NIH Research Scholar and from the Division of Intramural Research NIDCR, NIH. This work was supported by the Division of Intramural Research, NIDCR, NIH. NIH grant R03MH089480. NR 72 TC 6 Z9 6 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD SEP 21 PY 2012 VL 8 AR 70 DI 10.1186/1744-8069-8-70 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 077IW UT WOS:000314022100001 PM 22998799 ER PT J AU Nilubol, N Zhang, L Shen, M Zhang, YQ He, M Austin, CP Kebebew, E AF Nilubol, Naris Zhang, Lisa Shen, Min Zhang, Ya-Qin He, Mei Austin, Christopher P. Kebebew, Electron TI Four clinically utilized drugs were identified and validated for treatment of adrenocortical cancer using quantitative high-throughput screening SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Adrenocortical cancer; High throughput drug screening; Chemotherapy; Drug repurposing; Indication switching ID CARCINOMA CELL-LINE; CARDIAC-GLYCOSIDES; BREAST-CANCER; PROSTATE-CANCER; MELANOMA-CELLS; APOPTOSIS; DIGITALIS; THERAPY; INHIBITORS; SW-13 AB Background: Drug repurposing for cancer treatment is an emerging approach to discover clinically approved drugs that demonstrate antineoplastic effect. The effective therapeutics for patients with advanced adrenocortical carcinoma(ACC) are greatly needed. The objective of this study was to identify and validate drugs with antineoplastic effect in ACC cells using a novel quantitative high-throughput drug screening (qHTS) technique. Methods: A quantitative high-throughput proliferation assay of 2,816 clinically approved drugs was performed in the NCI-H295R ACC cell line. We validated the antiproliferative effect of candidate compounds in NCI-H295R cells. Further validation was performed in 3-dimensional multicellular aggregates (MCA) of NCI-H295R and SW-13 cell lines. Results: We identified 79 active compounds against ACC cells; 21 had an efficacy >= 60% and IC50 < 1 mu M. The top drug categories enriched were cardiotonic, antiseptic, and antineoplastic. We selected Bortezomib, ouabain, Methotrexate, pyrimethamine for validation. All had an antiproliferative effect in monolayer culture of NCI-H295R cells at clinical achievable serum level. Bortezomib and ouabain inhibited growth of MCA in both cell lines at a low concentration (10 fold below IC50). Methotrexate inhibited growth and caused disintegration of MCA in both cell lines at concentrations well below the maximum serum level (10 to 100 fold of IC50). Pyrimethamine caused growth inhibition in both cell lines at 10 fold of IC50 concentration. Conclusions: qHTS of previously approved compounds is an effective and efficient method to identify anticancer drugs for a rare cancer such as ACC. We have validated the antineoplastic effect of Bortezomib, ouabain, Methotrexate and pyrimethamine, which could be translated into clinical trials in patients with locally advanced and/or metastatic ACC. C1 [Nilubol, Naris; Zhang, Lisa; He, Mei; Kebebew, Electron] NCI, NIH, Endocrine Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Shen, Min; Zhang, Ya-Qin; Austin, Christopher P.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Nilubol, N (reprint author), NCI, NIH, Endocrine Oncol Branch, Ctr Canc Res, Rm 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM niluboln@mail.nih.gov FU Paul LoGerfo Research Award; American Association of Endocrine Surgeons; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The research activities performed in this manuscript were supported in part by 1) 2011 The Paul LoGerfo Research Award, the American Association of Endocrine Surgeons, and 2) the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 46 TC 14 Z9 14 U1 0 U2 3 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 SEP 21 PY 2012 VL 10 AR 198 DI 10.1186/1479-5876-10-198 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 037MF UT WOS:000311108700001 PM 22999104 ER PT J AU Wen, XB Cao, DJ Jones, RW Li, JP Szu, SS Hoshino, Y AF Wen, Xiaobo Cao, Dianjun Jones, Ronald W. Li, Jianping Szu, Shousun Hoshino, Yasutaka TI Construction and characterization of human rotavirus recombinant VP8* subunit parenteral vaccine candidates SO VACCINE LA English DT Article DE Rotavirus; Vaccine; Subunit vaccine; VP8*protein; P type ID SEVERE COMBINED IMMUNODEFICIENCY; SEROTYPIC CHARACTERIZATION; PROTECTIVE IMMUNITY; PORCINE CIRCOVIRUS; ESCHERICHIA-COLI; SPIKE PROTEIN; INFECTION; GASTROENTERITIS; DIARRHEA; STRAINS AB Two currently licensed live oral rotavirus vaccines (Rotarix (R) and RotaTeq (R)) are highly efficacious against severe rotavirus diarrhea. However, the efficacy of such vaccines in selected low-income African and Asian countries is much lower than that in middle or high-income countries. Additionally, these two vaccines have recently been associated with rare case of intussusception in vaccinated infants. We developed a novel recombinant subunit parenteral rotavirus vaccine which may be more effective in low-income countries and also avert the potential problem of intussusception. Truncated recombinant VP8* (Delta VP8*) protein of human rotavirus strain Wa P[8], DS-1 P[4] or 1076 P[6] expressed in Escherichia coli was highly soluble and was generated in high yield. Guinea pigs hyperimmunized intramuscularly with each of the Delta VP8* proteins (i.e., P[8], P[4] or P[6]) developed high levels of homotypic as well as variable levels of heterotypic neutralizing antibodies. Moreover, the selected Delta VP8* proteins when administered to mice at a clinically relevant dosage, route and schedule, elicited high levels of serum anti-VP8* IgG and/or neutralizing antibodies. Our data indicated that the Delta VP8* proteins may be a plausible additional candidate as new parenteral rotavirus vaccines. Published by Elsevier Ltd. C1 [Wen, Xiaobo; Cao, Dianjun; Jones, Ronald W.; Hoshino, Yasutaka] NIAID, Rotavirus Vaccine Dev Sect, Labs Infect Dis, NIH, Bethesda, MD 20892 USA. [Li, Jianping; Szu, Shousun] NICHD, Lab Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. RP Hoshino, Y (reprint author), NIAID, Rotavirus Vaccine Dev Sect, Labs Infect Dis, NIH, Bldg 50,Room 6308, Bethesda, MD 20892 USA. EM thoshino@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), USA FX We thank Elias Gonzales for technical assistance. We extend our appreciation to Dr. Albert Z. Kapikian for his support to this project. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), USA. NR 66 TC 12 Z9 13 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 21 PY 2012 VL 30 IS 43 BP 6121 EP 6126 DI 10.1016/j.vaccine.2012.07.078 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 017UO UT WOS:000309616700003 PM 22885016 ER PT J AU Papaneri, AB Wirblich, C Cooper, K Jahrling, PB Schnell, MJ Blaney, JE AF Papaneri, Amy B. Wirblich, Christoph Cooper, Kurt Jahrling, Peter B. Schnell, Matthias J. Blaney, Joseph E. TI Further characterization of the immune response in mice to inactivated and live rabies vaccines expressing Ebola virus glycoprotein SO VACCINE LA English DT Article DE Ebola virus; Rabies virus; Vaccine; T cell; Multivalent; Platform ID PROTECTS NONHUMAN-PRIMATES; RESPIRATORY-TRACT; HEMORRHAGIC-FEVER; VECTORED VACCINE; INFECTION; IMMUNIZATION; CHALLENGE; DISEASE; MARBURG AB We have previously developed (a) replication-competent, (b) replication-deficient, and (c) chemically inactivated rabies virus (RABV) vaccines expressing Ebola virus (EBOV) glycoprotein (GP) that induce humoral immunity against each virus and confer protection from both lethal RABV and mouse-adapted EBOV challenge in mice. Here, we expand our investigation of the immunogenic properties of these bivalent vaccines in mice. Both live and killed vaccines induced primary EBOV GP-specific T-cells and a robust recall response as measured by interferon-gamma ELISPOT assay. In addition to cellular immunity, an effective filovirus vaccine will likely require a multivalent humoral immune response against multiple virus species. As a proof-of-principle experiment, we demonstrated that inactivated RV-GP could be formulated with another inactivated RABV vaccine expressing the nontoxic fragment of botulinum neurotoxin A heavy chain (HC50) without a reduction in immunity to each component. Finally, we demonstrated that humoral immunity to GP could be induced by immunization of mice with inactivated RV-GP in the presence of pre-existing immunity to RABV. The ability of these novel vaccines to induce strong humoral and cellular immunity indicates that they should be further evaluated in additional animal models of infection. Published by Elsevier Ltd. C1 [Blaney, Joseph E.] NIAID, Emerging Viral Pathogens Sect, NIH, Integrated Res Facil, Ft Detrick, MD 21702 USA. [Wirblich, Christoph; Schnell, Matthias J.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Schnell, Matthias J.] Thomas Jefferson Univ, Jefferson Med Coll, Jefferson Vaccine Ctr, Philadelphia, PA 19107 USA. RP Blaney, JE (reprint author), NIAID, Emerging Viral Pathogens Sect, NIH, Integrated Res Facil, 8200 Res Plaza, Ft Detrick, MD 21702 USA. EM matthias.schnell@jefferson.edu; jblaney@niaid.nih.gov OI Papaneri, Amy/0000-0003-2144-2441 FU NIAID Division of Intramural Research FX These studies were supported in part by the NIAID Division of Intramural Research. We thank Nicholas Oberlander for contribution to the animal studies. NR 33 TC 12 Z9 13 U1 0 U2 13 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 SEP 21 PY 2012 VL 30 IS 43 BP 6136 EP 6141 DI 10.1016/j.vaccine.2012.07.073 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 017UO UT WOS:000309616700005 PM 22884661 ER PT J AU Wu, XS Martina, JA Hammer, JA AF Wu, Xufeng S. Martina, Jose A. Hammer, John A., III TI Melanoregulin is stably targeted to the melanosome membrane by palmitoylation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Dilute suppressor; Melanoregulin; Palmitoylation; Melanosome ID PROTEIN; MELANOCYTES; TRANSPORT; PATHWAY AB In mammals, pigments are made by melanocytes within a specialized organelle, the melanosome. Mature, pigment-laden melanosomes are then transferred to keratinocytes to drive the visible pigmentation of the animal's hair and skin. The dilute suppressor (dsu) locus encodes an extragenic suppressor of the pigmentation defect exhibited by mice lacking myosin Va (i.e. dilute mice). We recently showed that melanoregulin, the product of the dsu locus, functions as a negative regulator of a shedding mechanism that drives the intercellular transfer of melanosomes from the melanocyte to the keratinocyte. Here we address melanoregulin's localization within the melanocyte, as well as the molecular basis for its localization. First, we confirm and extend recently published results using exogenous, GFP-tagged melanoregulin by showing that endogenous melanoregulin also targets extensively to melanosomes. Second, using site-directed mutagenesis, metabolic labeling with H-3-palmitate, and an inhibitor of palmitoylation in vivo, we show that the targeting of melanoregulin to the limiting membranes of melanosomes in melanocytes and lysosomes in CV1 cells depends critically on the palmitoylation of one or more of six closely-spaced cysteine residues located near melanoregulin's N-terminus. Finally, using Fluorescence Recovery after Photobleaching (FRAP), we show that melanoregulin-GFP exhibits little if any tendency to cycle in and out of the melanosome membrane. We conclude that multiple palmitoylation serves to stably anchor melanoregulin in the melanosome membrane. Published by Elsevier Inc. C1 [Wu, Xufeng S.; Martina, Jose A.; Hammer, John A., III] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wu, XS (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Room 2523,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wux@nhlbi.nih.gov; hammerj@nhlbi.nih.gov OI Hammer, John/0000-0002-2496-5179 FU Intramural NIH HHS [Z01 HL000514-24] NR 16 TC 4 Z9 4 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 21 PY 2012 VL 426 IS 2 BP 209 EP 214 DI 10.1016/j.bbrc.2012.08.064 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 017DZ UT WOS:000309571600008 PM 22940130 ER PT J AU Kwong, PD Mascola, JR AF Kwong, Peter D. Mascola, John R. TI Human Antibodies that Neutralize HIV-1: Identification, Structures, and B Cell Ontogenies SO IMMUNITY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; GP120 ENVELOPE GLYCOPROTEIN; HIV-1-INFECTED INDIVIDUALS; POTENT NEUTRALIZATION; BROAD NEUTRALIZATION; CD4-BINDING SITE; RATIONAL DESIGN; 2G12 RECOGNIZES; GLYCAN SHIELD AB Antibodies that neutralize diverse strains of HIV-1 develop in similar to 20% of HIV-1-infected individuals, and isolation and structural characterization of these antibodies are revealing how they recognize the envelope glycoprotein spike. Broadly reactive neutralizing antibodies utilize just a few sites of spike vulnerability and converge on select modes of recognition. These antibodies have unusual features: uncommonly long complementarity-determining loops, extensive somatic mutation, or both. Recent advances in next(7) generation sequencing of antibody-gene transcripts are providing genetic records of the development of neutralizing antibodies. These records inform an understanding of the naive B cell repertoire, of somatic mutation, and of the resulting antibody features that are critical to effective HIV-1 neutralization; based on these, we propose an ontogeny and structure-based system of antibody classification. The human immune system is capable of developing antibodies that broadly neutralize HIV-1-and an increasingly detailed view is accumulating for how effective immunity against HIV-1 can be generated. C1 [Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov; jmascola@nih.gov FU Vaccine Research Center, NIAID, NIH FX We thank J. Boyington for glycan modeling; D. Burton, G. Nabel, and I. Wilson for discussions and comments; M. Connors for sharing 10E8 results; J. Stuckey for assistance with the figures, table, and movie; X. Wu for assistance with antibody sequence analysis; and members of the Structural Biology Section, the Structural Bioinformatics Core, and the Humoral Immunology Section, Vaccine Research Center, for discussions and comments on the manuscript. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH. NR 115 TC 221 Z9 226 U1 4 U2 62 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP 21 PY 2012 VL 37 IS 3 BP 412 EP 425 DI 10.1016/j.immuni.2012.08.012 PG 14 WC Immunology SC Immunology GA 011XG UT WOS:000309199000004 PM 22999947 ER PT J AU Hall, AO Beiting, DP Tato, C John, B Oldenhove, G Lombana, CG Pritchard, GH Silver, JS Bouladoux, N Stumhofer, JS Harris, TH Grainger, J Wojno, EDT Wagage, S Roos, DS Scott, P Turka, LA Cherry, S Reiner, SL Cua, D Belkaid, Y Elloso, MM Hunter, CA AF Hall, Aisling O'Hara Beiting, Daniel P. Tato, Cristina John, Beena Oldenhove, Guillaume Lombana, Claudia Gonzalez Pritchard, Gretchen Harms Silver, Jonathan S. Bouladoux, Nicolas Stumhofer, Jason S. Harris, Tajie H. Grainger, John Wojno, Ella D. Tait Wagage, Sagie Roos, David S. Scott, Philip Turka, Laurence A. Cherry, Sara Reiner, Steven L. Cua, Daniel Belkaid, Yasmine Elloso, M. Merle Hunter, Christopher A. TI The Cytokines Interleukin 27 and Interferon-gamma Promote Distinct Treg Cell Populations Required to Limit Infection-Induced Pathology SO IMMUNITY LA English DT Article ID REGULATORY T-CELLS; TOXOPLASMA-GONDII INFECTION; VIRAL-INFECTION; DENDRITIC CELLS; IFN-GAMMA; IN-VIVO; EXPRESSION; RESPONSES; IL-27; BET AB Interferon-gamma (IFN-gamma) promotes a population of T-bet(+) CXCR3(+) regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii, a similar population emerged that limited T cell responses and was dependent on IFN-gamma in the periphery but on IL-27 at mucosa! sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27(-/-) mice, and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-gamma or IL-27 have distinct transcriptional profiles. Thus, IFN-gamma and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation. C1 [Hall, Aisling O'Hara; John, Beena; Lombana, Claudia Gonzalez; Pritchard, Gretchen Harms; Silver, Jonathan S.; Stumhofer, Jason S.; Harris, Tajie H.; Wojno, Ella D. Tait; Wagage, Sagie; Scott, Philip; Hunter, Christopher A.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Beiting, Daniel P.; Roos, David S.; Cherry, Sara; Cua, Daniel] Univ Penn, Penn Genome Frontiers Inst, Dept Biol, Philadelphia, PA 19104 USA. [Tato, Cristina; Belkaid, Yasmine] DNAX Discovery Res, Merck Res Labs, Palo Alto, CA 94304 USA. [Reiner, Steven L.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Oldenhove, Guillaume; Bouladoux, Nicolas; Grainger, John] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Turka, Laurence A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Transplant Inst, Boston, MA 02215 USA. RP Hunter, CA (reprint author), Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. EM chunter@vet.upenn.edu FU state of Pennsylvania, NIH [AI 071302, AI084882, R21-AI090234-01, R37-AI28724, AI055428] FX This work was supported by the state of Pennsylvania, NIH grants AI 071302 and AI084882 (C.A.H.), R21-AI090234-01 (B.J.), R37-AI28724 (D.S.R.), and AI055428 (A.O.H.). We thank K.A. Platt at Lexicon Pharmaceuticals, Inc. for the generation of the Il27-/-mice. We thank I. Brodsky and D. Campbell for helpful discussions. NR 50 TC 130 Z9 137 U1 2 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP 21 PY 2012 VL 37 IS 3 BP 511 EP 523 DI 10.1016/j.immuni.2012.06.014 PG 13 WC Immunology SC Immunology GA 011XG UT WOS:000309199000015 PM 22981537 ER PT J AU Burbelo, PD Lebovitz, EE Bren, KE Bayat, A Paviol, S Wenzlau, JM Barriga, KJ Rewers, M Harlan, DM Iadarola, MJ AF Burbelo, Peter D. Lebovitz, Evan E. Bren, Kathleen E. Bayat, Ahmad Paviol, Scott Wenzlau, Janet M. Barriga, Katherine J. Rewers, Marian Harlan, David M. Iadarola, Michael J. TI Extrapancreatic Autoantibody Profiles in Type I Diabetes SO PLOS ONE LA English DT Article ID ANTIBODY-POSITIVE RELATIVES; PARIETAL-CELL ANTIBODIES; LUCIFERASE IMMUNOPRECIPITATION; AUTOIMMUNE MANIFESTATIONS; 1ST-DEGREE RELATIVES; ISLET-CELL; PREDICTION; CHILDREN; MELLITUS; RISK AB Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing beta-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-beta. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-beta (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D. C1 [Burbelo, Peter D.; Lebovitz, Evan E.; Bren, Kathleen E.; Bayat, Ahmad; Iadarola, Michael J.] NIH, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, Bethesda, MD 20892 USA. [Burbelo, Peter D.; Lebovitz, Evan E.; Bren, Kathleen E.; Bayat, Ahmad; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Paviol, Scott; Harlan, David M.] Univ Massachusetts, Sch Med, Diabet Ctr Excellence, Worcester, MA USA. [Wenzlau, Janet M.; Barriga, Katherine J.; Rewers, Marian] Univ Colorado Denver, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. RP Burbelo, PD (reprint author), NIH, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, Bldg 10, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov; David.Harlan@umassmemorial.org FU Division of Intramural Research, National Institute of Dental and Craniofacial Research; Diabetes and Endocrinology Research Center United States National Institutes of Health [P3057516]; Juvenile Diabetes Research Foundation Autoimmunity Prevention Center [-2007-1056]; [RO1 DK32493] FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research and from RO1 DK32493, Diabetes and Endocrinology Research Center United States National Institutes of Health P3057516 and a Juvenile Diabetes Research Foundation Autoimmunity Prevention Center Grant -2007-1056, Project 5. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 6 Z9 6 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 21 PY 2012 VL 7 IS 9 AR e45216 DI 10.1371/journal.pone.0045216 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014RG UT WOS:000309392800030 PM 23028856 ER PT J AU Dutta, D Williamson, CD Cole, NB Donaldson, JG AF Dutta, Dipannita Williamson, Chad D. Cole, Nelson B. Donaldson, Julie G. TI Pitstop 2 Is a Potent Inhibitor of Clathrin-Independent Endocytosis SO PLOS ONE LA English DT Article ID MEDIATED ENDOCYTOSIS; TERMINAL DOMAIN; SMALL MOLECULES; PATHWAY; PROTEINS; DYNAMIN; CARGO; CELLS; ENDOSOMES AB Clathrin independent endocytosis (CIE) is a form of endocytosis present in all cells that mediates the entry of nutrients, macromolecules and membrane proteins into cells. When compared to clathrin-dependent endocytosis (CDE), however, much less is known about the machinery involved in forming CIE endosomes. One way to distinguish CIE from CDE has been to deplete cells of coat proteins involved in CDE such as clathrin or the dynamin GTPase, leading to a block of CDE but not CIE. A drawback of such genetic manipulations is that depletion of proteins important for mediating CDE over a period of days can have complex indirect effects on cellular function. The identification of chemical compounds that specifically and rapidly block CDE or CIE would facilitate the determination of whether a process involved CDE or CIE. To date, all of those compounds have targeted CDE. Dynasore and the dynoles specifically target and block dynamin activity thus inhibiting CDE but not most forms of CIE. Recently, a new compound called pitstop 2 was identified as an inhibitor of the interaction of amphiphysin with the amino terminal domain of clathrin, and shown to inhibit CDE in cells. Here we show that pitstop 2 is also a potent inhibitor of CIE. The effects of pitstop 2 are not restricted to inhibition of clathrin since knockdown of clathrin fails to rescue the inhibition of endocytosis of CIE proteins by the drug. Thus pitstop 2 has additional cellular targets besides the amino terminal domain of clathrin and thus cannot be used to distinguish CIE from CDE. C1 [Dutta, Dipannita; Williamson, Chad D.; Cole, Nelson B.; Donaldson, Julie G.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM donaldsonj@helix.nih.gov FU Intramural Research Program in the National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH) [HL006060] FX The work was supported by the Intramural Research Program in the National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), HL006060. http://www.nhlbi.nih.gov/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 45 Z9 47 U1 3 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 21 PY 2012 VL 7 IS 9 AR e45799 DI 10.1371/journal.pone.0045799 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014RG UT WOS:000309392800098 PM 23029248 ER PT J AU Klug, JR Mathur, BN Kash, TL Wang, HD Matthews, RT Robison, AJ Anderson, ME Deutch, AY Lovinger, DM Colbran, RJ Winder, DG AF Klug, Jason R. Mathur, Brian N. Kash, Thomas L. Wang, Hui-Dong Matthews, Robert T. Robison, A. J. Anderson, Mark E. Deutch, Ariel Y. Lovinger, David M. Colbran, Roger J. Winder, Danny G. TI Genetic Inhibition of CaMKII in Dorsal Striatal Medium Spiny Neurons Reduces Functional Excitatory Synapses and Enhances Intrinsic Excitability SO PLOS ONE LA English DT Article ID PROTEIN-KINASE-II; LONG-TERM POTENTIATION; GLUR-A-DEFICIENT; POSTSYNAPTICALLY SILENT SYNAPSES; D-ASPARTATE RECEPTOR; SQUID GIANT SYNAPSE; AMPA RECEPTORS; RAT-BRAIN; DEVELOPMENTAL-CHANGES; BASAL GANGLIA AB Ca2+/calmodulin-dependent protein kinase II (CaMKII) is abundant in striatal medium spiny neurons (MSNs). CaMKII is dynamically regulated by changes in dopamine signaling, as occurs in Parkinson's disease as well as addiction. Although CaMKII has been extensively studied in the hippocampus where it regulates excitatory synaptic transmission, relatively little is known about how it modulates neuronal function in the striatum. Therefore, we examined the impact of selectively overexpressing an EGFP-fused CaMKII inhibitory peptide (EAC3I) in striatal medium spiny neurons (MSNs) using a novel transgenic mouse model. EAC3I-expressing cells exhibited markedly decreased excitatory transmission, indicated by a decrease in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs). This decrease was not accompanied by changes in the probability of release, levels of glutamate at the synapse, or changes in dendritic spine density. CaMKII regulation of the AMPA receptor subunit GluA1 is a major means by which the kinase regulates neuronal function in the hippocampus. We found that the decrease in striatal excitatory transmission seen in the EAC3I mice is mimicked by deletion of GluA1. Further, while CaMKII inhibition decreased excitatory transmission onto MSNs, it increased their intrinsic excitability. These data suggest that CaMKII plays a critical role in setting the excitability rheostat of striatal MSNs by coordinating excitatory synaptic drive and the resulting depolarization response. C1 [Klug, Jason R.; Kash, Thomas L.; Matthews, Robert T.; Robison, A. J.; Deutch, Ariel Y.; Colbran, Roger J.; Winder, Danny G.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. [Deutch, Ariel Y.; Colbran, Roger J.; Winder, Danny G.] Vanderbilt Univ, Sch Med, Ctr Mol Neurosci, Nashville, TN 37212 USA. [Matthews, Robert T.; Deutch, Ariel Y.; Colbran, Roger J.; Winder, Danny G.] Vanderbilt Univ, Sch Med, JF Kennedy Ctr Res Human Dev, Nashville, TN 37212 USA. [Wang, Hui-Dong; Deutch, Ariel Y.] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. [Deutch, Ariel Y.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN USA. [Mathur, Brian N.; Lovinger, David M.] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. [Anderson, Mark E.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Anderson, Mark E.] Univ Iowa, Dept Mol Physiol & Biophys, Iowa City, IA USA. RP Winder, DG (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. EM danny.winder@vanderbilt.edu RI Kash, Thomas/G-9625-2013; Winder, Danny/H-4857-2013; OI Robison, Alfred/0000-0002-4150-9570 FU United States National Institutes of Health (NIH) [NIH R01-DA019112, NIH R01-AA019455, NIH R01-MH063232]; Hobbs Discovery grant [NIH R01 HL079031, NIH R01 HL62494, NIH R01 HL70250]; Fondation Leducq for the Alliance for CaMKII Signaling FX Funding was provided by the United States National Institutes of Health (NIH) NIH R01-DA019112, NIH R01-AA019455 (D. G. W.), NIH R01-MH063232, Hobbs Discovery grant (R.J.C.), NIH R01 HL079031, NIH R01 HL62494, and NIH R01 HL70250 and supported by a grant from the Fondation Leducq for the Alliance for CaMKII Signaling (M. E. A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 133 TC 18 Z9 19 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 21 PY 2012 VL 7 IS 9 AR e45323 DI 10.1371/journal.pone.0045323 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014RG UT WOS:000309392800039 PM 23028932 ER PT J AU Lugar, PL Love, C Grammer, AC Dave, SS Lipsky, PE AF Lugar, Patricia L. Love, Cassandra Grammer, Amrie C. Dave, Sandeep S. Lipsky, Peter E. TI Molecular Characterization of Circulating Plasma Cells in Patients with Active Systemic Lupus Erythematosus SO PLOS ONE LA English DT Article ID INTERFERON-INDUCIBLE GENE; UNFOLDED PROTEIN RESPONSE; PERIPHERAL-BLOOD CELLS; BONE-MARROW; LYMPHOCYTE EGRESS; B-LYMPHOCYTES; DISEASE-ACTIVITY; EXPRESSION; DIFFERENTIATION; MAINTENANCE AB Systemic lupus erythematosus (SLE) is a generalized autoimmune disease characterized by abnormal B cell activation and the occurrence of increased frequencies of circulating plasma cells (PC). The molecular characteristics and nature of circulating PC and B cells in SLE have not been completely characterized. Microarray analysis of gene expression was used to characterize circulating PC in subjects with active SLE. Flow cytometry was used to sort PC and comparator B cell populations from active SLE blood, normal blood and normal tonsil. The gene expression profiles of the sorted B cell populations were then compared. SLE PC exhibited a similar gene expression signature as tonsil PC. The differences in gene expression between SLE PC and normal tonsil PC and tonsil plasmablasts (PB) suggest a mature Ig secreting cell phenotype in the former population. Despite this, SLE PC differed in expression of about half the genes from previously published gene expression profiles of normal bone marrow PC, indicating that these cells had not achieved a fully mature status. Abnormal expression of several genes, including CXCR4 and S1P(1), suggests a mechanism for the persistence of SLE PC in the circulation. All SLE B cell populations revealed an interferon (IFN) gene signature previously only reported in unseparated SLE peripheral blood mononuclear cells. These data indicate that SLE PC are a unique population of Ig secreting cells with a gene expression profile indicative of a mature, but not fully differentiated phenotype. C1 [Lugar, Patricia L.; Grammer, Amrie C.; Lipsky, Peter E.] NIH, Autoimmun Branch, Bethesda, MD 20892 USA. [Love, Cassandra; Dave, Sandeep S.] Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. RP Lugar, PL (reprint author), Duke Univ, Div Pulm Allergy & Crit Care, Durham, NC 27706 USA. EM patricia.lugar@duke.edu FU intramural NIH funding FX The research work was performed at the National Institutes of Health (NIH) and NIH Clinical Center and funded through intramural NIH funding. The NIH had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 52 TC 16 Z9 16 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 21 PY 2012 VL 7 IS 9 AR e44362 DI 10.1371/journal.pone.0044362 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014RG UT WOS:000309392800007 PM 23028528 ER PT J AU Schurman, SH Dunn, CA Greaves, R Yu, BB Ferrucci, L Croteau, DL Seidman, MM Bohr, VA AF Schurman, Shepherd H. Dunn, Christopher A. Greaves, Rebecca Yu, Binbing Ferrucci, Luigi Croteau, Deborah L. Seidman, Michael M. Bohr, Vilhelm A. TI Age-Related Disease Association of Endogenous gamma-H2AX Foci in Mononuclear Cells Derived from Leukapheresis SO PLOS ONE LA English DT Article ID DOUBLE-STRAND BREAKS; OBSTRUCTIVE SLEEP-APNEA; OXIDATIVE DNA-DAMAGE; MOLECULAR MARKER; HISTONE H2AX; VITAMIN-D; REPAIR; HYPERTENSION; LYMPHOCYTES; CANCER AB The phosphorylated form of histone H2AX (gamma-H2AX) forms immunohistochemically detectable foci at DNA double strand breaks. In peripheral blood mononuclear cells (PBMCs) derived from leukapheresis from patients enrolled in the Baltimore Longitudinal Study of Aging, gamma-H2AX foci increased in a linear fashion with regards to age, peaking at similar to 57 years. The relationship between the frequency of gamma-H2AX foci and age-related pathologies was assessed. We found a statistically significant (p = 0.023) 50% increase in foci in PBMCs derived from patients with a known history of vitamin D deficiency. In addition, there were trends toward increased gamma-H2AX foci in patients with cataracts (34% increase, p<0.10) and in sleep apnea patients (44%, p<0.10). Among patients >= 57 y/o, we found a significant (p = 0.037) 36% increase in the number of gamma-H2AX foci/cell for patients with hypertension compared to non-hypertensive patients. Our results support a role for increased DNA damage in the morbidity of age-related diseases. gamma-H2AX may be a biomarker for human morbidity in age-related diseases. C1 [Schurman, Shepherd H.; Dunn, Christopher A.; Greaves, Rebecca; Croteau, Deborah L.; Seidman, Michael M.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Yu, Binbing] NIA, Lab Epidemiol Demog & Biometry, NIH, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Schurman, Shepherd/0000-0002-9133-7906 FU National Institutes of Health FX Funding was provided by the Intramural Progam of the National Institutes of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 10 Z9 10 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 21 PY 2012 VL 7 IS 9 AR e45728 DI 10.1371/journal.pone.0045728 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014RG UT WOS:000309392800085 PM 23029205 ER PT J AU Srinivasan, S Simms, JA Nielsen, CK Lieske, SP Bito-Onon, JJ Yi, H Hopf, FW Bonci, A Bartlett, SE AF Srinivasan, Subhashini Simms, Jeffrey A. Nielsen, Carsten K. Lieske, Steven P. Bito-Onon, Jade J. Yi, Henry Hopf, Frederic Woodward Bonci, Antonello Bartlett, Selena E. TI The Dual Orexin/Hypocretin Receptor Antagonist, Almorexant, in the Ventral Tegmental Area Attenuates Ethanol Self-Administration SO PLOS ONE LA English DT Article ID LONG-EVANS RATS; ALCOHOL DEPENDENCE; INDUCED REINSTATEMENT; OREXIN-A; MESOLIMBIC DOPAMINE; NALTREXONE RESPONSE; REWARD-SEEKING; FOOD-INTAKE; NEURONS; INVOLVEMENT AB Recent studies have implicated the hypocretin/orexinergic system in reward-seeking behavior. Almorexant, a dual orexin/hypocretin R-1 and R-2 receptor antagonist, has proven effective in preclinical studies in promoting sleep in animal models and was in Phase III clinical trials for sleep disorders. The present study combines behavioral assays with in vitro biochemical and electrophysiological techniques to elucidate the role of almorexant in ethanol and sucrose intake. Using an operant self-administration paradigm, we demonstrate that systemic administration of almorexant decreased operant self-administration of both 20% ethanol and 5% sucrose. We further demonstrate that intra-ventral tegmental area (VTA) infusions, but not intra-substantia nigra infusions, of almorexant reduced ethanol self-administration. Extracellular recordings performed in VTA neurons revealed that orexin-A increased firing and this enhancement of firing was blocked by almorexant. The results demonstrate that orexin/hypocretin receptors in distinct brain regions regulate ethanol and sucrose mediated behaviors. C1 [Srinivasan, Subhashini; Simms, Jeffrey A.; Nielsen, Carsten K.; Lieske, Steven P.; Bito-Onon, Jade J.; Yi, Henry; Hopf, Frederic Woodward; Bartlett, Selena E.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA USA. [Bartlett, Selena E.] Queensland Univ Technol, Translat Res Inst, Brisbane, Qld 4001, Australia. [Bonci, Antonello] NIDA, Intramural Res Program, Baltimore, MD USA. [Bonci, Antonello] Univ Calif San Francisco, Dept Neurol, Emeryville, CA USA. [Bonci, Antonello] Johns Hopkins Univ, Solomon Snyder Dept Neurosci, Baltimore, MD USA. [Lieske, Steven P.] San Francisco VA Med Ctr, Dept Mental Hlth, San Francisco, CA USA. RP Bartlett, SE (reprint author), Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA USA. EM selena.bartlett@qut.edu.au RI Bartlett, Selena/J-1345-2012 OI Bartlett, Selena/0000-0002-1741-3958 FU Department of Defense, TATRC grant [W81XWH-10-1-0247]; state funding for medical research through UCSF FX The research was carried out with the help of Department of Defense, TATRC grant W81XWH-10-1-0247 (www.tatrc.org) awarded to S. E. B. and A. B. and the state funding for medical research through UCSF to S. E. B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 19 Z9 20 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 21 PY 2012 VL 7 IS 9 AR e44726 DI 10.1371/journal.pone.0044726 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014RG UT WOS:000309392800013 PM 23028593 ER PT J AU Kaelin, CB Xu, X Hong, LZ David, VA McGowan, KA Schmidt-Kuntzel, A Roelke, ME Pino, J Pontius, J Cooper, GM Manuel, H Swanson, WF Marker, L Harper, CK van Dyk, A Yue, BS Mullikin, JC Warren, WC Eizirik, E Kos, L O'Brien, SJ Barsh, GS Menotti-Raymond, M AF Kaelin, Christopher B. Xu, Xiao Hong, Lewis Z. David, Victor A. McGowan, Kelly A. Schmidt-Kuentzel, Anne Roelke, Melody E. Pino, Javier Pontius, Joan Cooper, Gregory M. Manuel, Hermogenes Swanson, William F. Marker, Laurie Harper, Cindy K. van Dyk, Ann Yue, Bisong Mullikin, James C. Warren, Wesley C. Eizirik, Eduardo Kos, Lidia O'Brien, Stephen J. Barsh, Gregory S. Menotti-Raymond, Marilyn TI Specifying and Sustaining Pigmentation Patterns in Domestic and Wild Cats SO SCIENCE LA English DT Article ID COAT COLOR; SKIN COLOR; EXPRESSION; GENETICS; FAMILY; MODEL AB Color markings among felid species display both a remarkable diversity and a common underlying periodicity. A similar range of patterns in domestic cats suggests a conserved mechanism whose appearance can be altered by selection. We identified the gene responsible for tabby pattern variation in domestic cats as Transmembrane aminopeptidase Q (Taqpep), which encodes a membrane-bound metalloprotease. Analyzing 31 other felid species, we identified Taqpep as the cause of the rare king cheetah phenotype, in which spots coalesce into blotches and stripes. Histologic, genomic expression, and transgenic mouse studies indicate that paracrine expression of Endothelin3 (Edn3) coordinates localized color differences. We propose a two-stage model in which Taqpep helps to establish a periodic pre-pattern during skin development that is later implemented by differential expression of Edn3. C1 [Kaelin, Christopher B.; Cooper, Gregory M.; Barsh, Gregory S.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Kaelin, Christopher B.; Hong, Lewis Z.; McGowan, Kelly A.; Manuel, Hermogenes; Barsh, Gregory S.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Xu, Xiao; David, Victor A.; Schmidt-Kuentzel, Anne; Roelke, Melody E.; Pino, Javier; O'Brien, Stephen J.; Menotti-Raymond, Marilyn] Frederick Natl Lab Canc Res, Lab Genom Divers, Frederick, MD 21702 USA. [Xu, Xiao; Yue, Bisong] Sichuan Univ, Coll Life Sci, Sichuan Key Lab Conservat Biol Endangered Wildlif, Chengdu 610064, Sichuan, Peoples R China. [Schmidt-Kuentzel, Anne; Marker, Laurie] Cheetah Conservat Fund, Otjiwarongo, Namibia. [Roelke, Melody E.; Pontius, Joan] Frederick Natl Lab Canc Res, SAIC Frederick, Frederick, MD 21702 USA. [Pino, Javier; Kos, Lidia] Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. [Swanson, William F.] Cincinnati Zoo & Bot Garden, Ctr Conservat & Res Endangered Wildlife, Cincinnati, OH 45220 USA. [Harper, Cindy K.] Univ Pretoria, Fac Vet Sci Onderstepoort, Vet Genet Lab, ZA-0002 Pretoria, South Africa. [van Dyk, Ann] Ann van Dyk Cheetah Ctr, De Wildt, South Africa. [Mullikin, James C.] NHGRI, Comparat Genom Unit, NIH, Rockville, MD 20892 USA. [Warren, Wesley C.] Washington Univ, Genome Ctr, St Louis, MO 63108 USA. [Eizirik, Eduardo] Pontificia Univ Catolica Rio Grande do Sul, Fac Biociencias, BR-90619900 Porto Alegre, RS, Brazil. [Eizirik, Eduardo] Inst Pro Carnivoros, Atibaia, Brazil. RP O'Brien, SJ (reprint author), St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Informat, St Petersburg, Russia. EM lgdchief@gmail.com; gbarsh@hudsonalpha.org RI Eizirik, Eduardo/K-8034-2012; OI Eizirik, Eduardo/0000-0002-9658-0999; O'Brien, Stephen J./0000-0001-7353-8301; Yue, Bisong/0000-0001-6731-538X FU Wild Cat Education and Conservation Fund; HudsonAlpha Institute for Biotechnology; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; federal funds [N01-CO-12400]; Genentech; National Institutes of Health FX We thank San Jose Animal Care and Services, Fix Our Ferals, the Berkeley East-Bay Humane Society, Pets In Need, the Monterey Animal Hospital, and the City of Huntsville Animal Shelter for assistance with sample collection; the Wild Cat Education and Conservation Fund for contributing king cheetah samples; R. Finn for assistance with Norwegian Forest Cat samples and phenotypes; H. Flick for domestic cat photographs; and J. C. Kaelin for help with feral cat sample collection. We thank the Production Sequencing Group of the Washington University School of Medicine Genome Center for cDNA sequencing. Namibian samples were collected with the approval of the Ministry of Environment and Tourism (permit 1532). Supported in part by the HudsonAlpha Institute for Biotechnology and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, using federal funds under contract N01-CO-12400. L.Z.H. and J.P. were supported by fellowships from Genentech and the National Institutes of Health, respectively. A.vD. is the founder and director of the Ann van Dyk Cheetah Centre, a nonprofit conservation organization. DNA sequence data for this study are available at http://genome.wustl.edu/genomes/view/felis_catus/ and the NIH Short Read Archive (SRA056885). NR 21 TC 24 Z9 28 U1 8 U2 99 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 SEP 21 PY 2012 VL 337 IS 6101 BP 1536 EP 1541 DI 10.1126/science.1220893 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007UC UT WOS:000308912900051 PM 22997338 ER PT J AU Hand, TW Dos Santos, LM Bouladoux, N Molloy, MJ Pagan, AJ Pepper, M Maynard, CL Elson, CO Belkaid, Y AF Hand, Timothy W. Dos Santos, Liliane M. Bouladoux, Nicolas Molloy, Michael J. Pagan, Antonio J. Pepper, Marion Maynard, Craig L. Elson, Charles O., III Belkaid, Yasmine TI Acute Gastrointestinal Infection Induces Long-Lived Microbiota-Specific T Cell Responses SO SCIENCE LA English DT Article ID GUT COMMENSAL BACTERIA; TOXOPLASMA-GONDII; CROHNS-DISEASE; INDUCTION; DOMINANT; EFFECTOR; IMMUNITY; NAIVE; IGA AB The mammalian gastrointestinal tract contains a large and diverse population of commensal bacteria and is also one of the primary sites of exposure to pathogens. How the immune system perceives commensals in the context of mucosal infection is unclear. Here, we show that during a gastrointestinal infection, tolerance to commensals is lost, and microbiota-specific T cells are activated and differentiate to inflammatory effector cells. Furthermore, these T cells go on to form memory cells that are phenotypically and functionally consistent with pathogen-specific T cells. Our results suggest that during a gastrointestinal infection, the immune response to commensals parallels the immune response against pathogenic microbes and that adaptive responses against commensals are an integral component of mucosal immunity. C1 [Hand, Timothy W.; Dos Santos, Liliane M.; Bouladoux, Nicolas; Molloy, Michael J.; Belkaid, Yasmine] NIAID, Mucosal Immun Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Dos Santos, Liliane M.] Univ Fed Minas Gerais, Lab Gnotobiol & Immunol, BR-31270901 Belo Horizonte, MG, Brazil. [Pagan, Antonio J.; Pepper, Marion] Univ Minnesota, Microbiol Immunol & Canc Biol Program, Minneapolis, MN 55455 USA. [Pepper, Marion] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Maynard, Craig L.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Elson, Charles O., III] Univ Alabama Birmingham, Mucosal HIV & Immunobiol Ctr, Birmingham, AL 35294 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immun Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID); CNPq-Brazil; NIH [DK071176, DK64400]; Crohn's and Colitis Foundation of America Career Development Award FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) (T. W. H., L. M. D., N.B., M.J.M., and Y.B.), CNPq-Brazil (L. M. D.), NIH grants DK071176 and DK64400 (C.O.E.) and The Crohn's and Colitis Foundation of America Career Development Award (C. L. M.). The authors thank M. Jenkins, A. Poholek, S. Kaech, N. Peters, J. Monteiro and the members of the Belkaid Lab for critical discussion and reading of the manuscript; the NIH Tetramer Core Facility for the T. gondii Me49 hypothetical protein tetramers; C. Eigsti, T. Moyer, E. Stregevsky, K. Holmes, and the NIAID Flow Cytometry Core for assistance with sorting; L. Koo and the NIAID Microscopy Core for assistance with 16S fluorescence in situ hybridization (FISH) images; and the NIAID Protein Biochemistry Core for CBir1 peptide. We thank the University of Alabama-Birmingham for sharing the CBir1 Tg mice by material transfer agreement. The data reported in this paper are tabulated in the main text and in the supplementary materials. The authors declare that they have no conflict of interest. NR 31 TC 122 Z9 123 U1 3 U2 30 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 SEP 21 PY 2012 VL 337 IS 6101 BP 1553 EP 1556 DI 10.1126/science.1220961 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007UC UT WOS:000308912900055 PM 22923434 ER PT J AU Bansal, S Meyers, LA AF Bansal, Shweta Meyers, Lauren Ancel TI The impact of past epidemics on future disease dynamics SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Contact heterogeneity; Networks; Polarized immunity; Leaky immunity; Pathogen evolution ID HEPATITIS-C VIRUS; INFLUENZA-A; PATHOGEN DIVERSITY; PARASITE VIRULENCE; CROSS-IMMUNITY; EVOLUTION; NETWORK; INFECTION; MODELS; STRAIN AB Many pathogens spread primarily via direct contact between infected and susceptible hosts. Thus, the patterns of contacts or contact network of a population fundamentally shape the course of epidemics. While there is a robust and growing theory for the dynamics of single epidemics in networks, we know little about the impacts of network structure on long-term epidemic or endemic transmission. For seasonal diseases like influenza, pathogens repeatedly return to populations with complex and changing patterns of susceptibility and immunity acquired through prior infection. Here, we develop two mathematical approaches for modeling consecutive seasonal outbreaks of a partially-immunizing infection in a population with contact heterogeneity. Using methods from percolation theory we consider both leaky immunity, where all previously infected individuals gain partial immunity, and polarized immunity, where a fraction of previously infected individuals are fully immune. By restructuring the epidemiologically active portion of their host population, such diseases limit the potential of future outbreaks. We speculate that these dynamics can result in evolutionary pressure to increase infectiousness. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Bansal, Shweta] Penn State Univ, Ctr Infect Dis Dynam, Mueller Lab 208, University Pk, PA 16802 USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Meyers, Lauren Ancel] Univ Texas Austin, Sect Integrat Biol, Austin, TX 78712 USA. [Meyers, Lauren Ancel] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Meyers, Lauren Ancel] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Bansal, S (reprint author), Penn State Univ, Ctr Infect Dis Dynam, Mueller Lab 208, University Pk, PA 16802 USA. EM shweta@sbansal.com OI Bansal, Shweta/0000-0002-1740-5421 FU RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; James F. McDonnell Foundation; National Science Foundation [DEB-0749097] FX The authors would like to thank Julia Gog and anonymous reviewers for their comments. This work was supported by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and grants from the James F. McDonnell Foundation and National Science Foundation (DEB-0749097) to L.A.M. NR 50 TC 9 Z9 9 U1 0 U2 20 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 SEP 21 PY 2012 VL 309 BP 176 EP 184 DI 10.1016/j.jtbi.2012.06.012 PG 9 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 988YA UT WOS:000307526200018 PM 22721993 ER PT J AU Hawrylycz, MJ Lein, ES Guillozet-Bongaarts, AL Shen, EH Ng, L Miller, JA van de Lagemaat, LN Smith, KA Ebbert, A Riley, ZL Abajian, C Beckmann, CF Bernard, A Bertagnolli, D Boe, AF Cartagena, PM Chakravarty, MM Chapin, M Chong, J Dalley, RA Daly, BD Dang, C Datta, S Dee, N Dolbeare, TA Faber, V Feng, D Fowler, DR Goldy, J Gregor, BW Haradon, Z Haynor, DR Hohmann, JG Horvath, S Howard, RE Jeromin, A Jochim, JM Kinnunen, M Lau, C Lazarz, ET Lee, C Lemon, TA Li, L Li, Y Morris, JA Overly, CC Parker, PD Parry, SE Reding, M Royall, JJ Schulkin, J Sequeira, PA Slaughterbeck, CR Smith, SC Sodt, AJ Sunkin, SM Swanson, BE Vawter, MP Williams, D Wohnoutka, P Zielke, HR Geschwind, DH Hof, PR Smith, SM Koch, C Grant, SGN Jones, AR AF Hawrylycz, Michael J. Lein, Ed S. Guillozet-Bongaarts, Angela L. Shen, Elaine H. Ng, Lydia Miller, Jeremy A. van de lagemaat, Louie N. Smith, Kimberly A. Ebbert, Amanda Riley, Zackery L. Abajian, Chris Beckmann, Christian F. Bernard, Amy Bertagnolli, Darren Boe, Andrew F. Cartagena, Preston M. Chakravarty, M. Mallar Chapin, Mike Chong, Jimmy Dalley, Rachel A. Daly, Barry David Dang, Chinh Datta, Suvro Dee, Nick Dolbeare, Tim A. Faber, Vance Feng, David Fowler, David R. Goldy, Jeff Gregor, Benjamin W. Haradon, Zeb Haynor, David R. Hohmann, John G. Horvath, Steve Howard, Robert E. Jeromin, Andreas Jochim, Jayson M. Kinnunen, Marty Lau, Christopher Lazarz, Evan T. Lee, Changkyu Lemon, Tracy A. Li, Ling Li, Yang Morris, John A. Overly, Caroline C. Parker, Patrick D. Parry, Sheana E. Reding, Melissa Royall, Joshua J. Schulkin, Jay Sequeira, Pedro Adolfo Slaughterbeck, Clifford R. Smith, Simon C. Sodt, Andy J. Sunkin, Susan M. Swanson, Beryl E. Vawter, Marquis P. Williams, Derric Wohnoutka, Paul Zielke, H. Ronald Geschwind, Daniel H. Hof, Patrick R. Smith, Stephen M. Koch, Christof Grant, Seth G. N. Jones, Allan R. TI An anatomically comprehensive atlas of the adult human brain transcriptome SO NATURE LA English DT Article ID CEREBRAL-CORTEX; NEOCORTEX; LISTS AB Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of similar to 900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography-the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function. C1 [Hawrylycz, Michael J.; Lein, Ed S.; Guillozet-Bongaarts, Angela L.; Shen, Elaine H.; Ng, Lydia; Miller, Jeremy A.; Smith, Kimberly A.; Ebbert, Amanda; Riley, Zackery L.; Abajian, Chris; Bernard, Amy; Bertagnolli, Darren; Boe, Andrew F.; Chakravarty, M. Mallar; Chapin, Mike; Chong, Jimmy; Dalley, Rachel A.; Dang, Chinh; Datta, Suvro; Dee, Nick; Dolbeare, Tim A.; Faber, Vance; Feng, David; Goldy, Jeff; Gregor, Benjamin W.; Haradon, Zeb; Hohmann, John G.; Howard, Robert E.; Jochim, Jayson M.; Kinnunen, Marty; Lau, Christopher; Lazarz, Evan T.; Lee, Changkyu; Lemon, Tracy A.; Li, Yang; Morris, John A.; Overly, Caroline C.; Parker, Patrick D.; Parry, Sheana E.; Reding, Melissa; Royall, Joshua J.; Slaughterbeck, Clifford R.; Sodt, Andy J.; Sunkin, Susan M.; Swanson, Beryl E.; Williams, Derric; Wohnoutka, Paul; Koch, Christof; Jones, Allan R.] Allen Inst Brain Sci, Seattle, WA 98103 USA. [van de lagemaat, Louie N.; Grant, Seth G. N.] Univ Edinburgh, Genes Cognit Programme, Edinburgh EH16 4SB, Midlothian, Scotland. [Beckmann, Christian F.] Univ Twente, MIRA Inst, Nijmegen, Netherlands. [Beckmann, Christian F.] Radboud Univ Nijmegen, Donders Inst, NL-6525 ED Nijmegen, Netherlands. [Cartagena, Preston M.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. [Chakravarty, M. Mallar] Ctr Addict & Mental Hlth Toronto, Kimel Family Translat Imaging Genet Lab, Toronto, ON M5S 2S1, Canada. [Daly, Barry David] Univ Maryland, Sch Med, Dept Diagnost Radiol, Med Ctr, Baltimore, MD 21201 USA. [Fowler, David R.] Univ Maryland, Dept Pathol, Sch Med, Baltimore, MD 21201 USA. [Haynor, David R.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Horvath, Steve] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Gonda Res Ctr, Los Angeles, CA 90095 USA. [Jeromin, Andreas] Banyan Biomarkers Inc, Alachua, FL 32615 USA. [Li, Ling] Off Chief Med Examiner, Baltimore, MD USA. [Li, Ling] Univ Maryland, Dept Pediat, Baltimore, MD 21201 USA. [Schulkin, Jay] Georgetown Univ, Sch Med, Dept Neurosci, Washington, DC 20007 USA. [Sequeira, Pedro Adolfo; Vawter, Marquis P.] Univ Calif Irvine, Funct Genom Lab, Dept Psychiat & Human Behav, Sch Med, Irvine, CA 92697 USA. [Smith, Simon C.] Histion LLC, Everett, WA 98204 USA. [Zielke, H. Ronald] Univ Maryland, Eunice Kennedy Shriver NICHD Brain & Tissue Bank, Baltimore, MD 21201 USA. [Geschwind, Daniel H.] Univ Calif Los Angeles, David Geffen Sch Med, Program Neurogenet, Dept Neurol, Los Angeles, CA 90095 USA. [Geschwind, Daniel H.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Los Angeles, CA 90095 USA. [Hof, Patrick R.] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY 10029 USA. [Hof, Patrick R.] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA. [Smith, Stephen M.] Univ Oxford, FMRIB, Oxford OX3 9DU, England. [Koch, Christof] CALTECH, Pasadena, CA 91125 USA. RP Hawrylycz, MJ (reprint author), Allen Inst Brain Sci, Seattle, WA 98103 USA. EM mikeh@alleninstitute.org RI Beckmann, Christian/E-6374-2012; Sequeira, Adolfo/K-7278-2015; OI Sequeira, Adolfo/0000-0003-3040-1190; Koch, Christof/0000-0001-6482-8067; Smith, Stephen/0000-0001-8166-069X FU Department of Health and Human Services Health Resources and Services Administration Awards [1C76HF15069-01-00, 1 1C76HF19619-01-00]; MRCD; Wellcome Trust; European Union Seventh Framework Programme [241498 EUROSPIN, 242167 SynSys, 241995 GENCODYS] FX We wish to thank the Allen Institute founders, P. G. Allen and J. Allen, for their vision, encouragement, and support. We express our gratitude to past and present Allen Institute staff members R. Adams, K. Aiona, A. Alpisa, J. Arnold, C. Bennet, K. Brouner, S. Butler, E. Byrnes, S. Caldejon, J. Campiche, A. Carey, J. Chen, C. Copeland, C. Cuhaciyan, T. Desta, N. Dotson, S. Faber, T. Fliss, E. Fulfs, G. Gee, T. Gilbert, L. Gourley, G. Gu, J. Heilman, N. Ivanov, K. Keyser, A. Kriedberg, J. Laoenkue, F. Lee, S. Levine, L. Luong, N. Mastan, N. Mosqueda, E. Mott, N. Motz, D. Muzia, K. Ngo, A. Oldre, E. Olson, J. Parente, J. Phillips, L. Potekhina, T. Roberts, K. Roll, D. Rosen, M. Sarreal, S. Shapouri, N. Shapovalova, C. Simpson, D. Simpson, M. Smith, N. Stewart, K. Sweeney, A. Szafer, L. Velasquez, U. Wagley, W. Wakeman, C. White and B. Youngstrom for their technical assistance. We thank C. Long for mechanical engineering contract work. We thank R. Gullapalli, A. McMillan and R. Morales for post-mortem magnetic resonance imaging and radiology interpretation of MR data; J. Cottrell, M. Davis, R. Johnson, K. Moraniec, R. Vigorito, A. Weldon and the NICHD Brain and Tissue Bank for Developmental Disorders for tissue acquisition and processing; J. Davis for donor coordination; F. Mamdani, M. Martin, E. Moon, L. Morgan, B. Rollins and D. Walsh for tissue processing and psychological autopsy (DW); D. Patel for magnetic resonance imaging; and J. Sonnen for consultation on tissue microneuropathology. We also thank the External RNA Controls Consortium (ERCC), the US National Institute of Standards (NIST) and Technology, and M. Salit for access to ERCC transcripts during Phase V testing. We are grateful to Beckman Coulter Genomics (formerly Cogenics) and their staff P. Hurban, E. Lobenhofer, K. Phillips, A. Rouse and S. Beaver for microarray data generation and design of the custom Agilent array. We also wish to thank the Allen Human Brain Atlas Advisory Council members D. Geschwind, R. Gibbs, P. Hof, E. Jones, C. Koch, C. Saper, L. Swanson, A. Toga and D. Van Essen for their scientific guidance and dedication to the successful execution of this project. The project described was supported in part by Grant Numbers 1C76HF15069-01-00 and 1 1C76HF19619-01-00 from the Department of Health and Human Services Health Resources and Services Administration Awards and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Health and Human Services Health Resources and Services Administration Awards. S. G. N. G and L. V. L. were supported by the MRCD, Wellcome Trust and European Union Seventh Framework Programme under grants 241498 EUROSPIN, 242167 SynSys, and 241995 GENCODYS Projects. NR 35 TC 427 Z9 432 U1 9 U2 95 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 20 PY 2012 VL 489 IS 7416 BP 391 EP 399 DI 10.1038/nature11405 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007AK UT WOS:000308860900037 PM 22996553 ER PT J AU Zenon, A Krauzlis, RJ AF Zenon, Alexandre Krauzlis, Richard J. TI Attention deficits without cortical neuronal deficits SO NATURE LA English DT Article ID SUPERIOR-COLLICULUS; VISUAL-CORTEX; SELECTIVE ATTENTION; MACAQUE MONKEY; AREAS MT; MODULATION; MICROSTIMULATION; INACTIVATION; SIGNALS; SHIFTS AB The ability to process relevant stimuli selectively is a fundamental function of the primate visual system. The best-understood correlate of this function is the enhanced response of neurons in the visual cortex to attended stimuli(1,2). However, recent results show that the superior colliculus (SC), a midbrain structure, also has a crucial role in visual attention(3-5). It has been assumed that the SC acts through the same well-known mechanisms in the visual cortex(3,5). Here we tested this hypothesis by transiently inactivating the SC during a motion-change-detection task and measuring responses in two visual cortical areas. We found that despite large deficits in visual attention, the enhanced responses of neurons in the visual cortex to attended stimuli were unchanged. These results show that the SC contributes to visual attention through mechanisms that are independent of the classic effects in the visual cortex, demonstrating that other processes must have key roles in visual attention. C1 [Zenon, Alexandre; Krauzlis, Richard J.] Salk Inst Biol Studies, Syst Neurobiol Lab, La Jolla, CA 92037 USA. [Zenon, Alexandre] Catholic Univ Louvain, Inst Neurosci, B-1200 Brussels, Belgium. [Krauzlis, Richard J.] NEI, Lab Sensorimotor Res, Bethesda, MD 20892 USA. RP Krauzlis, RJ (reprint author), Salk Inst Biol Studies, Syst Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM richard.krauzlis@nih.gov FU F.M. Kirby Foundation; National Eye Institute Intramural Research Program at the National Institutes of Health FX We thank E. Boehle, N. Dill and A. Karnik for technical assistance, and R. Wurtz for discussions and reading of the manuscript. This work was supported by the F.M. Kirby Foundation and the National Eye Institute Intramural Research Program at the National Institutes of Health. NR 37 TC 67 Z9 67 U1 1 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 20 PY 2012 VL 489 IS 7416 BP 434 EP U124 DI 10.1038/nature11497 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007AK UT WOS:000308860900046 PM 22972195 ER PT J AU Blakemore, C Clark, JM Nevalainen, T Oberdorfer, M Sussman, A AF Blakemore, Colin Clark, Judy MacArthur Nevalainen, Timo Oberdorfer, Michael Sussman, Arthur TI Implementing the 3Rs in Neuroscience Research: A Reasoned Approach SO NEURON LA English DT Editorial Material AB The 3Rs-replacement, reduction, and refinement-are aimed at minimizing the welfare costs to animals used in research. Some neuroscientists fear that implementing the 3Rs will prohibit essential studies. Others view them as fundamental ethical principles that improve the quality of research. A regulatory system that integrates science and welfare is most likely to deliver public confidence. C1 [Nevalainen, Timo] Univ Eastern Finland, Lab Anim Ctr, Kuopio 70800, Finland. [Blakemore, Colin] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England. [Clark, Judy MacArthur] Home Off, Anim Sci Regulat Unit, London SW1P 4DF, England. [Oberdorfer, Michael] NEI, NIH, Dickerson, MD 20842 USA. [Sussman, Arthur] MacArthur Fdn, Chicago, IL 60614 USA. RP Nevalainen, T (reprint author), Univ Eastern Finland, Lab Anim Ctr, Kuopio 70800, Finland. EM sp1dy@comcast.net NR 7 TC 6 Z9 7 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 20 PY 2012 VL 75 IS 6 BP 948 EP 950 DI 10.1016/j.neuron.2012.09.001 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 011XF UT WOS:000309198900007 PM 22998864 ER PT J AU Amadi-Obi, A Yu, CR Dambuza, I Kim, SH Marrero, B Egwuagu, CE AF Amadi-Obi, Ahjoku Yu, Cheng-Rong Dambuza, Ivy Kim, Sung-Hye Marrero, Bernadette Egwuagu, Charles E. TI Interleukin 27 Induces the Expression of Complement Factor H (CFH) in the Retina SO PLOS ONE LA English DT Article ID PIGMENT EPITHELIAL-CELLS; MACULAR DEGENERATION; TRANSCRIPTION FACTORS; B-CELL; INFLAMMATION; GENE; UVEITIS; DIFFERENTIATION; CYTOKINE; REGION AB Complement factor H (CFH) is a central regulator of the complement system and has been implicated in the etiology of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. In view of previous studies showing that reduced expression of CFH in the retina is a risk factor for developing AMD, there is significant interest in understanding how CFH expression is regulated in the retina. In this study, we have shown that the anti-inflammatory cytokine, IL-27, induced CFH expression in mouse retinal cells and human retinal pigmented epithelial cells (RPE) through STAT1-mediated up-regulation of Interferon Regulatory Factor-1 (IRF-1) and IRF-8. We further show that cells in the ganglion and inner-nuclear layers of the retina constitutively express IRF-1 and IRF-8 and enhanced CFH expression in the retina during ocular inflammation correlated with significant increase in the expression of IRF-1, IRF-8 and IL-27 (IL-27p28 and Ebi3). Our data thus reveal a novel role of IL-27 in regulating complement activation through up-regulation of CFH and suggest that defects in IL-27 signaling or expression may contribute to the reduction of CFH expression in the retina of patients with AMD. C1 [Amadi-Obi, Ahjoku; Yu, Cheng-Rong; Dambuza, Ivy; Kim, Sung-Hye; Marrero, Bernadette; Egwuagu, Charles E.] NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU National Eye Institute; National Institutes of Health FX The Intramural Research Programs of the National Eye Institute and National Institutes of Health provided funding for this research. 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 6 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2012 VL 7 IS 9 AR e45801 DI 10.1371/journal.pone.0045801 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014PT UT WOS:000309388900101 PM 23029250 ER PT J AU Lemaitre, M Carrat, F Rey, G Miller, M Simonsen, L Viboud, C AF Lemaitre, Magali Carrat, Fabrice Rey, Gregoire Miller, Mark Simonsen, Lone Viboud, Cecile TI Mortality Burden of the 2009 A/H1N1 Influenza Pandemic in France: Comparison to Seasonal Influenza and the A/H3N2 Pandemic SO PLOS ONE LA English DT Article ID UNITED-STATES; A H1N1; AGE DISTRIBUTION; LIFE LOST; EPIDEMICS; IMPACT; DEATHS; MORBIDITY; ENGLAND; SURVEILLANCE AB Background: The mortality burden of the 2009 A/H1N1 pandemic remains unclear in many countries due to delays in reporting of death statistics. We estimate the age- and cause-specific excess mortality impact of the pandemic in France, relative to that of other countries and past epidemic and pandemic seasons. Methods: We applied Serfling and Poisson excess mortality approaches to model weekly age-and cause-specific mortality rates from June 1969 through May 2010 in France. Indicators of influenza activity, time trends, and seasonal terms were included in the models. We also reviewed the literature for country-specific estimates of 2009 pandemic excess mortality rates to characterize geographical differences in the burden of this pandemic. Results: The 2009 A/H1N1 pandemic was associated with 1.0 (95% Confidence Intervals (CI) 0.2-1.9) excess respiratory deaths per 100,000 population in France, compared to rates per 100,000 of 44 (95% CI 43-45) for the A/H3N2 pandemic and 2.9 (95% CI 2.3-3.7) for average inter-pandemic seasons. The 2009 A/H1N1 pandemic had a 10.6-fold higher impact than inter-pandemic seasons in people aged 5-24 years and 3.8-fold lower impact among people over 65 years. Conclusions: The 2009 pandemic in France had low mortality impact in most age groups, relative to past influenza seasons, except in school-age children and young adults. The historical A/H3N2 pandemic was associated with much larger mortality impact than the 2009 pandemic, across all age groups and outcomes. Our 2009 pandemic excess mortality estimates for France fall within the range of previous estimates for high-income regions. Based on the analysis of several mortality outcomes and comparison with laboratory-confirmed 2009/H1N1 deaths, we conclude that cardio-respiratory and all-cause mortality lack precision to accurately measure the impact of this pandemic in high-income settings and that use of more specific mortality outcomes is important to obtain reliable age-specific estimates. C1 [Lemaitre, Magali; Miller, Mark; Simonsen, Lone; Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lemaitre, Magali; Carrat, Fabrice] INSERM, UMR S 707, Paris, France. [Carrat, Fabrice] UPMC Paris 6, UMR S 707, Paris, France. [Carrat, Fabrice] Hop St Antoine, AP HP, Publ Hlth Unit, F-75571 Paris, France. [Rey, Gregoire] CepiDC, INSERM, Le Vesinet, France. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. RP Lemaitre, M (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM maglemaitre@gmail.com OI CARRAT, fabrice/0000-0002-8672-7918; Simonsen, Lone/0000-0003-1535-8526 FU Fondation de la Recherche Medicale; Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health; International Influenza Unit, Office of Global Affairs, Department of Health and Human Services; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security FX This work was supported by a grant from Fondation de la Recherche Medicale (to M. Lemaitre) and by the in-house Influenza Research Program of the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, which is funded by the International Influenza Unit, Office of Global Affairs, Department of Health and Human Services. L. S. acknowledges support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 24 Z9 24 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2012 VL 7 IS 9 AR e45051 DI 10.1371/journal.pone.0045051 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014PT UT WOS:000309388900018 PM 23028756 ER PT J AU Yasgar, A Furdas, SD Maloney, DJ Jadhav, A Jung, M Simeonov, A AF Yasgar, Adam Furdas, Silviya D. Maloney, David J. Jadhav, Ajit Jung, Manfred Simeonov, Anton TI High-Throughput 1,536-Well Fluorescence Polarization Assays for alpha(1)-Acid Glycoprotein and Human Serum Albumin Binding SO PLOS ONE LA English DT Article ID PLASMA-PROTEIN BINDING; ALPHA-1-ACID GLYCOPROTEIN; DRUG DISCOVERY; LIGAND-BINDING; HIGH-AFFINITY; PRAZOSIN; SITES; METABOLISM AB Two major plasma proteins in humans are primarily responsible for drug binding, the alpha(1)-acid-glycoprotein (AGP) and human serum albumin (HSA). The availability of at least a semiquantitative high-throughput assay for assessment of protein binding is expected to aid in bridging the current gap between high-throughput screening and early lead discovery, where cell-based and biochemical assays are deployed routinely to test up to several million compounds rapidly, as opposed to the late-stage candidate drug profiling methods which test at most dozens of compounds at a time. Here, we describe the miniaturization of a pair of assays based on the binding-and displacement-induced changes in fluorescence polarization (FP) of fluorescent small molecule probes known to specifically target the drug-binding sites of these two proteins. A robust and reproducible assay performance was achieved in <= 4 mu L assay volume in 1,536-well format. The assays were tested against a validation set of 10 known protein binders, and the results compared favorably with data obtained using protein-coated beads with high-performance liquid chromatography analysis. The miniaturized assays were taken to a high-throughput level in a screen of the LOPAC(1280) collection of 1,280 pharmacologically active compounds. The adaptation of the AGP and HSA FP assays to a 1,536-well format should allow their use in early-stage profiling of large-size compound sets. C1 [Yasgar, Adam; Maloney, David J.; Jadhav, Ajit; Simeonov, Anton] NIH, Chem Genom Ctr, Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA. [Furdas, Silviya D.; Jung, Manfred] Univ Freiburg, Inst Pharmaceut Sci, D-79106 Freiburg, Germany. RP Simeonov, A (reprint author), NIH, Chem Genom Ctr, Natl Ctr Advancing Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM asimeono@mail.nih.gov RI Jung, Manfred/Q-8029-2016 OI Jung, Manfred/0000-0002-6361-7716 FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Intramural Research Program of the NHGRI, NIH FX This research was supported in part by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the NHGRI, NIH. No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 6 Z9 6 U1 1 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2012 VL 7 IS 9 AR e45594 DI 10.1371/journal.pone.0045594 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014PT UT WOS:000309388900081 PM 23029124 ER PT J AU Kuehl, WM Bergsagel, PL AF Kuehl, W. Michael Bergsagel, P. Leif TI MYC addiction: a potential therapeutic target in MM SO BLOOD LA English DT Editorial Material ID MULTIPLE-MYELOMA; ACTIVATION; CANCER C1 [Kuehl, W. Michael] NCI, Bethesda, MD 20892 USA. RP Kuehl, WM (reprint author), NCI, Bethesda, MD 20892 USA. FU NIA NIH HHS [R01 AG020686] NR 11 TC 22 Z9 24 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 SEP 20 PY 2012 VL 120 IS 12 BP 2351 EP 2352 PG 2 WC Hematology SC Hematology GA 009SD UT WOS:000309044600002 PM 22996653 ER PT J AU Klebanoff, CA Gattinoni, L AF Klebanoff, Christopher A. Gattinoni, Luca TI Stubborn Tregs limit T-cell therapy SO BLOOD LA English DT Editorial Material ID IMMUNOTHERAPY; ANTIGEN; CANCER; SINKS C1 [Klebanoff, Christopher A.; Gattinoni, Luca] NCI, Bethesda, MD 20892 USA. RP Klebanoff, CA (reprint author), NCI, Bethesda, MD 20892 USA. RI Gattinoni, Luca/A-2281-2008 OI Gattinoni, Luca/0000-0003-2239-3282 NR 10 TC 0 Z9 0 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 SEP 20 PY 2012 VL 120 IS 12 BP 2352 EP 2354 PG 5 WC Hematology SC Hematology GA 009SD UT WOS:000309044600003 PM 22996654 ER PT J AU Galis, ZS Hoots, WK Kiley, JP Lauer, MS AF Galis, Zorina S. Hoots, W. Keith Kiley, James P. Lauer, Michael S. TI On the value of portfolio diversity in heart, lung, and blood research SO BLOOD LA English DT Editorial Material ID BIOMEDICAL-RESEARCH; SCIENCE; NIH C1 [Lauer, Michael S.] NHLBI, Off Director, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Galis, Zorina S.] NHLBI, Vasc Biol & Hypertens Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Hoots, W. Keith] NHLBI, Off Director, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. [Kiley, James P.] NHLBI, Off Director, Div Lung Dis, NIH, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Off Director, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Rm 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov NR 27 TC 0 Z9 0 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 SEP 20 PY 2012 VL 120 IS 12 BP 2361 EP 2364 DI 10.1182/blood-2012-08-450643 PG 4 WC Hematology SC Hematology GA 009SD UT WOS:000309044600008 PM 22923497 ER PT J AU Slape, CI Saw, J Jowett, JBM Aplan, PD Strasser, A Jane, SM Curtis, DJ AF Slape, Christopher I. Saw, Jesslyn Jowett, Jeremy B. M. Aplan, Peter D. Strasser, Andreas Jane, Stephen M. Curtis, David J. TI Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; TRANSGENIC MICE DEVELOP; FAS-INDUCED APOPTOSIS; MOUSE MODEL; BETA-CELLS; DEATH; DISEASE; EXPRESSION; PROTEINS; CANCER AB Programmed cell death or apoptosis is a prominent feature of low-risk myelodysplastic syndromes (MDS), although the underlying mechanism remains controversial. High-risk MDS have less apoptosis associated with increased expression of the prosurvival BCL2-related proteins. To address the mechanism and pathogenic role of apoptosis and BCL2 expression in MDS, we used a mouse model resembling human MDS, in which the fusion protein NUP98-HOXD13 (NHD13) of the chromosomal translocation t(2;11)(q31;p15) is expressed in hematopoietic cells. Hematopoietic stem and progenitor cells from 3-month-old mice had increased rates of apoptosis associated with increased cell cycling and DNA damage. Gene expression profiling of these MDS progenitors revealed a specific reduction in Bcl2. Restoration of Bcl2 expression by a BCL2 transgene blocked apoptosis of the MDS progenitors, which corrected the macrocytic anemia. Blocking apoptosis also restored cell-cycle quiescence and reduced DNA damage in the MDS progenitors. We expected that preventing apoptosis would accelerate malignant transformation to acute myeloid leukemia (AML). However, contrary to expectations, preventing apoptosis of premalignant cells abrogated transformation to AML. In contrast to the current dogma that overcoming apoptosis is an important step toward cancer, this work demonstrates that gaining a survival advantage of premalignant cells may delay or prevent leukemic progression. (Blood. 2012;120(12):2475-2483) C1 [Slape, Christopher I.] Monash Univ, Cent Clin Sch, Alfred Ctr, Australian Ctr Blood Dis,Div Blood Canc, Melbourne, Vic 3004, Australia. [Slape, Christopher I.; Saw, Jesslyn; Jane, Stephen M.; Curtis, David J.] Royal Melbourne Hosp, Bone Marrow Res Labs, Parkville, Vic 3050, Australia. [Jowett, Jeremy B. M.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Strasser, Andreas] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. [Strasser, Andreas] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia. [Jane, Stephen M.; Curtis, David J.] Monash Univ, Alfred Hosp, Dept Clin Hematol, Melbourne, Vic 3181, Australia. RP Slape, CI (reprint author), Monash Univ, Cent Clin Sch, Alfred Ctr, Australian Ctr Blood Dis,Div Blood Canc, 99 Commercial Rd, Melbourne, Vic 3004, Australia. EM christopher.slape@monash.edu RI Strasser, Andreas/C-7581-2013; Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016; OI Slape, Christopher/0000-0002-8407-3092; Strasser, Andreas/0000-0002-5020-4891 FU National Health and Medical Research Council of Australia [628367, 461221]; Cancer Council of Victoria; Leukemia & Lymphoma Society (SCOR grant) [7413]; National Institutes of Health [CA43540]; Australian Government IRISS; Victorian State Government OIS; National Institutes of Health, National Cancer Institute; National Institutes of Health Technology Transfer office [NUP98-HOXD13] FX This work was supported by the National Health and Medical Research Council of Australia (Project Grant 628367, Program Grant 461221, NHMRC Australia Fellowship), the Cancer Council of Victoria, the Leukemia & Lymphoma Society (SCOR grant no. 7413), the National Institutes of Health (CA43540), and operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.; C.I.S. and P.D.A. receive royalties from the National Institutes of Health Technology Transfer office for the invention of NUP98-HOXD13 mice. The remaining authors declare no competing financial interests. NR 39 TC 15 Z9 15 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 SEP 20 PY 2012 VL 120 IS 12 BP 2475 EP 2483 DI 10.1182/blood-2012-05-430736 PG 9 WC Hematology SC Hematology GA 009SD UT WOS:000309044600021 PM 22855610 ER PT J AU Komiya, T Thomas, A Khozin, S Rajan, A Wang, YS Giaccone, G AF Komiya, Takefumi Thomas, Anish Khozin, Sean Rajan, Arun Wang, Yisong Giaccone, Giuseppe TI Response to Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID INHIBITOR; MET C1 [Komiya, Takefumi; Thomas, Anish; Khozin, Sean; Rajan, Arun; Wang, Yisong; Giaccone, Giuseppe] NCI, Bethesda, MD 20892 USA. RP Komiya, T (reprint author), NCI, Bethesda, MD 20892 USA. RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 NR 5 TC 12 Z9 12 U1 3 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 SEP 20 PY 2012 VL 30 IS 27 BP 3425 EP 3427 DI 10.1200/JCO.2012.42.4556 PG 3 WC Oncology SC Oncology GA 009XD UT WOS:000309057800026 PM 22891268 ER PT J AU Dunbar, CE Scheinberg, P Young, NS AF Dunbar, Cynthia E. Scheinberg, Phillip Young, Neal S. TI Eltrombopag in Refractory Aplastic Anemia REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Dunbar, Cynthia E.; Scheinberg, Phillip; Young, Neal S.] NHLBI, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov NR 4 TC 0 Z9 0 U1 1 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 SEP 20 PY 2012 VL 367 IS 12 BP 1163 EP 1163 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 007AS UT WOS:000308861800019 ER PT J AU Mamounas, EP Tang, G Paik, S Baehner, FL Liu, Q Jeong, JH Kim, SR Butler, SM Jamshidian, F Cherbavaz, DB Shak, S Julian, TB Lembersky, BC Wickerham, DL Costantino, JP Wolmark, N AF Mamounas, Eleftherios P. Tang, Gong Paik, Soonmyung Baehner, Frederick L. Liu, Qing Jeong, Jong-Hyeon Kim, Seong-Rim Butler, Steven M. Jamshidian, Farid Cherbavaz, Diana B. Shak, Steven Julian, Thomas B. Lembersky, Barry C. Wickerham, D. Lawrence Costantino, Joseph P. Wolmark, Norman TI Prognostic impact of the 21-gene recurrence score (RS) on disease-free and overall survival of node-positive, ER-positive breast cancer patients (pts) treated with adjuvant chemotherapy: Results from NSABP B-28. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Canton, OH USA. Aultman Hosp, Canton, OH USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Genom Hlth, Redwood City, CA USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. NSABP, Pittsburgh, PA USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. NR 0 TC 2 Z9 3 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2012 VL 30 IS 27 SU S MA 1 PG 1 WC Oncology SC Oncology GA V31OI UT WOS:000208892500002 ER PT J AU Althabe, F Belizan, JM Mazzoni, A Berrueta, M Hemingway-Foday, J Koso-Thomas, M McClure, E Chomba, E Garces, A Goudar, S Kodkany, B Saleem, S Pasha, O Patel, A Esamai, F Carlo, WA Krebs, NF Derman, RJ Goldenberg, RL Hibberd, P Liechty, EA Wright, LL Bergel, EF Jobe, AH Buekens, P AF Althabe, Fernando Belizan, Jose M. Mazzoni, Agustina Berrueta, Mabel Hemingway-Foday, Jay Koso-Thomas, Marion McClure, Elizabeth Chomba, Elwyn Garces, Ana Goudar, Shivaprasad Kodkany, Bhalchandra Saleem, Sarah Pasha, Omrana Patel, Archana Esamai, Fabian Carlo, Waldemar A. Krebs, Nancy F. Derman, Richard J. Goldenberg, Robert L. Hibberd, Patricia Liechty, Edward A. Wright, Linda L. Bergel, Eduardo F. Jobe, Alan H. Buekens, Pierre TI Antenatal corticosteroids trial in preterm births to increase neonatal survival in developing countries: study protocol SO REPRODUCTIVE HEALTH LA English DT Article DE Neonatal mortality; Antenatal corticosteroids; Implementation research; Preterm birth ID INFANTS; DEATHS AB Background: Preterm birth is a major cause of neonatal mortality, responsible for 28% of neonatal deaths overall. The administration of antenatal corticosteroids to women at high risk of preterm birth is a powerful perinatal intervention to reduce neonatal mortality in resource rich environments. The effect of antenatal steroids to reduce mortality and morbidity among preterm infants in hospital settings in developed countries with high utilization is well established, yet they are not routinely used in developing countries. The impact of increasing antenatal steroid use in hospital or community settings with low utilization rates and high infant mortality among premature infants due to lack of specialized services has not been well researched. There is currently no clear evidence about the safety of antenatal corticosteroid use for community-level births. Methods: We hypothesize that a multi country, two-arm, parallel cluster randomized controlled trial to evaluate whether a multifaceted intervention to increase the use of antenatal corticosteroids, including components to improve the identification of pregnancies at high risk of preterm birth and providing and facilitating the appropriate use of steroids, will reduce neonatal mortality at 28 days of life in preterm newborns, compared with the standard delivery of care in selected populations of six countries. 102 clusters in Argentina, Guatemala, Kenya, India, Pakistan, and Zambia will be randomized, and around 60,000 women and newborns will be enrolled. Kits containing vials of dexamethasone, syringes, gloves, and instructions for administration will be distributed. Improving the identification of women at high risk of preterm birth will be done by (1) diffusing recommendations for antenatal corticosteroids use to health providers, (2) training health providers on identification of women at high risk of preterm birth, (3) providing reminders to health providers on the use of the kits, and (4) using a color-coded tape to measure uterine height to estimate gestational age in women with unknown gestational age. In both intervention and control clusters, health providers will be trained in essential newborn care for low birth weight babies. The primary outcome is neonatal mortality at 28 days of life in preterm infants. C1 [Althabe, Fernando; Belizan, Jose M.; Mazzoni, Agustina; Berrueta, Mabel; Bergel, Eduardo F.] Inst Clin Effectiveness & Hlth Policy IECS, Buenos Aires, DF, Argentina. [Hemingway-Foday, Jay] RTI Int, Res Triangle Pk, NC 27709 USA. [Koso-Thomas, Marion] NICHHD, Ctr Res Mothers & Children Eunice Kennedy Shriver, NIH, Rockville, MD 20852 USA. [McClure, Elizabeth] RTI Int, Durham, NC 27709 USA. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Garces, Ana] IMSALUD, Guatemala City 01011, Guatemala. [Goudar, Shivaprasad] J N Med Coll, Dept Physiol, Belgaum 590010, Karnataka, India. [Goudar, Shivaprasad] J N Med Coll, Dept Med Educ, Belgaum 590010, Karnataka, India. [Kodkany, Bhalchandra] Jawaharlal Nehru Med Coll, KLEU Res Fdn, Belgaum 590010, Karnataka, India. [Saleem, Sarah; Pasha, Omrana] Aga Khan Univ, Coll Med, Dept Community Hlth Sci, Karachi 74800, Pakistan. [Patel, Archana] Indira Gandhi Govt Med Coll, Clin Epidemiol Unit, Dept Pediat, Nagpur 440013, Maharashtra, India. [Esamai, Fabian] Moi Univ, Sch Med, Eldoret 30100, Kenya. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Div Neonatol, Birmingham, AL USA. [Krebs, Nancy F.] Univ Colorado Denver, Aurora, CO 80045 USA. [Derman, Richard J.] Christiana Care, Dept OB GYN, Newark, DE 19718 USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet Gynecol, New York, NY 10032 USA. [Hibberd, Patricia] Massachusetts Gen Hosp Children, Dept Pediat, Div Global Hlth, Boston, MA 02114 USA. [Liechty, Edward A.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Res Mothers & Children, NIH, Rockville, MD 20852 USA. [Jobe, Alan H.] Cincinnati Childrens Hosp, Cincinnati, OH 45229 USA. [Buekens, Pierre] Tulane Sch Publ Hlth & Trop Med, Sch Publ Hlth, New Orleans, LA 70112 USA. RP Mazzoni, A (reprint author), Inst Clin Effectiveness & Hlth Policy IECS, Dr Emilio Ravignani 2024,C1414CPV, Buenos Aires, DF, Argentina. EM amazzoni@iecs.org.ar OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053; Belizan, Jose/0000-0002-8412-3010 FU NICHD NIH HHS [U01 HD042372, U01 HD058322, U10 HD076461, U10 HD078439] NR 20 TC 19 Z9 20 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4755 J9 REPROD HEALTH JI Reprod. Health PD SEP 19 PY 2012 VL 9 AR 22 DI 10.1186/1742-4755-9-22 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 070KV UT WOS:000313505900001 PM 22992312 ER PT J AU Ziccardi, L Vijayasarathy, C Bush, RA Sieving, PA AF Ziccardi, Lucia Vijayasarathy, Camasamudram Bush, Ronald A. Sieving, Paul A. TI Loss of Retinoschisin (RS1) Cell Surface Protein in Maturing Mouse Rod Photoreceptors Elevates the Luminance Threshold for Light-Driven Translocation of Transducin But Not Arrestin SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LINKED JUVENILE RETINOSCHISIS; IN-VIVO; DEPENDENT REDISTRIBUTION; RHODOPSIN REGENERATION; DARK-ADAPTATION; NIGHT BLINDNESS; A-WAVE; KINETICS; PHOTOTRANSDUCTION; RETINA AB Loss of retinoschisin (RS1) in Rs1 knock-out (Rs1-KO) retina produces a post-photoreceptor phenotype similar to X-linked retinoschisis in young males. However, Rs1 is expressed strongly in photoreceptors, and Rs1-KO mice have early reduction in the electroretinogram a-wave. We examined light-activated transducin and arrestin translocation in young Rs1-KO mice as a marker for functional abnormalities in maturing rod photoreceptors. We found a progressive reduction in luminance threshold for transducin translocation in wild-type (WT) retinas between postnatal days P18 and P60. At P21, the threshold in Rs1-KO retinas was 10-fold higher than WT, but it decreased to <2.5-fold higher by P60. Light-activated arrestin translocation and re-translocation of transducin in the dark were not affected. Rs1-KO rod outer segment (ROS) length was significantly shorter than WT at P21 but was comparable with WT at P60. These findings suggested a delay in the structural and functional maturation of Rs1-KO ROS. Consistent with this, transcription factors CRX and NRL, which are fundamental to maturation of rod protein expression, were reduced in ROS of Rs1-KO mice at P21 but not at P60. Expression of transducin was 15-30% lower in P21 Rs1-KO ROS and transducin GTPase hydrolysis was nearly twofold faster, reflecting a 1.7- to 2.5-fold increase in RGS9 (regulator of G-protein signaling) level. Transduction protein expression and activity levels were similar to WT at P60. Transducin translocation threshold elevation indicates photoreceptor functional abnormalities in young Rs1-KO mice. Rapid reduction in threshold coupled with age-related changes in transduction protein levels and transcription factor expression are consistent with delayed maturation of Rs1-KO photoreceptors. C1 [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. [Ziccardi, Lucia] IRCCS, GB Bietti Fdn, I-00198 Rome, Italy. [Vijayasarathy, Camasamudram; Bush, Ronald A.; Sieving, Paul A.] Natl Inst Deafness & Other Commun Disorders, Sect Translat Res Retinal & Macular Degenerat, Bethesda, MD 20892 USA. RP Sieving, PA (reprint author), NEI, NIH, 31 Ctr Dr,Room 6A03, Bethesda, MD 20892 USA. EM paulsieving@nei.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Deafness and Other Communication Disorders; National Eye Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Deafness and Other Communication Disorders, and the National Eye Institute. We thank Robert N. Fariss and Maria M. Campos for technical assistance with confocal imaging and immunohistochemistry and Maria C. Santos for assistance with animal breeding and experiments. NR 54 TC 7 Z9 7 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 19 PY 2012 VL 32 IS 38 BP 13010 EP 13021 DI 10.1523/JNEUROSCI.1913-12.2012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 012SY UT WOS:000309258100006 PM 22993419 ER PT J AU Roesch, MR Esber, GR Bryden, DW Cerri, DH Haney, ZR Schoenbaum, G AF Roesch, Matthew R. Esber, Guillem R. Bryden, Daniel W. Cerri, Domenic H. Haney, Zachary R. Schoenbaum, Geoffrey TI Normal Aging Alters Learning and Attention-Related Teaching Signals in Basolateral Amygdala SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ORBITOFRONTAL CORTEX; IMPULSIVE CHOICE; DELAYED REWARDS; WORKING-MEMORY; AGED RATS; REINFORCER DEVALUATION; PATHOLOGICAL GAMBLERS; ORIENTING RESPONSE; TASK; LESIONS AB Normal aging has been associated with an increased propensity to wait for rewards. When this is tested experimentally, rewards are typically offered at increasing delays. In this setting, persistent responding for delayed rewards in aged rats could reflect either changes in the evaluation of delayed rewards or diminished learning, perhaps due to the loss of subcortical teaching signals induced by changes in reward; the loss or diminution of such teaching signals would result in slower learning with progressive delay of reward, which would appear as persistent responding. Such teaching signals have commonly been reported in phasic firing of midbrain dopamine neurons; however, similar signals have also been found in reward-responsive neurons in the basolateral amygdala (ABL). Unlike dopaminergic teaching signals, those in ABL seem to reflect surprise, increasing when reward is either better or worse than expected. Accordingly, activity is correlated with attentional responses and with the speed of learning after surprising increases or decreases in reward. Here we examined whether these attention-related teaching signals might be altered in normal aging. Young (3-6 months) and aged (22-26 months) male Long-Evans rats were trained on a discounting task used previously to demonstrate these signals. As expected, aged rats were less sensitive to delays, and this change was associated with a loss of attentional changes in orienting behavior and neural activity. These results indicate that normal aging alters teaching signals in the ABL. Changes in these teaching signals may contribute to a host of age-related cognitive changes. C1 [Esber, Guillem R.; Schoenbaum, Geoffrey] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. [Roesch, Matthew R.; Bryden, Daniel W.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Roesch, Matthew R.; Bryden, Daniel W.] Univ Maryland, Program Neurosci & Cognit Sci, College Pk, MD 20742 USA. [Cerri, Domenic H.; Haney, Zachary R.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. RP Schoenbaum, G (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. EM mroesch@umd.edu; schoenbg@schoenbaumlab.org FU National Institute on Aging; National Institute on Drug Abuse FX This work was supported by grants from National Institute on Aging (G. S.) and National Institute on Drug Abuse (M. R. R.). This article was prepared in part while G. S. was employed at University of Maryland, Baltimore. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 55 TC 3 Z9 3 U1 1 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 SEP 19 PY 2012 VL 32 IS 38 BP 13137 EP 13144 DI 10.1523/JNEUROSCI.2393-12.2012 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 012SY UT WOS:000309258100017 PM 22993430 ER PT J AU Ling, X Cao, SS Cheng, QY Keefe, JT Rustum, YM Li, FZ AF Ling, Xiang Cao, Shousong Cheng, Qiuying Keefe, James T. Rustum, Youcef M. Li, Fengzhi TI A Novel Small Molecule FL118 That Selectively Inhibits Survivin, Mcl-1, XIAP and cIAP2 in a p53-Independent Manner, Shows Superior Antitumor Activity SO PLOS ONE LA English DT Article ID COLORECTAL-CANCER CELLS; DOWN-REGULATION; COLON-CANCER; INDUCED APOPTOSIS; MEDIATED APOPTOSIS; PROSTATE-CANCER; TOPOISOMERASE-I; DRUG-RESISTANCE; UP-REGULATION; LUNG-CANCER AB Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin-reporter systems (US 7,569,221 B2) via high throughput screening (HTS) of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a novel anticancer compound (designated FL118). FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 mM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status-independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2) in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118's effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly x 4 schedule. FL118 induced favorable body-weight-loss profiles (temporary and reversible) and was able to eliminate large tumors. Together, the molecular targeting features of FL118 plus its superior antitumor activity warrant its further development toward clinical trials. C1 [Ling, Xiang; Cao, Shousong; Cheng, Qiuying; Keefe, James T.; Rustum, Youcef M.; Li, Fengzhi] Roswell Pk Canc Inst, Dept Pharmacol, Buffalo, NY 14263 USA. [Ling, Xiang; Cao, Shousong; Cheng, Qiuying; Keefe, James T.; Rustum, Youcef M.; Li, Fengzhi] Roswell Pk Canc Inst, Dept Therapeut, Buffalo, NY 14263 USA. [Cao, Shousong] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Rustum, Youcef M.; Li, Fengzhi] Roswell Pk Canc Inst, NCI Supported Expt Therapeut Program, Buffalo, NY 14263 USA. RP Li, FZ (reprint author), Roswell Pk Canc Inst, Dept Pharmacol, Buffalo, NY 14263 USA. EM fengzhi.li@roswellpark.org FU National Institutes of Health (NIH) [CA109481, CA133241]; Mesothelioma Foundation (Alexandria, VA); NCI Cancer Center Core Support Grant [CA016056]; Mesothelioma Foundation FX This work was sponsored in part by National Institutes of Health (NIH) R01 Grants (CA109481, CA133241) and the Mesothelioma Foundation (Alexandria, VA) grant to FL, and by shared resources supported by NCI Cancer Center Core Support Grant to Roswell Park Cancer Institute (CA016056). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program (DTP), Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI) for providing chemical libraries and relevant hit analogs in the public domain they collected and/or synthesized as a major compound source during the process of our drug screening and characterization. We thank Mesothelioma Foundation for grant supporting. We would also like to thank Dr. Paul A. Spengler (University of Rochester) and Dr. Margot Ip (Roswell Park Cancer Institute - RPCI, Buffalo, NY) for critically reading and revising the manuscript, and Dr. Lili Tian (SUNY at Buffalo/RPCI) for acting as a statistics consultant, Dr. Bruce Dolnick (RPCI) for providing the DHFR antibody, Dr. Allen C. Gao (University of California, Davis), Dr. Daniel Chan (University of Colorado, Denver, CO) and Dr. Kunle Odunsi (RPCI) for providing several cancer cell lines, and Dr. Dario C. Altieri (Wistar Institute Cancer Center) for the pcDNA3-XIAP vector. We would also like to thank Mr. Andrew Haller (PhD student, RPCI) and Ms. Lileena Johnson (MS student, RPCI) for their involvement in testing gene expression and repeating some of the drug screening experiments. The author contribution to the studies is as follows: XL and FL were involved in designing the in vitro experiments. XL screened compound libraries and performed in vitro biochemical and cell-based studies. XL analyzed and organized the in vitro data. QC and JTK were involved in compound screening work. QC and XL did promoter-luciferase activity assays. SC, FL and YMR were involved in designing the animal model work. SC (major) and FL (minor) performed animal model work. SC analyzed and organized the in vivo data. YMR, SC and FL were involved in the regular three-person panel discussion for planning animal model work. FL initiated and overall supervised the project. FL was involved in compound formulation studies for animal model work and wrote the manuscript. All authors were involved in reading and revising the manuscript to reach the final version. NR 82 TC 25 Z9 26 U1 7 U2 41 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 19 PY 2012 VL 7 IS 9 AR e45571 DI 10.1371/journal.pone.0045571 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 014PP UT WOS:000309388400106 PM 23029106 ER PT J AU Bezrukov, SM Liu, X Karginov, VA Wein, AN Leppla, SH Popoff, MR Barth, H Nestorovich, EM AF Bezrukov, Sergey M. Liu, Xian Karginov, Vladimir A. Wein, Alexander N. Leppla, Stephen H. Popoff, Michel R. Barth, Holger Nestorovich, Ekaterina M. TI Interactions of High-Affinity Cationic Blockers with the Translocation Pores of B. anthracis, C. botulinum, and C. perfringens Binary Toxins SO BIOPHYSICAL JOURNAL LA English DT Article ID LIPID BILAYER-MEMBRANES; BETA-CYCLODEXTRIN DERIVATIVES; CURRENT NOISE-ANALYSIS; PROTECTIVE ANTIGEN; C2 TOXIN; IOTA-TOXIN; LETHAL FACTOR; PHENYLALANINE CLAMP; CHANNEL FUNCTION; IN-VIVO AB Cationic beta-cyclodextrin derivatives were recently introduced as highly effective, potentially universal blockers of three binary bacterial toxins: anthrax toxin of Bacillus anthracis, C2 toxin of Clostridium botulinum, and iota toxin of Clostridium perfringens. The binary toxins are made of two separate components: the enzymatic A component, which acts on certain intracellular targets, and the binding/translocation B component, which forms oligomeric channels in the target cell membrane. Here we studied the voltage and salt dependence of the rate constants of binding and dissociation reactions of two structurally different beta-cyclodextrins (AmPr beta CD and AMBnT beta CD) in the PA(63), C2IIa, and Ib channels (B components of anthrax, C2, and iota toxins, respectively). With all three channels, the blocker carrying extra hydrophobic aromatic groups on the thio-alkyl linkers of positively charged amino groups, AMBnT beta CD, demonstrated significantly stronger binding compared with AmPr beta CD. This effect is seen as an increased residence time of the blocker in the channels, whereas the time between blockages characterizing the binding reaction on-rate stays practically unchanged. Surprisingly, the voltage sensitivity, expressed as a slope of the logarithm of the blocker residence time as a function of voltage, turned out to be practically the same for all six cases studied, suggesting structural similarities among the three channels. Also, the more-effective AMBnT beta CD blocker shows weaker salt dependence of the binding and dissociation rate constants compared with AmPr beta CD. By estimating the relative contributions of the applied transmembrane field, long-range Coulomb, and salt-concentration-independent, short-range forces, we found that the latter represent the leading interaction, which accounts for the high efficiency of blockage. In a search for the putative groups in the channel lumen that are responsible for the short-range forces, we performed measurements with the F427A mutant of PA(63), which lacks the functionally important phenylalanine clamp. We found that the on-rates of the blockage were virtually conserved, but the residence times and, correspondingly, the binding constants dropped by more than an order of magnitude, which also reduced the difference between the efficiencies of the two blockers. C1 [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Bethesda, MD USA. [Wein, Alexander N.; Leppla, Stephen H.] NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. [Liu, Xian; Nestorovich, Ekaterina M.] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. [Karginov, Vladimir A.] Innovat Biol, Herndon, VA USA. [Popoff, Michel R.] Inst Pasteur, Dept Host Pathogen Interact, Paris, France. [Barth, Holger] Univ Ulm, Med Ctr, Inst Pharmacol & Toxicol, Ulm, Germany. RP Bezrukov, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Bethesda, MD USA. EM bezrukos@mail.nih.gov; nestorovich@cua.edu RI Barth, Holger/E-7920-2013; Popoff, Michel/O-7719-2016 OI Popoff, Michel/0000-0001-9305-8989 FU Intramural Research Programs of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases; Catholic University of America FX This study was supported by the Intramural Research Programs of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases, and by startup funds from The Catholic University of America. V.A.K. is an employee and shareholder of Innovative Biologics. NR 60 TC 12 Z9 12 U1 0 U2 9 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 SEP 19 PY 2012 VL 103 IS 6 BP 1208 EP 1217 DI 10.1016/j.bpj.2012.07.050 PG 10 WC Biophysics SC Biophysics GA 009HV UT WOS:000309017800013 PM 22995493 ER PT J AU Jayasinghe, M Shrestha, P Wu, XW Tehver, R Stan, G AF Jayasinghe, Manori Shrestha, Pooja Wu, Xiongwu Tehver, Riina Stan, George TI Weak Infra-Ring Allosteric Communications of the Archaeal Chaperonin Thermosome Revealed by Normal Mode Analysis SO BIOPHYSICAL JOURNAL LA English DT Article ID CRYSTAL-STRUCTURE; SUBSTRATE-BINDING; CRYOELECTRON MICROSCOPY; CYTOPLASMIC CHAPERONIN; MOLECULAR-DYNAMICS; FOLDING MACHINE; ATP HYDROLYSIS; II CHAPERONIN; GROEL; CCT AB Chaperonins are molecular machines that use ATP-driven cycles to assist misfolded substrate proteins to reach the native state. During the functional cycle, these machines adopt distinct nucleotide-dependent conformational states, which reflect large-scale allosteric changes in individual subunits. Distinct allosteric kinetics has been described for the two chaperonin classes. Bacterial (group I) chaperonins, such as GroEL, undergo concerted subunit motions within each ring, whereas archaeal and eukaryotic chaperonins (group II) undergo sequential subunit motions. We study these distinct mechanisms through a comparative normal mode analysis of monomer and double-ring structures of the archaeal chaperonin thermosome and GroEL. We find that thermosome monomers of each type exhibit common low-frequency behavior of normal modes. The observed distinct higher-frequency modes are attributed to functional specialization of these subunit types. The thermosome double-ring structure has larger contribution from higher-frequency modes, as it is found in the GroEL case. We find that long-range intersubunit correlation of amino-acid pairs is weaker in the thermosome ring than in GroEL. Overall, our results indicate that distinct allosteric behavior of the two chaperonin classes originates from different wiring of individual subunits as well as of the intersubunit communications. C1 [Stan, George] Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA. [Shrestha, Pooja] Univ Cincinnati, Dept Phys, Cincinnati, OH 45221 USA. [Jayasinghe, Manori] No Kentucky Univ, Dept Chem, Highland Hts, KY 41076 USA. [Wu, Xiongwu] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Tehver, Riina] Denison Univ, Dept Phys & Astron, Granville, OH 43023 USA. RP Stan, G (reprint author), Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA. EM george.stan@uc.edu FU American Heart Association; Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute; Denison University FX This work has been supported by a grant from the American Heart Association (to G.S.), by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (X.W.), and by startup funds from Denison University (R.T.). NR 55 TC 5 Z9 5 U1 1 U2 10 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 SEP 19 PY 2012 VL 103 IS 6 BP 1285 EP 1295 DI 10.1016/j.bpj.2012.07.049 PG 11 WC Biophysics SC Biophysics GA 009HV UT WOS:000309017800021 PM 22995501 ER PT J AU Kaddurah-Daouk, R Yuan, PX Boyle, SH Matson, W Wang, Z Zeng, ZB Zhu, HJ Dougherty, GG Yao, JK Chen, G Guitart, X Carlson, PJ Neumeister, A Zarate, C Krishnan, RR Manji, HK Drevets, W AF Kaddurah-Daouk, Rima Yuan, Peixiong Boyle, Stephen H. Matson, Wayne Wang, Zhi Zeng, Zhao Bang Zhu, Hongjie Dougherty, George G. Yao, Jeffrey K. Chen, Guang Guitart, Xavier Carlson, Paul J. Neumeister, Alexander Zarate, Carlos Krishnan, Ranga R. Manji, Husseini K. Drevets, Wayne TI Cerebrospinal Fluid Metabolome in Mood Disorders-Remission State has a Unique Metabolic Profile SO SCIENTIFIC REPORTS LA English DT Article ID MAJOR DEPRESSIVE DISORDER; GLOBAL BIOCHEMICAL APPROACH; CSF MONOAMINE METABOLITES; PARKINSONS-DISEASE; OXIDATIVE STRESS; ANTIDEPRESSANT TREATMENT; PSYCHIATRIC-DISORDERS; SEROTONIN TRANSPORTER; S-ADENOSYLMETHIONINE; BIPOLAR DISORDER AB Targeted metabolomics provides an approach to quantify metabolites involved in specific molecular pathways. We applied an electrochemistry-based, targeted metabolomics platform to define changes in tryptophan, tyrosine, purine and related pathways in the depressed and remitted phases of major depressive disorder (MDD). Biochemical profiles in the cerebrospinal fluid of unmedicated depressed (n=14; dMDD) or remitted MDD subjects (n=14; rMDD) were compared against those in healthy controls (n=18; HC). The rMDD group showed differences in tryptophan and tyrosine metabolism relative to the other groups. The rMDD group also had higher methionine levels and larger methionine-to-glutathione ratios than the other groups, implicating methylation and oxidative stress pathways. The dMDD sample showed nonsignificant differences in the same direction in several of the metabolic branches assessed. The reductions in metabolites associated with tryptophan and tyrosine pathways in rMDD may relate to the vulnerability this population shows for developing depressive symptoms under tryptophan or catecholamine depletion. C1 [Kaddurah-Daouk, Rima; Boyle, Stephen H.; Krishnan, Ranga R.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Yuan, Peixiong; Chen, Guang; Guitart, Xavier; Carlson, Paul J.; Neumeister, Alexander; Zarate, Carlos; Manji, Husseini K.; Drevets, Wayne] NIMH, NIH, Intramural Res Program, Bethesda, MD 20892 USA. [Matson, Wayne] Bedford VA Med Ctr, Dept Syst Biochem, Bedford, MA USA. [Wang, Zhi; Zeng, Zhao Bang; Zhu, Hongjie] N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Wang, Zhi; Zeng, Zhao Bang; Zhu, Hongjie] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Dougherty, George G.; Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Dougherty, George G.; Yao, Jeffrey K.] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Dept Psychiat, Pittsburgh, PA 15213 USA. [Krishnan, Ranga R.] Duke NUS Grad Med Sch, Singapore, Singapore. [Drevets, Wayne] Univ Oklahoma, Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, Wayne] Univ Oklahoma, Dept Psychiat, Tulsa, OK USA. RP Kaddurah-Daouk, R (reprint author), Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. EM Kaddu001@mc.duke.edu RI yuan, tao/Q-3137-2016; Chen, Guang/A-2570-2017 OI yuan, tao/0000-0002-0904-9770; FU NIH [R24 GM078233]; Department of Veterans Affairs Senior Research Scientist Award; Amgen; Bristol-Myers Squibb; CeNeRx; Corcept; GlaxoSmithKline; Johnson Johnson; Lundbeck; Merck; Organon; Pfizer; Sepracor; Wyeth; Rules Based Medicine; Eisai; Abbott FX This research was supported in part by funding from NIH R24 GM078233, "The Metabolomics Research Network" (R.K.-D.) and the Department of Veterans Affairs Senior Research Scientist Award (JKY). Earle Bain, M.D. performed many of the lumbar punctures. Michele Drevets, Ruth Tinsley and other clinical staff at Mood and Anxiety Disorder Program of NIMH assisted with patient recruitment and evaluation, and contributed to collecting and storing the CSF samples. The contents of this article do not represent the views of the Department of VeteransAffairs or the United States Government.; Rima Kaddurah-Daouk is equity holder in Metabolon Inc., a biotechnology company in the metabolomics domain, and also an inventor on patents in the metabolomics field. She has received funding or consultancy fees for BMS, Pfizer Inc., AstraZeneca and Lundbeck. George G. Dougherty owns shares of Pfizer and Merck. Carlos Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression. Dr. Zarate has assigned his patent rights on ketamine to the U.S. government. Ranga R Krishnan has received consultancy fees from Amgen, Bristol-Myers Squibb, CeNeRx, Corcept, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Merck, Organon, Pfizer, Sepracor, and Wyeth. Wayne Drevets has received consultancy fees from Pfizer, Rules Based Medicine, Eisai, Abbott, and Johnson & Johnson, and has a use patent filed on scopolamine in the treatment of depression. Peixiong Yuan, Stephen H. Boyle, Wayne Matson, Zhi Wang, Zhao-bang Zeng, Hongjie Zhu, Jeffrey Yao, Guang Chen, Xavier Guitart, Paul J. Carlson, Alexander Neumeister, and Husseini K. Manji have no relevant financial interests to disclose. NR 79 TC 17 Z9 18 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 19 PY 2012 VL 2 AR 667 DI 10.1038/srep00667 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007BI UT WOS:000308863400001 PM 22993692 ER PT J AU Luna, VM Morozov, A AF Luna, Victor M. Morozov, Alexei TI Input-specific excitation of olfactory cortex microcircuits SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE piriformcortex; interneuron; amygdala; olfaction; emotion; circuit; synapse; optogenetic ID POSTERIOR PIRIFORM CORTEX; RAT FRONTAL-CORTEX; MORPHOLOGICAL-CHARACTERISTICS; INHIBITORY INTERNEURONS; GABAERGIC INTERNEURONS; NEOCORTICAL NEURONS; NONPYRAMIDAL CELLS; ODOR QUALITY; MOUSE; SOMATOSTATIN AB Every higher-order association cortex receives a variety of synaptic signals from different regions of the brain. How these cortical networks are capable of differentially responding to these various extrinsic synaptic inputs remains unclear. To address this issue, we studied how the basolateral amygdala (BLA) and the anterior piriform cortex (aPC) were functionally connected to the association olfactory cortex, the posterior piriform cortex (pPC). We infected the BLA and aPC with adeno-associated virus expressing channelrhodopsin-2-Venus fusion protein (ChR2-AAV) and recorded the excitatory postsynaptic currents (EPSC) resulting from photostimulation of either BLA or aPC axons in the major classes of excitatory and inhibitory neurons of the pPC. We found that BLA and aPC axons evoked monosynaptic EPSCs in every type of pPC neuron, but each fiber system preferentially targeted one excitatory and one inhibitory neuronal subtype. BLA fibers were most strongly connected to deep pyramidal cells (DP) and fast-spiking interneurons (FS), while aPC axons formed the strongest synaptic connections with DPs and irregular-spiking interneurons (IR). Overall, our findings show that the pPC differentially responds to amygdaloid versus cortical inputs by utilizing distinct local microcircuits, each defined by one predominant interneuronal subtype: FS for the BLA and IR for the aPC. It would thus seem that preferential excitation of a single neuronal class could be sufficient for the pPC to generate unique electrophysiological outputs in response to divergent synaptic input sources. C1 [Luna, Victor M.; Morozov, Alexei] NIMH, Unit Behav Genet, Bethesda, MD 20852 USA. RP Luna, VM (reprint author), NIMH, Unit Behav Genet, 35 Convent Dr,Room 1C-1008, Bethesda, MD 20852 USA. EM lunavm@mail.nih.gov; morozova@mail.nih.gov FU Intramural Research Program of the NIMH FX The research was supported by the Intramural Research Program of the NIMH. Victor M. Luna performed and analyzed experiments. Victor M. Luna and Alexei Morozov designed the experiments and prepared the manuscript. The authors thank Drs. Wataru Ito and Hong-yuan Chu for helpful input on the manuscript, and Jiayang Li for technical assistance. NR 34 TC 5 Z9 5 U1 0 U2 14 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD SEP 19 PY 2012 VL 6 DI 10.3389/fncir.2012.00069 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 006ZH UT WOS:000308857800001 ER PT J AU Rodgers, GP Collins, FS AF Rodgers, Griffin P. Collins, Francis S. TI The Next Generation of Obesity Research No Time to Waste SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID LIFE-STYLE INTERVENTION; TRIAL; RISK C1 [Rodgers, Griffin P.; Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM griffin.rodgers@nih.gov NR 7 TC 14 Z9 14 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 SEP 19 PY 2012 VL 308 IS 11 BP 1095 EP 1096 DI 10.1001/2012.jama.11853 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 007AL UT WOS:000308861000022 PM 22990265 ER PT J AU Neeland, IJ Turer, AT Ayers, CR Powell-Wiley, TM Vega, GL Farzaneh-Far, R Grundy, SM Khera, A McGuire, DK de Lemos, JA AF Neeland, Ian J. Turer, Aslan T. Ayers, Colby R. Powell-Wiley, Tiffany M. Vega, Gloria L. Farzaneh-Far, Ramin Grundy, Scott M. Khera, Amit McGuire, Darren K. de Lemos, James A. TI Dysfunctional Adiposity and the Risk of Prediabetes and Type 2 Diabetes in Obese Adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; INSULIN-RESISTANCE; GENERAL-POPULATION; SEX-DIFFERENCES; PLASMA-LEVELS; BODY-FAT; ASSOCIATION; TISSUE; ATHEROSCLEROSIS; PREVALENCE AB Context The risk of type 2 diabetes mellitus is heterogeneous among obese individuals. Factors that discriminate prediabetes or diabetes risk within this population have not been well characterized. A dysfunctional adiposity phenotype, characterized by excess visceral fat and insulin resistance, may contribute to diabetes development in those with obesity. Objective To investigate associations between adiposity phenotypes and risk for incident prediabetes and diabetes in a multiethnic, population-based cohort of obese adults. Design, Setting, and Participants Among 732 obese participants (body mass index >= 30) aged 30 to 65 years without diabetes or cardiovascular disease enrolled between 2000 and 2002 in the Dallas Heart Study, we measured body composition by dual energy x-ray absorptiometry and magnetic resonance imaging (MRI); circulating adipokines and biomarkers of insulin resistance, dyslipidemia, and inflammation; and subclinical atherosclerosis and cardiac structure and function by computed tomography and MRI. Main Outcome Measures Incidence of diabetes through a median 7.0 years (interquartile range, 6.6-7.6) of follow-up. In a subgroup of 512 participants with normal fasting glucose values at baseline, incidence of the composite of prediabetes or diabetes was determined. Results Of the 732 participants (mean age, 43 years; 65% women; 71% non-white), 84 (11.5%) developed diabetes. In multivariable analysis, higher baseline visceral fat mass (odds ratio [OR] per 1 SD [1.4 kg], 2.4; 95% CI, 1.6-3.7), fructosamine level (OR per 1 SD [1.1 mu mol/L], 2.0; 95% CI, 1.4-2.7), fasting glucose level (OR per 1 SD [1.1 mu mol/L], 1.9; 95% CI, 1.4-2.6), family history of diabetes (OR, 2.3; 95% CI, 1.3-4.3), systolic blood pressure (OR per 10 mm Hg, 1.3; 95% CI, 1.1-1.5), and weight gain over follow-up (OR per 1 kg, 1.06; 95% CI, 1.02-1.10) were independently associated with diabetes, with no associations observed for body mass index, total body fat, or abdominal subcutaneous fat. Among the 512 participants with normal baseline glucose values, the composite outcome of prediabetes or diabetes occurred in 39.1% and was independently associated with baseline measurements of visceral fat mass; levels of fasting glucose, insulin, and fructosamine; older age; non-white race; family history of diabetes; and weight gain over follow-up (P < .05 for each) but not with measurements of general adiposity. Conclusion Excess visceral fat and insulin resistance, but not general adiposity, were independently associated with incident prediabetes and type 2 diabetes mellitus in obese adults. JAMA. 2012;308(11):1150-1159 www.jama.com C1 [Neeland, Ian J.; Turer, Aslan T.; Ayers, Colby R.; Farzaneh-Far, Ramin; Khera, Amit; McGuire, Darren K.; de Lemos, James A.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA. [Ayers, Colby R.; McGuire, Darren K.] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Vega, Gloria L.; Grundy, Scott M.] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dallas, TX 75390 USA. [Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP de Lemos, JA (reprint author), Univ Texas SW Med Ctr Dallas, Div Cardiol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM james.delemos@utsouthwestern.edu FU F. Hoffmann LaRoche; Genentech; sanofi-aventis; Daiichi Sankyo; Novo Nordisk; Tethys Bioscience; Roche Diagnostics; Abbott Diagnostics; Alere; AstraZeneca; Donald W. Reynolds Foundation; US Public Health Service General Clinical Research Center [M01-RR00633]; National Institutes of Health (NIH) [UL1DE019584, PL1DK081182]; National Heart, Lung, and Blood Institute (NHLBI) [T32HL007360]; Division of Intramural Research of the NHLBI of the NIH FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr McGuire reported having received consulting income from F. Hoffmann LaRoche, Genentech, sanofi-aventis, Daiichi Sankyo, Novo Nordisk, and Tethys Bioscience. Dr de Lemos reported having received grant support from Roche Diagnostics, Abbott Diagnostics, and Alere; consulting income from Tethys Bioscience, AstraZeneca, and Daiichi Sankyo; and lecture honoraria from Bristol-Myers Squibb/sanofi-aventis. No other disclosures were reported.; Grant support for the Dallas Heart Study was provided by the Donald W. Reynolds Foundation and by US Public Health Service General Clinical Research Center grant M01-RR00633, with additional support for the present study provided by grants UL1DE019584 and PL1DK081182 from the National Institutes of Health (NIH). Dr Neeland is supported by award T32HL007360 from the National Heart, Lung, and Blood Institute (NHLBI). Dr Powell-Wiley is funded by the Division of Intramural Research of the NHLBI of the NIH. Biomarker measurements were supported by investigator-initiated grants from Alere and Roche Diagnostics. NR 40 TC 149 Z9 157 U1 2 U2 30 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 SEP 19 PY 2012 VL 308 IS 11 BP 1150 EP 1159 DI 10.1001/2012.jama.11132 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 007AL UT WOS:000308861000031 PM 22990274 ER PT J AU Moitra, K Im, K Limpert, K Borsa, A Sawitzke, J Robey, R Yuhki, N Savan, R Huang, DW Lempicki, RA Bates, S Dean, M AF Moitra, Karobi Im, Kate Limpert, Katy Borsa, Alexander Sawitzke, Julie Robey, Rob Yuhki, Naoya Savan, Ram Huang, Da Wei Lempicki, Richard A. Bates, Susan Dean, Michael TI Differential Gene and MicroRNA Expression between Etoposide Resistant and Etoposide Sensitive MCF7 Breast Cancer Cell Lines SO PLOS ONE LA English DT Article ID DRUG-RESISTANCE; ANTIBIOTIC RESISTOME; TOPOISOMERASE-II; ORAL ETOPOSIDE; COMBINATION; MECHANISM; TRANSPORT; PROFILES; DECADES AB In order to develop targeted strategies for combating drug resistance it is essential to understand it's basic molecular mechanisms. In an exploratory study we have found several possible indicators of etoposide resistance operating in MCF7VP cells, including up-regulation of ABC transporter genes, modulation of miRNA, and alteration in copy numbers of genes. C1 [Moitra, Karobi; Im, Kate; Limpert, Katy; Borsa, Alexander; Sawitzke, Julie; Savan, Ram; Dean, Michael] Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Robey, Rob; Bates, Susan] NCI, Med Oncol Branch, Mol Therapeut Sect, Bethesda, MD 20892 USA. [Yuhki, Naoya] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Huang, Da Wei; Lempicki, Richard A.] SAIC Frederick, Lab Immunopathogenesis & Bioinformat, Clin Serv Program, Frederick, MD USA. RP Dean, M (reprint author), Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. EM deanm@mail.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU Intramural Research Program of the Frederick National Laboratory for Cancer Research, National Institutes of Health FX This research was supported (in part) by the Intramural Research Program of the Frederick National Laboratory for Cancer Research, National Institutes of Health. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 13 Z9 14 U1 3 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 18 PY 2012 VL 7 IS 9 AR e45268 DI 10.1371/journal.pone.0045268 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 040HS UT WOS:000311313900111 PM 23028896 ER PT J AU Petrizzo, A Tornesello, ML Napolitano, M D'Alessio, G Megna, AS Dolcetti, R De Re, V Wang, E Marincola, FM Buonaguro, FM Buonaguro, L AF Petrizzo, Annacarmen Tornesello, Maria Lina Napolitano, Maria D'Alessio, Giovanna Megna, Angelo Salomone Dolcetti, Riccardo De Re, Valli Wang, Ena Marincola, Franco M. Buonaguro, Franco M. Buonaguro, Luigi TI Multiparametric Analyses of Human PBMCs Loaded Ex Vivo with a Candidate Idiotype Vaccine for HCV-Related Lymphoproliferative Disorders SO PLOS ONE LA English DT Article ID HEPATITIS-C VIRUS; HUMAN DENDRITIC CELLS; NF-KAPPA-B; COLONY-STIMULATING FACTOR; BLOOD MONONUCLEAR-CELLS; GENE-EXPRESSION PROFILE; YELLOW-FEVER VACCINE; MIXED CRYOGLOBULINEMIA; FOLLICULAR LYMPHOMA; IMMUNE-RESPONSES AB Hepatitis C virus (HCV) has been identified as one of the major risk factors for type II mixed cryoglobulinemia (MC), during the clinical evolution of chronic hepatitis, which may lead to development of B cell non-Hodgkin's lymphoma (NHL). We have previously shown that the candidate idiotype vaccine, based on the IGKV3-20 light chain protein, is able to induce activation and maturation of circulating antigen presenting cells (APCs) in both HCV-positive and HCV-negative healthy control subjects, with production of Th2-type cytokines. Here, the effect of the recombinant IGKV3-20 protein on human peripheral blood mononuclear cells (PBMCs) from HCV-positive subjects, with known blood levels of cryoglobulins, is shown via gene expression profiling analysis combined to multiparameter flow cytometry and multiplex analyses of cytokines. C1 [Petrizzo, Annacarmen; Tornesello, Maria Lina; Buonaguro, Franco M.; Buonaguro, Luigi] Natl Canc Inst Fond G Pascale, Lab Mol Biol & Viral Oncogenesis, Naples, Italy. [Napolitano, Maria] Natl Canc Inst Fond G Pascale, Clin Immunol Lab, Naples, Italy. [D'Alessio, Giovanna; Megna, Angelo Salomone] Rummo Hosp, Div Infect Dis, Benevento, Italy. [Dolcetti, Riccardo] Natl Canc Inst, Ctr Riferimento Oncol, Canc Bioimmunotherapy Unit, Aviano, Italy. [Wang, Ena; Marincola, Franco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Franco M.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. RP Buonaguro, L (reprint author), Natl Canc Inst Fond G Pascale, Lab Mol Biol & Viral Oncogenesis, Naples, Italy. EM l.buonaguro@istitutotumori.na.it RI Tornesello, Maria Lina/A-1564-2009; Dolcetti, Riccardo/O-3832-2015; napolitano, maria/K-1615-2016; OI Tornesello, Maria Lina/0000-0002-3523-3264; Dolcetti, Riccardo/0000-0003-1625-9853; napolitano, maria/0000-0002-8996-3297; Buonaguro, Luigi/0000-0002-6380-7114 FU Italian Ministry of Research [ACC 4]; Associazione Italiana per la ricerca sul Cancro [10301]; Fondazione Federica per la Vita; University of Udine FX The study was funded by Italian Ministry of Research through the project "Alleanza Contro il Cancro'' (Contract No. ACC 4). AP was a Ph.D. student at University of Udine "Biomedical Science and Biotechnology'' and the recipient of a fellowship granted through the project. The work was partly supported by a grant from the Associazione Italiana per la ricerca sul Cancro (contract 10301 to RD) and the Fondazione Federica per la Vita (to RD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 3 Z9 3 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 18 PY 2012 VL 7 IS 9 AR e44870 DI 10.1371/journal.pone.0044870 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 040HS UT WOS:000311313900047 PM 23028651 ER PT J AU Giladi, M Friedberg, I Fang, XY Hiller, R Wang, YX Khananshvili, D AF Giladi, Moshe Friedberg, Itay Fang, Xianyang Hiller, Reuben Wang, Yun-Xing Khananshvili, Daniel TI G503 Is Obligatory for Coupling of Regulatory Domains in NCX Proteins SO BIOCHEMISTRY LA English DT Article ID SODIUM-CALCIUM EXCHANGE; CARDIAC NA+/CA2+ EXCHANGER; SMALL-ANGLE SCATTERING; NA+-CA2+ EXCHANGER; CA2+ SENSOR; SODIUM/CALCIUM EXCHANGER; CA2+-BINDING DOMAIN; CYTOPLASMIC CALCIUM; MUTATIONAL ANALYSIS; DYNAMIC PROPERTIES AB In multidomain proteins, interdomain linkers allow an efficient transfer of regulatory information, although it is unclear how the information encoded in the linker structure coins dynamic coupling. Allosteric regulation of NCX proteins involves Ca2+-driven tethering of regulatory CBD1 and CBD2 (through a salt bridge network) accompanied by alignment of CBDs and Ca2+ occlusion at the interface of the two CBDs. Here we investigated "alanine-walk" substitutions in the CBD1-CBD2 linker (501-HAGIFT-506) and found that among all linker residues, only G503 is obligatory for Ca2+-induced reorientations of CBDs and slow dissociation of occluded Ca2+. Moreover, swapping between positions A502 and G503 in the CBD1-CBD2 linker results in a complete loss of slow dissociation of occluded Ca2+, meaning that dynamic coupling of CBDs requires an exact pose of glycine at position 503. Therefore, accumulating data revealed that position 503 occupied by glycine is absolutely required for Ca2+-driven tethering of CBDs, which in turn limits the linker's flexibility and, thus, restricts CBD movements. Because G503 is extremely well conserved in eukaryotic NCX proteins, the information encoded in G503 is essential for dynamic coupling of the two-domain CBD tandem and, thus, for propagation of the allosteric signal. C1 [Giladi, Moshe; Friedberg, Itay; Hiller, Reuben; Khananshvili, Daniel] Tel Aviv Univ, Sackler Sch Med, Dept Physiol & Pharmacol, IL-69978 Ramat Aviv, Israel. [Fang, Xianyang; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. RP Khananshvili, D (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. EM dhanan@post.tau.ac.il OI Giladi, Moshe/0000-0002-8589-6920 FU Israeli Ministry of Health [2010-3-6266]; United States-Israeli Binational Science Foundation [2009-334]; Israel Science Foundation [23/10]; Bernstein foundation; Clore Scholars Program of the Clore Israel Foundation FX This work was partially funded by the Israeli Ministry of Health (Grant 2010-3-6266), the United States-Israeli Binational Science Foundation (Grant 2009-334), and the Israel Science Foundation (Grant 23/10). The support of the Bernstein foundation is highly appreciated. Moshe Giladi is supported by the Clore Scholars Program of the Clore Israel Foundation. NR 44 TC 8 Z9 8 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 18 PY 2012 VL 51 IS 37 BP 7313 EP 7320 DI 10.1021/bi300739z PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 005ZB UT WOS:000308787600011 PM 22924554 ER PT J AU Elagha, AA Fuisz, AR Weissman, G AF Elagha, Abdalla A. Fuisz, Anthon R. Weissman, Gaby TI Cardiac Magnetic Resonance Imaging Can Clearly Depict the Morphology and Determine the Significance of Cor Triatriatum SO CIRCULATION LA English DT Editorial Material ID DIAGNOSIS C1 [Elagha, Abdalla A.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Elagha, Abdalla A.] Cairo Univ Hosp, Dept Cardiol, Cairo, Egypt. [Fuisz, Anthon R.; Weissman, Gaby] Washington Hosp Ctr, Cardiol Sect, Dept Med, Washington, DC 20010 USA. RP Elagha, AA (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM elaghaa@mail.nih.gov OI Elagha, Abdalla/0000-0003-3136-2293 NR 6 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 18 PY 2012 VL 126 IS 12 BP 1511 EP 1513 DI 10.1161/CIRCULATIONAHA.112.105650 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 012TP UT WOS:000309259800021 PM 22988047 ER PT J AU Burgess, SM AF Burgess, Shawn M. TI The changing conditions of zebrafish mutants SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID GENES; IDENTIFICATION C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Burgess, SM (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov OI Burgess, Shawn/0000-0003-1147-0596 NR 14 TC 1 Z9 1 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 SEP 18 PY 2012 VL 109 IS 38 BP 15082 EP 15083 DI 10.1073/pnas.1212832109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012BS UT WOS:000309211000014 PM 22949684 ER PT J AU Tucci, P Agostini, M Grespi, F Markert, EK Terrinoni, A Vousden, KH Muller, PAJ Dotsch, V Kehrloesser, S Sayan, BS Giaccone, G Lowe, SW Takahashi, N Vandenabeele, P Knight, RA Levine, AJ Melino, G AF Tucci, Paola Agostini, Massimiliano Grespi, Francesca Markert, Elke K. Terrinoni, Alessandro Vousden, Karen H. Muller, Patricia A. J. Doetsch, Volker Kehrloesser, Sebastian Sayan, Berna S. Giaccone, Giuseppe Lowe, Scott W. Takahashi, Nozomi Vandenabeele, Peter Knight, Richard A. Levine, Arnold J. Melino, Gerry TI Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tumorigenesis; apoptosis; E-cadherin; PC3 cell; DU145 cell ID EPITHELIAL-MESENCHYMAL TRANSITION; BREAST-CANCER; P53 FAMILY; MUTANT P53; TUMOR; SUPPRESSOR; MIR-205; INVASION; GROWTH; ZEB1 AB p63 inhibits metastasis. Here, we show that p63 (both TAp63 and Delta Np63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial-mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti-miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre-miR-205 or silencing of mutated p53. In accordance with this in vitro data, Delta Np63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer. C1 [Tucci, Paola; Agostini, Massimiliano; Grespi, Francesca; Knight, Richard A.; Melino, Gerry] Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England. [Tucci, Paola] Univ Calabria, Dept Pharmacobiol, I-87036 Cosenza, Italy. [Grespi, Francesca; Melino, Gerry] Flanders Inst Biotechnol, Dept Mol Biomed Res, B-9052 Ghent, Belgium. [Grespi, Francesca] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. [Markert, Elke K.; Levine, Arnold J.] Inst Adv Study, Princeton, NJ 08540 USA. [Terrinoni, Alessandro; Melino, Gerry] Univ Roma Tor Vergata, I-00133 Rome, Italy. [Terrinoni, Alessandro; Takahashi, Nozomi; Melino, Gerry] Ist Ricovero Cura Carattere Sci, Ist Dermopat Immacolata, Biochem Lab, I-00133 Rome, Italy. [Vousden, Karen H.; Muller, Patricia A. J.] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. [Doetsch, Volker; Kehrloesser, Sebastian] Goethe Univ Frankfurt, Ctr Biomol Magnet Resonance, D-60438 Frankfurt, Germany. [Doetsch, Volker; Kehrloesser, Sebastian] Goethe Univ Frankfurt, Inst Biophys Chem, D-60438 Frankfurt, Germany. [Sayan, Berna S.] Univ Southampton, Fac Med, Canc Sci Unit, Southampton SO16 6YD, Hants, England. [Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lowe, Scott W.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Giaccone, G (reprint author), Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England. EM gm89@le.ac.uk RI Vandenabeele, Peter/C-8597-2009; TERRINONI, Alessandro/J-1533-2012; Jackson, Benjamin/C-4297-2012; Agostini, Massimiliano/G-9579-2014; Giaccone, Giuseppe/E-8297-2017; OI Kehrloesser, Sebastian/0000-0002-6791-2421; TERRINONI, Alessandro/0000-0002-7442-2252; Agostini, Massimiliano/0000-0003-3124-2072; Giaccone, Giuseppe/0000-0002-5023-7562; Grespi, Francesca/0000-0002-0369-7793 FU Medical Research Council, United Kingdom; Alleanza contro il Cancro [ACC12-ACC6]; Ministero Istruzione Universita Ricerca/Progetti di Ricerca di Interesse Nazionale [RBIP06LCA9_0023]; Associazione Italiana per la Ricerca sul Cancro [2008-2010_33-08]; Italian Human ProteomeNet [RBRN07BMCT]; Ministero della Salute [Ricerca Oncologica 26/07]; IDI-IRCCS [RF06 (convenzione 73), RF07 (convenzione 57)]; Flemish government [G.0017.12]; Flanders Institute for Biotechnology, Belgium; National Cancer Institute [Po1CA87497] FX We thank David Read for technical assistance with time-lapse microscopy. This work has been supported by the Medical Research Council, United Kingdom; Grants from "Alleanza contro il Cancro" (ACC12-ACC6), Ministero Istruzione Universita Ricerca/Progetti di Ricerca di Interesse Nazionale (RBIP06LCA9_0023), Associazione Italiana per la Ricerca sul Cancro (2008-2010_33-08), Italian Human ProteomeNet RBRN07BMCT, Ministero della Salute (Ricerca Oncologica 26/07), IDI-IRCCS RF06 (convenzione 73), RF07 (convenzione 57) (to G. M.), Odysseus Grant (G.0017.12) from the Flemish government and Flanders Institute for Biotechnology, Belgium (to G.M.), and Grant Po1CA87497 from the National Cancer Institute (to A.J.L. and S.W.L.). NR 27 TC 130 Z9 131 U1 4 U2 35 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 SEP 18 PY 2012 VL 109 IS 38 BP 15312 EP 15317 DI 10.1073/pnas.1110977109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012BS UT WOS:000309211000053 PM 22949650 ER PT J AU Wang, CC Lee, JE Cho, YW Xiao, Y Jin, QH Liu, CY Ge, K AF Wang, Chaochen Lee, Ji-Eun Cho, Young-Wook Xiao, Ying Jin, Qihuang Liu, Chengyu Ge, Kai TI UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EXPRESSION PATTERN; GENE; BRACHYURY; JMJD3; TARGET; CATENIN; BIOLOGY; FATE; PTIP AB To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knock-in male ES cells. Deletion of the X-chromosome-encoded UTX gene in male ES cells markedly decreases expression of the paralogous UTY gene encoded by Y chromosome, but has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. UTY, which lacks detectable demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/beta-catenin signaling-induced Brachyury expression in ES cells. Interestingly, male UTX KO embryos express normal levels of UTY and survive until birth. In contrast, female UTX KO mice, which lack the UTY gene, show embryonic lethality before embryonic day 11.5. Female UTX KO embryos show severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac, and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of H3K27 demethylase activity, and suggest that UTX and UTY are functionally redundant in ES cell differentiation and early embryonic development. C1 [Wang, Chaochen; Lee, Ji-Eun; Jin, Qihuang; Ge, Kai] NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Cho, Young-Wook] Korea Basic Sci Inst Chuncheon, Chuncheon Ctr, Chunchon 200701, Kangwon, South Korea. [Xiao, Ying] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Ge, K (reprint author), NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM kaig@niddk.nih.gov RI Lee, Ji-Eun/F-7891-2011; OI Lee, Ji-Eun/0000-0002-3768-7016; Ge, Kai/0000-0002-7442-5138 FU NIDDK, National Institutes of Health FX We thank R. Moon, D. Forrest, C. Deng, and C. Cepko for plasmids and reagents and C. Li for technical help on WISH. This work was supported by the Intramural Research Program of the NIDDK, National Institutes of Health (to K.G.). NR 32 TC 53 Z9 57 U1 0 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 18 PY 2012 VL 109 IS 38 BP 15324 EP 15329 DI 10.1073/pnas.1204166109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012BS UT WOS:000309211000055 PM 22949634 ER PT J AU Shi, TJ Fillmore, TL Sun, XF Zhao, R Schepmoes, AA Hossain, M Xie, F Wu, S Kim, JS Jones, N Moore, RJ Pasa-Tolic, L Kagan, J Rodland, KD Liu, T Tang, KQ Camp, DG Smith, RD Qian, WJ AF Shi, Tujin Fillmore, Thomas L. Sun, Xuefei Zhao, Rui Schepmoes, Athena A. Hossain, Mahmud Xie, Fang Wu, Si Kim, Jong-Seo Jones, Nathan Moore, Ronald J. Pasa-Tolic, Ljiljana Kagan, Jacob Rodland, Karin D. Liu, Tao Tang, Keqi Camp, David G., II Smith, Richard D. Qian, Wei-Jun TI Antibody-free, targeted mass-spectrometric approach for quantification of proteins at low picogram per milliliter levels in human plasma/serum SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE biomarker verification; systems biology; targeted proteomics ID PROSTATE-SPECIFIC ANTIGEN; PEPTIDE IMMUNOAFFINITY ENRICHMENT; QUANTITATIVE PROTEOMICS; MULTIPLEXED ASSAYS; FREE PSA; BIOMARKERS; CANCER; CHROMATOGRAPHY; VERIFICATION; SENSITIVITY AB Sensitive detection of low-abundance proteins in complex biological samples has typically been achieved by immunoassays that use antibodies specific to target proteins; however, de novo development of antibodies is associated with high costs, long development lead times, and high failure rates. To address these challenges, we developed an antibody-free strategy that involves PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing) for sensitive selected reaction monitoring (SRM)-based targeted protein quantification. The strategy capitalizes on high-resolution reversed-phase liquid chromatographic separations for analyte enrichment, intelligent selection of target fractions via on-line SRM monitoring of internal standards, and fraction multiplexing before nano-liquid chromatography-SRM quantification. Application of this strategy to human plasma/serum demonstrated accurate and reproducible quantification of proteins at concentrations in the 50-100 pg/mL range, which represents a major advance in the sensitivity of targeted protein quantification without the need for specific-affinity reagents. Application to a set of clinical serum samples illustrated an excellent correlation between the results obtained from the PRISM-SRM assay and those from clinical immunoassay for the prostate-specific antigen level. C1 [Shi, Tujin; Sun, Xuefei; Schepmoes, Athena A.; Hossain, Mahmud; Xie, Fang; Kim, Jong-Seo; Jones, Nathan; Moore, Ronald J.; Rodland, Karin D.; Liu, Tao; Tang, Keqi; Camp, David G., II; Smith, Richard D.; Qian, Wei-Jun] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Fillmore, Thomas L.; Zhao, Rui; Wu, Si; Pasa-Tolic, Ljiljana; Smith, Richard D.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Kagan, Jacob] NCI, Canc Prevent Div, Rockville, MD 20852 USA. RP Qian, WJ (reprint author), Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. EM weijun.qian@pnnl.gov RI Smith, Richard/J-3664-2012; Liu, Tao/A-9020-2013; Shi, Tujin/O-1789-2014 OI Smith, Richard/0000-0002-2381-2349; Liu, Tao/0000-0001-9529-6550; FU National Institutes of Health (NIH) [DP2OD006668]; NCI Early Detection Research Network [Y01-CN-05013-29]; NIH [8P41 GM103493, 5P41 RR018522, CA111244, U24-CA-160019]; US Department of Energy (DOE); DOE/Biological and Environmental Research (BER); DOE [DE-AC05-76RL0 1830] FX We thank Drs. Lori Sokoll and Daniel Chan at Johns Hopkins University for providing the clinical patient serum samples and corresponding immunoassay results and Dr. Arul Chinnaiyan at the University of Michigan for providing the sequences of TMPRSS2-ERG fusion constructs. Portions of this work were supported by National Institutes of Health (NIH) Director's New Innovator Award Program DP2OD006668; NCI Early Detection Research Network Interagency Agreement Y01-CN-05013-29; NIH Grants 8P41 GM103493, 5P41 RR018522, CA111244, and U24-CA-160019; and a US Department of Energy (DOE) Early Career Research award. The experimental work described herein was performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by DOE/Biological and Environmental Research (BER) and located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the DOE under Contract DE-AC05-76RL0 1830. NR 39 TC 85 Z9 86 U1 4 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 SEP 18 PY 2012 VL 109 IS 38 BP 15395 EP 15400 DI 10.1073/pnas.1204366109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012BS UT WOS:000309211000067 PM 22949669 ER PT J AU Lu, XJ Gibbs, JS Hickman, HD David, A Dolan, BP Jin, YT Kranz, DM Bennink, JR Yewdell, JW Varma, R AF Lu, Xiuju Gibbs, James S. Hickman, Heather D. David, Alexandre Dolan, Brian P. Jin, Yetao Kranz, David M. Bennink, Jack R. Yewdell, Jonathan W. Varma, Rajat TI Endogenous viral antigen processing generates peptide-specific MHC class I cell-surface clusters SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE MHC class; clustering; CD8 T cell recognition; dual-color TIRF imaging; antigen processing/presentation; intracellular trafficking ID ENDOPLASMIC-RETICULUM; INTRACELLULAR-LOCALIZATION; MEMBRANE-GLYCOPROTEINS; CYTOPLASMIC DOMAIN; MOLECULES; COMPLEX; KINETICS; GOLGI; TRANSPORT; PROTEINS AB Sensitivity is essential in CD8+ T-cell killing of virus-infected cells and tumor cells. Although the affinity of the T-cell receptor (TCR) for antigen is relatively low, the avidity of T cell-antigen-presenting cell interactions is greatly enhanced by increasing the valence of the interaction. It is known that TCRs cluster into protein islands after engaging their cognate antigen (peptides bound to MHC molecules). Here, we show that mouse K-b class I molecules segregate into preformed, long-lasting (hours) clusters on the antigen-presenting cell surface based on their bound viral peptide. Peptide-specific K-b clustering occurs when source antigens are expressed by vaccinia or vesicular stomatitis virus, either as proteasome-liberated precursors or free intracellular peptides. By contrast, K-b-peptide complexes generated by incubating cells with synthetic peptides are extensively intermingled on the cell surface. Peptide-specific complex sorting is first detected in the Golgi complex, and compromised by removing the K-b cytoplasmic tail. Peptide-specific clustering is associated with increased T-cell sensitivity: on a per-complex basis, endogenous SIINFEKL activates T cells more efficiently than synthetic SIINFEKL, and wild-type K-b presents endogenous SIINFEKL more efficiently than tailless K-b. We propose that endogenous processing generates peptide-specific clusters of class I molecules to maximize the sensitivity and speed of T-cell immunosurveillance. C1 [Lu, Xiuju; Gibbs, James S.; Hickman, Heather D.; David, Alexandre; Dolan, Brian P.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Jin, Yetao] US FDA, Chem Lab, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Kranz, David M.] Univ Illinois, Dept Biochem, Urbana, IL 61801 USA. [Varma, Rajat] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI Varma, Rajat/I-1209-2012; Jin, Yong-Su/L-4530-2013; OI Varma, Rajat/0000-0001-5131-0402; David, Alexandre/0000-0003-3365-1339 FU National Institute of Allergy and Infectious Diseases Division of Intramural Research and National Institutes of Health [P01 CA097296] FX We thank Phil Holler for original engineering of the 2C-m67 TCR, and Natalie Bowerman for development of the single-chain form of the TCR for detection. This work was generously supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research and National Institutes of Health Grant P01 CA097296 (to D.M.K.). NR 44 TC 24 Z9 24 U1 0 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 18 PY 2012 VL 109 IS 38 BP 15407 EP 15412 DI 10.1073/pnas.1208696109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012BS UT WOS:000309211000069 PM 22949678 ER PT J AU Mitchell, N Petralia, RS Currier, DG Wang, YX Kim, A Mattson, MP Yao, PJ AF Mitchell, Nicholas Petralia, Ronald S. Currier, Duane G. Wang, Ya-Xian Kim, Alvin Mattson, Mark P. Yao, Pamela J. TI Sonic hedgehog regulates presynaptic terminal size, ultrastructure and function in hippocampal neurons SO JOURNAL OF CELL SCIENCE LA English DT Article DE Sonic hedgehog; Hippocampal neurons; Synapse ID PRIMARY CILIA; SYNAPTIC VESICLES; NEUROTROPHIC FACTOR; PROLIFERATION; BRAIN; CEREBELLUM; LOCALIZATION; CYCLOPAMINE; PRECURSORS; MUTATIONS AB Sonic hedgehog (Shh) signaling is essential to the patterning of the embryonic neural tube, but its presence and function in the postmitotic differentiated neurons in the brain remain largely uncharacterized. We recently showed that Shh and its signaling components, Patched and Smoothened, are expressed in postnatal and adult hippocampal neurons. We have now examined whether Shh signaling has a function in these neurons. Using cultured hippocampal neurons as a model system, we found that presynaptic terminals become significantly larger in response to the application of Shh. Ultrastructural examination confirmed the enlarged presynaptic profiles and also revealed variable increases in the size of synaptic vesicles, with a resulting loss of uniformity. Furthermore, electrophysiological analyses showed significant increases in the frequency, but not the amplitude, of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in response to Shh, providing functional evidence of the selective role of Shh in presynaptic terminals. Thus, we conclude that Shh signaling regulates the structure and functional properties of presynaptic terminals of hippocampal neurons. C1 [Mitchell, Nicholas; Mattson, Mark P.; Yao, Pamela J.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mitchell, Nicholas; Kim, Alvin] St Bonaventure Univ, Dept Biol, St Bonaventure, NY 14778 USA. [Petralia, Ronald S.; Wang, Ya-Xian] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Currier, Duane G.] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. [Currier, Duane G.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov FU National Institute on Aging/National Institutes of Health; National Institute on Deafness and Other Communication Disorders/National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute on Aging/National Institutes of Health; and the National Institute on Deafness and Other Communication Disorders/National Institutes of Health. Deposited in PMC for release after 12 months. NR 55 TC 17 Z9 18 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2012 VL 125 IS 18 BP 4207 EP 4213 DI 10.1242/jcs.105080 PG 7 WC Cell Biology SC Cell Biology GA 033LD UT WOS:000310796800005 PM 22641692 ER PT J AU Fukushima, M Tomita, T Janoshazi, A Putney, JW AF Fukushima, Miwako Tomita, Takuro Janoshazi, Agnes Putney, James W. TI Alternative translation initiation gives rise to two isoforms of Orai1 with distinct plasma membrane mobilities SO JOURNAL OF CELL SCIENCE LA English DT Article DE Store-operated calcium entry; Calcium channels; Orai channels; Alternative translation initiation ID OPERATED CA2+ CHANNEL; CALCIUM-ENTRY; CRAC CHANNELS; FUNCTIONAL-CHARACTERIZATION; SPLICE VARIANTS; STORE; STIM1; SENSOR; PHOSPHORYLATION; INTERNALIZATION AB Store-operated calcium entry is an almost ubiquitous signaling pathway in eukaryotic cells. The plasma membrane store-operated channels are comprised of subunits of the recently discovered Orai proteins, the major one being Orai1. We have discovered that native Orai1, as well as expressed Orai1, exists in two forms in similar quantities: a longer form (Orai1 alpha) of approximately 33 kDa, and a shorter form (Orai1 beta) of approximately 23 kDa. The Orai1 beta form arises from alternative translation initiation from a methionine at position 64, and possibly also 71, in the longer Orai1 alpha form. In the sequence upstream of the initiation site of Orai1 beta, there is a polyarginine sequence previously suggested to be involved in interaction of Orai1 with plasma membrane phosphatidylinositol-4,5-bisphosphate. The loss of this phospholipid binding domain would be expected to influence the mobility of Orai1 protein in the plasma membrane. Indeed, experiments utilizing fluorescence recovery after photobleaching (FRAP) revealed that the recovery half-time for Orai1 beta was significantly faster than for Orai1 alpha. Since Orai1 must diffuse to sites of interaction with the Ca2+ sensor, STIM1, these two mobilities might provide for efficient recruitment of Orai1 subunits to sites of store-operated Ca2+ entry during agonist-induced Ca2+ signaling. C1 [Fukushima, Miwako; Tomita, Takuro; Janoshazi, Agnes; Putney, James W.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM Putney@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. Deposited in PMC for release after 12 months. NR 35 TC 19 Z9 20 U1 2 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2012 VL 125 IS 18 BP 4354 EP 4361 DI 10.1242/jcs.104919 PG 8 WC Cell Biology SC Cell Biology GA 033LD UT WOS:000310796800019 PM 22641696 ER PT J AU Chau, CH Figg, WD AF Chau, Cindy H. Figg, William D. TI Aflibercept in Pediatric Solid Tumors: Moving Beyond the Trap SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID VEGF-TRAP; CANCER AB Angiogenesis plays a pivotal role in the growth and metastasis of adult and pediatric solid tumors. Clinical investigation of angiogenesis inhibitors is currently under way for childhood cancers. While the pediatric study of aflibercept provides a proof-of-principle, challenges remain in developing clinical endpoints and biomarkers of angiogenesis for pediatric trials. Clin Cancer Res; 18(18); 4868-71. (c) 2012 AACR. C1 [Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural NIH HHS [ZIA SC006538-17] NR 10 TC 0 Z9 0 U1 0 U2 1 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 SEP 15 PY 2012 VL 18 IS 18 BP 4868 EP 4871 DI 10.1158/1078-0432.CCR-12-2212 PG 4 WC Oncology SC Oncology GA 022NI UT WOS:000309965700002 PM 22869868 ER PT J AU Gaedcke, J Grade, M Camps, J Sokilde, R Kaczkowski, B Schetter, AJ Difilippantonio, MJ Harris, CC Ghadimi, BM Moller, S Beissbarth, T Ried, T Litman, T AF Gaedcke, Jochen Grade, Marian Camps, Jordi Sokilde, Rolf Kaczkowski, Bogumil Schetter, Aaron J. Difilippantonio, Michael J. Harris, Curtis C. Ghadimi, B. Michael Moller, Soren Beissbarth, Tim Ried, Thomas Litman, Thomas TI The Rectal Cancer microRNAome - microRNA Expression in Rectal Cancer and Matched Normal Mucosa SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN COLORECTAL-CANCER; EPITHELIAL-MESENCHYMAL TRANSITION; REAL-TIME PCR; SUPPRESSES TUMORIGENICITY; PROMOTES APOPTOSIS; BREAST-CANCER; COLON; PROFILES; IDENTIFICATION; CARCINOMAS AB Purpose: miRNAs play a prominent role in a variety of physiologic and pathologic biologic processes, including cancer. For rectal cancers, only limited data are available on miRNA expression profiles, whereas the underlying genomic and transcriptomic aberrations have been firmly established. We therefore, aimed to comprehensively map the miRNA expression patterns of this disease. Experimental Design: Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 57 patients with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa miRNA expression profiles were subsequently established for all patients. The expression of selected miRNAs was validated using semi-quantitative real-time PCR. Results: Forty-nine miRNAs were significantly differentially expressed (log(2)-fold difference >0.5 and P < 0.001) between rectal cancer and normal rectal mucosa. The predicted targets for these miRNAs were enriched for the following pathways: Wnt, TGF-beta, mTOR, insulin, mitogen-activated protein kinase, and ErbB signaling. Thirteen of these 49 miRNAs seem to be rectal cancer-specific, and have not been previously reported for colon cancers: miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p. Of clinical impact, miR-135b expression correlated significantly with disease-free and cancer-specific survival in an independent multicenter cohort of 116 patients. Conclusion: This comprehensive analysis of the rectal cancer miRNAome uncovered novel miRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of this disease. Moreover, the identification and validation of miR-135b may help to identify novel molecular targets and pathways for therapeutic exploitation. Clin Cancer Res; 18(18); 4919-30. (c) 2012 AACR. C1 [Litman, Thomas] Univ Copenhagen, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, DK-2200 Copenhagen, Denmark. [Gaedcke, Jochen; Grade, Marian; Ghadimi, B. Michael] Univ Med Ctr, Dept Gen & Visceral Surg, Gottingen, Germany. [Beissbarth, Tim] Univ Med Ctr, Dept Med Stat, Gottingen, Germany. [Camps, Jordi; Difilippantonio, Michael J.; Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schetter, Aaron J.; Harris, Curtis C.] NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. [Difilippantonio, Michael J.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Sokilde, Rolf; Kaczkowski, Bogumil; Moller, Soren; Litman, Thomas] Exiqon AS, Dept Biomarker Discovery, Vedbaek, Denmark. [Kaczkowski, Bogumil] Univ Copenhagen, Bioinformat Ctr, DK-2200 Copenhagen, Denmark. [Moller, Soren] Novozymes, Bagsvaerd, Denmark. [Sokilde, Rolf] Lund Univ, Dept Oncol, Lund, Sweden. RP Litman, T (reprint author), Univ Copenhagen, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. EM tlitman@hotmail.com RI Beissbarth, Tim/B-3129-2013; Sokilde, Rolf/F-5138-2015; Kaczkowski, Bogumil/D-5336-2017 OI Beissbarth, Tim/0000-0001-6509-2143; Sokilde, Rolf/0000-0003-3010-3599; Kaczkowski, Bogumil/0000-0001-6554-5608 FU Deutsche Forschungsgemeinschaft [KFO 179]; Intramural Research Program of the NIH, National Cancer Institute FX This work was supported by the Deutsche Forschungsgemeinschaft (KFO 179) and by the Intramural Research Program of the NIH, National Cancer Institute. This work was part of a CRADA between the NCI and Exiqon A/S (CRADA #2254). NR 50 TC 72 Z9 76 U1 0 U2 16 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 SEP 15 PY 2012 VL 18 IS 18 BP 4919 EP 4930 DI 10.1158/1078-0432.CCR-12-0016 PG 12 WC Oncology SC Oncology GA 022NI UT WOS:000309965700010 PM 22850566 ER PT J AU Bender, JG Blaney, SM Borinstein, S Reid, JM Baruchel, S Ahern, C Ingle, AM Yamashiro, DJ Chen, A Weigel, B Adamson, PC Park, JR AF Bender, Julia Glade Blaney, Susan M. Borinstein, Scott Reid, Joel M. Baruchel, Sylvain Ahern, Charlotte Ingle, Ashish M. Yamashiro, Darrell J. Chen, Alice Weigel, Brenda Adamson, Peter C. Park, Julie R. TI A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CANCER; BLOCKADE; THERAPY; ANGIOGENESIS; BEVACIZUMAB; MECHANISMS; BIOMARKERS; REGRESSION; INHIBITOR AB Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept. Experimental Design: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose. Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2. Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting. Clin Cancer Res; 18(18); 5081-9. (c) 2012 AACR. C1 [Bender, Julia Glade] Columbia Univ, Div Pediat Oncol, Med Ctr, New York, NY 10032 USA. [Blaney, Susan M.; Ahern, Charlotte] Texas Childrens Canc Ctr, Houston, TX USA. [Borinstein, Scott] Childrens Hosp Vanderbilt, Nashville, TN USA. [Reid, Joel M.] Mayo Clin, Rochester, MN USA. [Baruchel, Sylvain] Univ Toronto, Hosp Sick Children, Toronto, ON M5S 1A1, Canada. [Ingle, Ashish M.] Childrens Oncol Grp, Operat Ctr, Arcadia, CA USA. [Chen, Alice] NCI, Canc Treatment Expt Program, Bethesda, MD 20892 USA. [Weigel, Brenda] Univ Minnesota, Amplatz Childrens Hosp, Minneapolis, MN USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Park, Julie R.] Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA. RP Bender, JG (reprint author), Columbia Univ, Div Pediat Oncol, Med Ctr, 161 Ft Washington Ave,IP 7, New York, NY 10032 USA. EM Jg589@columbia.edu FU Alex's Lemonade Stand Foundation; taybandz; Sanofi-Aventis; Phase I/Pilot Consortium Grant of the Children's Oncology Group from the NCI, NIH, Bethesda, Maryland [U01 CA97452] FX The study was supported by Alex's Lemonade Stand Foundation, taybandz, Sanofi-Aventis, and the Phase I/Pilot Consortium Grant U01 CA97452 of the Children's Oncology Group from the NCI, NIH, Bethesda, Maryland. NR 24 TC 9 Z9 9 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2012 VL 18 IS 18 BP 5081 EP 5089 DI 10.1158/1078-0432.CCR-12-0078 PG 9 WC Oncology SC Oncology GA 022NI UT WOS:000309965700025 ER PT J AU Chen, X Kim, YA Wang, B Song, Y Dinh, H Chen, GL AF Chen, Xian Kim, Yoo-Ah Wang, Bing Song, Yuan Dinh, Hieu Chen, Guanling TI Sniffer channel selection for monitoring wireless LANs SO COMPUTER COMMUNICATIONS LA English DT Article DE WLAN; Sniffer channel selection; Monitor AB Wireless sniffers are often used to monitor access points (APs) in wireless LANs (WLANs) for network management, fault detection, and traffic characterization. It is cost effective to deploy single-radio sniffers that can monitor multiple nearby APs. To achieve this, a sniffer needs to switch among multiple channels since these APs often operate on orthogonal channels. In this paper, we formulate and solve two optimization problems on sniffer channel selection. Both problems require that each AP be monitored by at least one sniffer. In addition, one optimization problem requires minimizing the maximum number of channels that a sniffer listens to, and the other requires minimizing the total number of channels that the sniffers listen to. We prove that both optimization problems are NP-hard. For each problem, we propose three algorithms to solve it, one based on integer programming (IP), one based on LP-relaxation, and the third based on a greedy heuristic. We evaluate the performance of the various algorithms using two real-world datasets. Our results show that, for each problem, all the three algorithms are effective in achieving their optimization goals, and overall, the LP-based algorithm outperforms the other two algorithms. (c) 2012 Elsevier B.V. All rights reserved. C1 [Chen, Xian; Wang, Bing; Song, Yuan; Dinh, Hieu] Univ Connecticut, Dept Comp Sci & Engn, Storrs, CT 06269 USA. [Kim, Yoo-Ah] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Chen, Guanling] Univ Massachusetts, Dept Comp Sci, Lowell, MA USA. RP Chen, X (reprint author), Univ Connecticut, Dept Comp Sci & Engn, Storrs, CT 06269 USA. EM xian.chen@engr.uconn.edu FU NSF CAREER award [0746841]; QSI Inc.; UConn Faculty Large Grant; Science and Technology Directorate of the U.S. Department of Homeland Security FX A preliminary version of this work appeared in [27]. This work was partially supported by NSF CAREER award 0746841, QSI Inc., UConn Faculty Large Grant, and the Science and Technology Directorate of the U.S. Department of Homeland Security under Award NBCH2050002. NR 27 TC 3 Z9 3 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0140-3664 J9 COMPUT COMMUN JI Comput. Commun. PD SEP 15 PY 2012 VL 35 IS 16 BP 1994 EP 2003 DI 10.1016/j.comcom.2012.06.005 PG 10 WC Computer Science, Information Systems; Engineering, Electrical & Electronic; Telecommunications SC Computer Science; Engineering; Telecommunications GA 020WJ UT WOS:000309847000005 ER PT J AU Nakajima, T Sano, K Mitsunaga, M Choyke, PL Kobayashi, H AF Nakajima, Takahito Sano, Kohei Mitsunaga, Makoto Choyke, Peter L. Kobayashi, Hisataka TI Real-time Monitoring of In Vivo Acute Necrotic Cancer Cell Death Induced by Near Infrared Photoimmunotherapy Using Fluorescence Lifetime Imaging SO CANCER RESEARCH LA English DT Article ID OVARIAN-CANCER; PROTEINS; DYNAMICS; SYSTEM; DOMAIN; MOUSE; MODEL; VITRO; MICE; GFP AB A new type of monoclonal antibody (mAb)-based, highly specific phototherapy (photoimmunotherapy; PIT) that uses a near infrared (NIR) phthalocyanine dye, IRDye700DX (IR700) conjugated with a mAb, has recently been described. NIR light exposure leads to immediate, target-selective necrotic cell death in vitro. Detecting immediate in vivo cell death is more difficult because it takes at least 3 days for the tumor to begin to shrink in size. In this study, fluorescence lifetime (FLT) was evaluated before and after PIT for monitoring the immediate cytotoxic effects of NIR mediated mAb-IR700 PIT. Anti-epidermal growth factor receptor (EGFR) panitumumab-IR700 was used for targeting EGFR-expressing A431 tumor cells. PIT with various doses of NIR light was conducted in cell pellets in vitro and in subcutaneously xenografted tumors inmice in vivo. FLT measurements were obtained before and 0, 6, 24, and 48 hours after PIT. In vitro, PIT at higher doses of NIR light immediately led to FLT shortening in A431 cells. In vivo PIT induced immediate shortening of FLT in treated tumors after a threshold NIR dose of 30 J/cm(2) or greater. In contrast, lower levels of NIR light (10 J/cm(2) or smaller) did not induce shortening of FLT. Prolongation of FLT in tissue surrounding the tumor site was noted 6 hours after PIT, likely reflecting phagocytosis bymacrophages. In conclusion, FLT imaging can be used to monitor the acute cytotoxic effects of mAb-IR700-induced PIT even before morphological changes can be seen in the targeted tumors. Cancer Res; 72(18); 4622-8. (C) 2012 AACR. C1 [Nakajima, Takahito; Sano, Kohei; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 27 TC 31 Z9 31 U1 1 U2 25 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 SEP 15 PY 2012 VL 72 IS 18 BP 4622 EP 4628 DI 10.1158/0008-5472.CAN-12-1298 PG 7 WC Oncology SC Oncology GA 016HH UT WOS:000309507900004 PM 22800710 ER PT J AU Mitchell, JB Anver, MR Sowers, AL Rosenberg, PS Figueroa, M Thetford, A Krishna, MC Albert, PS Cook, JA AF Mitchell, James B. Anver, Miriam R. Sowers, Anastasia L. Rosenberg, Philip S. Figueroa, Maria Thetford, Angela Krishna, Murali C. Albert, Paul S. Cook, John A. TI The Antioxidant Tempol Reduces Carcinogenesis and Enhances Survival in Mice When Administered after Nonlethal Total Body Radiation SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; CANCER CHEMOPREVENTION; CALORIE RESTRICTION; OXIDATIVE STRESS; BREAST-CANCER; NORMAL TISSUE; BONE-MARROW; FOOD-INTAKE; OLD-AGE; LEUKEMIA AB There is significant interest in the development of agents that can ameliorate radiation damage after exposure to radiation has occurred. Here we report that chronic supplementation of the antioxidant Tempol in the diet of mice can reduce body weight without toxicity, decrease cancer, and extend survival when administered after nonlethal total body radiation (TBI). These effects were apparent in two different strains of mice (C3H, CBA) exposed to TBI (3 Gy). Notably, delaying administration of the Tempol diet one month after TBI could also enhance survival. Tempol reduced the incidence of hematopoietic neoplasms (lymphomas) in both strains, whereas both the onset and incidence of nonhematopoietic neoplasms were reduced in CBA mice. These results encourage further study of Tempol as a chemopreventive, to reduce the incidence of radiation-induced second malignancies after a course of definitive radiation therapy. Tempol may also find applications to reduce the risk of cancers in populations exposed to nonlethal radiation due to nuclear accidents or terrorist attacks. Cancer Res; 72(18); 4846-55. (C)2012 AACR. C1 [Mitchell, James B.; Sowers, Anastasia L.; Figueroa, Maria; Thetford, Angela; Krishna, Murali C.; Cook, John A.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Rosenberg, Philip S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Anver, Miriam R.] NCI, Pathol Histotechnol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Albert, Paul S.] NICHD, Biostat & Bioinformat Branch, Bethesda, MD USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM jbm@helix.nih.gov FU NIAID; NCI; NIH [HHSN261200800001E] FX This research was supported by the NIAID Medical Countermeasures against Radiological and Nuclear Threats Program and the Intramural Research Program of the Center of Cancer Research, National Cancer Institute, NIH and in part with federal funds from the NCI, NIH, under Contract No. HHSN261200800001E. NR 49 TC 16 Z9 16 U1 0 U2 5 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 SEP 15 PY 2012 VL 72 IS 18 BP 4846 EP 4855 DI 10.1158/0008-5472.CAN-12-1879 PG 10 WC Oncology SC Oncology GA 016HH UT WOS:000309507900026 PM 22805306 ER PT J AU Gardin, JM Leifer, ES Kitzman, DW Cohen, G Landzberg, JS Cotts, W Wolfel, EE Safford, RE Bess, RL Fleg, JL AF Gardin, Julius M. Leifer, Eric S. Kitzman, Dalane W. Cohen, Gerald Landzberg, Joel S. Cotts, William Wolfel, Eugene E. Safford, Robert E. Bess, Renee L. Fleg, Jerome L. TI Usefulness of Doppler Echocardiographic Left Ventricular Diastolic Function and Peak Exercise Oxygen Consumption to Predict Cardiovascular Outcomes in Patients With Systolic Heart Failure (from HF-ACTION) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TRIAL INVESTIGATING OUTCOMES; PRESERVED EJECTION FRACTION; SOCIETY-OF-ECHOCARDIOGRAPHY; TISSUE DOPPLER; STANDARDS COMMITTEE; NATRIURETIC PEPTIDE; PROGNOSTIC VALUE; TASK-FORCE; RECOMMENDATIONS; DYSFUNCTION AB Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) was a multicenter, randomized controlled trial designed to examine the safety and efficacy of aerobic exercise training versus usual care in 2,331 patients with systolic heart failure (HF). In HF-ACTION patients with rest transthoracic echocardiographic measurements, the predictive value of 8 Doppler echocardiographic measurements-left ventricular (LV) diastolic dimension, mass, systolic (ejection fraction) and diastolic (mitral valve peak early diastolic/peak late diastolic [E/A] ratio, peak mitral valve early diastolic velocity/tissue Doppler peak early diastolic myocardial velocity [E/E'] ratio, and deceleration time) function, left atrial dimension, and mitral regurgitation severity-was examined for a primary end point of all-cause death or hospitalization and a secondary end point of cardiovascular disease death or HF hospitalization. Also compared was the prognostic value of echocardiographic variables versus peak oxygen consumption (Vo(2)). Mitral valve E/A and E/E' ratios were more powerful independent predictors of clinical end points than the LV ejection fraction but less powerful than peak Vo(2). In multivariate analyses for predicting the primary end point, adding E/A ratio to a basic demographic and clinical model increased the C-index from 0.61 to 0.62, compared with 0.64 after adding peak Vo(2). For the secondary end point, 6 echocardiographic variables, but not the LV ejection fraction or left atrial dimension, provided independent predictive power over the basic model. The addition of E/E' or E/A to the basic model increased the C-index from 0.70 to 0.72 and 0.73, respectively (all p values < 0.0001). Simultaneously adding E/A ratio and peak Vo(2) to the basic model increased the C-index to 0.75 (p < 0.0005). No echocardiographic variable was significantly related to the change from baseline to 3 months in exercise peak Vo(2). In conclusion, the addition of echocardiographic LV diastolic function variables improves the prognostic value of a basic demographic and clinical model for cardiovascular disease outcomes. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:862-869) C1 [Gardin, Julius M.; Cohen, Gerald; Bess, Renee L.] St John Hosp & Med Ctr, Detroit, MI USA. [Gardin, Julius M.; Landzberg, Joel S.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Leifer, Eric S.; Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Kitzman, Dalane W.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Cotts, William] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Wolfel, Eugene E.] Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. [Safford, Robert E.] Mayo Clin, Div Cardiovasc Dis, Jacksonville, FL 32224 USA. RP Gardin, JM (reprint author), St John Hosp & Med Ctr, Detroit, MI USA. EM jgardin@hackensackumc.org FU National Institutes of Health, Bethesda, Maryland FX This study was supported by funding from the National Institutes of Health, Bethesda, Maryland. NR 22 TC 4 Z9 4 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 SEP 15 PY 2012 VL 110 IS 6 BP 862 EP 869 DI 10.1016/j.amjcard.2012.05.015 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 012PZ UT WOS:000309250300017 PM 22683041 ER PT J AU Chuang, ML Massaro, JM Levitzky, YS Fox, CS Manders, ES Hoffmann, U O'Donnell, CJ AF Chuang, Michael L. Massaro, Joseph M. Levitzky, Yamini S. Fox, Caroline S. Manders, Emily S. Hoffmann, Udo O'Donnell, Christopher J. TI Prevalence and Distribution of Abdominal Aortic Calcium by Gender and Age Group in a Community-Based Cohort (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY CALCIUM; BEAM COMPUTED-TOMOGRAPHY; CARDIOVASCULAR-DISEASE; RISK-ASSESSMENT; CALCIFICATION; ATHEROSCLEROSIS; PREDICTION; MORTALITY; DEPOSITS; CT AB Abdominal aortic calcium (AAC) is associated with incident cardiovascular disease. However, the age- and gender-related distribution of AAC in a community-dwelling population free of standard cardiovascular disease risk factors has not been described. A total of 3,285 participants (aged 50.2 +/- 9.9 years) in the Framingham Heart Study Offspring and Third Generation cohorts underwent abdominal multidetector computed tomography from 1998 to 2005. The presence and amount of AAC was quantified (Agatston score) by an experienced reader using standardized criteria. A healthy referent subsample (n = 1,656, 803 men) free of hypertension, hyperlipidemia, diabetes, obesity, and smoking was identified, and participants were stratified by gender and age (<45, 45 to 54, 55 to 64, 65 to 74, and >= 75 years). The prevalence and burden of AAC increased monotonically and supralinearly with age in both genders but was greater in men than in women in each age group. For those <45 years old, <16% of the referent subsample participants had any quantifiable AAC. However, for those >65 years old, nearly 90% of the referent participants had >0 AAC. Across the entire study sample, AAC prevalence and burden similarly increased with greater age. Defining the 90th percentile of the referent group AAC as "high," the prevalence of high AAC was 19% for each gender in the overall study sample. The AAC also increased across categories of 10-year coronary heart disease risk, as calculated using the Framingham Risk Score, in the entire study sample. We found AAC to be widely prevalent, with the burden of AAC associated with 10-year coronary risk, in a white, free-living adult cohort. Published by Elsevier Inc. (Am J Cardiol 2012;110:891-896) C1 [Chuang, Michael L.; Massaro, Joseph M.; Levitzky, Yamini S.; Fox, Caroline S.; Manders, Emily S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Bethesda, MD 20892 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Fox, Caroline S.; Hoffmann, Udo; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, Bethesda, MD 20892 USA. EM odonnellc@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N01-HC-38038]; National Heart, Lung, and Blood Institute Division of Intramural Research, (Bethesda, Maryland) FX This project was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract numbers N01-HC-25195 and N01-HC-38038). Dr. O'Donnell is supported by the National Heart, Lung, and Blood Institute Division of Intramural Research, (Bethesda, Maryland). NR 27 TC 8 Z9 8 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 15 PY 2012 VL 110 IS 6 BP 891 EP 896 DI 10.1016/j.amjcard.2012.05.020 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 012PZ UT WOS:000309250300021 PM 22727181 ER PT J AU Wacholder, S AF Wacholder, Sholom TI Clinical Utility in Evaluation of Risk Models SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID INCREMENTAL VALUE; RELEVANT MEASURES; MARKERS; CAUTION C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Wacholder, S (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM WacholdS@mail.NIH.gov FU Intramural NIH HHS NR 7 TC 4 Z9 4 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2012 VL 176 IS 6 BP 495 EP 496 DI 10.1093/aje/kws255 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 010CY UT WOS:000309073300006 PM 22875758 ER PT J AU Howards, PP Schisterman, EF Poole, C Kaufman, JS Weinberg, CR AF Howards, Penelope P. Schisterman, Enrique F. Poole, Charles Kaufman, Jay S. Weinberg, Clarice R. TI "Toward a Clearer Definition of Confounding" Revisited With Directed Acyclic Graphs SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); causality; confounding factors (epidemiology); reproductive history ID SPONTANEOUS-ABORTION; CAUSAL DIAGRAMS; BIAS AB In a 1993 paper (Am J Epidemiol. 1993;137(1):18), Weinberg considered whether a variable that is associated with the outcome and is affected by exposure but is not an intermediate variable between exposure and outcome should be considered a confounder in etiologic studies. As an example, she examined the common practice of adjusting for history of spontaneous abortion when estimating the effect of an exposure on the risk of spontaneous abortion. She showed algebraically that such an adjustment could substantially bias the results even though history of spontaneous abortion would meet some definitions of a confounder. Directed acyclic graphs (DAGs) were introduced into epidemiology several years later as a tool with which to identify confounders. The authors now revisit Weinbergs paper using DAGs to represent scenarios that arise from her original assumptions. DAG theory is consistent with Weinbergs finding that adjusting for history of spontaneous abortion introduces bias in her original scenario. In the authors examples, treating history of spontaneous abortion as a confounder introduces bias if it is a descendant of the exposure and is associated with the outcome conditional on exposure or is a child of a collider on a relevant undirected path. Thoughtful DAG analyses require clear research questions but are easily modified for examining different causal assumptions that may affect confounder assessment. C1 [Howards, Penelope P.] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Poole, Charles] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Kaufman, Jay S.] McGill Univ, Fac Med, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Weinberg, Clarice R.] NIEHS, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Howards, PP (reprint author), Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, 1518 Clifton Rd NE,CNR 3029, Atlanta, GA 30322 USA. EM penelope.howards@emory.edu OI Kaufman, Jay/0000-0003-1606-401X; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences, National Institutes of Health [ZIA ES040006-14] FX This investigation was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Environmental Health Sciences (project ZIA ES040006-14), National Institutes of Health. J. S. K. was supported by the Canada Research Chairs program. NR 14 TC 41 Z9 42 U1 4 U2 28 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 SEP 15 PY 2012 VL 176 IS 6 BP 506 EP 511 DI 10.1093/aje/kws127 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 010CY UT WOS:000309073300008 PM 22904203 ER PT J AU Ullmann, CD Harlan, LC Shavers, VL Stevens, JL AF Ullmann, Claudio Dansky Harlan, Linda C. Shavers, Vickie L. Stevens, Jennifer L. TI A population-based study of therapy and survival for patients with head and neck cancer treated in the community SO CANCER LA English DT Article DE head and neck cancer; therapy; survival; oral cavity cancer; oropharyngeal cancer; laryngeal cancer ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; LARYNGEAL-CANCER; PLUS CETUXIMAB; UNITED-STATES; CHEMOTHERAPY; RADIATION; SURGERY; TRIAL AB BACKGROUND: The objective of this study was to examine patterns of care and survival in a population-based sample of patients with head and neck cancer (HNC) who were treated in the community or in hospitals that had residency training programs. METHODS: Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program were used to sample 1317 patients aged =20 years with invasive squamous HNC who were diagnosed during 2004 and who had vital status available through 2008. RESULTS: Treatment and survival were influenced by tumor site and disease stage. Patients who had stage I/II cancer of the oral cavity generally underwent surgery; patients with stage III oral cavity disease underwent surgery and received radiation; and patients with stage IV oral cavity disease underwent surgery and received chemoradiation. Patients with early stage cancer of the oropharynx either underwent surgery or received radiation and chemotherapy, and patients with late/unstaged oropharyngeal disease primarily received radiation and chemotherapy. Patients with early stage cancer of the larynx mainly received radiation alone, and patients with late stage laryngeal disease generally received chemoradiation. Cisplatin-based regimens were used most frequently. Overall, taxanes were used in 32% of regimens, and cetuximab was used in <3% of regimens. Patients aged =50 years, those with a Charlson comorbidity score =1, those with stage IV disease, and those with cancer located in the oral cavity or larynx had poorer survival. Although facilities with residency training programs treated more black patients and more patients with late stage disease, when adjusted for other factors, survival rates were similar to those reported in facilities with no such programs. CONCLUSIONS: Therapy generally followed accepted standards for 2004. Findings in particular tumor sites and stages may reflect the variability that still exists for the treatment of HNC. The use of taxanes and cetuximab is expected to increase based on new evidence of benefit. Reducing treatment-related toxicities and long-term functional deficits will be critical and especially important with the increase in human papillomavirus-related cancers. In addition, further attempts to improve survival for older patients are needed. Cancer 2012. (c) 2012 American Cancer Society. C1 [Ullmann, Claudio Dansky] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Harlan, Linda C.; Shavers, Vickie L.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Stevens, Jennifer L.] Informat Management Serv Inc, Silver Spring, MD USA. RP Ullmann, CD (reprint author), NCI, Canc Therapy Evaluat Program, 6130 Execut Blvd,MSC 7432, Bethesda, MD 20892 USA. EM danskyullc@mail.nih.gov FU National Cancer Institute [N01-PC-35133, N01-PC-35135, N01-PC-35141, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54403, N01-PC-54404, N01-PC-54405] FX This work was supported by the following grants from the National Cancer Institute: N01-PC-35133, N01-PC-35135, N01-PC-35141, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54403, N01-PC-54404, and N01-PC-54405. NR 23 TC 12 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2012 VL 118 IS 18 BP 4452 EP 4461 DI 10.1002/cncr.27419 PG 10 WC Oncology SC Oncology GA 000RB UT WOS:000308404100015 ER PT J AU Janeway, KA Barkauskas, DA Krailo, MD Meyers, PA Schwartz, CL Ebb, DH Seibel, NL Grier, HE Gorlick, R Marina, N AF Janeway, Katherine A. Barkauskas, Donald A. Krailo, Mark D. Meyers, Paul A. Schwartz, Cindy L. Ebb, David H. Seibel, Nita L. Grier, Holcombe E. Gorlick, Richard Marina, Neyssa TI Outcome for adolescent and young adult patients with osteosarcoma SO CANCER LA English DT Article DE osteosarcoma; adolescent; young adult; prognosis; outcome ID HIGH-GRADE OSTEOSARCOMA; END RESULTS PROGRAM; PROGNOSTIC-FACTORS; NONMETASTATIC OSTEOSARCOMA; MURAMYL TRIPEPTIDE; EWINGS-SARCOMA; TUMOR SIZE; CHEMOTHERAPY; IFOSFAMIDE; EXTREMITY AB BACKGROUND: There are conflicting data regarding age as a prognostic factor in osteosarcoma. The authors conducted a study evaluating the impact of age on prognosis in children and young adults with osteosarcoma enrolled on North American cooperative group trials. METHODS: Patients with high-grade osteosarcoma of any site enrolled on North American cooperative group trials CCG-7943, POG-9754, INT-0133, and AOST0121 were included in this study. Primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis were evaluated for their impact on overall survival (OS) and event-free survival (EFS). RESULTS: A total of 1054 patients were eligible and had complete data available for the study. Age was not significantly associated with any other presenting covariate analyzed except sex. Age 18 or older was associated with a statistically significant poorer EFS (P = .019) and OS (P = .043). The 10-year EFS and OS in patients <10, 10 to 17, and =18 years old were 55%, 55%, 37% and 68%, 60%, 41%, respectively. The poorer EFS in patients =18 years old was because of an increased rate of relapse. Presence of metastatic disease at diagnosis, poor histologic response, and pelvic tumor site were also associated with a poorer prognosis. In multivariate analysis, age continued to be associated with poorer EFS (P = .019) and OS (P = .049). CONCLUSIONS: In osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, histologic response, or metastatic disease at presentation. Cancer 2012.(c) 2012 American Cancer Society. C1 [Janeway, Katherine A.; Grier, Holcombe E.] Dana Farber Childrens Hosp Canc Ctr, Dept Pediat Hematol Oncol, Boston, MA USA. [Barkauskas, Donald A.; Krailo, Mark D.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Meyers, Paul A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. [Schwartz, Cindy L.] Hasbro Childrens Hosp, Providence, RI USA. [Schwartz, Cindy L.] Brown Univ, Providence, RI 02912 USA. [Ebb, David H.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Seibel, Nita L.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Div Pediat Hematol Oncol, Bronx, NY USA. [Marina, Neyssa] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Marina, Neyssa] Stanford Univ, Palo Alto, CA 94304 USA. RP Janeway, KA (reprint author), 450 Brookline Ave, Boston, MA 02215 USA. EM kjaneway@partners.org FU Children's Oncology Group Chair's grant [NIH U10 CA98543]; Human Specimen Banking grant [NIH U24 CA114766]; WWWW (QuadW) Foundation; Aflac/CureSearch for Children's Cancer AYA Cancer Research Program; Timothy O'Brien Trust Award; St. Baldrick's Foundation FX Supported by the Children's Oncology Group Chair's grant NIH U10 CA98543, Human Specimen Banking grant NIH U24 CA114766, and grants from the WWWW (QuadW) Foundation, Aflac/CureSearch for Children's Cancer AYA Cancer Research Program, Timothy O'Brien Trust Award, and St. Baldrick's Foundation. NR 24 TC 38 Z9 40 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2012 VL 118 IS 18 BP 4597 EP 4605 DI 10.1002/cncr.27414 PG 9 WC Oncology SC Oncology GA 000RB UT WOS:000308404100032 PM 22252521 ER PT J AU Ainsua-Enrich, E Alvarez-Errico, D Gilfillan, AM Picado, C Sayos, J Rivera, J Martin, M AF Ainsua-Enrich, Erola Alvarez-Errico, Damiana Gilfillan, Alasdair M. Picado, Cesar Sayos, Joan Rivera, Juan Martin, Margarita TI The Adaptor 3BP2 Is Required for Early and Late Events in Fc epsilon RI Signaling in Human Mast Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN-TYROSINE KINASE; HIGH-AFFINITY RECEPTOR; ANTIGEN RECEPTOR; IGE RECEPTOR; ACTIVATION; CHERUBISM; SYK; DEGRANULATION; TRANSDUCTION; CYTOTOXICITY AB Adaptor molecules are essential in organizing signaling molecules and in coordinating and compartmentalizing their activity. SH3-binding protein 2 (3BP2) is a cytoplasmic adaptor protein mainly expressed by hematopoietic cells that has been shown to act as a positive regulator in T, B, and NK cell signal transduction. 3BP2 is an important regulator of cytotoxic granule release in NK cells. Mast cells (MCs) similarly degranulate following Ag-dependent aggregation of the Fc epsilon RI on the cell surface. Activation of these cells induces the release of preformed inflammatory mediators and the de novo synthesis and secretion of cytokines and chemokines. Thus, MCs participate in both innate and acquired responses. We observed that 3BP2 is expressed in human MCs (huMCs) from diverse origins. Moreover, 3BP2 coimmunoprecipitates with essential MC signaling mediators such as Lyn, Syk, and phospholipase C gamma; thus, a role for this adaptor in MC function was postulated. In the present work, we used the short hairpin RNA lentiviral targeting approach to silence 3BP2 expression in huMCs. Our findings point to a requirement for 3BP2 in optimal immediate and late MCs responses such as degranulation and IL-8 or GM-CSF secretion. 3BP2 was determined to be necessary for optimal phosphorylation of Syk, linker for activation of T cells, and phospholipase C gamma(1), critical signals for calcium release from intracellular stores. Taken together, our results show that by participating in Fc epsilon RI- mediated signal transduction 3BP2 is an important regulator of huMC activation. Thus, 3BP2 could be a potential therapeutic target for IgE-dependent MC-mediated inflammatory disease. The Journal of Immunology, 2012, 189: 2727-2734. C1 [Ainsua-Enrich, Erola; Alvarez-Errico, Damiana; Martin, Margarita] Univ Barcelona, Fac Med, Biochem Unit, E-08036 Barcelona, Spain. [Ainsua-Enrich, Erola; Alvarez-Errico, Damiana; Picado, Cesar; Martin, Margarita] Inst Invest Biomed August Pi & Sunyer, Lab Immunoallergia Resp Clin & Expt, Barcelona 08036, Spain. [Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Picado, Cesar] Networking Res Ctr Resp Dis, Inst Hlth Carlos 3, Madrid 28029, Spain. [Sayos, Joan] Autonomous Univ Barcelona, Immunobiol Grp, Mol Biol & Biochem Res Ctr Nanomed, Vall Hebron Hosp,Nanomed Program,Res Inst, E-08035 Barcelona, Spain. [Sayos, Joan] Networking Res Ctr Bioengn Biomat & Nanomed, Inst Hlth Carlos 3, Madrid 28029, Spain. [Rivera, Juan] NIAMSD, Mol Immunol Sect, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Martin, M (reprint author), Univ Barcelona, Fac Med, Biochem Unit, Carrer Casanova 143, E-08036 Barcelona, Spain. EM martin_andorra@ub.edu RI Sayos, Joan/B-6119-2009 OI Sayos, Joan/0000-0002-4664-3461 FU Plan Nacional Ministerio de Ciencia e Innovacion (Spain) [SAF2009-07548]; Formacion de Personal Investigador (Spain) from Ministerio de Ciencia e Innovacion; Juan de la Cierva contract; Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III [CP06/00058]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This work was supported by Grant SAF2009-07548 from the Plan Nacional Ministerio de Ciencia e Innovacion (Spain). E. A.-E. is supported by a Formacion de Personal Investigador (Spain) fellowship from Ministerio de Ciencia e Innovacion. D. A.-E. is supported by a Juan de la Cierva contract. J.S. is supported by a Miguel Servet contract from Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III (CP06/00058). Work conducted in the laboratory of A. M. G. is supported by the Intramural Research Program within the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Work done in the J.R. laboratory is funded by the Intramural Research Program within the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 44 TC 8 Z9 9 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2012 VL 189 IS 6 BP 2727 EP 2734 DI 10.4049/jimmunol.1200380 PG 8 WC Immunology SC Immunology GA 004RK UT WOS:000308698600008 PM 22896635 ER PT J AU Quandt, JA Huh, J Baig, M Yao, K Ito, N Bryant, M Kawamura, K Pinilla, C McFarland, HF Martin, R Ito, K AF Quandt, Jacqueline A. Huh, Jaebong Baig, Mirza Yao, Karen Ito, Naoko Bryant, Mark Kawamura, Kazuyuki Pinilla, Clemencia McFarland, Henry F. Martin, Roland Ito, Kouichi TI Myelin Basic Protein-Specific TCR/HLA-DRB5*01:01 Transgenic Mice Support the Etiologic Role of DRB5*01:01 in Multiple Sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; CLASS-II GENES; HL-A ANTIGENS; INTERLEUKIN-7 RECEPTOR; HEALTHY-INDIVIDUALS; HLA-DR15 HAPLOTYPE; EFFECTOR FUNCTIONS; FINE SPECIFICITY; STRUCTURAL BASIS; SELF-PEPTIDE AB Genetic susceptibility to multiple sclerosis (MS) has been linked to the HLA-DR15 haplotype consisting of DRB1*15:01(DR2b) and DRB5*01:01(DR2a) alleles. Given almost complete linkage disequilibrium of the two alleles, recent studies suggested differential roles in susceptibility (DR2b) or protection from MS (DR2a). Our objective was to assess the potential contribution of DR2a to disease etiology in MS using a humanized model of autoimmunity. To assess the potential contribution of DR2a to disease etiology, we created DR2a humanized transgenic (Tg) mice and subsequently crossed them to Tg mice expressing TL3A6, an MS patient-derived myelin basic protein 83-99-specific TCR. In TL3A6/DR2a Tg mice, CD4 Tg T cells escape thymic and peripheral deletion and initiate spontaneous experimental autoimmune encephalomyelitis (EAE) at low rates, depending on the level of DR2a expression. The ability to induce active EAE was also increased in animals expressing higher levels of DR2a. Inflammatory infiltrates and neuronal damage were present throughout the spinal cord, consistent with a classical ascending EAE phenotype with minor involvement of the cerebellum, brainstem, and peripheral nerve roots in spontaneous, as well as actively induced, disease. These studies emphasize the pathologic contribution of the DR2a allele to the development of autoimmunity when expressed as the sole MHC class II molecule, as well as strongly argue for DR2a as a contributor to the CNS autoimmunity in MS. The Journal of Immunology, 2012, 189:2897-2908. C1 [Quandt, Jacqueline A.; Huh, Jaebong; Baig, Mirza; Yao, Karen; Kawamura, Kazuyuki; McFarland, Henry F.; Martin, Roland; Ito, Kouichi] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Ito, Naoko; Ito, Kouichi] Univ Med & Dent New Jersey, Dept Neurol, Piscataway, NJ 08854 USA. [Bryant, Mark] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Pinilla, Clemencia] Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. RP Quandt, JA (reprint author), Univ British Columbia, Dept Pathol & Lab Med, G227 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. EM jquandt@pathology.ubc.ca; itoko@umdnj.edu FU National Institutes of Health [R21 AI067474]; Multiple Sclerosis Society of Canada; National Multiple Sclerosis Society FX This work was supported by the National Institutes of Health intramural program and in part by National Institutes of Health Grant R21 AI067474 (to K. I.), with additional support from the Multiple Sclerosis National Research Institute. J.A.Q. was supported by fellowships from the Multiple Sclerosis Society of Canada and the National Multiple Sclerosis Society. NR 63 TC 11 Z9 11 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2012 VL 189 IS 6 BP 2897 EP 2908 DI 10.4049/jimmunol.1103087 PG 12 WC Immunology SC Immunology GA 004RK UT WOS:000308698600026 PM 22888134 ER PT J AU Wehr, NB Levine, RL AF Wehr, Nancy B. Levine, Rodney L. TI Wanted and wanting: Antibody against rnethionine sulfoxide SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Methionine sulfoxide; Anti-methionine sulfoxide antibody; Oxidative stress ID METHIONINE SULFOXIDE; GLUTAMINE-SYNTHETASE; OXIDATIVE MODIFICATION; REDUCTASE-A; PROTEINS; RESIDUES; CELLS; INACTIVATION; SURVIVAL; STRESS AB Methionine residues in protein can be oxidized by reactive oxygen or nitrogen species to generate methionine sulfoxide. This covalent modification has been implicated in processes ranging from normal cell signaling to neurodegenerative diseases. A general method for detecting methionine sulfoxide in proteins would be of great value in studying these processes, but development of a chemical or immunochemical technique has been elusive. Recently, an antiserum raised against an oxidized corn protein, DZS18, was reported to be specific for methionine sulfoxide in proteins (Arch. Biochem. Biophys. 485:35-40; 2009). However, data included in that report indicate that the antiserum is not specific. Utilizing well-characterized native and methionine-oxidized glutamine synthetase and aprotinin, we confirm that the antiserum does not possess specificity for methionine sulfoxide. (c) 2012 Elsevier Inc. All rights reserved. C1 [Wehr, Nancy B.; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2351, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural Research Program of the National Heart, Lung, and Blood Institute FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute. The authors declare no conflict of interest. NR 31 TC 19 Z9 20 U1 2 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 SEP 15 PY 2012 VL 53 IS 6 BP 1222 EP 1225 DI 10.1016/j.freeradbiomed.2012.06.036 PG 4 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 007QS UT WOS:000308903800002 PM 22771451 ER PT J AU Zhuang, J Ma, WZ Lago, CU Hwang, PM AF Zhuang, Jie Ma, Wenzhe Lago, Cory U. Hwang, Paul M. TI Metabolic regulation of oxygen and redox homeostasis by p53: Lessons from evolutionary biology? SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE p53; Oxygen; Oxidative stress; Redox; Antioxidant; Metabolism; Cancer; Mitochondria; Altitude; Free radicals ID TUMOR-SUPPRESSOR P53; FATTY-ACID OXIDATION; ANTIOXIDANT FUNCTION; DNA-BINDING; CANCER-CELLS; TARGET-GENE; MITOCHONDRIAL RESPIRATION; P53-DEPENDENT APOPTOSIS; P53-INDUCIBLE REGULATOR; FERREDOXIN REDUCTASE AB The genetic links between p53 and metabolic processes such as oxidative phosphorylation are being studied with increasing interest given that cellular metabolism seems to play an important role in tumorigenesis. This review focuses on how p53 regulation of various metabolic genes may influence redox homeostasis, as the genome is constantly susceptible to oxidative damage, a consequence of living in an aerobic environment. Because p53-like genetic sequences are also found in life forms that may not necessarily benefit from tumor suppression, an evolutionary introduction is given in an attempt to understand why p53 might regulate a basic cellular activity such as metabolism. The presented epidemiologic and experimental data suggest that one reason may be for the homeostatic regulation of oxygen, the essential substrate for reactive oxygen species generation. Published by Elsevier Inc. C1 [Zhuang, Jie; Ma, Wenzhe; Lago, Cory U.; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov FU Intramural Program of the National Heart, Lung, and Blood Institute, NIH FX We thank Ping-yuan Wang for invaluable discussions and assistance. This work was supported by the Intramural Program of the National Heart, Lung, and Blood Institute, NIH. NR 104 TC 17 Z9 18 U1 1 U2 13 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 SEP 15 PY 2012 VL 53 IS 6 BP 1279 EP 1285 DI 10.1016/j.freeradbiomed.2012.07.026 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 007QS UT WOS:000308903800007 PM 22841759 ER PT J AU Banerjee, S Jia, YP Siburt, CJP Abraham, B Wood, F Bonaventura, C Henkens, R Crumbliss, AL Alayash, AI AF Banerjee, Sambuddha Jia, Yiping Siburt, Claire J. Parker Abraham, Bindu Wood, Francine Bonaventura, Celia Henkens, Robert Crumbliss, Alvin L. Alayash, Abdu I. TI Haptoglobin alters oxygenation and oxidation of hemoglobin and decreases propagation of peroxide-induced oxidative reactions SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Haptoglobin; Hemoglobin; Peroxidase; Oxygen; Redox potential; Ferryl hemoglobin ID MASS-SPECTROMETRY; CARBON MONOXIDE; HEME-PROTEINS; ALPHA-CHAINS; MYOGLOBIN; KINETICS; COMPLEX; SPECTROELECTROCHEMISTRY; SULFHEMOGLOBIN; IDENTIFICATION AB We compared oxygenation and anaerobic oxidation reactions of a purified complex of human hemoglobin (Hb) and haptoglobin (Hb-Hp) to those of uncomplexed Hb. Under equilibrium conditions, Hb-Hp exhibited active-site heterogeneity and noncooperative, high-affinity O-2 binding (n(1/2)=0.88, P-1/2=0.33 mm Hg in inorganic phosphate buffer at pH 7 and 25 degrees C). Rapid-reaction kinetics also exhibited active-site heterogeneity, with a slower process of O-2 dissociation and a faster process of CO binding relative to uncomplexed Hb. Deoxygenated Hb-Hp had significantly reduced absorption at the lambda(max) of 430 nm relative to uncomplexed Fib, as occurs for isolated Hb subunits that lack T-state stabilization. Under comparable experimental conditions, the redox potential (E-1/2) of Hb-Hp was found to be +54 mV, showing that it is much more easily oxidized than uncomplexed Fib (E-1/2 =+125 mV). The Nernst plots for Hb-Hp oxidation showed no cooperativity and slopes less than unity indicated active-site heterogeneity. The redox potential of Hb-Hp was unchanged by pH over the range of 6.4-8.3. Exposure of Hb-Hp to excess hydrogen peroxide (H2O2) produced ferryl heme, which was found to be more kinetically inert in the Hb-Hp complex than in uncomplexed Hb. The negative shift in the redox potential of Hb-Hp and its stabilized ferryl state may be central elements in the protection against Fib-induced oxidative damage afforded by formation of the Hb-Hp complex. Published by Elsevier Inc. C1 [Banerjee, Sambuddha; Siburt, Claire J. Parker; Crumbliss, Alvin L.] Duke Univ, French Family Sci Ctr, Dept Chem, Durham, NC 27708 USA. [Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, CBER, NIH, Bethesda, MD 20892 USA. [Bonaventura, Celia; Henkens, Robert] Duke Univ, Nicholas Sch Environm, Marine Lab, Beaufort, NC 28516 USA. RP Alayash, AI (reprint author), US FDA, Lab Biochem & Vasc Biol, CBER, NIH, Bldg 29,Rm 112, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov FU CBER's MODSCI Funding; National Science Foundation [CHE 0809466]; Duke University FX This work was supported by CBER's MODSCI Funding (A.I.A.). A.L.C. thanks the National Science Foundation (CHE 0809466) and Duke University for financial support and the Santa Fe Institute for hospitality during the period this manuscript was written. We thank Dr. Jin Baek (CBER/FDA) for technical advice and suggestions for the immunoblot experiments. NR 46 TC 16 Z9 16 U1 0 U2 9 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 SEP 15 PY 2012 VL 53 IS 6 BP 1317 EP 1326 DI 10.1016/j.freeradbiomed.2012.07.023 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 007QS UT WOS:000308903800011 PM 22841869 ER PT J AU Davis, MF Zhou, L Ehrenshaft, M Ranguelova, K Gunawardena, P Chen, X Bonini, MG Mason, RP Campbell, SL AF Davis, Michael F. Zhou, Li Ehrenshaft, Marilyn Ranguelova, Kalina Gunawardena, Harsha P. Chen, Xian Bonini, Marcelo G. Mason, Ronald P. Campbell, Sharon L. TI Detection of Ras GTPase protein radicals through immuno-spin trapping SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Ras GTPase; Radical-mediated activation; Protein radical; Immuno-spin trapping; Free radicals ID GUANINE-NUCLEOTIDE EXCHANGE; TANDEM MASS-SPECTROMETRY; P21(RAS) S-NITROSYLATION; NITRIC-OXIDE; PULSE-RADIOLYSIS; TOP-DOWN; ONCOGENIC MUTANT; NITROGEN-DIOXIDE; RATE CONSTANTS; MECHANISM AB Over the past decade immuno-spin trapping (IST) has been used to detect and identify protein radical sites in numerous heme and metalloproteins. To date, however, the technique has had little application toward nonmetalloproteins. In this study, we demonstrate the successful application of IST in a system free of transition metals and present the first conclusive evidence of (NO)-N-center dot-mediated protein radical formation in the HRas GTPase. HRas is a nonmetalloprotein that plays a critical role in regulating cell-growth control. Protein radical formation in Ras GTPases has long been suspected of initiating premature release of bound guanine nucleotide. This action results in altered Ras activity both in vitro and in vivo. As described herein, successful application of IST may provide a means for detecting and identifying radical-mediated Ras activation in many different cancers and disease states in which Ras GTPases play an important role. (c) 2012 Elsevier Inc. All rights reserved. C1 [Davis, Michael F.; Zhou, Li; Gunawardena, Harsha P.; Chen, Xian; Campbell, Sharon L.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Davis, Michael F.; Campbell, Sharon L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Ehrenshaft, Marilyn; Ranguelova, Kalina; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Bonini, Marcelo G.] Univ Illinois, Sect Cardiol, Chicago, IL 60612 USA. RP Campbell, SL (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. EM campbesl@med.unc.edu FU National Institutes of Health [5R01 GM075431-04, RO1 CA089614]; Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill (Postdoctoral Training Grant) [5T32CA009156-35] FX We gratefully acknowledge research support from the National Institutes of Health (Grants 5R01 GM075431-04 and RO1 CA089614) and the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill (Postdoctoral Training Grant 5T32CA009156-35). NR 48 TC 7 Z9 7 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD SEP 15 PY 2012 VL 53 IS 6 BP 1339 EP 1345 DI 10.1016/j.freeradbiomed.2012.07.009 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 007QS UT WOS:000308903800013 PM 22819983 ER PT J AU Ramamoorthy, M Sykora, P Scheibye-Knudsen, M Dunn, C Kasmer, C Zhang, YQ Becker, KG Croteau, DL Bohr, VA AF Ramamoorthy, Mahesh Sykora, Peter Scheibye-Knudsen, Morten Dunn, Christopher Kasmer, Cindy Zhang, Yongqing Becker, Kevin G. Croteau, Deborah L. Bohr, Vilhelm A. TI Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Alzheimer disease; Oxidative stress; Array analysis; 8-OxoG; Oxidative DNA damage; Free radicals ID BASE EXCISION-REPAIR; MILD COGNITIVE IMPAIRMENT; TOPOISOMERASE-II ISOFORMS; AMYLOID PRECURSOR PROTEIN; MESSENGER-RNA STABILITY; SPINAL MOTOR-NEURONS; GENE SET ENRICHMENT; P53 TARGET WIG-1; DNA-DAMAGE; NEUROTROPHIC FACTOR AB Alzheimer disease (AD) is a major health problem in the United States, affecting one in eight Americans over the age of 65. The number of elderly suffering from AD is expected to continue to increase over the next decade, as the average age of the U.S. population increases. The risk factors for and etiology of AD are not well understood: however, recent studies suggest that exposure to oxidative stress may be a contributing factor. Here, microarray gene expression signatures were compared in AD-patient-derived fibroblasts and normal fibroblasts exposed to hydrogen peroxide or menadione (to simulate conditions of oxidative stress). Using the 23 K Illumina cDNA microarray to screen expression of > 14,000 human genes, we identified a total of 1017 genes that are chronically up- or downregulated in AD fibroblasts, 215 of which were also differentially expressed in normal human fibroblasts within 12 h after exposure to hydrogen peroxide or menadione. Pathway analysis of these 215 genes and their associated pathways revealed cellular functions that may be critically dysregulated by oxidative stress and play a critical role in the etiology and/or pathology of AD. We then examined the AD fibroblasts for the presence of oxidative DNA damage and found increased accumulation of 8-oxo-guanine. These results indicate the possible role of oxidative stress in the gene expression profile seen in AD. Published by Elsevier Inc. C1 [Ramamoorthy, Mahesh; Sykora, Peter; Scheibye-Knudsen, Morten; Dunn, Christopher; Kasmer, Cindy; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Ramamoorthy, Mahesh/0000-0002-2359-5647; Scheibye-Knudsen, Morten/0000-0002-6637-1280; Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health Intramural Program of the National Institute on Aging [Z01-AG000733-14] FX We thank Dr. Magda Masiak and Martin Borch Jensen for critically reading the manuscript. This work was supported by the National Institutes of Health Intramural Program of the National Institute on Aging (Z01-AG000733-14). NR 99 TC 24 Z9 25 U1 0 U2 7 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 SEP 15 PY 2012 VL 53 IS 6 BP 1371 EP 1380 DI 10.1016/j.freeradbiomed.2012.07.018 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 007QS UT WOS:000308903800016 PM 22885031 ER PT J AU Adjemian, J Olivier, KN Seitz, AE Falkinham, JO Holland, SM Prevots, DR AF Adjemian, Jennifer Olivier, Kenneth N. Seitz, Amy E. Falkinham, Joseph O., III Holland, Steven M. Prevots, D. Rebecca TI Spatial Clusters of Nontuberculous Mycobacterial Lung Disease in the United States SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE nontuberculous mycobacteria; pulmonary; spatial; cluster; epidemiology ID EPIDEMIOLOGY; INFECTION; AVIUM; PREVALENCE; SYSTEMS; INTRACELLULARE; SURVIVAL; NUMBERS; GROWTH; SOILS AB Rationale: Prevalence of pulmonary nontuberculous mycobacterial (PNTM) disease varies by geographic region, yet the factors driving these differences remain largely unknown. Objectives: To identify spatial clusters of PNTM disease at the county level and to describe environmental and sociodemographic factors predictive of disease. Methods: PNTM cases identified from a nationally representative sample of Medicare Part B beneficiaries from 1997 to 2007 were geocoded by county and state of residence. County-level PNTM case counts and Medicare population data were then uploaded into SaTScan to identify significant spatial clusters and low-risk areas of disease. High-risk and low-risk counties were then compared to identify significant sociodemographic and environmental differences. Measurements and Main Results: We identified seven significant (P < 0.05) clusters of PNTM cases. These high-risk areas encompassed 55 counties in 8 states, including parts of California, Florida, Hawaii, Louisiana, New York, Oklahoma, Pennsylvania, and Wisconsin. Five low-risk areas were also identified, which encompassed 746 counties in 23 states, mostly in the Midwest. Counties in high-risk areas were significantly larger, had greater population densities, and higher education and income levels than low-risk counties. High-risk counties also had higher mean daily potential evapotranspiration levels and percentages covered by surface water, and were more likely to have greater copper and sodium levels in the soil, although lower manganese levels. Conclusions: Specific environmental factors related to soil and water exposure appear to increase the risk of PNTM infection. Still, given that environmental sources of NTM are ubiquitous and PNTM disease is rare, both host susceptibility and environmental factors must be considered in explaining disease development. C1 [Adjemian, Jennifer; Seitz, Amy E.; Prevots, D. Rebecca] NIAID, Epidemiol Unit, NIH, Bethesda, MD 20892 USA. [Adjemian, Jennifer; Olivier, Kenneth N.; Seitz, Amy E.; Holland, Steven M.; Prevots, D. Rebecca] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Falkinham, Joseph O., III] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. RP Adjemian, J (reprint author), NIAID, Epidemiol Unit, NIH, Qrts 15 B-1,8 W Dr,MSC 2665, Bethesda, MD 20892 USA. EM jennifer.adjemian@nih.gov FU Division of Intramural Research, NIAID FX Supported by the Division of Intramural Research, NIAID. NR 36 TC 33 Z9 33 U1 0 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 SEP 15 PY 2012 VL 186 IS 6 BP 553 EP 558 DI 10.1164/rccm.201205-0913OC PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 006WG UT WOS:000308849800016 PM 22773732 ER PT J AU Robertson, K Jiang, H Kumwenda, J Supparatpinyo, K Evans, S Campbell, TB Price, R Tripathy, S Kumarasamy, N La Rosa, A Santos, B Silva, MT Montano, S Kanyama, C Faesen, S Murphy, R Hall, C Marra, CM Marcus, C Berzins, B Allen, R Housseinipour, M Amod, F Sanne, I Hakim, J Walawander, A Nair, A AF Robertson, K. Jiang, H. Kumwenda, J. Supparatpinyo, K. Evans, S. Campbell, T. B. Price, R. Tripathy, S. Kumarasamy, N. La Rosa, A. Santos, B. Silva, M. T. Montano, S. Kanyama, C. Faesen, S. Murphy, R. Hall, C. Marra, C. M. Marcus, C. Berzins, B. Allen, R. Housseinipour, M. Amod, F. Sanne, I. Hakim, J. Walawander, A. Nair, A. CA 5199 Study Team AIDS Clinical Trials Grp TI Improved Neuropsychological and Neurological Functioning Across Three Antiretroviral Regimens in Diverse Resource-Limited Settings: AIDS Clinical Trials Group Study A5199, the International Neurological Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID VIRUS-ASSOCIATED DEMENTIA; COGNITIVE IMPAIRMENT; COMPLEX; INFECTION; THERAPY; INDIVIDUALS; DISORDERS; NEUROAIDS; ZIMBABWE; RISK AB Background. AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings. Methods. Participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe were randomized to 3 antiretroviral treatment arms: A (lamivudine-zidovudine plus efavirenz, n = 289), B (atazanavir, emtricitabine, and didanosine-EC, n = 293), and C (emtricitabine-tenofovir-disoproxil fumarate plus efavirenz, n = 278) as part of the ACTG PEARLS study (A5175). Standardized neurological and neuropsychological (NP) screening examinations (grooved pegboard, timed gait, semantic verbal fluency, and finger tapping) were administered every 24 weeks from February 2006 to May 2010. Associations with neurological and neuropsychological function were estimated from linear and logistic regression models using generalized estimating equations. Results. The median weeks on study was 168 (Q1 = 96, Q3 = 192) for the 860 participants. NP test scores improved (P < .05) with the exception of semantic verbal fluency. No differences in neurological and neuropsychological functioning between treatment regimens were detected (P > .10). Significant country effects were noted on all NP tests and neurological outcomes (P < .01). Conclusions. The study detected no significant differences in neuropsychological and neurological outcomes between randomized ART regimens. Significant improvement occurred in neurocognitive and neurological functioning over time after initiation of ARTs. The etiology of these improvements is likely multifactorial, reflecting reduced central nervous system HIV infection, better general health, and practice effects. This study suggests that treatment with either of the World Health Organization -recommended first-line antiretroviral regimens in resource-limited settings will improve neuropsychological functioning and reduce neurological dysfunction. C1 [Robertson, K.] Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. [Jiang, H.; Evans, S.] Harvard Univ, Boston, MA 02115 USA. [Kumwenda, J.] Queen Elizabeth Cent Hosp, Blantyre, Malawi. [Supparatpinyo, K.] Chiang Mai Univ, Chiang Mai, Thailand. [Campbell, T. B.] Univ Colorado, Denver, CO 80202 USA. [Price, R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Tripathy, S.] Natl AIDS Res Inst, Pune, Maharashtra, India. [Kumarasamy, N.] YRGCARE Med Ctr, Madras, Tamil Nadu, India. [La Rosa, A.; Montano, S.] Asociac Civil Impacta Salud & Educ, Lima, Peru. NIAID, AIDS Clin Trials Grp, Div Aids, NIH, Bethesda, MD 20892 USA. [Santos, B.] Hosp Nossa Senhora Conceicao, Porto Alegre, RS, Brazil. [Silva, M. T.] Fiocruz MS, BR-21045900 Rio De Janeiro, Brazil. [Montano, S.] Naval Med Res Unit Six NAMRU 6, Lima, Peru. [Kanyama, C.; Housseinipour, M.] Kamuza Cent Hosp, Lilongwe, Malawi. [Faesen, S.; Sanne, I.] Helen Joseph Hosp, Johannesburg, South Africa. [Murphy, R.; Berzins, B.] Northwestern Univ, Chicago, IL 60611 USA. [Marra, C. M.] Univ Washington, Seattle, WA 98195 USA. [Allen, R.] Social Sci Syst, Bethesda, MD USA. Univ KwaZulu Natal, Sch Med, HIV Clin, Durban, South Africa. [Hakim, J.] Univ Zimbabwe, Harare, Zimbabwe. [Walawander, A.; Nair, A.] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. RP Robertson, K (reprint author), Univ N Carolina, Dept Neurol, 2128 Phys Off Bldg,170 Manning Dr, Chapel Hill, NC 27599 USA. EM kevinr@neurology.unc.edu OI Murphy, Robert/0000-0003-3936-2052 FU National Institute of Mental Health; AIDS Clinical Trials Group (ACTG); NIAID [U01AI068636]; General Clinical Research Center (GCRC); National Center for Research Resources; Statistical and Data Analysis Center (SDAC) [AI-068634]; NIH from ACTG [U01AI068636]; NIAID ACTU [AI069450]; CTU [AI69476, 5U01AI069426-03, AI069432, AI069518, BRS-ACURE-Q-08-00173-TOOI-OOO, AI069463, BRS-ACURE-Q-07-00143 T006, AI069399, AACTG.27.5199.06, 5 U01 AI069401, 5U01AI069417-03, U01A1069518, 5U01 AI069438-03, BRS- ACURE-Q-07-00141-T001-001, BRS-ACURE-Q-08-00007-T-002] FX The project described was supported by the National Institute of Mental Health, and the AIDS Clinical Trials Group (ACTG) funded by The NIAID Award number U01AI068636, General Clinical Research Center (GCRC) funded by the National Center for Research Resources, and Statistical and Data Analysis Center (SDAC) grant number AI-068634. C. M., R. A., K. S., A. L. R., B. B., B. S., C. M., C. H., R. W. P., S. T., J. H., and I. S. received NIH grant support from ACTG U01AI068636.; Thomas Campbell, MD, grant support from NIAID ACTU AI069450.; Deise Vieira, MD, and Marcus Tulius T. Silva MD-PhD-IPEC-FIOCRUZ (Site 12101) CTU grant number AI69476.; Umesh Lalloo, MD, FRCP, and Rosie Mngqibisa, MB ChB-Durban Adult HIV CRS (Site 11201) CTU grant 5U01AI069426-03.; Nagalingeshwaran Kumarasamy, MBBS, PhD, and Jabin Sharma-YRGCARE Medical Centre (Site 11701) CTU grant number AI069432.; Virginia M. Kayoyo and Franklin D. Kilembe, MPh-Franklin Kilembe University of North Carolina Project, Kamuzu Central Hospital, Lilongwe (Site 12001) CTU grant number AI069518.; Mauleen Waison and Rachel Mahachi-Parirenyatwa CRS (Site 30313) CTU grant number BRS-ACURE-Q-08-00173-TOOI-OOO.; Cynthia Firnhaber, MD, Sharla Faesen, and Daphne S. Radebe, BAWits HIV Clinical Research Site (Helen Joseph Hosp) (Site 11101) CTU grant AI069463; BRS-ACURE-Q-07-00143 T006.; Thira Sirisanthana, MD, and Daralak Tavornprasit-Research Institute for Health Sciences-Chiang Mai University (Site 11501) CTU grant numbers AI069399 and AACTG.27.5199.06.; Maria Siliprandi, MD, and Renata Londero, MD-Hospital Nossa Senhora da Conceicao CRS (Site 12201) CTU grant number 5 U01 AI069401.; Anjali A. Joglekar, MBBS, and Srikanth Prasad Tripathy, MD, MBBS-NARI Pune CRS (Site 11601) CTU grant number 5U01AI069417-03.; Ben Kalonga and Henry Chamba-College of Medicine-Johns Hopkins Project (Site 30301) CTU grant number U01A1069518.; Carlos Mosquera, MD, and Rosa Infante, MD-INMENSA-Lince CRS (Site 11302) CTU grant numbers 5U01 AI069438-03 and BRS- ACURE-Q-07-00141-T001-001.; Jorge Sanchez, MD, MPH, and Juan Carlos Hurtado, MD-Asociacion Civil Impacta Salud y Educacion (Site 11301) CTU grant numbers AI069438 and BRS-ACURE-Q-08-00007-T-002.; Manisha V. Ghate, MBBS, DCH, and Madhura Nene, MBBS-NARI-NIV Clinic (Site 11603) CTU grant number 5U01AI069417-03.; Dr Raman Gnagakhedkar and Usha Katti, MBBS-Dr Kotnis Dispensary, NARI (Site 11602) CTU grant number 5U01AI069417-03.; Dr Scott R Evans and Hongyu Jiang were funded in part by the Statistical and Data Management Center of the Adult AIDS Clinical Trials Group grant 1 U01 068634. NR 26 TC 22 Z9 22 U1 2 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2012 VL 55 IS 6 BP 868 EP 876 DI 10.1093/cid/cis507 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 995LF UT WOS:000308008900020 PM 22661489 ER PT J AU Glasco, DM Sittaramane, V Bryant, W Fritzsch, B Sawant, A Paudyal, A Stewart, M Andre, P Vilhais-Neto, GC Yang, YZ Song, MR Murdoch, JN Chandrasekhar, A AF Glasco, Derrick M. Sittaramane, Vinoth Bryant, Whitney Fritzsch, Bernd Sawant, Anagha Paudyal, Anju Stewart, Michelle Andre, Philipp Vilhais-Neto, Goncalo Cadete Yang, Yingzi Song, Mi-Ryoung Murdoch, Jennifer N. Chandrasekhar, Anand TI The mouse Wnt/PCP protein Vangl2 is necessary for migration of facial branchiomotor neurons, and functions independently of Dishevelled SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Facial branchiomotor neuron migration; Planar Cell Polarity signaling; Van Gogh-like 2; Disheveled; Protein tyrosine kinase 7; Looptail ID PLANAR-CELL-POLARITY; NEURAL-TUBE CLOSURE; CONVERGENT EXTENSION MOVEMENTS; MOTOR-NEURONS; PCP PATHWAY; GASTRULATION MOVEMENTS; ZEBRAFISH HINDBRAIN; REGULATE MIGRATION; WNT PATHWAY; GENE AB During development, facial branchiomotor (FBM) neurons, which innervate muscles in the vertebrate head, migrate caudally and radially within the brainstem to form a motor nucleus at the pial surface. Several components of the Wnt/planar cell polarity (PCP) pathway, including the transmembrane protein Vangl2, regulate caudal migration of FBM neurons in zebrafish, but their roles in neuronal migration in mouse have not been investigated in detail. Therefore, we analyzed FBM neuron migration in mouse looptail (Lp) mutants, in which Vangl2 is inactivated. In Vangl2(Lp/+) and Vangl2 (LP/LP) embryos, FBM neurons failed to migrate caudally from rhombomere (r) 4 into r6. Although caudal migration was largely blocked, many FBM neurons underwent normal radial migration to the pial surface of the neural tube. In addition, hindbrain patterning and FBM progenitor specification were intact, and FBM neurons did not transfate into other non-migratory neuron types, indicating a specific effect on caudal migration. Since loss-of-function in some zebrafish Wnt/PCP genes does not affect caudal migration of FBM neurons, we tested whether this was also the case in mouse. Embryos null for Ptk7, a regulator of PCP signaling, had severe defects in caudal migration of FBM neurons. However, FBM neurons migrated normally in Dishevelled (Dvl) 1/2 double mutants, and in zebrafish embryos with disrupted Dvl signaling, suggesting that Dvl function is essentially dispensable for FBM neuron caudal migration. Consistent with this, loss of Dvl2 function in Vangl2(Lp/+) embryos did not exacerbate the Vangl2(Lp/+) neuronal migration phenotype. These data indicate that caudal migration of FBM neurons is regulated by multiple components of the Wnt/PCP pathway, but, importantly, may not require Dishevelled function. Interestingly, genetic-interaction experiments suggest that rostra! FBM neuron migration, which is normally suppressed, depends upon Dvl function. (C) 2012 Elsevier Inc. All rights reserved. C1 [Glasco, Derrick M.; Sittaramane, Vinoth; Bryant, Whitney; Sawant, Anagha; Chandrasekhar, Anand] Univ Missouri, Bond Life Sci Ctr, Div Biol Sci, Columbia, MO 65211 USA. [Fritzsch, Bernd] Univ Iowa, Dept Biol Sci, Iowa City, IA 52242 USA. [Paudyal, Anju; Stewart, Michelle; Murdoch, Jennifer N.] Med Res Council Harwell, Dev Genet Sect, Didcot OX11 0RD, Oxon, England. [Paudyal, Anju; Murdoch, Jennifer N.] Royal Holloway Univ London, Sch Biol Sci, Ctr Biomed Sci, Egham TW20 0EX, Surrey, England. [Andre, Philipp; Yang, Yingzi] NHGRI, Dev Genet Sect, NIH, Bethesda, MD 20892 USA. [Vilhais-Neto, Goncalo Cadete] Univ Strasbourg, INSERM, U964, IGBMC,UMR 7104, F-67400 Illkirch Graffenstaden, France. [Song, Mi-Ryoung] Gwangju Inst Sci & Technol, Sch Life Sci, Bioimaging & Cell Dynam Res Ctr, Gwangiu 500712, South Korea. RP Chandrasekhar, A (reprint author), Univ Missouri, Bond Life Sci Ctr, Div Biol Sci, Room 340D,1201 Rollins St, Columbia, MO 65211 USA. EM AnandC@missouri.edu OI Fritzsch, Bernd/0000-0002-4882-8398 FU NIH predoctoral fellowship [1F31NS063513]; Bioimaging Research Center at GIST; Medical Research Council; NIH grant [NS040449] FX We thank members of the Chandrasekhar lab for discussion and fish care. We thank Olivier Pourquie and Sam Pfaff for the looptail and SE1::gfp mice, respectively. We thank Jane Johnson, Oni Mapp, Victoria Prince, Michelle Studer, Fadel Tissir, and Paul Trainor for probes and expression constructs. This work was supported by an NIH predoctoral fellowship 1F31NS063513 (DMG), the Bioimaging Research Center at GIST (MRS), the Medical Research Council (JNM), and NIH grant NS040449 (AC). NR 73 TC 21 Z9 22 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 15 PY 2012 VL 369 IS 2 BP 211 EP 222 DI 10.1016/j.ydbio.2012.06.021 PG 12 WC Developmental Biology SC Developmental Biology GA 996TG UT WOS:000308117100006 PM 22771245 ER PT J AU Yang, F Wei, Q Adelstein, RS Wang, PJ AF Yang, Fang Wei, Qize Adelstein, Robert S. Wang, P. Jeremy TI Non-muscle myosin IIB is essential for cytokinesis during male meiotic cell divisions SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Spermatogenesis; Meiosis; Cytokinesis; NMIIB; MYH10; Mouse ID INTERCELLULAR BRIDGES; CITRON KINASE; MALE MEIOSIS; MICE; DROSOPHILA; FERTILITY; ABLATION; SPERMATOCYTES; CONTRACTILE; EXPRESSION AB Cytokinesis, the final stage of cell division, bisects the cytoplasm into two daughter cells. In mitotic cells, this process depends on the activity of non-muscle myosin II (NMII), a family of actin-binding motor-proteins that participate in the formation of the cleavage furrow. The relevance of NMII for meiotic cell division, however, is poorly understood. The NMII family consists of three members, NMIIA, NMIIB, and NMIIC, containing different myosin heavy chains (MYH9, MYH10, and MYH14, respectively). We find that a single non-muscle myosin II, NMIIB, is required for meiotic cytokinesis in male but not female mice. Specifically, NMIIB-deficient spermatocytes exhibit cytokinetic failure in meiosis 1, resulting in bi-nucleated secondary spermatocytes. Additionally, cytokinetic failure at meiosis II gives rise to bi-nucleated or even tetra-nucleated spermatids. These multi-nucleated spermatids fail to undergo normal differentiation, leading to male infertility. In spite of the presence of multiple nonmuscle myosin II isoforms, we demonstrate that a single member, NMIIB, plays an essential and non-redundant role in cytokinesis during meiotic cell divisions of the male germline. (C) 2012 Elsevier Inc. All rights reserved. C1 [Yang, Fang; Wang, P. Jeremy] Univ Penn, Sch Vet Med, Dept Anim Biol, Ctr Anim Transgenesis & Germ Cell Res, Philadelphia, PA 19104 USA. [Wei, Qize] Kansas State Univ, Dept Biochem, Manhattan, KS 66506 USA. [Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, PJ (reprint author), Univ Penn, Sch Vet Med, Dept Anim Biol, Ctr Anim Transgenesis & Germ Cell Res, Philadelphia, PA 19104 USA. EM pwang@vet.upenn.edu OI Adelstein, Robert/0000-0002-8683-2144 FU National Institutes of Health/National Institute of General Medical Sciences [GM089893] FX We thank Martin Matzuk for the anti-TEX14 antibody, Prabu Reddi for anti-ACRV1 antibodies, Xuefei Ma for technical assistance Mary Anne Conti for comments on the manuscript, and Sigrid Eckardt for editing the manuscript. This work was supported by National Institutes of Health/National Institute of General Medical Sciences (Grant no. GM089893). The E7 anti-beta-tubul n monoclonal antibody was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa. NR 37 TC 10 Z9 11 U1 0 U2 12 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 SEP 15 PY 2012 VL 369 IS 2 BP 356 EP 361 DI 10.1016/j.ydbio.2012.07.011 PG 6 WC Developmental Biology SC Developmental Biology GA 996TG UT WOS:000308117100019 PM 22820068 ER PT J AU Stultz, BG Park, SY Mortin, MA Kennison, JA Hursh, DA AF Stultz, Brian G. Park, Sung Yeon Mortin, Mark A. Kennison, James A. Hursh, Deborah A. TI Hox proteins coordinate peripodial decapentaplegic expression to direct adult head morphogenesis in Drosophila SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Decapentaplegic; Labial; Deformed; Homothorax; Peripodial epithelium; Adult head ID WING IMAGINAL DISC; VISCERAL MESODERM; DEVELOPMENTAL ANALYSIS; EYE DISC; TRANSCRIPTIONAL ACTIVATION; MIDGUT MORPHOGENESIS; SHAPE DIFFERENCES; GENE; DPP; EXTRADENTICLE AB The Drosophila BMP, decapentaplegic (dpp), controls morphogenesis of the ventral adult head through expression limited to the lateral peripodial epithelium of the eye-antennal disc by a 3.5 kb enhancer in the 5' end of the gene. We recovered a 15 bp deletion mutation within this enhancer that identified a homeotic (Hox) response element that is a direct target of labial and the homeotic cofactors homothorax and extradenticle. Expression of labial and homothorax are required for dpp expression in the peripodial epithelium, while the Hox gene Deformed represses labial in this location, thus limiting its expression and indirectly that of dpp to the lateral side of the disc. The expression of these homeodomain genes is in turn regulated by the dpp pathway, as dpp signalling is required for labial expression but represses homothorax. This Hox-BMP regulatory network is limited to the peripodial epithelium of the eye-antennal disc, yet is crucial to the morphogenesis of the head, which fate maps suggest arises primarily from the disc proper, not the peripodial epithelium. Thus Hox/BMP interactions in the peripodial epithelium of the eye-antennal disc contribute inductively to the shape of the external form of the adult Drosophila head. Published by Elsevier Inc. C1 [Hursh, Deborah A.] US FDA, Cellular & Tissue Therapy Branch, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Stultz, Brian G.; Park, Sung Yeon; Hursh, Deborah A.] US FDA, Div Cell & Gene Therapy, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Mortin, Mark A.; Kennison, James A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Hursh, DA (reprint author), US FDA, Cellular & Tissue Therapy Branch, Ctr Biol Evaluat & Res, HFM 740 Bldg,29B Rm,1E16,8800 Rockville Pike, Bethesda, MD 20892 USA. EM deborah.hursh@fda.hhs.gov FU Intramural Research Program of the National Institutes of Health, NICHD; Center for Biologics Evaluation and Research, FDA; Center for Biologics Evaluation and Research; U.S. Department of Energy; U.S. Food and Drug Administration FX We thank Kathleen McGinnis for expert technical assistance and Aditya Sen for assistance in the construction of dpps-hc-GFP. We thank Bill McGinnis, Kevin Moses, Henry Sun, Deborah Andrew, Jessica Treisman, Gerard Campbell, Adi Salzberg, and the Bloomington Stock Center for stocks, Richard Mann for plasmids and antibody, and the Developmental Studies Hybridoma Bank for antibodies. We express our gratitude to Thom Kaufman and his lab for generously acceding to multiple requests for stocks and antibodies during this work. Brent McCright, Tehyen Chu, Malcolm Moos, and two anonymous reviewers made valuable comments that greatly improved the manuscript. This research was supported in part by the Intramural Research Program of the National Institutes of Health, NICHD, and by the Center for Biologics Evaluation and Research, FDA. S.Y. Park was supported by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 76 TC 4 Z9 4 U1 0 U2 7 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 SEP 15 PY 2012 VL 369 IS 2 BP 362 EP 376 DI 10.1016/j.ydbio.2012.07.012 PG 15 WC Developmental Biology SC Developmental Biology GA 996TG UT WOS:000308117100020 PM 22824425 ER PT J AU Kuang, YH Patel, JP Sodani, K Wu, CP Liao, LQ Patel, A Tiwari, AK Dai, CL Chen, X Fu, LW Ambudkar, SV Korlipara, VL Chen, ZS AF Kuang, Ye-Hong Patel, Jay P. Sodani, Kamlesh Wu, Chung-Pu Liao, Li-Qiu Patel, Atish Tiwari, Amit K. Dai, Chun-Ling Chen, Xiang Fu, Li-Wu Ambudkar, Suresh V. Korlipara, Vijaya L. Chen, Zhe-Sheng TI OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE OSI-930; ABC transporters; ABCG2; Multidrug resistance ID ABC TRANSPORTER SUPERFAMILY; SUBFAMILY-B MEMBER-1; IN-VITRO; IMATINIB MESYLATE; DRUG-RESISTANCE; P-GLYCOPROTEIN; CANCER-CELLS; BINDING; INHIBITOR; KIT AB OSI-930, a dual c-Kit and KDR tyrosine kinase inhibitor, is reported to have undergone a Phase I dose escalation study in patients with advanced solid tumors. A series of fifteen pyridyl and phenyl analogues of OSI-930 were designed and synthesized. Extensive screening of these compounds led to the discovery that nitropyridyl and ortho-nitrophenyl analogues, VKJP1 and VKJP3, were effective in reversing ABC subfamily G member 2 (ABCG2) transporter-mediated multidrug resistance (MDR). VKJP1 and VKJP3 significantly sensitized ABCG2-expressing cells to established substrates of ABCG2 including mitoxantrone, SN-38, and doxorubicin in a concentration-dependent manner, but not to the non-ABCG2 substrate cisplatin. However, they were unable to reverse ABCB1- or ABCC1-mediated MDR indicating their selectivity for ABCG2. Western blotting analysis was performed to evaluate ABCG2 expression and it was found that neither VKJP1 nor VKJP3 significantly altered ABCG2 protein expression for up to 72 h. [H-3]-mitoxantrone accumulation study demonstrated that VKJP1 and VKJP3 increased the intracellular accumulation of [H-3]-mitoxantrone, a substrate of ABCG2. VKJP1 and VKJP3 also remarkably inhibited the transport of [H-3]-methotrexate by ABCG2 membrane vesicles. Importantly, both VKJP1 and VKJP3 were efficacious in stimulating the activity of ATPase of ABCG2 and inhibited the photoaffinity labeling of this transporter by its substrate [I-125]-iodoarylazidoprazosin. The results suggested that VKJP1 and VKJP3, specifically inhibit the function of ABCG2 through direct interaction with its substrate binding site(s). Thus VKJP1 and VKJP3 represent a new class of drugs for reducing MDR in ABCG2 over-expressing tumors. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kuang, Ye-Hong; Patel, Jay P.; Sodani, Kamlesh; Patel, Atish; Tiwari, Amit K.; Dai, Chun-Ling; Korlipara, Vijaya L.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, Queens, NY 11439 USA. [Kuang, Ye-Hong; Chen, Xiang] Cent S Univ, Dept Dermatol, Xiang Ya Hosp, Changsha 410008, Hunan, Peoples R China. [Wu, Chung-Pu; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liao, Li-Qiu] Cent S Univ, Dept Breast Surg, Xiang Ya Hosp, Changsha 410008, Hunan, Peoples R China. [Dai, Chun-Ling; Fu, Li-Wu] Sun Yat Sen Univ, State Key Lab Oncol S China, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. RP Chen, X (reprint author), 87 Xiang Ya Rd, Changsha 410008, Hunan, Peoples R China. EM chenxck@yahoo.com; korlipav@stjohns.edu; chenz@stjohns.edu RI Patel, Atish/J-4699-2014 OI TIWARI, AMIT/0000-0002-7427-7155; Patel, Atish/0000-0002-5549-9166 FU NIH [1R15CA143701]; St. John's University Seed [579-1110]; National Natural Science Foundation of China [81000690]; Millions of Strategic Project of Xiang Ya Hospital; Central South University FX We thank Drs. S.E. Bates and R.W. Robey (National Cancer Institute, NIH) for the ABCB1, ABCG2 and ABCC1 transfectant cell lines and FTC; Drs. Michael M. Gottesman (NCI, NIH, Bethesda, USA) for KB-3-1 cells; Shin-ichi Akiyama (Kagoshima University, Japan) for KB-C2 and KB-CV60 cell lines and PAK104P and Selleck Chemical for OSI-930 (http://www.selleckchem.com/). This work was supported by funds from NIH R15 No. 1R15CA143701 (Z.S. Chen), St. John's University Seed Grant No. 579-1110, (Z.S. Chen), the National Natural Science Foundation of China No. 81000690 (Y.H. Kuang), the Millions of Strategic Project of Xiang Ya Hospital (Y.H. Kuang), the Freedom Explore Program of Central South University (Y.H. Kuang). NR 37 TC 7 Z9 7 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 15 PY 2012 VL 84 IS 6 BP 766 EP 774 DI 10.1016/j.bcp.2012.06.019 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 994BZ UT WOS:000307907200004 PM 22750060 ER PT J AU Blair, KS Geraci, M Smith, BW Hollon, N DeVido, J Otero, M Blair, JR Pine, DS AF Blair, Karina S. Geraci, Marilla Smith, Bruce W. Hollon, Nick DeVido, Jeffrey Otero, Marcela Blair, James R. Pine, Daniel S. TI Reduced Dorsal Anterior Cingulate Cortical Activity During Emotional Regulation and Top-Down Attentional Control in Generalized Social Phobia, Generalized Anxiety Disorder, and Comorbid Generalized Social Phobia/Generalized Anxiety Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anterior cingulate cortex; emotion regulation; generalized anxiety; imaging; social anxiety; top-down attentional control ID COGNITIVE REGULATION; TREATMENT RESPONSE; PREFRONTAL CORTEX; AMYGDALA; ACTIVATION; FACES; MODULATION; FMRI; NEUROBIOLOGY; INDIVIDUALS AB Background: Generalized social phobia (GSP) and generalized anxiety disorder (GAD) are both associated with emotion dysregulation. Research implicates dorsal anterior cingulate cortex in both explicit emotion regulation (EER) and top-down attentional control (TAC). Although studies have examined these processes in GSP or GAD, no work compares findings across the two disorders or examines functioning in cases comorbid for both disorders (GSP/GAD). Here we compare the neural correlates of EER and TAC in GSP, GAD, and GSP/GAD. Methods: Medication-free adults with GSP (EER n = 19; TAC n = 18), GAD (EER n = 17; TAC n = 17), GSP/GAD (EER n = 17; TAC n = 15), and no psychopathology (EER n = 18; TAC n = 18) participated. During EER, individuals alternatively viewed and upregulated and downregulated responses to emotional pictures. During TAC, they performed an emotional Stroop task. Results: For both tasks, significant group X condition interactions emerged in dorsal anterior cingulate cortex and parietal cortices. Healthy adults showed significantly increased recruitment during emotion regulation, relative to emotion-picture viewing. GAD, GSP, and GSP/GAD subjects showed no such increases, with all groups differing from healthy adults but not from each other. Evidence of emotion-related disorder-specificity emerged in medial prefrontal cortex and amygdala. This disorder-specific responding varied as a function of emotion content but not emotion-regulatory demands. Conclusions: GSP and GAD both involve reduced capacity for engaging emotion-regulation brain networks, whether explicitly or via TAC. A reduced ability to recruit regions implicated in top-down attention might represent a general risk factor for anxiety disorders. C1 [Blair, Karina S.; Geraci, Marilla; Hollon, Nick; DeVido, Jeffrey; Otero, Marcela; Blair, James R.; Pine, Daniel S.] NIMH, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Smith, Bruce W.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. RP Blair, JR (reprint author), NIMH, NIH, US Dept HHS, 15K North Dr,Rm 115A,MSC 2670, Bethesda, MD 20892 USA. EM peschark@mail.nih.gov FU Intramural Research Program of the 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. NR 49 TC 43 Z9 44 U1 16 U2 59 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 SEP 15 PY 2012 VL 72 IS 6 BP 476 EP 482 DI 10.1016/j.biopsych.2012.04.013 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 996IC UT WOS:000308077100008 PM 22592057 ER PT J AU Xie, YL Su, N Jin, M Qi, HB Yang, JB Li, C Du, XL Luo, FT Chen, B Shen, Y Huang, HY Xian, CJ Deng, CX Chen, L AF Xie, Yangli Su, Nan Jin, Min Qi, Huabing Yang, Junbao Li, Can Du, Xiaolan Luo, Fengtao Chen, Bo Shen, Yue Huang, Haiyang Xian, Cory J. Deng, Chuxia Chen, Lin TI Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia SO HUMAN MOLECULAR GENETICS LA English DT Article ID GROWTH-FACTOR RECEPTOR-3; BONE-GROWTH; CONSTITUTIVE ACTIVATION; NATRIURETIC PEPTIDE; PLATE CHONDROCYTES; PTH/PTHRP RECEPTOR; MAPK PATHWAY; ATDC5 CELLS; FGFR3; MUTATION AB Achondroplasia (ACH) and thanatophoric dysplasia (TD) are caused by gain-of-function mutations of fibroblast growth factor receptor 3 (FGFR3) and they are the most common forms of dwarfism and lethal dwarfism, respectively. Currently, there are few effective treatments for ACH. For the neonatal lethality of TD patients, no practical effective therapies are available. We here showed that systemic intermittent PTH (1-34) injection can rescue the lethal phenotype of TD type II (TDII) mice and significantly alleviate the retarded skeleton development of ACH mice. PTH-treated ACH mice had longer naso-anal length than ACH control mice, and the bone lengths of humeri and tibiae were rescued to be comparable with those of wild-type control mice. Our study also found that the premature fusion of cranial synchondroses in ACH mice was partially corrected after the PTH (1-34) treatment, suggesting that the PTH treatment may rescue the progressive narrowing of neurocentral synchondroses that cannot be readily corrected by surgery. In addition, we found that the PTH treatment can improve the osteopenia and bone structure of ACH mice. The increased expression of PTHrP and down-regulated FGFR3 level may be responsible for the positive effects of PTH on bone phenotype of ACH and TDII mice. C1 [Xie, Yangli; Su, Nan; Jin, Min; Qi, Huabing; Yang, Junbao; Li, Can; Du, Xiaolan; Luo, Fengtao; Chen, Bo; Shen, Yue; Huang, Haiyang; Chen, Lin] Third Mil Med Univ, Ctr Bone Metab & Repair, State Key Lab Trauma Burns & Combined Injury, Daping Hosp,Inst Surg Res, Chongqing 400042, Peoples R China. [Xian, Cory J.] Univ S Australia, Sch Pharm & Med Sci, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia. [Deng, Chuxia] NIDDKD, Genet Dev & Dis Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Chen, L (reprint author), Third Mil Med Univ, Ctr Bone Metab & Repair, State Key Lab Trauma Burns & Combined Injury, Daping Hosp,Inst Surg Res, Chongqing 400042, Peoples R China. EM linchen70@tmmu.edu.cn RI Xian, Cory/D-2646-2009; deng, chuxia/N-6713-2016 OI Xian, Cory/0000-0002-8467-2845; FU Special Funds for Major State Basic Research Program of China (973 program) [2012CB518106]; National Natural Science Foundation of China [81030036, 30530410, 30901527, 30971607] FX The work was supported by the Special Funds for Major State Basic Research Program of China (973 program) (grant number 2012CB518106), and grants from the National Natural Science Foundation of China (grant numbers 81030036, 30530410, 30901527 and 30971607). NR 67 TC 18 Z9 22 U1 0 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 15 PY 2012 VL 21 IS 18 BP 3941 EP 3955 DI 10.1093/hmg/dds181 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 998IJ UT WOS:000308230800001 PM 22634226 ER PT J AU Biswas, K Das, R Eggington, JM Qiao, HY North, SL Stauffer, S Burkett, SS Martin, BK Southon, E Sizemore, SC Pruss, D Bowles, KR Roa, BB Hunter, N Tessarollo, L Wenstrup, RJ Byrd, RA Sharan, SK AF Biswas, Kajal Das, Ranabir Eggington, Julie M. Qiao, Huanyu North, Susan L. Stauffer, Stacey Burkett, Sandra S. Martin, Betty K. Southon, Eileen Sizemore, Scott C. Pruss, Dmitry Bowles, Karla R. Roa, Benjamin B. Hunter, Neil Tessarollo, Lino Wenstrup, Richard J. Byrd, R. Andrew Sharan, Shyam K. TI Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay SO HUMAN MOLECULAR GENETICS LA English DT Article ID EXONIC SPLICING ENHANCERS; UNKNOWN CLINICAL-SIGNIFICANCE; BREAST-CANCER FAMILIES; SEQUENCE VARIANTS; UNCERTAIN SIGNIFICANCE; HOMOLOGOUS RECOMBINATION; UNCLASSIFIED VARIANTS; MUTATION CARRIERS; CLASSIFICATION; GENES AB Single-nucleotide substitutions and small in-frame insertions or deletions identified in human breast cancer susceptibility genes BRCA1 and BRCA2 are frequently classified as variants of unknown clinical significance (VUS) due to the availability of very limited information about their functional consequences. Such variants can most reliably be classified as pathogenic or non-pathogenic based on the data of their co-segregation with breast cancer in affected families and/or their co-occurrence with a pathogenic mutation. Biological assays that examine the effect of variants on protein function can provide important information that can be used in conjunction with available familial data to determine the pathogenicity of VUS. In this report, we have used a previously described mouse embryonic stem (mES) cell-based functional assay to characterize eight BRCA2 VUS that affect highly conserved amino acid residues and map to the N-terminal PALB2-binding or the C-terminal DNA-binding domains. For several of these variants, very limited co-segregation information is available, making it difficult to determine their pathogenicity. Based on their ability to rescue the lethality of Brca2-deficient mES cells and their effect on sensitivity to DNA-damaging agents, homologous recombination and genomic integrity, we have classified these variants as pathogenic or non-pathogenic. In addition, we have used homology-based modeling as a predictive tool to assess the effect of some of these variants on the structural integrity of the C-terminal DNA-binding domain and also generated a knock-in mouse model to analyze the physiological significance of a residue reported to be essential for the interaction of BRCA2 with meiosis-specific recombinase, DMC1. C1 [Sharan, Shyam K.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Das, Ranabir; Byrd, R. Andrew] NCI, Struct Biophys Lab, Frederick, MD 21702 USA. [Martin, Betty K.] NCI, SAIC Frederick, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Eggington, Julie M.; Sizemore, Scott C.; Pruss, Dmitry; Bowles, Karla R.; Roa, Benjamin B.; Wenstrup, Richard J.] Myriad Genetic Labs Inc, Salt Lake City, UT USA. [Qiao, Huanyu; Hunter, Neil] Univ Calif Davis, Dept Microbiol, Davis, CA 95616 USA. [Qiao, Huanyu; Hunter, Neil] Univ Calif Davis, Howard Hughes Med Inst, Davis, CA 95616 USA. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick Natl Lab Canc Res, Bldg 560,Room 32-31C,1050 Boyles St, Frederick, MD 21702 USA. EM sharans@mail.nih.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU Center for Cancer Research, National Cancer Institute, US National Institutes of Health; US National Cancer Institute, National Institutes of Health FX We thank Drs Jairaj Acharya, Suhwan Chang, Rajanikant Chittela, Ira Daar and Eswary Thirthagiri for helpful discussions and critical review of the manuscript. We also thank Jiro Wada (SAIC-Frederick, Inc., Scientific Publications, Graphics & Media Department) for illustrations. We thank Dr Maria Jasin for the DR-GFP plasmid and I-SceI expression vector. The research was sponsored by the Center for Cancer Research, National Cancer Institute, US National Institutes of Health.; Research supported by intramural funds from US National Cancer Institute, National Institutes of Health. NR 55 TC 14 Z9 14 U1 1 U2 5 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 SEP 15 PY 2012 VL 21 IS 18 BP 3993 EP 4006 DI 10.1093/hmg/dds222 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 998IJ UT WOS:000308230800005 PM 22678057 ER PT J AU Trabzuni, D Wray, S Vandrovcova, J Ramasamy, A Walker, R Smith, C Luk, C Gibbs, JR Dillman, A Hernandez, DG Arepalli, S Singleton, AB Cookson, MR Pittman, AM de Silva, R Weale, ME Hardy, J Ryten, M AF Trabzuni, Daniah Wray, Selina Vandrovcova, Jana Ramasamy, Adaikalavan Walker, Robert Smith, Colin Luk, Connie Gibbs, J. Raphael Dillman, Allissa Hernandez, Dena G. Arepalli, Sampath Singleton, Andrew B. Cookson, Mark R. Pittman, Alan M. de Silva, Rohan Weale, Michael E. Hardy, John Ryten, Mina TI MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROGRESSIVE-SUPRANUCLEAR-PALSY; ALZHEIMERS-DISEASE; CORTICOBASAL DEGENERATION; PARKINSONS-DISEASE; TAU HAPLOTYPE; TYROSINE KINASES; MESSENGER-RNA; PROTEIN-TAU; ISOFORMS; ASSOCIATION AB The MAPT (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy, corticobasal degeneration, Parksinsons disease and possibly Alzheimers disease, but also due its genetic evolution and complex alternative splicing features which are, to some extent, linked and so all the more intriguing. Therefore, obtaining robust information regarding the expression, splicing and genetic regulation of this gene within the human brain is of immense importance. In this study, we used 2011 brain samples originating from 439 individuals to provide the most reliable and coherent information on the regional expression, splicing and regulation of MAPT available to date. We found significant regional variation in mRNA expression and splicing of MAPT within the human brain. Furthermore, at the gene level, the regional distribution of mRNA expression and total tau protein expression levels were largely in agreement, appearing to be highly correlated. Finally and most importantly, we show that while the reported H1/H2 association with gene level expression is likely to be due to a technical artefact, this polymorphism is associated with the expression of exon 3-containing isoforms in human brain. These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene. C1 [Trabzuni, Daniah; Wray, Selina; Vandrovcova, Jana; Ramasamy, Adaikalavan; Luk, Connie; Gibbs, J. Raphael; Hernandez, Dena G.; Pittman, Alan M.; de Silva, Rohan; Hardy, John; Ryten, Mina] UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England. [Trabzuni, Daniah; Wray, Selina; Vandrovcova, Jana; Ramasamy, Adaikalavan; Luk, Connie; Gibbs, J. Raphael; Hernandez, Dena G.; Pittman, Alan M.; de Silva, Rohan; Hardy, John; Ryten, Mina] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Ramasamy, Adaikalavan; Weale, Michael E.] Kings Coll London, Dept Med & Mol Genet, Guys Hosp, London SE1 9RT, England. [Walker, Robert; Smith, Colin] Univ Edinburgh, MRC Sudden Death Brain Bank Project, Dept Neuropathol, Edinburgh EH8 9AG, Midlothian, Scotland. [Gibbs, J. Raphael; Dillman, Allissa; Hernandez, Dena G.; Arepalli, Sampath; Singleton, Andrew B.; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Ryten, M (reprint author), UCL Inst Neurol, Reta Lila Weston Inst, Queen Sq, London WC1N 3BG, England. EM mina.ryten@ucl.ac.uk RI Hardy, John/C-2451-2009; Wray, Selina/C-3682-2009; Weale, Michael/F-2587-2010; Ramasamy, Adaikalavan/G-2632-2010; Pittman, Alan/D-6231-2012; Singleton, Andrew/C-3010-2009; OI Wray, Selina/0000-0003-3062-7050; Weale, Michael/0000-0003-4593-1186; Ramasamy, Adaikalavan/0000-0002-7598-2892; Walker, Robert/0000-0001-7383-7846 FU MRC through the MRC Sudden Death Brain Bank; Cure PSP; Irene; Abe Pollin Fund for CBD Research; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; Alzheimer's Research UK; [G0901254]; [G0802462]; [G0501560] FX This work was supported by the MRC through the MRC Sudden Death Brain Bank (C. S.) and by a Project Grant (G0901254 to J.H. and M. W.), Training Fellowship (G0802462 to M. R.) and a Research Grant (G0501560 to R.d.S.). This project was further supported by the Cure PSP, Irene and Abe Pollin Fund for CBD Research (R.d.S. and J.H.). D. T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. S. W. is funded by an Alzheimer's Research UK research fellowship. NR 48 TC 46 Z9 47 U1 0 U2 12 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 SEP 15 PY 2012 VL 21 IS 18 BP 4094 EP 4103 DI 10.1093/hmg/dds238 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 998IJ UT WOS:000308230800014 PM 22723018 ER PT J AU Greenberg, DE Shoffner, AR Marshall-Batty, KR Arora, K Zhao, M Martin, R Ding, L Hammer, CH Shaw, PA Kuhns, DB Malech, HL Gallin, JI Zarember, KA Holland, SM AF Greenberg, David E. Shoffner, Adam R. Marshall-Batty, Kimberly R. Arora, Kriti Zhao, Ming Martin, Raynaldo Ding, Li Hammer, Carl H. Shaw, Pamela A. Kuhns, Douglas B. Malech, Harry L. Gallin, John I. Zarember, Kol A. Holland, Steven M. TI Serologic Reactivity to the Emerging Pathogen Granulibacter bethesdensis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; ACETIC-ACID BACTERIUM; METHYLOBACTERIUM-EXTORQUENS; MYCOBACTERIUM-TUBERCULOSIS; INDONESIAN SOURCES; HOST-DEFENSE; INFECTION; PATIENT; IDENTIFICATION; GLUCONOBACTER AB Background. Granulibacter bethesdensis is a recently described member of the Acetobacteraceae family that has been isolated from patients with chronic granulomatous disease (CGD). Its pathogenesis, environmental reservoir( s), and incidence of infection among CGD patients and the general population are unknown. Methods. Detected antigens were identified by mass spectroscopy after 2-dimensional electrophoresis and immunoaffinity chromatography. The prevalence of Granulibacter immunoreactivity was assessed through immunoblotting and enzyme-linked immunosorbent assay (ELISA). Results. Methanol dehydrogenase (MDH) and formaldehyde-activating enzyme were recognized during analysis of sera from infected patients. Unique patterns of immunoreactive bands were identified in Granulibacter extracts, compared with extracts of other Acetobacteraceae species. By use of criteria based on these specific bands, specimens from 79 of 175 CGD patients (45.1%) and 23 of 93 healthy donors (24.7%) reacted to all 11 bands. An ELISA that used native MDH to capture and detect immunoglobulin G was developed and revealed high-titer MDH seroreactivity in culture-confirmed cases and 5 additional CGD patients. Testing of samples collected prior to culture-confirmed infection demonstrated instances of recent seroconversion, as well as sustained seropositivity. Infection of CGD mice with G. bethesdensis confirmed acquisition of high-titer antibody-recognizing MDH. Conclusions. These serologic tests suggest that Granulibacter immunoreactivity is more common among CGD patients and, perhaps, among healthy donors than was previously suspected. This finding raises the possibility that clinical presentations of Granulibacter infection may be underappreciated. C1 [Greenberg, David E.; Shoffner, Adam R.; Marshall-Batty, Kimberly R.; Arora, Kriti; Ding, Li; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Malech, Harry L.; Gallin, John I.; Zarember, Kol A.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Shaw, Pamela A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Zhao, Ming; Martin, Raynaldo; Hammer, Carl H.] NIAID, Res Technol Branch, Rockville, MD USA. [Kuhns, Douglas B.] SAIC Frederick, Clin Serv Program, Frederick, MD USA. RP Greenberg, DE (reprint author), Univ Texas SW Med Ctr Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM david.greenberg@utsouthwestern.edu OI Malech, Harry/0000-0001-5874-5775 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 30 TC 4 Z9 4 U1 0 U2 2 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 SEP 15 PY 2012 VL 206 IS 6 BP 943 EP 951 DI 10.1093/infdis/jis431 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 998JI UT WOS:000308233500020 PM 22782953 ER PT J AU Wehr, NB Levine, RL AF Wehr, Nancy B. Levine, Rodney L. TI Quantitation of protein carbonylation by dot blot (vol 423, pg 241, 2012) SO ANALYTICAL BIOCHEMISTRY LA English DT Correction C1 [Wehr, Nancy B.; Levine, Rodney L.] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, Bldg 3, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 NR 1 TC 1 Z9 1 U1 1 U2 13 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 SEP 15 PY 2012 VL 428 IS 2 BP 107 EP 107 DI 10.1016/j.ab.2012.06.026 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 991FL UT WOS:000307686800004 ER PT J AU Pereira, MA Warner, BM Knobloch, TJ Weghorst, CM Lubet, RA Steele, VE Casto, BC AF Pereira, Michael A. Warner, Blake M. Knobloch, Thomas J. Weghorst, Christopher M. Lubet, Ronald A. Steele, Vernon E. Casto, Bruce C. TI Chemoprevention of mouse lung and colon tumors by suberoylanilide hydroxamic acid and atorvastatin SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE co-chemoprevention; mouse lung tumors; combinations; suberoylanilide hydroxamic acid; atorvastatin ID MESSENGER-RNA EXPRESSION; FEMALE A/J MICE; DNA METHYLATION; DIETARY MYOINOSITOL; COMBINATION; CANCER; BUDESONIDE; MODULATION; TUMORIGENESIS; PREVENTION AB Atorvastatin and suberoylanilide hydroxamic acid (SAHA) were evaluated for chemoprevention of mouse lung tumors. In Experiment 1, lung tumors were induced by vinyl carbamate in strain A/J mice followed by 500 mg/kg SAHA, 60 or 180 mg/kg atorvastatin, and combinations containing SAHA and atorvastatin administered in their diet. SAHA and both combinations, but not atorvastatin, decreased the multiplicity of lung tumors, including large adenomas and adenocarcinomas with the combinations demonstrating the greatest efficacy. In Experiment 2, lung tumors were induced by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol in strain A/J mice followed by 180 mg/kg atorvastatin, 500 mg/kg SAHA, or both drugs administered in the diet. SAHA and the combination of both drugs, but not atorvastatin alone, decreased the multiplicity of lung tumors and large tumors, with the combination demonstrating greater efficacy. In Experiment 3, lung tumors were induced by 1,2-dimethylhydrazine in Swiss-Webster mice followed by 160 mg/kg atorvastatin, 400 mg/kg SAHA, or a combination of both drugs administered in the diet. SAHA and the combination, but not atorvastatin, decreased the multiplicity of lung tumors with the combination demonstrating greater efficacy. The multiplicity of colon tumors was decreased by SAHA, atorvastatin, and the combination, without any significant difference in their efficacy. mRNA expression analysis of lung tumor bearing mice suggested that the enhanced chemopreventive activity of the combination is related to atorvastatin modulation of DNA repair, SAHA modulation of angiogenesis, and both drugs modulating invasion and metastasis pathways. Atorvastatin demonstrated chemoprevention activity as indicated by the enhancement of the efficacy of SAHA to prevent mouse lung tumors. C1 [Pereira, Michael A.; Warner, Blake M.; Knobloch, Thomas J.; Weghorst, Christopher M.; Casto, Bruce C.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Pereira, Michael A.; Knobloch, Thomas J.; Weghorst, Christopher M.; Casto, Bruce C.] Ohio State Univ, Div Med Oncol, Coll Med, Columbus, OH 43210 USA. [Warner, Blake M.; Knobloch, Thomas J.; Weghorst, Christopher M.; Casto, Bruce C.] Ohio State Univ, Div Environm Hlth Sci, Coll Publ Hlth, Columbus, OH 43210 USA. [Lubet, Ronald A.; Steele, Vernon E.] NCI, Canc Prevent Div, Rockville, MD USA. RP Pereira, MA (reprint author), Ohio State Univ, Ctr Comprehens Canc, 333 W 10th Ave, Columbus, OH 43210 USA. EM michael.pereira@osumc.edu OI Warner, Blake/0000-0002-4961-018X FU NCL [5R21CA135335, N01-CN-35116] FX Grant sponsor: NCL; Grant numbers: 5R21CA135335, N01-CN-35116 NR 33 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2012 VL 131 IS 6 BP 1277 EP 1286 DI 10.1002/ijc.27395 PG 10 WC Oncology SC Oncology GA 978JD UT WOS:000306735700027 PM 22161747 ER PT J AU O'Doherty, MG Freedman, ND Hollenbeck, AR Schatzkin, A Murray, LJ Cantwell, MM Abnet, CC AF O'Doherty, Mark G. Freedman, Neal D. Hollenbeck, Albert R. Schatzkin, Arthur Murray, Liam J. Cantwell, Marie M. Abnet, Christian C. TI Association of dietary fat intakes with risk of esophageal and gastric cancer in the NIH-AARP diet and health study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cohort; dietary fat; esophageal neoplasms; stomach neoplasms; prospective ID GASTROESOPHAGEAL-REFLUX SYMPTOMS; FOOD-FREQUENCY QUESTIONNAIRE; RETIRED-PERSONS DIET; ESOPHAGOGASTRIC JUNCTION; AMERICAN-ASSOCIATION; NATIONAL-INSTITUTES; RISING INCIDENCE; INCIDENCE RATES; HISTOLOGIC TYPE; ACID EXPOSURE AB The aim of our study was to investigate whether intakes of total fat and fat subtypes were associated with esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastric cardia or gastric noncardia adenocarcinoma. From 19951996, dietary intake data was reported by 494,978 participants of the NIH-AARP cohort. The 630 EAC, 215 ESCC, 454 gastric cardia and 501 gastric noncardia adenocarcinomas accrued to the cohort. Cox proportional hazards regression was used to examine the association between the dietary fat intakes, whilst adjusting for potential confounders. Although apparent associations were observed in energy-adjusted models, multivariate adjustment attenuated results to null [e.g., EAC energy adjusted hazard ratio (HR) and 95% confidence interval (95% CI) 1.66 (1.272.18) p for trend <0.01; EAC multivariate adjusted HR (95% CI) 1.17 (0.841.64) p for trend = 0.58]. Similar patterns were also observed for fat subtypes [e.g., EAC saturated fat, energy adjusted HR (95% CI) 1.79 (1.372.33) p for trend <0.01; EAC saturated fat, multivariate adjusted HR (95% CI) 1.27 (0.911.78) p for trend = 0.28]. However, in multivariate models an inverse association for polyunsaturated fat (continuous) was seen for EAC in subjects with a body mass index (BMI) in the normal range (18.5<25 kg/m2) [HR (95% CI) 0.76 (0.630.92)], that was not present in overweight subjects [HR (95% CI) 1.04 (0.961.14)], or in unstratified analysis [HR (95% CI) 0.97 (0.901.05)]. p for interaction = 0.02. Overall, we found null associations between the dietary fat intakes with esophageal or gastric cancer risk; although a protective effect of polyunsaturated fat intake was seen for EAC in subjects with a normal BMI. C1 [O'Doherty, Mark G.] Queens Univ Belfast, Inst Clin Sci, Canc Epidemiol Hlth Serv Res Grp, Ctr Publ Hlth, Belfast BT12 6BA, Antrim, North Ireland. [O'Doherty, Mark G.; Freedman, Neal D.; Schatzkin, Arthur; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP O'Doherty, MG (reprint author), Queens Univ Belfast, Inst Clin Sci, Canc Epidemiol Hlth Serv Res Grp, Ctr Publ Hlth, Block B,Grosvenor Rd, Belfast BT12 6BA, Antrim, North Ireland. EM m.odoherty@qub.ac.uk RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU All-Ireland National Cancer Institute Cancer Consortium Joint Research Project in Cancer; Health and Social Care Research & Development Office (Belfast, Northern Ireland); Intramural Research Program of the NIH, National Cancer Institute (Bethesda, MD, USA) FX This research was supported (in part) by the all-Ireland National Cancer Institute Cancer Consortium Joint Research Project in Cancer, supported by the Health and Social Care Research & Development Office (Belfast, Northern Ireland) and the Intramural Research Program of the NIH, National Cancer Institute (Bethesda, MD, USA). No conflicts of interest to declare. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. NR 49 TC 5 Z9 6 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2012 VL 131 IS 6 BP 1376 EP 1387 DI 10.1002/ijc.27366 PG 12 WC Oncology SC Oncology GA 978JD UT WOS:000306735700038 PM 22116732 ER PT J AU Wright, ME Bowen, P Virtamo, J Albanes, D Gann, PH AF Wright, Margaret E. Bowen, Phyllis Virtamo, Jarmo Albanes, Demetrius Gann, Peter H. TI Estimated phytanic acid intake and prostate cancer risk: A prospective cohort study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cohort study; diet; phytanic acid; prostate caner ID PLASMA FATTY-ACIDS; DAIRY-PRODUCTS; DIETARY-FAT; LIQUID-CHROMATOGRAPHY; PRISTANIC ACID; REFSUM-DISEASE; BETA-CAROTENE; CALCIUM; CONSUMPTION; NUTRITION AB Phytanic acid is a saturated fatty acid found predominantly in red meat and dairy products and may contribute to increases in prostate cancer risk that are observed with higher intakes of these foods. We constructed a novel summary measure of phytanic acid intake and prospectively examined its association with prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Studya cohort of Finnish male smokers aged 5069 years. Diet was assessed at baseline in 27,111 participants using a validated 276-item dietary questionnaire. Since phytanic acid is not currently included in food composition tables, we used the published phytanic acid content of 151 major food items to estimate total daily intake. During up to 21 years of follow-up, a total of 1,929 incident prostate cancer cases (including 438 advanced cases) were identified. Higher phytanic acid intake, though unrelated to the risk of localized disease [relative risks (RR) and 95% confidence intervals (CI) for increasing quartiles of intake = 1.00 (ref), 0.83 (0.681.01), 0.76 (0.620.94) and 0.91 (0.741.13); p trend = 0.23], was associated with increased risks of advanced prostate cancer [RR and 95% CI = 1.00 (ref), 1.43 (1.091.89), 1.31 (0.991.75) and 1.38 (1.021.89); p trend = 0.06]. This association appeared to be driven predominantly by phytanic acid obtained from dairy products (particularly butter). Our study indicates that phytanic acid may contribute to previously observed associations between high-fat animal foods (particularly dairy products) and prostate cancer risk, although some caution is warranted as it may be acting as a surrogate marker of dairy fat. C1 [Wright, Margaret E.; Gann, Peter H.] Univ Illinois, Dept Pathol, Coll Med, Chicago, IL 60612 USA. [Bowen, Phyllis] Univ Illinois, Dept Kinesiol & Nutr, Chicago, IL 60612 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Wright, ME (reprint author), Univ Illinois, Dept Pathol, Coll Med, 840 S Wood St,CSN 130, Chicago, IL 60612 USA. EM mewright@uic.edu RI Albanes, Demetrius/B-9749-2015; OI Bowen, Phyllis/0000-0002-2950-3694 FU American Cancer Society [MSRG-08-109-01-CCE] FX Grant sponsor: American Cancer Society; Grant number: MSRG-08-109-01-CCE NR 42 TC 12 Z9 12 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2012 VL 131 IS 6 BP 1396 EP 1406 DI 10.1002/ijc.27372 PG 11 WC Oncology SC Oncology GA 978JD UT WOS:000306735700040 PM 22120496 ER PT J AU D'Souza, G Burk, RD Zhong, Y Minkoff, H Massad, LS Xue, XN Watts, DH Anastos, K Palefsky, JM Levine, AM Colie, C Castle, PE Strickler, HD AF D'Souza, Gypsyamber Burk, Robert D. Zhong, Ye Minkoff, Howard Massad, L. Stewart Xue, Xiaonan Watts, D. Heather Anastos, Kathryn Palefsky, Joel M. Levine, Alexandra M. Colie, Christine Castle, Philip E. Strickler, Howard D. TI Cervicovaginal human papillomavirus (HPV)-infection before and after hysterectomy: evidence of different tissue tropism for oncogenic and nononcogenic HPV types in a cohort of HIV-positive and HIV-negative women SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE vaginal; HPV; hysterectomy; viral tropism; HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; VAGINAL HUMAN-PAPILLOMAVIRUS; INTERAGENCY HIV; NATURAL-HISTORY; RISK; CANCERS; PEOPLE; DNA AB Human papillomavirus (HPV) is detected in nearly all cervical cancers and approximately half of vaginal cancers. However, vaginal cancer is an order of magnitude less common than cervical cancer, not only in the general population but also among women with HIV/AIDS. It is interesting therefore that recent studies found that HPV was common in both normal vaginal and cervical tissue, with higher prevalence of nononcogenic HPV types in the vagina. In our investigation, we prospectively examined HPV infection in 86 HIV-positive and 17 HIV-negative women who underwent hysterectomy during follow-up in a longitudinal cohort. Cervicovaginal lavage specimens were obtained semi-annually and tested for HPV DNA by polymerase chain reaction. To address possible selection biases associated with having a hysterectomy, subjects acted as their own comparison groupbefore versus after hysterectomy. The average HPV prevalence was higher in HIV-positive than HIV-negative women both before (59% vs. 12%; p < 0.001) and after hysterectomy (56% vs. 6%; p < 0.001). Multivariate random effects models (within-individual comparisons) demonstrated significantly lower HPV prevalence [odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.590.85) after hysterectomy. The association of HPV prevalence with hysterectomy was similar among HIV-positive and HIV-negative women. However, hysterectomy had greater effects on oncogenic (OR = 0.48; 95% CI = 0.350.66) than nononcogenic HPV types (OR = 0.89; 95% CI = 0.711.11; Pinteraction = 0.002). Overall, we observed greater reductions in oncogenic than nononcogenic HPV prevalence after hysterectomy. If correct, these data could suggest that oncogenic HPV have greater tropism for cervical compared to vaginal epithelium, consistent with the lower incidence of vaginal than cervical cancer. C1 [D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Burk, Robert D.; Strickler, Howard D.] Albert Einstein Coll Med, Dept Pediat Microbiol & Immunol & Obstet Gynecol, Bronx, NY 10467 USA. [Burk, Robert D.; Zhong, Ye; Xue, Xiaonan] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Minkoff, Howard; Strickler, Howard D.] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Minkoff, Howard; Strickler, Howard D.] SUNY Downstate, Brooklyn, NY USA. [Massad, L. Stewart] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. [Anastos, Kathryn] Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA. [Palefsky, Joel M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Levine, Alexandra M.] Univ So Calif, Sch Med, Dept Internal Med, Los Angeles, CA 90033 USA. [Colie, Christine] Georgetown Univ, Sch Med, Dept Med, Washington, DC USA. [Castle, Philip E.] Amer Soc Clin Pathologists, Washington, DC USA. RP D'Souza, G (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St E6132B, Baltimore, MD 21205 USA. EM gdsouza@jhsph.edu FU National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute, the National Institute on Drug Abuse, the National Institute on Deafness and Other Communication Disorders, National Center for Research Resources [UL1 RR024131]; HPV DNA testing and statistical analysis [R01-CA085178] FX Grant sponsor: National Institute of Allergy and Infectious Diseases; Grant numbers: UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590; Grant sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Grant number: UO1-HD-32632; Grant sponsors: National Cancer Institute, the National Institute on Drug Abuse, the National Institute on Deafness and Other Communication Disorders, National Center for Research Resources; Grant number: UL1 RR024131 HPV DNA testing and statistical analysis in this study was funded through R01-CA085178 (to H.S.). Other data in this article were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). NR 23 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2012 VL 131 IS 6 BP 1472 EP 1478 DI 10.1002/ijc.27363 PG 7 WC Oncology SC Oncology GA 978JD UT WOS:000306735700048 PM 22120980 ER PT J AU Lin, SW Wheeler, DC Park, Y Cahoon, EK Hollenbeck, AR Freedman, DM Abnet, CC AF Lin, Shih-Wen Wheeler, David C. Park, Yikyung Cahoon, Elizabeth K. Hollenbeck, Albert R. Freedman, D. Michal Abnet, Christian C. TI Prospective study of ultraviolet radiation exposure and risk of cancer in the United States SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ultraviolet radiation; cancer; vitamin D; prospective ID CIRCULATING 25-HYDROXYVITAMIN D; NON-HODGKIN-LYMPHOMA; DIETARY VITAMIN-D; COLORECTAL-CANCER; BREAST-CANCER; SUN EXPOSURE; SOLAR-RADIATION; HUMAN-SKIN; SUNLIGHT; UV AB Ecologic studies have reported that solar ultraviolet radiation (UVR) exposure is associated with cancer; however, little evidence is available from prospective studies. We aimed to assess the association between an objective measure of ambient UVR exposure and risk of total and site-specific cancer in a large, regionally diverse cohort [450,934 white, non-Hispanic subjects (5071 years) in the prospective National Institutes of Health (NIH)-AARP Diet and Health Study] after accounting for individual-level confounding risk factors. Estimated erythemal UVR exposure from satellite Total Ozone Mapping Spectrometer (TOMS) data from NASA was linked to the US Census Bureau 2000 census tract (centroid) of baseline residence for each subject. We used Cox proportional hazards models adjusted for multiple potential confounders to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for quartiles of UVR exposure. Restricted cubic splines examined nonlinear relationships. Over 9 years of follow-up, UVR exposure was inversely associated with total cancer risk (N = 75,917; highest versus lowest quartile; HR = 0.97, 95% CI = 0.950.99; p-trend < 0.001). In site-specific cancer analyses, UVR exposure was associated with increased melanoma risk (highest versus lowest quartile; HR = 1.22, 95% CI = 1.131.32; p-trend < 0.001) and decreased risk of non-Hodgkin's lymphoma (HR = 0.82, 95% CI = 0.740.92) and colon (HR = 0.88, 95% CI = 0.820.96), squamous cell lung (HR = 0.86, 95% CI = 0.750.98), pleural (HR = 0.57, 95% CI = 0.380.84), prostate (HR = 0.91, 95% CI = 0.880.95), kidney (HR = 0.83, 95% CI = 0.730.94) and bladder (HR = 0.88, 95% CI = 0.810.96) cancers (all p-trend < 0.05). We also found nonlinear associations for some cancer sites, including the thyroid and pancreas. Our results add to mounting evidence for the influential role of UVR exposure on cancer. C1 [Lin, Shih-Wen] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lin, Shih-Wen] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Wheeler, David C.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Lin, SW (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 3019,MSC 7232, Bethesda, MD 20892 USA. EM lins4@mail.nih.gov RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; National Cancer Institute, NIH (Intramural Research Program) FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Grant sponsor: National Cancer Institute, NIH (Intramural Research Program) NR 50 TC 30 Z9 30 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2012 VL 131 IS 6 BP E1015 EP E1023 DI 10.1002/ijc.27619 PG 9 WC Oncology SC Oncology GA 978JD UT WOS:000306735700017 PM 22539073 ER PT J AU van der Marel, J Quint, WGV Schiffman, M van de Sandt, MM Zuna, RE Dunn, ST Smith, K Mathews, CA Gold, MA Walker, J Wentzensen, N AF van der Marel, Jacolien Quint, Wim G. V. Schiffman, Mark van de Sandt, Miekel M. Zuna, Rosemary E. Dunn, S. Terence Smith, Katherine Mathews, Cara A. Gold, Michael A. Walker, Joan Wentzensen, Nicolas TI Molecular mapping of high-grade cervical intraepithelial neoplasia shows etiological dominance of HPV16 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE CIN; HPV; colposcopy; LCM; genotyping ID HUMAN-PAPILLOMAVIRUS INFECTIONS; LINE PROBE ASSAY; EARLY END-POINTS; CANCER; WOMEN; DETERMINANTS; PROGRESSION; SPECIMENS; RISK AB Women with high-grade cervical intraepithelial neoplasia (HGCIN) frequently present with multiple cervical lesions and multiple concomitant Human papillomavirus (HPV) genotype infections. To elucidate HPV genotype attribution in different regions on the cervix, we performed molecular mapping of cervical disease in women with HGCIN. Thirteen subjects referred to colposcopy for abnormal cervical cancer screening results were included. A cervical smear and biopsies from 4 different areas on the cervix were collected. HPV genotyping using Linear Array (for cytology) or SPF10 LiPA25 (for histology) were performed in 13 smears, 52 whole sections from biopsies and 138 tissue regions isolated with laser capture microdissection (LCM). Twelve subjects had a diagnosis of CIN3 and one subject had a diagnosis of CIN2 based on the worst histology found in 4 biopsies. Eight of the 13 smears (62%) showed multiple genotype infections. Four of 13 women (31%) had multiple HPV infections in their biopsies. After performing LCM-PCR, only one woman (8%) had two different carcinogenic HPV types in morphologically distinct, but colliding HGCIN lesions. HPV16 was identified as the causal type in all women with HPV16 in cytology. A large proportion of other HPV types found in cervical smears were not detected at the tissue level. Using tissue-based genotyping and LCM-PCR analysis, we were able to attribute an individual HPV type to each area of CIN lesions. We demonstrate that HPV16 is even more etiologically dominant than previously thought, based on various genotype attribution models. C1 [Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. [van der Marel, Jacolien; Quint, Wim G. V.; van de Sandt, Miekel M.] DDL Diagnost Lab, Rijswijk, Netherlands. [Zuna, Rosemary E.; Dunn, S. Terence; Smith, Katherine; Mathews, Cara A.; Walker, Joan] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. [Zuna, Rosemary E.; Dunn, S. Terence; Smith, Katherine; Mathews, Cara A.; Walker, Joan] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Gold, Michael A.] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN 37232 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,Room 5024, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov FU Intramural Research Program of the National Cancer Institute FX Grant sponsor: Intramural Research Program of the National Cancer Institute NR 21 TC 25 Z9 25 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2012 VL 131 IS 6 BP E946 EP E953 DI 10.1002/ijc.27532 PG 8 WC Oncology SC Oncology GA 978JD UT WOS:000306735700010 PM 22419273 ER PT J AU Ogden, KM Ramanathan, HN Patton, JT AF Ogden, Kristen M. Ramanathan, Harish N. Patton, John T. TI Mutational analysis of residues involved in nucleotide and divalent cation stabilization in the rotavirus RNA-dependent RNA polymerase catalytic pocket SO VIROLOGY LA English DT Article DE RNA-dependent RNA polymerase; Rotavirus; Double-stranded RNA virus; Replication; Initiation; RNA catalysis; Priming loop ID DE-NOVO INITIATION; STRUCTURAL-ANALYSIS; MECHANISM; VIRUS; POLYMERIZATION; REASSORTMENT; RESOLUTION; COMPLEXES; PROTEINS; SEQUENCE AB The rotavirus RNA-dependent RNA polymerase (RdRp), VP1, contains canonical RdRp motifs and a priming loop that is hypothesized to undergo conformational rearrangements during RNA synthesis. In the absence of viral core shell protein VP2, VP1 fails to interact stably with divalent cations or nucleotides and has a retracted priming loop. To identify residues of potential import to nucleotide and divalent cation stabilization, we aligned VP1 of divergent rotaviruses and the structural homolog reovirus lambda 3. VP1 mutants were engineered and characterized for RNA synthetic capacity in vitro. Conserved aspartic acids in RdRp motifs A and C and arginines in motif F that likely stabilize divalent cations and nucleotides were required for efficient RNA synthesis. Mutation of individual priming loop residues diminished or enhanced RNA synthesis efficiency without obviating the need for VP2, which suggests that this structure serves as a dynamic regulatory element that links RdRp activity to particle assembly. Published by Elsevier Inc. C1 [Ogden, Kristen M.; Ramanathan, Harish N.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI RAMANATHAN, HARISH/B-1274-2013; Patton, John/P-1390-2014 OI RAMANATHAN, HARISH/0000-0001-6073-2981; FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health FX The authors would like to thank Michelle Arnold, Natalie Leach, Marco Morelli, Aitor Navarro, and Shane Trask for helpful discussions and critical reading of the manuscript and Tamara Bar-Magen for technical assistance. We also thank Stephen Harrison and Ethan Settembre for sharing findings regarding the location and orientation of VP1 within rotavirus particles. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. NR 35 TC 6 Z9 7 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2012 VL 431 IS 1-2 BP 12 EP 20 DI 10.1016/j.virol.2012.05.009 PG 9 WC Virology SC Virology GA 966MZ UT WOS:000305843400002 PM 22664357 ER PT J AU Ogden, KM Johne, R Patton, JT AF Ogden, Kristen M. Johne, Reimar Patton, John T. TI Rotavirus RNA polymerases resolve into two phylogenetically distinct classes that differ in their mechanism of template recognition SO VIROLOGY LA English DT Article DE Rotavirus; RNA polymerase; VP1; Polymerase structure; Double-stranded RNA virus ID GENOME SEQUENCE; I-TASSER; EVOLUTION AB Rotaviruses (RVs) are segmented double-stranded RNA viruses that cause gastroenteritis in mammals and birds. Within the RV genus, eight species (RVA-RVH) have been proposed. Here, we report the first RVF and RVG sequences for the viral RNA polymerase (VP1)-encoding segments and compare them to those of other RV species. Phylogenetic analyses indicate that the VP1 RNA segments and proteins resolve into two major clades, with RVA, RVC, RVD and RVF in clade A, and RVB, RVG and RVH in clade B. Plus-strand RNA of clade A viruses, and not clade B viruses, contain a 3'-proximal UGUG cassette that serves as the VP1 recognition signal. VP1 structures for a representative of each RV species were predicted using homology modeling. Structural elements involved in interactions with the UGUG cassette were conserved among VP1 of clade A, suggesting a conserved mechanism of viral RNA recognition for these viruses. Published by Elsevier Inc. C1 [Ogden, Kristen M.; Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Johne, Reimar] Fed Inst Risk Assessment, D-10589 Berlin, Germany. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6313,50 South Dr,MSC8007, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health (USA); Deutsche Forschungsgemeinschaft [JO 369/4-1] FX K.M.O. and J.T.P were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (USA). R.J. was supported by a grant from the Deutsche Forschungsgemeinschaft (JO 369/4-1). NR 20 TC 6 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2012 VL 431 IS 1-2 BP 50 EP 57 DI 10.1016/j.virol.2012.05.011 PG 8 WC Virology SC Virology GA 966MZ UT WOS:000305843400006 PM 22687427 ER PT J AU He, J Shi, LDZ Truong, LN Lu, CS Razavian, N Li, YJ Negrete, A Shiloach, J Berns, MW Wu, XH AF He, Jing Shi, Linda Z. Truong, Lan N. Lu, Chi-Sheng Razavian, Niema Li, Yongjiang Negrete, Alejandro Shiloach, Joseph Berns, Michael W. Wu, Xiaohua TI Rad50 Zinc Hook Is Important for the Mre11 Complex to Bind Chromosomal DNA Double-stranded Breaks and Initiate Various DNA Damage Responses SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID S-PHASE CHECKPOINT; MRE11-RAD50-NBS1 COMPLEX; CHROMATIN RETENTION; MAMMALIAN-CELLS; REPAIR COMPLEX; MRN COMPLEX; NBS1; ATM; PHOSPHORYLATION; PROTEIN AB The Mre11-Rad50-Nbs1 (MRN) complex plays critical roles in checkpoint activation and double-stranded break (DSB) repair. The Rad50 zinc hook domain mediates zinc-dependent intercomplex associations of MRN, which is important for DNA tethering. Studies in yeast suggest that the Rad50 zinc hook domain is essential for MRN functions, but its role in mammalian cells is not clear. We demonstrated that the human Rad50 hook mutants are severely defective in various DNA damage responses including ATM (Ataxia telangiectasia mutated) activation, homologous recombination, sensitivity to IR, and activation of the ATR pathway. By using live cell imaging, we observed that the Rad50 hook mutants fail to be recruited to chromosomal DSBs, suggesting a novel mechanism underlying the severe defects observed for the Rad50 hook mutants. In vitro analysis showed that Zn2+ promotes wild type but not the hook mutant of MR to bind double-stranded DNA. In vivo, the Rad50 hook mutants are defective in being recruited to chromosomal DSBs in both H2AX-proficient and -deficient cells, suggesting that the Rad50 hook mutants are impaired in direct binding to chromosomal DSB ends. We propose that the Rad50 zinc hook domain is important for the initial binding of MRN to DSBs, leading to ATM activation to phosphorylate H2AX, which recruits more MRN to the DSB-flanking chromosomal regions. Our studies reveal a critical role for the Rad50 zinc hook domain in establishing and maintaining MRN recruitment to chromosomal DSBs and suggest an important mechanism of how the Rad50 zinc hook domain contributes to DNA repair and checkpoint activation. C1 [He, Jing; Truong, Lan N.; Lu, Chi-Sheng; Razavian, Niema; Li, Yongjiang; Wu, Xiaohua] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Shi, Linda Z.; Berns, Michael W.] Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA. [Negrete, Alejandro; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. RP Wu, XH (reprint author), Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM xiaohwu@scripps.edu RI HE, JING/J-3099-2014 FU National Institutes of Health [CA102361, GM080677, CA140972, CA102361-07S1]; Beckman Laser Institute Inc., Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants CA102361, GM080677, CA140972, and CA102361-07S1 (to X. W). This work was also supported by funds from the Beckman Laser Institute Inc., Foundation (to M. W. B.). NR 38 TC 15 Z9 16 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2012 VL 287 IS 38 BP 31747 EP 31756 DI 10.1074/jbc.M112.384750 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 009XT UT WOS:000309059400016 PM 22833675 ER PT J AU Martin, B Chadwick, W Cong, WN Pantaleo, N Daimon, CM Golden, EJ Becker, KG Wood, WH Carlson, OD Egan, JM Maudsley, S AF Martin, Bronwen Chadwick, Wayne Cong, Wei-na Pantaleo, Nick Daimon, Caitlin M. Golden, Erin J. Becker, Kevin G. Wood, William H., III Carlson, Olga D. Egan, Josephine M. Maudsley, Stuart TI Euglycemic Agent-mediated Hypothalamic Transcriptomic Manipulation in the N171-82Q Model of Huntington Disease Is Related to Their Physiological Efficacy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSGENIC MOUSE MODEL; PRION-PROTEIN GENE; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; MUTATIONS; IDENTIFICATION; NEUROENDOCRINE; EXPRESSION; PEPTIDES; DEMENTIA AB Our aim was to employ novel analytical methods to investigate the therapeutic treatment of the energy regulation dysfunction occurring in a Huntington disease (HD) mouse model. HD is a neurodegenerative disorder that is characterized by progressive motor impairment and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. We determined the effects of three different euglycemic agents on HD progression using standard physiological and transcriptomic signature analyses. N171-82Q HD mice were treated with insulin, Exendin-4, and the newly developed GLP-1-Tf to determine whether these agents could improve energy regulation and delay disease progression. Blood glucose, insulin, metabolic hormone levels, and pancreatic morphology were assessed. Hypothalamic gene transcription, motor coordination, and life span were also determined. The N171-82Q mice exhibited significant alterations in hypothalamic gene transcription signatures and energy metabolism that were ameliorated, to varying degrees, by the different euglycemic agents. Exendin-4 or GLP-1-Tf (but not insulin) treatment also improved pancreatic morphology, motor coordination, and increased life span. Using hypothalamic transcription signature analyses, we found that the physiological efficacy variation of the drugs was evident in the degree of reversal of the hypothalamic HD pathological signature. Euglycemic agents targeting hypothalamic and energy regulation dysfunction in HD could potentially alter disease progression and improve quality of life in HD. C1 [Martin, Bronwen; Cong, Wei-na; Daimon, Caitlin M.; Golden, Erin J.] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Chadwick, Wayne; Pantaleo, Nick; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Becker, Kevin G.; Wood, William H., III] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Carlson, Olga D.; Egan, Josephine M.] NIA, Diabet Sect, NIH, Baltimore, MD 21224 USA. RP Martin, B (reprint author), NIA, Metab Unit, NIH, 251 Bayview Blvd,Ste 100, Baltimore, MD 21224 USA. EM martinbro@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health Intramural Research Program, NIA FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program, NIA. NR 55 TC 11 Z9 12 U1 1 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 SEP 14 PY 2012 VL 287 IS 38 BP 31766 EP 31782 DI 10.1074/jbc.M112.387316 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 009XT UT WOS:000309059400018 PM 22822065 ER PT J AU Richter, K Burch, L Chao, F Henke, D Jiang, CC Daly, J Zhao, ML Kissling, G Diaz, M AF Richter, Kathleen Burch, Lauranell Chao, Frank Henke, David Jiang, Chuancang Daly, Janssen Zhao, Ming-Lang Kissling, Grace Diaz, Marilyn TI Altered Pattern of Immunoglobulin Hypermutation in Mice Deficient in Slip-GC Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED CYTIDINE DEAMINASE; ACTIVATION-INDUCED DEAMINASE; SWITCH DNA RECOMBINATION; SOMATIC HYPERMUTATION; B-CELLS; IG HYPERMUTATION; LUPUS NEPHRITIS; MRL/LPR MICE; AID; ANTIBODY AB We recently identified a novel germinal center GTPase, SLIP-GC, that localizes to replication factories in B cells and that, when reduced, induces DNA breaks in lymphoma B cell lines in an activation-induced deaminase (AID)-dependent manner. Herein, we generated mice deficient in SLIP-GC and examined the impact of SLIP-GC deficiency in immunoglobulin hypermutation and class switch recombination, both AID-dependent mechanisms. SLIP-GC-deficient mice experienced a substantial increase in mutations at G:C base pairs at the region down-stream of JH4 in the immunoglobulin heavy chain locus. This change was reflected in the overall mutation frequency, and it was associated with an increase in transitions from G:C base pairs, a hallmark of AID-mediated deamination during replication. In addition, G:C transitions at non-immunoglobulin loci also increased in these mice. Given the intracellular localization of SLIP-GC to sites of replicating DNA, these results suggest that SLIP-GC protects replicating DNA from AID-mediated deamination of cytosines in both strands. C1 [Richter, Kathleen; Jiang, Chuancang; Daly, Janssen; Zhao, Ming-Lang; Diaz, Marilyn] NIEHS, Somat Hypermutat Grp, NIH, Res Triangle Pk, NC 27709 USA. [Burch, Lauranell; Chao, Frank; Henke, David] NIEHS, Mol Genet Core, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kissling, Grace] NIEHS, Biostat Branch, Environm Dis & Med Program, NIH, Res Triangle Pk, NC 27709 USA. RP Diaz, M (reprint author), NIEHS, Somat Hypermutat Grp, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM diaz@niehs.nih.gov FU Division of Intramural Research of the National Institutes of Health through the NIEHS [Z01 ES101603] FX This work was supported, in whole or in part, by Project Z01 ES101603 from the Division of Intramural Research of the National Institutes of Health through the NIEHS (to M. D.). NR 39 TC 1 Z9 2 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 14 PY 2012 VL 287 IS 38 BP 31856 EP 31865 DI 10.1074/jbc.M112.340661 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 009XT UT WOS:000309059400026 PM 22833677 ER PT J AU Xie, HR Sun, XF Piao, YL Jegga, AG Handwerger, S Ko, MSH Dey, SK AF Xie, Huirong Sun, Xiaofei Piao, Yulan Jegga, Anil G. Handwerger, Stuart Ko, Minoru S. H. Dey, Sudhansu K. TI Silencing or Amplification of Endocannabinoid Signaling in Blastocysts via CB1 Compromises Trophoblast Cell Migration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PREIMPLANTATION MOUSE EMBRYO; HYDROLYZING ACID AMIDASE; CANNABINOID RECEPTOR; MOLECULAR CHARACTERIZATION; IDIOPATHIC INFERTILITY; GENE-EXPRESSION; ANANDAMIDE; BRAIN; PALMITOYLETHANOLAMIDE; IMPLANTATION AB Endocannabinoid signaling plays key roles in multiple female reproductive events. Previous studies have shown an interesting phenomenon, that mice with either silenced or elevated endocannabinoid signaling via Cnr1 encoding CB1 show similar defects in several pregnancy events, including preimplantation embryo development. To unravel the downstream signaling of this phenomenon, microarray studies were performed using RNAs collected from WT, Cnr1(-/-), and Faah(-/-) mouse blastocysts on day 4 of pregnancy. The results indicate that about 100 genes show unidirectional changes under either silenced or elevated anandamide signaling via CB1. Functional enrichment analysis of the microarray data predicted that multiple biological functions and pathways are affected under aberrant endocannabinoid signaling. Among them, genes enriched in cell migration are suppressed in Cnr1(-/-) or Faah(-/-) blastocysts. Cell migration assays validated the prediction of functional enrichment analysis that cell mobility and spreading of either Cnr1(-/-) or Faah(-/-) trophoblast stem cells are compromised. Either silenced or elevated endocannabinoid signaling via CB1 causes similar changes in downstream targets in preimplantation embryos and trophoblast stem cells. This study provides evidence that a tightly regulated endocannabinoid signaling is critical to normal preimplantation embryo development and migration of trophoblast stem cells. C1 [Xie, Huirong; Sun, Xiaofei; Dey, Sudhansu K.] Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Perinatal Inst, Cincinnati, OH 45229 USA. [Jegga, Anil G.] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA. [Handwerger, Stuart] Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati, OH 45229 USA. [Piao, Yulan; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. [Ko, Minoru S. H.] Keio Univ, Sch Med, Dept Syst Med, Sakaguchi Lab, Tokyo 160, Japan. RP Dey, SK (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Perinatal Inst, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM sk.dey@cchmc.org RI Jegga, Anil/H-6140-2011; OI Jegga, Anil/0000-0002-4881-7752; Ko, Minoru/0000-0002-3530-3015 FU National Institutes of Health [DA006668]; National Institutes of Health, NIA; March of Dimes; Lalor Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grant DA006668 and the Intramural Research Program of the National Institutes of Health, NIA. This work was also supported by the March of Dimes.; Supported by a Lalor Foundation postdoctoral fellowship. NR 69 TC 19 Z9 20 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 SEP 14 PY 2012 VL 287 IS 38 BP 32288 EP 32297 DI 10.1074/jbc.M112.381145 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 009XT UT WOS:000309059400065 PM 22833670 ER PT J AU Sohn, EJ Park, J Kang, SI Wu, YP AF Sohn, Eun Jung Park, Junhong Kang, Soo-im Wu, Yun-Ping TI Accumulation of pre-let-7g and downregulation of mature let-7g with the depletion of EWS SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Ewing sarcoma gen; Primary microRNA; Precursor microRNA ID RNA-POLYMERASE-II; SARCOMA GENE EWS; EWING SARCOMA; NUCLEAR EXPORT; BINDING PROTEIN; DICER; TRANSCRIPTION; INTERFERENCE; ONCOPROTEINS; HTAF(II)68 AB EWS functions in RNA splicing and transcription by encoding an RNA binding protein, which results in the chromosomal translocation t(11;22)(q24;q12) found in Ewing sarcoma. EWS interacts with the microprocessor complex involving Drosha and DGCR8, which play roles as the cofactors of primary microRNA processing. However, the role of EWS in microRNA biogenesis has not been investigated. Here, we show that endogenous EWS interacts with endogenous Drosha by IP-western blotting. In addition, EWS knockout mouse decreased the expression of Drosha. The depletion of EWS results in the accumulation of precursor let-7g but down-regulates mature let-7g in U2OS cells. Consistently, mature let 7g was suppressed in both Ewing sarcoma cell and primary Ewing sarcoma. Also, expression levels of Dicer and CCND1 (Cyclin D1), which are known target genes of the let-7 family were upregulated. Our findings suggest that EWS mediates generation of mature let-7g from pre-let-7g. (C) 2012 Elsevier Inc. All rights reserved. C1 [Sohn, Eun Jung] Pusan Natl Univ, Sch Med, Korean Res Ctr Asbestos Related Dis, Yangsan 626870, Gyeongnam, South Korea. [Sohn, Eun Jung; Park, Junhong; Kang, Soo-im; Wu, Yun-Ping] NIDDK, Genet Dev & Dis Branch, NIH, Clarksburg, MD 20871 USA. RP Sohn, EJ (reprint author), Pusan Natl Univ, Sch Med, Korean Res Ctr Asbestos Related Dis, Yangsan 626870, Gyeongnam, South Korea. EM eunjungs93@gmail.com NR 31 TC 5 Z9 5 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 14 PY 2012 VL 426 IS 1 BP 89 EP 93 DI 10.1016/j.bbrc.2012.08.041 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 013NO UT WOS:000309312300016 PM 22910415 ER PT J AU Kastenmuller, W Torabi-Parizi, P Subramanian, N Lammermann, T Germain, RN AF Kastenmueller, Wolfgang Torabi-Parizi, Parizad Subramanian, Naeha Laemmermann, Tim Germain, Ronald N. TI A Spatially-Organized Multicellular Innate Immune Response in Lymph Nodes Limits Systemic Pathogen Spread SO CELL LA English DT Article ID CD8(+) T-CELLS; PSEUDOMONAS-AERUGINOSA; VACCINIA VIRUS; MACROPHAGE POLARIZATION; ANTIBODY-RESPONSES; SUBCAPSULAR SINUS; GAMMA PRODUCTION; IN-VIVO; B-CELLS; INFECTION AB The lymphatic network that transports interstitial fluid and antigens to lymph nodes constitutes a conduit system that can be hijacked by invading pathogens to achieve systemic spread unless dissemination is blocked in the lymph node itself. Here, we show that a network of diverse lymphoid cells (natural killer cells, gamma delta T cells, natural killer T cells, and innate-like CD8+ T cells) are spatially prepositioned close to lymphatic sinus-lining sentinel macrophages where they can rapidly and efficiently receive inflammasome-generated IL-18 and additional cytokine signals from the pathogen-sensing phagocytes. This leads to rapid IFN gamma secretion by the strategically positioned innate lymphocytes, fostering antimicrobial resistance in the macrophage population. Interference with this innate immune response loop allows systemic spread of lymph-borne bacteria. These findings extend our understanding of the functional significance of cellular positioning and local intercellular communication within lymph nodes while emphasizing the role of these organs as highly active locations of innate host defense. C1 [Kastenmueller, Wolfgang; Torabi-Parizi, Parizad; Subramanian, Naeha; Laemmermann, Tim; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Torabi-Parizi, Parizad] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kastenmuller, W (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. EM kastenmullerw@mail.nih.gov; rgermain@nih.gov FU NIAID; NIH; DFG; International Human Frontier Science Program; [KA 3091/1-1] FX This research was supported by the Intramural Research Program, NIAID, NIH, DFG, KA 3091/1-1 to W.K. and by a fellowship grant from the International Human Frontier Science Program to T.L. We thank A. Sher, Y. Belkaid, and K. Abdi for kindly providing mouse strains, B. Moss for generously providing pLW-73, E. Miao and B. Borlee for generously providing PA strains and E. Long for critically reading this manuscript. The authors would also like to thank Austin Rinker for technical support. NR 55 TC 115 Z9 115 U1 4 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 14 PY 2012 VL 150 IS 6 BP 1235 EP 1248 DI 10.1016/j.cell.2012.07.021 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 007ZY UT WOS:000308928100016 PM 22980983 ER PT J AU Qiang, W Tycko, R AF Qiang, Wei Tycko, Robert TI Zero-quantum stochastic dipolar recoupling in solid state nuclear magnetic resonance SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ANGLE-SPINNING NMR; ROTATING SOLIDS; CORRELATION SPECTROSCOPY; 3-DIMENSIONAL STRUCTURE; POLARIZATION TRANSFER; AMYLOID FIBRILS; PULSE SEQUENCES; PROTEIN; DIFFUSION; CONSTRAINTS AB We present the theoretical description and experimental demonstration of a zero-quantum stochastic dipolar recoupling (ZQ-SDR) technique for solid state nuclear magnetic resonance (NMR) studies of C-13-labeled molecules, including proteins, under magic-angle spinning (MAS). The ZQ-SDR technique combines zero-quantum recoupling pulse sequence blocks with randomly varying chemical shift precession periods to create randomly amplitude-and phase-modulated effective homonuclear magnetic dipole-dipole couplings. To a good approximation, couplings between different C-13 spin pairs become uncorrelated under ZQ-SDR, leading to spin dynamics (averaged over many repetitions of the ZQ-SDR sequence) that are fully described by an orientation-dependent N x N polarization transfer rate matrix for an N-spin system, with rates that are inversely proportional to the sixth power of internuclear distances. Suppression of polarization transfers due to non-commutivity of pairwise couplings (i.e., dipolar truncation) does not occur under ZQ-SDR, as we show both analytically and numerically. Experimental demonstrations are reported for uniformly C-13-labeled L-valine powder (at 14.1 T and 28.00 kHz MAS), uniformly C-13-labeled protein GB1 in microcrystalline form (at 17.6 T and 40.00 kHz MAS), and partially labeled C-13-labeled protein GB1 (at 14.1 T and 40.00 kHz MAS). The experimental results verify that spin dynamics under ZQ-SDR are described accurately by rate matrices and suggest the utility of ZQ-SDR in structural studies of C-13-labeled solids. [http://dx.doi.org/10.1063/1.4749258] C1 [Qiang, Wei; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Qiang, Wei/I-1053-2012 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 55 TC 2 Z9 2 U1 1 U2 32 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 14 PY 2012 VL 137 IS 10 AR 104201 DI 10.1063/1.4749258 PG 14 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 010NF UT WOS:000309100400011 PM 22979851 ER PT J AU Sayer, JM Aniana, A Louis, JM AF Sayer, Jane M. Aniana, Annie Louis, John M. TI Mechanism of Dissociative Inhibition of HIV Protease and Its Autoprocessing from a Precursor SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE retrovirus; HIV protease; dimerization inhibitor; antibody binding; polyprotein processing ID VIRUS TYPE-1 PROTEASE; DRUG-RESISTANCE; MONOCLONAL-ANTIBODY; CLINICAL INHIBITORS; INTERFACE PEPTIDES; STRUCTURAL BASIS; WILD-TYPE; IN-VITRO; DIMERIZATION; STABILITY AB Dimerization is indispensible for release of the human immunodeficiency virus protease (PR) from its precursor (Gag-Pol) and ensuing mature-like catalytic activity that is crucial for virus maturation. We show that a single-chain Fv fragment (scFv) of a previously reported monoclonal antibody (mAb1696), which recognizes the N-terminus of PR, dissociates a dimeric mature D25N PR mutant with an enhanced dimer dissociation constant (K-d) in the sub-micromolar range to form predominantly a monomer-scFv complex at a 1:1 ratio, along with small (5-10%) amounts of a dimer-scFv complex. Enzyme kinetics indicate a mixed mechanism of inhibition of the wild-type PR, which exhibits a K-d <10 nM, with effects both on K-m and k(cat) at an scFv-to-PR ratio of 10:1. ScFv binds to the N-terminal peptide P(1)QITLW(6) of PR and to PR monomers with dissociation constants of <= 30 nM and similar to 100 nM, respectively. Consistent with an similar to 400-fold increase in the dissociation of the antibody (K-Ab) on even addition of an acetyl group to P-1 of the peptide, the antibody fails to inhibit N-terminal autoprocessing of the PR from a model precursor (at similar to 5 mu M). However, subsequent to this cleavage, it sequesters the PR, thus blocking autoprocessing at its C-terminus. A second monoclonal antibody [PRM1 (human monoclonal antibody to PR)], which recognizes part of the flap region (residues 41-47) of the mature PR and its precursor, does not inhibit autoprocessing and ensuing catalytic activity. However, its failure to recognize drug-resistant clinical mutants of PR may be beneficial to monitor the selection of mutations in this region under drug pressure. Published by Elsevier Ltd. C1 [Sayer, Jane M.; Aniana, Annie; Louis, John M.] NIDDK, LCP, NIH, DHHS, Bethesda, MD 20892 USA. RP Louis, JM (reprint author), NIDDK, LCP, NIH, DHHS, Bldg 5,Room B2-29, Bethesda, MD 20892 USA. EM johnl@intra.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Intramural AIDS-Targeted Program of the Office of the Director, NIH FX We are grateful to Dr. Ad Bax for reading and conveying critical comments. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), and the Intramural AIDS-Targeted Program of the Office of the Director, NIH. PIs used in this study were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH. NR 43 TC 3 Z9 3 U1 0 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 14 PY 2012 VL 422 IS 2 BP 230 EP 244 DI 10.1016/j.jmb.2012.05.024 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 004KQ UT WOS:000308681000007 PM 22659320 ER PT J AU Chesson, HW Ekwueme, DU Saraiya, M Watson, M Lowy, DR Markowitz, LE AF Chesson, Harrell W. Ekwueme, Donatus U. Saraiya, Mona Watson, Meg Lowy, Douglas R. Markowitz, Lauri E. TI Estimates of the annual direct medical costs of the prevention and treatment of disease associated with human papillomavirus in the United States SO VACCINE LA English DT Article DE Human papillomavirus; Cost; Intraepithelial neoplasia; Vulvar, vaginal, anal, oral cavity, oropharyngeal, and cervical cancer; Genital warts; Health economics ID RECURRENT RESPIRATORY PAPILLOMATOSIS; CANCER SCREENING RATES; US HEALTH PLAN; HPV VACCINE; BURDEN; POPULATION; BENEFITS; IMPACT AB Estimates of the direct medical costs attributable to human papillomavirus (HPV) can help to quantify the economic burden of HPV and to illustrate the potential benefits of HPV vaccination. The purpose of this report was to update the estimated annual direct medical costs of the prevention and treatment of HPV-associated disease in the United States, for all HPV types. We included the costs of cervical cancer screening and follow-up and the treatment costs of the following HPV-associated health outcomes: cervical cancer, other anogenital cancers (anal, vaginal, vulvar and penile), oropharyngeal cancer, genital warts, and recurrent respiratory papillomatosis (RRP). We obtained updated incidence and cost estimates from the literature. The overall annual direct medical cost burden of preventing and treating HPV-associated disease was estimated to be $8.0 billion (2010 U.S. dollars). Of this total cost, about $6.6 billion (82.3%) was for routine cervical cancer screening and follow-up, $1.0 billion (12.0%) was for cancer (including $0.4 billion for cervical cancer and $0.3 billion for oropharyngeal cancer), $0.3 billion (3.6%) was for genital warts, and $0.2 billion (2.1%) was for RRP. Published by Elsevier Ltd. C1 [Chesson, Harrell W.; Markowitz, Lauri E.] Ctr Dis Control & Prevent, Div STD Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA 30333 USA. [Ekwueme, Donatus U.; Saraiya, Mona; Watson, Meg] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Lowy, Douglas R.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chesson, HW (reprint author), Ctr Dis Control & Prevent, Div STD Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Mail Stop E-80,1600 Clifton Rd, Atlanta, GA 30333 USA. EM HChesson@cdc.gov NR 27 TC 50 Z9 52 U1 1 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 14 PY 2012 VL 30 IS 42 BP 6016 EP 6019 DI 10.1016/j.vaccine.2012.07.056 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 009KS UT WOS:000309025300003 PM 22867718 ER PT J AU Hsieh, P AF Hsieh, Peggy TI DNA Mismatch Repair: Dr. Jekyll and Mr. Hyde? SO MOLECULAR CELL LA English DT Editorial Material ID MECHANISMS; CANCER; PCNA AB In this issue, Pena-Diaz et al. (2012) describe a pathway for somatic mutation in nonlymphoid cells termed noncanonical DNA mismatch repair, whereby the error-prone translesion polymerase Pol-eta substitutes for high-fidelity replicative polymerases to resynthesize excised regions opposite DNA damage. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Hsieh, P (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM peggyh@niddk.nih.gov FU Intramural NIH HHS [ZIA DK052029-05] NR 10 TC 1 Z9 1 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 14 PY 2012 VL 47 IS 5 BP 665 EP 666 DI 10.1016/j.molcel.2012.08.020 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 008QS UT WOS:000308972200001 PM 22980456 ER PT J AU Galis, ZS Hoots, WK Kiley, JP Lauer, MS AF Galis, Zorina S. Hoots, W. Keith Kiley, James P. Lauer, Michael S. TI On the Value of Portfolio Diversity in Heart, Lung, and Blood Research SO CIRCULATION RESEARCH LA English DT Editorial Material DE research funding; research policy; other research ID SCIENCE; NIH C1 [Lauer, Michael S.] NHLBI, Off Director, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Galis, Zorina S.] NHLBI, Vasc Biol & Hypertens Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Hoots, W. Keith] NHLBI, Off Director, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. [Kiley, James P.] NHLBI, Off Director, Div Lung Dis, NIH, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Off Director, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov NR 27 TC 7 Z9 7 U1 0 U2 0 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 SEP 14 PY 2012 VL 111 IS 7 BP 833 EP 836 DI 10.1161/CIRCRESAHA.112.279596 PG 4 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 007DK UT WOS:000308868800009 PM 22891047 ER PT J AU Fan, E Gifford, JM Chandolu, S Colantuoni, E Pronovost, PJ Needham, DM AF Fan, Eddy Gifford, Jeneen M. Chandolu, Satish Colantuoni, Elizabeth Pronovost, Peter J. Needham, Dale M. TI The functional comorbidity index had high inter-rater reliability in patients with acute lung injury SO BMC ANESTHESIOLOGY LA English DT Article DE Comorbidity; Intensive care unit; Reproducibility of results; Respiratory distress syndrome; Adult ID RESPIRATORY-DISTRESS-SYNDROME; PHYSICAL FUNCTION; CO-MORBIDITY; SURVIVORS; DISEASE; DISABILITY; OUTCOMES; CARE AB Background: The Functional Comorbidity Index (FCI) was recently developed to predict physical function in acute lung injury patients using comorbidity data. Our objectives were to determine: (1) the inter-rater reliability of the FCI collected using in-patient discharge summaries (primary objective); and (2) the accuracy and predictive validity of the FCI collected using hospital discharge summaries and admission records versus complete chart review (secondary objectives). Methods: For reliability, we evaluated the FCI's intraclass correlation coefficient (ICC) among trained research staff performing data collection for 421 acute lung injury patients enrolled in a prospective cohort study. For validity and accuracy, we compared the detection of FCI comorbidities across three types of inpatient medical records, and the association of the respective FCI scores obtained with patients' SF-36 physical function subscale (PFS) scores at 1-year follow-up. Results: Inter-rater reliability was near-perfect (ICC 0.91; 95% CI 0.89-0.94). Hospital admission records and discharge summaries (vs. complete chart review) significantly underestimated the total FCI score. However, using multivariable linear regression, FCI scores collected using each of the three types of inpatient medical records had similar associations with PFS, suggesting similar predictive value. Conclusions: Data collection using in-patient discharge summaries represents a reliable and valid method for collecting FCI comorbidity information. C1 [Fan, Eddy; Chandolu, Satish; Needham, Dale M.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD 21218 USA. [Fan, Eddy] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada. [Gifford, Jeneen M.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Colantuoni, Elizabeth] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Pronovost, Peter J.] Johns Hopkins Univ, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA. [Needham, Dale M.] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD USA. [Fan, Eddy] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. RP Fan, E (reprint author), Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD 21218 USA. EM efan@mtsinai.on.ca FU National Institutes of Health (Acute Lung Injury SCCOR) [P050 HL 73994]; Canadian Institutes of Health Research FX This research is supported by the National Institutes of Health (Acute Lung Injury SCCOR grant P050 HL 73994). EF is supported by a Fellowship Award from the Canadian Institutes of Health Research. The funding bodies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 20 TC 3 Z9 3 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2253 J9 BMC ANESTHESIOL JI BMC Anesthesiol. PD SEP 13 PY 2012 VL 12 AR 21 DI 10.1186/1471-2253-12-21 PG 8 WC Anesthesiology SC Anesthesiology GA 088OD UT WOS:000314843600001 PM 22974239 ER PT J AU Xiao, JB Westbroek, W Motabar, O Lea, WA Hu, X Velayati, A Zheng, W Southall, N Gustafson, AM Goldin, E Sidransky, E Liu, K Simeonov, A Tamargo, RJ Ribes, A Matalonga, L Ferrer, M Marugan, JJ AF Xiao, Jingbo Westbroek, Wendy Motabar, Omid Lea, Wendy A. Hu, Xin Velayati, Arash Zheng, Wei Southall, Noel Gustafson, Ann Marie Goldin, Ehud Sidransky, Ellen Liu, Ke Simeonov, Anton Tamargo, Rafael J. Ribes, Antonia Matalonga, Leslie Ferrer, Marc Marugan, Juan J. TI Discovery of a Novel Noniminosugar Acid alpha Glucosidase Chaperone Series SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID LYSOSOMAL STORAGE DISORDERS; GLYCOGENOSIS TYPE-II; DISEASE TYPE-II; PROMOTE PROTEIN STABILITY; SMALL MOLECULES; POMPE-DISEASE; IMINO SUGARS; FIBROBLASTS; INHIBITORS; MUTATIONS AB Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid a-glucosidase (GAA). Many disease-causing mutated GAA retain enzymatic activity but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease but remains expensive, inconvenient, and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small-molecule chaperones for specific LSDs. Here we identified a novel series of noniminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermostabilize GAA and increase GAA translocation to lysosomes in both wild-type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models. C1 [Xiao, Jingbo; Motabar, Omid; Lea, Wendy A.; Hu, Xin; Zheng, Wei; Southall, Noel; Liu, Ke; Simeonov, Anton; Ferrer, Marc; Marugan, Juan J.] NIH, NIH Chem Genom Ctr, NIH Ctr Translat Therapeut, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Westbroek, Wendy; Velayati, Arash; Gustafson, Ann Marie; Goldin, Ehud; Sidransky, Ellen; Tamargo, Rafael J.] NIH, Med Genet Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. [Ribes, Antonia; Matalonga, Leslie] Hosp Clin Barcelona, Inst Bioquim Clin, Serv Bioquim & Genet Mol, Barcelona, Spain. RP Marugan, JJ (reprint author), NIH, NIH Chem Genom Ctr, NIH Ctr Translat Therapeut, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM maruganj@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research [IJ54MH084681]; Intramural Research Program of the National Human Genome Research Institute; National Center for Advancing Translational Sciences, National Institutes of Health FX We thank William Leister, Jim Bougie, Chris Leclair, Thomas Daniel, Heather Baker, Paul Shinn, and Danielle van Leer for assistance with compounds purification, HRMS analysis, and compounds management. We also thank Allison Mandich and Mercedes Taylor for critical proofreading of the manuscript. This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research (IJ54MH084681) and the Intramural Research Program of the National Human Genome Research Institute and National Center for Advancing Translational Sciences, National Institutes of Health. NR 34 TC 12 Z9 13 U1 3 U2 18 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 SEP 13 PY 2012 VL 55 IS 17 BP 7546 EP 7559 DI 10.1021/jm3005543 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 004IT UT WOS:000308675800018 PM 22834902 ER PT J AU Perry, AM Cardesa-Salzmann, TM Meyer, PN Colomo, L Smith, LM Fu, K Greiner, TC Delabie, J Gascoyne, RD Rimsza, L Jaffe, ES Ott, G Rosenwald, A Braziel, RM Tubbs, R Cook, JR Staudt, LM Connors, JM Sehn, LH Vose, JM Lopez-Guillermo, A Campo, E Chan, WC Weisenburger, DD AF Perry, Anamarija M. Cardesa-Salzmann, Teresa M. Meyer, Paul N. Colomo, Luis Smith, Lynette M. Fu, Kai Greiner, Timothy C. Delabie, Jan Gascoyne, Randy D. Rimsza, Lisa Jaffe, Elaine S. Ott, German Rosenwald, Andreas Braziel, Rita M. Tubbs, Raymond Cook, James R. Staudt, Louis M. Connors, Joseph M. Sehn, Laurie H. Vose, Julie M. Lopez-Guillermo, Armando Campo, Elias Chan, Wing C. Weisenburger, Dennis D. TI A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma SO BLOOD LA English DT Article ID R-CHOP; ELDERLY-PATIENTS; RITUXIMAB; EXPRESSION; CHEMOTHERAPY; CLASSIFICATION; BIOMARKERS; SUBTYPES AB Biologic factors that predict the survival of patients with a diffuse large B-cell lymphoma, such as cell of origin and stromal signatures, have been discovered by gene expression profiling. We attempted to simulate these gene expression profiling findings and create a new biologic prognostic model based on immunohistochemistry. We studied 199 patients (125 in the training set, 74 in the validation set) with de novo diffuse large B-cell lymphoma treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies, and immunohistochemical stains were performed on paraffin-embedded tissue microarrays. In the model, 1 point was awarded for each adverse prognostic factor: nongerminal center B cell-like subtype, SPARC (secreted protein, acidic, and rich in cysteine) <5%, and microvascular density quartile 4. The model using these 3 biologic markers was highly predictive of overall survival and event-free survival in multivariate analysis after adjusting for the International Prognostic Index in both the training and validation sets. This new model delineates 2 groups of patients, 1 with a low biologic score (0-1) and good survival and the other with a high score (2-3) and poor survival. This new biologic prognostic model could be used with the International Prognostic Index to stratify patients for novel or risk-adapted therapies. (Blood. 2012;120(11):2290-2296) C1 [Perry, Anamarija M.; Meyer, Paul N.; Fu, Kai; Greiner, Timothy C.; Chan, Wing C.; Weisenburger, Dennis D.] Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Cardesa-Salzmann, Teresa M.; Colomo, Luis; Campo, Elias] Univ Barcelona, Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain. [Smith, Lynette M.] Univ Nebraska, Med Ctr, Dept Biostat, Omaha, NE USA. [Delabie, Jan] Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC, Canada. [Rimsza, Lisa] Univ Arizona, Ctr Canc, Dept Pathol, Tucson, AZ USA. [Jaffe, Elaine S.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, D-8700 Wurzburg, Germany. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR USA. [Tubbs, Raymond] Cleveland Clin, Dept Mol Pathol, Cleveland, OH USA. [Cook, James R.] Cleveland Clin, Dept Clin Pathol, Cleveland, OH USA. [Staudt, Louis M.] NCI, Ctr Canc Res, NIH, Bethesda, MD USA. [Connors, Joseph M.; Sehn, Laurie H.] British Columbia Canc Agcy, Dept Med, Vancouver, BC, Canada. [Vose, Julie M.] Univ Nebraska, Med Ctr, Dept Internal Med, Omaha, NE USA. [Lopez-Guillermo, Armando] Univ Barcelona, Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain. RP Weisenburger, DD (reprint author), 983135 Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. EM dweisenb@unmc.edu RI Colomo, Luis/A-2259-2016; OI Colomo, Luis/0000-0001-5236-5085; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 FU National Cancer Institute [U01-CA-114778] FX This work was supported by National Cancer Institute grant U01-CA-114778. NR 26 TC 25 Z9 25 U1 1 U2 8 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 SEP 13 PY 2012 VL 120 IS 11 BP 2290 EP 2296 DI 10.1182/blood-2012-05-430389 PG 7 WC Hematology SC Hematology GA 009RZ UT WOS:000309044200021 PM 22740447 ER PT J AU Acharya, P Luongo, TS Matz, J Schmidt, SD Chuang, G Georgiev, I Kessler, P Yang, Y Chames, P Martin, L Mascola, JR Kwong, PD AF Acharya, P. Luongo, T. S. Matz, J. Schmidt, S. D. Chuang, G. Georgiev, I. Kessler, P. Yang, Y. Chames, P. Martin, L. Mascola, J. R. Kwong, P. D. TI Structural definition of a novel CD4-induced epitope that is targeted by a single-headed immunoglobulin to effect broad and potent HIV neutralization SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Acharya, P.; Luongo, T. S.; Schmidt, S. D.; Chuang, G.; Georgiev, I.; Yang, Y.; Mascola, J. R.; Kwong, P. D.] NIH, Bethesda, MD 20892 USA. [Matz, J.; Chames, P.] INSERM, F-13258 Marseille, France. [Kessler, P.; Martin, L.] CEA, iBiTecs, Gif Sur Yvette, France. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP 13 PY 2012 VL 9 SU 2 AR P346 DI 10.1186/1742-4690-9-S2-P346 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100419 ER PT J AU Banerjee, K Balsitis, S Jamil, T Jones, C Dey, A Flandez, J Brito, L Cu, Y Beard, C Santra, S Pal, R Miller, N Valiante, NM Mason, P Barnett, SW Otten, GR AF Banerjee, K. Balsitis, S. Jamil, T. Jones, C. Dey, A. Flandez, J. Brito, L. Cu, Y. Beard, C. Santra, S. Pal, R. Miller, N. Valiante, N. M. Mason, P. Barnett, S. W. Otten, G. R. TI Prime-boost regimen potency and efficacy with alphavirus replicons (SIV antigen) in non-human primates challenged with low-dose intra-rectal SIVsmE660 SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Banerjee, K.; Balsitis, S.; Jamil, T.; Jones, C.; Dey, A.; Flandez, J.; Brito, L.; Cu, Y.; Beard, C.; Valiante, N. M.; Mason, P.; Barnett, S. W.; Otten, G. R.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Santra, S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Pal, R.] Adv Biosci Labs, Kensington, MD USA. [Miller, N.] NIAID, Div AIDS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR O8 DI 10.1186/1742-4690-9-S2-O8 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100009 ER PT J AU Bart, P Huang, Y Frahm, N Karuna, S Allen, M Kochar, NK Chappuis, S Gaillard, J Graham, B Pantaleo, G AF Bart, P. Huang, Y. Frahm, N. Karuna, S. Allen, M. Kochar, N. K. Chappuis, S. Gaillard, J. Graham, B. Pantaleo, G. TI rAd5 prime/NYVAC-B boost regimen is superior to NYVAC-B prime/rAd5 boost regimen for both response rates and magnitude of CD4 and CD8 T-cell responses SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Bart, P.; Chappuis, S.; Pantaleo, G.] CHU Vaudois, CH-1011 Lausanne, Switzerland. [Huang, Y.] SCHARP, Seattle, WA USA. [Frahm, N.; Karuna, S.; Kochar, N. K.] HVTN, Seattle, WA USA. [Allen, M.] NIAID, DAIDS, NIH, Bethesda, MD 20892 USA. [Graham, B.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RI Pantaleo, Giuseppe/K-6163-2016 NR 0 TC 2 Z9 2 U1 1 U2 3 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 SEP 13 PY 2012 VL 9 SU 2 AR O72 DI 10.1186/1742-4690-9-S2-O72 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100073 ER PT J AU Chakrabarti, BK Yu, F McKee, K Labranche, C Montefiori, D Mascola, JR Wyatt, RT AF Chakrabarti, B. K. Yu, F. McKee, K. Labranche, C. Montefiori, D. Mascola, J. R. Wyatt, R. T. TI Priming with DNA encoding functional trimers and boosting with soluble trimeric protein elicited tier 2 neutralizing antibodies in non-human primates SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Chakrabarti, B. K.; Yu, F.; Wyatt, R. T.] Scripps Res Inst, Int AIDS Vaccine Initiat, La Jolla, CA 92037 USA. [McKee, K.; Mascola, J. R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD USA. [Labranche, C.; Montefiori, D.] Duke Univ, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP 13 PY 2012 VL 9 SU 2 AR P314 DI 10.1186/1742-4690-9-S2-P314 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100387 ER PT J AU Chen, H Ndhlovu, ZM Liu, D Porter, LC Fang, JW Darko, S Brockman, MA Miura, T Brumme, ZL Schneidewind, A Piechocka-Trocha, A Cesa, KT Sela, J Cung, TD Toth, I Pereyra, F Yu, XG Douek, DC Kaufmann, DE Allen, TM Walker, BD AF Chen, H. Ndhlovu, Z. M. Liu, D. Porter, L. C. Fang, J. W. Darko, S. Brockman, M. A. Miura, T. Brumme, Z. L. Schneidewind, A. Piechocka-Trocha, A. Cesa, K. T. Sela, J. Cung, T. D. Toth, I. Pereyra, F. Yu, X. G. Douek, D. C. Kaufmann, D. E. Allen, T. M. Walker, B. D. TI T cell receptor clonotypes modulate the protective effect of human leukocyte antigen class I alleles in HIV-1 infection SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Chen, H.; Ndhlovu, Z. M.; Liu, D.; Porter, L. C.; Fang, J. W.; Brockman, M. A.; Miura, T.; Brumme, Z. L.; Schneidewind, A.; Piechocka-Trocha, A.; Cesa, K. T.; Sela, J.; Cung, T. D.; Toth, I.; Pereyra, F.; Yu, X. G.; Kaufmann, D. E.; Allen, T. M.; Walker, B. D.] Ragon Inst MGH MIT & Harvard, Charlestown, MA USA. [Darko, S.; Douek, D. C.] NIH, Vaccine Res Ctr, Chevy Chase, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP 13 PY 2012 VL 9 SU 2 AR P264 DI 10.1186/1742-4690-9-S2-P264 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100337 ER PT J AU Chuang, G Boyington, JC Nabel, GJ Kwong, PD Georgiev, I AF Chuang, G. Boyington, J. C. Nabel, G. J. Kwong, P. D. Georgiev, I. TI Transforming epitope-specific gp120 monomer-based probes into immunogens with N-linked glycan masking SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Chuang, G.; Boyington, J. C.; Nabel, G. J.; Kwong, P. D.; Georgiev, I.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR P318 DI 10.1186/1742-4690-9-S2-P318 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100391 ER PT J AU Dai, K Boyington, JC Shi, W Schmidt, SD Georgiev, I Lingwood, D Kwong, PD Mascola, JR Yang, Z Nabel, GJ AF Dai, K. Boyington, J. C. Shi, W. Schmidt, S. D. Georgiev, I. Lingwood, D. Kwong, P. D. Mascola, J. R. Yang, Z. Nabel, G. J. TI Hyperglycosylated resurfaced stabilized GP120 core as an immunogen elicits antibodies targeted at the CD4-binding site SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Dai, K.; Boyington, J. C.; Shi, W.; Schmidt, S. D.; Georgiev, I.; Lingwood, D.; Kwong, P. D.; Mascola, J. R.; Yang, Z.; Nabel, G. J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR P23 DI 10.1186/1742-4690-9-S2-P23 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100096 ER PT J AU Doria-Rose, NA Georgiev, I Staupe, RP O'Dell, S Chuang, G Gorman, J McLellan, JS Pancera, M Bonsignori, M Haynes, BF Burton, DR Koff, WC Kwong, PD Mascola, JR AF Doria-Rose, N. A. Georgiev, I. Staupe, R. P. O'Dell, S. Chuang, G. Gorman, J. McLellan, J. S. Pancera, M. Bonsignori, M. Haynes, B. F. Burton, D. R. Koff, W. C. Kwong, P. D. Mascola, J. R. TI A short segment in the HIV-1 gp120 V1/V2 region is a major determinant of neutralization resistance to PG9-like antibodies SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Doria-Rose, N. A.; Georgiev, I.; Staupe, R. P.; O'Dell, S.; Chuang, G.; Gorman, J.; McLellan, J. S.; Pancera, M.; Kwong, P. D.; Mascola, J. R.] NIH, Bethesda, MD 20892 USA. [Bonsignori, M.; Haynes, B. F.] Duke Univ, Durham, NC USA. [Burton, D. R.] Scripps Res Inst, La Jolla, CA 92037 USA. [Koff, W. C.] Int AIDS Vaccine Initiat, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR O29 DI 10.1186/1742-4690-9-S2-O29 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100030 ER PT J AU Enama, ME Jones, N Graham, BS Lane, HC AF Enama, M. E. Jones, N. Graham, B. S. Lane, H. C. TI Update on policy change proposal to end Institutional Biosafety Committee (IBC) review of rDNA vaccine clinical trials SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Enama, M. E.; Graham, B. S.] NIAID, VRC, NIH, Bethesda, MD 20892 USA. [Jones, N.] NIAID, OSPFM, NIH, Bethesda, MD 20892 USA. [Lane, H. C.] NIAID, DCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P241 DI 10.1186/1742-4690-9-S2-P241 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100314 ER PT J AU Etemad, B Redd, A Serwadda, D Lutalo, T Reynolds, S Gray, R Quinn, T Sagar, M AF Etemad, B. Redd, A. Serwadda, D. Lutalo, T. Reynolds, S. Gray, R. Quinn, T. Sagar, M. TI Envelopes found early after acquisition compared to those in the chronically infected partner do not have enhanced alpha4 beta7 binding or utilization SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Etemad, B.; Sagar, M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Redd, A.; Quinn, T.] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. [Serwadda, D.; Lutalo, T.] Makerere Univ, Kampala, Uganda. [Reynolds, S.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Gray, R.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. NR 0 TC 0 Z9 1 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 SEP 13 PY 2012 VL 9 SU 2 AR P149 DI 10.1186/1742-4690-9-S2-P149 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100222 ER PT J AU Franchini, G Pegu, P Gordon, S Keele, B Doster, M Guan, Y Ferrari, G Pal, R Ferrari, MG Whitney, S Hudacik, L Billings, E Rao, M Montefiori, D Venzon, D Fenizia, C Lifson, J Stablein, D Tartaglia, J Michael, N Kim, J AF Franchini, G. Pegu, P. Gordon, S. Keele, B. Doster, M. Guan, Y. Ferrari, G. Pal, R. Ferrari, M. G. Whitney, S. Hudacik, L. Billings, E. Rao, M. Montefiori, D. Venzon, D. Fenizia, C. Lifson, J. Stablein, D. Tartaglia, J. Michael, N. Kim, J. TI Antibodies to the envelope protein protect macaques from SIVmac251 acquisition in an immunization regimen that mimics the RV-144 Thai trial SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Franchini, G.; Pegu, P.; Gordon, S.; Doster, M.; Venzon, D.; Fenizia, C.] NCI, NIH, Bethesda, MD 20892 USA. [Keele, B.; Lifson, J.; Stablein, D.] NCI Frederick, Frederick, MD USA. [Guan, Y.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Pal, R.; Ferrari, M. G.; Whitney, S.; Hudacik, L.] Adv Biosci Labs, Rockville, MD USA. [Billings, E.; Rao, M.] USA, Inst Res, Silver Spring, MD USA. [Montefiori, D.] Duke Univ, Med Ctr, Durham, NC USA. [Tartaglia, J.] Sanofi Pasteur Inc, Swifter, PA USA. [Michael, N.; Kim, J.] Walter Reed Army Inst Res, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR O2 DI 10.1186/1742-4690-9-S2-O2 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100003 ER PT J AU Fuchs, JD Frank, I Kochar, N Elizaga, M Allen, M Carter, D Frahm, N Kalams, SA Mulligan, M Sheets, R Pensiero, M Clarke, D Eldridge, J AF Fuchs, J. D. Frank, I. Kochar, N. Elizaga, M. Allen, M. Carter, D. Frahm, N. Kalams, S. A. Mulligan, M. Sheets, R. Pensiero, M. Clarke, D. Eldridge, J. TI First-in-human phase I clinical trial of a recombinant vesicular stomatitis virus (rVSV)-based preventive HIV-1 vaccine SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Fuchs, J. D.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Frank, I.] Univ Penn, Philadelphia, PA 19104 USA. [Allen, M.; Sheets, R.; Pensiero, M.] NIH, Div Aids, Bethesda, MD 20892 USA. [Kalams, S. A.] Vanderbilt Univ, Nashville, TN 37235 USA. [Mulligan, M.] Emory Univ, Atlanta, GA 30322 USA. OI Allen, Mary/0000-0001-8163-0714 NR 0 TC 3 Z9 3 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR P134 DI 10.1186/1742-4690-9-S2-P134 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100207 ER PT J AU Fuchs, JD Morgan, C Bart, P Kochar, N Frahm, N Swann, E Gilbert, P DeRosa, S Graham, B Nabel, G Liao, H Haynes, B Tomaras, G AF Fuchs, J. D. Morgan, C. Bart, P. Kochar, N. Frahm, N. Swann, E. Gilbert, P. DeRosa, S. Graham, B. Nabel, G. Liao, H. Haynes, B. Tomaras, G. TI DNA and recombinant adenovirus serotype 35 and 5 preventive HIV-1 vaccines with Env A inserts elicit cross-clade binding and V1V2 antibodies SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Fuchs, J. D.; Tomaras, G.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Morgan, C.; Kochar, N.; Frahm, N.; Gilbert, P.; DeRosa, S.] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Bart, P.] CHU Vaudois, Lausanne, Switzerland. [Swann, E.] NIH, Div Aids, Bethesda, MD 20892 USA. [Graham, B.; Nabel, G.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Liao, H.; Haynes, B.; Tomaras, G.] Duke Univ, Durham, NC 27706 USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P136 DI 10.1186/1742-4690-9-S2-P136 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100209 ER PT J AU Georgiev, I Acharya, P Schmidt, SD Li, Y Wycuff, D Ofek, G Doria-Rose, N Luongo, TS Yang, Y Zhou, T Donald, BR Mascola, JR Kwong, PD AF Georgiev, I. Acharya, P. Schmidt, S. D. Li, Y. Wycuff, D. Ofek, G. Doria-Rose, N. Luongo, T. S. Yang, Y. Zhou, T. Donald, B. R. Mascola, J. R. Kwong, P. D. TI Design of epitope-specific probes for sera analysis and antibody isolation SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Georgiev, I.; Acharya, P.; Schmidt, S. D.; Ofek, G.; Doria-Rose, N.; Luongo, T. S.; Yang, Y.; Zhou, T.; Mascola, J. R.; Kwong, P. D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Li, Y.] Scripps Res Inst, La Jolla, CA 92037 USA. [Donald, B. R.] Duke Univ, Durham, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100123 ER PT J AU Goepfert, P Elizaga, M Montefiori, D Hural, J DeRosa, S Tomaras, G Seaton, K Sato, A Ouedraogo, L Donastorg, Y Cardinali, M Lama, J Baden, L Keefer, M McElrath, J Kalams, S Robinson, H AF Goepfert, P. Elizaga, M. Montefiori, D. Hural, J. DeRosa, S. Tomaras, G. Seaton, K. Sato, A. Ouedraogo, L. Donastorg, Y. Cardinali, M. Lama, J. Baden, L. Keefer, M. McElrath, J. Kalams, S. Robinson, H. TI Phase 2a safety and immunogenicity testing of DNA and recombinant modified vaccinia ankara virus vaccines expressing virus-like particles SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Goepfert, P.] Univ Alabama Birmingham, Birmingham, AL USA. [Elizaga, M.; Hural, J.; DeRosa, S.; Sato, A.; McElrath, J.] Fred Hutchinson Canc Res Inst, Seattle, WA 98104 USA. [Montefiori, D.; Tomaras, G.; Seaton, K.] Duke Univ, Durham, NC USA. [Ouedraogo, L.; Cardinali, M.] NIAID, Vaccine Clin Res Branch, Bethesda, MD 20892 USA. [Donastorg, Y.] Unidad Vacunas IDCP COIN DIGECITSS, Santo Dominago, Dominican Rep. [Lama, J.] Asociac Civil IMPACTA Salud & Educ, Lima, Peru. [Baden, L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Keefer, M.] Univ Rochester, Rochester, NY USA. [Kalams, S.] Vanderbilt Univ, Nashville, TN USA. [Robinson, H.] GeoVax Inc, Smyma, CA USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR O56 DI 10.1186/1742-4690-9-S2-O56 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100057 ER PT J AU Gorman, J McLellan, J Yang, Y Zhou, T Zhu, J Bangaru, S Bayless, N Alff, P Marshall, CP Kwong, PD AF Gorman, J. McLellan, J. Yang, Y. Zhou, T. Zhu, J. Bangaru, S. Bayless, N. Alff, P. Marshall, C. P. Kwong, P. D. TI Recombinant Env proteins that bind the quaternary-specific, V1/V2-directed PGT antibodies SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Gorman, J.; McLellan, J.; Yang, Y.; Zhou, T.; Zhu, J.; Kwong, P. D.] NIH, Bethesda, MD 20892 USA. [Bangaru, S.; Bayless, N.; Alff, P.; Marshall, C. P.] Avatar Biotechnol, Brooklyn, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P84 DI 10.1186/1742-4690-9-S2-P84 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100157 ER PT J AU Hessell, AJ Epson, E Moldt, B Rakasz, E Pandey, S Sutton, WF Brower, Z Hirsch, VM Burton, DR Haigwood, NL AF Hessell, A. J. Epson, E. Moldt, B. Rakasz, E. Pandey, S. Sutton, W. F. Brower, Z. Hirsch, V. M. Burton, D. R. Haigwood, N. L. TI Biodistribution of neutralizing monoclonal antibodies IgG1 b12 and LALA in mucosal and lymphatic tissues of rhesus macaques SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Hessell, A. J.; Epson, E.; Pandey, S.; Sutton, W. F.; Brower, Z.; Haigwood, N. L.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Moldt, B.; Burton, D. R.] Scripps Res Inst, La Jolla, CA 92037 USA. [Rakasz, E.] Univ Wisconsin, Madison, WI USA. [Hirsch, V. M.] NIAID, NIH, Bethesda, MD 20892 USA. [Burton, D. R.] IAVI Neutralizing Antibody Ctr, La Jolla, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P204 DI 10.1186/1742-4690-9-S2-P204 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100277 ER PT J AU Joyce, M Zhang, B Zhou, T Moquin, S Wu, X Louder, M Zhang, Z Georgiev, I Zhu, J Shapiro, L Mascola, JR Nabel, GJ Kwong, PD AF Joyce, M. Zhang, B. Zhou, T. Moquin, S. Wu, X. Louder, M. Zhang, Z. Georgiev, I. Zhu, J. Shapiro, L. Mascola, J. R. Nabel, G. J. Kwong, P. D. TI Characteristics of HIV-1 gp120 molecules that bind ancestor, intermediate and mature forms of VRC01-like antibodies SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Joyce, M.; Zhang, B.; Zhou, T.; Moquin, S.; Wu, X.; Louder, M.; Zhang, Z.; Georgiev, I.; Zhu, J.; Shapiro, L.; Mascola, J. R.; Nabel, G. J.; Kwong, P. D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 NR 0 TC 0 Z9 0 U1 0 U2 5 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 SEP 13 PY 2012 VL 9 SU 2 AR P68 DI 10.1186/1742-4690-9-S2-P68 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100141 ER PT J AU Koblin, B Metch, B Morgan, C Novak, R Swann, E Metzger, D Lucy, D Dunbar, D Graham, P Madenwald, T Escamia, G Frank, I AF Koblin, B. Metch, B. Morgan, C. Novak, R. Swann, E. Metzger, D. Lucy, D. Dunbar, D. Graham, P. Madenwald, T. Escamia, G. Frank, I. TI Feasibility of recruiting high-risk women in the US for HIV vaccine efficacy trials (HVTN 906) SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Koblin, B.; Lucy, D.] New York Blood Ctr, New York, NY 10021 USA. [Metch, B.; Escamia, G.] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Morgan, C.; Madenwald, T.] Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, Seattle, WA 98104 USA. [Novak, R.; Graham, P.] Univ Illinois, Chicago, IL USA. [Swann, E.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Metzger, D.; Dunbar, D.; Frank, I.] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P123 DI 10.1186/1742-4690-9-S2-P123 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100196 ER PT J AU Koerner, C Fadda, L Kumar, S van Teijlingen, N Piechocka-Trocha, A Carrington, M Altfeld, M AF Koerner, C. Fadda, L. Kumar, S. van Teijlingen, N. Piechocka-Trocha, A. Carrington, M. Altfeld, M. TI HLA-Cw*0102-restricted HIV-1 p24 epitope variants can modulate the binding of the inhibitory KIR2DL2 receptor and primary NK cell function SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Koerner, C.; Fadda, L.; Kumar, S.; van Teijlingen, N.; Piechocka-Trocha, A.; Altfeld, M.] Ragon Inst MGH MIT & Harvard, Charlestown, MA USA. [Carrington, M.] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P177 DI 10.1186/1742-4690-9-S2-P177 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100250 ER PT J AU Kwa, S Sadagopal, S Hong, J Gangadhara, S Basu, R Lai, L Iyer, S Araki, K Earl, PL Wyatt, L Villinger, F Moss, B Ahmed, R Amara, RR AF Kwa, S. Sadagopal, S. Hong, J. Gangadhara, S. Basu, R. Lai, L. Iyer, S. Araki, K. Earl, P. L. Wyatt, L. Villinger, F. Moss, B. Ahmed, R. Amara, R. R. TI CD40L adjuvant for DNA/MVA vaccine: enhanced protection from acquisition of neutralization sensitive & neutralization resistant mucosal SIV infections SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Kwa, S.; Sadagopal, S.; Hong, J.; Gangadhara, S.; Basu, R.; Lai, L.; Iyer, S.; Araki, K.; Villinger, F.; Ahmed, R.; Amara, R. R.] Emory Univ, Atlanta, GA 30322 USA. [Earl, P. L.; Wyatt, L.; Moss, B.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P365 DI 10.1186/1742-4690-9-S2-P365 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100438 ER PT J AU Kwon, Y Georgiev, I O'Dell, S Shi, W Chuang, G Yang, Y Zhang, B Zhu, J Nabel, GJ Mascola, JR Kwong, PD AF Kwon, Y. Georgiev, I. O'Dell, S. Shi, W. Chuang, G. Yang, Y. Zhang, B. Zhu, J. Nabel, G. J. Mascola, J. R. Kwong, P. D. TI Structure-guided modification and optimization of antibody VRC07 SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Kwon, Y.; Georgiev, I.; O'Dell, S.; Shi, W.; Chuang, G.; Yang, Y.; Zhang, B.; Zhu, J.; Nabel, G. J.; Mascola, J. R.; Kwong, P. D.] NIH, Kensington, MD USA. RI Kwon, Young Do/A-6957-2010 NR 0 TC 0 Z9 0 U1 1 U2 3 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 SEP 13 PY 2012 VL 9 SU 2 AR O34 DI 10.1186/1742-4690-9-S2-O34 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100035 ER PT J AU Li, J Valentin, A Kulkarni, V Alicea, C Beach, RK Rosati, M Jalah, R Reed, S Felber, BK Pavlakis, GN AF Li, J. Valentin, A. Kulkarni, V. Alicea, C. Beach, R. Kelly Rosati, M. Jalah, R. Reed, S. Felber, B. K. Pavlakis, G. N. TI Co-immunization with HIV Env DNA and protein elicit long-lasting strong cellular and humoral immune responses SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Li, J.; Valentin, A.; Kulkarni, V.; Alicea, C.; Beach, R. Kelly; Rosati, M.; Jalah, R.; Felber, B. K.; Pavlakis, G. N.] Frederick Natl Lab Canc Res, Frederick, MD USA. [Reed, S.] Infect Dis Res Inst, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR P340 DI 10.1186/1742-4690-9-S2-P340 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100413 ER PT J AU Li, Y O'Dell, S Wilson, R Wu, X Schmidt, SD Hogerkorp, C Louder, MK Longo, N Poulsen, C Guenaga, J Chakrabarti, B Doria-Rose, N Roederer, M Connors, M Mascola, JR Wyatt, RT AF Li, Y. O'Dell, S. Wilson, R. Wu, X. Schmidt, S. D. Hogerkorp, C. Louder, M. K. Longo, N. Poulsen, C. Guenaga, J. Chakrabarti, B. Doria-Rose, N. Roederer, M. Connors, M. Mascola, J. R. Wyatt, R. T. TI HIV-1 neutralizing antibodies display dual specificity for the primary and coreceptor binding sites and preferential recognition of fully-cleaved Env SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Li, Y.; Wilson, R.; Poulsen, C.; Guenaga, J.; Chakrabarti, B.; Wyatt, R. T.] Scripps Res Inst, IAVI, La Jolla, CA 92037 USA. [O'Dell, S.; Wu, X.; Schmidt, S. D.; Hogerkorp, C.; Louder, M. K.; Longo, N.; Doria-Rose, N.; Roederer, M.; Mascola, J. R.] NIAID, VRC, NIH, Bethesda, MD 20892 USA. RI Poulsen, Christian/M-4638-2014 NR 0 TC 0 Z9 0 U1 0 U2 3 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 SEP 13 PY 2012 VL 9 SU 2 AR P99 DI 10.1186/1742-4690-9-S2-P99 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100172 ER PT J AU Liang, F Sandgren, KJ Fausther-Bovendo, H O'hagan, D Seubert, A De Gregorio, E Rao, S Sullivan, N Seder, RA Koup, RA Lore, K AF Liang, F. Sandgren, K. J. Fausther-Bovendo, H. O'hagan, D. Seubert, A. De Gregorio, E. Rao, S. Sullivan, N. Seder, R. A. Koup, R. A. Lore, K. TI Infiltration of dendritic cells and antigen uptake in the muscle after injection of HIV-1 Env gp120 in adjuvant SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Fausther-Bovendo, H.; Rao, S.; Sullivan, N.; Seder, R. A.; Koup, R. A.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [O'hagan, D.; Seubert, A.; De Gregorio, E.] Novartis Vaccines & Diagnost, Cambridge, MD USA. [Liang, F.; Sandgren, K. J.; Lore, K.] Karolinska Inst, Stockholm, Sweden. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR O16 DI 10.1186/1742-4690-9-S2-O16 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100017 ER PT J AU Liao, L Bonsignori, M Hwang, K Moody, AM Park, R Crawford, S Chen, H Jeffries, TL Cooper, M Lu, X De, R Karasavvas, N Rerks-Ngarm, S Nitayaphan, S Kaewkungwal, J Tovanabutra, S Pitisuttithum, P Tartaglia, J Sinangil, F Kim, J Michael, NL Tomaras, GD Yang, Z Dai, K Pancera, M Nabel, GJ Mascola, JR Kwong, PD Pinter, A Zolla-Pazner, S Alam, MS Haynes, BF AF Liao, L. Bonsignori, M. Hwang, K. Moody, A. M. Park, R. Crawford, S. Chen, H. Jeffries, T. L. Cooper, M. Lu, X. De, R. Karasavvas, N. Rerks-Ngarm, S. Nitayaphan, S. Kaewkungwal, J. Tovanabutra, S. Pitisuttithum, P. Tartaglia, J. Sinangil, F. Kim, J. Michael, N. L. Tomaras, G. D. Yang, Z. Dai, K. Pancera, M. Nabel, G. J. Mascola, J. R. Kwong, P. D. Pinter, A. Zolla-Pazner, S. Alam, M. S. Haynes, B. F. TI Design of an HIV Env antigen that binds with high affinity to antibodies against linear, conformational and broadly neutralizing epitopes within V1/V2 SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Liao, L.; Bonsignori, M.; Hwang, K.; Moody, A. M.; Park, R.; Crawford, S.; Chen, H.; Jeffries, T. L.; Cooper, M.; Lu, X.; De, R.; Tomaras, G. D.; Alam, M. S.; Haynes, B. F.] Duke Univ, Med Ctr, Durham, NC USA. [Karasavvas, N.; Tovanabutra, S.; Kim, J.; Michael, N. L.] Walter Reed Army Inst Res, US MHRP, Silver Spring, MD USA. [Rerks-Ngarm, S.] Minist Publ Hlth, Dept Dis Control, Nonthaburi, Thailand. [Nitayaphan, S.] AFRIMS, US Army Med Component, Dept Retrovirol, Bangkok, Thailand. [Kaewkungwal, J.] Mahidol Univ, Fac Trop Med, BIOPHICS, Bangkok 10700, Thailand. [Tartaglia, J.] Sanofi Pasteur, Dept Res & Dev, Swiftwater, PA USA. [Sinangil, F.] Global Solut Infect Dis, San Francisco, CA USA. [Yang, Z.; Dai, K.; Pancera, M.; Nabel, G. J.; Mascola, J. R.; Kwong, P. D.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Pinter, A.] Univ Med & Dent New Jersey, New Jersey Med Sch, Publ Hlth Res Inst Ctr, Newark, NJ 07103 USA. [Zolla-Pazner, S.] Vet Affairs New York Harbor Healthcare Syst, New York, NY USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 1 Z9 1 U1 0 U2 5 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 SEP 13 PY 2012 VL 9 SU 2 AR O31 DI 10.1186/1742-4690-9-S2-O31 PG 2 WC Virology SC Virology GA 015UO UT WOS:000309472100032 ER PT J AU Liyanage, NP Pegu, P Gordon, S Cameron, M Foulds, K Doster, M Vaccari, M Koup, R Roederer, M Sekaly, R Franchini, G AF Liyanage, N. P. Pegu, P. Gordon, S. Cameron, M. Foulds, K. Doster, M. Vaccari, M. Koup, R. Roederer, M. Sekaly, R. Franchini, G. TI RV144-like trial in macaques using ALVAC-SIV & gp120 induces innate immunity and increases the frequency of NK22 & NKG2A+cells in mucosal tissues SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Liyanage, N. P.; Pegu, P.; Gordon, S.; Doster, M.; Vaccari, M.; Franchini, G.] Anim Models & Retroviral Vaccines Sect, Bethesda, MD USA. [Foulds, K.; Koup, R.; Roederer, M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP 13 PY 2012 VL 9 SU 2 AR O14 DI 10.1186/1742-4690-9-S2-O14 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100015 ER PT J AU Longo, NS Doria-Rose, N McKee, K O'Dell, S Louder, MK Yang, Z Bailer, R Mascola, JR AF Longo, N. S. Doria-Rose, N. McKee, K. O'Dell, S. Louder, M. K. Yang, Z. Bailer, R. Mascola, J. R. TI Isolation of broadly neutralizing HIV-1 antibodies from high-throughput single B cell culture SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Longo, N. S.; Doria-Rose, N.; McKee, K.; O'Dell, S.; Louder, M. K.; Yang, Z.; Bailer, R.; Mascola, J. R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 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 SEP 13 PY 2012 VL 9 SU 2 AR P91 DI 10.1186/1742-4690-9-S2-P91 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100164 ER PT J AU Lynch, RM Tran, L Wu, X Li, Y Lee, B Mascola, J AF Lynch, R. M. Tran, L. Wu, X. Li, Y. Lee, B. Mascola, J. TI Characterizing the fitness cost of viral escape from the HIV-1 broadly neutralizing monoclonal antibody VRC01 SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Lynch, R. M.; Tran, L.; Wu, X.; Mascola, J.] NIAID, NIH, Bethesda, MD 20892 USA. [Li, Y.] Scripps Res Inst, La Jolla, CA 92037 USA. [Lee, B.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 3 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 SEP 13 PY 2012 VL 9 SU 2 AR P87 DI 10.1186/1742-4690-9-S2-P87 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100160 ER PT J AU McLellan, JS Gorman, J Bonsignori, M Hwang, K Liao, H Rerks-Ngarm, S Nitayaphan, S Michael, NL Kim, JH Haynes, BF Kwong, PD AF McLellan, J. S. Gorman, J. Bonsignori, M. Hwang, K. Liao, H. Rerks-Ngarm, S. Nitayaphan, S. Michael, N. L. Kim, J. H. Haynes, B. F. Kwong, P. D. TI V1/V2-directed antibodies elicited in RV144 vaccinees bind to a structurally polymorphic site SO RETROVIROLOGY LA English DT Meeting Abstract C1 [McLellan, J. S.; Gorman, J.; Kwong, P. D.] NIH, Bethesda, MD 20892 USA. [Bonsignori, M.; Hwang, K.; Liao, H.; Haynes, B. F.] Duke Human Vaccine Inst, Durham, NC USA. [Rerks-Ngarm, S.] Dept Dis Control, Bangkok, Thailand. [Nitayaphan, S.] Dept Retrovirol, Bangkok, Thailand. [Nitayaphan, S.] AFRIM, Bangkok, Thailand. [Michael, N. L.; Kim, J. H.] US Mil HIV Res Program, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P107 DI 10.1186/1742-4690-9-S2-P107 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100180 ER PT J AU Montefiori, DC Huang, Y Karuna, S Allen, M Kochar, N Chappuis, S Gaillard, J Tomaras, G Graham, B Bart, P Pantaleo, G AF Montefiori, D. C. Huang, Y. Karuna, S. Allen, M. Kochar, N. Chappuis, S. Gaillard, J. Tomaras, G. Graham, B. Bart, P. Pantaleo, G. TI rAd5/NYVAC-B is superior to NYVAC-B/rAd5 and is dependent on rAd5 dose for neutralizing antibody responses against HIV-1 SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Montefiori, D. C.; Tomaras, G.] Duke Univ, Med Ctr, Durham, NC USA. [Huang, Y.; Kochar, N.] SCHARP, Seattle, WA USA. [Karuna, S.] Fred Hutchinson Canc Res Ctr, HVTN, Seattle, WA 98104 USA. [Allen, M.] NIAID, NIH, Bethesda, MD 20892 USA. [Chappuis, S.; Gaillard, J.; Bart, P.; Pantaleo, G.] Univ Lausanne Hosp, Lausanne, Switzerland. [Graham, B.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RI Tomaras, Georgia/J-5041-2016; Pantaleo, Giuseppe/K-6163-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P132 DI 10.1186/1742-4690-9-S2-P132 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100205 ER PT J AU Mothe, B Llano, A Rosati, M Perez-Alvarez, S Kulkarni, V Chowdhury, B Alicea, C Beach, RK Sardesai, NY Pavlakis, GN Felber, BK Brander, C AF Mothe, B. Llano, A. Rosati, M. Perez-Alvarez, S. Kulkarni, V. Chowdhury, B. Alicea, C. Beach, R. K. Sardesai, N. Y. Pavlakis, G. N. Felber, B. K. Brander, C. TI A minimal T-cell immunogen designed to cover HIV-1 specificities associated with control is immunogenic in mice and breaks CTL immunodominance SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Rosati, M.; Kulkarni, V.; Chowdhury, B.; Alicea, C.; Beach, R. K.; Pavlakis, G. N.; Felber, B. K.] NCI Frederick, Frederick, MD USA. [Sardesai, N. Y.] Inovio Biomed Corp, Blue Bell, PA USA. [Mothe, B.; Llano, A.; Perez-Alvarez, S.; Brander, C.] ICREA, IrsiCaixa AIDS Res Inst HIVACAT, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR P305 DI 10.1186/1742-4690-9-S2-P305 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100378 ER PT J AU Nemazee, D Doyle-Cooper, C Ota, T Cooper, AB Huber, M Falkowska, E Doores, K Hangartner, L Le, K Sok, D Jardine, J Lifson, J Wu, X Mascola, JR Poignard, P Binley, JM Chakrabarti, BK Schief, WR Wyatt, RT Burton, DR AF Nemazee, D. Doyle-Cooper, C. Ota, T. Cooper, A. B. Huber, M. Falkowska, E. Doores, K. Hangartner, L. Le, K. Sok, D. Jardine, J. Lifson, J. Wu, X. Mascola, J. R. Poignard, P. Binley, J. M. Chakrabarti, B. K. Schief, W. R. Wyatt, R. T. Burton, D. R. TI Engineered mice and B cell lines expressing broadly neutralizing antibodies and their unmutated precursors: tools for HIV vaccinology SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Nemazee, D.; Doyle-Cooper, C.; Ota, T.; Cooper, A. B.; Huber, M.; Falkowska, E.; Doores, K.; Hangartner, L.; Le, K.; Sok, D.; Jardine, J.; Poignard, P.] Scripps Res Inst, La Jolla, CA 92037 USA. [Lifson, J.] Frederick Natl Lab Canc Res, Frederick, MD USA. [Wu, X.; Mascola, J. R.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Binley, J. M.] Torrey Pines Inst, La Jolla, CA USA. RI Hangartner, Lars/H-3503-2011; poignard, pascal/N-6678-2013 NR 0 TC 0 Z9 0 U1 0 U2 9 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 SEP 13 PY 2012 VL 9 SU 2 AR O41 DI 10.1186/1742-4690-9-S2-O41 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100042 ER PT J AU Ofek, G Zhu, J Yang, Y Zhang, B Mckee, K Louder, M Huang, J Laub, L Connors, M Mascola, J Kwong, PD AF Ofek, G. Zhu, J. Yang, Y. Zhang, B. Mckee, K. Louder, M. Huang, J. Laub, L. Connors, M. Mascola, J. Kwong, P. D. TI 454 pyrosequencing and bioinformatics analysis of the lineage of the broad and potent gp41-directed antibody 10e8 SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Huang, J.; Laub, L.; Connors, M.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD USA. [Ofek, G.; Zhu, J.; Yang, Y.; Zhang, B.; Mckee, K.; Louder, M.; Mascola, J.; Kwong, P. D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 SEP 13 PY 2012 VL 9 SU 2 AR O40 DI 10.1186/1742-4690-9-S2-O40 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100041 ER PT J AU Pancera, M McLellan, JS Shahzad-ul-Hussan, S Doria-Rose, N Zhang, B Yang, Y Burton, DR Koff, WC Bewley, CA Kwong, PD AF Pancera, M. McLellan, J. S. Shahzad-ul-Hussan, S. Doria-Rose, N. Zhang, B. Yang, Y. Burton, D. R. Koff, W. C. Bewley, C. A. Kwong, P. D. TI Structural comparison of somatically related PG9 and PG16 in complex with their epitope reveals differences in glycan recognition SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Pancera, M.; McLellan, J. S.; Shahzad-ul-Hussan, S.; Doria-Rose, N.; Zhang, B.; Yang, Y.; Burton, D. R.; Koff, W. C.; Bewley, C. A.; Kwong, P. D.] NIAID, NIH, VRC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 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 SEP 13 PY 2012 VL 9 SU 2 AR P74 DI 10.1186/1742-4690-9-S2-P74 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100147 ER PT J AU Pavlakis, GN Kulkarni, V Valentin, A Rosati, M Sardesai, NY Mothe, B Brander, C LeGall, S Weiner, DB Rolland, M Mullins, JI Felber, BK AF Pavlakis, G. N. Kulkarni, V. Valentin, A. Rosati, M. Sardesai, N. Y. Mothe, B. Brander, C. LeGall, S. Weiner, D. B. Rolland, M. Mullins, J. I. Felber, B. K. TI DNA vaccines expressing conserved elements provide potent and broad immune responses SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Sardesai, N. Y.] Inovio Pharmaceut Inc, Blue Bell, PA USA. [Mothe, B.; Brander, C.] IrsiCaixa HIVACAT, Barcelona, Spain. [LeGall, S.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Weiner, D. B.] Univ Penn, Philadelphia, PA 19104 USA. [Rolland, M.] US Mil HIV Res Program, Rockville, MD USA. [Mullins, J. I.] Univ Washington, Seattle, WA 98195 USA. [Felber, B. K.] Frederick Natl Lab Canc Res, Frederick, MD USA. RI Weiner, David/H-8579-2014 NR 0 TC 0 Z9 0 U1 0 U2 3 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 SEP 13 PY 2012 VL 9 SU 2 AR O67 DI 10.1186/1742-4690-9-S2-O67 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100068 ER PT J AU Penezina, O Clapham, D Collins, J Kovalenko, V Krueger, N Rodriguez-Chavez, IR Busch, MP Levin, AE AF Penezina, O. Clapham, D. Collins, J. Kovalenko, V. Krueger, N. Rodriguez-Chavez, I. R. Busch, M. P. Levin, A. E. TI New HIV peptide-based immunoassay resolves vaccine-induced seropositivity in HIV vaccine (Phase III) trial participants SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Penezina, O.; Clapham, D.; Collins, J.; Kovalenko, V.; Krueger, N.; Levin, A. E.] Immunetics, Boston, MA USA. [Busch, M. P.] Blood Syst Res Inst, San Francisco, CA USA. [Rodriguez-Chavez, I. R.] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 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 SEP 13 PY 2012 VL 9 SU 2 AR P120 DI 10.1186/1742-4690-9-S2-P120 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100193 ER PT J AU Rao, M Karasavvas, N Pinter, A Liao, H Bonsignori, M Mathieson, B Zolla-Pazner, S Haynes, BF Michael, NL Kim, JH Alving, CR Peachman, KK AF Rao, M. Karasavvas, N. Pinter, A. Liao, H. Bonsignori, M. Mathieson, B. Zolla-Pazner, S. Haynes, B. F. Michael, N. L. Kim, J. H. Alving, C. R. Peachman, K. K. TI Detection of antibodies to the alpha 4 beta 7 integrin binding site on HIV-1 gp120 V2 loop using a novel cell adhesion assay SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Rao, M.; Michael, N. L.; Kim, J. H.; Alving, C. R.] US Mil HIV Res Program, WRAIR, Silver Spring, MD USA. [Karasavvas, N.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Pinter, A.] Int Cente, Publ Hlth Res Inst Ctr, Newark, NJ USA. [Liao, H.; Bonsignori, M.; Haynes, B. F.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Mathieson, B.] NIH, Off AIDS Res, Bethesda, MD 20892 USA. [Zolla-Pazner, S.] NYU, Sch Med, New York, NY USA. [Peachman, K. K.] US Mil HIV Res Program, WRAIR HJF, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR P71 DI 10.1186/1742-4690-9-S2-P71 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100144 ER PT J AU Riou, C Abrahams, M Mlisana, K Koup, R Roederer, M Karim, SA de Bruyn, G Williamson, C Gray, CM Burgers, WA AF Riou, C. Abrahams, M. Mlisana, K. Koup, R. Roederer, M. Karim, S. Abdool de Bruyn, G. Williamson, C. Gray, C. M. Burgers, W. A. TI Increased differentiation associates with decreased polyfunctionality for HIV but not CMV-specific CD8+T cell responses SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Abrahams, M.; Williamson, C.; Burgers, W. A.] Univ Cape Town, Div Virol, ZA-7925 Cape Town, South Africa. [Mlisana, K.; Karim, S. Abdool] Univ KwaZulu Natal, CAPRISA, Durban, South Africa. [Mlisana, K.] Univ KwaZulu Natal, Dept Med Microbiol, Durban, South Africa. [Koup, R.; Roederer, M.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [de Bruyn, G.] Chris Hani Baragwanath Hosp, Perinatal HIV Res Unit, Johannesburg, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP 13 PY 2012 VL 9 SU 2 AR P250 DI 10.1186/1742-4690-9-S2-P250 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100323 ER PT J AU Robinson, H Kannanganat, S Gangadhara, S Lai, L Yu, T Kozlowski, P Earl, P Moss, B Amara, RR AF Robinson, H. Kannanganat, S. Gangadhara, S. Lai, L. Yu, T. Kozlowski, P. Earl, P. Moss, B. Amara, R. R. TI GM-CSF co-expressing DNA/MVA vaccine, prevention of acquisition by two series of SIVE660 challenges followed by a series of SIV251 challenges SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Robinson, H.] GeoVax Inc, Smyrna, GA USA. [Kannanganat, S.; Gangadhara, S.; Lai, L.; Yu, T.; Amara, R. R.] Emory Univ, Atlanta, GA 30322 USA. [Kozlowski, P.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Earl, P.; Moss, B.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P25 DI 10.1186/1742-4690-9-S2-P25 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100098 ER PT J AU Rudicell, RS Georgiev, I Yang, Z O'Dell, S Kwon, Y Zhu, J Wu, X Kwong, PD Mascola, JR Nabel, GJ AF Rudicell, R. S. Georgiev, I. Yang, Z. O'Dell, S. Kwon, Y. Zhu, J. Wu, X. Kwong, P. D. Mascola, J. R. Nabel, G. J. TI Partial germline reversions can increase VRC07 potency and breadth SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Rudicell, R. S.; Georgiev, I.; Yang, Z.; O'Dell, S.; Kwon, Y.; Zhu, J.; Wu, X.; Kwong, P. D.; Mascola, J. R.; Nabel, G. J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RI Kwon, Young Do/A-6957-2010 NR 0 TC 0 Z9 0 U1 0 U2 2 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 SEP 13 PY 2012 VL 9 SU 2 AR P101 DI 10.1186/1742-4690-9-S2-P101 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100174 ER PT J AU Sastry, M Xu, L Bhattacharya, S Nabel, GJ Bewley, CA Kwong, PD AF Sastry, M. Xu, L. Bhattacharya, S. Nabel, G. J. Bewley, C. A. Kwong, P. D. TI NMR spectroscopy of HIV-1 gp120 outer domain SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Sastry, M.; Xu, L.; Nabel, G. J.; Kwong, P. D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bhattacharya, S.] New York Struct Biol Ctr, New York, NY USA. [Bewley, C. A.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P20 DI 10.1186/1742-4690-9-S2-P20 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100093 ER PT J AU Sholukh, AM Siddappa, NB Shanmuganathan, V Lakhashe, SK Rasmussen, RA Watkins, JD Vyas, HK Mukhtar, MM Hemashettar, G Thorat, S Yoon, JK Villinger, F Novembre, FJ Landucci, G Forthal, DN Ratcliffe, S Robert-Guroff, M Polonis, V Montefiori, DC Ertl, HC Ruprecht, RM AF Sholukh, A. M. Siddappa, N. B. Shanmuganathan, V. Lakhashe, S. K. Rasmussen, R. A. Watkins, J. D. Vyas, H. K. Mukhtar, M. M. Hemashettar, G. Thorat, S. Yoon, J. K. Villinger, F. Novembre, F. J. Landucci, G. Forthal, D. N. Ratcliffe, S. Robert-Guroff, M. Polonis, V. Montefiori, D. C. Ertl, H. C. Ruprecht, R. M. TI Passive immunization with polyclonal anti-SHIV IgG: partial protection or increased acquisition of heterologous tier 2 SHIV - depending on IgG dose SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Villinger, F.; Novembre, F. J.] Yerkes Natl Primate Res Ctr, Atlanta, GA USA. [Villinger, F.; Novembre, F. J.] Emory Univ, Atlanta, GA 30322 USA. [Landucci, G.; Forthal, D. N.] Univ Calif Irvine, Div Infect Dis, Irvine, CA USA. [Ratcliffe, S.] Univ Penn, Philadelphia, PA 19104 USA. [Robert-Guroff, M.] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Polonis, V.] Walter Reed Army Inst Res, Mil HIV Res Program, Silver Spring, MD USA. [Montefiori, D. C.] Duke Univ, Sch Med, Dept Surg, Durham, NC USA. [Ertl, H. C.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Sholukh, A. M.; Siddappa, N. B.; Lakhashe, S. K.; Rasmussen, R. A.; Watkins, J. D.; Vyas, H. K.; Mukhtar, M. M.; Thorat, S.; Ruprecht, R. M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 PG 2 WC Virology SC Virology GA 015UO UT WOS:000309472100114 ER PT J AU Spearman, P Tomaras, G Montefiori, D Huang, Y Ahmed, H Elizaga, M Hural, J McElrath, J Ouedraogo, L Pensiero, M Butler, C Kalams, S Overton, ET Barnett, S Group, N AF Spearman, P. Tomaras, G. Montefiori, D. Huang, Y. Ahmed, H. Elizaga, M. Hural, J. McElrath, J. Ouedraogo, L. Pensiero, M. Butler, C. Kalams, S. Overton, E. T. Barnett, S. Group, N. TI Rapid development of cross-clade neutralizing antibody responses after clade B gp120/gp140 protein priming and clade c gp140 protein boosting SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Spearman, P.; Group, N.] Emory Univ, Atlanta, GA 30322 USA. [Tomaras, G.; Montefiori, D.] Duke Human Vaccine Inst, Dept Surg, Durham, NC USA. [Huang, Y.; Ahmed, H.; Elizaga, M.; Hural, J.; McElrath, J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Ouedraogo, L.; Pensiero, M.; Butler, C.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Kalams, S.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Overton, E. T.] Univ Alabama Birmingham, Birmingham, AL USA. [Barnett, S.] Novartis Vaccines & Diagnost, Cambridge, MA USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR P137 DI 10.1186/1742-4690-9-S2-P137 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100210 ER PT J AU Tuero, I Robert-Guroff, M AF Tuero, I. Robert-Guroff, M. TI Changes in gd T cell function and gut homing receptors following SIV infection of rhesus macaques SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Tuero, I.; Robert-Guroff, M.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR P271 DI 10.1186/1742-4690-9-S2-P271 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100344 ER PT J AU van Teijlingen, NH Korner, C Fadda, L Brander, C Carrington, MN van Baarle, D Altfeld, M AF van Teijlingen, N. H. Koerner, C. Fadda, L. Brander, C. Carrington, M. N. van Baarle, D. Altfeld, M. TI HIV-1 p24 derived epitopes modulate KIR2DL2-binding to HLA-Cw03 SO RETROVIROLOGY LA English DT Meeting Abstract C1 [van Teijlingen, N. H.; van Baarle, D.] UMC Utrecht, Utrecht, Netherlands. [Koerner, C.; Fadda, L.; Altfeld, M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Brander, C.] IrsiCaixa Inst Recerca Sida, Barcelona, Spain. [Carrington, M. N.] NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 SEP 13 PY 2012 VL 9 SU 2 AR P180 DI 10.1186/1742-4690-9-S2-P180 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100253 ER PT J AU Williams, WB Jones, K Krambrink, A Grove, D Liu, P Yates, NL Moody, MA Ferrari, G Pollara, J Moodie, Z Morgan, CA Liao, H Montefiori, DC Ochsenbauer, C Kappes, J Hammer, S Mascola, J Koup, R Corey, L Nabel, G Gilbert, P Churchyard, G Keefer, M Graham, BS Haynes, BF Tomaras, GD AF Williams, W. B. Jones, K. Krambrink, A. Grove, D. Liu, P. Yates, N. L. Moody, M. A. Ferrari, G. Pollara, J. Moodie, Z. Morgan, C. A. Liao, H. Montefiori, D. C. Ochsenbauer, C. Kappes, J. Hammer, S. Mascola, J. Koup, R. Corey, L. Nabel, G. Gilbert, P. Churchyard, G. Keefer, M. Graham, B. S. Haynes, B. F. Tomaras, G. D. TI Multiple antibody specificities (gp41, V1V2, and V3) elicited in the phase II multiclade (A, B, C) HIV-1 DNA prime, rAd5 boost vaccine trial SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Williams, W. B.; Jones, K.; Liu, P.; Yates, N. L.; Moody, M. A.; Ferrari, G.; Pollara, J.; Liao, H.; Montefiori, D. C.; Keefer, M.; Graham, B. S.; Haynes, B. F.; Tomaras, G. D.] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC USA. [Krambrink, A.; Grove, D.; Moodie, Z.; Morgan, C. A.; Gilbert, P.] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Ochsenbauer, C.; Kappes, J.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Hammer, S.] Columbia Univ, Med Ctr, New York, NY USA. [Mascola, J.; Koup, R.; Nabel, G.; Graham, B. S.] Natl Inst Allergy & Infect, Vaccine Res Ctr, Bethesda, MD USA. [Corey, L.] Univ Washington, Seattle, WA 98195 USA. [Churchyard, G.] Aurum Inst, Johannesburg, South Africa. [Keefer, M.] Univ Rochester, Med Ctr, Div Infect Dis, Rochester, NY 14642 USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 0 Z9 0 U1 0 U2 3 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 SEP 13 PY 2012 VL 9 SU 2 AR O55 DI 10.1186/1742-4690-9-S2-O55 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100056 ER PT J AU Zhang, Z Wu, X Longo, N Zhang, B Zhu, J Nisc, C Mullikin, JC Wu, L Nabel, GJ Connors, M Kwong, PD Mascola, JR Shapiro, L AF Zhang, Z. Wu, X. Longo, N. Zhang, B. Zhu, J. Nisc, C. Mullikin, J. C. Wu, L. Nabel, G. J. Connors, M. Kwong, P. D. Mascola, J. R. Shapiro, L. TI Deep sequencing with longitudinal sampling of a VRC01-like-antibody response in a chronically infected individual SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Zhang, Z.; Shapiro, L.] Columbia Univ, New York, NY USA. [Wu, X.; Longo, N.; Zhang, B.; Zhu, J.; Wu, L.; Nabel, G. J.; Kwong, P. D.; Mascola, J. R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nisc, C.; Mullikin, J. C.] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 13 PY 2012 VL 9 SU 2 AR O36 DI 10.1186/1742-4690-9-S2-O36 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100037 ER PT J AU Zhou, T Moquin, S Lynch, R Wu, X Zhu, J Yang, Y Zhang, B Mascola, JR Kwong, PD AF Zhou, T. Moquin, S. Lynch, R. Wu, X. Zhu, J. Yang, Y. Zhang, B. Mascola, J. R. Kwong, P. D. TI Structural definition for a new modality of broad and potent antibody neutralization at the CD4-binding site on HIV-1 gp120 SO RETROVIROLOGY LA English DT Meeting Abstract C1 [Zhou, T.; Moquin, S.; Lynch, R.; Wu, X.; Zhu, J.; Yang, Y.; Zhang, B.; Mascola, J. R.; Kwong, P. D.] NIAID, NIH, Bethesda, MD 20892 USA. RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 NR 0 TC 1 Z9 1 U1 0 U2 3 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 SEP 13 PY 2012 VL 9 SU 2 AR P57 DI 10.1186/1742-4690-9-S2-P57 PG 1 WC Virology SC Virology GA 015UO UT WOS:000309472100130 ER PT J AU Schoen, RE Pinsky, PF Prorok, PC AF Schoen, Robert E. Pinsky, Paul F. Prorok, Philip C. TI Screening Flexible Sigmoidoscopy for Colon Cancer REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Schoen, Robert E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Pinsky, Paul F.; Prorok, Philip C.] NCI, Bethesda, MD 20892 USA. RP Schoen, RE (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. EM rschoen@pitt.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 13 PY 2012 VL 367 IS 11 BP 1065 EP 1066 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 003ZE UT WOS:000308649100020 ER PT J AU Glazko, GV Zybailov, BL Rogozin, IB AF Glazko, Galina V. Zybailov, Boris L. Rogozin, Igor B. TI Computational Prediction of Polycomb-Associated Long Non-Coding RNAs SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; X-CHROMOSOME; DARK-MATTER; XIST RNA; GENOME; CHROMATIN; TRANSCRIPTION; IDENTIFICATION; COMPLEXES; ELEMENTS AB Among thousands of long non-coding RNAs (lncRNAs) only a small subset is functionally characterized and the functional annotation of lncRNAs on the genomic scale remains inadequate. In this study we computationally characterized two functionally different parts of human lncRNAs transcriptome based on their ability to bind the polycomb repressive complex, PRC2. This classification is enabled by the fact that while all lncRNAs constitute a diverse set of sequences, the classes of PRC2-binding and PRC2 non-binding lncRNAs possess characteristic combinations of sequence-structure patterns and, therefore, can be separated within the feature space. Based on the specific combination of features, we built several machine-learning classifiers and identified the SVM-based classifier as the best performing. We further showed that the SVM-based classifier is able to generalize on the independent data sets. We observed that this classifier, trained on the human lncRNAs, can predict up to 59.4% of PRC2-binding lncRNAs in mice. This suggests that, despite the low degree of sequence conservation, many lncRNAs play functionally conserved biological roles. C1 [Glazko, Galina V.] Univ Arkansas Med Sci, Div Biomed Informat, Little Rock, AR 72205 USA. [Zybailov, Boris L.] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. [Rogozin, Igor B.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Glazko, GV (reprint author), Univ Arkansas Med Sci, Div Biomed Informat, Little Rock, AR 72205 USA. EM gvglazko@uams.edu; blzybaylov@uams.edu FU Arkansas Translational Research Institute; academic home at the University of Arkansas for Medical Sciences (UAMS), National Institutes of Health (NIH) grant [UL1RR029884]; UAMS Biochemistry Department Chair special fund; Intramural Research Program of the National Library of Medicine at the NIH FX This publication in part was supported by the Arkansas Translational Research Institute, with an academic home at the University of Arkansas for Medical Sciences (UAMS), National Institutes of Health (NIH) grant UL1RR029884; and by the UAMS Biochemistry Department Chair special fund to Dr. Kevin Raney. IBR was supported by the Intramural Research Program of the National Library of Medicine at the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 14 Z9 15 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2012 VL 7 IS 9 AR e44878 DI 10.1371/journal.pone.0044878 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 005ZK UT WOS:000308788700047 PM 23028655 ER PT J AU Shriner, D Herbert, A Doumatey, AP Zhou, J Huang, HX Erdos, MR Chen, GJ Gerry, NP Christman, MF Adeyemo, A Rotimi, CN AF Shriner, Daniel Herbert, Alan Doumatey, Ayo P. Zhou, Jie Huang, Hanxia Erdos, Michael R. Chen, Guanjie Gerry, Norman P. Christman, Michael F. Adeyemo, Adebowale Rotimi, Charles N. TI Multiple Loci Associated with Renal Function in African Americans SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; GENOME-WIDE ASSOCIATION; POPULATION-STRUCTURE; ADMIXED POPULATIONS; SERUM CREATININE; UNITED-STATES; VARIANTS; ANCESTRY; RISK; GENE AB The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a two-fold higher rate than European Americans. One of the two defining variables underlying staging of chronic kidney disease is the glomerular filtration rate. Meta-analysis in individuals of European ancestry has identified 23 genetic loci associated with the estimated glomerular filtration rate (eGFR). We conducted a follow-up study of these 23 genetic loci using a population-based sample of 1,018 unrelated admixed African Americans. We included in our follow-up study two variants in APOL1 associated with end-stage kidney disease discovered by admixture mapping in admixed African Americans. To address confounding due to admixture, we estimated local ancestry at each marker and global ancestry. We performed regression analysis stratified by local ancestry and combined the resulting regression estimates across ancestry strata using an inverse variance-weighted fixed effects model. We found that 11 of the 24 loci were significantly associated with eGFR in our sample. The effect size estimates were not significantly different between the subgroups of individuals with two copies of African ancestry vs. two copies of European ancestry for any of the 11 loci. In contrast, allele frequencies were significantly different at 10 of the 11 loci. Collectively, the 11 loci, including four secondary signals revealed by conditional analyses, explained 14.2% of the phenotypic variance in eGFR, in contrast to the 1.4% explained by the 24 loci in individuals of European ancestry. Our findings provide insight into the genetic basis of variation in renal function among admixed African Americans. C1 [Shriner, Daniel; Doumatey, Ayo P.; Zhou, Jie; Huang, Hanxia; Chen, Guanjie; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Herbert, Alan] Boston Univ, Sch Med, Dept Genet & Genom, Boston, MA 02118 USA. [Erdos, Michael R.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Gerry, Norman P.; Christman, Michael F.] Coriell Inst Med Res, Camden, NJ USA. RP Shriner, D (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. EM shrinerda@mail.nih.gov; rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health [S06GM008016-320107, S06GM008016-380111]; National Institutes of Health grant [2M01RR010284]; Intramural Research Program of the Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362] FX The Howard University Family Study was supported by National Institutes of Health grants S06GM008016-320107 and S06GM008016-380111. Enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). Genotyping support was provided by the Coriell Institute for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 3 Z9 3 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2012 VL 7 IS 9 AR e45112 DI 10.1371/journal.pone.0045112 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 005ZK UT WOS:000308788700088 PM 23028791 ER PT J AU Mattison, JA Roth, GS Beasley, TM Tilmont, EM Handy, AM Herbert, RL Longo, DL Allison, DB Young, JE Bryant, M Barnard, D Ward, WF Qi, WB Ingram, DK de Cabo, R AF Mattison, Julie A. Roth, George S. Beasley, T. Mark Tilmont, Edward M. Handy, April M. Herbert, Richard L. Longo, Dan L. Allison, David B. Young, Jennifer E. Bryant, Mark Barnard, Dennis Ward, Walter F. Qi, Wenbo Ingram, Donald K. de Cabo, Rafael TI Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study SO NATURE LA English DT Article ID T-CELL SENESCENCE; DIETARY RESTRICTION; LIFE-SPAN; AGE; MORTALITY; DISEASE; MODEL; RATS; MICE; INFLAMMATION AB Calorie restriction (CR), a reduction of 10-40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function(1,2), motor coordination(3) and resistance to sarcopenia(4) in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7-14 years)(5) and a preliminary report with a small number of CR monkeys(6). Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity andmortality, and similar to what has been shown in rodents(7-9), study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate. C1 [Mattison, Julie A.; Tilmont, Edward M.; Handy, April M.; Young, Jennifer E.] NIA, Lab Expt Gerontol, NIH, Anim Ctr, Dickerson, MD 20842 USA. [Roth, George S.] GeroScience, Pylesville, MD 21132 USA. [Beasley, T. Mark] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Handy, April M.] SoBran Inc, Burtonsville, MD 20866 USA. [Herbert, Richard L.] NIAID, NIH, Anim Ctr, Dickerson, MD 20842 USA. [Longo, Dan L.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Allison, David B.] Univ Alabama Birmingham, Off Energet, Birmingham, AL 35294 USA. [Bryant, Mark; Barnard, Dennis] NIH, Off Director, Diagnost & Res Serv Branch, Bethesda, MD 20814 USA. [Ward, Walter F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Qi, Wenbo] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Ingram, Donald K.] Louisiana State Univ, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. [de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP Mattison, JA (reprint author), NIA, Lab Expt Gerontol, NIH, Anim Ctr, 16701 Elmer Sch Rd,Bldg 103, Dickerson, MD 20842 USA. EM mattisonj@mail.nih.gov; Donald.Ingram@pbrc.edu; deCaboRa@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Allison, David/0000-0003-3566-9399; , rafael/0000-0003-2830-5693 FU NIH, National Institute on Aging FX We thank the animal care staff and technicians, both past and present, especially J. Travis and M. Szarowicz; K. Vaughan for her editorial help; and the many collaborators that have contributed to this project. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 30 TC 349 Z9 357 U1 10 U2 139 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 SEP 13 PY 2012 VL 489 IS 7415 BP 318 EP + DI 10.1038/nature11432 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 003UC UT WOS:000308635900047 PM 22932268 ER PT J AU Cukierski, WJ Nandy, K Gudla, P Meaburn, KJ Misteli, T Foran, DJ Lockett, SJ AF Cukierski, William J. Nandy, Kaustav Gudla, Prabhakar Meaburn, Karen J. Misteli, Tom Foran, David J. Lockett, Stephen J. TI Ranked retrieval of segmented nuclei for objective assessment of cancer gene repositioning SO BMC BIOINFORMATICS LA English DT Article ID CHROMOSOME TERRITORIES; GENOME ARCHITECTURE; IMAGE SEGMENTATION; ORGANIZATION; CHROMATIN; CELLS; TISSUE; FISH; TRANSCRIPTION; EXPRESSION AB Background: Correct segmentation is critical to many applications within automated microscopy image analysis. Despite the availability of advanced segmentation algorithms, variations in cell morphology, sample preparation, and acquisition settings often lead to segmentation errors. This manuscript introduces a ranked-retrieval approach using logistic regression to automate selection of accurately segmented nuclei from a set of candidate segmentations. The methodology is validated on an application of spatial gene repositioning in breast cancer cell nuclei. Gene repositioning is analyzed in patient tissue sections by labeling sequences with fluorescence in situ hybridization (FISH), followed by measurement of the relative position of each gene from the nuclear center to the nuclear periphery. This technique requires hundreds of well-segmented nuclei per sample to achieve statistical significance. Although the tissue samples in this study contain a surplus of available nuclei, automatic identification of the well-segmented subset remains a challenging task. Results: Logistic regression was applied to features extracted from candidate segmented nuclei, including nuclear shape, texture, context, and gene copy number, in order to rank objects according to the likelihood of being an accurately segmented nucleus. The method was demonstrated on a tissue microarray dataset of 43 breast cancer patients, comprising approximately 40,000 imaged nuclei in which the HES5 and FRA2 genes were labeled with FISH probes. Three trained reviewers independently classified nuclei into three classes of segmentation accuracy. In man vs. machine studies, the automated method outperformed the inter-observer agreement between reviewers, as measured by area under the receiver operating characteristic (ROC) curve. Robustness of gene position measurements to boundary inaccuracies was demonstrated by comparing 1086 manually and automatically segmented nuclei. Pearson correlation coefficients between the gene position measurements were above 0.9 (p < 0.05). A preliminary experiment was conducted to validate the ranked retrieval in a test to detect cancer. Independent manual measurement of gene positions agreed with automatic results in 21 out of 26 statistical comparisons against a pooled normal (benign) gene position distribution. Conclusions: Accurate segmentation is necessary to automate quantitative image analysis for applications such as gene repositioning. However, due to heterogeneity within images and across different applications, no segmentation algorithm provides a satisfactory solution. Automated assessment of segmentations by ranked retrieval is capable of reducing or even eliminating the need to select segmented objects by hand and represents a significant improvement over binary classification. The method can be extended to other high-throughput applications requiring accurate detection of cells or nuclei across a range of biomedical applications. C1 [Cukierski, William J.; Foran, David J.] Rutgers State Univ, New Brunswick, NJ 08903 USA. [Cukierski, William J.; Foran, David J.] Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Cukierski, William J.; Foran, David J.] Univ Med & Dent New Jersey, New Brunswick, NJ 08903 USA. [Nandy, Kaustav; Gudla, Prabhakar; Lockett, Stephen J.] Sci Applicat Int Corp Frederick Inc, Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Adv Technol Program, Frederick, MD 21702 USA. [Meaburn, Karen J.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Cukierski, WJ (reprint author), Rutgers State Univ, New Brunswick, NJ 08903 USA. EM wcuk@eden.rutgers.edu OI Meaburn, Karen/0000-0002-1327-5957 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health [5R01CA156386-06]; National Cancer Institute [1R01CA161375-01A1]; National Library of Medicine [1R01LM011119-0]; Department of Defense [BC073689] FX Imaging was performed by the National Cancer Institute Fluorescent Imaging Facility, Bethesda, MD. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.; Additional support was provided, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by grants from the National Institutes of Health through contract 5R01CA156386-06, by the National Cancer Institute through contract 1R01CA161375-01A1, and by the National Library of Medicine through contract 1R01LM011119-0. KJM was supported by a Breast Cancer Idea Award from the Department of Defense (BC073689). The authors express their gratitude to Jake Kirkwood and David Hou for assisting with annotation. NR 43 TC 4 Z9 4 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 12 PY 2012 VL 13 AR 232 DI 10.1186/1471-2105-13-232 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 029WM UT WOS:000310527800001 PM 22971117 ER PT J AU Forbes, EK de Cassan, SC Llewellyn, D Biswas, S Goodman, AL Cottingham, MG Long, CA Pleass, RJ Hill, AVS Hill, F Draper, SJ AF Forbes, Emily K. de Cassan, Simone C. Llewellyn, David Biswas, Sumi Goodman, Anna L. Cottingham, Matthew G. Long, Carole A. Pleass, Richard J. Hill, Adrian V. S. Hill, Fergal Draper, Simon J. TI T Cell Responses Induced by Adenoviral Vectored Vaccines Can Be Adjuvanted by Fusion of Antigen to the Oligomerization Domain of C4b-Binding Protein SO PLOS ONE LA English DT Article ID PRIME-BOOST IMMUNIZATION; MEROZOITE SURFACE PROTEIN-1; AMYLOID-P COMPONENT; IN-VITRO; RECOMBINANT ADENOVIRUS; MEDIATED PROTECTION; PLASMODIUM-BERGHEI; C4-BINDING PROTEIN; NONHUMAN-PRIMATES; IMMUNE-RESPONSES AB Viral vectored vaccines have been shown to induce both T cell and antibody responses in animals and humans. However, the induction of even higher level T cell responses may be crucial in achieving vaccine efficacy against difficult disease targets, especially in humans. Here we investigate the oligomerization domain of the alpha-chain of C4b-binding protein (C4 bp) as a candidate T cell "molecular adjuvant" when fused to malaria antigens expressed by human adenovirus serotype 5 (AdHu5) vectored vaccines in BALB/c mice. We demonstrate that i) C-terminal fusion of an oligomerization domain can enhance the quantity of antigen-specific CD4(+) and CD8(+) T cell responses induced in mice after only a single immunization of recombinant AdHu5, and that the T cells maintain similar functional cytokine profiles; ii) an adjuvant effect is observed for AdHu5 vectors expressing either the 42 kDa C-terminal domain of Plasmodium yoelii merozoite surface protein 1 (PyMSP1(42)) or the 83 kDa ectodomain of P. falciparum strain 3D7 apical membrane antigen 1 (PfAMA1), but not a candidate 128kDa P. falciparum MSP1 biallelic fusion antigen; iii) following two homologous immunizations of AdHu5 vaccines, antigen-specific T cell responses are further enhanced, however, in both BALB/c mice and New Zealand White rabbits no enhancement of functional antibody responses is observed; and iv) that the T cell adjuvant activity of C4 bp is not dependent on a functional Fc-receptor gamma-chain in the host, but is associated with the oligomerization of small (<80 kDa) antigens expressed by recombinant AdHu5. The oligomerization domain of C4 bp can thus adjuvant T cell responses induced by AdHu5 vectors against selected antigens and its clinical utility as well as mechanism of action warrant further investigation. C1 [Forbes, Emily K.; de Cassan, Simone C.; Llewellyn, David; Biswas, Sumi; Goodman, Anna L.; Cottingham, Matthew G.; Hill, Adrian V. S.; Draper, Simon J.] Univ Oxford, Jenner Inst, Oxford, England. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Pleass, Richard J.] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Hill, Fergal] Imaxio SA, Lyon, France. RP Forbes, EK (reprint author), Univ Oxford, Jenner Inst, Oxford, England. EM ekforbes@hotmail.com RI Draper, Simon/F-1758-2011; Pleass, Richard/L-4148-2015 OI Draper, Simon/0000-0002-9415-1357; Pleass, Richard/0000-0001-7438-8296 FU Wellcome Trust; EMVDA (European Malaria Vaccine Development Association, a European Commission); European Community [242095]; Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health; PATH Malaria Vaccine Initiative FX This work was funded by the Wellcome Trust and the EMVDA (European Malaria Vaccine Development Association, a European Commission FP6-funded consortium). The research leading to these results has also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement No 242095. In addition, this work was supported in part by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, and also by the PATH Malaria Vaccine Initiative who support the GIA Reference Center. AVSH and SJD are Jenner Investigators. AVSH is a Wellcome Trust Principal Research Fellow. SJD is a MRC Career Development Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, except that the design of the rabbit study and the GIA analysis was performed following discussion with PATH MVI. NR 45 TC 10 Z9 11 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 12 PY 2012 VL 7 IS 9 AR e44943 DI 10.1371/journal.pone.0044943 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 005GJ UT WOS:000308738500096 PM 22984589 ER PT J AU Aladjem, MI AF Aladjem, Mirit I. TI Rif1 choreographs DNA replication timing SO EMBO JOURNAL LA English DT Editorial Material ID MAMMALIAN-CELLS; CHROMATIN; REGULATOR; PROGRAM; DOMAINS; YEAST AB Eukaryotic cells duplicate their genome in a predetermined order that appears to reflect a fundamental property of chromatin. Each chromosomal region replicates at a consistent, developmental- and tissue-specific time during the S phase of the cell cycle, and regions that replicate at the same time form distinct patterns in three-dimensional nuclear space. Although orderly progression of DNA replication is important for insuring stable genetic and epigenetic inheritance, the mechanisms underlying replication patterns have yet to be elucidated. Two reports in The EMBO Journal now identify a protein, Rif1, as a novel global determinant of the mammalian DNA replication program, and provide a link between higher order chromatin assembly and proper cell-cycle progression. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Aladjem, MI (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov RI Aladjem, Mirit/G-2169-2010 OI Aladjem, Mirit/0000-0002-1875-3110 NR 18 TC 1 Z9 1 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 12 PY 2012 VL 31 IS 18 BP 3650 EP 3652 DI 10.1038/emboj.2012.238 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 006HC UT WOS:000308809100002 PM 22892565 ER PT J AU Xiong, W Wu, XW Li, FY Cheng, KJ Rice, KC Lovinger, DM Zhang, L AF Xiong, Wei Wu, Xiongwu Li, Fuying Cheng, Kejun Rice, Kenner C. Lovinger, David M. Zhang, Li TI A Common Molecular Basis for Exogenous and Endogenous Cannabinoid Potentiation of Glycine Receptors (April, pg 5200, 2012) SO JOURNAL OF NEUROSCIENCE LA English DT Correction C1 [Li, Fuying; Cheng, Kejun; Rice, Kenner C.] NIDA, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA. [Li, Fuying; Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. NR 1 TC 1 Z9 1 U1 0 U2 1 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 SEP 12 PY 2012 VL 32 IS 37 BP 12979 EP 12979 DI 10.1523/JNEUROSCI.3366-12.2012 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 006FV UT WOS:000308805800034 ER PT J AU Grishaev, A Anthis, NJ Clore, GM AF Grishaev, Alexander Anthis, Nicholas J. Clore, G. Marius TI Contrast-Matched Small-Angle X-ray Scattering from a Heavy-Atom-Labeled Protein in Structure Determination: Application to a Lead-Substituted Calmodulin-Peptide Complex SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; BIOLOGICAL MACROMOLECULES; NMR; ACTIVATION; BINDING; REFINEMENT; SAXS; VIEW AB The information content in 1-D solution X-ray scattering profiles is generally restricted to low-resolution shape and size information that, on its own, cannot lead to unique 3-D structures of biological macromolecules comparable to all-atom models derived from. X-ray crystallography or NMR spectroscopy. Here we show that contrast-matched X-ray scattering data collected on a protein incorporating specific heavy-atom labels in 65% aqueous sucrose buffer can dramatically enhance the power of conventional small- and wide-angle X-ray scattering (SAXS/WAXS) measurements. Under contrast-matching conditions the protein is effectively invisible and the main contribution to the X-ray scattering intensity arises from the heavy atoms, allowing direct extraction of pairwise distances between them. In combination with conventional aqueous SAXS/WAXS data, supplemented by NMR-derived residual dipolar couplings (RDCs) measured in a weakly aligning medium, we show that it is possible to position protein domains relative to one another within a precision of 1 angstrom. We demonstrate this approach with respect to the determination of domain positions in a complex between calmodulin, in which the four Ca2+ ions have been substituted by Pb2+, and a target peptide. The uniqueness of the resulting solution is established by an exhaustive search, over all models compatible with the experimental data, and could not have been achieved using aqueous SAXS and RDC data alone. Moreover, we show that the correct structural solution can be recovered using only contrast-matched SAXS and aqueous SAXS/WAXS data. C1 [Grishaev, Alexander; Anthis, Nicholas J.; Clore, G. Marius] NIDDK, Labs Chem Phys, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Labs Chem Phys, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU program of NIDDK; Intramural AIDS Antiviral Program of the Office of the Director of the NIH FX We thank A. Base for useful discussions, and S. Seifert and X. Zuo for assistance with SAXS data collection. This work was supported by the intramural program of NIDDK and the Intramural AIDS Antiviral Program of the Office of the Director of the NIH (G.M.C.). The shared beamline resource (PUP-77 agreement between NCI, NIH, and Argonne National Laboratory) at the APS is acknowledged. NR 21 TC 13 Z9 13 U1 0 U2 14 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 SEP 12 PY 2012 VL 134 IS 36 BP 14686 EP 14689 DI 10.1021/ja306359z PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 002YK UT WOS:000308574800014 PM 22908850 ER PT J AU Fay, MP Follmann, DA Lynn, F Schiffer, JM Stark, GV Kohberger, R Quinn, CP Nuzum, EO AF Fay, Michael P. Follmann, Dean A. Lynn, Freyja Schiffer, Jarad M. Stark, Gregory V. Kohberger, Robert Quinn, Conrad P. Nuzum, Edwin O. TI Anthrax Vaccine-Induced Antibodies Provide Cross-Species Prediction of Survival to Aerosol Challenge SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID RECOMBINANT PROTECTIVE ANTIGEN; LETHAL TOXIN NEUTRALIZATION; SURROGATE END-POINTS; IN-VITRO CORRELATE; BACILLUS-ANTHRACIS; PREPARED INVITRO; CLINICAL-TRIALS; INHALATIONAL ANTHRAX; IMMUNOGLOBULIN-G; SPORE CHALLENGE AB Because clinical trials to assess the efficacy of vaccines against anthrax are not ethical or feasible, licensure for new anthrax vaccines will likely involve the Food and Drug Administration's "Animal Rule," a set of regulations that allow approval of products based on efficacy data only in animals combined with immunogenicity and safety data in animals and humans. U.S. government-sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. We examined data from 21 of those studies to determine whether an immunological bridge based on lethal toxin neutralization activity assay (TNA) can predict survival against an inhalation anthrax challenge within and across species and genera. The 21 studies were classified into 11 different settings, each of which had the same animal species, vaccine type and formulation, vaccination schedule, time of TNA measurement, and challenge time. Logistic regression models determined the contribution of vaccine dilution dose and TNA on prediction of survival. For most settings, logistic models using only TNA explained more than 75% of the survival effect of the models with dose additionally included. Cross-species survival predictions using TNA were compared to the actual survival and shown to have good agreement (Cohen's kappa ranged from 0.55 to 0.78). In one study design, cynomolgus macaque data predicted 78.6% survival in rhesus macaques (actual survival, 83.0%) and 72.6% in rabbits (actual survival, 64.6%). These data add support for the use of TNA as an immunological bridge between species to extrapolate data in animals to predict anthrax vaccine effectiveness in humans. C1 [Fay, Michael P.; Follmann, Dean A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Lynn, Freyja; Nuzum, Edwin O.] NIAID, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. [Schiffer, Jarad M.; Quinn, Conrad P.] Ctr Dis Control & Prevent, Div Bacterial Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Stark, Gregory V.] Battelle Mem Inst, Columbus, OH 43201 USA. [Kohberger, Robert] Blair & Co, Greenwich, CT 06830 USA. RP Fay, MP (reprint author), NIAID, Biostat Res Branch, 6700B Rockledge Dr, Bethesda, MD 20892 USA. EM mfay@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU Battelle Biomedical Research Center (NIAID) [N01-AI-25494, N01-AI-30061]; CDC [200-2000-100065] FX We acknowledge the Battelle Biomedical Research Center (NIAID contracts N01-AI-25494 and N01-AI-30061, and CDC contract 200-2000-100065) and the USAMRIID for conduct of studies that generated the data analyzed in this paper. NR 62 TC 18 Z9 18 U1 0 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 12 PY 2012 VL 4 IS 151 AR 151ra126 DI 10.1126/scitranslmed.3004073 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 006FX UT WOS:000308806000005 PM 22972844 ER PT J AU Pierson, TC Yewdell, JW AF Pierson, Theodore C. Yewdell, Jonathan W. TI Measles immunometrics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID VIRUS INFECTION; ANTIGEN PRESENTATION; RHESUS-MONKEYS; CLEARANCE; PERSISTENCE; ANTIBODY; RNA C1 [Pierson, Theodore C.; Yewdell, Jonathan W.] NIH, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIH, Viral Dis Lab, Bldg 10, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov NR 17 TC 0 Z9 0 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 SEP 11 PY 2012 VL 109 IS 37 BP 14724 EP 14725 DI 10.1073/pnas.1212243109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012AP UT WOS:000309208000017 PM 22936050 ER PT J AU Canugovi, C Yoon, JS Feldman, NH Croteau, DL Mattson, MP Bohr, VA AF Canugovi, Chandrika Yoon, Jeong Seon Feldman, Neil H. Croteau, Deborah L. Mattson, Mark P. Bohr, Vilhelm A. TI Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BASE-EXCISION-REPAIR; OXIDATIVE STRESS; DNA-DAMAGE; MITOCHONDRIAL DYSFUNCTION; CEREBRAL-ISCHEMIA; GLYCOSYLASES; PATHWAY; NEUROPROTECTION; SURVIVAL; NEURONS AB Recent findings suggest that neurons can efficiently repair oxidatively damaged DNA, and that both DNA damage and repair are enhanced by activation of excitatory glutamate receptors. However, in pathological conditions such as ischemic stroke, excessive DNA damage can trigger the death of neurons. Oxidative DNA damage is mainly repaired by base excision repair (BER), a process initiated by DNA glycosylases that recognize and remove damaged DNA bases. Endonuclease VIII-like 1 (NEIL1) is a DNA glycosylase that recognizes a broad range of oxidative lesions. Here, we show that mice lacking NEIL1 exhibit impaired memory retention in a water maze test, but no abnormalities in tests of motor performance, anxiety, or fear conditioning. NEIL1 deficiency results in increased brain damage and a defective functional outcome in a focal ischemia/reperfusion model of stroke. The incision capacity on a 5-hydroxyuracil-containing bubble substrate was lower in the ipsilateral side of ischemic brains and in the mitochondrial lysates of unstressed old NEIL1-deficient mice. These results indicate that NEIL1 plays an important role in learning and memory and in protection of neurons against ischemic injury. C1 [Canugovi, Chandrika; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Yoon, Jeong Seon; Feldman, Neil H.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU National Institutes of Health, National Institute on Aging FX We thank Dr. Steven Lloyd (Oregon Health and Science University) for the generous gift of NEIL1 knockout mice, Drs. V. Popuri and L. K. Hoh for critically reviewing this manuscript, and Chris Morrell for statistical assistance. This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 30 TC 34 Z9 36 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 SEP 11 PY 2012 VL 109 IS 37 BP 14948 EP 14953 DI 10.1073/pnas.1204156109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012AP UT WOS:000309208000052 PM 22927410 ER PT J AU Lin, WHW Kouyos, RD Adams, RJ Grenfell, BT Griffin, DE AF Lin, Wen-Hsuan W. Kouyos, Roger D. Adams, Robert J. Grenfell, Bryan T. Griffin, Diane E. TI Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immune responses; within-host modeling; virus clearance ID REGULATORY T-CELLS; TRANSCRIPTION FACTOR FOXP3; ANTIGENIC MODULATION; RHESUS MACAQUES; CLEARANCE; ANTIBODY; MODEL; EXPRESSION; IMMUNITY; MONKEYS AB Measles virus (MeV) is the poster child for acute infection followed by lifelong immunity. However, recent work shows the presence of MeV RNA in multiple sites for up to 3 mo after infection in a proportion of infected children. Here, we use experimental infection of rhesus macaques to show that prolonged RNA presence is characteristic of primary infection. We found that viral RNA persisted in the blood, respiratory tract, or lymph nodes four to five times longer than the infectious virus and that the clearance of MeV RNA from blood happened in three phases: rapid decline coincident with clearance of infectious virus, a rebound phase with increases up to 10-fold, and a phase of slow decrease to undetectable levels. To examine the effect of individual host immune factors on MeV load dynamics further, we developed a mathematical model that expressed viral replication and elimination in terms of the strength of MeV-specific T-cell responses, antibody responses, target cell limitations, and immunosuppressive activity of regulatory T cells. Based on the model, we demonstrate that viral dynamics, although initially regulated by T cells, require antibody to eliminate viral RNA. These results have profound consequences for our view of acute viral infections, the development of prolonged immunity, and, potentially, viral evolution. C1 [Lin, Wen-Hsuan W.; Griffin, Diane E.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Kouyos, Roger D.; Grenfell, Bryan T.] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Adams, Robert J.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Griffin, DE (reprint author), Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. EM dgriffin@jhsph.edu RI Kouyos, Roger/G-6226-2014 OI Kouyos, Roger/0000-0002-9220-8348 FU National Institutes of Health; Bill and Melinda Gates Foundation; Marjorie Gilbert Scholarship; Research and Policy for Infectious Disease Dynamics Program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center; Swiss National Science Foundation [PA00P3_131498] FX We thank Dr. David I. Watkins (University of Wisconsin) for macaque MHC typing; Dr. Sebastien Ballesteros (Princeton University) and Dr. Chien-Hsiung Pan and Dr. William Moss (Johns Hopkins University) for helpful discussions; and Debra Hauer and Brandyn Lau (Johns Hopkins University) for technical assistance. This work was supported by grants from the National Institutes of Health (to D. E. G.); the Bill and Melinda Gates Foundation (to D. E. G. and B. T. G.); a Marjorie Gilbert Scholarship (to W.-H. W. L.); the Research and Policy for Infectious Disease Dynamics Program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (to B. T. G.); and the Swiss National Science Foundation Grant PA00P3_131498 (to R. D. K). NR 45 TC 22 Z9 22 U1 1 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 SEP 11 PY 2012 VL 109 IS 37 BP 14989 EP 14994 DI 10.1073/pnas.1211138109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012AP UT WOS:000309208000059 PM 22872860 ER PT J AU Grosset, J Almeida, D Converse, PJ Tyagi, S Li, SY Ammerman, NC Pym, AS Wallengren, K Hafner, R Lalloo, U Swindells, S Bishai, WR AF Grosset, Jacques Almeida, Deepak Converse, Paul J. Tyagi, Sandeep Li, Si-Yang Ammerman, Nicole C. Pym, Alexander S. Wallengren, Kristina Hafner, Richard Lalloo, Umesh Swindells, Susan Bishai, William R. TI Modeling early bactericidal activity in murine tuberculosis provides insights into the activity of isoniazid and pyrazinamide SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemotherapy; Mycobacterium ID PULMONARY TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; ANTITUBERCULOSIS DRUGS; MOXIFLOXACIN; RIFAMPIN; CHEMOTHERAPY; PA-824; MICE AB Standard tuberculosis (TB) treatment includes an initial regimen containing drugs that are both rapidly bactericidal (isoniazid) and sterilizing (rifampin and pyrazinamide), and ethambutol to help prevent the emergence of drug resistance. Antagonism between isoniazid and pyrazinamide has been demonstrated in a TB treatment mouse model. Because isoniazid's bactericidal activity is greatest during the initial two treatment days, we hypothesized that removing isoniazid after the second day would increase the effectiveness of the standard regimen. To test this hypothesis, we developed a mouse model to measure the early bactericidal activity (EBA) of drug regimens designed to analyze the essentiality of both isoniazid and pyrazinamide during the first 14 d of therapy. Our results clearly indicate that discontinuation of isoniazid after the second day of treatment increases the EBA of standard therapy in the mouse model, whereas omitting pyrazinamide during the first 14 d was detrimental. Substitution of moxifloxacin for isoniazid on day 3 did not increase the EBA compared with only removing isoniazid after day 2. Our data show that a mouse model can be used to analyze the EBA of TB drugs, and our findings support pursuing clinical trials to evaluate the possible benefit of removing isoniazid after the first 2 treatment days. C1 [Grosset, Jacques; Almeida, Deepak; Converse, Paul J.; Tyagi, Sandeep; Li, Si-Yang; Ammerman, Nicole C.; Bishai, William R.] Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD 21231 USA. [Grosset, Jacques; Ammerman, Nicole C.; Pym, Alexander S.; Wallengren, Kristina; Bishai, William R.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, KwaZulu Natal Res Inst TB & HIV, ZA-4001 Durban, South Africa. [Hafner, Richard] NIAID, Div AIDS, NIH, Dept Hlth & Human Serv, Bethesda, MD 20817 USA. [Lalloo, Umesh] Univ KwaZulu Natal, Dept Pulmonol, Nelson R Mandela Sch Med, ZA-4001 Durban, South Africa. [Swindells, Susan] Univ Nebraska Med Ctr, Dept Internal Med, HIV Clin, Omaha, NE 68198 USA. [Bishai, William R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Grosset, J (reprint author), Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD 21231 USA. EM jgrosse4@jhmi.edu OI Pym, Alexander/0000-0002-6260-8180 FU Howard Hughes Medical Institute; National Institutes of Health (NIH) [AI 37856, AI 36973, AI 79590]; NIH Division of AIDS FX This work was supported by the Howard Hughes Medical Institute; National Institutes of Health (NIH) Grants AI 37856, AI 36973, and AI 79590; and a supplement from the NIH Division of AIDS. NR 22 TC 18 Z9 18 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 11 PY 2012 VL 109 IS 37 BP 15001 EP 15005 DI 10.1073/pnas.1203636109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012AP UT WOS:000309208000061 PM 22927424 ER PT J AU Zoppoli, G Regairaz, M Leo, E Reinhold, WC Varma, S Ballestrero, A Doroshow, JH Pommier, Y AF Zoppoli, Gabriele Regairaz, Marie Leo, Elisabetta Reinhold, William C. Varma, Sudhir Ballestrero, Alberto Doroshow, James H. Pommier, Yves TI Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HER2-POSITIVE BREAST-CANCER; ADJUVANT CHEMOTHERAPY; IMATINIB MESYLATE; DRUG-SENSITIVITY; TUMOR; LINES; TRASTUZUMAB; CELLMINER; TRIAL; PANEL AB DNA-damaging agents (DDAs) constitute the backbone of treatment for most human tumors. Here we used the National Cancer Institute Antitumor Cell Line Panel (the NCI-60) to identify predictors of cancer cell response to topoisomerase I (Top1) inhibitors, a widely used class of DDAs. We assessed the NCI-60 transcriptome using Affymetrix Human Exon 1.0 ST microarrays and correlated the in vitro activity of four Top1 inhibitors with gene expression in the 60 cell lines. A single gene, Schlafen-11 (SLFN11), showed an extremely significant positive correlation with the response not only to Top1 inhibitors, but also to Top2 inhibitors, alkylating agents, and DNA synthesis inhibitors. Using cells with endogenously high and low SLFN11 expression and siRNA-mediated silencing, we show that SLFN11 is causative in determining cell death and cell cycle arrest in response to DDAs in cancer cells from different tissues of origin. We next analyzed SLFN11 expression in ovarian and colorectal cancers and normal corresponding tissues from The Cancer Genome Atlas database and observed that SLFN11 has a wide expression range. We also observed that high SLFN11 expression independently predicts overall survival in a group of ovarian cancer patients treated with cisplatin-containing regimens. We conclude that SLFN11 expression is causally associated with the activity of DDAs in cancer cells, has a broad expression range in colon and ovarian adenocarcinomas, and may behave as a biomarker for prediction of response to DDAs in the clinical setting. C1 [Zoppoli, Gabriele; Regairaz, Marie; Leo, Elisabetta; Reinhold, William C.; Varma, Sudhir; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zoppoli, Gabriele; Ballestrero, Alberto] Univ Genoa, Dept Internal Med, I-16132 Genoa, Italy. [Zoppoli, Gabriele; Ballestrero, Alberto] Ist Ricovero & Cura Carattere Sci Azienda Osped U, Inst Nazl Ric Canc, I-16132 Genoa, Italy. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Zoppoli, G (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zoppoli@gmail.com; pommier@nih.gov RI Varma, Sudhir/N-8763-2014; Zoppoli, Gabriele/B-6935-2016 OI Varma, Sudhir/0000-0002-4096-4782; Zoppoli, Gabriele/0000-0003-3890-5588 FU Center for Cancer Research, Intramural Program of the National Cancer Institute; Division of Cancer Treatment and Diagnosis, Extramural Program of the National Cancer Institute (National Institutes of Health); Associazione Italiana per la Ricerca sul Cancro [MFAG 10570] FX G.Z. thanks Dr. D. Bedognetti and P. Blandini for insightful suggestions. This work was supported by the Center for Cancer Research, Intramural Program of the National Cancer Institute; by the Division of Cancer Treatment and Diagnosis, Extramural Program of the National Cancer Institute (National Institutes of Health); and by an Associazione Italiana per la Ricerca sul Cancro "My First AIRC Grant" ID MFAG 10570 (to G.Z.). The results of the present work were presented in part as a poster at the American Association for Cancer Research Annual Meeting, March 31-April 4, Chicago. NR 23 TC 35 Z9 37 U1 1 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 SEP 11 PY 2012 VL 109 IS 37 BP 15030 EP 15035 DI 10.1073/pnas.1205943109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012AP UT WOS:000309208000066 PM 22927417 ER PT J AU Pybus, OG Suchard, MA Lemey, P Bernardin, FJ Rambaut, A Crawford, FW Gray, RR Arinaminpathy, N Stramer, SL Busch, MP Delwart, EL AF Pybus, Oliver G. Suchard, Marc A. Lemey, Philippe Bernardin, Flavien J. Rambaut, Andrew Crawford, Forrest W. Gray, Rebecca R. Arinaminpathy, Nimalan Stramer, Susan L. Busch, Michael P. Delwart, Eric L. TI Unifying the spatial epidemiology and molecular evolution of emerging epidemics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phylogeny; phylogeography; transmission ID WEST-NILE-VIRUS; PHYLOGENETIC ANALYSIS; TRAVELING-WAVES; RABIES VIRUS; SPREAD RATES; DYNAMICS; MODELS; DISPERSAL; EMERGENCE; TIME AB We introduce a conceptual bridge between the previously unlinked fields of phylogenetics and mathematical spatial ecology, which enables the spatial parameters of an emerging epidemic to be directly estimated from sampled pathogen genome sequences. By using phylogenetic history to correct for spatial autocorrelation, we illustrate how a fundamental spatial variable, the diffusion coefficient, can be estimated using robust nonparametric statistics, and how heterogeneity in dispersal can be readily quantified. We apply this framework to the spread of the West Nile virus across North America, an important recent instance of spatial invasion by an emerging infectious disease. We demonstrate that the dispersal of West Nile virus is greater and far more variable than previously measured, such that its dissemination was critically determined by rare, long-range movements that are unlikely to be discerned during field observations. Our results indicate that, by ignoring this heterogeneity, previous models of the epidemic have substantially overestimated its basic reproductive number. More generally, our approach demonstrates that easily obtainable genetic data can be used to measure the spatial dynamics of natural populations that are otherwise difficult or costly to quantify. C1 [Pybus, Oliver G.; Gray, Rebecca R.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Suchard, Marc A.; Crawford, Forrest W.] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Lemey, Philippe] Katholieke Univ Leuven, Dept Microbiol & Immunol, Rega Inst, B-3000 Louvain, Belgium. [Bernardin, Flavien J.; Busch, Michael P.; Delwart, Eric L.] Blood Syst Res Inst, San Francisco, CA 94118 USA. [Bernardin, Flavien J.; Busch, Michael P.; Delwart, Eric L.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Arinaminpathy, Nimalan] Princeton Univ, Dept Ecol & Evolut, Princeton, NJ 08544 USA. [Stramer, Susan L.] Amer Red Cross, Sci Support Off, Gaithersburg, MD 20877 USA. RP Pybus, OG (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM oliver.pybus@zoo.ox.ac.uk OI Pybus, Oliver/0000-0002-8797-2667; Delwart, Eric/0000-0002-6296-4484; Rambaut, Andrew/0000-0003-4337-3707 FU Royal Society; National Institutes of Health [R01 GM086887]; Centers for Disease Control/National Center for Infectious Diseases [R01-CI-000214]; UK Medical Research Council; European Research Council Seventh Framework Programme [260864]; Institute for Mathematical Sciences, National University of Singapore FX We thank Eddie Holmes, Mike Bonsall, Sunetra Gupta, John Drake, Robert May, and Paul Harvey for discussion. Support for this work was provided by the Royal Society (O.G.P. and A.R.); National Institutes of Health Grant R01 GM086887 (to M. A. S. and F.W. C.); Centers for Disease Control/National Center for Infectious Diseases Grant R01-CI-000214 (to F.J.B, M. P. B., and E. L. D.); UK Medical Research Council (R. R. G.); European Research Council Seventh Framework Programme Grant 260864 (to P. L.); and the Institute for Mathematical Sciences, National University of Singapore (M.A.S. and P.L.). NR 42 TC 60 Z9 60 U1 1 U2 61 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 SEP 11 PY 2012 VL 109 IS 37 BP 15066 EP 15071 DI 10.1073/pnas.1206598109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 012AP UT WOS:000309208000072 PM 22927414 ER PT J AU Cookson, MR AF Cookson, Mark R. TI Evolution of Neurodegeneration SO CURRENT BIOLOGY LA English DT Review ID FAMILIAL PARKINSONS-DISEASE; MUTANT ALPHA-SYNUCLEIN; IN-VIVO; PATHOLOGICAL FEATURES; COMMON VARIANTS; G2019S MUTATION; KINASE-ACTIVITY; CELL-DEATH; LRRK2; GENETICS AB A number of neurodegenerative diseases principally affect humans as they age and are characterized by the loss of specific groups of neurons in different brain regions. Although these disorders are generally sporadic, it is now clear that many of them have a substantial genetic component. As genes are the raw material with which evolution works, we might benefit from understanding these genes in an evolutionary framework. Here, I will discuss how we can understand whether evolution has shaped genes involved in neurodegeneration and the implications for practical issues, such as our choice of model systems for studying these diseases, and more theoretical concerns, such as the level of selection against these phenotypes. C1 NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 99 TC 6 Z9 6 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 11 PY 2012 VL 22 IS 17 BP R753 EP R761 DI 10.1016/j.cub.2012.07.008 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 006WH UT WOS:000308849900023 PM 22975006 ER PT J AU Kellman, P Wilson, JR Xue, H Bandettini, WP Shanbhag, SM Druey, KM Ugander, M Arai, AE AF Kellman, Peter Wilson, Joel R. Xue, Hui Bandettini, W. Patricia Shanbhag, Sujata M. Druey, Kirk M. Ugander, Martin Arai, Andrew E. TI Extracellular volume fraction mapping in the myocardium, part 2: initial clinical experience SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Fibrosis; Edema; Gadolinium; Myocardial infarction; Hypertrophic cardiomyopathy; Dilated cardiomyopathy; Myocarditis; Systemic capillary leak syndrome ID CARDIOVASCULAR MAGNETIC-RESONANCE; INVERSION-RECOVERY; BLOOD-FLOW; FIBROSIS; HEART; QUANTIFICATION; VALIDATION; INFARCTION; HUMANS AB Background: Diffuse myocardial fibrosis, and to a lesser extent global myocardial edema, are important processes in heart disease which are difficult to assess or quantify with cardiovascular magnetic resonance (CMR) using conventional late gadolinium enhancement (LGE) or T1-mapping. Measurement of the myocardial extracellular volume fraction (ECV) circumvents factors that confound T1-weighted images or T1-maps. We hypothesized that quantitative assessment of myocardial ECV would be clinically useful for detecting both focal and diffuse myocardial abnormalities in a variety of common and uncommon heart diseases. Methods: A total of 156 subjects were imaged including 62 with normal findings, 33 patients with chronic myocardial infarction (MI), 33 with hypertrophic cardiomyopathy (HCM), 15 with non-ischemic dilated cardiomyopathy (DCM), 7 with acute myocarditis, 4 with cardiac amyloidosis, and 2 with systemic capillary leak syndrome (SCLS). Motion corrected ECV maps were generated automatically from T1-maps acquired pre- and post-contrast calibrated by blood hematocrit. Abnormally-elevated ECV was defined as >2SD from the mean ECV in individuals with normal findings. In HCM the size of regions of LGE was quantified as the region >2 SD from remote. Results: Mean ECV of 62 normal individuals was 25.4 +/- 2.5% (m +/- SD), normal range 20.4%-30.4%. Mean ECV within the core of chronic myocardial infarctions (without MVO) (N = 33) measured 68.5 +/- 8.6% (p < 0.001 vs normal). In HCM, the extent of abnormally elevated ECV correlated to the extent of LGE (r = 0.72, p < 0.001) but had a systematically greater extent by ECV (mean difference 19 +/- 7% of slice). Abnormally elevated ECV was identified in 4 of 16 patients with non-ischemic DCM (38.1 +/- 1.9% (p < 0.001 vs normal) and LGE in the same slice appeared "normal" in 2 of these 4 patients. Mean ECV values in other disease entities ranged 32-60% for cardiac amyloidosis (N = 4), 40-41% for systemic capillary leak syndrome (N = 2), and 39-56% within abnormal regions affected by myocarditis (N = 7). Conclusions: ECV mapping appears promising to complement LGE imaging in cases of more homogenously diffuse disease. The ability to display ECV maps in units that are physiologically intuitive and may be interpreted on an absolute scale offers the potential for detection of diffuse disease and measurement of the extent and severity of abnormal regions. C1 [Kellman, Peter; Wilson, Joel R.; Bandettini, W. Patricia; Shanbhag, Sujata M.; Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Xue, Hui] Siemens Corp Res, Princeton, NJ USA. [Druey, Kirk M.] NIAID, NIH, Bethesda, MD 20892 USA. [Ugander, Martin] Univ Hosp, Karolinska Inst & Karolinska, Dept Clin Physiol, Stockholm, Sweden. RP Kellman, P (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kellmanp@nhlbi.nih.gov OI Ugander, Martin/0000-0003-3665-2038 FU Intramural NIH HHS [ZID HL006140-01, ZIA HL004607-14, ZID HL006140-02, ZIE HL006139-01, ZIE HL006139-02] NR 15 TC 90 Z9 92 U1 2 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD SEP 11 PY 2012 VL 14 AR 64 DI 10.1186/1532-429X-14-64 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 012HB UT WOS:000309225700001 PM 22967246 ER PT J AU Florez, JC Jablonski, KA McAteer, JB Franks, PW Mason, CC Mather, K Horton, E Goldberg, R Dabelea, D Kahn, SE Arakaki, RF Shuldiner, AR Knowler, WC AF Florez, Jose C. Jablonski, Kathleen A. McAteer, Jarred B. Franks, Paul W. Mason, Clinton C. Mather, Kieren Horton, Edward Goldberg, Ronald Dabelea, Dana Kahn, Steven E. Arakaki, Richard F. Shuldiner, Alan R. Knowler, William C. CA Diabetes Prevention Program Res TI Effects of Genetic Variants Previously Associated with Fasting Glucose and Insulin in the Diabetes Prevention Program SO PLOS ONE LA English DT Article ID PLASMA-GLUCOSE; PROINSULIN LEVELS; LIFE-STYLE; BASE-LINE; FOLLOW-UP; LOCI; RISK; POLYMORPHISM; HOMEOSTASIS; MTNR1B AB Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P=0.002) and GCKR (P=0.001). We noted impaired beta-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired beta-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program. C1 [Florez, Jose C.; McAteer, Jarred B.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.; McAteer, Jarred B.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Florez, Jose C.; McAteer, Jarred B.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.; Horton, Edward] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Franks, Paul W.] Lund Univ, Dept Clin Sci, Lund Univ Diabet Ctr, Malmo, Sweden. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Mason, Clinton C.; Knowler, William C.] NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Mather, Kieren] Indiana Univ Sch Med, Div Endocrinol, Indianapolis, IN USA. [Horton, Edward] Joslin Diabet Ctr, Boston, MA 02215 USA. [Goldberg, Ronald] Univ Miami, Lipid Disorders Clin, Div Endocrinol Diabet & Metab, Miami, FL USA. [Goldberg, Ronald] Univ Miami, Diabet Res Inst, Miami, FL USA. [Dabelea, Dana] Univ Colorado, Dept Prevent Med & Biometr, Denver, CO 80202 USA. [Dabelea, Dana] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Arakaki, Richard F.] Univ Hawaii, Dept Med Clin Res, Honolulu, HI 96822 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM jcflorez@partners.org RI de Bakker, Paul/B-8730-2009; Uwaifo, Gabriel/M-2361-2016; OI de Bakker, Paul/0000-0001-7735-7858; Uwaifo, Gabriel/0000-0002-6962-9304; Franks, Paul/0000-0002-0520-7604; Kahn, Steven/0000-0001-7307-9002 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health [U01DK048489]; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Office of Research on Women's Health; Centers for Disease Control and Prevention; American Diabetes Association; intramural research program of the NIDDK [R01 DK072041]; Swedish Research Council; Novo Nordisk; Swedish Diabetes Association; Swedish Heart-Lung Foundation; McKesson BioServices Corp.; Matthews Media Group, Inc.; Henry M. Jackson Foundation FX 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, and the collection, management, analysis, and interpretation of the data, through Award Number U01DK048489. 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, and the Department of Veterans Affairs 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 Office of Research on Women's Health, the Centers for Disease Control and Prevention, and the American Diabetes Association. This research was also supported, in part, by the intramural research program of the NIDDK, and by R01 DK072041 to JCF, KAJ and ARS. PWF was supported by the Swedish Research Council, Novo Nordisk, Swedish Diabetes Association, and the Swedish Heart-Lung Foundation. The Investigators gratefully acknowledge the commitment and dedication of the participants of the DPP. The opinions expressed are those of the investigators and do not necessarily reflect the official views of the funding agencies. A complete list of Centers, investigators, and staff can be found in the Appendix. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; JCF has received consulting honoraria from Novartis, Pfizer and Eli Lilly. Bristol-Myers Squibb and Parke-Davis provided medication. 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 authors also received funding from the commercial source Novo Nordisk. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. NR 31 TC 10 Z9 11 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 11 PY 2012 VL 7 IS 9 AR e44424 DI 10.1371/journal.pone.0044424 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 003VE UT WOS:000308638700060 PM 22984506 ER PT J AU Rachel, RA Nagashima, K O'Sullivan, TN Frost, LS Stefano, FP Marigo, V Boesze-Battaglia, K AF Rachel, Rivka A. Nagashima, Kunio O'Sullivan, T. Norene Frost, Laura S. Stefano, Frank P. Marigo, Valeria Boesze-Battaglia, Kathleen TI Melanoregulin, Product of the dsu Locus, Links the BLOC-Pathway and Oa1 in Organelle Biogenesis SO PLOS ONE LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; OCULAR ALBINISM TYPE-1; PROTEIN-COUPLED RECEPTOR; COAT-COLOR PHENOTYPE; DILUTE SUPPRESSOR; GENE-PRODUCT; MELANOSOME TRANSPORT; MYOSIN-VA; MOUSE; HOMOLOG AB Humans with Hermansky-Pudlak Syndrome (HPS) or ocular albinism (OA1) display abnormal aspects of organelle biogenesis. The multigenic disorder HPS displays broad defects in biogenesis of lysosome-related organelles including melanosomes, platelet dense granules, and lysosomes. A phenotype of ocular pigmentation in OA1 is a smaller number of macromelanosomes, in contrast to HPS, where in many cases the melanosomes are smaller than normal. In these studies we define the role of the Mreg(dsu) gene, which suppresses the coat color dilution of Myo5a, melanophilin, and Rab27a mutant mice in maintaining melanosome size and distribution. We show that the product of the Mreg(dsu) locus, melanoregulin (MREG), interacts both with members of the HPS BLOC-2 complex and with Oa1 in regulating melanosome size. Loss of MREG function facilitates increase in the size of micromelanosomes in the choroid of the HPS BLOC-2 mutants ruby, ruby2, and cocoa, while a transgenic mouse overexpressing melanoregulin corrects the size of retinal pigment epithelium (RPE) macromelanosomes in Oa1(ko/ko) mice. Collectively, these results suggest that MREG levels regulate pigment incorporation into melanosomes. Immunohistochemical analysis localizes melanoregulin not to melanosomes, but to small vesicles in the cytoplasm of the RPE, consistent with a role for this protein in regulating membrane interactions during melanosome biogenesis. These results provide the first link between the BLOC pathway and Oa1 in melanosome biogenesis, thus supporting the hypothesis that intracellular G-protein coupled receptors may be involved in the biogenesis of other organelles. Furthermore these studies provide the foundation for therapeutic approaches to correct the pigment defects in the RPE of HPS and OA1. C1 [Rachel, Rivka A.] NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. [Nagashima, Kunio] SAIC Frederick, Frederick Natl Lab Canc Res, Frederick, MD USA. [O'Sullivan, T. Norene] NCI, Frederick, MD 21701 USA. [Frost, Laura S.; Stefano, Frank P.; Boesze-Battaglia, Kathleen] Univ Penn, Dept Biochem, Philadelphia, PA 19104 USA. [Stefano, Frank P.] Univ Penn, Sch Dent Med, Live Cell Imaging Core, Philadelphia, PA 19104 USA. [Marigo, Valeria] Univ Modena & Reggio Emilia, Dept Biomed Sci, Modena, Italy. RP Rachel, RA (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. EM battagli@dental.upenn.edu RI Marigo, Valeria/B-7947-2015 OI Marigo, Valeria/0000-0002-4428-2084 FU Vision of Children; National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Eye Institute [EY-10420, EY018705]; National Cancer Institute [HHSN26120080001E]; Vision of Children Foundation FX We thank the following individuals for expert technical assistance, with animals: Deborah Swing, Erika Truffer, Stephanie Springer, Holly Morris and Rob Koogle; with genotyping: Deborah Householder and Anna Trivett; with electron microscopy: Michelle Gignac; Alvina Bragin for expert technical assistance. We thank the Vision of Children for facilitating this collaboration and for funding productive meetings, and Drs. Nancy Jenkins and Neal Copeland for supporting the majority of the work in their laboratory at the National Cancer Institute.; This project was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, extramural grants from the National Eye Institute, EY-10420 and EY018705 (KBB), federal funds from the National Cancer Institute under contract HHSN26120080001E (KN), and by the Vision of Children Foundation (VM). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 50 TC 4 Z9 4 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 11 PY 2012 VL 7 IS 9 AR e42446 DI 10.1371/journal.pone.0042446 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 003VE UT WOS:000308638700005 PM 22984402 ER PT J AU Scherer, RW Sieving, PC Ervin, AM Dickersin, K AF Scherer, Roberta W. Sieving, Pamela C. Ervin, Ann-Margret Dickersin, Kay TI Can We Depend on Investigators to Identify and Register Randomized Controlled Trials? SO PLOS ONE LA English DT Article ID CLINICAL-TRIALS; REGISTRATION; PUBLICATION; STATEMENT AB Purpose: To reduce publication bias, systematic reviewers are advised to search conference abstracts to identify randomized controlled trials (RCTs) conducted in humans and not published in full. We assessed the information provided by authors to aid identification of RCTs for reviews. Methods: We handsearched the Association for Research in Vision and Ophthalmology (ARVO) meeting abstracts for 2004 to 2009 to identify reports of RCTs. We compared our classification with that of authors (requested by ARVO 2004-2006), and authors' report of trial registration (required by ARVO 2007-2009). Results: Authors identified their study as a clinical trial for 169/191 (88%; 95% CI, 84-93) RCTs we identified for 2004, 174/212 (82%; 95% CI, 77-87) for 2005 and 162/215 (75%; 95% CI, 70-81) for 2006. Authors provided registration information for 107/172 (62%; 95% CI, 55-69) RCTs for 2007, 103/153 (67%; 95% CI, 60-75) for 2008, and 126/171 (74%; 95% CI, 67-80) for 2009. Most RCT authors providing a trial register name specified ClinicalTrials.gov (276/312; 88%; 95% CI, 85-92) and provided a valid ClinicalTrials.gov registration number (261/276; 95%; 95% CI, 92-97). Based on information provided by authors, trial registration information would be accessible for 48% (83/172) (95% CI, 41-56) of all ARVO abstracts describing RCTs in 2007, 63% (96/153) (95% CI, 55-70) in 2008, and 70% in 2009 (118/171) (95% CI, 62-76). Conclusions: Authors of abstracts describing RCTs frequently did not classify them as clinical trials nor comply with reporting trial registration information, as required by the conference organizers. Systematic reviewers cannot rely on authors to identify relevant unpublished trials or report trial registration, if present. C1 [Scherer, Roberta W.; Ervin, Ann-Margret; Dickersin, Kay] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Sieving, Pamela C.] Natl Inst Hlth Lib, NIH, Bethesda, MD USA. RP Scherer, RW (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. EM rscherer@jhsph.edu OI Sieving, Pamela/0000-0003-3794-5000 FU National Eye Institute, National Institutes of Health [U01EY020522-02] FX Funding for this project was provided by the National Eye Institute, National Institutes of Health (U01EY020522-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 6 Z9 6 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 11 PY 2012 VL 7 IS 9 AR e44183 DI 10.1371/journal.pone.0044183 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 003VE UT WOS:000308638700048 PM 22984474 ER PT J AU Budhu, A Wang, XW AF Budhu, Anuradha Wang, Xin Wei TI Transforming the Microenvironment: A Trick of the Metastatic Cancer Cell SO CANCER CELL LA English DT Editorial Material ID HEPATOCELLULAR-CARCINOMA AB Creating a permissive microenvironment is a strategy employed by tumor cells to disseminate. In this issue of Cancer Cell, Yang et al. identify the molecular signaling events that connect hepatitis infection with TGF beta activity and T regulatory cell recruitment to establish a favorable microenvironment for tumor metastasis. C1 [Budhu, Anuradha; Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, 37 Convent Dr, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 NR 10 TC 6 Z9 6 U1 0 U2 3 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 SEP 11 PY 2012 VL 22 IS 3 BP 279 EP 280 DI 10.1016/j.ccr.2012.08.018 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 005FH UT WOS:000308735400001 PM 22975368 ER PT J AU Tsai, YC Weissman, AM AF Tsai, Yien Che Weissman, Allan M. TI A Ubiquitin-Binding Rhomboid Protease Aimed at ERADication SO DEVELOPMENTAL CELL LA English DT Editorial Material ID INTRAMEMBRANE PROTEOLYSIS; ENDOPLASMIC-RETICULUM; TRAFFICKING; DISLOCATION C1 [Tsai, Yien Che; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21701 USA. RP Tsai, YC (reprint author), NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, 1050 Boyles St, Frederick, MD 21701 USA. EM tsaiyien@mail.nih.gov; weissmaa@mail.nih.gov OI Tsai, Yien Che/0000-0001-9624-1092 FU Intramural NIH HHS [ZIA BC009392-17] NR 9 TC 2 Z9 2 U1 0 U2 3 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 SEP 11 PY 2012 VL 23 IS 3 BP 454 EP 456 DI 10.1016/j.devcel.2012.08.015 PG 3 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 005UU UT WOS:000308776400004 PM 22975320 ER PT J AU Gudlaugsson, J Gudnason, V Aspelund, T Siggeirsdottir, K Olafsdottir, AS Jonsson, PV Arngrimsson, SA Harris, TB Johannsson, E AF Gudlaugsson, Janus Gudnason, Vilmundur Aspelund, Thor Siggeirsdottir, Kristin Olafsdottir, Anna S. Jonsson, Palmi V. Arngrimsson, Sigurbjorn A. Harris, Tamara B. Johannsson, Erlingur TI Effects of a 6-month multimodal training intervention on retention of functional fitness in older adults: A randomized-controlled cross-over design SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Physical activity; Functional fitness; SPPB; 6 MW; Strength; Cross-over design ID AMERICAN-HEART-ASSOCIATION; QUALITY-OF-LIFE; PHYSICAL-ACTIVITY; EXERCISE CAPACITY; MUSCLE STRENGTH; SPORTS-MEDICINE; PUBLIC-HEALTH; PERFORMANCE; MORTALITY; PEOPLE AB Background: Older adults have the highest rates of disability, functional dependence and use of healthcare resources. Training interventions for older individuals are of special interest where regular physical activity (PA) has many health benefits. The main purpose of this study was to assess the immediate and long-term effects of a 6-month multimodal training intervention (MTI) on functional fitness in old adults. Methods: For this study, 117 participants, 71 to 90 years old, were randomized in immediate intervention group and a control group (delayed intervention group). The intervention consisted of daily endurance and twice-a-week strength training. The method was based on a randomized-controlled cross-over design. Short Physical Performance Battery (SPPB), 8 foot up-and-go test, strength performance, six min walking test (6 MW), physical activity, BMI and quality of life were obtained at baseline, after a 6-month intervention- and control phase, again after 6-month crossover- and delayed intervention phase, and after anadditional 6-month follow-up. Results: After 6 months of MTI, the intervention group improved in physical performance compared with the control group via Short Physical Performance Battery (SPPB) score (mean diff = 0.6, 95 % CI: 0.1, 1.0) and 8-foot up-and-go test (mean diff = -1.0 s, 95 % CI: -1.5, -0.6), and in endurance performance via 6-minute walking test (6 MW) (mean diff = 44.2 meters, 95 % CI: 17.1, 71.2). In strength performance via knee extension the intervention group improved while control group declined (mean diff = 55.0 Newton, 95 % CI: 28.4, 81.7), and also in PA (mean diff = 125.9 cpm, 95 % CI: 96.0, 155.8). Long-term effects of MTI on the particpants was assesed by estimating the mean difference in the variables measured between time-point 1 and 4: SPPB (1.1 points, 95 % CI: 0.8, 1.4); 8-foot up-and-go (-0.9 s, 95 % CI: -1.2, -0.6); 6 MW (18.7 m, 95 % CI: 6.5, 31.0); knee extension (4.2 Newton, 95 % CI: -10.0, 18.3); hand grip (6.7 Newton, 95 % CI: -4.4, 17.8); PA (-4.0 cpm, 95 % CI: -33.9, 26.0); BMI (-0.6 kg/m(2), 95 % CI: -0.9, -0.3) and Icelandic quality of life (0.3 points, 95 % CI: -0.7, 1.4). Conclusions: Our results suggest that regular MTI can improve and prevent decline in functional fitness in older individuals, influence their lifestyle and positively affect their ability to stay independent, thus reducing the need for institutional care. C1 [Gudlaugsson, Janus; Olafsdottir, Anna S.; Arngrimsson, Sigurbjorn A.; Johannsson, Erlingur] Univ Iceland, Ctr Res Sport & Hlth Sci, Laugarvatn, Iceland. [Gudnason, Vilmundur; Aspelund, Thor; Siggeirsdottir, Kristin] Iceland Heart Assoc, Reykjavik, Iceland. [Gudnason, Vilmundur; Aspelund, Thor; Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Jonsson, Palmi V.] Landspitali Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Baltimore, MD 21224 USA. RP Johannsson, E (reprint author), Univ Iceland, Ctr Res Sport & Hlth Sci, Laugarvatn, Iceland. EM erljo@hi.is RI Olafsdottir, Anna/A-8804-2013; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Olafsdottir, Anna/0000-0002-7258-1727; Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU Icelandic Centre for Research; University of Iceland Research Fund; Ministry of Education, Science and Culture Sport Fund; Association of Municipalities in the Capital Area; Fitness Centre Laugar; Public Health Institute of Iceland; Icelandic Heart Association FX This research project was supported by The Icelandic Centre for Research, The University of Iceland Research Fund, The Ministry of Education, Science and Culture Sport Fund, The Association of Municipalities in the Capital Area, The Fitness Centre Laugar, The Public Health Institute of Iceland and The Icelandic Heart Association. NR 27 TC 12 Z9 12 U1 1 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD SEP 10 PY 2012 VL 9 DI 10.1186/1479-5868-9-107 PG 11 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 063JG UT WOS:000312992600001 PM 22963328 ER PT J AU Kim, TH Jo, YG Jiang, HH Lim, SM Youn, YS Lee, S Chen, XY Byun, Y Lee, KC AF Kim, Tae Hyung Jo, Young Gi Jiang, Hai Hua Lim, Sung Mook Youn, Yu Seok Lee, Seulki Chen, Xiaoyuan Byun, Youngro Lee, Kang Choon TI PEG-transferrin conjugated TRAIL (TNF-related apoptosis-inducing ligand) for therapeutic tumor targeting SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE TRAIL; Transferrin; PEGylation; Passive tumor targeting; Active tumor targeting ID RECEPTOR-MEDIATED ENDOCYTOSIS; ANTITUMOR-ACTIVITY; DELIVERY; CELLS; PHARMACOKINETICS; DOXORUBICIN; STABILITY; PROTEINS; EFFICACY; SAFETY AB Transferrin (Tf) is considered an effective tumor-targeting agent, and PEGylation effectively prolongs in vivo pharmacokinetics by delaying excretion via the renal route. The authors describe the active tumor targeting of long-acting Tf-PEG-TNF-related apoptosis-inducing ligand conjugate (Tf-PEG-TRAIL) for effective cancer therapy. Tf-PEG-TRAIL was prepared using a two-step N-terminal specific PEGylation procedure using different PEGs (Mw: 3.4, 5, 10 kDa). Eventually, only 10 kDa PEG was linked to Tf and TRAIL because TRAIL (66 kDa) and Tf (81 kDa) were too large to link to 3.4 and 5 kDa PEG. The final conjugate Tf-PEG(10K)-TRAIL was successfully purified and characterized by SDS-PAGE, western blotting. To determine the specific binding of Tf-PEG(10K)-TRAIL to Tf receptor, competitive receptor binding assays were performed on K 562 cells. The results obtained demonstrate that the affinity of Tf-PEG10K-TRAIL for Tf receptor is similar to that of native Tf. In contrast, PEG(10K)-TRAIL demonstrated no specificity. Biodistribution patterns and antitumor effects were investigated in C57BL6 mice bearing B16F10 murine melanomas and BALB/c athymic mice bearing HCT116. Tumor accumulation of Tf-PEG(10K)-TRAIL was 5.2 fold higher (at 2 h) than TRAIL, because Tf-PEG(10K)-TRAIL has both passive and active tumor targeting ability. Furthermore, the suppression of tumors by Tf-PEG(10K)-TRAIL was 3.6 and 1.5 fold those of TRAIL and PEG(10K)-TRAIL, respectively. These results suggest that Tf-PEG(10K)-TRAIL is a superior pharmacokinetic conjugate that potently targets tumors and that it should be viewed as a potential cancer therapy. (C) 2012 Elsevier B. V. All rights reserved. C1 [Lee, Kang Choon] Sungkyunkwan Univ, Drug Targeting Lab, Coll Pharm, Suwon 440746, South Korea. [Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Byun, Youngro] Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea. RP Lee, KC (reprint author), Sungkyunkwan Univ, Drug Targeting Lab, Coll Pharm, 300 Chonchon Dong, Suwon 440746, South Korea. EM kclee@skku.edu RI BYUN, YOUNG RO/D-5735-2013 FU Converging Research Center Program through the National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-K000796] FX This work was supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-K000796). NR 25 TC 22 Z9 22 U1 1 U2 36 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD SEP 10 PY 2012 VL 162 IS 2 BP 422 EP 428 DI 10.1016/j.jconrel.2012.07.021 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 029OY UT WOS:000310506400020 PM 22824780 ER PT J AU Parylak, SL Cottone, P Sabino, V Rice, KC Zorrilla, EP AF Parylak, Sarah L. Cottone, Pietro Sabino, Valentina Rice, Kenner C. Zorrilla, Eric P. TI Effects of CB1 and CRF1 receptor antagonists on binge-like eating in rats with limited access to a sweet fat diet: Lack of withdrawal-like responses SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Binge eating; Palatable food intake; Sucrose or sugar or fat or food addiction; Obesity; Withdrawal anxiety; Corticotropin-releasing factor or corticotropin-releasing hormone or CRF or CRH; Endocannabinoid or cannabinoid type 1 receptor; Surinabant or rimonabant ID CONDITIONED FLAVOR PREFERENCES; FOOD-ANTICIPATORY ACTIVITY; CANNABINOID RECEPTOR; PALATABLE FOOD; INDUCED INCREASES; PREFERRED FOOD; DEPENDENT RATS; CHRONIC STRESS; RELAPSE MODEL; FEMALE RATS AB Positive reinforcement (e.g., appetitive, rewarding properties) has often been hypothesized to maintain excessive intake of palatable foods. Recently, rats receiving intermittent access to high sucrose diets showed binge-like intake with withdrawal-like signs upon cessation of access, suggesting negative reinforcement mechanisms contribute as well. Whether intermittent access to high fat diets also produces withdrawal-like syndromes is controversial. The present study therefore tested the hypothesis that binge-like eating and withdrawal-like anxiety would arise in a novel model of binge eating based on daily 10-min access to a sweet fat diet (35% fat kcal, 31% sucrose kcal). Within 2-3 weeks, female Wistar rats developed binge-like intake comparable to levels seen previously for high sucrose diets (similar to 40% of daily caloric intake within 10 min) plus excess weight gain and adiposity, but absent increased anxiety-like behavior during elevated plus-maze or defensive withdrawal tests after diet withdrawal. Binge-like intake was unaffected by pretreatment with the corticotropin-releasing factor type 1 (CRF1) receptor antagonist R121919, and corticosterone responses to restraint stress did not differ between sweet-fat binge rats and chow-fed controls. In contrast, pretreatment with the cannabinoid type 1 (CB1) receptor antagonist SR147778 dose-dependently reduced binge-like intake, albeit less effectively than in ad lib chow or sweet fat controls. A priming dose of the sweet fat diet did not precipitate increased anxiety-like behavior, but rather increased plus-maze locomotor activity. The results suggest that CB1-dependent positive reinforcement rather than CRFI-dependent negative reinforcement mechanisms predominantly maintain excessive intake in this limited access model of sweet-fat diet binges. (C) 2012 Elsevier Inc. All rights reserved. C1 [Parylak, Sarah L.; Cottone, Pietro; Sabino, Valentina; Zorrilla, Eric P.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Parylak, Sarah L.; Zorrilla, Eric P.] Univ Calif San Diego, Grad Program Neurosci, La Jolla, CA 92093 USA. [Cottone, Pietro; Sabino, Valentina] Boston Univ, Sch Med, Dept Pharmacol, Lab Addict Disorders, Boston, MA 02118 USA. [Cottone, Pietro; Sabino, Valentina] Boston Univ, Sch Med, Dept Psychiat, Lab Addict Disorders, Boston, MA 02118 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, Bethesda, MD 20892 USA. RP Zorrilla, EP (reprint author), Scripps Res Inst, Comm Neurobiol Addict Disorders, SP30-2400,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM sparylak@ucsd.edu; cottone@bu.edu; vsabino@bu.edu; kennerr@mail.nih.gov; ezorrilla@scripps.edu RI Cottone, Pietro/F-5291-2012; Sabino, Valentina/F-5290-2012 OI Cottone, Pietro/0000-0003-1320-1672; Sabino, Valentina/0000-0002-6680-1279 FU Pearson Center for Alcoholism and Addiction Research; Harold L Dorris Neurological Research Institute; NIH [DK070118, DK076896, DA023680, DA026690, 1T32NS061847]; Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX The authors thank Michael Arends for editorial assistance with the manuscript and Jean Kim and Daniel Le for technical assistance. Financial support for this work was provided by the Pearson Center for Alcoholism and Addiction Research, the Harold L Dorris Neurological Research Institute, and grants DK070118, DK076896, DA023680, DA026690, and 1T32NS061847 from the NIH. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This is manuscript number 21675 from The Scripps Research Institute. NR 82 TC 18 Z9 18 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD SEP 10 PY 2012 VL 107 IS 2 BP 231 EP 242 DI 10.1016/j.physbeh.2012.06.017 PG 12 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 023OK UT WOS:000310044100008 PM 22776620 ER PT J AU Kellman, P Wilson, JR Xue, H Ugander, M Arai, AE AF Kellman, Peter Wilson, Joel R. Xue, Hui Ugander, Martin Arai, Andrew E. TI Extracellular volume fraction mapping in the myocardium, part 1: evaluation of an automated method SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Extracellular; Diffuse fibrosis; Edema; Late enhancement; Motion correction; Co-registration ID CARDIOVASCULAR MAGNETIC-RESONANCE; INVERSION-RECOVERY; GADOPENTETATE DIMEGLUMINE; INFARCTION; FIBROSIS; T1; QUANTIFICATION; OPTIMIZATION; ENHANCEMENT; VALIDATION AB Background: Disturbances in the myocardial extracellular volume fraction (ECV), such as diffuse or focal myocardial fibrosis or edema, are hallmarks of heart disease. Diffuse ECV changes are difficult to assess or quantify with cardiovascular magnetic resonance (CMR) using conventional late gadolinium enhancement (LGE), or pre- or post-contrast T1-mapping alone. ECV measurement circumvents factors that confound T1-weighted images or T1-maps, and has been shown to correlate well with diffuse myocardial fibrosis. The goal of this study was to develop and evaluate an automated method for producing a pixel-wise map of ECV that would be adequately robust for clinical work flow. Methods: ECV maps were automatically generated from T1-maps acquired pre- and post-contrast calibrated by blood hematocrit. The algorithm incorporates correction of respiratory motion that occurs due to insufficient breath-holding and due to misregistration between breath-holds, as well as automated identification of the blood pool. Images were visually scored on a 5-point scale from non-diagnostic (1) to excellent (5). Results: The quality score of ECV maps was 4.23 +/- 0.83 (m +/- SD), scored for n = 600 maps from 338 patients with 83% either excellent or good. Co-registration of the pre- and post-contrast images improved the image quality for ECV maps in 81% of the cases. ECV of normal myocardium was 25.4 +/- 2.5% (m +/- SD) using motion correction and co-registration values and was 31.5 +/- 8.7% without motion correction and co-registration. Conclusions: Fully automated motion correction and co-registration of breath-holds significantly improve the quality of ECV maps, thus making the generation of ECV-maps feasible for clinical work flow. C1 [Kellman, Peter; Wilson, Joel R.; Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Xue, Hui] Siemens Corp Res, Princeton, NJ USA. [Ugander, Martin] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Ugander, Martin] Karolinska Univ Hosp, Stockholm, Sweden. RP Kellman, P (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kellmanp@nhlbi.nih.gov OI Ugander, Martin/0000-0003-3665-2038 FU Intramural NIH HHS [ZID HL006140-02, ZIE HL006139-01, ZIE HL006139-02, ZIA HL004607-14, ZID HL006140-01] NR 27 TC 84 Z9 85 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD SEP 10 PY 2012 VL 14 AR 63 DI 10.1186/1532-429X-14-63 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 012HA UT WOS:000309225600001 PM 22963517 ER PT J AU McCahill, LE Yothers, G Sharif, S Petrelli, NJ Lai, LL Bechar, N Giguere, JK Dakhil, SR Fehrenbacher, L Lopa, SH Wagman, LD O'Connell, MJ Wolmark, N AF McCahill, Laurence E. Yothers, Greg Sharif, Saima Petrelli, Nicholas J. Lai, Lily Lau Bechar, Naftali Giguere, Jeffrey K. Dakhil, Shaker R. Fehrenbacher, Louis Lopa, Samia H. Wagman, Lawrence D. O'Connell, Michael J. Wolmark, Norman TI Primary mFOLFOX6 Plus Bevacizumab Without Resection of the Primary Tumor for Patients Presenting With Surgically Unresectable Metastatic Colon Cancer and an Intact Asymptomatic Colon Cancer: Definitive Analysis of NSABP Trial C-10 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID IV COLORECTAL-CANCER; NONOPERATIVE MANAGEMENT; PALLIATIVE RESECTION; CHEMOTHERAPY; SURGERY; MORBIDITY; MORTALITY; SURVIVAL AB Purpose Major concerns surround combining chemotherapy with bevacizumab in patients with colon cancer presenting with an asymptomatic intact primary tumor (IPT) and synchronous yet unresectable metastatic disease. Surgical resection of asymptomatic IPT is controversial. Patients and Methods Eligibility for this prospective, multicenter phase II trial included Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, asymptomatic IPT, and unresectable metastases. All received infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) combined with bevacizumab. The primary end point was major morbidity events, defined as surgical resection because of symptoms at or death related to the IPT. A 25% major morbidity rate was considered acceptable. Secondary end points included overall survival (OS) and minor morbidity related to IPT requiring hospitalization, transfusion, or nonsurgical intervention. Results Ninety patients registered between March 2006 and June 2009: 86 were eligible with follow-up, median age was 58 years, and 52% were female. Median follow-up was 20.7 months. There were 12 patients (14%) with major morbidity related to IPT: 10 required surgery (eight, obstruction; one, perforation; and one, abdominal pain), and two patients died. The 24-month cumulative incidence of major morbidity was 16.3% (95% CI, 7.6% to 25.1%). Eleven IPTs were resected without a morbidity event: eight for attempted cure and three for other reasons. Two patients had minor morbidity events only: one hospitalization and one nonsurgical intervention. Median OS was 19.9 months (95% CI, 15.0 to 27.2 months). Conclusion This trial met its primary end point. Combining mFOLFOX6 with bevacizumab did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to IPT. Survival was not compromised. These patients can be spared initial noncurative resection of their asymptomatic IPT. J Clin Oncol 30:3223-3228. (C) 2012 by American Society of Clinical Oncology C1 [McCahill, Laurence E.] Michigan State Univ, St Marys Hlth Care, Richard J Lacks Canc Ctr, Grand Rapids, MI 49503 USA. [McCahill, Laurence E.; Yothers, Greg; Sharif, Saima; Petrelli, Nicholas J.; Lai, Lily Lau; Bechar, Naftali; Giguere, Jeffrey K.; Dakhil, Shaker R.; Fehrenbacher, Louis; Lopa, Samia H.; Wagman, Lawrence D.; O'Connell, Michael J.; Wolmark, Norman] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Yothers, Greg; Lopa, Samia H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Sharif, Saima; Wolmark, Norman] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. [McCahill, Laurence E.] Michigan State Univ, Lansing, MI USA. [Petrelli, Nicholas J.] Christiana Care, Helen F Graham Canc Ctr, Newark, DE USA. [Lai, Lily Lau; Wagman, Lawrence D.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Fehrenbacher, Louis] Kaiser Permanente, Vallejo, CA USA. [Wagman, Lawrence D.] St Joseph Hosp, Ctr Canc Prevent & Treatment, Orange, CA USA. [Bechar, Naftali] No Indiana Canc Res Consortium, Community Clin Oncol Program CCOP, Kokomo, IN USA. [Bechar, Naftali] Howard Reg Hlth Syst, Kokomo, IN USA. [Giguere, Jeffrey K.] CCOP, Greenville, SC USA. [Dakhil, Shaker R.] CCOP, Wichita, KS USA. RP McCahill, LE (reprint author), Michigan State Univ, St Marys Hlth Care, Richard J Lacks Canc Ctr, 250 Cherry St, Grand Rapids, MI 49503 USA. EM mccahill@trinity-health.org OI Yothers, Greg/0000-0002-7965-7333 FU NCI NIH HHS [U10 CA037377, U10 CA012027, U10 CA069651, U10 CA069974, U24 CA114732] NR 23 TC 58 Z9 62 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2012 VL 30 IS 26 BP 3223 EP 3228 DI 10.1200/JCO.2012.42.4044 PG 6 WC Oncology SC Oncology GA 004UR UT WOS:000308707100021 PM 22869888 ER PT J AU Freidlin, B McShane, LM Polley, MYC Korn, EL AF Freidlin, Boris McShane, Lisa M. Polley, Mei-Yin C. Korn, Edward L. TI Randomized Phase II Trial Designs With Biomarkers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; COLORECTAL-CANCER; CETUXIMAB; PLACEBO; BENEFIT; ISSUES AB Efficient development of targeted therapies that may only benefit a fraction of patients requires clinical trial designs that use biomarkers to identify sensitive subpopulations. Various randomized phase III trial designs have been proposed for definitive evaluation of new targeted treatments and their associated biomarkers (eg, enrichment designs and biomarker-stratified designs). Before proceeding to phase III, randomized phase II trials are often used to decide whether the new therapy warrants phase III testing. In the presence of a putative biomarker, the phase II trial should also provide information as to what type of biomarker phase III trial is appropriate. A randomized phase II biomarker trial design is proposed, which, after completion, recommends the type of phase III trial to be used for the definitive testing of the therapy and the biomarker. The recommendations include the possibility of proceeding to a randomized phase III of the new therapy with or without using the biomarker and also the possibility of not testing the new therapy further. Evaluations of the proposed trial design using simulations and published data demonstrate that it works well in providing recommendations for phase III trial design. C1 [Freidlin, Boris] NCI, Biometr Res Branch, Bethesda, MD 20852 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, EPN 8129, Bethesda, MD 20852 USA. EM freidlinb@ctep.nci.nih.gov NR 19 TC 31 Z9 33 U1 1 U2 10 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 SEP 10 PY 2012 VL 30 IS 26 BP 3304 EP 3309 DI 10.1200/JCO.2012.43.3946 PG 6 WC Oncology SC Oncology GA 004UR UT WOS:000308707100032 PM 22869885 ER PT J AU Saloustros, E Stratakis, CA AF Saloustros, Emmanouil Stratakis, Constantine A. TI Potential Late Effect of Gonadotropin-Releasing Hormone Agonists in Combination With Chemotherapy for Early Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID RANDOMIZED-TRIAL; OVARIAN-FUNCTION; TRIPTORELIN; PREVENTION; MENOPAUSE C1 [Saloustros, Emmanouil; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Saloustros, E (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. OI Saloustros, Emmanouil /0000-0002-0485-0120 NR 8 TC 2 Z9 2 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 SEP 10 PY 2012 VL 30 IS 26 BP 3311 EP 3312 DI 10.1200/JCO.2012.42.6197 PG 3 WC Oncology SC Oncology GA 004UR UT WOS:000308707100035 PM 22649148 ER PT J AU Kelly, RJ Carter, CA Giaccone, G AF Kelly, Ronan J. Carter, Corey A. Giaccone, Giuseppe TI HER2 Mutations in Non-Small-Cell Lung Cancer Can Be Continually Targeted SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID PHASE-II; TRASTUZUMAB C1 [Kelly, Ronan J.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Carter, Corey A.] Natl Naval Med Ctr, Bethesda, MD USA. [Giaccone, Giuseppe] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kelly, RJ (reprint author), Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 9 TC 15 Z9 15 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 SEP 10 PY 2012 VL 30 IS 26 BP 3318 EP 3319 DI 10.1200/JCO.2012.43.4902 PG 4 WC Oncology SC Oncology GA 004UR UT WOS:000308707100043 PM 22649146 ER PT J AU Araujo, THA Souza-Brito, LI Libin, P Deforche, K Edwards, D de Albuquerque, AE Vandamme, AM Galvao-Castro, B Alcantara, LC AF Almeida Araujo, Thessika Hialla Souza-Brito, Leandro Inacio Libin, Pieter Deforche, Koen Edwards, Dustin de Albuquerque-Junior, Antonio Eduardo Vandamme, Anne-Mieke Galvao-Castro, Bernardo Junior Alcantara, Luiz Carlos TI A Public HTLV-1 Molecular Epidemiology Database for Sequence Management and Data Mining SO PLOS ONE LA English DT Article ID VIRUS TYPE-I; T-CELL LEUKEMIA; BLOOD-DONORS; INFECTION AB Background: It is estimated that 15 to 20 million people are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). At present, there are more than 2,000 unique HTLV-1 isolate sequences published. A central database to aggregate sequence information from a range of epidemiological aspects including HTLV-1 infections, pathogenesis, origins, and evolutionary dynamics would be useful to scientists and physicians worldwide. Described here, we have developed a database that collects and annotates sequence data and can be accessed through a user- friendly search interface. The HTLV-1 Molecular Epidemiology Database website is available at http://htlv1db.bahia.fiocruz.br/. Methodology/Principal Findings: All data was obtained from publications available at GenBank or through contact with the authors. The database was developed using Apache Webserver 2.1.6 and SGBD MySQL. The webpage interfaces were developed in HTML and sever-side scripting written in PHP. The HTLV-1 Molecular Epidemiology Database is hosted on the Goncalo Moniz/FIOCRUZ Research Center server. There are currently 2,457 registered sequences with 2,024 (82.37%) of those sequences representing unique isolates. Of these sequences, 803 (39.67%) contain information about clinical status (TSP/HAM, 17.19%; ATL, 7.41%; asymptomatic, 12.89%; other diseases, 2.17%; and no information, 60.32%). Further, 7.26% of sequences contain information on patient gender while 5.23% of sequences provide the age of the patient. Conclusions/Significance: The HTLV-1 Molecular Epidemiology Database retrieves and stores annotated HTLV-1 proviral sequences from clinical, epidemiological, and geographical studies. The collected sequences and related information are now accessible on a publically available and user- friendly website. This open-access database will support clinical research and vaccine development related to viral genotype. C1 [Almeida Araujo, Thessika Hialla; de Albuquerque-Junior, Antonio Eduardo; Galvao-Castro, Bernardo; Junior Alcantara, Luiz Carlos] Fundacao Oswaldo Cruz, Goncalo Moniz Res Center, Salvador, BA, Brazil. [Souza-Brito, Leandro Inacio; Galvao-Castro, Bernardo; Junior Alcantara, Luiz Carlos] Bahia Fdn Sci Dev, Bahia Sch Med & Publ Hlth, Salvador, BA, Brazil. [Libin, Pieter; Vandamme, Anne-Mieke] Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium. [Edwards, Dustin] NCI, Anim Models & Retroviral Vaccines Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Libin, Pieter; Deforche, Koen] MyBioData, Rotselaar, Belgium. [Vandamme, Anne-Mieke] Univ Nova Lisboa, Ctr Malaria & Outras Doencas Trop, Inst Higiene & Med Trop, P-1200 Lisbon, Portugal. RP Araujo, THA (reprint author), Fundacao Oswaldo Cruz, Goncalo Moniz Res Center, Salvador, BA, Brazil. EM lalcan@bahia.fiocruz.br RI Vandamme, Anne Mieke/I-4127-2012; santos, sofia/I-1637-2012 OI Vandamme, Anne Mieke/0000-0002-6594-2766; FU Brazilian Ministry of Health [TC120/2010] FX This work was supported by funds from Brazilian Ministry of Health (TC120/2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 8 Z9 8 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 10 PY 2012 VL 7 IS 9 AR e42123 DI 10.1371/journal.pone.0042123 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 005KD UT WOS:000308748400002 PM 22970114 ER PT J AU Duprez, DA Neuhaus, J Kuller, LH Tracy, R Belloso, W De Wit, S Drummond, F Lane, HC Ledergerber, B Lundgren, J Nixon, D Paton, NI Prineas, RJ Neaton, JD AF Duprez, Daniel A. Neuhaus, Jacqueline Kuller, Lewis H. Tracy, Russell Belloso, Waldo De Wit, Stephane Drummond, Fraser Lane, H. Clifford Ledergerber, Bruno Lundgren, Jens Nixon, Daniel Paton, Nicholas I. Prineas, Ronald J. Neaton, James D. CA INSIGHT SMART Study Grp TI Inflammation, Coagulation and Cardiovascular Disease in HIV-Infected Individuals SO PLOS ONE LA English DT Article ID CORONARY-HEART-DISEASE; ANTIRETROVIRAL THERAPY; D-DIMER; MYOCARDIAL-INFARCTION; OPPORTUNISTIC DISEASE; RISK; BIOMARKERS; DEATH; ATHEROSCLEROSIS; INTERLEUKIN-6 AB Background: The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors. Methods: A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1st quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models. Results: There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference). Conclusions: In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals. C1 [Duprez, Daniel A.; Neuhaus, Jacqueline; Neaton, James D.] Univ Minnesota, Minneapolis, MN 55455 USA. [Kuller, Lewis H.] Univ Pittsburgh, Pittsburgh, PA USA. [Tracy, Russell] Univ Vermont, Burlington, VT USA. [Belloso, Waldo] Hosp Italiano Buenos Aires, Buenos Aires, DF, Argentina. [De Wit, Stephane] St Pierre Hosp, Brussels, Belgium. [Drummond, Fraser] Univ New S Wales, Fac Med, Kirby Inst, Sydney, NSW, Australia. [Lane, H. Clifford] NIAID, NIH, Bethesda, MD 20892 USA. [Ledergerber, Bruno] Univ Zurich, Univ Zurich Hosp, Zurich, Switzerland. [Lundgren, Jens] Univ Copenhagen, Copenhagen, Denmark. [Nixon, Daniel] Virginia Commonwealth Univ, Richmond, VA USA. [Paton, Nicholas I.] MRC, Clin Trials Unit, London, England. [Prineas, Ronald J.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Duprez, DA (reprint author), Univ Minnesota, Minneapolis, MN 55455 USA. EM dupre007@umn.edu RI Infektiologie, USZ/A-6921-2011; SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; Ledergerber, Bruno/B-5656-2009; OI Ledergerber, Bruno/0000-0002-6881-4401; Lundgren, Jens/0000-0001-8901-7850 FU NIAD, United States National Institutes of Health [UO1AI068641, U01AI042170, U01AI046362] FX Support for this work was provided by NIAD, United States National Institutes of Health grants UO1AI068641, U01AI042170, and U01AI046362. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 175 Z9 175 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 10 PY 2012 VL 7 IS 9 AR e44454 DI 10.1371/journal.pone.0044454 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 005KD UT WOS:000308748400019 PM 22970224 ER PT J AU Zhang, MY Yuan, TT Li, JJ Borges, AR Watkins, JD Guenaga, J Yang, Z Wang, YP Wilson, R Li, YX Polonis, VR Pincus, SH Ruprecht, RM Dimitrov, DS AF Zhang, Mei-Yun Yuan, Tingting Li, Jingjing Borges, Andrew Rosa Watkins, Jennifer D. Guenaga, Javier Yang, Zheng Wang, Yanping Wilson, Richard Li, Yuxing Polonis, Victoria R. Pincus, Seth H. Ruprecht, Ruth M. Dimitrov, Dimiter S. TI Identification and Characterization of a Broadly Cross-Reactive HIV-1 Human Monoclonal Antibody That Binds to Both gp120 and gp41 SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODIES; IN-VIVO; CRYSTAL-STRUCTURE; ENVELOPE PROTEIN; PHAGE LIBRARY; POTENT; CELL; FUSION; RECOGNIZES AB Identification of broadly cross-reactive HIV-1-neutralizing antibodies (bnAbs) may assist vaccine immunogen design. Here we report a novel human monoclonal antibody (mAb), designated m43, which co-targets the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (Env). M43 bound to recombinant gp140 s from various primary isolates, to membrane-associated Envs on transfected cells and HIV-1 infected cells, as well as to recombinant gp120 s and gp41 fusion intermediate structures containing N-trimer structure, but did not bind to denatured recombinant gp140 s and the CD4 binding site (CD4bs) mutant, gp120 D368R, suggesting that the m43 epitope is conformational and overlaps the CD4bs on gp120 and the N-trimer structure on gp41. M43 neutralized 34% of the HIV-1 primary isolates from different clades and all the SHIVs tested in assays based on infection of peripheral blood mononuclear cells (PBMCs) by replication-competent virus, but was less potent in cell line-based pseudovirus assays. In contrast to CD4, m43 did not induce Env conformational changes upon binding leading to exposure of the coreceptor binding site, enhanced binding of mAbs 2F5 and 4E10 specific for the membrane proximal external region (MPER) of gp41 Envs, or increased gp120 shedding. The overall modest neutralization activity of m43 is likely due to the limited binding of m43 to functional Envs which could be increased by antibody engineering if needed. M43 may represent a new class of bnAbs targeting conformational epitopes overlapping structures on both gp120 and gp41. Its novel epitope and possibly new mechanism(s) of neutralization could helpdesign improved vaccine immunogens and candidate therapeutics. C1 [Zhang, Mei-Yun; Yuan, Tingting; Li, Jingjing; Yang, Zheng] Univ Hong Kong, AIDS Inst, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Zhang, Mei-Yun; Yuan, Tingting; Li, Jingjing; Yang, Zheng] Univ Hong Kong, Dept Microbiol, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Borges, Andrew Rosa] Henry M Jackson Fdn, Dept Vaccine Res, US Mil HIV Res Program, Rockville, MD USA. [Watkins, Jennifer D.; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Watkins, Jennifer D.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. [Guenaga, Javier; Wilson, Richard; Li, Yuxing] Scripps Res Inst, Dept Immunol & Microbial Sci, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Wang, Yanping; Dimitrov, Dimiter S.] NCI, CCRNP, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Polonis, Victoria R.] Walter Reed Army Inst Res, Div Retrovirol, US Mil HIV Res Program, Rockville, MD USA. [Pincus, Seth H.] Childrens Hosp, New Orleans, LA USA. [Pincus, Seth H.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. RP Zhang, MY (reprint author), Univ Hong Kong, AIDS Inst, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. EM zhangmy@hku.hk OI Yang, Zheng/0000-0003-0217-6694 FU Intramural Research Program of the University of Hong Kong; Hong Kong Research Grants Council (RGC) General Research Fund (GRF) grant [785210]; National Institutes of Health (NIH) [R37 AI034266, P01 AI048240]; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; Bill and Melinda Gates Foundation FX This work was supported by the Intramural Research Program of the University of Hong Kong, and by Hong Kong Research Grants Council (RGC) General Research Fund (GRF) grant #785210 to MYZ, National Institutes of Health (NIH) R37 AI034266 and P01 AI048240 to RMR, and by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and the Bill and Melinda Gates Foundation to DSD. 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 United States Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 16 Z9 16 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 10 PY 2012 VL 7 IS 9 AR e44241 DI 10.1371/journal.pone.0044241 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 005KD UT WOS:000308748400013 PM 22970187 ER PT J AU Hansen, L Marino-Ramirez, L Landsman, D AF Hansen, Loren Marino-Ramirez, Leonardo Landsman, David TI Differences in local genomic context of bound and unbound motifs SO GENE LA English DT Article DE Gene regulation; Yeast; Transcription factors; Genomic features; Machine learning ID TRANSCRIPTION FACTOR-BINDING; YEAST SACCHAROMYCES-CEREVISIAE; REGULATORY ELEMENTS; CHROMATIN-STRUCTURE; EUKARYOTIC GENOME; SEQUENCE MOTIFS; BUDDING YEAST; WIDE MAP; PROTEIN; SITES AB Understanding gene regulation is a major objective in molecular biology research. Frequently, transcription is driven by transcription factors (TFs) that bind to specific DNA sequences. These motifs are usually short and degenerate, rendering the likelihood of multiple copies occurring throughout the genome due to random chance as high. Despite this, TFs only bind to a small subset of sites, thus prompting our investigation into the differences between motifs that are bound by TFs and those that remain unbound. Here we constructed vectors representing various chromatin- and sequence-based features for a published set of bound and unbound motifs representing nine TFs in the budding yeast Saccharomyces cerevisiae. Using a machine learning approach, we identified a set of features that can be used to discriminate between bound and unbound motifs. We also discovered that some TFs bind most or all of their strong motifs in intergenic regions. Our data demonstrate that local sequence context can be strikingly different around motifs that are bound compared to motifs that are unbound. We concluded that there are multiple combinations of genomic features that characterize bound or unbound motifs. Published by Elsevier B.V. C1 [Hansen, Loren; Marino-Ramirez, Leonardo; Landsman, David] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Hansen, Loren] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Marino-Ramirez, Leonardo] PanAmer Bioinformat Inst, Santa Marta, Magdalena, Colombia. RP Marino-Ramirez, L (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, 8900 Rockville Pike, Bethesda, MD 20894 USA. EM marino@ncbi.nlm.nih.gov RI Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU National Institutes of Health, National Library of Medicine; National Center for Biotechnology Information FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine and National Center for Biotechnology Information. NR 64 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD SEP 10 PY 2012 VL 506 IS 1 BP 125 EP 134 DI 10.1016/j.gene.2012.06.005 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 998SJ UT WOS:000308260400018 PM 22692006 ER PT J AU Finkel, T AF Finkel, Toren TI Relief with Rapamycin: mTOR Inhibition Protects against Radiation-Induced Mucositis SO CELL STEM CELL LA English DT Editorial Material ID HEMATOPOIETIC STEM-CELLS AB In this issue of Cell Stem Cell, Iglesias-Bartolome et al. (2012) show that mTOR inhibition with rapamycin protects against mucositis in mice, suggesting potential treatment strategies against this harmful side effect of anticancer therapies. In normal tissues, rapamycin prevents epithelial stem cell senescence by reducing oxidative stress through increased MnSOD. C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU Intramural NIH HHS [Z01 HL005012-12] NR 8 TC 2 Z9 2 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 SEP 7 PY 2012 VL 11 IS 3 BP 287 EP 288 DI 10.1016/j.stem.2012.08.003 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 018DW UT WOS:000309641300004 PM 22958927 ER PT J AU Mao, JJ Robey, PG Prockop, DJ AF Mao, Jeremy J. Robey, Pamela G. Prockop, Darwin J. TI Stem Cells in the Face: Tooth Regeneration and Beyond SO CELL STEM CELL LA English DT Review ID MARROW STROMAL CELLS; EPITHELIAL PROGENITOR CELLS; EXFOLIATED DECIDUOUS TEETH; HUMAN PERIODONTAL-LIGAMENT; BONE-MARROW; IN-VIVO; MOUSE INCISORS; MYOCARDIAL-INFARCTION; MESENCHYMAL CELLS; DENTAL EPITHELIUM AB The face distinguishes one person from another. Postnatal orofacial tissues harbor rare cells that exhibit stem cell properties. Despite unmet clinical needs for reconstruction of tissues lost in congenital anomalies, infections, trauma, or tumor resection, how orofacial stem/progenitor cells contribute to tissue development, pathogenesis, and regeneration is largely obscure. This perspective article critically analyzes the current status of our understanding of orofacial stem/progenitor cells, identifies gaps in our knowledge, and highlights pathways for the development of regenerative therapies. C1 [Mao, Jeremy J.] Columbia Univ, Med Ctr, Ctr Craniofacial Regenerat, New York, NY 10032 USA. [Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Prockop, Darwin J.] Texas A&M Univ, Hlth Sci Ctr, Inst Regenerat Med Scott & White, Temple, TX 76502 USA. RP Mao, JJ (reprint author), Columbia Univ, Med Ctr, Ctr Craniofacial Regenerat, 630 W 168 St,PH7E, New York, NY 10032 USA. EM jmao@columbia.edu RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU NIH [R01DE018248, R01EB009663, RC2DE020767, R01HL073755, P01RR17447, R21EY020962]; New York Stem Cell Foundation Grant FX We thank Dr. N. Lumelsky from NIH/NIDCR for her critical comments and Dr. M. Embree for interactions with medical graphics for illustration. The work for composition of this manuscript is supported by NIH grants R01DE018248, R01EB009663, and RC2DE020767 (to J.J.M.); New York Stem Cell Foundation Grant (to J.J.M.); and NIH grants R01HL073755, P01RR17447, and R21EY020962 (to D.J.P.). All three authors conceived the general framework of the manuscript. J.J.M. composed the first draft and revised the manuscript. P.G.R. and D.J.P. provided insightful and critical suggestions and participated in the revision of the manuscript. NR 117 TC 39 Z9 40 U1 2 U2 67 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 SEP 7 PY 2012 VL 11 IS 3 BP 291 EP 301 DI 10.1016/j.stem.2012.08.010 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 018DW UT WOS:000309641300005 PM 22958928 ER PT J AU Iglesias-Bartolome, R Patel, V Cotrim, A Leelahavanichkul, K Molinolo, AA Mitchell, JB Gutkind, JS AF Iglesias-Bartolome, Ramiro Patel, Vyomesh Cotrim, Ana Leelahavanichkul, Kantima Molinolo, Alfredo A. Mitchell, James B. Gutkind, J. Silvio TI mTOR Inhibition Prevents Epithelial Stem Cell Senescence and Protects from Radiation-Induced Mucositis SO CELL STEM CELL LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; MAMMALIAN TARGET; AGING PHENOTYPES; STRESS-RESPONSE; CANCER PATIENTS; RAPAMYCIN; HEAD; NECK; TUMOR; SKIN AB The integrity of the epidermis and mucosal epithelia is highly dependent on resident self-renewing stem cells, which makes them vulnerable to physical and chemical insults compromising the repopulating capacity of the epithelial stem cell compartment. This is frequently the case in cancer patients receiving radiation or chemotherapy, many of whom develop mucositis, a debilitating condition involving painful and deep mucosal ulcerations. Here, we show that inhibiting the mammalian target of rapamycin (mTOR) with rapamycin increases the clonogenic capacity of primary human oral keratinocytes and their resident self-renewing cells by preventing stem cell senescence. This protective effect of rapamycin is mediated by the increase in expression of mitochondrial superoxide dismutase (MnSOD), and the consequent inhibition of ROS formation and oxidative stress. mTOR inhibition also protects from the loss of proliferative basal epithelial stem cells upon ionizing radiation in vivo, thereby preserving the integrity of the oral mucosa and protecting from radiation-induced mucositis. C1 [Iglesias-Bartolome, Ramiro; Patel, Vyomesh; Leelahavanichkul, Kantima; Molinolo, Alfredo A.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20852 USA. [Cotrim, Ana] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20852 USA. [Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20852 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20852 USA. EM sg39v@nih.gov RI Iglesias-Bartolome, Ramiro/H-4460-2014 OI Iglesias-Bartolome, Ramiro/0000-0002-0792-1254 FU Intramural Research Program of the National Institutes of Health; National Institute of Dental and Craniofacial Research; Human Frontier Science Program [RGP0041-2011] FX We thank Bruce J. Baum (NIH, NIDCR) and Thomas Bugge (NIH, NIDCR) for comments and discussions. We thank Mina Konigsberg (Universidad Autonoma, Mexico) for insightful suggestions regarding oxidative stress and senescence. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research, and by the Human Frontier Science Program Grant #RGP0041-2011. NR 59 TC 97 Z9 98 U1 0 U2 13 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 SEP 7 PY 2012 VL 11 IS 3 BP 401 EP 414 DI 10.1016/j.stem.2012.06.007 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 018DW UT WOS:000309641300013 PM 22958932 ER PT J AU Dumas, LJ O'Bleness, MS Davis, JM Dickens, CM Anderson, N Keeney, JG Jackson, J Sikela, M Raznahan, A Giedd, J Rapoport, J Nagamani, SSC Erez, A Brunetti-Pierri, N Sugalski, R Lupski, JR Fingerlin, T Cheung, SW Sikela, JM AF Dumas, Laura J. O'Bleness, Majesta S. Davis, Jonathan M. Dickens, C. Michael Anderson, Nathan Keeney, J. G. Jackson, Jay Sikela, Megan Raznahan, Armin Giedd, Jay Rapoport, Judith Nagamani, Sandesh S. C. Erez, Ayelet Brunetti-Pierri, Nicola Sugalski, Rachel Lupski, James R. Fingerlin, Tasha Cheung, Sau Wai Sikela, James M. TI DUF1220-Domain Copy Number Implicated in Human Brain-Size Pathology and Evolution SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PRIMATE EVOLUTION; GENE; REARRANGEMENTS; DUPLICATIONS; 1Q21.1; EVI5 AB DUF1220 domains show the largest human-lineage-specific increase in copy number of any protein-coding region in the human genome and map primarily to 1q21, where deletions and reciprocal duplications have been associated with microcephaly and macrocephaly, respectively. Given these findings and the high correlation between DUF1220 copy number and brain size across primate lineages (R-2 = 0.98; p = 1.8 x 10(-6)), DUF1220 sequences represent plausible candidates for underlying 1q21-associated brain-size pathologies. To investigate this possibility, we used specialized bioinformatics tools developed for scoring highly duplicated DUF1220 sequences to implement targeted 1q21 array comparative genomic hybridization on individuals (n = 42) with 1q21-associated microcephaly and macrocephaly. We show that of all the 1q21 genes examined (n = 53), DUF1220 copy number shows the strongest association with brain size among individuals with 1q21-associated microcephaly, particularly with respect to the three evolutionarily conserved DUF1220 clades CON1(p = 0.0079), CON2 (p = 0.0134), and CON3 (p = 0.0116). Interestingly, all 1q21 DUF1220-encoding genes belonging to the NBPF family show significant correlations with frontal-occipital-circumference Z scores in the deletion group. In a similar survey of a nondisease population, we show that DUF1220 copy number exhibits the strongest correlation with brain gray-matter volume (CON1, p = 0.0246; and CON2, p = 0.0334). Notably, only DUF1220 sequences are consistently significant in both disease and nondisease populations. Taken together, these data strongly implicate the loss of DUF1220 copy number in the etiology of 1q21-associated microcephaly and support the view that DUF1220 domains function as general effectors of evolutionary, pathological, and normal variation in brain size. C1 [Dumas, Laura J.; O'Bleness, Majesta S.; Davis, Jonathan M.; Dickens, C. Michael; Anderson, Nathan; Keeney, J. G.; Jackson, Jay; Sikela, Megan; Sikela, James M.] Univ Colorado, Sch Med, Dept Biochem & Mol Genet, Aurora, CO 80045 USA. [Dumas, Laura J.; O'Bleness, Majesta S.; Davis, Jonathan M.; Dickens, C. Michael; Anderson, Nathan; Keeney, J. G.; Jackson, Jay; Sikela, Megan; Sikela, James M.] Univ Colorado, Sch Med, Human Med Genet Program, Aurora, CO 80045 USA. [Dumas, Laura J.; O'Bleness, Majesta S.; Davis, Jonathan M.; Dickens, C. Michael; Anderson, Nathan; Keeney, J. G.; Jackson, Jay; Sikela, Megan; Sikela, James M.] Univ Colorado, Sch Med, Neurosci Program, Aurora, CO 80045 USA. [Davis, Jonathan M.; Fingerlin, Tasha] Univ Colorado, Sch Publ Hlth, Dept Epidemiol, Aurora, CO 80045 USA. [Raznahan, Armin; Giedd, Jay; Rapoport, Judith] NIMH, NIH, Bethesda, MD 20892 USA. [Nagamani, Sandesh S. C.; Erez, Ayelet; Lupski, James R.; Cheung, Sau Wai] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Brunetti-Pierri, Nicola] Telethon Inst Genet & Med, I-80131 Naples, Italy. [Brunetti-Pierri, Nicola] Univ Naples Federico II, Dept Pediat, I-80131 Naples, Italy. [Sugalski, Rachel] Brooke Army Med Ctr, San Antonio, TX 78234 USA. RP Sikela, JM (reprint author), Univ Colorado, Sch Med, Dept Biochem & Mol Genet, Aurora, CO 80045 USA. EM james.sikela@ucdenver.edu RI Raznahan, Armin/F-4534-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Brunetti-Pierri, Nicola/0000-0002-6895-8819 FU National Institutes of Health (NIH) [R01 MH081203-1, R01 AA11853-11]; Butcher Foundation; JFK Partners, University of Colorado; Maternal Child Health Bureau; Leadership Education in Neurodevelopmental Disabilities grant [T73MC11044]; National Institute on Alcohol Abuse and Alcoholism/National Institute on Drug Abuse [5T32AA007464-32]; American Recovery and Reinvestment Act grant [R01 AA011853-12S1]; NIH Computational Bioscience Program Training Grant [5T15 LM009451-05]; National Institute of Mental Health [R01 MH0811203-02S1]; Coleman Institute for Cognitive Disabilities; Fondazione Telethon FX We thank Pawel Stankiewicz, Martin Kennedy, John Hokanson, and Mark Johnston for helpful comments; Scott Vacha and Amir Ben-Dor for help with aCGH analyses; Andrew Fortna for programming expertise; Gunter Scherer and Elaine Spector for blood draws and DNA isolations; and Jake Saunders for graphics help. We also thank Oxford Gene Technology for high-quality aCGH services. This work was supported by National Institutes of Health (NIH) grants R01 MH081203-1 and R01 AA11853-11 to J.M.S. and a Butcher Foundation grant to J.M.S. and T.F. J.D. was supported in part by JFK Partners, University of Colorado funding from the Maternal Child Health Bureau, and Leadership Education in Neurodevelopmental Disabilities grant T73MC11044. M.O. was supported by a postdoctoral fellowship from the National Institute on Alcohol Abuse and Alcoholism/National Institute on Drug Abuse (5T32AA007464-32). C.M.D. was supported by American Recovery and Reinvestment Act grant R01 AA011853-12S1 and by an NIH Computational Bioscience Program Training Grant (5T15 LM009451-05). N.A. was supported by National Institute of Mental Health Supplementary Grant R01 MH0811203-02S1; J.K. was supported in part through a Graduate Assistantship from the Coleman Institute for Cognitive Disabilities. J.M.S. is a founder and shareholder of GATC Science. J.R.L. is a consultant for Athena Diagnostics, holds stock ownership of 23andMe and Ion Torrent Systems, and is a coinventor on multiple United States and European patents for DNA diagnostics. The Baylor College of Medicine and Department of Molecular and Human Genetics derive revenue from molecular genetics testing clinical services provided by the Medical Genetics Laboratories (https://www.bcm.edu/geneticlabs). NR 17 TC 36 Z9 36 U1 3 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP 7 PY 2012 VL 91 IS 3 BP 444 EP 454 DI 10.1016/j.ajhg.2012.07.016 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 004LL UT WOS:000308683100005 PM 22901949 ER PT J AU Bick, AG Flannick, J Ito, K Cheng, S Vasan, RS Parfenov, MG Herman, DS DePalma, SR Gupta, N Gabriel, SB Funke, BH Rehm, HL Benjamin, EJ Aragam, J Taylor, HA Fox, ER Newton-Cheh, C Kathiresan, S O'Donnell, CJ Wilson, JG Altshuler, DM Hirschhorn, JN Seidman, JG Seidman, C AF Bick, Alexander G. Flannick, Jason Ito, Kaoru Cheng, Susan Vasan, Ramachandran S. Parfenov, Michael G. Herman, Daniel S. DePalma, Steven R. Gupta, Namrata Gabriel, Stacey B. Funke, Birgit H. Rehm, Heidi L. Benjamin, Emelia J. Aragam, Jayashri Taylor, Herman A., Jr. Fox, Ervin R. Newton-Cheh, Christopher Kathiresan, Sekar O'Donnell, Christopher J. Wilson, James G. Altshuler, David M. Hirschhorn, Joel N. Seidman, J. G. Seidman, Christine TI Burden of Rare Sarcomere Gene Variants in the Framingham and Jackson Heart Study Cohorts SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; CARDIOMYOPATHY; ASSOCIATION; RISK; MASS; HYPERTENSION; POPULATION; VALIDATION; DISEASE; PROFILE AB Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis. C1 [Bick, Alexander G.; Ito, Kaoru; Parfenov, Michael G.; Herman, Daniel S.; DePalma, Steven R.; Hirschhorn, Joel N.; Seidman, J. G.; Seidman, Christine] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Bick, Alexander G.; Flannick, Jason; Gupta, Namrata; Gabriel, Stacey B.; Altshuler, David M.; Hirschhorn, Joel N.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Flannick, Jason; Newton-Cheh, Christopher; Kathiresan, Sekar; Altshuler, David M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Cheng, Susan; Aragam, Jayashri; Seidman, Christine] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.; Newton-Cheh, Christopher; Kathiresan, Sekar; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. [Funke, Birgit H.; Rehm, Heidi L.] Partners Ctr Personalized Genet Med, Lab Mol Med, Cambridge, MA 02139 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Taylor, Herman A., Jr.; Fox, Ervin R.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Taylor, Herman A., Jr.] Jackson State Univ, Jackson, MS 39217 USA. [Newton-Cheh, Christopher; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Funke, Birgit H.; Rehm, Heidi L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Taylor, Herman A., Jr.] Tougaloo Coll, Tougaloo, MS 39174 USA. [Seidman, Christine] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Seidman, C (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM cseidman@genetics.med.harvard.edu RI Altshuler, David/A-4476-2009; OI Benjamin, Emelia/0000-0003-4076-2336; Altshuler, David/0000-0002-7250-4107; Bick, Alexander/0000-0001-5824-9595; Ramachandran, Vasan/0000-0001-7357-5970 FU National Human Genome Research Institute [U54 HG003067]; National Heart, Lung and Blood Institute [HL080494-05, N01-HC-95170, N01-HC-95171, N01-HC-95172, N01-HC-25195, 6R01-NS 17950]; Howard Hughes Medical Institute; NIH Medical Scientist Training Program fellowship [5T32GM007753-33]; Ellison Foundation; National Institute for Minority Health and Health Disparities; National Institute of Biomedical Imaging and Bioengineering; Affymetrix, Inc. [N02-HL-6-4278]; [K99HL107642] FX We gratefully acknowledge the contribution of Framingham and Jackson Heart Study cohort participants. This work was supported by grants from the National Human Genome Research Institute (Medical Sequencing Program grant U54 HG003067, to the Broad Institute PI, Lander), the National Heart, Lung and Blood Institute (HL080494-05 to C.E.S. and J.G.S.), and the Howard Hughes Medical Institute (to C.E.S). A.G.B. and D.S.H. are supported by NIH Medical Scientist Training Program fellowship 5T32GM007753-33. S.C. is supported in part by grant K99HL107642 and the Ellison Foundation. The Jackson Heart Study is supported by contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172 from the National Heart, Lung, and Blood Institute, the National Institute for Minority Health and Health Disparities, and additional support from the National Institute of Biomedical Imaging and Bioengineering. The Framingham Heart Study was supported by contracts N01-HC-25195 and 6R01-NS 17950 from the National Heart, Lung and Blood Institute and genotyping services from Affymetrix, Inc. (contract No. N02-HL-6-4278 for the SNP Health Association Resource [SHARe] project). NR 28 TC 48 Z9 48 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP 7 PY 2012 VL 91 IS 3 BP 513 EP 519 DI 10.1016/j.ajhg.2012.07.017 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 004LL UT WOS:000308683100011 PM 22958901 ER PT J AU Omar, B Banke, E Guirguis, E Akesson, L Manganiello, V Lyssenko, V Groop, L Gomez, MF Degerman, E AF Omar, Bilal Banke, Elin Guirguis, Emilia Akesson, Lina Manganiello, Vincent Lyssenko, Valeriya Groop, Leif Gomez, Maria F. Degerman, Eva TI Regulation of the pro-inflammatory cytokine osteopontin by GIP in adipocytes - A role for the transcription factor NFAT and phosphodiesterase 3B SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Osteopontin; GIP; Adipocytes; NFAT; Phosphodiesterase 3B ID ACTIVATED T-CELLS; GASTRIC-INHIBITORY POLYPEPTIDE; GLYCOGEN-SYNTHASE KINASE-3; ADIPOSE-TISSUE; INSULIN-RESISTANCE; NUCLEAR FACTOR; PROTEIN-KINASE; LINKING OBESITY; SMOOTH-MUSCLE; EXPRESSION AB The incretin - glucose-dependent insulinotropic polypeptide (GIP) - and the pro-inflammatory cytokine osteopontin are known to have important roles in the regulation of adipose tissue functions. In this work we show that GIP stimulates lipogenesis and osteopontin expression in primary adipocytes. The GIP-induced increase in osteopontin expression was inhibited by the NFAT (the transcription factor nuclear factor of activated T-cells) inhibitor A-285222. Also, the NFAT kinase glycogen synthase kinase (GSK) 3 was upregulated by GIP. To test whether cAMP might be involved in GIP-mediated effects on osteopontin a number of strategies were used. Thus, the beta 3-adrenergic receptor agonist CL316,243 stimulated osteopontin expression, an effects which was mimicked by OPC3911, a specific inhibitor of phosphodiesterase 3. Furthermore, treatment of phosphodiesterase 38 knock-out mice with CL316,243 resulted in a dramatic upregulation of osteopontin in adipose tissue which was not the case in wild-type mice. In summary, we delineate mechanisms by which GIP stimulates osteopontin in adipocytes. Given the established link between osteopontin and insulin resistance, our data suggest that GIP by stimulating osteopontin expression, also could promote insulin resistance in adipocytes. (C) 2012 Elsevier Inc. All rights reserved. C1 [Omar, Bilal; Banke, Elin; Degerman, Eva] Lund Univ, Biomed Ctr, Dept Expt Med Sci Diabet Metab & Endocrinol, S-22184 Lund, Sweden. [Guirguis, Emilia; Manganiello, Vincent] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. [Akesson, Lina] Lund Univ, Dept Clin Sci, Diabet & Celiac Dis Unit, Clin Res Ctr, Malmo, Sweden. [Lyssenko, Valeriya; Groop, Leif] Lund Univ, Clin Res Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Gomez, Maria F.] Lund Univ, Clin Res Ctr, Dept Clin Sci, Vasc ET Coupling, Malmo, Sweden. RP Banke, E (reprint author), Lund Univ, Biomed Ctr, Dept Expt Med Sci Diabet Metab & Endocrinol, C11,Solvegatan 19, S-22184 Lund, Sweden. EM elin.banke@med.lu.se RI Gomez, Maria/D-3696-2014 OI Gomez, Maria/0000-0001-6210-3142 FU Swedish Research Council [2010-3362, 6589, 2009-1039, 2011-3900]; European Research Council [GA269045]; Knut & Alice Wallenberg foundation; LUDC (Lund University Diabetes Centre); Swedish Diabetes Association; Novo Nordisk Foundations, Denmark; Swedish Society of Medicine; Albert Pahlsson; NHLBI FX We thank Ann Kristin Holmen Pahlbrink and Eva Ohlson for excellent technical assistance. This work was supported by the Swedish Research Council (Project grants 2010-3362 to ED, 6589 and 2009-1039 to LG and 2011-3900 to MFG), by an Advanced Research Grant from the European Research Council to LG (GA269045), by a grant from Knut & Alice Wallenberg foundation and by LUDC (Lund University Diabetes Centre). Grants were also obtained from the following foundations: Swedish Diabetes Association; Novo Nordisk Foundations, Denmark; The Swedish Society of Medicine and Albert Pahlsson. EG and VM were supported by the NHLBI Intramural Research Program. NR 32 TC 8 Z9 8 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 7 PY 2012 VL 425 IS 4 BP 812 EP 817 DI 10.1016/j.bbrc.2012.07.157 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 009HU UT WOS:000309017700020 PM 22892131 ER PT J AU Zhang, F Huang, XL Qian, CQ Zhu, L Hida, N Niu, G Chen, XY AF Zhang, Fan Huang, Xinglu Qian, Chunqi Zhu, Lei Hida, Naoki Niu, Gang Chen, Xiaoyuan TI Synergistic enhancement of iron oxide nanoparticle and gadolinium for dual-contrast MRI SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE MRI; Gd-DTPA; Iron oxide; RGD; Dual contrast ID HEPATOCELLULAR-CARCINOMA; HEPATIC METASTASES; CIRRHOTIC LIVER; DRUG DISCOVERY; LYMPH-NODES; GD-DTPA; AGENTS; LYMPHOGRAPHY; CANCER; INTEGRIN AB Purpose: The use of MR contrast agents allows accurate diagnosis by exerting an influence on the longitudinal (T-1) or transverse (T-2) relaxation time of the surrounding tissue. In this study, we combined the use of iron oxide (IO) particles and nonspecific extracellular gadolinium chelate (Gd) in order to further improve the sensitivity and specificity of lesion detection. Procedures: With a 7-Tesla scanner, pre-contrasted, IO-enhanced and dual contrast agent enhanced MRIs were performed in phantom, normal animals, and animal models of lymph node tumor metastases and orthotopic brain tumor. For the dual-contrast (DC) MRI, we focused on the evaluation of T-2 weighted DC MRI with IO administered first, then followed by the injection of a bolus of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA). Results: Based on the C/N ratios and MRI relaxometry, the synergistic effect of coordinated administration of Gd-DTPA and IO was observed and confirmed in phantom, normal liver and tumor models. At 30 min after administration of Feridex, Gd-DTPA further decreased T-2 relaxation in liver immediately after the injection. Additional administration of Gd-DTPA also immediately increased the signal contrast between tumor and brain parenchyma and maximized the C/N ratio to -4.12 +/- 0.71. Dual contrast MRI also enhanced the delineation of tumor borders and small lesions. Conclusions: DC-MRI will be helpful to improve diagnostic accuracy and decrease the threshold size for lesion detection. (C) 2012 Elsevier Inc. All rights reserved. C1 [Zhang, Fan; Huang, Xinglu; Zhu, Lei; Hida, Naoki; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Qian, Chunqi] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Zhang, Fan; Qian, Chunqi; Zhu, Lei] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Niu, G (reprint author), 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. EM niug@mail.nih.gov; shawn.chen@nih.gov RI Qian, Chunqi/A-7481-2012; Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81201086] FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). F. Zhang is partly supported by the National Science Foundation of China (NSFC) (81201086). NR 30 TC 12 Z9 12 U1 5 U2 35 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 7 PY 2012 VL 425 IS 4 BP 886 EP 891 DI 10.1016/j.bbrc.2012.07.168 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 009HU UT WOS:000309017700032 PM 22898051 ER PT J AU Chen, WZ Feng, Y Wang, YP Zhu, ZY Dimitrov, DS AF Chen, Weizao Feng, Yang Wang, Yanping Zhu, Zhongyu Dimitrov, Dimiter S. TI Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE HIV-1; gp120; Stabilization; CD4; CD4i antibody; CD4bs antibody ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; NEUTRALIZING ANTIBODIES; CD4-BOUND STATE; RECEPTOR; BROAD; IMMUNOGENICITY; STABILIZATION; INDIVIDUALS; INHIBITORS AB Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibit decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion. Published by Elsevier Inc. C1 [Chen, Weizao; Feng, Yang; Wang, Yanping; Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21702 USA. [Wang, Yanping] NCI, Basic Res Program, Sci Applicat Int Corp Frederick Inc, NIH, Frederick, MD 21702 USA. RP Chen, WZ (reprint author), Miller Dr,Bldg 469,Room 144, Frederick, MD 21702 USA. EM chenw3@mail.nih.gov FU NIH, National Cancer Institute, Frederick National Laboratory for Cancer Research FX This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, Frederick National Laboratory for Cancer Research. NR 26 TC 3 Z9 3 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 7 PY 2012 VL 425 IS 4 BP 931 EP 937 DI 10.1016/j.bbrc.2012.08.013 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 009HU UT WOS:000309017700040 PM 22906742 ER PT J AU Yang, ZL Martens, CA Bruno, DP Porcella, SF Moss, B AF Yang, Zhilong Martens, Craig A. Bruno, Daniel P. Porcella, Stephen F. Moss, Bernard TI Pervasive Initiation and 3 '-End Formation of Poxvirus Postreplicative RNAs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VACCINIA VIRUS INTERMEDIATE; NUCLEOSIDE TRIPHOSPHATE PHOSPHOHYDROLASES; EARLY MESSENGER-RNAS; TRANSCRIPTION TERMINATION; POLY(A) POLYMERASE; DNA-REPLICATION; NONCODING RNAS; LATE GENES; NPH-II; GENOME AB Poxviruses are large DNA viruses that replicate within the cytoplasm and encode a complete transcription system, including a multisubunit RNA polymerase, stage-specific transcription factors, capping and methylating enzymes, and a poly(A) polymerase. Expression of the more than 200 open reading frames by vaccinia virus, the prototype poxvirus, is temporally regulated: early mRNAs are synthesized immediately after infection, whereas intermediate and late mRNAs are synthesized following genome replication. The postreplicative transcripts are heterogeneous in length and overlap the entire genome, which pose obstacles for high resolution mapping. We used tag-based methods in conjunction with high throughput cDNA sequencing to determine the precise 5'-capped and 3'-polyadenylated ends of postreplicative RNAs. Polymerase slippage during initiation of intermediate and late RNA synthesis results in a 5'-poly(A) leader that allowed the unambiguous identification of true transcription start sites. Ninety RNA start sites were located just upstream of intermediate and late open reading frames, but many more appeared anomalous, occurring within coding and non-coding regions, indicating pervasive transcription initiation. We confirmed the presence of functional promoter sequences upstream of representative anomalous start sites and demonstrated that alternative start sites within open reading frames could generate truncated isoforms of proteins. In an analogous manner, poly(A) sequences allowed accurate mapping of the numerous 3'-ends of postreplicative RNAs, which were preceded by a pyrimidine-rich sequence in the DNA coding strand. The distribution of postreplicative promoter sequences throughout the genome provides enormous transcriptional complexity, and the large number of previously unmapped RNAs may have novel functions. C1 [Yang, Zhilong; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Martens, Craig A.; Bruno, Daniel P.; Porcella, Stephen F.] NIAID, Res Technol Sect, Genom Unit, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr,MSC 3210, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU National Institutes of Health Grant from the Division of Intramural Research, NIAID [A1000307-31] FX This work was supported, in whole or in part, by National Institutes of Health Grant ZIA A1000307-31 from the Division of Intramural Research, NIAID. NR 65 TC 11 Z9 11 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 SEP 7 PY 2012 VL 287 IS 37 BP 31050 EP 31060 DI 10.1074/jbc.M112.390054 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 006AK UT WOS:000308791300018 PM 22829601 ER PT J AU Yahiro, K Satoh, M Nakano, M Hisatsune, J Isomoto, H Sap, J Suzuki, H Nomura, F Noda, M Moss, J Hirayama, T AF Yahiro, Kinnosuke Satoh, Mamoru Nakano, Masayuki Hisatsune, Junzo Isomoto, Hajime Sap, Jan Suzuki, Hidekazu Nomura, Fumio Noda, Masatoshi Moss, Joel Hirayama, Toshiya TI Low-density Lipoprotein Receptor-related Protein-1 (LRP1) Mediates Autophagy and Apoptosis Caused by Helicobacter pylori VacA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE-PHOSPHATASE-BETA; GASTRIC EPITHELIAL-CELLS; ANION-SELECTIVE CHANNELS; VACUOLATING-CYTOTOXIN; MITOCHONDRIAL APOPTOSIS; TUMOR-GROWTH; LIPID RAFTS; T-CELL; TOXIN; DEATH AB In Helicobacter pylori infection, vacuolating cytotoxin (VacA)-induced mitochondrial damage leading to apoptosis is believed to be a major cause of cell death. It has also been proposed that VacA-induced autophagy serves as a host mechanism to limit toxin-induced cellular damage. Apoptosis and autophagy are two dynamic and opposing processes that must be balanced to regulate cell death and survival. Here we identify the low-density lipoprotein receptor-related protein-1 (LRP1) as the VacA receptor for toxin-induced autophagy in the gastric epithelial cell line AZ-521, and show that VacA internalization through binding to LRP1 regulates the autophagic process including generation of LC3-II from LC3-I, which is involved in formation of autophagosomes and autolysosomes. Knockdown of LRP1 and Atg5 inhibited generation of LC3-II as well as cleavage of PARP, a marker of apoptosis, in response to VacA, whereas caspase inhibitor, benzyloxycarbonyl-VAD-fluoromethylketone (Z-VAD-fmk), and necroptosis inhibitor, Necrostatin-1, did not inhibit VacA-induced autophagy, suggesting that VacA-induced autophagy via LRP1 binding precedes apoptosis. Other VacA receptors such as RPTP alpha, RPTP beta, and fibronectin did not affect VacA-induced autophagy or apoptosis. Therefore, we propose that the cell surface receptor, LRP1, mediates VacA-induced autophagy and apoptosis. C1 [Nakano, Masayuki; Hisatsune, Junzo; Hirayama, Toshiya] Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. [Yahiro, Kinnosuke; Noda, Masatoshi] Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chiba 2608670, Japan. [Satoh, Mamoru; Nomura, Fumio] Chiba Univ, Grad Sch Med, Dept Mol Diag, Chiba 2608670, Japan. [Hisatsune, Junzo] Hiroshima Univ, Grad Sch Biomed Sci, Dept Bacteriol, Hiroshima 7348551, Japan. [Isomoto, Hajime] Nagasaki Univ Hosp, Dept Gastroenterol & Hepatol, Nagasaki 8528523, Japan. [Sap, Jan] Univ Paris Diderot, CNRS, UMR 7216, Sorbonne Paris Cite, Paris, France. [Suzuki, Hidekazu] Keio Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, Tokyo 1608582, Japan. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Hirayama, T (reprint author), Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. EM hirayama@net.nagasaki-u.ac.jp RI Suzuki, Hidekazu/J-4396-2013 FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Improvement of Research Environment for Young Researchers from the Japan Science and Technology Agency; National Institutes of Health, NHLBI FX This work was supported by Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Improvement of Research Environment for Young Researchers from the Japan Science and Technology Agency.; Supported by the Intramural Research Program, National Institutes of Health, NHLBI. NR 54 TC 33 Z9 35 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 SEP 7 PY 2012 VL 287 IS 37 BP 31104 EP 31115 DI 10.1074/jbc.M112.387498 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 006AK UT WOS:000308791300023 PM 22822085 ER PT J AU Szekeres, M Nadasy, GL Turu, G Soltesz-Katona, E Toth, ZE Balla, A Catt, KJ Hunyady, L AF Szekeres, Maria Nadasy, Gyoergy L. Turu, Gabor Soltesz-Katona, Eszter Toth, Zsuzsanna E. Balla, Andras Catt, Kevin J. Hunyady, Laszlo TI Angiotensin II Induces Vascular Endocannabinoid Release, Which Attenuates Its Vasoconstrictor Effect via CB1 Cannabinoid Receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MUSCLE RESISTANCE ARTERIES; CORONARY-ARTERIES; SIGNAL-TRANSDUCTION; CARDIOVASCULAR PHARMACOLOGY; NITRIC-OXIDE; RAT AORTA; MECHANISMS; HYPERTENSION; ANANDAMIDE; REACTIVITY AB In the vascular system angiotensin II (Ang II) causes vasoconstriction via the activation of type 1 angiotensin receptors. Earlier reports have shown that in cellular expression systems diacylglycerol produced during type 1 angiotensin receptor signaling can be converted to 2-arachidonoylglycerol, an important endocannabinoid. Because activation of CB1 cannabinoid receptors (CB1R) induces vasodilation and reduces blood pressure, we have tested the hypothesis that Ang II-induced 2-arachidonoylglycerol release can modulate its vasoconstrictor action in vascular tissue. Rat and mouse skeletal muscle arterioles and mouse saphenous arteries were isolated, pressurized, and subjected to microangiometry. Vascular expression of CB1R was demonstrated using Western blot and RT-PCR. In accordance with the functional relevance of these receptors WIN55212, a CB1R agonist, caused vasodilation, which was absent in CB1R knock-out mice. Inhibition of CB(1)Rs using O2050, a neutral antagonist, enhanced the vasoconstrictor effect of Ang II in wild type but not in CB1R knock-out mice. Inverse agonists of CB1R (SR141716 and AM251) and inhibition of diacylglycerol lipase using tetrahydrolipstatin also augmented the Ang II-induced vasoconstriction, suggesting that endocannabinoid release modulates this process via CB1R activation. This effect was independent of nitric-oxide synthase activity and endothelial function. These data demonstrate that Ang II stimulates vascular endocannabinoid formation, which attenuates its vasoconstrictor effect, suggesting that endocannabinoid release from the vascular wall and CB1R activation reduces the vasoconstrictor and hypertensive effects of Ang II. C1 [Hunyady, Laszlo] Semmelweis Univ, Fac Med, Dept Physiol, H-1444 Budapest, Hungary. [Nadasy, Gyoergy L.] Semmelweis Univ, Inst Human Physiol & Clin Expt Res, H-1444 Budapest, Hungary. [Toth, Zsuzsanna E.] Semmelweis Univ, Neuromorphol & Neuroendocrine Res Lab, H-1444 Budapest, Hungary. [Balla, Andras; Hunyady, Laszlo] Semmelweis Univ, Lab Mol Physiol, H-1444 Budapest, Hungary. Hungarian Acad Sci, H-1444 Budapest, Hungary. [Catt, Kevin J.] NICHD, Sect Hormonal Regulat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Hunyady, L (reprint author), Semmelweis Univ, Fac Med, Dept Physiol, POB 259, H-1444 Budapest, Hungary. EM Hunyady@eok.sote.hu OI Balla, Andras/0000-0002-6450-2793; Turu, Gabor/0000-0002-4421-3812 FU Hungarian National Science Foundation [OTKA NK-100883, NK-72661, OTKA TO32019]; Hungarian Ministry of National Resources [ETT 495/09]; National Development Agency, Hungary [TAMOP 4.2.1.B-09/1/KMR-2010-0001] FX This work was supported by grants from the Hungarian National Science Foundation (OTKA NK-100883, NK-72661, OTKA TO32019), Hungarian Ministry of National Resources (ETT 495/09), and from the National Development Agency, Hungary (TAMOP 4.2.1.B-09/1/KMR-2010-0001). NR 50 TC 14 Z9 14 U1 1 U2 14 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 SEP 7 PY 2012 VL 287 IS 37 BP 31540 EP 31550 DI 10.1074/jbc.M112.346296 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 006AK UT WOS:000308791300066 PM 22787147 ER PT J AU Perez-Berna, AJ Ortega-Esteban, A Menendez-Conejero, R Winkler, DC Menendez, M Steven, AC Flint, SJ de Pablo, PJ San Martin, C AF Perez-Berna, Ana J. Ortega-Esteban, Alvaro Menendez-Conejero, Rosa Winkler, Dennis C. Menendez, Margarita Steven, Alasdair C. Flint, S. Jane de Pablo, Pedro J. San Martin, Carmen TI The Role of Capsid Maturation on Adenovirus Priming for Sequential Uncoating SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR-PORE COMPLEX; VIRAL-DNA; CRYOELECTRON TOMOGRAPHY; VIRUS ENTRY; CELL ENTRY; PROTEIN; TYPE-2; STABILITY; MICROSCOPY; INFECTION AB Adenovirus assembly concludes with proteolytic processing of several capsid and core proteins. Immature virions containing precursor proteins lack infectivity because they cannot properly uncoat, becoming trapped in early endosomes. Structural studies have shown that precursors increase the network of interactions maintaining virion integrity. Using different biophysical techniques to analyze capsid disruption in vitro, we show that immature virions are more stable than the mature ones under a variety of stress conditions and that maturation primes adenovirus for highly cooperative DNA release. Cryoelectron tomography reveals that under mildly acidic conditions mimicking the early endosome, mature virions release pentons and peripheral core contents. At higher stress levels, both mature and immature capsids crack open. The virus core is completely released from cracked capsids in mature virions, but it remains connected to shell fragments in the immature particle. The extra stability of immature adenovirus does not equate with greater rigidity, because in nanoindentation assays immature virions exhibit greater elasticity than the mature particles. Our results have implications for the role of proteolytic maturation in adenovirus assembly and uncoating. Precursor proteins favor assembly by establishing stable interactions with the appropriate curvature and preventing premature ejection of contents by tightly sealing the capsid vertices. Upon maturation, core organization is looser, particularly at the periphery, and interactions preserving capsid curvature are weakened. The capsid becomes brittle, and pentons are more easily released. Based on these results, we hypothesize that changes in core compaction during maturation may increase capsid internal pressure to trigger proper uncoating of adenovirus. C1 [Perez-Berna, Ana J.; Menendez-Conejero, Rosa; San Martin, Carmen] Univ Autonoma Madrid, Ctr Nacl Biotecnol, Dept Macromol Struct, E-28049 Madrid, Spain. [Ortega-Esteban, Alvaro; de Pablo, Pedro J.] Univ Autonoma Madrid, Dept Condensed Matter Phys, E-28049 Madrid, Spain. [Menendez, Margarita] CSIC, Inst Quim Fis Rocasolano, E-28006 Madrid, Spain. [Menendez, Margarita] CIBER Enfermedades Resp, Madrid 28006, Spain. [Winkler, Dennis C.; Steven, Alasdair C.] NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Flint, S. Jane] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. RP San Martin, C (reprint author), Univ Autonoma Madrid, Ctr Nacl Biotecnol, Dept Macromol Struct, Darwin 3, E-28049 Madrid, Spain. EM carmen@cnb.csic.es RI San Martin, Carmen/A-4074-2010; Menendez, Margarita/M-1795-2014; Ortega-Esteban, Alvaro/M-7458-2015; Perez-Berna, Ana/G-2789-2016; De Pablo Gomez, Pedro/L-9392-2014 OI San Martin, Carmen/0000-0001-9799-175X; Menendez, Margarita/0000-0002-3267-4443; Ortega-Esteban, Alvaro/0000-0001-9642-0568; De Pablo Gomez, Pedro/0000-0003-2386-3186 FU National Institutes of Health [GM037705, AI1058172]; Ministry of Science and Innovation of Spain [BFU2010-16382/BMC, MAT2008-02533, PIB2010US-00233, FIS2011-29493, FIS2010-10552-E, FIS2011-16090-E, BFU2009-10052]; Local Madrid Government [P2009/MAT-1467]; Juan de la Cierva Postdoctoral Contract from the Ministry of Science and Innovation of Spain [JCI-2009-05187]; Spain CSIC Travel Grant [PA1002892]; Ministry of Education of Spain; Instituto de Salud Carlos III of Spain [FI08/00035] FX This work was supported, in whole or in part, by National Institutes of Health Grants GM037705 and AI1058172 (to S. J. F.). This work was also supported by Ministry of Science and Innovation of Spain Grants BFU2010-16382/BMC (to C. S. M.), MAT2008-02533, PIB2010US-00233, and FIS2011-29493 (to P. J. P.), FIS2010-10552-E and FIS2011-16090-E (to C. S. M. and P. J. P.), and BFU2009-10052 (to M. M.), and by Local Madrid Government Grant P2009/MAT-1467 (to P. J. P.).; Recipient of Juan de la Cierva Postdoctoral Contract JCI-2009-05187 from the Ministry of Science and Innovation of Spain and recipient of additional support from Spain CSIC Travel Grant PA1002892.; Recipient of FPU predoctoral fellowship from the Ministry of Education of Spain.; Recipient of Predoctoral Fellowship FI08/00035 from the Instituto de Salud Carlos III of Spain. NR 65 TC 37 Z9 39 U1 1 U2 20 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 SEP 7 PY 2012 VL 287 IS 37 BP 31582 EP 31595 DI 10.1074/jbc.M112.389957 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 006AK UT WOS:000308791300070 PM 22791715 ER PT J AU Bolton, DL Santra, S Swett-Tapia, C Custers, J Song, KM Balachandran, H Mach, L Naim, H Kozlowski, PA Lifton, M Goudsmit, J Letvin, N Roederer, M Radosevic, K AF Bolton, Diane L. Santra, Sampa Swett-Tapia, Cindy Custers, Jerome Song, Kaimei Balachandran, Harikrishnan Mach, Linh Naim, Hussein Kozlowski, Pamela A. Lifton, Michelle Goudsmit, Jaap Letvin, Norman Roederer, Mario Radosevic, Katarina TI Priming T-cell responses with recombinant measles vaccine vector in a heterologous prime-boost setting in non-human primates SO VACCINE LA English DT Article DE Measles virus; Adenovirus; Mucosal immunization; Heterologous prime-boost ID NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; RHESUS-MONKEYS; VIRUS VACCINE; IMMUNIZATION; PATHOGENESIS; RESCUE; SINGLE; INDUCE; SPREAD AB Licensed live attenuated virus vaccines capable of expressing transgenes from other pathogens have the potential to reduce the number of childhood immunizations by eliciting robust immunity to multiple pathogens simultaneously. Recombinant attenuated measles virus (rMV) derived from the Edmonston Zagreb vaccine strain was engineered to express simian immunodeficiency virus (SIV) Gag protein for the purpose of evaluating the immunogenicity of rMV as a vaccine vector in rhesus macaques. rMV-Gag immunization alone elicited robust measles-specific humoral and cellular responses, but failed to elicit transgene (Gag)-specific immune responses, following aerosol or intratracheal/intramuscular delivery. However, when administered as a priming vaccine to a heterologous boost with recombinant adenovirus serotype 5 expressing the same transgene, rMV-Gag significantly enhanced Gag-specific T lymphocyte responses following rAd5 immunization. Gag-specific humoral responses were not enhanced, however, which may be due to either the transgene or the vector. Cellular response priming by rMV against the transgene was highly effective even when using a suboptimal dose of rAd5 for the boost. These data demonstrate feasibility of using rMV as a priming component of heterologous prime-boost vaccine regimens for pathogens requiring strong cellular responses. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Swett-Tapia, Cindy; Custers, Jerome; Naim, Hussein; Goudsmit, Jaap; Radosevic, Katarina] Crucell Holland BV, NL-2301 CA Leiden, Netherlands. [Bolton, Diane L.; Song, Kaimei; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Santra, Sampa; Balachandran, Harikrishnan; Mach, Linh; Lifton, Michelle; Letvin, Norman] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Kozlowski, Pamela A.] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA 70112 USA. RP Radosevic, K (reprint author), Crucell Holland BV, NL-2301 CA Leiden, Netherlands. EM katarina.radosevic@crucell.com FU NIH grant [AI058896]; Louisiana Vaccine Center; South Louisiana Institute for Infectious Disease Research; Louisiana Board of Regents; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; Harvard University CFAR and CAVD; NIH (NIAID) [NO1AI60018] FX This work was supported in part by NIH grant AI058896 and the Louisiana Vaccine Center and the South Louisiana Institute for Infectious Disease Research sponsored by the Louisiana Board of Regents, by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, by Harvard University CFAR and CAVD, and by the NIH (NIAID) contract NO1AI60018. NR 41 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 7 PY 2012 VL 30 IS 41 BP 5991 EP 5998 DI 10.1016/j.vaccine.2012.06.029 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 009LA UT WOS:000309026100014 PM 22732429 ER PT J AU Banerjee, A Berezhkovskii, A Nossal, R AF Banerjee, Anand Berezhkovskii, Alexander Nossal, Ralph TI Distributions of lifetime and maximum size of abortive clathrin-coated pits SO PHYSICAL REVIEW E LA English DT Article ID MEMBRANE CURVATURE; ENDOCYTOSIS AB Clathrin-mediated endocytosis is a complex process through which eukaryotic cells internalize nutrients, antigens, growth factors, pathogens, etc. The process occurs via the formation of invaginations on the cell membrane, called clathrin-coated pits (CCPs). Over the years, much has been learned about the mechanism of CCP assembly, but a complete understanding of the assembly process still remains elusive. In recent years, using fluorescence microscopy, studies have been done to determine the statistical properties of CCP formation. In this paper, using a recently proposed coarse-grained, stochastic model of CCP assembly [Banerjee, Berezhkovskii, and Nossal, Biophys. J. 102, 2725 (2012)], we suggest new ways of analyzing such experimental data. To be more specific, we derive analytical expressions for the distribution of maximum size of abortive CCPs, and the probability density of their lifetimes. Our results show how these functions depend on the kinetic and energetic parameters characterizing the assembly process, and therefore could be useful in extracting information about the mechanism of CCP assembly from experimental data. We find excellent agreement between our analytical results and those obtained from kinetic Monte Carlo simulations of the assembly process. C1 [Banerjee, Anand; Nossal, Ralph] NIH, Program Phys Biol, Eunice Kennedy Shriver Inst Child Hlth & Human De, Bethesda, MD 20892 USA. [Berezhkovskii, Alexander] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Banerjee, A (reprint author), NIH, Program Phys Biol, Eunice Kennedy Shriver Inst Child Hlth & Human De, Bldg 10, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Institutes of Health (NIH)-Eunice Kennedy Shriver National Institute of Child Health and Human Development; Center for Information Technology FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH)-Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Center for Information Technology. NR 24 TC 1 Z9 1 U1 0 U2 5 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD SEP 7 PY 2012 VL 86 IS 3 AR 031907 DI 10.1103/PhysRevE.86.031907 PN 1 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 001LB UT WOS:000308461100008 PM 23030944 ER PT J AU Guo, XM Kesimer, M Tolun, G Zheng, XH Xu, Q Lu, J Sheehan, JK Griffith, JD Li, XL AF Guo, Xiumei Kesimer, Mehmet Tolun, Goekhan Zheng, Xunhai Xu, Qing Lu, Jing Sheehan, John K. Griffith, Jack D. Li, Xiaoling TI The NAD(+)-dependent protein deacetylase activity of SIRT1 is regulated by its oligomeric status SO SCIENTIFIC REPORTS LA English DT Article ID CELLULAR-RESPONSE; IN-VITRO; PHOSPHORYLATION; STRESS; SURVIVAL; HOMOLOG; DYRK1A; DBC1; P53 AB SIRT1, a NAD(+)-dependent protein deacetylase, is an important regulator in cellular stress response and energy metabolism. While the list of SIRT1 substrates is growing, how the activity of SIRT1 is regulated remains unclear. We have previously reported that SIRT1 is activated by phosphorylation at a conserved Thr522 residue in response to environmental stress. Here we demonstrate that phosphorylation of Thr522 activates SIRT1 through modulation of its oligomeric status. We provide evidence that nonphosphorylated SIRT1 protein is aggregation-prone in vitro and in cultured cells. Conversely, phosphorylated SIRT1 protein is largely in the monomeric state and more active. Our findings reveal a novel mechanism for environmental regulation of SIRT1 activity, which may have important implications in understanding the molecular mechanism of stress response, cell survival, and aging. C1 [Guo, Xiumei; Xu, Qing; Lu, Jing; Li, Xiaoling] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Kesimer, Mehmet; Sheehan, John K.] Univ N Carolina, Dept Biochem, Chapel Hill, NC 27599 USA. [Kesimer, Mehmet; Sheehan, John K.] Univ N Carolina, Dept Biophys, Chapel Hill, NC 27599 USA. [Tolun, Goekhan; Griffith, Jack D.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Tolun, Goekhan; Griffith, Jack D.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Zheng, Xunhai] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Li, XL (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM lix3@niehs.nih.gov RI TOLUN, Gokhan/D-1971-2012; Zheng, Xunhai/G-1187-2015 OI TOLUN, Gokhan/0000-0001-6166-9451; Zheng, Xunhai/0000-0003-0390-2491 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES102205]; [GM31819]; [ES13773] FX We thank Drs. Yanshun Liu, Paul Wade, and members of Li laboratory for critical reading and suggestions of the manuscript. We also thank Baozhong Zhao for technical supports, the NIEHS Protein Expression Core facility for large-scale protein purification, and the Fluorescence Microscopy and Imaging Center for helping in confocal imaging and data analyses. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to X.L. (Z01 ES102205), and grants GM31819 and ES13773 to J.D.G. NR 27 TC 14 Z9 14 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 7 PY 2012 VL 2 AR 640 DI 10.1038/srep00640 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001BN UT WOS:000308434900001 PM 22962634 ER PT J AU de Jong, S Chepelev, I Janson, E Strengman, E van den Berg, LH Veldink, JH Ophoff, RA AF de Jong, Simone Chepelev, Iouri Janson, Esther Strengman, Eric van den Berg, Leonard H. Veldink, Jan H. Ophoff, Roel A. TI Common inversion polymorphism at 17q21.31 affects expression of multiple genes in tissue-specific manner SO BMC GENOMICS LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; TAU-GENE; HAPLOTYPE; DISEASE; ASSOCIATION; REGION; FAMILY; LOCUS; CRHR1 AB Background: Chromosome 17q21.31 contains a common inversion polymorphism of approximately 900 kb in populations with European ancestry. Two divergent MAPT haplotypes, H1 and H2 are described with distinct linkage disequilibrium patterns across the region reflecting the inversion status at this locus. The MAPT H1 haplotype has been associated with progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and Alzheimer's disease, while the H2 is linked to recurrent deletion events associated with the 17q21.31 microdeletion syndrome, a disease characterized by developmental delay and learning disability. Results: In this study, we investigate the effect of the inversion on the expression of genes in the 17q21.31 region. We find the expression of several genes in and at the borders of the inversion to be affected; specific either to whole blood or different regions of the human brain. The H1 haplotype was found to be associated with an increased expression of LRRC37A4, PLEKH1M and MAPT. In contrast, a decreased expression of MGC57346, LRRC37A and CRHR1 was associated with H1. Conclusions: Studies thus far have focused on the expression of MAPT in the inversion region. However, our results show that the inversion status affects expression of other genes in the 17q21.31 region as well. Given the link between the inversion status and different neurological diseases, these genes may also be involved in disease pathology, possibly in a tissue-specific manner. C1 [de Jong, Simone; Janson, Esther; Strengman, Eric] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CG Utrecht, Netherlands. [de Jong, Simone; Ophoff, Roel A.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Psychiat, NL-3508 GA Utrecht, Netherlands. [de Jong, Simone; Strengman, Eric; Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA. [Chepelev, Iouri] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [van den Berg, Leonard H.; Veldink, Jan H.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, NL-3584 CX Utrecht, Netherlands. RP Ophoff, RA (reprint author), Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Psychiat, NL-3508 GA Utrecht, Netherlands. EM rophoff@mednet.ucla.edu OI de Jong, Simone/0000-0002-8002-7195 FU US National Institutes of Health [MH078075, NS058980]; Amyotrophic Lateral Sclerosis Association FX The authors thank Carolien de Kovel for statistical support. This work was supported by funding from the US National Institutes of Health MH078075 and NS058980 (RAO) and the Amyotrophic Lateral Sclerosis Association (RAO and LHvdB). NR 25 TC 12 Z9 12 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD SEP 6 PY 2012 VL 13 AR 458 DI 10.1186/1471-2164-13-458 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 100XQ UT WOS:000315739000001 PM 22950410 ER PT J AU Dunham, I Kundaje, A Aldred, SF Collins, PJ Davis, C Doyle, F Epstein, CB Frietze, S Harrow, J Kaul, R Khatun, J Lajoie, BR Landt, SG Lee, BK Pauli, F Rosenbloom, KR Sabo, P Safi, A Sanyal, A Shoresh, N Simon, JM Song, L Trinklein, ND Altshuler, RC Birney, E Brown, JB Cheng, C Djebali, S Dong, XJ Dunham, I Ernst, J Furey, TS Gerstein, M Giardine, B Greven, M Hardison, RC Harris, RS Herrero, J Hoffman, MM Iyer, S Kellis, M Khatun, J Kheradpour, P Kundaje, A Lassmann, T Li, QH Lin, X Marinov, GK Merkel, A Mortazavi, A Parker, SCJ Reddy, TE Rozowsky, J Schlesinger, F Thurman, RE Wang, J Ward, LD Whitfield, TW Wilder, SP Wu, W Xi, HLS Yip, KY Zhuang, JL Bernstein, BE Birney, E Dunham, I Green, ED Gunter, C Snyder, M Pazin, MJ Lowdon, RF Dillon, LAL Adams, LB Kelly, CJ Zhang, J Wexler, JR Green, ED Good, PJ Feingold, EA Bernstein, BE Birney, E Crawford, GE Dekker, J Elnitski, L Farnham, PJ Gerstein, M Giddings, MC Gingeras, TR Green, ED Guigo, R Hardison, RC Hubbard, TJ Kellis, M Kent, WJ Lieb, JD Margulies, EH Myers, RM Snyder, M Stamatoyannopoulos, JA Tenenbaum, SA Weng, ZP White, KP Wold, B Khatun, J Yu, Y Wrobel, J Risk, BA Gunawardena, HP Kuiper, HC Maier, CW Xie, L Chen, X Giddings, MC Bernstein, BE Epstein, CB Shoresh, N Ernst, J Kheradpour, P Mikkelsen, TS Gillespie, S Goren, A Ram, O Zhang, XL Wang, L Issner, R Coyne, MJ Durham, T Ku, M Truong, T Ward, LD Altshuler, RC Eaton, ML Kellis, M Djebali, S Davis, CA Merkel, A Dobin, A Lassmann, T Mortazavi, A Tanzer, A Lagarde, J Lin, W Schlesinger, F Xue, CH Marinov, GK Khatun, J Williams, BA Zaleski, C Rozowsky, J Roeder, M Kokocinski, F Abdelhamid, RF Alioto, T Antoshechkin, I Baer, MT Batut, P Bell, I Bell, K Chakrabortty, S Chen, X Chrast, J Curado, J Derrien, T Drenkow, J Dumais, E Dumais, J Duttagupta, R Fastuca, M Fejes-Toth, K Ferreira, P Foissac, S Fullwood, MJ Gao, H Gonzalez, D Gordon, A Gunawardena, HP Howald, C Jha, S Johnson, R Kapranov, P King, B Kingswood, C Li, GL Luo, OJ Park, E Preall, JB Presaud, K Ribeca, P Risk, BA Robyr, D Ruan, XA Sammeth, M Sandhu, KS Schaeffer, L See, LH Shahab, A Skancke, J Suzuki, AM Takahashi, H Tilgner, H Trout, D Walters, N Wang, HE Wrobel, J Yu, YB Hayashizaki, Y Harrow, J Gerstein, M Hubbard, TJ Reymond, A Antonarakis, SE Hannon, GJ Giddings, MC Ruan, YJ Wold, B Carninci, P Guigo, R Gingeras, TR Rosenbloom, KR Sloan, CA Learned, K Malladi, VS Wong, MC Barber, G Cline, MS Dreszer, TR Heitner, SG Karolchik, D Kent, WJ Kirkup, VM Meyer, LR Long, JC Maddren, M Raney, BJ Furey, TS Song, LY Grasfeder, LL Giresi, PG Lee, BK Battenhouse, A Sheffield, NC Simon, JM Showers, KA Safi, A London, D Bhinge, AA Shestak, C Schaner, MR Kim, SK Zhang, ZZZ Mieczkowski, PA Mieczkowska, JO Liu, Z McDaniell, RM Ni, YY Rashid, NU Kim, MJ Adar, S Zhang, ZC Wang, TY Winter, D Keefe, D Birney, E Iyer, VR Lieb, JD Crawford, GE Li, GL Sandhu, KS Zheng, MZ Wang, P Luo, OJ Shahab, A Fullwood, MJ Ruan, XA Ruan, YJ Myers, RM Pauli, F Williams, BA Gertz, J Marinov, GK Reddy, TE Vielmetter, J Partridge, EC Trout, D Varley, KE Gasper, C Bansal, A Pepke, S Jain, P Amrhein, H Bowling, KM Anaya, M Cross, MK King, B Muratet, MA Antoshechkin, I Newberry, KM Mccue, K Nesmith, AS Fisher-Aylor, KI Pusey, B DeSalvo, G Parker, SL Balasubramanian, S Davis, NS Meadows, SK Eggleston, T Gunter, C Newberry, JS Levy, SE Absher, DM Mortazavi, A Wong, WH Wold, B Blow, MJ Visel, A Pennachio, LA Elnitski, L Margulies, EH Parker, SCJ Petrykowska, HM Abyzov, A Aken, B Barrell, D Barson, G Berry, A Bignell, A Boychenko, V Bussotti, G Chrast, J Davidson, C Derrien, T Despacio-Reyes, G Diekhans, M Ezkurdia, I Frankish, A Gilbert, J Gonzalez, JM Griffiths, E Harte, R Hendrix, DA Howald, C Hunt, T Jungreis, I Kay, M Khurana, E Kokocinski, F Leng, J Lin, MF Loveland, J Lu, Z Manthravadi, D Mariotti, M Mudge, J Mukherjee, G Notredame, C Pei, BK Rodriguez, JM Saunders, G Sboner, A Searle, S Sisu, C Snow, C Steward, C Tanzer, A Tapanari, E Tress, ML van Baren, MJ Walters, N Washietl, S Wilming, L Zadissa, A Zhang, ZD Brent, M Haussler, D Kellis, M Valencia, A Gerstein, M Reymond, A Guigo, R Harrow, J Hubbard, TJ Landt, SG Frietze, S Abyzov, A Addleman, N Alexander, RP Auerbach, RK Balasubramanian, S Bettinger, K Bhardwaj, N Boyle, AP Cao, AR Cayting, P Charos, A Cheng, Y Cheng, C Eastman, C Euskirchen, G Fleming, JD Grubert, F Habegger, L Hariharan, M Harmanci, A Iyengar, S Jin, VX Karczewski, KJ Kasowski, M Lacroute, P Lam, H Lamarre-Vincent, N Leng, J Lian, J Lindahl-Allen, M Min, RQ Miotto, B Monahan, H Moqtaderi, Z Mu, XMJ O'Geen, H Ouyang, ZQ Patacsil, D Pei, BK Raha, D Ramirez, L Reed, B Rozowsky, J Sboner, A Shi, MY Sisu, C Slifer, T Witt, H Wu, LF Xu, XQ Yan, KK Yang, XQ Yip, KY Zhang, ZD Struhl, K Weissman, SM Gerstein, M Farnham, PJ Snyder, M Tenenbaum, SA Penalva, LO Doyle, F Karmakar, S Landt, SG Bhanvadia, RR Choudhury, A Domanus, M Ma, LJ Moran, J Patacsil, D Slifer, T Victorsen, A Yang, XQ Snyder, M White, KP Auer, T Centanin, L Eichenlaub, M Gruhl, F Heermann, S Hoeckendorf, B Inoue, D Kellner, T Kirchmaier, S Mueller, C Reinhardt, R Schertel, L Schneider, S Sinn, R Wittbrodt, B Wittbrodt, J Weng, ZP Whitfield, TW Wang, J Collins, PJ Aldred, SF Trinklein, ND Partridge, EC Myers, RM Dekker, J Jain, G Lajoie, BR Sanyal, A Balasundaram, G Bates, DL Byron, R Canfield, TK Diegel, MJ Dunn, D Ebersol, AK Frum, T Garg, K Gist, E Hansen, RS Boatman, L Haugen, E Humbert, R Jain, G Johnson, AK Johnson, EM Kutyavin, TV Lajoie, BR Lee, K Lotakis, D Maurano, MT Neph, SJ Neri, FV Nguyen, ED Qu, HZ Reynolds, AP Roach, V Rynes, E Sabo, P Sanchez, ME Sandstrom, RS Sanyal, A Shafer, AO Stergachis, AB Thomas, S Thurman, RE Vernot, B Vierstra, J Vong, S Wang, H Weaver, MA Yan, YQ Zhang, MH Akey, JM Bender, M Dorschner, MO Groudine, M MacCoss, MJ Navas, P Stamatoyannopoulos, G Kaul, R Dekker, J Stamatoyannopoulos, JA Dunham, I Beal, K Brazma, A Flicek, P Herrero, J Johnson, N Keefe, D Lukk, M Luscombe, NM Sobral, D Vaquerizas, JM Wilder, SP Batzoglou, S Sidow, A Hussami, N Kyriazopoulou-Panagiotopoulou, S Libbrecht, MW Schaub, MA Kundaje, A Hardison, RC Miller, W Giardine, B Harris, RS Wu, W Bickel, PJ Banfai, B Boley, NP Brown, JB Huang, HY Li, QH Li, JJ Noble, WS Bilmes, JA Buske, OJ Hoffman, MM Sahu, AD Kharchenko, PV Park, PJ Baker, D Taylor, J Weng, ZP Iyer, S Dong, XJ Greven, M Lin, XY Wang, J Xi, HLS Zhuang, JL Gerstein, M Alexander, RP Balasubramanian, S Cheng, C Harmanci, A Lochovsky, L Min, R Mu, XMJ Rozowsky, J Yan, KK Yip, KY Birney, E AF Dunham, Ian Kundaje, Anshul Aldred, Shelley F. Collins, Patrick J. Davis, CarrieA. Doyle, Francis Epstein, Charles B. Frietze, Seth Harrow, Jennifer Kaul, Rajinder Khatun, Jainab Lajoie, Bryan R. Landt, Stephen G. Lee, Bum-Kyu Pauli, Florencia Rosenbloom, Kate R. Sabo, Peter Safi, Alexias Sanyal, Amartya Shoresh, Noam Simon, Jeremy M. Song, Lingyun Trinklein, Nathan D. Altshuler, Robert C. Birney, Ewan Brown, James B. Cheng, Chao Djebali, Sarah Dong, Xianjun Dunham, Ian Ernst, Jason Furey, Terrence S. Gerstein, Mark Giardine, Belinda Greven, Melissa Hardison, Ross C. Harris, Robert S. Herrero, Javier Hoffman, Michael M. Iyer, Sowmya Kellis, Manolis Khatun, Jainab Kheradpour, Pouya Kundaje, Anshul Lassmann, Timo Li, Qunhua Lin, Xinying Marinov, Georgi K. Merkel, Angelika Mortazavi, Ali Parker, Stephen C. J. Reddy, Timothy E. Rozowsky, Joel Schlesinger, Felix Thurman, Robert E. Wang, Jie Ward, Lucas D. Whitfield, Troy W. Wilder, Steven P. Wu, Weisheng Xi, Hualin S. Yip, Kevin Y. Zhuang, Jiali Bernstein, Bradley E. Birney, Ewan Dunham, Ian Green, Eric D. Gunter, Chris Snyder, Michael Pazin, Michael J. Lowdon, Rebecca F. Dillon, Laura A. L. Adams, Leslie B. Kelly, Caroline J. Zhang, Julia Wexler, Judith R. Green, Eric D. Good, Peter J. Feingold, Elise A. Bernstein, Bradley E. Birney, Ewan Crawford, Gregory E. Dekker, Job Elnitski, Laura Farnham, Peggy J. Gerstein, Mark Giddings, Morgan C. Gingeras, Thomas R. Green, Eric D. Guigo, Roderic Hardison, Ross C. Hubbard, Timothy J. Kellis, Manolis Kent, W. James Lieb, Jason D. Margulies, Elliott H. Myers, Richard M. Snyder, Michael Stamatoyannopoulos, John A. Tenenbaum, Scott A. Weng, Zhiping White, Kevin P. Wold, Barbara Khatun, Jainab Yu, Yanbao Wrobel, John Risk, Brian A. Gunawardena, Harsha P. Kuiper, Heather C. Maier, Christopher W. Xie, Ling Chen, Xian Giddings, Morgan C. Bernstein, Bradley E. Epstein, Charles B. Shoresh, Noam Ernst, Jason Kheradpour, Pouya Mikkelsen, Tarjei S. Gillespie, Shawn Goren, Alon Ram, Oren Zhang, Xiaolan Wang, Li Issner, Robbyn Coyne, Michael J. Durham, Timothy Ku, Manching Truong, Thanh Ward, Lucas D. Altshuler, Robert C. Eaton, Matthew L. Kellis, Manolis Djebali, Sarah Davis, Carrie A. Merkel, Angelika Dobin, Alex Lassmann, Timo Mortazavi, Ali Tanzer, Andrea Lagarde, Julien Lin, Wei Schlesinger, Felix Xue, Chenghai Marinov, Georgi K. Khatun, Jainab Williams, Brian A. Zaleski, Chris Rozowsky, Joel Roeder, Maik Kokocinski, Felix Abdelhamid, Rehab F. Alioto, Tyler Antoshechkin, Igor Baer, Michael T. Batut, Philippe Bell, Ian Bell, Kimberly Chakrabortty, Sudipto Chen, Xian Chrast, Jacqueline Curado, Joao Derrien, Thomas Drenkow, Jorg Dumais, Erica Dumais, Jackie Duttagupta, Radha Fastuca, Megan Fejes-Toth, Kata Ferreira, Pedro Foissac, Sylvain Fullwood, Melissa J. Gao, Hui Gonzalez, David Gordon, Assaf Gunawardena, Harsha P. Howald, Cedric Jha, Sonali Johnson, Rory Kapranov, Philipp King, Brandon Kingswood, Colin Li, Guoliang Luo, Oscar J. Park, Eddie Preall, Jonathan B. Presaud, Kimberly Ribeca, Paolo Risk, Brian A. Robyr, Daniel Ruan, Xiaoan Sammeth, Michael Sandhu, Kuljeet Singh Schaeffer, Lorain See, Lei-Hoon Shahab, Atif Skancke, Jorgen Suzuki, Ana Maria Takahashi, Hazuki Tilgner, Hagen Trout, Diane Walters, Nathalie Wang, Huaien Wrobel, John Yu, Yanbao Hayashizaki, Yoshihide Harrow, Jennifer Gerstein, Mark Hubbard, Timothy J. Reymond, Alexandre Antonarakis, Stylianos E. Hannon, Gregory J. Giddings, Morgan C. Ruan, Yijun Wold, Barbara Carninci, Piero Guigo, Roderic Gingeras, Thomas R. Rosenbloom, Kate R. Sloan, Cricket A. Learned, Katrina Malladi, Venkat S. Wong, Matthew C. Barber, Galtp. Cline, Melissa S. Dreszer, Timothy R. Heitner, Steven G. Karolchik, Donna Kent, W. James Kirkup, Vanessa M. Meyer, Laurence R. Long, Jeffrey C. Maddren, Morgan Raney, Brian J. Furey, Terrence S. Song, Lingyun Grasfeder, Linda L. Giresi, Paul G. Lee, Bum-Kyu Battenhouse, Anna Sheffield, Nathan C. Simon, Jeremy M. Showers, Kimberly A. Safi, Alexias London, Darin Bhinge, Akshay A. Shestak, Christopher Schaner, Matthew R. Kim, Seul Ki Zhang, Zhuzhu Z. Mieczkowski, Piotr A. Mieczkowska, Joanna O. Liu, Zheng McDaniell, Ryan M. Ni, Yunyun Rashid, Naim U. Kim, Min Jae Adar, Sheera Zhang, Zhancheng Wang, Tianyuan Winter, Deborah Keefe, Damian Birney, Ewan Iyer, Vishwanath R. Lieb, Jason D. Crawford, Gregory E. Li, Guoliang Sandhu, Kuljeet Singh Zheng, Meizhen Wang, Ping Luo, Oscar J. Shahab, Atif Fullwood, Melissa J. Ruan, Xiaoan Ruan, Yijun Myers, Richard M. Pauli, Florencia Williams, Brian A. Gertz, Jason Marinov, Georgi K. Reddy, Timothy E. Vielmetter, Jost Partridge, E. Christopher Trout, Diane Varley, Katherine E. Gasper, Clarke Bansal, Anita Pepke, Shirley Jain, Preti Amrhein, Henry Bowling, Kevin M. Anaya, Michael Cross, Marie K. King, Brandon Muratet, Michael A. Antoshechkin, Igor Newberry, Kimberly M. Mccue, Kenneth Nesmith, Amy S. Fisher-Aylor, Katherine I. Pusey, Barbara DeSalvo, Gilberto Parker, Stephanie L. Balasubramanian, Sreeram Davis, Nicholas S. Meadows, Sarah K. Eggleston, Tracy Gunter, Chris Newberry, J. Scott Levy, Shawn E. Absher, Devin M. Mortazavi, Ali Wong, Wing H. Wold, Barbara Blow, Matthew J. Visel, Axel Pennachio, Len A. Elnitski, Laura Margulies, Elliott H. Parker, Stephen C. J. Petrykowska, Hanna M. Abyzov, Alexej Aken, Bronwen Barrell, Daniel Barson, Gemma Berry, Andrew Bignell, Alexandra Boychenko, Veronika Bussotti, Giovanni Chrast, Jacqueline Davidson, Claire Derrien, Thomas Despacio-Reyes, Gloria Diekhans, Mark Ezkurdia, Iakes Frankish, Adam Gilbert, James Gonzalez, Jose Manuel Griffiths, Ed Harte, Rachel Hendrix, David A. Howald, Cedric Hunt, Toby Jungreis, Irwin Kay, Mike Khurana, Ekta Kokocinski, Felix Leng, Jing Lin, Michael F. Loveland, Jane Lu, Zhi Manthravadi, Deepa Mariotti, Marco Mudge, Jonathan Mukherjee, Gaurab Notredame, Cedric Pei, Baikang Rodriguez, Jose Manuel Saunders, Gary Sboner, Andrea Searle, Stephen Sisu, Cristina Snow, Catherine Steward, Charlie Tanzer, Andrea Tapanari, Electra Tress, Michael L. van Baren, Marijke J. Walters, Nathalie Washietl, Stefan Wilming, Laurens Zadissa, Amonida Zhang, Zhengdong Brent, Michael Haussler, David Kellis, Manolis Valencia, Alfonso Gerstein, Mark Reymond, Alexandre Guigo, Roderic Harrow, Jennifer Hubbard, Timothy J. Landt, Stephen G. Frietze, Seth Abyzov, Alexej Addleman, Nick Alexander, Roger P. Auerbach, Raymond K. Balasubramanian, Suganthi Bettinger, Keith Bhardwaj, Nitin Boyle, Alan P. Cao, Alina R. Cayting, Philip Charos, Alexandra Cheng, Yong Cheng, Chao Eastman, Catharine Euskirchen, Ghia Fleming, Joseph D. Grubert, Fabian Habegger, Lukas Hariharan, Manoj Harmanci, Arif Iyengar, Sushma Jin, Victor X. Karczewski, Konrad J. Kasowski, Maya Lacroute, Phil Lam, Hugo Lamarre-Vincent, Nathan Leng, Jing Lian, Jin Lindahl-Allen, Marianne Min, Renqiang Miotto, Benoit Monahan, Hannah Moqtaderi, Zarmik Mu, Xinmeng J. O'Geen, Henriette Ouyang, Zhengqing Patacsil, Dorrelyn Pei, Baikang Raha, Debasish Ramirez, Lucia Reed, Brian Rozowsky, Joel Sboner, Andrea Shi, Minyi Sisu, Cristina Slifer, Teri Witt, Heather Wu, Linfeng Xu, Xiaoqin Yan, Koon-Kiu Yang, Xinqiong Yip, Kevin Y. Zhang, Zhengdong Struhl, Kevin Weissman, Sherman M. Gerstein, Mark Farnham, Peggy J. Snyder, Michael Tenenbaum, Scott A. Penalva, Luiz O. Doyle, Francis Karmakar, Subhradip Landt, Stephen G. Bhanvadia, Raj R. Choudhury, Alina Domanus, Marc Ma, Lijia Moran, Jennifer Patacsil, Dorrelyn Slifer, Teri Victorsen, Alec Yang, Xinqiong Snyder, Michael White, Kevin P. Auer, Thomas Centanin, Lazaro Eichenlaub, Michael Gruhl, Franziska Heermann, Stephan Hoeckendorf, Burkhard Inoue, Daigo Kellner, Tanja Kirchmaier, Stephan Mueller, Claudia Reinhardt, Robert Schertel, Lea Schneider, Stephanie Sinn, Rebecca Wittbrodt, Beate Wittbrodt, Jochen Weng, Zhiping Whitfield, Troy W. Wang, Jie Collins, Patrick J. Aldred, Shelley F. Trinklein, Nathan D. Partridge, E. Christopher Myers, Richard M. Dekker, Job Jain, Gaurav Lajoie, Bryan R. Sanyal, Amartya Balasundaram, Gayathri Bates, Daniel L. Byron, Rachel Canfield, Theresa K. Diegel, Morgan J. Dunn, Douglas Ebersol, Abigail K. Frum, Tristan Garg, Kavita Gist, Erica Hansen, R. Scott Boatman, Lisa Haugen, Eric Humbert, Richard Jain, Gaurav Johnson, Audra K. Johnson, Ericka M. Kutyavin, Tattyana V. Lajoie, Bryan R. Lee, Kristen Lotakis, Dimitra Maurano, Matthew T. Neph, Shane J. Neri, Fiedencio V. Nguyen, Eric D. Qu, Hongzhu Reynolds, Alex P. Roach, Vaughn Rynes, Eric Sabo, Peter Sanchez, Minerva E. Sandstrom, Richard S. Sanyal, Amartya Shafer, Anthony O. Stergachis, Andrew B. Thomas, Sean Thurman, Robert E. Vernot, Benjamin Vierstra, Jeff Vong, Shinny Wang, Hao Weaver, Molly A. Yan, Yongqi Zhang, Miaohua Akey, Joshua M. Bender, Michael Dorschner, Michael O. Groudine, Mark MacCoss, Michael J. Navas, Patrick Stamatoyannopoulos, George Kaul, Rajinder Dekker, Job Stamatoyannopoulos, John A. Dunham, Ian Beal, Kathryn Brazma, Alvis Flicek, Paul Herrero, Javier Johnson, Nathan Keefe, Damian Lukk, Margus Luscombe, Nicholas M. Sobral, Daniel Vaquerizas, Juan M. Wilder, Steven P. Batzoglou, Serafim Sidow, Arend Hussami, Nadine Kyriazopoulou-Panagiotopoulou, Sofia Libbrecht, Max W. Schaub, Marc A. Kundaje, Anshul Hardison, Ross C. Miller, Webb Giardine, Belinda Harris, Robert S. Wu, Weisheng Bickel, Peter J. Banfai, Balazs Boley, Nathan P. Brown, James B. Huang, Haiyan Li, Qunhua Li, Jingyi Jessica Noble, William Stafford Bilmes, Jeffrey A. Buske, Orion J. Hoffman, Michael M. Sahu, Avinash D. Kharchenko, Peter V. Park, Peter J. Baker, Dannon Taylor, James Weng, Zhiping Iyer, Sowmya Dong, Xianjun Greven, Melissa Lin, Xinying Wang, Jie Xi, Hualin S. Zhuang, Jiali Gerstein, Mark Alexander, Roger P. Balasubramanian, Suganthi Cheng, Chao Harmanci, Arif Lochovsky, Lucas Min, Renqiang Mu, Xinmeng J. Rozowsky, Joel Yan, Koon-Kiu Yip, Kevin Y. Birney, Ewan CA ENCODE Project Consortium TI An integrated encyclopedia of DNA elements in the human genome SO NATURE LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; CHROMOSOME CONFORMATION CAPTURE; HUMAN-CELLS; IN-VIVO; CHROMATIN; REGIONS; MOUSE; MAPS; WIDE; DETERMINANTS AB The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research. C1 [Dunham, Ian; Birney, Ewan; Herrero, Javier; Wilder, Steven P.; Keefe, Damian; Brazma, Alvis; Flicek, Paul; Lukk, Margus; Sobral, Daniel] European Bioinformat Inst EMBL EBI, Vertebrate Genom Grp, Hinxton CB10 1SD, Cambs, England. [Kundaje, Anshul; Batzoglou, Serafim; Sidow, Arend; Hussami, Nadine; Kyriazopoulou-Panagiotopoulou, Sofia; Libbrecht, Max W.; Schaub, Marc A.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Aldred, Shelley F.; Collins, Patrick J.; Trinklein, Nathan D.] SwitchGear Genom, Menlo Pk, CA 94025 USA. [Davis, CarrieA.; Schlesinger, Felix; Gingeras, Thomas R.; Davis, Carrie A.; Dobin, Alex; Lin, Wei; Xue, Chenghai; Zaleski, Chris; Baer, Michael T.; Batut, Philippe; Bell, Kimberly; Chakrabortty, Sudipto; Drenkow, Jorg; Fastuca, Megan; Fejes-Toth, Kata; Gordon, Assaf; Jha, Sonali; Preall, Jonathan B.; Presaud, Kimberly; See, Lei-Hoon; Wang, Huaien; Hannon, Gregory J.; Frankish, Adam; Ebersol, Abigail K.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Doyle, Francis; Bernstein, Bradley E.; Tenenbaum, Scott A.] SUNY Albany, Albany, NY 12203 USA. [Epstein, Charles B.; Shoresh, Noam; Bernstein, Bradley E.; Mikkelsen, Tarjei S.; Zhang, Xiaolan; Wang, Li; Issner, Robbyn; Coyne, Michael J.; Durham, Timothy; Truong, Thanh; Loveland, Jane] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Frietze, Seth; Farnham, Peggy J.; Witt, Heather] USC Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Harrow, Jennifer; Hubbard, Timothy J.; Kokocinski, Felix; Aken, Bronwen; Barrell, Daniel; Barson, Gemma; Berry, Andrew; Bignell, Alexandra; Boychenko, Veronika; Davidson, Claire; Despacio-Reyes, Gloria; Frankish, Adam; Gilbert, James; Gonzalez, Jose Manuel; Griffiths, Ed; Hunt, Toby; Kay, Mike; Manthravadi, Deepa; Mudge, Jonathan; Mukherjee, Gaurab; Saunders, Gary; Searle, Stephen; Snow, Catherine; Steward, Charlie; Tapanari, Electra; Wilming, Laurens; Zadissa, Amonida] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England. [Kaul, Rajinder] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. 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[Lee, Bum-Kyu; Battenhouse, Anna; Bhinge, Akshay A.; Liu, Zheng; McDaniell, Ryan M.; Ni, Yunyun; Adar, Sheera; Zhang, Zhancheng; Wang, Tianyuan; Iyer, Vishwanath R.] Univ Texas Austin, Ctr Syst & Synthet Biol, Inst Cellular & Mol Biol, Sect Mol Genet & Microbiol, Austin, TX 78712 USA. [Pauli, Florencia; Reddy, Timothy E.; Gunter, Chris; Myers, Richard M.; Gertz, Jason; Partridge, E. Christopher; Varley, Katherine E.; Bansal, Anita; Bowling, Kevin M.; Cross, Marie K.; Muratet, Michael A.; Newberry, Kimberly M.; Nesmith, Amy S.; Pusey, Barbara; Parker, Stephanie L.; Davis, Nicholas S.; Meadows, Sarah K.; Eggleston, Tracy; Newberry, J. Scott; Levy, Shawn E.; Absher, Devin M.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Rosenbloom, Kate R.; Kent, W. 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[Auer, Thomas; Centanin, Lazaro; Eichenlaub, Michael; Gruhl, Franziska; Heermann, Stephan; Hoeckendorf, Burkhard; Inoue, Daigo; Kellner, Tanja; Kirchmaier, Stephan; Mueller, Claudia; Reinhardt, Robert; Schertel, Lea; Schneider, Stephanie; Sinn, Rebecca; Wittbrodt, Beate; Wittbrodt, Jochen] Univ Heidelberg, Ctr Organismal Studies, D-69120 Heidelberg, Germany. [Balasundaram, Gayathri; Byron, Rachel; Zhang, Miaohua; Bender, Michael; Groudine, Mark] Fred Hutchinson Canc Res Ctr, Basic Sci Div, Seattle, WA 98109 USA. [Ebersol, Abigail K.; Frum, Tristan; Hansen, R. Scott; Boatman, Lisa; Johnson, Ericka M.; Lotakis, Dimitra; Nguyen, Eric D.; Sanchez, Minerva E.; Yan, Yongqi; Navas, Patrick; Stamatoyannopoulos, George] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Garg, Kavita] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Dorschner, Michael O.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Beal, Kathryn; Johnson, Nathan] European Bioinformat Inst EMBL EBI, Microarray Informat Grp, Hinxton CB10 1SD, Cambs, England. [Keefe, Damian; Luscombe, Nicholas M.; Vaquerizas, Juan M.] European Bioinformat Inst EMBL EBI, Genom & Regulatory Syst Grp, Hinxton CB10 1SD, Cambs, England. [Keefe, Damian] Stanford Univ, Dept Genet, Dept Pathol, Stanford, CA 94305 USA. [Noble, William Stafford] Dept Comp Sci & Engn, Seattle, WA 98195 USA. [Bilmes, Jeffrey A.] Univ Washington, Dept Elect Engn, Seattle, WA 98195 USA. [Kharchenko, Peter V.; Park, Peter J.] Harvard Univ, Ctr Biomed Informat, Sch Med, Boston, MA 02115 USA. [Baker, Dannon; Taylor, James] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Baker, Dannon; Taylor, James] Emory Univ, Dept Math & Comp Sci, Atlanta, GA 30322 USA. RP Dunham, I (reprint author), European Bioinformat Inst EMBL EBI, Vertebrate Genom Grp, Hinxton CB10 1SD, Cambs, England. RI Alioto, Tyler/K-7267-2015; Hubbard, Tim/C-2567-2008; Tanzer, Andrea/L-3147-2015; Valencia, Alfonso/I-3127-2015; Hariharan, Manoj/N-2855-2015; Blow, Matthew/G-6369-2012; Vaquerizas, Juan/F-2676-2011; Boyle, Alan/I-1848-2014; Notredame, Cedric/G-3868-2010; Mu, Xinmeng/P-2562-2016; Taylor, James/F-1026-2011; Visel, Axel/A-9398-2009; Carninci, Piero/K-1568-2014; Dong, Xianjun/N-3867-2014; Antonarakis, Stylianos/N-8866-2014; Djebali, Sarah/O-9817-2014; wang, baocheng/B-7805-2008; SANYAL, AMARTYA/D-7240-2015; Johnson, Rory/H-2961-2015; Brown, James/H-2971-2015; Guigo, Roderic/D-1303-2010; Ezkurdia, Iakes/H-9334-2015; Fullwood, Melissa/G-5713-2011; Heermann, Stephan/J-8586-2015; Sobral, Daniel/B-4786-2014; Sammeth, Michael/C-1157-2014; cheng, yong/I-4270-2012; Mikkelsen, Tarjei/A-1306-2007; Li, Jingyi Jessica/K-2037-2012; Alexander, Roger/A-8643-2008; Xu, Weihong/C-4175-2012; Khurana, Ekta/C-4933-2013; Wittbrodt, Joachim/D-4735-2014; Yan, Koon-Kiu/A-5940-2009; Yu, Yanbao/G-3035-2010; Ferreira, Pedro/J-6379-2013; Lassmann, Timo/A-8271-2008; Abyzov, Alexej/M-4284-2013; Li, Guoliang/I-1494-2015; OI Johnson, Nathan/0000-0002-2783-9047; Wilming, Laurens/0000-0002-4154-7358; Dreszer, Timothy/0000-0002-7328-1283; Gilbert, James/0000-0001-8079-3159; Sisu, Cristina/0000-0001-9371-0797; Merkel, Angelika/0000-0001-5164-6803; Snow, Catherine/0000-0002-1672-3532; Abyzov, Alexej/0000-0001-5405-6729; Dunham, Ian/0000-0003-2525-5598; Furey, Terry/0000-0001-5546-9672; Gonzalez, Jose M/0000-0001-5569-0705; Sheffield, Nathan/0000-0001-5643-4068; Alioto, Tyler/0000-0002-2960-5420; Hubbard, Tim/0000-0002-1767-9318; Tanzer, Andrea/0000-0003-2873-4236; Valencia, Alfonso/0000-0002-8937-6789; Hariharan, Manoj/0000-0002-1006-5372; Blow, Matthew/0000-0002-8844-9149; Vaquerizas, Juan/0000-0002-6583-6541; Boyle, Alan/0000-0002-2081-1105; Notredame, Cedric/0000-0003-1461-0988; Mu, Xinmeng/0000-0002-8079-0828; Taylor, James/0000-0001-5079-840X; Gingeras, Thomas/0000-0001-9106-3573; Sandhu, Kuljeet/0000-0001-7632-6339; Visel, Axel/0000-0002-4130-7784; Carninci, Piero/0000-0001-7202-7243; Dong, Xianjun/0000-0002-8052-9320; Antonarakis, Stylianos/0000-0001-8907-5823; Djebali, Sarah/0000-0002-0599-1267; wang, baocheng/0000-0002-8236-8014; SANYAL, AMARTYA/0000-0002-2109-4478; Johnson, Rory/0000-0003-4607-2782; Guigo, Roderic/0000-0002-5738-4477; Ezkurdia, Iakes/0000-0001-9074-5302; Fullwood, Melissa/0000-0003-0321-7865; Heermann, Stephan/0000-0001-7374-8886; Sobral, Daniel/0000-0003-3955-0117; Sammeth, Michael/0000-0002-6528-9883; Mikkelsen, Tarjei/0000-0002-8133-3135; Li, Jingyi Jessica/0000-0002-9288-5648; Alexander, Roger/0000-0002-2967-7395; Wittbrodt, Joachim/0000-0001-8550-7377; Yu, Yanbao/0000-0003-2994-1974; Ferreira, Pedro/0000-0003-3838-8664; Lassmann, Timo/0000-0002-0138-2691; Sboner, Andrea/0000-0001-6915-3070; Hunt, Toby/0000-0001-8377-0841; Foissac, Sylvain/0000-0002-2631-5356; Aken, Bronwen/0000-0002-3032-4095; Saunders, Gary/0000-0002-7468-0008; Ward, Lucas/0000-0002-8017-809X; Brazma, Alvis/0000-0001-5988-7409; Centanin, Lazaro/0000-0003-3889-4524; Winter, Deborah/0000-0003-1806-673X; Birney, Ewan/0000-0001-8314-8497; Rozowsky, Joel/0000-0002-3565-0762; Bussotti, Giovanni/0000-0002-4078-7413; Hoffman, Michael/0000-0002-4517-1562; Davidson, Claire/0000-0002-4910-8202; Pazin, Michael/0000-0002-7561-3640; Li, Guoliang/0000-0003-1601-6640; Marinov, Georgi/0000-0003-1822-7273; Karczewski, Konrad/0000-0003-2878-4671; Farnham, Peggy/0000-0003-4469-7914; Herrero, Javier/0000-0001-7313-717X; Haugen, Eric/0000-0001-7444-8981; Wilder, Steven/0000-0001-8049-2559; Gunter, Chris/0000-0001-9369-7537; Flicek, Paul/0000-0002-3897-7955 FU NHGRI [U54HG004570, U01HG004695, U54HG004563, U54HG004557, U54HG004555, U41HG004568, U54HG004576, U54HG004558, U54HG004592]; American Recovery and Reinvestment Act (ARRA) funds from the NHGRI [U54HG004570, U54HG004563, U41HG004568, U54HG004592, R01HG003143, RC2HG005591, U01HG004561, RC2HG005679, R01HG003541, R01HG003988]; Intramural Research Program of the NHGRI [ZIAHG200323, ZIAHG200341]; United States Department of Energy Joint Genome Institute, Department of Energy, University of California [DE-AC02-05CH11231]; [R01HG003700]; [R01HG004456-03]; [U01HG004571] FX We thank additional members of our laboratories and institutions who have contributed to the experimental and analytical components of this project. We thank D. Leja for assistance with production of the figures. The Consortium is funded by grants from the NHGRI as follows: production grants: U54HG004570 (B. E. Bernstein); U01HG004695 (E. Birney); U54HG004563 (G. E. Crawford); U54HG004557 (T. R. Gingeras); U54HG004555 (T. J. Hubbard); U41HG004568 (W. J. Kent); U54HG004576 (R. M. Myers); U54HG004558 (M. Snyder); U54HG004592 (J. A. Stamatoyannopoulos). Pilot grants: R01HG003143 (J. Dekker); RC2HG005591 and R01HG003700 (M. C. Giddings); R01HG004456-03 (Y. Ruan); U01HG004571 (S. A. Tenenbaum); U01HG004561 (Z. Weng); RC2HG005679 (K. P. White). This project was supported in part by American Recovery and Reinvestment Act (ARRA) funds from the NHGRI through grants U54HG004570, U54HG004563, U41HG004568, U54HG004592, R01HG003143, RC2HG005591, R01HG003541, U01HG004561, RC2HG005679 and R01HG003988(L. Pennacchio). In addition, work from NHGRI Groups was supported by the Intramural Research Program of the NHGRI (L. Elnitski, ZIAHG200323; E. H. Margulies, ZIAHG200341). Research in the Pennachio laboratory was performed at Lawrence Berkeley National Laboratory and at the United States Department of Energy Joint Genome Institute, Department of Energy Contract DE-AC02-05CH11231, University of California. NR 75 TC 4019 Z9 4103 U1 101 U2 790 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 6 PY 2012 VL 489 IS 7414 BP 57 EP 74 DI 10.1038/nature11247 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 999WW UT WOS:000308347000039 ER PT J AU Farias, GG Cuitino, L Guo, XL Ren, XF Jarnik, M Mattera, R Bonifacino, JS AF Farias, Ginny G. Cuitino, Loreto Guo, Xiaoli Ren, Xuefeng Jarnik, Michal Mattera, Rafael Bonifacino, Juan S. TI Signal-Mediated, AP-1/Clathrin-Dependent Sorting of Transmembrane Receptors to the Somatodendritic Domain of Hippocampal Neurons SO NEURON LA English DT Article ID MANNOSE 6-PHOSPHATE RECEPTORS; POLARIZED EPITHELIAL-CELLS; AP-1 CLATHRIN-ADAPTER; CANINE KIDNEY-CELLS; TRANSFERRIN RECEPTOR; BASOLATERAL POLARITY; ADENOVIRUS RECEPTOR; CYTOPLASMIC DOMAIN; MEMBRANE-PROTEINS; LIVING CELLS AB Plasma membranes of the somatodendritic and axonal domains of neurons are known to have different protein compositions, but the molecular mechanisms that determine this polarized protein distribution remain poorly understood. Herein we show that somatodendritic sorting of various transmembrane receptors in rat hippocampal neurons is mediated by recognition of signals within the cytosolic domains of the proteins by the mu 1A subunit of the adaptor protein-1 (AP-1) complex. This complex, in conjunction with clathrin, functions in the neuronal soma to exclude somatodendritic proteins from axonal transport carriers. Perturbation of this process affects dendritic spine morphology and decreases the number of synapses. These findings highlight the primary recognition event that underlies somatodendritic sorting and contribute to the evolving view of AP-1 as a global regulator of cell polarity. C1 [Farias, Ginny G.; Cuitino, Loreto; Guo, Xiaoli; Ren, Xuefeng; Jarnik, Michal; Mattera, Rafael; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM bonifacinoj@helix.nih.gov RI Guo, Xiaoli/O-3906-2014; OI Bonifacino, Juan S./0000-0002-5673-6370 FU NICHD, NIH FX We thank X. Zhu and N. Tsai for expert technical assistance, D. Arnold, G. Bloom, F. Brodsky, E. Gundelfinger, K. Howell, P. Kammermeier, J. Lippincott-Schwartz, G. Mardones, M. Nonet, M. Parsons, T. Ryan, L. Traub, S. Vicini, and B. Winckler for kind gifts of reagents, and J. Hurley for helpful discussions and critical reading of the manuscript. This work was funded by the Intramural Program of NICHD, NIH. NR 62 TC 47 Z9 47 U1 1 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 6 PY 2012 VL 75 IS 5 BP 810 EP 823 DI 10.1016/j.neuron.2012.07.007 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 004LX UT WOS:000308684300009 PM 22958822 ER PT J AU Luo, Y Niu, SQ Ichiye, T AF Luo, Yan Niu, Shuqiang Ichiye, Toshiko TI Understanding Rubredoxin Redox Sites by Density Functional Theory Studies of Analogues SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID IRON-SULFUR CLUSTERS; CLOSTRIDIUM-PASTEURIANUM RUBREDOXIN; ELECTRONIC-STRUCTURE; BASIS-SETS; PHOTOELECTRON-SPECTROSCOPY; REORGANIZATION ENERGY; REDUCTION POTENTIALS; SYNTHETIC ANALOGS; ACTIVE-SITES; PROTEINS AB Determining the redox energetics of redox site analogues of metalloproteins is essential in unraveling the various contributions to electron transfer properties of these proteins. Since studies of the [4Fe-4S] analogues show that the energies are dependent on the ligand dihedral angles, broken symmetry density functional theory (BS-DFT) with the B3LYP functional and double-c basis sets calculations of optimized geometries and electron detachment energies of [1Fe] rubredoxin analogues are compared to crystal structures and gas-phase photoelectron spectroscopy data, respectively, for [Fe(SCH3)(4)](0/1-/2-), [Fe(S-2-o-xyl)(2)](0/1-2-) and Na+[Fe(S-2-o-xyl)(2)](1-/2-) in different conformations. In particular, the study of Na+[Fe(S-2-o-xyl)(2)](1-/2-) is the only direct comparison of calculated and experimental gas phase detachment energies for the 1-/2- couple found in the rubredoxins. These results show that variations in the inner sphere energetics by up to similar to 0.4 eV can be caused by differences in the ligand dihedral angles in either or both redox states. Moreover, these results indicate that the protein stabilizes the conformation that favors reduction. In addition, the free energies and reorganization energies of oxidation and reduction as well as electrostatic potential charges are calculated, which can be used as estimates in continuum electrostatic calculations of electron transfer properties of [1Fe] proteins. C1 [Luo, Yan; Niu, Shuqiang; Ichiye, Toshiko] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Ichiye, Toshiko] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Ichiye, T (reprint author), Georgetown Univ, Dept Chem, Washington, DC 20057 USA. EM ti9@georgetown.edu FU National Institutes of Health [GM045303]; Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute in the Laboratory of Computational Biology [Z99-TW999999-03]; U.S. DOE's Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory; Battelle [EMSL38793, st39962] FX This work was supported by a grant from the National Institutes of Health (GM045303) and by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute in the Laboratory of Computational Biology (Z99-TW999999-03). The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the U.S. Government. Computational resources from the William G. McGowan Foundation are gratefully acknowledged. The calculations were performed at the EMSL, a national user facility sponsored by the U.S. DOE's Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory, operated for DOE by Battelle, under the grant EMSL38793 and st39962. NR 51 TC 5 Z9 5 U1 2 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 SEP 6 PY 2012 VL 116 IS 35 BP 8918 EP 8924 DI 10.1021/jp3057509 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 999UC UT WOS:000308339500014 PM 22881577 ER PT J AU Esworthy, RS Kim, BW Rivas, GE Leto, TL Doroshow, JH Chu, FF AF Esworthy, R. Steven Kim, Byung-Wook Rivas, Guillermo E. Leto, Thomas L. Doroshow, James H. Chu, Fong-Fong TI Analysis of Candidate Colitis Genes in the Gdac1 Locus of Mice Deficient in Glutathione Peroxidase-1 and-2 SO PLOS ONE LA English DT Article ID CYTOSOLIC PHOSPHOLIPASE A(2); INFLAMMATORY-BOWEL-DISEASE; INTESTINAL EPITHELIUM; BINDING-PROTEIN; DUAL OXIDASE; CELL-CYCLE; EXPRESSION; MOUSE; RESPONSES; GPX2 AB Background: Mice that are deficient for glutathione peroxidases 1 and 2 (GPX) show large variations in the penetrance and severity of colitis in C57BL/6J and 129S1/SvImJ backgrounds. We mapped a locus contributing to this difference to distal chromosome 2 (similar to 119-133 mbp) and named it glutathione peroxidase-deficiency-associated colitis 1 (Gdac1). The aim of this study was to identify the best gene candidates within the Gdac1 locus contributing to the murine colitis phenotype. Method/Principal Findings: We refined the boundaries of Gdac1 to 118-125 mbp (95% confidence interval) by increasing sample size and marker density across the interval. The narrowed region contains 128 well-annotated protein coding genes but it excludes Fermt1, a human inflammatory bowel disease candidate that was within the original boundaries of Gdac1. The locus we identified may be the Cdcs3 locus mapped by others studying IL10-knockout mice. Using in silico analysis of the 128 genes, based on published colon expression data, the relevance of pathways to colitis, gene mutations, presence of non-synonymous-single-nucleotide polymorphisms (nsSNPs) and whether the nsSNPs are predicted to have an impact on protein function or expression, we excluded 42 genes. Based on a similar analysis, twenty-five genes from the remaining 86 genes were analyzed for expression-quantitative-trait loci, and another 15 genes were excluded. Conclusion/Significance: Among the remaining 10 genes, we identified Pla2g4f and Duox2 as the most likely colitis gene candidates, because GPX metabolizes PLA2G4F and DUOX2 products. Pla2g4f is a phospholipase A2 that has three potentially significant nsSNP variants and showed expression differences across mouse strains. PLA2G4F produces arachidonic acid, which is a substrate for lipoxygenases and, in turn, for GPXs. DUOX2 produces H2O2 and may control microbial populations. DUOX-1 and -2 control microbial populations in mammalian lung and in the gut of several insects and zebrafish. Dysbiosis is a phenotype that differentiates 129S1/SvImJ from C57BL/6J and may be due to strain differences in DUOX2 activity. C1 [Esworthy, R. Steven; Kim, Byung-Wook; Chu, Fong-Fong] Beckman Res Inst City Hope, Dept Radiat Biol, Duarte, CA USA. [Leto, Thomas L.] NIAID, Host Def Lab, NIH, Rockville, MD USA. [Doroshow, James H.] NCI, NIH, Bethesda, MD 20892 USA. RP Esworthy, RS (reprint author), Beckman Res Inst City Hope, Dept Radiat Biol, Duarte, CA USA. EM fchu@coh.org FU National Institutes of Health [R01CA114569] FX This work was partially supported by National Institutes of Health R01CA114569 (FFC)http://projectreporter.nih.gov/reporter_searchresults.cfm. No additional external funding sources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 7 Z9 7 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 6 PY 2012 VL 7 IS 9 AR e44262 DI 10.1371/journal.pone.0044262 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001KC UT WOS:000308458400052 PM 22970191 ER PT J AU Kronforst, KD Mancuso, CJ Pettengill, M Ninkovic, J Coombs, MRP Stevens, C Otto, M Mallard, C Wang, XY Goldmann, D Levy, O AF Kronforst, Kenny D. Mancuso, Christy J. Pettengill, Matthew Ninkovic, Jana Coombs, Melanie R. Power Stevens, Chad Otto, Michael Mallard, Carina Wang, Xiaoyang Goldmann, Donald Levy, Ofer TI A Neonatal Model of Intravenous Staphylococcus epidermidis Infection in Mice < 24 h Old Enables Characterization of Early Innate Immune Responses SO PLOS ONE LA English DT Article ID COAGULASE-NEGATIVE STAPHYLOCOCCI; MOUSE MODEL; HUMAN NEWBORN; IN-VITRO; SEPSIS; AUREUS; BLOOD; SUSCEPTIBILITY; VIRULENCE; PATHOGEN AB Staphylococcus epidermidis (SE) causes late onset sepsis and significant morbidity in catheterized preterm newborns. Animal models of SE infection are useful in characterizing disease mechanisms and are an important approach to developing improved diagnostics and therapeutics. Current murine models of neonatal bacterial infection employ intraperitoneal or subcutaneous routes at several days of age, and may, therefore, not accurately reflect distinct features of innate immune responses to bacteremia. In this study we developed, validated, and characterized a murine model of intravenous (IV) infection in neonatal mice <24 hours (h) old to describe the early innate immune response to SE. C57BL/6 mice <24 h old were injected IV with 10(6), 10(7), 10(8) colony-forming units (CFU) of SE 1457, a clinical isolate from a central catheter infection. A prospective injection scoring system was developed and validated, with only high quality injections analyzed. Newborn mice were euthanized between 2 and 48 h post-injection and spleen, liver, and blood collected to assess bacterial viability, gene expression, and cytokine production. High quality IV injections demonstrated inoculum-dependent infection of spleen, liver and blood. Within 2 h of injection, SE induced selective transcription of TLR2 and MyD88 in the liver, and increased systemic production of plasma IL-6 and TNF-alpha. Despite clearance of bacteremia and solid organ infection within 48 h, inoculum-dependent impairment in weight gain was noted. We conclude that a model of IV SE infection in neonatal mice <24 h old is feasible, demonstrating inoculum-dependent infection of solid organs and a pattern of bacteremia, rapid and selective innate immune activation, and impairment of weight gain typical of infected human neonates. This novel model can now be used to characterize immune ontogeny, evaluate infection biomarkers, and assess preventative and therapeutic modalities. C1 [Kronforst, Kenny D.; Mancuso, Christy J.; Pettengill, Matthew; Ninkovic, Jana; Stevens, Chad; Goldmann, Donald; Levy, Ofer] Boston Childrens Hosp, Boston, MA USA. [Pettengill, Matthew; Ninkovic, Jana; Goldmann, Donald; Levy, Ofer] Harvard Univ, Sch Med, Boston, MA USA. [Coombs, Melanie R. Power] Dalhousie Univ, Halifax, NS, Canada. [Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Mallard, Carina; Wang, Xiaoyang] Univ Gothenburg, Gothenburg, Sweden. RP Kronforst, KD (reprint author), Boston Childrens Hosp, Boston, MA USA. EM ofer.levy@childrens.harvard.edu OI Coombs, Melanie/0000-0002-2036-8414; Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [RO1 AI067353-01A1, 3R01AI067353-05S1] FX Financial support provided by National Institute of Allergy and Infectious Diseases, National Institutes of Health RO1 AI067353-01A1 and Administrative Supplement 3R01AI067353-05S1 (to OL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 12 Z9 16 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 6 PY 2012 VL 7 IS 9 AR e43897 DI 10.1371/journal.pone.0043897 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001KC UT WOS:000308458400022 PM 22970147 ER PT J AU Sohn, JJ Schetter, AJ Yfantis, HG Ridnour, LA Horikawa, I Khan, MA Robles, AI Hussain, SP Goto, A Bowman, ED Hofseth, LJ Bartkova, J Bartek, J Wogan, GN Wink, DA Harris, CC AF Sohn, Jane J. Schetter, Aaron J. Yfantis, Harris G. Ridnour, Lisa A. Horikawa, Izumi Khan, Mohammed A. Robles, Ana I. Hussain, S. Perwez Goto, Akiteru Bowman, Elise D. Hofseth, Lorne J. Bartkova, Jirina Bartek, Jiri Wogan, Gerald N. Wink, David A. Harris, Curtis C. TI Macrophages, Nitric Oxide and microRNAs Are Associated with DNA Damage Response Pathway and Senescence in Inflammatory Bowel Disease SO PLOS ONE LA English DT Article ID ONCOGENE-INDUCED SENESCENCE; ULCERATIVE-COLITIS; CELLULAR SENESCENCE; COLORECTAL-CANCER; CROHNS-DISEASE; SYNTHASE EXPRESSION; SUSCEPTIBILITY LOCI; BREAST-CANCER; TUMOR-GROWTH; IN-VIVO AB Background: Cellular senescence can be a functional barrier to carcinogenesis. We hypothesized that inflammation modulates carcinogenesis through senescence and DNA damage response (DDR). We examined the association between senescence and DDR with macrophage levels in inflammatory bowel disease (IBD). In vitro experiments tested the ability of macrophages to induce senescence in primary cells. Inflammation modulating microRNAs were identified in senescence colon tissue for further investigation. Methodology/Principal Findings: Quantitative immunohistochemistry identified protein expression by colon cell type. Increased cellular senescence (HP1 gamma; P = 0.01) or DDR (gamma H2A.X; P = 0.031, phospho-Chk2, P = 0.014) was associated with high macrophage infiltration in UC. Co-culture with macrophages (ANA-1) induced senescence in .80% of primary cells (fibroblasts MRC5, WI38), illustrating that macrophages induce senescence. Interestingly, macrophage-induced senescence was partly dependent on nitric oxide synthase, and clinically relevant NO center dot levels alone induced senescence. NO center dot induced DDR in vitro, as detected by immunofluorescence. In contrast to UC, we noted in Crohn's disease (CD) that senescence (HP1 gamma; P < 0.001) and DDR (gamma H2A.X; P < 0.05, phospho-Chk2; P < 0.001) were higher, and macrophages were not associated with senescence. We hypothesize that nitric oxide may modulate senescence in CD; epithelial cells of CD had higher levels of NOS2 expression than in UC (P = 0.001). Microarrays and quantitative-PCR identified miR-21 expression associated with macrophage infiltration and NOS2 expression. Conclusions: Senescence was observed in IBD with senescence-associated beta-galactosidase and HP1 gamma. Macrophages were associated with senescence and DDR in UC, and in vitro experiments with primary human cells showed that macrophages induce senescence, partly through NO center dot, and that NO center dot can induce DDR associated with senescence. Future experiments will investigate the role of NO center dot and miR-21 in senescence. This is the first study to implicate macrophages and nitrosative stress in a direct effect on senescence and DDR, which is relevant to many diseases of inflammation, cancer, and aging. C1 [Sohn, Jane J.; Schetter, Aaron J.; Horikawa, Izumi; Khan, Mohammed A.; Robles, Ana I.; Hussain, S. Perwez; Goto, Akiteru; Bowman, Elise D.; Harris, Curtis C.] Natl Canc Inst, Ctr Canc Res, Human Carcinogenesis Lab, Bethesda, MD USA. [Yfantis, Harris G.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Yfantis, Harris G.] Univ Maryland, Sch Med, Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Ridnour, Lisa A.; Wink, David A.] Natl Canc Inst, Radiat Biol Branch, Bethesda, MD USA. [Hofseth, Lorne J.] Univ S Carolina, S Carolina Coll Pharm, Dept Pharmaceut & Biomed Sci, Columbia, SC USA. [Bartkova, Jirina; Bartek, Jiri] Canc Soc Res Ctr, Copenhagen, Denmark. [Bartek, Jiri] Palacky Univ, Fac Med & Dent, Inst Mol & Translat Med, Olomouc, Czech Republic. [Wogan, Gerald N.] MIT, Ctr Environm Hlth Sci, Dept Biol Engn, Cambridge, MA USA. RP Sohn, JJ (reprint author), Natl Canc Inst, Ctr Canc Res, Human Carcinogenesis Lab, Bethesda, MD USA. EM Curtis_Harris@nih.gov RI Bartek, Jiri/G-5870-2014 FU National Cancer Institute; Danish Cancer Society; Danish National Research Foundation; European Commission FX This research was supported by the Intramural Research Program of the National Cancer Institute. Dr. Sohn was supported by the Cancer Research Training Award Fellowship from the National Cancer Institute. Dr. Bartkova and Dr. Bartek were supported by the Danish Cancer Society, the Danish National Research Foundation, and the European Commission (projects: Infla-Care, Biomedreg and DDResponse). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 18 Z9 19 U1 1 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 6 PY 2012 VL 7 IS 9 AR e44156 DI 10.1371/journal.pone.0044156 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001KC UT WOS:000308458400040 PM 22970173 ER PT J AU Zhuang, ZP Yang, CZ Lorenzo, F Merino, M Fojo, T Kebebew, E Popovic, V Stratakis, CA Prchal, JT Pacak, K AF Zhuang, Zhengping Yang, Chunzhang Lorenzo, Felipe Merino, Maria Fojo, Tito Kebebew, Electron Popovic, Vera Stratakis, Constantine A. Prchal, Josef T. Pacak, Karel TI Somatic HIF2A Gain-of-Function Mutations in Paraganglioma with Polycythemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPOXIA-INDUCIBLE FACTORS; PHEOCHROMOCYTOMA; HIF-1-ALPHA; CANCER; ERYTHROCYTOSIS; TUMORIGENESIS; HIF-2-ALPHA; INHIBITION; GENE AB Hypoxia-inducible factors are transcription factors controlling energy, iron metabolism, erythropoiesis, and development. When these proteins are dysregulated, they contribute to tumorigenesis and cancer progression. However, mutations in genes encoding a subunits of hypoxia-inducible factors (HIF-alpha) have not previously been identified in any cancer. Here we report two novel somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2 alpha (HIF2A) in two patients, one presenting with paraganglioma and the other with paraganglioma and somatostatinoma, both of whom had polycythemia. The two mutations were associated with increased HIF-2 alpha activity and increased protein half-life. C1 [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Zhuang, Zhengping; Yang, Chunzhang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Surg Neurol Branch, NINDS, NIH, Bethesda, MD 20892 USA. [Merino, Maria] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Fojo, Tito] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kebebew, Electron] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NCI, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Lorenzo, Felipe; Prchal, Josef T.] Univ Utah, Div Hematol, Associated Reg & Univ Pathologists Labs, Sch Med, Salt Lake City, UT USA. [Lorenzo, Felipe; Prchal, Josef T.] Univ Utah, Sch Med, Vet Affairs Med Ctr, Salt Lake City, UT USA. [Prchal, Josef T.] Univ Utah, Sch Med, Eccles Inst Human Genet, Salt Lake City, UT USA. [Popovic, Vera] Univ Belgrade, Fac Med, Belgrade, Serbia. [Popovic, Vera] Clin Ctr Serbia, Dept Neuroendocrinol, Belgrade, Serbia. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Program Reprod & Adult Endocrinol, NIH, Bldg 10,CRC Rm 1E-3140,10 Ctr Dr, MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU National Institute of Neurological Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 25 TC 124 Z9 128 U1 2 U2 17 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 SEP 6 PY 2012 VL 367 IS 10 BP 922 EP 930 DI 10.1056/NEJMoa1205119 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 999VO UT WOS:000308343300009 PM 22931260 ER PT J AU Hu, G Horswell, R Wang, YJ Li, W Besse, J Xiao, K Chen, HL Keller, JN Heymsfield, SB Ryan, DH Katzmarzyk, PT AF Hu, Gang Horswell, Ronald Wang, Yujie Li, Wei Besse, Jay Xiao, Ke Chen, Honglei Keller, Jeffrey N. Heymsfield, Steven B. Ryan, Donna H. Katzmarzyk, Peter T. TI Body Mass Index and the Risk of Dementia among Louisiana Low Income Diabetic Patients SO PLOS ONE LA English DT Article ID AGED FINNISH MEN; TO-HIP RATIO; IGF-I LEVELS; PHYSICAL-ACTIVITY; LATE-LIFE; WAIST CIRCUMFERENCE; ALZHEIMER-DISEASE; CARDIOMETABOLIC RISK; FOLLOW-UP; OBESITY AB Background: The association between obesity and dementia risk remains debatable and no studies have assessed this association among diabetic patients. The aim of our study was to investigate the association between body mass index (BMI) and dementia risk among middle and low income diabetic patients. Methodology/Principal Findings: The sample included 44,660 diabetic patients (19,618 white and 25,042 African American) 30 to 96 years of age without a history of dementia in the Louisiana State University Hospital-Based Longitudinal Study. During a mean follow-up period of 3.9 years, 388 subjects developed incident dementia. The age-and sex-adjusted hazards ratios (HRs) for incident dementia at different levels of BMI (<= 25, 25-26.9, 27-29.9, 30-34.9, and >= 35 kg/m(2)) were 1.00, 0.53 (95% CI 0.34-0.83), 0.29 (0.18-0.45), 0.37 (0.25-0.56), and 0.31 (0.21-0.48) (P-trend<0.001) in white diabetic patients, and 1.00, 1.00 (95% CI 0.62-1.63), 0.62 (0.39-0.98), 0.56 (0.36-0.86), and 0.65 (0.43-1.01) (P-trend = 0.029) in African American diabetic patients. Further adjustment for other confounding factors affected the results only slightly. There was a significant interaction between race and BMI on dementia risk (chi(2) = 5.52, 1df, p<0.025), such that the association was stronger in white patients. In stratified analyses, the multivariate-adjusted inverse association between BMI and risk of dementia was present in subjects aged 55-64 years, 65-74 years, and >= 75 years, in men and women, in non-smokers and smokers, and in subjects with different types of health insurance. Conclusions/Significance: Higher baseline BMI was associated with a lower risk of dementia among diabetic patients, and this association was stronger among white than among African American diabetic patients. C1 [Hu, Gang; Horswell, Ronald; Wang, Yujie; Li, Wei; Keller, Jeffrey N.; Heymsfield, Steven B.; Ryan, Donna H.; Katzmarzyk, Peter T.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Horswell, Ronald; Besse, Jay; Xiao, Ke] Louisiana State Univ, Div Hlth Care Serv, Baton Rouge, LA 70803 USA. [Wang, Yujie] Louisiana State Univ, Sch Human Ecol, Ctr Agr, Baton Rouge, LA 70803 USA. [Xiao, Ke] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, New Orleans, LA USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Hu, G (reprint author), Pennington Biomed Res Ctr, Baton Rouge, LA USA. EM gang.hu@pbrc.edu OI Katzmarzyk, Peter/0000-0002-9280-6022; Chen, Honglei/0000-0003-3446-7779 FU Louisiana State University's Improving Clinical Outcomes Network (LSU ICON); Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences [Z01-ES-101986] FX This work was supported by Louisiana State University's Improving Clinical Outcomes Network (LSU ICON), and Dr. Chen was supported by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES-101986). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 13 Z9 13 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2012 VL 7 IS 9 AR e44537 DI 10.1371/journal.pone.0044537 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001MC UT WOS:000308463800072 PM 22957079 ER PT J AU Veal, CD Freeman, PJ Jacobs, K Lancaster, O Jamain, S Leboyer, M Albanes, D Vaghela, RR Gut, I Chanock, SJ Brookes, AJ AF Veal, Colin D. Freeman, Peter J. Jacobs, Kevin Lancaster, Owen Jamain, Stephane Leboyer, Marion Albanes, Demetrius Vaghela, Reshma R. Gut, Ivo Chanock, Stephen J. Brookes, Anthony J. TI A mechanistic basis for amplification differences between samples and between genome regions SO BMC GENOMICS LA English DT Article DE DNA amplification; DNA denaturation; C plus G; Illumina infinium ID COPY NUMBER VARIATION; PCR AMPLIFICATION; AMPLIFIED DNA; GC CONTENT; PERFORMANCE; ACCURATE; REPEATS; RATIOS; WAVES AB Background: For many analytical methods the efficiency of DNA amplification varies across the genome and between samples. The most affected genome regions tend to correlate with high C + G content, however this relationship is complex and does not explain why the direction and magnitude of effects varies considerably between samples. Results: Here, we provide evidence that sequence elements that are particularly high in C + G content can remain annealed even when aggressive melting conditions are applied. In turn, this behavior creates broader 'Thermodynamically Ultra-Fastened' (TUF) regions characterized by incomplete denaturation of the two DNA strands, so reducing amplification efficiency throughout these domains. Conclusions: This model provides a mechanistic explanation for why some genome regions are particularly difficult to amplify and assay in many procedures, and importantly it also explains inter-sample variability of this behavior. That is, DNA samples of varying quality will carry more or fewer nicks and breaks, and hence their intact TUF regions will have different lengths and so be differentially affected by this amplification suppression mechanism with 'higher' quality DNAs being the most vulnerable. A major practical consequence of this is that inter-region and inter-sample variability can be largely overcome by employing routine fragmentation methods (e. g. sonication or restriction enzyme digestion) prior to sample amplification. C1 [Veal, Colin D.; Freeman, Peter J.; Lancaster, Owen; Vaghela, Reshma R.; Brookes, Anthony J.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Jacobs, Kevin; Albanes, Demetrius; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Jacobs, Kevin] NCI, Core Genotyping Facil, SAIC Frederick Inc, Gaithersburg, MD USA. [Jamain, Stephane; Leboyer, Marion] INSERM, U955, F-94000 Creteil, France. [Jamain, Stephane; Leboyer, Marion] Univ Paris Est, Fac Med, F-94000 Creteil, France. [Jamain, Stephane; Leboyer, Marion] Hop H Mondor A Chenevier, AP HP, Dept Psychiat, F-94000 Creteil, France. [Gut, Ivo] Ctr Nacl Anal Genom, Barcelona 08028, Spain. RP Brookes, AJ (reprint author), Univ Leicester, Dept Genet, Univ Rd, Leicester LE1 7RH, Leics, England. EM ajb97@le.ac.uk RI Albanes, Demetrius/B-9749-2015; OI Jamain, Stephane/0000-0002-4321-4100; Causey-Freeman, Peter/0000-0002-5838-5404; Veal, Colin/0000-0002-9840-2512; Lancaster, Owen/0000-0002-0451-9702 FU Action Medical Research [SP4139, SP4483]; European Union [FP7/2007-2013]; READNA [HEALTH-F4-2008-201418] FX This research was supported by Action Medical Research (grants SP4139 and SP4483) and by the European Union's Seventh Framework Programme (FP7/2007-2013) project READNA (grant agreement HEALTH-F4-2008-201418). We wish to recognize earlier collaborations particularly with Nancy J Cox from the Division of Biological Sciences, University of Chicago and Paul H Dear and Bernard Konfortov of the MRC laboratory of Molecular Biology (University of Cambridge) that contributed to pointing our experiments towards identifying the TUF phenomenon. The authors wish to thank Ed Schwalbe (University of Newcastle) and Nathalie Zahra (University of Leicester) for their technical support. NR 30 TC 15 Z9 15 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD SEP 5 PY 2012 VL 13 AR 455 DI 10.1186/1471-2164-13-455 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 022BA UT WOS:000309928800001 PM 22950736 ER PT J AU Topol, I Collins, J Mironov, V Savitsky, A Nemukhin, A AF Topol, Igor Collins, Jack Mironov, Vladimir Savitsky, Alexander Nemukhin, Alexander TI Modeling absorption of the kindling fluorescent protein with the neutral form of the chromophore SO INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY LA English DT Article DE fluorescent proteins; optical spectra; intermolecular interactions; density functional theory; ZINDO ID MOLECULAR-DYNAMICS; ANEMONIA-SULCATA; GFP CHROMOPHORE; EXCITED-STATE; ASFP595; ENVIRONMENT; CHROMOPROTEIN; FEMTOSECOND; EXCITATIONS; KFP AB Kindling fluorescent protein (KFP) is an important member of the colored proteins family widely used as biomarkers in living cells. We apply quantum chemistry modeling of KFP properties by computing structure and spectra of a large molecular cluster mimicking the chromophore-containing pocket, assuming the protonated (neutral) form of the chromophore in the trans configuration. We provide evidence that this protein conformation accounts for the previously observed but unassigned absorption band at 445 nm. We demonstrate that the structure and charge of the amino acid residues nearest to the chromophore play a role in the shifts in the absorption wave length, thus underlying a strong role of intermolecular interactions when considering properties of the fluorescent proteins. (c) 2012 Wiley Periodicals, Inc. C1 [Topol, Igor; Collins, Jack] NCI, Adv Biomed Comp Ctr, Informat Syst Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. [Mironov, Vladimir; Savitsky, Alexander; Nemukhin, Alexander] Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119991, Russia. [Savitsky, Alexander] Russian Acad Sci, AN Bach Inst Biochem, Moscow 119071, Russia. [Nemukhin, Alexander] Russian Acad Sci, NM Emanuel Inst Biochem Phys, Moscow 119334, Russia. RP Topol, I (reprint author), NCI, Adv Biomed Comp Ctr, Informat Syst Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. EM topoli@mail.nih.gov RI Mironov, Vladimir/I-4712-2012; Savitsky, Alexander/O-9799-2015; Nemukhin, Alexander/P-9662-2015 OI Mironov, Vladimir/0000-0002-9454-5823; FU National Institutes of Health [HHSN261200800001E]; Russian Foundation for Basic Research [10-03-00085]; Russian Academy of Sciences (Program of Molecular and Cell Biology); National Cancer Institute FX Contract grant sponsor: National Cancer Institute and National Institutes of Health (HHSN261200800001E).; Contract grant sponsor: Russian Foundation for Basic Research; contract grant number: 10-03-00085.; Contract grant sponsor: Russian Academy of Sciences (Program of Molecular and Cell Biology). NR 44 TC 6 Z9 6 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7608 J9 INT J QUANTUM CHEM JI Int. J. Quantum Chem. PD SEP 5 PY 2012 VL 112 IS 17 SI SI BP 2947 EP 2951 DI 10.1002/qua.24134 PG 5 WC Chemistry, Physical; Mathematics, Interdisciplinary Applications; Physics, Atomic, Molecular & Chemical SC Chemistry; Mathematics; Physics GA 980TC UT WOS:000306915000012 ER PT J AU Fang, EF Zhang, CZY Zhang, L Wong, JH Chan, YS Pan, WL Dan, XL Yin, CM Cho, CH Ng, TB AF Fang, Evandro Fei Zhang, Chris Zhi Yi Zhang, Lin Wong, Jack Ho Chan, Yau Sang Pan, Wen Liang Dan, Xiu Li Yin, Cui Ming Cho, Chi Hin Ng, Tzi Bun TI Trichosanthin Inhibits Breast Cancer Cell Proliferation in Both Cell Lines and Nude Mice by Promotion of Apoptosis SO PLOS ONE LA English DT Article ID RIBOSOME-INACTIVATING PROTEIN; RICIN-A-CHAIN; ANTITUMOR-ACTIVITY; MOMORDICA-CHARANTIA; HIV DISEASE; IN-VITRO; ANTI-HIV; ABORTIFACIENT; REPLICATION; MECHANISMS AB Breast cancer ranks as a common and severe neoplasia in women with increasing incidence as well as high risk of metastasis and relapse. Translational and laboratory-based clinical investigations of new/novel drugs are in progress. Medicinal plants are rich sources of biologically active natural products for drug development. The 27-kDa trichosanthin (TCS) is a ribosome inactivating protein purified from tubers of the Chinese herbal plant Trichosanthes kirilowii Maximowicz (common name Tian Hua Fen). In this study, we extended the potential medicinal applications of TCS from HIV, ferticide, hydatidiform moles, invasive moles, to breast cancer. We found that TCS manifested anti-proliferative and apoptosis-inducing activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cells. Flow cytometric analysis disclosed that TCS induced cell cycle arrest. Further studies revealed that TCS-induced tumor cell apoptosis was attributed to activation of both caspase-8 and caspase-9 regulated pathways. The subsequent events including caspase-3 activation, and increased PARP cleavage. With regard to cell morphology, stereotypical apoptotic features were observed. Moreover, in comparison with control, TCS-treated nude mice bearing MDA-MB-231 xenograft tumors exhibited significantly reduced tumor volume and tumor weight, due to the potent effect of TCS on tumor cell apoptosis as determined by the increase of caspase-3 activation, PARP cleavage, and DNA fragmentation using immunohistochemistry. Considering the clinical efficacy and relative safety of TCS on other human diseases, this work opens up new therapeutic avenues for patients with estrogen-dependent and/or estrogen-independent breast cancers. C1 [Fang, Evandro Fei; Zhang, Lin; Wong, Jack Ho; Chan, Yau Sang; Pan, Wen Liang; Dan, Xiu Li; Yin, Cui Ming; Cho, Chi Hin; Ng, Tzi Bun] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Zhang, Chris Zhi Yi] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol So China, Guangzhou 510275, Guangdong, Peoples R China. [Zhang, Chris Zhi Yi] Sun Yat Sen Univ, Ctr Canc, Dept Pathol, Guangzhou 510275, Guangdong, Peoples R China. RP Fang, EF (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM fangfei1030@yahoo.com.cn; b021770@mailserv.cuhk.edu.hk RI ZHANG , Lin/O-9109-2015; Cho, Chi Hin/C-6543-2014 OI Cho, Chi Hin/0000-0002-7658-3260 NR 52 TC 25 Z9 29 U1 2 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2012 VL 7 IS 9 AR e41592 DI 10.1371/journal.pone.0041592 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001MC UT WOS:000308463800009 PM 22957017 ER PT J AU Ridnour, LA Barasch, KM Windhausen, AN Dorsey, TH Lizardo, MM Yfantis, HG Lee, DH Switzer, CH Cheng, RYS Heinecke, JL Brueggemann, E Hines, HB Khanna, C Glynn, SA Ambs, S Wink, DA AF Ridnour, Lisa A. Barasch, Kimberly M. Windhausen, Alisha N. Dorsey, Tiffany H. Lizardo, Michael M. Yfantis, Harris G. Lee, Dong H. Switzer, Christopher H. Cheng, Robert Y. S. Heinecke, Julie L. Brueggemann, Ernst Hines, Harry B. Khanna, Chand Glynn, Sharon A. Ambs, Stefan Wink, David A. TI Nitric Oxide Synthase and Breast Cancer: Role of TIMP-1 in NO-mediated Akt Activation SO PLOS ONE LA English DT Article ID ERYTHROID CELL-SURVIVAL; TISSUE INHIBITOR; TUMOR PROGRESSION; EPITHELIAL-CELLS; POOR SURVIVAL; S-NITROSATION; EXPRESSION; METALLOPROTEINASE-1; APOPTOSIS; PREDICTS AB Prediction of therapeutic response and cancer patient survival can be improved by the identification of molecular markers including tumor Akt status. A direct correlation between NOS2 expression and elevated Akt phosphorylation status has been observed in breast tumors. Tissue inhibitor matrix metalloproteinase-1 (TIMP-1) has been proposed to exert oncogenic properties through CD63 cell surface receptor pathway initiation of pro-survival PI3k/Akt signaling. We employed immunohistochemistry to examine the influence of TIMP-1 on the functional relationship between NOS2 and phosphorylated Akt in breast tumors and found that NOS2-associated Akt phosphorylation was significantly increased in tumors expressing high TIMP-1, indicating that TIMP-1 may further enhance NO-induced Akt pathway activation. Moreover, TIMP-1 silencing by antisense technology blocked NO-induced PI3k/Akt/BAD phosphorylation in cultured MDA-MB-231 human breast cancer cells. TIMP-1 protein nitration and TIMP-1/CD63 co-immunoprecipitation was observed at NO concentrations that induced PI3k/Akt/BAD pro-survival signaling. In the survival analysis, elevated tumor TIMP-1 predicted poor patient survival. This association appears to be mainly restricted to tumors with high NOS2 protein. In contrast, TIMP-1 did not predict poor survival in patient tumors with low NOS2 expression. In summary, our findings suggest that tumors with high TIMP-1 and NOS2 behave more aggressively by mechanisms that favor Akt pathway activation. C1 [Ridnour, Lisa A.; Barasch, Kimberly M.; Windhausen, Alisha N.; Switzer, Christopher H.; Cheng, Robert Y. S.; Heinecke, Julie L.; Glynn, Sharon A.; Wink, David A.] NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. [Dorsey, Tiffany H.; Glynn, Sharon A.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Lizardo, Michael M.; Khanna, Chand] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Yfantis, Harris G.; Lee, Dong H.] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Brueggemann, Ernst; Hines, Harry B.] USAMRIID, Ft Detrick, MD USA. RP Ridnour, LA (reprint author), NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. EM ridnourl@mail.nih.gov; wink@mail.nih.gov RI Glynn, Sharon/D-7136-2013; Switzer, Christopher/D-9203-2013; OI Glynn, Sharon/0000-0003-1459-2580; Cheng, Robert/0000-0003-0287-6439 FU United States National Institutes of Health, National Cancer Institute; Center for Cancer Research FX The Intramural Research Program of the United States National Institutes of Health, National Cancer Institute, and Center for Cancer Research supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 19 Z9 19 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 5 PY 2012 VL 7 IS 9 AR e44081 DI 10.1371/journal.pone.0044081 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 001MC UT WOS:000308463800037 PM 22957045 ER PT J AU Wu, ZH Xing, JH AF Wu, Zhanghan Xing, Jianhua TI Functional Roles of Slow Enzyme Conformational Changes in Network Dynamics SO BIOPHYSICAL JOURNAL LA English DT Article ID LEAF NITRATE REDUCTASE; SINGLE-MOLECULE; POSITIVE FEEDBACK; ESCHERICHIA-COLI; PROTEIN DYNAMICS; INTRACELLULAR PH; NOISE; CATALYSIS; BEHAVIOR; BINDING AB Extensive studies from different fields reveal that many macromolecules, especially enzymes, show slow transitions among different conformations. This phenomenon is named such things as dynamic disorder, heterogeneity, hysteretic or mnemonic enzymes across these different fields, and has been directly demonstrated by single molecule enzymology and NMR studies recently. We analyzed enzyme slow conformational changes in the context of regulatory networks. A single enzymatic reaction with slow conformational changes can filter upstream network noises, and can either resonantly respond to the system stimulus at certain frequencies or respond adaptively for sustained input signals of the network fluctuations. It thus can serve as a basic functional motif with properties that are normally for larger intermolecular networks in the field of systems biology. We further analyzed examples including enzymes functioning against pH fluctuations, metabolic state change of Artemia embryos, and kinetic insulation of fluctuations in metabolic networks. The study also suggests that hysteretic enzymes may be building blocks of synthetic networks with various properties such as narrow-banded filtering. The work fills the missing gap between studies on enzyme biophysics and network level dynamics, and reveals that the coupling between the two is functionally important; it also suggests that the conformational dynamics of some enzymes may be evolutionally selected. C1 [Wu, Zhanghan; Xing, Jianhua] Virginia Tech, Dept Biol Sci, Blacksburg, VA 24061 USA. [Wu, Zhanghan] NHLBI, NIH, Bethesda, MD 20892 USA. RP Xing, JH (reprint author), Virginia Tech, Dept Biol Sci, Blacksburg, VA 24061 USA. EM jxing@vt.edu RI Xing, Jianhua/A-8101-2012 OI Xing, Jianhua/0000-0002-3700-8765 FU National Science Foundation grant [EF-1038636] FX This work is supported by National Science Foundation grant No. EF-1038636. NR 50 TC 7 Z9 7 U1 1 U2 16 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 SEP 5 PY 2012 VL 103 IS 5 BP 1052 EP 1059 DI 10.1016/j.bpj.2012.08.008 PG 8 WC Biophysics SC Biophysics GA 002DC UT WOS:000308510200023 PM 23009855 ER PT J AU Gu, ZL Lamb, PW Yakel, JL AF Gu, Zhenglin Lamb, Patricia W. Yakel, Jerrel L. TI Cholinergic Coordination of Presynaptic and Postsynaptic Activity Induces Timing-Dependent Hippocampal Synaptic Plasticity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; CENTRAL-NERVOUS-SYSTEM; HEBBIAN PLASTICITY; CALCIUM INDICATORS; RAT HIPPOCAMPUS; NEURAL ACTIVITY; BARREL CORTEX; MEMORY; NEURONS; SYNAPSES AB Correlated presynaptic and postsynaptic activity is the key factor in inducing Hebbian plasticity and memory. However, little is known about the physiological events that could mediate such coordination. Correlated cholinergic input induces spike timing-dependent plasticity-like hippocampal synaptic plasticity. Cholinergic receptors are localized to both presynaptic and postsynaptic glutamatergic sites and thus have the potential to coordinate presynaptic and postsynaptic activity to induce plasticity. By directly monitoring presynaptic and postsynaptic activities with genetically encoded calcium indicators in mouse septohippocampal cocultures, we found interactive but independent presynaptic and postsynaptic modulations in the cholinergic-dependent synaptic plasticity. Neither presynaptic nor postsynaptic modulation alone is sufficient, but instead a coordinated modulation at both sites is required to induce the plasticity. Therefore, we propose that correlated cholinergic input can coordinate presynaptic and postsynaptic activities to induce timing-dependent synaptic plasticity, providing a novel mechanism by which neuromodulators precisely modulate network activity and plasticity with high efficiency and temporal precision. C1 [Gu, Zhenglin; Lamb, Patricia W.; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), POB 12233,Mail Drop F2-08, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We thank Drs. Charles Romeo, Negin Martin, and Bernd Gloss for virus packaging; Charles J. Tucker and Agnus Janoshazi for assistance with fluorescent microscopy; and Drs. Serena Dudek and Christian Erxleben for comments on the manuscript. We also thank Dr. Karl Deisseroth at Stanford University for ChR2 and synapsin promoter-driven AAV vectors, Dr. Loren Looger at Janelia Farm Research Campus for GCaMP3, Dr. Robert Campbell at University of Alberta for R-GECO1, and Dr. James Wilson at University of Pennsylvania for AAV serotype 9 helper plasmid. NR 51 TC 32 Z9 34 U1 1 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 5 PY 2012 VL 32 IS 36 BP 12337 EP 12348 DI 10.1523/JNEUROSCI.2129-12.2012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 004JG UT WOS:000308677300004 PM 22956824 ER PT J AU Zapata, A Pontis, S Schepers, RJ Wang, RZ Oh, E Stein, A Backman, CM Worley, P Enguita, M Abad, MA Trullas, R Shippenberg, TS AF Zapata, Agustin Pontis, Silvia Schepers, Raf J. Wang, Ruizhong Oh, Eric Stein, Alexandra Baeckman, Cristina M. Worley, Paul Enguita, Marta Alba Abad, M. Trullas, Ramon Shippenberg, Toni S. TI Alleviation of Neuropathic Pain Hypersensitivity by Inhibiting Neuronal Pentraxin 1 in the Rostral Ventromedial Medulla SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HYPOXIC-ISCHEMIC INJURY; SPARED NERVE INJURY; DESCENDING FACILITATION; EXCITATORY SYNAPSES; PERSISTENT PAIN; NEONATAL BRAIN; NP1; HYPERALGESIA; PLASTICITY; ALLODYNIA AB Peripheral nerve injury causes spontaneous and long-lasting pain, hyperalgesia, and allodynia. Excitatory amino acid receptor-dependent increases in descending facilitatory drive from the brainstem rostral ventromedial medulla (RVM) contribute to injury-evoked hypersensitivity. Although increased excitability likely reflects changes in synaptic efficacy, the cellular mechanisms underlying injury-induced synaptic plasticity are poorly understood. Neuronal pentraxin 1 (NP1), a protein with exclusive CNS expression, is implicated in synaptogenesis and AMPA receptor recruitment to immature synapses. Its role in the adult brain and in descending pain facilitation is unknown. Here, we use the spared nerve injury (SNI) model in rodents to examine this issue. We show that SNI increases RVMNP1 expression and constitutive deletion or silencing NP1 in the RVM, before or after SNI, attenuates allodynia and hyperalgesia in rats. Selective rescue of RVM NP1 expression restores behavioral hypersensitivity of knock-out mice, demonstrating a key role of RVM NP1 in the pathogenesis of neuropathic pain. C1 [Zapata, Agustin] NIDA, Integrat Neurosci Branch, IRP, NIH, Baltimore, MD 21224 USA. [Baeckman, Cristina M.] NIDA, Cellular Neurobiol Branch, NIH, Baltimore, MD 21224 USA. [Worley, Paul] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Enguita, Marta; Alba Abad, M.; Trullas, Ramon] Inst Invest Biomed Barcelona CSIC IDIBAPS, Neurobiol Unit, Barcelona 08036, Spain. [Enguita, Marta; Alba Abad, M.; Trullas, Ramon] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona 08036, Spain. RP Zapata, A (reprint author), NIDA, Integrat Neurosci Branch, IRP, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM Azapata@mail.nih.gov RI backman, cristina/C-1276-2013; Trullas, Ramon/D-2197-2016 OI Trullas, Ramon/0000-0001-7951-9881 FU NIDA Intramural Research Program; Ministerio de Economia y Competitividad of Spain [SAF2008-03514, SAF2011-23550]; [NS39156] FX These studies were supported by the NIDA Intramural Research Program and by Grants SAF2008-03514 and SAF2011-23550 from Ministerio de Economia y Competitividad of Spain (to R. T.) and Grant NS39156 (to P.W.). NR 31 TC 1 Z9 2 U1 1 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 SEP 5 PY 2012 VL 32 IS 36 BP 12431 EP 12436 DI 10.1523/JNEUROSCI.2730-12.2012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 004JG UT WOS:000308677300014 PM 22956834 ER PT J AU Singer, R Mawson, P Derby, N Rodriguez, A Kizima, L Menon, R Goldman, D Kenney, J Aravantinou, M Seidor, S Gettie, A Blanchard, J Piatak, M Lifson, JD Fernandez-Romero, JA Robbiani, M Zydowsky, TM AF Singer, Rachel Mawson, Paul Derby, Nina Rodriguez, Aixa Kizima, Larisa Menon, Radhika Goldman, Daniel Kenney, Jessica Aravantinou, Meropi Seidor, Samantha Gettie, Agegnehu Blanchard, James Piatak, Michael, Jr. Lifson, Jeffrey D. Fernandez-Romero, Jose A. Robbiani, Melissa Zydowsky, Thomas M. TI An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; IN-VITRO RELEASE; VAGINAL RINGS; RHESUS MACAQUES; HIV PREVENTION; MICROBICIDE; DELIVERY; DAPIVIRINE; TENOFOVIR; EFFICACY AB Microbicides may prevent HIV and sexually transmitted infections (STIs) in women; however, determining the optimal means of delivery of active pharmaceutical ingredients remains a major challenge. We previously demonstrated that a vaginal gel containing the non-nucleoside reverse transcriptase inhibitor MIV-150 partially protected macaques from SHIV-RT (simian/HIV reverse transcriptase) infection, and the addition of zinc acetate rendered the gel significantly protective. We test the activity of MIV-150 without the addition of zinc acetate when delivered from either ethylene vinyl acetate (EVA) or silicone intravaginal rings (IVRs). MIV-150 was successfully delivered, because it was detected in vaginal fluids and tissues by radioimmunoassay in pharmacokinetic studies. Moreover, EVA IVRs significantly protected macaques from SHIV-RT infection. Our results demonstrate that MIV-150-containing IVRs have the potential to prevent HIV infection and highlight the possible use of IVRs for delivering drugs that block HIV and other STIs. C1 [Singer, Rachel; Mawson, Paul; Derby, Nina; Rodriguez, Aixa; Kizima, Larisa; Menon, Radhika; Goldman, Daniel; Kenney, Jessica; Aravantinou, Meropi; Seidor, Samantha; Fernandez-Romero, Jose A.; Robbiani, Melissa; Zydowsky, Thomas M.] Populat Council, Ctr Biomed Res, New York, NY 10065 USA. [Gettie, Agegnehu] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10065 USA. [Blanchard, James] Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD 21702 USA. RP Robbiani, M (reprint author), Populat Council, Ctr Biomed Res, New York, NY 10065 USA. EM mrobbiani@popcouncil.org; tzydowsky@popcouncil.org FU United States Agency for International Development (USAID) [GPO-A-00-04-00019-00]; Swedish Ministry of Foreign Affairs; Swedish International Development Cooperation Agency; NIH [RR00164]; National Cancer Institute, NIH [HHSN261200800001E] FX Supported by the United States Agency for International Development (USAID) Cooperative Agreement GPO-A-00-04-00019-00, the Swedish Ministry of Foreign Affairs, the Swedish International Development Cooperation Agency, the NIH base grant RR00164, and with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. The contents of this manuscript are the sole responsibility of the Population Council and do not necessarily reflect the views or policies of USAID or the U. S. government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the material in this article has been published or is under consideration elsewhere, including the Internet. M. R. is a 2002 Elizabeth Glaser Scientist. NR 46 TC 27 Z9 27 U1 0 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 5 PY 2012 VL 4 IS 150 DI 10.1126/scitranslmed.3003936 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 004JE UT WOS:000308677100009 ER PT J AU Kaess, BM Rong, J Larson, MG Hamburg, NM Vita, JA Levy, D Benjamin, EJ Vasan, RS Mitchell, GF AF Kaess, Bernhard M. Rong, Jian Larson, Martin G. Hamburg, Naomi M. Vita, Joseph A. Levy, Daniel Benjamin, Emelia J. Vasan, Ramachandran S. Mitchell, Gary F. TI Aortic Stiffness, Blood Pressure Progression, and Incident Hypertension SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PULSE-WAVE VELOCITY; FLOW-MEDIATED DILATION; CORONARY-HEART-DISEASE; ARTERIAL STIFFNESS; CARDIOVASCULAR EVENTS; RISK-FACTORS; INDEPENDENT PREDICTOR; OLDER-ADULTS; COMMUNITY; INCREASE AB Context Vascular stiffness increases with advancing age and is a major risk factor for age-related morbidity and mortality. Vascular stiffness and blood pressure pulsatility are related; however, temporal relationships between vascular stiffening and blood pressure elevation have not been fully delineated. Objective To examine temporal relationships among vascular stiffness, central hemodynamics, microvascular function, and blood pressure progression. Design, Setting, and Participants Longitudinal community-based cohort study conducted in Framingham, Massachusetts. The present investigation is based on the 2 latest examination cycles (cycle 7: 1998-2001; cycle 8: 2005-2008 [last visit: January 25, 2008]) of the Framingham Offspring study (recruited: 1971-1975). Temporal relationships among blood pressure and 3 measures of vascular stiffness and pressure pulsatility derived from arterial tonometry (carotid-femoral pulse wave velocity [CFPWV], forward wave amplitude [FWA], and augmentation index) were examined over a 7-year period in 1759 participants (mean [SD] age: 60 [9] years; 974 women). Main Outcome Measures The primary outcomes were blood pressure and incident hypertension during examination cycle 8. The secondary outcomes were CFPWV, FWA, and augmentation index during examination cycle 8. Results In a multivariable-adjusted regression model, higher FWA (beta, 1.3 [95% CI, 0.5-2.1] mm Hg per 1 SD; P = .002) and higher CFPWV (beta, 1.5 [95% CI, 0.5-2.6] mm Hg per 1 SD; P = .006) during examination cycle 7 were jointly associated with systolic blood pressure during examination cycle 8. Similarly, in a model that included systolic and diastolic blood pressure and additional risk factors during examination cycle 7, higher FWA (odds ratio [OR], 1.6 [95% CI, 1.3-2.0] per 1 SD; P < .001), augmentation index (OR, 1.7 [95% CI, 1.4-2.0] per 1 SD; P < .001), and CFPWV (OR, 1.3 [95% CI, 1.0-1.6] per 1 SD; P = .04) were associated with incident hypertension during examination cycle 8 (338 cases [32%] in 1048 participants without hypertension during examination cycle 7). Conversely, blood pressure during examination cycle 7 was not associated with CFPWV during examination cycle 8. Higher resting brachial artery flow (OR, 1.23 [95% CI, 1.04-1.46]) and lower flow-mediated dilation (OR, 0.80 [95% CI, 0.67-0.96]) during examination cycle 7 were associated with incident hypertension (in models that included blood pressure and tonometry measures collected during examination cycle 7). Conclusion In this cohort, higher aortic stiffness, FWA, and augmentation index were associated with higher risk of incident hypertension; however, initial blood pressure was not independently associated with risk of progressive aortic stiffening. JAMA. 2012;308(9):875-881 C1 [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA 02062 USA. [Kaess, Bernhard M.; Rong, Jian; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kaess, Bernhard M.] Univ Hosp Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Prevent Med & Epidemiol Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Cardiol Sect, Boston, MA 02215 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Hamburg, Naomi M.; Vita, Joseph A.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Bethesda, MD 20892 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 1 Edgewater Dr,Ste 201A, Norwood, MA 02062 USA. EM garyfmitchell@mindspring.com OI Hamburg, Naomi/0000-0001-5504-5589; Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health, National Heart, Lung, and Blood Institute [NO1-HC25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385]; Donald W. Reynolds Foundation FX This work was supported through contracts NO1-HC25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, and HL107385 with the National Institutes of Health, National Heart, Lung, and Blood Institute, and a grant from the Donald W. Reynolds Foundation. NR 26 TC 259 Z9 262 U1 0 U2 31 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 SEP 5 PY 2012 VL 308 IS 9 BP 875 EP 881 DI 10.1001/2012.jama.10503 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 999ET UT WOS:000308292900017 PM 22948697 ER PT J AU Schelbert, EB Cao, JJ Sigurdsson, S Aspelund, T Kellman, P Aletras, AH Dyke, CK Thorgeirsson, G Eiriksdottir, G Launer, LJ Gudnason, V Harris, TB Arai, AE AF Schelbert, Erik B. Cao, Jie J. Sigurdsson, Sigurdur Aspelund, Thor Kellman, Peter Aletras, Anthony H. Dyke, Christopher K. Thorgeirsson, Gudmundur Eiriksdottir, Gudny Launer, Lenore J. Gudnason, Vilmundur Harris, Tamara B. Arai, Andrew E. TI Prevalence and Prognosis of Unrecognized Myocardial Infarction Determined by Cardiac Magnetic Resonance in Older Adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID Q-WAVE; CONTRAST; ENHANCEMENT; TOMOGRAPHY; MORTALITY; REYKJAVIK; SYMPTOMS; INJURY; MRI; AGE AB Context Unrecognized myocardial infarction (MI) is prognostically important. Electrocardiography (ECG) has limited sensitivity for detecting unrecognized MI (UMI). Objective Determine prevalence and mortality risk for UMI detected by cardiac magnetic resonance (CMR) imaging or ECG among older individuals. Design, Setting, and Participants ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling cohort of older individuals in Iceland, data for 936 participants aged 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes. Main Outcome Measures Prevalence and mortality of MI through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI). Results Of 936 participants, 91 had recognized MI (RMI) (9.7%; 95% CI, 8% to 12%), and 157 had UMI detected by CMR (17%; 95% CI, 14% to 19%), which was more prevalent than the 46 UMI detected by ECG (5%; 95% CI, 4% to 6%; P < .001). Participants with diabetes (n = 337) had more UMI detected by CMR than by ECG (n = 72; 21%; 95% CI, 17% to 26%, vs n = 15; 4%; 95% CI, 2% to 7%; P < .001). Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 30 of 91 participants (33%; 95% CI, 23% to 43%) with RMI died, and 44 of 157 participants (28%; 95% CI, 21% to 35%) with UMI died, both higher rates than the 119 of 688 participants (17%; 95% CI, 15% to 20%) with no MI who died. Unrecognized MI by CMR improved risk stratification for mortality over RMI (NRI, 0.34; 95% CI, 0.16 to 0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (hazard ratio [HR], 1.45; 95% CI, 1.02 to 2.06, absolute risk increase [ARI], 8%) and significantly improved risk stratification for mortality (NRI, 0.16; 95% CI, 0.01 to 0.31), but UMI by ECG did not (HR, 0.88; 95% CI, 0.45 to 1.73; ARI, -2%; NRI, -0.05; 95% CI, -0.17 to 0.05). Compared with those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; 95% CI, 28% to 43%, or 56/157, vs 73%; 95% CI, 63% to 82%, or 66/91; P < .001). Conclusions In a community-based cohort of older individuals, the prevalence of UMI by CMR was higher than the prevalence of RMI and was associated with increased mortality risk. In contrast, UMI by ECG prevalence was lower than that of RMI and was not associated with increased mortality risk. C1 [Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Launer, Lenore J.; Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Sigurdsson, Sigurdur; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Thorgeirsson, Gudmundur; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Schelbert, Erik B.] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA USA. [Cao, Jie J.] SUNY Stony Brook, St Francis Hosp, Roslyn, NY USA. [Dyke, Christopher K.] Alaska Heart Inst, Anchorage, AK USA. RP Arai, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, 10 Ctr Dr,Bldg 10,Room B1D416,MSC 1061, Bethesda, MD 20892 USA. EM araia@nih.gov RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015; OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Schelbert, Erik/0000-0003-0356-4437; Aletras, Anthony/0000-0002-3786-3817 FU National Heart, Lung, and Blood Institute [Z01 HL004607-08 CE]; National Institute on Aging [N01-AG-12100]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Medstar Research Institute [2003-145]; T. Franklin Williams Scholarship Award; Atlantic Philanthropies; John A. Hartford Foundation; Association of Specialty Professors; American Heart Association [10GRNT4580000] FX This study was funded by the National Heart, Lung, and Blood Institute Intramural Research Program (Z01 HL004607-08 CE), the National Institute on Aging Intramural Research Program (N01-AG-12100), Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study was approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Medstar Research Institute (project 2003-145). Dr Schelbert is supported by a T. Franklin Williams Scholarship Award, funding for which is provided by Atlantic Philanthropies, the John A. Hartford Foundation, the Association of Specialty Professors, and the American Heart Association. Dr Cao is supported by an American Heart Association Grant-in-Aid (10GRNT4580000). NR 29 TC 91 Z9 96 U1 0 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 SEP 5 PY 2012 VL 308 IS 9 BP 890 EP 897 DI 10.1001/2012.jama.11089 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 999ET UT WOS:000308292900019 PM 22948699 ER PT J AU Shakes, LA Du, HS Wolf, HM Hatcher, C Norford, DC Precht, P Sen, R Chatterjee, PK AF Shakes, Leighcraft A. Du, Hansen Wolf, Hope M. Hatcher, Charles Norford, Derek C. Precht, Patricia Sen, Ranjan Chatterjee, Pradeep K. TI Using BAC transgenesis in zebrafish to identify regulatory sequences of the amyloid precursor protein gene in humans SO BMC GENOMICS LA English DT Article ID ALZHEIMERS-DISEASE; ENHANCER DETECTION; PROMOTER ACTIVITY; NESTED DELETIONS; IDENTIFICATION; EXPRESSION; APP; CONSERVATION; TRANSPOSONS; MUTATIONS AB Background: Non-coding DNA in and around the human Amyloid Precursor Protein (APP) gene that is central to Alzheimer's disease (AD) shares little sequence similarity with that of appb in zebrafish. Identifying DNA domains regulating expression of the gene in such situations becomes a challenge. Taking advantage of the zebrafish system that allows rapid functional analyses of gene regulatory sequences, we previously showed that two discontinuous DNA domains in zebrafish appb are important for expression of the gene in neurons: an enhancer in intron 1 and sequences 28-31 kb upstream of the gene. Here we identify the putative transcription factor binding sites responsible for this distal cis-acting regulation, and use that information to identify a regulatory region of the human APP gene. Results: Functional analyses of intron 1 enhancer mutations in enhancer-trap BACs expressed as transgenes in zebrafish identified putative binding sites of two known transcription factor proteins, E4BP4/NFIL3 and Forkhead, to be required for expression of appb. A cluster of three E4BP4 sites at -31 kb is also shown to be essential for neuron-specific expression, suggesting that the dependence of expression on upstream sequences is mediated by these E4BP4 sites. E4BP4/NFIL3 and XFD1 sites in the intron enhancer and E4BP4/NFIL3 sites at -31 kb specifically and efficiently bind the corresponding zebrafish proteins in vitro. These sites are statistically over-represented in both the zebrafish appb and the human APP genes, although their locations are different. Remarkably, a cluster of four E4BP4 sites in intron 4 of human APP exists in actively transcribing chromatin in a human neuroblastoma cell-line, SHSY5Y, expressing APP as shown using chromatin immunoprecipitation (ChIP) experiments. Thus although the two genes share little sequence conservation, they appear to share the same regulatory logic and are regulated by a similar set of transcription factors. Conclusion: The results suggest that the clock-regulated and immune system modulator transcription factor E4BP4/NFIL3 likely regulates the expression of both appb in zebrafish and APP in humans. It suggests potential human APP gene regulatory pathways, not on the basis of comparing DNA primary sequences with zebrafish appb but on the model of conservation of transcription factors. C1 [Shakes, Leighcraft A.; Wolf, Hope M.; Hatcher, Charles; Norford, Derek C.; Chatterjee, Pradeep K.] N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, Durham, NC 27707 USA. [Shakes, Leighcraft A.; Wolf, Hope M.; Hatcher, Charles; Norford, Derek C.; Chatterjee, Pradeep K.] N Carolina Cent Univ, Dept Chem, Durham, NC 27707 USA. [Du, Hansen; Precht, Patricia; Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Chatterjee, PK (reprint author), N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, 1801 Fayetteville St, Durham, NC 27707 USA. EM pchatterjee@nccu.edu OI Wolf, Hope/0000-0003-0888-5272 FU National Center on Minority Health and Health Disparities [P20MD000175]; North Carolina Biotechnology Center FX The project described was supported by Award Number P20MD000175 from the National Center on Minority Health and Health Disparities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center on Minority Health and Health Disparities or the National Institutes of Health, and funds from the North Carolina Biotechnology Center. We thank Ms. Cicely Williams, Rosalind Grays, Connie Keys, Crystal McMichael, Camilla Felton and Darlene Laws for support and encouragement. PKC would like to thank Drs. Ken Harewood and Sean Kimbro for encouragement and funding support. NR 43 TC 6 Z9 6 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD SEP 4 PY 2012 VL 13 AR 451 DI 10.1186/1471-2164-13-451 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 085WB UT WOS:000314643900001 PM 22947103 ER PT J AU Jordan, JJ Menendez, D Sharav, J Beno, I Rosenthal, K Resnick, MA Haran, TE AF Jordan, Jennifer J. Menendez, Daniel Sharav, Jenia Beno, Itai Rosenthal, Karin Resnick, Michael A. Haran, Tali E. TI Low-level p53 expression changes transactivation rules and reveals superactivating sequences SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE basal level transcription; DNA twist flexibility; DNA dissociation kinetics ID DNA-BINDING SPECIFICITY; TUMOR-SUPPRESSOR P53; IARC TP53 DATABASE; COOPERATIVE BINDING; MUTATION ANALYSIS; TARGET GENES; RECOGNITION; PROMOTER; MECHANISM; TETRAMER AB Transcriptional activation by the tumor suppressor p53 is considered to depend on cellular level, although there are few systems where this dependence on cellular level of p53 has been directly addressed. Previously, we reported that transactivation from p53 targets was sensitive to both p53 amount and DNA sequence, with some sequences being responsive to much lower p53 levels than others when examined in yeast model systems or human cells. Because p53 is normally present at low levels and perturbations might lead to small increases, we examined transactivation under limiting p53. Unlike the positive relationship between transactivation and binding affinity from target sequences at high cellular levels of human p53 in yeast, no such relationship was found at low levels. However, transactivation in the yeast system and the torsional flexibility of target sequences were highly correlated, revealing a unique structural relationship between transcriptional function and sequence. Surprisingly, a few sequences supported high transactivation at low p53 levels in yeast or when transfected into human cells. On the basis of kinetic and flexibility analyses the "supertransactivation" property was due to low binding off rates of flexible target sites. Interestingly, a supertransactivation response element can differentiate transcriptional capacities of many breast cancer-associated p53 mutants. Overall, these studies, which are relevant to other transcription factors, address the extent to which transactivation properties of p53 target sequences are determined by their intrinsic physical properties and reveal unique rules of engagement of target sequences at low p53 levels. C1 [Jordan, Jennifer J.; Menendez, Daniel; Resnick, Michael A.] NIEHS, Chromosome Stabil Sect, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Sharav, Jenia; Beno, Itai; Rosenthal, Karin; Haran, Tali E.] Technion Israel Inst Technol, Dept Biol, IL-32000 Technion, Haifa, Israel. RP Resnick, MA (reprint author), NIEHS, Chromosome Stabil Sect, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM Resnick@niehs.nih.gov; bitali@tx.technion.ac.il OI Haran, Tali E./0000-0002-9700-3392 FU Department of Defense Breast Cancer Research Program Predoctoral Trainee Award [BC051212]; National Institute on Environmental Health Sciences intramural research funds [Z01-ES065079]; Israel Science Foundation [104405]; Israel Cancer Association [20112012]; Israel Cancer Research Fund [800005] FX We thank Zippi Shakked for purified WT p53DBD protein and for helpful discussions, Alberto Inga during development of the yeast system and Con-A discussions, and Carl Anderson, Leping Li, and Michael Fried for comments on the manuscript. Support for this work was provided by Department of Defense Breast Cancer Research Program Predoctoral Trainee Award BC051212 (to J.J.J.); by National Institute on Environmental Health Sciences intramural research funds, Project Z01-ES065079 (to M.A.R., D.M., and J.J.J.); and by Israel Science Foundation Grant 104405, Israel Cancer Association Grant 20112012, and Israel Cancer Research Fund Grant 800005 (to T.E. H., J.S., K.R., and I.B.). NR 37 TC 13 Z9 13 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 4 PY 2012 VL 109 IS 36 BP 14387 EP 14392 DI 10.1073/pnas.1205971109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007TZ UT WOS:000308912600027 PM 22908277 ER PT J AU Shen, XY Li, CC Aponte, AM Shen, RF Billings, EM Moss, J Vaughan, M AF Shen, Xiaoyan Li, Chun-Chun Aponte, Angel M. Shen, Rong-Fong Billings, Eric M. Moss, Joel Vaughan, Martha TI Brefeldin A-inhibited ADP-ribosylation factor activator BIG2 regulates cell migration via integrin beta 1 cycling and actin remodeling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NUCLEOTIDE-EXCHANGE PROTEIN; TRANS-GOLGI NETWORK; ARP2/3 COMPLEX; RECYCLING ENDOSOMES; ENDOCYTIC TRANSPORT; MEMBRANE; ARF6; TRAFFICKING; DYNAMICS; ADHESION AB Brefeldin A-inhibited guanine nucleotide-exchange protein (BIG)2 activates ADP-ribosylation factors, similar to 20-kDa GTPase proteins critical for continuity of intracellular vesicular trafficking by accelerating the replacement of ADP-ribosylation factor-bound GDP with GTP. Mechanisms of additional BIG2 function(s) are less clear. Here, the participation of BIG2 in integrin beta 1 cycling through actin dynamics during cell migration was identified using small interfering RNA (siRNA) and difference gel electrophoresis analyses. After a 72-h incubation with BIG2 siRNA, levels of cytosolic Arp2, Arp3, cofilin-1, phosphocofilin, vinculin, and Grb2, known to be involved in the effects of integrin beta 1-extracellular matrix interactions on actin function and cell translocation, were increased. Treatment of HeLa cells with BIG2 siRNA resulted in perinuclear accumulation of integrin beta 1 and its delayed return to the cell surface. Motility of BIG2-depleted cells was simultaneously decreased, as were actin-based membrane protrusions and accumulations of Arp2, Arp3, cofilin, and phosphocofilin at the leading edges of migrating cells, in wound-healing assays. Taken together, these data reveal a mechanism(s) through which BIG2 may coordinate actin cytoskeleton mechanics and membrane traffic in cell migration via integrin beta 1 action and actin functions. C1 [Shen, Xiaoyan; Li, Chun-Chun; Moss, Joel; Vaughan, Martha] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Aponte, Angel M.; Shen, Rong-Fong] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Billings, Eric M.] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Vaughan, M (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. EM vaughanm@nhlbi.nih.gov FU NIH NHLBI FX We thank Daniela Malide and Christian Combs [Light Microscopy Core Facility, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)] and Mark A. Knepper (Systems Biology Center, NHLBI, NIH) for their invaluable help. This research was supported by the Intramural Research Program of the NIH NHLBI. NR 51 TC 8 Z9 8 U1 0 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 4 PY 2012 VL 109 IS 36 BP 14464 EP 14469 DI 10.1073/pnas.1211877109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007TZ UT WOS:000308912600040 PM 22908276 ER PT J AU Cheng, KT Alevizos, I Liu, XB Swaim, WD Yin, HG Feske, S Oh-hora, M Ambudkar, IS AF Cheng, Kwong Tai Alevizos, Ilias Liu, Xibao Swaim, Wiliam D. Yin, Hongen Feske, Stefan Oh-hora, Masatsugu Ambudkar, Indu S. TI STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine gland autoimmune disease, Sjogren's syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunology; knockout mice; Orai1; rheumatology ID STROMAL INTERACTION MOLECULE-1; CALCIUM SENSORS STIM1; PLASMA-MEMBRANE; SALIVARY-GLANDS; CELL FUNCTION; MICE LACKING; CA2+ STORE; MUTATION; ORAI1; CRAC AB Primary Sjogren's Syndrome (pSS) is an autoimmune disease involving salivary and other exocrine glands that leads to progressive lymphocytic infiltration into the gland, tissue damage, and secretory defects. The mechanism underlying this disease remains poorly understood. Here we report that mice with T-cell-targeted deletion of Stromal Interaction Molecule (STIM) 1 and STIM2 [double-knockout (DKO)] mice develop spontaneous and severe pSS-like autoimmune disease, displaying major hallmarks of the disease. In DKO mice, diffuse lymphocytic infiltration was seen in submandibular glands, a major target of pSS, by age 6 wk, progressing to severe inflammation by age 12 wk. Sjogren's syndrome- specific autoantibodies (SSA/Ro and SSB/La) were detected in the serum, and progressive salivary gland destruction and loss of fluid secretion were also seen. Importantly, we report that peripheral blood mononuclear cells as well as lymphocytic infiltrates in submandibular glands from patients with pSS demonstrated significant reductions in STIM1 and STIM2 proteins. Store-operated calcium entry was also reduced in peripheral blood mononuclear cells from pSS patients compared with those from healthy controls. Thus, deficiency of STIM1 and STIM2 proteins in T cells, and consequent defects in Ca2+ signaling, are associated with salivary gland autoimmunopathy in DKO mice and pSS patients. These data reveal a previously unreported link between STIM1 and STIM2 proteins and pSS. C1 [Cheng, Kwong Tai; Liu, Xibao; Swaim, Wiliam D.; Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, NIH, Bethesda, MD 20892 USA. [Alevizos, Ilias] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, NIH, Bethesda, MD 20892 USA. [Yin, Hongen] Natl Inst Dent & Craniofacial Res, AAV Biol Unit, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Feske, Stefan] NYU, Langone Med Ctr, Dept Pathol, New York, NY 10016 USA. [Oh-hora, Masatsugu] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Global Ctr Excellence Program, Int Res Ctr Mol Sci Tooth & Bone Dis, Tokyo 1138549, Japan. [Oh-hora, Masatsugu] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Cell Signaling, Tokyo 1138549, Japan. [Oh-hora, Masatsugu] Japan Sci & Technol Agcy JST, Precursory Res Embryon Sci & Technol PRESTO Progr, Tokyo 1138549, Japan. RP Ambudkar, IS (reprint author), Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, NIH, Bethesda, MD 20892 USA. EM iambudkar@dir.nidcr.nih.gov OI Feske, Stefan/0000-0001-5431-8178 FU Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Development FX We thank Dr. Anjana Rao for providing the DKO mice and for helpful discussions during the course of this work and manuscript preparation. We also thank Dr. Gabor Illei for providing the clinical data and samples and for insightful and helpful discussions during the course of this work and we thank the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Development, for continued support and funding. NR 41 TC 24 Z9 24 U1 1 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 SEP 4 PY 2012 VL 109 IS 36 BP 14544 EP 14549 DI 10.1073/pnas.1207354109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007TZ UT WOS:000308912600054 PM 22904194 ER PT J AU Farci, P Wollenberg, K Diaz, G Engle, RE Lai, ME Klenerman, P Purcell, RH Pybus, OG Alter, HJ AF Farci, Patrizia Wollenberg, Kurt Diaz, Giacomo Engle, Ronald E. Lai, Maria Eliana Klenerman, Paul Purcell, Robert H. Pybus, Oliver G. Alter, Harvey J. TI Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hepatitis C virus; slow progressors; rapid progressors; liver fibrosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; LIVER FIBROSIS; STELLATE CELLS; CHRONIC INFECTION; HCV; PERSISTENCE; CLEARANCE; RESPONSES; DISEASE; SERUM AB Chronic hepatitis C may follow a mild and stable disease course or progress rapidly to cirrhosis and liver-related death. The mechanisms underlying the different rates of disease progression are unknown. Using serial, prospectively collected samples from cases of transfusion-associated hepatitis C, we identified outcome-specific features that predict long-term disease severity. Slowly progressing disease correlated with an early alanine aminotransferase peak and antibody seroconversion, transient control of viremia, and significant induction of IFN-gamma and MIP-1 beta, all indicative of an effective, albeit insufficient, adaptive immune response. By contrast, rapidly progressive disease correlated with persistent and significant elevations of alanine aminotransferase and the profibrogenic chemokine MCP-1 (CCL-2), greater viral diversity and divergence, and a higher rate of synonymous substitution. This study suggests that the long-term course of chronic hepatitis C is determined early in infection and that disease severity is predicted by the evolutionary dynamics of hepatitis C virus and the level of MCP-1, a chemokine that appears critical to the induction of progressive fibrogenesis and, ultimately, the ominous complications of cirrhosis. C1 [Farci, Patrizia] NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wollenberg, Kurt] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Diaz, Giacomo] Univ Cagliari, Dept Biomed Sci, I-09123 Cagliari, Italy. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Lai, Maria Eliana] Univ Cagliari, Dept Med Sci, I-09042 Cagliari, Italy. [Klenerman, Paul] Univ Oxford, Oxford OX1 3SY, England. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Alter, Harvey J.] NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Farci, P (reprint author), NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM pfarci@niaid.nih.gov; halter@dtm.cc.nih.gov OI Pybus, Oliver/0000-0002-8797-2667 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; Royal Society of the United Kingdom FX We thank R. Strazzera, S. Farci, D. Cao, R. Scioscia, C. Schechterly, K. Prims, and A. Tice for their technical assistance; P. Lusso for helpful discussions; H. Newman for editorial assistance; and the National Institute of Allergy and Infectious Diseases Office of Cyber Infrastructure and Computational Biology and the National Institutes of Health Biowulf cluster for infrastructure support. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. O.G.P. is funded by The Royal Society of the United Kingdom. NR 43 TC 22 Z9 22 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 SEP 4 PY 2012 VL 109 IS 36 BP 14562 EP 14567 DI 10.1073/pnas.1210592109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007TZ UT WOS:000308912600057 PM 22829669 ER PT J AU Cunningham, L Finckbeiner, S Hyde, RK Southall, N Marugan, J Yedavalli, VRK Dehdashti, SJ Reinhold, WC Alemu, L Zhao, L Yeh, JRJ Sood, R Pommier, Y Austin, CP Jeang, KT Zheng, W Liu, P AF Cunningham, Lea Finckbeiner, Steven Hyde, R. Katherine Southall, Noel Marugan, Juan Yedavalli, Venkat R. K. Dehdashti, Seameen Jean Reinhold, William C. Alemu, Lemlem Zhao, Ling Yeh, Jing-Ruey Joanna Sood, Raman Pommier, Yves Austin, Christopher P. Jeang, Kuan-Teh Zheng, Wei Liu, Paul TI Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBF beta interaction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACUTE MYELOID-LEUKEMIA; VIRAL GENE-EXPRESSION; INFECTIONS IN-VITRO; TAT ANTAGONIST; TRANSGENIC ZEBRAFISH; BETA-SUBUNIT; FUSION; LEUKEMOGENESIS; HEMATOPOIESIS; BINDING AB Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genes RUNX1 or CBFB, account for similar to 24% of adult acute myeloid leukemia (AML) and 25% of pediatric acute lymphocytic leukemia (ALL). Current treatments for CBF leukemias are associated with significant morbidity and mortality, with a 5-y survival rate of similar to 50%. We hypothesize that the interaction between RUNX1 and CBF beta is critical for CBF leukemia and can be targeted for drug development. We developed high-throughput AlphaScreen and time-resolved fluorescence resonance energy transfer (TR-FRET) methods to quantify the RUNX1-CBF beta interaction and screen a library collection of 243,398 compounds. Ro5-3335, a benzodiazepine identified from the screen, was able to interact with RUNX1 and CBF beta directly, repress RUNX1/CBFB-dependent transactivation in reporter assays, and repress runx1-dependent hematopoiesis in zebrafish embryos. Ro5-3335 preferentially killed human CBF leukemia cell lines, rescued preleukemic phenotype in a RUNX1-ETO transgenic zebrafish, and reduced leukemia burden in amouse CBFB-MYH11 leukemia model. Our data thus confirmed that RUNX1-CBF beta interaction can be targeted for leukemia treatment and we have identified a promising lead compound for this purpose. C1 [Southall, Noel; Marugan, Juan; Dehdashti, Seameen Jean; Austin, Christopher P.; Zheng, Wei] NIAID, Natl Ctr Advancing Translat Sci, NIH, Bethesda, MD 20892 USA. [Cunningham, Lea; Finckbeiner, Steven; Hyde, R. Katherine; Alemu, Lemlem; Zhao, Ling; Sood, Raman; Liu, Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Sood, Raman] NHGRI, Zebrafish Core, NIH, Bethesda, MD 20892 USA. [Yedavalli, Venkat R. K.; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, NIH, Bethesda, MD 20892 USA. [Reinhold, William C.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yeh, Jing-Ruey Joanna] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. RP Zheng, W (reprint author), NIAID, Natl Ctr Advancing Translat Sci, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov; pliu@mail.nih.gov RI Southall, Noel/H-8991-2012; Liu, Paul/A-7976-2012; Zheng, Wei/J-8889-2014 OI Southall, Noel/0000-0003-4500-880X; Liu, Paul/0000-0002-6779-025X; Zheng, Wei/0000-0003-1034-0757 FU National Institutes of Health (NIH) [X01 MH083259-01, CA140188, AG031300]; Molecular Libraries Initiative of the NIH Roadmap for Medical Research; Intramural Research Program of NHGRI, NIH [CA140188, AG031300]; Johns Hopkins-National Cancer Institute Pediatric Hematology/Oncology Fellowship; NIH FX The authors thank Pingjun Zhu for assistance in the assay development; Sam Michael for the robotic screen; Paul Shinn for the compound management; Jingjun Hong and Yawen Bai for advice on protein purification; Joel Morris and Jerry Collins for compounds; Kevin Bishop, Trang Jennifer Nguyen, the National Human Genome Research Institute (NHGRI) mouse, zebrafish, flow cytometry, cytogenetics, and microscopy cores for technical assistance; Shelly Hoogstraten-Miller and Irene Ginty for help with mouse experiments and nursing care; Xin Xu for PK analysis; Urraca L. Tavarez for demonstrating how to knead dough; Jerrold Ward and Dave Bodine for evaluating histology sections; members of the P. L. laboratory, Alan Wayne, and David Loeb, for helpful discussions; and Francis Collins for critical reading of the manuscript. This work was supported by National Institutes of Health (NIH) Grant X01 MH083259-01 (to P. L.), the Molecular Libraries Initiative of the NIH Roadmap for Medical Research, the Intramural Research Program of NHGRI, NIH, and NIH grants CA140188 and AG031300 (to J.-R.J.Y.). L. C. was a fellow in the joint Johns Hopkins-National Cancer Institute Pediatric Hematology/Oncology Fellowship program and a recipient of the competitive NIH intramural loan repayment program. NR 41 TC 27 Z9 28 U1 0 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 4 PY 2012 VL 109 IS 36 BP 14592 EP 14597 DI 10.1073/pnas.1200037109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 007TZ UT WOS:000308912600062 PM 22912405 ER PT J AU Bluemke, DA Yang, E AF Bluemke, David A. Yang, Eunice TI Hypertrophic Cardiomyopathy Refining the Lens of Cardiac Magnetic Resonance to Evaluate Late Gadolinium Enhancement SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE cardiac magnetic resonance; hypertrophic cardiomyopathy; late gadolinium enhancement; myocardial fibrosis ID MYOCARDIAL FIBROSIS; DELAYED ENHANCEMENT; HEART; LISINOPRIL; REGRESSION; PRESSURE C1 [Bluemke, David A.; Yang, Eunice] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA CL090019-02, ZIA EB000072-02] NR 18 TC 3 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 4 PY 2012 VL 60 IS 10 BP 930 EP 931 DI 10.1016/j.jacc.2012.05.023 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 000XV UT WOS:000308425000011 PM 22935465 ER PT J AU Wong, TC Piehler, K Meier, CG Testa, SM Klock, AM Aneizi, AA Shakesprere, J Kellman, P Shroff, SG Schwartzman, DS Mulukutla, SR Simon, MA Schelbert, EB AF Wong, Timothy C. Piehler, Kayla Meier, Christopher G. Testa, Stephen M. Klock, Amanda M. Aneizi, Ali A. Shakesprere, Jonathan Kellman, Peter Shroff, Sanjeev G. Schwartzman, David S. Mulukutla, Suresh R. Simon, Marc A. Schelbert, Erik B. TI Association Between Extracellular Matrix Expansion Quantified by Cardiovascular Magnetic Resonance and Short-Term Mortality SO CIRCULATION LA English DT Article DE collagen; magnetic resonance imaging; mortality; myocardial fibrosis ID HYPERTENSIVE HEART-DISEASE; IDIOPATHIC DILATED CARDIOMYOPATHY; LEFT-VENTRICULAR HYPERTROPHY; DIFFUSE MYOCARDIAL FIBROSIS; HUMANS; INFARCTION; REGRESSION; DYSFUNCTION; REGISTRATION; EDEMA AB Background-Extracellular matrix expansion may be a fundamental feature of adverse myocardial remodeling, it appears to be treatable, and its measurement may improve risk stratification. Yet, the relationship between mortality and extracellular matrix is not clear because of difficulties with its measurement. To assess its relationship with outcomes, we used novel, validated cardiovascular magnetic resonance techniques to quantify the full spectrum of extracellular matrix expansion not readily detectable by conventional cardiovascular magnetic resonance. Methods and Results-We recruited 793 consecutive patients at the time of cardiovascular magnetic resonance without amyloidosis or hypertrophic cardiomyopathy as well as 9 healthy volunteers (ages 20-50 years). We measured the extracellular volume fraction (ECV) to quantify the extracellular matrix expansion in myocardium without myocardial infarction. ECV uses gadolinium contrast as an extracellular space marker based on T1 measures of blood and myocardium pre-and post-gadolinium contrast and hematocrit measurement. In volunteers, ECV ranged from 21.7% to 26.2%, but in patients it ranged from 21.0% to 45.8%, indicating considerable burden. There were 39 deaths over a median follow-up of 0.8 years (interquartile range 0.5-1.2 years), and 43 individuals who experienced the composite end point of death/cardiac transplant/left ventricular assist device implantation. In Cox regression models, ECV related to all-cause mortality and the composite end point (hazard ratio, 1.55; 95% confidence interval, 1.27-1.88 and hazard ratio, 1.48; 95% confidence interval, 1.23-1.78, respectively, for every 3% increase in ECV), adjusting for age, left ventricular ejection fraction, and myocardial infarction size. Conclusions-ECV measures of extracellular matrix expansion may predict mortality as well as other composite end points (death/cardiac transplant/left ventricular assist device implantation). (Circulation. 2012; 126: 1206-1216.) C1 [Schelbert, Erik B.] Univ Pittsburgh, Sch Med, UPMC Heart & Vasc Inst, Clin & Translat Sci Inst, Pittsburgh, PA 15213 USA. [Wong, Timothy C.; Piehler, Kayla; Meier, Christopher G.; Testa, Stephen M.; Klock, Amanda M.; Aneizi, Ali A.; Shakesprere, Jonathan; Schwartzman, David S.; Mulukutla, Suresh R.; Simon, Marc A.; Schelbert, Erik B.] Univ Pittsburgh, Dept Med, Sch Med, Pittsburgh, PA 15213 USA. [Wong, Timothy C.; Piehler, Kayla; Meier, Christopher G.; Testa, Stephen M.; Klock, Amanda M.; Aneizi, Ali A.; Shakesprere, Jonathan; Schelbert, Erik B.] Univ Pittsburgh, Cardiovasc Magnet Resonance Ctr, Sch Med, Pittsburgh, PA 15213 USA. [Wong, Timothy C.; Schwartzman, David S.; Mulukutla, Suresh R.; Simon, Marc A.; Schelbert, Erik B.] Univ Pittsburgh, Inst Heart & Vasc, Sch Med, Pittsburgh, PA 15213 USA. [Mulukutla, Suresh R.] Univ Pittsburgh, Ctr Qual Outcomes & Clin Res, Sch Med, Pittsburgh, PA 15213 USA. [Kellman, Peter] NHLBI, NIH, Bethesda, MD 20892 USA. [Shroff, Sanjeev G.; Simon, Marc A.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. RP Schelbert, EB (reprint author), Univ Pittsburgh, Sch Med, UPMC Heart & Vasc Inst, Clin & Translat Sci Inst, 200 Lothrop St,PUH A349, Pittsburgh, PA 15213 USA. EM schelberteb@upmc.edu OI Wong, Timothy/0000-0002-1045-2698 FU Siemens Cardiovascular MR Research and Development; Pittsburgh Foundation [M2009-0068]; American Heart Association Scientist Development Grant [09SDG2180083]; T. Franklin Williams Scholarship Award; Atlantic Philanthropies, Inc; John A. Hartford Foundation; Association of Specialty Professors; American Heart Association; Agency for Healthcare Research and Quality [K12 HS19461-01]; McGinnis Endowed Chair funds; National Center for Research Resources (NCRR) [UL1 RR024153]; National Institutes of Health (NIH) FX This work was supported by Siemens Cardiovascular MR Research and Development. Dr Schelbert is supported by a grant from The Pittsburgh Foundation, Grant M2009-0068, and an American Heart Association Scientist Development Grant (09SDG2180083) including a T. Franklin Williams Scholarship Award; funding provided by Atlantic Philanthropies, Inc, the John A. Hartford Foundation, the Association of Specialty Professors, and the American Heart Association. Dr Wong is supported by a grant K12 HS19461-01 from the Agency for Healthcare Research and Quality. Dr Shroff is supported by the McGinnis Endowed Chair funds. This work was also supported by grant number UL1 RR024153 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Research funds did not pay for clinically indicated CMR scans. NR 37 TC 151 Z9 157 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 4 PY 2012 VL 126 IS 10 BP 1206 EP 1216 DI 10.1161/CIRCULATIONAHA.111.089409 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 999ZS UT WOS:000308356100015 PM 22851543 ER PT J AU McManus, DD Rienstra, M Benjamin, EJ AF McManus, David D. Rienstra, Michiel Benjamin, Emelia J. TI An Update on the Prognosis of Patients With Atrial Fibrillation SO CIRCULATION LA English DT Review ID C-REACTIVE PROTEIN; CONGESTIVE-HEART-FAILURE; RISK-FACTORS; ISCHEMIC-STROKE; LIFETIME RISK; MYOCARDIAL-INFARCTION; UNITED-STATES; MORTALITY; DEATH; ANTICOAGULATION C1 [McManus, David D.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [McManus, David D.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Div Cardiovasc Med, Dept Med,Cardiac Electrophysiol Sect, Worcester, MA 01655 USA. [McManus, David D.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP McManus, DD (reprint author), Univ Massachusetts, Sch Med, Div Cardiol, Worcester, MA 01655 USA. EM mcmanusd@ummhc.org OI Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU National Institutes of Health [KL2RR031981, U01HL105268, HL092577, RO1AG028321, RC1-HL01056, 1R01HL102214] FX Drs McManus and Benjamin are supported by grants from the National Institutes of Health (DDM: KL2RR031981, U01HL105268) and (EJB: HL092577, RO1AG028321, RC1-HL01056, 1R01HL102214). NR 54 TC 46 Z9 49 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 4 PY 2012 VL 126 IS 10 BP E143 EP E146 DI 10.1161/CIRCULATIONAHA.112.129759 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 999ZS UT WOS:000308356100002 PM 22949543 ER PT J AU Arlt, VM Poirier, MC Sykes, SE John, K Moserova, M Stiborova, M Wolf, CR Henderson, CJ Phillips, DH AF Arlt, Volker M. Poirier, Miriam C. Sykes, Sarah E. John, Kaarthik Moserova, Michaela Stiborova, Marie Wolf, C. Roland Henderson, Colin J. Phillips, David H. TI Exposure to benzo[a]pyrene of Hepatic Cytochrome P450 Reductase Null (HRN) and P450 Reductase Conditional Null (RCN) mice: Detection of benzo[a]pyrene diol epoxide-DNA adducts by immunohistochemistry and P-32-postlabelling SO TOXICOLOGY LETTERS LA English DT Article DE Benzo[a]pyrene; Cytochrome P450; Cytochrome P450 oxidoreductase; DNA adducts; Immunohistochemistry; Polycyclic aromatic hydrocarbon ID ANTICANCER DRUG ELLIPTICINE; METABOLIC-ACTIVATION; GENE-EXPRESSION; KNOCKOUT MICE; IN-VIVO; ENVIRONMENTAL-POLLUTANT; GASTROINTESTINAL-TRACT; HUMAN TISSUES; MOUSE MODEL; DETOXICATION AB Benzo[a]pyrene (BaP) is a widespread environmental carcinogen activated by cytochrome P450 (P450) enzymes. In Hepatic P450 Reductase Null (HRN) and Reductase Conditional Null (RCN) mice, P450 oxidoreductase (Por) is deleted specifically in hepatocytes, resulting in the loss of essentially all hepatic P450 function. Treatment of HRN mice with a single i.p. or oral dose of BaP (12.5 or 125 mg/kg body weight) resulted in higher DNA adduct levels in liver (up to 10-fold) than in wild-type (WT) mice, indicating that hepatic P450s appear to be more important for BaP detoxification in vivo. Similar results were obtained in RCN mice. We tested whether differences between hepatocytes and non-hepatocytes in P450 activity may underlie the increased liver BaP-DNA binding in HRN mice. Cellular localisation by immunohistochemistry of BaP-DNA adducts showed that HRN mice have ample capacity for formation of BaP-DNA adducts in liver, indicating that the metabolic process does not result in the generation of a reactive species different from that formed in WT mice. However, increased protein expression of cytochrome b(5) in hepatic microsomes of HRN relative to WT mice suggests that cytochrome b5 may modulate the P450-mediated bioactivation of BaP in HRN mice, partially substituting the function of Por. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Arlt, Volker M.; Phillips, David H.] Kings Coll London, Analyt & Environm Sci Div, MRC HPA Ctr Environm & Hlth, London WC2R 2LS, England. [Poirier, Miriam C.; Sykes, Sarah E.; John, Kaarthik] NCI, Carcinogen DNA Interact Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Sykes, Sarah E.] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. [Moserova, Michaela; Stiborova, Marie] Charles Univ Prague, Fac Sci, Dept Biochem, Prague, Czech Republic. [Wolf, C. Roland; Henderson, Colin J.] Univ Dundee, Jacqui Wood Canc Ctr, Med Res Inst, Div Canc Res, Dundee, Scotland. RP Arlt, VM (reprint author), Kings Coll London, Analyt & Environm Sci Div, MRC HPA Ctr Environm & Hlth, London WC2R 2LS, England. EM volker.arlt@kcl.ac.uk RI Stiborova, Marie/A-5982-2015; OI Stiborova, Marie/0000-0001-5430-4403; Phillips, David/0000-0001-8509-3485; Arlt, Volker Manfred/0000-0003-4314-9318 FU Cancer Research UK; ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility) European Union Network of Excellence; Grant Agency of the Czech Republic [P301/10/0356]; University grant UNCE [42] FX This study was supported by Cancer Research UK and ECNIS2 (Environmental Cancer Risk, Nutrition and Individual Susceptibility) European Union Network of Excellence. Work at Charles University is supported by the Grant Agency of the Czech Republic (grant P301/10/0356) and by the University grant UNCE#42. We would like to acknowledge the Comparative Molecular Pathology Unit at the National Cancer Institute, National Institutes of Health for their assistance with the slide scanning. NR 40 TC 19 Z9 19 U1 0 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 3 PY 2012 VL 213 IS 2 BP 160 EP 166 DI 10.1016/j.toxlet.2012.06.016 PG 7 WC Toxicology SC Toxicology GA 005SH UT WOS:000308769700004 PM 22759596 ER PT J AU Gandara, DR Edelman, MJ Giaccone, G Ramalingam, SS Guerra, WM Bowser, AD Mortimer, J West, HL AF Gandara, D. R. Edelman, M. J. Giaccone, G. Ramalingam, S. S. Guerra, W. M. Bowser, A. D. Mortimer, J. West, H. L. TI Development and Utilization of an Online Tool to Guide Choice of First-line and Maintenance Therapy (Tx) for Patients (Pts) With Advanced Non-Small-Cell Lung Cancer (NSCLC) SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article; Proceedings Paper CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY SEP 06-08, 2012 CL Chicago, IL C1 [Gandara, D. R.; Mortimer, J.] Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. [Edelman, M. J.] Univ Maryland, Baltimore, MD 21201 USA. [Giaccone, G.] NCI, Bethesda, MD 20892 USA. [Ramalingam, S. S.] Emory Univ, Atlanta, GA 30322 USA. [Guerra, W. M.; Bowser, A. D.] Clin Care Opt, Reston, VA USA. [West, H. L.] Swedish Canc Inst, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2012 VL 7 IS 9 SU 4 BP S271 EP S271 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 118OO UT WOS:000317035000178 ER PT J AU Kesarwala, AH Lu, DJ Xanthopoulos, E Apisarnthanarax, S Evans, T Aggarwal, C Cohen, RB Langer, CJ Rengan, R Simone, CB AF Kesarwala, A. H. Lu, D. J. Xanthopoulos, E. Apisarnthanarax, S. Evans, T. Aggarwal, C. Cohen, R. B. Langer, C. J. Rengan, R. Simone, C. B. TI The Role of Advanced Imaging in Assessing Response to Definitive Chemoradiation Prior to Prophylactic Cranial Irradiation in Limited-Stage Small Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article; Proceedings Paper CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY SEP 06-08, 2012 CL Chicago, IL C1 [Kesarwala, A. H.] NCI, Bethesda, MD 20892 USA. [Lu, D. J.; Xanthopoulos, E.; Apisarnthanarax, S.; Evans, T.; Aggarwal, C.; Cohen, R. B.; Langer, C. J.; Rengan, R.; Simone, C. B.] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2012 VL 7 IS 9 SU 4 BP S280 EP S281 PG 2 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 118OO UT WOS:000317035000202 ER PT J AU Kesarwala, AH Ko, C O'Meara, WP Ning, H Haglund, KE Xanthopoulos, E Rengan, R AF Kesarwala, A. H. Ko, C. O'Meara, W. P. Ning, H. Haglund, K. E. Xanthopoulos, E. Rengan, R. TI Feasibility of Proton Therapy For Elective Nodal Irradiation in Patients with Locally Advanced Non-small Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article; Proceedings Paper CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY SEP 06-08, 2012 CL Chicago, IL C1 [Kesarwala, A. H.; Ning, H.; Haglund, K. E.] NCI, Bethesda, MD 20892 USA. [Ko, C.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [O'Meara, W. P.] Lahey Clin Fdn, Burlington, MA USA. [Xanthopoulos, E.; Rengan, R.] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2012 VL 7 IS 9 SU 4 BP S251 EP S251 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 118OO UT WOS:000317035000127 ER PT J AU Lindorfer, MA Wiestner, A Zent, CS Taylor, RP AF Lindorfer, Margaret A. Wiestner, Adrian Zent, Clive S. Taylor, Ronald P. TI Monoclonal antibody (mAb)-based cancer therapy Is it time to reevaluate dosing strategies? SO ONCOIMMUNOLOGY LA English DT Editorial Material DE immunomonitoring; therapeutic antibodies; therapeutic trials; CD20 mAbs; trogocytosis ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CD20 LOSS; COMPLEMENT AB Compelling evidence indicates Type I CD20 immunotherapeutic mAbs promote targeted tumor cell elimination exclusively via immune effector functions, which can be exhausted/saturated. mAb dosing paradigms should therefore take into account the capacity of these cytotoxic mechanisms, leading to the conclusion that lower doses, given frequently, may be far more effective. C1 [Lindorfer, Margaret A.; Taylor, Ronald P.] Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Wiestner, Adrian] NHLBI, Hematol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Zent, Clive S.] Mayo Clin, Div Hematol, Rochester, MN USA. RP Taylor, RP (reprint author), Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. EM rpt@virginia.edu NR 10 TC 17 Z9 18 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 J9 ONCOIMMUNOLOGY JI OncoImmunology PD SEP PY 2012 VL 1 IS 6 BP 959 EP 961 DI 10.4161/onci.20368 PG 3 WC Oncology; Immunology SC Oncology; Immunology GA 108FE UT WOS:000316276400026 ER PT J AU Chi, YH Chen, CY Jeang, KT AF Chi, Ya-Hui Chen, Chia-Yen Jeang, Kuan-Teh TI Reversal of laminopathies: the curious case of SUN1 SO NUCLEUS-AUSTIN LA English DT Article DE SUN1; nuclear envelope; progeria; lamin; aging ID GILFORD-PROGERIA-SYNDROME; INNER NUCLEAR-MEMBRANE; MUSCULAR-DYSTROPHY; PROTEIN SUN1; LAMIN-A; ENVELOPE; DISEASE; MICE; CONNECTION; EXPRESSION AB Mutations in the LMNA gene are associated with a spectrum of human dystrophic diseases termed the "nuclear laminopathies." We recently found that the accumulation of the inner nuclear envelope proteins SUN 1 is pathogenic in progeric and dystrophic laminopathies. This conclusion arose from the unexpected observation that the deletion of Sun1, instead of accelerating aging, actually ameliorated the progeric and dystrophic phenotypes in Lmna-deficient mice. In human cells, knocking down SUN 1 corrected the nuclear aberrancies and the senescent tendencies of HGPS (Hutchinson-Gilford progeria syndrome) skin fibroblasts. Here we offer additional comments on the contributions of SUN 1 and the process of normal protein turnover to cellular aging. C1 [Chi, Ya-Hui] Natl Hlth Res Inst, Inst Cellular & Syst Med, Zhunan, Taiwan. [Chen, Chia-Yen; Jeang, Kuan-Teh] NIAID, NIH, Bethesda, MD 20892 USA. RP Chi, YH (reprint author), Natl Hlth Res Inst, Inst Cellular & Syst Med, Zhunan, Taiwan. EM ychi@nhri.org.tw RI Chi, Ya-Hui/B-1080-2010 FU NIAID intramural funds; NHRI, Taiwan [NHRI 01A1-CSPP13-014]; NSC, Taiwan [NSC 98-2320-B-400-009-MY3] FX Our work was supported by NIAID intramural funds, the NHRI, Taiwan (NHRI 01A1-CSPP13-014), and NSC, Taiwan (NSC 98-2320-B-400-009-MY3). NR 37 TC 4 Z9 4 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1949-1034 J9 NUCLEUS-AUSTIN JI Nucleus-Austin PD SEP-OCT PY 2012 VL 3 IS 5 BP 418 EP 421 DI 10.4161/nucl.21714 PG 4 WC Cell Biology SC Cell Biology GA 103SC UT WOS:000315938200008 PM 22895095 ER PT J AU Voulgaraki, A Kedem, B Graubard, BI AF Voulgaraki, Anastasia Kedem, Benjamin Graubard, Barry I. TI SEMIPARAMETRIC REGRESSION IN TESTICULAR GERM CELL DATA SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Multivariate density ratio model; kernel; random covariates; diagnostic; Nadaraya-Watson; GAM ID GOODNESS-OF-FIT; DENSITY-ESTIMATION; MODELS; INFORMATION; LIKELIHOOD; TUMORS; RISK AB It is possible to approach regression analysis with random covariates from a semiparametric perspective where information is combined from multiple multivariate sources. The approach assumes a semiparametric density ratio model where multivariate distributions are "regressed" on a reference distribution. A kernel density estimator can be constructed from many data sources in conjunction with the semiparametric model. The estimator is shown to be more efficient than the traditional single-sample kernel density estimator, and its optimal bandwidth is discussed in some detail. Each multivariate distribution and the corresponding conditional expectation (regression) of interest are estimated from the combined data using all sources. Graphical and quantitative diagnostic tools are suggested to assess model validity. The method is applied in quantifying the effect of height and age on weight of germ cell testicular cancer patients. Comparisons are made with multiple regression, generalized additive models (GAM) and nonparametric kernel regression. C1 [Voulgaraki, Anastasia; Kedem, Benjamin] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Graubard, Barry I.] NCI, Rockville, MD 20852 USA. RP Voulgaraki, A (reprint author), Univ Maryland, Dept Math, College Pk, MD 20742 USA. EM avoulgar@math.umd.edu; bnk@math.umd.edu; graubarb@exchange.nih.gov FU NSF [DMS-10-07647] FX Supported by NSF Grant DMS-10-07647. NR 35 TC 4 Z9 4 U1 2 U2 4 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD SEP PY 2012 VL 6 IS 3 BP 1185 EP 1208 DI 10.1214/12-AOAS552 PG 24 WC Statistics & Probability SC Mathematics GA 083IR UT WOS:000314457400016 ER PT J AU Steele, S Bilchik, A Eberhardt, J Kalina, P Nissan, A Johnson, E Avital, I Stojadinovic, A AF Steele, Scott Bilchik, Anton Eberhardt, John Kalina, Philip Nissan, Aviram Johnson, Eric Avital, Itzhak Stojadinovic, Alexander TI Using Machine-Learned Bayesian Belief Networks to Predict Perioperative Risk of Clostridium Difficile Infection Following Colon Surgery SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE Clostridium difficile; Bayesian belief network; pseudomembranous colitis; colectomy; NIS ID DISEASE; SEVERITY; COLITIS; ANTIBIOTICS; COLECTOMY; DIARRHEA; AMERICA AB Background: Clostridium difficile (C-Diff) infection following colorectal resection is an increasing source of morbidity and mortality. Objective: We sought to determine if machine-learned Bayesian belief networks (ml-BBNs) could preoperatively provide clinicians with postoperative estimates of C-Diff risk. Methods: We performed a retrospective modeling of the Nationwide Inpatient Sample (NIS) national registry dataset with independent set validation. The NIS registries for 2005 and 2006 were used for initial model training, and the data from 2007 were used for testing and validation. International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes were used to identify subjects undergoing colon resection and postoperative C-Diff development. The ml-BBNs were trained using a stepwise process. Receiver operating characteristic (ROC) curve analysis was conducted and area under the curve (AUC), positive predictive value (PPV), and negative predictive value (NPV) were calculated. Results: From over 24 million admissions, 170,363 undergoing colon resection met the inclusion criteria. Overall, 1.7% developed postoperative C-Diff. Using the ml-BBN to estimate C-Diff risk, model AUC is 0.75. Using only known a priori features, AUC is 0.74. The model has two configurations: a high sensitivity and a high specificity configuration. Sensitivity, specificity, PPV, and NPV are 81.0%, 50.1%, 2.6%, and 99.4% for high sensitivity and 55.4%, 81.3%, 3.5%, and 99.1% for high specificity. C-Diff has 4 first-degree associates that influence the probability of C-Diff development: weight loss, tumor metastases, inflammation/infections, and disease severity. Conclusions: Machine-learned BBNs can produce robust estimates of postoperative C-Diff infection, allowing clinicians to identify high-risk patients and potentially implement measures to reduce its incidence or morbidity. (Interact J Med Res 2012;1(2):e6) doi:10.2196/ijmr.2131 C1 [Steele, Scott; Johnson, Eric] Madigan Army Med Ctr, Dept Surg, Tacoma, WA 98431 USA. [Bilchik, Anton] Calif Oncol Res Inst, Los Angeles, CA USA. [Eberhardt, John; Kalina, Philip] DecisionQ Corp, Washington, DC USA. [Nissan, Aviram] Rabin Med Ctr, Dept Surg, Petah Tiqwa, Israel. [Avital, Itzhak] NIH, Surg Branch, Bethesda, MD 20892 USA. [Stojadinovic, Alexander] Walter Reed Natl Mil Med Ctr, Dept Surg, Div Surg Oncol, Bethesda, MD USA. RP Steele, S (reprint author), Madigan Army Med Ctr, Dept Surg, Bldg 9040,Jackson Ave, Tacoma, WA 98431 USA. EM harkersteele@mac.com FU United States Military Cancer Institute (USMCI), Washington, DC; Henry M. Jackson Foundation (HJF) for the Advancement of Military Medicine, Rockville, MD; California Oncology Research Institute (CORI), Los Angeles, CA FX This clinical research effort was supported, in part, by the United States Military Cancer Institute (USMCI), Washington, DC, the Henry M. Jackson Foundation (HJF) for the Advancement of Military Medicine, Rockville, MD, and the California Oncology Research Institute (CORI), Los Angeles, CA. Our team is comprised partly of military service members and employees of the US Government. This work was prepared as part of our official duties. Title 17 USC 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U. S. C. 101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties. The views expressed in this presentation are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the United States Government. NR 31 TC 0 Z9 0 U1 2 U2 6 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD SEP-OCT PY 2012 VL 14 IS 5 AR e6 DI 10.2196/ijmr.2131 PG 14 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 092GN UT WOS:000315108100003 ER PT J AU Milaneschi, Y Simonsick, EM Vogelzangs, N Strotmeyer, ES Yaffe, K Harris, TB Tolea, MI Ferrucci, L Penninx, BWJH AF Milaneschi, Yuri Simonsick, Eleanor M. Vogelzangs, Nicole Strotmeyer, Elsa S. Yaffe, Kristine Harris, Tamara B. Tolea, Magdalena I. Ferrucci, Luigi Penninx, Brenda W. J. H. CA Hlth Aging Body Composition Study TI Leptin, Abdominal Obesity, and Onset of Depression in Older Men and Women SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID BODY-FAT DISTRIBUTION; C-REACTIVE PROTEIN; PLASMA LEPTIN; INSULIN-RESISTANCE; METABOLIC SYNDROME; DIABETES-MELLITUS; MAJOR DEPRESSION; SEX-DIFFERENCES; ADIPOSE-TISSUE; SERUM LEPTIN AB Objective: The mechanisms that underlie the association between abdominal obesity and depression risk in older persons are not well known, but the "leptin hypothesis" of depression suggests that leptin resistance may be involved in mood regulation. We tested whether high circulatory concentration of leptin, alone and in combination with visceral adiposity, is associated with onset of depression in a sample of older persons. Method: Participants were 1,220 men and 1,282 women aged 70-79 years and enrolled in the Health, Aging, and Body Composition study. Serum concentration of leptin and abdominal visceral fat, ascertained by computed tomography, were assessed at baseline (April 1997-June 1998). Onset of depression, the primary outcome measure, was defined as a Center for Epidemiologic Studies-Depression Scale 10-item score >= 10 and/or new antidepressant medication use at any annual visit over a 5-year follow-up. Results: Higher leptin level was associated with the risk of depression onset in men with high levels of visceral fat (hazard ratio [HR] =1.25; 95% CI, 1.06-1.46; P = .01) but not in those with normal visceral fat (HR = 0.98; 95% CI, 0.80-1.19; P = .80) (leptin-by-visceral fat, P = .04). No interaction between leptin and visceral fat was detected in the analysis focusing on women (P = .90). Conclusions: In older men, high leptin level was associated with an increased onset of depressive symptoms, especially in the presence of abdominal obesity, suggesting that underlying leptin resistance may play a role in this link. Differences in visceral fat levels and metabolic consequences may explain the absence of this association in women. These findings suggest a potential biological link between depression, obesity, and their joint association with negative health outcomes. J Clin Psychiatry 2012;73(9):1205-1211 (c) Copyright 2012 Physicians Postgraduate Press, Inc. C1 [Milaneschi, Yuri; Vogelzangs, Nicole; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, GGZ InGeest, Dept Psychiat, NL-1081 HL Amsterdam, Netherlands. [Milaneschi, Yuri; Simonsick, Eleanor M.; Tolea, Magdalena I.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Strotmeyer, Elsa S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Milaneschi, Y (reprint author), Vrije Univ Amsterdam Med Ctr, GGZ InGeest, Dept Psychiat, AJ Ernststr 1187, NL-1081 HL Amsterdam, Netherlands. EM y.milaneschi@ggzingeest.nl RI Strotmeyer, Elsa/F-3015-2014; OI Strotmeyer, Elsa/0000-0002-4093-6036 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; Intramural Research Program of the National Institutes of Health-National Institute on Aging FX The Health, Aging, and Body Composition (Health ABC) study is supported by the National Institute on Aging (N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106) and partly by the Intramural Research Program of the National Institutes of Health-National Institute on Aging. NR 46 TC 35 Z9 36 U1 2 U2 15 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD SEP PY 2012 VL 73 IS 9 BP 1205 EP 1211 DI 10.4088/JCP.11m07552 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 090SN UT WOS:000315000400005 PM 22687702 ER PT J AU Cookson, MR AF Cookson, Mark R. TI Parkinsonism Due to Mutations in PINK1, Parkin, and DJ-1 and Oxidative Stress and Mitochondrial Pathways SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID RECESSIVE JUVENILE PARKINSONISM; CYSTEINE-SULFINIC ACID; DISEASE PROTEIN DJ-1; DROSOPHILA DJ-1; DOPAMINERGIC-NEURONS; CRYSTAL-STRUCTURE; ALPHA-SYNUCLEIN; GENE DJ-1; PINK1/PARKIN PATHWAY; MOTOR DEFICITS AB Three genes have been identified that cause, in humans, autosomally inherited parkinsonism. These are PARK2, encoding the E3 ubiquitin ligase parkin; PINK1, a mitochondrial kinase; and PARK7, which codes for the protein DJ-1. In several experimental systems, it has been shown that all three proteins impact mitochondrial function and/or oxidative stress responses. These are probably related because mitochondria produce oxidative stress in neurons. Moreover, it is clear that there are relationships between these genes, with a single pathway linking PINK1 and parkin and a parallel relationship with DJ-1. Work in progress in the field is aimed at understanding these relationships in more depth. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This research is supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 89 TC 44 Z9 44 U1 0 U2 17 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD SEP PY 2012 VL 2 IS 9 AR a009415 DI 10.1101/cshperspect.a009415 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080YP UT WOS:000314280800010 PM 22951446 ER PT J AU Brislin, SJ White, SF Meffert, H Sinclair, SH Pine, DS Blair, JR AF Brislin, Sarah J. White, Stuart F. Meffert, Harma Sinclair, Stephen H. Pine, Daniel S. Blair, James R. TI CALLOUS-UNEMOTIONAL TRAITS MODULATE NEURAL RESPONSES ASSOCIATED WITH PERFORMANCE IN A SOCIAL EXCHANGE GAME SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 52nd Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 19-23, 2012 CL New Orleans, LA SP Soc Psychophysiol Res DE Callous-Unemotional Traits; Social Exchange Game; fMRI C1 [Brislin, Sarah J.] Florida State Univ, Tallahassee, FL 32306 USA. [White, Stuart F.; Meffert, Harma; Sinclair, Stephen H.; Pine, Daniel S.; Blair, James R.] NIMH, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2012 VL 49 SU 1 SI SI BP S62 EP S62 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 080VN UT WOS:000314272300340 ER PT J AU Cuthbert, BN AF Cuthbert, Bruce N. TI PSYCHOPATHOLOGY: DIMENSIONS TO RESEARCH DOMAIN CRITERIA SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 52nd Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 19-23, 2012 CL New Orleans, LA SP Soc Psychophysiol Res C1 [Cuthbert, Bruce N.] NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2012 VL 49 SU 1 SI SI BP S7 EP S8 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 080VN UT WOS:000314272300038 ER PT J AU Forbes, CE Poore, JC Barbey, AK Krueger, F Solomon, J Lipsky, RH Hodgkinson, CA Goldman, D Grafman, J AF Forbes, Chad E. Poore, Joshua C. Barbey, Aron K. Krueger, Frank Solomon, Jeffrey Lipsky, Robert H. Hodgkinson, Colin A. Goldman, David Grafman, Jordan TI BDNF POLYMORPHISM-DEPENDENT OFC AND DLPFC PLASTICITY DIFFERENTIALLY MODERATES IMPLICIT AND EXPLICIT BIAS SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 52nd Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 19-23, 2012 CL New Orleans, LA SP Soc Psychophysiol Res DE Implicit and Explicit Social Bias; BDNF/Neural Plasticity; TBI C1 [Forbes, Chad E.] Univ Delaware, Newark, DE 19716 USA. [Barbey, Aron K.] Univ Illinois, Chicago, IL 60680 USA. [Krueger, Frank] George Mason Univ, Fairfax, VA 22030 USA. [Lipsky, Robert H.] Inova Fairfax Hosp, Falls Church, VA USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2012 VL 49 SU 1 SI SI BP S115 EP S115 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 080VN UT WOS:000314272300618 ER PT J AU Grillon, C AF Grillon, Christian TI DEFENSIVE RESPONDING IN MOOD AND ANXIETY DISORDERS SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 52nd Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 19-23, 2012 CL New Orleans, LA SP Soc Psychophysiol Res C1 [Grillon, Christian] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2012 VL 49 SU 1 SI SI BP S12 EP S12 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 080VN UT WOS:000314272300068 ER PT J AU Hong, M Shechner, T Britton, JC Spiro, CN Mash, JA Pine, DS Fox, NA AF Hong, Melanie Shechner, Tomer Britton, Jennifer C. Spiro, Carolyn N. Mash, Jamie A. Pine, Daniel S. Fox, Nathan A. TI NOVEL PEDIATRIC FEAR CONDITIONING PARADIGM: A PSYCHOPHYSIOLOGICAL STUDY SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 52nd Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 19-23, 2012 CL New Orleans, LA SP Soc Psychophysiol Res DE Fear conditioning; Development; Anxiety Disorders C1 [Hong, Melanie; Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. [Shechner, Tomer; Britton, Jennifer C.; Spiro, Carolyn N.; Mash, Jamie A.; Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. RI Britton, Jennifer/J-4501-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2012 VL 49 SU 1 SI SI BP S32 EP S32 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 080VN UT WOS:000314272300182 ER PT J AU Schmitz, A Grillon, C Merikangas, KR AF Schmitz, Anja Grillon, Christian Merikangas, Kathleen R. TI FEAR- AND ANXIETY-POTENTIATED STARTLE AS POTENTIAL ENDOPHENOTYPES FOR ANXIETY DISORDERS SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 52nd Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 19-23, 2012 CL New Orleans, LA SP Soc Psychophysiol Res DE anxiety; startle; endophenotype C1 [Schmitz, Anja; Grillon, Christian; Merikangas, Kathleen R.] NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2012 VL 49 SU 1 SI SI BP S112 EP S113 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 080VN UT WOS:000314272300605 ER PT J AU White, SF Pope, K Sinclair, S Brislin, SJ Williams, WC Pine, DS Blair, JR AF White, Stuart F. Pope, Kayla Sinclair, Stephen Brislin, Sarah J. Williams, W. C. Pine, Daniel S. Blair, James R. TI DISRUPTED EXPECTED-VALUE AND PREDICTION ERROR SIGNALING DURING A PASSIVE AVOIDANCE TASK IS MODULATED BY PSYCHOPATHIC TRAITS IN YOUTH WITH DISRUPTIVE BEHAVIOR DISORDERS SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 52nd Annual Meeting of the Society-for-Psychophysiological-Research CY SEP 19-23, 2012 CL New Orleans, LA SP Soc Psychophysiol Res C1 [White, Stuart F.; Sinclair, Stephen; Brislin, Sarah J.; Williams, W. C.; Pine, Daniel S.; Blair, James R.] NIMH, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2012 VL 49 SU 1 SI SI BP S6 EP S6 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 080VN UT WOS:000314272300027 ER PT J AU Swank, AM Horton, J Fleg, JL Fonarow, GC Keteyian, S Goldberg, L Wolfel, G Handberg, EM Bensimhon, D Illiou, MC Vest, M Ewald, G Blackburn, G Leifer, E Cooper, L Kraus, WE AF Swank, Ann M. Horton, John Fleg, Jerome L. Fonarow, Gregg C. Keteyian, Steven Goldberg, Lee Wolfel, Gene Handberg, Eileen M. Bensimhon, Dan Illiou, Marie-Christine Vest, Marianne Ewald, Greg Blackburn, Gordon Leifer, Eric Cooper, Lawton Kraus, William E. CA HF-ACTION Investigators TI Modest Increase in Peak VO2 Is Related to Better Clinical Outcomes in Chronic Heart Failure Patients Results From Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training SO CIRCULATION-HEART FAILURE LA English DT Article DE exercise testing; heart failure; peak oxygen uptake ID LEFT-VENTRICULAR DYSFUNCTION; RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; PROGNOSTIC VALUE; CARDIAC TRANSPLANTATION; OXYGEN-CONSUMPTION; HF-ACTION; CAPACITY; IMPROVEMENT; SAFETY AB Background-The prognostic ability of a single measurement of peak oxygen uptake (VO2) is well established in patients with chronic heart failure. The relation between a change in peak VO2 and clinical outcomes is not well defined. Methods and Results-This investigation determined whether an increase in peak VO2 was associated with a lower risk of the primary end point of time to all-cause mortality or all-cause hospitalization and 3 secondary end points. In Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training, an exercise training trial for patients with systolic heart failure, cardiopulmonary exercise tests were performed at baseline and approximate to 3 months later in 1620 participants. Median peak VO2 in the combined sample increased from 15.0 (11.9-18.0 Q1-Q3) to 15.4 (12.3-18.7 Q1-Q3) mL.kg(-1).min(-1). Every 6% increase in peak VO2, adjusted for other significant predictors, was associated with a 5% lower risk of the primary end point (hazard ratio=0.95; CI=0.93-0.98; P<0.001); a 4% lower risk of the secondary end point of time to cardiovascular mortality or cardiovascular hospitalization (hazard ratio=0.96; CI=0.94-0.99; P<0.001); an 8% lower risk of cardiovascular mortality or heart failure hospitalization (hazard ratio=0.92; CI=0.88-0.96; P<0.001); and a 7% lower all-cause mortality (hazard ratio=0.93; CI=0.90-0.97; P<0.001). Conclusions-Among patients with chronic systolic heart failure, a modest increase in peak VO2 over 3 months was associated with a more favorable outcome. Monitoring the change in peak VO2 for such patients may have benefit in assessing prognosis. C1 [Swank, Ann M.] Univ Louisville, Exercise Physiol Lab, FACSM, CSCS, Louisville, KY 40292 USA. [Horton, John] Duke Clin Res Inst, Durham, NC USA. [Fleg, Jerome L.; Cooper, Lawton] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Leifer, Eric] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Fonarow, Gregg C.] Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Keteyian, Steven] Henry Ford Hosp, Dept Med, Div Cardiovasc Med, Detroit, MI 48202 USA. [Goldberg, Lee] Univ Penn, Philadelphia, PA 19104 USA. [Wolfel, Gene] Univ Colorado Denver, Div Cardiol, Aurora, CO USA. [Handberg, Eileen M.] Univ Florida, Div Cardiovasc Med, Gainesville, FL USA. [Bensimhon, Dan] LeBauer Cardiovasc Res Fdn, Greensboro, NC USA. [Illiou, Marie-Christine] APHP Corentin Celton, Cardiac Rehabil Dept, Issy Les Moulineaux, France. [Vest, Marianne] Univ Hosp Cleveland, Case Med Ctr, Cleveland, OH 44106 USA. [Ewald, Greg] Washington Univ, Sch Med, Div Cardiol, St Louis, MO USA. [Blackburn, Gordon] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Kraus, William E.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. RP Swank, AM (reprint author), Univ Louisville, Exercise Physiol Lab, FACSM, CSCS, Louisville, KY 40292 USA. EM swank@louisville.edu OI Goldberg, Lee/0000-0002-7906-9638; Kraus, William E/0000-0003-1930-9684 FU National Heart, Lung, and Blood Institute [5U01HL063747, 5U01HL066461, 5U01HL068973, 5U01HL066501, 5U01HL066482, 5U01HL064250, 5U01HL066494, 5U01HL064257, 5U01HL068980, 5U01HL064265, 5U01HL064264]; National Institute on Aging [R37AG118915, P60AG010484] FX Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training was funded by grants 5U01HL063747, 5U01HL066461, 5U01HL068973, 5U01HL066501, 5U01HL066482, 5U01HL064250, 5U01HL066494, 5U01HL064257, 5U01HL068980, 5U01HL064265, 5U01HL064264 from the National Heart, Lung, and Blood Institute and grants R37AG118915 and P60AG010484 from the National Institute on Aging. NR 40 TC 37 Z9 39 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD SEP PY 2012 VL 5 IS 5 BP 579 EP 585 DI 10.1161/CIRCHEARTFAILURE.111.965186 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 071GV UT WOS:000313579500009 PM 22773109 ER PT J AU Kagan, JM Rosas, SR Siskind, RL Campbell, RD Gondwe, D Munroe, D Trochim, WMK Schouten, JT AF Kagan, Jonathan M. Rosas, Scott R. Siskind, Rona L. Campbell, Russell D. Gondwe, Daniel Munroe, David Trochim, William M. K. Schouten, Jeffrey T. TI Community-Researcher Partnerships at NIAID HIV/AIDS Clinical Trials Sites: Insights for Evaluation and Enhancement SO PROGRESS IN COMMUNITY HEALTH PARTNERSHIPS-RESEARCH EDUCATION AND ACTION LA English DT Article DE Community-based participatory research; community health research; process issues; HIV/AIDS; needs assessment; education; evaluation studies; health care evaluation mechanisms; health care access and evaluation ID HIV PREVENTION RESEARCH; KNOWLEDGE-TRANSLATION; ADVISORY BOARDS; PUBLIC-HEALTH; GLOBAL HEALTH; ENGAGEMENT; CONSULTATION; CHALLENGES; PROMOTION AB Background: Community engagement has been a corner-stone of National Institute of Allergy and Infectious Diseases (NIAID)'s HIV/AIDS clinical trials programs since 1990. Stakeholders now consider this critical to success, hence the impetus to develop evaluation approaches. Objectives: The purpose was to assess the extent to which community advisory boards (CABs) at HIV/AIDS trials sites are being integrated into research activities. Methods: CABs and research staff (RS) at NIAID research sites were surveyed for how each viewed (a) the frequency of activities indicative of community involvement, (b) the means for identifying, prioritizing, and supporting CAB needs, and (c) mission and operational challenges. Results: Overall, CABs and RS share similar views about the frequency of community involvement activities. Cluster analysis reveals three groups of sites based on activity frequency ratings, including a group notable for CAB-RS discordance. Conclusions: Assessing differences between community and researcher perceptions about the frequency of and challenges posed by specific engagement activities may prove useful in developing evaluation tools for assessing community engagement in collaborative research settings. C1 [Kagan, Jonathan M.] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Siskind, Rona L.] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Campbell, Russell D.; Schouten, Jeffrey T.] Fred Hutchinson Canc Res Ctr, HIV AIDS Network Coordinat, Seattle, WA USA. [Gondwe, Daniel] Univ Malawi, Coll Med, Zomba, Malawi. [Trochim, William M. K.] Cornell Univ, Dept Policy Anal & Management, Ithaca, NY 14853 USA. RP Kagan, JM (reprint author), NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. FU NCRR NIH HHS [UL1 RR024996-05, UL1 RR024996, UL1RR024996]; NIAID NIH HHS [U01AI068614, U01 AI068614-05, U01 AI068614, N01AI-50022, N01 AI050022, N01AI50022] NR 39 TC 4 Z9 4 U1 2 U2 8 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1557-0541 J9 PROG COMM HLTH PARTN JI Prog. Community Health Partnersh. PD FAL PY 2012 VL 6 IS 3 SI SI BP 311 EP 320 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 068WI UT WOS:000313396500012 PM 22982844 ER PT J AU Kanter, MM Kris-Etherton, PM Fernandez, ML Vickers, KC Katz, DL AF Kanter, Mitchell M. Kris-Etherton, Penny M. Fernandez, Maria Luz Vickers, Kasey C. Katz, David L. TI Exploring the Factors That Affect Blood Cholesterol and Heart Disease Risk: Is Dietary Cholesterol as Bad for You as History Leads Us to Believe? SO ADVANCES IN NUTRITION LA English DT Article; Proceedings Paper CT Symposium on Exploring the Factors that Impact Blood Cholesterol and Heart Disease Risk - Is Dietary Cholesterol as Bad for You as History Leads us to Believe Given at the Annual Experimental Biology Meeting CY APR 13, 2011 CL Washington, DC SP Amer Soc Nutr, Nutr Translation RIS ID HIGH-DENSITY-LIPOPROTEIN; EGG CONSUMPTION; ENDOTHELIAL FUNCTION; CARDIOVASCULAR-DISEASE; PLASMA-LIPOPROTEINS; HEALTHY POPULATIONS; ELDERLY POPULATION; HDL CHOLESTEROL; RESTRICTED DIET; INCREASE AB This paper summarizes presentations given at the 2011 Experimental Biology meetings about the latest research and a paleoanthropological perspective pertaining to the relationship between dietary cholesterol intake and cardiovascular disease risk. For much of the past 50 years, a great deal of the scientific literature regarding dietary fat and cholesterol intake has indicated a strong positive correlation with heart disease. In recent years, however, there have been a number of epidemiological studies that did not support a relationship between cholesterol intake and cardiovascular disease. Further, a number of recent clinical trials that looked at the effects of long-term egg consumption (as a vehicle for dietary cholesterol) reported no negative impact on various indices of cardiovascular health and disease. Coupled with data indicating that the impact of lowering dietary cholesterol intake on serum LDL levels is small compared with other dietary and lifestyle factors, there is a need to consider how otherwise healthy foods can be incorporated in the diet to meet current dietary cholesterol recommendations. Because eggs are a healthful food, it is particularly important that sensible strategies be recommended for inclusions of eggs in a healthy diet. Adv. Nutr. 3: 711-717, 2012. C1 [Kanter, Mitchell M.] Egg Nutr Ctr, Park Ridge, IL USA. [Kris-Etherton, Penny M.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Fernandez, Maria Luz] Univ Connecticut, Dept Nutr Sci, Storrs, CT USA. [Vickers, Kasey C.] NHLBI, Bethesda, MD 20892 USA. [Katz, David L.] Yale Univ, Prevent Res Ctr, New Haven, CT USA. RP Kanter, MM (reprint author), Egg Nutr Ctr, Park Ridge, IL USA. EM mkanter@enc-online.org OI Katz, David/0000-0001-6845-6192 NR 52 TC 24 Z9 25 U1 3 U2 47 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 2161-8313 EI 2156-5376 J9 ADV NUTR JI Adv. Nutr. PD SEP PY 2012 VL 3 IS 5 BP 711 EP 717 DI 10.3945/an.111.001321 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 066LL UT WOS:000313222200008 PM 22983850 ER PT J AU Guha, R Willighagen, E AF Guha, Rajarshi Willighagen, Egon TI A Survey of Quantitative Descriptions of Molecular Structure SO CURRENT TOPICS IN MEDICINAL CHEMISTRY LA English DT Review DE Descriptor; QSAR; toolkit; predictive model ID STRUCTURE-PROPERTY RELATIONSHIP; GLASS-TRANSITION TEMPERATURES; AMINO-ACID DESCRIPTORS; SURFACE-AREA; AUTO-CORRELATION; POROUS MATERIALS; NEURAL NETWORKS; DRUG COMPOUNDS; ALPHA-SHAPES; PREDICTION AB Numerical characterization of molecular structure is a first step in many computational analysis of chemical structure data. These numerical representations, termed descriptors, come in many forms, ranging from simple atom counts and invariants of the molecular graph to distribution of properties, such as charge, across a molecular surface. In this article we first present a broad categorization of descriptors and then describe applications and toolkits that can be employed to evaluate them. We highlight a number of issues surrounding molecular descriptor calculations such as versioning and reproducibility and describe how some toolkits have attempted to address these problems. C1 [Guha, Rajarshi] NIH, Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Willighagen, Egon] Maastricht Univ, Dept Bioinformat BiGCaT, NL-6200 MD Maastricht, Netherlands. RP Guha, R (reprint author), NIH, Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM rajarshi.guha@gmail.com RI Willighagen, Egon/C-6136-2008 OI Willighagen, Egon/0000-0001-7542-0286 FU Intramural NIH HHS [ZIB TR000004-01] NR 86 TC 4 Z9 4 U1 0 U2 28 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0266 J9 CURR TOP MED CHEM JI Curr. Top. Med. Chem. PD SEP PY 2012 VL 12 IS 18 BP 1946 EP 1956 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 069JG UT WOS:000313430900002 PM 23110530 ER PT J AU Borstnik, U Miller, BT Brooks, BR Janezic, D AF Borstnik, Urban Miller, Benjamin T. Brooks, Bernard R. Janezic, Dusanka TI Implementation of the force decomposition machine for molecular dynamics simulations SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE Personal computer clusters; Beowulf clusters; Network topologies; Interconnection architectures ID PERFORMANCE; PROGRAM; SYSTEMS; CHARMM AB We present the design and implementation of the force decomposition machine (FDM), a cluster of personal computers (PCs) that is tailored to running molecular dynamics (MD) simulations using the distributed diagonal force decomposition (DDFD) parallelization method. The cluster interconnect architecture is optimized for the communication pattern of the DDFD method. Our implementation of the FDM relies on standard commodity components even for networking. Although the cluster is meant for DDFD MD simulations, it remains general enough for other parallel computations. An analysis of several MD simulation runs on both the FDM and a standard PC cluster demonstrates that the FDM's interconnect architecture provides a greater performance compared to a more general cluster interconnect. (C) 2012 Elsevier Inc. All rights reserved. C1 [Borstnik, Urban; Janezic, Dusanka] Natl Inst Chem, SI-1000 Ljubljana, Slovenia. [Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, NIH, Rockville, MD 20892 USA. [Janezic, Dusanka] Univ Primorska, FAMNIT, SI-6000 Koper, Slovenia. RP Janezic, D (reprint author), Natl Inst Chem, Hajdrihova 19, SI-1000 Ljubljana, Slovenia. EM urban@cmm.ki.si; btmiller@nhlbi.nih.gov; brb@nih.gov; dusa@cmm.ki.si OI Miller, Benjamin/0000-0003-1647-0122 FU Slovenian Research Agency [P1-0002]; NIH, NHLBI FX The authors would like to acknowledge the financial support of the Slovenian Research Agency under Grant No. P1-0002. This research was supported in part by the Intramural Research Program of the NIH, NHLBI. The authors would also like to thank Dr. Milan Hodoscek for his valuable insights and Rishi P. Singh for assistance assembling the FDM. NR 29 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD SEP PY 2012 VL 38 BP 243 EP 247 DI 10.1016/j.jmgm.2012.06.015 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 068UX UT WOS:000313392800025 PM 23085166 ER PT J AU Cora, MC King, D Betz, LJ Wilson, R Travlos, GS AF Cora, Michelle C. King, Debra Betz, Laura J. Wilson, Ralph Travlos, Greg S. TI Artifactual Changes in Sprague-Dawley Rat Hematologic Parameters after Storage of Samples at 3 degrees C and 21 degrees C SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID BLOOD FOLLOWING STORAGE; ROOM-TEMPERATURE; CELL COUNT; ANALYZER; STABILITY; CANINE; FILM; DOG AB Circumstances can occur that prevent timely analysis of blood samples. The purpose of this study was to characterize artifactual changes in rat hematologic parameters after storage of samples at 3 and 21 degrees C and to document the effects of storage on peripheral blood smear findings. EDTA-treated blood samples were collected from 12 male Sprague Dawley rats. Samples were analyzed on an impedance hematology analyzer within 5 min after collection and then at 6, 24, 48, and 72 h after storage at 3 degrees C or 21 degrees C. Corresponding blood smears were examined microscopically. RBC count and hemoglobin concentration had not changed after 72 h at either temperature. At 3 degrees C, the instrument-derived hematocrit and manually measured PCV remained unchanged for 72 h. Compared with 0-h values, platelet counts and MCV at 6 h and MPV at 24 h were higher at either temperature. In general, WBC count and neutrophil and lymphocyte percentages were unchanged for at least 48 h at either temperature. Prominent blood smear findings were smudge cells, pyknotic leukocytes, echinocytes, and spheroechinocytes. Although some observed changes were within analytic variability or clinically negligible, the best practice likely is to measure hematologic parameters within 6 h after collection. In the event of delayed analysis, specimens should be stored in the refrigerator, and care must be taken not to misinterpret artifactual changes as pathologic findings. C1 [Cora, Michelle C.; King, Debra; Wilson, Ralph; Travlos, Greg S.] NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. [Betz, Laura J.] SRA Int, Durham, NC USA. RP Cora, MC (reprint author), NIEHS, Cellular & Mol Pathol Branch, Natl Toxicol Program, Natl Inst Hlth, POB 12233, Res Triangle Pk, NC 27709 USA. EM coramc@niehs.nih.gov NR 24 TC 2 Z9 2 U1 0 U2 5 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2012 VL 51 IS 5 BP 616 EP 621 PG 6 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 067NV UT WOS:000313303300012 PM 23312091 ER PT J AU Malik, M Segars, J Catherino, WH AF Malik, Minnie Segars, James Catherino, William H. TI x Integrin beta 1 regulates leiomyoma cytoskeletal integrity and growth SO MATRIX BIOLOGY LA English DT Article DE Uterine leiomyoma; Extracellular matrix; Integrin beta 1; Cytoskeletal integrity; RhoA; Laminins ID SERUM RESPONSE FACTOR; EXTRACELLULAR-MATRIX; UTERINE LEIOMYOMA; ACTIN CYTOSKELETON; CELL-ADHESION; TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; NORMAL MYOMETRIUM; HEPATIC-FIBROSIS; GENE-EXPRESSION AB Uterine leiomyomas are characterized by an excessive extracellular matrix, increased mechanical stress, and increased active RhoA. Previously, we observed that mechanical signaling was attenuated in leiomyoma, but the mechanisms responsible remain unclear. Integrins, especially integrin beta 1, are transmembrane adhesion receptors that couple extracellular matrix stresses to the intracellular cytoskeleton to influence cell proliferation and differentiation. Here we characterized integrin and laminin to signaling in leiomyoma cells. We observed a 2.25 +/- 0.32 fold increased expression of integrin beta 1 in leiomyoma cells, compared to myometrial cells. Antibody-mediated inhibition of integrin beta 1 led to significant growth inhibition in leiomyoma cells and a loss of cytoskeletal integrity. Specifically, polymerization of actin filaments and formation of focal adhesions were reduced by inhibition of integrin beta 1. Inhibition of integrin beta 1 in leiomyoma cells led to 0.81 +/- 0.02 fold decrease in active RhoA, and resembled levels found in serum-starved cells. Likewise, inhibition of integrin beta 1 was accompanied by a decrease in phospho-ERK. Compared to myometrial cells, leiomyoma cells demonstrated increased expression of integrin alpha 6 subunit to laminin receptor (1.91 +/- 0.11 fold), and increased expression of laminin 5 alpha (1.52 +/- 0.02), laminin 5 beta (3.06 +/- 0.92), and laminin 5 gamma (1.66 +/- 0.06). Of note, leiomyoma cells grown on laminin matrix appear to realign themselves. Taken together, the findings reveal that the attenuated mechanical signaling in leiomyoma cells is accompanied by an increased expression and a dependence on integrin beta 1 signaling in leiomyoma cells, compared to myometrial cells. Published by Elsevier B.V. C1 [Malik, Minnie; Segars, James; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Segars, James; Catherino, William H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept OB GYN, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM william.catherino@usuhs.edu OI Malik, Minnie/0000-0003-1129-6575 FU Intramural NIH HHS [ZIE HD008737-11] NR 87 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD SEP-OCT PY 2012 VL 31 IS 7-8 BP 389 EP 397 DI 10.1016/j.matbio.2012.09.005 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 066MQ UT WOS:000313225300004 PM 23023061 ER PT J AU Rao, CV Mohammed, A Janakiram, NB Li, Q Ritchie, RL Lightfoot, S Vibhudutta, A Steele, VE AF Rao, Chinthalapally V. Mohammed, Altaf Janakiram, Naveena B. Li, Qian Ritchie, Rebekah L. Lightfoot, Stan Vibhudutta, Awasthi Steele, Vernon E. TI Inhibition of Pancreatic Intraepithelial Neoplasia Progression to Carcinoma by Nitric Oxide-Releasing Aspirin in p48(Cre/+)-LSL-Kras(G12D/+) Mice SO NEOPLASIA LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ENGINEERED MOUSE MODELS; CANCER CELL-GROWTH; COLON-CANCER; RISK; PREVENTION; CYCLOOXYGENASE-2; LESIONS; CHEMOPREVENTION; ADENOCARCINOMA AB Nitric oxide-releasing aspirin (NO-aspirin) represents a novel class of promising chemopreventive agents. Unlike conventional nonsteroidal anti-inflammatory drugs, NO-aspirin seems to be free of adverse effects while retaining the beneficial activities of its parent compound. The effect of NO-aspirin on pancreatic carcinogenesis was investigated by assessing the development of precursor pancreatic lesions and adenocarcinomas in Kras(G12D/+) transgenic mice that recapitulate human pancreatic cancer progression. Six-week-old male p48(Cre/+)-LSL-Kras(G12D/+) transgenic mice (20 per group) were fed diets containing 0, 1000, or 2000 ppm NO-aspirin. The development of pancreatic tumors was monitored by positron emission tomography imaging. All mice were killed at the age of 41 weeks and assessed for pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) and for molecular changes in the tumors. Our results reveal that NO-aspirin at 1000 and 2000 ppm significantly suppressed pancreatic tumor weights, PDAC incidence, and carcinoma in situ (PanIN-3 lesions). The degree of inhibition of PanIN-3 and carcinoma was more pronounced with NO-aspirin at 1000 ppm (58.8% and 48%, respectively) than with 2000 ppm (47% and 20%, respectively). NO-aspirin at 1000 ppm significantly inhibited the spread of carcinoma in the pancreas (similar to 97%; P < .0001). Decreased expression of cyclooxygenase (COX; with similar to 42% inhibition of total COX activity), inducible nitric oxide synthase, proliferating cell nuclear antigen, Bcl-2, cyclin D1, and beta-catenin was observed, with induction of p21, p38, and p53 in the pancreas of NO-aspirin-treated mice. These results suggest that low-dose NO-aspirin possesses inhibitory activity against pancreatic carcinogenesis by modulating multiple molecular targets. Neoplasia (2012) 14, 778-787 C1 [Rao, Chinthalapally V.; Mohammed, Altaf; Janakiram, Naveena B.; Li, Qian; Ritchie, Rebekah L.] Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev,Coll Med, Hematol Oncol Sect,Peggy & Charles Stephenson Can, Oklahoma City, OK 73104 USA. [Lightfoot, Stan] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Vibhudutta, Awasthi] Univ Oklahoma, Hlth Sci Ctr, Dept Pharmaceut Sci, Coll Pharm, Oklahoma City, OK 73104 USA. [Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev,Coll Med, Hematol Oncol Sect,Peggy & Charles Stephenson Can, 975 NE 10th St,BRC Bldg 2,Room 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU National Cancer Institute [N01CN-53300] FX We acknowledge the support from the National Cancer Institute (N01CN-53300). NR 37 TC 22 Z9 23 U1 1 U2 9 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD SEP PY 2012 VL 14 IS 9 BP 778 EP U127 DI 10.1593/neo.121026 PG 11 WC Oncology SC Oncology GA 068DR UT WOS:000313345200001 PM 23019409 ER PT J AU Nash, T AF Nash, Theodore TI Edema surrounding calcified intracranial cysticerci: clinical manifestations, natural history, and treatment SO PATHOGENS AND GLOBAL HEALTH LA English DT Article DE Neurocysticercosis; Taenia solium; Calcifications; Perilesional edema ID RURAL GUATEMALAN COMMUNITIES; TAENIA-SOLIUM TAENIASIS; PERILESIONAL EDEMA; NEUROCYSTICERCOSIS LESIONS; CEREBRAL CYSTICERCOSIS; PRAZIQUANTEL THERAPY; STATUS-EPILEPTICUS; MRI ABNORMALITIES; ANDEAN COMMUNITY; EPILEPSY AB Calcified granulomas are the most common radiological finding in neurocysticercosis (10-20% of endemic populations). A small proportion serves as foci of seizure activity, which results in large numbers of persons with epilepsy. Calcified granulomas are not all the same. Some demonstrate blood-brain barrier dysfunction (magnetic resonance imaging enhancement) most likely due to the presence of inflammation, visualizable scolices, and/or gliosis. About half the patients with a recent history of seizures, positive serology, and only calcified lesions develop perilesional edema at the time of a seizure recurrence. The natural history, treatment, and pathophysiology of this phenomenon are not well studied. Episodes are usually associated with seizures or other neurological manifestations, resolve by 4-6 weeks, sometimes occur repeatedly, and usually involve a subset of the same calcifications. Treatment is supportive. Histopathological examination of one calcification associated with multiple perilesional edema episodes revealed significant inflammation and supports the concept that perilesional edema is inflammatory in nature. This most likely is due to host responses to released or newly recognized parasite antigen and/or upregulation of the host immune response. Immunosuppressive and anti-inflammatory agents may be useful in prevention and/or treatment of this phenomenon. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Nash, T (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike,Bldg 45, Bethesda, MD 20892 USA. EM tnash@niaid.nih.gov FU intramural NIAID, research program, NIH FX This work was supported by the intramural NIAID, research program, NIH. NR 52 TC 11 Z9 11 U1 0 U2 4 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 2047-7724 J9 PATHOG GLOB HEALTH JI Pathog. Glob. Health PD SEP PY 2012 VL 106 IS 5 BP 275 EP 279 DI 10.1179/2047773212Y.0000000026 PG 5 WC Public, Environmental & Occupational Health; Parasitology; Tropical Medicine SC Public, Environmental & Occupational Health; Parasitology; Tropical Medicine GA 068IK UT WOS:000313359700005 PM 23265551 ER PT J AU Carlsson, J Tosh, DK Phan, K Gao, ZG Jacobson, KA AF Carlsson, Jens Tosh, Dilip K. Phan, Khai Gao, Zhan-Guo Jacobson, Kenneth A. TI Structure-Activity Relationships and Molecular Modeling of 1,2,4-Triazoles as Adenosine Receptor Antagonists SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE 1,2,4-Triazole; A(2A) adenosine receptor; antagonist; molecular docking; structure-activity relationship ID A(2A) RECEPTOR; SUBTYPE-SELECTIVITY; LIGAND; DOCKING; PREDICTION; DISCOVERY; RESIDUES AB The structure-activity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A(2A) adenosine receptor (hA(2A)AR) was explored. Thirty-three analogs of a ligand that was discovered in a structure-based virtual screen against the hA(2A)AR were tested in hA(1), A(2A), and A(3) radioligand binding assays and in functional assays for the A(2B)AR subtype. As a series of closely related analogs of the initial lead, 1, did not display improved binding affinity or selectivity, molecular docking was used to guide the selection of more distantly related molecules. This resulted in the discovery of 32, a hA(2A)AR antagonist (K-i 200 nM) with high ligand efficiency. In light of the SAR for the 1,2,4-triazole scaffold, we also investigated the binding mode of these compounds based on docking to several A(2A)AR crystal structures. C1 [Carlsson, Jens] Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res, SE-10691 Stockholm, Sweden. [Tosh, Dilip K.; Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Carlsson, J (reprint author), Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res, SE-10691 Stockholm, Sweden. EM jens.carlsson@dbb.su.se; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Carlsson, Jens/0000-0003-4623-2977 FU NIDDK Intramural Res. Program; Knut and Alice Wallenberg Foundation FX Supported by the NIDDK Intramural Res. Program (to K.A.J.) and the Knut and Alice Wallenberg Foundation (to J.C.). NR 21 TC 10 Z9 12 U1 0 U2 8 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 SEP PY 2012 VL 3 IS 9 BP 715 EP 720 DI 10.1021/ml300097g PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 055KW UT WOS:000312416200010 PM 23342198 ER PT J AU Erhardt, A Akula, N Schumacher, J Czamara, D Karbalai, N Muller-Myhsok, B Mors, O Borglum, A Kristensen, AS Woldbye, DPD Koefoed, P Eriksson, E Maron, E Metspalu, A Nurnberger, J Philibert, RA Kennedy, J Domschke, K Reif, A Deckert, J Otowa, T Kawamura, Y Kaiya, H Okazaki, Y Tanii, H Tokunaga, K Sasaki, T Ioannidis, JPA McMahon, FJ Binder, EB AF Erhardt, A. Akula, N. Schumacher, J. Czamara, D. Karbalai, N. Mueller-Myhsok, B. Mors, O. Borglum, A. Kristensen, A. S. Woldbye, D. P. D. Koefoed, P. Eriksson, E. Maron, E. Metspalu, A. Nurnberger, J. Philibert, R. A. Kennedy, J. Domschke, K. Reif, A. Deckert, J. Otowa, T. Kawamura, Y. Kaiya, H. Okazaki, Y. Tanii, H. Tokunaga, K. Sasaki, T. Ioannidis, J. P. A. McMahon, F. J. Binder, E. B. TI Replication and meta-analysis of TMEM132D gene variants in panic disorder SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID GENOME-WIDE ASSOCIATION; JAPANESE POPULATION; CANDIDATE GENE AB A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n 1038 cases and n 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations. Translational Psychiatry (2012) 2, e156; doi:10.1038/tp.2012.85; published online 4 September 2012 C1 [Erhardt, A.; Czamara, D.; Karbalai, N.; Mueller-Myhsok, B.; Binder, E. B.] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Akula, N.; McMahon, F. J.] NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Schumacher, J.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Mors, O.; Kristensen, A. S.] Aarhus Univ, Dept Psychiat, Aarhus, Denmark. [Borglum, A.] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Woldbye, D. P. D.; Koefoed, P.] Univ Copenhagen, Dept Neurosci & Pharmacol, Copenhagen, Denmark. [Eriksson, E.] Univ Gothenburg, Gothenburg, Sweden. [Metspalu, A.] Univ Tartu, Inst Mol & Cell Biol, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Metspalu, A.] Estonian Bioctr, Tartu, Estonia. [Nurnberger, J.] Indiana Univ, Dept Psychiat, Indianapolis, IN 46204 USA. [Philibert, R. A.] Univ Iowa, Iowa City, IA USA. [Kennedy, J.] Univ Toronto, Toronto, ON, Canada. [Domschke, K.; Reif, A.; Deckert, J.] Univ Wurzburg, Dept Psychiat, D-8700 Wurzburg, Germany. [Otowa, T.] Univ Tokyo, Grad Sch Med, Dept Neuropsychiat, Tokyo, Japan. [Kawamura, Y.] Nagoya Mental Clin, Res Ctr Pan Disorder, Nagoya, Aichi, Japan. [Kaiya, H.] Akasaka Mental Clin, Tokyo, Japan. [Kaiya, H.] Res Ctr PanIC Disorder, Nagoya, Aichi, Japan. [Okazaki, Y.] Tokyo Metropolitan Matsuzawa Hosp, Dept Neurol, Tokyo, Japan. [Tanii, H.] Mie Univ, Grad Sch Med, Dept Neuropsychiat, Tsu, Mie, Japan. [Tokunaga, K.] Univ Tokyo, Grad Sch Med, Dept Human Genet, Tokyo, Japan. [Sasaki, T.] Univ Tokyo, Grad Sch Educ, Lab Hlth Educ, Tokyo, Japan. [Ioannidis, J. P. A.] Stanford Univ, Stanford Prevent Res Ctr, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ioannidis, J. P. A.] Stanford Univ, Stanford Prevent Res Ctr, Dept Stat, Stanford, CA 94305 USA. [Ioannidis, J. P. A.] Stanford Univ, Stanford Prevent Res Ctr, Dept Med, Stanford, CA 94305 USA. RP Erhardt, A (reprint author), Max Planck Inst Psychiat, Kraepelin St 2-10, D-80804 Munich, Germany. EM erhardt@mpipsykl.mpg.de RI Domschke, Katharina/I-7921-2013; Binder, Elisabeth/K-8905-2014; Schumacher, Johannes/F-4970-2015; OI Schumacher, Johannes/0000-0001-9217-6457; McMahon, Francis/0000-0002-9469-305X; Nurnberger, John/0000-0002-7674-1767 FU NIMH Intramural Research Program; Deutsche Forschungsgemeinschaft [SFB-TRR-58] FX We thank all the collaborators from the initial study to TMEM132D for their excellent contributions, especially Marcella Rietschel, Markus Noethen, Sven Cichon, Borwin Bandelow, Wolfgang Meier, Ludwig Czibere and Rainer Landgraf. We thank the support by the NIMH Intramural Research Program (FJM, NA, JS), and the grant support to Andreas Reif, Jurgen Deckert and Katharina Domschke by the Deutsche Forschungsgemeinschaft, SFB-TRR-58, projects C2 and Z2. NR 16 TC 21 Z9 21 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD SEP PY 2012 VL 2 AR e156 DI 10.1038/tp.2012.85 PG 6 WC Psychiatry SC Psychiatry GA 062DT UT WOS:000312900000001 PM 22948381 ER PT J AU Lahat, A Perez-Edgar, K Degnan, KA Guyer, AE Lejuez, CW Ernst, M Pine, DS Fox, NA AF Lahat, A. Perez-Edgar, K. Degnan, K. A. Guyer, A. E. Lejuez, C. W. Ernst, M. Pine, D. S. Fox, N. A. TI Early childhood temperament predicts substance use in young adults SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE behavioral inhibition; longitudinal; striatal function; substance use; temperament ID ALCOHOL-USE DISORDER; BEHAVIORAL-INHIBITION; ADOLESCENT ALCOHOL; QUESTIONNAIRE; RISK; INVOLVEMENT; STRIATUM; STIMULI; ANXIETY AB Behavioral inhibition (BI) is an important early childhood marker of risk for later psychiatric problems. The current 20-year prospective, longitudinal study focused on individual differences in this early temperament and adolescent brain function. As adolescents, 83 participants initially identified in infancy with the temperament of BI were assessed using functional imaging to examine striatal responses to incentives. Five years later, as young adults, these participants provided self-report of their substance use. Our findings show that children's early temperament interacts with their striatal sensitivity to incentives in adolescence to predict their level of substance use in young adulthood. Those young adults who, as children, showed the highest levels of BI reported the greatest substance use if, as adolescents, they also exhibited striatal hypersensitivity to incentives. These longitudinal data delineate one developmental pathway involving early biology and brain mechanisms for substance use in young adulthood. Translational Psychiatry (2012) 2, e157; doi:10.1038/tp.2012.87; published online 4 September 2012 C1 [Lahat, A.; Degnan, K. A.; Fox, N. A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Perez-Edgar, K.] Penn State Univ, Ctr Child Study, University Pk, PA 16802 USA. [Guyer, A. E.] Univ Calif Davis, Ctr Mind & Brain, Dept Human & Community Dev, Davis, CA 95616 USA. [Lejuez, C. W.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Ernst, M.; Pine, D. S.] NIMH, Sect Dev Affect Neurosci, Bethesda, MD 20892 USA. RP Fox, NA (reprint author), Univ Maryland, Dept Human Dev, 3304 Benjamin Bldg, College Pk, MD 20742 USA. EM fox@umd.edu OI Perez-Edgar, Koraly/0000-0003-4051-9563 FU NIH extramural grants [HD17899, MH074454, K01 MH073569-01A1]; Intramural Research Program of the National Institute of Mental Health, NIH Career Development Grant [MH080076] FX This research was supported by NIH extramural grants HD17899, MH074454 (NAF) and K01 MH073569-01A1 (KPE), and the Intramural Research Program of the National Institute of Mental Health, NIH Career Development Grant MH080076 (AEG). NR 51 TC 7 Z9 7 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD SEP PY 2012 VL 2 AR e157 DI 10.1038/tp.2012.87 PG 6 WC Psychiatry SC Psychiatry GA 062DT UT WOS:000312900000002 PM 22948382 ER PT J AU Meier, S Mattheisen, M Vassos, E Strohmaier, J Treutlein, J Josef, F Breuer, R Degenhardt, F Muhleisen, TW Muller-Myhsok, B Steffens, M Schmael, C McMahon, FJ Nothen, MM Cichon, S Schulze, TG Rietschel, M AF Meier, S. Mattheisen, M. Vassos, E. Strohmaier, J. Treutlein, J. Josef, F. Breuer, R. Degenhardt, F. Muehleisen, T. W. Mueller-Myhsok, B. Steffens, M. Schmael, C. McMahon, F. J. Noethen, M. M. Cichon, S. Schulze, T. G. Rietschel, M. CA Bipolar Disorder Genome Study BiGS TI Genome-wide significant association between a 'negative mood delusions' dimension in bipolar disorder and genetic variation on chromosome 3q26.1 SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE bipolar disorder; delusions; factor dimensions; genome-wide; SLC2A2; subphenotype ID LINKAGE; SCHIZOPHRENIA; DEPRESSION; PEDIGREES; SUSCEPTIBILITY; ACTIVATION; EXPRESSION; PHENOTYPE; PSYCHOSIS; FAMILIES AB Research suggests that clinical symptom dimensions may be more useful in delineating the genetics of bipolar disorder (BD) than standard diagnostic models. To date, no study has applied this concept to data from genome-wide association studies (GWAS). We performed a GWAS of factor dimensions in 927 clinically well-characterized BD patients of German ancestry. Rs9875793, which is located in an intergenic region of 3q26.1 and in the vicinity of the solute carrier family 2 (facilitated glucose transporter), member 2 gene (SLC2A2), was significantly associated with the factor analysis-derived dimension 'negative mood delusions' (n = 927; P = 4.65 x 10(-8), odds ratio (OR) = 2.66). This dimension was comprised of the symptoms delusions of poverty, delusions of guilt and nihilistic delusions. In case-control analyses, significant association with the G allele of rs9875793 was only observed in the subgroup of BD patients who displayed symptoms of 'negative mood delusions' (allelic chi(2) model: P-G = 0.0001, OR = 1.92; item present, n = 89). Further support for the hypothesis that rs9875793 is associated with BD in patients displaying 'negative mood delusions' symptom, such as delusions of guilt, was obtained from an European American sample (GAIN/TGEN), which included 1247 BD patients and 1434 controls (P-EA = 0.028, OR = 1.27). Translational Psychiatry (2012) 2, e165; doi:10.1038/tp.2012.81; published online 25 September 2012 C1 [Meier, S.; Strohmaier, J.; Treutlein, J.; Josef, F.; Breuer, R.; Schmael, C.; Rietschel, M.] Heidelberg Univ, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-68159 Mannheim, Germany. [Mattheisen, M.; Degenhardt, F.; Muehleisen, T. W.; Noethen, M. M.; Cichon, S.] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Mattheisen, M.] Univ Bonn, Inst Genom Math, Bonn, Germany. [Mattheisen, M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Vassos, E.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Degenhardt, F.; Muehleisen, T. W.; Noethen, M. M.; Cichon, S.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Mueller-Myhsok, B.] Max Planck Inst Psychiat, Dept Stat Genet, D-80804 Munich, Germany. [Steffens, M.] Univ Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany. [McMahon, F. J.] NIMH, Human Genet Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Noethen, M. M.] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany. [Cichon, S.] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. [Schulze, T. G.] Univ Gottingen, Univ Med Ctr, Dept Psychiat & Psychotherapy, Sect Psychiat Genet, D-37075 Gottingen, Germany. RP Schulze, TG (reprint author), Univ Gottingen, Univ Med Ctr, Dept Psychiat & Psychotherapy, Sect Psychiat Genet, Von Siebold St 5, D-37075 Gottingen, Germany. EM thomas.schulze@med.uni-goettingen.de; marcella.rietschel@zi-mannheim.de RI Vassos, Evangelos/F-9825-2013; McInnis, Melvin/F-6963-2012; Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Mattheisen, Manuel/B-4949-2012; OI Vassos, Evangelos/0000-0001-6363-0438; McInnis, Melvin/0000-0002-0375-6247; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Mattheisen, Manuel/0000-0002-8442-493X; McMahon, Francis/0000-0002-9469-305X; Nothen, Markus/0000-0002-8770-2464 FU German Federal Ministry of Education and Research (BMBF) within the National Genome Research Network plus (NGFNplus); MooDS-Net [01GS08144, 01GS08147]; European Union [HEALTH-F4-2009-242257]; Alfried Krupp von Bohlen und Halbach-Stiftung; BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; Heinz Nixdorf Foundation; Helmholtz Center Munich; German Research Center for Environmental Health FX We are grateful to all of the patients who participated in this study. We also thank the probands from the community-based cohorts of PopGen, KORA and the Heinz Nixdorf Recall (HNR) study. This study was supported by the German Federal Ministry of Education and Research (BMBF) within the context of the National Genome Research Network plus (NGFNplus) and the MooDS-Net (Grant 01GS08144 to SC and MMN; Grant 01GS08147 to MR). MR was also supported by the seventh framework program of the European Union (ADAMS project, HEALTH-F4-2009-242257). MMN also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. The KORA research platform was initiated and financed by the Helmholtz Center Munich, the German Research Center for Environmental Health, which is funded by the BMBF and by the State of Bavaria. The KORA research was supported by the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The Heinz Nixdorf Recall cohort was established with the support of the Heinz Nixdorf Foundation. NR 37 TC 7 Z9 8 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD SEP PY 2012 VL 2 AR e165 DI 10.1038/tp.2012.81 PG 6 WC Psychiatry SC Psychiatry GA 062DT UT WOS:000312900000008 PM 23010768 ER PT J AU Costa, JA Leal-Pinto, E Henderson, SC Zabel, T Hawkins, ME Hanss, B AF Costa, Justin A. Leal-Pinto, Edgar Henderson, Scott C. Zabel, Troy Hawkins, Mary E. Hanss, Basil TI Use of a Pteridine Moiety to Track DNA Uptake in Cells SO PTERIDINES LA English DT Article DE DNA uptake monitoring; fluroescence label; methylisoxathopterin ID NUCLEIC-ACID CHANNEL; CYTOSOLIC MALATE-DEHYDROGENASE; TRANSMEMBRANE PROTEIN SID-1; CELLULAR UPTAKE; PHOSPHOROTHIOATE OLIGONUCLEOTIDES; MODIFIED OLIGODEOXYNUCLEOTIDES; GUANOSINE-ANALOG; TRANSPORT; RATES; LOCALIZATION AB Fluorescence labeled oligonucleotides have a long history of being used to monitor nucleic acid transport and uptake. However, it is not known if the fluorescent moiety itself physically limits the number of pathways that can be used by the cell due to steric, hydrophobic, or other chemical characteristics. Here, we report a method for comparing the uptake kinetics of oligonucleotides labeled either with the fluorescent pteridine, 3-methyl-8-(2-deoxy-beta-D-ribofuranosyl) isoxanthopterin (3MI), or the common fluorophore 5-carboxyfluorescein (5-FAM). We use a multiphoton microscopic technique to monitor nucleic acid uptake LLC-PK1, a pig renal tubular cell line that is known to have multiple uptake pathways. We find that the two fluorophores enter the cells at different rates, suggesting that choice of fluorescent moiety influences the uptake pathway used by a cell. Finally, we reconstituted an LLC-PK1 membrane channel that is selective for nucleic acids in planar lipid bilayers, and tested the ability of the labeled nucleic acids to permeate the channel. We find that 3MI, and not 5-FAM labeled oligonucleotides can traverse the plasma membrane through the channel. These results have implications for future studies aimed at delivering pteridine moieties to cells and for tracking nucleic acid transport into tissues. C1 [Costa, Justin A.; Hanss, Basil] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. [Leal-Pinto, Edgar] Virginia Commonwealth Univ, Med Ctr, Dept Physiol & Biophys, Richmond, VA USA. [Henderson, Scott C.] Virginia Commonwealth Univ, Med Ctr, Dept Anat & Neurobiol, Richmond, VA USA. [Zabel, Troy] S Denver Nephrol, Denver, CO USA. [Hawkins, Mary E.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Hanss, B (reprint author), Mt Sinai Sch Med, Dept Med, Div Nephrol, Box 1243,1 Gustave Levy Pl, New York, NY 10029 USA. EM basil.hanss@mssm.edu FU NIH-NCI [5R24 CA095823]; NSF [DBI-9724504]; NIH [1S10 RR0 9145]; NIDDK/NIH [DK065838]; National Institute of General Medical Sciences [T32GM062754] FX Microscopy was performed at the MSSM-Microscopy Shared Resource Facility, supported with funding from NIH-NCI shared resources grant (5R24 CA095823), NSF Major Research Instrumentation grant (DBI-9724504) and NIH shared instrumentation grant (1S10 RR0 9145). These studies were supported by a grant from the NIDDK/NIH to BH (DK065838). Justin Costa is a trainee in the Integrated Pharmacological Sciences Training Program supported by grant T32GM062754 from the National Institute of General Medical Sciences. NR 38 TC 0 Z9 0 U1 1 U2 7 PU INT SOC PTERIDINOLOGY PI INNSBRUCK PA C/O DR. ERIKA ARTNER-DWORZAK, UNIV INNSBRUCK, FRITZ PREGL STRASSE 3, A-6020 INNSBRUCK, AUSTRIA SN 0933-4807 J9 PTERIDINES JI Pteridines PD SEP PY 2012 VL 23 IS 3 BP 81 EP 89 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 056LG UT WOS:000312490400001 ER PT J AU Mosavel, M Rafie, C Cadet, DL Ayers, A AF Mosavel, Maghboeba Rafie, Carlin Cadet, Debbie L. Ayers, Antoinette TI Opportunities to Reduce Cancer Barriers: Community Town Halls and Provider Focus Groups SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Town halls; Cancer; Community-engaged; Community health educator; Needs assessment ID BREAST; WOMEN AB This paper presents the findings from town hall meetings held with community residents and focus groups with health care providers. A total of five town halls (N = 139) were conducted. Four were conducted in English and a fifth was conducted in Spanish to obtain the input of the local Hispanic community. Surveys were provided to town hall participants to assess their perceptions of cancer and screening as well as their cancer screening behaviors. Participants were asked questions designed to determine local gaps and needs in health and cancer care, and their attitudes regarding breast cancer resources, education, treatment, and clinical trials. Additionally, four focus groups (N = 45) were held with a wide range of providers to obtain their perspectives on barriers to breast cancer screening, local cancer prevention and care, and clinical trials. Results indicate gaps in local resources and support services, particularly in terms of education and integrated care. C1 [Mosavel, Maghboeba] Virginia Commonwealth Univ, Dept Social & Behav Hlth, Sch Med, Richmond, VA 23298 USA. [Rafie, Carlin; Cadet, Debbie L.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA. [Ayers, Antoinette] VCU Massey Canc Ctr, NCI, NON, Project CHAT Petersburg, Richmond, VA USA. RP Mosavel, M (reprint author), Virginia Commonwealth Univ, Dept Social & Behav Hlth, Sch Med, 1 Capitol Sq,9th Floor,830 E Main St,POB 980149, Richmond, VA 23298 USA. EM mmosavel@vcu.edu; crafie@vcu.edu; dcadet@vcu.edu; aayers@vcu.edu FU VCU Massey Cancer Center; Paint it Pink in Petersburg; Petersburg Department of Social Services; Cameron Foundation; National Cancer Institute [3U10 CA052784-20S2] FX We would like to thank the town hall participants as well as the health care providers for sharing their views with us. We would also like to thank the members of the research team including Amber Cox, Carol Covington, Soyoung Hwang, Antonio Villa, and Ellyn Leighton-Herrmann for their assistance with various parts of this project including recruitment, data analysis, and/or assistance with manuscript preparation. Our appreciation is further extended to VCU Massey Cancer Center, Paint it Pink in Petersburg, the Petersburg Department of Social Services, and the Cameron Foundation for their support. This study was made possible by funding received from the National Cancer Institute (3U10 CA052784-20S2). NR 19 TC 3 Z9 3 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD SEP PY 2012 VL 27 IS 4 BP 641 EP 648 DI 10.1007/s13187-012-0423-3 PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 054EY UT WOS:000312328000008 PM 23055135 ER PT J AU Rinaldi, C Bott, LC Chen, KL Harmison, GG Katsuno, M Sobue, G Pennuto, M Fischbeck, KH AF Rinaldi, Carlo Bott, Laura C. Chen, Ke-lian Harmison, George G. Katsuno, Masahisa Sobue, Gen Pennuto, Maria Fischbeck, Kenneth H. TI Insulin like Growth Factor (IGF)-1 Administration Ameliorates Disease Manifestations in a Mouse Model of Spinal and Bulbar Muscular Atrophy SO MOLECULAR MEDICINE LA English DT Article ID MOTOR-NEURON DISEASE; ANDROGEN RECEPTOR; FACTOR-I; TRINUCLEOTIDE REPEAT; BINDING PROTEIN-3; TRANSGENIC MICE; IGF-I; PATHOLOGY; NEURODEGENERATION; OVEREXPRESSION AB Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by polyglutamine expansion in the androgen receptor. Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations. Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity. No effective disease-modifying therapy is currently available for this disease. Our recent studies have demonstrated that insulinlike growth factor (IGF)-1 reduces the mutant androgen receptor toxicity through activation of Akt in vitro, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a noncirculating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1-treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00271 C1 [Rinaldi, Carlo; Bott, Laura C.; Chen, Ke-lian; Harmison, George G.; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Rinaldi, Carlo] Univ Naples Federico II, Dept Neurol Sci, Naples, Italy. [Bott, Laura C.] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. [Katsuno, Masahisa; Sobue, Gen] Nagoya Univ, Grad Sch Med, Dept Neurol, Nagoya, Aichi 4648601, Japan. [Pennuto, Maria] Italian Inst Technol, Dept Neurosci & Brain Technol, Genoa, Italy. RP Rinaldi, C (reprint author), NINDS, Neurogenet Branch, NIH, 35 Convent Dr,Bldg 35,Porter Bldg,2A114, Bethesda, MD 20892 USA. EM rinaldic@ninds.nih.gov RI Katsuno, Masahisa/I-7502-2014; OI Pennuto, Maria/0000-0001-8634-0767 FU NINDS intramural funds; Telethon-Italy [GGP10037]; Kennedy's Disease Association; Muscular Dystrophy Association [196646] FX This work was supported by NINDS intramural funds. The work was also supported by grants from Telethon-Italy (GGP10037), the Kennedy's Disease Association and the Muscular Dystrophy Association (196646) to M Pennuto. NR 48 TC 24 Z9 24 U1 0 U2 4 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD SEP PY 2012 VL 18 IS 9 BP 1261 EP 1268 DI 10.2119/molmed.2012.00271 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 055LO UT WOS:000312418000002 PM 22952056 ER PT J AU Lingen, MW Szabo, E AF Lingen, Mark W. Szabo, Eva TI Validation of LOH Profiles for Assessing Oral Cancer Risk SO CANCER PREVENTION RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; HUMAN-PAPILLOMAVIRUS; EPITHELIAL DYSPLASIA; PREMALIGNANT LESIONS; CHROMOSOME 3P; OROPHARYNGEAL CANCER; NECK CANCERS; COPY NUMBER; FOLLOW-UP; HEAD AB This perspective examines the report by Zhang and colleagues in this issue of the journal (beginning on page 1081) on the validation and refinement of a set of risk markers for oral premalignant lesion progression that incorporates loss of heterozygosity markers. The perspective also discusses some of the challenges and opportunities of incorporating predictive biomarkers into monitoring and refined enrollment criteria for prevention studies. Cancer Prev Res; 5(9); 1075-7. (c) 2012 AACR. C1 [Lingen, Mark W.] Univ Chicago, Dept Pathol, Med Ctr, Chicago, IL 60637 USA. [Szabo, Eva] NCI, Lung & Upper Aerodigest Canc Res Grp, Dept Hlth & Human Serv, Div Canc Prevent,NIH, Bethesda, MD 20892 USA. RP Lingen, MW (reprint author), Univ Chicago, Dept Pathol, Med Ctr, 5841 S Maryland Ave,MC 6101, Chicago, IL 60637 USA. EM Mark.Lingen@uchospitals.edu FU NIDCR NIH HHS [R01 DE012322] NR 28 TC 3 Z9 3 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2012 VL 5 IS 9 BP 1075 EP 1077 DI 10.1158/1940-6207.CAPR-12-0294 PG 3 WC Oncology SC Oncology GA 049VC UT WOS:000312010500002 PM 22911110 ER PT J AU Oi, N Chen, HY Kim, MO Lubet, RA Bode, AM Dong, ZG AF Oi, Naomi Chen, Hanyong Kim, Myoung Ok Lubet, Ronald A. Bode, Ann M. Dong, Zigang TI Taxifolin Suppresses UV-Induced Skin Carcinogenesis by Targeting EGFR and PI3K SO CANCER PREVENTION RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; PERFORMANCE LIQUID-CHROMATOGRAPHY; RHIZOMA-SMILACIS-GLABRAE; NF-KAPPA-B; ULTRAVIOLET-RADIATION; HUMAN KERATINOCYTES; ACTIVATION; EXPRESSION; CANCER; IRRADIATION AB Skin cancer is one of the most commonly diagnosed cancers in the United States. Taxifolin reportedly exerts multiple biologic effects, but the molecular mechanisms and direct target(s) of taxifolin in skin cancer chemoprevention are still unknown. In silico computer screening and kinase profiling results suggest that the EGF receptor (EGFR), phosphoinositide 3-kinase (PI3K), and Src are potential targets for taxifolin. Pull-down assay results showed that EGFR, PI3K, and Src directly interacted with taxifolin in vitro, whereas taxifolin bound to EGFR and PI3K, but not to Src in cells. ATP competition and in vitro kinase assay data revealed that taxifolin interacted with EGFR and PI3K at the ATP-binding pocket and inhibited their kinase activities. Western blot analysis showed that taxifolin suppressed UVB-induced phosphorylation of EGFR and Akt, and subsequently suppressed their signaling pathways in JB6 P+ mouse skin epidermal cells. Expression levels and promoter activity of COX-2 and prostaglandin E-2 (PGE(2)) generation induced by UVB were also attenuated by taxifolin. The effect of taxifolin on UVB-induced signaling pathways and PGE(2) generation was reduced in EGFR knockout murine embryonic fibroblasts (MEF) compared with EGFR wild-type MEFs. Taxifolin also inhibited EGF-induced cell transformation. Importantly, topical treatment of taxifolin to the dorsal skin significantly suppressed tumor incidence, volume, and multiplicity in a solar UV (SUV)-induced skin carcinogenesis mouse model. Further analysis showed that the taxifolin-treated group had a substantial reduction in SUV-induced phosphorylation of EGFR and Akt in mouse skin. These results suggest that taxifolin exerts chemopreventive activity against UV-induced skin carcinogenesis by targeting EGFR and PI3K. Cancer Prev Res; 5(9); 1103-14. (C) 2012 AACR. C1 [Oi, Naomi; Chen, Hanyong; Kim, Myoung Ok; Bode, Ann M.; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Kim, Myoung Ok] Kyungpook Natl Univ, Sch Anim Sci & Biotechnol, Sangju, South Korea. [Lubet, Ronald A.] NCI, Bethesda, MD 20892 USA. RP Dong, ZG (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. EM zgdong@hi.umn.edu FU Hormel Foundation; NIH [R37 CA081064, CA027502, CA120388, ES016548] FX This work was supported by the Hormel Foundation and NIH grants R37 CA081064, CA027502, CA120388, and ES016548. NR 46 TC 14 Z9 14 U1 2 U2 19 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2012 VL 5 IS 9 BP 1103 EP 1114 DI 10.1158/1940-6207.CAPR-11-0397 PG 12 WC Oncology SC Oncology GA 049VC UT WOS:000312010500006 PM 22805054 ER PT J AU Crew, KD Brown, P Greenlee, H Bevers, TB Arun, B Hudis, C McArthur, HL Chang, J Rimawi, M Vornik, L Cornelison, TL Wang, AT Hibshoosh, H Ahmed, A Terry, MB Santella, RM Lippman, SM Hershman, DL AF Crew, Katherine D. Brown, Powel Greenlee, Heather Bevers, Therese B. Arun, Banu Hudis, Clifford McArthur, Heather L. Chang, Jenny Rimawi, Mothaffar Vornik, Lana Cornelison, Terri L. Wang, Antai Hibshoosh, Hanina Ahmed, Aqeel Terry, Mary Beth Santella, Regina M. Lippman, Scott M. Hershman, Dawn L. TI Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor-Negative Breast Cancer SO CANCER PREVENTION RESEARCH LA English DT Article ID GREEN TEA POLYPHENOLS; EPIGALLOCATECHIN GALLATE; LUNG-CANCER; PROSTATE-CANCER; BETA-CAROTENE; HIGH-RISK; MAMMOGRAPHIC DENSITY; POSTMENOPAUSAL WOMEN; KI-67 EXPRESSION; CHINESE WOMEN AB Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade >= II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg(grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. Cancer Prev Res; 5(9); 1144-54. (C) 2012 AACR. C1 [Crew, Katherine D.; Greenlee, Heather; Wang, Antai; Hibshoosh, Hanina; Ahmed, Aqeel; Terry, Mary Beth; Santella, Regina M.; Hershman, Dawn L.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Hudis, Clifford; McArthur, Heather L.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Brown, Powel; Bevers, Therese B.; Arun, Banu; Vornik, Lana; Lippman, Scott M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Chang, Jenny] Methodist Hosp, Ctr Canc, Houston, TX 77030 USA. [Rimawi, Mothaffar] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Cornelison, Terri L.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Crew, KD (reprint author), Columbia Univ, Herbert Irving Comprehens Canc Ctr, 161 Ft Washington Ave,10-1072, New York, NY 10032 USA. EM kd59@columbia.edu FU National Cancer Institute [N01-CN-35159]; National Institute of Environmental Health Sciences [ES009089]; American Cancer Society [ACS MRSG-08-02101-CNE] FX The study was supported by the National Cancer Institute (grant N01-CN-35159), the National Institute of Environmental Health Sciences (grant ES009089), and the American Cancer Society (grant ACS MRSG-08-02101-CNE). NR 50 TC 27 Z9 27 U1 0 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2012 VL 5 IS 9 BP 1144 EP 1154 DI 10.1158/1940-6207.CAPR-12-0117 PG 11 WC Oncology SC Oncology GA 049VC UT WOS:000312010500010 PM 22827973 ER PT J AU Dumonteil, E Bottazzi, ME Zhan, B Heffernan, MJ Jones, K Valenzuela, JG Kamhawi, S Ortega, J Rosales, SPD Lee, BY Bacon, KM Fleischer, B Slingsby, BT Cravioto, MB Tapia-Conyer, R Hotez, PJ AF Dumonteil, Eric Bottazzi, Maria Elena Zhan, Bin Heffernan, Michael J. Jones, Kathryn Valenzuela, Jesus G. Kamhawi, Shaden Ortega, Jaime de Leon Rosales, Samuel Ponce Lee, Bruce Y. Bacon, Kristina M. Fleischer, Bernhard Slingsby, B. T. Cravioto, Miguel Betancourt Tapia-Conyer, Roberto Hotez, Peter J. TI Accelerating the development of a therapeutic vaccine for human Chagas disease: rationale and prospects SO EXPERT REVIEW OF VACCINES LA English DT Article DE Chagas disease; Mesoamerica; Mexico; Tc24; therapeutic vaccine; Trypanosoma cruzi; trypomastigote antigen; TSA-1; vaccine ID TRYPANOSOMA-CRUZI INFECTION; NEGLECTED TROPICAL DISEASES; CD8(+) T-CELLS; DNA VACCINES; HEART-DISEASE; NONHUMAN-PRIMATES; IMMUNE-RESPONSES; ECONOMIC VALUE; LATIN-AMERICA; UNITED-STATES AB Chagas disease is a leading cause of heart disease affecting approximately 10 million people in Latin America and elsewhere worldwide. The two major drugs available for the treatment of Chagas disease have limited efficacy in Trypanosoma cruzi-infected adults with indeterminate (patients who have seroconverted but do not yet show signs or symptoms) and determinate (patients who have both seroconverted and have clinical disease) status; they require prolonged treatment courses and are poorly tolerated and expensive. As an alternative to chemotherapy, an injectable therapeutic Chagas disease vaccine is under development to prevent or delay Chagasic cardiomyopathy in patients with indeterminate or determinate status. The bivalent vaccine will be comprised of two recombinant T cruzi antigens, Tc24 and TSA-1, formulated on alum together with the Toll-like receptor 4 agonist, E6020. Proof-of-concept for the efficacy of these antigens was obtained in preclinical testing at the Autonomous University of Yucatan. Here the authors discuss the potential for a therapeutic Chagas vaccine as well as the progress made towards such a vaccine, and the authors articulate a roadmap for the development of the vaccine as planned by the nonprofit Sabin Vaccine Institute Product Development Partnership and Texas Children's Hospital Center for Vaccine Development in collaboration with an international consortium of academic and industrial partners in Mexico, Germany, Japan, and the USA. C1 [Bottazzi, Maria Elena; Zhan, Bin; Heffernan, Michael J.; Jones, Kathryn; Hotez, Peter J.] Baylor Coll Med, Natl Sch Trop Med, Sabin Vaccine Inst, Houston, TX 77030 USA. [Bottazzi, Maria Elena; Zhan, Bin; Heffernan, Michael J.; Jones, Kathryn; Hotez, Peter J.] Baylor Coll Med, Natl Sch Trop Med, Texas Childrens Hosp Ctr Vaccine Dev, Dept Pediat,Sect Pediat Trop Med, Houston, TX 77030 USA. [Bottazzi, Maria Elena; Zhan, Bin; Heffernan, Michael J.; Jones, Kathryn; Hotez, Peter J.] Baylor Coll Med, Natl Sch Trop Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Dumonteil, Eric] Dr Hideo Noguchi Autonomous Univ Yucatan UADY, Lab Parasitol, Ctr Invest Reg, Merida, Mexico. [Valenzuela, Jesus G.; Kamhawi, Shaden] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Ortega, Jaime] Inst Politecn Nacl CINVESTAV IPN, Ctr Invest & Estudios Avanzados, Dept Biotecnol & Bioingn, Mexico City, DF, Mexico. [de Leon Rosales, Samuel Ponce] Lab Biol & React Mexico BIRMEX, Mexico City, DF, Mexico. [Lee, Bruce Y.; Bacon, Kristina M.] Univ Pittsburgh, Publ Hlth Computat & Operat Res PHICOR, Pittsburgh, PA USA. [Fleischer, Bernhard] Bernhard Nocht Inst Trop Med, Hamburg, Germany. [Slingsby, B. T.] Eisai & Co Ltd, Tokyo, Japan. [Cravioto, Miguel Betancourt; Tapia-Conyer, Roberto] ICSS, Mexico City, DF, Mexico. RP Hotez, PJ (reprint author), Baylor Coll Med, Natl Sch Trop Med, Sabin Vaccine Inst, Houston, TX 77030 USA. EM hotez@bcm.edu RI Ortega-Lopez, Jaime/A-1364-2008; OI Ortega-Lopez, Jaime/0000-0001-9136-9994; Hotez, Peter/0000-0001-8770-1042; Dumonteil, Eric/0000-0001-9376-0209 FU Carlos Slim Institute of Health; Southwest Electronic Energy Medical Research Institute FX Michael Heffernan is a co-inventor on three patent applications pertaining to the pH-sensitive microparticles discussed in this manuscript. Several of the authors are involved in various aspects of the development and possible future manufacture of a potential vaccine currently in development against Chagas disease. The Carlos Slim Institute of Health and the Southwest Electronic Energy Medical Research Institute are providing financial support for the Chagas disease vaccine initiative. Eisai Co., Ltd is providing access to the E6020 adjuvant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 75 TC 42 Z9 42 U1 4 U2 27 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD SEP PY 2012 VL 11 IS 9 BP 1043 EP 1055 DI 10.1586/ERV.12.85 PG 13 WC Immunology SC Immunology GA 050HH UT WOS:000312043400009 PM 23151163 ER PT J AU Gogtay, N Hua, X Stidd, R Boyle, CP Lee, S Weisinger, B Chavez, A Giedd, JN Clasen, L Toga, AW Rapoport, JL Thompson, PM AF Gogtay, Nitin Hua, Xue Stidd, Reva Boyle, Christina P. Lee, Suh Weisinger, Brian Chavez, Alex Giedd, Jay N. Clasen, Liv Toga, Arthur W. Rapoport, Judith L. Thompson, Paul M. TI Delayed White Matter Growth Trajectory in Young Nonpsychotic Siblings of Patients With Childhood-Onset Schizophrenia SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID TENSOR-BASED MORPHOMETRY; CORTICAL BRAIN-DEVELOPMENT; VOXEL-BASED MORPHOMETRY; IMAGE REGISTRATION; HEALTHY SIBLINGS; GRAY-MATTER; ABNORMALITIES; METAANALYSIS; MRI; VOLUMES AB Context: Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. Objective: To study WM growth differences in nonpsychotic siblings of patients with COS. Design: Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. Setting: National Institutes of Health Clinical Center, Bethesda, Maryland. Participants: Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1 [5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9 [5.3] years; 29 male, 28 female). Main Outcome Measure: White matter growth rates. Results: We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to < 14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P = .004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. Conclusions: In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age. C1 [Hua, Xue; Boyle, Christina P.; Lee, Suh; Toga, Arthur W.; Thompson, Paul M.] Univ Calif Los Angeles, Sch Med, Dept Neurol, Imaging Genet Ctr,Lab Neuro Imaging, Los Angeles, CA 90095 USA. [Gogtay, Nitin; Stidd, Reva; Weisinger, Brian; Chavez, Alex; Giedd, Jay N.; Clasen, Liv; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Thompson, PM (reprint author), Univ Calif Los Angeles, Sch Med, Dept Neurol, Imaging Genet Ctr,Lab Neuro Imaging, Neurosci Res Bldg 225E,635 Charles Young Dr, Los Angeles, CA 90095 USA. EM thompson@loni.ucla.edu RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Chavez, Alexis/0000-0003-1322-4532 FU National Institute for Biomedical Imaging and Bioengineering [EB01651, R01 EB007813, R01 EB008281, R01 EB008432]; National Center for Research Resources [RR019771, P41 RR013642]; National Institute on Aging [AG016570, R01 AG020098]; National Institute of Child Health and Human Development [R01 HD050735]; National Institutes of Health; National Institute of Mental Health FX This research was supported by grants EB01651, R01 EB007813, R01 EB008281, and R01 EB008432 from the National Institute for Biomedical Imaging and Bioengineering; RR019771 from the National Center for Research Resources; AG016570 and R01 AG020098 from the National Institute on Aging; and R01 HD050735 from the National Institute of Child Health and Human Development (Dr Thompson). Additional support was provided by grants P41 RR013642 (Dr Toga) from the National Center for Research Resources, a component of the National Institutes of Health, and National Institute of Mental Health intramural funding (Drs Gogtay, Clasen, Rapoport, and Giedd; Ms Stidd; and Messrs Weisinger and Chavez). NR 50 TC 19 Z9 19 U1 0 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD SEP PY 2012 VL 69 IS 9 BP 875 EP 884 PG 10 WC Psychiatry SC Psychiatry GA 998FM UT WOS:000308222800002 PM 22945617 ER PT J AU Merikangas, KR Cui, LH Kattan, G Carlson, GA Youngstrom, EA Angst, J AF Merikangas, Kathleen Ries Cui, Lihong Kattan, G. Carlson, Gabrielle A. Youngstrom, Eric A. Angst, Jules TI Mania With and Without Depression in a Community Sample of US Adolescents SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID COMORBIDITY SURVEY REPLICATION; SUPPLEMENT NCS-A; PEDIATRIC BIPOLAR DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; MENTAL-HEALTH SURVEY; SPECTRUM DISORDERS; SUBTHRESHOLD BIPOLARITY; YOUNG ADULTHOOD; NATIONAL TRENDS; MOOD DISORDERS AB Context: There are limited data on the manifestations of mania in general community samples of adolescents. Objective: To present the prevalence and clinical correlates of mania with and without depressive episodes in a representative sample of US adolescents. Design: Cross-sectional survey of adolescents using a modified version of the Composite International Diagnostic Interview. Participants: Ten thousand one hundred twenty-three adolescents aged 13 to 18 years identified in household and school settings. Main Outcome Measures: Mania/hypomania with or without depression among those who met DSM-IV criteria for bipolar I or II disorder or major depressive disorder. Results: Two and a half percent of youth met criteria for lifetime bipolar I or II disorder and 1.7%, for mania only. Twelve-month rates of mania with and without depression were 2.2% and 1.3%, respectively. There was a nearly 2-fold increase in rates of mania from ages 13-14 to 17-18 years. Mania with depression was associated with a greater number of all indictors of clinical severity including symptom number and severity, role disability, severe impairment, comorbidity, and treatment compared with depression alone, whereas correlates of mania were similar among those with mania with or without depression. Conclusions: The increasing prevalence of bipolar disorder with increasing age and the comparable rate of bipolar disorder with those of adult samples highlight adolescence as the peak period of onset of mania. The clinical significance of mania plus depression as demonstrated by a 1 in 5 suicide attempt rate and nearly 2 months per year of role impairment in adolescence has important implications for early intervention. The evidence for independence of mania from depression warrants additional scrutiny in the diagnostic nomenclature and etiologic dissection of bipolar disorder. C1 [Merikangas, Kathleen Ries; Cui, Lihong; Kattan, G.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Carlson, Gabrielle A.] SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. [Youngstrom, Eric A.] Univ N Carolina, Chapel Hill, NC USA. [Angst, Jules] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bldg 35,Room 1A201,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov FU BMS/Otsuka; GlaxoSmithKline; Merck; National Institute of Mental Health [Z01 MH002808-08, U01-MH60220] FX Dr Carlson received research support from BMS/Otsuka, GlaxoSmithKline, and Merck. Dr Youngstrom has received travel support from Bristol-Myers Squibb and consulted with Lundbeck.; This work was supported by grant Z01 MH002808-08 from the Intramural Research Program of the National Institute of Mental Health. The NCS-A and the larger program of related NCS surveys are supported by grant U01-MH60220 from the National Institute of Mental Health. NR 56 TC 54 Z9 54 U1 6 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD SEP PY 2012 VL 69 IS 9 BP 943 EP 951 DI 10.1001/archgenpsychiatry.2012.38 PG 9 WC Psychiatry SC Psychiatry GA 998FM UT WOS:000308222800009 PM 22566563 ER PT J AU Martin, C Heinze, C Busch, M Franke, G Hentschke, M Duhring, SB Buttner, H Kotasinska, M Wischnewski, V Buck, F Molin, S Otto, M Rohde, H AF Martin, C. Heinze, C. Busch, M. Franke, G. Hentschke, M. Duhring, S. Bayard Buettner, H. Kotasinska, M. Wischnewski, V. Buck, F. Molin, S. Otto, M. Rohde, H. TI SarA is a negative regulator of Staphylococcus epidermidis biofilm formation SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) CY SEP 30-OCT 03, 2012 CL Hamburg, GERMANY SP German Soc Hyg & Microbiol (DGHM) C1 [Martin, C.; Heinze, C.; Busch, M.; Franke, G.; Hentschke, M.; Buettner, H.; Kotasinska, M.; Wischnewski, V.; Rohde, H.] UK Hamburg Eppendorf, Med Mikrobiol, Hamburg, Germany. [Duhring, S. Bayard; Molin, S.] Tech Univ Denmark, Ctr Syst Microbiol, Copenhagen, Denmark. [Buck, F.] UK Hamburg Eppendorf, Klin Chem, Hamburg, Germany. [Otto, M.] NIH, Lab Human Bacterial Pathogenesis, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD SEP PY 2012 VL 302 SU 1 BP 73 EP 73 PG 1 WC Microbiology; Virology SC Microbiology; Virology GA 044BB UT WOS:000311593300260 ER PT J AU Kretschmer, D Nikola, N Rautenberg, M Otto, M Peschel, A AF Kretschmer, D. Nikola, N. Rautenberg, M. Otto, M. Peschel, A. TI C-terminal truncation of staphylococcal beta-type phenol-soluble modulins shifts the specificity for different members of the human formyl-peptide receptors SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) CY SEP 30-OCT 03, 2012 CL Hamburg, GERMANY SP German Soc Hyg & Microbiol (DGHM) C1 [Otto, M.] NIAID, US NIH, Lab Human Bacterial Pathogenesis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD SEP PY 2012 VL 302 SU 1 BP 129 EP 129 PG 1 WC Microbiology; Virology SC Microbiology; Virology GA 044BB UT WOS:000311593300464 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI The new genomic world: Hypothesis-generating modes of basic and clinical research, and clinical care SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract CT British Human Genetics Conference CY SEP 17-19, 2012 CL Univ Warwick, Coventry, ENGLAND HO Univ Warwick C1 [Biesecker, Leslie G.] NHGRI, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2012 VL 49 SU 1 BP S41 EP S41 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 032YW UT WOS:000310758500056 ER PT J AU Clowes, V Edwards, TL Angus, K Warren, J Harbour, ME Hopkins, CR Hong, C Blackstone, C Hanna, M Reid, E AF Clowes, Virginia Edwards, T. L. Angus, K. Warren, J. Harbour, M. E. Hopkins, C. R. Hong, C. Blackstone, C. Hanna, M. Reid, E. TI The hereditary spastic paraplegia proteins spartin and maspardin interact in a pathway that regulates BMP signaling SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract CT British Human Genetics Conference CY SEP 17-19, 2012 CL Univ Warwick, Coventry, ENGLAND HO Univ Warwick C1 [Clowes, Virginia; Edwards, T. L.; Angus, K.; Warren, J.; Harbour, M. E.; Reid, E.] Addenbrookes Hosp, Cambridge Inst Med Res, Cambridge, England. [Hopkins, C. R.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA. [Hong, C.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Div Cardiovasc Med, Nashville, TN 37232 USA. [Blackstone, C.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Hanna, M.] Texas A&M Univ, Dept Biol & Environm Sci, Commerce, TX 75428 USA. EM vec22@cam.ac.uk NR 0 TC 0 Z9 0 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2012 VL 49 SU 1 BP S94 EP S94 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 032YW UT WOS:000310758500185 ER PT J AU Dumanski, JP Forsberg, LA Rasi, C Razzaghian, HR Pakalapati, G Waite, L Thilbeault, KS Ronowicz, A Wineinger, NE Tiwari, HK Boomsma, D Westerman, MP Harris, JR Lyle, R Essand, M Eriksson, F Assimes, TL Iribarren, C Strachan, E O'Hanlon, TP Rider, LG Miller, FW Giedraitis, V Lannfelt, L Ingelsson, M Piotrowski, A Pedersen, NL Absher, D AF Dumanski, Jan P. Forsberg, L. A. Rasi, C. Razzaghian, H. R. Pakalapati, G. Waite, L. Thilbeault, K. Stanton Ronowicz, A. Wineinger, N. E. Tiwari, H. K. Boomsma, D. Westerman, M. P. Harris, J. R. Lyle, R. Essand, M. Eriksson, F. Assimes, T. L. Iribarren, C. Strachan, E. O'Hanlon, T. P. Rider, L. G. Miller, F. W. Giedraitis, V. Lannfelt, L. Ingelsson, M. Piotrowski, A. Pedersen, N. L. Absher, D. TI Age-related accumulation of somatic structural changes in the nuclear genome of human blood cells in vivo SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract CT British Human Genetics Conference CY SEP 17-19, 2012 CL Univ Warwick, Coventry, ENGLAND HO Univ Warwick C1 [Dumanski, Jan P.; Forsberg, L. A.; Rasi, C.; Razzaghian, H. R.; Pakalapati, G.; Essand, M.; Eriksson, F.] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Waite, L.; Thilbeault, K. Stanton; Absher, D.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Ronowicz, A.; Piotrowski, A.] Med Univ Gdansk, Dept Biol, PL-80416 Gdansk, Poland. [Wineinger, N. E.; Tiwari, H. K.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Boomsma, D.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Westerman, M. P.] Mt Sinai Hosp Med Ctr, Chicago, IL 60608 USA. [Harris, J. R.] Norwegian Inst Publ Hlth, Dept Genes & Environm, Oslo, Norway. [Lyle, R.] Oslo Univ Hosp, Dept Med Genet, N-0407 Oslo, Norway. [Assimes, T. L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Iribarren, C.] Kaiser Fdn Res Inst, Oakland, CA 94612 USA. [Strachan, E.] Univ Washington, Twin Registry, Seattle, WA 98104 USA. [Strachan, E.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. [O'Hanlon, T. P.; Rider, L. G.; Miller, F. W.] NIEHS, Environm Autoimmun Grp, NIH 10, Bethesda, MD 20892 USA. [Giedraitis, V.; Lannfelt, L.; Ingelsson, M.] Uppsala Univ, Div Mol Geriatr, Rudbeck Lab, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden. [Pedersen, N. L.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. EM jan.dumanski@igp.uu.se NR 0 TC 0 Z9 0 U1 1 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2012 VL 49 SU 1 BP S42 EP S42 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 032YW UT WOS:000310758500060 ER PT J AU Kiselyov, KK Ahuja, M Rybalchenko, V Patel, S Muallem, S AF Kiselyov, Kirill K. Ahuja, Malini Rybalchenko, Volodymyr Patel, Sandip Muallem, Shmuel TI The intracellular Ca2+ channels of membrane traffic SO CHANNELS LA English DT Article DE organelles; TRPMLs; TPCs; calcium; membrane traffic; fusion; fission ID ADENINE-DINUCLEOTIDE PHOSPHATE; LYSOSOME-RELATED ORGANELLES; VARITINT-WADDLER PHENOTYPE; MUCOLIPIDOSIS TYPE-IV; CYCLIC ADP-RIBOSE; 2-PORE CHANNELS; CATION CHANNEL; SENSITIVE CA2+; INOSITOL TRISPHOSPHATE; STORAGE DISORDERS AB Regulation of organellar fusion and fission by Ca2+ has emerged as a central paradigm in intracellular membrane traffic. Originally formulated for Ca2+-driven SNARE-mediated exocytosis in the presynaptic terminals, it was later expanded to explain membrane traffic in other exocytic events within the endo-lysosomal system. The list of processes and conditions that depend on the intracellular membrane traffic includes aging, antigen and lipid processing, growth factor signaling and enzyme secretion. Characterization of the ion channels that regulate intracellular membrane fusion and fission promises novel pharmacological approaches in these processes when their function becomes aberrant. The recent identification of Ca2+ permeability through the intracellular ion channels comprising the mucolipin (TRPMLs) and the two-pore channels (TPCs) families pinpoints the candidates for the Ca2+ channel that drive intracellular membrane traffic. The present review summarizes the recent developments and the current questions relevant to this topic. C1 [Ahuja, Malini; Rybalchenko, Volodymyr; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Kiselyov, Kirill K.] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Patel, Sandip] UCL, Dept Cell & Dev Biol, London, England. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. EM shmuel.muallem@nih.gov RI Patel, Sandip/O-9591-2015 OI Patel, Sandip/0000-0001-7247-2013 FU Biotechnology and Biological Sciences Research Council [BB/G013721/1] NR 92 TC 11 Z9 11 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6950 J9 CHANNELS JI Channels PD SEP-OCT PY 2012 VL 6 IS 5 BP 344 EP 351 DI 10.4161/chan.21723 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 030JT UT WOS:000310567700002 PM 22907062 ER PT J AU Gallo, A Baldini, C Teos, L Mosca, M Bombardieri, S Alevizos, I AF Gallo, A. Baldini, C. Teos, L. Mosca, M. Bombardieri, S. Alevizos, I. TI Emerging trends in Sjogren's syndrome: basic and translational research SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Review DE Sjogren's syndrome; microRNAs; proteomics ID SALIVARY BIOMARKERS; MASS-SPECTROMETRY; PROTEOME ANALYSIS; CLASSIFICATION CRITERIA; RHEUMATOID-ARTHRITIS; GEL-ELECTROPHORESIS; GENE-TRANSFER; WHOLE SALIVA; MURINE MODEL; MICRORNAS AB This review will address the 'state of the art' of novel genomic and proteomic biomarkers for primary Sjogren's syndrome (pSS) and the current status and potential of gene transfer to salivary glands in restoring the function of salivary glands. C1 [Baldini, C.] Univ Pisa, Dipartimento Reumatol, Rheumatol Unit, I-56126 Pisa, Italy. [Gallo, A.; Teos, L.; Alevizos, I.] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Baldini, C (reprint author), Univ Pisa, Dipartimento Reumatol, Rheumatol Unit, Via Roma 67, I-56126 Pisa, Italy. EM chiara.baldini74@gmail.com OI BALDINI, CHIARA/0000-0002-4454-1824 NR 62 TC 15 Z9 15 U1 0 U2 5 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD SEP-OCT PY 2012 VL 30 IS 5 BP 779 EP 784 PG 6 WC Rheumatology SC Rheumatology GA 033VG UT WOS:000310828600022 PM 23009759 ER PT J AU Baldini, C Gallo, A Perez, P Mosca, M Alevizos, I Bombardieri, S AF Baldini, C. Gallo, A. Perez, P. Mosca, M. Alevizos, I. Bombardieri, S. TI Saliva as an ideal milieu for emerging diagnostic approaches in primary Sjogren's syndrome SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Review DE Primary Sjogren's syndrome; saliva; proteomics; miRNAs ID PROTEOME ANALYSIS; LYMPHOMA DEVELOPMENT; GEL-ELECTROPHORESIS; RHEUMATIC-DISEASES; MASS-SPECTROMETRY; PAROTID-SALIVA; WHOLE SALIVA; BIOMARKERS; SIALOCHEMISTRY; IDENTIFICATION AB This review will summarise the state of the art of salivary diagnostics in primary Sjogren's syndrome exploring the potential usefulness of both traditional and emerging biotechnologies for primary Sjogren's syndrome non-invasive and early detection. C1 [Baldini, C.] Univ Pisa, Dipartimento Reumatol, Rheumatol Unit, I-56126 Pisa, Italy. [Gallo, A.; Perez, P.; Alevizos, I.] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Baldini, C (reprint author), Univ Pisa, Dipartimento Reumatol, Rheumatol Unit, Via Roma 67, I-56126 Pisa, Italy. EM chiara.baldini74@gmail.com OI BALDINI, CHIARA/0000-0002-4454-1824 NR 71 TC 17 Z9 19 U1 0 U2 7 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD SEP-OCT PY 2012 VL 30 IS 5 BP 785 EP 790 PG 6 WC Rheumatology SC Rheumatology GA 033VG UT WOS:000310828600023 PM 23009763 ER PT J AU Gorden, P Zadeh, ES Cochran, E Brown, RJ AF Gorden, Phillip Zadeh, Elika Safar Cochran, Elaine Brown, Rebecca J. TI SYNDROMIC INSULIN RESISTANCE: MODELS FOR THE THERAPEUTIC BASIS OF THE METABOLIC SYNDROME AND OTHER TARGETS OF INSULIN RESISTANCE SO ENDOCRINE PRACTICE LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Association-of-Clinical-Endocrinologists (AACE) CY MAY 23-27, 2012 CL Philadelphia, PA SP Amer Assoc Clin Endocrinologists (AACE) ID CONGENITAL LEPTIN DEFICIENCY; BLOOD-GLUCOSE CONTROL; LONG-TERM EFFICACY; SEVERE LIPODYSTROPHY; RECEPTOR AUTOANTIBODIES; REPLACEMENT THERAPY; RECOMBINANT LEPTIN; DIABETES-MELLITUS; HORMONE RECEPTOR; CLINICAL-COURSE AB Objective: To investigate. the link between insulin resistance and the metabolic syndrome how to develop treatment approaches. Methods: We present 3 cases of extreme syndromic insulin resistance: lipodystrophy, autoantibodies to the insulin receptor, and mutations in the insulin receptor gene, with accompanying discussion of pathophysiology and treatment. Results: In lipodystrophy, insulin resistance is a direct consequence of leptin deficiency, and thus leptin replacement reverses metabolic syndrome abnormalities, including diabetes and hypertriglyceridemia. The insulin "receptoropathies," including autoantibodies to the insulin receptor and insulin receptor gene mutations, are characterized by extreme insulin resistance and ovarian hyperandrogenism, without dyslipidemia or fatty liver disease. Autoantibodies to the insulin receptor can be treated using an immunosuppressive paradigm adapted from treatment of other autoimmune and neoplastic conditions. Leptin treatment has shown some success in treating hyperglycemia in patients with insulin receptor gene mutations. Treatment for this condition remains inadequate, and novel therapies that bypass insulin receptor signaling, such as enhancers of brown adipose tissue, are needed. Conclusions: We present a clinical approach to the treatment of syndromic insulin resistance. The study of rare diseases that replicate the metabolic syndrome, with clear-cut pathophysiology, promotes understanding of novel physiology and development of targeted therapies that may be applicable to the broader population with obesity, insulin resistance, and diabetes. (Endocr Pract. 2012; 18:763-771) C1 [Gorden, Phillip; Zadeh, Elika Safar; Cochran, Elaine; Brown, Rebecca J.] NIDDKD, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Gorden, P (reprint author), 10 Ctr Dr,CRC Room 6-5940, Bethesda, MD 20892 USA. EM phillipg@intra.niddk.nih.gov FU Intramural NIH HHS [ZIA DK047052-07, ZIA DK047050-07] NR 62 TC 3 Z9 3 U1 2 U2 4 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD SEP-OCT PY 2012 VL 18 IS 5 BP 763 EP 771 DI 10.4158/EP12139.RA PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 031PH UT WOS:000310653900018 PM 23047930 ER PT J AU Gudmundsson, EF Gudnason, V Sigurdsson, S Launer, LJ Harris, TB Aspelund, T AF Gudmundsson, Elias Freyr Gudnason, Vilmundur Sigurdsson, Sigurdur Launer, Lenore J. Harris, Tamara B. Aspelund, Thor TI Coronary artery calcium distributions in older persons in the AGES-Reykjavik study SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Coronary artery calcium; Epidemiology; Older persons; Skewed distribution; ZINB; Statistical modelling ID RISK-FACTORS; HEART-DISEASE; SUBCLINICAL ATHEROSCLEROSIS; COMPUTED-TOMOGRAPHY; CALCIFICATION; MESA; SCORE; RACE/ETHNICITY; EVENTS; ADULTS AB Coronary Artery Calcium (CAC) is a sign of advanced atherosclerosis and an independent risk factor for cardiac events. Here, we describe CAC-distributions in an unselected aged population and compare modelling methods to characterize CAC-distribution. CAC is difficult to model because it has a skewed and zero inflated distribution with over-dispersion. Data are from the AGES-Reykjavik sample, a large population based study [2002-2006] in Iceland of 5,764 persons aged 66-96 years. Linear regressions using logarithmic- and Box-Cox transformations on CAC+1, quantile regression and a Zero-Inflated Negative Binomial model (ZINB) were applied. Methods were compared visually and with the PRESS-statistic, R-2 and number of detected associations with concurrently measured variables. There were pronounced differences in CAC according to sex, age, history of coronary events and presence of plaque in the carotid artery. Associations with conventional coronary artery disease (CAD) risk factors varied between the sexes. The ZINB model provided the best results with respect to the PRESS-statistic, R-2, and predicted proportion of zero scores. The ZINB model detected similar numbers of associations as the linear regression on ln(CAC+1) and usually with the same risk factors. C1 [Gudmundsson, Elias Freyr; Gudnason, Vilmundur; Sigurdsson, Sigurdur; Aspelund, Thor] Iceland Heart Assoc, Res Inst, IS-201 Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Aspelund, Thor] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. RP Aspelund, T (reprint author), Iceland Heart Assoc, Res Inst, Holtasmari 1, IS-201 Kopavogur, Iceland. EM aspelund@hjarta.is RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU National Institutes of Health (NIH) [N01-AG-12100]; National Institute on Aging, Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This work was supported by the National Institutes of Health (NIH) contract N01-AG-12100; the National Institute on Aging, in part by the Intramural Research Program; Hjartavernd (the Icelandic Heart Association); and the Althingi (the Icelandic Parliament). NR 38 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD SEP PY 2012 VL 27 IS 9 BP 673 EP 687 DI 10.1007/s10654-012-9730-6 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 030SF UT WOS:000310589700002 PM 22990371 ER PT J AU Hsieh, K Lee, YK Londos, C Raaka, BM Dalen, KT Kimmel, AR AF Hsieh, Kai Lee, Yun Kyung Londos, Constantine Raaka, Bruce M. Dalen, Knut Tomas Kimmel, Alan R. TI Perilipin family members preferentially sequester to either triacylglycerol-specific or cholesteryl-ester-specific intracellular lipid storage droplets SO JOURNAL OF CELL SCIENCE LA English DT Article DE PLIN; ADRP; TIP47; LSDP5; S3-12; Triacylglyceride; Cholesterol; Fatty acids; Lipolysis ID DIFFERENTIATION-RELATED PROTEIN; PAT-FAMILY; ENDOPLASMIC-RETICULUM; 3T3-L1 ADIPOCYTES; BRASSICA TAPETUM; TIP47; LIPOLYSIS; OBESITY; ALPHA; ADIPOPHILIN AB Perilipin family proteins (Plins) coat the surface of intracellular neutral lipid storage droplets in various cell types. Studies across diverse species demonstrate that Plins regulate lipid storage metabolism through recruitment of lipases and other regulatory proteins to lipid droplet surfaces. Mammalian genomes have distinct Plin gene members and additional protein forms derived from specific mRNA splice variants. However, it is not known if the different Plins have distinct functional properties. Using biochemical, cellular imaging and flow cytometric analyses, we now show that within individual cells of various types, the different Plin proteins preferentially sequester to separate pools of lipid storage droplets. By examining ectopically expressed GFP fusions and all endogenous Plin protein forms, we demonstrate that different Plins sequester to different types of lipid droplets that are composed of either triacylcerides or cholesterol esters. Furthermore, Plins with strong association preferences to triacylceride (or cholesterol ester) droplets can re-direct the relative intracellular triacylceride-cholesterol ester balance toward the targeted lipid. Our data suggest diversity of Plin function, alter previous assumptions about shared collective actions of the Plins, and indicate that each Plin can have separate and unique functions. C1 [Hsieh, Kai; Lee, Yun Kyung; Londos, Constantine; Dalen, Knut Tomas; Kimmel, Alan R.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Raaka, Bruce M.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Dalen, Knut Tomas] Univ Oslo, Fac Med, Inst Basic Med Sci, Dept Nutr, N-0316 Oslo, Norway. RP Kimmel, AR (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov RI Dalen, Knut Tomas/C-4719-2016 OI Dalen, Knut Tomas/0000-0002-0270-5982 FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; Henning and Johan Throne-Holst's Foundation FX This work was supported by the Intramural Research Program of the National Institutes of Health; the National Institute of Diabetes and Digestive and Kidney Diseases; and a travel grant from the Henning and Johan Throne-Holst's Foundation to K. T. D. Deposited in PMC for release after 12 months. NR 41 TC 56 Z9 57 U1 0 U2 15 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 1 PY 2012 VL 125 IS 17 BP 4067 EP 4076 DI 10.1242/jcs.104943 PG 10 WC Cell Biology SC Cell Biology GA 030PJ UT WOS:000310582300016 PM 22685330 ER PT J AU Adl, SM Simpson, AGB Lane, CE Lukes, J Bass, D Bowser, SS Brown, MW Burki, F Dunthorn, M Hampl, V Heiss, A Hoppenrath, M Lara, E le Gall, L Lynn, DH McManus, H Mitchell, EAD Mozley-Stanridge, SE Parfrey, LW Pawlowski, J Rueckert, S Shadwick, L Schoch, CL Smirnov, A Spiegel, FW AF Adl, Sina M. Simpson, Alastair G. B. Lane, Christopher E. Lukes, Julius Bass, David Bowser, Samuel S. Brown, Matthew W. Burki, Fabien Dunthorn, Micah Hampl, Vladimir Heiss, Aaron Hoppenrath, Mona Lara, Enrique le Gall, Line Lynn, Denis H. McManus, Hilary Mitchell, Edward A. D. Mozley-Stanridge, Sharon E. Parfrey, Laura W. Pawlowski, Jan Rueckert, Sonja Shadwick, Laura Schoch, Conrad L. Smirnov, Alexey Spiegel, Frederick W. TI The Revised Classification of Eukaryotes SO JOURNAL OF EUKARYOTIC MICROBIOLOGY LA English DT Article DE Algae; amoebae; biodiversity; ciliates; flagellates; fungi; parasites; protozoa; systematics; taxonomy ID MARINE GREGARINES APICOMPLEXA; HIGHER-LEVEL CLASSIFICATION; RIBOSOMAL-RNA PHYLOGENIES; RED ALGAL GENERA; N. GEN.; MOLECULAR PHYLOGENY; SMALL-SUBUNIT; SSU-RDNA; EVOLUTIONARY RELATIONSHIPS; MULTIGENE ANALYSES AB This revision of the classification of eukaryotes, which updates that of Adl etal. [J. Eukaryot. Microbiol. 52 (2005) 399], retains an emphasis on the protists and incorporates changes since 2005 that have resolved nodes and branches in phylogenetic trees. Whereas the previous revision was successful in re-introducing name stability to the classification, this revision provides a classification for lineages that were then still unresolved. The supergroups have withstood phylogenetic hypothesis testing with some modifications, but despite some progress, problematic nodes at the base of the eukaryotic tree still remain to be statistically resolved. Looking forward, subsequent transformations to our understanding of the diversity of life will be from the discovery of novel lineages in previously under-sampled areas and from environmental genomic information. C1 [Adl, Sina M.] Univ Saskatchewan, Dept Soil Sci, Saskatoon, SK S7N 5A8, Canada. [Adl, Sina M.; Simpson, Alastair G. B.; Heiss, Aaron] Dalhousie Univ, Dept Biol, Halifax, NS B3H 4R2, Canada. [Lane, Christopher E.] Univ Rhode Isl, Dept Biol Sci, Kingston, RI 02881 USA. [Lukes, Julius] Univ S Bohemia, Ctr Biol, Ceske Budejovice, Czech Republic. [Lukes, Julius] Univ S Bohemia, Fac Sci, Inst Parasitol, Ceske Budejovice, Czech Republic. [Bass, David] Nat Hist Museum, Dept Zool, London SW7 5BD, England. [Bowser, Samuel S.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. [Brown, Matthew W.] Dalhousie Univ, Dept Biochem, Halifax, NS B3H 4R2, Canada. [Burki, Fabien] Univ British Columbia, Dept Bot, Vancouver, BC V6T 1Z4, Canada. [Dunthorn, Micah] Univ Kaiserslautern, Dept Ecol, D-67663 Kaiserslautern, Germany. [Hampl, Vladimir] Charles Univ Prague, Dept Parasitol, Prague 12843 2, Czech Republic. [Hoppenrath, Mona] DZMB Deutsch Zentrum Marine Biodiversitatsforsch, Forschungsinst Senckenberg, D-26382 Wilhelmshaven, Germany. [Lara, Enrique] Univ Neuchatel, Inst Biol, CH-2009 Neuchatel, Switzerland. [le Gall, Line] Museum Natl Hist Nat, Systemat Adaptat & Evolut UMR 7138, F-75231 Paris 05, France. [Lynn, Denis H.; Mitchell, Edward A. D.] Univ Guelph, Dept Integrat Biol, Guelph, ON N1G 2W1, Canada. [McManus, Hilary] Le Moyne Coll, Dept Biol Sci, Syracuse, NY 13214 USA. [Mozley-Stanridge, Sharon E.] Middle Georgia Coll, Dept Biol, Cochran, GA 31014 USA. [Parfrey, Laura W.] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Pawlowski, Jan] Univ Geneva, Dept Genet & Evolut, CH-1211 Geneva 4, Switzerland. [Rueckert, Sonja] Edinburgh Napier Univ, Sch Life Sport & Social Sci, Edinburgh EH11 4BN, Midlothian, Scotland. [Shadwick, Laura] Univ Arkansas, Dept Biol Sci, Fayetteville, AR 72701 USA. [Schoch, Conrad L.] NLM, GenBank Taxon, NIH, NCBI, Bethesda, MD 20892 USA. [Smirnov, Alexey] St Petersburg State Univ, Dept Invertebrate Zool, St Petersburg 199034, Russia. RP Adl, SM (reprint author), Univ Saskatchewan, Dept Soil Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada. EM sina.adl@usask.ca RI Hampl, Vladimir/A-4339-2008; Rueckert, Sonja/E-4695-2011; Mitchell, Edward/B-7259-2013; Le Gall, Line/E-1884-2014; Lukes, Julius/H-6760-2012; Burki, Fabien/F-4818-2010; Smirnov, Alexey/K-3743-2013; Adl, Sina/R-3187-2016; OI Brown, Matthew/0000-0002-1254-0608; Lara, Enrique/0000-0001-8500-522X; Hampl, Vladimir/0000-0002-5430-7564; Mitchell, Edward/0000-0003-0358-506X; Le Gall, Line/0000-0001-7807-4569; Lukes, Julius/0000-0002-0578-6618; Smirnov, Alexey/0000-0002-9844-5344; Simpson, Alastair/0000-0002-4133-1709; Pawlowski, Jan/0000-0003-2421-388X FU International Society of Protistologists; NIH, National Library of Medicine FX S.M.A. is grateful to the International Society of Protistologists for the opportunity to initiate and mediate discussions among many colleagues towards revising this classification. C.L.S. was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Authors after the first four are listed alphabetically. NR 211 TC 481 Z9 504 U1 31 U2 367 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5234 J9 J EUKARYOT MICROBIOL JI J. Eukaryot. Microbiol. PD SEP-OCT PY 2012 VL 59 IS 5 BP 429 EP 493 DI 10.1111/j.1550-7408.2012.00644.x PG 65 WC Microbiology SC Microbiology GA 033OC UT WOS:000310806200001 PM 23020233 ER PT J AU Alter, HJ Mikovits, JA Switzer, WM Ruscetti, FW Lo, SC Klimas, N Komaroff, AL Montoya, JG Bateman, L Levine, S Peterson, D Levin, B Hanson, MR Genfi, A Bhat, M Zheng, HQ Wang, R Li, BJ Hung, GC Lee, LL Sameroff, S Heneine, W Coffin, J Hornig, M Lipkin, WI AF Alter, Harvey J. Mikovits, Judy A. Switzer, William M. Ruscetti, Francis W. Lo, Shyh-Ching Klimas, Nancy Komaroff, Anthony L. Montoya, Jose G. Bateman, Lucinda Levine, Susan Peterson, Daniel Levin, Bruce Hanson, Maureen R. Genfi, Afia Bhat, Meera Zheng, HaoQiang Wang, Richard Li, Bingjie Hung, Guo-Chiuan Lee, Li Ling Sameroff, Stephen Heneine, Walid Coffin, John Hornig, Mady Lipkin, W. Ian TI A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus SO MBIO LA English DT Article ID RETROVIRUS XMRV; UNITED-STATES; MOUSE DNA; BLOOD; SEQUENCES; FAILURE; ABSENCE; CELLS; CONTAMINATION; INFECTION AB The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. IMPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen dediscovery that may be helpful to others working in this field. C1 [Genfi, Afia; Bhat, Meera; Sameroff, Stephen; Hornig, Mady; Lipkin, W. Ian] Columbia Univ, Ctr Infect & Immun, New York, NY 10027 USA. [Coffin, John] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Alter, Harvey J.; Wang, Richard] NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Switzer, William M.; Zheng, HaoQiang; Heneine, Walid] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Mikovits, Judy A.] Mikovits Consulting, Oxnard, CA USA. [Ruscetti, Francis W.] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD USA. [Lo, Shyh-Ching; Li, Bingjie; Hung, Guo-Chiuan] US FDA, Tissue Safety Lab, Off Cellular Tissue & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Klimas, Nancy] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Klimas, Nancy] Miami Vet Affairs Med Ctr, Miami, FL USA. [Montoya, Jose G.] Stanford Univ, Infect Dis Clin, Palo Alto, CA 94304 USA. [Komaroff, Anthony L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bateman, Lucinda] Fatigue Consultat Clin, Salt Lake City, UT USA. [Levine, Susan] Levine Clin, New York, NY USA. [Peterson, Daniel] Simmaron Res Inst, Incline Village, NV USA. [Levin, Bruce] Columbia Univ, Dept Biostat, New York, NY USA. [Hanson, Maureen R.; Lee, Li Ling] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA. RP Lipkin, WI (reprint author), Columbia Univ, Ctr Infect & Immun, New York, NY 10027 USA. EM wil2001@columbia.edu OI Hanson, Maureen/0000-0001-8141-3058 FU National Institutes of Health [AI1057158] FX This study was funded by National Institutes of Health award AI1057158 (NBC-Lipkin). NR 39 TC 19 Z9 20 U1 3 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2012 VL 3 IS 5 AR e00266-12 DI 10.1128/mBio.00266-12 PG 7 WC Microbiology SC Microbiology GA 030QK UT WOS:000310585000015 ER PT J AU Fauci, AS AF Fauci, Anthony S. TI Research on Highly Pathogenic H5N1 Influenza Virus: The Way Forward SO MBIO LA English DT Editorial Material ID TRANSMISSION; FERRETS AB The voluntary moratorium on gain-of-function research related to the transmissibility of highly pathogenic H5N1 influenza virus should continue, pending the resolution of critical policy questions concerning the rationale for performing such experiments and how best to report their results. The potential benefits and risks of these experiments must be discussed and understood by multiple stakeholders, including the general public, and all decisions regarding such research must be made in a transparent manner. C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 5 TC 3 Z9 3 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2012 VL 3 IS 5 AR e00359-12 DI 10.1128/mBio.00359-12 PG 2 WC Microbiology SC Microbiology GA 030QK UT WOS:000310585000039 ER PT J AU Pal-Bhowmick, I Andersen, J Srinivasan, P Narum, DL Bosch, J Miller, LH AF Pal-Bhowmick, Ipsita Andersen, John Srinivasan, Prakash Narum, David L. Bosch, Juergen Miller, Louis H. TI Binding of Aldolase and Glyceraldehyde-3-Phosphate Dehydrogenase to the Cytoplasmic Tails of Plasmodium falciparum Merozoite Duffy Binding-Like and Reticulocyte Homology Ligands SO MBIO LA English DT Article ID TRAP-LIKE PROTEIN; MALARIA PARASITE; CELL INVASION; APICOMPLEXAN PARASITES; ACTIN CYTOSKELETON; GLYCOLYTIC ENZYMES; HUMAN ERYTHROCYTES; ANONYMOUS PROTEIN; GLIDING MOTILITY; DOMAIN AB Invasion of erythrocytes by Plasmodium falciparum requires a connection between the cytoplasmic tail of the parasite's ligands for its erythrocyte receptors and the actin-myosin motor of the parasite. For the thromobospondin-related anonymous protein (TRAP) ligand on Plasmodium sporozoites, aldolase forms this connection and requires tryptophan and negatively charged amino acids in the ligand's cytoplasmic tail. Because of the importance of the Duffy binding-like (DBL) and the reticulocyte homology (RH) ligand families in erythrocyte binding and merozoite invasion, we characterized the ability of their cytoplasmic tails to bind aldolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), both of which bind actin. We tested the binding of the cytoplasmic peptides of the two ligand families to aldolase and GAPDH. Only the cytoplasmic peptides of some RH ligands showed strong binding to aldolase, and the binding depended on the presence of an aromatic amino acid (phenylalanine or tyrosine), rather than tryptophan, in the context of negatively charged amino acids. The binding was confirmed by surface plasmon resonance analysis and was found to represent affinity similar to that seen with TRAP. An X-ray crystal structure of aldolase at 2.5 angstrom in the presence of RH2b peptide suggested that the binding site location was near the TRAP-binding site. GAPDH bound to some of the cytoplasmic tails of certain RH and DBL ligands in an aromatic amino acid-dependent manner. Thus, the connection between Plasmodium merozoite ligands and erythrocyte receptors and the actin motor can be achieved through the activity of either aldolase or GAPDH by mechanisms that do not require tryptophan but, rather, other aromatic amino acids. IMPORTANCE The invasion of the Plasmodium merozoite into erythrocytes is a critical element in malaria pathogenesis. It is important to understand the molecular details of this process, as this machinery can be a target for both vaccine and drug development. In Plasmodium sporozoites and Toxoplasma tachyzoites, invasion involves a glycolytic enzyme aldolase, linking the cytoplasmic tail domains of the parasite ligands to the actin-myosin motor that drives invasion. This binding requires a tryptophan that cannot be replaced by other aromatic residues. Here we show that aldolase binds the cytoplasmic tails of some P. falciparum merozoite erythrocyte-binding ligands but that the binding involves aromatic residues other than tryptophan. The biological relevance of aldolase binding to cytoplasmic tails of parasite ligands in invasion is demonstrated by our observation that RH2b but not RH2a binds to aldolase and, as previously shown, that RH2b but not RH2a is required for P. falciparum invasion of erythrocytes. C1 [Pal-Bhowmick, Ipsita; Andersen, John; Srinivasan, Prakash; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Bosch, Juergen] Johns Hopkins Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD USA. [Bosch, Juergen] Johns Hopkins Malaria Res Inst, Baltimore, MD USA. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM lmiller@niaid.nih.gov RI Bosch, Jurgen/E-9370-2011 OI Bosch, Jurgen/0000-0002-2624-4105 FU Bloomberg Family Foundation; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was partially funded through the Bloomberg Family Foundation. This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 37 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2012 VL 3 IS 5 AR e00292-12 DI 10.1128/mBio.00292-12 PG 8 WC Microbiology SC Microbiology GA 030QK UT WOS:000310585000025 ER PT J AU Taubenberger, JK Baltimore, D Doherty, PC Markel, H Morens, DM Webster, RG Wilson, IA AF Taubenberger, Jeffery K. Baltimore, David Doherty, Peter C. Markel, Howard Morens, David M. Webster, Robert G. Wilson, Ian A. TI Reconstruction of the 1918 Influenza Virus: Unexpected Rewards from the Past SO MBIO LA English DT Article ID PANDEMIC INFLUENZA; A VIRUSES; BACTERIAL PNEUMONIA; VACCINE PROTECTS; HEMAGGLUTININ; HOST; POLYMERASE; FERRETS; REASSORTMENT; TRANSMISSION AB The influenza pandemic of 1918-1919 killed approximately 50 million people. The unusually severe morbidity and mortality associated with the pandemic spurred physicians and scientists to isolate the etiologic agent, but the virus was not isolated in 1918. In 1996, it became possible to recover and sequence highly degraded fragments of influenza viral RNA retained in preserved tissues from several 1918 victims. These viral RNA sequences eventually permitted reconstruction of the complete 1918 virus, which has yielded, almost a century after the deaths of its victims, novel insights into influenza virus biology and pathogenesis and has provided important information about how to prevent and control future pandemics. C1 [Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Baltimore, David] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Doherty, Peter C.] Univ Melbourne, Dept Microbiol & Immunol, Melbourne, Vic, Australia. [Markel, Howard] Univ Michigan, Med Ctr, Ctr Hist Med, Ann Arbor, MI USA. [Markel, Howard] Univ Michigan, Med Ctr, Dept Pediat & Communicable Dis, Ann Arbor, MI USA. [Morens, David M.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. [Webster, Robert G.] St Jude Childrens Res Hosp, Dept Infect Dis, Div Virol, Memphis, TN 38105 USA. [Wilson, Ian A.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov RI Doherty, Peter Charles/C-4185-2013 OI Doherty, Peter Charles/0000-0002-5028-3489 FU NIH; NIAID FX This work was supported in part by the Intramural Research Program of the NIH and the NIAID (J.K.T.). NR 60 TC 12 Z9 13 U1 4 U2 36 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2012 VL 3 IS 5 AR e00201-12 DI 10.1128/mBio.00201-12 PG 5 WC Microbiology SC Microbiology GA 030QK UT WOS:000310585000006 ER PT J AU Waterman, SR Park, YD Raja, M Qiu, J Hammoud, DA O'Halloran, TV Williamson, PR AF Waterman, Scott R. Park, Yoon-Dong Raja, Meera Qiu, Jin Hammoud, Dima A. O'Halloran, Thomas V. Williamson, Peter R. TI Role of CTR4 in the Virulence of Cryptococcus neoformans SO MBIO LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; IN-VITRO; LACCASE; YEAST; GENE; INFECTION; PATHOGEN; IDENTIFICATION; EXPRESSION; TRANSPORT AB While research has identified an important contribution for metals, such as iron, in microbial pathogenesis, the roles of other transition metals, such as copper, remain mostly unknown. Recent evidence points to a requirement for copper homeostasis in the virulence of Cryptococcus neoformans based on a role for a CUF1 copper regulatory factor in mouse models and in a human patient cohort. C. neoformans is an important fungal pathogen that results in an estimated 600,000 AIDS-related deaths yearly. In the present studies, we found that a C. neoformans mutant lacking the CUF1-dependent copper transporter, CTR4, grows normally in rich medium at 37 degrees C but has reduced survival in macrophages and attenuated virulence in a mouse model. This reduced survival and virulence were traced to a growth defect under nutrient-restricted conditions. Expression studies using a full-length CTR4-fluorescent fusion reporter construct demonstrated robust expression in macrophages, brain, and lung, the latter shown by ex vivo fluorescent imaging. Inductively coupled mass spectroscopy (ICP-MS) was used to probe the copper quota of fungal cells grown in defined medium and recovered from brain, which suggested a role for a copper-protective function of CTR4 in combination with cell metallothioneins under copper-replete conditions. In summary, these data suggest a role for CTR4 in copper-related homeostasis and subsequently in fungal virulence. IMPORTANCE Crytococcus neoformans is a significant global fungal pathogen, and copper homeostasis is a relatively unexplored aspect of microbial pathogenesis that could lead to novel therapeutics. Previous studies correlated expression levels of a Ctr4 copper transporter to development of meningoencephalitis in a patient cohort of solid-organ transplants, but a direct role for Ctr4 in mammalian pathogenesis has not been demonstrated. The present studies utilize a Delta ctr4 mutant strain which revealed an important role for CTR4 in C. neoformans infections in mice and relate the gene product to homeostatic control of copper and growth under nutrient-restricted conditions. Robust expression levels of CTR4 during fungal infection were exploited to demonstrate expression and lung cryptococcal disease using ex vivo fluorescence imaging. In summary, these studies are the first to directly demonstrate a role for a copper transporter in fungal disease and provide an ex vivo imaging tool for further study of cryptococcal gene expression and pathogenesis. C1 [Waterman, Scott R.; Park, Yoon-Dong; Qiu, Jin; Williamson, Peter R.] Univ Illinois, Coll Med, Dept Med, Infect Dis Sect, Chicago, IL 60680 USA. [Waterman, Scott R.; Park, Yoon-Dong; Qiu, Jin; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Raja, Meera; O'Halloran, Thomas V.] Northwestern Univ, Dept Chem, Evanston, IL USA. [Raja, Meera; O'Halloran, Thomas V.] Northwestern Univ, Chem Life Proc Inst, Evanston, IL USA. [Hammoud, Dima A.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Williamson, PR (reprint author), Univ Illinois, Coll Med, Dept Med, Infect Dis Sect, Chicago, IL 60680 USA. EM williamsonpr@mail.nih.gov RI Hammoud, Dima/C-2286-2015 FU United States Public Health Service [NIH-AI45995, AI49371]; Veteran's Administration; NIH, NIAID FX This work was supported, in part, by United States Public Health Service grants NIH-AI45995 and AI49371 (P. R. W.) and a merit award from the Veteran's Administration (P. R. W.). This research was also supported, in part, by the Intramural Research Program of the NIH, NIAID. NR 47 TC 9 Z9 10 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2012 VL 3 IS 5 AR e00285-12 DI 10.1128/mBio.00285-12 PG 11 WC Microbiology SC Microbiology GA 030QK UT WOS:000310585000021 ER PT J AU Switzer, CH Glynn, SA Cheng, RYS Ridnour, LA Green, JE Ambs, S Wink, DA AF Switzer, Christopher H. Glynn, Sharon A. Cheng, Robert Y. -S. Ridnour, Lisa A. Green, Jeffrey E. Ambs, Stefan Wink, David A. TI S-Nitrosylation of EGFR and Src Activates an Oncogenic Signaling Network in Human Basal-Like Breast Cancer SO MOLECULAR CANCER RESEARCH LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; NITRIC-OXIDE SYNTHASE; MOLECULAR-MECHANISMS; TYROSINE KINASE; POOR SURVIVAL; BETA-CATENIN; PHENOTYPE; TUMORS; EXPRESSION; GROWTH AB Increased inducible nitric oxide synthase (NOS2) expression in breast tumors is associated with decreased survival of estrogen receptor negative (ER-) breast cancer patients. We recently communicated the preliminary observation that nitric oxide (NO) signaling results in epidermal growth factor receptor (EGFR) tyrosine phosphorylation. To further define the role of NO in the pathogenesis of ER- breast cancer, we examined the mechanism of NO-induced EGFR activation in human ER- breast cancer. NO was found to activate EGFR and Src by a mechanism that includes S-nitrosylation. NO, at physiologically relevant concentrations, induced an EGFR/Src-mediated activation of oncogenic signal transduction pathways (including c-Myc, Akt, and beta-catenin) and the loss of PP2A tumor suppressor activity. In addition, NO signaling increased cellular EMT, expression and activity of COX-2, and chemoresistance to adriamycin and paclitaxel. When connected into a network, these concerted events link NO to the development of a stem cell-like phenotype, resulting in the upregulation of CD44 and STAT3 phosphorylation. Our observations are also consistent with the finding that NOS2 is associated with a basal-like transcription pattern in human breast tumors. These results indicate that the inhibition of NOS2 activity or NO signaling networks may have beneficial effects in treating basal-like breast cancer patients. Mol Cancer Res; 10(9); 1203-15. (C) 2012 AACR. C1 [Switzer, Christopher H.; Glynn, Sharon A.; Cheng, Robert Y. -S.; Ridnour, Lisa A.; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Glynn, Sharon A.; Ambs, Stefan] NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Wink, DA (reprint author), Bldg 10,Room B3-B35, Bethesda, MD 20892 USA. EM wink@mail.nih.gov RI Glynn, Sharon/D-7136-2013; Switzer, Christopher/D-9203-2013; OI Glynn, Sharon/0000-0003-1459-2580; Cheng, Robert/0000-0003-0287-6439 FU Center for Cancer Research, National Cancer Institute, NIH [1ZIASC007281-18] FX This work was supported by the intramural program of the Center for Cancer Research, National Cancer Institute, NIH (1ZIASC007281-18). NR 47 TC 33 Z9 33 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD SEP PY 2012 VL 10 IS 9 BP 1203 EP 1215 DI 10.1158/1541-7786.MCR-12-0124 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 031NI UT WOS:000310648300007 PM 22878588 ER PT J AU Fitzgerald, DP Emerson, DL Qian, YZ Anwar, T Liewehr, DJ Steinberg, SM Silberman, S Palmieri, D Steeg, PS AF Fitzgerald, Daniel P. Emerson, David L. Qian, Yongzhen Anwar, Talha Liewehr, David J. Steinberg, Seth M. Silberman, Sandra Palmieri, Diane Steeg, Patricia S. TI TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID IN-VIVO; DRUG-RESISTANCE; PHASE-II; MICROTUBULE; PACLITAXEL; PATUPILONE; THERAPY; ANTHRACYCLINES; OUTGROWTH; EFFICACY AB Brain metastases of breast and other cancers remain resistant to chemotherapeutic regimens that are effective systemically, in part due to the blood-brain barrier. We report that TPI-287, a new microtubule-stabilizing agent, displays in vitro cytotoxic activity similar to taxanes and epothilones. Unlike the taxanes, TPI-287 is permeable through the blood-brain barrier. Brain-to-plasma ratios of TPI-287 after a single injection typically exceeded one and were as high as 63.8 in the rat and 14.1 in the mouse. A brain-tropic derivative of the MDA-MB-231 triple-negative breast cancer cell line, 231-BR, was used to test whether TPI-287 may be efficacious at preventing or treating brain metastases. TPI-287 had growth inhibitory effects comparable with paclitaxel when 231-BR tumor cells were injected into the mammary fat pad. Brain metastatic colonization was determined by intracardiac injection of 231-BR cells, with treatment beginning on day 3 to 4 postinjection, culminating in a histologic count of brain metastases in brains necropsied days 25 to 28 postinjection. In this assay, paclitaxel, ixabepilone, and nab paclitaxel did not have significant inhibitory activity. TPI-287 was ineffective in the same assay using a 6 mg/kg every week schedule; however an 18 mg/kg dose delivered on days 3, 7, and 11 significantly reduced the outgrowth of brain metastases (55% reduction, P = 0.028) and reduced proliferation in brain metastases (16% reduction, P = 0.008). When TPI-287 treatment was delayed until days 18, 22, and 26 postinjection, efficacy was reduced (17% reduction, not significant). These data suggest that TPI-287 may have efficacy when administered early in the course of the disease. Mol Cancer Ther; 11(9); 1959-67. (C) 2012 AACR. C1 [Fitzgerald, Daniel P.; Anwar, Talha; Palmieri, Diane; Steeg, Patricia S.] NCI, Womens Canc Sect, Lab Mol Pharmacol, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Emerson, David L.] Bolder Biopath Inc, Boulder, CO USA. [Qian, Yongzhen] NCI, Lab Anim Sci Program, Sci Applicat Int Corp, Frederick, MD 21701 USA. [Silberman, Sandra] Quintiles Inc, Durham, NC USA. RP Steeg, PS (reprint author), NIH, Bldg 37,Room 1122, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov RI Palmieri, Diane/B-4258-2015 FU Glaxo-SmithKline; Millenium Pharmaceuticals; National Cancer Institute; US Department of Defense [W81 XWH-062-0033] FX P.S. Steeg received research support from Glaxo-SmithKline and Millenium Pharmaceuticals. S. Silberman is a consultant and member of the advisory board for Archer Biosciences, Inc. No potential conflicts of interest were disclosed by the other authors.; This work was supported by the Intramural Research program of the National Cancer Institute, and by the US Department of Defense Breast Cancer Research Program, Grant Number: W81 XWH-062-0033 awarded to P.S. Steeg. NR 39 TC 28 Z9 28 U1 0 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2012 VL 11 IS 9 BP 1959 EP 1967 DI 10.1158/1535-7163.MCT-12-0061 PG 9 WC Oncology SC Oncology GA 031KK UT WOS:000310638000012 PM 22622283 ER PT J AU Sen, R Natarajan, K Bhullar, J Shukla, S Fang, HB Cai, L Chen, ZS Ambudkar, SV Baer, MR AF Sen, Rupashree Natarajan, Karthika Bhullar, Jasjeet Shukla, Suneet Fang, Hong-Bin Cai, Ling Chen, Zhe-Sheng Ambudkar, Suresh V. Baer, Maria R. TI The Novel BCR-ABL and FLT3 Inhibitor Ponatinib Is a Potent Inhibitor of the MDR-Associated ATP-Binding Cassette Transporter ABCG2 SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID BREAST-CANCER RESISTANCE; ACUTE MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITORS; P-GLYCOPROTEIN ABCB1; MULTIDRUG-RESISTANCE; IMATINIB MESYLATE; EXPERIMENTAL-DESIGN; BRAIN ACCUMULATION; DRUG TRANSPORTER; CELL-LINE AB Ponatinib is a novel tyrosine kinase inhibitor with potent activity against BCR-ABL with mutations, including T315I, and also against fms-like tyrosine kinase 3. We tested interactions between ponatinib at pharmacologically relevant concentrations of 50 to 200 nmol/L and the MDR-associated ATP-binding cassette (ABC) proteins ABCB1, ABCC1, and ABCG2. Ponatinib enhanced uptake of substrates of ABCG2 and ABCB1, but not ABCC1, in cells overexpressing these proteins, with a greater effect on ABCG2 than on ABCB1. Ponatinib potently inhibited [I-125]-IAAP binding to ABCG2 and ABCB1, indicating binding to their drug substrate sites, with IC50 values of 0.04 and 0.63 mu mol/L, respectively. Ponatinib stimulated ABCG2 ATPase activity in a concentration-dependent manner and stimulated ABCB1 ATPase activity at low concentrations, consistent with it being a substrate of both proteins at pharmacologically relevant concentrations. The ponatinib IC50 values of BCR-ABL-expressing K562 cells transfected with ABCB1 and ABCG2 were approximately the same as and 2-fold higher than that of K562, respectively, consistent with ponatinib being a substrate of both proteins, but inhibiting its own transport, and resistance was also attenuated to a small degree by ponatinib-induced downregulation of ABCB1 and ABCG2 cell-surface expression on resistant K562 cells. Ponatinib at pharmacologically relevant concentrations produced synergistic cytotoxicity with ABCB1 and ABCG2 substrate chemotherapy drugs and enhanced apoptosis induced by these drugs, including daunorubicin, mitoxantrone, topotecan, and flavopiridol, in cells overexpressing these transport proteins. Combinations of ponatinib and chemotherapy drugs warrant further testing. Mol Cancer Ther; 11(9); 2033-44. (C) 2012 AACR. C1 [Sen, Rupashree; Natarajan, Karthika; Bhullar, Jasjeet; Fang, Hong-Bin; Cai, Ling; Baer, Maria R.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Baer, Maria R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Fang, Hong-Bin] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Zhe-Sheng] St Johns Univ, Queens, NY USA. RP Baer, MR (reprint author), Univ Maryland, Greenebaum Canc Ctr, 22 S Greene St, Baltimore, MD 21201 USA. EM mbaer@umm.edu RI Natarajan, Karthika/G-7206-2012; OI Natarajan, Karthika/0000-0001-7435-1477 FU Leukemia and Lymphoma Society; University of Maryland; Baltimore UMMG Cancer Research Grant [CH 649 CRF]; State of Maryland Department of Health and Mental Hygiene (DHMH); NCI Cancer Center [P30 CA134274]; NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX The study was supported by a Leukemia and Lymphoma Society Translational Research Award (M. R. Baer), University of Maryland, Baltimore UMMG Cancer Research Grant #CH 649 CRF, State of Maryland Department of Health and Mental Hygiene (DHMH) under the Cigarette Restitution Fund Program (M. R. Baer), NCI Cancer Center Support Grant P30 CA134274 (UMGCC), and NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (S. Shukla, S.V. Ambudkar). NR 49 TC 23 Z9 25 U1 1 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2012 VL 11 IS 9 BP 2033 EP 2044 DI 10.1158/1535-7163.MCT-12-0302 PG 12 WC Oncology SC Oncology GA 031KK UT WOS:000310638000019 PM 22778153 ER PT J AU Takeuchi, N Hogeweg, P AF Takeuchi, Nobuto Hogeweg, Paulien TI Evolutionary dynamics of RNA-like replicator systems: A bioinformatic approach to the origin of life SO PHYSICS OF LIFE REVIEWS LA English DT Review DE RNA world; Early evolution; What is life; Protocell; Mathematical modeling; Computational modeling ID POLYMERASE RIBOZYME EFFICIENCY; SEQUENCE STRUCTURE MAPS; HIGH MUTATION-RATES; SECONDARY STRUCTURES; ERROR-THRESHOLD; PREBIOTIC EVOLUTION; NEUTRAL NETWORKS; GROUP SELECTION; EXHAUSTIVE ENUMERATION; FINITE POPULATIONS AB We review computational studies on prebiotic evolution, focusing on informatic processes in RNA-like replicator systems. In particular, we consider the following processes: the maintenance of information by replicators with and without interactions, the acquisition of information by replicators having a complex genotype phenotype map, the generation of information by replicators having a complex genotype phenotype interaction map, and the storage of information by replicators serving as dedicated templates. Focusing on these informatic aspects, we review studies on quasi-species, error threshold, RNA-folding genotype-phenotype map. hypercycle, multilevel selection (including spatial self-organization, classical group selection, and compartmentalization), and the origin of DNA-like replicators. In conclusion, we pose a future question for theoretical studies on the origin of life. Published by Elsevier B.V. C1 [Takeuchi, Nobuto] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Takeuchi, Nobuto; Hogeweg, Paulien] Univ Utrecht, Theoret Biol & Bioinformat Grp, NL-3584 CH Utrecht, Netherlands. RP Takeuchi, N (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM takeuchi@ncbi.nlm.nih.gov FU Netherlands Organization for Scientific Research [612.060.522]; Intramural Research Program of the NIH, National Library of Medicine; JSPS FX This research was in part supported by the Netherlands Organization for Scientific Research, exact sciences (612.060.522), by the Intramural Research Program of the NIH, National Library of Medicine, and by the JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at the NIH. NR 135 TC 28 Z9 28 U1 0 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1571-0645 EI 1873-1457 J9 PHYS LIFE REV JI Phys. Life Rev. PD SEP PY 2012 VL 9 IS 3 BP 219 EP 263 DI 10.1016/j.plrev.2012.06.001 PG 45 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA 031US UT WOS:000310668500001 PM 22727399 ER PT J AU Takeuchi, N Hogeweg, P AF Takeuchi, Nobuto Hogeweg, Paulien TI Reply to the commentaries on "Evolutionary dynamics of RNA-like replicator systems: A bioinformatic approach to the origin of life" SO PHYSICS OF LIFE REVIEWS LA English DT Editorial Material ID ERROR-THRESHOLD; FUNCTIONAL COMPLEXITY; FINITE POPULATIONS; MULLERS RATCHET; RECOMBINATION; SELECTION; INFORMATION; GROWTH; MACROMOLECULES; COEXISTENCE C1 [Takeuchi, Nobuto] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Hogeweg, Paulien] Univ Utrecht, Theoret Biol & Bioinformat Grp, NL-3584 CH Utrecht, Netherlands. RP Takeuchi, N (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM takeuchi@ncbi.nlm.nih.gov NR 54 TC 1 Z9 1 U1 0 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1571-0645 J9 PHYS LIFE REV JI Phys. Life Rev. PD SEP PY 2012 VL 9 IS 3 BP 279 EP 284 DI 10.1016/j.plrev.2012.07.009 PG 6 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA 031US UT WOS:000310668500009 ER PT J AU Gorospe, M AF Gorospe, Myriam TI RNA-binding proteins: Post-transcriptional control of aging traits An introduction to a series of review articles SO AGEING RESEARCH REVIEWS LA English DT Editorial Material C1 NIH, Natl Inst Aging Intramural Res Program, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIH, Natl Inst Aging Intramural Res Program, Lab Mol Biol & Immunol, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov FU Intramural NIH HHS NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 J9 AGEING RES REV JI Ageing Res. Rev. PD SEP PY 2012 VL 11 IS 4 SI SI BP 421 EP 422 DI 10.1016/j.arr.2012.09.001 PG 2 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 024RU UT WOS:000310127100001 PM 22999313 ER PT J AU Abdelmohsen, K Srikantan, S Kang, MJ Gorospe, M AF Abdelmohsen, Kotb Srikantan, Subramanya Kang, Min-Ju Gorospe, Myriam TI Regulation of senescence by microRNA biogenesis factors SO AGEING RESEARCH REVIEWS LA English DT Review DE Primary microRNA; Precursor microRNA; Microprocessor; Drosha; Dicer; RISC; Senescence ID RNA-BINDING PROTEIN; HUMAN-DIPLOID FIBROBLASTS; SQUAMOUS-CELL CARCINOMA; NEGATIVE FEEDBACK LOOP; TARGET MESSENGER-RNAS; REPLICATIVE SENESCENCE; PREMATURE SENESCENCE; TUMOR-SUPPRESSOR; GENE-EXPRESSION; CANCER CELLS AB Senescence represents a state of indefinite growth arrest in cells that have reached the end of their replicative life span, have become damaged, or express aberrant levels of cancer-related proteins. While senescence is widely considered to represent a tumor-suppressive mechanism, the accumulation of senescent cells in tissues of older organisms is believed to underlie age-associated losses in physiologic function and age-related diseases. With the emergence of microRNAs (miRNAs) as a major class of molecular regulators of senescence, we review the transcriptional and post-transcriptional factors that control senescence-associated microRNA biosynthesis. Focusing on their enhancement or repression of senescence, we describe the transcription factors that govern the synthesis of primary (pri-)miRNAs, the proteins that control the nuclear processing of pri-miRNAs into precursor (pre-)miRNAs, including RNA editing enzymes, RNases, and RNA helicases, and the cytoplasmic proteins that affect the final processing of pre-miRNAs into mature miRNAs. We discuss how miRNA biogenesis proteins promote or inhibit senescence, and thus influence the senescent phenotype that affects normal tissue function and pathology. Published by Elsevier B.V. C1 [Abdelmohsen, Kotb; Srikantan, Subramanya; Kang, Min-Ju; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, IRP, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA, Lab Mol Biol & Immunol, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov; myriam-gorospe@nih.gov OI srikantan, subramanya/0000-0003-1810-6519; abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institute on Aging-Intramural Research Program of the National Institutes of Health FX This work was supported in its entirety by the National Institute on Aging-Intramural Research Program of the National Institutes of Health. NR 168 TC 19 Z9 19 U1 0 U2 27 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD SEP PY 2012 VL 11 IS 4 SI SI BP 491 EP 500 DI 10.1016/j.arr.2012.01.003 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 024RU UT WOS:000310127100009 PM 22306790 ER PT J AU Mattheisen, M Bunyavanich, S Himes, BE Gauderman, WJ Bleecker, ER Meyers, DA London, SJ Gilliland, FD Burchard, EG Martinez, FD Williams, LK Barnes, KC Ober, C Nicolae, DL Laird, NM Raby, BA Lasky-Su, J Lange, C Weiss, ST AF Mattheisen, Manuel Bunyavanich, Supinda Himes, Blanca E. Gauderman, W. James Bleecker, Eugene R. Meyers, Deborah A. London, Stephanie J. Gilliland, Frank D. Burchard, Esteban G. Martinez, Fernando D. Williams, L. Keoki Barnes, Kathleen C. Ober, Carole Nicolae, Dan L. Laird, Nan M. Raby, Benjamin A. Lasky-Su, Jessica Lange, Christoph Weiss, Scott T. TI Integrative analysis of case-control and family based association studies - lessons we have learned SO ANNALS OF HUMAN GENETICS LA English DT Meeting Abstract CT European Mathematical Genetics Meeting CY APR 12-13, 2012 CL Gottingen, GERMANY C1 [Mattheisen, Manuel; Bunyavanich, Supinda; Himes, Blanca E.; Raby, Benjamin A.; Lasky-Su, Jessica; Weiss, Scott T.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Mattheisen, Manuel; Bunyavanich, Supinda; Himes, Blanca E.; Raby, Benjamin A.; Lasky-Su, Jessica; Weiss, Scott T.] Harvard Univ, Sch Med, Boston, MA USA. [Mattheisen, Manuel; Laird, Nan M.; Lange, Christoph] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Gauderman, W. James; Gilliland, Frank D.] Univ So Calif, Los Angeles, CA USA. [Bleecker, Eugene R.; Meyers, Deborah A.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [London, Stephanie J.] NIEHS, Res Triangle Pk, NC 27709 USA. [Burchard, Esteban G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Martinez, Fernando D.] Univ Arizona, Tucson, AZ USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA. [Barnes, Kathleen C.] Johns Hopkins Univ, Baltimore, MD USA. [Ober, Carole; Nicolae, Dan L.] Univ Chicago, Chicago, IL 60637 USA. [Lange, Christoph] Univ Bonn, Bonn, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD SEP PY 2012 VL 76 BP 419 EP 419 PN 5 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 986WQ UT WOS:000307377000032 ER PT J AU Marullo, L Cornes, BK Dupuis, J Meigs, JB Morris, A Prokopenko, I AF Marullo, Letizia Cornes, Belinda K. Dupuis, Josee Meigs, James B. Morris, Andrew Prokopenko, Inga TI Estimating the fraction of established metabolic trait loci with discernible pleiotropic effects SO ANNALS OF HUMAN GENETICS LA English DT Meeting Abstract CT European Mathematical Genetics Meeting CY APR 12-13, 2012 CL Gottingen, GERMANY C1 [Marullo, Letizia; Morris, Andrew; Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Marullo, Letizia] Univ Ferrara, Dept Evolutionary Biol, Genet Sect, I-44100 Ferrara, Italy. [Cornes, Belinda K.; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Cornes, Belinda K.; Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Morris, Andrew; Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD SEP PY 2012 VL 76 BP 427 EP 428 PN 5 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 986WQ UT WOS:000307377000053 ER PT J AU Meier, S Mattheisen, M Vassos, E Strohmaier, J Treutlein, J Frank, J Breuer, R Degenhardt, F Muhleisen, TW Muller-Myhsok, B Steffens, M Schmael, C McMahon, FJ Nothen, MM Cichon, S Schulze, TG Rietschel, M AF Meier, Sandra Mattheisen, Manuel Vassos, Evangelos Strohmaier, Jana Treutlein, Jens Frank, Josef Breuer, Rene Degenhardt, Franziska Muehleisen, Thomas W. Mueller-Myhsok, Bertram Steffens, Michael Schmael, Christine McMahon, Francis J. Noethen, Markus M. Cichon, Sven Schulze, Thomas G. Rietschel, Marcella TI Genome-wide significant association between a "Negative Mood Delusions" dimension in bipolar disorder and genetic variation on chromosome 3q26.1 SO ANNALS OF HUMAN GENETICS LA English DT Meeting Abstract CT European Mathematical Genetics Meeting CY APR 12-13, 2012 CL Gottingen, GERMANY C1 [Meier, Sandra; Strohmaier, Jana; Treutlein, Jens; Frank, Josef; Breuer, Rene; Schmael, Christine; Rietschel, Marcella] Cent Inst Mental Hlth, D-6800 Mannheim, Germany. [Mattheisen, Manuel] Inst Genom Math, Bonn, Germany. [Mattheisen, Manuel] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Vassos, Evangelos] Kings Coll London, London WC2R 2LS, England. [Degenhardt, Franziska; Muehleisen, Thomas W.; Noethen, Markus M.; Cichon, Sven] Life & Brain Ctr, Bonn, Germany. [Degenhardt, Franziska; Muehleisen, Thomas W.; Noethen, Markus M.; Cichon, Sven] Univ Bonn, Inst Human Genet, Bonn, Germany. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-8000 Munich, Germany. [McMahon, Francis J.] NIMH, Bethesda, MD 20892 USA. [Schulze, Thomas G.] Univ Gottingen, Gottingen, Germany. RI Muller-Myhsok, Bertram/A-3289-2013; Vassos, Evangelos/F-9825-2013; Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014 OI Vassos, Evangelos/0000-0001-6363-0438; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD SEP PY 2012 VL 76 BP 428 EP 428 PN 5 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 986WQ UT WOS:000307377000055 ER PT J AU Prokopenko, I Ma, C Magi, R Chen, H Voight, BF Qi, LU Van Zuydam, N Grallert, H Yengo, L Dina, CT Thorleifsson, G Fucshberger, C Liang, LM Mueller-Nurasyi, M Willems, SM Kao, LD Navarro, P Steinthorsdottir, V Boehnke, M Dupuis, J Mccarthy, MI Scott, LJ AF Prokopenko, Inga Ma, Clement Maegi, Reedik Chen, Han Voight, Benjamin F. Qi, L. U. Van Zuydam, Natalie Grallert, Harald Yengo, Loic Dina, Chris-Tian Thorleifsson, Gudmar Fucshberger, Christian Liang, Liming Mueller-Nurasyi, Martina Willems, Sara M. Kao, Linda Navarro, Pau Steinthorsdottir, Valgerdur Boehnke, Michael Dupuis, Josee Mccarthy, Mark I. Scott, Laura J. CA Consortium Diagram TI Search for novel type 2 diabetes susceptibility loci using genome-wide association studies imputed from a 1000 Genomes references panel SO ANNALS OF HUMAN GENETICS LA English DT Meeting Abstract CT European Mathematical Genetics Meeting CY APR 12-13, 2012 CL Gottingen, GERMANY C1 [Prokopenko, Inga; Maegi, Reedik; Mccarthy, Mark I.] Univ Oxford, WTCHG, Oxford, England. [Prokopenko, Inga; Mccarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Ma, Clement; Fucshberger, Christian; Boehnke, Michael; Scott, Laura J.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Ma, Clement; Fucshberger, Christian; Boehnke, Michael; Scott, Laura J.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Maegi, Reedik] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Chen, Han; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Voight, Benjamin F.] Broad Inst Harvard & MIT, Boston, MA USA. [Voight, Benjamin F.] Univ Penn, Dept Pharmacol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Qi, L. U.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Qi, L. U.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Qi, L. U.] Harvard Univ, Sch Med, Boston, MA USA. [Van Zuydam, Natalie] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland. [Van Zuydam, Natalie] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland. [Grallert, Harald] German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Yengo, Loic] Inst Pasteur, Ctr Immunol & Biol Parasitaire, CNRS, Unite Mixte Rech UMR8199, F-59019 Lille, France. [Dina, Chris-Tian] INSERM, UMR915, Inst Thorax, Nantes, France. [Dina, Chris-Tian] Univ Nantes, Nantes, France. [Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur] deCODE Genet, Reykjavik, Iceland. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mueller-Nurasyi, Martina] German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Willems, Sara M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Kao, Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Navarro, Pau] Western Gen Hosp, Human Genet Unit, MRC, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. RI Grallert, Harald/B-3424-2013; Dina, Christian/D-3535-2015 OI Dina, Christian/0000-0002-7722-7348 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD SEP PY 2012 VL 76 BP 429 EP 430 PN 5 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 986WQ UT WOS:000307377000058 ER PT J AU Kim, YS Nwe, K Milenic, DE Brechbiel, MW Satz, S Baidoo, KE AF Kim, Young-Seung Nwe, Kido Milenic, Diane E. Brechbiel, Martin W. Satz, Stanley Baidoo, Kwamena E. TI Synthesis and characterization of alpha(v)beta(3)-targeting peptidomimetic chelate conjugates for PET and SPECT imaging SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Integrin alpha(v)beta(3); NODAGA; DOTAGA; Peptidomimetics; Antagonist; Ga-68; Pb-203; PET imaging; SPECT imaging ID IN-VIVO EVALUATION; TUMOR; ANTIBODY; DOTA; COMPLEXES; PEPTIDES; LEAD(II); LIGANDS; PB-203; PROBE AB There is growing interest in small peptidomimetic alpha(v)beta(3) integrin antagonists that are readily synthesized and characterized and can be easily handled using physiological conditions. Peptidomimetic 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-[N-(3-amino-neopenta-1-carbamyl)] -aminoethylsulfonyl-amino-beta-alanine (IAC) was successfully conjugated to 1-(1-carboxy-3-carbo-t-but-oxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODA-GA(tBu)(3)) and 1-(1-carboxy-3-carbotertbutoxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA-GA(tBu)(4)) and radiolabeled with In-111, Ga-67 and Pb-203. Results of a radioimmunoassay demonstrated binding to purified alpha(v)beta(3) integrin when 14 equiv of integrin were added to the reaction. Based on this promising result, investigations are moving forward to evaluate the NODA-GA-IAC and DOTA-GA-IAC conjugates for targeting tumor associated angiogenesis and alpha(v)beta(3) integrin positive tumors to define their PET and SPECT imaging qualities as well as their potential for delivery of therapeutic radionuclides. Published by Elsevier Ltd. C1 [Kim, Young-Seung; Nwe, Kido; Milenic, Diane E.; Brechbiel, Martin W.; Baidoo, Kwamena E.] NCI, Radioimmune & Inorgan Chem Sect, ROB, NIH, Bethesda, MD 20892 USA. [Satz, Stanley] Adv Imaging Projects Inc, Doral, FL USA. RP Baidoo, KE (reprint author), NCI, Radioimmune & Inorgan Chem Sect, ROB, NIH, 10 Ctr Dr,MSC 1002,Rm B3B69, Bethesda, MD 20892 USA. EM baidook@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 22 TC 3 Z9 3 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 1 PY 2012 VL 22 IS 17 BP 5517 EP 5522 DI 10.1016/j.bmcl.2012.07.024 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 995WV UT WOS:000308046400031 PM 22853992 ER PT J AU Chen, XJ Nacif, MS Liu, ST Sibley, C Summers, RM Bluemke, DA Yao, JH AF Chen, Xinjian Nacif, Marcelo S. Liu, Songtao Sibley, Christopher Summers, Ronald M. Bluemke, David A. Yao, Jianhua TI A Framework of Whole Heart Extracellular Volume Fraction Estimation for Low-Dose Cardiac CT Images SO IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE LA English DT Article DE Cardiac CT (CCT); extracellular volume (ECV) fraction; myocardium segmentation; registration ID MAGNETIC-RESONANCE; SEGMENTATION; REGISTRATION; ALGORITHMS; MODELS; MOTION; QUANTIFICATION; CONSTRUCTION; FIBROSIS; VISION AB Cardiac CT (CCT) is widely available and has been validated for the detection of focal myocardial scar using a delayed enhancement technique in this paper. CCT, however, has not been previously evaluated for quantification of diffuse myocardial fibrosis. In our investigation, we sought to evaluate the potential of low-dose CCT for the measurement of myocardial whole heart extracellular volume (ECV) fraction. ECV is altered under conditions of increased myocardial fibrosis. A framework consisting of three main steps was proposed for CCT whole heart ECV estimation. First, a shape-constrained graph cut (GC) method was proposed for myocardium and blood pool segmentation on postcontrast image. Second, the symmetric demons deformable registration method was applied to register precontrast to postcontrast images. So the correspondences between the voxels from precontrast to postcontrast images were established. Finally, the whole heart ECV value was computed. The proposed method was tested on 20 clinical low-dose CCT datasets with precontrast and postcontrast images. The preliminary results demonstrated the feasibility and efficiency of the proposed method. C1 [Nacif, Marcelo S.; Liu, Songtao; Sibley, Christopher; Summers, Ronald M.; Bluemke, David A.; Yao, Jianhua] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Chen, Xinjian] Soochow Univ, Sch Elect & Informat Engn, Suzhou 215006, Jiangsu, Peoples R China. RP Yao, JH (reprint author), NIH, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM xjchen@suda.edu.cn; marcelo.nacif@mail.nih.gov; songtao.liu@mail.nih.gov; christopher.sibley@mail.nih.gov; rsummers@mail.nih.gov; bluemked@mail.nih.gov; jyao@mail.nih.gov RI Sibley, Christopher/C-9900-2013; Chen, Xinjian/E-8592-2016; OI Bluemke, David/0000-0002-8323-8086 FU Intramural Research Program of the Clinical Center, National Institutes of Health FX This work was supported in part by the Intramural Research Program of the Clinical Center, National Institutes of Health. NR 50 TC 7 Z9 8 U1 0 U2 5 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1089-7771 EI 1558-0032 J9 IEEE T INF TECHNOL B JI IEEE T. Inf. Technol. Biomed. PD SEP PY 2012 VL 16 IS 5 SI SI BP 842 EP 851 DI 10.1109/TITB.2012.2204405 PG 10 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA 008YP UT WOS:000308992800006 PM 22711778 ER PT J AU Xu, JJ Smith, MK Chu, J Ding, GW Chang, DF Sharp, GB Qian, HZ Lu, L Bi, AM Wang, N AF Xu, J. J. Smith, M. K. Chu, J. Ding, G. W. Chang, D. F. Sharp, G. B. Qian, H. Z. Lu, L. Bi, A. M. Wang, N. TI Dynamics of the HIV epidemic in southern China: sexual and drug-using behaviours among female sex workers and male clients in Yunnan SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE HIV; STI; IDU; female sex workers; male clients; prevalence; drug use; China ID TRANSMITTED-DISEASES; RISK BEHAVIORS; COTE-DIVOIRE; CONDOM USE; TRANSMISSION; INFECTION; THAILAND; BRIDGE; USERS; POPULATION AB To examine the HIV/sexually transmitted infection (STI)-related risk behaviours among community-based female sex workers (FSWs) and their clients in Yunnan Province, China, we performed a cross-sectional study of 705 FSWs and 100 male clients. We found that HIV seroprevalence among FSWs was 13.0% and the most prevalent STI was herpes simplex virus type 2 (HSV-2) (71.1%), followed by Chlamydia trachomatis (18.1%) and syphilis (8.8%). The 20% of FSWs who reported injection drug use also reported needle-sharing behaviours in the last three months. Drug-using FSWs had substantially higher HIV and HSV-2 prevalence, serviced more clients and had a longer history of sex work than non-using FSWs. In total, 57.0% of male clients did not consistently use condoms with FSWs, 2.0% reported illicit drug use and 17.0% had STI symptoms in the last year. The dual risk behaviours of drug-using FSWs and clients place them at greater risk of HIV infection. Intervention programmes must adopt comprehensive methods. C1 [Xu, J. J.; Smith, M. K.; Chu, J.; Ding, G. W.; Wang, N.] Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing, Peoples R China. [Xu, J. J.] China Med Univ, Key Lab Immunol, Hosp 1, Shenyang, Liaoning Provin, Peoples R China. [Chang, D. F.; Bi, A. M.] Kaiyuan Cty Ctr Dis Control & Prevent, Kaiyuan, Yunnan Province, Peoples R China. [Sharp, G. B.] NIAID, NIH, Bethesda, MD USA. [Qian, H. Z.] Vanderbilt Univ, Sch Med, Inst Global Hlth, Kunming City, Peoples R China. [Lu, L.] Yunnan Prov Ctr Dis Control & Prevent, Kunming City, Peoples R China. RP Wang, N (reprint author), Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing, Peoples R China. EM xjjbeijing@gmail.com; wangnbj@163.com FU National Institute of Allergy and Infectious Diseases (NIAID), of the US National Institutes of Health (NIH) under China Integrated Programs for Research on AIDS (CIPRA) [U19 AI51915]; National Center for STD Control Center in Nanjing FX The authors thank the staff at Kaiyuan CDC, Yunnan Provincial CDC and National Center for STD Control Center in Nanjing for their cooperation in laboratory testing and their enthusiastic help and support throughout the implementation of the project. We thank the FSWs and male clients who participated in the study. We would also like to thank Gerald Sharp for a review of this manuscript.; This study was sponsored in part by the National Institute of Allergy and Infectious Diseases (NIAID), of the US National Institutes of Health (NIH) under China Integrated Programs for Research on AIDS (CIPRA), grant number U19 AI51915. NR 36 TC 6 Z9 6 U1 1 U2 11 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0956-4624 EI 1758-1052 J9 INT J STD AIDS JI Int. J. STD AIDS PD SEP PY 2012 VL 23 IS 9 BP 670 EP 675 DI 10.1258/ijsa.2009.009128 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 023QI UT WOS:000310049100016 PM 23033525 ER PT J AU Nwe, K Kim, YS Milenic, DE Baidoo, KE Brechbiel, MW AF Nwe, Kido Kim, Young-Seung Milenic, Diane E. Baidoo, Kwamena E. Brechbiel, Martin W. TI 111In-and 203Pb-labeled cyclic arginine-glycine-aspartic acid peptide conjugate as an av ss 3 integrin-binding radiotracer SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE click chemistry; aminooxy DOTA; RGD peptide; 203Pb ID BIFUNCTIONAL CHELATING-AGENTS; POSITRON-EMISSION-TOMOGRAPHY; RGD PEPTIDES; TUMOR UPTAKE; IN-VIVO; DOTA; PHARMACOKINETICS; BIODISTRIBUTION; EXPRESSION; ANTIBODY AB Methodology for site-specific modification and chelate conjugation of a cyclic arginine-glycine-aspartic acid (cRGD) peptide for the preparation of a radiotracer molecular imaging agent suitable for detecting av beta 3 integrin is described. The method involves functionalizing the peptide with an aldehyde moiety and conjugation to a 1,4,7,10-tetraazacyclododecane-N,N',N?,N?-tetraacetic acid derivative that possesses an aldehyde reactive aminooxy group. The binding assay of the 111In-labeled peptide conjugate with av beta 3 integrin showed 60% bound when four equivalents of the integrin was added, a reasonable binding affinity for a monovalent modified RGD peptide. C1 [Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Rm B3B69, 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 39 TC 3 Z9 4 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD SEP PY 2012 VL 55 IS 11 BP 423 EP 426 DI 10.1002/jlcr.2965 PG 4 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 026FP UT WOS:000310260300006 PM 23162207 ER PT J AU Dallaire, A Garand, C Paquet, ER Mitchell, SJ de Cabo, R Simard, MJ Lebel, M AF Dallaire, Alexandra Garand, Chantal Paquet, Eric R. Mitchell, Sarah J. de Cabo, Rafael Simard, Martin J. Lebel, Michel TI Down regulation of miR-124 in both Werner syndrome DNA helicase mutant mice and mutant Caenorhabditis elegans wrn-1 reveals the importance of this microRNA in accelerated aging SO AGING-US LA English DT Article DE Werner syndrome; aging; microRNA; liver; mouse; nematode ID SYNDROME PROTEIN; SYNDROME GENE; LIFE-SPAN; RECQ HELICASE; MOUSE LUNG; ELEGANS; EXPRESSION; EXONUCLEASE; INSULIN; CELLS AB Small non-coding microRNAs are believed to be involved in the mechanism of aging but nothing is known on the impact of microRNAs in the progeroid disorder Werner syndrome (WS). WS is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN ortholog exhibit many phenotypic features of WS, including a pro-oxidant status and a shorter mean life span. Caenorhabditis elegans (C. elegans) with a nonfunctional wrn-1 DNA helicase also exhibit a shorter life span. Thus, both models are relevant to study the expression of microRNAs involved in WS. In this study, we show that miR-124 expression is lost in the liver of Wrn helicase mutant mice. Interestingly, the expression of this conserved miR-124 in whole wrn-1 mutant worms is also significantly reduced. The loss of mir-124 in C. elegans increases reactive oxygen species formation and accumulation of the aging marker lipofuscin, reduces whole body ATP levels and results in a reduction in life span. Finally, supplementation of vitamin C normalizes the median life span of wrn-1 and mir-124 mutant worms. These results suggest that biological pathways involving WRN and miR-124 are conserved in the aging process across different species. C1 [Dallaire, Alexandra; Garand, Chantal; Paquet, Eric R.; Simard, Martin J.; Lebel, Michel] Univ Laval, Ctr Rech Cancerol, Hop Hotel Dieu Quebec, Quebec City, PQ G1R 2J6, Canada. [Mitchell, Sarah J.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Mitchell, Sarah J.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. RP Lebel, M (reprint author), Univ Laval, Ctr Rech Cancerol, Hop Hotel Dieu Quebec, Quebec City, PQ G1R 2J6, Canada. EM michel.lebel@crhdq.ulaval.ca RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU National Institute of Health National Center for Research Resources; Canadian Institutes of Health Research; National Institute on Aging of the National Institutes of Health, USA; National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (RIMS Project) [2010-01671] FX We would like to thank Dr. Patrick Laprise (Centre de Recherche en Cancerologie de l'Universite Laval, Canada) for allowing us to use his COPAS Biosort instrument. Nematode strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institute of Health National Center for Research Resources. This work was supported by the Canadian Institutes of Health Research to M. L. and M.J.S. R.d.C. is supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health, USA. S.J.M. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (RIMS Project ID 2010-01671). M.J.S. is a Junior II scholar from the Fonds de la Recherche en Sante du Quebec. NR 46 TC 14 Z9 15 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD SEP PY 2012 VL 4 IS 9 BP 636 EP 647 PG 12 WC Cell Biology SC Cell Biology GA 024SD UT WOS:000310128000006 PM 23075628 ER PT J AU Baradaran-Heravi, A Raams, A Lubieniecka, J Cho, KS DeHaai, KA Basiratnia, M Mari, PO Xue, YT Rauth, M Olney, AH Shago, M Choi, KH Weksberg, RA Nowaczyk, MJM Wang, WD Jaspers, NGJ Boerkoel, CF AF Baradaran-Heravi, Alireza Raams, Anja Lubieniecka, Joanna Cho, Kyoung Sang DeHaai, Kristi A. Basiratnia, Mitra Mari, Pierre-Olivier Xue, Yutong Rauth, Michael Olney, Ann Haskins Shago, Mary Choi, Kunho Weksberg, Rosanna A. Nowaczyk, Malgorzata J. M. Wang, Weidong Jaspers, Nicolaas G. J. Boerkoel, Cornelius F. TI SMARCAL1 Deficiency Predisposes to Non-Hodgkin Lymphoma and Hypersensitivity to Genotoxic Agents In Vivo SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Schimke immuno-osseous dysplasia; non-Hodgkin lymphoma; T-cell immunodeficiency; genotoxic agents ID IMMUNO-OSSEOUS DYSPLASIA; ROTHMUND-THOMSON-SYNDROME; V(D)J RECOMBINATION; ANNEALING HELICASE; WERNER-SYNDROME; REPAIR; HARP/SMARCAL1; MUTATIONS; PATHWAYS; PATIENT AB Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder with prominent skeletal, renal, immunological, and ectodermal abnormalities. It is caused by mutations of SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response protein. To determine the relationship of this function to the SIOD phenotype, we profiled the cancer prevalence in SIOD and assessed if defects of nucleotide excision repair (NER) and nonhomologous end joining (NHEJ), respectively, explained the ectodermal and immunological features of SIOD. Finally, we determined if Smarcal1(del/del) mice had hypersensitivity to irinotecan (CPT-11), etoposide, and hydroxyurea (HU) and whether exposure to these agents induced features of SIOD. Among 71 SIOD patients, three had non-Hodgkin lymphoma (NHL) and one had osteosarcoma. We did not find evidence of defective NER or NHEJ; however, Smarcal1-deficient mice were hypersensitive to several genotoxic agents. Also, CPT-11, etoposide, and HU caused decreased growth and loss of growth plate chondrocytes. These data, which identify an increased prevalence of NHL in SIOD and confirm hypersensitivity to DNA damaging agents in vivo, provide guidance for the management of SIOD patients. (C) 2012 Wiley Periodicals, Inc. C1 [Baradaran-Heravi, Alireza; Lubieniecka, Joanna; Choi, Kunho; Boerkoel, Cornelius F.] Univ British Columbia, Dept Med Genet, Child & Family Res Inst, Vancouver, BC, Canada. [Raams, Anja; Mari, Pierre-Olivier; Jaspers, Nicolaas G. J.] Erasmus MC, Dept Genet, Rotterdam, Netherlands. [Cho, Kyoung Sang] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Cho, Kyoung Sang] Konkuk Univ, Dept Biol Sci, Seoul, South Korea. [DeHaai, Kristi A.; Olney, Ann Haskins] Univ Nebraska Med Ctr, Munroe Meyer Inst Genet & Rehabil, Omaha, NE USA. [Basiratnia, Mitra] Shiraz Univ Med Sci, Dept Pediat Nephrol, Shiraz, Iran. [Xue, Yutong; Wang, Weidong] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Rauth, Michael] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Shago, Mary] Hosp Sick Children, Dept Paediat, Lab Med, Toronto, ON M5G 1X8, Canada. [Shago, Mary; Weksberg, Rosanna A.] Univ Toronto, Toronto, ON, Canada. [Weksberg, Rosanna A.] Hosp Sick Children, Div Clin Genet, Toronto, ON M5G 1X8, Canada. [Nowaczyk, Malgorzata J. M.] McMaster Univ, Dept Pathol, Hamilton, ON, Canada. [Nowaczyk, Malgorzata J. M.] McMaster Univ, Dept Pediat, Hamilton, ON, Canada. [Basiratnia, Mitra] Shiraz Univ Med Sci, Nephrol Urol Res Ctr, Shiraz, Iran. [Nowaczyk, Malgorzata J. M.] McMaster Univ, Dept Mol Med, Hamilton, ON, Canada. RP Boerkoel, CF (reprint author), Childrens & Womens Hlth Ctr BC, Dept Med Genet, Prov Med Genet Program, 4500 Oak St,Rm C234, Vancouver, BC V6H 3N1, Canada. EM boerkoel@interchange.ubc.ca RI Mari, Pierre-Olivier/A-1140-2011 FU March of Dimes; Gillson Longenbaugh Foundation; Dana Foundation; New Investigator Development Award, Microscopy, and Administrative Cores of the Mental Retardation and Developmental Disabilities Research Center at Baylor College of Medicine; Burroughs Wellcome Foundation; National Institute of Diabetes, Digestive, and Kidney Diseases, NIH [R21DK065725]; Association Autour D'Emeric Emeric et D'Anthony; Little Giants Foundation; Intramural Research Program of the National Institute on Aging, National Institute of Health (US) [Z01 AG000657-08]; National Institute of Health (US); Intramural Research Program of the National Institute on Aging [Z01 AG000657-08] FX The authors thank Dr. Jan M. Friedman, Dr. Catherine Pallen, Dr. Thomas Lucke, and Dr. Shirin Kalyan for critical review of this article. This study was supported in part by grants from the March of Dimes (C.F. Boerkoel), the Gillson Longenbaugh Foundation (C.F. Boerkoel), the Dana Foundation (C.F. Boerkoel), the New Investigator Development Award, Microscopy, and Administrative Cores of the Mental Retardation and Developmental Disabilities Research Center at Baylor College of Medicine (C.F. Boerkoel), the Burroughs Wellcome Foundation (C.F. Boerkoel), the National Institute of Diabetes, Digestive, and Kidney Diseases, NIH (R21DK065725, C.F. Boerkoel), the Association Autour D'Emeric Emeric et D'Anthony (C.F. Boerkoel), and The Little Giants Foundation. This work is supported in part by the Intramural Research Program of the National Institute on Aging (Z01 AG000657-08), National Institute of Health (US). C.F. Boerkoel is a scholar of the Michael Smith Foundation for Health Research.; Grant sponsor: March of Dimes; Grant sponsor: Gillson Longenbaugh Foundation; Grant sponsor: Dana Foundation; Grant sponsor: New Investigator Development Award, Microscopy, and Administrative Cores of the Mental Retardation and Developmental Disabilities Research Center at Baylor College of Medicine; Grant sponsor: Burroughs Wellcome Foundation; Grant sponsor: National Institute of Diabetes, Digestive, and Kidney Diseases, NIH; Grant number: R21DK065725; Grant sponsor: Association Autour D'Emeric et D'Anthony; Grant sponsor: The Little Giants Foundation; Grant sponsor: Intramural Research Program of the National Institute on Aging; Grant number: Z01 AG000657-08; Grant sponsor: National Institute of Health (US). NR 41 TC 16 Z9 16 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD SEP PY 2012 VL 158A IS 9 BP 2204 EP 2213 DI 10.1002/ajmg.a.35532 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 023WU UT WOS:000310068700016 PM 22888040 ER PT J AU Acosta, MT Bearden, CE Castellanos, XF Cutting, L Elgersma, Y Gioia, G Gutmann, DH Lee, YS Legius, E Muenke, M North, K Parada, LF Ratner, N Hunter-Schaedle, K Silva, AJ AF Acosta, Maria T. Bearden, Carrie E. Castellanos, Xavier F. Cutting, Laurie Elgersma, Ype Gioia, Gerard Gutmann, David H. Lee, Yong-Seok Legius, Eric Muenke, Maximillian North, Kathryn Parada, Luis F. Ratner, Nancy Hunter-Schaedle, Kim Silva, Alcino J. TI The Learning Disabilities Network (LeaDNet): Using Neurofibromatosis Type 1 (NF1) as a Paradigm for Translational Research SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Review DE neurofibromatosis type 1; learning disabilities; RAS/MAPK pathway; neurodevelopmental disorders; Learning Disabilities Network ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; MOUSE MODEL; COGNITIVE PROFILE; GENE-PRODUCT; DEFICITS; CHILDREN; MICE; MEMORY; HETEROZYGOSITY; LOVASTATIN AB Learning disabilities and other cognitive disorders represent one of the most important unmet medical needs and a significant source of lifelong disability. To accelerate progress in this area, an international consortium of researchers and clinicians, the Learning Disabilities Network (LeaDNet), was established in 2006. Initially, LeaDNet focused on neurofibromatosis type 1 (NF1), a common single gene disorder with a frequency of 1:3,000. Although NF1 is best recognized as an inherited tumor predisposition syndrome, learning, cognitive, and neurobehavioral deficits account for significant morbidity in this condition and can have a profound impact on the quality of life of affected individuals. Recently, there have been groundbreaking advances in our understanding of the molecular, cellular, and neural systems underpinnings of NF1-associated learning deficits in animal models, which precipitated clinical trials using a molecularly targeted treatment for these deficits. However, much remains to be learned about the spectrum of cognitive, neurological, and psychiatric phenotypes associated with the NF1 clinical syndrome. In addition, there is a pressing need to accelerate the identification of specific clinical targets and treatments for these phenotypes. The successes with NF1 have allowed LeaDNet investigators to broaden their initial focus to other genetic disorders characterized by learning disabilities and cognitive deficits including other RASopathies (caused by changes in the Ras signaling pathway). The ultimate mission of LeaDNet is to leverage an international translational consortium of clinicians and neuroscientists to integrate bench-to-bedside knowledge across a broad range of cognitive genetic disorders, with the goal of accelerating the development of rational and biologically based treatments. (C) 2012 Wiley Periodicals, Inc. C1 [Acosta, Maria T.] Childrens Natl Med Ctr, Dept Neurol, Gilbert Neurofibromatosis Inst, Washington, DC 20010 USA. [Acosta, Maria T.; Muenke, Maximillian] NHGRI, NIH, Bethesda, MD 20892 USA. [Bearden, Carrie E.; Silva, Alcino J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Castellanos, Xavier F.] NYU, New York, NY USA. [Cutting, Laurie] Vanderbilt Univ, Nashville, TN USA. [Elgersma, Ype] Erasmus Univ, Rotterdam, Netherlands. [Gutmann, David H.] Washington Univ, Sch Med, St Louis, MO USA. [Lee, Yong-Seok] Katholieke Univ Leuven, Louvain, Belgium. [Legius, Eric; North, Kathryn] Univ Sydney, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [Parada, Luis F.] Univ Texas SW, Dallas, TX USA. [Ratner, Nancy] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Hunter-Schaedle, Kim] Childrens Tumor Fdn, New York, NY USA. RP Acosta, MT (reprint author), Childrens Natl Med Ctr, Dept Neurol, Gilbert Neurofibromatosis Inst, 111 Michigan Av NW, Washington, DC 20010 USA. EM macosta@childrensnational.org RI Parada, luis/B-9400-2014; North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Silva, Alcino/0000-0001-5525-0494; Castellanos, Francisco/0000-0001-9192-9437 FU NIMH NIH HHS [R34 MH089299] NR 57 TC 10 Z9 10 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD SEP PY 2012 VL 158A IS 9 BP 2225 EP 2232 DI 10.1002/ajmg.a.35535 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 023WU UT WOS:000310068700019 PM 22821737 ER PT J AU da Silva, FA Li, M Rato, S Maia, S Malho, R Warren, K Harrich, D Craigie, R Barbas, CF Goncalves, J AF da Silva, Frederico Aires Li, Min Rato, Sylvie Maia, Sara Malho, Rui Warren, Kylie Harrich, David Craigie, Robert Barbas, Carlos F., III Goncalves, Joao TI Recombinant rabbit single-chain antibodies bind to the catalytic and C-terminal domains of HIV-1 integrase protein and strongly inhibit HIV-1 replication SO BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY LA English DT Article DE intracellular antibodies; single-chain variable fragment; HIV-1 integrase protein; HIV-1 neutralization; gene therapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; DNA STRAND TRANSFER; VIRAL LIFE-CYCLE; TYPE-1 INTEGRASE; MONOCLONAL-ANTIBODIES; INTRACELLULAR ANTIBODIES; GENE-THERAPY; IN-VITRO; REVERSE TRANSCRIPTION; PHAGE DISPLAY AB The human immunodeficiency virus type 1 (HIV-1) integrase (IN) protein plays an important role during the early stages of the retroviral life cycle and therefore is an attractive target for therapeutic intervention. We immunized rabbits with HIV-1 IN protein and developed a combinatorial single-chain variable fragment (scFv) library against IN. Five different scFv antibodies with high binding activity and specificity for IN were identified. These scFvs recognize the catalytic and C-terminal domains of IN and block the strand-transfer process. Cells expressing anti-INscFvs were highly resistant to HIV-1 replication due to an inhibition of the integration process itself. These results provide proof-of-concept that rabbit anti-INscFv intrabodies can be designed to block the early stages of HIV-1 replication without causing cellular toxicity. Therefore, these anti-INscFvs may be useful agents for intracellular immunization-based gene therapy strategies. Furthermore, because of their epitope binding characteristics, these scFvs can be used also as new tools to study the structure and function of HIV-1 IN protein. C1 [da Silva, Frederico Aires; Rato, Sylvie; Maia, Sara; Goncalves, Joao] Univ Lisbon, Fac Farm, URIA Ctr Patogenese Mol, P-1699 Lisbon, Portugal. [da Silva, Frederico Aires; Rato, Sylvie; Maia, Sara; Goncalves, Joao] IMM, Lisbon, Portugal. [Li, Min; Craigie, Robert] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Malho, Rui] Univ Lisbon, Fac Ciencias Lisboa, BioFIG, P-1699 Lisbon, Portugal. [Warren, Kylie; Harrich, David] Queensland Inst Med Res, Div Infect Dis & Immunol, Brisbane, Qld 4006, Australia. [Barbas, Carlos F., III] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Barbas, Carlos F., III] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Goncalves, J (reprint author), URIA Ctr Patogenese Mol, Fac Farm Lisboa, Av Das Forcas Armadas, P-1649019 Lisbon, Portugal. EM carlos@scripps.edu; joao.goncalves@ff.ul.pt RI Maia, Sara/B-2513-2013; iMed.ULisboa, iMed.ULisboa/C-6292-2014; Goncalves, Joao/B-2013-2008; iMed.ULisboa, M2B /B-5277-2014; Malho, Rui/I-4503-2012; OI Maia, Sara/0000-0001-8638-0566; Goncalves, Joao/0000-0002-1245-3715; Malho, Rui/0000-0001-5287-869X; Aires da Silva, Frederico/0000-0002-3821-419X; Rato, Sylvie/0000-0002-0204-0335 FU Fundacao para a Ciencia e Tecnologia [PCTI/BIA-MIC/60038/2004, SFRH/BD/17039/2004, SFRH/BPD/21011/2004]; NIDDK of the National Institutes of Health; NIH AIDS Targeted Antiviral Program; National Institutes of Health [R01GM065059] FX We thank Dr. Zeger Debyser for providing the plasmid pCEP-IN. The envelope plasmid pMD.G was kindly provided by Dr. Didier Trono. HeLa CD4 LTR-beta-Gal cells, plasmid HIV-1NL4-3 and HIV-1 IN peptides were obtained from the AIDS Research and Reference Reagent Program. This work was supported by grants from the Fundacao para a Ciencia e Tecnologia (PCTI/BIA-MIC/60038/2004). F.A.S. was supported with a doctoral fellowship from Fundacao para a Ciencia e Tecnologia (SFRH/BD/17039/2004). S.M. was supported with a post-doctoral fellowship from Fundacao para a Ciencia e Tecnologia (SFRH/BPD/21011/2004). R.C. was supported by the intramural research programs of the NIDDK of the National Institutes of Health and by the NIH AIDS Targeted Antiviral Program. C. B. was supported by a grant from the National Institutes of Health (R01GM065059). The authors declare no conflict of interest. NR 66 TC 3 Z9 3 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-4513 J9 BIOTECHNOL APPL BIOC JI Biotechnol. Appl. Biochem. PD SEP-OCT PY 2012 VL 59 IS 5 BP 353 EP 366 DI 10.1002/bab.1034 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 023WN UT WOS:000310067800006 PM 23586912 ER PT J AU Rosen, LS Hurwitz, HI Wong, MK Goldman, J Mendelson, DS Figg, WD Spencer, S Adams, BJ Alvarez, D Seon, BK Theuer, CP Leigh, BR Gordon, MS AF Rosen, Lee S. Hurwitz, Herbert I. Wong, Michael K. Goldman, Jonathan Mendelson, David S. Figg, William D. Spencer, Shawn Adams, Bonne J. Alvarez, Delia Seon, Ben K. Theuer, Charles P. Leigh, Bryan R. Gordon, Michael S. TI A Phase I First-in-Human Study of TRC105 (Anti-Endoglin Antibody) in Patients with Advanced Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID HEREDITARY HEMORRHAGIC TELANGIECTASIA; MONOCLONAL-ANTIBODIES; TUMOR VASCULATURE; CD105; ANGIOGENESIS; BEVACIZUMAB; EXPRESSION; THERAPY; XENOGRAFTS AB Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods: Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. Results: Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months. Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. Clin Cancer Res; 18(17); 4820-9. (C) 2012 AACR. C1 [Rosen, Lee S.; Goldman, Jonathan] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Hurwitz, Herbert I.] Duke Univ, Med Ctr, Durham, NC USA. [Wong, Michael K.; Seon, Ben K.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Mendelson, David S.; Gordon, Michael S.] Pinnacle Oncol Hematol, Scottsdale, AZ USA. [Figg, William D.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Spencer, Shawn] NCI, SAIC Frederick Inc, Bethesda, MD 20892 USA. [Adams, Bonne J.; Alvarez, Delia; Theuer, Charles P.; Leigh, Bryan R.] TRACON Pharmaceut, San Diego, CA USA. RP Rosen, LS (reprint author), Univ Calif Los Angeles, Dept Med, 2020 Santa Monica Blvd,Suite 600, Santa Monica, CA 90404 USA. EM lrosen@mednet.ucla.edu RI Figg Sr, William/M-2411-2016 FU TRACON; TRACON Pharmaceuticals Inc, San Diego, CA; Center for Cancer Research of the National Cancer Institute, NIH [HHSN261200800001E] FX H.I. Hurwitz has received research support from TRACON. B.J. Adams, D. Alvarez, C. P. Theuer, and B. R. Leigh are employees of TRACON. No potential conflicts of interest were disclosed by the other authors.; This research was supported by TRACON Pharmaceuticals Inc, San Diego, CA and by the Center for Cancer Research of the National Cancer Institute, NIH, under Contract Number HHSN261200800001E. NR 34 TC 80 Z9 84 U1 1 U2 12 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 SEP 1 PY 2012 VL 18 IS 17 BP 4820 EP 4829 DI 10.1158/1078-0432.CCR-12-0098 PG 10 WC Oncology SC Oncology GA 022MW UT WOS:000309964500036 PM 22767667 ER PT J AU Dunleavy, K Roschewski, M Wilson, WH AF Dunleavy, Kieron Roschewski, Mark Wilson, Wyndham H. TI Lymphomatoid Granulomatosis and Other Epstein-Barr Virus Associated Lymphoproliferative Processes SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Article DE Lymphomatoid granulomatosis; LYG; Epstein-Barr virus; EBV; Lymphoma; LMP-1; EBNA-1; Lymphoproliferative disorders; Cytotoxic T-lymphocyte; Cellular therapy; Interferon ID T-CELL LYMPHOMA; PRIMARY EFFUSION LYMPHOMA; RHEUMATOID-ARTHRITIS; BURKITTS-LYMPHOMA; HODGKINS-DISEASE; CLINICAL-IMPLICATIONS; LINE AKATA; VIRAL LOAD; EBV; DISORDERS AB We now recognize that the Epstein-Barr virus (EBV), which is a member of the gamma-herpesvirus family, plays a pivotal role in the development of several lymphomas and lymphoproliferative disorders that include B-cell, T-cell and NK-cell processes. While over recent years, EBV associated lymphomas that arise in patients with known defects in cellular immunity are relatively well characterized, these diseases are becoming increasingly recognized in patients without overt immunodeficiency. Improved understanding of the biology of these lymphomas including elucidating the role that EBV plays in their pathogenesis has paved the way for improved therapies targeted at critical signaling pathways as well as the development of novel cellular therapies. In this review, we focus on recent progress that has been made in the biology and treatment of the rare EBV-associated disorder lymphomatoid granulomatosis (LYG) and also discuss other EBV-associated processes that occur in both immunocompetent and immunocompromised hosts. C1 [Dunleavy, Kieron; Roschewski, Mark; Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), NCI, Metab Branch, Ctr Canc Res, Bldg 10,Room 4N-115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov; wilsonw@mail.nih.gov OI Roschewski, Mark/0000-0003-0278-2635 FU National Cancer Institute FX Supported by the Intramural Research Program of the National Cancer Institute. NR 62 TC 17 Z9 18 U1 0 U2 6 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD SEP PY 2012 VL 7 IS 3 BP 208 EP 215 DI 10.1007/s11899-012-0132-3 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 023DE UT WOS:000310012300005 PM 22814713 ER PT J AU Dunleavy, K Grant, C Eberle, FC Pittaluga, S Jaffe, ES Wilson, WH AF Dunleavy, Kieron Grant, Cliona Eberle, Franziska C. Pittaluga, Stefania Jaffe, Elaine S. Wilson, Wyndham H. TI Gray Zone Lymphoma: Better Treated Like Hodgkin Lymphoma or Mediastinal Large B-Cell Lymphoma? SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Article DE Hematologic malignancy; Lymphomas; Hodgkin lymphoma; Hodgkin's disease; Classic Hodgkin lymphoma of the nodular sclerosis type; CHL-NS; Mediastinal lymphoma; Primary mediastinal large B-cell lymphoma; PMBL; Mediastinal gray zone lymphoma; MGZL; Gray zone lymphoma; GZL; Thymic B cell; Diffuse large B-cell lymphoma; DLBCL; Epigenetics; Gene expression profiling; Radiation therapy; Chemotherapy; Immunophenotyping; Microenvironment ID REED-STERNBERG CELLS; CHILDHOOD-CANCER SURVIVOR; RADIATION-THERAPY; LONG-TERM; ABVD CHEMOTHERAPY; CD23 EXPRESSION; GERMINAL CENTER; DISEASE; FEATURES; CHOP AB Although primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma of the nodular sclerosis type (CHL-NS) are distinct diseases, they share several clinical characteristics and biologic features. Given that, it is not surprising that there exist mediastinal lymphomas that do not fit well into either category but have clinical and morphologic features overlapping and transitional between PMBL and CHL-NS. The term mediastinal gray zone lymphoma (MGZL) has been used for these tumors, which are included in the World Health Organization classification as "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma." Although several studies have evaluated different therapeutic strategies in PMBL and CHL-NS, there is a paucity of prospective experience treating MGZL, given its rarity and relatively recent recognition. Historically, diseases that today would be categorized as MGZL were probably called " anaplastic large-cell lymphoma Hodgkin-like," and their outcome with standard approaches was poor, with short overall survivals. In this review-following a discussion of the biology and clinical features of MGZL, and how they compare to PMBL and CHL-NS-we outline how the treatment of PMBL and CHL-NS has evolved in recent years, and how we believe MGZL should be approached therapeutically. C1 [Dunleavy, Kieron; Grant, Cliona; Wilson, Wyndham H.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Eberle, Franziska C.] Univ Tubingen, Dept Dermatol, Tubingen, Germany. [Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wilson, WH (reprint author), NCI, Metab Branch, Ctr Canc Res, Bldg 10,Room 4N-115,9000 Rockville Pk, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 FU National Cancer Institute FX Supported by the Intramural Research Program of the National Cancer Institute. NR 57 TC 22 Z9 22 U1 0 U2 5 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD SEP PY 2012 VL 7 IS 3 BP 241 EP 247 DI 10.1007/s11899-012-0130-5 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 023DE UT WOS:000310012300010 PM 22833351 ER PT J AU Schecter, A Szabo, DT Miller, J Gent, TL Malik-Bass, N Petersen, M Paepke, O Colacino, JA Hynan, LS Harris, TR Malla, S Birnbaum, LS AF Schecter, Arnold Szabo, David T. Miller, James Gent, Tyra L. Malik-Bass, Noor Petersen, Malte Paepke, Olaf Colacino, Justin A. Hynan, Linda S. Harris, T. Robert Malla, Sunitha Birnbaum, Linda S. TI Hexabromocyclododecane (HBCD) Stereoisomers in US Food from Dallas, Texas SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE Dallas; Texas; food; HBCD; hexabromocyclododecane; stereoisomers ID BROMINATED FLAME RETARDANTS; POLYBROMINATED DIPHENYL ETHERS; TETRABROMOBISPHENOL-A; DIETARY EXPOSURE; UNITED-STATES; INDOOR DUST; CONSUMPTION; METABOLISM; ALPHA; GAMMA AB BACKGROUND: Hexabromocyclododecane (HBCD) is a brominated flame retardant used in polystyrene foams in thermal insulation and electrical equipment. The HBCD commercial mixture consists mainly of alpha, beta, and gamma stereoisomers. Health concerns of HBCD exposure include alterations in immune and reproductive systems, neurotoxic effects, and endocrine disruption. Stereoisomer-specific levels of HBCD have not been measured previously in U.S. food. OBJECTIVES: We measured HBCD stereoisomer levels in U.S. foods from Dallas, Texas, supermarkets. METHODS: Convenience samples of commonly consumed foods were purchased from supermarkets in Dallas in 2009-2010. Food samples included a wide variety of lipid-rich foods: fish, peanut butter, poultry, pork, and beef. Thirty-six individual food samples were collected in 2010 and analyzed for alpha-, beta-, and gamma-HBCD stereoisomers using liquid chromatography tandem mass spectrometry (LC-MS/MS). Ten pooled food samples previously collected in 2009 for a study of total HBCD levels using gas chromatography mass spectrometry (GC-MS), were reanalyzed for alpha-, beta-, and gamma-HBCD stereoisomers using LC-MS/MS. RESULTS: Of the 36 measured individual foods, 15 (42%) had detectable levels of HBCD. Median (ranges) of alpha- and gamma-HBCD concentrations were 0.003 (< 0.005-1.307) and 0.005 (< 0.010-0.143) ng/g wet weight (ww), respectively; beta-HBCD was present in three samples with a median (range) of 0.003 (< 0.005-0.019) ng/g ww. Median levels (range) for alpha-, beta-, and gamma-HBCD, in pooled samples were 0.077 (0.010-0.310), 0.008 (< 0.002-0.070), and 0.024 (0.012-0.170) ng/g ww, respectively. CONCLUSIONS: alpha-HBCD was detected most frequently and at highest concentrations, followed by gamma-, and then beta-HBCD, in food samples from Dallas, Texas. Food may be a substantial contributor to the elevated a-HBCD levels observed in humans. These data suggest that larger and more representative sampling should be conducted. C1 [Schecter, Arnold; Miller, James; Gent, Tyra L.; Malik-Bass, Noor; Harris, T. Robert; Malla, Sunitha] Univ Texas Sch Publ Hlth, Dallas, TX 75390 USA. [Szabo, David T.] US EPA, Natl Ctr Environm Assessment, Arlington, VA USA. [Petersen, Malte; Paepke, Olaf] Eurofins Gfa GmbH Lab, Hamburg, Germany. [Colacino, Justin A.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Hynan, Linda S.] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Hynan, Linda S.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Birnbaum, Linda S.] NCI, NIH, US Dept HHS, Washington, DC USA. [Birnbaum, Linda S.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Schecter, A (reprint author), Univ Texas Sch Publ Hlth, 6011 Harry Hines Blvd,V8-122E, Dallas, TX 75390 USA. EM arnold.schecter@utsouthwestern.edu OI Hynan, Linda/0000-0002-4642-7769 FU Gustavus and Louise Pfeiffer Research Foundation; National Institute of Environmental Health Sciences (NIEHS); U.S. Environmental Protection Agency (EPA), Office of Research and Development; NIEHS [T32 ES007062]; National Human Genome Research Institute [T32 HG00040] FX This study was partially funded by the Gustavus and Louise Pfeiffer Research Foundation and partially funded by the National Institute of Environmental Health Sciences (NIEHS). Support in part was also provided by an appointment to the Research Participation Program for the U.S. Environmental Protection Agency (EPA), Office of Research and Development, administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the U.S. Department of Energy and the U.S. EPA. M. Petersen and O. Paepke are both employed by Eurofins Gfa GmbH Laboratory, Hamburg, Germany. Support for J. Colacino was provided by training grants from the NIEHS (T32 ES007062) and the National Human Genome Research Institute (T32 HG00040). NR 44 TC 17 Z9 17 U1 7 U2 91 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2012 VL 120 IS 9 BP 1260 EP 1264 DI 10.1289/ehp.1204993 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 005YV UT WOS:000308786900022 PM 22647707 ER PT J AU Qu, W Tokar, EJ Kim, AJ Bell, MW Waalkes, MP AF Qu, Wei Tokar, Erik J. Kim, Andrew J. Bell, Matthew W. Waalkes, Michael P. TI Chronic Cadmium Exposure in Vitro Causes Acquisition of Multiple Tumor Cell Characteristics in Human Pancreatic Epithelial Cells SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE cadmium; cancer cell qualities; pancreatic cancer; pancreatic epithelial cells ID CANCER STEM-CELLS; INDUCED MALIGNANT TRANSFORMATION; IDENTIFICATION; SURVIVAL; CARCINOGENESIS; PROPAGATION; EXPRESSION; RECEPTOR; CULTURE; GROWTH AB BACKGROUND: Cancer may be a stem cell (SC)-based disease involving formation of cancer SCs (CSCs) potentially arising from transformation of normal SCs. Cadmium has been linked to human pancreatic cancer. OBJECTIVE: We studied cadmium exposure of human pancreatic ductal epithelial (HPDE) cells and whether SCs may be targeted in this process. METHODS: We chronically exposed HPDE cells to low level cadmium (1 mu M) for 5 29 weeks. Non-adherent spheroid formation was used to indicate CSC-like cell production, and we assessed tumor cell characteristics in such spheres. Assessed tumor cell characteristics including secretion of matrix metalloproteinase-9 (MMP-9), invasion, and colony formation were fortified by evaluating expression of relevant genes by real-time reverse transcription polymerase chain reaction and by Western blot. RESULTS: Increased MMP-9 secretion and overexpression of the pancreatic cancer marker S100P occurred in chronic (29 weeks of exposure) cadmium-exposed (CCE) cells. CCE cells also showed markedly higher colony formation and invasion, typical of cancer cells. Floating "spheres" of viable cells, known to contain an abundance of normal SCs or CSCs, form in vitro with many cell types. CCE cells produced 3-fold more spheres than control cells and were more invasive, secreted more MMP-9, and overexpressed markers for pancreatic SCs/CSCs (i.e., CXCR4, OCT4, CD44) and S100P, a marker for pancreatic cancer. CCE-derived spheres rapidly produced aggressive, highly branched, and poorly differentiated glandular-like structures in Matrigel. CONCLUSIONS: Chronic cadmium exposure produced multiple tumor cell characteristics in HPDE cells and CCE cell derived spheres. These data support the plausibility of cadmium as a human pancreatic carcinogen. C1 [Qu, Wei; Tokar, Erik J.; Kim, Andrew J.; Bell, Matthew W.; Waalkes, Michael P.] NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program,NIH,US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program,NIH,US Dept HHS, Mail Drop E1-07,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Waalkes@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research was supported by the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). NR 42 TC 11 Z9 13 U1 1 U2 15 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 2012 VL 120 IS 9 BP 1265 EP 1271 DI 10.1289/ehp.1205082 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 005YV UT WOS:000308786900023 PM 22626610 ER PT J AU Brown, V George, DT Schwandt, M Lionetti, T Heilig, M AF Brown, V. George, D. T. Schwandt, M. Lionetti, T. Heilig, M. TI Short- and Long-Term Impacts on Craving due to the Administration of IV Alcohol and Exposure to Alcohol Related Cues in an Inpatient Study SO JOURNAL OF MENTAL HEALTH POLICY AND ECONOMICS LA English DT Meeting Abstract C1 [Brown, V.; George, D. T.; Schwandt, M.; Lionetti, T.; Heilig, M.] NIAAA, NIH, Lab Clin & Translat Studies, Sect Clin Assessment & Treatment Evaluat, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT CTR MENTAL HEALTH POLICY & ECONOMICS-ICMPE PI MILANO PA VIA DANIELE CRESPI 7, MILANO, 20123, ITALY SN 1091-4358 J9 J MENT HEALTH POLICY JI J. Ment. Health Policy Econ. PD SEP PY 2012 VL 15 SU 1 BP S4 EP S4 PG 1 WC Health Policy & Services; Psychiatry SC Health Care Sciences & Services; Psychiatry GA 025LF UT WOS:000310190000009 ER PT J AU Riley, WT AF Riley, William T. TI Application of Patient Reported Outcomes Measurement Information System (PROMIS) to Mental Health SO JOURNAL OF MENTAL HEALTH POLICY AND ECONOMICS LA English DT Meeting Abstract C1 [Riley, William T.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT CTR MENTAL HEALTH POLICY & ECONOMICS-ICMPE PI MILANO PA VIA DANIELE CRESPI 7, MILANO, 20123, ITALY SN 1091-4358 J9 J MENT HEALTH POLICY JI J. Ment. Health Policy Econ. PD SEP PY 2012 VL 15 SU 1 BP S18 EP S18 PG 1 WC Health Policy & Services; Psychiatry SC Health Care Sciences & Services; Psychiatry GA 025LF UT WOS:000310190000039 ER PT J AU Huang, CY Qin, J AF Huang, Chiung-Yu Qin, Jing TI Composite Partial Likelihood Estimation Under Length-Biased Sampling, With Application to a Prevalent Cohort Study of Dementia SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Backward and forward recurrence time; Cross-sectional sampling; Random truncation; Renewal processes ID PSEUDO-PARTIAL LIKELIHOOD; COX REGRESSION-MODEL; NONPARAMETRIC-ESTIMATION; SURVIVAL-DATA; DISTRIBUTIONS AB The Canadian Study of Health and Aging (CSHA) employed a prevalent cohort design to study survival after onset of dementia, where patients with dementia were sampled and the onset time of dementia was determined retrospectively. The prevalent cohort sampling scheme favors individuals who survive longer. Thus, the observed survival times are subject to length bias. In recent years, there has been a rising interest in developing estimation procedures for prevalent cohort survival data that not only account for length bias but also actually exploit the incidence distribution of the disease to improve efficiency. This article considers semiparametric estimation of the Cox model for the time from dementia onset to death under a stationarity assumption with respect to the disease incidence. Under the stationarity condition, the semiparametric maximum likelihood estimation is expected to be fully efficient yet difficult to perform for statistical practitioners, as the likelihood depends on the baseline hazard function in a complicated way. Moreover, the asymptotic properties of the semiparametric maximum likelihood estimator are not well-studied. Motivated by the composite likelihood method (Besag 1974), we develop a composite partial likelihood method that retains the simplicity of the popular partial likelihood estimator and can be easily performed using standard statistical software. When applied to the CSHA data, the proposed method estimates a significant difference in survival between the vascular dementia group and the possible Alzheimer's disease group, while the partial likelihood method for left-truncated and right-censored data yields a greater standard error and a 95% confidence interval covering 0, thus highlighting the practical value of employing a more efficient methodology. To check the assumption of stable disease for the CSHA data, we also present new graphical and numerical tests in the article. The R code used to obtain the maximum composite partial likelihood estimator for the CSHA data is available in the online Supplementary Material, posted on the journal web site. C1 [Huang, Chiung-Yu; Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Huang, CY (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huangchi@niaid.nih.gov; jingqin@niaid.nih.gov FU National Health Research and Development Program (NHRDP) of Health Canada [6606-3954-MC(S)]; Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, NHRDP [6603-1417-302(R)]; Bayer Incorporated; British Columbia Health Research Foundation [38 (93-2), 34 (96-1)] FX Chiung-Yu Huang is Mathematical Statistician, Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 (E-mail: huangchi@niaid.nih.gov). Jing Qin is Mathematical Statistician, Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 (E-mail: jingqin@niaid.nih.gov). The authors thank Professors Ian McDowell, Masoud Asgharian, and Christina Wolfson for kindly sharing the Canadian Study of Health and Aging data. The core study was funded by the National Health Research and Development Program (NHRDP) of Health Canada Project 6606-3954-MC(S). Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, NHRDP Project 6603-1417-302(R), Bayer Incorporated, and the British Columbia Health Research Foundation Projects 38 (93-2) and 34 (96-1). The authors also thank the Associate Editor, the referee, Dr Dean Follmann, and Dr Michael Proschan for their comments that improved the presentation of this article. NR 34 TC 10 Z9 11 U1 1 U2 9 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD SEP PY 2012 VL 107 IS 499 BP 946 EP 957 DI 10.1080/01621459.2012.682544 PG 12 WC Statistics & Probability SC Mathematics GA 020FC UT WOS:000309793400011 PM 24000265 ER PT J AU Resnik, DB AF Resnik, David B. TI The Ethics of Inheritable Genetic Modification SO JOURNAL OF VALUE INQUIRY LA English DT Book Review C1 [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 1 TC 0 Z9 0 U1 2 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0022-5363 J9 J VALUE INQUIRY JI J. Value Inq. PD SEP PY 2012 VL 46 IS 3 BP 383 EP 385 DI 10.1007/s10790-012-9341-1 PG 3 WC Ethics; Philosophy SC Social Sciences - Other Topics; Philosophy GA 026ZA UT WOS:000310320400009 ER PT J AU Ravina, B Marek, K Eberly, S Oakes, D Kurlan, R Ascherio, A Beal, F Beck, J Flagg, E Galpern, WR Harman, J Lang, AE Schwarzschild, M Tanner, C Shoulson, I AF Ravina, Bernard Marek, Kenneth Eberly, Shirley Oakes, David Kurlan, Roger Ascherio, Alberto Beal, Flint Beck, James Flagg, Emily Galpern, Wendy R. Harman, Jennifer Lang, Anthony E. Schwarzschild, Michael Tanner, Caroline Shoulson, Ira TI Dopamine transporter imaging is associated with long-term outcomes in Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; dopamine transporter; imaging; prognosis ID MONTREAL COGNITIVE ASSESSMENT; RATING-SCALE; WORKING-MEMORY; SCREENING TOOL; BASAL GANGLIA; PROGRESSION; PERFORMANCE; IMPAIRMENT; MODULATION; SYMPTOMS AB Dopamine (DA) transporter (DAT) imaging has been studied as a diagnostic tool for degenerative parkinsonism. Our aim was to measure the prognostic value of imaging for motor and nonmotor outcomes in Parkinson's disease (PD). We prospectively evaluated a Parkinson's cohort after enrollment in a de novo clinical trial with a battery of motor (UPDRS), cognitive (Montreal Cognitive Assessment), and behavioral measures. DAT imaging with [123I][beta]-CIT and single-photon emission computerized tomography (SPECT) was performed at baseline and after 22 months. In total, 491 (91%) of the 537 subjects had evidence of DA deficiency on their baseline scan, consistent with PD, and were included in the analyses. The cohort was followed for 5.5 (0.8) years, with a mean duration of diagnosis of 6.3 (1.2). Lower striatal binding at baseline was independently associated with higher risk for clinical milestones and measures of disease severity, including motor-related disability, falling and postural instability, cognitive impairment, psychosis, and clinically important depressive symptoms. Subjects in the bottom quartile for striatal binding, compared to the top quartile, had an odds ratio (95% confidence interval) of 3.3 (1.7, 6.7) for cognitive impairment and 12.9 (2.6, 62.4) for psychosis. Change from baseline in imaging after 22 months was also independently associated with motor, cognitive, and behavioral outcomes. DAT imaging with [123I][beta]-CIT and SPECT, shortly after the diagnosis of PD, was independently associated with clinically important long-term motor and nonmotor outcomes. These results should be treated as hypothesis generating and require confirmation. (c) 2012 Movement Disorder Society C1 [Ravina, Bernard] Biogen Idec Inc, Cambridge Ctr 14, Cambridge, MA 02142 USA. [Marek, Kenneth] Inst Neurodegenerat Disorders, New Haven, CT USA. [Eberly, Shirley; Oakes, David; Harman, Jennifer] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Kurlan, Roger] Atlantic Neurosci Inst, Summit, NJ USA. [Ascherio, Alberto; Schwarzschild, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Beal, Flint] Cornell Univ, Sch Med, New York, NY 10021 USA. [Beck, James] Parkinsons Dis Fdn, New York, NY USA. [Galpern, Wendy R.] NINDS, Bethesda, MD 20892 USA. [Lang, Anthony E.] Univ Toronto, Toronto, ON, Canada. [Tanner, Caroline] Parkinsons Inst, Sunnyvale, CA USA. RP Ravina, B (reprint author), Biogen Idec Inc, Cambridge Ctr 14, Cambridge, MA 02142 USA. EM Bernard.ravina@biogenidec.com OI Beck, James/0000-0002-4884-9893 FU National Institute of Neurological Disorders and Stroke [5U01NS050095]; Department of Defense Neurotoxin Exposure Treatment Parkinson's Research Program [W23RRYX7022N606, W81XWH-06-1-0679]; Michael J. Fox Foundation (MJFF); Parkinson's Disease Foundation (PDF); Cephalon Inc.; Lundbeck Inc. FX This study was sponsored by the National Institute of Neurological Disorders and Stroke (5U01NS050095), the Department of Defense Neurotoxin Exposure Treatment Parkinson's Research Program (W23RRYX7022N606 and W81XWH-06-1-0679), the Michael J. Fox Foundation (MJFF), the Parkinson's Disease Foundation (PDF), Cephalon Inc., and Lundbeck Inc. NR 30 TC 35 Z9 35 U1 1 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2012 VL 27 IS 11 BP 1392 EP 1397 DI 10.1002/mds.25157 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 021WG UT WOS:000309915500013 PM 22976926 ER PT J AU Ross, GW Duda, JE Abbott, RD Pellizzari, E Petrovitch, H Miller, DB O'Callaghan, JP Tanner, CM Noorigian, JV Masaki, K Launer, L White, LR AF Ross, G. Webster Duda, John E. Abbott, Robert D. Pellizzari, Edo Petrovitch, Helen Miller, Diane B. O'Callaghan, James P. Tanner, Caroline M. Noorigian, Joseph V. Masaki, Kamal Launer, Lenore White, Lon R. TI Brain organochlorines and Lewy pathology: The Honolulu-Asia aging study SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; Lewy body; organochlorines; pesticides ID PARKINSONS-DISEASE; PESTICIDE EXPOSURE; SUBSTANTIA-NIGRA; BREAST-CANCER; RISK; SERUM; DIELDRIN; PARAQUAT; MIDLIFE; HAWAII AB Although organochlorines have been reported more frequently in Parkinson's disease (PD) brains than in controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during midlife, represent a population well suited to determining the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS. The study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites. With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found in at least 1 brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. The prevalence of Lewy pathology was 75% (6 of 8) among brains with any 2 of the 3 compounds, 48.8% (79 of 162) among those with 1, and 32.7% (18 of 55) for those with neither (P = .007 test for trend). Although findings persisted after removing cases with PD and dementia with Lewy bodies and after adjustment for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (P = .013), the results were insignificant when correcting for multiple testing. Although consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study. (c) 2012 Movement Disorder Society C1 [Ross, G. Webster; Petrovitch, Helen] VA Pacific Isl Hlth Care Syst, Honolulu, HI 96819 USA. [Ross, G. Webster; Petrovitch, Helen; Masaki, Kamal; White, Lon R.] Honolulu Asia Aging Study, Kuakini Med Ctr, Honolulu, HI USA. [Ross, G. Webster; Abbott, Robert D.; Petrovitch, Helen] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. [Ross, G. Webster; Petrovitch, Helen; Masaki, Kamal; White, Lon R.] Univ Hawai, John A Burns Sch Med, Dept Med, Honolulu, HI USA. [Ross, G. Webster; Petrovitch, Helen; Masaki, Kamal; White, Lon R.] Univ Hawai, John A Burns Sch Med, Dept Geriatr, Honolulu, HI USA. [Duda, John E.; Noorigian, Joseph V.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Duda, John E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Abbott, Robert D.] Univ Virginia, Sch Med, Div Biostat, Charlottesville, VA 22908 USA. [Pellizzari, Edo] Res Triangle Inst, Res Triangle Pk, NC 27709 USA. [Miller, Diane B.; O'Callaghan, James P.] NIOSH, Ctr Dis Control, Morgantown, WV USA. [Tanner, Caroline M.] Parkinsons Inst, Sunnyvale, CA USA. [Launer, Lenore] NIA, NIH, Bethesda, MD 20892 USA. RP Ross, GW (reprint author), VA Pacific Isl Hlth Care Syst, 459 Patterson Rd, Honolulu, HI 96819 USA. EM george.ross@va.gov RI O'Callaghan, James/O-2958-2013 FU United States Department of the Army [DAMD17-98-1-8621]; National Institutes of Health, National Institute of Neurological Disorders and Stroke [5 R01 NS041265]; National Institute on Aging [1 U01 AG19349, 5 R01 AG017155]; Office of Research and Development, Medical Research Service Department of Veterans Affairs; NIH, National Institute on Aging; Department of Defense; Department of Veterans Affairs; NIH FX This work was supported by United States Department of the Army, Grant DAMD17-98-1-8621; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Grant 5 R01 NS041265; National Institute on Aging Grants 1 U01 AG19349 and 5 R01 AG017155; and the Office of Research and Development, Medical Research Service Department of Veterans Affairs and was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; G. Webster Ross received research support from the Department of Defense; NIA, NIH; NINDS, NIH; and the Department of Veterans Affairs. John E. Duda and Joseph V. Noorigian received research support from NINDS, NIH. Robert D. Abbott received research support from the Department of Defense; NIA, NIH; and NINDS, NIH. Edo Pellizzari received research support from the Department of Defense. Helen Petrovitch received research support from the Department of Defense; NIA, NIH; and NINDS, NIH. Diane B. Miller and James P. O'Callaghan received research support from NIH. Caroline M. Tanner received research support from the Department of Defense; NIA, NIH; and NINDS, NIH. Kamal Masaki received research support from the NIA, NIH. Lenore Launer has nothing to disclose. Lon R. White received research support from the Department of Defense; NIA, NIH; and NINDS, NIH. NR 38 TC 4 Z9 4 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2012 VL 27 IS 11 BP 1418 EP 1424 DI 10.1002/mds.25144 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 021WG UT WOS:000309915500017 PM 22976848 ER PT J AU Faraji, F Pang, YL Walker, RC Borges, RN Yang, L Hunter, KW AF Faraji, Farhoud Pang, Yanli Walker, Renard C. Borges, Rosan Nieves Yang, Li Hunter, Kent W. TI Cadm1 Is a Metastasis Susceptibility Gene That Suppresses Metastasis by Modifying Tumor Interaction with the Cell-Mediated Immunity SO PLOS GENETICS LA English DT Article ID BREAST-CANCER; LUNG-CANCER; TSLC1; EXPRESSION; PROGRESSION; CARCINOMA; MOLECULE; PROMOTER; HYPERMETHYLATION; IDENTIFICATION AB Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis. We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly, Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell-mediated immunity, which was partially phenocopied by depleting CD8(+) T cells in immune-competent mice. Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors. C1 [Faraji, Farhoud; Walker, Renard C.; Borges, Rosan Nieves; Hunter, Kent W.] NCI, Metastasis Susceptibil Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Faraji, Farhoud] St Louis Univ, Sch Med, St Louis, MO USA. [Faraji, Farhoud] NIH, Howard Hughes Med Inst, Res Scholars Program, Chevy Chase, MD USA. [Pang, Yanli; Yang, Li] NCI, Tumor Microenvironm Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD USA. RP Faraji, F (reprint author), NCI, Metastasis Susceptibil Sect, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov OI Faraji, Farhoud/0000-0001-5078-813X FU National Institutes of Health (NIH); NCI; Center for Cancer Research; Intramural Research Program [ZIA BC 011255]; Howard Hughes Medical Institute-NIH Research Scholars Program FX This work was supported by the National Institutes of Health (NIH), NCI, Center for Cancer Research, Intramural Research Program (Grant# ZIA BC 011255), and the Howard Hughes Medical Institute-NIH Research Scholars Program (http://www.hhmi.org/cloister/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 27 Z9 27 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2012 VL 8 IS 9 AR e1002926 DI 10.1371/journal.pgen.1002926 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 020NK UT WOS:000309817900011 PM 23028344 ER PT J AU Sandholm, N Salem, RM McKnight, AJ Brennan, EP Forsblom, C Isakova, T McKay, GJ Williams, WW Sadlier, DM Makinen, VP Swan, EJ Palmer, C Boright, AP Ahlqvist, E Deshmukh, HA Keller, BJ Huang, HT Ahola, AJ Fagerholm, E Gordin, D Harjutsalo, V He, B Heikkila, O Hietala, K Kyto, J Lahermo, P Lehto, M Lithovius, R Osterholm, AM Parkkonen, M Pitkaniemi, J Rosengard-Barlund, M Saraheimo, M Sarti, C Soderlund, J Soro-Paavonen, A Syreeni, A Thorn, LM Tikkanen, H Tolonen, N Tryggvason, K Tuomilehto, J Waden, J Gill, GV Prior, S Guiducci, C Mirel, DB Taylor, A Hosseini, SM Parving, HH Rossing, P Tarnow, L Ladenvall, C Alhenc-Gelas, F Lefebvre, P Rigalleau, V Roussel, R Tregouet, DA Maestroni, A Maestroni, S Falhammar, H Gu, TW Mollsten, A Cimponeriu, D Ioana, M Mota, M Mota, E Serafinceanu, C Stavarachi, M Hanson, RL Nelson, RG Kretzler, M Colhoun, HM Panduru, NM Gu, HF Brismar, K Zerbini, G Hadjadj, S Marre, M Groop, L Lajer, M Bull, SB Waggott, D Paterson, AD Savage, DA Bain, SC Martin, F Hirschhorn, JN Godson, C Florez, JC Groop, PH Maxwell, AP AF Sandholm, Niina Salem, Rany M. McKnight, Amy Jayne Brennan, Eoin P. Forsblom, Carol Isakova, Tamara McKay, Gareth J. Williams, Winfred W. Sadlier, Denise M. Makinen, Ville-Petteri Swan, Elizabeth J. Palmer, Cameron Boright, Andrew P. Ahlqvist, Emma Deshmukh, Harshal A. Keller, Benjamin J. Huang, Huateng Ahola, Aila J. Fagerholm, Emma Gordin, Daniel Harjutsalo, Valma He, Bing Heikkila, Outi Hietala, Kustaa Kyto, Janne Lahermo, Paivi Lehto, Markku Lithovius, Raija Osterholm, Anne-May Parkkonen, Maija Pitkaniemi, Janne Rosengard-Barlund, Milla Saraheimo, Markku Sarti, Cinzia Soderlund, Jenny Soro-Paavonen, Aino Syreeni, Anna Thorn, Lena M. Tikkanen, Heikki Tolonen, Nina Tryggvason, Karl Tuomilehto, Jaakko Waden, Johan Gill, Geoffrey V. Prior, Sarah Guiducci, Candace Mirel, Daniel B. Taylor, Andrew Hosseini, S. Mohsen Parving, Hans-Henrik Rossing, Peter Tarnow, Lise Ladenvall, Claes Alhenc-Gelas, Francois Lefebvre, Pierre Rigalleau, Vincent Roussel, Ronan Tregouet, David-Alexandre Maestroni, Anna Maestroni, Silvia Falhammar, Henrik Gu, Tianwei Mollsten, Anna Cimponeriu, Danut Ioana, Mihai Mota, Maria Mota, Eugen Serafinceanu, Cristian Stavarachi, Monica Hanson, Robert L. Nelson, Robert G. Kretzler, Matthias Colhoun, Helen M. Panduru, Nicolae Mircea Gu, Harvest F. Brismar, Kerstin Zerbini, Gianpaolo Hadjadj, Samy Marre, Michel Groop, Leif Lajer, Maria Bull, Shelley B. Waggott, Daryl Paterson, Andrew D. Savage, David A. Bain, Stephen C. Martin, Finian Hirschhorn, Joel N. Godson, Catherine Florez, Jose C. Groop, Per-Henrik Maxwell, Alexander P. CA DCCT-EDIC Res Grp TI New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; RENAL-FUNCTION; NATURAL-HISTORY; COLLAGEN CHAINS; AF4/FMR2 FAMILY; GROWTH-FACTOR; NEPHROPATHY; EXPRESSION; RISK; GENE AB Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN. C1 [Sandholm, Niina; Forsblom, Carol; Makinen, Ville-Petteri; Ahola, Aila J.; Fagerholm, Emma; Gordin, Daniel; Harjutsalo, Valma; Heikkila, Outi; Hietala, Kustaa; Kyto, Janne; Lehto, Markku; Lithovius, Raija; Parkkonen, Maija; Rosengard-Barlund, Milla; Saraheimo, Markku; Soderlund, Jenny; Soro-Paavonen, Aino; Syreeni, Anna; Thorn, Lena M.; Tolonen, Nina; Waden, Johan; Groop, Per-Henrik] Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. [Sandholm, Niina; Forsblom, Carol; Makinen, Ville-Petteri; Ahola, Aila J.; Fagerholm, Emma; Gordin, Daniel; Harjutsalo, Valma; Heikkila, Outi; Lehto, Markku; Lithovius, Raija; Parkkonen, Maija; Rosengard-Barlund, Milla; Saraheimo, Markku; Soderlund, Jenny; Soro-Paavonen, Aino; Syreeni, Anna; Thorn, Lena M.; Tolonen, Nina; Waden, Johan; Groop, Per-Henrik] Univ Helsinki, Cent Hosp, Dept Med, Div Nephrol, Helsinki, Finland. [Sandholm, Niina] Aalto Univ, Dept Biomed Engn & Computat Sci, Espoo, Finland. [Salem, Rany M.; Palmer, Cameron; Guiducci, Candace; Mirel, Daniel B.; Taylor, Andrew; Hirschhorn, Joel N.; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Salem, Rany M.; Palmer, Cameron; Hirschhorn, Joel N.] Childrens Hosp, Dept Endocrinol, Endocrine Res Unit, Boston, MA 02115 USA. [Salem, Rany M.; Williams, Winfred W.; Hirschhorn, Joel N.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [McKnight, Amy Jayne; McKay, Gareth J.; Swan, Elizabeth J.; Savage, David A.; Maxwell, Alexander P.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Brennan, Eoin P.; Sadlier, Denise M.; Martin, Finian; Godson, Catherine] Univ Coll Dublin, Sch Med & Med Sci, Conway Inst, Diabet Res Ctr, Dublin 2, Ireland. [Brennan, Eoin P.; Sadlier, Denise M.; Martin, Finian; Godson, Catherine] Mater Misericordiae Univ Hosp, Dublin 7, Ireland. [Isakova, Tamara] Univ Miami, Div Nephrol & Hypertens, Miami, FL USA. [Williams, Winfred W.; Taylor, Andrew; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Makinen, Ville-Petteri] Univ Oulu, Bioctr Oulu, Dept Internal Med, Inst Clin Med, Oulu, Finland. [Makinen, Ville-Petteri] Univ Oulu, Clin Res Ctr, Oulu, Finland. [Boright, Andrew P.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Ahlqvist, Emma; Ladenvall, Claes; Groop, Leif] Lund Univ, Skane Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Deshmukh, Harshal A.; Colhoun, Helen M.] Univ Dundee, Wellcome Trust Ctr Mol Med, Dundee, Scotland. [Keller, Benjamin J.] Eastern Michigan Univ, Ypsilanti, MI 48197 USA. [Huang, Huateng] Univ Michigan, Div Nephrol, Ann Arbor, MI 48109 USA. [Harjutsalo, Valma; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [He, Bing; Osterholm, Anne-May; Tryggvason, Karl] Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, Stockholm, Sweden. [Hietala, Kustaa; Kyto, Janne] Univ Helsinki, Cent Hosp, Dept Ophthalmol, Helsinki, Finland. [Lahermo, Paivi] Inst Mol Med Finland, Helsinki, Finland. [Pitkaniemi, Janne; Sarti, Cinzia] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Tikkanen, Heikki] Univ Helsinki, Inst Clin Med, Unit Sports & Exercise Med, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Tuomilehto, Jaakko] Hosp Univ La Paz, Red RECAVA Grp RD06 0014 0015, Madrid, Spain. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Gill, Geoffrey V.] Univ Liverpool, Univ Hosp Aintree, Diabet Endocrine Unit, Ctr Clin Sci, Liverpool L69 3BX, Merseyside, England. [Prior, Sarah; Bain, Stephen C.] Swansea Univ, Inst Life Sci, Swansea, W Glam, Wales. [Hosseini, S. Mohsen] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada. [Hosseini, S. Mohsen; Paterson, Andrew D.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. Natl Inst Diabet & Digest & Kidney Dis NIDDK, NIH, Bethesda, MD USA. [DCCT-EDIC Res Grp] George Washington Univ, Div Biostat, Washington, DC USA. [Parving, Hans-Henrik] Univ Copenhagen Hosp, Dept Med Endocrinol, DK-2100 Copenhagen, Denmark. [Parving, Hans-Henrik; Rossing, Peter; Tarnow, Lise] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark. [Rossing, Peter; Tarnow, Lise; Lajer, Maria] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Alhenc-Gelas, Francois] Univ Paris 06, Paris Descartes Univ, INSERM, U872, Paris, France. [Lefebvre, Pierre] CHU Sart Tilman, B-4000 Liege, Belgium. [Rigalleau, Vincent] CHU Bordeaux, Bordeaux, France. [Roussel, Ronan; Marre, Michel] Hop Bichat Claude Bernard, AP HP, F-75877 Paris, France. [Roussel, Ronan; Marre, Michel] Univ Paris Diderot, UMR 738, Paris, France. [Roussel, Ronan] Ctr Rech Cordeliers, Equipe 2, INSERM, UMR872, Paris, France. [Tregouet, David-Alexandre] Univ Paris 06, ICAN Inst Cardiometab & Nutr, INSERM, UMR S 937, Paris, France. [Maestroni, Anna; Maestroni, Silvia; Zerbini, Gianpaolo] Ist Sci San Raffaele, Complicat Diabet Unit, Div Metab & Cardiovasc Sci, I-20132 Milan, Italy. [Falhammar, Henrik; Gu, Tianwei; Gu, Harvest F.; Brismar, Kerstin] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Falhammar, Henrik; Brismar, Kerstin] Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden. [Mollsten, Anna] Umea Univ, Dept Clin Sci, Umea, Sweden. [Cimponeriu, Danut; Stavarachi, Monica] Univ Bucharest, Dept Genet, Bucharest, Romania. [Ioana, Mihai; Mota, Maria; Mota, Eugen] Univ Med & Pharm Craiova, Craiova, Romania. [Serafinceanu, Cristian; Panduru, Nicolae Mircea] Carol Davila Univ Med & Pharm, Bucharest, Romania. [Hanson, Robert L.; Nelson, Robert G.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Kretzler, Matthias] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Hadjadj, Samy] Univ Poitiers, CHU Poitiers Endocrinol, Poitiers, France. [Hadjadj, Samy] CHU Poitiers, INSERM, CIC0802, Poitiers, France. [Marre, Michel] INSERM, Genet Determinants Type Diabet & Its Vasc Complic, Paris, France. [Bull, Shelley B.; Waggott, Daryl] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Bull, Shelley B.; Paterson, Andrew D.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Biostat, Toronto, ON, Canada. [Groop, Per-Henrik] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Maxwell, Alexander P.] Belfast City Hosp, Reg Nephrol Unit, Belfast BT9 7AD, Antrim, North Ireland. RP Sandholm, N (reprint author), Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. EM joelh@broadinstitute.org; catherine.godson@ucd.ie; jcflorez@partners.org; per-henrik.groop@helsinki.fi; a.p.maxwell@qub.ac.uk RI Tolonen, Nina/F-2819-2012; Hosseini, Mohsen/K-7133-2013; Huang, Huateng/G-9516-2015; Bull, Shelley/A-1920-2013; Paterson, Andrew/A-4088-2011; Tregouet, David-Alexandre/E-3961-2016; Palmer, Colin/C-7053-2008; OI Sandholm, Niina/0000-0003-4322-6942; rossing, peter/0000-0002-1531-4294; Colhoun, Helen/0000-0002-8345-3288; Maxwell, Alexander P./0000-0002-6110-7253; Falhammar, Henrik/0000-0002-5622-6987; Brismar, Kerstin/0000-0002-5241-514X; Hosseini, Mohsen/0000-0003-3626-9928; Marre, Michel/0000-0002-3071-1837; Makinen, Ville-Petteri/0000-0002-7262-2656; Paterson, Andrew/0000-0002-9169-118X; Palmer, Colin/0000-0002-6415-6560; McKnight, Amy Jayne/0000-0002-7482-709X; Waggott, Daryl/0000-0001-8016-9620 FU Diabetes UK; Juvenile Diabetes Research Foundation; Diabetes UK Studentship; Folkhalsan Research Foundation; Wilhelm and Else Stockmann Foundation; Liv och Halsa Foundation; Helsinki University Central Hospital Research Funds (EVO); Sigrid Juselius Foundation; Signe and Arne Gyllenberg Foundation; Finska Lakaresallskapet; TEKES; European Union's Seventh Framework Program (FP7) for the Innovative Medicine Initiative; Orion-Farmos Research Foundation; US Ireland R&D partnership award; Science Foundation Ireland [SFI/08/US/B1517]; Northern Ireland Research Development office; NIH NIDDK [R01 DK081923]; Juvenile Diabetes Research Foundation post doctoral fellowship (JDRF) [3-2011-70]; Health Research Board Ireland; Family Erling-Persson Foundation; Swedish Medical Research Council; Knut and Alice Wallengberg Foundation; Swedish Diabetes Society Foundation; Novo Nordisk Foundation; European Union's Seventh Framework Program (FP7) for the Innovative Medicine Initiative [IMI/115006]; ENGAGE; European Commission [QLG2-CT-2001-01669]; Danish Diabetes Association; Sehested Hansen Foundation; National Institute of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health; General Clinical Research Center Program, NCRR; National Institute of Diabetes and Digestive and Kidney Diseases [N01-DK-6-2204, R01-DK-077510]; Canadian Network of Centres of Excellence in Mathematics; Genome Canada through the Ontario Genomics Institute; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; French Ministry of Health (Programmes Hospitaliers de Recherche Clinique); Societe Francophone du Diabete; Association Francaise des Diabetiques; Hoffman La Roche; Fibrotech; [CNCSIS-PNCDI-II-RU-PD 133/2010]; [CNCSIS-PNCDI-II-RU-TD 66/2007]; [CNCSIS-PNCDI-II-RU-PI-CE-ID 1194/2009] FX United Kingdom: The Warren 3/UK GoKinD Study Group was jointly funded by Diabetes UK and the Juvenile Diabetes Research Foundation. EJ Swan is supported by Diabetes UK Studentship. The Golden Years cohort, established by GV Gill, AH Barnett, SC Bain, was funded by Diabetes UK. FinnDiane: The FinnDiane Study was supported by grants from the Folkhalsan Research Foundation, the Wilhelm and Else Stockmann Foundation, Liv och Halsa Foundation, Helsinki University Central Hospital Research Funds (EVO), the Sigrid Juselius Foundation, the Signe and Arne Gyllenberg Foundation, Finska Lakaresallskapet, TEKES, the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement IMI/115006 (the SUMMIT consortium). V-P Makinen is supported by Orion-Farmos Research Foundation. Boston: The GENIE Consortium is supported by a US Ireland R&D partnership award funded by Science Foundation Ireland under Grant No. SFI/08/US/B1517, The Northern Ireland Research Development office, and NIH NIDDK R01 DK081923 to JN Hirschhorn, JC Florez, and P-H Groop. RM Salem was supported by a Juvenile Diabetes Research Foundation post doctoral fellowship (JDRF # 3-2011-70). Dublin: The ROI collection was supported by funding from the Health Research Board Ireland to Hugh R. Brady. Sweden (Stockholm and Umea samples): Supported by Family Erling-Persson Foundation and Swedish Medical Research Council. Karolinska Institutet: Supported by Knut and Alice Wallengberg Foundation, Swedish Diabetes Society Foundation, Swedish Medical Research Council, and Novo Nordisk Foundation. SDR (Scania Diabetes Registry): The research at Lund University diabetes Centre was supported by the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement IMI/115006 (the SUMMIT consortium). E Ahlqvist was funded by a grant from ENGAGE. Romania: The RomDiane study was supported by Projects CNCSIS-PNCDI-II-RU-PD 133/2010, CNCSIS-PNCDI-II-RU-TD 66/2007, and CNCSIS-PNCDI-II-RU-PI-CE-ID 1194/2009. Steno: The study was made possible through support from the European Commission through contract QLG2-CT-2001-01669, the Danish Diabetes Association, and the Sehested Hansen Foundation. DCCT/EDIC: The DCCCT/EDIC Research Group is sponsored through research contracts from the National Institute of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institutes of Health. The Diabetes Control and Complications Trial (DCCT) and its follow-up the Epidemiology of Diabetes Interventions and Complications (EDIC) study were conducted by the DCCT/EDIC Research Group and supported by National Institute of Health grants and contracts and by the General Clinical Research Center Program, NCRR. SB Bull held a Canadian Institutes of Health Research (CIHR) Senior Investigator award (2002-7). AD Patterson holds a Canada Research Chair in the Genetics of Complex Diseases. This work has received support from National Institute of Diabetes and Digestive and Kidney Diseases Contract N01-DK-6-2204, National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-077510, and support from the Canadian Network of Centres of Excellence in Mathematics and from Genome Canada through the Ontario Genomics Institute. eQTL analysis in Pima Indians: This work was supported, in part, by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.; France: GENEDIAB/GENESIS studies were supported by grants from the French Ministry of Health (Programmes Hospitaliers de Recherche Clinique), from the Societe Francophone du Diabete, and from the Association Francaise des Diabetiques. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; JC Florez has received consulting honoraria from Novartis, Lilly, and Pfizer. M Kretzler received grant support from Hoffman La Roche and Fibrotech. P-H Groop has received lecture honorariums from Abbot, Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, Novartis, Novo Nordisk, MSD, and research grants from Eli Lilly and Roche. P-H Groop is also an advisory board member of Boehringer Ingelheim and Novartis. NR 61 TC 83 Z9 86 U1 3 U2 34 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2012 VL 8 IS 9 AR e1002921 DI 10.1371/journal.pgen.1002921 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 020NK UT WOS:000309817900008 PM 23028342 ER PT J AU Yang, XB Sun, JL Gao, Y Tan, AH Zhang, HY Hu, YL Feng, JJ Qin, X Tao, S Chen, Z Kim, ST Peng, T Liao, M Lin, XL Zhang, ZF Tang, MZ Li, L Mo, LJ Liang, ZJ Shi, DY Huang, Z Huang, XH Liu, M Liu, Q Zhang, SJ Trent, JM Zheng, SL Xu, JF Mo, ZN AF Yang, Xiaobo Sun, Jielin Gao, Yong Tan, Aihua Zhang, Haiying Hu, Yanling Feng, Junjie Qin, Xue Tao, Sha Chen, Zhuo Kim, Seong-Tae Peng, Tao Liao, Ming Lin, Xiaoling Zhang, Zengfeng Tang, Minzhong Li, Li Mo, Linjian Liang, Zhengjia Shi, Deyi Huang, Zhang Huang, Xianghua Liu, Ming Liu, Qian Zhang, Shijun Trent, Jeffrey M. Zheng, S. Lilly Xu, Jianfeng Mo, Zengnan TI Genome-Wide Association Study for Serum Complement C3 and C4 Levels in Healthy Chinese Subjects SO PLOS GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; FACTOR-H; 2 PARTS; DEFICIENCY; DISEASE; GENE; IMMUNOLOGY; COMPONENTS; FAMILIES; PATHWAY AB Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33 x 10(-11) and P = 1.83 x 10(-9), respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5' and 3' of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19 x 10(-22) to 5.62 x 10(-97). HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P<0.05). Our study is the first GWAS report which shows genetic components influence the levels of complement C3 and C4. Our significant findings provide novel insights of their related autoimmune, infectious diseases, and molecular mechanisms. C1 [Yang, Xiaobo; Zhang, Haiying] Guangxi Med Univ, Sch Publ Hlth, Dept Occupat Hlth & Environm Hlth, Nanning, Guangxi, Peoples R China. [Yang, Xiaobo; Gao, Yong; Tan, Aihua; Zhang, Haiying; Hu, Yanling; Liao, Ming; Zhang, Shijun; Mo, Zengnan] Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning, Guangxi, Peoples R China. [Sun, Jielin; Feng, Junjie; Tao, Sha; Chen, Zhuo; Kim, Seong-Tae; Zheng, S. Lilly; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Gao, Yong; Lin, Xiaoling; Xu, Jianfeng] Fudan Univ, Sch Life Sci, Fudan VARI Ctr Genet Epidemiol, Shanghai 200433, Peoples R China. [Hu, Yanling; Li, Li] Guangxi Med Univ, Med Sci Res Ctr, Nanning, Guangxi, Peoples R China. [Qin, Xue] Guangxi Med Univ, Affiliated Hosp 1, Dept Clin Lab, Nanning, Guangxi, Peoples R China. [Peng, Tao] Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Nanning, Guangxi, Peoples R China. [Peng, Tao] NCI, Lab Genom Divers, NIH, Frederick, MD 21701 USA. [Zhang, Zengfeng] Guangxi Med Univ, Sch Preclin Med, Dept Microbiol, Nanning, Guangxi, Peoples R China. [Tang, Minzhong] Beijing Univ Technol, Coll Life Sci & Bioengn, Beijing, Peoples R China. [Mo, Linjian; Mo, Zengnan] Guangxi Med Univ, Affiliated Hosp 1, Inst Urol & Nephrol, Nanning, Guangxi, Peoples R China. [Liang, Zhengjia; Shi, Deyi; Huang, Zhang] Fangchenggang First Peoples Hosp, Med Examinat Ctr, Fangchenggang, Guangxi, Peoples R China. [Huang, Xianghua] Guigang Peoples Hosp, Med Examinat Ctr, Guigang, Guangxi, Peoples R China. [Liu, Ming] Yulin First Peoples Hosp, Med Examinat Ctr, Yulin, Guangxi, Peoples R China. [Liu, Qian] Guangxi Med Univ, Affiliated Hosp 1, Inst Cardiovasc Dis, Nanning, Guangxi, Peoples R China. [Trent, Jeffrey M.; Xu, Jianfeng] Van Andel Res Inst, Ctr Genet Epidemiol, Grand Rapids, MI USA. [Xu, Jianfeng] Fudan Univ, Huashan Hosp, Inst Urol, Shanghai 200433, Peoples R China. RP Yang, XB (reprint author), Guangxi Med Univ, Sch Publ Hlth, Dept Occupat Hlth & Environm Hlth, Nanning, Guangxi, Peoples R China. EM zengnanmo@hotmail.com RI chen, zhuo/E-7041-2012; Yang, Xiaobo/G-3854-2016; Kim, Seong-Tae/E-4474-2017 OI Kim, Seong-Tae/0000-0001-7436-1405 FU National Natural Science Foundation of China [81060234, 30945204, 30360124, 30260110]; Key Program and University Talents Highland Innovation Team of Guangxi [2012012D003, GJR201147-09]; Chairman Science and Technology Fund and Tackle Program of Guangxi [1116-03, GKG1298003-07-01]; Guangxi Science Fund for Distinguished Young Scholars [2012GXNSFFA060009]; Guangxi Provincial Department of Finance and Education [2009GJCJ150]; Fudan-VARI Center for Genetic Epidemiology; Fudan University Institute of Urology FX This study was partially supported by grants from the National Natural Science Foundation of China (81060234, 30945204, 30360124, 30260110), Key Program and University Talents Highland Innovation Team of Guangxi (2012012D003, GJR201147-09), Chairman Science and Technology Fund and Tackle Program of Guangxi (1116-03, GKG1298003-07-01), Guangxi Science Fund for Distinguished Young Scholars (2012GXNSFFA060009), Guangxi Provincial Department of Finance and Education (2009GJCJ150), intramural funding from Fudan-VARI Center for Genetic Epidemiology, and intramural funding from Fudan University Institute of Urology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 20 Z9 20 U1 2 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2012 VL 8 IS 9 AR e1002916 DI 10.1371/journal.pgen.1002916 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 020NK UT WOS:000309817900006 PM 23028341 ER PT J AU Vinuelas, J Kaneko, G Coulon, A Beslon, G Gandrillon, O AF Vinuelas, Jose Kaneko, Gael Coulon, Antoine Beslon, Guillaume Gandrillon, Olivier TI Towards experimental manipulation of stochasticity in gene expression SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE Chromatin; Circular causality; Gene expression noise; Stochasticity; Trichostatin A; 5-Azacytidine ID TO-CELL VARIABILITY; SINGLE-CELL; HISTONE ACETYLATION; CHROMATIN STRUCTURE; POSITIVE-FEEDBACK; TRICHOSTATIN-A; CANCER-CELLS; STEM-CELL; NOISE; DIFFERENTIATION AB For decades, most of molecular biology was driven by the "central dogma" in which the phenotype is defined by the genotype following a fully deterministic point of view. However, during the last 10 years, a wealth of studies has demonstrated that a given genotype can generate multiple phenotypes in identical environmental conditions, mainly because of the inherently probabilistic nature of the transcription process. It has also been shown that cells can tune this variability at the molecular level. Although previously described as a useless "noise", stochastic gene expression has now been shown by many authors to be an essential part of diverse biological processes. Chromatin dynamics having a central role in higher eukaryotes, we decided to investigate its involvement in the generation and control of stochasticity in gene expression (SGE). Our experiments reveal that the chromatin environment of a gene plays an important role in regulating SGE. Indeed, we find that histone acetylation and DNA methylation significantly affect SGE, suggesting that cells are able to adjust the variability of the expression of their genes through modification of chromatin marks. Given that the alteration of chromatin marks is itself subject to the expression of chromatin modifiers, our results shed light on a complex circular causality with on the one hand, the effect of gene expression on chromatin and on the other hand, the influence of the local chromatin environment of a gene on the dynamics of its expression. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Vinuelas, Jose; Kaneko, Gael; Gandrillon, Olivier] Univ Lyon 1, Ctr Genet & Physiol Mol & Cellulaire CGPhiMC, CNRS, UMR5534, F-69622 Lyon, France. [Coulon, Antoine] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Kaneko, Gael; Beslon, Guillaume] Univ Lyon, INSA Lyon, INRIA,UMR5205, Lab InfoRmat Image & Syst Informat LIRIS,CNRS, F-69621 Lyon, France. RP Gandrillon, O (reprint author), Univ Lyon 1, Ctr Genet & Physiol Mol & Cellulaire CGPhiMC, CNRS, UMR5534, F-69622 Lyon, France. EM olivier.gandrillon@univ-lyon1.fr RI Beslon, Guillaume/D-7369-2014; Coulon, Antoine/A-9006-2012 FU Institut rhonalpin des systemes complexes (IXXI); Reseau National des Systemes Complexes (RNSC); ANR grant [ANR 2011 BSV6 014 01]; CNRS post-doctoral grant FX We thank Francois Chatelain, Alexandra Fuchs and Manuel Thery for helpful discussions and support during the early stages of the project. This work was supported by fundings from the Institut rhonalpin des systemes complexes (IXXI) and from the Reseau National des Systemes Complexes (RNSC). Part of the project was also supported by an ANR grant (ANR 2011 BSV6 014 01). JV is supported by a CNRS post-doctoral grant and GK is a PhD fellow from the Region Rhone-Alpes. NR 103 TC 8 Z9 8 U1 2 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD SEP PY 2012 VL 110 IS 1 SI SI BP 44 EP 53 DI 10.1016/j.pbiomolbio.2012.04.010 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 018VK UT WOS:000309694500008 PM 22609563 ER PT J AU Hill, MJ Chason, RJ Payson, MD Segars, JH Csokmay, JM AF Hill, Micah J. Chason, Rebecca J. Payson, Mark D. Segars, James H. Csokmay, John M. TI GnRH antagonist rescue in high responders at risk for OHSS results in excellent assisted reproduction outcomes SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Article DE assisted reproduction; cancellation; GnRH antagonist rescue; infertility; IVF; OHSS ID OVARIAN HYPERSTIMULATION SYNDROME; IN-VITRO FERTILIZATION; OOCYTE DONATION; WOMEN; PREVENTION AB Gonadotrophin-releasing hormone (GnRH) antagonist rescue is performed by replacing a GnRH agonist with a GnRH antagonist in patients with rapidly rising serum oestradiol who are at risk of ovarian hyperstimulation syndrome (OHSS) during stimulation. It results in a rapid reduction in serum oestradiol, allowing for the avoidance of cycle cancellation and the continuation of exogenous gonadotrophin administration. A total of 387 patients who underwent GnRH antagonist rescue for ovarian hyperresponse were compared with 271 patients who did not receive GnRH antagonist rescue and had oestradiol concentrations >4000 pg/ml on the day of human chorionic gonadotrophin (HCG) administration. GnRH antagonist rescue decreased the mean oestradiol concentration by 35% on the first day of use. There was no difference in oocyte maturity (82% versus 83%) or fertilization rate (69% versus 67%) between the antagonist rescue and comparison groups, respectively. The percentage of high-grade embryos on day 3 and the blastocyst development rate were also similar between groups. The live-birth rate was 41.9% in the antagonist rescue group and 36.9% in the comparison group. GnRH antagonist rescue enabled cycle completion with high live-birth rates in patients at risk for OHSS. GnRH antagonist was associated with high oocyte quality, blastocyst development and pregnancy. RBM Online (c) 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. C1 [Hill, Micah J.; Chason, Rebecca J.; Payson, Mark D.; Csokmay, John M.] Walter Reed Natl Mil Med Ctr, Washington, DC USA. [Hill, Micah J.; Chason, Rebecca J.; Payson, Mark D.; Segars, James H.; Csokmay, John M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Hill, MJ (reprint author), Walter Reed Natl Mil Med Ctr, Washington, DC USA. EM hillmicah@mail.nih.gov FU intramural research programme of the Program in Reproductive and Adult Endocrinology (NICHD, NIH) FX This research was supported, in part, by intramural research programme of the Program in Reproductive and Adult Endocrinology (NICHD, NIH). NR 18 TC 13 Z9 13 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1472-6483 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD SEP PY 2012 VL 25 IS 3 BP 284 EP 291 DI 10.1016/j.rbmo.2012.05.004 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 017PQ UT WOS:000309603100010 PM 22796230 ER PT J AU Samuels, Y Prickett, D Wei, X Lin, JC Teer, JK Rosenberg, SA AF Samuels, Y. Prickett, D. Wei, X. Lin, J. C. Teer, J. K. Rosenberg, S. A. TI TOWARDS DECIPHERING THE GENETIC LANDSCAPE IN MELANOMA SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 37th Congress of the European-Society-for-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol (ESMO) C1 [Samuels, Y.; Prickett, D.; Wei, X.; Teer, J. K.] NHGRI, NIH, Bethesda, MD 20892 USA. [Lin, J. C.] Washington Univ, Sch Med, St Louis, MO USA. [Rosenberg, S. A.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2012 VL 23 SU 9 BP 25 EP 25 PG 1 WC Oncology SC Oncology GA 014XL UT WOS:000309409000011 ER PT J AU Gril, B AF Gril, B. TI HOW NEW INSIGHTS IN THE BIOLOGY OF BRAIN METASTASES MAY LEAD TO THE IDENTIFICATION OF NEW EFFECTIVE MEDICAL THERAPIES SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 37th Congress of the European-Society-for-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol (ESMO) C1 [Gril, B.] NCI, Womens Canc Sect, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2012 VL 23 SU 9 BP 62 EP 62 PG 1 WC Oncology SC Oncology GA 014XL UT WOS:000309409000119 ER PT J AU Sahebjam, S Bedard, P Castonguay, V Chen, H Ivy, SP Oza, AM Chen, EX Hirte, HW Siu, L Hotte, SJ AF Sahebjam, S. Bedard, P. Castonguay, V. Chen, H. Ivy, S. P. Oza, A. M. Chen, E. X. Hirte, H. W. Siu, L. Hotte, S. J. TI A PHASE I STUDY OF THE COMBINATION OF RO4929097 (RO) AND CEDIRANIB (CD) IN PATIENTS WITH ADVANCED SOLID TUMORS (PJC-004/NCI 8503) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 37th Congress of the European-Society-for-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol (ESMO) C1 [Sahebjam, S.; Castonguay, V.; Oza, A. M.; Chen, E. X.; Siu, L.] Princess Margaret Hosp, Drug Dev Program, Toronto, ON, Canada. [Bedard, P.] Princess Margaret Hosp, Dept Med Oncol, Toronto, ON M4X 1K9, Canada. [Chen, H.; Ivy, S. P.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Hirte, H. W.; Hotte, S. J.] Juravinski Canc Ctr, Hamilton, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2012 VL 23 SU 9 BP 155 EP 156 PG 2 WC Oncology SC Oncology GA 014XL UT WOS:000309409000440 ER PT J AU Diaz-Padilla, I Hotte, SJ Ivy, SP Oza, AM Hirte, HW Razak, ARA Chen, EX Garcia, IB Siu, L Bedard, P AF Diaz-Padilla, I. Hotte, S. J. Ivy, S. P. Oza, A. M. Hirte, H. W. Razak, A. R. A. Chen, E. X. Garcia, I. Brana Siu, L. Bedard, P. TI A PHASE IB COMBINATION STUDY OF RO4929097 (RO), A GAMMA-SECRETASE INHIBITOR, AND TEMSIROLIMUS (TEM) IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 37th Congress of the European-Society-for-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol (ESMO) C1 [Diaz-Padilla, I.; Oza, A. M.; Razak, A. R. A.; Chen, E. X.; Garcia, I. Brana; Siu, L.; Bedard, P.] Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. [Hotte, S. J.; Hirte, H. W.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Ivy, S. P.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2012 VL 23 SU 9 BP 156 EP 156 PG 1 WC Oncology SC Oncology GA 014XL UT WOS:000309409000442 ER PT J AU O'Connell, MJ Lee, M Lopatin, M Yothers, G Clark-Langone, KM Millward, C Paik, S Sharif, S Shak, S Wolmark, N AF O'Connell, M. J. Lee, M. Lopatin, M. Yothers, G. Clark-Langone, K. M. Millward, C. Paik, S. Sharif, S. Shak, S. Wolmark, N. TI THE 12-GENE COLON CANCER RECURRENCE SCORE (RS) PREDICTS RECURRENCE IN STAGE II AND III COLON CANCER PATIENTS TREATED WITH 5FU/LV (FU) AND 5FU/LV plus OXALIPLATIN (FU+OX): VALIDATION IN NSABP C07 SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 37th Congress of the European-Society-for-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol (ESMO) C1 [O'Connell, M. J.; Paik, S.; Sharif, S.; Wolmark, N.] Natl Surg Adjuvant Breast & Bowel Project, NSABP, Pittsburgh, PA USA. [Lee, M.; Shak, S.] Genom Hlth Inc, Oncol Dev, Redwood City, CA USA. [Lopatin, M.] Genom Hlth Inc, Biostat, Redwood City, CA USA. [Yothers, G.] NSABP, Biostat Ctr, Pittsburgh, PA USA. [Clark-Langone, K. M.] Genom Hlth Inc, Dev Lab, Redwood City, CA USA. [Millward, C.] Genom Hlth Inc, Pathol, Redwood City, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2012 VL 23 SU 9 BP 179 EP 180 PG 2 WC Oncology SC Oncology GA 014XL UT WOS:000309409001006 ER PT J AU Codesido, MB Wilkerson, J Gayo, LR Alonso, MR Garcia, PN Ochoa, AM Martin, AJM Suarez, SA Alfonso, PG Fojo, T AF Blanco Codesido, M. Wilkerson, J. Rodriguez Gayo, L. Rodriguez Alonso, M. Nava Garcia, P. Matas Ochoa, A. Munoz Martin, A. J. Alvarez Suarez, S. Garcia Alfonso, P. Fojo, T. TI ASSESSMENT AND COMPARISON OF TREATMENT EFFICACY IN PATIENTS WITH COLORECTAL CANCER (CRC), USING A NOVEL METHODOLOGY TO ESTIMATE THE RATE OF TUMOR REGRESSION (D) AND GROWTH (G) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 37th Congress of the European-Society-for-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol (ESMO) C1 [Blanco Codesido, M.] Hosp Gen Univ Gregorio Maranon, Med Oncol Serv, Madrid, Spain. [Wilkerson, J.; Fojo, T.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Rodriguez Gayo, L.; Rodriguez Alonso, M.; Nava Garcia, P.; Matas Ochoa, A.; Munoz Martin, A. J.; Alvarez Suarez, S.; Garcia Alfonso, P.] Hosp Univ Gregorio Maranon, Serv Oncol, Madrid, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2012 VL 23 SU 9 BP 198 EP 198 PG 1 WC Oncology SC Oncology GA 014XL UT WOS:000309409001062 ER PT J AU Messina, M Sinagra, E Dolcimascolo, S Rizzolo, CA Puccia, F Mocciaro, F Marasa, S Perricone, G Bedognetti, D Sinagra, D AF Messina, M. Sinagra, E. Dolcimascolo, S. Rizzolo, C. A. Puccia, F. Mocciaro, F. Marasa, S. Perricone, G. Bedognetti, D. Sinagra, D. TI COLORECTAL CANCER IN PATIENTS WITH TYPE 2 DIEBETES MELLITUS: RETROSPECTIVE ANALYSIS OF 741 CASES SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 37th Congress of the European-Society-for-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol (ESMO) C1 [Messina, M.] Casa Cure Orestano, Oncol Unit, Palermo, Italy. [Sinagra, E.; Mocciaro, F.; Perricone, G.] Univ Palermo, Hosp V Cervello, Palermo, Italy. [Dolcimascolo, S.] Univ Palermo, AOUP Paolo Giaccone, Endocrinol Unit, Palermo, Italy. [Marasa, S.] Univ Palermo, AOUP Paolo Giaccone, Pathol Unit, Palermo, Italy. [Bedognetti, D.] NIH, Lab Immunol & Mol Biol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2012 VL 23 SU 9 BP 215 EP 215 PG 1 WC Oncology SC Oncology GA 014XL UT WOS:000309409001120 ER PT J AU Gardneron, E Figg, W Johnston, DS Alexander, HR AF Gardneron, E. Figg, W. Johnston, D. S. Alexander, H. R., Jr. CA Phase 3 Principle Investigators TI PERCUTANEOUS HEPATIC PERFUSION (CHEMOSAT (R) OR CS-PHP) OF MELPHALAN IN PATIENTS (PTS) WITH HEPATIC METASTASES FROM MELANOMA: PHASE III PHARMACOKINETIC ANALYSIS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 37th Congress of the European-Society-for-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol (ESMO) C1 [Phase 3 Principle Investigators] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Johnston, D. S.] Delcath Syst Inc, Pharmaceut Res & Dev, New York, NY USA. [Alexander, H. R., Jr.] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2012 VL 23 SU 9 BP 246 EP 246 PG 1 WC Oncology SC Oncology GA 014XL UT WOS:000309409001227 ER EF