FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Waters, AM Pittaway, M Mogg, K Bradley, BP Pine, DS AF Waters, Allison M. Pittaway, Michelle Mogg, Karin Bradley, Brendan P. Pine, Daniel S. TI Attention training towards positive stimuli in clinically anxious children SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Attention bias; Anxiety; Attention bias modification training; Cognitive behavioural therapy ID GENERALIZED ANXIETY DISORDER; CHILDHOOD ANXIETY; EXPERIMENTAL MANIPULATION; MODIFICATION PROGRAM; BIAS; INDIVIDUALS; VULNERABILITY; SYMPTOMS; THERAPY; THREAT AB Objective: Attention bias modification training (ABMT) is a promising treatment. Nevertheless, few studies examine its effectiveness in anxious children. This study examined the efficacy of such an ABMT protocol in pediatric anxiety. Method: 37 anxious children were randomly assigned to one of two ABMT conditions. In the attention-towards-positive (ATP) condition, children searched 3 x 3 matrices for a happy face amongst angry faces. In the attention-training-control (ATC) condition, they searched for a bird amongst flowers. Children completed 160 trials in each of four training sessions per week for three weeks at home (1920 total trials). Clinical and attention bias measures were assessed before and after ABMT. Results: Children randomized to ATP showed greater post-training attention bias towards happy faces than children randomized to ATC. ATP also produced significantly greater reductions in clinician-rated diagnostic severity and number of diagnoses, compared to ATC. In the ATP group, 50% of children who completed training did not meet criteria for their principal diagnosis, compared to 8% in the ATC group. Conclusion: Training anxious children to focus attention on positive features of their environment may be a promising treatment. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Waters, Allison M.; Pittaway, Michelle] Griffith Univ, Sch Appl Psychol, Mt Gravatt, Qld 4122, Australia. [Mogg, Karin; Bradley, Brendan P.] Univ Southampton, Sch Psychol, Southampton SO9 5NH, Hants, England. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. RP Waters, AM (reprint author), Griffith Univ, Sch Appl Psychol, Mt Gravatt, Qld 4122, Australia. EM a.waters@griffith.edu.au RI Mogg, Karin/C-1181-2008; Bradley, Brendan/B-9724-2008; OI Mogg, Karin/0000-0002-2738-7378; Waters, Allison/0000-0003-2453-793X; Bradley, Brendan/0000-0003-2801-4271 FU Australian Research Council [DP1095536] FX The Australian Research Council Grant DP1095536 supported this research. NR 33 TC 40 Z9 43 U1 1 U2 40 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD APR PY 2013 VL 4 SI SI BP 77 EP 84 DI 10.1016/j.dcn.2012.09.004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 113FJ UT WOS:000316651600008 PM 23063461 ER PT J AU Wilson, TE DeMarini, DM Dertinger, SD Engelward, BP Hanawalt, PC MacGregor, JT Smith-Roe, SL Witt, KL Yauk, CL Ljungman, M Schwartz, JL Klein, CB AF Wilson, Thomas E. DeMarini, David M. Dertinger, Stephen D. Engelward, Bevin P. Hanawalt, Philip C. MacGregor, James T. Smith-Roe, Stephanie L. Witt, Kristine L. Yauk, Carole L. Ljungman, Mats Schwartz, Jeffrey L. Klein, Catherine B. TI Building on the past, shaping the future: The environmental mutagenesis and genomics society SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE genetics; epigenetics; toxicology; DNA repair; mutation research; mutagen ID GENETIC TOXICOLOGY; ORIGINS AB In late 2012, the members of the Environmental Mutagen Society voted to change its name to the Environmental Mutagenesis and Genomics Society. Here, we describe the thought process that led to adoption of the new name, which both respects the rich history of a Society founded in 1969 and reflects the many advances in our understanding of the nature and breadth of gene-environment interactions during the intervening 43 years. Environ. Mol. Mutagen. 54:153157, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Wilson, Thomas E.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Wilson, Thomas E.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. [DeMarini, David M.] US EPA, Integrated Syst Toxicol Div, Res Triangle Pk, NC 27711 USA. [Dertinger, Stephen D.] Litron Labs, Rochester, NY USA. [Engelward, Bevin P.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Hanawalt, Philip C.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. [MacGregor, James T.] Toxicol Consulting Serv, Bonita Springs, FL USA. [Smith-Roe, Stephanie L.; Witt, Kristine L.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Yauk, Carole L.] Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. [Ljungman, Mats] Univ Michigan, Sch Med, Dept Radiat Oncol, Ann Arbor, MI USA. [Ljungman, Mats] Univ Michigan, Sch Med, Translat Oncol Program, Ann Arbor, MI USA. [Schwartz, Jeffrey L.] Univ Washington, Sch Med, Dept Radiat Oncol, Seattle, WA 98195 USA. [Klein, Catherine B.] NYU, Sch Med, Dept Environm Med, Tuxedo Pk, NY USA. RP Wilson, TE (reprint author), Univ Michigan, Sch Med, Dept Pathol, 2065 BSRB,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM wilsonte@umich.edu OI Yauk, Carole/0000-0003-4919-876X NR 11 TC 0 Z9 0 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD APR PY 2013 VL 54 IS 3 BP 153 EP 157 DI 10.1002/em.21765 PG 5 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 107OM UT WOS:000316227700001 PM 23444128 ER PT J AU Siitonen, A Majounie, E Federoff, M Ding, J Majamaa, K Singleton, AB AF Siitonen, A. Majounie, E. Federoff, M. Ding, J. Majamaa, K. Singleton, A. B. TI Mutations in EIF4G1 are not a common cause of Parkinson's disease SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Letter DE 1000 genomes; DNA sequencing; neurodegenerative diseases; Sanger; single nucleotide polymorphism C1 [Siitonen, A.; Majamaa, K.] Univ Oulu, Dept Clin Med, FIN-90014 Oulu, Finland. [Siitonen, A.; Majamaa, K.] Oulu Univ Hosp, Dept Neurol, Oulu, Finland. [Majounie, E.; Federoff, M.; Ding, J.; Singleton, A. B.] NIA, Mol Genet Sect, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. RP Siitonen, A (reprint author), Univ Oulu, Dept Neurol, POB 5000, FIN-90014 Oulu, Finland. EM Ari.Siitonen@iki.fi RI Singleton, Andrew/C-3010-2009 FU Intramural NIH HHS; NIA NIH HHS [Z01 AG000958-09] NR 6 TC 7 Z9 7 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD APR PY 2013 VL 20 IS 4 BP e59 EP e59 DI 10.1111/ene.12051 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 107ZC UT WOS:000316258800003 PM 23490116 ER PT J AU Larsen, BR Steffensen, SDR Nielsen, NVL Friis, S Godiksen, S Bornholdt, J Soendergaard, C Nonboe, AW Andersen, MN Poulsen, SS Szabo, R Bugge, TH Lin, CY Skovbjerg, H Jensen, JK Vogel, LK AF Larsen, Brian R. Steffensen, Simon D. R. Nielsen, Nis V. L. Friis, Stine Godiksen, Sine Bornholdt, Jette Soendergaard, Christoffer Nonboe, Annika W. Andersen, Martin N. Poulsen, Steen S. Szabo, Roman Bugge, Thomas H. Lin, Chen-Yong Skovbjerg, Hanne Jensen, Jan K. Vogel, Lotte K. TI Hepatocyte growth factor activator inhibitor-2 prevents shedding of matriptase SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Matriptase; HAI-2; HAI-1; Shedding ID SERINE-PROTEASE INHIBITOR; PLACENTAL DEVELOPMENT; ZYMOGEN ACTIVATION; BARRIER FUNCTION; EXPRESSION; CELLS; CARCINOGENESIS; PURIFICATION; 1/MATRIPTASE; ECTODOMAIN AB Hepatocyte growth factor activator inhibitor-2 (HAI-2) is an inhibitor of many proteases in vitro, including the membrane-bound serine protease, matriptase. Studies of knock-out mice have shown that HAI-2 is essential for placental development only in mice expressing matriptase, suggesting that HAI-2 is important for regulation of matriptase. Previous studies have shown that recombinant expression of matriptase was unsuccessful unless co-expressed with another HAI, HAI-1. In the present study we show that when human matriptase is recombinantly expressed alone in the canine cell line MDCK, then human matriptase mRNA can be detected and the human matriptase ectodomain is shed to the media, suggesting that matriptase expressed alone is rapidly transported through the secretory pathway and shed. Whereas matriptase expressed together with HAI-1 or HAI-2 accumulates on the plasma membrane where it is activated, as judged by cleavage at Arg614 and increased peptidolytic activity of the cell extracts. Mutagenesis of Kunitz domain 1 but not Kunitz domain 2 abolished this function of HAI-2. HAI-2 seems to carry out its function intracellularly as this is where the vast majority of HAI-2 is located and since HAI-2 could not be detected on the basolateral plasma membrane where matriptase resides. However, minor amounts of HAI-2 not undergoing endocytosis could be detected on the apical plasma membrane. Our results suggest that Kunitz domain 1 of HAI-2 cause matriptase to accumulate in a membrane-bound form on the basolateral plasma membrane. (C) 2013 Elsevier Inc. All rights reserved. C1 [Larsen, Brian R.; Steffensen, Simon D. R.; Friis, Stine; Godiksen, Sine; Bornholdt, Jette; Soendergaard, Christoffer; Nonboe, Annika W.; Skovbjerg, Hanne; Vogel, Lotte K.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Cellular & Mol Med, DK-2200 Copenhagen N, Denmark. [Nielsen, Nis V. L.; Jensen, Jan K.] Aarhus Univ, Fac Sci, Dept Mol Biol & Genet, Danish Chinese Ctr Proteases & Canc, DK-8000 Aarhus C, Denmark. [Godiksen, Sine; Bornholdt, Jette] Univ Copenhagen, Fac Sci, Dept Biol, DK-2100 Copenhagen, Denmark. [Andersen, Martin N.; Poulsen, Steen S.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark. [Szabo, Roman; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD 20892 USA. [Lin, Chen-Yong] Univ Maryland, Greenebaum Canc Ctr, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Skovbjerg, Hanne] Amager Hosp, Dept Med, DK-2300 Copenhagen S, Denmark. RP Vogel, LK (reprint author), Blegdamsvej 3,Bldg 18-4, DK-2200 Copenhagen N, Denmark. EM vogel@sund.ku.dk OI Soendergaard, Christoffer/0000-0002-2943-6911; Andersen, Martin Nybo/0000-0003-1125-1553 FU Harboe Foundation; Brothers Hartmanns Foundation; A.P. Mollers Foundation for the Advancement of Medical Science; Lundbeck Foundation; Architect Holger Hjortenberg and Hustru Dagmar Hjortenbergs Foundation; Else and Mogens Wedell-Wedellsborg Foundation; Aage and Johanne Louis-Hansens Foundation; NIDCR; Danish Cancer Society FX This work was supported by The Harboe Foundation, The Brothers Hartmanns Foundation, The A.P. Mollers Foundation for the Advancement of Medical Science, The Lundbeck Foundation, Architect Holger Hjortenberg and Hustru Dagmar Hjortenbergs Foundation, Else and Mogens Wedell-Wedellsborg Foundation, Aage and Johanne Louis-Hansens Foundation, The NIDCR Intramural Programs and The Danish Cancer Society. NR 28 TC 8 Z9 8 U1 1 U2 8 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD APR 1 PY 2013 VL 319 IS 6 BP 918 EP 929 DI 10.1016/j.yexcr.2013.01.008 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 109NF UT WOS:000316374600014 PM 23333561 ER PT J AU Jin, LY Qin, LZ Xia, DS Liu, XB Fan, ZP Zhang, CM Gu, LK He, JQ Ambudkar, IS Deng, DJ Wang, SL AF Jin, Luyuan Qin, Lizheng Xia, Dengsheng Liu, Xibao Fan, Zhipeng Zhang, Chunmei Gu, Liankun He, Junqi Ambudkar, Indu S. Deng, Dajun Wang, Songlin TI Active secretion and protective effect of salivary nitrate against stress in human volunteers and rats SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Stress; Salivary glands; Saliva; Nitrate; Nitrite; Nitric oxide; Gastric ulcer; Free radicals ID DIETARY INORGANIC NITRATE; MUCOSAL BLOOD-FLOW; NITRIC-OXIDE; PAROTID-GLANDS; GERM-FREE; GENERATION; PRESSURE; PLASMA; CANCER; THERAPEUTICS AB Up to 25% of the circulating nitrate in blood is actively taken up, concentrated, and secreted into saliva by the salivary glands. Salivary nitrate can be reduced to nitrite by the commensal bacteria in the oral cavity or stomach and then further converted to nitric oxide (NO) in vivo, which may play a role in gastric protection. However, whether salivary nitrate is actively secreted in human beings has not yet been determined. This study was designed to determine whether salivary nitrate is actively secreted in human beings as an acute stress response and what role salivary nitrate plays in stress-induced gastric injury. To observe salivary nitrate function under stress conditions, alteration of salivary nitrate and nitrite was analyzed among 22 healthy volunteers before and after a strong stress activity, jumping down from a platform at the height of 68 m. A series of stress indexes was analyzed to monitor the stress situation. We found that both the concentration and the total amount of nitrate in mixed saliva were significantly increased in the human volunteers immediately after the jump, with an additional increase 1 h later (p < 0.01). Saliva nitrite reached a maximum immediately after the jump and was maintained 1 h later. To study the biological functions of salivary nitrate and nitrite in stress protection, we further carried out a water-immersion-restraint stress (WIRS) assay in male adult rats with bilateral parotid and submandibular duct ligature (BPSDL). Intragastric nitrate, nitrite, and NO; gastric mucosal blood flow; and gastric ulcer index (UI) were monitored and nitrate was administrated in drinking water to compensate for nitrate secretion in BPSDL animals. Significantly decreased levels of intragastric nitrate, nitrite, and NO and gastric mucosal blood flow were measured in BPSDL rats during the WIRS assay compared to sham control rats (p < 0.05). Recovery was observed in the BPSDL rats upon nitrate administration. The WIRS-induced UI was significantly higher in the BPSDL animals compared to controls, and nitrate administration rescued the WIRS-induced gastric injury in BPSDL rats. In conclusion, this study suggests that stress promotes salivary nitrate secretion and nitrite formation, which may play important roles in gastric protection against stress-induced injury via the nitrate-dependent NO pathway. (C) 2012 Elsevier Inc. All rights reserved. C1 [Jin, Luyuan; Qin, Lizheng; Xia, Dengsheng; Fan, Zhipeng; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Beijing 100050, Peoples R China. [Jin, Luyuan; Qin, Lizheng; Xia, Dengsheng; Fan, Zhipeng; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Beijing 100050, Peoples R China. [Liu, Xibao; Ambudkar, Indu S.] NIDCR, Mol Physiol & Therapeut Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gu, Liankun; Deng, Dajun] Peking Univ, Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Minist Educ,Div Etiol, Beijing 100142, Peoples R China. [He, Junqi; Wang, Songlin] Capital Med Univ, Sch Basic Med, Dept Biochem & Mol Biol, Beijing 100069, Peoples R China. RP Deng, DJ (reprint author), Peking Univ, Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Minist Educ,Div Etiol, Beijing 100142, Peoples R China. EM dengdajun@bjmu.edu.cn RI Deng, Dajun/D-4605-2009 OI Deng, Dajun/0000-0001-5161-5943 FU National Natural Science Foundation of China [30430690, 30125042, 81170975]; Beijing Municipal Committee for Science and Technology [Z121100005212004] FX This study was supported by grants from the National Natural Science Foundation of China (30430690, 30125042, and 81170975) and Beijing Municipal Committee for Science and Technology (Z121100005212004). The authors acknowledge the volunteers who participated in this study. NR 38 TC 12 Z9 12 U1 2 U2 23 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 APR PY 2013 VL 57 BP 61 EP 67 DI 10.1016/j.freeradbiomed.2012.12.015 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 105AC UT WOS:000316037000007 PM 23277147 ER PT J AU Doroshow, JH Gaur, S Markel, S Lu, J van Balgooy, J Synold, TW Xi, BX Wu, XW Juhasz, A AF Doroshow, James H. Gaur, Shikha Markel, Susan Lu, Jiamo van Balgooy, Josephus Synold, Timothy W. Xi, Bixin Wu, Xiwei Juhasz, Agnes TI Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer cells and xenografts SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE NADPH oxidase; Nox1; Diphenyleneiodonium; Colon cancer; Gene expression; Free radicals ID SMOOTH-MUSCLE-CELLS; S-PHASE-TRANSITION; DIPHENYLENE IODONIUM; OXIDATIVE STRESS; PROTEIN-KINASE; NOX FAMILY; ACTIVATION; ROS; OVEREXPRESSION; NEUTROPHILS AB Iodonium-class flavoprotein dehydrogenase inhibitors have been demonstrated to possess antiproliferative potential and to inhibit reactive oxygen production in human tumor cells, although the mechanism(s) that explains the relationship between altered cell growth and the generation of reactive oxygen species (ROS) remains an area of active investigation. Because of the ability of these compounds to inhibit the activity of flavoprotein-containing epithelial NADPH oxidases, we chose to examine the effects of several iodonium-class flavoprotein inhibitors on human colon cancer cell lines that express high, functional levels of a single such oxidase (NADPH oxidase 1, or Nox1). We found that diphenyleneiodonium. (DPI); di-2-thienyliodonium (DTI), and iodonium diphenyl inhibited the growth of Caco2, HT-29, and LS-174 T colon cancer cells at concentrations (10-250 nM for DPI, 0.5-2.5 mu M for DTI, and 155 nM to 10 mu M for iodonium diphenyl) substantially lower than needed for DU145 human prostate cancer cells, which do not possess functional NADPH oxidase activity. Drug treatment was associated with decreased H2O2 production and diminished intracellular ROS levels, lasting up to 24 h, after short-term (1-h) exposure to the iodonium analogs. Decreased tumor cell proliferation was caused, in part, by a profound block in cell cycle progression at the G(1)/S interface in both LS-174 land HT-29 cells exposed to either DPI or DTI; and the G(1) block was produced, for LS-174 T cells, by upregulation of p27 and a drug concentration-related decrease in the expression of cyclins D1, A, and E that was partially prevented by exogenous H2O2. Not only did DPI and DTI decrease intracellular ROS, they both also significantly decreased the mRNA expression levels of Nox1, potentially contributing to the prolonged reduction in tumor cell reactive oxygen levels. We also found that DPI and DTI significantly decreased, the growth of both HT-29 and LS-174 T human tumor xenografts, at dose levels that produced peak plasma concentrations similar to those utilized for our in vitro experiments. These findings suggest that iodonium analogs have therapeutic potential for NADPH oxidase-containing human colon cancers. in vivo and that at least part of their antineoplastic mechanism of action may be related. to targeting Nox1 Published by Elsevier Inc. C1 [Doroshow, James H.; Lu, Jiamo; Juhasz, Agnes] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Gaur, Shikha; Markel, Susan; van Balgooy, Josephus; Synold, Timothy W.; Xi, Bixin] City Hope Comprehens Canc Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA. [Wu, Xiwei] City Hope Comprehens Canc Ctr, Bioinformat Grp, Duarte, CA 91010 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, Bldg 31,Room 3A-4431,Ctr Dr NIH, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU Center for Cancer Research; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health FX This work was supported by federal funds from the Center for Cancer Research and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 49 TC 11 Z9 11 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 APR PY 2013 VL 57 BP 162 EP 175 DI 10.1016/j.freeradbiomed.2013.01.002 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 105AC UT WOS:000316037000016 PM 23314043 ER PT J AU McCauley, MP Blake, KD Meissner, HI Viswanath, K AF McCauley, M. P. Blake, K. D. Meissner, H. I. Viswanath, K. TI The social group influences of US health journalists and their impact on the newsmaking process SO HEALTH EDUCATION RESEARCH LA English DT Article ID NATIONAL-SURVEY; MEDIA COVERAGE; CANCER CONTROL; NEWS MEDIA; DISPARITIES; WOMEN; REPORTERS; SCIENCE; CARE; OPPORTUNITIES AB The news media play a vital role in disseminating health information, yet little is known about the social characteristics of health journalists or the impact they have on the newsmaking process. This study examines how the social group influences of US health journalists impact two important aspects of news production-'media agenda-setting' and 'framing'. Using data from a national survey of health and medical science journalists, the authors conducted multivariable logistic regression analyses to study the links between the gender, age and race/ethnicity of respondents, and the ways in which they utilized news sources, other resources, news priorities and story angles. Female respondents were more likely than males to say that educating people to make informed decisions and disseminating new, accurate information are important priorities. Female and minority journalists were more likely than white males to use a variety of sources, and to say it is important to develop the health and scientific literacy of audiences and influence public health behaviors. The gender and race/ethnicity of journalists play an important role in the production of health news. Health educators can foster improved coverage by learning more about the life experiences of health journalists and developing better working relationships with them. C1 [McCauley, M. P.; Viswanath, K.] Harvard Univ, Dept Soc Human Dev & Hlth, Sch Publ Hlth, Boston, MA 02215 USA. [McCauley, M. P.; Viswanath, K.] Dana Farber Canc Inst, McGraw Patterson Ctr Populat Sci, Boston, MA 02215 USA. [Blake, K. D.] NCI, Hlth Commun & Informat Res Branch, NIH, Bethesda, MD 20892 USA. [Meissner, H. I.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP McCauley, MP (reprint author), Harvard Univ, Dept Soc Human Dev & Hlth, Sch Publ Hlth, Boston, MA 02215 USA. EM michael_mccauley@dfci.harvard.edu RI McCauley, Michael/C-3642-2014 OI McCauley, Michael/0000-0003-3851-1765 FU NCI NIH HHS [R25 CA057713] NR 70 TC 7 Z9 7 U1 4 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD APR PY 2013 VL 28 IS 2 BP 339 EP 351 DI 10.1093/her/cys086 PG 13 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 108DY UT WOS:000316273100013 PM 22907539 ER PT J AU Raza, MH Gertz, EM Mundorff, J Lukong, J Kuster, J Schaffer, AA Drayna, D AF Raza, M. Hashim Gertz, E. Michael Mundorff, Jennifer Lukong, Joseph Kuster, Judith Schaeffer, Alejandro A. Drayna, Dennis TI Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance SO HUMAN GENETICS LA English DT Article ID TWIN; PEDIGREES; GENOME; SAMPLE; EPIDEMIOLOGY; SIMULATION; DISORDERS; MUTATIONS; CHILDREN; ETIOLOGY AB We describe a pedigree of 71 individuals from the Republic of Cameroon in which at least 33 individuals have a clinical diagnosis of persistent stuttering. The high concentration of stuttering individuals suggests that the pedigree either contains a single highly penetrant gene variant or that assortative mating led to multiple stuttering-associated variants being transmitted in different parts of the pedigree. No single locus displayed significant linkage to stuttering in initial genome-wide scans with microsatellite and SNP markers. By dividing the pedigree into five subpedigrees, we found evidence for linkage to previously reported loci on 3q and 15q, and to novel loci on 2p, 3p, 14q, and a different region of 15q. Using the two-locus mode of Superlink, we showed that combining the recessive locus on 2p and a single-locus additive representation of the 15q loci is sufficient to achieve a two-locus score over 6 on the entire pedigree. For this 2p + 15q analysis, we show LOD scores ranging from 4.69 to 6.57, and the scores are sensitive to which marker is chosen for 15q. Our findings provide strong evidence for linkage at several loci. C1 [Raza, M. Hashim; Mundorff, Jennifer; Lukong, Joseph; Drayna, Dennis] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Gertz, E. Michael; Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Kuster, Judith] Minnesota State Univ, Dept Speech Hearing & Rehabil Serv, Mankato, MN USA. RP Drayna, D (reprint author), 5 Res Court,Room 2B-46, Rockville, MD 20850 USA. EM drayna@nidcd.nih.gov OI Gertz, E. Michael/0000-0001-8390-4387 FU Intramural Research Program of the NIH, NIDCD [Z01-000046-11]; NLM [LM000097]; Stuttering Foundation FX This study was supported by the Intramural Research Program of the NIH, NIDCD (Z01-000046-11) and the NLM (LM000097), and by the Stuttering Foundation. We are especially grateful to the members of family CAMST01 for their participation. We thank Bailey Levis for genotyping during the early stages of this project, and Drs. Thomas Friedman and Robert Morell for suggestions that improved the manuscript. NR 46 TC 4 Z9 4 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD APR PY 2013 VL 132 IS 4 BP 385 EP 396 DI 10.1007/s00439-012-1252-5 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 109DI UT WOS:000316345400002 PM 23239121 ER PT J AU Sun, JL Tao, S Gao, Y Peng, T Tan, AH Zhang, HY Yang, XB Qin, X Hu, YL Feng, JJ Kim, ST Lin, XL Wu, YM Zhang, J Li, ZX Li, L Mo, LJ Liang, ZJ Shi, DY Huang, Z Huang, XH Liu, M Liu, Q Zhang, SJ Zheng, SL Xu, JF Mo, ZN AF Sun, Jielin Tao, Sha Gao, Yong Peng, Tao Tan, Aihua Zhang, Haiying Yang, Xiaobo Qin, Xue Hu, Yanling Feng, Junjie Kim, Seong-Tae Lin, Xiaoling Wu, Yongming Zhang, Ju Li, Zhixian Li, Li Mo, Linjian Liang, Zhengjia Shi, Deyi Huang, Zhang Huang, Xianghua Liu, Ming Liu, Qian Zhang, Shijun Zheng, S. Lilly Xu, Jianfeng Mo, Zengnan TI Genome-wide association study identified novel genetic variant on SLC45A3 gene associated with serum levels prostate-specific antigen (PSA) in a Chinese population SO HUMAN GENETICS LA English DT Article ID CANCER; MEN AB Prostate-specific antigen (PSA) is a commonly used cancer biomarker for prostate cancer, and is often included as part of routine physical examinations in China. Serum levels of PSA may be influenced by genetic factors as well as other factors. A genome-wide association study (GWAS) conducted in a European population successfully identified six genetic loci that were significantly associated with PSA level. In this study, we aimed to identify common genetic variants that are associated with serum level of PSA in a Chinese population. We also evaluated the effects of those variants by creating personalized PSA cutoff values. A two-stage GWAS of PSA level was performed among men age 20-69 years and self-reported cancer-free participants that underwent routine physical examinations at several hospitals in Guangxi Province, China. Single nucleotide polymorphisms (SNPs) significantly associated with PSA levels in the first stage of sample (N = 1,999) were confirmed in the second stage of sample (N = 1,496). Multivariate linear regression was used to assess the independent contribution of confirmed SNPs and known covariates, such as age, to the level of PSA. SNPs in three regions were significantly associated with levels of PSA in this two-stage GWAS, and had combined P values between 4.62 x 10(-17) and 6.45 x 10(-37). The three regions are located on 1q32.1 at SLC45A3, 10q11.23 at MSMB, and 19q13.33 at KLK3. The region 1q32.1 at SLC45A3 was identified as a novel locus. Genetic variants contributed significantly more to the variance of PSA level than known covariates such as age. Personalized cutoff values of serum PSA, calculated based on the inheritance of these associated SNPs, differ considerably among individuals. Identification of these genetic markers provides new insight into the molecular mechanisms of PSA. Taking individual variation into account, these genetic variants may improve the performance of PSA to predict prostate cancer. C1 [Sun, Jielin; Tao, Sha; Feng, Junjie; Kim, Seong-Tae; Zheng, S. Lilly; Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Gao, Yong; Wu, Yongming; Mo, Linjian; Mo, Zengnan] Guangxi Med Univ, Affiliated Hosp 1, Inst Urol & Nephrol, Nanning 530021, Guangxi, Peoples R China. [Gao, Yong; Tan, Aihua; Zhang, Haiying; Yang, Xiaobo; Qin, Xue; Hu, Yanling; Li, Zhixian; Zhang, Shijun; Mo, Zengnan] Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning 530021, Guangxi, Peoples R China. [Peng, Tao] Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Nanning 530021, Guangxi, Peoples R China. [Peng, Tao] NCI, Lab Genom Divers, NIH, Frederick, MD 21701 USA. [Zhang, Haiying; Yang, Xiaobo] Guangxi Med Univ, Sch Publ Hlth, Dept Occupat Hlth & Environm Hlth, Nanning 530021, Guangxi, Peoples R China. [Qin, Xue] Guangxi Med Univ, Affiliated Hosp 1, Dept Clin Lab, Nanning 530021, Guangxi, Peoples R China. [Hu, Yanling; Li, Li] Guangxi Med Univ, Med Sci Res Ctr, Nanning 530021, Guangxi, Peoples R China. [Lin, Xiaoling; Xu, Jianfeng] Fudan Univ, Sch Life Sci, Fudan VARI Ctr Genet Epidemiol, Shanghai 200433, Peoples R China. [Zhang, Ju] Nankai Univ, Coll Life Sci, Dept Biochem & Mol Biol, State Key Lab Med Chem Biol, Tianjin 300071, 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 530021, Guangxi, Peoples R China. [Xu, Jianfeng] Fudan Univ, Huashan Hosp, Inst Urol, Shanghai 200433, Peoples R China. RP Mo, ZN (reprint author), Guangxi Med Univ, Affiliated Hosp 1, Inst Urol & Nephrol, Nanning 530021, Guangxi, Peoples R China. EM zengnanmo@hotmail.com RI Yang, Xiaobo/G-3854-2016; Kim, Seong-Tae/E-4474-2017 OI Kim, Seong-Tae/0000-0001-7436-1405 FU General Program of National Natural Science Foundation of China [30945204, 30360124, 30260110]; Guangxi Provincial Department of Finance and Education [2009GJCJ150]; Fudan-VARI Center for genetic Epidemiology; Fudan University Institute of Urology FX We thank the local research teams from Fangchenggang First People's Hospital, Guigang People's Hospital and Yulin First People's Hospital for their contribution to the recruitment of study subjects. We thank X-W Zou, H-C Zheng and O Li at the Genergy Biotechnology (Shanghai) Co., Ltd, for their assistance in the genotyping. Finally, we thank all study subjects for participating in the study. This work was partially supported by the General Program of National Natural Science Foundation of China (30945204, 30360124, 30260110), the Guangxi Provincial Department of Finance and Education (2009GJCJ150), and intramural funding from Fudan-VARI Center for genetic Epidemiology and intramural funding from Fudan University Institute of Urology. NR 17 TC 9 Z9 10 U1 2 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD APR PY 2013 VL 132 IS 4 BP 423 EP 429 DI 10.1007/s00439-012-1254-3 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 109DI UT WOS:000316345400006 PM 23269536 ER PT J AU Ballew, BJ Yeager, M Jacobs, K Giri, N Boland, J Burdett, L Alter, BP Savage, SA AF Ballew, Bari J. Yeager, Meredith Jacobs, Kevin Giri, Neelam Boland, Joseph Burdett, Laurie Alter, Blanche P. Savage, Sharon A. TI Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita SO HUMAN GENETICS LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; SYNDROME GENE; T-COFFEE; VARIANTS; CANCER; LENGTH; SUSCEPTIBILITY; ANTICIPATION; MAINTENANCE; COMPLEX AB Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer predisposition syndrome caused by aberrant telomere biology. The classic triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC, but substantial clinical heterogeneity exists; the clinically severe variant Hoyeraal Hreidarsson syndrome (HH) also includes cerebellar hypoplasia, severe immunodeficiency, enteropathy, and intrauterine growth retardation. Germline mutations in telomere biology genes account for approximately one-half of known DC families. Using exome sequencing, we identified mutations in RTEL1, a helicase with critical telomeric functions, in two families with HH. In the first family, two siblings with HH and very short telomeres inherited a premature stop codon from their mother who has short telomeres. The proband from the second family has HH and inherited a premature stop codon in RTEL1 from his father and a missense mutation from his mother, who also has short telomeres. In addition, inheritance of only the missense mutation led to very short telomeres in the proband's brother. Targeted sequencing identified a different RTEL1 missense mutation in one additional DC proband who has bone marrow failure and short telomeres. Both missense mutations affect the helicase domain of RTEL1, and three in silico prediction algorithms suggest that they are likely deleterious. The nonsense mutations both cause truncation of the RTEL1 protein, resulting in loss of the PIP box; this may abrogate an important protein-protein interaction. These findings implicate a new telomere biology gene, RTEL1, in the etiology of DC. C1 [Ballew, Bari J.; Giri, Neelam; Alter, Blanche P.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Yeager, Meredith; Jacobs, Kevin; Boland, Joseph; Burdett, Laurie] NCI, Canc Genom Res Lab, SAIC Frederick Inc, Frederick, MD 20877 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd EPS 7018, Rockville, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Westat, Inc. [N02-CP-91026, N02-CP-11019, HHSN261200655001C] FX This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health and by contracts N02-CP-91026, N02-CP-11019, and HHSN261200655001C with Westat, Inc. NR 36 TC 74 Z9 76 U1 0 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD APR PY 2013 VL 132 IS 4 BP 473 EP 480 DI 10.1007/s00439-013-1265-8 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 109DI UT WOS:000316345400011 PM 23329068 ER PT J AU Perry, JRB Corre, T Esko, T Chasman, DI Fischer, K Franceschini, N He, CY Kutalik, Z Mangino, M Rose, LM Smith, AV Stolk, L Sulem, P Weedon, MN Zhuang, WV Arnold, A Ashworth, A Bergmann, S Buring, JE Burri, A Chen, C Cornelis, MC Couper, DJ Goodarzi, MO Gudnason, V Harris, T Hofman, A Jones, M Kraft, P Launer, L Laven, JSE Li, G McKnight, B Masciullo, C Milani, L Orr, N Psaty, BM Ridker, PM Rivadeneira, F Sala, C Salumets, A Schoemaker, M Traglia, M Waeber, G Chanock, SJ Demerath, EW Garcia, M Hankinson, SE Hu, FB Hunter, DJ Lunetta, KL Metspalu, A Montgomery, GW Murabito, JM Newman, AB Ong, KK Spector, TD Stefansson, K Swerdlow, AJ Thorsteinsdottir, U Van Dam, RM Uitterlinden, AG Visser, JA Vollenweider, P Toniolo, D Murray, A AF Perry, John R. B. Corre, Tanguy Esko, Tonu Chasman, Daniel I. Fischer, Krista Franceschini, Nora He, Chunyan Kutalik, Zoltan Mangino, Massimo Rose, Lynda M. Smith, Albert Vernon Stolk, Lisette Sulem, Patrick Weedon, Michael N. Zhuang, Wei V. Arnold, Alice Ashworth, Alan Bergmann, Sven Buring, Julie E. Burri, Andrea Chen, Constance Cornelis, Marilyn C. Couper, David J. Goodarzi, Mark O. Gudnason, Vilmundur Harris, Tamara Hofman, Albert Jones, Michael Kraft, Peter Launer, Lenore Laven, Joop S. E. Li, Guo McKnight, Barbara Masciullo, Corrado Milani, Lili Orr, Nicholas Psaty, Bruce M. Ridker, Paul M. Rivadeneira, Fernando Sala, Cinzia Salumets, Andres Schoemaker, Minouk Traglia, Michela Waeber, Gerard Chanock, Stephen J. Demerath, Ellen W. Garcia, Melissa Hankinson, Susan E. Hu, Frank B. Hunter, David J. Lunetta, Kathryn L. Metspalu, Andres Montgomery, Grant W. Murabito, Joanne M. Newman, Anne B. Ong, Ken K. Spector, Tim D. Stefansson, Kari Swerdlow, Anthony J. Thorsteinsdottir, Unnur Van Dam, Rob M. Uitterlinden, Andre G. Visser, Jenny A. Vollenweider, Peter Toniolo, Daniela Murray, Anna CA ReproGen Consortium TI A genome-wide association study of early menopause and the combined impact of identified variants SO HUMAN MOLECULAR GENETICS LA English DT Article ID PREMATURE OVARIAN FAILURE; NATURAL MENOPAUSE; AGE; LOCI; HERITABILITY; DAUGHTERS; SMOKING; MOTHERS AB Early menopause (EM) affects up to 10 of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for 30 of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking. C1 [Perry, John R. B.; Weedon, Michael N.; Murray, Anna] Univ Exeter, Sch Med, Exeter EX1 2LU, Devon, England. [Perry, John R. B.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Perry, John R. B.; Mangino, Massimo; Burri, Andrea; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Corre, Tanguy; Kutalik, Zoltan; Bergmann, Sven] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Corre, Tanguy; Kutalik, Zoltan; Bergmann, Sven] Swiss Inst Bioinformat, Lausanne, Switzerland. [Corre, Tanguy; Masciullo, Corrado; Sala, Cinzia; Traglia, Michela; Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Esko, Tonu; Fischer, Krista; Milani, Lili; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Salumets, Andres] Univ Tartu, Dept Obstet & Gynecol, EE-50090 Tartu, Estonia. [Chasman, Daniel I.; Rose, Lynda M.; Buring, Julie E.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Chasman, Daniel I.; Buring, Julie E.; Kraft, Peter; Ridker, Paul M.; Hankinson, Susan E.; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Couper, David J.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [He, Chunyan] Indiana Univ Sch Med, Dept Publ Hlth, Indianapolis, IN USA. [He, Chunyan] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Stolk, Lisette; Rivadeneira, Fernando; Uitterlinden, Andre G.; Visser, Jenny A.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Hofman, Albert; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Laven, Joop S. E.] Erasmus MC, Div Reprod Med, Rotterdam, Netherlands. [Stolk, Lisette; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] Netherlands Consortium Hlth Aging, Rotterdam, Netherlands. [Sulem, Patrick; Stefansson, Kari; Thorsteinsdottir, Unnur] Decode Genet, IS-105 Reykjavik, Iceland. [Zhuang, Wei V.; Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Arnold, Alice; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Li, Guo; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Ashworth, Alan; Orr, Nicholas] Inst Canc Res, Breakthrough Res Ctr, London SW3 6JB, England. [Buring, Julie E.; Ridker, Paul M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Chen, Constance; Kraft, Peter; Hankinson, Susan E.; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cornelis, Marilyn C.; Kraft, Peter; Hu, Frank B.; Hunter, David J.; Van Dam, Rob M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Bethesda, MD USA. [Harris, Tamara; Launer, Lenore; Garcia, Melissa] NIA, NIH, Bethesda, MD 20892 USA. [Jones, Michael; Schoemaker, Minouk; Swerdlow, Anthony J.] Inst Canc Res, Epidemiol Sect, Sutton SM2 5NG, Surrey, England. [Kraft, Peter; Hankinson, Susan E.; Hu, Frank B.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Salumets, Andres] Competence Ctr Reprod Med & Biol, Tartu, Estonia. [Waeber, Gerard; Vollenweider, Peter] CHU Vaudois, Univ Lausanne Hosp, Div Internal Med, Lausanne, Switzerland. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Demerath, Ellen W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Montgomery, Grant W.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Ong, Ken K.] Addenbrookes Hosp, Inst Metab Sci, Epidemiol Unit, MRC, Cambridge, England. [Ong, Ken K.] Univ Cambridge, Dept Paediat, Cambridge, England. [Van Dam, Rob M.] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Van Dam, Rob M.] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 117595, Singapore. [Toniolo, Daniela] Inst Mol Genet, I-27100 Pavia, Italy. RP Murray, A (reprint author), Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX1 2LU, Devon, England. EM anna.murray@pms.ac.uk RI Smith, Albert Vernon/K-5150-2015; Montgomery, Grant/B-7148-2008; Rivadeneira, Fernando/O-5385-2015; mangino, massimo/F-5134-2011; Colaus, PsyColaus/K-6607-2013; van Dam, Rob/F-9674-2010; Newman, Anne/C-6408-2013; Visser, Jenny /F-8156-2011; Salumets, Andres/J-2278-2015; Milani, Lili/C-8759-2011; Gudnason, Vilmundur/K-6885-2015; OI Murray, Anna/0000-0002-2351-2522; Schoemaker, Minouk/0000-0001-8403-2234; Esko, Tonu/0000-0003-1982-6569; Smith, Albert Vernon/0000-0003-1942-5845; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441; mangino, massimo/0000-0002-2167-7470; Murabito, Joanne/0000-0002-0192-7516; Lunetta, Kathryn/0000-0002-9268-810X; van Dam, Rob/0000-0002-7354-8734; Newman, Anne/0000-0002-0106-1150; Salumets, Andres/0000-0002-1251-8160; Milani, Lili/0000-0002-5323-3102; Gudnason, Vilmundur/0000-0001-5696-0084; MARONGIU, MARA/0000-0002-7321-2384 FU Wellcome Trust [092447/Z/10/Z] FX J.R.B.P. is funded by the Wellcome Trust as a Sir Henry Wellcome Postdoctoral Research Fellow (092447/Z/10/Z). Funding details for individual studies is provided in supplementary information. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 26 TC 33 Z9 34 U1 2 U2 17 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 APR 1 PY 2013 VL 22 IS 7 BP 1465 EP 1472 DI 10.1093/hmg/dds551 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 108MH UT WOS:000316297000018 PM 23307926 ER PT J AU Galis, ZS Thrasher, T Reid, DM Stanley, DV Oh, YS AF Galis, Zorina S. Thrasher, Terry Reid, Diane M. Stanley, Dennis V. Oh, Young S. TI Investing in High Blood Pressure Research A National Institutes of Health Perspective SO HYPERTENSION LA English DT Review ID HEART; HYPERTENSION; LUNG; ASSOCIATION; DISEASE; RISK C1 [Galis, Zorina S.; Thrasher, Terry; Reid, Diane M.; Stanley, Dennis V.; Oh, Young S.] NHLBI, Div Cardiovasc Sci, Vasc Biol & Hypertens Branch, NIH, Bethesda, MD 20892 USA. RP Galis, ZS (reprint author), NHLBI, Vasc Biol & Hypertens Branch, Div Cardiovasc Sci, 6701 Rockledge Dr,8116, Bethesda, MD 20892 USA. EM zorina.galis@nih.gov NR 32 TC 13 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2013 VL 61 IS 4 BP 757 EP + DI 10.1161/HYPERTENSIONAHA.111.00770 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 106AC UT WOS:000316112800014 PM 23438933 ER PT J AU Mewton, N Opdahl, A Choi, EY Almeida, ALC Kawel, N Wu, CO Burke, GL Liu, ST Liu, K Bluemke, DA Lima, JAC AF Mewton, Nathan Opdahl, Anders Choi, Eui-Young Almeida, Andre L. C. Kawel, Nadine Wu, Colin O. Burke, Gregory L. Liu, Songtao Liu, Kiang Bluemke, David A. Lima, Joao A. C. TI Left Ventricular Global Function Index by Magnetic Resonance Imaging-A Novel Marker for Assessment of Cardiac Performance for the Prediction of Cardiovascular Events The Multi-Ethnic Study of Atherosclerosis SO HYPERTENSION LA English DT Article DE ejection fraction; heart failure; left ventricle; LV global function index; LV mass ID HYPERTENSIVE HEART-DISEASE; EJECTION FRACTION; MYOCARDIAL FIBROSIS; SYSTOLIC FUNCTION; RISK-FACTORS; FAILURE; MASS; GEOMETRY; OUTCOMES; DYSFUNCTION AB Left ventricular (LV) function is generally assessed independent of structural remodeling and vice versa. The purpose of this study was to evaluate a novel LV global function index (LVGFI) that integrates LV structure with global function and to assess its predictive value for cardiovascular (CV) events throughout adult life in a multiethnic population of men and women without history of CV diseases at baseline. A total of 5004 participants in the Multi-Ethnic Study of Atherosclerosis underwent a cardiac magnetic resonance study and were followed up for a median of 7.2 years. The LVGFI by cardiac magnetic resonance was defined by the ratio of stroke volume divided by LV total volume defined as the sum of mean LV cavity and myocardial volumes. Cox proportional hazard models were constructed to predict the end points of heart failure, hard CV events, and a combined end point of all CV events after adjustment for established risk factors, calcium score, and biomarkers. A total of 579 (11.6%) CV events were observed during the follow-up period. In adjusted models, the end points of heart failure, hard CV events, and all events were all significantly associated with LVGFI (heart failure, hazard ratio=0.64, P<0.0001; hard CV events, hazard ratio=0.79, P=0.007; all events, hazard ratio=0.79, P<0.0001). LVGFI had a significant independent predictive value in the multivariable models for all CV event categories. The LVGFI was a powerful predictor of incident HF, hard CV events, and a composite end point, including all events in this multiethnic cohort. (Hypertension. 2013;61:770-778.). Online Data Supplement C1 [Mewton, Nathan; Opdahl, Anders; Choi, Eui-Young; Almeida, Andre L. C.; Lima, Joao A. C.] Johns Hopkins Univ Hosp, Sch Med, Div Cardiol, Dept Med, Baltimore, MD 21287 USA. [Wu, Colin O.] NHLBI, Bethesda, MD 20892 USA. [Burke, Gregory L.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Liu, Songtao; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Kawel, Nadine] NIH, Bethesda, MD 20892 USA. [Mewton, Nathan] Hop Cardiovasc & Pneumol Louis Pradel, Ctr Invest, Clin Lyon, Lyon, France. [Opdahl, Anders] Oslo Univ Hosp, Rikshosp, Dept Cardiol, Oslo, Norway. RP Lima, JAC (reprint author), Johns Hopkins Univ Hosp, 600 North Wolfe St,Blalock 524D1, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Opdahl, Anders/I-7580-2015; OI Opdahl, Anders/0000-0002-0599-592X; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute supported [N01-HC-95159, N01-HC-95169]; French Federation of Cardiology; Raagholt Research Foundation; Norwegian Cardiovascular Society; Musaeus Aarsvold Foundation; US-Norway Fulbright Foundation; Sorensen Research Foundation, Oslo, Norway FX The National Heart, Lung, and Blood Institute supported this project (contracts N01-HC-95159 through N01-HC-95169). The French Federation of Cardiology supported Dr Nathan Mewton with a Post-Doctoral Research Grant at the Johns Hopkins Hospital. The Raagholt Research Foundation supported Dr Anders Opdahl with a Post-Doctoral Research Grant at the Johns Hopkins Hospital. The Norwegian Cardiovascular Society supported Dr Anders Opdahl with a Post-Doctoral Research Grant at the Johns Hopkins Hospital. The Musaeus Aarsvold Foundation supported Dr Anders Opdahl with a Post-Doctoral Research Grant at the Johns Hopkins Hospital. The US-Norway Fulbright Foundation supported Dr Anders Opdahl with a Post-Doctoral Research Grant at the Johns Hopkins Hospital. The Sorensen Research Foundation, Oslo, Norway, supported Dr Anders Opdahl with a Post-Doctoral Research Grant at the Johns Hopkins Hospital. NR 31 TC 19 Z9 20 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2013 VL 61 IS 4 BP 770 EP + DI 10.1161/HYPERTENSIONAHA.111.198028 PG 18 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 106AC UT WOS:000316112800018 PM 23424238 ER PT J AU Saveria, T Oleinikov, AV Wiliamson, K Chaturvedi, R Lograsso, J Keitany, GJ Fried, M Duffy, P AF Saveria, Tracy Oleinikov, Andrew V. Wiliamson, Kathryn Chaturvedi, Richa Lograsso, Joe Keitany, Gladys J. Fried, Michal Duffy, Patrick TI Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue SO INFECTION AND IMMUNITY LA English DT Article ID PREGNANCY-ASSOCIATED MALARIA; CROSS-REACTIVE ANTIBODIES; CHONDROITIN-SULFATE; INFECTED ERYTHROCYTES; BLOCKING ANTIBODIES; VAR GENE; ADHESION; PFEMP1; TRANSCRIPTION; TRANSMISSION AB Placental malaria (PM) is characterized by infected erythrocytes (IEs) that selectively bind to chondroitin sulfate A (CSA) and sequester in placental tissue. Variant surface antigen 2-CSA (VAR2CSA), a Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) protein family member, is expressed on the surface of placental IEs and mediates adherence to CSA on the surface of syncytiotrophoblasts. This transmembrane protein contains 6 Duffy binding-like (DBL) domains which might contribute to the specific adhesive properties of IEs. Here, we use laboratory isolate 3D7 VAR2CSA DBL domains expressed in Escherichia coli to generate antibodies specific for this protein. Flow cytometry results showed that antibodies generated against DBL4 epsilon, DBL5 epsilon, DBL6 epsilon, and tandem double domains of DBL4-DBL5 and DBL5-DBL6 all bind to placental parasite isolates and to lab strains selected for CSA binding but do not bind to children's parasites. Antisera to DBL4 epsilon and to DBL5 epsilon inhibit maternal IE binding to placental tissue in a manner comparable to that for plasma collected from multigravid women. These antibodies also inhibit binding to CSA of several field isolates derived from pregnant women, while antibodies to double domains do not enhance the functional immune response. These data support DBL4 epsilon and DBL5 epsilon as vaccine candidates for pregnancy malaria and demonstrate that E. coli is a feasible tool for the large-scale manufacture of a vaccine based on these VAR2CSA domains. C1 [Saveria, Tracy; Oleinikov, Andrew V.; Wiliamson, Kathryn; Chaturvedi, Richa; Lograsso, Joe; Keitany, Gladys J.; Duffy, Patrick] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Fried, Michal; Duffy, Patrick] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Fried, Michal; Duffy, Patrick] Univ Washington, Dept Global Hlth, Program Pathobiol, Seattle, WA 98195 USA. RP Duffy, P (reprint author), Seattle Biomed Res Inst, 4 Nickerson St, Seattle, WA 98109 USA. EM patrick.duffy@nih.gov FU Bill and Melinda Gates Foundation FX Support for this work was provided by a grant from the Bill and Melinda Gates Foundation. NR 38 TC 5 Z9 5 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2013 VL 81 IS 4 BP 1031 EP 1039 DI 10.1128/IAI.00978-12 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 108RM UT WOS:000316313700002 PM 23319559 ER PT J AU Fukuda, Y Tsai, HF Myers, TG Bennett, JE AF Fukuda, Yuichi Tsai, Huei-Fung Myers, Timothy G. Bennett, John E. TI Transcriptional Profiling of Candida glabrata during Phagocytosis by Neutrophils and in the Infected Mouse Spleen SO INFECTION AND IMMUNITY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; OXIDATIVE STRESS; GENE-EXPRESSION; ALBICANS; DEGRADATION; RESISTANCE; VIRULENCE; PATHWAYS; MICE AB Expression microarray analysis of Candida glabrata following phagocytosis by human neutrophils was performed, and results were compared with those from C. glabrata incubated under conditions of carbohydrate or nitrogen deprivation. Twenty genes were selected to represent the major cell processes altered by phagocytosis or nutrient deprivation. Quantitative real-time PCR (qRT-PCR) with TaqMan chemistry was used to assess expression of the same genes in spleens of mice infected intravenously with Candida glabrata. The results in spleen closely paralleled gene expression in neutrophils or following carbohydrate deprivation. Fungal cells responded by upregulating alternative energy sources through gluconeogenesis, glyoxylate cycle, and long-chain fatty acid metabolism. Autophagy was likely employed to conserve intracellular resources. Aspartyl protease upregulation occurred and may represent defense against attacks on cell wall integrity. Downregulated genes were in the pathways of protein and ergosterol synthesis. Upregulation of the sterol transport gene AUS1 suggested that murine cholesterol may have been used to replace ergosterol, as has been reported in vitro. C. glabrata isolates in spleens of gp91(phox-/-) knockout mice with reduced oxidative phagocyte defenses were grossly similar although with a reduced level of response. These results are consistent with reported results of other fungi responding to phagocytosis, indicating that a rapid shift in metabolism is required for growth in a carbohydrate-limited intracellular environment. C1 [Fukuda, Yuichi; Tsai, Huei-Fung; Bennett, John E.] NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Myers, Timothy G.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov FU Division of Intramural Research, NIAID FX This work was supported by the Division of Intramural Research, NIAID. NR 32 TC 12 Z9 35 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2013 VL 81 IS 4 BP 1325 EP 1333 DI 10.1128/IAI00851-12 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 108RM UT WOS:000316313700029 PM 23403555 ER PT J AU Wu, YZ Antony, S Hewitt, SM Jiang, GJ Yang, SX Meitzler, JL Juhasz, A Lu, JM Liu, H Doroshow, JH Roy, K AF Wu, Yonghzong Antony, Smitha Hewitt, Stephen M. Jiang, Guojian Yang, Sherry X. Meitzler, Jennifer L. Juhasz, Agnes Lu, Jiamo Liu, Han Doroshow, James H. Roy, Krishnendu TI Functional activity and tumor-specific expression of dual oxidase 2 in pancreatic cancer cells and human malignancies characterized with a novel monoclonal antibody SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE dual oxidase; NADPH oxidase; reactive oxygen species; pancreatic cancer; gene expression ID GENE-EXPRESSION; HYDROGEN-PEROXIDE; NADPH OXIDASES; DUOX GENES; INFLAMMATION; PROTEINS; ADJACENT; TISSUES; ROS AB Dual oxidase 2 (Duox2), one of the seven members of the NADPH oxidase gene family, plays a critical role in generating H2O2, for thyroid hormone biosynthesis and as an integral part of the host defense system of the respiratory epithelium and the gastrointestinal tract. Recent evidence suggests that the regulation of Duox2 expression is under the control of pro-inflammatory cytokines and that Duox2-induced reactive oxygen species (ROS) contribute to the inflammation-related tissue injury that occurs in two pre-malignant, inflammatory conditions: chronic pancreatitis and inflammatory bowel disease. Because no reliable Duox antibodies are commercially available, we report the development of a murine monoclonal antibody (MAb) to Duox2 (clone Duox S-12) and its use for the characterization of Duox2 expression in human tumors, tumor cell lines and normal tissues. Duox S-12 specifically detected both endogenously- and ectopically-expressed Duox2 protein by immunoblotting, immunofluorescence microscopy and immunohistochemistry (where both membranous and cytoplasmic staining were present). Duox2 expression detected by Duox S-12 was functionally coupled to the generation of H2O2, in pancreatic cancer cells that expressed Duox2 and its cognate maturation factor DuoxA2. Although Duox S-12 recognizes ectopically expressed Duox1 protein because of the extensive amino acid homology between Duox1 and Duox2, the lack of substantial Duoxl mRNA expression in human tumors (except thyroid cancer) allowed us to evaluate Duox2 expression across a wide range of normal and malignant tissues by immunohistochemistry. Duox2 was expressed at elevated levels in many human cancers, most notably tumors of the prostate, lung, colon and breast while brain tumors and lymphomas demonstrated the lowest frequency of expression. The Duox-specific monoclonal antibody described here provides a promising tool for the further examination of the role of Duox-dependent reactive oxygen production in inflammation-related carcinogenesis, where alterations in oxidant tone play a critical role in cell growth and proliferation. C1 [Wu, Yonghzong; Antony, Smitha; Jiang, Guojian; Meitzler, Jennifer L.; Juhasz, Agnes; Lu, Jiamo; Liu, Han; Doroshow, James H.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yang, Sherry X.; Meitzler, Jennifer L.; Doroshow, James H.; Roy, Krishnendu] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, Bldg 31,Room 3A-44,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Division of Cancer Treatment and Diagnosis; Center for Cancer Research of the National Cancer Institute, National Institutes of Health FX This study was supported by the Division of Cancer Treatment and Diagnosis and the Center for Cancer Research of the National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. In addition, we wish to thank Dr Thomas Leto of the National Institute of Allergy and Infectious Diseases, NIH for his kind gift of the HA-Duox1 plasmid and Dr Helmut Grasberger, of the University of Michigan, for his kind gift of the HA-Duox2 and Myc-DuoxA2 plasmids. NR 25 TC 12 Z9 12 U1 1 U2 10 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD APR PY 2013 VL 42 IS 4 BP 1229 EP 1238 DI 10.3892/ijo.2013.1821 PG 10 WC Oncology SC Oncology GA 111HA UT WOS:000316511200013 PM 23404210 ER PT J AU Azad, N Dasari, A Arcaroli, J Taylor, GE Laheru, DA Carducci, MA McManus, M Quackenbush, K Wright, JJ Hidalgo, M Diaz, LA Donehower, RC Zhao, M Rudek, MA Messersmith, WA AF Azad, Nilofer Dasari, Arvind Arcaroli, John Taylor, Gretchen E. Laheru, Daniel A. Carducci, Michael A. McManus, Martine Quackenbush, Kevin Wright, John J. Hidalgo, Manuel Diaz, Luis A., Jr. Donehower, Ross C. Zhao, Ming Rudek, Michelle A. Messersmith, Wells A. TI Phase I pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Sorafenib; Cetuximab; Irinotecan; Pharmacokinetics; Colorectal cancer ID ENDOTHELIAL GROWTH-FACTOR; ANTITUMOR-ACTIVITY; SOLID TUMORS; PLUS IRINOTECAN; RAS MUTATIONS; III TRIAL; CHEMOTHERAPY; COMBINATION; RECEPTOR; BEVACIZUMAB AB Background This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC). Methods Patients with metastatic, pretreated CRC were treated at five dose levels. Results Eighteen patients were recruited with median age 56.5 years. In the first five patients treated, 2 irinotecan related DLTs were observed. With reduced dose intensity irinotecan, there were no further DLTs. The most common toxicities were diarrhea, nausea/vomiting, fatigue, anorexia and rash. DLTs included neutropenia and thrombocytopenia. Two patients had partial responses (one with a KRAS mutation) and 8 had stable disease (8-36 weeks). The median progression free survival (PFS) and overall survival (OS) were 2.5 and 4.7 months respectively. Pharmacokinetic analyses suggest sorafenib and metabolite exposure correlate with OS and DLTs. Conclusions The recommended phase II dose (RP2D) is irinotecan 100 mg/m(2) i.v. days 1, 8; cetuximab 400 mg/m(2) i.v. days 1 and 250 mg/m(2) i.v. weekly; and sorafenib 400 mg orally twice daily in advanced, pretreated CRC. The combination resulted in a modest response rate. C1 [Azad, Nilofer; Taylor, Gretchen E.; Laheru, Daniel A.; Carducci, Michael A.; Hidalgo, Manuel; Diaz, Luis A., Jr.; Donehower, Ross C.; Zhao, Ming; Rudek, Michelle A.] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Dasari, Arvind; Arcaroli, John; McManus, Martine; Quackenbush, Kevin; Messersmith, Wells A.] Univ Colorado, Ctr Canc, Aurora, CO 80045 USA. [Wright, John J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Rudek, MA (reprint author), Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Bunting Blaustein Canc Res Bldg,Room 1M52,1650 Or, Baltimore, MD 21231 USA. EM mrudek2@jhmi.edu; Wells.Messersmith@ucdenver.edu RI HIDALGO, MANUEL/I-4995-2015 OI HIDALGO, MANUEL/0000-0002-3765-3318 FU NIH/NCI [1K23CA115500, 1R21CA117125, U01 CA070095]; Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH) [P30 CA006973, UL1 RR025005]; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1RR025005]; NIH Roadmap for Medical Research; Bayer (major) via University of Colorado Cancer Center FX This research was supported by NIH/NCI grant 1K23CA115500 (WM), 1R21CA117125 (WM), U01 CA070095 (MC), and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005). This publication was made possible by Grant Number UL1RR025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.; Dr. Messersmith has received commercial clinical research grant support from Bayer (major) via University of Colorado Cancer Center. NR 34 TC 5 Z9 6 U1 1 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD APR PY 2013 VL 31 IS 2 BP 345 EP 354 DI 10.1007/s10637-012-9820-z PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 105OQ UT WOS:000316081900010 PM 22615057 ER PT J AU Stewart, BA Klar, AJS AF Stewart, Barbara A. Klar, Amar J. S. TI Can Bronchoscopic Airway Anatomy Be an Indicator of Autism? SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Autism spectrum disorder etiology; Doublets; Airway double branching; Airway anomaly ID SPECTRUM DISORDERS; EARLY INTERVENTION; DIAGNOSIS; CHILDREN; DEFINITION; PREVALENCE; LOBE; AGE AB Bronchoscopic evaluations revealed that some children have double branching of bronchi (designated "doublets") in the lower lungs airways, rather than normal, single branching. Retrospective analyses revealed only one commonality in them: all subjects with doublets also had autism or autism spectrum disorder (ASD). That is, 49 subjects exhibited the presence of initial normal anatomy in upper airway followed by doublets in the lower airway. In contrast, the normal branching pattern was noted in all the remaining 410 subjects who did not have a diagnosis of autism/ASD. We propose that the presence of doublets might be an objective, reliable, and valid biologic marker of autism/ASD. C1 [Stewart, Barbara A.] St Josephs Hosp, Pediat Pulm Dept, Childrens Hlth Ctr, Phoenix, AZ 85013 USA. [Klar, Amar J. S.] NIH, Gene Regulat & Chromosome Biol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Stewart, BA (reprint author), St Josephs Hosp, Pediat Pulm Dept, Childrens Hlth Ctr, Phoenix, AZ 85013 USA. EM tinkdoc@cox.net; klara@mail.nih.gov FU Intramural NIH HHS NR 37 TC 1 Z9 1 U1 2 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD APR PY 2013 VL 43 IS 4 BP 911 EP 916 DI 10.1007/s10803-012-1635-4 PG 6 WC Psychology, Developmental SC Psychology GA 109KG UT WOS:000316365400015 PM 22926922 ER PT J AU Prasad, V Jorgenson, J Ioannidis, JPA Cifu, A AF Prasad, Vinay Jorgenson, Joel Ioannidis, John P. A. Cifu, Adam TI Observational studies often make clinical practice recommendations: an empirical evaluation of authors' attitudes SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Review DE Epidemiology; Clinical trials; Observational studies; Randomized trials; Hierarchy of research design; Reversal ID CONTROLLED-TRIALS; MEDICAL REVERSAL; CANCER; EPIDEMIOLOGY; FALSE AB Objectives: Although observational studies provide useful descriptive and correlative information, their role in the evaluation of medical interventions remains contentious. There has been no systematic evaluation of authors' attitudes toward their own nonrandomized studies and how often they recommend specific medical practices. Study Design and Setting: We reviewed all original articles of nonrandomized studies published in 2010 in New England Journal of Medicine, Lancet, Journal of the American Medical Association, and Annals of Internal Medicine, We classified articles based on whether authors recommend a medical practice and whether they state that a randomized trial is needed to support their recommendation. We also examined the types of logical extrapolations used by authors who did advance recommendations. Results: Of the 631 original articles published in 2010, 298 (47%) articles were eligible observational studies. In 167 (56%) of 298 studies, authors recommended a medical practice based on their results. Only 24 (14%) of 167 studies stated that a randomized controlled trial (RCT) should be done to validate the recommendation, whereas the other 143 articles made a total of 149 logical extrapolations to recommend specific medical practices. Recommendations without a call for a randomized trial were most common in studies of modifiable factors (59%), but they were also common in studies reporting incidence or prevalence (51%), studies examining novel tests (41%), and association studies of nonmodifiable factors (32%). Conclusion: The authors of observational studies often extrapolate their results to make recommendations concerning a medical practice, typically without first calling for a RCT. Published by Elsevier Inc. C1 [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Jorgenson, Joel] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Cifu, Adam] Univ Chicago, Med Ctr, Dept Med, Pritzker Sch Med, Chicago, IL 60637 USA. RP Cifu, A (reprint author), Univ Chicago, Med Ctr, Dept Med, Pritzker Sch Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM acifu@medicine.bsd.uchicago.edu NR 33 TC 27 Z9 27 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD APR PY 2013 VL 66 IS 4 BP 361 EP 366 DI 10.1016/j.jclinepi.2012.11.005 PG 6 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 103QX UT WOS:000315935100004 PM 23384591 ER PT J AU Austin, PC Tu, JV Ho, JE Levy, D Lee, DS AF Austin, Peter C. Tu, Jack V. Ho, Jennifer E. Levy, Daniel Lee, Douglas S. TI Using methods from the data-mining and machine-learning literature for disease classification and prediction: a case study examining classification of heart failure subtypes SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Boosting; Classification trees; Bagging; Random forests; Classification; Regression trees; Support vector machines; Regression methods; Prediction; Heart failure ID REDUCED EJECTION FRACTION; LOGISTIC-REGRESSION; MORTALITY; TREES AB Objective: Physicians classify patients into those with or without a specific disease. Furthermore, there is often interest in classifying patients according to disease etiology or subtype. Classification trees are frequently used to classify patients according to the presence or absence of a disease. However, classification trees can suffer from limited accuracy. In the data-mining and machine-learning literature, alternate classification schemes have been developed. These include bootstrap aggregation (bagging), boosting, random forests, and support vector machines. Study Design and Setting: We compared the performance of these classification methods with that of conventional classification trees to classify patients with heart failure (HF) according to the following subtypes: HF with preserved ejection fraction (HFPEF) and HF with reduced ejection fraction. We also compared the ability of these methods to predict the probability of the presence of HFPEF with that of conventional logistic regression. Results: We found that modern, flexible tree-based methods from the data-mining literature offer substantial improvement in prediction and classification of HF subtype compared with conventional classification and regression trees. However, conventional logistic regression had superior performance for predicting the probability of the presence of HFPEF compared with the methods proposed in the data-mining literature. Conclusion: The use of tree-based methods offers superior performance over conventional classification and regression trees for predicting and classifying HF subtypes in a population-based sample of patients from Ontario, Canada. However, these methods do not offer substantial improvements over logistic regression for predicting the presence of HFPEF. (C) 2013 Elsevier Inc. All rights reserved. C1 [Austin, Peter C.; Tu, Jack V.; Lee, Douglas S.] Inst Clin Evaluat Sci, Toronto, ON M4N 3M5, Canada. [Austin, Peter C.; Tu, Jack V.; Lee, Douglas S.] Univ Toronto, Inst Hlth Management Policy & Evaluat, Toronto, ON, Canada. [Austin, Peter C.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Tu, Jack V.] Univ Toronto, Div Cardiol, Sunnybrook Schulich Heart Ctr, Toronto, ON, Canada. [Tu, Jack V.; Lee, Douglas S.] Univ Toronto, Fac Med, Toronto, ON, Canada. [Ho, Jennifer E.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ho, Jennifer E.; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Ho, Jennifer E.] Boston Univ, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Levy, Daniel] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Lee, Douglas S.] Univ Toronto, Univ Hlth Network, Dept Med, Toronto, ON, Canada. RP Austin, PC (reprint author), Inst Clin Evaluat Sci, G106,2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. EM peter.austin@ices.on.ca RI Lee, Douglas/J-4315-2014; OI Ho, Jennifer/0000-0002-7987-4768; Austin, Peter/0000-0003-3337-233X FU Institute for Clinical Evaluative Sciences (ICES); Ontario Ministry of Health and Long-Term Care (MOHLTC); Canadian Institutes of Health Research (CIHR) [MOP 86508]; Heart and Stroke Foundation; Canada Research Chair in Health Services Research; Career Investigator Award from the Heart and Stroke Foundation; CIHR Team Grant in Cardiovascular Outcomes Research FX This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. This research was supported by an operating grant from the Canadian Institutes of Health Research (CIHR) (MOP 86508). Dr Austin is supported in part by a Career Investigator award from the Heart and Stroke Foundation. Dr Tu is supported by a Canada Research Chair in Health Services Research and a Career Investigator Award from the Heart and Stroke Foundation. Dr Lee is a clinician-scientist of the CIHR. The data used in this study were obtained from the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study. The EFFECT study was funded by a CIHR Team Grant in Cardiovascular Outcomes Research. NR 38 TC 28 Z9 28 U1 5 U2 37 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD APR PY 2013 VL 66 IS 4 BP 398 EP 407 DI 10.1016/j.jclinepi.2012.11.008 PG 10 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 103QX UT WOS:000315935100010 PM 23384592 ER PT J AU Hamidovic, A Goodloe, RJ Young, TR Styn, MA Mukamal, KJ Choquet, H Kasberger, JL Buxbaum, SG Papanicolaou, GJ White, W Volcik, K Spring, B Hitsman, B Levy, D Jorgenson, E AF Hamidovic, Ajna Goodloe, Robert J. Young, Taylor R. Styn, Mindi A. Mukamal, Kenneth J. Choquet, Helene Kasberger, Jay L. Buxbaum, Sarah G. Papanicolaou, George J. White, Wendy Volcik, Kelly Spring, Bonnie Hitsman, Brian Levy, Daniel Jorgenson, Eric TI Genetic Analysis of a Population Heavy Drinking Phenotype Identifies Risk Variants in Whites SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE alcohol consumption; alcoholism; cholecystokinin; methylenetetrahydrofolate dehydrogenase ID GENOME-WIDE ASSOCIATION; ALCOHOL-CONSUMPTION; PLASMA HOMOCYSTEINE; ENVIRONMENTAL CONTRIBUTIONS; ANTISOCIAL PERSONALITY; CHOLECYSTOKININ GENE; PROMOTER REGION; FEMALE TWINS; SAMPLE; DEPENDENCE AB Genetic association studies thus far have used detailed diagnoses of alcoholism to identify loci associated with risk. This proof-of-concept analysis examined whether population data of lifetime heaviest alcohol consumption may be used to identify genetic loci that modulate risk We conducted a genetic association study in European Americans between variants in approximately 2100 genes and alcohol consumption as part of the Candidate gene Association Resource project. We defined cases as individuals with a history of drinking 5 or more drinks per day almost every day of the week and controls as current light drinkers (1-5 drinks per week). We cross-validated identified single nucleotide polymorphisms in a meta-analysis of 2 cohorts of unrelated individuals-Atherosclerosis Risk in. Communities (ARIC) and Cardiovascular Health Study (CHS)-and in a separate cohort of related individuals -Framingham Heart Study (FHS). The most significant variant in the meta-analysis of ARIC and CHS was rs6933598 in methylenetetrahydrofolate dehydrogenase (P = 7.46 x 10(-05)) with a P value in FHS of 0.042. The top variants in FITS were rs12249562 in cubulin (P = 3.03 x 10(-05)) and rs9839267 near chole-cystoldnin (P = 3.05 x 10(-05)) with a P value of 0.019 for rs9839267 in CHS. We have here shown feasibility in evaluating lifetime incidence of heavy alcohol drinking from population-based studies for the purpose of conducting genetic association analyses. C1 [Hamidovic, Ajna; Spring, Bonnie; Hitsman, Brian] Northwestern Univ, Chicago, IL 60611 USA. [Goodloe, Robert J.; Jorgenson, Eric] Vanderbilt Univ, Med Ctr, Ctr Human Genet, Nashville, TN USA. [Young, Taylor R.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Styn, Mindi A.] Univ Pittsburgh, Sch Nursing, Dept Hlth & Community Syst, Pittsburgh, PA 15261 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Choquet, Helene; Kasberger, Jay L.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, San Francisco, CA 94143 USA. [Buxbaum, Sarah G.] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. [Papanicolaou, George J.] NHLBI, Div Cardiovasc Sci, Prevent & Populat Sci Program, Bethesda, MD 20892 USA. [White, Wendy] Tougaloo Coll, Nat Sci Div, Tougaloo, MS USA. [Volcik, Kelly] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Human Genet Ctr, Houston, TX USA. [Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Hamidovic, A (reprint author), Northwestern Univ, 680 N Lakeshore Dr,Suite 1400, Chicago, IL 60611 USA. EM a-hamidovic@northwestern.edu RI Buxbaum, Sarah/E-1970-2013 OI Buxbaum, Sarah/0000-0002-4886-3564 FU MD Scientist Fellowship in Genetic Medicine (Northerstern Memorial Foundation); National Research Service Award (NIH/NIDA) [F32DA024920]; Dr. Bonnie Spring's Professional Account at Northwestern Feinberg School of Medicine; NIAAA [R21 AA021223-01]; National Heart, Lung and Blood Institute; NHLBI [HHSN268200960009C] FX All sources of support: MD Scientist Fellowship in Genetic Medicine (Northerstern Memorial Foundation; PI: A. Hamidovic), National Research Service Award F32DA024920 (NIH/NIDA; PI: A. Hamidovic), Dr. Bonnie Spring's Professional Account at Northwestern Feinberg School of Medicine, NIAAA R21 AA021223-01, E. Jorgenson). The Candidate gene Association Resource (CARe) wishes to acknowledge the support of the National Heart, Lung and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research (NHLBI contract number HHSN268200960009C). The following eight parent studies have contributed parent study data, ancillary study data, and DNA samples through the Broad Institute (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the Atherosclerosis Risk in Communities (ARK) study, the CHS, the Cleveland Family Study (CFS), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Framingham Heart Study, the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). Individual study funding attributions can be obtained at http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx. NR 53 TC 0 Z9 0 U1 0 U2 15 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 APR PY 2013 VL 33 IS 2 BP 206 EP 210 DI 10.1097/JCP.0b013e318287009a PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 108NX UT WOS:000316303700010 PM 23422394 ER PT J AU Ferrer, RA Portnoy, DB Klein, WMP AF Ferrer, Rebecca A. Portnoy, David B. Klein, William M. P. TI Worry and Risk Perceptions as Independent and Interacting Predictors of Health Protective Behaviors SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID BREAST-CANCER RISK; PHYSICAL-ACTIVITY; PERCEIVED RISK; BELIEF MODEL; METAANALYSIS; PREVENTION; COMMUNICATION; INFORMATION; VACCINATION; INTENTIONS AB Worry and risk perceptions are generally found to be independently associated with health-promoting behaviors, although it is unknown whether they interact in ways that potentially dampen the effect of either construct on behavior. In this hypothesis-generating study, cancer-related worry and risk perception, and their interaction, were used to predict odds of meeting 5-a-day fruit and vegetable consumption guidelines and engaging in any exercise using data from a nationally representative sample (N=10,230). Risk perception was not associated with either behavior; worry was associated only with exercise (OR=1.77, 95% CI: 1.16, 2.70, p<.01). More important, their interaction was associated with these behaviors in a counterintuitive manner; among those higher in worry, higher levels of risk perception were associated with lower vegetable consumption (OR=0.79, 95% CI: 0.62, 1.00, p<.05) and exercise (OR=0.77, 95% CI: 0.63, 0.95, p=.01). These results suggest the hypothesis that, among people high in worry, attempts to increase risk perception could be counterproductive. These and related findings suggest the importance of distinguishing worry from risk perception, and future research is necessary to determine the causal nature of these associations. C1 [Ferrer, Rebecca A.; Portnoy, David B.; Klein, William M. P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Rockville, MD 20852 USA. [Portnoy, David B.] NIH, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. RP Ferrer, RA (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 4089A, Rockville, MD 20852 USA. EM ferrerra@mail.nih.gov OI Portnoy, David/0000-0003-2175-9457 NR 50 TC 16 Z9 16 U1 1 U2 19 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD APR 1 PY 2013 VL 18 IS 4 BP 397 EP 409 DI 10.1080/10810730.2012.727954 PG 13 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA 109RV UT WOS:000316387100004 PM 23272708 ER PT J AU Puntervoll, HE Yang, XHR Vetti, HH Bachmann, IM Avril, MF Benfodda, M Catricala, C Dalle, S Duval-Modeste, AB Ghiorzo, P Grammatico, P Harland, M Hayward, NK Hu, HH Jouary, T Martin-Denavit, T Ozola, A Palmer, JM Pastorino, L Pjanova, D Soufir, N Steine, SJ Stratigos, AJ Thomas, L Tinat, J Tsao, H Veinalde, R Tucker, MA Bressac-de Paillerets, BBD Newton-Bishop, JA Goldstein, AM Akslen, LA Molven, A AF Puntervoll, Hanne Eknes Yang, Xiaohong R. Vetti, Hildegunn Hoberg Bachmann, Ingeborg M. Avril, Marie Francoise Benfodda, Meriem Catricala, Caterina Dalle, Stephane Duval-Modeste, Anne B. Ghiorzo, Paola Grammatico, Paola Harland, Mark Hayward, Nicholas K. Hu, Hui-Han Jouary, Thomas Martin-Denavit, Tanguy Ozola, Aija Palmer, Jane M. Pastorino, Lorenza Pjanova, Dace Soufir, Nadem Steine, Solrun J. Stratigos, Alexander J. Thomas, Luc Tinat, Julie Tsao, Hensin Veinalde, Ruta Tucker, Margaret A. Bressac-de Paillerets, Brigitte Newton-Bishop, Julia A. Goldstein, Alisa M. Akslen, Lars A. Molven, Anders TI Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID 1 RECEPTOR MC1R; CDKN2A MUTATIONS; CUTANEOUS MELANOMA; RED HAIR; MALIGNANT-MELANOMA; PANCREATIC-CANCER; DYSPLASTIC NEVI; INCREASED RISK; ATYPICAL NEVI; GENE VARIANTS AB Background CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. Methods All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. Results Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010). Conclusion Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation. C1 [Puntervoll, Hanne Eknes; Bachmann, Ingeborg M.; Steine, Solrun J.; Akslen, Lars A.; Molven, Anders] Univ Bergen, Sect Pathol, Gade Inst, N-5021 Bergen, Norway. [Yang, Xiaohong R.; Tucker, Margaret A.; Goldstein, Alisa M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Vetti, Hildegunn Hoberg] Haukeland Hosp, Ctr Med Genet & Mol Med, Western Norway Familial Canc Ctr, N-5021 Bergen, Norway. [Bachmann, Ingeborg M.] Haukeland Hosp, Dept Dermatol, N-5021 Bergen, Norway. [Avril, Marie Francoise] Univ Paris 05, Hop Cochin Tarnier, AP HP, Paris, France. [Benfodda, Meriem; Hu, Hui-Han; Soufir, Nadem] Univ Paris 07, St Louis Hosp, AP HP, Dept Genet,Bichat Hosp, Paris, France. [Benfodda, Meriem; Hu, Hui-Han; Soufir, Nadem] Univ Paris 07, INSERM, St Louis Hosp, Cutaneous Res Ctr,U976, Paris, France. [Catricala, Caterina] IRCCS, San Gallicano Dermatol Inst, Dept Dermatol Oncol, Rome, Italy. [Dalle, Stephane; Martin-Denavit, Tanguy; Thomas, Luc] Univ Lyon 1, Hosp Civils Lyon, Ctr Hosp Lyon Sud, Unit Dermatol, F-69365 Lyon, France. [Duval-Modeste, Anne B.] Rouen Univ Hosp, Dept Dermatol, Rouen, France. [Ghiorzo, Paola; Pastorino, Lorenza] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Ghiorzo, Paola; Pastorino, Lorenza] San Martino IST Res Hosp, Lab Genet Rare Hereditary Canc, Genoa, Italy. [Grammatico, Paola] Univ Roma La Sapienza, Dept Mol Med, S Camillo Forlanini Hosp, Rome, Italy. [Harland, Mark; Newton-Bishop, Julia A.] St James Univ Hosp, Leeds Canc Res UK Ctr, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds, W Yorkshire, England. [Hayward, Nicholas K.; Palmer, Jane M.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Jouary, Thomas] Serv Dermatol, Unite Cancerol Cutanee, Bordeaux, France. [Ozola, Aija; Pjanova, Dace; Veinalde, Ruta] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Stratigos, Alexander J.] Univ Athens, Sch Med, Andreas Sygros Hosp, Dept Dermatol,Dermatooncol Unit, GR-11527 Athens, Greece. [Tinat, Julie] Rouen Univ Hosp, Dept Genet, Rouen, France. [Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Bressac-de Paillerets, Brigitte] Inst Cancerol Gustave Roussy, Serv Genet, Dept Biopathol, Villejuif, France. [Bressac-de Paillerets, Brigitte] Fdn Jean Dausset, INSERM, U946, Paris, France. [Akslen, Lars A.] Univ Bergen, Ctr Canc Biomarkers, Gade Inst, N-5021 Bergen, Norway. [Akslen, Lars A.; Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. RP Molven, A (reprint author), Univ Bergen, Haukeland Univ Hosp, Gade Inst, Sect Pathol, N-5021 Bergen, Norway. EM anders.molven@gades.uib.no RI Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; Akslen, Lars /C-1202-2017; OI hayward, nicholas/0000-0003-4760-1033; Akslen, Lars /0000-0003-2710-9543; Newton Bishop, Julia/0000-0001-9147-6802; Veinalde, Ruta/0000-0001-9190-5574 FU European Commission [LSHC-CT-2006-018702]; Cancer Research UK [C588/A4994, C588/A10589, C8216/A6129]; US National Institutes of Health (NIH) [CA83115]; University of Bergen; INSERM Research Fellowship; INCA; Norwegian Cancer Society [71512-PR-2006-0356]; Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Leeds Cancer Research UK Centre [C37059/A11941]; Latvian Council of Science [10.0010.8]; National Health and Medical Research Council of Australia; Italian Ministry of Health; PRIN; Sapienza University of Rome; Institut National du Cancer PHRC [AOM 07, 195, N107004]; Lyon 1 University; Hospices Civils de Lyon; Ligue Contre le Cancer du Rhone; NIH [K24 CA149202] FX The GenoMEL study was funded by the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702), by Cancer Research UK Programme Awards (C588/A4994 and C588/A10589), by a Cancer Research UK Project grant (C8216/A6129), and by a grant from the US National Institutes of Health (NIH; CA83115). This research was also supported by a PhD fellowship from the University of Bergen to HEP, an INSERM Research Fellowship for hospital based scientists and an INCA coordinator or grant to BB-de P, and grants from the following sources: Norwegian Cancer Society (71512-PR-2006-0356); Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Leeds Cancer Research UK Centre (C37059/A11941); Latvian Council of Science (No. 10.0010.8); National Health and Medical Research Council of Australia; Italian Ministry of Health; PRIN 2008; Sapienza University of Rome; Institut National du Cancer PHRC 2007 (AOM 07, 195, N107004); Lyon 1 University; Hospices Civils de Lyon; Ligue Contre le Cancer du Rhone; and NIH (K24 CA149202). NR 41 TC 38 Z9 39 U1 3 U2 15 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 APR PY 2013 VL 50 IS 4 BP 264 EP U82 DI 10.1136/jmedgenet-2012-101455 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 106AW UT WOS:000316114800008 PM 23384855 ER PT J AU Song, JH Fang, ZZ Zhu, LL Cao, YF Hu, CM Ge, GB Zhao, DW AF Song, Jin-Hui Fang, Zhong-Ze Zhu, Liang-Liang Cao, Yun-Feng Hu, Cui-Min Ge, Guang-Bo Zhao, De-Wei TI Glucuronidation of the broad-spectrum antiviral drug arbidol by UGT isoforms SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article DE arbidol; glucuronidation; UDP-glucuronosyltransferases (UGTs) ID HUMAN UDP-GLUCURONOSYLTRANSFERASES; MYCOPHENOLIC-ACID; HUMAN LIVER; IN-VITRO; GENETIC POLYMORPHISMS; VIRUS; PHARMACOKINETICS; IDENTIFICATION; METABOLISM; BIOACTIVATION AB Objectives The aim of this work was to identify the uridine glucuronosyltransferase (UGT) isoforms involved in the metabolism of the broad-spectrum antiviral drug arbidol. Methods A human liver microsome (HLM) incubation system was employed to catalyse the formation of arbidol glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards arbidol was screened. A combination of kinetic analysis and chemical inhibition study was used to determine the UGT isoforms involved in arbidol's glucuronidation. Key findings The arbidol glucuronide was detected when arbidol was incubated with HLMs in the presence of UDP-glucuronic acid. The EadieHofstee plot showed that glucuronidation of arbidol was best fit to the MichaelisMenten kinetic model, and Km and apparent Vmax were calculated to be 8.0 +/- 0.7m and 2.03 +/- 0.05nmol/min/mg protein, respectively. Assessment of a panel of recombinant UGT isoforms revealed that UGT1A1, UGT1A3 and UGT1A9 could catalyse the glucuronidation of arbidol. Kinetic analysis and chemical inhibition study demonstrated that UGT1A9 was the predominant UGT isoform involved in arbidol glucuronidation in HLMs. Conclusions The major contribution of UGT1A9 towards arbidol glucuronidation was demonstrated in this study. C1 [Song, Jin-Hui; Zhao, De-Wei] Dalian Univ, Affiliated Zhongshan Hosp, Dept Orthoped, Dalian 116001, Peoples R China. [Fang, Zhong-Ze] Liaoning Med Univ, Jinzhou, Peoples R China. [Cao, Yun-Feng] Shanghai Inst Planned Parenthood Res, Shanghai Engineer & Technol Res Ctr Reprod Hlth D, Key Lab Contracept & Devices Res NPFPC, Shanghai, Peoples R China. [Zhu, Liang-Liang; Ge, Guang-Bo] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China. [Fang, Zhong-Ze; Hu, Cui-Min] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zhao, DW (reprint author), Dalian Univ, Affiliated Zhongshan Hosp, Dept Orthoped, Dalian 116001, Peoples R China. EM zhaodewei2000@163.com FU National Key Technology RD Program [2012BAI7B02]; National Science & Technology Major Project of China [2012ZX09501001, 2012ZX09506001, 2012ZX10002011]; National Natural Science Foundation of China [81202586, 81001473, 81273590] FX This work was supported by the National Key Technology R&D Program (2012BAI7B02), the National Science & Technology Major Project of China (2012ZX09501001, 2012ZX09506001 & 2012ZX10002011), and the National Natural Science Foundation of China (81202586, 81001473 & 81273590). NR 36 TC 19 Z9 19 U1 0 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3573 EI 2042-7158 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD APR PY 2013 VL 65 IS 4 BP 521 EP 527 DI 10.1111/jphp.12014 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 108KO UT WOS:000316292000006 PM 23488780 ER PT J AU Gill, JM Saligan, L Lee, H Rotolo, S Szanton, S AF Gill, Jessica M. Saligan, Leorey Lee, Henna Rotolo, Susan Szanton, Sarah TI Women in recovery from PTSD have similar inflammation and quality of life as non-traumatized controls SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE Health; Inflammation; Resilience; Trauma; Women ID POSTTRAUMATIC-STRESS-DISORDER; HEALTH-CARE UTILIZATION; ALPHA-INDUCED CHANGES; INTERFERON-ALPHA; METABOLIC SYNDROME; PSYCHOMETRIC PROPERTIES; DEPRESSIVE SYMPTOMS; VIETNAM VETERANS; HEART-DISEASE; WAR VETERANS AB Objective: Post-traumatic stress disorder (PTSD) is associated with greater concentrations of inflammatory biomarkers as well as substantial medical burden; however, it is not clear if these morbidity risks change following recovery from PTSD. In this study we compare women who have-recovered from PTSD, to those with current PTSD, and healthy controls on their perceived health and inflammatory and metabolic biomarkers. Methods: We studied 3 groups of women: those with current PTSD, those who reported recovery from PTSD, and healthy non-traumatized controls, which were determined using standard diagnostic instruments. We obtained a morning blood sample and examined concentrations of inflammatory biomarkers of: interleukin 6 (IL-6) and c-reactive protein (CRP), and lipid concentrations. Lastly, we evaluated health related quality of life (HRQOL). Results: Women who had recovered from PTSD had a similar HRQOL and inflammatory biomarkers as non-traumatized controls. Their concentrations of inflammatory biomarkers were lower than women with current PTSD, and similar to non-traumatized controls. Conclusion: Health perception as well as biological indicators of health significantly differ in women in recovery from PTSD, compared to those who remain symptomatic. These findings suggest that the psychological recovery is associated with normal levels of inflammatory biomarkers and HRQOL. (C) 2012 Published by Elsevier Inc. C1 [Gill, Jessica M.; Saligan, Leorey; Lee, Henna] NINR, NIH, Bethesda, MD 20892 USA. [Gill, Jessica M.] George Mason Univ, Sch Nursing, Fairfax, VA 22030 USA. [Rotolo, Susan] Inova Hlth Serv, Falls Church, VA USA. [Szanton, Sarah] Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21218 USA. RP Gill, JM (reprint author), 10 Ctr Dr, Bethesda, MD 20892 USA. EM gillj@mail.nih.gov NR 86 TC 15 Z9 15 U1 7 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 EI 1879-1360 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD APR PY 2013 VL 74 IS 4 BP 301 EP 306 DI 10.1016/j.jpsychores.2012.10.013 PG 6 WC Psychiatry SC Psychiatry GA 112IT UT WOS:000316586600006 PM 23497831 ER PT J AU Borkenau, P McCrae, RR Terracciano, A AF Borkenau, Peter McCrae, Robert R. Terracciano, Antonio TI Do men vary more than women in personality? A study in 51 cultures SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE Cross-cultural research; Individualism; Multilevel modeling; Sex differences; Variability ID SEX-DIFFERENCES; GENDER-DIFFERENCES; VARIABILITY; TRAITS; METAANALYSIS; FEMALES; MALES AB Do men vary more than women in personality? Evolutionary, genetic, and cultural arguments suggest that hypothesis. In this study we tested it using 12,156 college student raters from 51 cultures who described a person they knew well on the 3rd-person version of the Revised NEO Personality Inventory. In most cultures, male targets varied more than female targets, and ratings by female informants varied more than ratings by male informants, which may explain why higher variances for men are not found in self-reports. Variances were higher in more developed, and effects of target sex were stronger in more individualistic societies. It seems that individualistic cultures enable a less restricted expression of personality, resulting in larger variances and particularly so among men. (C) 2012 Elsevier Inc. All rights reserved. C1 [Borkenau, Peter] Univ Halle Wittenberg, Dept Psychol, D-06099 Halle, Germany. [Terracciano, Antonio] Florida State Univ, Coll Med, Dept Geriatr, Tallahassee, FL 32306 USA. [Terracciano, Antonio] NIA, Baltimore, MD 21224 USA. RP Borkenau, P (reprint author), Univ Halle Wittenberg, Dept Psychol, D-06099 Halle, Germany. EM p.borkenau@psych.uni-halle.de RI terracciano, antonio/B-1884-2008 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000180-25, ZIA AG000180-26] NR 39 TC 6 Z9 6 U1 3 U2 31 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD APR PY 2013 VL 47 IS 2 BP 135 EP 144 DI 10.1016/j.jrp.2012.12.001 PG 10 WC Psychology, Social SC Psychology GA 111ND UT WOS:000316527100001 PM 23559686 ER PT J AU Tiseo, M Rajan, A Thomas, A Giaccone, G AF Tiseo, Marcello Rajan, Arun Thomas, Anish Giaccone, Giuseppe TI "Pseudocavitation" in Thymic Carcinoma During Treatment with Sunitinib SO JOURNAL OF THORACIC ONCOLOGY LA English DT Editorial Material C1 [Tiseo, Marcello; Rajan, Arun; Thomas, Anish; Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, 12N-226,10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU Intramural NIH HHS [Z01 BC010854-01] NR 0 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD APR PY 2013 VL 8 IS 4 BP 511 EP 512 DI 10.1097/JTO.0b013e318284378f PG 2 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 107HO UT WOS:000316206600023 PM 23486269 ER PT J AU Brooks-Russell, A Foshee, VA Ennett, ST AF Brooks-Russell, Ashley Foshee, Vangie A. Ennett, Susan T. TI Predictors of Latent Trajectory Classes of Physical Dating Violence Victimization SO JOURNAL OF YOUTH AND ADOLESCENCE LA English DT Article DE Adolescent dating violence; Physical victimization; Trajectories; Growth mixture model ID VARIABLE-CENTERED ANALYSES; ADOLESCENT SUBSTANCE USE; HIGH-SCHOOL-STUDENTS; ALCOHOL-USE; HIGH-RISK; DEVELOPMENTAL TRAJECTORIES; FEMALE ADOLESCENTS; GENDER-DIFFERENCES; PARTNER VIOLENCE; ADULT OUTCOMES AB This study identified classes of developmental trajectories of physical dating violence victimization from grades 8 to 12 and examined theoretically-based risk factors that distinguished among trajectory classes. Data were from a multi-wave longitudinal study spanning 8th through 12th grade (n = 2,566; 51.9 % female). Growth mixture models were used to identify trajectory classes of physical dating violence victimization separately for girls and boys. Logistic and multinomial logistic regressions were used to identify situational and target vulnerability factors associated with the trajectory classes. For girls, three trajectory classes were identified: a low/non-involved class; a moderate class where victimization increased slightly until the 10th grade and then decreased through the 12th grade; and a high class where victimization started at a higher level in the 8th grade, increased substantially until the 10th grade, and then decreased until the 12th grade. For males, two classes were identified: a low/non-involved class, and a victimized class where victimization increased slightly until the 9th grade, decreased until the 11th grade, and then increased again through the 12th grade. In bivariate analyses, almost all of the situational and target vulnerability risk factors distinguished the victimization classes from the non-involved classes. However, when all risk factors and control variables were in the model, alcohol use (a situational vulnerability) was the only factor that distinguished membership in the moderate trajectory class from the non-involved class for girls; anxiety and being victimized by peers (target vulnerability factors) were the factors that distinguished the high from the non-involved classes for the girls; and victimization by peers was the only factor distinguishing the victimized from the non-involved class for boys. These findings contribute to our understanding of the heterogeneity in physical dating violence victimization during adolescence and the malleable risk factors associated with each trajectory class for boys and girls. C1 [Brooks-Russell, Ashley] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Foshee, Vangie A.; Ennett, Susan T.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, Chapel Hill, NC USA. RP Brooks-Russell, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd Room 7B13, Bethesda, MD 20892 USA. EM ashley.russell@nih.gov RI Brooks-Russell, Ashley/F-8364-2014 OI Brooks-Russell, Ashley/0000-0002-7728-8423 FU NIDA NIH HHS [R01 DA013459, R01DA16669]; PHS HHS [R49CCV423114] NR 77 TC 17 Z9 17 U1 1 U2 15 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0047-2891 J9 J YOUTH ADOLESCENCE JI J. Youth Adolesc. PD APR PY 2013 VL 42 IS 4 SI SI BP 566 EP 580 DI 10.1007/s10964-012-9876-2 PG 15 WC Psychology, Developmental SC Psychology GA 107GF UT WOS:000316202400007 PM 23212350 ER PT J AU Crane, FL Navas, P Low, H Sun, IL de Cabo, R AF Crane, Frederick L. Navas, Placido Low, Hans Sun, Iris L. de Cabo, Rafael TI Sirtuin Activation: A Role for Plasma Membrane in the Cell Growth Puzzle SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Transplasma membrane; electron transport system; RedOx; Sirtuin; NAD; Cell growth ID ELECTRON-TRANSPORT; REDOX SYSTEM; EMBRYONIC FIBROBLASTS; UP-REGULATION; HL-60 CELLS; LIFE-SPAN; NADH; TRANSFERRIN; INHIBITION; STRESS AB For more than 20 years, the observation that impermeable oxidants can stimulate cell growth has not been satisfactorily explained. The discovery of sirtuins provides a logical answer to the puzzle. The NADH-dependent transplasma membrane electron transport system, which is stimulated by growth factors and interventions such as calorie restriction, can transfer electrons to external acceptors and protect against stress-induced apoptosis. We hypothesize that the activation of plasma membrane electron transport contributes to the cytosolic NAD pool required for sirtuin to activate transcription factors necessary for cell growth and survival. C1 [Crane, Frederick L.; Low, Hans] Purdue Univ, Dept Biol, W Lafayette, IN 47907 USA. [Navas, Placido] Karolinska Inst, Dept Mol Med, Stockholm, Sweden. [Sun, Iris L.] Univ Pablo de Olavide, CSIC, Inst Salud Carlos III, CIBERER,CABD, Seville 41013, Spain. [de Cabo, Rafael] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Lab Expt Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM deCaboRa@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Spanish Ministerio de Sanidad (FIS) [PI11/00078]; National Institutes of Health (NIH) [1R01AG028125-01A1]; Intramural Research Program of the NIA/NIH FX We would like to acknowledge financial support from Spanish Ministerio de Sanidad (FIS; grant PI11/00078), National Institutes of Health (NIH; grant 1R01AG028125-01A1), and the Intramural Research Program of the NIA/NIH. NR 31 TC 4 Z9 4 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2013 VL 68 IS 4 BP 368 EP 370 DI 10.1093/gerona/gls184 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 108DX UT WOS:000316273000004 PM 23033342 ER PT J AU Coen, PM Jubrias, SA Distefano, G Amati, F Mackey, DC Glynn, NW Manini, TM Wohlgemuth, SE Leeuwenburgh, C Cummings, SR Newman, AB Ferrucci, L Toledo, FGS Shankland, E Conley, KE Goodpaster, BH AF Coen, Paul M. Jubrias, Sharon A. Distefano, Giovanna Amati, Francesca Mackey, Dawn C. Glynn, Nancy W. Manini, Todd M. Wohlgemuth, Stephanie E. Leeuwenburgh, Christiaan Cummings, Steven R. Newman, Anne B. Ferrucci, Luigi Toledo, Frederico G. S. Shankland, Eric Conley, Kevin E. Goodpaster, Bret H. TI Skeletal Muscle Mitochondrial Energetics Are Associated With Maximal Aerobic Capacity and Walking Speed in Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Muscle; Mitochondria; Aging; Walking speed ID PHYSICAL PERFORMANCE-MEASURES; LOWER-EXTREMITY FUNCTION; IN-VIVO; OXIDATIVE CAPACITY; CELLULAR ENERGETICS; BODY-COMPOSITION; GAIT PARAMETERS; MASS; AGE; EFFICIENCY AB Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults. Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO2 peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATP(max)) of vastus lateralis was determined in vivo by P-31 magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O-2 consumption) was characterized using ATP(max) per St3 respiration (ATP(max)/St3). In vitro St3 respiration was significantly correlated with in vivo ATP(max) (r(2) = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO2 peak (r(2) = .33, p = .006). ATP(max) (r(2) = .158, p = .03) and VO2 peak (r(2) = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATP(max)/St3 and VO2 peak in a multiple linear regression model improved the prediction of preferred walking speed (r(2) = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed. Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age. C1 [Coen, Paul M.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA 15260 USA. [Coen, Paul M.; Distefano, Giovanna; Amati, Francesca; Toledo, Frederico G. S.; Goodpaster, Bret H.] Univ Pittsburgh, Div Endocrinol & Metab, Pittsburgh, PA 15260 USA. [Jubrias, Sharon A.; Shankland, Eric; Conley, Kevin E.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Mackey, Dawn C.; Cummings, Steven R.] Calif Pacific Med Ctr Res Inst, San Francisco, CA USA. [Glynn, Nancy W.; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Manini, Todd M.; Wohlgemuth, Stephanie E.; Leeuwenburgh, Christiaan] Univ Florida, Gainesville, FL USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Coen, PM (reprint author), Univ Pittsburgh, Dept Hlth & Phys Act, Trees Hall Rm 134D,Allequippa St & Darragh St, Pittsburgh, PA 15260 USA. EM pmc17@pitt.edu RI Toledo, Frederico/G-9071-2013; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Amati, Francesca/0000-0002-1731-0262; Coen, Paul/0000-0002-2805-2115; Glynn, Nancy/0000-0003-2265-0162 FU Pittsburgh Claude D. Pepper Older Americans Independence Center [P30 AG024827]; National Institute of Aging; ARRA funds [1RC2AG036594, 1RC2AG036606]; National Institute of Arthritis and Musculoskeletal and Skin [R01 AR 41928]; National Center for Research Resources (NCRR) [UL1 RR024153] FX The Study of Energy and Aging (SEA) Pilot was supported by the Pittsburgh Claude D. Pepper Older Americans Independence Center (P30 AG024827), the National Institute of Aging, with ARRA funds (1RC2AG036594, 1RC2AG036606), National Institute of Arthritis and Musculoskeletal and Skin (R01 AR 41928), and by the National Center for Research Resources (NCRR) (UL1 RR024153). NR 41 TC 55 Z9 55 U1 3 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2013 VL 68 IS 4 BP 447 EP 455 DI 10.1093/gerona/gls196 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 108DX UT WOS:000316273000015 PM 23051977 ER PT J AU White, DK Neogi, T Nevitt, MC Peloquin, CE Zhu, YY Boudreau, RM Cauley, JA Ferrucci, L Harris, TB Satterfield, SM Simonsick, EM Strotmeyer, ES Zhang, YQ AF White, Daniel K. Neogi, Tuhina Nevitt, Michael C. Peloquin, Christine E. Zhu, Yanyan Boudreau, Robert M. Cauley, Jane A. Ferrucci, Luigi Harris, Tamara B. Satterfield, Susan M. Simonsick, Eleanor M. Strotmeyer, Elsa S. Zhang, Yuqing TI Trajectories of Gait Speed Predict Mortality in Well-Functioning Older Adults: The Health, Aging and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Gait speed; Older adults; Mortality ID DWELLING ELDERLY-PEOPLE; PHYSICAL FUNCTION; WALKING SPEED; MUSCULOSKELETAL PAIN; PERFORMANCE; AGE; METAANALYSIS; EXERCISE; WOMEN; DISABILITY AB Although gait speed slows with age, the rate of slowing varies greatly. To date, little is known about the trajectories of gait speed, their correlates, and their risk for mortality in older adults. Gait speed during a 20-m walk was measured for a period of 8 years in initially well-functioning men and women aged 7079 years participating in the Health, Aging and Body Composition study. We described the trajectories of gait speed and examined their correlates using a group-based mixture model. Also risk associated with different gait speed trajectories on all-cause mortality was estimated using a Cox-proportional hazard model. Of 2,364 participants (mean age, 73.52.9 years; 52% women), we identified three gait speed trajectories: slow (n 637), moderate (n 1,209), and fast decline (n 518). Those with fast decline slowed 0.030 m/s per year or 2.4% per year from baseline to the last follow-up visit. Women, blacks, and participants who were obese, had limited knee extensor strength, and had low physical activity were more likely to have fast decline than their counterparts. Participants with fast decline in gait speed had a 90% greater risk of mortality than those with slow decline. Despite being well-functioning at baseline, a quarter of older adults experienced fast decline in gait speed, which was associated with an increased risk of mortality. C1 [White, Daniel K.] Boston Univ, Dept Phys Therapy & Athlet Training, Coll Hlth & Rehabil Sci, Sargent Coll, Boston, MA 02215 USA. [Neogi, Tuhina; Peloquin, Christine E.; Zhu, Yanyan; Zhang, Yuqing] Boston Univ, Sch Med, Clin Epidemiol Res & Training Unit, Boston, MA 02215 USA. [Nevitt, Michael C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Boudreau, Robert M.; Cauley, Jane A.; Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Ferrucci, Luigi; Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Satterfield, Susan M.] Univ Tennessee, Memphis, TN USA. RP White, DK (reprint author), Boston Univ, Dept Phys Therapy & Athlet Training, Boston, MA 02215 USA. EM dwtbn@bu.edu RI Strotmeyer, Elsa/F-3015-2014; OI Strotmeyer, Elsa/0000-0002-4093-6036; Boudreau, Robert/0000-0003-0162-5187; Neogi, Tuhina/0000-0002-9515-1711; Cauley, Jane A/0000-0003-0752-4408 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR0124590]; Boston Claude D. Pepper Older Americans Independence Center from the National Institutes on Aging [P30-AG031679]; Foundation for Physical Therapy Geriatrics Research Grant; American College of Rheumatology Research and Education Foundation Rheumatology Investigator Award; National Institute of Arthritis and Musculoskeletal and Skin at the National Institutes of Health [AR47785]; Intramural Research Program of the NIH, National Institute on Aging FX This work was supported by National Institute on Aging (NIA) (grant numbers N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050) the National Institute of Nursing Research (grant number R01-NR0124590; the Boston Claude D. Pepper Older Americans Independence Center from the National Institutes on Aging (grant number P30-AG031679); the Foundation for Physical Therapy Geriatrics Research Grant; the American College of Rheumatology Research and Education Foundation Rheumatology Investigator Award; and the National Institute of Arthritis and Musculoskeletal and Skin at the National Institutes of Health (grant number AR47785).; This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 34 TC 42 Z9 43 U1 3 U2 29 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2013 VL 68 IS 4 BP 456 EP 464 DI 10.1093/gerona/gls197 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 108DX UT WOS:000316273000016 PM 23051974 ER PT J AU Thomas, A Maltzman, J Hassan, R AF Thomas, Anish Maltzman, Julia Hassan, Raffit TI Farletuzumab in lung cancer SO LUNG CANCER LA English DT Review DE Adenocarcinoma; Farletuzumab; Folate receptor alpha; Monoclonal antibody; Non-small cell lung cancer; Immunohistochemistry ID FOLATE-RECEPTOR-ALPHA; BINDING-PROTEIN; OVARIAN-CANCER; MONOCLONAL-ANTIBODY; TARGETED THERAPY; NORMAL-TISSUES; EXPRESSION; ADENOCARCINOMA; CHEMOTHERAPY; CARCINOMAS AB Folate is essential for proliferating cells and folate transport pathways and folate-dependent metabolic processes show promise as targets for anti-neoplastic therapy. Folate receptor a (FOLR1), a folate transporter, is an attractive target for anti-neoplastic therapy due to its high affinity for folate, restricted range of expression in normal tissue and differential over-expression in malignant tissue. FOLR1 is expressed in non-small cell lung cancer, with a higher expression in adenocarcinoma compared with squamous cell carcinoma. Farletuzumab is a monoclonal antibody targeting FOLR1 which in pre-clinical studies led to cytotoxicity of FOLR1-expressing cells, inhibited tumor growth in animal models and showed limited reactivity with normal tissue. In phase I/II trials, farletuzumab was well tolerated as a single-agent and in combination, without additive toxicity with chemotherapy. An ongoing phase II, double blind, placebo-controlled study is evaluating farletuzumab in patients with FOLR1 expressing metastatic adenocarcinoma of lung. Published by Elsevier Ireland Ltd. C1 [Thomas, Anish] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. [Maltzman, Julia] Morphotek, Exton, PA 19341 USA. [Hassan, Raffit] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov OI Thomas, Anish/0000-0003-3293-3115 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute; Morphotek FX All authors contributed to data interpretation, manuscript development and final approval of the manuscript for submission. RH is the guarantor of the manuscript. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and under a Cooperative Research and Development Agreement between Morphotek and the National Cancer Institute. NR 36 TC 12 Z9 13 U1 2 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD APR PY 2013 VL 80 IS 1 BP 15 EP 18 DI 10.1016/j.lungcan.2012.12.021 PG 4 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 112KH UT WOS:000316590600003 PM 23357463 ER PT J AU Han, PKJ Klabunde, CN Noone, AM Earle, CC Ayanian, JZ Ganz, PA Virgo, KS Potosky, AL AF Han, Paul K. J. Klabunde, Carrie N. Noone, Anne-Michelle Earle, Craig C. Ayanian, John Z. Ganz, Patricia A. Virgo, Katherine S. Potosky, Arnold L. TI Physicians' Beliefs About Breast Cancer Surveillance Testing are Consistent With Test Overuse SO MEDICAL CARE LA English DT Article DE breast cancer; survivorship care; surveillance; screening; overuse ID PRIMARY-CARE-PHYSICIANS; FOLLOW-UP CARE; HEALTH-CARE; SURVIVORS; QUALITY; COST; UNCERTAINTY; PERCEPTIONS; VIGNETTES; OVERUTILIZATION AB Background: Overuse of surveillance testing for breast cancer survivors is an important problem but its extent and determinants are incompletely understood. The objectives of this study were to determine the extent to which physicians' breast cancer surveillance testing beliefs are consistent with test overuse, and to identify factors associated with these beliefs. Methods: During 2009-2010, a cross-sectional survey of US medical oncologists and primary care physicians (PCPs) was carried out. Physicians responded to a clinical vignette ascertaining beliefs about appropriate breast cancer surveillance testing. Multivariable analyses examined the extent to which test beliefs were consistent with overuse and associated with physician and practice characteristics and physician perceptions, attitudes, and practices. Results: A total of 1098 medical oncologists and 980 PCPs completed the survey (response rate 57.5%). Eighty-four percent of PCPs [95% confidence interval (CI), 81.4%-86.5%] and 72% of oncologists (95% CI, 69.8%-74.7%) reported beliefs consistent with blood test overuse, whereas 50% of PCPs (95% CI, 47.3%-53.8%) and 27% of oncologists (95% CI, 23.9%-29.3%) reported beliefs consistent with imaging test overuse. Among PCPs, factors associated with these beliefs included smaller practice size, lower patient volume, and practice ownership. Among oncologists, factors included older age, international medical graduate status, lower self-efficacy (confidence in knowledge), and greater perceptions of ambiguity (conflicting expert recommendations) regarding survivorship care. Conclusions: Beliefs consistent with breast cancer surveillance test overuse are common, greater for PCPs and blood tests than for oncologists and imaging tests, and associated with practice characteristics and perceived self-efficacy and ambiguity about testing. These results suggest modifiable targets for efforts to reduce surveillance test overuse. C1 [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04101 USA. [Han, Paul K. J.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Klabunde, Carrie N.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Noone, Anne-Michelle] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Earle, Craig C.] Ontario Inst Canc Res, Toronto, ON, Canada. [Ayanian, John Z.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Hlth Care Policy,Div Gen Med, Boston, MA 02115 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med, Los Angeles, CA 90024 USA. [Virgo, Katherine S.] Amer Canc Soc, Intramural Res Dept, Hlth Serv Res Program, Atlanta, GA 30329 USA. [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Han, PKJ (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, 590 Forest Ave,Suite 200, Portland, ME 04101 USA. EM hanp@mmc.org OI Han, Paul/0000-0003-0165-1940 FU National Cancer Institute [HSN261200700068C]; American Cancer Society FX Support for the Survey of Physicians' Attitudes Regarding the Care of Cancer Survivors (SPARCCS) was provided by the National Cancer Institute (contract number HSN261200700068C) and the American Cancer Society through its intramural research funds. P.K.J.H. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 51 TC 12 Z9 13 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD APR PY 2013 VL 51 IS 4 BP 315 EP 323 DI 10.1097/MLR.0b013e31827da908 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 107HS UT WOS:000316207100007 PM 23269111 ER PT J AU Mihara, T Izumikawa, K Kakeya, H Ngamskulrungroj, P Umeyama, T Takazono, T Tashiro, M Nakamura, S Imamura, Y Miyazaki, T Ohno, H Yamamoto, Y Yanagihara, K Miyzaki, Y Kohno, S AF Mihara, Tomo Izumikawa, Koichi Kakeya, Hiroshi Ngamskulrungroj, Popchai Umeyama, Takashi Takazono, Takahiro Tashiro, Masato Nakamura, Shigeki Imamura, Yoshifumi Miyazaki, Taiga Ohno, Hideaki Yamamoto, Yoshihiro Yanagihara, Katsunori Miyzaki, Yoshitsugu Kohno, Shigeru TI Multilocus sequence typing of Cryptococcus neoformans in non-HIV associated cryptococcosis in Nagasaki, Japan SO MEDICAL MYCOLOGY LA English DT Article DE MLST; C. neoformans; Japan; ST 5; VNII ID VAR. GRUBII SEROTYPE; SPECIES COMPLEX; MOLECULAR EPIDEMIOLOGY; GATTII; DIVERSITY; VARIETIES; GENOTYPE; STRAINS; CHINA AB Cryptococcosis is primarily caused by two Cryptococcus species, i.e., Cryptococcus neoformans and C. gattii. Both include several genetically diverse subgroups that can be differentiated using various molecular strain typing methods. Since little is known about the molecular epidemiology of the C. neoformans/C. gattii species complex in Japan, we conducted a molecular epidemiological analysis of 35 C. neoformans isolates from non-HIV patients in Nagasaki, Japan and 10 environmental isolates from Thailand. All were analyzed using URA5-restriction fragment length polymorphism (RFLP) and multilocus sequence typing (MLST). Combined sequence data for all isolates were evaluated with the neighbor-joining method. All were found to be serotype A and mating type MAT alpha. Thirty-two of the 35 clinical isolates molecular type VNI, while the three remaining isolates were VNII as determined through the URA5-RFLP method. Thirty-one of the VNI isolates were identified as MLST sequence type (ST) 5, the remaining one was ST 32 and the three VNII isolates were found to be ST 43. All the environmental isolates were identified as molecular type VNI (four MLST ST 5 and six ST 4). Our study shows that C. neoformans isolates in Nagasaki are genetically homogeneous, with most of the isolates being ST 5. C1 [Mihara, Tomo; Izumikawa, Koichi; Kakeya, Hiroshi; Takazono, Takahiro; Tashiro, Masato; Nakamura, Shigeki; Imamura, Yoshifumi; Miyazaki, Taiga; Yamamoto, Yoshihiro; Kohno, Shigeru] Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Microbiol & Immunol, Nagasaki 8528501, Japan. [Ngamskulrungroj, Popchai] NIAID, NIH, Bethesda, MD 20892 USA. [Ngamskulrungroj, Popchai] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Microbiol, Bangkok 10700, Thailand. [Umeyama, Takashi; Ohno, Hideaki; Miyzaki, Yoshitsugu] Natl Inst Infect Dis, Dept Chemotherapy & Mycoses, Tokyo, Japan. [Yanagihara, Katsunori] Nagasaki Univ Hosp, Dept Lab Med, Nagasaki, Japan. RP Izumikawa, K (reprint author), Nagasaki Univ, Grad Sch Biomed Sci Nagasaki, Dept Mol Microbiol & Immunol, 1-7-1 Sakamoto, Nagasaki 8528501, Japan. EM koizumik@nagasaki-u.ac.jp OI Umeyama, Takashi/0000-0002-6635-4288 FU Ministry of Health, Labour and Welfare of Japan [H23-shinkou-ippan-018] FX This work was partly supported by a grant from the Ministry of Health, Labour and Welfare of Japan (H23-shinkou-ippan-018). We thank Dr June Kwon-Chung, National Institutes of Health, Bethesda, MD, USA, for her advice and support, about the methods, manipulation and interpretation of data, and for providing the Cryptococcus reference strains used in this study. Also, we thank Assoc. Prof. Wieland Meyer and Dr Luciana Trilles for their help with allele and sequence type designation. NR 39 TC 11 Z9 12 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD APR PY 2013 VL 51 IS 3 BP 252 EP 260 DI 10.3109/13693786.2012.708883 PG 9 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 107OQ UT WOS:000316228100004 PM 22901045 ER PT J AU Mason, C Xiao, LR Imayama, I Duggan, CR Foster-Schubert, KE Kong, A Campbell, KL Wang, CY Villasenor, A Neuhouser, ML Alfano, CM Blackburn, GL McTiernan, A AF Mason, Caitlin Xiao, Liren Imayama, Ikuyo Duggan, Catherine R. Foster-Schubert, Karen E. Kong, Angela Campbell, Kristin L. Wang, Ching-Yun Villasenor, Adriana Neuhouser, Marian L. Alfano, Catherine M. Blackburn, George L. McTiernan, Anne TI Influence of Diet, Exercise, and Serum Vitamin D on Sarcopenia in Postmenopausal Women SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE CALORIC RESTRICTION; WEIGHT LOSS; 25-HYDROXYVITAMIN D; AGING ID WEIGHT-LOSS; BODY-COMPOSITION; MUSCLE STRENGTH; D DEFICIENCY; PHYSICAL-ACTIVITIES; OLDER PERSONS; ELDERLY-WOMEN; HIP FRACTURE; LEAN MASS; BONE LOSS AB MASON, C., L. XIAO, I. IMAYAMA, C. R. DUGGAN, K. E. FOSTER-SCHUBERT, A. KONG, K. L. CAMPBELL, C.-Y. WANG, A. VILLASENOR, M. L. NEUHOUSER, C. M. ALFANO, G. L. BLACKBURN, and A. MCTIERNAN. Influence of Diet, Exercise, and Serum Vitamin D on Sarcopenia in Postmenopausal Women. Med. Sci. Sports Exerc., Vol. 45, No. 4, pp. 607-614, 2013. Purpose: The objective of this study is to investigate the effects of 12 months of dietary weight loss and/or aerobic exercise on lean mass and the measurements defining sarcopenia in postmenopausal women and to examine the potential moderating effect of serum 25-hydroxyvitamin D (25(OH) D) and age. Methods: Four hundred thirty-nine overweight and obese postmenopausal women were randomized to diet modification (N = 118), exercise (N = 117), diet + exercise (N = 117), or control (N = 87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 min.d(-1), 5 d.wk(-1), of moderate-to-vigorous intensity aerobic activity. Total and appendicular lean mass (ALM) were quantified by dual x-ray absorptiometry at baseline and 12 months. A skeletal muscle index (SMI = ALM (kg) /height (m(2))) and the prevalence of sarcopenia (SMI <5.67 kg.m(-2)) were calculated. Serum 25(OH) D was assayed using a competitive chemiluminescent immunoassay. Results: Dietary weight loss resulted in a significant decrease in lean mass and a borderline significant decrease in ALM and SMI compared with controls. In contrast, aerobic exercise significantly preserved ALM and SMI. Diet + exercise attenuated the loss of ALM and SMI compared with diet alone and did not result in significant loss of total mass or ALM compared with controls. Neither serum 25(OH) D nor age was significant moderators of the intervention effects. Conclusions: Aerobic exercise added to dietary weight loss can attenuate the loss of ALM during weight loss and may be effective for the prevention and treatment of sarcopenia among overweight and obese postmenopausal women. C1 [Mason, Caitlin; Xiao, Liren; Imayama, Ikuyo; Duggan, Catherine R.; Wang, Ching-Yun; Villasenor, Adriana; Neuhouser, Marian L.; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Foster-Schubert, Karen E.; Wang, Ching-Yun; Neuhouser, Marian L.; McTiernan, Anne] Univ Washington, Seattle, WA 98195 USA. [Kong, Angela] Univ Illinois, Chicago, IL USA. [Campbell, Kristin L.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Blackburn, George L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Nutr, Boston, MA 02215 USA. [Alfano, Catherine M.] Ohio State Univ, Columbus, OH 43210 USA. [Alfano, Catherine M.] NCI, Bethesda, MD 20892 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, Prevent Ctr, M4-B874,POB 19024, Seattle, WA 98109 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015; Biguzzi, Felipe/E-4724-2015 OI Duggan, Catherine/0000-0001-7369-4021; FU NIH [R01 CA102504, U54-CA116847, 5KL2RR025015-03]; Canadian Institutes of Health Research (CIHR); NCI [R25 CA094880, 2R25CA057699-16] FX This study was funded through NIH R01 CA102504 and U54-CA116847. CM and KLC were supported by fellowships from the Canadian Institutes of Health Research (CIHR).; KFS received support from NIH 5KL2RR025015-03.; AK was supported by NCI R25 CA094880 and is now supported by NCI 2R25CA057699-16. NR 41 TC 10 Z9 11 U1 1 U2 39 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD APR PY 2013 VL 45 IS 4 BP 607 EP 614 DI 10.1249/MSS.0b013e31827aa3fa PG 8 WC Sport Sciences SC Sport Sciences GA 109ZK UT WOS:000316410600001 PM 23190588 ER PT J AU Jin, GL Mizutani, A Fukuda, T Otani, T Yan, T Vila, MP Murakami, H Kudoh, T Hirohata, S Kasai, T Salomon, DS Seno, M AF Jin, Guoliang Mizutani, Akifumi Fukuda, Takayuki Otani, Takayuki Yan, Ting Vila, Marta Prieto Murakami, Hiroshi Kudoh, Takayuki Hirohata, Satoshi Kasai, Tomonari Salomon, David S. Seno, Masaharu TI Eosinophil cationic protein enhances stabilization of beta-catenin during cardiomyocyte differentiation in P19CL6 embryonal carcinoma cells SO MOLECULAR BIOLOGY REPORTS LA English DT Article DE Eosinophil cationic protein; Cardiomyocyte differentiation; P19CL6 cells; Wnt signaling ID WNT SIGNALING PATHWAY; WNT/BETA-CATENIN; CARDIAC DIFFERENTIATION; TRANSCRIPTION FACTORS; PROGENITOR CELLS; STEM-CELLS; EXPRESSION; INHIBITION; ACTIVATION; DISEASE AB Prior to gastrulation, the Wnt signaling pathway through stabilized beta-catenin enhances the differentiation of mouse ES cell into cardiomyocytes. We have recently shown that cardiomyocyte differentiation is enhanced by eosinophil cationic protein (ECP) through accelerated expression of marker genes of early cardiac differentiation. Furthermore, ECP enhanced the expression of Wnt3a in P19CL6 cells which were stimulated to differentiate into cardiomyocytes by DMSO. Following these findings, we evaluated in this study the potential of ECP to activate the Wnt/beta-catenin signaling pathway during cardiomyocyte differentiation. Analysis by real time qPCR revealed that ECP increased the expression of Frizzled genes such as Frizzled-1, -2, -4 and -10 in P19CL6 cells in the presence of DMSO. The increased expression of those Wnt receptors was found to inhibit the phosphorylation of beta-catenin resulting in the stabilization and translocation of beta-catenin into the nucleus of P19CL6 cells during the early stages of cardiomyocyte differentiation. When assessed for beta-catenin/TCF transcriptional activity with a TCF-luciferase (TOP/FOP) assay, ECP enhanced luciferase activity in P19CL6 cells during 48 h after transfection with TOP/FOP flash reporter in a stoichiometric manner. Collectively, this suggests that ECP can activate a canonical Wnt/beta-catenin signaling pathway by enhancing the stabilization of beta-catenin during cardiomyocyte differentiation. C1 [Jin, Guoliang; Mizutani, Akifumi; Fukuda, Takayuki; Otani, Takayuki; Yan, Ting; Vila, Marta Prieto; Murakami, Hiroshi; Kudoh, Takayuki; Kasai, Tomonari; Seno, Masaharu] Okayama Univ, Grad Sch Nat Sci & Technol, Dept Chem & Biotechnol, Lab Nanobiotechnol, Okayama 7008530, Japan. [Jin, Guoliang] Xuzhou Med Coll, Affiliated Hosp, Dept Neurol, Xuzhou 221002, Jiangsu, Peoples R China. [Hirohata, Satoshi] Okayama Univ, Grad Sch Med Dent & Pharmacol, Dept Mol Biol & Biochem, Okayama 7008558, Japan. [Salomon, David S.] NCI, Lab Canc Prevent, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Seno, M (reprint author), Okayama Univ, Grad Sch Nat Sci & Technol, Dept Chem & Biotechnol, Lab Nanobiotechnol, Okayama 7008530, Japan. EM mseno@cc.okayama-u.ac.jp RI Hirohata, Satoshi/B-2253-2011; SENO, Masaharu /B-2092-2011 OI Hirohata, Satoshi/0000-0002-4815-5891; SENO, Masaharu /0000-0001-8547-6259 FU Ministry of Education, Culture, Sports, Science and Technology; Japan Science and Technology Agency (JST); Chugoku Industrial Innovation Center FX This research was supported in part by the Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research, by Japan Science and Technology Agency (JST), and by Chugoku Industrial Innovation Center. NR 28 TC 2 Z9 2 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-4851 EI 1573-4978 J9 MOL BIOL REP JI Mol. Biol. Rep. PD APR PY 2013 VL 40 IS 4 BP 3165 EP 3171 DI 10.1007/s11033-012-2390-5 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 107MH UT WOS:000316221100044 PM 23271121 ER PT J AU Sullivan, PF Daly, MJ Ripke, S Lewis, CM Lin, DY Wray, NR Neale, B Levinson, DF Breen, G Byrne, EM Wray, NR Levinson, DF Rietschel, M Hoogendijk, W Ripke, S Sullivan, PF Hamilton, SP Levinson, DF Lewis, CM Ripke, S Weissman, MM Wray, NR Breuer, R Cichon, S Degenhardt, F Frank, J Gross, M Herms, S Hoefels, S Maier, W Mattheisen, M Noethen, MM Rietschel, M Schulze, TG Steffens, M Treutlein, J Boomsma, DI De Geus, EJ Hoogendijk, W Hottenga, JJ Jung-Ying, T Lin, DY Middeldorp, CM Nolen, WA Penninx, BP Smit, JH Sullivan, PF van Grootheest, G Willemsen, G Zitman, FG Coryell, WH Knowles, JA Lawson, WB Levinson, DF Potash, JB Scheftner, WA Shi, JX Weissman, MM Holsboer, F Muglia, P Tozzi, F Blackwood, DHR Boomsma, DI De Geus, EJ Hottenga, JJ MacIntyre, DJ McIntosh, A McLean, A Middeldorp, CM Nolen, WA Penninx, BP Ripke, S Smit, JH Sullivan, PF van Grootheest, G Willemsen, G Zitman, FG van den Oord, EJCG Holsboer, F Lucae, S Binder, E Muller-Myhsok, B Ripke, S Czamara, D Kohli, MA Ising, M Uhr, M Bettecken, T Barnes, MR Breen, G Craig, IW Farmer, AE Lewis, CM McGuffin, P Muglia, P Byrne, E Gordon, SD Heath, AC Henders, AK Hickie, IB Madden, PAF Martin, NG Montgomery, GM Nyholt, DR Pergadia, ML Wray, NR Hamilton, SP McGrath, PJ Shyn, SI Slager, SL Oskarsson, H Sigurdsson, E Stefansson, H Stefansson, K Steinberg, S Thorgeirsson, T Levinson, DF Potash, JB Shi, JX Weissman, MM Guipponi, M Lewis, G O'Donovan, M Tansey, KE Uher, R Coryell, WH Knowles, JA Lawson, WB Levinson, DF Potash, JB Scheftner, WA Shi, JX Weissman, MM Castro, VM Churchill, SE Fava, M Gainer, VS Gallagher, PJ Goryachev, S Iosifescu, DV Kohane, IS Murphy, SN Perlis, RH Smoller, JW Weilburg, JB Kutalik, Z Preisig, M Grabe, HJ Nauck, M Schulz, A Teumer, A Volzke, H Landen, M Lichtenstein, P Magnusson, P Pedersen, N Viktorin, A AF Sullivan, Patrick F. Daly, Mark J. Ripke, Stephan Lewis, Cathryn M. Lin, Dan-Yu Wray, Naomi R. Neale, Benjamin Levinson, Douglas F. Breen, Gerome Byrne, Enda M. Wray, Naomi R. Levinson, Douglas F. Rietschel, Marcella Hoogendijk, Witte Ripke, Stephan Sullivan, Patrick F. Hamilton, Steven P. Levinson, Douglas F. Lewis, Cathryn M. Ripke, Stephan Weissman, Myrna M. Wray, Naomi R. Breuer, Rene Cichon, Sven Degenhardt, Franziska Frank, Josef Gross, Magdalena Herms, Stefan Hoefels, Susanne Maier, Wolfgang Mattheisen, Manuel Noeethen, Markus M. Rietschel, Marcella Schulze, Thomas G. Steffens, Michael Treutlein, Jens Boomsma, Dorret I. De Geus, Eco J. Hoogendijk, Witte Hottenga, Jouke Jan Jung-Ying, Tzeng Lin, Dan-Yu Middeldorp, Christel M. Nolen, Willem A. Penninx, Brenda P. Smit, Johannes H. Sullivan, Patrick F. van Grootheest, Gerard Willemsen, Gonneke Zitman, Frans G. Coryell, William H. Knowles, James A. Lawson, William B. Levinson, Douglas F. Potash, James B. Scheftner, William A. Shi, Jianxin Weissman, Myrna M. Holsboer, Florian Muglia, Pierandrea Tozzi, Federica Blackwood, Douglas H. R. Boomsma, Dorret I. De Geus, Eco J. Hottenga, Jouke Jan MacIntyre, Donald J. McIntosh, Andrew McLean, Alan Middeldorp, Christel M. Nolen, Willem A. Penninx, Brenda P. Ripke, Stephan Smit, Johannes H. Sullivan, Patrick F. van Grootheest, Gerard Willemsen, Gonneke Zitman, Frans G. van den Oord, Edwin J. C. G. Holsboer, Florian Lucae, Susanne Binder, Elisabeth Mueller-Myhsok, Bertram Ripke, Stephan Czamara, Darina Kohli, Martin A. Ising, Marcus Uhr, Manfred Bettecken, Thomas Barnes, Michael R. Breen, Gerome Craig, Ian W. Farmer, Anne E. Lewis, Cathryn M. McGuffin, Peter Muglia, Pierandrea Byrne, Enda Gordon, Scott D. Heath, Andrew C. Henders, Anjali K. Hickie, Ian B. Madden, Pamela A. F. Martin, Nicholas G. Montgomery, Grant M. Nyholt, Dale R. Pergadia, Michele L. Wray, Naomi R. Hamilton, Steven P. McGrath, Patrick J. Shyn, Stanley I. Slager, Susan L. Oskarsson, Hoegni Sigurdsson, Engilbert Stefansson, Hreinn Stefansson, Kari Steinberg, Stacy Thorgeirsson, Thorgeir Levinson, Douglas F. Potash, James B. Shi, Jianxin Weissman, Myrna M. Guipponi, Michel Lewis, Glyn O'Donovan, Michael Tansey, Katherine E. Uher, Rudolf Coryell, William H. Knowles, James A. Lawson, William B. Levinson, Douglas F. Potash, James B. Scheftner, William A. Shi, Jianxin Weissman, Myrna M. Castro, Victor M. Churchill, Susanne E. Fava, Maurizio Gainer, Vivian S. Gallagher, Patience J. Goryachev, Sergey Iosifescu, Dan V. Kohane, Isaac S. Murphy, Shawn N. Perlis, Roy H. Smoller, Jordan W. Weilburg, Jeffrey B. Kutalik, Zoltan Preisig, Martin Grabe, Hans J. Nauck, Matthias Schulz, Andrea Teumer, Alexander Voelzke, Henry Landen, Mikael Lichtenstein, Paul Magnusson, Patrik Pedersen, Nancy Viktorin, Alexander CA Psychiat GWAS Consortium TI A mega-analysis of genome-wide association studies for major depressive disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE genetics; genome-wide association study; major depressive disorder; mega-analysis; meta-analysis ID CARDIOVASCULAR RISK-FACTORS; NATIONAL COMORBIDITY SURVEY; SEROTONIN TRANSPORTER GENE; BIPOLAR DISORDER; SUSCEPTIBILITY LOCI; PSYCHIATRIC-DISORDERS; MENTAL-DISORDERS; MOOD DISORDERS; TWIN REGISTRY; HUMAN HEIGHT AB Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5x10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9x10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status. Molecular Psychiatry (2013) 18, 497-511; doi:10.1038/mp.2012.21; published online 3 April 2012 C1 [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Daly, Mark J.; Ripke, Stephan] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Wray, Naomi R.] Univ Queensland, Queensland Inst Med Res, Brisbane, Qld 4072, Australia. [Lewis, Cathryn M.; Breen, Gerome; Craig, Ian W.; Farmer, Anne E.; McGuffin, Peter; Tansey, Katherine E.; Uher, Rudolf] Kings Coll London, Inst Psychiat, London, England. [Hamilton, Steven P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Weissman, Myrna M.; McGrath, Patrick J.] Columbia Univ, New York, NY 10027 USA. [Blackwood, Douglas H. R.; MacIntyre, Donald J.; McIntosh, Andrew; McLean, Alan] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Boomsma, Dorret I.; De Geus, Eco J.; Hottenga, Jouke Jan; Middeldorp, Christel M.; Willemsen, Gonneke] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Cichon, Sven; Degenhardt, Franziska; Gross, Magdalena; Herms, Stefan; Hoefels, Susanne; Maier, Wolfgang; Mattheisen, Manuel; Noeethen, Markus M.; Steffens, Michael] Univ Bonn, Bonn, Germany. [Heath, Andrew C.; Madden, Pamela A. F.; Pergadia, Michele L.] Washington Univ, St Louis, MO USA. [Byrne, Enda M.; Gordon, Scott D.; Henders, Anjali K.; Martin, Nicholas G.; Montgomery, Grant M.; Nyholt, Dale R.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Penninx, Brenda P.; Smit, Johannes H.; van Grootheest, Gerard] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Coryell, William H.; Potash, James B.] Univ Iowa, Iowa City, IA 52242 USA. [Rietschel, Marcella; Breuer, Rene; Frank, Josef; Treutlein, Jens] Heidelberg Univ, Cent Inst Mental Hlth, Heidelberg, Germany. [Sullivan, Patrick F.; Lin, Dan-Yu] Univ N Carolina, Chapel Hill, NC 27515 USA. [Shi, Jianxin] NCI, Bethesda, MD 20892 USA. [Grabe, Hans J.; Nauck, Matthias; Schulz, Andrea; Teumer, Alexander; Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. [Lichtenstein, Paul; Magnusson, Patrik; Pedersen, Nancy; Viktorin, Alexander] Karolinska Inst, S-10401 Stockholm, Sweden. [Fava, Maurizio; Gallagher, Patience J.; Iosifescu, Dan V.; Murphy, Shawn N.; Smoller, Jordan W.; Weilburg, Jeffrey B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kutalik, Zoltan] Univ Lausanne, CH-1015 Lausanne, Switzerland. [O'Donovan, Michael] Cardiff Univ, Cardiff CF10 3AX, S Glam, Wales. [Guipponi, Michel] Univ Geneva, CH-1211 Geneva 4, Switzerland. [Hickie, Ian B.] Univ Sydney, Sydney, NSW 2006, Australia. Univ Birmingham, Birmingham B15 2TT, W Midlands, England. [Jung-Ying, Tzeng] N Carolina State Univ, Raleigh, NC 27695 USA. [Knowles, James A.] Univ So Calif, Los Angeles, CA 90089 USA. [Kohane, Isaac S.] Brigham & Womens Hosp, Boston, MA 02115 USA. Queen Mary Univ London, London, England. [Lawson, William B.] Howard Univ, Washington, DC USA. [Lewis, Glyn] Univ Bristol, Bristol BS8 1TH, Avon, England. Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Nolen, Willem A.] Univ Groningen, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands. [Scheftner, William A.] Rush Univ, Med Ctr, Chicago, IL USA. [Shyn, Stanley I.] Univ Washington, Seattle, WA 98195 USA. [Slager, Susan L.] Mayo Clin, Rochester, MN 55905 USA. [van den Oord, Edwin J. C. G.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Zitman, Frans G.] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [Levinson, Douglas F.] Stanford Univ, Stanford, CA 94305 USA. RP Sullivan, PF (reprint author), Univ N Carolina, Dept Genet, CB 7264, Chapel Hill, NC 27599 USA. EM pfsulliv@med.unc.edu RI Lewis, Glyn/E-9944-2012; Breen, Gerome/A-5540-2010; Wray, Naomi/C-8639-2015; Mattheisen, Manuel/B-4949-2012; Magnusson, Patrik/C-4458-2017; Schulze, Thomas/H-2157-2013; Nolen, Willem/E-9006-2014; McGrath, Patrick/I-6410-2013; Lewis, Cathryn/A-5225-2010; Tansey, Katherine/B-1033-2013; McGuffin, Peter/A-1565-2012; McIntosh, Andrew/B-9379-2008; Uher, Rudolf/A-5477-2008; Colaus, PsyColaus/K-6607-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; van Grootheest, Gerard/C-6942-2014; Sigurdsson, Engilbert/D-2486-2014; OI Lewis, Glyn/0000-0001-5205-8245; Breen, Gerome/0000-0003-2053-1792; Wray, Naomi/0000-0001-7421-3357; Mattheisen, Manuel/0000-0002-8442-493X; MacIntyre, Donald J/0000-0001-6963-1335; Hamilton, Steven/0000-0001-8106-6260; Craig, Ian/0000-0002-4063-1005; McGrath, Patrick/0000-0001-7217-7321; Lewis, Cathryn/0000-0002-8249-8476; Tansey, Katherine/0000-0002-9663-3376; McGuffin, Peter/0000-0002-9888-2907; McIntosh, Andrew/0000-0002-0198-4588; Uher, Rudolf/0000-0002-2998-0546; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; van Grootheest, Gerard/0000-0003-4350-6661; Sigurdsson, Engilbert/0000-0001-9404-7982; de Geus, Eco/0000-0001-6022-2666; Landen, Mikael/0000-0002-4496-6451; lichtenstein, paul/0000-0003-3037-5287; Viktorin, Alexander/0000-0003-2141-2816; Stefansson, Hreinn/0000-0002-9331-6666; Nothen, Markus/0000-0002-8770-2464; Middeldorp, Christel/0000-0002-6218-0428; Thorgeirsson, Thorgeir/0000-0002-5149-7040 FU NIMH [MH085520, MH080403, MH061686, MH059542, MH075131, MH059552, MH059541, MH060912, MH086026, MH081802, MH072802, N01MH90003]; German Federal Ministry of Education and Research; National Genome Research Network 2 (NGFN-2); National Genome Research Network plus (NGFNplus); Integrated Genome Research Network (IG) MooDS [01GS08144, 01GS08147]; European Union [LSHM-CT-2006-037761, PIAP-GA-2008-218251, HEALTH-F2-2009-223423]; Medical Research Council (UK); Mental Health Research Network; Innovative Medicines Initiative [115008]; National Alliance for Research on Schizophrenia and Depression; i2b2 Center (Informatics for Integrating Biology and the Bedside); NIH [U54LM008748]; BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression [01ES0811]; Netherlands Organization for Scientific Research (MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20, 56-464-14192, 10-000-1002]; Center for Medical Systems Biology (NWO Genomics); Biobanking and Biomolecular Resources Research Infrastructure; VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam; NBIC/BioAssist/RK [2008.024]; European Science Foundation [EU/QLRT-2001-01254]; European Community; ENGAGE [HEALTH-F4-2007-201413]; European Science Council (ERC) [230374]; Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health; GAIN; Netherlands Organization for Scientific Research (NOW-VENI grant) [916-76-125]; Swiss National Science Foundation [3200B0-105993, 3200B0-118'308, 33CSC0-122661]; GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery - Verona, RD); Australian National Health; Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667]; Australian Research Council [FT0991360, FT0991022]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health [AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951, U01 DK066134]; Center for Inherited Disease Research (Baltimore, MD, USA); UK Medical Research Council; GlaxoSmithKline [G0701420]; National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London; Maudsley NHS Foundation Trust; Institute of Psychiatry, King's College London; UK Medical Research Council [G0000647]; European Commission [LSHB-CT-2003-503428]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Federal Ministry of Education and Research; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; German Research Foundation [DFG: GR 1912/5-1]; Swedish Ministry for Higher Education; Swedish Research Council [M-2005-1112]; GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254]; Swedish Foundation for Strategic Research; Wellcome Trust [076113, 085475]; [U54 RR020278]; [RC2MH089916] FX We thank the thousands of people with MDD who donated time and effort to make this research possible. The PGC was funded by NIMH Grants MH085520 (lead PI PFS) and MH080403. We thank our colleagues in the PGC Bipolar Disorder Working Group who allowed pre-publication access to their GWAS mega-analysis results for the MDD-BIP cross-disorder analyses. The Bonn/Mannheim (BoMa) GWAS was supported by the German Federal Ministry of Education and Research, within the context of the National Genome Research Network 2 (NGFN-2), the National Genome Research Network plus (NGFNplus) and the Integrated Genome Research Network (IG) MooDS (Grant 01GS08144 to S Cichon and MM Noethen, and Grant 01GS08147 to M Rietschel). The work at deCODE was funded by European Union Grants LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene) and HEALTH-F2-2009-223423 (Project PsychCNVs). GenPod was funded by the Medical Research Council (UK) and supported by the Mental Health Research Network. Genotyping of the GenPod sample was funded by the Innovative Medicines Initiative Joint Undertaking under Grant Agreement number 115008 (NEWMEDS). The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (DF Levinson), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (JB Potash), MH059541 (WA Scheftner) and MH060912 (MM Weissman). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The Depression Genes and Networks ARRA grant was funded by RC2MH089916. Funding for the Harvard i2b2 sample was provided by a subcontract to RH Perlis and JW Smoller as part of the i2b2 Center (Informatics for Integrating Biology and the Bedside), an NIH-funded National Center for Biomedical Computing based at Partners HealthCare System (U54LM008748, PI: IS Kohane), and by an NIMH Grant to RH Perlis (MH086026). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000.; Funding was from: the Netherlands Organization for Scientific Research (MagW/ZonMW Grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). CM Middeldorp was supported by the Netherlands Organization for Scientific Research (NOW-VENI grant 916-76-125). The PsyCoLaus study was supported by grants from the Swiss National Science Foundation (#3200B0-105993, #3200B0-118'308, 33CSC0-122661) and from GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery - Verona, R&D). We express our gratitude to the Lausanne inhabitants who volunteered to participate in the PsyCoLaus study. We also thank V Mooser, G Weaber and P Vollenweider who initiated the CoLaus project. Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (FT0991360, FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. RADIANT was funded by: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG. SHIP-LEGEND is funded by the German Research Foundation (DFG: GR 1912/5-1). Genotyping of STARstarD was supported by an NIMH Grant to SP Hamilton (MH072802).; STARstarD was funded by the National Institute of Mental Health (contract N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (U01 DK066134). This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. NR 87 TC 105 Z9 106 U1 13 U2 119 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD APR PY 2013 VL 18 IS 4 BP 497 EP 511 DI 10.1038/mp.2012.21 PG 15 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112CE UT WOS:000316568600016 ER PT J AU Abbas, AK Benoist, C Bluestone, JA Campbell, DJ Ghosh, S Hori, S Jiang, SP Kuchroo, VK Mathis, D Roncarolo, MG Rudensky, A Sakaguchi, S Shevach, EM Vignali, DAA Ziegler, SF AF Abbas, Abul K. Benoist, Christophe Bluestone, Jeffrey A. Campbell, Daniel J. Ghosh, Sankar Hori, Shohei Jiang, Shuiping Kuchroo, Vijay K. Mathis, Diane Roncarolo, Maria Grazia Rudensky, Alexander Sakaguchi, Shimon Shevach, Ethan M. Vignali, Dario A. A. Ziegler, Steve F. TI Regulatory T cells: recommendations to simplify the nomenclature SO NATURE IMMUNOLOGY LA English DT Letter C1 [Abbas, Abul K.] Univ Calif San Francisco, Sch Med, Dept Pathol, San Francisco, CA 94143 USA. [Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA USA. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Campbell, Daniel J.; Ziegler, Steve F.] Benaroya Res Inst, Immunol Program, Seattle, WA USA. [Ghosh, Sankar] Columbia Univ Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA. [Hori, Shohei] RIKEN Res Ctr Allergy & Immunol, Res Unit Immune Homeostasis, Yokohama, Kanagawa, Japan. [Jiang, Shuiping] Immunis Clin, Beijing, Peoples R China. [Kuchroo, Vijay K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Roncarolo, Maria Grazia] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, Div Regenerat Med Stem Cells & Gene Therapy, I-20132 Milan, Italy. [Rudensky, Alexander] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10021 USA. [Sakaguchi, Shimon] Osaka Univ, World Premier Initiat Immunol Frontier Res Ctr, Expt Immunol Lab, Osaka, Japan. [Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Vignali, Dario A. A.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. RP Abbas, AK (reprint author), Univ Calif San Francisco, Sch Med, Dept Pathol, San Francisco, CA 94143 USA. EM dario.vignali@stjude.org RI Sakaguchi, Shimon/C-9535-2009; OI RONCAROLO, Maria Grazia/0000-0002-2193-9186 FU Telethon [TGT11E01] NR 0 TC 176 Z9 183 U1 4 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD APR PY 2013 VL 14 IS 4 BP 307 EP 308 PG 2 WC Immunology SC Immunology GA 113EG UT WOS:000316648700001 PM 23507634 ER PT J AU Bell, BD Kitajima, M Larson, RP Stoklasek, TA Pang, K Sakamoto, K Wagner, KU Reizis, B Hennighausen, L Ziegler, SF AF Bell, Bryan D. Kitajima, Masayuki Larson, Ryan P. Stoklasek, Thomas A. Pang, Kristen Sakamoto, Kazuhito Wagner, Kay-Uwe Reizis, Boris Hennighausen, Lothar Ziegler, Steven F. TI The transcription factor STAT5 is critical in dendritic cells for the development of T(H)2 but not T(H)1 responses SO NATURE IMMUNOLOGY LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; MEDIATED SIGNAL-TRANSDUCTION; ATOPIC-DERMATITIS; T-CELLS; FLUORESCEIN ISOTHIOCYANATE; CONTACT HYPERSENSITIVITY; IMMUNE-RESPONSES; TSLP; INFLAMMATION; SKIN AB Dendritic cells (DCs) are critical in immune responses, linking innate and adaptive immunity. We found here that DC-specific deletion of the transcription factor STAT5 was not critical for development but was required for T helper type 2 (T(H)2), but not T(H)1, allergic responses in both the skin and lungs. Loss of STAT5 in DCs led to the inability to respond to thymic stromal lymphopoietin (TSLP). STAT5 was required for TSLP-dependent DC activation, including upregulation of the expression of costimulatory molecules and chemokine production. Furthermore, T(H)2 responses in mice with DC-specific loss of STAT5 resembled those seen in mice deficient in the receptor for TSLP. Our results show that the TSLP-STAT5 axis in DCs is a critical component for the promotion of type 2 immunity at barrier surfaces. C1 [Bell, Bryan D.; Kitajima, Masayuki; Larson, Ryan P.; Stoklasek, Thomas A.; Pang, Kristen; Ziegler, Steven F.] Benaroya Res Inst Virginia Mason, Program Immunol, Seattle, WA USA. [Bell, Bryan D.; Kitajima, Masayuki; Larson, Ryan P.; Stoklasek, Thomas A.; Ziegler, Steven F.] Univ Washington, Dept Immunol, Sch Med, Seattle, WA 98195 USA. [Sakamoto, Kazuhito; Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA. [Reizis, Boris] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY USA. [Hennighausen, Lothar] US Natl Inst Hlth, Lab Genet & Physiol, Bethesda, MD USA. RP Ziegler, SF (reprint author), Benaroya Res Inst Virginia Mason, Program Immunol, Seattle, WA USA. EM sziegler@benaroyaresearch.org OI Reizis, Boris/0000-0003-1140-7853 FU US National Institutes of Health [R01-AI068731, R01-AR056113, R01-AR055695, P01-HL098067, 5T32AI007411-19] FX We thank D. Kaplan (University of Minnesota) for langerin-Cre mice; I. Forster (University of Bonn) for mice with a transgene encoding GFP in the Ccl17locus; T. Nakayama (Chiba University) for pMX-Cre-IRES-GFP; D. Rawlings and H. Kerns (Seattle Children's Research Institute) for Btk- and Tec-deficient bone marrow; J. Hamerman and D. Campbell for discussions of the manuscript; S. Ma and W Xu for technical support; and M. Warren and S. McCarty for administrative support. Supported by the US National Institutes of Health (R01-AI068731, R01-AR056113, R01-AR055695 and P01-HL098067 to S.F.Z., and 5T32AI007411-19 to B.D.B.). NR 40 TC 53 Z9 56 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD APR PY 2013 VL 14 IS 4 BP 364 EP 371 DI 10.1038/ni.2541 PG 8 WC Immunology SC Immunology GA 113EG UT WOS:000316648700011 PM 23435120 ER PT J AU Becerra, SP Notario, V AF Becerra, S. Patricia Notario, Vicente TI The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential SO NATURE REVIEWS CANCER LA English DT Review ID EPITHELIUM-DERIVED FACTOR; ENDOTHELIAL GROWTH-FACTOR; CEREBELLAR GRANULE CELLS; ANTI-ANGIOGENIC ACTIVITY; ORTHOTOPIC OSTEOSARCOMA GROWTH; FACTOR INHIBITS ANGIOGENESIS; ADIPOSE TRIGLYCERIDE LIPASE; RETINAL-PIGMENT EPITHELIUM; MEDIATED GENE-TRANSFER; TUMOR-GROWTH AB The potent actions of pigment epithelium-derived factor (PEDF) on tumour-associated cells, and its extracellular localization and secretion, stimulated research on this multifunctional serpin. Such studies have identified several PEDF receptors and downstream signalling pathways. Known cellular PEDF responses have expanded from the initial discovery that PEDF induces retinoblastoma cell differentiation to its anti-angiogenic, antitumorigenic and antimetastatic properties. Although the diversity of PEDF activities seems to be complex, they are consistent with the varied mechanisms that regulate this multimodal factor. If PEDF is to be used for cancer management, a deeper appreciation of its many functions and mechanisms of action is needed. C1 [Becerra, S. Patricia] NEI, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Notario, Vicente] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. RP Becerra, SP (reprint author), NEI, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM becerrap@nei.nih.gov FU US National Institutes of Health (NIH) [1ZIA-EY000306]; US National Cancer Institute (NCI) [R01-CA134727] FX This work was supported in part by the intramural research program of the US National Institutes of Health (NIH) (Project number 1ZIA-EY000306) to S. P. B. and by grant R01-CA134727 from the US National Cancer Institute (NCI) to V.N. NR 178 TC 67 Z9 71 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD APR PY 2013 VL 13 IS 4 BP 258 EP 271 DI 10.1038/nrc3484 PG 14 WC Oncology SC Oncology GA 111YH UT WOS:000316557500013 PM 23486238 ER PT J AU Rangel, A Race, B Striebel, J Chesebro, B AF Rangel, A. Race, B. Striebel, J. Chesebro, B. TI Non-amyloid and amyloid prion protein deposits in prion-infected mice differ in blockage of interstitial brain fluid SO NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY LA English DT Article DE basement membrane; brain interstitial fluid; cerebral amyloid angiopathy; glycophosphatidylinositol anchor; prion ID 87V MURINE SCRAPIE; ALZHEIMERS-DISEASE; ANGIOPATHY; PATHOLOGY; PATHOPHYSIOLOGY; DISORDERS; PHENOTYPE; PRNP AB Aims Prion diseases are characterized by brain deposits of misfolded aggregated protease-resistant prion protein (PrP), termed PrPres. In humans and animals, PrPres is found as either disorganized non-amyloid aggregates or organized amyloid fibrils. Both PrPres forms are found in extracellular spaces of the brain. Thus, both might block drainage of brain interstitial fluid (ISF). The present experiments studied whether ISF blockage occurred during amyloid and/or non-amyloid prion diseases. Methods Various-sized fluorescein-labelled ISF tracers were stereotactically inoculated into the striatum of adult mice. At times from 5min to 77h, uninfected and scrapie-infected mice were compared. C57BL/10 mice expressing wild-type anchored PrP, which develop non-amyloid PrPres similar to humans with sporadic CreutzfeldtJakob disease, were compared with Tg44+/+ mice (transgenic mice secreting anchorless PrP) expressing anchorless PrP, which develop amyloid PrPres similar to certain human familial prion diseases. Results In C57BL/10 mice, extensive non-amyloid PrPres aggregate deposition was not associated with abnormal clearance kinetics of tracers. In contrast, scrapie-infected Tg44+/+ mice showed blockage of tracer clearance and colocalization of tracer with perivascular PrPres amyloid. Conclusions As tracer localization and clearance was normal in infected C57BL/10 mice, ISF blockage was not an important pathogenic mechanism in this model. Therefore, ISF blockage is unlikely to be a problem in non-amyloid human prion diseases such as sporadic CreutzfeldtJakob disease. In contrast, partial ISF blockage appeared to be a possible pathogenic mechanism in Tg44+/+ mice. Thus this mechanism might also influence human amyloid prion diseases where expression of anchorless or mutated PrP results in perivascular amyloid PrPres deposition and cerebral amyloid angiopathy. C1 [Rangel, A.; Race, B.; Striebel, J.; Chesebro, B.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM bchesebro@nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors thank Dan Long, Lori Lubke and Nancy Kurtz for histological technical support. We also thank Drs Martin Jeffrey and Suzette Priola for calling our attention to previous studies of the ISF system, Drs Suzette Priola, Byron Caughey and John Portis for critical evaluation of the manuscript, Lynne Raymond for assistance in breeding the transgenic mice, Katie Phillips for assistance with the stereotactic surgeries, Jeffrey Severson for animal husbandry, Anita Mora for assistance with digital figures, and Drs Gerald Baron and David Dorward for assistance with confocal microscopy. This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 31 TC 4 Z9 4 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0305-1846 J9 NEUROPATH APPL NEURO JI Neuropathol. Appl. Neurobiol. PD APR PY 2013 VL 39 IS 3 BP 217 EP 230 DI 10.1111/j.1365-2990.2012.01303.x PG 14 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 107BD UT WOS:000316188800002 PM 22998478 ER PT J AU Sambataro, F Mattay, VS Thurin, K Safrin, M Rasetti, R Blasi, G Callicott, JH Weinberger, DR AF Sambataro, Fabio Mattay, Venkata S. Thurin, Kristina Safrin, Martin Rasetti, Roberta Blasi, Giuseppe Callicott, Joseph H. Weinberger, Daniel R. TI Altered Cerebral Response During Cognitive Control: A Potential Indicator of Genetic Liability for Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE response inhibition; functional magnetic resonance imaging; anterior cingulate; heritability; intermediate phenotype ID ANTERIOR CINGULATE CORTEX; WORKING-MEMORY; EFFECTIVE CONNECTIVITY; ONSET SCHIZOPHRENIA; PREFRONTAL CORTEX; NETWORK DYNAMICS; DYSFUNCTION; RELATIVES; INHIBITION; RISK AB Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. Altogether, 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-level-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task ('flanker task') to identify brain activity and connectivity associated with response inhibition and conflict monitoring, and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls. During response inhibition, again similar to patients with schizophrenia, siblings showed decreased activity in the anterior cingulate (ACC), along with increased functional coupling with the dorsolateral prefrontal cortex (PFC) when compared to normal controls. Our findings show altered ACC activity and PFC connectivity in unaffected siblings and patients with schizophrenia during response inhibition. These results suggest that such changes in the neural activity underlying aspects of cognitive control may represent a potential intermediate phenotype for the investigation of the genetic basis of schizophrenia. Neuropsychopharmacology (2013) 38, 846-853; doi:10.1038/npp.2012.250; published online 9 January 2013 C1 [Sambataro, Fabio] Ist Italiano Tecnol UNIPr, Brain Ctr Motor & Social Cognit, Parma, Italy. [Sambataro, Fabio; Mattay, Venkata S.; Thurin, Kristina; Safrin, Martin; Rasetti, Roberta; Blasi, Giuseppe; Callicott, Joseph H.; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Mattay, Venkata S.; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP Weinberger, DR (reprint author), Lieber Inst Brain Dev, Johns Hopkins Med Campus,855 North Wolfe St, Baltimore, MD 21205 USA. EM drweinberger@libd.org RI Sambataro, Fabio/E-3426-2010; Callicott, Joseph/C-9102-2009 OI Sambataro, Fabio/0000-0003-2102-416X; Callicott, Joseph/0000-0003-1298-3334 FU National Institute of Mental Health, NIH, Bethesda, MD, USA FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. NR 44 TC 14 Z9 14 U1 3 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2013 VL 38 IS 5 BP 846 EP 853 DI 10.1038/npp.2012.250 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 106RB UT WOS:000316161300013 PM 23299932 ER PT J AU Farrell, MS Pei, Y Wan, YH Yadav, PN Daigle, TL Urban, DJ Lee, HM Sciaky, N Simmons, A Nonneman, RJ Huang, XP Hufeisen, SJ Guettier, JM Moy, SS Wess, J Caron, MG Calakos, N Roth, BL AF Farrell, Martilias S. Pei, Ying Wan, Yehong Yadav, Prem N. Daigle, Tanya L. Urban, Daniel J. Lee, Hyeong-Min Sciaky, Noah Simmons, Arkeen Nonneman, Randal J. Huang, Xi-Ping Hufeisen, Sandy J. Guettier, Jean-Marc Moy, Sheryl S. Wess, Juergen Caron, Marc G. Calakos, Nicole Roth, Bryan L. TI A G alpha(s) DREADD Mouse for Selective Modulation of cAMP Production in Striatopallidal Neurons SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE DREADD; striatopallidal; amphetamine; G-alpha-s; striatum; Gs ID PROTEIN-COUPLED RECEPTORS; BEHAVIORAL SENSITIZATION; SYNAPTIC PLASTICITY; DOPAMINE-RECEPTORS; NUCLEUS-ACCUMBENS; ADENOSINE A(2A); GENE-EXPRESSION; REMOTE-CONTROL; DISORDERS; COCAINE AB Here, we describe a newly generated transgenic mouse in which the Gs DREADD (rM3Ds), an engineered G protein-coupled receptor, is selectively expressed in striatopallidal medium spiny neurons (MSNs). We first show that in vitro, rM3Ds can couple to G alpha(olf) and induce cAMP accumulation in cultured neurons and HEK-T cells. The rM3Ds was then selectively and stably expressed in striatopallidal neurons by creating a transgenic mouse in which an adenosine2A (adora2a) receptor-containing bacterial artificial chromosome was employed to drive rM3Ds expression. In the adora2A-rM3Ds mouse, activation of rM3Ds by clozapine-N-oxide (CNO) induces DARPP-32 phosphorylation, consistent with the known consequence of activation of endogenous striatal G alpha(s)-coupled GPCRs. We then tested whether CNO administration would produce behavioral responses associated with striatopallidal G(s) signaling and in this regard CNO dose-dependently decreases spontaneous locomotor activity and inhibits novelty induced locomotor activity. Last, we show that CNO prevented behavioral sensitization to amphetamine and increased AMPAR/NMDAR ratios in transgene-expressing neurons of the nucleus accumbens shell. These studies demonstrate the utility of adora2a-rM3Ds transgenic mice for the selective and noninvasive modulation of G alpha(s) signaling in specific neuronal populations in vivo. This unique tool provides a new resource for elucidating the roles of striatopallidal MSN G alpha(s) signaling in other neurobehavioral contexts. Neuropsychopharmacology (2013) 38, 859-862; doi:10.1038/npp.2012.251; published online 16 January 2013 C1 [Farrell, Martilias S.; Pei, Ying; Yadav, Prem N.; Urban, Daniel J.; Lee, Hyeong-Min; Sciaky, Noah; Huang, Xi-Ping; Hufeisen, Sandy J.; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Wan, Yehong; Caron, Marc G.; Calakos, Nicole] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Daigle, Tanya L.; Caron, Marc G.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Simmons, Arkeen] Elizabeth City State Univ, Elizabeth City, NC USA. [Nonneman, Randal J.; Moy, Sheryl S.; Roth, Bryan L.] Univ N Carolina, Carolina Inst Dev Disabil, Chapel Hill, NC 27599 USA. [Guettier, Jean-Marc; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. [Moy, Sheryl S.; Roth, Bryan L.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Caron, Marc G.; Calakos, Nicole] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. [Roth, Bryan L.] Univ N Carolina, Program Neurosci, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. RP Roth, BL (reprint author), Univ N Carolina, Chapel Hill Med Sch, Dept Pharmacol, Genet Med Bldg Room 4072, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu RI Lee, HM/D-2777-2011; Roth, Bryan/F-3928-2010 FU NIH [1F31MH091921, RO1MH61887, U19MH82441]; NIMH Psychoactive Drug Screening Program; Michael Hooker Chair in Pharmacology; NICHD [P30 HD03110, 5R37-MH-073853, 1F32-DA030026]; NIH; Forest Laboratories; NeuroSearch; F Hoffmann La Roche; Lundbeck USA; Merck; Omeros; [R01NS064577]; [K02NS054840] FX This work was funded by NIH Grant # 1F31MH091921 to MSF and RO1MH61887, U19MH82441, the NIMH Psychoactive Drug Screening Program and the Michael Hooker Chair in Pharmacology to BLR, R01NS064577 and K02NS054840 to NC, NICHD Grant #P30 HD03110 to Joe Piven (UNC), 5R37-MH-073853 to MCG, and 1F32-DA030026 to TLD.; Dr Roth's research is supported by the NIH. Dr Roth has consulted for Otsuka Pharmaceuticals, Merck, Sunovion, Albany Molecular Research, Pfizer Pharmaceuticals, Finnegan, Henderson, Farabow, Garrett And Dunner, L.l.p, and Venrock. Dr Roth receives compensation for serving as Associate Editor of the Journal of Clinical Investigation. MGC has received funds for Sponsored Research Agreements unrelated to this work from Forest Laboratories, NeuroSearch, F Hoffmann La Roche and Lundbeck USA, as well as consulting fees from Merck and Omeros. An unrestricted gift to Duke University was provided by Lundbeck USA to support Neuroscience research unrelated to this work in the laboratory of MGC MSF, YP, YW, PNY, TLD, NS, AS, RJN, XH, SJH, JMG, SSM, JW, and NC report no conflict of interest and have nothing to disclose. NR 39 TC 34 Z9 35 U1 0 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2013 VL 38 IS 5 BP 854 EP 862 DI 10.1038/npp.2012.251 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 106RB UT WOS:000316161300014 PM 23303063 ER PT J AU Turtzo, LC Budde, MD Gold, EM Lewis, BK Janes, L Yarnell, A Grunberg, NE Watson, W Frank, JA AF Turtzo, L. Christine Budde, Matthew D. Gold, Eric M. Lewis, Bobbi K. Janes, Lindsay Yarnell, Angela Grunberg, Neil E. Watson, William Frank, Joseph A. TI The evolution of traumatic brain injury in a rat focal contusion model SO NMR IN BIOMEDICINE LA English DT Article DE traumatic brain injury; controlled cortical impact; MRI; hemorrhage; autofluorescence ID CONTROLLED CORTICAL IMPACT; GADOLINIUM OXIDE NANOPARTICLES; CENTRAL-NERVOUS-SYSTEM; MARROW STROMAL CELLS; NEURAL STEM-CELLS; SUPERFICIAL SIDEROSIS; HEAD-INJURY; VASCULAR DISRUPTION; FEMALE RATS; IN-VIVO AB Serial MRI facilitates the in vivo analysis of the intra- and intersubject evolution of traumatic brain injury lesions. Despite the availability of MRI, the natural history of experimental focal contusion lesions in the controlled cortical impact (CCI) rat model has not been well described. We performed CCI on rats and MRI during the acute to chronic stages of cerebral injury to investigate the time course of changes in the brain. Female Wistar rats underwent CCI of their left motor cortex with a flat impact tip driven by an electromagnetic piston. In vivo MRI was performed at 7T serially over 6weeks post-CCI. The appearances of CCI-induced lesions and lesion-associated cortical volumes were variable on MRI, with the percentage change in cortical volume of the CCI ipsilateral side relative to the contralateral side ranging from 18% within 2h of injury on day 0 to a peak of 35% on day 1, and a trough of 28% by week 5/6, with an average standard deviation of +/- 14% at any given time point. In contrast, the percentage change in cortical volume of the ipsilateral side relative to the contralateral side in control rats was not significant (1 +/- 2%). Hemorrhagic conversion within and surrounding the CCI lesion occurred between days 2 and 9 in 45% of rats, with no hemorrhage noted on the initial scan. Furthermore, hemorrhage and hemosiderin within the lesion were positive for Prussian blue and highly autofluorescent on histological examination. Although some variation in injuries may be technique related, the divergence of similar lesions between initial and final scans demonstrates the inherent biological variability of the CCI rat model. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 [Turtzo, L. Christine; Gold, Eric M.; Janes, Lindsay] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Turtzo, L. Christine; Budde, Matthew D.; Gold, Eric M.; Lewis, Bobbi K.; Janes, Lindsay; Frank, Joseph A.] NIH, Frank Lab, Bethesda, MD 20892 USA. [Yarnell, Angela; Grunberg, Neil E.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Watson, William] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Turtzo, LC (reprint author), NIH, Frank Lab, Bldg 10,Room B1N256 MSC 1074,10 Ctr Dr, Bethesda, MD 20892 USA. EM l.turtzo@nih.gov; jafrank@helix.nih.gov FU Department of Defense through the Center for Neuroscience and Regenerative Medicine [300604-8.01-60855]; Intramural Research Program of the Clinical Center at the National Institutes of Health FX This work was supported by funding from the Department of Defense through the Center for Neuroscience and Regenerative Medicine (Henry M. Jackson Foundation Award #300604-8.01-60855) and from the Intramural Research Program of the Clinical Center at the National Institutes of Health. NR 78 TC 7 Z9 7 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD APR PY 2013 VL 26 IS 4 BP 468 EP 479 DI 10.1002/nbm.2886 PG 12 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 107IK UT WOS:000316209200014 PM 23225324 ER PT J AU Seidel, J Xi, WZ Kakareka, JW Pohida, TJ Jagoda, EM Green, MV Choyke, PL AF Seidel, Jurgen Xi, Wenze Kakareka, John W. Pohida, Thomas J. Jagoda, Elaine M. Green, Michael V. Choyke, Peter L. TI Performance characteristics of a positron projection imager for mouse whole-body imaging SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Pre-clinical imaging; Cancer drug development; Mouse whole-body imaging; Positron projection imaging ID EMISSION MAMMOGRAPHY PEM; SYSTEM AB Introduction: We describe a prototype positron projection imager (PPI) for visualizing the whole-body biodistribution of positron-emitting compounds in mouse-size animals. The final version of the PPI will be integrated into the MONICA portable dual-gamma camera system to allow the user to interchangeably image either single photon or positron-emitting compounds in a shared software and hardware environment. Methods: A Mouse is placed in the mid-plane between two identical, opposed, pixelated LYSO arrays separated by 21.8-cm and in time coincidence. An image of the distribution of positron decays in the animal is formed on this mid-plane by coincidence events that fall within a small cone angle perpendicular to the two detectors and within a user-specified energy window. We measured the imaging performance of this device with phantoms and in tests performed in mice injected with various compounds labeled with positron-emitting isotopes. Results: Representative performance measurements yielded the following results (energy window 250-d650 keV, cone angle 3.5 degrees): resolution in the image mid-plane, 1.66-mm (FWHM), resolution +/- 1.5-cm above and below the image plane, 2.2-mm (FWHM), sensitivity: 0.237-cps/kBq (8.76-cps/mu Ci) F-18 (0.024% absolute). Energy resolution was 15.9% with a linear-count-rate operating range of 0-14.8 MBq (0-400 mu Ci) and a corrected sensitivity variation across the field-of-view of <3%. Whole-body distributions of [F-18] FDG and [F-18] fluoride were well visualized in mice of typical size. Conclusion: Performance measurements and field studies indicate that the PPI is well suited to whole-body positron projection imaging of mice. When integrated into the MONICA gamma camera system, the PPI may be particularly useful early in the drug development cycle where, like MONICA, basic whole-body biodistribution data can direct future development of the agent under study and where logistical factors (e.g., available imaging space, non-portability, and cost) may be limitations. Published by Elsevier Inc. C1 [Seidel, Jurgen; Xi, Wenze; Jagoda, Elaine M.; Green, Michael V.; Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Seidel, Jurgen; Xi, Wenze; Green, Michael V.] SAIC Frederick, Frederick, MD USA. [Kakareka, John W.; Pohida, Thomas J.] NIH, Signal Proc & Instrumentat Sect, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM pchoyke@mail.nih.gov OI Kakareka, John/0000-0003-0072-0035 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program, National Institutes of Health, Center for Information Technology FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was also supported by the Intramural Research Program, National Institutes of Health, Center for Information Technology. NR 11 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 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD APR PY 2013 VL 40 IS 3 BP 321 EP 330 DI 10.1016/j.nucmedbio.2012.12.003 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 111FP UT WOS:000316507400003 PM 23402672 ER PT J AU Koo, E Chang, JR Agron, E Clemons, TE Sperduto, RD Ferris, FL Chew, EY AF Koo, Euna Chang, Jessica R. Agron, Elvira Clemons, Traci E. Sperduto, Robert D. Ferris, Frederick L., III Chew, Emily Y. CA Age-Related Eye Dis Study Res Grp TI Ten-Year Incidence Rates of Age-Related Cataract in the Age-Related Eye Disease Study (AREDS): AREDS Report No. 33 SO OPHTHALMIC EPIDEMIOLOGY LA English DT Article DE cataract; classification; incidence; lens; photographic ID BEAVER DAM EYE; VISUAL IMPAIRMENT; LENS OPACITIES; UNITED-STATES; POPULATION; PREVALENCE; INTERVAL; SURGERY; ADULTS; CARE AB Purpose: To investigate the long-term incidence of age-related cataract and cataract surgery in the Age-Related Eye Disease Study (AREDS) cohort. Methods: Baseline and annual lens photographs of participants, aged 55-80 years, were graded centrally for nuclear, cortical, and posterior subcapsular (PSC) lens opacities using the AREDS System for Classifying Cataracts. Progression from a baseline status of no or mild lens opacity to at least moderate severity was analyzed and cumulative incidence estimated rates were calculated for each lens opacity type and cataract surgery stratified by age, sex, race, age-related macular degeneration category, multivitamin (Centrum) use and history of diabetes. Results: The ten-year cumulative incidence was 43.6% for any cataract, 23.1% for nuclear cataract, 22.0% for cortical cataract, 13.1% for PSC cataract, and 26.8% for cataract surgery. The 5-and 10-year incidence rates of all cataract types and cataract surgery were significantly higher with increasing age. Females had a higher incidence of any, nuclear and cortical cataract and cataract surgery (p=0.02-0.05). Incidence of cortical cataract was higher in non-white participants (p=0.001). Conclusions: These results are largely consistent with the results of previous observational studies. Long-term incidence rates of type-specific cataract can be useful in designing clinical studies of age-related cataract. C1 [Koo, Euna; Agron, Elvira; Ferris, Frederick L., III; Chew, Emily Y.] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Chang, Jessica R.] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.; Sperduto, Robert D.] EMMES Corp, Rockville, MD USA. RP Chew, EY (reprint author), NEI, NIH, Bldg 10,CRC Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU National Eye Institute/National Institutes of Health, Department of Health and Human Services, Bethesda, MD; NIH; Pfizer; Howard Hughes Medical Institute-National Institutes of Health Scholars Program FX This study is supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health, Department of Health and Human Services, Bethesda, MD. The first two authors receive support from a public-private partnership supported jointly by the NIH and Pfizer for the Clinical Research Training Program at the National Institutes of Health (Euna Koo) and the Howard Hughes Medical Institute-National Institutes of Health Scholars Program (Jessica R. Chang). NR 20 TC 6 Z9 6 U1 0 U2 16 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0928-6586 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD APR PY 2013 VL 20 IS 2 BP 71 EP 81 DI 10.3109/09286586.2012.759598 PG 11 WC Ophthalmology SC Ophthalmology GA 110BZ UT WOS:000316418400001 PM 23510310 ER PT J AU Clemons, TE Gillies, MC Chew, EY Bird, AC Peto, T Wang, JJ Mitchell, P Ramdas, WD Vingerling, JR AF Clemons, Traci E. Gillies, Mark C. Chew, Emily Y. Bird, Alan C. Peto, Tunde Wang, Jie Jin Mitchell, Paul Ramdas, Wishal D. Vingerling, Johannes R. CA Macular Telangiectasia Project Res TI Medical Characteristics of Patients with Macular Telangiectasia Type 2 (MacTel Type 2) MacTel Project Report No. 3 SO OPHTHALMIC EPIDEMIOLOGY LA English DT Article DE Cohort Study; diabetes; idiopathic macular telangiectasia; macular telangiectasia type 2; retinal disease ID JUXTAFOVEOLAR RETINAL TELANGIECTASIS; DIABETIC-RETINOPATHY; PREVALENCE; EYE AB Purpose: To determine whether the prevalences of various systemic conditions in participants of the MacTel Project Natural History Observation (NHO) Study differ from the corresponding prevalences in the general population. Methods: This report compares the prevalence of systemic disease in participants of the NHO Study with age- and sex-matched controls from three population-based studies from the US, the Netherlands and Australia. Bootstrap simulations were used to evaluate the impact and reliability of the computed statistics. Results: We identified a number of systemic conditions that appear to be more prevalent in cases with macular telangiectasia (MacTel) Type 2 than in the general population that were matched for age and sex with the MacTel cases. Patients with MacTel Type 2 had significantly increased prevalence of diabetes mellitus, higher prevalence of obesity, hypertension and history of cardiovascular disease, compared to their same-aged peers in generally older communities. Conclusion: Systemic disease associated with MacTel Type 2 may help to improve understanding of possible causes of MacTel Type 2. It is hoped that future studies will help to improve our understanding of the pathogenesis of the condition and lead to potential treatments for this ocular disease. C1 [Clemons, Traci E.] EMMES Corp, Rockville, MD 20850 USA. [Gillies, Mark C.] Univ Sydney, Save Sight Inst, Sydney, NSW 2006, Australia. [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. [Bird, Alan C.; Peto, Tunde] Moorfields Eye Hosp, London, England. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Millennium Inst, Ctr Vis Res, Sydney, NSW 2006, Australia. [Ramdas, Wishal D.; Vingerling, Johannes R.] Erasmus Univ, Dept Ophthalmol & Epidemiol, Rotterdam, Netherlands. RP Clemons, TE (reprint author), EMMES Corp, 401 N Washington St Suite 700, Rockville, MD 20850 USA. EM tclemons@emmes.com RI Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014 OI Wang, Jie Jin/0000-0001-9491-4898; NR 17 TC 2 Z9 2 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0928-6586 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD APR PY 2013 VL 20 IS 2 BP 109 EP 113 DI 10.3109/09286586.2013.766757 PG 5 WC Ophthalmology SC Ophthalmology GA 110BZ UT WOS:000316418400006 PM 23510315 ER PT J AU Panlilio, LV Justinova, Z Goldberg, SR AF Panlilio, Leigh V. Justinova, Zuzana Goldberg, Steven R. TI Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Endocannabinoid system; CB1 receptors; Nuclear receptors; Behavior; Drug abuse; Animal models ID ACID-AMIDE-HYDROLASE; CONDITIONED PLACE PREFERENCE; CANNABINOID CB1 RECEPTOR; CHRONIC DELTA-9-TETRAHYDROCANNABINOL TREATMENT; BRAIN-STIMULATION REWARD; VENTRAL TEGMENTAL AREA; INDUCED BEHAVIORAL SENSITIZATION; INTRACRANIAL SELF-STIMULATION; VOLUNTARY ALCOHOL-CONSUMPTION; NUCLEUS-ACCUMBENS DOPAMINE AB Enhancing the effects of endogenously-released cannabinoid ligands in the brain might provide therapeutic effects more safely and effectively than administering drugs that act directly at the cannabinoid receptor. Inhibitors of fatty acid amide hydrolase (FAAH) prevent the breakdown of endogenous ligands for cannabinoid receptors and peroxisome proliferator-activated receptors (PPAR), prolonging and enhancing the effects of these ligands when they are naturally released. This review considers recent research on the effects of FAAH inhibitors and PPAR activators in animal models of addiction and cognition (specifically learning and memory). These studies show that FAAH inhibitors can produce potentially therapeutic effects, some through cannabinoid receptors and some through PPAR. These effects include enhancing certain forms of learning, counteracting the rewarding effects of nicotine and alcohol, relieving symptoms of withdrawal from cannabis and other drugs, and protecting against relapse-like reinstatement of drug self-administration. Since FAAH inhibition might have a wide range of therapeutic actions but might also share some of the adverse effects of cannabis, it is noteworthy that at least one FAAH-inhibiting drug (URB597) has been found to have potentially beneficial effects but no indication of liability for abuse or dependence. Although these areas of research are new, the preliminary evidence indicates that they might lead to improved therapeutic interventions and a better understanding of the brain mechanisms underlying addiction and memory. Published by Elsevier Inc. C1 [Panlilio, Leigh V.; Justinova, Zuzana; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Justinova, Zuzana] Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Sch Med, Baltimore, MD 21228 USA. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sgoldber@mail.nih.gov RI Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; Department of Psychiatry, MPRC, University of Maryland School of Medicine FX Preparation of this manuscript was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services and Department of Psychiatry, MPRC, University of Maryland School of Medicine. NR 331 TC 37 Z9 37 U1 3 U2 31 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD APR PY 2013 VL 138 IS 1 BP 84 EP 102 DI 10.1016/j.pharmthera.2013.01.003 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 111KQ UT WOS:000316520600007 PM 23333350 ER PT J AU Chen, MY Shanbhag, SM Arai, AE AF Chen, Marcus Y. Shanbhag, Sujata M. Arai, Andrew E. TI Submillisievert Median Radiation Dose for Coronary Angiography with a Second-Generation 320-Detector Row CT Scanner in 107 Consecutive Patients SO RADIOLOGY LA English DT Article ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; ACUTE CHEST-PAIN; IMAGE-QUALITY; DIAGNOSTIC-ACCURACY; ITERATIVE RECONSTRUCTION; ARTERY-DISEASE; HEART-RATE; EXPOSURE; PERFORMANCE; MULTICENTER AB Purpose: To (a) use a new second-generation wide-volume 320-detector row computed tomographic (CT) scanner to explore optimization of radiation exposure in coronary CT angiography in an unselected and consecutive cohort of patients referred for clinical purposes and (b) compare estimated radiation exposure and image quality with that from a cohort of similar patients who underwent imaging with a previous first-generation CT system. Materials and Methods: The study was approved by the institutional review board, and all subjects provided written consent. Coronary CT angiography was performed in 107 consecutive patients with a new second-generation 320-detector row unit. Estimated radiation exposure and image quality were compared with those from 100 consecutive patients who underwent imaging with a previous first-generation scanner. Effective radiation dose was estimated by multiplying the dose-length product by an effective dose conversion factor of 0.014 mSv/mGy . cm and reported with size-specific dose estimates (SSDEs). Image quality was evaluated by two independent readers. Results: The mean age of the 107 patients was 55.4 years +/- 12.0 (standard deviation); 57 patients (53.3%) were men. The median body mass index was 27.3 kg/m(2) (range, 18.1-47.2 kg/m(2)); however, 71 patients (66.4%) were overweight, obese, or morbidly obese. A tube potential of 100 kV was used in 97 patients (90.6%), single-volume acquisition was used in 104 (97.2%), and prospective electrocardiographic gating was used in 106 (99.1%). The mean heart rate was 57.1 beats per minute +/- 11.2 (range, 34-96 beats per minute), which enabled single-heartbeat scans in 100 patients (93.4%). The median radiation dose was 0.93 mSv (interquartile range [IQR], 0.58-1.74 mSv) with the second-generation unit and 2.67 mSv (IQR, 1.68-4.00 mSv) with the first-generation unit (P < .0001). The median SSDE was 6.0 mGy (IQR, 4.1-10.0 mGy) with the second-generation unit and 13.2 mGy (IQR, 10.2-18.6 mGy) with the first-generation unit (P < .0001). Overall, the radiation dose was less than 0.5 mSv for 23 of the 107 CT angiography examinations (21.5%), less than 1 mSv for 58 (54.2%), and less than 4 mSv for 103 (96.3%). All studies were of diagnostic quality, with most having excellent image quality. Three of four image quality indexes were significantly better with the second-generation unit compared with the first-generation unit. Conclusion: The combination of a gantry rotation time of 275 msec, wide volume coverage, iterative reconstruction, automated exposure control, and larger x-ray power generator of the second-generation CT scanner provides excellent image quality over a wide range of body sizes and heart rates at low radiation doses. (c) RSNA, 2013 C1 [Chen, Marcus Y.; Shanbhag, Sujata M.; Arai, Andrew E.] NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Chen, MY (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH,US Dept HHS, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM marcus.chen@nih.gov FU National Institutes of Health [HL006138-02] FX This research was supported by the National Institutes of Health (grant HL006138-02). NR 39 TC 60 Z9 63 U1 1 U2 8 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2013 VL 267 IS 1 BP 76 EP 85 DI 10.1148/radiol.13122621 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112AX UT WOS:000316565000008 PM 23340461 ER PT J AU Nayak, TK Bernardo, M Milenic, DE Choyke, PL Brechbiel, MW AF Nayak, Tapan K. Bernardo, Marcelino Milenic, Diane E. Choyke, Peter L. Brechbiel, Martin W. TI Orthotopic Pleural Mesothelioma in Mice: SPECT/CT and MR Imaging with HER1- and HER2-targeted Radiolabeled Antibodies SO RADIOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; MALIGNANT MESOTHELIOMA; PHASE-II; EXPRESSION; STIMULATION; CANCER AB Purpose: To evaluate the potential of anti-human epidermal growth factor receptor (HER) 1- and anti-HER2-targeted radio-labeled antibodies and magnetic resonance (MR) imaging for imaging of orthotopic malignant pleural mesothelioma (MPM) in mouse models. Materials and Methods: Animal studies with 165 mice were performed in accordance with National Institutes of Health guidelines for the humane use of animals, and all procedures were approved by the institutional Animal Care and Use Committee. Flow cytometry studies were performed to evaluate HER1 and HER2 expression in NCI-H226 and MSTO-211H mesothelioma cells. Biodistribution and single photon emission computed tomography (SPECT)/computed tomography (CT) imaging studies were performed in mice (four or five per group, depending on tumor growth) bearing subcutaneous and orthotopic MPM tumors by using HER1- and HER2-targeted indium 111 (In-111)- and iodine 125 (I-125)-labeled panitumumab and trastuzumab, respectively. Longitudinal MR imaging over 5 weeks was performed in three mice bearing orthotopic tumors to monitor tumor growth and metastases. SPECT/CT/MR imaging studies were performed at the final time point in the orthotopic models (n = 3). The standard unpaired Student t test was used to compare groups. Results: Orthotopic tumors and pleural effusions were clearly visualized at MR imaging 3 weeks after tumor cell inoculation. At 2 days after injection, the mean In-111-panitumumab uptake of 29.6% injected dose (ID) per gram +/- 2.2 (standard error of the mean) was significantly greater than the In-111-trastuzumab uptake of 13.6% ID/g +/- 1.0 and the I-125-panitumumab uptake of 7.4% ID/g +/- 1.2 (P = .0006 and P = .0001, respectively). MR imaging fusion with SPECT/CT provided more accurate information about In-111-panitumumab localization in the tumor, as the tumor was poorly visualized at CT alone. Conclusion: This study demonstrates the utility of radiolabeled anti-HER1 antibodies in the imaging of MPM in preclinical models. (C)RSNA, 2013 C1 [Nayak, Tapan K.; Milenic, Diane E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino] NCI, SAIC Frederick, Dept Imaging Phys, Frederick, MD 21701 USA. RP Nayak, TK (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B69F, Bethesda, MD 20892 USA. EM tapann@gmail.com OI Nayak, Tapan/0000-0002-3706-6092 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; U.S. Department of Health and Human Services FX All authors are employees of the National Cancer Institute, National Institutes of Health. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the U.S. Department of Health and Human Services. NR 22 TC 5 Z9 5 U1 0 U2 7 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2013 VL 267 IS 1 BP 173 EP 182 DI 10.1148/radiol.12121021 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112AX UT WOS:000316565000018 PM 23329660 ER PT J AU Kudo, K Christensen, S Sasaki, M Ostergaard, L Shirato, H Ogasawara, K Wintermark, M Warach, S AF Kudo, Kohsuke Christensen, Soren Sasaki, Makoto Ostergaard, Leif Shirato, Hiroki Ogasawara, Kuniaki Wintermark, Max Warach, Steven CA Stroke Imaging Repository STIR Inv TI Accuracy and Reliability Assessment of CT and MR Perfusion Analysis Software Using a Digital Phantom SO RADIOLOGY LA English DT Article ID FINAL INFARCT VOLUME; ACUTE STROKE; DYNAMIC CT; PREDICTION; FLOW; OCCLUSION; BRAIN; DELAY; MODEL; MAPS AB Purpose: To design a digital phantom data set for computed tomography (CT) perfusion and perfusion-weighted imaging on the basis of the widely accepted tracer kinetic theory in which the true values of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and tracer arrival delay are known and to evaluate the accuracy and reliability of postprocessing programs using this digital phantom. Materials and Methods: A phantom data set was created by generating concentration-time curves reflecting true values for CBF (2.5-87.5 mL/100 g per minute), CBV (1.0-5.0 mL/100 g), MTT (3.4-24 seconds), and tracer delays (0-3.0 seconds). These curves were embedded in human brain images. The data were analyzed by using 13 algorithms each for CT and magnetic resonance (MR), including five commercial vendors and five academic programs. Accuracy was assessed by using the Pearson correlation coefficient (r) for true values. Delay-, MTT-, or CBV-dependent errors and correlations between time to maximum of residue function (T-max) were also evaluated. Results: In CT, CBV was generally well reproduced (r > 0.9 in 12 algorithms), but not CBF and MTT (r > 0.9 in seven and four algorithms, respectively). In MR, good correlation (r > 0.9) was observed in one-half of commercial programs, while all academic algorithms showed good correlations for all parameters. Most algorithms had delay-dependent errors, especially for commercial software, as well as CBV dependency for CBF or MTT calculation and MTT dependency for CBV calculation. Correlation was good in T-max except for one algorithm. Conclusion: The digital phantom readily evaluated the accuracy and characteristics of the CT and MR perfusion analysis software. All commercial programs had delay-induced errors and/or insufficient correlations with true values, while academic programs for MR showed good correlations with true values. (C) RSNA, 2012 C1 [Kudo, Kohsuke; Sasaki, Makoto] Iwate Med Univ, Div Ultra High Field MRI, Morioka, Iwate 0208505, Japan. [Kudo, Kohsuke; Sasaki, Makoto] Iwate Med Univ, Dept Radiol, Morioka, Iwate 0208505, Japan. [Ogasawara, Kuniaki] Iwate Med Univ, Dept Neurosurg, Morioka, Iwate 0208505, Japan. [Christensen, Soren] Univ Melbourne, Royal Melbourne Hosp, Dept Neurol, Melbourne, Vic 3050, Australia. [Christensen, Soren] Univ Melbourne, Royal Melbourne Hosp, Dept Radiol, Melbourne, Vic 3050, Australia. [Ostergaard, Leif] Arhus Univ Hosp, Dept Neuroradiol, Ctr Functionally Integrat Neurosci, Aarhus, Denmark. [Shirato, Hiroki] Hokkaido Univ, Grad Sch Med, Dept Radiol, Sapporo, Hokkaido, Japan. [Wintermark, Max] Univ Virginia, Dept Radiol, Charlottesville, VA USA. [Warach, Steven] NINDS, NIH, Bethesda, MD 20892 USA. RP Kudo, K (reprint author), Iwate Med Univ, Div Ultra High Field MRI, 19-1 Uchimaru, Morioka, Iwate 0208505, Japan. EM kokudo@iwate-med.ac.jp RI Shirato, Hiroki/A-7068-2010; Ostergaard, Leif/A-9281-2008; OI Ostergaard, Leif/0000-0003-2930-6997; Wintermark, Max/0000-0002-6726-3951 FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Science; Council for Science and Technology Policy; Medical Image Lab; Lundbeck; Hitachi Medical; Hitachi; Varian Medical Systems; Shimadzu; Hokkaido Electric Power; Elekta K. K.; Accuthera; Tanaka Kikinzoku Kogyo K. K.; Medikit; Mitsubishi Heavy Industries; Philips Electronics Japan; Fujifilm Medical; Sumitomo Heavy Industries; Asahikawa Medical University; Nakashima Medical; Hokkaido Gastrointestinal Cancer Study group; GE Healthcare FX Supported in part by a Grant-in-Aid for Strategic Medical Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by the Japan Society for the Promotion of Science through the Funding Program for Next Generation World-Leading Researchers (NEXT Program) initiated by the Council for Science and Technology Policy.; S.W. is an employee of the National Institute of Neurological Disorders and Stroke, National Institutes of Health.; K. K. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: was paid consultancy fee by Medical Image Lab and received payment for lectures including service on speakers bureaus by GE Healthcare and Hitachi Medical Corporation. Other relationships: none to disclose. S. C. No relevant conflicts of interest to disclose. M. S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author was paid consultancy fee by Lundbeck; institution was paid consultancy fee by Hitachi Medical; was paid for lectures including service on speakers bureaus by GE Healthcare, Otsuka Pharma, Mitsubishi Pharma, Daiichi Pharma, J-Mac System, Hitachi Medical, Olea Medical, Bayer, Sanofi, and Esai. Other relationships: none to disclose. L.O. No relevant conflicts of interest to disclose. H. S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: paid for board membership by the Japanese Organization of Radiotherapy Quality Management and for consultancy by Medical Image Lab; institution received grants from Hitachi, Hitachi Medical, Varian Medical Systems, Shimadzu, Hokkaido Electric Power, and Elekta K. K.; institution received collaborative research grants from Accuthera, Tanaka Kikinzoku Kogyo K. K., Medikit, Mitsubishi Heavy Industries, Philips Electronics Japan, Fujifilm Medical, Sumitomo Heavy Industries, Shimadzu, Asahikawa Medical University, Nakashima Medical, Hokkaido Gastrointestinal Cancer Study group; institution received consigned research grants from Fujifilm Medical; received payment for lectures including service on speakers bureaus from Moroo, Hitachi, Chiyoda Technol, Japan Society of Medical Physics, Olympus, Varian Medical Systems, and ORIX Life Insurance. Other relationships: none to disclose. K. O. No relevant conflicts of interest to disclose. M. W. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution received a grant from GE Healthcare. Other relationships: none to disclose. S. W. No relevant conflicts of interest to disclose. NR 22 TC 36 Z9 36 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2013 VL 267 IS 1 BP 201 EP 211 DI 10.1148/radiol.12112618 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112AX UT WOS:000316565000021 PM 23220899 ER PT J AU Jain, R Poisson, L Narang, J Gutman, D Scarpace, L Hwang, SN Holder, C Wintermark, M Colen, RR Kirby, J Freymann, J Brat, DJ Jaffe, C Mikkelsen, T AF Jain, Rajan Poisson, Laila Narang, Jayant Gutman, David Scarpace, Lisa Hwang, Scott N. Holder, Chad Wintermark, Max Colen, Rivka R. Kirby, Justin Freymann, John Brat, Daniel J. Jaffe, Carl Mikkelsen, Tom TI Genomic Mapping and Survival Prediction in Glioblastoma: Molecular Subclassification Strengthened by Hemodynamic Imaging Biomarkers SO RADIOLOGY LA English DT Article ID CEREBRAL BLOOD-VOLUME; GENE-EXPRESSION; MICROARRAY ANALYSIS; TUMOR GRADE; GLIOMAS; MR; MULTIFORME; PROGRESSION; PROGNOSIS; SUBTYPES AB Purpose: To correlate tumor blood volume, measured by using dynamic susceptibility contrast material-enhanced T2*-weighted magnetic resonance (MR) perfusion studies, with patient survival and determine its association with molecular subclasses of glioblastoma (GBM). Materials and Methods: This HIPAA-compliant retrospective study was approved by institutional review board. Fifty patients underwent dynamic susceptibility contrast-enhanced T2*-weighted MR perfusion studies and had gene expression data available from the Cancer Genome Atlas. Relative cerebral blood volume (rCBV) (maximum rCBV [rCBV(max)] and mean rCBV [rCBV(mean)]) of the contrast-enhanced lesion as well as rCBV of the nonenhanced lesion (rCBV(NEL)) were measured. Patients were subclassified according to the Verhaak and Phillips classification schemas, which are based on similarity to defined genomic expression signature. We correlated rCBV measures with the molecular subclasses as well as with patient overall survival by using Cox regression analysis. Results: No statistically significant differences were noted for rCBV(max), rCBV(mean) of contrast-enhanced lesion or rCBV(NEL) between the four Verhaak classes or the three Phillips classes. However, increased rCBV measures are associated with poor overall survival in GBM. The rCBV(max) (P = .0131) is the strongest predictor of overall survival regardless of potential confounders or molecular classification. Interestingly, including the Verhaak molecular GBM classification in the survival model clarifies the association of rCBV(mean) with patient overall survival (hazard ratio: 1.46, P = .0212) compared with rCBV(mean) alone (hazard ratio: 1.25, P = .1918). Phillips subclasses are not predictive of overall survival nor do they affect the predictive ability of rCBV measures on overall survival. Conclusion: The rCBV(max) measurements could be used to predict patient overall survival independent of the molecular subclasses of GBM; however, Verhaak classifiers provided additional information, suggesting that molecular markers could be used in combination with hemodynamic imaging biomarkers in the future. (C)RSNA, 2012 C1 [Jain, Rajan; Narang, Jayant] Henry Ford Hlth Syst, Div Neuroradiol, Dept Radiol, Detroit, MI 48202 USA. [Jain, Rajan; Scarpace, Lisa; Mikkelsen, Tom] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI 48202 USA. [Poisson, Laila] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Gutman, David; Brat, Daniel J.] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Gutman, David; Brat, Daniel J.] Emory Univ, Sch Med, Dept Lab Med, Atlanta, GA USA. [Hwang, Scott N.; Holder, Chad] Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. [Wintermark, Max] Univ Virginia, Dept Radiol, Charlottesville, VA USA. [Colen, Rivka R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Kirby, Justin; Freymann, John] NCI, Clin Res Directorate, CMRP, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jaffe, Carl] Boston Univ, Dept Radiol, Boston, MA 02215 USA. RP Jain, R (reprint author), Henry Ford Hlth Syst, Div Neuroradiol, Dept Radiol, 2799 W Grand Blvd, Detroit, MI 48202 USA. EM rajanj@rad.hfh.edu RI Narang, Jayant/L-6510-2013; OI Hwang, Scott/0000-0002-6496-2087; Wintermark, Max/0000-0002-6726-3951 FU National Institutes of Health [HHSN261200800001E]; GE Healthcare; Philips Healthcare; NIH; Merck Schering; Roche Genentech FX This research was supported by the National Institutes of Health (grant HHSN261200800001E).; R.J. No relevant conflicts of interest to disclose. L. P. No relevant conflicts of interest to disclose. J.N. No relevant conflicts of interest to disclose. D. G. No relevant conflicts of interest to disclose. L. S. No relevant conflicts of interest to disclose. S.N.H. No relevant conflicts of interest to disclose. C. H. No relevant conflicts of interest to disclose. M. W. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: grants/grants pending to institution from GE Healthcare, Philips Healthcare, NIH. Other relationships: none to disclose. R. R. C. No relevant conflicts of interest to disclose. J.K. No relevant conflicts of interest to disclose. J.F. No relevant conflicts of interest to disclose. D.J.B. No relevant conflicts of interest to disclose. C.J. No relevant conflicts of interest to disclose. T. M. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: consultancy for Merck Schering and Roche Genentech; payment for lectures including service on speakers' bureaus for Merck Schering and Roche Genentech; payment for development of educational presentations from Merck Schering. Other relationships: none to disclose. NR 22 TC 48 Z9 50 U1 0 U2 5 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2013 VL 267 IS 1 BP 212 EP 220 DI 10.1148/radiol.12120846 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112AX UT WOS:000316565000022 PM 23238158 ER PT J AU Rockey, SJ AF Rockey, Sally J. TI POLICING ETHICS SO SCIENTIFIC AMERICAN LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Rockey, SJ (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD APR PY 2013 VL 308 IS 4 BP 8 EP 8 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111KB UT WOS:000316519100002 ER PT J AU Kerrin, A Weldon, S Chung, AHK Craig, T Simpson, AJ O'Kane, CM McAuley, DF Taggart, CC AF Kerrin, Aoife Weldon, Sinead Chung, Allen Hung-Kang Craig, Thelma Simpson, A. John O'Kane, Cecilia M. McAuley, Danny Francis Taggart, Clifford C. TI Proteolytic cleavage of elafin by 20S proteasome may contribute to inflammation in acute lung injury SO THORAX LA English DT Article ID ELASTASE-SPECIFIC INHIBITOR; RESPIRATORY-DISTRESS-SYNDROME; LEUKOCYTE PROTEINASE-INHIBITOR; NEUTROPHIL ELASTASE; EPITHELIAL-CELLS; BACTERIAL LIPOPOLYSACCHARIDE; CYSTIC-FIBROSIS; PRE-ELAFIN; EXPRESSION; DEGRADATION AB Rationale We hypothesise that elafin levels in acute lung injury (ALI) decrease over time due, in part, to proteolytic degradation as observed in other lung diseases. Objectives The aim of this study was to characterise temporal changes in elafin concentration in patients with ALI and to evaluate whether a decrease in elafin levels is due to elevated protease activity. Methods Bronchoalveolar lavage fluid (BALF) was obtained from patients with ALI within 48 h of onset of ALI (day 0), at day 3 and at day 7. Elafin levels were quantified by ELISA. Elafin susceptibility to proteolytic cleavage by ALI BALF was assessed by Western blot and by high-performance liquid chromatography-mass spectrometry. Measurements and main results Elafin levels were found to be significantly increased at the onset of ALI compared with healthy volunteers and fell significantly by day 7 compared with day 0. In contrast, levels of secretory leukocyte protease inhibitor did not decrease over time. This decrease in elafin was due to cleavage by the 20S proteasome which was significantly increased in ALI BALF. Incubation of ALI BALF with the proteasome inhibitor epoxomicin confirmed that 20S proteasome protease activity was responsible for proteolytic cleavage of elafin, resulting in diminished anti-elastase activity. In addition, free neutrophil elastase activity significantly increased in ALI BALF from day 0 to day 7. Conclusions Elafin concentrations fall within the pulmonary compartment over the course of ALI as a result of proteolytic degradation. This loss of elafin may predispose people, in part, to excessive inflammation in ALI. C1 [Kerrin, Aoife; Weldon, Sinead; Craig, Thelma; O'Kane, Cecilia M.; McAuley, Danny Francis; Taggart, Clifford C.] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Infect & Immun, Belfast BT9 7BL, Antrim, North Ireland. [Chung, Allen Hung-Kang] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Simpson, A. John] Univ Newcastle, Inst Cellular Med, Newcastle, NSW 2300, Australia. RP Taggart, CC (reprint author), Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Infect & Immun, Hlth Sci Bldg,97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland. EM c.taggart@qub.ac.uk RI Taggart, Clifford/G-4492-2014; Weldon, Sinead/J-5451-2014 OI Weldon, Sinead/0000-0001-5628-6624 FU Intramural Research Program of the National Heart, Lung, and Blood Institute; Northern Ireland Chest Heart and Stroke Association [200941]; HSC Research and Development; Critical Care Translational Research Group; Department of Education and Learning and Sir Jules Thorn Charitable Trust FX Northern Ireland Chest Heart and Stroke Association (200941), HSC Research and Development, the Critical Care Translational Research Group, Critical Care Translational Research Group, Department of Education and Learning and Sir Jules Thorn Charitable Trust (AJS). This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (AHKC). NR 37 TC 5 Z9 5 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD APR PY 2013 VL 68 IS 4 BP 315 EP 321 DI 10.1136/thoraxjnl-2012-202536 PG 7 WC Respiratory System SC Respiratory System GA 103WO UT WOS:000315950400004 PM 23242946 ER PT J AU Kappen, C Yaworsky, PJ Muller, YL Salbaum, JM AF Kappen, Claudia Yaworsky, Paul J. Muller, Yunhua L. Salbaum, J. Michael TI Transgenic studies on homeobox genes in nervous system development: spina bifida in Isl1 transgenic mice SO TRANSGENIC RESEARCH LA English DT Article DE Binary transgenic system; Transactivator; VP16; Hox genes; Hoxd4; Hoxc8; Isl1; Motorneurons; Ventral neural tube; Mesoderm; Cell proliferation; Pbx1; Transcriptional target; Spina bifida; Neural tube closure ID STEM-CELLS; HOX GENE; HOMEOTIC TRANSFORMATIONS; DIFFERENTIAL DISPLAY; REGULATORY ELEMENTS; EXPRESSION PATTERN; PARAXIAL MESODERM; RESPONSE ELEMENT; BINDING-PROTEIN; AXIAL SKELETON AB To develop in vivo assays for homeobox gene function in neural development, we generated transgenic mice in which the expression of a homeobox gene is altered only within the nervous system, in neurons or neuronal precursor cells. Transgenic expression of Hoxc8 did not result in gross abnormalities, while a Hoxd4 transgene caused death shortly after birth. In neural progenitor cells, the motorneuron-specific homeodomain transcription factor Isl1 induced early developmental defects, including absence of anterior neural structures, profound defects in the neuroepithelium and defective neural tube closure. A fraction of Isl1 transgenic mice exhibited spina bifida. Isl1 transgene expression was also associated with decreased proliferation and increased Pbx1 expression in the ventral neural tube. Our results suggest a function for some homeobox genes in development of the nervous system, and that cell-type- and region-specific transgenic models will be useful to identify the cellular and molecular targets of homeobox transcription factors in nervous system development. C1 [Kappen, Claudia] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Dept Dev Biol, Baton Rouge, LA 70810 USA. [Yaworsky, Paul J.] Pfizer Res Technol Ctr, Cambridge, MA 02140 USA. [Muller, Yunhua L.] Natl Inst Diabet & Kidney Dis, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ 85004 USA. [Salbaum, J. Michael] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Lab Regulat Gene Express, Baton Rouge, LA 70810 USA. RP Kappen, C (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, Dept Dev Biol, 6400 Perkins Rd, Baton Rouge, LA 70810 USA. EM claudia.kappen@pbrc.edu; Paul.Yaworsky@pfizer.com; ymuller@mail.nih.gov; michael.salbaum@pbrc.edu FU Arizona Disease Control Research Commission; Mayo Foundation for Medical Education and Research; Neurosciences Support Corporation; R. Lounsbery Foundation; University of Nebraska Research Initiative; Peggy M. Pennington Cole Chair for Maternal Biology; NIH [RO1-HD34706, RO1-HD055528] FX We are grateful to Drs. Andy McMahon for providing the rat nestin enhancer, Thomas Edlund for the Isl1 cDNA, Gerry Byrne for the IE-Hoxc8 and NFL-TSV plasmids, MiMi Macias for making the IE-Hoxd4 and IE-Isl1 constructs, to her and Dr. H. (Tina) Dinh Treece for performing RT-PCR assays, to Diane Costanzo, Scott Hanson, and Jacalyn Mac-Gowan for genotyping of transgenic mice, to Anita Jennings for histology, to Tom Bargar for electron microscopy, and to Drs. David Gardner, Y. Gloria Yueh, and Gabriela Pavlinkova for discussions. The initial transgenic mouse strains were generated at Mayo Clinic Scottsdale, and additional analyses performed at University of Nebraska Medical Center and Pennington Biomedical Research Center. Portions of this work were supported by the Arizona Disease Control Research Commission and Mayo Foundation for Medical Education and Research (to C. K.), The Neurosciences Support Corporation and the R. Lounsbery Foundation (to J.M.S.), the University of Nebraska Research Initiative (to C. K. and J.M.S.), the Peggy M. Pennington Cole Chair for Maternal Biology (to C. K.), and NIH grants RO1-HD34706 (to C. K., with a supplement to G. P.) and RO1-HD055528 (to J.M.S.). NR 76 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD APR PY 2013 VL 22 IS 2 BP 343 EP 358 DI 10.1007/s11248-012-9643-x PG 16 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 105KE UT WOS:000316065900007 PM 23054727 ER PT J AU Savman, K Heyes, MP Svedin, P Karlsson, A AF Savman, Karin Heyes, Melvyn P. Svedin, Pernilla Karlsson, Anna TI Microglia/Macrophage-Derived Inflammatory Mediators Galectin-3 and Quinolinic Acid are Elevated in Cerebrospinal Fluid from Newborn Infants After Birth Asphyxia SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Hypoxic-ischemic brain injury; Microglia; Neonate; Cerebrospinal fluid galectin-3; Quinolinic acid ID ISCHEMIC BRAIN-INJURY; KYNURENINE PATHWAY METABOLISM; HYPOXIA-ISCHEMIA; NEONATAL ENCEPHALOPATHY; MICROGLIAL CELLS; NEUROLOGICAL DISEASE; CYTOKINE RESPONSE; CEREBRAL-PALSY; NADPH-OXIDASE; L-TRYPTOPHAN AB Activation of microglia/macrophages is important in neonatal hypoxic-ischemic (HI) brain injury. Based on experimental studies, we identified macrophage/microglia-derived mediators with potential neurotoxic effects after neonatal HI and examined them in cerebrospinal fluid (CSF) from newborn infants after birth asphyxia. Galectin-3 is a novel inflammatory mediator produced by microglia/macrophages. Galectin-3 is chemotactic for inflammatory cells and activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase resulting in production and release of reactive oxygen species (ROS). Matrix metalloproteinase-9 (MMP-9) is a tissue-degrading protease expressed by activated microglia in the immature brain after HI. Both galectin-3 and MMP-9 contribute to brain injury in animal models for neonatal HI. Quinolinic acid (QUIN) is a neurotoxic N-methyl-d-aspartate (NMDA) receptor agonist also produced by activated microglia/macrophages. Galectin-3 and MMP-9 were measured by ELISA and QUIN by mass spectrometry. Asphyxiated infants (n = 20) had higher levels of galectin-3 (mean (SEM) 2.64 (0.43) ng/mL) and QUIN (335.42 (58.9) nM) than controls (n = 15) (1.36 (0.46) ng/mL and 116.56 (16.46) nM, respectively), p < 0.05 and p < 0.01. Infants with septic infections (n = 10) did not differ from controls. Asphyxiated infants with abnormal outcome had higher levels of galectin-3 (3.96 (0.67) ng/mL) than those with normal outcome (1.76 (0.32) ng/mL), p = 0.02, and the difference remained significant in the clinically relevant group of infants with moderate encephalopathy. MMP-9 was detected in few infants with no difference between groups. The potentially neurotoxic macrophage/microglia-derived mediators galectin-3 and QUIN are increased in CSF after birth asphyxia and could serve as markers and may contribute to injury. C1 [Savman, Karin] Univ Gothenburg, Perinatal Ctr, Dept Pediat, Sahlgrenska Acad, S-41685 Gothenburg, Sweden. [Savman, Karin; Svedin, Pernilla] Univ Gothenburg, Dept Neurosci & Physiol, Sahlgrenska Acad, S-41685 Gothenburg, Sweden. [Heyes, Melvyn P.] NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. [Karlsson, Anna] Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, Sahlgrenska Acad, S-41346 Gothenburg, Sweden. [Savman, Karin] Queen Silvia Childrens Hosp, Perinatal Ctr, S-41685 Gothenburg, Sweden. RP Savman, K (reprint author), Queen Silvia Childrens Hosp, Perinatal Ctr, S-41685 Gothenburg, Sweden. EM karin.savman@pediat.gu.se FU Frimurar-Barnhus Foundation; Wilhelm and Martina Lundgren Foundation; Linnea and Josef Carlsson Foundation; Jerring Foundation; Goteborg Medical Society; Gustaf the Vth 80-Year Foundation FX This work was supported by the Frimurar-Barnhus Foundation, the Wilhelm and Martina Lundgren Foundation, Linnea and Josef Carlsson Foundation, The Jerring Foundation, Goteborg Medical Society, and the Gustaf the Vth 80-Year Foundation. NR 56 TC 13 Z9 14 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 J9 TRANSL STROKE RES JI Transl. Stroke Res. PD APR PY 2013 VL 4 IS 2 BP 228 EP 235 DI 10.1007/s12975-012-0216-3 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 109WB UT WOS:000316399200011 PM 23807898 ER PT J AU Benninghoff, J Rauh, W Brantl, V Schloesser, RJ Moessner, R Moller, HJ Rujescu, D AF Benninghoff, Jens Rauh, Werner Brantl, Victor Schloesser, Robert J. Moessner, Rainald Moeller, Hans-Juergen Rujescu, Dan TI Cholinergic impact on neuroplasticity drives muscarinic M1 receptor mediated differentiation into neurons SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Article DE Biological psychiatry; dementia; pharmacotherapy; neuroplasticity; acetylcholine ID ADULT HIPPOCAMPAL NEUROGENESIS; PRECURSOR CELL-PROLIFERATION; EPIDERMAL-GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; ALZHEIMERS-DISEASE; RAT HIPPOCAMPUS; DENTATE GYRUS; ACETYLCHOLINE-RELEASE; PROGENITOR CELLS AB Objectives. Increasing evidence indicates that canonical neurotransmitters act as regulatory signals during neuroplasticity. Here, we report that muscarinic cholinergic neurotransmission stimulates differentiation of adult neural stem cells in vitro. Methods. Adult neural stem cells (ANSC) dissociated from the adult mouse hippocampus were expanded in culture with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Results. Carbachol (CCh), an analog of acetylcholine (ACh) significantly enhanced de novo differentiation into neurons on bFGF-and EGF-deprived stem cells as shown by the percentage of TUJ1 positive cells. By contrast, pirenzepine (PIR), a muscarinic M1 receptor antagonist, reduced the generation of neurons. Conclusion. Activation of cholinergic signaling drives the de novo differentiation of uncommitted stem cells into neurons. These effects appear to be predominantly mediated via the muscarinic M1 receptor subtype. C1 [Benninghoff, Jens; Rauh, Werner; Brantl, Victor; Moeller, Hans-Juergen; Rujescu, Dan] LMU Univ Munich, Dept Psychiat, Munich, Germany. [Schloesser, Robert J.] NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Programm, NIH, Bethesda, MD 20892 USA. [Moessner, Rainald] Univ Bonn, Dept Psychiat, Bonn, Germany. RP Benninghoff, J (reprint author), Dept Psychiat, Nussbaumstr 7, D-80336 Munich, Germany. EM jens.benninghoff@med.uni-muenchen.de NR 50 TC 2 Z9 2 U1 1 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD APR PY 2013 VL 14 IS 3 BP 241 EP 246 DI 10.3109/15622975.2011.624121 PG 6 WC Psychiatry SC Psychiatry GA 109FL UT WOS:000316351700006 PM 22022845 ER PT J AU Yuan, ZX Rapoport, SI Soldin, SJ Remaley, AT Taha, AY Kellom, M Gu, JH Sampson, M Ramsden, CE AF Yuan, Zhi-Xin Rapoport, Stanley I. Soldin, Steven J. Remaley, Alan T. Taha, Ameer Y. Kellom, Matthew Gu, Jianghong Sampson, Maureen Ramsden, Christopher E. TI Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry SO BIOMEDICAL CHROMATOGRAPHY LA English DT Article DE Q-TOFMS; hydroxy-octadecadienoic acid; oxo-octadecadienoic acid; linoleic acid; rat plasma ID LOW-DENSITY-LIPOPROTEIN; HYDROXY FATTY-ACIDS; LIPID-PEROXIDATION; HYDROXYOCTADECADIENOIC ACID; ELECTROSPRAY-IONIZATION; LIQUID-CHROMATOGRAPHY; OXIDATION-PRODUCTS; ARACHIDONIC-ACID; DISEASE; BLOOD AB Linoleic acid (LA) and LA-esters are the precursors of LA hydroperoxides, which are readily converted to 9- and 13-hydroxy-octadecadienoic acid (HODE) and 9- and 13-oxo-octadecadienoic acid (oxo ODE) metabolites in vivo. These four oxidized LA metabolites (OXLAMs) have been implicated in a variety of pathological conditions. Therefore, their accurate measurement may provide mechanistic insights into disease pathogenesis. Here we present a novel quadrupole time-of-flight mass spectrometry (Q-TOFMS) method for quantitation and identification of target OXLAMs in rat plasma. In this method, the esterified OXLAMs were base-hydrolyzed and followed by liquidliquid extraction. Quantitative analyses were based on one-point standard addition with isotope dilution. The Q-TOFMS data of target metabolites were acquired and multiple reaction monitoring extracted-ion chromatograms were generated post-acquisition with a 10ppm extraction window. The limit of quantitation was 9.735.9nmol/L depending on the metabolite. The method was reproducible with a coefficient of variation of <18.5%. Mean concentrations of target metabolites in rat plasma were 57.8, 123.2, 218.1 and 57.8nmol/L for 9-HODE, 13-HODE, 9-oxoODE and 13-oxoODE, respectively. Plasma levels of total OXLAMs were 456.9nmol/L, which correlated well with published concentrations obtained by gas chromatography/mass spectrometry (GC/MS). The concentrations were also obtained utilizing a standard addition curve approach. The calibration curves were linear with correlation coefficients of >0.991. Concentrations of 9-HODE, 13-HODE, 9-oxoODE and 13-oxoODE were 84.0, 138.6, 263.0 and 69.5nmol/L, respectively, which were consistent with the results obtained from one-point standard addition. Target metabolites were simultaneously characterized based on the accurate Q-TOFMS data. This is the first study of secondary LA metabolites using Q-TOFMS. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Yuan, Zhi-Xin; Rapoport, Stanley I.; Taha, Ameer Y.; Kellom, Matthew] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Ramsden, Christopher E.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Soldin, Steven J.; Remaley, Alan T.; Gu, Jianghong; Sampson, Maureen] NIH, Dept Lab Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Yuan, ZX (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM yuanz2@mail.nih.gov FU National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism; Warren Grant Magnuson Clinical Center, National Institutes of Health FX No author has a conflict of interest with regard to this manuscript. The research was supported by the intramural programs of the National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, and Warren Grant Magnuson Clinical Center, National Institutes of Health. NR 41 TC 5 Z9 5 U1 2 U2 35 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-3879 J9 BIOMED CHROMATOGR JI Biomed. Chromatogr. PD APR PY 2013 VL 27 IS 4 BP 422 EP 432 DI 10.1002/bmc.2809 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA 103LV UT WOS:000315919000003 PM 23037960 ER PT J AU Kovalchik, SA AF Kovalchik, Stephanie A. TI Aggregate-data estimation of an individual patient data linear random effects meta-analysis with a patient covariate-treatment interaction term SO BIOSTATISTICS LA English DT Article DE Clinical trials; Meta-analysis; Random effects models; Statistical methods in Health service research ID META-REGRESSION; SUBGROUP ANALYSES; LEVEL DATA; TRIALS; HETEROGENEITY; STATISTICS; VARIANCE AB Individual patient-data meta-analysis of randomized controlled trials is the gold standard for investigating how patient factors modify the effectiveness of treatment. Because participant data from primary studies might not be available, reliable alternatives using published data are needed. In this paper, I show that the maximum likelihood estimates of a participant-level linear random effects meta-analysis with a patient covariate-treatment interaction can be determined exactly from aggregate data when the model's variance components are known. I provide an equivalent aggregate-data EM algorithm and supporting software with the R package for the estimation of the "interaction meta-analysis" when the variance components are unknown. The properties of the methodology are assessed with simulation studies. The usefulness of the methods is illustrated with analyses of the effect modification of cholesterol and age on pravastatin in the multicenter placebo-controlled regression growth evaluation statin study. When a participant-level meta-analysis cannot be performed, aggregate-data interaction meta-analysis is a useful alternative for exploring individual-level sources of treatment effect heterogeneity. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Kovalchik, SA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8047, Rockville, MD 20892 USA. EM kovalchiksa@mail.nih.gov FU NIH/NCI FX This research was supported by the intramural research program of the NIH/NCI. NR 27 TC 4 Z9 4 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD APR PY 2013 VL 14 IS 2 BP 273 EP 283 DI 10.1093/biostatistics/kxs035 PG 11 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 106FC UT WOS:000316127100006 PM 23001065 ER PT J AU Pfeiffer, RM AF Pfeiffer, Ruth M. TI Extensions of criteria for evaluating risk prediction models for public health applications SO BIOSTATISTICS LA English DT Article DE Area under the receiver operator characteristics curve (ROC); AUC; Discrimination; Discriminatory accuracy; Risk models; Study design ID PROSTATE-CANCER; SUSCEPTIBILITY; CURVE AB We recently proposed two novel criteria to assess the usefulness of risk prediction models for public health applications. The proportion of cases followed, PCF(p), is the proportion of individuals who will develop disease who are included in the proportion p of individuals in the population at highest risk. The proportion needed to follow-up, PNF(q), is the proportion of the general population at highest risk that one needs to follow in order that a proportion q of those destined to become cases will be followed (Pfeiffer, R.M. and Gail, M.H., 2011. Two criteria for evaluating risk prediction models. Biometrics 67, 1057-1065). Here, we extend these criteria in two ways. First, we introduce two new criteria by integrating PCF and PNF over a range of values of q or p to obtain iPCF, the integrated PCF, and iPNF, the integrated PNF. A key assumption in the previous work was that the risk model is well calibrated. This assumption also underlies novel estimates of iPCF and iPNF based on observed risks in a population alone. The second extension is to propose and study estimates of PCF, PNF, iPCF, and iPNF that are consistent even if the risk models are not well calibrated. These new estimates are obtained from case-control data when the outcome prevalence in the population is known, and from cohort data, with baseline covariates and observed health outcomes. We study the efficiency of the various estimates and propose and compare tests for comparing two risk models, both of which were evaluated in the same validation data. C1 NIH, Biostat Branch, Bethesda, MD 20892 USA. RP Pfeiffer, RM (reprint author), NIH, Biostat Branch, Bldg 10, Bethesda, MD 20892 USA. EM pfeiffer@mail.nih.gov FU Division of Cancer Epidemiology and Genetics, National Cancer Institute FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute. NR 15 TC 1 Z9 2 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD APR PY 2013 VL 14 IS 2 BP 366 EP 381 DI 10.1093/biostatistics/kxs037 PG 16 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 106FC UT WOS:000316127100013 PM 23087412 ER PT J AU Chen, F Wang, Z Bhattacharyya, T AF Chen, Foster Wang, Zhong Bhattacharyya, Timothy TI Convergence of Outcomes for Hip Fracture Fixation by Nails and Plates SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID TROCHANTERIC FRACTURES; INTERTROCHANTERIC FRACTURES; INTRAMEDULLARY NAIL; GAMMA-NAIL; SCREW; ADOPTION; TRIAL; FEMUR AB Recent popularity of intramedullary nails over sliding hip screws for treatment of intertrochanteric fractures is concerning given the absence of evidence for clinical superiority for nailing yet the presence of reimbursement differences. We describe the change in outcomes of both procedures across a 15-year span and address the role of reimbursements in the setting of shifting patterns in use. A 5% sample of Medicare enrollees from 1993 to 2007 was used. Cohorts were generated along diagnostic and procedure codes. Trends in device use by hospital type, surgical times, and rate of revision surgeries were compared. Historic reimbursements were examined. Since 2005, intramedullary nail fixation has become the more common treatment in government, nonprofit, and for-profit hospitals. Before 1999, intramedullary nailing required 36 minutes longer to perform than plate-and-screw fixation on average, and had higher revision surgery rates (hazard ratio, 2.48; CI, 1.37-4.48) and 1-year mortality (hazard ratio, 1.42; CI, 1.01-1.99). These differences were not significant since 2000. Reimbursement differences have been consistently in favor of intramedullary nails. Intramedullary nailing of intertrochanteric fractures has become as safe and efficient as the sliding hip screws, but has been more popular since 2006. Reimbursements were favorable for intramedullary nails in times of low and high use. These results argue against the reimbursement difference as the sole driving force for use of intramedullary nails. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Chen, Foster] Univ Calif San Diego, San Diego Sch Med, La Jolla, CA 92093 USA. [Chen, Foster; Wang, Zhong; Bhattacharyya, Timothy] NIH, Bethesda, MD 20892 USA. RP Bhattacharyya, T (reprint author), NIH, 10 Ctr Dr,Mail Code 1468, Bethesda, MD 20892 USA. EM timothy.bhattacharyya@nih.gov FU Clinical Research Training Program; National Institutes of Health (NIH); Pfizer Inc; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH FX One or more of the authors (FC) has received funding from the Clinical Research Training Program, a research program made possible through a public-private partnership supported jointly by the National Institutes of Health (NIH) and Pfizer Inc (through a grant to the Foundation for NIH from Pfizer Inc). One or more of the authors (FC, ZW, TB) also were supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH. NR 19 TC 3 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD APR PY 2013 VL 471 IS 4 BP 1349 EP 1355 DI 10.1007/s11999-012-2694-8 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 097YW UT WOS:000315510400044 PM 23184670 ER PT J AU Graves, JP Edin, ML Bradbury, JA Gruzdev, A Cheng, J Lih, FB Masinde, TA Qu, W Clayton, NP Morrison, JP Tomer, KB Zeldin, DC AF Graves, Joan P. Edin, Matthew L. Bradbury, J. Alyce Gruzdev, Artiom Cheng, Jennifer Lih, Fred B. Masinde, Tiwanda A. Qu, Wei Clayton, Natasha P. Morrison, James P. Tomer, Kenneth B. Zeldin, Darryl C. TI Characterization of Four New Mouse Cytochrome P450 Enzymes of the CYP2J Subfamily SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID ARACHIDONIC-ACID EPOXYGENASE; SOLUBLE EPOXIDE HYDROLASE; ISCHEMIA-REPERFUSION INJURY; EPOXYEICOSATRIENOIC ACIDS; MOLECULAR-CLONING; FUNCTIONAL-SIGNIFICANCE; HYPERPOLARIZING FACTORS; LIVER MICROSOMES; CDNA CLONING; MICE LACKING AB The cytochrome P450 superfamily encompasses a diverse group of enzymes that catalyze the oxidation of various substrates. The mouse CYP2J subfamily includes members that have wide tissue distribution and are active in the metabolism of arachidonic acid (AA), linoleic acid (LA), and other lipids and xenobiotics. The mouse Cyp2j locus contains seven genes and three pseudogenes located in a contiguous 0.62 megabase cluster on chromosome 4. We describe four new mouse CYP2J isoforms (designated CYP2J8, CYP2J11, CYP2J12, and CYP2J13). The four cDNAs contain open reading frames that encode polypeptides with 62-84% identity with the three previously identified mouse CYP2Js. All four new CYP2J proteins were expressed in Sf21 insect cells. Each recombinant protein metabolized AA and LA to epoxides and hydroxy derivatives. Specific antibodies, mRNA probes, and polymerase chain reaction primer sets were developed for each mouse CYP2J to examine their tissue distribution. CYP2J8 transcripts were found in the kidney, liver, and brain, and protein expression was confirmed in the kidney and brain (neuropil). CYP2J11 transcripts were most abundant in the kidney and heart, with protein detected primarily in the kidney (proximal convoluted tubules), liver, and heart (cardiomyocytes). CYP2J12 transcripts were prominently present in the brain, and CYP2J13 transcripts were detected in multiple tissues, with the highest expression in the kidney. CYP2J12 and CYP2J13 protein expression could not be determined because the antibodies developed were not immunospecific. We conclude that the four new CYP2J isoforms might be involved in the metabolism of AA and LA to bioactive lipids in mouse hepatic and extrahepatic tissues. C1 [Graves, Joan P.; Edin, Matthew L.; Bradbury, J. Alyce; Gruzdev, Artiom; Cheng, Jennifer; Zeldin, Darryl C.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Lih, Fred B.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Masinde, Tiwanda A.; Clayton, Natasha P.] NIEHS, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Qu, Wei] NIEHS, Natl Toxicol Program Lab, NIH, Res Triangle Pk, NC 27709 USA. [Morrison, James P.] Pathol Associates Inc, Charles River Labs, Durham, NC USA. RP Zeldin, DC (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Bldg 101,Room A214, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013; OI Edin, Matthew/0000-0002-7042-500X FU Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Z01 ES025034] FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01 ES025034]. NR 48 TC 8 Z9 10 U1 0 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD APR PY 2013 VL 41 IS 4 BP 763 EP 773 DI 10.1124/dmd.112.049429 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 105XM UT WOS:000316106000012 PM 23315644 ER PT J AU Abrudan, J Ramalho-Ortigao, M O'Neil, S Stayback, G Wadsworth, M Bernard, M Shoue, D Emrich, S Lawyer, P Kamhawi, S Rowton, ED Lehane, MJ Bates, PA Valenzeula, JG Tomlinson, C Appelbaum, E Moeller, D Thiesing, B Dillon, R Clifton, S Lobo, NF Wilson, RK Collins, FH McDowell, MA AF Abrudan, J. Ramalho-Ortigao, M. O'Neil, S. Stayback, G. Wadsworth, M. Bernard, M. Shoue, D. Emrich, S. Lawyer, P. Kamhawi, S. Rowton, E. D. Lehane, M. J. Bates, P. A. Valenzeula, J. G. Tomlinson, C. Appelbaum, E. Moeller, D. Thiesing, B. Dillon, R. Clifton, S. Lobo, N. F. Wilson, R. K. Collins, F. H. McDowell, M. A. TI The characterization of the Phlebotomus papatasi transcriptome SO INSECT MOLECULAR BIOLOGY LA English DT Review DE sand fly; phebotomine; transcriptome ID PROPHENOLOXIDASE-ACTIVATING SYSTEM; MOSQUITO ANOPHELES-GAMBIAE; INNATE IMMUNE-RESPONSE; BETA-1,3-GLUCAN RECOGNITION PROTEIN; MULTIPLE SEQUENCE ALIGNMENT; LUTZOMYIA-LONGIPALPIS; AEDES-AEGYPTI; DROSOPHILA-MELANOGASTER; PERITROPHIC MATRIX; BOMBYX-MORI AB As important vectors of human disease, phlebotomine sand flies are of global significance to human health, transmitting several emerging and re-emerging infectious diseases. The most devastating of the sand fly transmitted infections are the leishmaniases, causing significant mortality and morbidity in both the Old and New World. Here we present the first global transcriptome analysis of the Old World vector of cutaneous leishmaniasis, Phlebotomus papatasi (Scopoli) and compare this transcriptome to that of the New World vector of visceral leishmaniasis, Lutzomyia longipalpis. A normalized cDNA library was constructed using pooled mRNA from Phlebotomus papatasi larvae, pupae, adult males and females fed sugar, blood, or blood infected with Leishmania major. A total of 47615 generated sequences was cleaned and assembled into 17120 unique transcripts. Of the assembled sequences, 50% (8837 sequences) were classified using Gene Ontology (GO) terms. This collection of transcripts is comprehensive, as demonstrated by the high number of different GO categories. An in-depth analysis revealed 245 sequences with putative homology to proteins involved in blood and sugar digestion, immune response and peritrophic matrix formation. Twelve of the novel genes, including one trypsin, two peptidoglycan recognition proteins (PGRP) and nine chymotrypsins, have a higher expression level during larval stages. Two novel chymotrypsins and one novel PGRP are abundantly expressed upon blood feeding. This study will greatly improve the available genomic resources for P.papatasi and will provide essential information for annotation of the full genome. C1 [Abrudan, J.; Ramalho-Ortigao, M.; Stayback, G.; Wadsworth, M.; Bernard, M.; Shoue, D.; Lobo, N. F.; Collins, F. H.; McDowell, M. A.] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [O'Neil, S.; Emrich, S.] Univ Notre Dame, Notre Dame, IN 46556 USA. [Lawyer, P.] NIAID, Intracellular Parasite Biol Sect, Parasit Dis Lab, NIH, Rockville, MD USA. [Kamhawi, S.; Valenzeula, J. G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Rowton, E. D.] Walter Reed Army Inst Res, Entomol Program, Silver Spring, MD USA. [Lehane, M. J.] Univ Liverpool, Liverpool Sch Trop Med, Vector Grp, Liverpool L3 5QA, Merseyside, England. [Bates, P. A.; Dillon, R.] Univ Lancaster, Div Biomed & Life Sci, Fac Hlth & Med, Lancaster, England. [Tomlinson, C.; Appelbaum, E.; Moeller, D.; Thiesing, B.; Clifton, S.; Wilson, R. K.] Washington Univ, Genome Inst, St Louis, MO USA. RP McDowell, MA (reprint author), Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. EM mcdowell.11@nd.edu OI Bates, Paul/0000-0001-6861-5421; Dillon, Rod/0000-0002-3551-0030 FU National Human Genome Research Institute; Defense Advanced Research Projects Agency [W911NF0410380]; Telemedicine and Advanced Technology Research Center [W81XWH-10-1-0085]; VectorBase [NIH/NIAID HHSN72200900039C]; NSF MRI Grant [DBI-0420980] FX This project was supported by the National Human Genome Research Institute and in part by an award from the Defense Advanced Research Projects Agency (#W911NF0410380) and Telemedicine and Advanced Technology Research Center (#W81XWH-10-1-0085) to Mary Ann McDowell. This project was also supported by VectorBase (NIH/NIAID HHSN72200900039C. The assembly was performed on the Notre Dame Biocomplexity Cluster (University of Notre Dame, Notre Dame, IN, USA) supported in part by NSF MRI Grant No. DBI-0420980. BLAST searches were performed on the Biocompute server at Notre Dame. NR 109 TC 6 Z9 6 U1 1 U2 53 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1075 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD APR PY 2013 VL 22 IS 2 BP 211 EP 232 DI 10.1111/imb.12015 PG 22 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 102OO UT WOS:000315854100007 PM 23398403 ER PT J AU Hueper, K Parikh, MA Prince, MR Schoenfeld, C Liu, C Bluemke, DA Dashnaw, SM Goldstein, TA Hoffman, EA Lima, JA Skrok, J Zheng, J Barr, RG Vogel-Claussen, J AF Hueper, Katja Parikh, Megha A. Prince, Martin R. Schoenfeld, Christian Liu, Chia Bluemke, David A. Dashnaw, Stephen M. Goldstein, Thomas A. Hoffman, Eric A. Lima, Joao A. Skrok, Jan Zheng, Jie Barr, R. Graham Vogel-Claussen, Jens TI Quantitative and Semiquantitative Measures of Regional Pulmonary Microvascular Perfusion by Magnetic Resonance Imaging and Their Relationships to Global Lung Perfusion and Lung Diffusing Capacity The Multiethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study SO INVESTIGATIVE RADIOLOGY LA English DT Article DE pulmonary microvascular blood flow; chronic obstructive pulmonary disease (COPD); dynamic contrast-enhanced MRI; quantitative perfusion maps; lung diffusing capacity ID BLOOD-FLOW; REFERENCE VALUES; STANDARDIZATION; QUANTIFICATION; COPD; SPIROMETRY; VOLUMES; SAMPLE; ADULTS; TIME AB Objectives: The aim of this study was to evaluate the quantitative and semi-quantitative measures of regional pulmonary parenchymal perfusion in patients with chronic obstructive pulmonary disease (COPD) in relationship to global lung perfusion (GLP) and lung diffusing capacity (DLCO). Materials and Methods: A total of 143 participants in the Multiethnic Study of Atherosclerosis COPD Study were examined by dynamic contrast-enhanced pulmonary perfusion magnetic resonance imaging (MRI) at 1.5 T. Pulmonary microvascular blood flow (PBF) was calculated on a pixel-by-pixel basis by using a dual-bolus technique and the Fermi function model. Semiquantitative parameters for regional pulmonary microvascular perfusion were calculated from signal intensity-time curves in the lung parenchyma. Intraoberserver and interobserver coefficients of variation (CVs) and correlations between quantitative and semiquantitative MRI parameters and with GLP and DLCO were determined. Results: Quantitative and semiquantitative parameters of pulmonary microvascular perfusion were reproducible, with CVs for all parameters of less than 10%. Furthermore, these MRI parameters were correlated with GLP and DLCO, and there was good agreement between PBF and GLP. Quantitative and semiquantitative MRI parameters were closely correlated (eg, r = 0.86 for maximum signal increase with PBF). In participants without COPD, the physiological distribution of pulmonary perfusion could be determined by regional MRI measurements. Conclusion: Regional pulmonary microvascular perfusion can reliably be quantified from dynamic contrast-enhanced MRI. Magnetic resonance imaging-derived quantitative and semiquantitative perfusion measures correlate with GLP and DLCO. C1 [Hueper, Katja; Liu, Chia; Lima, Joao A.; Skrok, Jan; Vogel-Claussen, Jens] Johns Hopkins Univ, Baltimore, MD USA. [Hueper, Katja; Schoenfeld, Christian; Vogel-Claussen, Jens] Hannover Med Sch, Biomed Res Endstage & Obstruct Lung Dis Hannover, D-30625 Hannover, Germany. [Parikh, Megha A.; Prince, Martin R.; Dashnaw, Stephen M.; Barr, R. Graham] Columbia Univ, Med Ctr, New York, NY USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. [Goldstein, Thomas A.] Stanford Univ, Stanford, CA 94305 USA. [Hoffman, Eric A.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Zheng, Jie] Washington Univ, Sch Med, St Louis, MO USA. RP Vogel-Claussen, J (reprint author), Hannover Med Sch, Dept Radiol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM vogel-claussen.jens@mh-hannover.de RI Hueper, Katja/J-9566-2016; Prince, Martin/S-6850-2016 OI Hueper, Katja/0000-0002-3195-4400; FU National Institutes of Health/National Heart Lung Blood Institute [R01-HL093081, R01-HL077612, R01-HL075476, N01-HC95159-HC95169] FX The Multiethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study was supported by the National Institutes of Health/National Heart Lung Blood Institute R01-HL093081, R01-HL077612, R01-HL075476, and N01-HC95159-HC95169. NR 34 TC 15 Z9 15 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD APR PY 2013 VL 48 IS 4 BP 223 EP 230 DI 10.1097/RLI.0b013e318281057d PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 105YQ UT WOS:000316109000007 PM 23385398 ER PT J AU Shapiro, JM Oyen, ML AF Shapiro, Jenna M. Oyen, Michelle L. TI Hydrogel Composite Materials for Tissue Engineering Scaffolds SO JOM LA English DT Article ID DOUBLE NETWORK HYDROGELS; MESENCHYMAL STEM-CELLS; DONOR-SITE MORBIDITY; MECHANICAL-PROPERTIES; CARTILAGE TISSUE; NUCLEUS PULPOSUS; ELECTROSPUN SCAFFOLDS; OSTEOGENIC DIFFERENTIATION; BIOMEDICAL APPLICATIONS; COLLAGEN NANOFIBERS AB Hydrogels are appealing for biomaterials applications due to their compositional similarity with highly hydrated natural biological tissues. However, for structurally demanding tissue engineering applications, hydrogel use is limited by poor mechanical properties. Here, composite materials approaches are considered for improving hydrogel properties while attempting to more closely mimic natural biological tissue structures. A variety of composite material microstructures is explored, based on multiple hydrogel constituents, particle reinforcement, electrospun nanometer to micrometer diameter polymer fibers with single and multiple fiber networks, and combinations of these approaches to form fully three-dimensional fiber-reinforced hydrogels. Natural and synthetic polymers are examined for formation of a range of scaffolds and across a range of engineered tissue applications. Following a discussion of the design and fabrication of composite scaffolds, interactions between living biological cells and composite scaffolds are considered across the full life cycle of tissue engineering from scaffold fabrication to in vivo use. We conclude with a summary of progress in this area to date and make recommendations for continuing research and for advanced hydrogel scaffold development. C1 [Shapiro, Jenna M.; Oyen, Michelle L.] Univ Cambridge, Dept Engn, Cambridge CB2 1PZ, England. [Shapiro, Jenna M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Shapiro, JM (reprint author), Univ Cambridge, Dept Engn, Cambridge CB2 1PZ, England. EM mlo29@cam.ac.uk OI Oyen, Michelle/0000-0002-3428-748X FU National Institutes of Health through the NIH-Cambridge Scholars Program FX The authors acknowledge Daniel G.T. Strange for providing the SEM image shown in Fig. 3b, Anne Bahnweg for assistance with SEM image collection, and Matthew G. Rees for technical assistance. J.M.S. acknowledges funding from the National Institutes of Health through the NIH-Cambridge Scholars Program. NR 111 TC 20 Z9 20 U1 3 U2 130 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1047-4838 J9 JOM-US JI JOM PD APR PY 2013 VL 65 IS 4 BP 505 EP 516 DI 10.1007/s11837-013-0575-6 PG 12 WC Materials Science, Multidisciplinary; Metallurgy & Metallurgical Engineering; Mineralogy; Mining & Mineral Processing SC Materials Science; Metallurgy & Metallurgical Engineering; Mineralogy; Mining & Mineral Processing GA 105NO UT WOS:000316078500007 ER PT J AU Redd, AD Quinn, TC AF Redd, Andrew D. Quinn, Thomas C. TI Phylogenetic Relatedness of HIV-1 Donor and Recipient Populations Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter C1 [Redd, Andrew D.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD USA. RP Quinn, TC (reprint author), Johns Hopkins Univ, Sch Med, Rangos Bldg,Room 531,855 N Wolfe St, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu NR 2 TC 0 Z9 0 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 APR 1 PY 2013 VL 207 IS 7 BP 1182 EP 1183 DI 10.1093/infdis/jit022 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 099SX UT WOS:000315643100021 PM 23315325 ER PT J AU Mahar, JE Bok, K Green, KY Kirkwood, CD AF Mahar, Jackie E. Bok, Karin Green, Kim Y. Kirkwood, Carl D. TI The Importance of Intergenic Recombination in Norovirus GII.3 Evolution SO JOURNAL OF VIROLOGY LA English DT Article ID NORWALK-LIKE VIRUSES; BLOOD GROUP ANTIGENS; ACUTE GASTROENTERITIS; HUMAN CALICIVIRUSES; MOLECULAR EPIDEMIOLOGY; MAXIMUM-LIKELIHOOD; MITOCHONDRIAL-DNA; GENETIC DIVERSITY; GII-4 NOROVIRUS; CAPSID PROTEIN AB Norovirus genotype II.3 (GII.3) strains are a major cause of sporadic gastroenteritis. Intergenic recombination between the capsid and RNA-dependent RNA polymerase (RdRp) genes is common and results in the acquisition of an alternative RdRp genotype. This study aimed to explore the evolution of the GII. 3 capsid gene, focusing on the influence of intergenic recombination. The capsid genes from six GII. 3 norovirus strains, collected from Australian children between 2001 and 2010, were sequenced and aligned with 66 GII. 3 capsid sequences from GenBank, spanning 1975 to 2010. The GII. 3 capsid gene evolved at a rate of 4.16 x 10(-3) to 6.97 x 10(-3) nucleotide substitutions/site/year from 1975 to 2010 and clustered into five temporally sequential lineages. Clustering of the GII. 3 capsid gene sequences was associated with intergenic recombination and switches between RdRp genotypes GII.3, GII.a, GII.b, GII.12, and an undefined ancestral RdRp. Comparison of the substitution rate of the GII. 3 and GII.b RdRps suggested that RdRp switching allows a higher evolutionary rate, leading to increased genetic diversity and adaptability. Alignment of GII. 3 capsid sequences revealed 36 lineage-specific conserved amino acid substitutions, four of which were under positive selection. Many conserved substitutions were within predicted antibody binding regions and close to host attachment factor binding sites. In conclusion, evolution of GII. 3 noroviruses was primarily driven by intergenic recombination. The acquisition of new RdRps may lead to a faster mutation rate and increased genetic diversity, improving overall GII. 3 fitness. C1 [Mahar, Jackie E.; Kirkwood, Carl D.] Royal Childrens Hosp, Enter Virus Grp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Mahar, Jackie E.; Kirkwood, Carl D.] La Trobe Univ, Dept Microbiol, Bundoora, Vic 3083, Australia. [Bok, Karin; Green, Kim Y.] NIAID, Caliciviruses Sect, Infect Dis Lab, NIH,DHHS, Bethesda, MD 20892 USA. RP Mahar, JE (reprint author), Royal Childrens Hosp, Enter Virus Grp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia. EM jemahar@students.latrobe.edu.au; carl.kirkwood@mcri.edu.au FU Victorian Government's Operational Infrastructure Support Program; Intramural Research Program of the NIH, NIAID FX This study was supported by the Victorian Government's Operational Infrastructure Support Program and the Intramural Research Program of the NIH, NIAID. NR 71 TC 19 Z9 23 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 APR PY 2013 VL 87 IS 7 BP 3687 EP 3698 DI 10.1128/JVI.03056-12 PG 12 WC Virology SC Virology GA 103ZC UT WOS:000315957100007 PM 23325692 ER PT J AU Matsuno, K Weisend, C da Rosa, APAT Anzick, SL Dahlstrom, E Porcella, SF Dorward, DW Yu, XJ Tesh, RB Ebihara, H AF Matsuno, Keita Weisend, Carla da Rosa, Amelia P. A. Travassos Anzick, Sarah L. Dahlstrom, Eric Porcella, Stephen F. Dorward, David W. Yu, Xue-Jie Tesh, Robert B. Ebihara, Hideki TI Characterization of the Bhanja Serogroup Viruses (Bunyaviridae): a Novel Species of the Genus Phlebovirus and Its Relationship with Other Emerging Tick-Borne Phleboviruses SO JOURNAL OF VIROLOGY LA English DT Article ID M-SEGMENT REASSORTMENT; GENETIC-CHARACTERIZATION; NUCLEOCAPSID PROTEIN; UUKUNIEMI-VIRUS; ANTIGENIC GROUP; PALMA VIRUS; PUNTA-TORO; FEVER; RNA; SEQUENCE AB Bhanja virus (BHAV) and its antigenically close relatives Forecariah virus (FORV), Kismayo virus (KISV), and Palma virus (PALV) are thought to be members of the family Bunyaviridae, but they have not been assigned to a genus or species. Despite their broad geographical distribution and reports that BHAV causes sporadic cases of febrile illness and encephalitis in humans, the public health importance of the Bhanja serogroup viruses remains unclear, due in part to the lack of sequence and biochemical information for the virus proteins. In order to better define the molecular characteristics of this group, we determined the full-length sequences of the L, M, and S genome segments of multiple isolates of BHAV as well as FORV and PALV. The genome structures of these Bhanja viruses are similar to those of viruses belonging to the genus Phlebovirus. Functional domains and amino acid motifs in the viral proteins that are conserved among other known phleboviruses were also identified in proteins of the BHAV group. Phylogenetic and serological analyses revealed that the BHAVs are most closely related to the novel emerging tick-borne phleboviruses severe fever with thrombocytopenia syndrome virus and Heartland virus, which have recently been implicated as causing severe acute febrile illnesses associated with thrombocytopenia in humans in China and the United States. Our results indicate that the Bhanja serogroup viruses constitute a single novel species in the genus Phlebovirus. The results of this study should facilitate epidemiological surveillance for other, similar tick-borne phleboviruses that may represent unrecognized causes of febrile illness in humans. C1 [Matsuno, Keita; Weisend, Carla; Ebihara, Hideki] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Anzick, Sarah L.; Dahlstrom, Eric; Porcella, Stephen F.; Dorward, David W.] NIAID, Res Technol Branch, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [da Rosa, Amelia P. A. Travassos; Yu, Xue-Jie; Tesh, Robert B.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Yu, Xue-Jie; Tesh, Robert B.] Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. RP Ebihara, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. EM ebiharah@niaid.nih.gov FU Intramural Research Program of the NIH; NIH [HHSN272201000040I/HHSN27200004/D4] FX This work was supported by the Intramural Research Program of the NIH. A.P.A.T.D.R., X.-J.Y., and R.B.T. were supported by NIH contract HHSN272201000040I/HHSN27200004/D4. NR 54 TC 34 Z9 40 U1 4 U2 23 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 APR PY 2013 VL 87 IS 7 BP 3719 EP 3728 DI 10.1128/JVI.02845-12 PG 10 WC Virology SC Virology GA 103ZC UT WOS:000315957100010 PM 23325688 ER PT J AU Day, PM Thompson, CD Schowalter, RM Lowy, DR Schiller, JT AF Day, Patricia M. Thompson, Cynthia D. Schowalter, Rachel M. Lowy, Douglas R. Schiller, John T. TI Identification of a Role for the trans-Golgi Network in Human Papillomavirus 16 Pseudovirus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID DYNEIN LIGHT-CHAIN; MINOR CAPSID PROTEIN; VIRUS-LIKE PARTICLES; SORTING NEXIN 17; BREFELDIN-A; IN-VITRO; RETROGRADE TRANSPORT; LYSOSOME BIOGENESIS; TYPE-16 INFECTION; DEPENDENT PATHWAY AB Human papillomavirus 16 (HPV16) enters its host cells by a process that most closely resembles macropinocytosis. Uncoating occurs during passage through the endosomal compartment, and the low pH encountered in this environment is essential for infection. Furin cleavage of the minor capsid protein, L2, and cyclophilin B-mediated separation of L2 and the viral genome from the major capsid protein, L1, are necessary for escape from the late endosome (LE). Following this exodus, L2 and the genome are found colocalized at the ND10 nuclear subdomain, which is essential for efficient pseudogenome expression. However, the route by which L2 and the genome traverse the intervening cytoplasm between these two subcellular compartments has not been determined. This study extends our understanding of this phase in PV entry in demonstrating the involvement of the Golgi complex. With confocal microscopic analyses involving 5-ethynyl-2'-deoxyuridine (EdU)-labeled pseudogenomes and antibodies to virion and cellular proteins, we found that the viral pseudogenome and L2 travel to the trans-Golgi network (TGN) following exit from the LE, while L1 is retained. This transit is dependent upon furin cleavage of L2 and can be prevented pharmacologically with either brefeldin A or golgicide A, inhibitors of anterograde and retrograde Golgi trafficking. Additionally, Rab9a and Rab7b were determined to be mediators of this transit, as expression of dominant negative versions of these proteins, but not Rab7a, significantly inhibited HPV16 pseudovirus infection. C1 [Day, Patricia M.; Thompson, Cynthia D.; Schowalter, Rachel M.; Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Day, PM (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM pmd@nih.gov RI Kim, Seongman/N-6910-2014 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 54 TC 38 Z9 38 U1 0 U2 17 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 APR PY 2013 VL 87 IS 7 BP 3862 EP 3870 DI 10.1128/JVI.03222-12 PG 9 WC Virology SC Virology GA 103ZC UT WOS:000315957100023 PM 23345514 ER PT J AU Shao, HP Calvo, KR Gronborg, M Tembhare, PR Kreitman, RJ Stetler-Stevenson, M Yuan, CM AF Shao, Haipeng Calvo, Katherine R. Groenborg, Marlene Tembhare, Prashant R. Kreitman, Robert J. Stetler-Stevenson, Maryalice Yuan, Constance M. TI Distinguishing hairy cell leukemia variant from hairy cell leukemia: Development and validation of diagnostic criteria SO LEUKEMIA RESEARCH LA English DT Article DE Hairy cell leukemia; Hairy cell leukemia variant; Flow cytometry; Immunophenotype, HCL, HCL v, CD11c, CD25, CD103, CD123 ID RESIDUAL DISEASE DETECTION; FLOW-CYTOMETRY; LYMPHOPROLIFERATIVE DISORDERS; IMMUNOPHENOTYPIC ANALYSIS; 2-CHLORODEOXYADENOSINE; CD123; CHAIN; CLADRIBINE; EXPERIENCE; RITUXIMAB AB Hairy cell leukemia (HCL) and hairy cell leukemia-variant (HCL-v) are rare diseases with overlapping clinico-pathological features. We performed flow cytometry analysis (FCM) of 213 cases (169 HCL, 35 HCL-v, 9 splenic marginal zone lymphoma (SMZL)), correlating results with available corresponding clinical and morphological data. FCM distinguished HCL-v from HCL and SMZL based solely upon expression of four antigens (CD11c, CD25, CD103, CD123) combined with B-cell markers (CD19, CD20, CD22). HCL-v expressed bright CD20, bright CD22, CD11c(100%), CD103(100%), dim(40%) or negative(60%) CD123, and uniformly lacked CD25(100%). HCL expressed bright CD20, bright CD22, bright CD11c, bright CD25, CD103, and bright homogeneous CD123(100%). Aberrant expression of CD5(2%/3%), CD10(12%/3%), CD23(21%/11%), CD38(14%/0%), CD2(2%/9%), CD4(0.5%/0%) and CD13(0.5%/3%), was observed in HCL/HCL-v, respectively. SMZL cases were CD103(-) and CD123(-) except for one case with dim CD123. HCL showed significantly greater marrow infiltration over HCL-v. Prominent nucleoli were observed in most HCL-v but rarely in HCL. A third of HCL and HCL-v marrows were hypocellular or aplastic-appearing. Detection of BRAFV600E mutation and annexin A1 were examined in a subset of cases to further validate FCM diagnostic criteria. HCL-v was negative for both annexin A1 (100%) and BRAFV600E mutation (100%), in contrast to HCL (74% positive for annexin A1; 76% positive for BRAFV600E mutation). HCL-v is resistant to traditional HCL therapy, making accurate diagnosis imperative. We have defined FCM criteria for differentiation of HCL-v from HCL and SMZL. Published by Elsevier Ltd. C1 [Groenborg, Marlene; Tembhare, Prashant R.; Stetler-Stevenson, Maryalice; Yuan, Constance M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Kreitman, Robert J.] NCI, Labs Mol Biol & Clin Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shao, Haipeng] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. RP Yuan, CM (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 2N108,9000 Rockville Pike, Bethesda, MD 20892 USA. EM yuanc@mail.nih.gov RI Calvo, Katherine/A-8109-2009; OI Calvo, Katherine/0000-0002-0771-4191 FU Intramural Research Program of the NIH, NCI FX The authors wish to thank Catharine McCoy, Linda Weaver, Gregory Jasper, and Christine Aguhar at the NCI flow cytometry laboratory for graciously providing FCM access, and technical expertise. We are grateful to Jaime Hahn for assistance with retrieving slides. This work was supported in part by the Intramural Research Program of the NIH, NCI. NR 39 TC 16 Z9 16 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD APR PY 2013 VL 37 IS 4 BP 401 EP 409 DI 10.1016/j.leukres.2012.11.021 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 100ZN UT WOS:000315744500010 PM 23347903 ER PT J AU Wu, M LaGasse, LL Wouldes, TA Arria, AM Wilcox, T Derauf, C Newman, E Shah, R Smith, LM Neal, CR Huestis, MA DellaGrotta, S Lester, BM AF Wu, Min LaGasse, Linda L. Wouldes, Trecia A. Arria, Amelia M. Wilcox, Tara Derauf, Chris Newman, Elana Shah, Rizwan Smith, Lynne M. Neal, Charles R. Huestis, Marilyn A. DellaGrotta, Sheri Lester, Barry M. TI Predictors of Inadequate Prenatal Care in Methamphetamine-Using Mothers in New Zealand and the United States SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Methamphetamine; Adequate prenatal care; New Zealand; Kessner Index; Child protective services ID INNER-CITY WOMEN; NEW-YORK-CITY; DRUG-USE; PREGNANT-WOMEN; HEALTH-INSURANCE; ANTENATAL CARE; LOW-INCOME; PSYCHOSOCIAL FACTORS; BIRTH-WEIGHT; MEDICAL-CARE AB This study compared patterns of prenatal care among mothers who used methamphetamine (MA) during pregnancy and non-using mothers in the US and New Zealand (NZ), and evaluated associations among maternal drug use, child protective services (CPS) referral, and inadequate prenatal care in both countries. The sample consisted of 182 mothers in the MA-Exposed and 196 in the Comparison groups in the US, and 107 mothers in the MA-Exposed and 112 in the Comparison groups in NZ. Positive toxicology results and/or maternal report of MA use during pregnancy were used to identify MA use. Information about sociodemographics, prenatal care and prenatal substance use was collected by maternal interview. MA-use during pregnancy is associated with lower socioeconomic status, single marital status, and CPS referral in both NZ and the US. Compared to their non-using counterparts, MA-using mothers in the US had significantly higher rates of inadequate prenatal care. No association was found between inadequate care and MA-use in NZ. In the US, inadequate prenatal care was associated with CPS referral, but not in NZ. Referral to CPS for drug use only composed 40 % of all referrals in the US, but only 15 % of referrals in NZ. In our study population, prenatal MA-use and CPS referral eclipse maternal sociodemographics in explanatory power for inadequate prenatal care. The predominant effect of CPS referral in the US is especially interesting, and should encourage further research on whether the US policy of mandatory reporting discourages drug-using mothers from seeking antenatal care. C1 [Wu, Min; LaGasse, Linda L.; Wouldes, Trecia A.; DellaGrotta, Sheri; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Brown Ctr Study Children Risk, Providence, RI 02912 USA. [Wu, Min; LaGasse, Linda L.; Wouldes, Trecia A.; DellaGrotta, Sheri; Lester, Barry M.] Brown Univ, Women & Infants Hosp, Providence, RI USA. [Wouldes, Trecia A.] Univ Auckland, Fac Med & Hlth Sci, Dept Psychol Med, Auckland 1, New Zealand. [Arria, Amelia M.] Univ Maryland, Sch Publ Hlth, Ctr Young Adult Hlth & Dev, Family Sci Dept, College Pk, MD 20742 USA. [Derauf, Chris; Neal, Charles R.] Univ Hawaii, John A Burns Sch Med, Dept Pediat, Honolulu, HI 96822 USA. [Newman, Elana] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [Shah, Rizwan] Iowa Hlth, Blank Hosp Reg Child Protect Ctr, Des Moines, IA USA. [Smith, Lynne M.] Harbor UCLA Med Ctr, LABioMed Inst, Dept Pediat, Los Angeles, CA USA. [Smith, Lynne M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Wu, M (reprint author), Brown Univ, Warren Alpert Med Sch, Brown Ctr Study Children Risk, Providence, RI 02912 USA. EM min_wu@hms.harvard.edu OI Arria, Amelia/0000-0002-6360-9265; Wouldes, Trecia/0000-0002-6609-8464 FU Intramural NIH HHS [ZIA DA000433-11, Z01 DA000433-09, ZIA DA000433-10, Z01 DA000433-08, ZIA DA000433-12, ZIA DA000433-13]; NCATS NIH HHS [UL1 TR000124]; NIDA NIH HHS [R01 DA021757, R01DA021757, R01 DA014948] NR 76 TC 3 Z9 3 U1 0 U2 5 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 APR PY 2013 VL 17 IS 3 BP 566 EP 575 DI 10.1007/s10995-012-1033-8 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 104UN UT WOS:000316021200023 PM 22588827 ER PT J AU Luke, JJ Rubinstein, LV Smith, GL Ivy, SP Harris, PJ AF Luke, Jason J. Rubinstein, Lawrence V. Smith, Gary L. Ivy, S. Percy Harris, Pamela J. TI Similar efficacy for phase I trials in comparison with DTIC for advanced malignant melanoma: an analysis of melanoma outcomes in CTEP-sponsored phase I trials 1995-2011 SO MELANOMA RESEARCH LA English DT Article DE chemotherapy; CTEP; dacarbazine; melanoma; phase I ID METASTATIC MELANOMA; CLINICAL-TRIALS; ONCOLOGY TRIALS; SOLID TUMORS; CANCER; DACARBAZINE; SURVIVAL; THERAPY; ETHICS; TEMOZOLOMIDE AB After ipilimumab, vemurafenib, and interleukin-2, standard of care chemotherapy for melanoma remains dacarbazine (response rate similar to 9%). Despite this, many physicians hesitate to refer patients to phase I protocols given a perceived lack of clinical benefit and potential for harm. To better understand the validity of these perceptions, the experience of all patients with melanoma treated on phase I trials sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program (NCI-CTEP) from 1995 to 2011 were analyzed and compared with the pooled results of six contemporary phase III trials of dacarbazine. A total of 937 patients with melanoma were treated in 148 CTEP phase I trials. The majority were men with a median of two prior therapies (46% receiving prior dacarbazine). Response and clinical benefit rates in these trials were not clinically different from those of dacarbazine (phase I: 6.3 and 26.8% vs. dacarbazine: 8.8 and 27.9%) although grades 3 and 4 toxicity was significantly higher (54 vs. 28%). Efficacy and toxicity were generally consistent within phase I subgroups (targeted agents, immunotherapies, or chemotherapeutics) though targeted therapy was associated with a lower response rate, immunotherapy higher incidence of grade 4 toxicity. Thus, the perception of limited efficacy of phase I trials for patients with melanoma was disproven, whereas the perception of toxicity was observed. However, this difference in toxicity may have been largely because of the nature of phase I vs. phase III trials (i.e. more heavily pretreated) and because of the phase I trials often being multiagent as opposed to dacarbazine alone. Melanoma Res 23:152-158 (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Luke, Jason J.] Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02215 USA. [Rubinstein, Lawrence V.; Smith, Gary L.; Ivy, S. Percy; Harris, Pamela J.] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Luke, JJ (reprint author), Dana Farber Canc Inst, Melanoma Dis Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM jason_luke@dfci.harvard.edu NR 29 TC 2 Z9 2 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD APR PY 2013 VL 23 IS 2 BP 152 EP 158 DI 10.1097/CMR.0b013e32835f73b2 PG 7 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 101YM UT WOS:000315810300009 PM 23411478 ER PT J AU Salum, GA Mogg, K Bradley, BP Gadelha, A Pan, P Tamanaha, AC Moriyama, T Graeff-Martins, AS Jarros, RB Polanczyk, G do Rosario, MC Leibenluft, E Rohde, LA Manfro, GG Pine, DS AF Salum, G. A. Mogg, K. Bradley, B. P. Gadelha, A. Pan, P. Tamanaha, A. C. Moriyama, T. Graeff-Martins, A. S. Jarros, R. B. Polanczyk, G. do Rosario, M. C. Leibenluft, E. Rohde, L. A. Manfro, G. G. Pine, D. S. TI Threat bias in attention orienting: evidence of specificity in a large community-based study SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Anxiety; attention; cognition; emotion; phobias ID GENERALIZED-ANXIETY-DISORDER; PREFRONTAL CORTEX ACTIVATION; COMMON MENTAL-DISORDERS; ANGRY FACES; SELECTIVE ATTENTION; EMOTIONAL FACES; ADOLESCENT PSYCHOPATHOLOGY; TIME-COURSE; CHILDREN; INFORMATION AB Background. Preliminary research implicates threat-related attention biases in paediatric anxiety disorders. However, major questions exist concerning diagnostic specificity, effects of symptom-severity levels, and threat-stimulus exposure durations in attention paradigms. This study examines these issues in a large, community school-based sample. Method. A total of 2046 children (ages 6-12 years) were assessed using the Development and Well Being Assessment (DAWBA), Childhood Behavior Checklist (CBCL) and dot-probe tasks. Children were classified based on presence or absence of 'fear-related' disorders, 'distress-related' disorders, and behavioural disorders. Two dot-probe tasks, which differed in stimulus exposure, assessed attention biases for happy-face and threat-face cues. The main analysis included 1774 children. Results. For attention bias scores, a three-way interaction emerged among face-cue emotional valence, diagnostic group, and internalizing symptom severity (F=2.87, p<0.05). This interaction reflected different associations between internalizing symptom severity and threat-related attention bias across diagnostic groups. In children with no diagnosis (n=1411, mean difference=11.03, S.E.=3.47, df=1, p<0.001) and those with distress-related disorders (n=66, mean difference=10.63, S.E.=5.24, df=1, p<0.05), high internalizing symptoms predicted vigilance towards threat. However, in children with fear-related disorders (n=86, mean difference=-11.90, S.E.=5.94, df=1, p<0.05), high internalizing symptoms predicted an opposite tendency, manifesting as greater bias away from threat. These associations did not emerge in the behaviour-disorder group (n=211). Conclusions. The association between internalizing symptoms and biased orienting varies with the nature of developmental psychopathology. Both the form and severity of psychopathology moderates threat-related attention biases in children. C1 [Salum, G. A.; Jarros, R. B.; Rohde, L. A.; Manfro, G. G.] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Mogg, K.; Bradley, B. P.] Univ Southampton, Southampton, Hants, England. [Gadelha, A.; Pan, P.; Tamanaha, A. C.; Moriyama, T.; Graeff-Martins, A. S.; do Rosario, M. C.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Moriyama, T.; Graeff-Martins, A. S.; Polanczyk, G.; Rohde, L. A.] Univ Sao Paulo, Sao Paulo, Brazil. [Leibenluft, E.; Pine, D. S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. RP Salum, GA (reprint author), Hosp Clin Porto Alegre, Ramiro Barcelos 2350,Room 2202, BR-90035003 Porto Alegre, RS, Brazil. EM gsalumjr@gmail.com RI Pan, Pedro/I-5167-2013; Rohde, Luis Augusto/A-6426-2008; Bradley, Brendan/B-9724-2008; Polanczyk, Guilherme/C-2345-2012; Psiquiatria, Inct/I-1060-2013; Mogg, Karin/C-1181-2008; Tamanaha, Ana Carina/J-5942-2012; Graeff-Martins, Ana Soledade/K-1974-2012; Salum, Giovanni/A-7849-2010 OI Pan, Pedro/0000-0002-1943-6520; Rohde, Luis Augusto/0000-0002-4552-4188; Gadelha, Ary/0000-0002-0993-8017; Polanczyk, Guilherme/0000-0003-2311-3289; Mogg, Karin/0000-0002-2738-7378; Bradley, Brendan/0000-0003-2801-4271; Tamanaha, Ana Carina/0000-0001-9915-6299; Salum, Giovanni/0000-0002-7537-7289 FU CNPq; CAPES; FAPESP; AstraZeneca; Eli Lilly; Janssen-Cilag; Novartis; National Council for Scientific and Technological Development (CNPq, Brazil); Abbott; Shire; FAPERGS; FIPEHCPA FX We thank the children and families for their participation, which made this research possible; the other members of the high-risk cohort research team (Dr Euripedes Constantino Miguel, Dr Rodrigo Affonseca-Bressan, Dr Pedro Gomes de Alvarenga and Dr Helena Brentani); the collaborators for the neuropsychological evaluation (Bruno Sini Scarpato, Sandra Lie Ribeiro do Valle and Carolina Araujo); Dr Robert Goodman for his research support regarding the DAWBA instrument procedures and Dr Bacy Fleitlich-Bilyk for her clinical supervision. We also thank the NIMH Intramural Research Program. This work is supported by the following Brazilian government agencies: CNPq, CAPES and FAPESP.; Giovanni Abrahao Salum has received a CNPq sandwich Ph.D. scholarship [sandwich period at National Institutes of Mental Health (NIMH)] and is currently in receipt of a CAPES doctoral scholarship. Ary Gadelha is in receipt of continuous medical education support from AstraZeneca, Eli Lilly and Janssen-Cilag. Pedro Pan is in receipt of research support from CNPq and CAPES and continuous medical education support from AstraZeneca, Eli Lilly and Janssen-Cilag. Ana Carina Tamanaha is in receipt of a post-doctoral fellowship from FAPESP. Tais Moriyama has received a CNPq Ph.D. scholarship and is in receipt of continuous medical education support from AstraZeneca, Eli Lilly and Janssen-Cilag. Ana Soledade Graeff-Martins is in receipt of a post-doctoral fellowship from CNPq. Guilherme Vanoni Polanczyk has served as a speaker and/or consultant to Eli Lilly, Novartis, and Shire Pharmaceuticals, developed educational material for Janssen-Cilag, and receives unrestricted research support from Novartis and from the National Council for Scientific and Technological Development (CNPq, Brazil). Maria Conceicao do Rosario receives research support from Brazilian government institutions (CNPQ) and has worked in the last 5 years as a speaker for Novartis and Shire. Luis Augusto Rohde was on the speakers' bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis and Shire in the last 3 years (received less than US$10 000 per year, which is less than 5% of L.A.R.'s gross income per year). L. A. R. also received travel awards (air tickets and hotel costs) from Novartis and Janssen-Cilag in 2010 for participation at two child psychiatric meetings. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by L. A. R. received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years; Abbott, Eli Lilly, Janssen-Cilag, Novartis, and Shire. Gisele Gus Manfro receives research support from Brazilian government institutions (CNPQ, FAPERGS, FIPEHCPA). NR 46 TC 47 Z9 47 U1 9 U2 47 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD APR PY 2013 VL 43 IS 4 BP 733 EP 745 DI 10.1017/S0033291712001651 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 105MB UT WOS:000316073500006 PM 22850475 ER PT J AU Zustiak, SP Wei, YQ Leach, JB AF Zustiak, Silviya P. Wei, Yunqian Leach, Jennie B. TI Protein-Hydrogel Interactions in Tissue Engineering: Mechanisms and Applications SO TISSUE ENGINEERING PART B-REVIEWS LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; POLY(ETHYLENE GLYCOL) HYDROGELS; SUBSEQUENT TRIGGERED RELEASE; COLLAGEN-BASED COMPOSITE; NEURAL STEM-CELLS; HYALURONIC-ACID; AFFINITY-BINDING; FACTOR DELIVERY; SURFACE IMMOBILIZATION; ALGINATE BIOMATERIAL AB Recent advances in our understanding of the sophistication of the cellular microenvironment and the dynamics of tissue remodeling during development, disease, and regeneration have increased our appreciation of the current challenges facing tissue engineering. As this appreciation advances, we are better equipped to approach problems in the biology and therapeutics of even more complex fields, such as stem cells and cancer. To aid in these studies, as well as the established areas of tissue engineering, including cardiovascular, musculoskeletal, and neural applications, biomaterials scientists have developed an extensive array of materials with specifically designed chemical, mechanical, and biological properties. Herein, we highlight an important topic within this area of biomaterials research, protein-hydrogel interactions. Due to inherent advantages of hydrated scaffolds for soft tissue engineering as well as specialized bioactivity of proteins and peptides, this field is well-posed to tackle major needs within emerging areas of tissue engineering. We provide an overview of the major modes of interactions between hydrogels and proteins (e.g., weak forces, covalent binding, affinity binding), examples of applications within growth factor delivery and three-dimensional scaffolds, and finally future directions within the area of hydrogel-protein interactions that will advance our ability to control the cell-biomaterial interface. C1 [Zustiak, Silviya P.] NICHHD, NIH, Bethesda, MD 20892 USA. [Wei, Yunqian; Leach, Jennie B.] Univ Maryland, Dept Chem Biochem & Environm Engn, Baltimore, MD 21250 USA. RP Leach, JB (reprint author), Univ Maryland, Dept Chem Biochem & Environm Engn, Eng 314,1000 Hilltop Circle, Baltimore, MD 21250 USA. EM jleach@umbc.edu FU Intramural Research Program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX We acknowledge NIH-NINDS R01NS065205 and funds from the Intramural Research Program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH for supporting this work. NR 134 TC 15 Z9 15 U1 7 U2 167 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3368 EI 1937-3376 J9 TISSUE ENG PART B-RE JI Tissue Eng. Part B-Rev. PD APR PY 2013 VL 19 IS 2 BP 160 EP 171 DI 10.1089/ten.teb.2012.0458 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 099VS UT WOS:000315651800006 PM 23150926 ER PT J AU Wolff, L Bies, J AF Wolff, Linda Bies, Juraj TI p15Ink4b Functions in determining hematopoietic cell fates: Implications for its role as a tumor suppressor SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Leukemia; Tumor suppressor; Hematopoiesis; Methylation; Immune surveillance; Erythropoiesis ID ACUTE MYELOID-LEUKEMIA; DENDRITIC CELLS; TRANSCRIPTION FACTORS; DNA METHYLATION; POOR-PROGNOSIS; P15(INK4B); PU.1; INACTIVATION; GENES; HYPERMETHYLATION AB The p15Ink4b gene is frequently hypermethylated in myeloid neoplasia and has been demonstrated to be a tumor suppressor. Since it is a member of the INK4b family of cyclin-dependent kinase inhibitors, it was initially presumed that its loss in leukemic blasts caused a dysregulation of the cell cycle. However, animal model experiments over the last several years have produced a very different picture of how p15Ink4b functions in hematopoietic cells and how its loss contributes to myelodysplastic syndrome and myeloid leukemia. It is clear now, that in early hematopoietic progenitors, p15Ink4b functions outside of its canonical role as a cell cycle inhibitor. Its functions are involved in signal transduction and influence the development of erythroid, monocytic and dendritic cells. Published by Elsevier Inc. C1 [Wolff, Linda; Bies, Juraj] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Wolff, L (reprint author), NCI, Cellular Oncol Lab, Room 4124,37 Convent Dr, Bethesda, MD 20892 USA. EM wolffl@mail.nih.gov; biesj@mail.nih.gov FU National Cancer Institute, Center for Cancer Research, NIH FX This work was supported by the intramural research program of the National Cancer Institute, Center for Cancer Research, NIH NR 43 TC 9 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 EI 1096-0961 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD APR PY 2013 VL 50 IS 4 BP 227 EP 231 DI 10.1016/j.bcmd.2013.01.006 PG 5 WC Hematology SC Hematology GA AD8IE UT WOS:000333508900001 PM 23403260 ER PT J AU Schairer, C Soliman, AS Omar, S Khaled, H Eissa, S Ben Ayed, F Khalafallah, S Ben Ayoub, W Kantor, ED Merajver, S Swain, SM Gail, M Brown, LM AF Schairer, Catherine Soliman, Amr S. Omar, Sherif Khaled, Hussein Eissa, Saad Ben Ayed, Farhat Khalafallah, Samir Ben Ayoub, Wided Kantor, Elizabeth D. Merajver, Sofia Swain, Sandra M. Gail, Mitchell Brown, Linda Morris TI Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in Egypt and Tunisia SO CANCER MEDICINE LA English DT Article DE Edema; Egypt; erythema; inflammatory breast cancer; peau d'orange; Tunisia AB The diagnosis of inflammatory breast cancer (IBC) is largely clinical and therefore inherently somewhat subjective. The objective of this study was to evaluate the diagnosis of IBC at two centers in North Africa where a higher proportion of breast cancer is diagnosed as IBC than in the United States (U.S.). Physicians prospectively enrolled suspected IBC cases at the National Cancer Institute (NCI) - Cairo, Egypt, and the Institut Salah Azaiz (ISA), Tunisia, recorded extent and duration of signs/symptoms of IBC on standardized forms, and took digital photographs of the breast. After second-level review at study hospitals, photographs and clinical information for confirmed IBC cases were reviewed by two U.S. oncologists. We calculated percent agreement between study hospital and U.S. oncologist diagnoses. Among cases confirmed by at least one U.S. oncologist, we calculated median extent and duration of signs and Spearman correlations. At least one U.S. oncologist confirmed the IBC diagnosis for 69% (39/50) of cases with photographs at the NCI-Cairo and 88% (21/24) of cases at the ISA. All confirmed cases had at least one sign of IBC (erythema, edema, peau d'orange) that covered at least one-third of the breast. The median duration of signs ranged from 1 to 3 months; extent and duration of signs were not statistically significantly correlated. From the above-mentioned outcomes, it can be concluded that the diagnosis of a substantial proportion of IBC cases is unambiguous, but a subset is difficult to distinguish from other types of locally advanced breast cancer. Among confirmed cases, the extent of signs was not related to delay in diagnosis. C1 [Schairer, Catherine; Gail, Mitchell; Brown, Linda Morris] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Soliman, Amr S.] Univ Nebraska, Med Ctr, Coll Publ Hlth, Dept Epidemiol, Omaha, NE 68198 USA. [Omar, Sherif] Cairo Univ, Natl Canc Inst, Dept Surg, Cairo 11796, Egypt. [Khaled, Hussein] Cairo Univ, Natl Canc Inst, Cairo 11796, Egypt. [Eissa, Saad] Cairo Univ, Natl Canc Inst, Dept Pathol, Cairo 11796, Egypt. [Ben Ayed, Farhat; Khalafallah, Samir; Ben Ayoub, Wided] Inst Salah Azaiz, Tunis 1006, Tunisia. [Kantor, Elizabeth D.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Merajver, Sofia] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Swain, Sandra M.] Natl Naval Med Ctr, Med Oncol Branch, Bethesda, MD 20889 USA. RP Schairer, C (reprint author), NCI, 6120 Execut Blvd,Rm 8026, Rockville, MD 20852 USA. EM schairec@exchange.nih.gov OI Kantor, Elizabeth/0000-0002-9124-5323; Swain, Sandra/0000-0002-1320-3830 FU National Cancer Institute FX This study was supported by intramural funds from the National Cancer Institute. NR 19 TC 4 Z9 4 U1 1 U2 2 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 APR PY 2013 VL 2 IS 2 BP 178 EP 184 DI 10.1002/cam4.48 PG 7 WC Oncology SC Oncology GA V36KI UT WOS:000209210600006 PM 23634285 ER PT J AU Towner, PH AF Towner, Philip H. TI The two letters to Timothy, The letter to Titus SO CATHOLIC BIBLICAL QUARTERLY LA English DT Book Review C1 [Towner, Philip H.] Amer Bible Soc, Nida Inst Bibl Scholarship, New York, NY 10023 USA. RP Towner, PH (reprint author), Amer Bible Soc, Nida Inst Bibl Scholarship, New York, NY 10023 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU CATHOLIC BIBLICAL ASSOC AMER PI WASHINGTON PA CATHOLIC UNIV AMERICA, 620 MICHIGAN AVE, NE, WASHINGTON, DC 20064 USA SN 0008-7912 EI 2163-2529 J9 CATH BIBLICAL QUART JI Cathol. Biblic. Q. PD APR PY 2013 VL 75 IS 2 BP 360 EP 361 PG 2 WC Religion SC Religion GA V38OZ UT WOS:000209354000023 ER PT J AU Wang, XS AF Wang, Xiaosheng TI Discovery of molecular associations among aging, stem cells, and cancer based on gene expression profiling SO CHINESE JOURNAL OF CANCER LA English DT Review DE Cancer; aging; stem cells; gene expression profiling; cancer informatics ID EMBRYONIC STEM; TRANSCRIPTIONAL NETWORK; KEY REGULATORS; HUMAN KIDNEY; HUMAN MUSCLE; HUMAN SKIN; SIGNATURE; TUMORS; PLURIPOTENCY; DISEASES AB The emergence of a huge volume of "omics". data enables a computational approach to the investigation of the biology of cancer. The cancer informatics approach is a useful supplement to the traditional experimental approach. I reviewed several reports that used a bioinformatics approach to analyze the associations among aging, stem cells, and cancer by microarray gene expression profiling. The high expression of aging- or human embryonic stem cell-related molecules in cancer suggests that certain important mechanisms are commonly underlying aging, stem cells, and cancer. These mechanisms are involved in cell cycle regulation, metabolic process, DNA damage response, apoptosis, p53 signaling pathway, immune/inflammatory response, and other processes, suggesting that cancer is a developmental and evolutional disease that is strongly related to aging. Moreover, these mechanisms demonstrate that the initiation, proliferation, and metastasis of cancer are associated with the deregulation of stem cells. These findings provide insights into the biology of cancer. Certainly, the findings that are obtained by the informatics approach should be justified by experimental validation. This review also noted that next-generation sequencing data provide enriched sources for cancer informatics study. C1 NCI, Biometr Res Branch, NIH, Rockville, MD 20852 USA. RP Wang, XS (reprint author), NCI, Biometr Res Branch, NIH, Rockville, MD 20852 USA. EM xiaosheng.wang@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 47 TC 3 Z9 3 U1 2 U2 10 PU SUN YAT SEN UNIV MED SCI WHO PI GUANGZHOU PA 651 DONGFENG RD E, GUANGZHOU, GUANGDONG 510060, PEOPLES R CHINA SN 1000-467X EI 1944-446X J9 CHIN J CANCER JI Chin. J. Cancer PD APR PY 2013 VL 32 IS 4 BP 155 EP 161 DI 10.5732/cjc.012.10114 PG 7 WC Oncology SC Oncology GA AM1ZT UT WOS:000339648500002 PM 23298462 ER PT J AU Uchida, N Hanawa, H Yamamoto, M Shimada, T AF Uchida, Naoya Hanawa, Hideki Yamamoto, Motoko Shimada, Takashi TI The Chicken Hypersensitivity Site 4 Core Insulator Blocks Promoter Interference in Lentiviral Vectors SO HUMAN GENE THERAPY METHODS LA English DT Article ID HUMAN HEMATOPOIETIC-CELLS; TRANSGENE EXPRESSION; CHS4 INSULATOR; GENE-THERAPY; INTERNAL PROMOTERS; RETROVIRAL VECTORS; IN-VIVO; CHROMATIN; ACTIVATION; GENERATION AB Lentiviral vectors, including double internal promoters, can be used to express two transgenes in a single vector construct; however, transcriptional activities from double internal promoters are often inhibited by promoter interference. To determine whether the chicken hypersensitivity site 4 insulator (cHS4) could block promoter interference, lentiviral vectors including an MSCV-U3 promoter (Mp) and an EF1 alpha promoter (Ep) were generated, and transgene expression was evaluated among transduced cells. In the Ep-Mp configuration, transcriptional activity from Mp was much lower, while Mp-Ep had similar transcription levels from both promoters. The cHS4 core insulator increased expression levels from Mp in HeLa cells, hematopoietic cell lines, and mouse peripheral blood cells following hematopoietic stem cell transplantation transduced with the Mp-Ep configured vector. This blocking function was mainly mediated by barrier activity regions in the insulator but not by CCCTC-binding factor (CTCF) binding sites. Cytosine-phosphate-guanine (CpG) methylation did not contribute to this barrier activity. In summary, combining the cHS4 insulator in double promoter vectors can improve transgene expression levels in various cell lines and mouse hematopoietic repopulating cells. These findings are useful for developing hematopoietic stem cell gene therapy. C1 [Uchida, Naoya; Hanawa, Hideki; Yamamoto, Motoko; Shimada, Takashi] Nippon Med Sch, Tokyo 1138602, Japan. [Uchida, Naoya] Nippon Med Sch, Dept Internal Med, Div Hematol, Tokyo 1138602, Japan. [Uchida, Naoya] NIDDK, Mol & Clin Hematol, NHLBI, NIH, Bethesda, MD 20892 USA. RP Uchida, N (reprint author), NIH, Mol & Clin Hematol Branch, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM uchidan@nhlbi.nih.gov FU NHLBI/NIDDK FX We thank Drs. John Tisdale and Matthew Hsieh in Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institute (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health for the preparation and editing of our manuscript. This work was supported in part by the intramural programs of NHLBI/NIDDK. NR 24 TC 8 Z9 8 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1946-6536 EI 1946-6544 J9 HUM GENE THER METHOD JI Hum. Gene Ther. Methods PD APR PY 2013 VL 24 IS 2 BP 117 EP 124 DI 10.1089/hgtb.2012.152 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AI4LD UT WOS:000336835900006 PM 23448496 ER PT J AU Rosenbaum, M Ravussin, Y Leibel, RL AF Rosenbaum, Michael Ravussin, Yann Leibel, Rudolph L. TI Does diet composition have structural consequences in the hypothalamus? SO MOLECULAR METABOLISM LA English DT Editorial Material C1 [Rosenbaum, Michael; Leibel, Rudolph L.] Columbia Univ Coll Phys & Surg, Dept Pediat, Div Mol Genet, 630 West 168th St, New York, NY 10032 USA. [Ravussin, Yann] NIH, Bethesda, MD 20892 USA. RP Leibel, RL (reprint author), Columbia Univ Coll Phys & Surg, Dept Pediat, Div Mol Genet, 630 West 168th St, New York, NY 10032 USA. FU NCATS NIH HHS [UL1 TR000040]; NIDDK NIH HHS [R01 DK064773] NR 9 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2212-8778 J9 MOL METAB JI Mol. Metab. PD APR PY 2013 VL 2 IS 2 BP 58 EP 59 DI 10.1016/j.molmet.2013.01.005 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V42UC UT WOS:000209637700002 PM 24199148 ER PT J AU Borges, IT Shea, CD Ohayon, J Jones, BC Stone, RD Ostuni, J Shiee, N McFarland, H Bielekova, B Reich, DS AF Borges, Isabela T. Shea, Colin D. Ohayon, Joan Jones, Blake C. Stone, Roger D. Ostuni, John Shiee, Navid McFarland, Henry Bielekova, Bibiana Reich, Daniel S. TI The effect of daclizumab on brain atrophy in relapsing-remitting multiple sclerosis SO MULTIPLE SCLEROSIS AND RELATED DISORDERS LA English DT Article DE Multiple sclerosis; Brain atrophy; Gray matter; Brain volume; Dactizumab; Interferon beta AB Daclizumab is a monoclonal antibody that reduces inflammation in multiple sclerosis (MS). Through a retrospective analysis, our objective was to determine whether daclizumab treatment reduces the rate of brain structure atrophy in comparison to a mixture of other disease-modifying therapies (mainly different interferon beta preparations). We analyzed MRI examinations (1332 scans from 70 MS cases) obtained between 2000 and 2011 in a single center and processed with an automated brain segmentation method. We used mixed-effects multivariable linear regression models to determine whether a median of 4.3 years of daclizumab therapy in 26 patients altered rates of brain-volume change, controlling for variations in MRI protocol. The control group consisted of 44 patients not treated with daclizumab. We found that supratentorial brain volume declined by 5.17 ml per year (95% confidence limits: 3.58-6.77) off daclizumab therapy. On daclizumab, the annual rate of volume loss decreased to 3.72 ml (p=0.01). The rate of ventricular enlargement decreased from 1.26 to 0.42 ml per year (p<0.001). Focused analysis suggests that reduction in gray matter atrophy rate most likely underlies these results. In summary, in this retrospective analysis, daclizumab therapy substantially decreased the rate of brain atrophy in relapsing-remitting MS in comparison to other disease-modifying therapies, predominantly interferon beta. (C) 2012 Elsevier B.V. All rights reserved. C1 [Borges, Isabela T.; Shea, Colin D.; Ohayon, Joan; Jones, Blake C.; Stone, Roger D.; Ostuni, John; McFarland, Henry; Bielekova, Bibiana; Reich, Daniel S.] NINDS, NIH, Bethesda, MD 20892 USA. [Shiee, Navid] NIH, Radiol & Imaging Sci Clin Ctr, Rochester, MN USA. [Shiee, Navid] Henry M Jackson Fdn Adv Mil Med, Ctr Neurosci & Regenerat Med, Bethesda, MD USA. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Unit, NIH, 10 Ctr Dr,MSC 1400,Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM daniel.reich@nih.gov OI Borges, Isabela/0000-0002-4208-8253 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX The Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, supported all aspects of this study, including data acquisition and analysis. There was no support from any industry sources. NR 50 TC 13 Z9 15 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2211-0348 EI 2211-0356 J9 MULT SCLER RELAT DIS JI Mult. Scler. Relat. Disord. PD APR PY 2013 VL 2 IS 2 BP 133 EP 140 DI 10.1016/j.msard.2012.10.002 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA V37LC UT WOS:000209276300012 PM 23580931 ER PT J AU Kramer, M Dees, C Huang, JG Schlottmann, I Palumbo-Zerr, K Zerr, P Gelse, K Beyer, C Distler, A Marquez, VE Distler, O Schett, G Distler, JHW AF Kraemer, Marlene Dees, Clara Huang, Jingang Schlottmann, Inga Palumbo-Zerr, Katrin Zerr, Pawel Gelse, Kolja Beyer, Christian Distler, Alfiya Marquez, Victor E. Distler, Oliver Schett, Georg Distler, Joerg H. W. TI Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID SYSTEMIC-SCLEROSIS; EXTRACELLULAR-MATRIX; SCLERODERMA FIBROBLASTS; COLLAGEN EXPRESSION; T-CELLS; METHYLATION; DISEASE; EPIGENETICS; MECHANISMS; PREVENTS AB Objectives Epigenetic modifications such as DNA methylation and histone acetylation have been implicated in the pathogenesis of systemic sclerosis. However, histone methylation has not been investigated so far. We therefore aimed to evaluate the role of the trimethylation of histone H3 on lysine 27 (H3K27me3) on fibroblast activation and fibrosis. Methods H3K27me3 was inhibited by 3-deazaneplanocin A (DZNep) in cultured fibroblasts and in two murine models of dermal fibrosis. Fibrosis was analysed by assessment of the dermal thickening, determination of the hydroxyproline content and by quantification of the numbers of myofibroblasts. The expression of fos-related antigen 2 (fra-2) was assessed by real-time PCR, western blot and immunohistochemistry and modulated by siRNA. Results Inhibition of H3K27me3 stimulated the release of collagen in cultured fibroblasts in a time and dose-dependent manner. Treatment with DZNep exacerbated fibrosis induced by bleomycin or by overexpression of a constitutively active transforming growth factor beta receptor type I. Moreover, treatment with DZNep alone was sufficient to induce fibrosis. Inhibition of H3K27me3 induced the expression of the profibrotic transcription factor fra-2 in vitro and in vivo. Knockdown of fra-2 completely prevented the profibrotic effects of DZNep. Conclusions These data demonstrate a novel role of H3 Lys27 histone methylation in fibrosis. In contrast to other epigenetic modifications such as DNA methylation and histone acetylation, H3 Lys27 histone methylation acts as a negative regulator of fibroblast activation in vitro and in vivo by repressing the expression of fra-2. C1 [Kraemer, Marlene; Dees, Clara; Huang, Jingang; Schlottmann, Inga; Palumbo-Zerr, Katrin; Zerr, Pawel; Beyer, Christian; Distler, Alfiya; Schett, Georg; Distler, Joerg H. W.] Univ Erlangen Nurnberg, Dept Internal Med 3, D-91054 Erlangen, Germany. [Kraemer, Marlene; Dees, Clara; Huang, Jingang; Schlottmann, Inga; Palumbo-Zerr, Katrin; Zerr, Pawel; Beyer, Christian; Distler, Alfiya; Schett, Georg; Distler, Joerg H. W.] Univ Erlangen Nurnberg, Inst Clin Immunol, D-91054 Erlangen, Germany. [Gelse, Kolja] Univ Erlangen Nurnberg, Dept Orthopaed Trauma Surg, D-91054 Erlangen, Germany. [Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Distler, Oliver] Univ Zurich Hosp, Ctr Expt Rheumatol, CH-8091 Zurich, Switzerland. [Distler, Oliver] Univ Zurich Hosp, Zurich Ctr Integrat Human Physiol, CH-8091 Zurich, Switzerland. RP Distler, JHW (reprint author), Univ Erlangen Nurnberg, Dept Internal Med 3, Ulmenweg 18, D-91054 Erlangen, Germany. EM joerg.distler@uk-erlangen.de OI Beyer, Christian/0000-0003-0319-662X FU Deutsche Forschungsgesellschaft [DI 1537/1-1, DI 1537/2-1, DI 1537/4-1, DI 1537/5-1, AK 144/1-1, SCHE 1583/7-1]; IZKF in Erlangen [A20, A40]; ELAN-Programme of the University of Erlangen-Nuremberg; Career Support Award of Medicine of the Ernst Jung Foundation; Intramural Research Programme of the NIH, National Cancer Institute, Center for Cancer Research FX This study was funded by grants DI 1537/1-1, DI 1537/2-1, DI 1537/4-1, DI 1537/5-1, AK 144/1-1 and SCHE 1583/7-1 of the Deutsche Forschungsgesellschaft, grants A20 and A40 of the IZKF in Erlangen, the ELAN-Programme of the University of Erlangen-Nuremberg and the Career Support Award of Medicine of the Ernst Jung Foundation. This research was supported in part by the Intramural Research Programme of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 29 Z9 30 U1 0 U2 16 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD APR PY 2013 VL 72 IS 4 BP 614 EP 620 DI 10.1136/annrheumdis-2012-201615 PG 7 WC Rheumatology SC Rheumatology GA 096BJ UT WOS:000315378500024 PM 22915621 ER PT J AU Andersen, DK AF Andersen, Dana K. TI Diabetes and cancer: placing the association in perspective SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE cancer; diabetes; metformin; obesity; pancreatic cancer; pancreatic polypeptide; pancreatogenic diabetes ID LIFE-STYLE INTERVENTION; POPULATION-BASED COHORT; PANCREATIC-CANCER; GLUCOSE-METABOLISM; K-RAS; RISK; MELLITUS; METFORMIN; INSULIN; MORTALITY AB Purpose of review The association of diabetes and cancer has received increased attention as data have emerged to indicate that the type of diabetes treatment may influence the risk of cancer, and that the risk of cancer among diabetic individuals can be reduced by intervention. The association of diabetes and pancreatic cancer is particularly strong, but often misunderstood. Long-standing type 1 diabetes and type 2 diabetes increase the risk for this malignancy, but the cancer can also induce pancreatogenic, or type 3c, diabetes as well. Recent findings This review covers the recent findings which help to clarify these relationships, and offers guidance for prevention, early detection, and treatment. Obesity and, separately, diabetes increase the risk of several common malignancies by about two-fold. This risk is reduced by successful treatments. Type 3c diabetes is more common than previously realized, and strategies to differentiate type 3c diabetes from type 2 diabetes, to identify those candidates who will benefit from screening studies, are discussed. Summary The death rate because of pancreatic and other cancers can be reduced by an aggressive approach to reversing obesity and hyperinsulinemia, achieving good glycemic control in diabetic patients, and identifying at an early timepoint those patients with pancreatogenic diabetes. C1 [Andersen, Dana K.] NIDDK, Clin Studies Program, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Andersen, DK (reprint author), NIDDK, Div Digest Dis & Nutr, NIH, 2 Democracy Plaza,Room 659, Bethesda, MD 20892 USA. EM andersendk@niddk.nih.gov NR 53 TC 11 Z9 12 U1 0 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1752-296X J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD APR PY 2013 VL 20 IS 2 BP 81 EP 86 DI 10.1097/MED.0b013e32835eddd3 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 097ND UT WOS:000315479900001 PM 23422245 ER PT J AU De Boeck, A Pauwels, P Hensen, K Rummens, JL Westbroek, W Hendrix, A Maynard, D Denys, H Lambein, K Braems, G Gespach, C Bracke, M De Wever, O AF De Boeck, Astrid Pauwels, Patrick Hensen, Karen Rummens, Jean-Luc Westbroek, Wendy Hendrix, An Maynard, Dawn Denys, Hannelore Lambein, Kathleen Braems, Geert Gespach, Christian Bracke, Marc De Wever, Olivier TI Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling SO GUT LA English DT Article ID HUMAN COLON-CANCER; GROWTH-FACTOR RECEPTOR; TUMOR MICROENVIRONMENT; METASTATIC NICHE; ERBB RECEPTORS; TENASCIN-C; IN-VIVO; HEREGULIN; KINASE; MYOFIBROBLASTS AB Objective Bone marrow-derived mesenchymal stem cells (BM-MSC) migrate to primary tumours and drive tumour progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC). Design Paracrine interactions of BM-MSC with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumour xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane neuregulin 1 (tNRG1), HER2 and HER3 expression was analysed in primary CRC (n = 54), adjacent normal colorectal tissues (n = 4), liver metastases (n = 3) and adjacent normal liver tissues (n = 3) by immunohistochemistry. Results BM-MSC stimulate invasion, survival and tumorigenesis of CRC through the release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signalling cascade in CRC cells. Similarly, tumour-associated mesenchymal cells (T-MC) in CRC demonstrate high tNRG1 expression, which is significantly associated with advanced Union for International Cancer Control stage (p = 0.005) and invasion depth (p = 0.04) and decreased 5-year progression-free survival (p = 0.01). HER2 and HER3 show membrane localisation in cancer cells of CRC tissue. Conclusion Paracrine NRG1/HER3 signals initiated by BM-MSC and T-MC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis in CRC. C1 [De Boeck, Astrid; Hendrix, An; Bracke, Marc; De Wever, Olivier] Ghent Univ Hosp, Dept Radiat Oncol & Expt Canc Res, Lab Expt Canc Res, B-9000 Ghent, Belgium. [Pauwels, Patrick] Univ Antwerp, Dept Pathol, Antwerp, Belgium. [Hensen, Karen; Rummens, Jean-Luc] Jesse Hosp, Lab Expt Hematol, Hasselt, Belgium. [Westbroek, Wendy; Maynard, Dawn] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Hendrix, An; Denys, Hannelore] Ghent Univ Hosp, Dept Med Oncol, Ghent, Belgium. [Lambein, Kathleen] Ghent Univ Hosp, Dept Pathol, Ghent, Belgium. [Braems, Geert] Ghent Univ Hosp, Dept Gynaecol, Ghent, Belgium. [Gespach, Christian] Univ Paris 06, INSERM, UMR Mol & Clin Oncol S938, Ctr Rech St Antoine, Paris, France. RP De Wever, O (reprint author), Ghent Univ Hosp, Dept Radiat Oncol & Expt Canc Res, Lab Expt Canc Res, De Pintelaan 185, B-9000 Ghent, Belgium. EM olivier.dewever@ugent.be RI de wever, olivier/J-3094-2013 OI de wever, olivier/0000-0002-5453-760X FU National Human Genome Research Institute; Centrum voor Gezwelziekten; Flemish community and France [I.2007.03, T.2009.14, T.2010.14]; Vlaamse Liga tegen Kanker, Stichting tegen Kanker; Bijzonder Onderzoeksfonds UGent; ADB [1148408N]; Fund for Scientific Research-Flanders FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, Centrum voor Gezwelziekten, the Scientific Exchange Program between the Flemish community and France (I.2007.03, T.2009.14, T.2010.14), Vlaamse Liga tegen Kanker, Stichting tegen Kanker, Bijzonder Onderzoeksfonds UGent, travel grant (AH and ODW), a doctoral grant (ADB; 1148408N) and a postdoctoral researcher (ODW) from the Fund for Scientific Research-Flanders. NR 57 TC 52 Z9 52 U1 1 U2 30 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD APR PY 2013 VL 62 IS 4 BP 550 EP 560 DI 10.1136/gutjnl-2011-301393 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 099CB UT WOS:000315595800011 PM 22535374 ER PT J AU Leng, Y Fessler, EB Chuang, DM AF Leng, Yan Fessler, Emily Bame Chuang, De-Maw TI Neuroprotective effects of the mood stabilizer lamotrigine against glutamate excitotoxicity: roles of chromatin remodelling and Bcl-2 induction SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Bcl-2; glutamate; histone deacetylase; lamotrigine; neuroprotection ID HISTONE DEACETYLASE INHIBITION; GLYCOGEN-SYNTHASE KINASE-3; TRANSGENIC MOUSE MODEL; VALPROIC ACID; BIPOLAR DISORDER; IN-VIVO; CEREBRAL-ISCHEMIA; PROTEIN BCL-2; DOUBLE-BLIND; HUMAN BRAIN AB Lamotrigine (LTG), a phenyltriazine derivative and anti-epileptic drug, has emerged as an effective first-line treatment for bipolar mood disorder. Like the other mood stabilizers lithium and valproate, LTG also has neuroprotective properties but its exact mechanisms remain poorly defined. The present study utilized rat cerebellar granule cells (CGCs) to examine the neuroprotective effects of LTG against glutamate-induced excitotoxicity and to investigate potential underlying mechanisms. CGCs pretreated with LTG were challenged with an excitotoxic dose of glutamate. Pretreatment caused a time-and concentration-dependent inhibition of glutamate excitotoxicity with nearly full protection at higher doses (>= 100 mu M), as revealed by cell viability assays and morphology. LTG treatment increased levels of acetylated histone H3 and H4 as well as dose-and time-dependently enhanced B-cell lymphoma-2 (Bcl-2) mRNA and protein levels; these changes were associated with up-regulation of the histone acetylation and activity of the Bcl-2 promoter. Importantly, lentiviral-mediated Bcl-2 silencing by shRNA reduced both LTG-induced Bcl-2 mRNA up-regulation and neuroprotection against glutamate excitotoxicity. Finally, the co-presence of a sub-effective concentration of LTG (10 mM) with lithium or valproate produced synergistic neuroprotection. Together, our results demonstrate that the neuroprotective effects of LTG against glutamate excitotoxicity likely involve histone deacetylase inhibition and downstream up-regulation of anti-apoptotic protein Bcl-2. These underlying mechanisms may contribute to the clinical efficacy of LTG in treating bipolar disorder and warrant further investigation. C1 [Leng, Yan; Fessler, Emily Bame; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, 10 Ctr Dr,MSC1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU NIMH, NIH; Hsu Family Foundation FX This study was supported by the Intramural Research Program of NIMH, NIH and a gift fund from the Hsu Family Foundation. The authors thank members in the Molecular Neurobiology Section, NIMH, NIH, notably Dr Chi-Tso Chiu, Dr Joshua Hunsberger and Peter Leeds, for their helpful discussions and assistance. NR 69 TC 14 Z9 15 U1 0 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD APR PY 2013 VL 16 IS 3 BP 607 EP 620 DI 10.1017/S1461145712000429 PG 14 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 098DX UT WOS:000315527600011 PM 22564541 ER PT J AU Moya, PR Wendland, JR Salemme, J Fried, RL Murphy, DL AF Moya, Pablo R. Wendland, Jens R. Salemme, Jennifer Fried, Ruby L. Murphy, Dennis L. TI miR-15a and miR-16 regulate serotonin transporter expression in human placental and rat brain raphe cells SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE miR-15a; miR-16; serotonin transporter; SERT; SLC6A4 ID OBSESSIVE-COMPULSIVE DISORDER; PROMOTER POLYMORPHISM; TARGET SITE; GENE; ASSOCIATION; DEPRESSION; ACTIVATION; RECEPTORS; VARIANTS; LEUKEMIA AB The serotonin transporter (SERT) is a key regulatory molecule in serotonergic transmission implicated in numerous biological processes relevant to human disorders. Recently, it was shown that SERT expression is controlled by miR-16 in mouse brain. Here, we show that SERT expression is regulated additionally by miR-15a as well as miR-16 in human and rat tissues. This post-transcriptional regulation was observed and characterized in reporter assays and likewise when endogenous SERT expression was evaluated in human placental choriocarcinoma JAR cells and rat brain raphe RN46A cells - two cell lines that endogenously express SERT. Similar effects for miR-16 to those of miR-15a were found in both human and rat cell lines. The effects of miR-15a and miR-16 were comparable in extent to those originally reported for miR-16 in mice. These findings represent a novel layer of complexity for SERT expression regulation exerted by the mir-15a/16 cluster, whose genes are adjacently located at human chromosome 13q14.3. C1 [Moya, Pablo R.; Salemme, Jennifer; Fried, Ruby L.; Murphy, Dennis L.] NIMH, Clin Sci Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Wendland, Jens R.] F Hoffmann La Roche & Co Ltd, Pharma Res & Early Dev, CH-4002 Basel, Switzerland. RP Moya, PR (reprint author), NIMH, Clin Sci Lab, 10-3D41,10 Ctr Dr, Bethesda, MD 20892 USA. EM moyap@mail.nih.gov 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. The authors also thank James Nagle and Debbie Kauffman, from the NINDS DNA sequencing core facility, for outstanding technical assistance with sequencing the SLC6A4 3'-UTR and reporter constructs, and Dr Scott R. Whittemore, University of Louisville, for providing us with the RN46A cell line. NR 37 TC 15 Z9 19 U1 1 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD APR PY 2013 VL 16 IS 3 BP 621 EP 629 DI 10.1017/S1461145712000454 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 098DX UT WOS:000315527600012 PM 22564678 ER PT J AU Tao, MH Marian, C Shields, PG Potischman, N Nie, J Krishnan, SS Berry, DL Kallakury, BV Ambrosone, C Edge, SB Trevisan, M Winston, J Freudenheim, JL AF Tao, M-H Marian, C. Shields, P. G. Potischman, N. Nie, J. Krishnan, S. S. Berry, D. L. Kallakury, B. V. Ambrosone, C. Edge, S. B. Trevisan, M. Winston, J. Freudenheim, J. L. TI Exposures in early life: associations with DNA promoter methylation in breast tumors SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Article DE breast cancer; early-life exposure; epidemiology; epigenetics; promoter methylation ID NEW-YORK EXPOSURES; CANCER-RISK; BIRTH-WEIGHT; SMOKE EXPOSURE; BODY-MASS; METAANALYSIS; HYPERMETHYLATION; INFANCY; COHORT; MILK AB There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case-control study. Promoter methylation of E-cadherin, p16 and RAR-beta(2) genes was assessed in archived tumor blocks from 803 cases with real-time methylation-specific PCR. Unconditional logistic regression was used for case-case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth and weight at age 20. In case-case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E-cadherin promoter methylation (OR = 2.79, 95% CI, 1.15-6.82, for <= 2.5 v. 2.6-2.9 kg); higher adult height with RAR-beta(2) methylation (OR = 3.34, 95% CI, 1.19-9.39, for >= 1.65 v. <1.60 m); and not having been breastfed with p16 methylation (OR = 2.75, 95% CI, 1.14-6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of >= 1 of the three genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early-life exposures that persist into adulthood and affect breast cancer risk. C1 [Tao, M-H] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY 10029 USA. [Marian, C.; Shields, P. G.; Krishnan, S. S.] Ohio State Univ, Ctr Canc, Columbus, OH 43210 USA. [Potischman, N.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Nie, J.; Trevisan, M.; Freudenheim, J. L.] SUNY Buffalo, Dept Social & Prevent Med, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14260 USA. [Berry, D. L.; Kallakury, B. V.] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. [Ambrosone, C.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Edge, S. B.] Roswell Pk Canc Inst, Dept Surg, Buffalo, NY 14263 USA. [Trevisan, M.] CUNY, Sch Biomed Educ, New York, NY 10021 USA. [Winston, J.] Potomac Hosp, Woodbridge, VA USA. RP Tao, MH (reprint author), Mt Sinai Sch Med, Inst Translat Epidemiol, POB 1057, New York, NY 10029 USA. EM menghua.tao@mssm.edu RI Marian, Catalin/B-1750-2012; OI Marian, Catalin/0000-0002-7749-1384 FU National Institute on Alcohol Abuse and Alcoholism [P50-AA09802]; Department of Defense [DAMD 179616202, DAMD 17030446]; National Cancer Institute [R01CA 092040] FX This study would not have been possible without the support of all the study participants and the research staff of the WEB Study. This work was supported in part by the National Institute on Alcohol Abuse and Alcoholism (P50-AA09802), the Department of Defense (DAMD 179616202, DAMD 17030446) and the National Cancer Institute (R01CA 092040). NR 46 TC 1 Z9 1 U1 0 U2 11 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD APR PY 2013 VL 4 IS 2 BP 182 EP 190 DI 10.1017/S2040174412000694 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 100GO UT WOS:000315685800009 PM 25054684 ER PT J AU Cui, CH Noronha, A Morikawa, H Alvarez, VA Stuber, GD Szumlinski, KK Kash, TL Roberto, M Wilcox, MV AF Cui, Changhai Noronha, Antonio Morikawa, Hitoshi Alvarez, Veronica A. Stuber, Garret D. Szumlinski, Karen K. Kash, Thomas L. Roberto, Marisa Wilcox, Mark V. TI New insights on neurobiological mechanisms underlying alcohol addiction SO NEUROPHARMACOLOGY LA English DT Review DE Alcohol; Dependence; Addiction; Metaplasticity; CRF; VTA; BNST; mGluR; Binge drinking; Dendritic spines ID CORTICOTROPIN-RELEASING-FACTOR; VENTRAL TEGMENTAL AREA; LONG-TERM POTENTIATION; CHRONIC ETHANOL-CONSUMPTION; MIDBRAIN DOPAMINE NEURONS; EXCITATORY SYNAPTIC-TRANSMISSION; DENDRITIC SPINE MORPHOLOGY; AMINOBUTYRIC-ACID RELEASE; IN-THE-DARK; STRIA TERMINALIS AB Alcohol dependence/addiction is mediated by complex neural mechanisms that involve multiple brain circuits and neuroadaptive changes in a variety of neurotransmitter and neuropeptide systems. Although recent studies have provided substantial information on the neurobiological mechanisms that drive alcohol drinking behavior, significant challenges remain in understanding how alcohol-induced neuroadaptations occur and how different neurocircuits and pathways cross-talk. This review article highlights recent progress in understanding neural mechanisms of alcohol addiction from the perspectives of the development and maintenance of alcohol dependence. It provides insights on cross talks of different mechanisms and reviews the latest studies on metaplasticity, structural plasticity, interface of reward and stress pathways, and cross-talk of different neural signaling systems involved in binge-like drinking and alcohol dependence. Published by Elsevier Ltd. C1 [Cui, Changhai; Noronha, Antonio] NIAAA, Div Neurosci & Behav, NIH, Bethesda, MD 20892 USA. [Morikawa, Hitoshi] Univ Texas Austin, Waggoner Ctr Alcohol & Addict Res, Austin, TX 78712 USA. [Alvarez, Veronica A.; Wilcox, Mark V.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Stuber, Garret D.] Univ N Carolina, UNC Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA. [Stuber, Garret D.] Univ N Carolina, UNC Sch Med, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA. [Szumlinski, Karen K.] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. [Kash, Thomas L.] Univ N Carolina, UNC Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Roberto, Marisa] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. RP Cui, CH (reprint author), NIAAA, Div Neurosci & Behav, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM changhai.cui@nih.gov; anoronha@willco.niaaa.nih.gov RI Kash, Thomas/G-9625-2013; Alvarez, Veronica /E-9745-2015; Stuber, Garret/E-1160-2011 OI Alvarez, Veronica /0000-0003-2611-8675; FU NIH [R01AA015521, DA015687]; NIAAA [ZIA-AA000421]; ABMRF; [R01DA032750]; [R21DA029325]; [R01AA016650]; [R01DA024038]; [U01AA020911]; [R00AA017668]; [R01AA17447]; [R01AA015566]; [P60AA06420]; [R01AA016985] FX The work was supported by NIH grants R01AA015521 and DA015687 to HM, NIAAA intramural program ZIA-AA000421 to VAA, R01DA032750, R21DA029325, and ABMRF grant to GDS, R01AA016650 and R01DA024038 to KKS, U01AA020911 and R00AA017668 to TLK, R01AA17447, R01AA015566, P60AA06420, and R01AA016985 to MR. NR 144 TC 27 Z9 29 U1 2 U2 71 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD APR PY 2013 VL 67 BP 223 EP 232 DI 10.1016/j.neuropharm.2012.09.022 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 097ME UT WOS:000315477400025 PM 23159531 ER PT J AU Herman, MA Kallupi, M Luu, G Oleata, CS Heilig, M Koob, GF Ciccocioppo, R Roberto, M AF Herman, Melissa A. Kallupi, Marsida Luu, George Oleata, Christopher S. Heilig, Markus Koob, George F. Ciccocioppo, Roberto Roberto, Marisa TI Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: Alcohol and CRF effects SO NEUROPHARMACOLOGY LA English DT Article DE Amygdala; GABA; Alcohol; CRF; CRF1 antagonist; Electrophysiology ID CORTICOTROPIN-RELEASING-FACTOR; AMINOBUTYRIC-ACID RELEASE; ETHANOL-DEPENDENT RATS; SYNAPTIC GABA(A) RECEPTORS; CROSS-FOSTERING ANALYSIS; PREFERRING MSP RATS; PROTEIN-KINASE; SPONTANEOUS NEUROTRANSMISSION; CONDITIONED FEAR; CENTRAL SYNAPSES AB The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. Alcohol dependence is associated with increased corticotropin releasing factor (CRF) influence on CeA GABA release and CRF type 1 receptor (CRF1) antagonists prevent the excessive alcohol consumption associated with dependence. Genetically selected Marchigian Sardinian (msP) rats have an overactive extrahypothalamic CRF1 system, are highly sensitive to stress, and display an innate preference for alcohol. The present study examined differences in CeA GABAergic transmission and the effects of ethanol, CRF and a CRF1 antagonist in msP, Sprague Dawley, and Wistar rats using an electrophysiological approach. We found no significant differences in membrane properties or mean amplitude of evoked GABA(A)-inhibitory postsynaptic potentials (IPSPs). However, paired-pulse facilitation (PPF) ratios of evoked IPSPs were significantly lower and spontaneous miniature inhibitory postsynaptic current (mIPSC) frequencies were higher in msP rats, suggesting increased CeA GABA release in msP as compared to Sprague Dawley and Wistar rats. The sensitivity of spontaneous GABAergic transmission to ethanol (44 mM), CRF (200 nM) and CRF1 antagonist (R121919, 1 mu M) was comparable in msP, Sprague Dawley, and Wistar rats. However, a history of ethanol drinking significantly increased the baseline mIPSC frequency and decreased the effects of a CRF1 antagonist in msP rats, suggesting increased GABA release and decreased CRF1 sensitivity. These results provide electrophysiological evidence that msP rats display distinct CeA GABAergic activity as compared to Sprague Dawley and Wistar rats. The elevated GABAergic transmission observed in naive msP rats is consistent with the neuroadaptations reported in Sprague Dawley rats after the development of ethanol dependence. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Herman, Melissa A.; Kallupi, Marsida; Luu, George; Oleata, Christopher S.; Koob, George F.; Roberto, Marisa] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Kallupi, Marsida; Ciccocioppo, Roberto] Univ Camerino, Sch Pharm, Pharmacol Unit, I-62032 Camerino, Italy. [Heilig, Markus] NIAAA, Lab Clin & Translat Sci, NIH, Bethesda, MD 20892 USA. RP Roberto, M (reprint author), Scripps Res Inst, Comm Neurobiol Addict Disorders, SP30-1150,10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM mroberto@scripps.edu RI koob, george/P-8791-2016; OI Heilig, Markus/0000-0003-2706-2482; Kallupi, Marsida/0000-0002-8688-709X FU NIH [AA017447, AA015566, AA006420, AA016985, F32AA020430, AA008459] FX This is manuscript number 21980 from The Scripps Research Institute. We thank Jenica Tapocik and Sun Hui at The National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, for their technical assistance with genotyping. Supported by grants from NIH: AA017447, AA015566, AA006420, AA016985, F32AA020430 and AA008459. The compound R121919 was synthesized and generously contributed by Dr. Kenner Rice at the Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD. NR 69 TC 14 Z9 15 U1 2 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD APR PY 2013 VL 67 BP 337 EP 348 DI 10.1016/j.neuropharm.2012.11.026 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 097ME UT WOS:000315477400038 PM 23220399 ER PT J AU Orru, M Guitart, X Karcz-Kubicha, M Solinas, M Justinova, Z Barodia, SK Zanoveli, J Cortes, A Lluis, C Casado, V Moeller, FG Ferre, S AF Orru, Marco Guitart, Xavier Karcz-Kubicha, Marzena Solinas, Marcello Justinova, Zuzana Barodia, Sandeep Kumar Zanoveli, Janaina Cortes, Antoni Lluis, Carme Casado, Vicent Moeller, F. Gerard Ferre, Sergi TI Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans SO NEUROPHARMACOLOGY LA English DT Article DE Caffeine; Paraxanthine; Psychostimulant; Dopamine release; Phosphodiesterase inhibitor; Rat striatum; Drug discrimination ID ADENOSINE RECEPTOR ANTAGONISTS; NITRIC-OXIDE SYNTHASE; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; A(2A) RECEPTORS; NUCLEUS-ACCUMBENS; LOCOMOTOR BEHAVIOR; DOPAMINE RELEASE; PLACE PREFERENCE; CELL-MEMBRANE; RAT STRIATUM AB Caffeine induces locomotor activation by its ability to block adenosine receptors. Caffeine is metabolized to several methylxanthines, with paraxanthine being the main metabolite in humans. In this study we show that in rats paraxanthine has a stronger locomotor activating effect than caffeine or the two other main metabolites of caffeine, theophylline and theobromine. As previously described for caffeine, the locomotor activating doses of paraxanthine more efficiently counteract the locomotor depressant effects of an adenosine A(1) than an adenosine A(2A) receptor agonist. In drug discrimination experiments in rats trained to discriminate a maximal locomotor activating dose of caffeine, paraxanthine, unlike theophylline, generalized poorly to caffeine suggesting the existence of additional mechanisms other than adenosine antagonism in the behavioral effects of paraxanthine. Pretreatment with the nitric oxide inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) reduced the locomotor activating effects of paraxanthine, but not caffeine. On the other hand, pretreatment with the selective cGMP-preferring phosphodiesterase PDE9 inhibitor BAY 73-6691, increased locomotor activity induced by caffeine, but not paraxanthine. Ex vivo experiments demonstrated that paraxanthine, but not caffeine, can induce cGMP accumulation in the rat striatum. Finally, in vivo microdialysis experiments showed that paraxanthine, but not caffeine, significantly increases extracellular levels of dopamine in the dorsolateral striatum, which was blocked by L-NAME. These findings indicate that inhibition of cGMP-preferring PDE is involved in the locomotor activating effects of the acute administration of paraxanthine. The present results demonstrate a unique psychostimulant profile of paraxanthine, which might contribute to the reinforcing effects of caffeine in humans. Published by Elsevier Ltd. C1 [Orru, Marco; Guitart, Xavier; Karcz-Kubicha, Marzena; Solinas, Marcello; Justinova, Zuzana; Barodia, Sandeep Kumar; Zanoveli, Janaina; Ferre, Sergi] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Solinas, Marcello] INSERM, U1084, Expt & Clin Neurosci Lab, Neurobiol & Neuropharmacol Addict Grp, Poitiers, France. [Cortes, Antoni; Lluis, Carme; Casado, Vicent] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, Barcelona, Spain. [Zanoveli, Janaina] Univ Fed Parana, Dept Pharmacol, BR-80060000 Curitiba, Parana, Brazil. [Moeller, F. Gerard] Univ Texas Hlth Sci Ctr Houston, Dept Psychiat & Behav Sci, Ctr Neurobehav Res Addict, Houston, TX USA. RP Ferre, S (reprint author), NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011; Ferre, Sergi/K-6115-2014; Solinas, Marcello/M-3500-2016; Casado, Vicent/K-1660-2014; OI Justinova, Zuzana/0000-0001-5793-7484; Ferre, Sergi/0000-0002-1747-1779; Solinas, Marcello/0000-0002-0664-5964; Casado, Vicent/0000-0002-1764-3825 FU NIDA Intramural Research Program FX Supported by funding from NIDA Intramural Research Program. NR 59 TC 13 Z9 14 U1 2 U2 55 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD APR PY 2013 VL 67 BP 476 EP 484 DI 10.1016/j.neuropharm.2012.11.029 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 097ME UT WOS:000315477400051 PM 23261866 ER PT J AU Deo, AJ Huang, YY Hodgkinson, CA Xin, YR Oquendo, MA Dwork, AJ Arango, V Brent, DA Goldman, D Mann, JJ Haghighi, F AF Deo, Anthony J. Huang, Yung-yu Hodgkinson, Colin A. Xin, Yurong Oquendo, Maria A. Dwork, Andrew J. Arango, Victoria Brent, David A. Goldman, David Mann, J. John Haghighi, Fatemeh TI A large-scale candidate gene analysis of mood disorders: evidence of neurotrophic tyrosine kinase receptor and opioid receptor signaling dysfunction SO PSYCHIATRIC GENETICS LA English DT Article DE linkage and association; mood disorders; neurotrophic tyrosine kinase receptor; opioid receptor; type 2; kappa 1 ID MAJOR DEPRESSIVE DISORDER; GENOME-WIDE ASSOCIATION; AND/OR LINKAGE DISEQUILIBRIUM; MESSENGER-RNA EXPRESSION; PROBE LEVEL DATA; SUICIDAL-BEHAVIOR; BIPOLAR DISORDER; POPULATION STRATIFICATION; ANTIDEPRESSANT RESPONSE; CLINICAL PREDICTORS AB Background Despite proven heritability, little is known about the genetic architecture of mood disorders. Although a number of family and case-control studies have examined the genetics of mood disorders, none have carried out joint linkage-association studies and sought to validate the results with gene expression analyses in an independent cohort. Methods We present findings from a large candidate gene study that combines linkage and association analyses using families and singletons, providing a systematic candidate gene investigation of mood disorder. For this study, 876 individuals were recruited, including 83 families with 313 individuals and 563 singletons. This large-scale candidate gene analysis included 130 candidate genes implicated in addictive and other psychiatric disorders. These data showed significant genetic associations for 28 of these candidate genes, although none remained significant after correction for multiple testing. To evaluate the functional significance of these 28 candidate genes in mood disorders, we examined the transcriptional profiles of these genes within the dorsolateral prefrontal cortex and anterior cingulate for 21 cases with mood disorders and 25 nonpsychiatric controls, and carried out a pathway analysis to identify points of high connectivity suggestive of particular molecular pathways that may be dysregulated. Results Two primary gene candidates were supported by the linkage-association, gene expression profiling, and network analysis: neurotrophic tyrosine kinase receptor, type 2 (NTRK2), and the opioid receptor, kappa 1 (OPRK1). Conclusion This study supports a role for NTRK2 and OPRK1 signaling in the pathophysiology of mood disorder. The unique approach incorporating evidence from multiple experimental and computational modalities enhances confidence in these findings. Psychiatr Genet 23:47-55 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Psychiatric Genetics 2013, 23:47-55 C1 [Deo, Anthony J.; Huang, Yung-yu; Xin, Yurong; Oquendo, Maria A.; Dwork, Andrew J.; Arango, Victoria; Mann, J. John; Haghighi, Fatemeh] Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Div Mol Imaging & Neuropathol, New York, NY 10032 USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Sect Human Neurogenet, Neurogenet Lab, Rockville, MD 20852 USA. [Brent, David A.] Western Psychiat Inst & Clin, Dept Child & Adolescent Psychiat, Pittsburgh, PA USA. RP Haghighi, F (reprint author), Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Div Mol Imaging & Neuropathol, 1051 Riverside Dr,Box 42, New York, NY 10032 USA. EM fgh3@columbia.edu RI Arango, Victoria/K-9377-2015; Goldman, David/F-9772-2010 OI Arango, Victoria/0000-0001-8811-400X; Goldman, David/0000-0002-1724-5405 FU [MH40210]; [MH62185]; [MH64168]; [K22 HG2915]; [MH074118]; [MH59710]; [MH48514] FX This work is supported by grants MH40210, MH62185, MH64168, K22 HG2915, MH074118, MH59710, and MH48514. The analyses were carried out on computing resources supported by the National Science Foundation under the following NSF programs: Partnerships for Advanced Computational Infrastructure, Distributed Terascale Facility (DTF) and Terascale Extensions: Enhancements to the Extensible Terascale Facility. NR 76 TC 10 Z9 10 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8829 EI 1473-5873 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD APR PY 2013 VL 23 IS 2 BP 47 EP 55 DI 10.1097/YPG.0b013e32835d7028 PG 9 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 098CK UT WOS:000315522800001 PM 23277131 ER PT J AU Laditka, SB Laditka, JN Liu, R Price, AE Friedman, DB Wu, B Bryant, LL Corwin, SJ Ivey, SL AF Laditka, Sarah B. Laditka, James N. Liu, Rui Price, Anna E. Friedman, Daniela B. Wu, Bei Bryant, Lucinda L. Corwin, Sara J. Ivey, Susan L. TI How do older people describe others with cognitive impairment? A multiethnic study in the United States SO AGEING & SOCIETY LA English DT Article DE Alzheimer's disease; brain health; cognition; dementia; focus groups; memory; qualitative research; senility ID ALZHEIMER-DISEASE; PHYSICAL-ACTIVITY; HEALTHY BRAIN; DEMENTIA; AMERICANS; BELIEFS; ADULTS; PERCEPTIONS; POPULATION; PREVALENCE AB We studied how older people describe others with cognitive impairment. Forty-two focus groups represented African Americans, American Indians, Chinese Americans, Latinos, Vietnamese Americans, and Whites other than Latinos (Whites) (N=396, ages 50+), in nine locations in the United States of America. Axial coding connected categories and identified themes. The constant comparison method compared themes across ethnic groups. African Americans, American Indians and Whites emphasised memory loss. African Americans, American Indians, Latinos and Whites stressed withdrawal, isolation and repetitive speech. African Americans, American Indians, Vietnamese Americans and Whites emphasised 'slow thinking'. Only Whites described mood swings and personality changes. Many participants attributed dementia to stress. Terms describing others with dementia included 'Alzheimer's', 'dementia', 'senile' and 'crazy'. Euphemisms were common ('senior moment', 'old timer's disease'). Responses focused on memory, with limited mention of other cognitive functions. Differences among ethnic groups in descriptions of cognitive health and cognitive impairment underscore the need to tailor public health messages about cognitive health to ways that people construe its loss, and to their interest in maintaining it, so that messages and terms used are familiar, understandable and relevant to the groups for which they are designed. Health promotion efforts should develop ethnically sensitive ways to address the widely held misperception that even serious cognitive impairment is a normal characteristic of ageing and also to address stigma associated with cognitive impairment. C1 [Laditka, Sarah B.; Laditka, James N.] Univ N Carolina, Dept Publ Hlth Sci, Charlotte, NC 28223 USA. [Liu, Rui] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Price, Anna E.] Sacred Heart Univ, Dept Phys Therapy & Human Movement Sci, Fairfield, CT USA. [Friedman, Daniela B.; Corwin, Sara J.] Univ S Carolina, Dept Hlth Promot Educ & Behav, Columbia, SC 29208 USA. [Wu, Bei] Duke Univ, Sch Nursing, Durham, NC USA. [Bryant, Lucinda L.] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Community & Behav Hlth, Aurora, CO USA. [Ivey, Susan L.] Univ Calif Berkeley, Sch Publ Hlth, Div Community Hlth & Human Dev, Berkeley, CA 94720 USA. RP Laditka, SB (reprint author), Univ N Carolina, Dept Publ Hlth Sci, 9201 Univ City Blvd, Charlotte, NC 28223 USA. EM sladitka@uncc.edu NR 48 TC 7 Z9 7 U1 3 U2 36 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0144-686X EI 1469-1779 J9 AGEING SOC JI Ageing Soc. PD APR PY 2013 VL 33 BP 369 EP 392 DI 10.1017/S0144686X11001255 PN 3 PG 24 WC Gerontology SC Geriatrics & Gerontology GA 091XP UT WOS:000315083400001 ER PT J AU Ghirlando, R Felsenfeld, G AF Ghirlando, Rodolfo Felsenfeld, Gary TI Chromatin structure outside and inside the nucleus SO BIOPOLYMERS LA English DT Review DE chromatin; nuclear organization; 30 nm fiber ID HIGHER-ORDER STRUCTURE; NUCLEOSOME CORE PARTICLE; BETA-GLOBIN LOCUS; 30 NM; CRYOELECTRON MICROSCOPY; LINKER HISTONE; HUMAN GENOME; IN-SITU; FIBER; ORGANIZATION AB The structure of the 30-nm chromatin fiber has provided, over the years, an important reference in chromatin studies. Originally derived from electron microscopic studies of soluble chromatin fibers released by restriction digestion, the gross structural features of such fragments have been supported by biophysical methods such as low angle X-ray and neutron scattering, sedimentation, light scattering, and electric dichroism. Electron microscopy and sedimentation velocity measurements demonstrated that reconstituted chromatin fibers, prepared from repeating arrays of high affinity nucleosome positioning sequences, retain the same overall features as observed for native chromatin fibers. It had been suggested that the 30 nm fiber might be the form assumed in vivo by transcriptionally silent chromatin, but individual gene or genome-wide studies of chromatin released from nuclei do not reveal any such simple correlation. Furthermore, even though the 30 nm fiber has been thought to represent an intermediate in the hierarchical folding of DNA into chromosomes, most analyses of chromatin folding within the nucleus do not detect any regular extended compact structures. However, there are important exceptions in chicken erythroid cell nuclei as well as in transcribed regions that form extended loops. Localized domains within the nucleus, either at the surface of chromosome domains or constrained as a specialized kind of constitutive heterochromatin by specific DNA binding proteins, may adopt 30 nm fiber-like structures. (c) 2012 Wiley Periodicals, Inc. Biopolymers 99: 225232, 2013. C1 [Ghirlando, Rodolfo; Felsenfeld, Gary] 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 Contract grant sponsor: Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH NR 63 TC 10 Z9 10 U1 2 U2 81 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD APR PY 2013 VL 99 IS 4 SI SI BP 225 EP 232 DI 10.1002/bip.22157 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 089RB UT WOS:000314926600002 PM 23348669 ER PT J AU Minton, AP AF Minton, Allen P. TI Quantitative assessment of the relative contributions of steric repulsion and chemical interactions to macromolecular crowding SO BIOPOLYMERS LA English DT Article DE excluded volume; steric repulsion; weak binding; equivalent hard particle model ID PROTEIN-PROTEIN INTERACTIONS; BOVINE SERUM-ALBUMIN; MODEL; VOLUME; CONSEQUENCES; MIXTURES AB The term macromolecular crowding denotes the combined effects of high volume fractions of nominally unrelated macromolecules upon the equilibrium and transport properties of all macrosolutes, dilute as well as concentrated, in the crowded medium. We present a formal partitioning of the total crowding effect into contributions from steric exclusion (excluded volume) and weak, nonspecific attractive interactions between a concentrated crowding agent and reactant and product species present at trace concentration. A numerical example of the combined effect of both steric and chemical interactions between crowder and tracer upon the reversible dimerization of tracer is presented, based upon reasonable estimates of the magnitude of both repulsive and attractive interactions between tracer and crowder species. (c) 2012Wiley Periodicals, Inc. Biopolymers 99: 239244, 2013. C1 NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 FU National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX Contract grant sponsor: Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH NR 23 TC 50 Z9 50 U1 1 U2 64 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD APR PY 2013 VL 99 IS 4 SI SI BP 239 EP 244 DI 10.1002/bip.22163 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 089RB UT WOS:000314926600004 PM 23348671 ER PT J AU Thanos, PK Robison, LS Robinson, JK Michaelides, M Wang, GJ Volkow, ND AF Thanos, Panayotis K. Robison, Lisa S. Robinson, John K. Michaelides, Michael Wang, Gene-Jack Volkow, Nora D. TI Obese rats with deficient leptin signaling exhibit heightened sensitivity to olfactory food cues SO SYNAPSE LA English DT Article DE novelty-seeking; food restriction; olfactory stimulus; leptin; obesity ID BINGE-EATING DISORDER; RECEPTOR MESSENGER-RNA; LONG-TERM POTENTIATION; DOPAMINE D2 RECEPTOR; ZUCKER RATS; NOVELTY-SEEKING; INDIVIDUAL-DIFFERENCES; ENERGY-BALANCE; ANXIETY-LIKE; WEIGHT-LOSS AB The Zucker rat is used as a model of genetic obesity, and while Zucker rats have been well studied for their reduced sensitivity to leptin signaling and subsequent weight gain, little work has examined their responses to environmental signals that are associated with hedonic feeding. This study evaluated the effects of a high-fat food olfactory cue (bacon) in stimulating nose-poke food-seeking behavior on first exposure (novel) and after a period of access for consumption (familiar) in lean and obese Zucker rats at either 4 or 12 months of age, and under ad-lib fed (unrestricted; U) or chronically food-restricted (70% of ad-lib; R) conditions. Baseline nose-poke levels were comparable amongst all groups. At 4 months of age, only ObU rats displayed increased behavioral activation to familiar food cues. Twelve-month-old Ob rats, regardless of diet, exhibited substantially greater food-seeking behavior when exposed to both the novel and familiar olfactory cues. A strong positive correlation between body weight and nose-poke entries for the familiar food cue was observed at both ages, while this correlation for the novel food cue was significant in 12month-old rats only. Similarly, there were strong positive correlations between food intake and poke entries for the familiar food cue was observed at both ages, while this correlation for the novel food cue was significant in 12month-old rats only. Although it is possible that differences in olfactory sensitivity contribute to these behavioral effects, our findings support the interactions between food intake, obesity, and food-seeking behavior and are consistent with leptin inhibiting the brain's reactivity to food cues and suggest that the enhanced sensitivity to the food cues with leptin deficiency is likely to contribute to overeating and weight gain. Synapse, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Thanos, Panayotis K.; Robison, Lisa S.; Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD 20892 USA. [Thanos, Panayotis K.; Robison, Lisa S.; Michaelides, Michael; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Thanos, Panayotis K.; Robison, Lisa S.; Robinson, John K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11790 USA. RP Thanos, PK (reprint author), NIAAA, Lab Neuroimaging, NIH, Bethesda, MD 20892 USA. EM thanos@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 FU NIAAA [AA11034, AA07574, AA07611]; SULI program; IRTA program FX Contract grant sponsor: NIAAA; Contract grant numbers: AA11034, AA07574, AA07611; Contract grant sponsors: SULI and IRTA programs NR 58 TC 11 Z9 11 U1 0 U2 40 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 J9 SYNAPSE JI Synapse PD APR PY 2013 VL 67 IS 4 BP 171 EP 178 DI 10.1002/syn.21627 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 093BU UT WOS:000315167500002 PM 23172699 ER PT J AU Terracciano, A Iacono, D O'Brien, RJ Troncoso, JC An, Y Sutin, AR Ferrucci, L Zonderman, AB Resnick, SM AF Terracciano, Antonio Iacono, Diego O'Brien, Richard J. Troncoso, Juan C. An, Yang Sutin, Angelina R. Ferrucci, Luigi Zonderman, Alan B. Resnick, Susan M. TI Personality and resilience to Alzheimer's disease neuropathology: a prospective autopsy study SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Dementia; Asymptomatic; Personality; Neuroticism; Depression; Conscientiousness; Prospective cohort study; Autopsy; Neurofibrillary tangles; A beta neuritic plaques; Neuropathology ID DEPRESSIVE SYMPTOMS; 5-FACTOR MODEL; NEUROFIBRILLARY TANGLES; PSYCHOLOGICAL DISTRESS; COGNITIVE IMPAIRMENT; DEMENTIA; RISK; OLDER; LIFE; AGE AB Alzheimer's disease (AD) neuropathology is found at autopsy in approximately 30% of cognitively normal older individuals. We examined whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (mean 11 +/- 7 years) before onset of dementia and up to 30 years (mean 15 +/- 7 years) before death in a cohort (n = 111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: odds ratio, 2.0; 95% confidence interval, 1.2-3.5), or lower scores on order and competence (conscientiousness: odds ratio, 0.4; 95% confidence interval, 0.2-0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r = 0.26), low agreeableness (r = -0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for the extent of neurofibrillary tangles and A beta neuritic plaques. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology. Published by Elsevier Ltd. C1 [Terracciano, Antonio; An, Yang; Sutin, Angelina R.; Ferrucci, Luigi; Zonderman, Alan B.; Resnick, Susan M.] NIA, NIH, Baltimore, MD 21224 USA. [Terracciano, Antonio; Sutin, Angelina R.] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Iacono, Diego] Karolinska Inst, Brain Bank, Dept Neurobiol, Stockholm, Sweden. [Iacono, Diego; Troncoso, Juan C.] Johns Hopkins Univ, Div Neuropathol, Baltimore, MD USA. [O'Brien, Richard J.; Troncoso, Juan C.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Terracciano, A (reprint author), NIH Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM TerraccianoA@mail.nih.gov RI terracciano, antonio/B-1884-2008; OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institutes of Health, National Institute on Aging; Johns Hopkins University Alzheimer's Disease Research Center [NIA P50AG05146] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and The Johns Hopkins University Alzheimer's Disease Research Center (NIA P50AG05146). NR 50 TC 17 Z9 17 U1 1 U2 53 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 APR PY 2013 VL 34 IS 4 BP 1045 EP 1050 DI 10.1016/j.neurobiolaging.2012.08.008 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 086ST UT WOS:000314708000004 PM 23040035 ER PT J AU Kumar, A Gibbs, JR Beilina, A Dillman, A Kumaran, R Trabzuni, D Ryten, M Walker, R Smith, C Traynor, BJ Hardy, J Singleton, AB Cookson, MR AF Kumar, Azad Gibbs, J. Raphael Beilina, Alexandra Dillman, Allissa Kumaran, Ravindran Trabzuni, Daniah Ryten, Mina Walker, Robert Smith, Colin Traynor, Bryan J. Hardy, John Singleton, Andrew B. Cookson, Mark R. TI Age-associated changes in gene expression in human brain and isolated neurons SO NEUROBIOLOGY OF AGING LA English DT Article DE Aging; Cerebral cortex; Cerebellum; Purkinje cells; Microarrays ID ALZHEIMERS-DISEASE; MOUSE; CLONING; IDENTIFICATION; TRANSCRIPTOME; LONGEVITY; BIOLOGY; BLOOD; LISTS AB Previous studies have suggested that there are genes whose expression levels are associated with chronological age. However, which genes show consistent age association across studies, and which are specific to a given organism or tissue remains unresolved. Here, we reassessed this question using 2 independently ascertained series of human brain samples from 2 anatomic regions, the frontal lobe of the cerebral cortex and cerebellum. Using microarrays to estimate gene expression, we found 60 associations between expression and chronological age that were statistically significant and were replicated in both series in at least 1 tissue. There were a greater number of significant associations in the frontal cortex compared with the cerebellum. We then repeated the analysis in a subset of samples using laser capture microdissection to isolate Purkinje neurons from the cerebellum. We were able to replicate 5 gene associations from either frontal cortex or cerebellum in the Purkinje cell dataset, suggesting that there is a subset of genes which have robust changes with aging. Of these, the most consistent and strongest association was with expression of RHBDL3, a rhomboid protease family member. We confirmed several hits using an independent technique (quantitative reverse transcriptase polymerase chain reaction) and in an independent published sample series that used a different array platform. We also interrogated larger patterns of age-related gene expression using weighted gene correlation network analysis. We found several modules that showed significant associations with chronological age and, of these, several that showed negative associations were enriched for genes encoding components of mitochondria. Overall, our results show that there is a distinct and reproducible gene signature for aging in the human brain. Published by Elsevier Ltd. C1 [Kumar, Azad; Gibbs, J. Raphael; Beilina, Alexandra; Dillman, Allissa; Kumaran, Ravindran; Traynor, Bryan J.; Singleton, Andrew B.; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Gibbs, J. Raphael; Trabzuni, Daniah; Ryten, Mina; Hardy, John] UCL Inst Nerurol, Dept Mol Neurosci, London, England. [Walker, Robert; Smith, Colin] Univ Edinburgh, Dept Neuropathol, Edinburgh, Midlothian, Scotland. [Dillman, Allissa] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. 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 RI Hardy, John/C-2451-2009; Traynor, Bryan/G-5690-2010; Singleton, Andrew/C-3010-2009; Trabzuni, Daniah/C-4034-2012 OI Walker, Robert/0000-0001-7383-7846; Trabzuni, Daniah/0000-0003-4826-9570 FU NIH, National Institute on Aging [ZO1-AG000947, Z01-AG000185]; UK Medical Research Council [G0802462]; Medical Research Council [G0901254]; King Faisal Specialist Hospital and Research Centre, Saudi Arabia FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (ZO1-AG000947 and Z01-AG000185) and by the UK Medical Research Council Biomedical Informatics Postdoctoral Training Fellowship (G0802462 to MR) and Medical Research Council Project Grant (grant G0901254 to JH). D. T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. The authors thank the LCM core facility at the National Cancer Institute for help with microdissection. NR 36 TC 15 Z9 15 U1 2 U2 33 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 APR PY 2013 VL 34 IS 4 BP 1199 EP 1209 DI 10.1016/j.neurobiolaging.2012.10.021 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 086ST UT WOS:000314708000021 PM 23177596 ER PT J AU Schupf, N Barral, S Perls, T Newman, A Christensen, K Thyagarajan, B Province, M Rossi, WK Mayeux, R AF Schupf, Nicole Barral, Sandra Perls, Thomas Newman, Anne Christensen, Kaare Thyagarajan, Bharat Province, Michael Rossi, Winifred K. Mayeux, Richard TI Apolipoprotein E and familial longevity SO NEUROBIOLOGY OF AGING LA English DT Article DE Exceptional longevity; Familial longevity; Offspring; APOE; TOMM40 ID GENOME-WIDE ASSOCIATION; E POLYMORPHISM; E GENOTYPE; APOE; MORTALITY; FREQUENCY; SURVIVAL; GENE; AGE; NONAGENARIANS AB Exceptional longevity is associated with substantial heritability. The epsilon 4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the epsilon 2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n = 2307) and spouse controls (n = 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE epsilon 4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p = 0.005 and OR, 0.70; p = 0.002) and the likelihood of carrying an APOE epsilon 2 allele was higher (OR, 1.5; p = 0.007) among family members in the offspring generation than among their spouse controls. Our findings support the hypothesis that both reduction in the frequency of the epsilon 4 allele and increase in the frequency of the epsilon 2 allele contribute to longevity. (C) 2013 Elsevier Inc. All rights reserved. C1 [Schupf, Nicole; Barral, Sandra; Mayeux, Richard] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. [Perls, Thomas] Boston Univ, Med Ctr, Geriatr Sect, Boston, MA USA. [Newman, Anne] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Christensen, Kaare] Univ So Denmark, Danish Aging Res Ctr, Odense, Denmark. [Christensen, Kaare] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Christensen, Kaare] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, DK-5000 Odense, Denmark. [Thyagarajan, Bharat] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Province, Michael] Washington Univ, Sch Med, Div Stat Genom, Data Management Coordinating Ctr, St Louis, MO USA. [Rossi, Winifred K.] NIA, Bethesda, MD 20892 USA. RP Schupf, N (reprint author), Taub Inst Res Alzheimers Dis & Aging Brain, P&S Box Unit 16,630 W 168th St, New York, NY 10032 USA. EM ns24@columbia.edu RI Christensen, Kaare/C-2360-2009; Newman, Anne/C-6408-2013; OI Christensen, Kaare/0000-0002-5429-5292; Newman, Anne/0000-0002-0106-1150; Perls, Thomas/0000-0002-2492-4334 FU National Institute on Aging (NIA) [U01-AG023712, U01-AG23744, U01-AG023746, U01-AG023749, U01-AG023755]; NIH/NIA [P01 AG08761]; VELUX Foundation FX The work is supported by the National Institute on Aging (NIA cooperative agreements U01-AG023712, U01-AG23744, U01-AG023746, U01-AG023749, and U01-AG023755). The Danish 1905-cohort is funded by NIH/NIA, P01 AG08761. The Danish Aging Research Center is funded by the VELUX Foundation. NR 32 TC 17 Z9 18 U1 0 U2 12 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 APR PY 2013 VL 34 IS 4 BP 1287 EP 1291 DI 10.1016/j.neurobiolaging.2012.08.019 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 086ST UT WOS:000314708000029 PM 23040522 ER PT J AU Yeh, TH Lai, SC Weng, YH Kuo, HC Wu-Chou, YH Huang, CL Chen, RS Chang, HC Traynor, B Lu, CS AF Yeh, Tu-Hsueh Lai, Szu-Chia Weng, Yi-Hsin Kuo, Hung-Chou Wu-Chou, Yah-Huei Huang, Chia-Ling Chen, Rou-Shayn Chang, Hsiu-Chen Traynor, Bryan Lu, Chin-Song TI Screening for C9orf72 repeat expansions in parkinsonian syndromes SO NEUROBIOLOGY OF AGING LA English DT Article DE C9orf72; GGGGCC hexanucleotide repeat expansion; Frontotemporal dementia (FTD); Parkinson's disease with dementia (PDD); Progressive supranuclear palsy (PSP); Corticobasal syndrome (CBS); Dementia with Lewy bodies (DLB) AB Parkinsonism might precede, coincide, or follow the behavioral or language-predominant cognitive impairments characteristic of frontotemporal dementia (FTD). In this study, we analyze the hexanucleotide repeat expansions within C9orf72 gene in various parkinsonian syndromes because it is a recently identified important genetic cause of FTD. The expanded hexanucleotide repeat is only identified in our familial FTD patients but not in patients with predominant parkinsonism. The lack of association between abnormal C9orf72 repeat expansion and parkinsonian syndromes might imply pathogenic mechanisms other than tau or Lewy body pathology. (C) 2013 Elsevier Inc. All rights reserved. C1 [Yeh, Tu-Hsueh; Lai, Szu-Chia; Weng, Yi-Hsin; Chen, Rou-Shayn; Chang, Hsiu-Chen; Lu, Chin-Song] Linkou Med Ctr, Chang Gung Mem Hosp, Dept Neurol, Sect Movement Disorders, Tao Yuan, Taiwan. [Yeh, Tu-Hsueh; Lai, Szu-Chia; Weng, Yi-Hsin; Kuo, Hung-Chou; Wu-Chou, Yah-Huei; Chen, Rou-Shayn; Chang, Hsiu-Chen; Lu, Chin-Song] Chang Gung Univ, Tao Yuan, Taiwan. [Yeh, Tu-Hsueh; Lai, Szu-Chia; Weng, Yi-Hsin; Wu-Chou, Yah-Huei; Chen, Rou-Shayn; Chang, Hsiu-Chen; Lu, Chin-Song] Linkou Med Ctr, Chang Gung Mem Hosp, Neurosci Res Ctr, Tao Yuan, Taiwan. [Kuo, Hung-Chou] Linkou Med Ctr, Chang Gung Mem Hosp, Dept Neurol, Sect Neuromuscular Disorders, Tao Yuan, Taiwan. [Wu-Chou, Yah-Huei] Linkou Med Ctr, Chang Gung Mem Hosp, Human Mol Genet Lab, Tao Yuan, Taiwan. [Huang, Chia-Ling] St Pauls Hosp, Dept Neurol, Tao Yuan, Taiwan. [Traynor, Bryan] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Lu, CS (reprint author), Chang Gung Mem Hosp, Dept Neurol, Sect Movement Disorders, 5 Fu Shin St, Tao Yuan 33305, Taiwan. EM c81214@adm.cgmh.org.tw RI Traynor, Bryan/G-5690-2010 FU National Science Council Taiwan [NSC 100-2321-B-182A-004-]; Chang Gung Medical Foundation Taiwan [BMRPG390041]; Chang Gung University [EMRPD1B0311]; Intramural Research Program of the NIH, National Institute on Aging [Z01-AG000949-02] FX We thank all the participants for their contributions. This work was supported by the National Science Council Taiwan (grant number: NSC 100-2321-B-182A-004- to T-H Yeh), the Chang Gung Medical Foundation Taiwan (grant number: BMRPG390041 to C-S Lu), and the Chang Gung University (grant number: EMRPD1B0311 to C-S Lu). This work was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging (Z01-AG000949-02). We are grateful to the DNA Sequencing Core Laboratory and Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Linkou, for technical assistance. NR 0 TC 2 Z9 2 U1 0 U2 7 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 APR PY 2013 VL 34 IS 4 AR 1311. e3 DI 10.1016/j.neurobiolaging.2012.09.002 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 086ST UT WOS:000314708000038 PM 23063644 ER PT J AU Jao, T Vertes, PE Alexander-Bloch, AF Tang, IN Yu, YC Chen, JH Bullmore, ET AF Jao, Tun Vertes, Petra E. Alexander-Bloch, Aaron F. Tang, I-Ning Yu, Ya-Chih Chen, Jyh-Horng Bullmore, Edward T. TI Volitional eyes opening perturbs brain dynamics and functional connectivity regardless of light input SO NEUROIMAGE LA English DT Article DE Eyes open/ eyes closed; Visual input; Resting state; Brain dynamics; Brain network ID RESTING-STATE FMRI; LOW-FREQUENCY FLUCTUATION; DEFAULT MODE NETWORK; SMALL-WORLD NETWORKS; HUMAN VISUAL-CORTEX; ECHO-PLANAR MRI; CEREBRAL-CORTEX; MOTOR CORTEX; ALPHA-RHYTHM; POSTERIOR CINGULATE AB The act of opening (or closing) one's eyes has long been demonstrated to impact on brain function. However, the eyes open condition is usually accompanied by visual input, and this effect may have been a significant confounding factor in previous studies. To clarify this situation, we extended the traditional eyes open/closed study to a two-factor balanced, repeated measures resting state fMRI (rs-fMRI) experiment, in which light on/off was also included as a factor. In 16 healthy participants, we estimated the univariate properties of the BOLD signal, as well as a bivariate measure of functional connectivity and multivariate network topology measures. Across all these measures, we demonstrate that human brain adopts a distinctive configuration when eyes are open (compared to when eyes are closed) independently of exogenous light input: (i) the eyes open states were associated with decreased BOLD signal variance (P-value = 0.0004), decreased fractional amplitude of low frequency fluctuation (fALFF. P-value = 0.0061), and decreased Hurst exponent (H. P-value = 0.0321) mainly in the primary and secondary sensory cortical areas, the insula, and the thalamus. (ii) The strength of functional connectivity (FC) between the posterior cingulate cortex (PCC), a major component of the default mode network (DMN), and the bilateral perisylvian and perirolandic regions was also significantly decreased during eyes open states. (iii) On the other hand, the average network connection distance increased during eyes open states (P-value = 0.0139). Additionally, the metrics of univariate, bivariate, and multivariate analyses in this study are significantly correlated. In short, we have shown that the marked effects on the dynamics and connectivity of fMRI time series brought by volitional eyes open or closed are simply endogenous and irrespective of exogenous visual stimulus. The state of eyes open (or closed) may thus be an important factor to control in design of rs-fMRI and even other cognitive block or event-related experiments. (c) 2012 Elsevier Inc. All rights reserved. C1 [Jao, Tun; Vertes, Petra E.; Alexander-Bloch, Aaron F.; Bullmore, Edward T.] Univ Cambridge, Brain Mapping Unit, Cambridge, England. [Jao, Tun; Vertes, Petra E.; Alexander-Bloch, Aaron F.; Bullmore, Edward T.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. [Vertes, Petra E.] Univ Cambridge, Cavendish Lab, Cambridge CB3 0HE, England. [Alexander-Bloch, Aaron F.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Alexander-Bloch, Aaron F.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Tang, I-Ning; Yu, Ya-Chih; Chen, Jyh-Horng] Natl Taiwan Univ, Dept Elect Engn, Interdisciplinary MRI MRS Lab, Taipei 106, Taiwan. [Bullmore, Edward T.] Addenbrookes Hosp, GlaxoSmithKline, Clin Unit Cambridge, Cambridge, England. [Bullmore, Edward T.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England. RP Chen, JH (reprint author), Natl Taiwan Univ, Room 706,Ming Da Bldg,Sec 4,1 Roosevelt Rd, Taipei 106, Taiwan. EM jhchen@ntu.edu.tw; etb23@cam.ac.uk RI Bullmore, Edward/C-1706-2012; OI Bullmore, Edward/0000-0002-8955-8283; Alexander-Bloch, Aaron/0000-0001-6554-1893; Jao, Tun/0000-0002-9379-2398; Vertes, Petra E./0000-0002-0992-3210 FU National Science Council, Taiwan [NSC 99-2321-B-002-007]; Medical Research Council; Wellcome Trust; Ministry of Education, Taiwan FX This research was funded by the National Science Council (NSC 99-2321-B-002-007), Taiwan. The Behavioural and Clinical Neuroscience Institute is supported by the Medical Research Council and the Wellcome Trust. Tun Jao is supported by the Ministry of Education, Taiwan. EB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline, plc. We would like to thank Dr. Changwei W. Wu and Yun-An Huang of National Taiwan University for their helpful discussions on experimental design. NR 110 TC 31 Z9 31 U1 3 U2 31 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 APR 1 PY 2013 VL 69 BP 21 EP 34 DI 10.1016/j.neuroimage.2012.12.007 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 085PX UT WOS:000314627800003 PM 23266698 ER PT J AU Goh, JO Beason-Held, LL An, Y Kraut, MA Resnick, SM AF Goh, Joshua O. Beason-Held, Lori L. An, Yang Kraut, Michael A. Resnick, Susan M. TI Frontal function and executive processing in older adults: Process and region specific age-related longitudinal functional changes SO NEUROIMAGE LA English DT Article DE Aging; Longitudinal; Cross-sectional; Brain function; Executive processing ID ALZHEIMERS-DISEASE; AGING BRAIN; MEMORY; INTERFERENCE; ACTIVATION; COMPENSATE; DECLINE; SPAN; FMRI AB Longitudinal studies on aging brain function have shown declines in frontal activity as opposed to the over-recruitment shown in cross-sectional studies. Such mixed findings suggest that age-related changes in frontal activity may be process- and region-specific, having varied associations across different frontal regions involved in distinct cognitive processes, rather than generalized across the frontal cortex. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined individual differences through cross-sectional associations at baseline evaluation and longitudinal changes in regional cerebral blood flow (rCBF) in relation to different executive abilities in cognitively normal older adults. We found that, at baseline, greater rCBF in middle frontal regions correlated with better performance in abstraction and chunking, but greater rCBF in the insula and a distinct middle frontal region correlated with poorer inhibition and discrimination, respectively. In addition, increases in frontal rCBF over time were associated with longitudinal declines in abstraction, chunking, inhibition, discrimination, switching, and manipulation. These findings indicate process- and region-specific, rather than uniform, age-related changes in frontal brain-behavior associations, and also suggest that longitudinally high-levels of frontal engagement reflect declining rather than stable cognition. Published by Elsevier Inc. C1 [Goh, Joshua O.; Beason-Held, Lori L.; An, Yang; Resnick, Susan M.] NIA, Lab Behav Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Kraut, Michael A.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. RP Goh, JO (reprint author), 251 Bayview Blvd,Suite 100,Rm 4B316, Baltimore, MD 21224 USA. EM joshua.goh@nih.gov RI GOH, JOSHUA/C-8063-2016 OI GOH, JOSHUA/0000-0001-7808-5452 FU Intramural Research Program of the National Institute on Aging; National Institutes of Health, USA; Research and Development Contract [N01-AG-3-2124] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA, and by Research and Development Contract N01-AG-3-2124. NR 37 TC 11 Z9 11 U1 1 U2 33 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 1 PY 2013 VL 69 BP 43 EP 50 DI 10.1016/j.neuroimage.2012.12.026 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 085PX UT WOS:000314627800005 PM 23266746 ER PT J AU Zhang, XC Lee, MR Salmeron, BJ Stein, DJ Hong, LE Geng, XJ Ross, TJ Li, N Hodgkinson, C Shen, PH Yang, YH Goldman, D Stein, EA AF Zhang, Xiaochu Lee, Mary R. Salmeron, Betty Jo Stein, Dan J. Hong, L. Elliot Geng, Xiujuan Ross, Thomas J. Li, Nan Hodgkinson, Colin Shen, Pei-Hong Yang, Yihong Goldman, David Stein, Elliot A. TI Prefrontal white matter impairment in substance users depends upon the catechol-o-methyl transferase (COMT) val158met polymorphism SO NEUROIMAGE LA English DT Article DE Imaging; Genetics; Nicotine; Addiction; COMT; DTI ID DIFFUSION TENSOR TRACTOGRAPHY; IOWA GAMBLING TASK; NICOTINE DEPENDENCE; HUMAN BRAIN; METHAMPHETAMINE ABUSERS; SPATIAL STATISTICS; SMOKING INITIATION; COCAINE DEPENDENCE; DOPAMINE RELEASE; METHYLTRANSFERASE AB Individuals addicted to most chemical substances present with hypoactive dopaminergic systems as well as altered prefrontal white matter structure. Prefrontal dopaminergic tone is under genetic control and is influenced by and modulates descending cortico-striatal glutamatergic pathways that in turn, regulate striatal dopamine release. The catechol-O-methyltransferase (COMT) gene contains an evolutionarily recent and common functional variant at codon 108/158 (rs4680) that plays an important role in modulating prefrontal dopaminergic tone. To determine if the COMT val158met genotype influences white matter integrity (i.e., fractional anisotropy (FA)) in substance users, 126 healthy controls and 146 substance users underwent genotyping and magnetic resonance imaging. A general linear model with two between-subjects factors (COMT genotype and addiction status) was performed using whole brain diffusion tensor imaging (DTI) to assess FA A significant Genotype x Drug Use status interaction was found in the left prefrontal cortex. Post-hoc analysis showed reduced prefrontal FA only in Met/Met homozygotes who were also drug users. These data suggest that Met/Met homozygous individuals, in the context of addiction, have increased susceptibility to white matter structural alterations, which might contribute to previously identified structural and functional prefrontal cortical deficits in addiction. Published by Elsevier Inc. C1 [Zhang, Xiaochu; Lee, Mary R.; Salmeron, Betty Jo; Geng, Xiujuan; Ross, Thomas J.; Yang, Yihong; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Stein, Dan J.] Univ Cape Town, Dept Psychiat & Mental Hlth, ZA-7925 Cape Town, South Africa. [Hong, L. Elliot] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. [Hodgkinson, Colin; Shen, Pei-Hong; Goldman, David] NIAAA, Neurogenet Lab, DICBR, NIH, Rockville, MD 20852 USA. [Zhang, Xiaochu; Li, Nan] Chinese Acad Sci, Key Lab Brain Funct & Dis, Hefei 230027, Peoples R China. [Zhang, Xiaochu; Li, Nan] Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Peoples R China. RP Lee, MR (reprint author), 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM leemary@mail.nih.gov RI Zhang, Xiaochu/O-9592-2014; Goldman, David/F-9772-2010; Salmeron, Betty Jo/M-1793-2016; Stein, Dan/A-1752-2008; OI Zhang, Xiaochu/0000-0002-7541-0130; Goldman, David/0000-0002-1724-5405; Salmeron, Betty Jo/0000-0003-1699-9333; Stein, Dan/0000-0001-7218-7810; Ross, Thomas/0000-0002-7745-3572 FU Intramural Research Program of NIDA; Intramural Research Program of NIAAA; National Natural Science Foundation of China [31171083, 31230032]; Chinese Academy of Sciences the Hundred Talents Program [BJ2070000047]; Fundamental Research Funds for the Central Universities of China [WK2070000007] FX This study was supported by the Intramural Research Programs of NIDA and NIAAA. XZ is partially supported by the National Natural Science Foundation of China (31171083, 31230032), the Chinese Academy of Sciences the Hundred Talents Program (BJ2070000047), and the Fundamental Research Funds for the Central Universities of China (WK2070000007). We thank Kimberly Slater, Loretta Spurgeon and Catherine Demers for their assistance in conducting this study. NR 61 TC 8 Z9 8 U1 3 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 1 PY 2013 VL 69 BP 62 EP 69 DI 10.1016/j.neuroimage.2012.11.056 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 085PX UT WOS:000314627800007 PM 23219927 ER PT J AU Voss, JG Dobra, A Morse, C Kovacs, JA Danner, RL Munson, PJ Logan, C Rangel, Z Adelsberger, JW McLaughlin, M Adams, LD Raju, R Dalakas, MC AF Voss, Joachim G. Dobra, Adrian Morse, Caryn Kovacs, Joseph A. Danner, Robert L. Munson, Peter J. Logan, Carolea Rangel, Zoila Adelsberger, Joseph W. McLaughlin, Mary Adams, Larry D. Raju, Raghavan Dalakas, Marinos C. TI Fatigue-Related Gene Networks Identified in CD14(+) Cells Isolated From HIV-Infected Patients-Part I: Research Findings SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE CD14; fatigue; cofilin 2; Bayesian inference; prokineticin 2; HIV ID ACTIVE ANTIRETROVIRAL THERAPY; MITOCHONDRIAL TOXICITY; VIRAL PERSISTENCE; EXPRESSION; VIRUS; PROTEIN; PATHOGENESIS; MONOCYTES; MEN; DNA AB Purpose: Human immunodeficiency virus (HIV)-related fatigue (HRF) is multicausal and potentially related to mitochondrial dysfunction caused by antiretroviral therapy with nucleoside reverse transcriptase inhibitors (NRTIs). Methodology: The authors compared gene expression profiles of CD14(+) cells of low versus high fatigued, NRTI-treated HIV patients to healthy controls (n = 5/group). The authors identified 32 genes predictive of low versus high fatigue and 33 genes predictive of healthy versus HIV infection. The authors constructed genetic networks to further elucidate the possible biological pathways in which these genes are involved. Relevance for nursing practice: Genes including the actin cytoskeletal regulatory proteins Prokineticin 2 and Cofilin 2 along with mitochondrial inner membrane proteins are involved in multiple pathways and were predictors of fatigue status. Previously identified inflammatory and signaling genes were predictive of HIV status, clearly confirming our results and suggesting a possible further connection between mitochondrial function and HIV. Isolated CD14(+) cells are easily accessible cells that could be used for further study of the connection between fatigue and mitochondrial function of HIV patients. Implication for Practice: The findings from this pilot study take us one step closer to identifying biomarker targets for fatigue status and mitochondrial dysfunction. Specific biomarkers will be pertinent to the development of methodologies to diagnosis, monitor, and treat fatigue and mitochondrial dysfunction. C1 [Voss, Joachim G.; Dobra, Adrian; Adams, Larry D.] Univ Washington, Sch Nursing, Biobehav Nursing & Hlth Syst Dept, Seattle, WA 98195 USA. [Dobra, Adrian] Univ Washington, Dept Stat, Seattle, WA 98195 USA. [Morse, Caryn; Kovacs, Joseph A.; McLaughlin, Mary] NIAID, Bethesda, MD 20892 USA. [Morse, Caryn; Kovacs, Joseph A.; Danner, Robert L.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Danner, Robert L.; Logan, Carolea] NIH, Dept Crit Care Med, Ctr Clin, Funct Genom & Prote Facil, Bethesda, MD 20892 USA. [Munson, Peter J.; Rangel, Zoila] NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD 20892 USA. [Adelsberger, Joseph W.] NCI, NIH, AIDS Monitoring Lab, Frederick, MD 21701 USA. [Raju, Raghavan] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Dalakas, Marinos C.] Univ London Imperial Coll Sci Technol & Med, London, England. RP Voss, JG (reprint author), Univ Washington, Sch Nursing, Box 357266, Seattle, WA 98195 USA. EM vossj@uw.edu FU K-22 National Institute of Nursing Research [NR008672-01]; NIH [05-ClinicalCenter-0127] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Grant support: K-22 National Institute of Nursing Research NR008672-01, NIH 05-ClinicalCenter-0127. NR 64 TC 3 Z9 3 U1 1 U2 20 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 J9 BIOL RES NURS JI Biol. Res. Nurs. PD APR PY 2013 VL 15 IS 2 BP 137 EP 151 DI 10.1177/1099800411421957 PG 15 WC Nursing SC Nursing GA 082BU UT WOS:000314367500002 PM 23324479 ER PT J AU Voss, JG Dobra, A Morse, C Kovacs, JA Raju, R Danner, RL Munson, PJ Logan, C Rangel, Z Adelsberger, JW McLaughlin, M Adams, LD Dalakas, MC AF Voss, Joachim G. Dobra, Adrian Morse, Caryn Kovacs, Joseph A. Raju, Raghavan Danner, Robert L. Munson, Peter J. Logan, Carolea Rangel, Zoila Adelsberger, Joseph W. McLaughlin, Mary Adams, Larry D. Dalakas, Marinos C. TI Fatigue-Related Gene Networks Identified in CD14(+) Cells Isolated From HIV-Infected Patients-Part II: Statistical Analysis SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE CD14; genetic network; Bayesian inference; liquid association; HIV ID EXPRESSION DATA; VIRAL PERSISTENCE; CLASSIFICATION; DISCOVERY; MICROARRAYS; MODELS; ARRAYS; MICE; MEN AB Purpose: In limited samples of valuable biological tissues, univariate ranking methods of microarray analyses often fail to show significant differences among expression profiles. In order to allow for hypothesis generation, novel statistical modeling systems can be greatly beneficial. The authors applied new statistical approaches to solve the issue of limited experimental data to generate new hypotheses in CD14(+) cells of patients with HIV-related fatigue (HRF) and healthy controls. Methodology: We compared gene expression profiles of CD14(+) cells of nucleoside reverse transcriptase inhibitor (NRTI)-treated HIV patients with low versus high fatigue to healthy controls (n = 5 each). With novel Bayesian modeling procedures, the authors identified 32 genes predictive of low versus high fatigue and 33 genes predictive of healthy versus HIV infection. Sparse association and liquid association networks further elucidated the possible biological pathways in which these genes are involved. Relevance for nursing practice: Genetic networks developed in a comprehensive Bayesian framework from small sample sizes allow nursing researchers to design future research approaches to address such issues as HRF. Implication for practice: The findings from this pilot study may take us one step closer to the development of useful biomarker targets for fatigue status. Specific and reliable tests are needed to diagnosis, monitor and treat fatigue and mitochondrial dysfunction. C1 [Voss, Joachim G.; Dobra, Adrian; Adams, Larry D.] Univ Washington, Sch Nursing, Biobehav Nursing & Hlth Syst Dept, Seattle, WA 98195 USA. [Dobra, Adrian] Univ Washington, Dept Stat, Seattle, WA 98195 USA. [Morse, Caryn; McLaughlin, Mary] NIAID, Bethesda, MD 20892 USA. [Morse, Caryn; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Raju, Raghavan] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Danner, Robert L.; Logan, Carolea] NIH, Dept Crit Care Med, Funct Genom & Prote Facil, Ctr Clin, Bethesda, MD 20892 USA. [Munson, Peter J.; Rangel, Zoila] NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD 20892 USA. [Adelsberger, Joseph W.] NCI, AIDS Monitoring Lab, NIH, Frederick, MD 21701 USA. [Dalakas, Marinos C.] Univ London Imperial Coll Sci Technol & Med, London, England. RP Voss, JG (reprint author), Univ Washington, Sch Nursing, Biobehav Nursing & Hlth Syst Dept, Box 357 266,Room T 624B, Seattle, WA 98195 USA. EM vossj@u.washington.edu FU K-22 National Institute of Nursing Research [NR008672-01]; NIH [05-ClinicalCenter-0127] FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article: Grant support: K-22 National Institute of Nursing Research NR008672-01, NIH 05-ClinicalCenter-0127. NR 45 TC 1 Z9 1 U1 0 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 EI 1552-4175 J9 BIOL RES NURS JI Biol. Res. Nurs. PD APR PY 2013 VL 15 IS 2 BP 152 EP 159 DI 10.1177/1099800411423307 PG 8 WC Nursing SC Nursing GA 082BU UT WOS:000314367500003 PM 22084402 ER PT J AU Duffy, A Rahma, O Greten, TF AF Duffy, Austin Rahma, Osama Greten, Tim F. TI Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: Results from a randomized trial of the GERMAN AIO CRC Study Group SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter C1 [Duffy, Austin; Rahma, Osama; Greten, Tim F.] NCI, GI Malignancies Sect, Bethesda, MD 20892 USA. RP Duffy, A (reprint author), NCI, GI Malignancies Sect, Bethesda, MD 20892 USA. EM duffya@mail.nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 5 TC 3 Z9 3 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD APR 1 PY 2013 VL 132 IS 7 BP 1718 EP 1718 DI 10.1002/ijc.27805 PG 1 WC Oncology SC Oncology GA 079NN UT WOS:000314177500026 PM 22930464 ER PT J AU Zhang, SP Chen, HS Pfeiffer, RM AF Zhang, Shunpu Chen, Huann-Sheng Pfeiffer, Ruth M. TI A combined p-value test for multiple hypothesis testing SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Bonferoni test; Simes test; Combined p-value test; Family-wise error rate; Fisher's product test; Rank truncated product (RIP) test; Truncated product method ID GENOMEWIDE ASSOCIATION; BONFERRONI PROCEDURE; TRUNCATED PRODUCT AB Tests that combine p-values, such as Fisher's product test, are popular to test the global null hypothesis H-0 that each of n component null hypotheses, H-1, ... ,H-n, is true versus the alternative that at least one of H-1, ... ,H-n is false, since they are more powerful than classical multiple tests such as the Bonferroni test and the Simes tests. Recent modifications of Fisher's product test, popular in the analysis of large scale genetic studies include the truncated product method (TPM) of Zaykin et al. (2002), the rank truncated product (RTP) test of Dudbridge and Koeleman (2003) and more recently, a permutation based test-the adaptive rank truncated product (ARTP) method of Yu et al. (2009). The TPM and RIP methods require users' specification of a truncation point. The ARTP method improves the performance of the RTP method by optimizing selection of the truncation point over a set of pre-specified candidate points. In this paper we extend the ARTP by proposing to use all the possible truncation points (1, ... ,n} as the candidate truncation points. Furthermore, we derive the theoretical probability distribution of the test statistic under the global null hypothesis H-0. Simulations are conducted to compare the performance of the proposed test with the Bonferroni test, the Simes test, the RTP test, and Fisher's product test. The simulation results show that the proposed test has higher power than the Bonferroni test and the Simes test, as well as the RIP method. It is also significantly more powerful than Fisher's product test when the number of truly false hypotheses is small relative to the total number of hypotheses, and has comparable power to Fisher's product test otherwise. (C) 2012 Elsevier B.V. All rights reserved. C1 [Zhang, Shunpu] Univ Nebraska, Dept Stat, Lincoln, NE 68583 USA. [Chen, Huann-Sheng] NCI, Stat Methodol & Applicat Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Zhang, SP (reprint author), Univ Nebraska, Dept Stat, Lincoln, NE 68583 USA. EM szhang3@unl.edu RI Chen, Huann-Sheng/D-6328-2013 OI Chen, Huann-Sheng/0000-0002-5905-8050 NR 15 TC 4 Z9 4 U1 0 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD APR PY 2013 VL 143 IS 4 BP 764 EP 770 DI 10.1016/j.jspi.2012.10.004 PG 7 WC Statistics & Probability SC Mathematics GA 079UW UT WOS:000314198700009 ER PT J AU Wade, BSC Stockman, M McLaughlin, MJ Raznahan, A Lalonde, F Giedd, JN AF Wade, Benjamin Seavey Cutler Stockman, Michael McLaughlin, Michael Joseph Raznahan, Armin Lalonde, Francois Giedd, Jay Norman TI Improved corpus callosum area measurements by analysis of adjoining parasagittal slices SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Power analysis; Coefficient of variation; Sample size AB The corpus callosum (CC) is a bundle of approximately 180 million axons connecting homologous areas of the left and right cerebral cortex. Because CC projections are topographically organized, regional CC morphological abnormalities may reflect regional cortical developmental abnormalities. We assess the variance characteristics of three CC area measurement techniques by comparing a single midsagittal slice versus three slices (midsagittal plus one parasagittal on each side) and five slices (midsagittal plus two parasagittal on each side). CC images were partitioned into five subregions using the Hofer-Frahm scheme under the three methods and variance was examined via two complementary data sets. In the first, to control for intersubject variability, 12 scans were acquired from a single subject over the course of 3 h. In the second, we used scans from 56 healthy male volunteers between the ages of 10 and 27 years (mean=17.47, S.D.=3.42). Increasing the number of slices from one to three to five diminished the coefficient of variation (CV) within subregions and increased the power to detect differences between groups. A power analysis was conducted for the sample under each method to determine the sample size necessary to discern a given percent change (delta) ranging from 1 to 20% iteratively. Published by Elsevier Ireland Ltd. C1 [Wade, Benjamin Seavey Cutler; Stockman, Michael; McLaughlin, Michael Joseph; Raznahan, Armin; Lalonde, Francois; Giedd, Jay Norman] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Wade, BSC (reprint author), NIMH, Child Psychiat Branch, 10 Ctr Dr,MSC 1367,Bldg 10,Room 4C110, Bethesda, MD 20892 USA. EM benjamin.wade@nih.gov RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU Intramural NIH HHS [Z99 MH999999] NR 6 TC 2 Z9 3 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD MAR 30 PY 2013 VL 211 IS 3 BP 221 EP 225 DI 10.1016/j.pscychresns.2012.05.004 PG 5 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 123HN UT WOS:000317379100005 PM 23149042 ER PT J AU Zhang, LM Alter, HJ Wang, HP Jia, SZ Wang, E Marincola, FM Shih, JWK Wang, RY AF Zhang, Lumin Alter, Harvey J. Wang, Haiping Jia, Shuaizheng Wang, Ena Marincola, Francesco M. Shih, James W. -K. Wang, Richard Y. TI The modulation of hepatitis C virus 1a replication by PKR is dependent on NF-kB mediated interferon beta response in Huh7.5.1 cells SO VIROLOGY LA English DT Article DE PKR silencing; NF-kB activation; IFN-beta; HCV1a replication ID PROTEIN-KINASE PKR; I-KAPPA-B; IMMORTALIZED HUMAN HEPATOCYTES; CORE PROTEIN; CULTURE-SYSTEM; RNA; ACTIVATION; EXPRESSION; INFECTION; IFN AB Protein kinase R (PKR), a sensor of double-stranded RNA, plays an important role in the host response to viral infection. Hepatitis C genotype 2a virus (HCV2a) has been shown to induce PKR activation to suppress the translation of antiviral interferon stimulated genes (ISGs), suggesting that PKR inhibitor can be beneficial for treating chronically HCV-infected patients in conjunction with interferon alpha and ribavirin. However, in this study, we found that PKR inhibition using siRNA PKR, shRNA PKR or PKR inhibitor enhanced HCV 1 a replication and rendered Huh7.5.1 cells more susceptible to HCV1a infection. Additionally, PKR silencing suppressed NF-kB activation and NF-kB mediated STAT1 phosphorylation in Huh7.5.1 cells and HCV1a persistently infected Huh7.5.1 cells (2HDD4). These effects were accompanied by a reduction of interferon beta response and thereby enhanced HCV1a replication in Huh7.5.1 cells. We conclude that host cells can employ PKR activation to restrict HCV1a replication through regulation of NF-kB expression. Published by Elsevier Inc. C1 [Zhang, Lumin; Alter, Harvey J.; Wang, Ena; Marincola, Francesco M.; Wang, Richard Y.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Wang, Haiping] Acad Mil Med Sci, Affiliated Hosp, Dept Transfus Med, Beijing, Peoples R China. [Jia, Shuaizheng] Beijing Inst Transfus Med, Beijing, Peoples R China. [Shih, James W. -K.] Xiamen Univ, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen, Peoples R China. RP Wang, RY (reprint author), NIH, Dept Transfus Med, Bldg 10,Room 1C-711,10 Ctr Dr, Bethesda, MD 20892 USA. EM rwang@cc.nih.gov FU Warren G. Magnuson Clinical Center, NIH Intramural Research Program FX This study was supported by the Warren G. Magnuson Clinical Center, NIH Intramural Research Program. We thank Dr. Francis Chisari for providing us with Huh7.5.1 cells, Dr. Stanley Lemon for providing us with H77S plasmids, and Dr. Keijei Mitamura for providing us with IMY-4 and IMY-N9 cell lines. We would also like to appreciate the help from Dr. Liang Jack and Dr. Li Qisheng. They kindly provided JFH1 virus and JFH1/1a chimeric virus. We also greatly appreciated Dr. Sonia Voiculescu's assistance in the review of manuscript. NR 44 TC 8 Z9 9 U1 0 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2013 VL 438 IS 1 BP 28 EP 36 DI 10.1016/j.virol.2013.01.015 PG 9 WC Virology SC Virology GA 104ZW UT WOS:000316036400005 PM 23399035 ER PT J AU Malecka, KA Szentpetery, Z Peterson, JR AF Malecka, Kimberly A. Szentpetery, Zsofia Peterson, Jeffrey R. TI Synergistic Activation of p21-activated Kinase 1 by Phosphatidylinositol 4,5-Bisphosphate and Rho GTPases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR SIGNALING COMPLEXES; PROTEIN-KINASE; N-WASP; PTDINS(4,5)P-2 SYNTHESIS; PLASMA-MEMBRANE; ARP2/3 COMPLEX; CELL POLARITY; LIVING CELLS; CDC42; ACTIN AB Autoinhibited p21-activated kinase 1 (Pak1) can be activated in vitro by the plasma membrane-bound Rho GTPases Rac1 and Cdc42 as well as by the lipid phosphatidylinositol (4,5)-bisphosphate (PIP2). Activator binding is mediated by a GTPase-binding motif and an adjacent phosphoinositide-binding motif. Whether these two classes of activators play alternative, additive, or synergistic roles in Pak1 activation is unknown, as is their contributions to Pak1 activation in vivo. To address these questions, we developed a system to mimic the membrane anchoring of Rho GTPases by creating liposomes containing both PIP2 and a Ni2+-NTA modified lipid capable of binding hexahistidine-tagged Cdc42. We find that among all biologically relevant phosphoinositides, only PIP2 is able to synergistically activate Pak1 in concert with Cdc42. Membrane binding of the kinase was highly sensitive to the spatial density of PIP2 and Pak1 demonstrated dramatically enhanced affinity for Cdc42 anchored in a PIP2 environment. To validate these findings in vivo, we utilized an inducible recruitment system to drive the ectopic synthesis of PIP2 on Golgi membranes, which normally have active Cdc42 but lack significant concentrations of PIP2. Pak1 was recruited to PIP2-containing membranes in a manner dependent on the ability of Pak1 to bind to both PIP2 and Cdc42. These findings provide a mechanistic explanation for the essential role of both phosphoinositides and GTPases in Pak1 recruitment and activation. In contrast, Ack, another Cdc42 effector kinase that lacks an analogous phosphoinositide-binding motif, fails to show the same enhancement of membrane binding and activation by PIP2, thus indicating that regulation by PIP2 and Cdc42 could provide a combinatorial code for activation of different GTPase effectors in different subcellular locations. C1 [Malecka, Kimberly A.; Peterson, Jeffrey R.] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA. [Szentpetery, Zsofia] Eunice Kennedy Shriver NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Peterson, JR (reprint author), 333 Cottman Ave, Philadelphia, PA 19111 USA. EM Jeffrey.peterson@fccc.edu FU National Institutes of Health [GM083025, T32 CA009035, P30 CA006927]; FCCC Keystone Program in Head Neck Cancer FX This work was supported, in whole or in part, by National Institutes of Health Grants GM083025 (to J. R. P.), T32 CA009035 (to K. Malecka), and P30 CA006927 to the Fox Chase Cancer Center. Additional support was provided by the FCCC Keystone Program in Head & Neck Cancer. NR 61 TC 4 Z9 4 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 29 PY 2013 VL 288 IS 13 BP 8887 EP 8897 DI 10.1074/jbc.M112.428904 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200010 PM 23393142 ER PT J AU Phillips, DD Fattah, RJ Crown, D Zhang, Y Liu, SH Moayeri, M Fischer, ER Hansen, BT Ghirlando, R Nestorovich, EM Wein, AN Simons, L Leppla, SH Leysath, CE AF Phillips, Damilola D. Fattah, Rasem J. Crown, Devorah Zhang, Yi Liu, Shihui Moayeri, Mahtab Fischer, Elizabeth R. Hansen, Bryan T. Ghirlando, Rodolfo Nestorovich, Ekaterina M. Wein, Alexander N. Simons, Lacy Leppla, Stephen H. Leysath, Clinton E. TI Engineering Anthrax Toxin Variants That Exclusively Form Octamers and Their Application to Targeting Tumors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STAPHYLOCOCCAL ALPHA-HEMOLYSIN; PROTECTIVE ANTIGEN; LETHAL FACTOR; SEDIMENTATION-VELOCITY; MAMMALIAN-CELLS; PORE FORMATION; KINASE-KINASE; OLIGOMERIZATION; ULTRACENTRIFUGATION; INTERNALIZATION AB Anthrax toxin protective antigen (PA) delivers its effector proteins into the host cell cytosol through formation of an oligomeric pore, which can assume heptameric or octameric states. By screening a highly directed library of PA mutants, we identified variants that complement each other to exclusively form octamers. These PA variants were individually nontoxic and demonstrated toxicity only when combined with their complementary partner. We then engineered requirements for activation by matrix metalloproteases and urokinase plasminogen activator into two of these variants. The resulting therapeutic toxin specifically targeted cells expressing both tumor associated proteases and completely stopped tumor growth in mice when used at a dose far below that which caused toxicity. This scheme for obtaining intercomplementing subunits can be employed with other oligomeric proteins and potentially has wide application. C1 [Phillips, Damilola D.; Fattah, Rasem J.; Crown, Devorah; Zhang, Yi; Liu, Shihui; Moayeri, Mahtab; Wein, Alexander N.; Simons, Lacy; Leppla, Stephen H.; Leysath, Clinton E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.; Hansen, Bryan T.] NIAID, Electron Microscopy Unit, Res Technol Branch, NIH, Hamilton, MT 59840 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Nestorovich, Ekaterina M.] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. RP Leysath, CE (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM leysathce@niaid.nih.gov FU Intramural Research Program of NIAID from the National Institutes of Health; Intramural Research Program of NIDDK from the National Institutes of Health FX This work was supported in part by the Intramural Research Programs of NIAID and NIDDK from the National Institutes of Health. NR 32 TC 13 Z9 14 U1 1 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 MAR 29 PY 2013 VL 288 IS 13 BP 9058 EP 9065 DI 10.1074/jbc.M113.452110 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200025 PM 23393143 ER PT J AU Corpe, CP Eck, P Wang, J Al-Hasani, H Levine, M AF Corpe, Christopher P. Eck, Peter Wang, Jin Al-Hasani, Hadi Levine, Mark TI Intestinal Dehydroascorbic Acid (DHA) Transport Mediated by the Facilitative Sugar Transporters, GLUT2 and GLUT8 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID L-ASCORBIC-ACID; ISOLATED RAT ADIPOCYTES; VITAMIN-C; GLUCOSE TRANSPORTERS; HEXOSE TRANSPORTERS; XENOPUS OOCYTES; IRON-METABOLISM; MOUSE; CELLS; INHIBITION AB Intestinal vitamin C (Asc) absorption was believed to be mediated by the Na+-dependent ascorbic acid transporter SVCT1. However, Asc transport across the intestines of SVCT1 knockout mice is normal indicating that alternative ascorbic acid transport mechanisms exist. To investigate these mechanisms, rodents were gavaged with Asc or its oxidized form dehydroascorbic acid (DHA), and plasma Asc concentrations were measured. Asc concentrations doubled following DHA but not Asc gavage. We hypothesized that the transporters responsible were facilitated glucose transporters (GLUTs). Using Xenopus oocyte expression, we investigated whether facilitative glucose transporters GLUT2 and GLUT5-12 transported DHA. Only GLUT2 and GLUT8, known to be expressed in intestines, transported DHA with apparent transport affinities (K-m) of 2.33 and 3.23 mM and maximal transport rates (V-max) of 25.9 and 10.1 pmol/min/oocyte, respectively. Maximal rates for DHA transport mediated by GLUT2 and GLUT8 in oocytes were lower than maximal rates for 2-deoxy-D-glucose (V-max of 224 and 32 pmol/min/oocyte for GLUT2 and GLUT8, respectively) and fructose (V-max of 406 and 116 pmol/min/oocyte for GLUT2 and GLUT8, respectively). These findings may be explained by differences in the exofacial binding of substrates, as shown by inhibition studies with ethylidine glucose. DHA transport activity in GLUT2- and GLUT8-expressing oocytes was inhibited by glucose, fructose, and by the flavonoids phloretin and quercetin. These studies indicate intestinal DHA transport may be mediated by the facilitative sugar transporters GLUT2 and GLUT8. Furthermore, dietary sugars and flavonoids in fruits and vegetables may modulate Asc bioavailability via inhibition of small intestinal GLUT2 and GLUT8. C1 [Corpe, Christopher P.; Eck, Peter; Wang, Jin; Al-Hasani, Hadi; Levine, Mark] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RP Corpe, CP (reprint author), Kings Coll London, Diabet & Nutr Sci Div, Sch Med, Room 3-114,Franklin Wilkins Bldg,150 Stamford St, London SE1 9NH, England. RI WANG, Jin/A-8327-2012; OI WANG, Jin/0000-0002-0062-2489; Eck, Peter/0000-0003-2371-9774 FU National Institutes of Health Intramural Research Program Grant from NIDDK [DK054506-15] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program Grant DK054506-15 from NIDDK. NR 33 TC 25 Z9 25 U1 0 U2 15 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 MAR 29 PY 2013 VL 288 IS 13 BP 9092 EP 9101 DI 10.1074/jbc.M112.436790 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200029 PM 23396969 ER PT J AU Kong, E Peng, SY Chandra, G Sarkar, C Zhang, ZJ Bagh, MB Mukherjee, AB AF Kong, Eryan Peng, Shiyong Chandra, Goutam Sarkar, Chinmoy Zhang, Zhongjian Bagh, Maria B. Mukherjee, Anil B. TI Dynamic Palmitoylation Links Cytosol-Membrane Shuttling of Acyl-protein Thioesterase-1 and Acyl-protein Thioesterase-2 with That of Proto-oncogene H-Ras Product and Growth-associated Protein-43 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEURONAL DEVELOPMENT; LYSOPHOSPHOLIPASE I; MOLECULAR-CLONING; EXPRESSION; IDENTIFICATION; LOCALIZATION; PURIFICATION; PALMITATE; ACYLATION AB Acyl-protein thioesterase-1 (APT1) and APT2 are cytosolic enzymes that catalyze depalmitoylation of membrane-anchored, palmitoylated H-Ras and growth-associated protein-43 (GAP-43), respectively. However, the mechanism(s) of cytosol-membrane shuttling of APT1 and APT2, required for depalmitoylating their substrates H-Ras and GAP-43, respectively, remained largely unknown. Here, we report that both APT1 and APT2 undergo palmitoylation on Cys-2. Moreover, blocking palmitoylation adversely affects membrane localization of both APT1 and APT2 and that of their substrates. We also demonstrate that APT1 not only catalyzes its own depalmitoylation but also that of APT2 promoting dynamic palmitoylation (palmitoylation-depalmitoylation) of both thioesterases. Furthermore, shRNA suppression of APT1 expression or inhibition of its thioesterase activity by palmostatin B markedly increased membrane localization of APT2, and shRNA suppression of APT2 had virtually no effect on membrane localization of APT1. In addition, mutagenesis of the active site Ser residue to Ala (S119A), which renders catalytic inactivation of APT1, also increased its membrane localization. Taken together, our findings provide insight into a novel mechanism by which dynamic palmitoylation links cytosol-membrane trafficking of APT1 and APT2 with that of their substrates, facilitating steady- state membrane localization and function of both. C1 [Kong, Eryan; Peng, Shiyong; Chandra, Goutam; Sarkar, Chinmoy; Zhang, Zhongjian; Bagh, Maria B.; Mukherjee, Anil B.] Eunice Kennedy Shriver NICHD, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov RI Peng, Shiyong/D-6391-2014 OI Peng, Shiyong/0000-0003-0697-3674 FU National Institutes of Health Intramural Program of the Eunice Kennedy-Shriver NICHD FX This work was supported in whole by National Institutes of Health Intramural Program of the Eunice Kennedy-Shriver NICHD. NR 33 TC 22 Z9 22 U1 0 U2 12 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 MAR 29 PY 2013 VL 288 IS 13 BP 9112 EP 9125 DI 10.1074/jbc.M112.421073 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200031 PM 23396970 ER PT J AU Gonzalez-Sancho, JM Greer, YE Abrahams, CL Takigawa, Y Baljinnyam, B Lee, KH Lee, KS Rubin, JS Brown, AMC AF Gonzalez-Sancho, Jose M. Greer, Yoshimi Endo Abrahams, Cristina L. Takigawa, Yutaka Baljinnyam, Bolormaa Lee, Kyung Ho Lee, Kyung S. Rubin, Jeffrey S. Brown, Anthony M. C. TI Functional Consequences of Wnt-induced Dishevelled 2 Phosphorylation in Canonical and Noncanonical Wnt Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STABILIZE BETA-CATENIN; PROTEIN ASSEMBLIES; NEURITE OUTGROWTH; DIX DOMAIN; PATHWAY; MECHANISM; DROSOPHILA; WINGLESS; CELL; ACTIVATION AB Dishevelled (Dvl) proteins are intracellular effectors of Wnt signaling that have essential roles in both canonical and noncanonical Wnt pathways. It has long been known that Wnts stimulate Dvl phosphorylation, but relatively little is known about its functional significance. We have previously reported that both Wnt3a and Wnt5a induce Dvl2 phosphorylation that is associated with an electrophoretic mobility shift and loss of recognition by monoclonal antibody 10B5. In the present study, we mapped the 10B5 epitope to a 16-amino acid segment of human Dvl2 (residues 594-609) that contains four Ser/Thr residues. Alanine substitution of these residues (P4m) eliminated the mobility shift induced by either Wnt3a or Wnt5a. The Dvl2 P4m mutant showed a modest increase in canonical Wnt/beta-catenin signaling activity relative to wild type. Consistent with this finding, Dvl2 4Pm preferentially localized to cytoplasmic puncta. In contrast to wild-type Dvl2, however, the P4m mutant was unable to rescue Wnt3a-dependent neurite outgrowth in TC-32 cells following suppression of endogenous Dvl2/3. Earlier work has implicated casein kinase 1 delta/epsilon as responsible for the Dvl mobility shift, and a CK1 delta in vitro kinase assay confirmed that Ser(594), Thr(595), and Ser(597) of Dvl2 are CK1 targets. Alanine substitution of these three residues was sufficient to abrogate the Wnt-dependent mobility shift. Thus, we have identified a cluster of Ser/Thr residues in the C-terminal domain of Dvl2 that are Wnt-induced phosphorylation (WIP) sites. Our results indicate that phosphorylation at the WIP sites reduces Dvl accumulation in puncta and attenuates beta-catenin signaling, whereas it enables noncanonical signaling that is required for neurite outgrowth. C1 [Gonzalez-Sancho, Jose M.; Abrahams, Cristina L.; Takigawa, Yutaka; Brown, Anthony M. C.] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. [Greer, Yoshimi Endo; Baljinnyam, Bolormaa; Rubin, Jeffrey S.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Kyung Ho; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Brown, AMC (reprint author), Weill Cornell Med Coll, Dept Cell & Dev Biol, 1300 York Ave, New York, NY 10065 USA. EM amcbrown@med.cornell.edu OI Gonzalez Sancho, Jose Manuel/0000-0001-5875-1964 FU National Institutes of Health Grant [R01 CA123238]; Ministerio de Educacion, Cultura, y Deportes, of Spain; New York State Department of Health postdoctoral Fellowship [NYS C021339]; [F32 CA117662] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 CA123238 (to A. M. C. B.) and Postdoctoral Fellowship F32 CA117662 (to C. L. A.). This work was also supported by a fellowship from the Ministerio de Educacion, Cultura, y Deportes, of Spain (to J. M. G.-S.), by New York State Department of Health postdoctoral Fellowship NYS C021339 (to Y. T.), and by charitable donations to Strang Cancer Prevention Center. This research also was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 54 TC 18 Z9 18 U1 3 U2 17 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 MAR 29 PY 2013 VL 288 IS 13 BP 9428 EP 9437 DI 10.1074/jbc.M112.448480 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200059 PM 23396967 ER PT J AU Greer, YE Fields, AP Brown, AMC Rubin, JS AF Greer, Yoshimi Endo Fields, Alan P. Brown, Anthony M. C. Rubin, Jeffrey S. TI Atypical Protein Kinase C iota Is Required for Wnt3a-dependent Neurite Outgrowth and Binds to Phosphorylated Dishevelled 2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AXON GUIDANCE; NEURONAL POLARITY; EWINGS-SARCOMA; PKC-ZETA; WNT; CELLS; RYK; CENTROSOME; PATHWAY; GROWTH AB Previously we reported that Wnt3a-dependent neurite outgrowth in Ewing sarcoma family tumor cell lines was mediated by Frizzled3, Dishevelled (Dvl), and c-Jun N-terminal kinase (Endo, Y., Beauchamp, E., Woods, D., Taylor, W. G., Toretsky, J. A., Uren, A., and Rubin, J. S. (2008) Mol. Cell. Biol. 28, 2368-2379). Subsequently, we observed that Dvl2/3 phosphorylation correlated with neurite outgrowth and that casein kinase 1 delta, one of the enzymes that mediate Wnt3a-dependent Dvl phosphorylation, was required for neurite extension (Greer, Y. E., and Rubin, J. S. (2011) J. Cell Biol. 192, 993-1004). However, the functional relevance of Dvl phosphorylation in neurite outgrowth was not established. Dvl1 has been shown by others to be important for axon specification in hippocampal neurons via an interaction with atypical PKC zeta, but the role of Dvl phosphorylation was not evaluated. Here we report that Ewing sarcoma family tumor cells express PKC iota but not PKC zeta. Wnt3a stimulated PKC iota activation and caused a punctate distribution of pPKC iota in the neurites and cytoplasm, with a particularly intense signal at the centrosome. Knockdown of PKC iota expression with siRNA reagents blocked neurite formation in response to Wnt3a. Aurothiomalate, a specific inhibitor of PKC iota/Par6 binding, also suppressed neurite extension. Wnt3a enhanced the co-immunoprecipitation of endogenous PKC iota and Dvl2. Although FLAG-tagged wild-type Dvl2 immunoprecipitated with PKC iota, a phosphorylation-deficient Dvl2 derivative did not. This derivative also was unable to rescue neurite outgrowth when endogenous Dvl2/3 was suppressed by siRNA (Gonzalez-Sancho, J. M., Greer, Y. E., Abrahams, C. L., Takigawa, Y., Baljinnyam, B., Lee, K. H., Lee, K. S., Rubin, J. S., and Brown, A. M. (2013) J. Biol. Chem. 288, 9428-9437). Taken together, these results suggest that site-specific Dvl2 phosphorylation is required for Dvl2 association with PKC iota. This interaction is likely to be one of the mechanisms essential for Wnt3a-dependent neurite outgrowth. C1 [Greer, Yoshimi Endo; Rubin, Jeffrey S.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fields, Alan P.] Mayo Clin, Coll Med, Dept Canc Biol, Jacksonville, FL 32224 USA. [Brown, Anthony M. C.] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. RP Rubin, JS (reprint author), NCI, Bldg 37,Rm 2042,37 Convent Dr,MSC 4256, Bethesda, MD 20892 USA. EM rubinj@mail.nih.gov FU National Institutes of Health [R01 CA123238, R01 CA081436-15]; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Florida Biomedical Research Program [KG05-339710-03] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA123238 (to A. M. C. B.) and R01 CA081436-15 (to A. P. F.). This work was also supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Florida Biomedical Research Program Grant KG05-339710-03 (to A. P. F.). NR 43 TC 5 Z9 6 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 29 PY 2013 VL 288 IS 13 BP 9438 EP 9446 DI 10.1074/jbc.M112.448282 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200060 PM 23396968 ER PT J AU Guzik-Lendrum, S Heissler, SM Billington, N Takagi, Y Yang, Y Knight, PJ Homsher, E Sellers, JR AF Guzik-Lendrum, Stephanie Heissler, Sarah M. Billington, Neil Takagi, Yasuharu Yang, Yi Knight, Peter J. Homsher, Earl Sellers, James R. TI Mammalian Myosin-18A, a Highly Divergent Myosin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR GENE; SMOOTH-MUSCLE MYOSIN; PHOSPHORYLATION-DEPENDENT REGULATION; REGULATORY LIGHT-CHAIN; RABBIT SKELETAL-MUSCLE; PDZ-CONTAINING MYOSIN; ACTIN-BINDING SITE; HEAVY-MEROMYOSIN; MOTOR DOMAIN; ADENOSINE-TRIPHOSPHATASE AB The Mus musculus myosin-18A gene is expressed as two alternatively spliced isoforms, alpha and beta, with reported roles in Golgi localization, in maintenance of cytoskeleton, and as receptors for immunological surfactant proteins. Both myosin-18A isoforms feature a myosin motor domain, a single predicted IQ motif, and a long coiled-coil reminiscent of myosin-2. The myosin-18A alpha isoform, additionally, has an N-terminal PDZ domain. Recombinant heavy meromyosin- and subfragment-1 (S1)-like constructs for both myosin-18A alpha and -18 beta species were purified from the baculovirus/Sf9 cell expression system. These constructs bound both essential and regulatory light chains, indicating an additional noncanonical light chain binding site in the neck. Myosin-18A alpha-S1 and -18A beta-S1 molecules bound actin weakly with K-d values of 4.9 and 54 mu M, respectively. The actin binding data could be modeled by assuming an equilibrium between two myosin conformations, a competent and an incompetent form to bind actin. Actin binding was unchanged by presence of nucleotide. Both myosin-18A isoforms bound N-methylanthraniloyl- nucleotides, but the rate of ATP hydrolysis was very slow (<0.002 s(-1)) and not significantly enhanced by actin. Phosphorylation of the regulatory light chain had no effect on ATP hydrolysis, and neither did the addition of tropomyosin or of GOLPH3, a myosin-18A binding partner. Electron microscopy of myosin-18A-S1 showed that the lever is strongly angled with respect to the long axis of the motor domain, suggesting a pre-power stroke conformation regardless of the presence of ATP. These data lead us to conclude that myosin-18A does not operate as a traditional molecular motor in cells. C1 [Homsher, Earl; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Yang, Yi] Hunan Agr Univ, Coll Vet Med, Lab Funct Prote, Changsha 410128, Hunan, Peoples R China. [Knight, Peter J.] Univ Leeds, Astbury Ctr Struct Mol Biol, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. [Homsher, Earl] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, NIH, 50 South Dr,B50-3523, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov OI Billington, Neil/0000-0003-2306-0228 FU Electron Microscopy Core Facility of the NHLBI FX We thank Fang Zhang for technical assistance with myosin-18A experiments and protein purification, Melanie Barzik and John A. Hammer III (NHLBI, National Institutes of Health) for providing a full-length clone of mouse myosin-18A alpha and -beta as starting points for cloning in this project, and Kathryn Callahan (NIDDK, National Institutes of Health) for assistance with filter binding assays. We thank the NHLBI Proteomics Core Facility, which provided excellent service. We thank the Electron Microscopy Core Facility of the NHLBI for support and the use of facilities. NR 71 TC 23 Z9 23 U1 1 U2 21 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 29 PY 2013 VL 288 IS 13 BP 9532 EP 9548 DI 10.1074/jbc.M112.441238 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200068 PM 23382379 ER PT J AU Mardones, GA Burgos, PV Lin, Y Kloer, DP Magadan, JG Hurley, JH Bonifacino, JS AF Mardones, Gonzalo A. Burgos, Patricia V. Lin, Yimo Kloer, Daniel P. Magadan, Javier G. Hurley, James H. Bonifacino, Juan S. TI Structural Basis for the Recognition of Tyrosine-based Sorting Signals by the mu 3A Subunit of the AP-3 Adaptor Complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CLATHRIN-ASSOCIATED PROTEINS; LYSOSOMAL MEMBRANE-PROTEINS; HERMANSKY-PUDLAK-SYNDROME; MEDIUM CHAINS; ENDOCYTIC MACHINERY; CYTOPLASMIC TAIL; BETA-3A SUBUNIT; AP2 COMPLEX; RECEPTOR; BINDING AB Tyrosine-based signals fitting the YXX empty set motif mediate sorting of transmembrane proteins to endosomes, lysosomes, the basolateral plasma membrane of polarized epithelial cells, and the somatodendritic domain of neurons through interactions with the homologous mu 1, mu 2, mu 3, and mu 4 subunits of the corresponding AP-1, AP-2, AP-3, and AP-4 complexes. Previous x-ray crystallographic analyses identified distinct binding sites for YXX empty set signals on mu 2 and mu 4, which were located on opposite faces of the proteins. To elucidate the mode of recognition of YXX empty set signals by other members of the mu family, we solved the crystal structure at 1.85 angstrom resolution of the C-terminal domain of the mu 3 subunit of AP-3 (isoform A) in complex with a peptide encoding a YXX empty set signal (SDYQRL) from the trans-Golgi network protein TGN38. The mu 3A C-terminal domain consists of an immunoglobulin-like beta-sandwich organized into two sub-domains, A and B. The YXX empty set signal binds in an extended conformation to a site on mu 3A subdomain A, at a location similar to the YXX empty set -binding site on mu 2 but not mu 4. The binding sites on mu 3A and mu 2 exhibit similarities and differences that account for the ability of both proteins to bind distinct sets of YXX empty set signals. Biochemical analyses confirm the identification of the mu 3A site and show that this protein binds YXX empty set signals with 14-19 mu M affinity. The surface electrostatic potential of mu 3A is less basic than that of mu 2, in part explaining the association of AP-3 with intracellular membranes having less acidic phosphoinositides. C1 [Mardones, Gonzalo A.; Burgos, Patricia V.] Univ Austral Chile, Inst Fisiol, Fac Med, Valdivia 5110566, Chile. [Mardones, Gonzalo A.; Burgos, Patricia V.] Univ Austral Chile, Ctr Invest Sur Austral Enfermedades Sistema Nervi, Valdivia 5110566, Chile. [Mardones, Gonzalo A.; Burgos, Patricia V.; Lin, Yimo; Magadan, Javier G.; Bonifacino, Juan S.] NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Kloer, Daniel P.; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mardones, GA (reprint author), Univ Austral Chile, Inst Fisiol, Fac Med, Valdivia 5110566, Chile. EM gonzalo.mardones@uach.cl; hurley@helix.nih.gov; juan@helix.nih.gov FU Fondo Nacional de Desarrollo Cientifico y Tecnologico of Chile [1100896]; Intramural Program of NICHD, National Institutes of Health; Intramural Program of NIDDK, National Institutes of Health; U. S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX This work was supported by Grant 1100896 from Fondo Nacional de Desarrollo Cientifico y Tecnologico of Chile (to G. A. M.), and the Intramural Programs of NICHD (to J. S. B.) and NIDDK (to J. H. H.), National Institutes of Health. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Basic Energy Sciences, Office of Science under Contract W-31-109-Eng-38. NR 48 TC 14 Z9 14 U1 0 U2 11 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 MAR 29 PY 2013 VL 288 IS 13 BP 9563 EP 9571 DI 10.1074/jbc.M113.450775 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200070 PM 23404500 ER PT J AU Lionakis, MS Holland, SM AF Lionakis, Michail S. Holland, Steven M. TI CARD9: at the intersection of mucosal and systemic antifungal immunity SO BLOOD LA English DT Editorial Material ID DECTIN-1 C1 [Lionakis, Michail S.; Holland, Steven M.] NIH, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIH, Bethesda, MD 20892 USA. NR 10 TC 5 Z9 5 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 28 PY 2013 VL 121 IS 13 BP 2377 EP 2378 DI 10.1182/blood-2013-01-480434 PG 4 WC Hematology SC Hematology GA 182RT UT WOS:000321762400004 PM 23538230 ER PT J AU Gotlib, J Pardanani, A Akin, C Reiter, A George, T Hermine, O Kluin-Nelemans, H Hartmann, K Sperr, WR Brockow, K Schwartz, LB Orfao, A DeAngelo, DJ Arock, M Sotlar, K Horny, HP Metcalfe, DD Escribano, L Verstovsek, S Tefferi, A Valent, P AF Gotlib, Jason Pardanani, Animesh Akin, Cem Reiter, Andreas George, Tracy Hermine, Olivier Kluin-Nelemans, Hanneke Hartmann, Karin Sperr, Wolfgang R. Brockow, Knut Schwartz, Lawrence B. Orfao, Alberto DeAngelo, Daniel J. Arock, Michel Sotlar, Karl Horny, Hans-Peter Metcalfe, Dean D. Escribano, Luis Verstovsek, Srdan Tefferi, Ayalew Valent, Peter TI International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITOR; MAST-CELL LEUKEMIA; OF-THE-LITERATURE; PHASE-II TRIAL; C-KIT MUTATION; INTERFERON-ALPHA; IMATINIB MESYLATE; SPANISH NETWORK; CLADRIBINE AB Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials. C1 [Gotlib, Jason; George, Tracy] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Pardanani, Animesh; Tefferi, Ayalew] Mayo Clin, Rochester, MN USA. [Akin, Cem] Harvard Univ, Sch Med, Boston, MA USA. [Akin, Cem] Brigham & Womens Hosp, Boston, MA 02115 USA. [Reiter, Andreas] Univ Med Mannheim, Med Klin 3, Mannheim, Germany. [Hermine, Olivier] Paris Descartes Univ, CNRS, Unite Mixte Rech 8147, Paris, France. [Hermine, Olivier] Paris Descartes Univ, Necker Hosp, Paris, France. [Kluin-Nelemans, Hanneke] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Hartmann, Karin] Univ Cologne, D-50931 Cologne, Germany. [Sperr, Wolfgang R.; Valent, Peter] Med Univ Vienna, Vienna, Austria. [Brockow, Knut] Biederstein Tech Univ, Munich, Germany. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Richmond, VA USA. [Orfao, Alberto; Escribano, Luis] Univ Salamanca, E-37008 Salamanca, Spain. [DeAngelo, Daniel J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Arock, Michel] Grp Hosp Pitie Salpetriere, Cent Hematol Lab, F-75634 Paris, France. [Arock, Michel] Ecole Normale Super, LBPA, CNRS UMR 8113, F-75231 Paris, France. [Sotlar, Karl; Horny, Hans-Peter] Univ Munich, Munich, Germany. [Metcalfe, Dean D.] NIAID, NIH, Bethesda, MD 20892 USA. [Verstovsek, Srdan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Gotlib, J (reprint author), Stanford Canc Inst, 875 Blake Wilbur Dr,Room 2324, Stanford, CA 94305 USA. EM jason.gotlib@stanford.edu RI Hartmann, Karin/N-4865-2015; OI Hartmann, Karin/0000-0002-4595-8226; Akin, Cem/0000-0001-6301-4520 FU Charles and Ann Johnson Foundation; Division of Intramural Research, NIAID, National Institutes of Health; Ministerio de Sanidad y Asuntos Sociales [FIS PS09/00032]; Austrian Science Fund (FWF) SFB-project [F4704-B20] FX This work was supported in part by the Charles and Ann Johnson Foundation (J.G.), the Division of Intramural Research, NIAID, National Institutes of Health (D. D. M), a grant by the Ministerio de Sanidad y Asuntos Sociales (FIS PS09/00032) (L. E.), and by the Austrian Science Fund (FWF) SFB-project F4704-B20. NR 58 TC 35 Z9 35 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 28 PY 2013 VL 121 IS 13 BP 2393 EP 2401 DI 10.1182/blood-2012-09-458521 PG 9 WC Hematology SC Hematology GA 182RT UT WOS:000321762400009 PM 23325841 ER PT J AU Muranski, P Restifo, NP AF Muranski, Pawel Restifo, Nicholas P. TI Essentials of Th17 cell commitment and plasticity SO BLOOD LA English DT Review ID GRAFT-VERSUS-HOST; ROR-GAMMA-T; TRANSCRIPTION FACTOR GATA-3; INFLAMMATORY-BOWEL-DISEASE; PATHOGENIC T(H)17 CELLS; PROMOTE TUMOR-GROWTH; CYTOKINE GM-CSF; TGF-BETA; IN-VIVO; HELPER-CELLS AB CD4(+) T helper (Th) cells exist in a variety of epigenetic states that determine their function, phenotype, and capacity for persistence. These polarization states include Th1, Th2, Th17, and Foxp3(+) T regulatory cells, as well as the more recently described T follicular helper, Th9, and Th22 cells. Th17 cells express the master transcriptional regulator retinoic acid-related orphan receptor gamma thymus and produce canonical interleukin (IL)-17A and IL-17F cytokines. Th17 cells display a great degree of context-dependent plasticity, as they are capable of acquiring functional characteristics of Th1 cells. This late plasticity may contribute to the protection against microbes, plays a role in the development of autoimmunity, and is necessary for antitumor activity of Th17 cells in adoptive cell transfer therapy models. Moreover, plasticity of this subset is associated with higher in vivo survival and self-renewal capacity and less senescence than Th1 polarized cells, which have less plasticity and more phenotypic stability. New findings indicate that subset polarization of CD4(+) T cells not only induces characteristic patterns of surface markers and cytokine production but also has a maturational aspect that affects a cell's ability to survive, respond to secondary stimulation, and form long-term immune memory. C1 [Muranski, Pawel] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Restifo, Nicholas P.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Muranski, P (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,3E-5288, Bethesda, MD 20892 USA. EM muranskp@mail.nih.gov OI Restifo, Nicholas P./0000-0003-4229-4580 FU Center for Cancer Research, National Cancer Institute-National Institutes of Health; National Heart, Lung, and Blood Institute; National Institutes of Health Center for Regenerative Medicine FX This work was supported by the Center for Cancer Research, National Cancer Institute-National Institutes of Health Intramural Research Program, the National Heart, Lung, and Blood Institute Intramural Program, and the National Institutes of Health Center for Regenerative Medicine. NR 204 TC 113 Z9 121 U1 5 U2 38 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 28 PY 2013 VL 121 IS 13 BP 2402 EP 2414 DI 10.1182/blood-2012-09-378653 PG 13 WC Hematology SC Hematology GA 182RT UT WOS:000321762400010 PM 23325835 ER PT J AU Yang, CZ Sun, MG Matro, J Huynh, TT Rahimpour, S Prchal, JT Lechan, R Lonser, R Pacak, K Zhuang, ZP AF Yang, Chunzhang Sun, Michael G. Matro, Joey Huynh, Thanh T. Rahimpour, Shervin Prchal, Josef T. Lechan, Ronald Lonser, Russell Pacak, Karel Zhuang, Zhengping TI Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas SO BLOOD LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; GENE; ERYTHROCYTOSIS; HYDROXYLATION; HIF-2-ALPHA; INHIBITION; PROTEIN AB Hypoxia-inducible factors (HIFs) control the cellular response to hypoxia and, when dysregulated, contribute to tumorigenesis. Previously, we identified 2 gain-of-function somatic mutations in patients presenting with multiple paragangliomas or somatostatinomas, and polycythemia. Here, we report 2 additional unique HIF2A mutations, which disrupt the hydroxylation domain recognized by prolyl hydroxylase domain-2 containing protein, leading to stabilization of HIF-2 alpha and increased expression of hypoxia-related genes. C1 [Yang, Chunzhang; Sun, Michael G.; Rahimpour, Shervin; Lonser, Russell; Zhuang, Zhengping] NINDS, NIH, Surg Neurol Branch, Bethesda, MD 20894 USA. [Matro, Joey; Huynh, Thanh T.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Prchal, Josef T.] Associated Reg & Univ Pathologists & Vet Adm Hosp, Div Hematol, Salt Lake City, UT USA. [Prchal, Josef T.] Univ Utah, Sch Med, Eccles Inst Human Genet, Salt Lake City, UT USA. [Lechan, Ronald] Tufts Med Ctr, Div Endocrinol, Boston, MA USA. RP Zhuang, ZP (reprint author), NINDS, NIH, 9000 Rockville Pike,Bldg 10,Room 7N246, Bethesda, MD 20894 USA. EM karel@mail.nih.gov; zhuangp@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported 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 14 TC 31 Z9 31 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 28 PY 2013 VL 121 IS 13 BP 2563 EP 2566 DI 10.1182/blood-2012-10-460972 PG 4 WC Hematology SC Hematology GA 182RT UT WOS:000321762400027 PM 23361906 ER PT J AU Wuchty, S Vazquez, A Bozdag, S Bauer, PO AF Wuchty, Stefan Vazquez, Alexei Bozdag, Serdar Bauer, Peter O. TI Genome-wide associations of signaling pathways in glioblastoma multiforme SO BMC MEDICAL GENOMICS LA English DT Article ID GLOBAL GENE-EXPRESSION; COPY-NUMBER ALTERATION; CORE PATHWAYS; CANCER; DISEASE; GLIOMA; DISCOVERY; PROFILES; SUBTYPES; REVEALS AB Background: eQTL analysis is a powerful method that allows the identification of causal genomic alterations, providing an explanation of expression changes of single genes. However, genes mediate their biological roles in groups rather than in isolation, prompting us to extend the concept of eQTLs to whole gene pathways. Methods: We combined matched genomic alteration and gene expression data of glioblastoma patients and determined associations between the expression of signaling pathways and genomic copy number alterations with a non-linear machine learning approach. Results: Expectedly, over-expressed pathways were largely associated to tag-loci on chromosomes with signature alterations. Surprisingly, tag-loci that were associated to under-expressed pathways were largely placed on other chromosomes, an observation that held for composite effects between chromosomes as well. Indicating their biological relevance, identified genomic regions were highly enriched with genes having a reported driving role in gliomas. Furthermore, we found pathways that were significantly enriched with such driver genes. Conclusions: Driver genes and their associated pathways may represent a functional core that drive the tumor emergence and govern the signaling apparatus in GBMs. In addition, such associations may be indicative of drug combinations for the treatment of brain tumors that follow similar patterns of common and diverging alterations. C1 [Wuchty, Stefan] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. [Vazquez, Alexei] Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ 08901 USA. [Vazquez, Alexei] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ 08901 USA. [Bozdag, Serdar] Marquette Univ, Dept Math Stat & Comp Sci, Milwaukee, WI 53233 USA. [Bauer, Peter O.] Natl Canc Inst, Natl Inst Hlth, NINDS, Bethesda, MD 20892 USA. RP Wuchty, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM wuchtys@ncbi.nlm.nih.gov FU National Institutes of Health/Department of Health and Human Service (DHHS) (Intramural Research program of the National Library of Medicine) FX This work was supported by the National Institutes of Health/Department of Health and Human Service (DHHS) (Intramural Research program of the National Library of Medicine). NR 45 TC 2 Z9 2 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD MAR 28 PY 2013 VL 6 AR 11 DI 10.1186/1755-8794-6-11 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 124MK UT WOS:000317468300001 PM 23537212 ER PT J AU Klein, F Diskin, R Scheid, JF Gaebler, C Mouquet, H Georgiev, IS Pancera, M Zhou, TQ Incesu, RB Fu, BZ Gnanapragasam, PNP Oliveira, TY Seaman, MS Kwong, PD Bjorkman, PJ Nussenzweig, MC AF Klein, Florian Diskin, Ron Scheid, Johannes F. Gaebler, Christian Mouquet, Hugo Georgiev, Ivelin S. Pancera, Marie Zhou, Tongqing Incesu, Reha-Baris Fu, Brooks Zhongzheng Gnanapragasam, Priyanthi N. P. Oliveira, Thiago Y. Seaman, Michael S. Kwong, Peter D. Bjorkman, Pamela J. Nussenzweig, Michel C. TI Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization SO CELL LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; MEMORY B-CELLS; CHIMERIC VIRUS; 3-DIMENSIONAL STRUCTURE; RATIONAL DESIGN; DOMAIN EXCHANGE; CD4 BINDING; ANTIGEN; EPITOPE AB Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generated by a fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen. The CDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and less tolerant of mutations. Here, we report that in contrast to most antibodies, including those with limited HIV-1 neutralizing activity, most bNAbs require somatic mutations in their FWRs. Structural and functional analyses reveal that somatic mutations in FWR residues enhance breadth and potency by providing increased flexibility and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential role beyond scaffolding the CDR loops and their unusual contribution to potency and breadth should be considered in HIV-1 vaccine design. C1 [Klein, Florian; Scheid, Johannes F.; Gaebler, Christian; Mouquet, Hugo; Incesu, Reha-Baris; Oliveira, Thiago Y.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Diskin, Ron; Fu, Brooks Zhongzheng; Gnanapragasam, Priyanthi N. P.; Bjorkman, Pamela J.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Bjorkman, Pamela J.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. [Diskin, Ron] Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel. [Scheid, Johannes F.] Charite, D-10117 Berlin, Germany. [Gaebler, Christian] Tech Univ Dresden, Fac Med Carl Gustav Carus, D-01307 Dresden, Germany. [Georgiev, Ivelin S.; Pancera, Marie; Zhou, Tongqing; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Incesu, Reha-Baris] Univ Klinikum Hamburg Eppendorf, D-20246 Hamburg, Germany. [Oliveira, Thiago Y.] Univ Sao Paulo, Dept Genet, Med Sch Ribeirao Preto, Natl Inst Sci & Technol Stem Cells & Cell Therapy, BR-14051140 Ribeirao Preto, SP, Brazil. [Oliveira, Thiago Y.] Ctr Cell Based Therapy, BR-14051140 Ribeirao Preto, SP, Brazil. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@rockefeller.edu RI Zhou, Tongqing/A-6880-2010; Mouquet, Hugo/M-2750-2014; OI Zhou, Tongqing/0000-0002-3935-4637; Oliveira, Thiago/0000-0002-2654-0879 FU German Research Foundation (DFG) [KL 2389/1-1]; Stavros Niarchos Foundation; Robert Mapplethorpe Foundation; German National Academic Foundation; Vaccine Research Center, NIAID, NIH; Bill and Melinda Gates Foundation [1032144, 38660, OPP1033115]; CHAVI-ID Award [UM1AI100663]; NIH grant [AI081677] FX We thank Louise Scharf for her help on generating structural images and Kai-Hui Yao for technical assistance. We thank Paola Marchovecchio and Han Gan for preparation of 3BNC60P61A as well as the members of the Nussenzweig and Bjorkman laboratory for helpful discussions. We also thank R. Wyatt for the YU2-gp140 plasmid; Davide Corti and Antonio Lanzavecchia for the HJ16 plasmids, and Francine McCutchan, Beatrice Hahn, David Montefiori, Michael Thomson, Ronald Swanstrom, Lynn Morris, Jerome Kim, Linqi Zhang, Dennis Ellenberger, and Carolyn Williamson for contributing HIV-1 envelope plasmids used in neutralization assays. F.K. was supported by the German Research Foundation (DFG, KL 2389/1-1), the Stavros Niarchos Foundation and the Robert Mapplethorpe Foundation. C.G. and R.-B.I. were supported by The German National Academic Foundation. I.G., M.P., T.Z., and P.D.K. were supported by intramural funding to the Vaccine Research Center, NIAID, NIH. M.S.S., P.J.B., and M.C.N. were supported by the Bill and Melinda Gates Foundation (M.S.S., Comprehensive Antibody Vaccine Immune Monitoring Consortium grant 1032144; P.J.B. and M.C.N., Collaboration for AIDS Vaccine Discovery grants 38660 [P.J.B.] and OPP1033115 [M.C.N.]). M.C.N is supported by the CHAVI-ID Award UM1AI100663 and The NIH grant AI081677. M.C.N. and P.J.B. are HHMI investigators. NR 62 TC 159 Z9 160 U1 2 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 28 PY 2013 VL 153 IS 1 BP 126 EP 138 DI 10.1016/j.cell.2013.03.018 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 116AI UT WOS:000316853700011 PM 23540694 ER PT J AU Hou, YJ Zhao, YY Xiong, B Cui, XS Kim, NH Xu, YX Sun, SC AF Hou, Yan-Jun Zhao, Yong-Yan Xiong, Bo Cui, Xiang-Shun Kim, Nam-Hyung Xu, Yin-Xue Sun, Shao-Chen TI Mycotoxin-Containing Diet Causes Oxidative Stress in the Mouse SO PLOS ONE LA English DT Article ID BLOOD PHAGOCYTIC-ACTIVITY; DEOXYNIVALENOL VOMITOXIN; SUPEROXIDE-DISMUTASE; BALB/C MICE; ZEARALENONE; ANTIOXIDANTS; RATS; CHICKENS; TOXICITY; BROILERS AB Mycotoxins which mainly consist of Aflatoxin (AF), Zearalenone (ZEN) and Deoxynivalenol (DON) are commonly found in many food commodities. Although each component has been shown to cause liver toxicity and oxidative stress in several species, there is no evidence regarding the effect of naturally contained multiple mycotoxins on tissue toxicity and oxidative stress in vivo. In the present study, mycotoxins-contaminated maize (AF 597 mu g/kg, ZEN 729 mu g/kg, DON 3.1 mg/kg maize) was incorporated into the diet at three different doses (0, 5 and 20%) to feed the mice, and blood and tissue samples were collected to examine the oxidative stress related indexes. The results showed that the indexes of liver, kidney and spleen were all increased and the liver and kidney morphologies changed in the mycotoxin-treated mice. Also, the treatment resulted in the elevated glutathione peroxidase (GPx) activity and malondialdehyde (MDA) level in the serum and liver, indicating the presence of the oxidative stress. Moreover, the decrease of catalase (CAT) activity in the serum, liver and kidney as well as superoxide dismutase (SOD) activity in the liver and kidney tissue further confirmed the occurrence of oxidative stress. In conclusion, our data indicate that the naturally contained mycotoxins are toxic in vivo and able to induce the oxidant stress in the mouse. C1 [Hou, Yan-Jun; Zhao, Yong-Yan; Xu, Yin-Xue; Sun, Shao-Chen] Nanjing Agr Univ, Coll Anim Sci & Technol, Nanjing, Jiangsu, Peoples R China. [Xiong, Bo] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Cui, Xiang-Shun; Kim, Nam-Hyung] Chungbuk Natl Univ, Dept Anim Sci, Cheongju, South Korea. RP Xu, YX (reprint author), Nanjing Agr Univ, Coll Anim Sci & Technol, Nanjing, Jiangsu, Peoples R China. EM xuyinxue@njau.edu.cn; sunsc@njau.edu.cn FU Fundamental Research Funds for the Central Universities [KYRC201202]; Biogreen 21 Program, RDA, Republic of Korea [PJ0090802013, PJ0090982013] FX This work was supported by the Fundamental Research Funds for the Central Universities (KYRC201202); and the Biogreen 21 Program (PJ0090802013, PJ0090982013), RDA, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 22 Z9 22 U1 3 U2 37 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 MAR 28 PY 2013 VL 8 IS 3 AR e60374 DI 10.1371/journal.pone.0060374 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 121RP UT WOS:000317262200111 PM 23555961 ER PT J AU Kulkarni, V Rosati, M Valentin, A Ganneru, B Singh, AK Yan, J Rolland, M Alicea, C Beach, RK Zhang, GM Le Gall, S Broderick, KE Sardesai, NY Heckerman, D Mothe, B Brander, C Weiner, DB Mullins, JI Pavlakis, GN Felber, BK AF Kulkarni, Viraj Rosati, Margherita Valentin, Antonio Ganneru, Brunda Singh, Ashish K. Yan, Jian Rolland, Morgane Alicea, Candido Beach, Rachel Kelly Zhang, Gen-Mu Le Gall, Sylvie Broderick, Kate E. Sardesai, Niranjan Y. Heckerman, David Mothe, Beatriz Brander, Christian Weiner, David B. Mullins, James I. Pavlakis, George N. Felber, Barbara K. TI HIV-1 p24(gag) Derived Conserved Element DNA Vaccine Increases the Breadth of Immune Response in Mice SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; VIRAL REPLICATION CAPACITY; LYMPHOCYTE RESPONSES; EPITOPE PRESENTATION; DISEASE PROGRESSION; MEMBRANE PROTEIN-1; ESCAPE MUTATIONS; TYPE-1 PROTEINS; RHESUS-MONKEYS AB Viral diversity is considered a major impediment to the development of an effective HIV-1 vaccine. Despite this diversity, certain protein segments are nearly invariant across the known HIV-1 Group M sequences. We developed immunogens based on the highly conserved elements from the p24(gag) region according to two principles: the immunogen must (i) include strictly conserved elements of the virus that cannot mutate readily, and (ii) exclude both HIV regions capable of mutating without limiting virus viability, and also immunodominant epitopes located in variable regions. We engineered two HIV-1 p24(gag) DNA immunogens that express 7 highly Conserved Elements (CE) of 12-24 amino acids in length and differ by only 1 amino acid in each CE ('toggle site'), together covering >99% of the HIV-1 Group M sequences. Altering intracellular trafficking of the immunogens changed protein localization, stability, and also the nature of elicited immune responses. Immunization of C57BL/6 mice with p55(gag) DNA induced poor, CD4(+) mediated cellular responses, to only 2 of the 7 CE; in contrast, vaccination with p24CE DNA induced cross-clade reactive, robust T cell responses to 4 of the 7 CE. The responses were multifunctional and composed of both CD4(+) and CD8(+) T cells with mature cytotoxic phenotype. These findings provide a method to increase immune response to universally conserved Gag epitopes, using the p24CE immunogen. p24CE DNA vaccination induced humoral immune responses similar in magnitude to those induced by p55(gag), which recognize the virus encoded p24(gag) protein. The inclusion of DNA immunogens composed of conserved elements is a promising vaccine strategy to induce broader immunity by CD4(+) and CD8(+) T cells to additional regions of Gag compared to vaccination with p55(gag) DNA, achieving maximal cross-clade reactive cellular and humoral responses. C1 [Kulkarni, Viraj; Alicea, Candido; Beach, Rachel Kelly; Zhang, Gen-Mu; Felber, Barbara K.] Frederick Natl Lab Canc Res, Human Retrovirus Pathogenesis Sect, Ctr Canc Res, Frederick, MD USA. [Rosati, Margherita; Valentin, Antonio; Ganneru, Brunda; Singh, Ashish K.; Beach, Rachel Kelly; Zhang, Gen-Mu; Pavlakis, George N.] Frederick Natl Lab Canc Res, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD USA. [Yan, Jian; Weiner, David B.] Univ Penn, Philadelphia, PA 19104 USA. [Rolland, Morgane; Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Rolland, Morgane; Mullins, James I.] Univ Washington, Dept Med, Seattle, WA USA. [Rolland, Morgane; Mullins, James I.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Le Gall, Sylvie] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Broderick, Kate E.; Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue Bell, PA USA. [Heckerman, David] Microsoft Res, Redmond, WA USA. [Mothe, Beatriz; Brander, Christian] Autonomous Univ Barcelona, IrsiCaixa AIDS Res Inst HIVACAT, Barcelona, Spain. [Brander, Christian] ICREA, Barcelona, Spain. RP Pavlakis, GN (reprint author), Frederick Natl Lab Canc Res, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD USA. EM pavlakig@mail.nih.gov; felberb@mail.nih.gov RI Weiner, David/H-8579-2014; bebarta, vikhyat/K-3476-2015; OI Brander, Christian/0000-0002-0548-5778 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH); Bill and Melinda Gates Foundation; Red de Investigacion de Sida (RIS) [RD06/04]; Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Spanish FIPSE [36-0737-09] FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH). This work was funded by Bill and Melinda Gates Foundation and was supported in part by the Red de Investigacion de Sida (RIS) (RD06/04), Instituto de Salud Carlos III (ISCIII), Madrid, Spain and the Spanish FIPSE 36-0737-09. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 14 Z9 15 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 MAR 28 PY 2013 VL 8 IS 3 AR e60245 DI 10.1371/journal.pone.0060245 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 121RP UT WOS:000317262200102 PM 23555935 ER PT J AU Miura, K Diakite, M Diouf, A Doumbia, S Konate, D Keita, AS Moretz, SE Tullo, G Zhou, H Lopera-Mesa, TM Anderson, JM Fairhurst, RM Long, CA AF Miura, Kazutoyo Diakite, Mahamadou Diouf, Ababacar Doumbia, Saibou Konate, Drissa Keita, Abdoul S. Moretz, Samuel E. Tullo, Gregory Zhou, Hong Lopera-Mesa, Tatiana M. Anderson, Jennifer M. Fairhurst, Rick M. Long, Carole A. TI Relationship between Malaria Incidence and IgG Levels to Plasmodium falciparum Merozoite Antigens in Malian Children: Impact of Hemoglobins S and C SO PLOS ONE LA English DT Article ID SICKLE-CELL TRAIT; APICAL MEMBRANE ANTIGEN-1; ANTIBODY-RESPONSES; IMMUNE-RESPONSES; IMMUNOGLOBULIN-G; IN-VITRO; INFECTED ERYTHROCYTES; ACQUIRED-IMMUNITY; SURFACE PROTEIN-1; VACCINE AB Heterozygous hemoglobin (Hb) AS (sickle-cell trait) and HbAC are hypothesized to protect against Plasmodium falciparum malaria in part by enhancing naturally-acquired immunity to this disease. To investigate this hypothesis, we compared antibody levels to four merozoite antigens from the P. falciparum 3D7 clone (apical membrane antigen 1, AMA1-3D7; merozoite surface protein 1, MSP1-3D7; 175 kDa erythrocyte-binding antigen, EBA175-3D7; and merozoite surface protein 2, MSP2-3D7) in a cohort of 103 HbAA, 73 HbAS and 30 HbAC children aged 3 to 11 years in a malaria-endemic area of Mali. In the 2009 transmission season we found that HbAS, but not HbAC, significantly reduced the risk of malaria compared to HbAA. IgG levels to MSP1 and MSP2 at the start of this transmission season inversely correlated with malaria incidence after adjusting for age and Hb type. However, HbAS children had significantly lower IgG levels to EBA175 and MSP2 compared to HbAA children. On the other hand, HbAC children had similar IgG levels to all four antigens. The parasite growth-inhibitory activity of purified IgG samples did not differ significantly by Hb type. Changes in antigen-specific IgG levels during the 2009 transmission and 2010 dry seasons also did not differ by Hb type, and none of these IgG levels dropped significantly during the dry season. These data suggest that sickle-cell trait does not reduce the risk of malaria by enhancing the acquisition of IgG responses to merozoite antigens. C1 [Miura, Kazutoyo; Diouf, Ababacar; Moretz, Samuel E.; Tullo, Gregory; Zhou, Hong; Lopera-Mesa, Tatiana M.; Anderson, Jennifer M.; Fairhurst, Rick M.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Diakite, Mahamadou; Doumbia, Saibou; Konate, Drissa; Keita, Abdoul S.] Univ Bamako, Fac Med Pharm & Odontostomatol, Bamako, Mali. RP Miura, K (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM kmiura@niaid.nih.gov; clong@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases/NIH; PATH/Malaria Vaccine Initiative FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases/NIH. The GIA Reference Center was supported by the PATH/Malaria Vaccine Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 4 Z9 4 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 MAR 28 PY 2013 VL 8 IS 3 AR e60182 DI 10.1371/journal.pone.0060182 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 121RP UT WOS:000317262200093 PM 23555917 ER PT J AU Shimada, M Abe, S Takahashi, T Shiozaki, K Okuda, M Mizukami, H Klinman, DM Ozawa, K Okuda, K AF Shimada, Masaru Abe, Shinya Takahashi, Toru Shiozaki, Kazumasa Okuda, Mitsue Mizukami, Hiroaki Klinman, Dennis M. Ozawa, Keiya Okuda, Kenji TI Prophylaxis and Treatment of Alzheimer's Disease by Delivery of an Adeno-Associated Virus Encoding a Monoclonal Antibody Targeting the Amyloid Beta Protein SO PLOS ONE LA English DT Article ID PHASE-I TRIAL; TRANSGENIC MICE; MOUSE MODEL; A-BETA(42) IMMUNIZATION; IMMUNE-RESPONSE; MEMORY DEFICITS; SKELETAL-MUSCLE; BRAIN DELIVERY; GENE DELIVERY; VIRAL VECTOR AB We previously reported on a monoclonal antibody (mAb) that targeted amyloid beta (A beta) protein. Repeated injection of that mAb reduced the accumulation of A beta protein in the brain of human A beta transgenic mice (Tg2576). In the present study, cDNA encoding the heavy and light chains of this mAb were subcloned into an adeno-associated virus type 1 (AAV) vector with a 2A/furin adapter. A single intramuscular injection of 3.0x10(10) viral genome of these AAV vectors into C57BL/6 mice generated serum anti-A beta Ab levels up to 0.3 mg/ml. Anti-A beta Ab levels in excess of 0.1 mg/ml were maintained for up to 64 weeks. The effect of AAV administration on A beta levels in vivo was examined. A significant decrease in A beta levels in the brain of Tg2576 mice treated at 5 months (prophylactic) or 10 months (therapeutic) of age was observed. These results support the use of AAV vector encoding anti-A beta Ab for the prevention and treatment of Alzheimer's disease. C1 [Shimada, Masaru; Abe, Shinya; Takahashi, Toru; Okuda, Kenji] Yokohama City Univ, Dept Mol Biodef Res, Yokohama, Kanagawa 232, Japan. [Shiozaki, Kazumasa] Yokohama City Univ, Dept Psychiat, Yokohama, Kanagawa 232, Japan. [Okuda, Mitsue] Okuda Dent Clin, Yokohama, Kanagawa, Japan. [Mizukami, Hiroaki; Ozawa, Keiya] Jichi Med Sch, Ctr Mol Med, Div Genet Therapeut, Mibu, Tochigi, Japan. [Klinman, Dennis M.] NCI, Expt Immunol Lab, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. RP Okuda, K (reprint author), Yokohama City Univ, Dept Mol Biodef Res, Yokohama, Kanagawa 232, Japan. EM kokuda@chojuken.net RI Mizukami, Hiroaki/D-7674-2013 OI Mizukami, Hiroaki/0000-0001-8954-874X FU Ministry of Education, Science, Sports, Culture of Japan; Ministry of Health and Welfare of Japan FX This work was supported in part by a grant-in-aid for the Ministry of Education, Science, Sports, Culture of Japan, and the Ministry of Health and Welfare of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 7 Z9 7 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 28 PY 2013 VL 8 IS 3 AR e57606 DI 10.1371/journal.pone.0057606 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 121RP UT WOS:000317262200002 PM 23555563 ER PT J AU Harding, J Roberts, RM Mirochnitchenko, O AF Harding, John Roberts, R. Michael Mirochnitchenko, Oleg TI Large animal models for stem cell therapy SO STEM CELL RESEARCH & THERAPY LA English DT Review ID IN-UTERO TRANSPLANTATION; MPTP-TREATED MONKEYS; TYROSINE-HYDROXYLASE; DOPAMINERGIC-NEURONS; ADIPOSE-TISSUE; PIGS; VIVO; XENOTRANSPLANTATION; ENGRAFTMENT; DISEASE AB The field of regenerative medicine is approaching translation to clinical practice, and significant safety concerns and knowledge gaps have become clear as clinical practitioners are considering the potential risks and benefits of cell-based therapy. It is necessary to understand the full spectrum of stem cell actions and preclinical evidence for safety and therapeutic efficacy. The role of animal models for gaining this information has increased substantially. There is an urgent need for novel animal models to expand the range of current studies, most of which have been conducted in rodents. Extant models are providing important information but have limitations for a variety of disease categories and can have different size and physiology relative to humans. These differences can preclude the ability to reproduce the results of animal-based preclinical studies in human trials. Larger animal species, such as rabbits, dogs, pigs, sheep, goats, and non-human primates, are better predictors of responses in humans than are rodents, but in each case it will be necessary to choose the best model for a specific application. There is a wide spectrum of potential stem cell-based products that can be used for regenerative medicine, including embryonic and induced pluripotent stem cells, somatic stem cells, and differentiated cellular progeny. The state of knowledge and availability of these cells from large animals vary among species. In most cases, significant effort is required for establishing and characterizing cell lines, comparing behavior to human analogs, and testing potential applications. Stem cell-based therapies present significant safety challenges, which cannot be addressed by traditional procedures and require the development of new protocols and test systems, for which the rigorous use of larger animal species more closely resembling human behavior will be required. In this article, we discuss the current status and challenges of and several major directions for the future development of large animal models to facilitate advances in stem cell-based regenerative medicine. C1 [Harding, John; Mirochnitchenko, Oleg] NIH, Div Comparat Medicine ORIP DPCPSI OD, Bethesda, MD 20892 USA. [Roberts, R. Michael] Univ Missouri, CS Bond Life Sci Ctr 240B, Div Anim Sci, Columbia, MO 65211 USA. RP Mirochnitchenko, O (reprint author), NIH, Div Comparat Medicine ORIP DPCPSI OD, 6701 Democracy Blvd,Suite 943-950, Bethesda, MD 20892 USA. EM oleg.mirochnitchenko@nih.gov FU National Institutes of Health [R01HD069979] FX This work was supported by National Institutes of Health grant R01HD069979 (RMR). The views and opinions expressed in this article do not necessarily represent those of the National Institutes of Health. NR 50 TC 29 Z9 30 U1 4 U2 34 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD MAR 28 PY 2013 VL 4 AR 23 DI 10.1186/scrt171 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 122OY UT WOS:000317328600001 PM 23672797 ER PT J AU Vytal, KE Cornwell, BR Letkiewicz, AM Arkin, NE Grillon, C AF Vytal, Katherine E. Cornwell, Brian R. Letkiewicz, Allison M. Arkin, Nicole E. Grillon, Christian TI The complex interaction between anxiety and cognition: insight from spatial and verbal working memory SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE anxiety; working memory; cognition; startle; electromyography; performance ID OBSESSIVE-COMPULSIVE DISORDER; REGIONAL BRAIN ACTIVITY; THREAT-EVOKED ANXIETY; PANIC DISORDER; PREFRONTAL CORTEX; TASK-PERFORMANCE; NEGATIVE EMOTION; FUNCTIONAL MRI; AMYGDALA; WORRY AB Anxiety can be distracting, disruptive, and incapacitating. Despite problems with empirical replication of this phenomenon, one fruitful avenue of study has emerged from working memory (WM) experiments where a translational method of anxiety induction (risk of shock) has been shown to disrupt spatial and verbal WM performance. Performance declines when resources (e.g., spatial attention, executive function) devoted to goal-directed behaviors are consumed by anxiety. Importantly, it has been shown that anxiety-related impairments in verbal WM depend on task difficulty, suggesting that cognitive load may be an important consideration in the interaction between anxiety and cognition. Here we use both spatial and verbal WM paradigms to probe the effect of cognitive load on anxiety-induced WM impairment across task modality. Subjects performed a series of spatial and verbal n-back tasks of increasing difficulty (1, 2, and 3-back) while they were safe or at risk for shock. Startle reflex was used to probe anxiety. Results demonstrate that induced-anxiety differentially impacts verbal and spatial WM, such that low and medium-load verbal WM is more susceptible to anxiety-related disruption relative to high-load, and spatial WM is disrupted regardless of task difficulty. Anxiety impacts both verbal and spatial processes, as described by correlations between anxiety and performance impairment, albeit the effect on spatial WM is consistent across load. Demanding WM tasks may exert top-down control over higher-order cortical resources engaged by anxious apprehension, however high-load spatial WM may continue to experience additional competition from anxiety-related changes in spatial attention, resulting in impaired performance. By describing this disruption across task modalities, these findings inform current theories of emotion-cognition interactions and may facilitate development of clinical interventions that seek to target cognitive impairments associated with anxiety. C1 [Vytal, Katherine E.; Letkiewicz, Allison M.; Arkin, Nicole E.; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Cornwell, Brian R.] Swinburne Univ Technol, Fac Life & Social Sci, Hawthorn, Vic 3122, Australia. RP Vytal, KE (reprint author), NIMH, 15K North Dr, Bethesda, MD 20892 USA. EM katye.vytal@nih.gov FU National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health. NR 64 TC 18 Z9 18 U1 8 U2 84 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD MAR 28 PY 2013 VL 7 AR 93 DI 10.3389/fnhum.2013.00093 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 114FN UT WOS:000316726600001 PM 23542914 ER PT J AU Neres, J Engelhart, CA Drake, EJ Wilson, DJ Fu, P Boshoff, HI Barry, CE Gulick, AM Aldrich, CC AF Neres, Joao Engelhart, Curtis A. Drake, Eric J. Wilson, Daniel J. Fu, Peng Boshoff, Helena I. Barry, Clifton E., III Gulick, Andrew M. Aldrich, Courtney C. TI Non-Nucleoside Inhibitors of BasE, an Adenylating Enzyme in the Siderophore Biosynthetic Pathway of the Opportunistic Pathogen Acinetobacter baumannii SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IRON ACQUISITION FUNCTIONS; MYCOBACTERIUM-TUBERCULOSIS; FLUORESCENCE POLARIZATION; ASSEMBLY-LINE; ANTIBIOTICS; VIRULENCE; IDENTIFICATION; INFECTIONS; RESISTANCE; GENES AB Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high-throughput screening against BasE, which is involved in siderophore biosynthesis in A. baumannii, and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a K-D of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveals that they bind in a unique orientation in the active site, occupying all three substrate binding sites, and thus can be considered as multisubstrate inhibitors. These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity. C1 [Neres, Joao; Engelhart, Curtis A.; Wilson, Daniel J.; Fu, Peng; Aldrich, Courtney C.] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. [Engelhart, Curtis A.] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. [Drake, Eric J.; Gulick, Andrew M.] SUNY Buffalo, Hauptman Woodward Inst, Buffalo, NY 14203 USA. [Drake, Eric J.; Gulick, Andrew M.] SUNY Buffalo, Dept Biol Struct, Buffalo, NY 14203 USA. [Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Sect, Bethesda, MD 20892 USA. RP Aldrich, CC (reprint author), Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. EM aldri015@umn.edu RI Barry, III, Clifton/H-3839-2012; Neres, Joao/A-1241-2011 OI Neres, Joao/0000-0003-4488-2423 FU National Institutes of Health [AI070219, GM-068440]; Intramural Research Program of the NIAID in the National Institutes of Health FX This research was supported by grants from the National Institutes of Health (Grant AI070219 to C.C.A. and Grant GM-068440 to A.M.G.) and the Intramural Research Program of the NIAID in the National Institutes of Health (to C.E.B.). We thank Dr. Michael Walters (Institute for Therapeutics Discovery and Development, University of Minnesota) for assistance with the parallel synthesis and Prof. David H. Sherman (Life Sciences Institute, University of Michigan) for plasmids pUC18 and pKC1139. NR 65 TC 10 Z9 10 U1 0 U2 14 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 MAR 28 PY 2013 VL 56 IS 6 BP 2385 EP 2405 DI 10.1021/jm301709s PG 21 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 118NM UT WOS:000317032200018 PM 23437866 ER PT J AU Sassano, MF Doak, AK Roth, BL Shoichet, BK AF Sassano, Maria F. Doak, Allison K. Roth, Bryan L. Shoichet, Brian K. TI Colloidal Aggregation Causes Inhibition of G Protein-Coupled Receptors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGH-THROUGHPUT; PROMISCUOUS INHIBITORS; ORAL BIOAVAILABILITY; FALSE POSITIVES; SMALL MOLECULES; IN-VITRO; IDENTIFICATION; ACTIVATION; DISCOVERY; CELLS AB Colloidal aggregation is the dominant mechanism for artifactual inhibition of soluble proteins, and controls against it are now widely deployed. Conversely, investigating this mechanism for membrane-bound receptors has proven difficult. Here we investigate the activity of four well-characterized aggregators against three G protein-coupled receptors (GPCRs) recognizing peptide and protein ligands. Each of the aggregators was active at micromolar concentrations against the three GPCRs in cell-based assays. This activity could be attenuated by either centrifugation of the inhibitor stock solution or by addition of Tween-80 detergent. In the absence of agonist, the aggregators acted as inverse agonists, consistent with a direct receptor interaction. Meanwhile, several literature GPCR ligands that resemble aggregators themselves formed colloids, by both physical and enzymological tests. These observations suggest that some GPCRs may be artifactually antagonized by colloidal aggregates, an effect that merits the attention of investigators in this field. C1 [Sassano, Maria F.; Roth, Bryan L.] Univ North Carolina Chapel Hill Sch Med, Dept Pharmacol, Chapel Hill, NC 27759 USA. [Sassano, Maria F.; Roth, Bryan L.] Univ North Carolina Chapel Hill Sch Med, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27759 USA. [Doak, Allison K.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. RP Roth, BL (reprint author), Univ North Carolina Chapel Hill Sch Med, Dept Pharmacol, Chapel Hill, NC 27759 USA. EM bryan_roth@med.unc.edu; bshoichet@gmail.com RI sassano, maria/G-4941-2013; Roth, Bryan/F-3928-2010 FU NIH [GM71630]; Michael Hooker Chair of Protein Therapeutics and Translational Proteomics, the NIMH Psychoactive Drug Screening Program [U19MH82441] FX Supported by NIH grants GM71630 (to BKS) and by the Michael Hooker Chair of Protein Therapeutics and Translational Proteomics, the NIMH Psychoactive Drug Screening Program and U19MH82441 (to BLR). We thank J. Karpiak and R. Coleman for reading this manuscript and R. Coleman for the Table of Contents graphic. NR 52 TC 39 Z9 39 U1 1 U2 19 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 MAR 28 PY 2013 VL 56 IS 6 BP 2406 EP 2414 DI 10.1021/jm301749y PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 118NM UT WOS:000317032200019 PM 23437772 ER PT J AU Romagnoli, R Baraldi, PG Salvador, MK Preti, D Tabrizi, MA Bassetto, M Brancale, A Hamel, E Castagliuolo, I Bortolozzi, R Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Salvador, Maria Kimatrai Preti, Delia Tabrizi, Mojgan Aghazadeh Bassetto, Marcella Brancale, Andrea Hamel, Ernest Castagliuolo, Ignazio Bortolozzi, Roberta Basso, Giuseppe Viola, Giampietro TI Synthesis and Biological Evaluation of 2-(Alkoxycarbonyl)-3-Anilinobenzo[b]thiophenes and Thieno[2,3-b]pyridines as New Potent Anticancer Agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TUBULIN-BINDING AGENTS; CELL-DEATH; MICROTUBULE INHIBITORS; ANTIMITOTIC AGENTS; NATURAL-PRODUCTS; DRUG-RESISTANCE; APOPTOSIS; COLCHICINE; CANCER; POLYMERIZATION AB Two new series of inhibitors of tubulin polymerization based on the 2-(alkoxycarbonyl)-3-(3',4',5'-trimethoxyanilino)benzo[b]thiophene and thieno[2,3-b]pyridine molecular skeletons were synthesized and evaluated for antiproliferative activity on a panel of cancer cell lines, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. Antiproliferative activity was strongly dependent on the position of the methyl group on the benzene portion of the benzo[b]thiophene nucleus, with the greatest activity observed when the methyl was located at the C-6 position. Also, in the smaller thieno[2,3-b]pyridine series, the introduction of the methyl group at the C-6 position resulted in improvement of antiproliferative activity to the nanomolar level. The most active compounds (4i and 4n) did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. Compound 4i significantly inhibited in vivo the growth of a syngeneic hepatocellular carcinoma in Balb/c mice. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Bassetto, Marcella; Brancale, Andrea] Univ Ferrara, Dipartimento Sci Farmaceut, I-44121 Ferrara, Italy. [Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Bassetto, Marcella; Brancale, Andrea] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Castagliuolo, Ignazio] Univ Padua, Dipartimento Med Mol, I-35121 Padua, Italy. [Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dipartimento Salute Donna & Bambino, Lab Oncoematol, I-35128 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44121 Ferrara, Italy. EM rmr@unife.it; pgb@unife.it; giampietro.viola1@unipd.it RI Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; CASTAGLIUOLO, IGNAZIO/K-9963-2016; Viola, Giampietro/I-4095-2012; Aghazadeh Tabrizi, Mojgan/I-9169-2014; Brancale, Andrea/N-9445-2014; Bortolozzi, Roberta/D-4950-2015; preti, delia/G-9916-2015 OI CASTAGLIUOLO, IGNAZIO/0000-0001-9888-7030; Bassetto, Marcella/0000-0002-2491-5868; BASSO, GIUSEPPE/0000-0002-2634-9302; Viola, Giampietro/0000-0001-9329-165X; Brancale, Andrea/0000-0002-9728-3419; Bortolozzi, Roberta/0000-0002-3357-4815; preti, delia/0000-0002-1075-3781 FU Intramural NIH HHS [Z99 CA999999] NR 60 TC 32 Z9 32 U1 3 U2 42 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 MAR 28 PY 2013 VL 56 IS 6 BP 2606 EP 2618 DI 10.1021/jm400043d PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 118NM UT WOS:000317032200035 PM 23445496 ER PT J AU Kim, HJ Kim, NC Wang, YD Scarborough, EA Moore, J Diaz, Z MacLea, KS Freibaum, B Li, SQ Molliex, A Kanagaraj, AP Carter, R Boylan, KB Wojtas, AM Rademakers, R Pinkus, JL Greenberg, SA Trojanowski, JQ Traynor, BJ Smith, BN Topp, S Gkazi, AS Miller, J Shaw, CE Kottlors, M Kirschner, J Pestronk, A Li, YR Ford, AF Gitler, AD Benatar, M King, OD Kimonis, VE Ross, ED Weihl, CC Shorter, J Taylor, JP AF Kim, Hong Joo Kim, Nam Chul Wang, Yong-Dong Scarborough, Emily A. Moore, Jennifer Diaz, Zamia MacLea, Kyle S. Freibaum, Brian Li, Songqing Molliex, Amandine Kanagaraj, Anderson P. Carter, Robert Boylan, Kevin B. Wojtas, Aleksandra M. Rademakers, Rosa Pinkus, Jack L. Greenberg, Steven A. Trojanowski, John Q. Traynor, Bryan J. Smith, Bradley N. Topp, Simon Gkazi, Athina-Soragia Miller, Jack Shaw, Christopher E. Kottlors, Michael Kirschner, Janbernd Pestronk, Alan Li, Yun R. Ford, Alice Flynn Gitler, Aaron D. Benatar, Michael King, Oliver D. Kimonis, Virginia E. Ross, Eric D. Weihl, Conrad C. Shorter, James Taylor, J. Paul TI Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS SO NATURE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; RNA-BINDING PROTEINS; DROSOPHILA MODEL; SACCHAROMYCES-CEREVISIAE; FRONTOTEMPORAL DEMENTIA; MULTIPLE ALIGNMENT; STRESS GRANULES; VCP MUTATIONS; TDP-43; DISEASE AB Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone. C1 [Kim, Hong Joo; Kim, Nam Chul; Moore, Jennifer; Freibaum, Brian; Li, Songqing; Molliex, Amandine; Kanagaraj, Anderson P.; Taylor, J. Paul] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38120 USA. [Wang, Yong-Dong] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38120 USA. [Scarborough, Emily A.; Diaz, Zamia; Ford, Alice Flynn; Shorter, James] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA 19104 USA. [MacLea, Kyle S.; Ross, Eric D.] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Carter, Robert] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38120 USA. [Boylan, Kevin B.; Wojtas, Aleksandra M.; Rademakers, Rosa] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Pinkus, Jack L.; Greenberg, Steven A.] Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Sch Med, Boston, MA 02115 USA. [Trojanowski, John Q.; Smith, Bradley N.] Univ Penn, Dept Pathol & Lab Med, Inst Aging, Philadelphia, PA 19104 USA. [Trojanowski, John Q.; Smith, Bradley N.] Univ Penn, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Philadelphia, PA 19104 USA. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Topp, Simon; Gkazi, Athina-Soragia; Miller, Jack; Shaw, Christopher E.] Kings Coll London, Ctr Neurodegenerat Res, Dept Clin Neurosci, Inst Psychiat, London SE5 8AF, England. [Kottlors, Michael; Kirschner, Janbernd] Univ Childrens Hosp Freiburg, Div Neuropediat & Muscle Disorders, D-79106 Freiburg, Germany. [Pestronk, Alan; Weihl, Conrad C.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Li, Yun R.] Univ Penn, Med Sci Training Program, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gitler, Aaron D.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Benatar, Michael] Univ Miami, Neurol Dept, Miller Sch Med, Miami, FL 33136 USA. [King, Oliver D.] Boston Biomed Res Inst, Watertown, MA 02472 USA. [Kimonis, Virginia E.] Univ Calif Irvine, Dept Pediat, Div Genet & Metab, Irvine, CA 92696 USA. RP Taylor, JP (reprint author), St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38120 USA. EM jshorter@mail.med.upenn.edu; JPaul.Taylor@STJUDE.ORG RI Traynor, Bryan/G-5690-2010; Smith, Bradley/H-6107-2013; Wang, Yong-Dong/K-3563-2013; Kirschner, Janbernd/H-7418-2016; OI Kirschner, Janbernd/0000-0003-1618-7386; topp, simon/0000-0002-5200-3284; Ross, Eric/0000-0002-6473-9977 FU ALSAC; Packard Foundation; National Institutes of Health (NIH) [NS053825]; ALS Association; NIH [AG032953, DP2OD002177, NS067354, AG031867]; Ellison Medical Foundation; National Science Foundation [MCB-1023771] FX We thank the patients whose participation made this work possible. We thank the St Jude Pediatric Cancer Genome Project and J. Zhang in particular for providing access to control sequencing data. We thank C. Gellera, B. Baloh, M. Harms, S. Krause, G. Dreyfuss and T. Cundy for sharing reagents. We thank S. Donkervoort and S. Mumm for coordinating samples, and A. Taylor for editorial assistance. J.P.T. was supported by ALSAC, the Packard Foundation and the National Institutes of Health (NIH) (NS053825); J.P.T. and M. B. were supported by the ALS Association; J.Q.T. was supported by the NIH (AG032953); J.S. was supported by the NIH (DP2OD002177 and NS067354) and the Ellison Medical Foundation; E. D. R. was supported by the National Science Foundation (MCB-1023771). C. C. W. was supported by the NIH (AG031867). NR 37 TC 320 Z9 329 U1 106 U2 204 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 28 PY 2013 VL 495 IS 7442 BP 467 EP + DI 10.1038/nature11922 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 113QN UT WOS:000316682800037 PM 23455423 ER PT J AU Lurie, N Manolio, T Patterson, AP Collins, F Frieden, T AF Lurie, Nicole Manolio, Teri Patterson, Amy P. Collins, Francis Frieden, Thomas TI Research as a Part of Public Health Emergency Response SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Lurie, Nicole] Dept Hlth & Human Serv, Off Assistant Secretary Preparedness & Response, Washington, DC USA. [Manolio, Teri; Patterson, Amy P.; Collins, Francis] NIH, Bethesda, MD 20892 USA. [Frieden, Thomas] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Lurie, N (reprint author), Dept Hlth & Human Serv, Off Assistant Secretary Preparedness & Response, Washington, DC USA. NR 4 TC 44 Z9 44 U1 0 U2 5 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 MAR 28 PY 2013 VL 368 IS 13 BP 1251 EP 1255 DI 10.1056/NEJMsb1209510 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 116FU UT WOS:000316869000017 PM 23534565 ER PT J AU Palumbo, T Faucz, FR Azevedo, M Xekouki, P Iliopoulos, D Stratakis, CA AF Palumbo, T. Faucz, F. R. Azevedo, M. Xekouki, P. Iliopoulos, D. Stratakis, C. A. TI Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway SO ONCOGENE LA English DT Article DE microRNAs; growth-hormone producing adenomas; Carney complex; acromegaly; pituitary hyperplasia; protein kinase A ID MCCUNE-ALBRIGHT-SYNDROME; CELL SELF-RENEWAL; CARNEY COMPLEX; MICRORNA GENES; BREAST-CANCER; BMI-1; EXPRESSION; ADENOMAS; PROLIFERATION; MUTATIONS AB MicroRNAs (miRNAs) have been involved in the pathogenesis of different types of cancer; however, their function in pituitary tumorigenesis remains poorly understood. Cyclic-AMP-dependent protein kinase-defective pituitaries occasionally form aggressive growth-hormone (GH)-producing pituitary tumors in the background of hyperplasia caused by haploinsufficiency of the protein kinase's main regulatory subunit, PRKAR1A. The molecular basis for this development remains unknown. We have identified a 17-miRNA signature of pituitary tumors formed in the background of hyperplasia (caused in half of the cases by PRKAR1A-mutations). We selected two miRNAs on the basis of their functional screen analysis: inhibition of miR-26b expression and upregulation of miR-128 suppressed the colony formation ability and invasiveness of pituitary tumor cells. Furthermore, we identified that miR-26b and miR-128 affected pituitary tumor cell behavior through regulation of their direct targets, PTEN and BMI1, respectively. In addition, we found that miR-128 through BMI1 direct binding on the PTEN promoter affected PTEN expression levels and AKT activity in the pituitary tumor cells. Our in vivo data revealed that inhibition of miR-26b and overexpression of miR-128 could suppress pituitary GH3 tumor growth in xenografts. Taken together, we have identified a miRNA signature for GH-producing pituitary tumors and found that miR-26b and miR-128 regulate the activity of the PTEN-AKT pathway in these tumors. This is the first suggestion of the possible involvement of miRNAs regulating the PTEN-AKT pathway in GH-producing pituitary tumor formation in the context of hyperplasia or due to germline PRKAR1A defects. MiR-26b suppression and miR-128 upregulation could have therapeutic potential in GH-producing pituitary tumor patients. Oncogene (2013) 32, 1651-1659; doi: 10.1038/onc.2012.190; published online 21 May 2012 C1 [Palumbo, T.; Iliopoulos, D.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Palumbo, T.; Iliopoulos, D.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Faucz, F. R.; Azevedo, M.; Xekouki, P.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD USA. [Faucz, F. R.] Pontificia Univ Catolica Parana, Grp Adv Mol Invest, Grad Program Hlth Sci, Ctr Biol & Sci, Curitiba, Parana, Brazil. RP Iliopoulos, D (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM Dimitrios_iliopoulos@dfci.harvard.edu; stratakc@mail.nih.gov FU Intramural NIH HHS [ZIA HD008920-02] NR 49 TC 45 Z9 52 U1 4 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 28 PY 2013 VL 32 IS 13 BP 1651 EP 1659 DI 10.1038/onc.2012.190 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 116AY UT WOS:000316855800005 PM 22614013 ER PT J AU Cashion, A Stanfill, A Thomas, F Xu, LJ Suttee, T Eason, J Ensell, M Homayouni, R AF Cashion, Ann Stanfill, Ansley Thomas, Fridtjof Xu, Lijing Suttee, Thomas Eason, James Ensell, Mang Homayouni, Ramin TI Expression Levels of Obesity-Related Genes Are Associated with Weight Change in Kidney Transplant Recipients SO PLOS ONE LA English DT Article ID SUBCUTANEOUS ADIPOSE-TISSUE; CARBOXYPEPTIDASE-E; APOLIPOPROTEIN-M; METABOLIC SYNDROME; LEPTIN; GAIN; DOPAMINE; SAMPLES AB Background:The aim of this study was to investigate the association of gene expression profiles in subcutaneous adipose tissue with weight change in kidney transplant recipients and to gain insights into the underlying mechanisms of weight gain. Methodology/Principal Findings: A secondary data analysis was done on a subgroup (n=26) of existing clinical and gene expression data from a larger prospective longitudinal study examining factors contributing to weight gain in transplant recipients. Measurements taken included adipose tissue gene expression profiles at time of transplant, baseline and six-month weight, and demographic data. Using multivariate linear regression analysis controlled for race and gender, expression levels of 1553 genes were significantly (p<0.05) associated with weight change. Functional analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes classifications identified metabolic pathways that were enriched in this dataset. Furthermore, GeneIndexer literature mining analysis identified a subset of genes that are highly associated with obesity in the literature and Ingenuity pathway analysis revealed several significant gene networks associated with metabolism and endocrine function. Polymorphisms in several of these genes have previously been linked to obesity. Conclusions/Significance: We have successfully identified a set of molecular pathways that taken together may provide insights into the mechanisms of weight gain in kidney transplant recipients. Future work will be done to determine how these pathways may contribute to weight gain. C1 [Cashion, Ann; Stanfill, Ansley; Ensell, Mang] Univ Tennessee, Ctr Hlth Sci, Dept Acute & Chron Care, Coll Nursing, Memphis, TN 38163 USA. [Cashion, Ann] NINR, NIH, Bethesda, MD 20892 USA. [Thomas, Fridtjof] Univ Tennessee, Ctr Hlth Sci, Dept Biostat & Epidemiol, Memphis, TN 38163 USA. [Xu, Lijing; Suttee, Thomas; Homayouni, Ramin] Univ Memphis, Dept Biol, Memphis, TN 38152 USA. [Eason, James] Methodist Univ Hosp Transplant Inst, Memphis, TN USA. [Eason, James] Univ Tennessee, Ctr Hlth Sci, Dept Surg, Transplant Div, Memphis, TN 38163 USA. RP Cashion, A (reprint author), Univ Tennessee, Ctr Hlth Sci, Dept Acute & Chron Care, Coll Nursing, Memphis, TN 38163 USA. EM ann.cashion@nih.gov FU NIH-NINR [USPHS R01 009270, USPHS 009270-0352] FX This work was supported by NIH-NINR USPHS R01 009270 and NIH-NINR USPHS 009270-0352 (ARRA Summer Research Supplement Funds). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 10 Z9 10 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 27 PY 2013 VL 8 IS 3 AR e59962 DI 10.1371/journal.pone.0059962 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 124QO UT WOS:000317480700075 PM 23544116 ER PT J AU Murgai, M Thomas, J Cherepanova, O Delviks-Frankenberry, K Deeble, P Pathak, VK Rekosh, D Owens, G AF Murgai, Meera Thomas, James Cherepanova, Olga Delviks-Frankenberry, Krista Deeble, Paul Pathak, Vinay K. Rekosh, David Owens, Gary TI Xenotropic MLV envelope proteins induce tumor cells to secrete factors that promote the formation of immature blood vessels SO RETROVIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; CHRONIC-FATIGUE-SYNDROME; PROSTATE-CANCER; RETROVIRUS XMRV; HOST-RANGE; METASTASIS; GAMMARETROVIRUSES; ONCOGENESIS; RECEPTOR; SAMPLES AB Background: Xenotropic Murine leukemia virus-Related Virus (XMRV) is a gamma-retrovirus initially reported to be present within familial human prostate tumors and the blood of patients with chronic fatigue syndrome. Subsequent studies however were unable to replicate these findings, and there is now compelling evidence that the virus evolved through rare retroviral recombination events in human tumor cell lines established through murine xenograft experiments. There is also no direct evidence that XMRV infection has any functional effects that contribute to tumor pathogenesis. Results: Herein we describe an additional xenotropic MLV, "B4rv", found in a cell line derived from xenograft experiments with the human prostate cancer LNCaP cell line. When injected subcutaneously in nude mice, LNCaP cells infected with XMRV or B4rv formed larger tumors that were highly hemorrhagic and displayed poor pericyte/smooth muscle cell (SMC) investment, markers of increased metastatic potential. Conditioned media derived from XMRV- or B4rv-infected LNCaPs, but not an amphotropic MLV control virus infected LNCaPs, profoundly decreased expression of marker genes in cultured SMC, consistent with inhibition of SMC differentiation/maturation. Similar effects were seen with a chimeric virus of the amphotropic MLV control virus containing the XMRV env gene, but not with an XMRV chimeric virus containing the amphotropic MLV env gene. UV-inactivated XMRV and pseudovirions that were pseudotyped with XMRV envelope protein also produce conditioned media that downregulated SMC marker gene expression in vitro. Conclusions: Together these results indicate that xenotropic MLV envelope proteins are sufficient to induce the production of factors by tumor cells that suppress vascular SMC differentiation, providing evidence for a novel mechanism by which xenotropic MLVs might alter tumor pathogenesis by disrupting tumor vascular maturation. Although it is highly unlikely that either XMRV or B4Rv themselves infect humans and are pathogenic, the results suggest that xenograft approaches commonly used in the study of human cancer promote the evolution of novel retroviruses with pathogenic properties. C1 [Murgai, Meera; Cherepanova, Olga; Owens, Gary] Univ Virginia, Sch Med Charlottesville, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA. [Thomas, James] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Deeble, Paul] Mary Baldwin Coll, Dept Biol, Staunton, VA 24401 USA. [Delviks-Frankenberry, Krista; Pathak, Vinay K.] Natl Canc Inst, Viral Mutat Sect, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Rekosh, David] Univ Virginia, Myles H Thaler Ctr AIDS & Human Retrovirus Res, Charlottesville, VA 22908 USA. [Rekosh, David] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA. RP Owens, G (reprint author), Univ Virginia, Sch Med Charlottesville, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA. EM gko@virginia.edu RI Delviks-Frankenberry, Krista/M-4822-2013 FU NIH [R01 HL057353, R01 HL098538, R01 HL087867]; American Heart Association [11POST7760009] FX We would like to thank Mary E. McCanna, Rupa S. Tripathi, Melissa Bevard and Dr. Elizabeth Greene for their knowledge and technical expertise, Dr Sarah J. Parsons for providing us with the C4 cell lines, Dr Kimberly Kelly for providing a C4-2 B4 cell line, and Dr Alan Rein for providing us with MoMLV-4070a. This work was supported by NIH grants R01 HL057353, R01 HL098538, and R01 HL087867 (to GKO). Ms. Murgai is supported by the American Heart Association Predoctoral Fellowship 11POST7760009. NR 35 TC 3 Z9 3 U1 0 U2 7 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 MAR 27 PY 2013 VL 10 AR 34 DI 10.1186/1742-4690-10-34 PG 14 WC Virology SC Virology GA 163FU UT WOS:000320322200001 PM 23537062 ER PT J AU Kumar, NP Gopinath, V Sridhar, R Hanna, LE Banurekha, VV Jawahar, MS Nutman, TB Babu, S AF Kumar, Nathella Pavan Gopinath, Venugopal Sridhar, Rathinam Hanna, Luke E. Banurekha, Vaithilingam V. Jawahar, Mohideen S. Nutman, Thomas B. Babu, Subash TI IL-10 Dependent Suppression of Type 1, Type 2 and Type 17 Cytokines in Active Pulmonary Tuberculosis SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-BETA; T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; IMMUNE-RESPONSE; INTERFERON-GAMMA; INFECTION; IL-23; MACROPHAGES; EXPRESSION; CONTRIBUTE AB Background: Although Type 1 cytokine responses are considered protective in pulmonary tuberculosis (PTB), their role as well as those of Type 2, 17 and immunoregulatory cytokines in tuberculous lymphadenitis (TBL) and latent tuberculosis (LTB) have not been well studied. Aim and Methods: To identify cytokine responses associated with pulmonary tuberculosis (TB), TB lymphadenitits and latent TB, we examined mycobacterial antigen-specific immune responses of PTB, TBL and LTB individuals. More specifically, we examined ESAT-6 and CFP-10 induced Type 1, Type 2 and Type 17 cytokine production and their regulation using multiplex ELISA. Results:PTB individuals exhibited a significantly lower baseline as well as antigen-specific production of Type 1 (IFN gamma, TNF alpha and IL-2); Type 2 (IL-4) and Type 17 (IL-17A and IL-17F) cytokines in comparison to both TBL and LTB individuals. TBL individuals exhibited significantly lower antigen-specific IFN gamma responses alone in comparison to LTB individuals. Although, IL-10 levels were not significantly higher, neutralization of IL-10 during antigen stimulation resulted in significantly enhanced production of IFN gamma, IL-4 and IL-17A in PTB individuals, indicating that IL-10 mediates (at least partially) the suppression of cytokine responses in PTB. Conclusion: Pulmonary TB is characterized by an IL-10 dependent antigen-specific suppression of Type 1, Type 2 and Type 17 cytokines, reflecting an important association of these cytokines in the pathogenesis of active TB. C1 [Kumar, Nathella Pavan; Gopinath, Venugopal; Babu, Subash] NIH, Int Ctr Excellence Res, Chennai, Tamil Nadu, India. [Kumar, Nathella Pavan; Gopinath, Venugopal; Hanna, Luke E.; Banurekha, Vaithilingam V.; Jawahar, Mohideen S.] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Sridhar, Rathinam] Govt Stanley Med Hosp, Chennai, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), NIH, Int Ctr Excellence Res, Chennai, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 9 Z9 9 U1 0 U2 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 MAR 27 PY 2013 VL 8 IS 3 AR e59572 DI 10.1371/journal.pone.0059572 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 124QO UT WOS:000317480700035 PM 23544075 ER PT J AU Lu, C Liu, XG Wan, PY Yu, P AF Lu, Chi Liu, Xiaoguang Wan, Pingyu Yu, Ping TI Thiourea-Assisted Phosphate Conversion Coating on Mild Steel and Characterizations by Cathodic Polarization and Linear Polarization SO INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH LA English DT Article ID ELECTROCHEMICAL IMPEDANCE SPECTROSCOPY; PHOSPHORIC-ACID SOLUTION; CORROSION-INHIBITORS; HYDROCHLORIC-ACID; HYDROGEN-SULFIDE; IRON; DERIVATIVES; DESICCATION; PERFORMANCE; STABILITY AB Using highly acidic phosphating solutions that dissolve rust, brush-on phosphating for large-scale steel structures can reduce the cost of rust removal, without the need of a post-treatment rinse. In very low pH medium, the presence of thiourea helps the formation of high-quality conversion films. A hydrogen sulfide acceleration mechanism is proposed, based on cathodic polarization data and previous studies. The formed films are amorphous and contain high water content, therefore a rather long post-treatment desiccation period is required and supported by analyzing the linear polarization resistance values in a desiccation model. C1 [Lu, Chi] Univ Kentucky, Dept Elect & Comp Engn, Lexington, KY 40506 USA. [Lu, Chi; Liu, Xiaoguang; Wan, Pingyu] Beijing Univ Chem Technol, Coll Sci, Beijing 100029, Peoples R China. [Yu, Ping] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lu, C (reprint author), Univ Kentucky, Dept Elect & Comp Engn, Lexington, KY 40506 USA. EM chi_lu_uky@yahoo.com FU Ministry of Chemical Industry of China FX This work was supported in part by multiple funding sources from the Ministry of Chemical Industry of China (a predecessor of China Petroleum and Chemical Industry Federation). We appreciate the editorial assistance of the NIH Fellows Editorial Board. NR 69 TC 4 Z9 4 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0888-5885 J9 IND ENG CHEM RES JI Ind. Eng. Chem. Res. PD MAR 27 PY 2013 VL 52 IS 12 BP 4547 EP 4555 DI 10.1021/ie303204j PG 9 WC Engineering, Chemical SC Engineering GA 118NH UT WOS:000317031700021 ER PT J AU Hayward, JA Tachedjian, M Cui, J Field, H Holmes, EC Wang, LF Tachedjian, G AF Hayward, Joshua A. Tachedjian, Mary Cui, Jie Field, Hume Holmes, Edward C. Wang, Lin-Fa Tachedjian, Gilda TI Identification of diverse full-length endogenous betaretroviruses in megabats and microbats SO RETROVIROLOGY LA English DT Article DE Retrovirus; Betaretrovirus; Endogenous; Evolution; Bats; Pteropus; Myotis; Rhinolophus ID MAMMARY-TUMOR VIRUS; JAAGSIEKTE SHEEP RETROVIRUS; PFIZER MONKEY VIRUS; MURINE LEUKEMIA-VIRUS; NUCLEOTIDE-SEQUENCE; RESPONSIVE ELEMENT; BREAST-CANCER; PROTEIN; BATS; GENOME AB Background: Betaretroviruses infect a wide range of species including primates, rodents, ruminants, and marsupials. They exist in both endogenous and exogenous forms and are implicated in animal diseases such as lung cancer in sheep, and in human disease, with members of the human endogenous retrovirus-K (HERV-K) group of endogenous betaretroviruses (beta ERVs) associated with human cancers and autoimmune diseases. To improve our understanding of betaretroviruses in an evolutionarily distinct host species, we characterized beta ERVs present in the genomes and transcriptomes of mega- and microbats, which are an important reservoir of emerging viruses. Results: A diverse range of full-length beta ERVs were discovered in mega- and microbat genomes and transcriptomes including the first identified intact endogenous retrovirus in a bat. Our analysis revealed that the genus Betaretrovirus can be divided into eight distinct sub-groups with evidence of cross-species transmission. Betaretroviruses are revealed to be a complex retrovirus group, within which one sub-group has evolved from complex to simple genomic organization through the acquisition of an env gene from the genus Gammaretrovirus. Molecular dating suggests that bats have contended with betaretroviral infections for over 30 million years. Conclusions: Our study reveals that a diverse range of betaretroviruses have circulated in bats for most of their evolutionary history, and cluster with extant betaretroviruses of divergent mammalian lineages suggesting that their distribution may be largely unrestricted by host species barriers. The presence of beta ERVs with the ability to transcribe active viral elements in a major animal reservoir for viral pathogens has potential implications for public health. C1 [Hayward, Joshua A.; Tachedjian, Gilda] Burnet Inst, Ctr Virol, Retroviral Biol & Antivirals Lab, Melbourne, Vic 3004, Australia. [Hayward, Joshua A.; Tachedjian, Gilda] Monash Univ, Dept Microbiol, Clayton, Vic 3800, Australia. [Tachedjian, Mary; Wang, Lin-Fa] CSIRO Anim Food & Hlth Sci, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. [Cui, Jie; Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Cui, Jie; Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Field, Hume] Queensland Ctr Emerging Infect Dis, Dept Agr Fisheries & Forestry, Brisbane, Qld 4007, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Wang, Lin-Fa] Duke NUS Grad Med Sch, Emerging Infect Dis Program, Singapore, Singapore. [Wang, Lin-Fa] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. [Tachedjian, Gilda] Monash Univ, Dept Med, Melbourne, Vic 3004, Australia. RP Tachedjian, G (reprint author), Burnet Inst, Ctr Virol, Retroviral Biol & Antivirals Lab, Melbourne, Vic 3004, Australia. EM gildat@burnet.edu.au OI Tachedjian, Gilda/0000-0002-7733-7037; Cui, Jie/0000-0001-8176-9951; Holmes, Edward/0000-0001-9596-3552 FU Burnet Institute; Perpetual Philanthropic Services; Australian Postgraduate Award; Monash University; National Health and Medical Research Council of Australia (NHMRC) [543105]; NHMRC; OCE Science Leader award FX We thank Gary Crameri, Carol de Jong and Craig Smith for the provision of tissues from R. megaphyllus. This study was funded by the Burnet Institute and Perpetual Philanthropic Services. JAH was supported by an Australian Postgraduate Award, Monash University, GT was supported by the National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship 543105, and ECH was supported by an NHMRC Australia Fellowship. The work conducted at the Australian Animal Health Laboratory was partially supported by an OCE Science Leader award to L-FW. The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute. NR 71 TC 20 Z9 20 U1 2 U2 31 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 MAR 27 PY 2013 VL 10 AR 35 DI 10.1186/1742-4690-10-35 PG 19 WC Virology SC Virology GA 121FO UT WOS:000317228500001 PM 23537098 ER PT J AU Lamas, GA Goertz, C Boineau, R Mark, DB Rozema, T Nahin, RL Lindblad, L Lewis, EF Drisko, J Lee, KL AF Lamas, Gervasio A. Goertz, Christine Boineau, Robin Mark, Daniel B. Rozema, Theodore Nahin, Richard L. Lindblad, Lauren Lewis, Eldrin F. Drisko, Jeanne Lee, Kerry L. CA TACT Investigators TI Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction The TACT Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-ARTERY-DISEASE; ISCHEMIC-HEART-DISEASE; INTERMITTENT CLAUDICATION; ENDOTHELIAL FUNCTION; CLINICAL-TRIALS; DOUBLE-BLIND; VITAMIN-C; THERAPY; ATHEROSCLEROSIS; PREVENTION AB Importance Chelation therapy with disodium EDTA has been used for more than 50 years to treat atherosclerosis without proof of efficacy. Objective To determine if an EDTA-based chelation regimen reduces cardiovascular events. Design, Setting, and Participants Double-blind, placebo-controlled, 2 x 2 factorial randomized trial enrolling 1708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less. Participants were recruited at 134 US and Canadian sites. Enrollment began in September 2003 and follow-up took place until October 2011 (median, 55 months). Two hundred eighty-nine patients (17% of total; n=115 in the EDTA group and n=174 in the placebo group) withdrew consent during the trial. Interventions Patients were randomized to receive 40 infusions of a 500-mL chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs placebo (n=869) and an oral vitamin-mineral regimen vs an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Fifteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) because of adverse events. Main Outcome Measures The prespecified primary end point was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. This report describes the intention-to-treat comparison of EDTA chelation vs placebo. To account for multiple interim analyses, the significance threshold required at the final analysis was P=.036. Results Qualifying previous MIs occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, and 31% were diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P=. 035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P=. 64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]). Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results. Conclusions and Relevance Among stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI. C1 [Lamas, Gervasio A.] Columbia Univ, Div Cardiol, Mt Sinai Med Ctr, Miami Beach, FL 33140 USA. [Goertz, Christine] Palmer Ctr Chiropract Res, Davenport, IA USA. [Boineau, Robin] NHLBI, Bethesda, MD 20892 USA. [Nahin, Richard L.] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Mark, Daniel B.; Lindblad, Lauren; Lee, Kerry L.] Duke Clin Res Inst, Durham, NC USA. [Rozema, Theodore] Biogenesis Med Ctr, Landrum, SC USA. [Lewis, Eldrin F.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lewis, Eldrin F.] Harvard Univ, Sch Med, Boston, MA USA. [Drisko, Jeanne] Univ Kansas, Med Ctr, Kansas City, MO USA. RP Lamas, GA (reprint author), Columbia Univ, Div Cardiol, Mt Sinai Med Ctr, 4300 Alton Rd, Miami Beach, FL 33140 USA. EM gervasio.lamas@msmc.com OI Nahin, Richard/0000-0002-3682-4816; Mark, Daniel/0000-0001-6340-8087 FU NCCAM [U01AT001156]; NHLBI [U01HL092607] FX The NCCAM (grant U01AT001156) and the NHLBI (grant U01HL092607) provided sole support for this study. NR 38 TC 58 Z9 59 U1 2 U2 23 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 MAR 27 PY 2013 VL 309 IS 12 BP 1241 EP 1250 DI 10.1001/jama.2013.2107 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 112WO UT WOS:000316625200024 PM 23532240 ER PT J AU Redfield, MM Chen, HH Borlaug, BA Semigran, MJ Lee, KL Lewis, G LeWinter, MM Rouleau, JL Bull, DA Mann, DL Deswal, A Stevenson, LW Givertz, MM Ofili, EO O'Connor, CM Felker, GM Goldsmith, SR Bart, BA McNulty, SE Ibarra, JC Lin, G Oh, JK Patel, MR Kim, RJ Tracy, RP Velazquez, EJ Anstrom, KJ Hernandez, AF Mascette, AM Braunwald, E AF Redfield, Margaret M. Chen, Horng H. Borlaug, Barry A. Semigran, Marc J. Lee, Kerry L. Lewis, Gregory LeWinter, Martin M. Rouleau, Jean L. Bull, David A. Mann, Douglas L. Deswal, Anita Stevenson, Lynne W. Givertz, Michael M. Ofili, Elizabeth O. O'Connor, Christopher M. Felker, G. Michael Goldsmith, Steven R. Bart, Bradley A. McNulty, Steven E. Ibarra, Jenny C. Lin, Grace Oh, Jae K. Patel, Manesh R. Kim, Raymond J. Tracy, Russell P. Velazquez, Eric J. Anstrom, Kevin J. Hernandez, Adrian F. Mascette, Alice M. Braunwald, Eugene CA RELAX Trial TI Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PULMONARY-HYPERTENSION; RIGHT VENTRICLE; OXYGEN-UPTAKE; SILDENAFIL; DYSFUNCTION; PREVENTS; 1-YEAR; RATS; HEMODYNAMICS; ASSOCIATION AB Importance Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). Objective To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Design Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction >= 50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. Interventions Sildenafil (n=113) or placebo (n=103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Main Outcome Measures Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. Results Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m(2)), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P=.90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P=.85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P=.92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Conclusion and Relevance Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. Trial Registration clinicaltrials.gov Identifier: NCT00763867 JAMA. 2013; 309(12): 1268-1277 Published online March 11, 2013. doi: 10.1001/jama.2013.2024 www.jama.com C1 [Redfield, Margaret M.; Chen, Horng H.; Borlaug, Barry A.; Lin, Grace; Oh, Jae K.] Mayo Clin, Dept Med, Rochester, MN 55905 USA. [Semigran, Marc J.; Lewis, Gregory] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lee, Kerry L.; Anstrom, Kevin J.] Duke Clin Res Inst, Dept Biostat & Bioinformat, Durham, NC USA. [Velazquez, Eric J.; Hernandez, Adrian F.] Duke Clin Res Inst, Dept Med, Durham, NC USA. [McNulty, Steven E.] Duke Clin Res Inst, Dept Stat, Durham, NC USA. [Ibarra, Jenny C.] Duke Clin Res Inst, Dept Project Management, Durham, NC USA. [LeWinter, Martin M.] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol & Biochem, Burlington, VT 05405 USA. [Rouleau, Jean L.] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Rouleau, Jean L.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Bull, David A.] Univ Utah, Dept Surg, Salt Lake City, UT USA. [Mann, Douglas L.] Barnes Jewish Hosp, Dept Med, St Louis, MO 63110 USA. [Deswal, Anita] Michael E DeBakey VA Med Ctr, Dept Med, Houston, TX USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Stevenson, Lynne W.; Givertz, Michael M.; Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Ofili, Elizabeth O.] Morehouse Sch Med, Dept Med, Atlanta, GA 30310 USA. [O'Connor, Christopher M.; Felker, G. Michael; Patel, Manesh R.; Kim, Raymond J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Kim, Raymond J.] Duke Univ, Med Ctr, Duke Cardiovasc Magnet Resonance Ctr, Durham, NC USA. Duke Heart Ctr, Durham, NC USA. [Goldsmith, Steven R.; Bart, Bradley A.] Hennepin Cty Med Ctr, Dept Med, Minneapolis, MN 55415 USA. [Mascette, Alice M.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Redfield, MM (reprint author), Mayo Clin, Div Cardiovasc Dis, 200 1st St SW,Guggenheim 9, Rochester, MN 55905 USA. EM redfield.margaret@mayo.edu RI Hernandez, Adrian F./A-7818-2016; OI Hernandez, Adrian F./0000-0003-3387-9616; Mann, Douglas /0000-0002-2516-0145 FU National Institutes of Health (NIH); Medscape; Medscape, Amgen; GlaxoSmithKline; Atcor Medical and Gilead; National Heart, Lung, and Blood Institute; National Institute on Minority Health and Health Disparities; Roche Diagnostics; Amgen; Novartis; Ikaria; Acetlion Pharma; Heartware; ResMed; Pozen; GE Healthcare; Johnson Johnson; Gilead; Critical Diagnostics; BG Medicine; Otsuka; Astellas; Novella; Novella, Cytokinetics; Capricor; Singulex; Bristol-Myers Squibb; Amylin; National Heart, Lung, and Blood Institute [U10HL084904, U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, U10HL084931]; National Center for Advancing Translational Sciences [UL1TR000454]; National Institute on Minority Health and Health Disparities [8 U54 MD007588] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Redfield reported receiving financial support from the National Institutes of Health (NIH) and royalties from Annexon. Dr Chen reported receiving funding for patents that his institution has licensed to Nile Therapeutics and Annexon with other patents pending at the US Patent and Trademark Office. He also reported that he has royalties with Nile Therapeutics, Annexon, and Up To Date. Dr Borlaug reported receiving consulting fees from Medscape, Amgen, and GlaxoSmithKline and receiving financial support from Atcor Medical and Gilead. Dr Semigran reported receiving financial support from the NIH for participation in the Heart Failure Network and from Bayer. Dr Lee reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr LeWinter reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Bull reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Deswal reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Stevenson reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Givertz reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Ofili reported receiving financial support from the NIH, receiving consulting fees from Merck, Novartis, and Arbor Pharmaceuticals and lecture fees from Arbor Pharmaceuticals. She is currently employed by the Morehouse School of Medicine and has grants pending from the National Heart, Lung, and Blood Institute and National Institute on Minority Health and Health Disparities. DrO'Connor reported receiving consulting fees from Roche Diagnostics, Amgen, Novartis, Ikaria, Acetlion Pharma, Heartware, ResMed, Pozen, GE Healthcare, Johnson & Johnson, Gilead, Critical Diagnostics, BG Medicine, Otsuka, Astellas, Novella, Cytokinetics, and Capricor; holding stock options with Neurotronik/Interventional Autonomics Corporation; editing American College of Cardiology; and coowning Cardiology Consulting Associates. Dr Felker reported receiving financial support from the NIH; consulting fees from Novartis, Amgen, Trevena, Roche Diagnostics, Merck, Singulex, and BG Medicine; and funding from Amgen, Otsuka, and Roche Diagnostics. Dr Bart reported receiving financial support from the NIH for participation in the Heart Failure Network. Ms Ibarra reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Oh received financial support from the NIH for the Echo Core Lab. Dr Patel has received consulting fees from Genzyme, Baxter, Jensen, and Bayer, and his financial institution receives financial support from AstraZeneca, Johnson & Johnson, and Maquet. Dr Kim reported receiving financial support from the NIH as the Heart Failure Network Data Coordinating Center and MRI Core Lab, and funding for a patent with Northwestern University. His institution has received a grant from Siemens. Dr Tracy reported receiving financial support from the NIH for participation in the Heart Failure Network, and consulting fees fromMerck, Tibotec-Johnson & Johnson, and Abbott. He has also given expert testimony about biomarkers in blood clotting and is the owner of Haematologic Technologies. Dr Velazquez reported receiving financial support from the NIH for participation in the Heart Failure Network.; Dr Anstrom reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Hernandez reported receiving financial support from the NIH for participation in the Heart Failure Network and consulting fees from AstraZeneca, Corthera, Janseen, and Bristol-Myers Squibb. His institution has received funding from Amylin, Johnson & Johnson, and Bristol-Myers Squibb. Dr Braunwald reported receiving consulting fees from Merck, Daiichi Sankyo, Genzyme, Amorcyte, Medicines Co, MC Communications, Ikaria, CardioRentis, sanofiaventis; funding (or pending funding) from AstraZeneca, Johnson & Johnson, Merck, sanofi-aventis, Daiichi Sankyo, GlaxoSmithKline, Bristol-Myers Squibb, Beckman Coulter, Roche Diagnostics, and Pfizer; compensation for lectures for Eli Lilly, Merck, CVRx (no compensation), CV Therapeutics (now Gilead), Daiichi Sankyo, MC Communications, Manarini International, Medscape, and Bayer; and payment for devel-opment of educational presentations from MC Communications. No other disclosures were reported.; This work was supported by grants U10HL084904 (for the data coordinating center), and U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, and U10HL084931 (for the clinical centers) from the National Heart, Lung, and Blood Institute. This work is also supported by grant UL1TR000454 from the National Center for Advancing Translational Sciences and grant 8 U54 MD007588 from the National Institute on Minority Health and Health Disparities. Pfizer provided study drug (sildenafil and matched placebo). NR 31 TC 305 Z9 313 U1 5 U2 36 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 27 PY 2013 VL 309 IS 12 BP 1268 EP 1277 DI 10.1001/jama.2013.2024 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 112WO UT WOS:000316625200027 PM 23478662 ER PT J AU Pogorzala, LA Mishra, SK Hoon, MA AF Pogorzala, Leah A. Mishra, Santosh K. Hoon, Mark A. TI The Cellular Code for Mammalian Thermosensation SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CAPSAICIN RECEPTOR; VANILLOID RECEPTOR; TRPA1 CONTRIBUTES; PAIN PATHWAY; COLD; NEURONS; MICE; CHANNEL; TRPM8; NOCICEPTORS AB Mammalian somatosenory neurons respond to thermal stimuli and allow animals to reliably discriminate hot from cold and to select their preferred environments. Previously, we generated mice that are completely insensitive to temperatures from noxious cold to painful heat (-5 to 55 degrees C) by ablating several different classes of nociceptor early in development. In the present study, we have adopted a selective ablation strategy in adult mice to study this phenotype and have demonstrated that separate populations of molecularly defined neurons respond to hot and cold. TRPV1-expressing neurons are responsible for all behavioral responses to temperatures between 40 and 50 degrees C, whereas TRPM8 neurons are required for cold aversion. We also show that more extreme cold and heat activate additional populations of nociceptors, including cells expressing Mrgprd. Therefore, although eliminating Mrgprd neurons alone does not affect behavioral responses to temperature, when combined with ablation of TRPV1 or TRPM8 cells, it significantly decreases responses to extreme heat and cold, respectively. Ablation of TRPM8 neurons distorts responses to preferred temperatures, suggesting that the pleasant thermal sensation of warmth may in fact just reflect reduced aversive input from TRPM8 and TRPV1 neurons. As predicted by this hypothesis, mice lacking both classes of thermosensor exhibited neither aversive nor attractive responses to temperatures between 10 and 50 degrees C. Our results provide a simple cellular basis for mammalian thermosensation whereby two molecularly defined classes of sensory neurons detect and encode both attractive and aversive cues. C1 [Pogorzala, Leah A.; Mishra, Santosh K.; Hoon, Mark A.] NIDCR, Mol Genet Unit, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. RP Hoon, MA (reprint author), NIDCR, Mol Genet Unit, Lab Sensory Biol, NIH, Bldg 49,Room 1A16,49 Convent Dr, Bethesda, MD 20892 USA. EM mark.hoon@nih.gov FU National Institute of Dental and Craniofacial Research (NIDCR)-National Institutes of Health FX This research was supported by the intramural research program of the National Institute of Dental and Craniofacial Research (NIDCR)-National Institutes of Health (M. A. H.). We thank Dr. David Anderson for providing Mrgprd-DTR mice, Nick Ryba for encouragement and helpful advice, and Drs. Minh Nguyen and Lars von Buchholtz and members of the Molecular Genetics Unit for valuable suggestions. Transgenic mice were generated by Andrew Cho in the NIDCR Core Facility. NR 41 TC 43 Z9 43 U1 1 U2 23 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 MAR 27 PY 2013 VL 33 IS 13 BP 5533 EP 5541 DI 10.1523/JNEUROSCI.5788-12.2013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 117JD UT WOS:000316948600011 PM 23536068 ER PT J AU Korn, EL McShane, LM Freidlin, B AF Korn, Edward L. McShane, Lisa M. Freidlin, Boris TI Statistical Challenges in the Evaluation of Treatments for Small Patient Populations SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Review ID ARRHYTHMIA SUPPRESSION TRIAL; RANDOMIZED CLINICAL-TRIALS; HIGH-DOSE CHEMOTHERAPY; GASTROINTESTINAL STROMAL TUMORS; EFFECTIVE SUBSEQUENT THERAPIES; CHRONIC MYELOGENOUS LEUKEMIA; DATA-MONITORING COMMITTEES; VENTRICULAR ASSIST DEVICE; GILFORD PROGERIA SYNDROME; CHRONIC MYELOID-LEUKEMIA AB The development of a new treatment typically involves evaluation of its efficacy in a large clinical trial in which patients are randomly assigned either the new treatment or the standard of care. Results from these large randomized clinical trials allow for a definitive and unbiased assessment of the clinical benefit of the new treatment over the standard one. For rare diseases or for small patient subgroups identified within the context of a common disease, it may not be possible to conduct a large randomized trial. In this Review, we discuss alternative clinical study designs and statistical challenges that arise when attempting to assure that study results yield robust conclusions about the safety and effectiveness of a new medical product. C1 [Korn, Edward L.; McShane, Lisa M.; Freidlin, Boris] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, MSC 9735, Bethesda, MD 20892 USA. EM lm5h@nih.gov NR 93 TC 5 Z9 5 U1 0 U2 7 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 MAR 27 PY 2013 VL 5 IS 178 AR 178sr3 DI 10.1126/scitranslmed.3004018 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 115EL UT WOS:000316795300006 PM 23536014 ER PT J AU Fa, S Pogrmic-Majkic, K Dakic, V Kaisarevic, S Hrubik, J Andric, N Stojilkovic, SS Kovacevic, R AF Fa, Svetlana Pogrmic-Majkic, Kristina Dakic, Vanja Kaisarevic, Sonja Hrubik, Jelena Andric, Nebojsa Stojilkovic, Stanko S. Kovacevic, Radmila TI Acute effects of hexabromocyclododecane on Leydig cell cyclic nucleotide signaling and steroidogenesis in vitro SO TOXICOLOGY LETTERS LA English DT Article DE Endocrine disrupters; Hexabromocyclododecane; Leydig cell steroidogenesis; cAMP-signalling; Mitochondrial membrane potential ID BROMINATED FLAME RETARDANTS; ACUTE REGULATORY PROTEIN; RAT TESTICULAR ANDROGENESIS; GENE-EXPRESSION; TESTOSTERONE PRODUCTION; PERFLUORODECANOIC ACID; CHOLESTEROL TRANSPORT; INHIBITION; EXPOSURE; ATRAZINE AB Hexabromocyclododecane (HBCDD), an additive brominated flame retardant routinely added to various consumer products, was reported to have toxic effects upon biota, including endocrine disruption. In this study, the potential toxicity of HBCDD was tested in peripubertal rat Leydig cells in vitro during 6 h exposure. HBCDD inhibited human chorionic gonadotropin-and forskolin-supported cAMP accumulation and steroidogenesis. It also inhibited basal cAMP production, but elevated basal steroidogenesis. The expression of several cAMP-dependent genes, including steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, and 3 beta-hydroxysteroid dehydrogenase, was also inhibited by HBCDD treatment. Nevertheless, this was not accompanied by a decrease in steroidogenic acute regulatory protein expression, as documented by western blot analysis, and activity of steroidogenic enzymes, as documented by unaffected steroidogenesis in the presence of permeable 22(R)-hydroxycholesterol. However, HBCDD caused significant decrease in mitochondrial membrane potential in untreated and human chorionic gonadotropin-treated cells. This indicates that HBCDD acute toxicity in Leydig cells reflects changes in mitochondrial membrane potential-dependent cAMP production and basal and cAMP-regulated cholesterol transport. This in turn facilitates basal but inhibits cAMP-dependent steroidogenesis. Acute effects of HBCDD treatment on transcription are also indicative of its sustained effects on Leydig cell function. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Fa, Svetlana; Pogrmic-Majkic, Kristina; Dakic, Vanja; Kaisarevic, Sonja; Hrubik, Jelena; Andric, Nebojsa; Kovacevic, Radmila] Univ Novi Sad, Fac Sci, Dept Biol & Ecol, Lab Ecotoxicol, Novi Sad 21000, Serbia. [Stojilkovic, Stanko S.] NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Kovacevic, R (reprint author), Univ Novi Sad, Fac Sci, Dept Biol & Ecol, Dositej Obradovic Sq 2, Novi Sad 21000, Serbia. EM radmila.kovacevic@dbe.uns.ac.rs FU Ministry of Science, Republic of Serbia [173037]; Autonomic Province of Vojvodina [2570]; Eunce Kennedy Shiver National Institute of Health and Human Development FX We are grateful to Drs. D. M. Stocco for providing StAR antiserum and G. D. Niswender for the supply of testosterone and progesterone antiserums. This work is supported by the Ministry of Science, Republic of Serbia (grant no. 173037), by the Autonomic Province of Vojvodina (grant no. 2570) and a Eunce Kennedy Shiver National Institute of Health and Human Development intramural grant. NR 47 TC 6 Z9 6 U1 1 U2 22 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 MAR 27 PY 2013 VL 218 IS 1 BP 81 EP 90 DI 10.1016/j.toxlet.2013.01.009 PG 10 WC Toxicology SC Toxicology GA 095TK UT WOS:000315357400012 PM 23347875 ER PT J AU Afshin, A Abioye, AI Ajala, ON Nguyen, AB See, KC Mozaffarian, D AF Afshin, Ashkan Abioye, Ajibola I. Ajala, Oluremi N. Nguyen, Anh B. See, Kay C. Mozaffarian, Dariush TI Effectiveness of Mass Media Campaigns for Improving Dietary Behaviors: A Systematic Review and Meta-analysis SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Diet; Health education; Nutrition C1 [Afshin, Ashkan; Abioye, Ajibola I.; Ajala, Oluremi N.; See, Kay C.; Mozaffarian, Dariush] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Nguyen, Anh B.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P087 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100226 ER PT J AU Agyemang, P Ayers, C Lian, M Das, S Hoehner, C Leonard, T Berrigan, D Ballard-Barbash, R Powell-Wiley, TM AF Agyemang, Priscilla Ayers, Colby Lian, Min Das, Sandeep Hoehner, Christine Leonard, Tammy Berrigan, David Ballard-Barbash, Rachel Powell-Wiley, Tiffany M. TI Neighborhood-Level Socioeconomic Deprivation Predicts Weight Gain in a Multi-Ethnic Population: Longitudinal Data from the Dallas Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Social Determinants of Health; Health disparities; Longitudinal studies C1 [Agyemang, Priscilla; Berrigan, David; Ballard-Barbash, Rachel; Powell-Wiley, Tiffany M.] NIH, Bethesda, MD 20892 USA. [Ayers, Colby; Das, Sandeep] Univ Texas Southwestern Med Cntr, Dallas, TX USA. [Lian, Min; Hoehner, Christine] Washington Univ, Sch Med, St Louis, MO USA. [Leonard, Tammy] Univ Texas Dallas, Richardson, TX 75083 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP88 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100135 ER PT J AU Allen, NB Chan, C Kiefe, C Wei, GN Person, S Sidney, S Bibbins-Domingo, K Goff, D AF Allen, Norrina B. Chan, Cheeling Kiefe, Catarina Wei, Gina Person, Sharina Sidney, Steve Bibbins-Domingo, Kirsten Goff, David TI Gender and Racial Disparities in Access to Health Care: The Coronary Artery Risk in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Health services research; Health disparities C1 [Allen, Norrina B.; Chan, Cheeling] Northwestern Univ, Chicago, IL 60611 USA. [Kiefe, Catarina; Person, Sharina] Univ Massachusetts, Sch Med, Worcester, MA USA. [Wei, Gina] NHLBI, Bethesda, MD 20892 USA. [Sidney, Steve] Kaiser Permanente, Div Rsch, Oakland, CA USA. [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Goff, David] Colorado Sch Publ Hlth, Denver, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P343 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100461 ER PT J AU Auer, R Vittinghoff, E Kiefe, C Reis, JP Rodondi, N Khodneva, YA Kertesz, SG Cornuz, J Pletcher, MJ AF Auer, Reto Vittinghoff, Eric Kiefe, Catharina Reis, Jared P. Rodondi, Nicolas Khodneva, Yulia A. Kertesz, Stefan G. Cornuz, Jacques Pletcher, Mark J. TI Smoking Cessation and Long-term Changes in Physical Activity Level: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Physical activity; Smoking; Longitudinal studies C1 [Auer, Reto; Vittinghoff, Eric; Pletcher, Mark J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kiefe, Catharina] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Reis, Jared P.] NHLBI, Bethesda, MD 20892 USA. [Rodondi, Nicolas] Univ Bern, Bern, Switzerland. [Khodneva, Yulia A.] Univ Alabama Birmingham, Birmingham, AL USA. [Kertesz, Stefan G.] Birmingham VA Med Cntr, Birmingham, AL USA. [Cornuz, Jacques] Univ Lausanne, Lausanne, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P142 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100279 ER PT J AU Azeem, A Yeboah, J Bertoni, A Burke, G Turkbey, E Szklo, M Herrington, D AF Azeem, Amir Yeboah, Joseph Bertoni, Alain Burke, Gregory Turkbey, Evrim Szklo, Moyses Herrington, David TI Association of Hemoglobin A1C with Cardiovascular Disease and All-Cause Mortality in Individuals without Diabetes - The Multi-Ethnic Study of Atherosclerosis SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Cardiovascular disease; Risk factors; Glucose C1 [Azeem, Amir; Yeboah, Joseph; Bertoni, Alain; Burke, Gregory; Herrington, David] Wake Forest Sch Med, Winston Salem, NC USA. [Turkbey, Evrim] NIH, Bethesda, MD 20892 USA. [Szklo, Moyses] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P278 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100398 ER PT J AU Bidulescu, A Liu, JN Morris, AA Vaccarino, V Quyyumi, AA Gibbons, GH AF Bidulescu, Aurelian Liu, Jinnan Morris, Alanna A. Vaccarino, Viola Quyyumi, Arshed A. Gibbons, Gary H. TI Race and Gender Differences in the Association between Vitamin D and Adiponectin and its Relationship with Body Mass Index: The Meta-Health Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Obesity; Gender; Health disparities C1 [Bidulescu, Aurelian; Liu, Jinnan] Morehouse Sch Med Cardio Rsrch, Atlanta, GA USA. [Morris, Alanna A.; Vaccarino, Viola; Quyyumi, Arshed A.] Emory Univ, Atlanta, GA 30322 USA. [Gibbons, Gary H.] NHLBI, NIH, Bethesda, MD 20892 USA. RI Bidulescu, Aurelian/N-2617-2014 OI Bidulescu, Aurelian/0000-0001-8211-8309 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P284 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100404 ER PT J AU Carson, AP Steffes, MW Carr, IJ Kim, Y Gross, MD Carnethon, MR Reis, JP Loria, CM Jacobs, DR Lewis, CE AF Carson, April P. Steffes, Michael W. Carr, I. J. Kim, Yongin Gross, Myron D. Carnethon, Mercedes R. Reis, Jared P. Loria, Catherine M. Jacobs, David R. Lewis, Cora E. TI Hemoglobin A1c and Progression of Coronary Artery Calcification: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Calcification C1 [Carson, April P.; Kim, Yongin; Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. [Steffes, Michael W.; Gross, Myron D.; Jacobs, David R.] Univ Minnesota, Minneapolis, MN USA. [Carr, I. J.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Carnethon, Mercedes R.] Northwestern Univ, Chicago, IL 60611 USA. [Reis, Jared P.; Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P384 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100502 ER PT J AU Cartv, CL Hindorff, LA Buyske, S Haessler, J Fesinmeyer, MD Carlson, CS Rao, DC Chakravarti, A Fornage, M North, KE Kooperberg, C Franceschini, N AF Cartv, Cara L. Hindorff, Lucia A. Buyske, Steven Haessler, Jeff Fesinmeyer, Megan D. Carlson, Chris S. Rao, D. C. Chakravarti, Aravinda Fornage, Myriam North, Kari E. Kooperberg, Charles Franceschini, Nora CA Population Architecture Using TI Investigation of Blood Pressure Genetic Loci in African Americans using the Metabochip SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Blood pressure; Genomics C1 [Cartv, Cara L.; Haessler, Jeff; Fesinmeyer, Megan D.; Carlson, Chris S.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hindorff, Lucia A.] NHGRI, Bethesda, MD 20892 USA. [Buyske, Steven] Rutgers State Univ, Piscataway, NJ USA. [Rao, D. C.] Washington Univ, St Louis, MO USA. [Chakravarti, Aravinda] Johns Hopkins Univ, Baltimore, MD USA. [Fornage, Myriam] Univ Texas Houston, Houston, TX USA. [North, Kari E.; Franceschini, Nora] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP60 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100108 ER PT J AU Caughey, M Laura, L Avery, C Ni, HY Astor, B Matsushita, K Wruck, L Rosamond, W AF Caughey, Melissa Laura, Loehr Avery, Christy Ni, Hanyu Astor, Brad Matsushita, Kunihiro Wruck, Lisa Rosamond, Wayne TI Prevalence and Outcomes of Anemia in Patients Hospitalized with Acute Decompensated Heart Failure: The ARIC Study Community Surveillance SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Heart failure; Blood cells; Country level epidemiologic data C1 [Caughey, Melissa; Laura, Loehr; Avery, Christy; Wruck, Lisa; Rosamond, Wayne] Univ N Carolina, Chapel Hill, NC USA. [Ni, Hanyu] NHLBI, Bethesda, MD 20892 USA. [Astor, Brad] Univ Wisconsin, Madison, WI USA. [Matsushita, Kunihiro] Johns Hopkins, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P013 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100155 ER PT J AU Chuang, ML Gona, P Salton, CJ Tsao, CW Yeon, SB O'Donnelll, CJ Manning, WJ AF Chuang, Michael L. Gona, Philimon Salton, Carol J. Tsao, Connie W. Yeon, Susan B. O'Donnelll, Christopher J. Manning, Warren J. TI Association of Clinical Characteristics and Cardiopulmonary Risk Factors with Aortic and Pulmonary Arterial Enlargement by Magnetic Resonance SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Aorta; Magnetic resonance imaging; Risk factors C1 [Chuang, Michael L.; Gona, Philimon; Tsao, Connie W.; O'Donnelll, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Salton, Carol J.; Yeon, Susan B.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P388 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100506 ER PT J AU Cogswell, M Wang, CY Chen, TC Pfeiffer, C Elliott, P Gillespie, C Carriquiry, A Sempos, C Liu, K Perrine, C Swanson, C Caldwell, K Loria, C AF Cogswell, Mary Wang, Chia-Yih Chen, Te-Ching Pfeiffer, Christine Elliott, Paul Gillespie, Cathleen Carriquiry, Alicia Sempos, Christopher Liu, Kiang Perrine, Cria Swanson, Christine Caldwell, Kathleen Loria, Catherine TI Validity of Predictive Equations for 24-Hour Urine Sodium Excretion in Young Black and Other Adults SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Sodium; Epidemiologic methods; Nutrition C1 [Cogswell, Mary; Pfeiffer, Christine; Gillespie, Cathleen; Perrine, Cria; Caldwell, Kathleen] CDC, Atlanta, GA 30333 USA. [Wang, Chia-Yih; Chen, Te-Ching] CDC, Hyattsville, MD USA. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, London, England. [Carriquiry, Alicia] Iowa State Univ, Ames, IA USA. [Sempos, Christopher; Swanson, Christine; Loria, Catherine] NIH, Rockville, MD USA. [Liu, Kiang] Northwestern Univ, Evanston, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP78 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100125 ER PT J AU Defago, MD Gu, DF Hixson, JE Shimmin, LC Rice, TK Gu, CC Jaquish, CE Liu, DP He, J Kelly, TN AF Defago, Maria D. Gu, Dongfeng Hixson, James E. Shimmin, Lawrence C. Rice, Treva K. Gu, Charles C. Jaquish, Cashell E. Liu, Depei He, Jiang Kelly, Tanika N. TI Common Genetic Variants in the Endothelial System Predict Blood Pressure Response to Sodium Intake: The GenSalt Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Sodium; Blood pressure; Genetics C1 [Defago, Maria D.] Inst Efectividad Clin & Sanitaria, Buenos Aires, DF, Argentina. [Gu, Dongfeng] Cardiovasc Inst, Beijing, Peoples R China. [Gu, Dongfeng] Fuwai Hosp, Beijing, Peoples R China. [Hixson, James E.; Shimmin, Lawrence C.] Univ Texas Houston, Houston, TX USA. [Rice, Treva K.; Gu, Charles C.] Washington Univ, St Louis, MO USA. [Jaquish, Cashell E.] NHLBI, Bethesda, MD 20892 USA. [Liu, Depei] Chinese Acad Med Sci, Beijing 100730, Peoples R China. [Liu, Depei] Peking Union Med Coll, Beijing 100021, Peoples R China. [He, Jiang; Kelly, Tanika N.] Tulane Univ, New Orleans, LA 70118 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP68 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100116 ER PT J AU Djousse, L Benkeser, D Arnold, A Kizer, J Zieman, S Tracy, R Gottdiener, J Mozaffarian, D Siscovick, D Mukamal, K Ix, J AF Djousse, Luc Benkeser, David Arnold, Alice Kizer, Jorge Zieman, Susan Tracy, Russell Gottdiener, John Mozaffarian, Dariush Siscovick, David Mukamal, Kenneth Ix, Joachim TI Plasma Free Fatty Acids are Positively Associated with Incident Heart Failure in the Cardiovascular Health Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Fatty acids; Nutrition; Heart failure C1 [Djousse, Luc; Mozaffarian, Dariush] Brigham & Womens Hosp, Boston, MA 02115 USA. [Djousse, Luc] Harvard Univ, Sch Med, Boston Vet Affairs Healthcare Syst, Boston, MA USA. [Benkeser, David; Arnold, Alice; Siscovick, David] Univ Washington, Seattle, WA 98195 USA. [Kizer, Jorge] Weill Cornell Med Coll, New York, NY USA. [Zieman, Susan] NIA, Bethesda, MD 20892 USA. [Tracy, Russell] Univ Vermont, Colchester, VT USA. [Gottdiener, John] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Mozaffarian, Dariush; Mukamal, Kenneth] Harvard Univ, Sch Med, Boston, MA USA. [Mukamal, Kenneth] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ix, Joachim] Vet Affairs San Diego Heathcare Syst, San Diego, CA USA. [Ix, Joachim] Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP02 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100054 ER PT J AU Dutton, G Loria, C Carnethon, M Durant, N Gordon-Larsen, P Jacobs, D Shikany, J Reis, J Sidney, S Lewis, CE AF Dutton, Gareth Loria, Catherine Carnethon, Mercedes Durant, Nefertiti Gordon-Larsen, Penny Jacobs, David Shikany, James Reis, Jared Sidney, Stephen Lewis, Cora E. TI Secular and Aging-Related Weight Gain Slows among US Adults: The CARDIA Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Obesity; Racial/ethnic disparties C1 [Dutton, Gareth; Durant, Nefertiti; Shikany, James; Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. [Loria, Catherine; Reis, Jared] NHLBI, Bethesda, MD 20892 USA. [Carnethon, Mercedes] Northwestern Univ, Chicago, IL 60611 USA. [Gordon-Larsen, Penny] Univ N Carolina, Chapel Hill, NC USA. [Jacobs, David] Univ Minnesota, Minneapolis, MN USA. [Sidney, Stephen] Kaiser Permanente, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P021 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100162 ER PT J AU Franceschini, N Buyske, S Hindorff, LA Kooperberg, C Boerwinkle, E AF Franceschini, Nora Buyske, Steve Hindorff, Lucia A. Kooperberg, Charles Boerwinkle, Eric TI Association of Genetic Variants with Incident Coronary Heart Disease in African Americans SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Coronary artery disease; Genetics C1 [Franceschini, Nora] Univ N Carolina, Chapel Hill, NC USA. [Buyske, Steve] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Kooperberg, Charles] Fred Hutchinson Canc Rsch Cntr Carolina, Seattle, WA USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP35 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100085 ER PT J AU Garg, V Vedanthan, R Islami, F Pourshams, A Poutschi, H Khademi, H Naemi, M Malekshah, AFT Jafari, E Salahi, R Kamangar, F Pharoah, PD Abnet, CC Brennan, P Dawsey, SM Fuster, V Boffetta, P Malekzadeh, R AF Garg, Vaani Vedanthan, Rajesh Islami, Farhad Pourshams, Akram Poutschi, Hossein Khademi, Hooman Naemi, Mohammad Malekshah, Akbar Fazel-Tabar Jafari, Elham Salahi, Rasool Kamangar, Farin Pharoah, Paul D. Abnet, Christian C. Brennan, Paul Dawsey, Sanford M. Fuster, Valentin Boffetta, Paolo Malekzadeh, Reza TI Associations between Anthropometric Indices and the Prevalence of Heart Disease in Iran: The Golestan Cohort Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Heart disease; Obesity; International Issues C1 [Garg, Vaani; Vedanthan, Rajesh; Islami, Farhad; Fuster, Valentin; Boffetta, Paolo] Mt Sinai Sch Med, New York, NY USA. [Pourshams, Akram; Poutschi, Hossein; Khademi, Hooman; Malekshah, Akbar Fazel-Tabar; Jafari, Elham; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Naemi, Mohammad; Salahi, Rasool] Gorgan Univ Med Sci, Sch Med, Dept Internal Med, Gorgan, Iran. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P108 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100246 ER PT J AU Gibbs, BB Reis, JP Schelbert, EB Sidney, S Craft, LL Lima, J Lewis, CE AF Gibbs, Bethany Barone Reis, Jared P. Schelbert, Erik B. Sidney, Steve Craft, Lynette L. Lima, Joao Lewis, Cora E. TI Sedentary Screen Time is Associated with Higher Left Ventricular Mass and Posterior Wall Thickness in the Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Physical activity; Echocardiography; Obesity C1 [Gibbs, Bethany Barone; Schelbert, Erik B.] Univ Pittsburgh, Pittsburgh, PA USA. [Reis, Jared P.] NHLBI, Bethesda, MD 20892 USA. [Sidney, Steve] Kaiser Permanente, Oakland, CA USA. [Craft, Lynette L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Lima, Joao] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA 055 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100047 ER PT J AU Joehanes, R Ying, SX Johnson, AD O'Connor, GT DeMeo, DL O'Donnell, CJ Munson, PJ Levy, D AF Joehanes, Roby Ying, Sai-xia Johnson, Andrew D. O'Connor, George T. DeMeo, Dawn L. O'Donnell, Christopher J. Munson, Peter J. Levy, Daniel TI Gene Expression Signatures of Tobacco Exposure SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Smoking; Gene expression; Genomncs C1 [Joehanes, Roby; Ying, Sai-xia; Munson, Peter J.] NIH, Bethesda, MD 20892 USA. [Johnson, Andrew D.; O'Donnell, Christopher J.; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [O'Connor, George T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [DeMeo, Dawn L.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RI Johnson, Andrew/G-6520-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA 053 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100045 ER PT J AU Justice, A North, K Loos, R Vedantam, S Day, F Berndt, S Gustafsson, S Locke, A Powell, C Bratati, K Croteau-Chonka, D Winkler, T Scherag, A Barroso, I Beckmann, J Lindgren, C Pers, T Visscher, P Willer, C Yang, J Mohlke, K Hirschorn, J Ingelsson, E Boehnke, M Speliotes, E AF Justice, Anne North, Kari Loos, Ruth Vedantam, Sailaja Day, Felix Berndt, Sonja Gustafsson, Stefan Locke, Adam Powell, Corey Bratati, Kahali Croteau-Chonka, Damien Winkler, Thomas Scherag, Andre Barroso, Ines Beckmann, Jacqui Lindgren, Cecilia Pers, Tune Visscher, Peter Willer, Cristen Yang, Jian Mohlke, Karen Hirschorn, Joel Ingelsson, Erik Boehnke, Michael Speliotes, Elizabeth TI Meta-analysis of Genetic Associations in up to 339,224 Individuals Identify 66 New Loci for Bmi, Confirming a Neuronal Contribution to Body Weight Regulation and Implicating Several Novel Pathways SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Genetics; Obesity; Genomics C1 [Justice, Anne; North, Kari] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Loos, Ruth] Mt Sinai Sch Med, New York, NY USA. [Vedantam, Sailaja] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Day, Felix] Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England. [Berndt, Sonja] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gustafsson, Stefan; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Locke, Adam; Willer, Cristen; Boehnke, Michael] Univ Michigan, Dept Biostat, Cntr Stat Genet, Ann Arbor, MI 48109 USA. [Powell, Corey; Bratati, Kahali] Univ Michigan, Dept Internal Med Gastroenterol, Ann Arbor, MI 48109 USA. [Croteau-Chonka, Damien; Mohlke, Karen] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Winkler, Thomas] Univ Regensburg, Inst Epidemiol & Prevent Med, Med Cntr, D-93053 Regensburg, Germany. [Scherag, Andre] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Barroso, Ines] Wellcome Trust Sanger Inst, Hinxton, England. [Barroso, Ines] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Rsch Labs, Cambridge CB2 2QQ, England. [Beckmann, Jacqui] CHU Vaudois, Univ Hosp, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Beckmann, Jacqui] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Lindgren, Cecilia] Univ Oxford, Wellcome Trust Cntr Human Genet, Oxford, England. [Pers, Tune] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Visscher, Peter; Yang, Jian] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia. [Hirschorn, Joel] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschorn, Joel] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschorn, Joel] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Hirschorn, Joel] Broad Inst, Metab Initiat, Boston, MA USA. [Hirschorn, Joel] Broad Inst, Program Med & Populat Genet, Boston, MA USA. [Hirschorn, Joel] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Speliotes, Elizabeth] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA 050 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100042 ER PT J AU Kaplan, R Aviles-Santa, LM Parrinello, CM Castaneda, S Hankinson, AL Isasi, CR Birnbaum-Weitzman, O Kim, R Daviglus, ML Talavera, GA Schneiderman, N Cai, JW AF Kaplan, Robert Aviles-Santa, Larissa M. Parrinello, Christina M. Castaneda, Sheila Hankinson, Arlene L. Isasi, Carmen R. Birnbaum-Weitzman, Orit Kim, Ryung Daviglus, Martha L. Talavera, Gregory A. Schneiderman, Neil Cai, Jianwen TI Severe Obesity is Associated with Dramatic Increase in Cardiovascular Disease Risk Factor Prevalence: Hispanic Community Health Study/Study of Latinos (HCHS/SOL) SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Obesity; Health disparities; Risk factors C1 [Kaplan, Robert; Parrinello, Christina M.; Isasi, Carmen R.; Kim, Ryung] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Aviles-Santa, Larissa M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Castaneda, Sheila; Talavera, Gregory A.] San Diego State Univ, San Diego, CA 92182 USA. [Hankinson, Arlene L.; Daviglus, Martha L.] Northwestern Univ, Chicago, IL 60611 USA. [Birnbaum-Weitzman, Orit; Schneiderman, Neil] Univ Miami, Miami, FL USA. [Cai, Jianwen] UNC Publ Hlth, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P292 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100412 ER PT J AU Kershaw, KN Hankinson, A Lewis, CE Liu, K Loria, CM Reis, JP Carnethon, MR AF Kershaw, Kiarri N. Hankinson, Arlene Lewis, Cora E. Liu, Kiang Loria, Catherine M. Reis, Jared P. Carnethon, Mercedes R. TI Positive and Negative Aspects of Social Relationships are Differentially Associated with Longitudinal Increases in Body Mass Index and Waist Circumference: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Social Determinants of Health; Obesity; Stress C1 [Kershaw, Kiarri N.; Hankinson, Arlene; Liu, Kiang; Carnethon, Mercedes R.] Northwestern Univ, Chicago, IL 60611 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. [Loria, Catherine M.; Reis, Jared P.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P119 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100257 ER PT J AU Leon, BM Miller, BV Zalos, G Chen, KY Sumner, AE Cannon, RO AF Leon, Benjamin M. Miller, Bernard V. Zalos, Gloria Chen, Kong Y. Sumner, Anne E. Cannon, Richard O. TI Reduced Fat Mass and Improved Insulin Sensitivity in Overweight Black Women after Completion of 6-month Worksite Weight Loss Program SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Obesity; Insulin; Health disparities C1 [Leon, Benjamin M.; Miller, Bernard V.; Zalos, Gloria; Chen, Kong Y.; Sumner, Anne E.; Cannon, Richard O.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P297 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100417 ER PT J AU Liu, JK Coady, S Hickson, DA Taylor, HA Fox, CS AF Liu, Jiankang Coady, Sean Hickson, DeMarc A. Taylor, Herman A. Fox, Caroline S. TI Neck Circumference as a New Clinical Predictor of Incident Diabetes Mellitus: Results from 9-Year Follow-Up of the Jackson Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Obesity; Diabetes mellitus C1 [Liu, Jiankang; Hickson, DeMarc A.; Taylor, Herman A.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Coady, Sean; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Coady, Sean; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P431 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100548 ER PT J AU McMahon, GM O'Seaghdha, CM Hwang, SJ Meigs, JB Fox, CS AF McMahon, Gearoid M. O'Seaghdha, Conall M. Hwang, Shih-Jen Meigs, James B. Fox, Caroline S. TI The Association of the CUBN Polymorphism rs1801239 and the Association of Albuminuria and Cardiovascular Disease in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Cardiovascular disease; Risk factors; Renal function C1 [McMahon, Gearoid M.; O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [McMahon, Gearoid M.; O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Cntr Populat Studies, Framingham, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P309 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100428 ER PT J AU McMahon, GM Preis, SR Hwang, SJ Fox, CS AF McMahon, Gearoid M. Preis, Sarah R. Hwang, Shih-Jen Fox, Caroline S. TI Long Term Risk-Factor Profiles for Chronic Kidney Disease in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Longitudinal studies; Risk factors; Renal function C1 [McMahon, Gearoid M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [McMahon, Gearoid M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Preis, Sarah R.] Boston Univ, Sch Publ Hlth, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP74 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100121 ER PT J AU Meyer, M Teng, Y Schneiderman, N Llabre, M Cowie, C Carnethon, M Kaplan, R Giachello, A Gallo, L Loehr, L Barnharts, J Aviles-Santa, L Heiss, G AF Meyer, Michelle Teng, Yanping Schneiderman, Neil Llabre, Maria Cowie, Catherine Carnethon, Mercedes Kaplan, Robert Giachello, Aida Gallo, Linda Loehr, Laura Barnharts, Janice Aviles-Santa, Larissa Heiss, Gerardo TI Diversity in Hispanic Background and Burden of Metabolic Syndrome Abnormalities: A Report from the HCHS/SOL SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Metabolism; Cardiovascular disease; Racial/ethnic disparities C1 [Meyer, Michelle; Teng, Yanping; Loehr, Laura; Heiss, Gerardo] Univ N Carolina, Chapel Hill, NC USA. [Schneiderman, Neil; Llabre, Maria] Univ Miami, Coral Gables, FL 33124 USA. [Cowie, Catherine] NIDDK, Bethesda, MD 20892 USA. [Carnethon, Mercedes; Giachello, Aida] Northwestern Univ, Chicago, IL 60611 USA. [Kaplan, Robert; Barnharts, Janice] Einstein Coll Med, Bronx, NY USA. [Gallo, Linda] San Diego State Univ, San Diego, CA 92182 USA. [Aviles-Santa, Larissa] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P437 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100554 ER PT J AU Reis, JP Launer, L Terry, JG Loria, CM Sidney, S Yaffe, K Jacobs, DR Whitlow, CT Zhu, N Carr, JJ AF Reis, Jared P. Launer, Lenore Terry, James G. Loria, Catherine M. Sidney, Stephen Yaffe, Kristine Jacobs, David R. Whitlow, Christopher T. Zhu, Na Carr, J. J. TI Subclinical Atherosclerosis and Cognitive Functioning in Middle-Aged Black and White Adults: The CARDIA Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Calcification; Aging C1 [Reis, Jared P.; Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. [Launer, Lenore] NIA, Bethesda, MD 20892 USA. [Terry, James G.; Whitlow, Christopher T.; Carr, J. J.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Sidney, Stephen] Kaiser Permanente, Oakland, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Jacobs, David R.; Zhu, Na] Univ Minnesota, Minneapolis, MN USA. RI Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P043 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100184 ER PT J AU Rodriguez, CJ Swett, K Agarwal, SK Folsom, AR Loehr, LR Fox, ER Ni, HY Rosamond, WD Chang, PP AF Rodriguez, Carlos J. Swett, Katrina Agarwal, Sunil K. Folsom, Aaron R. Loehr, Laura R. Fox, Ervin R. Ni, Hanyu Rosamond, Wayne D. Chang, Patricia P. TI Systolic Blood Pressure Control among Hypertensives and Incident Heart Failure: The Atherosclerosis Risk in Communities Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Blood pressure; Heart failure; Hypertension C1 [Rodriguez, Carlos J.; Swett, Katrina] Wake Forest Univ, Winston Salem, NC 27109 USA. [Agarwal, Sunil K.] Johns Hopkins Univ, Baltimore, MD USA. [Folsom, Aaron R.] Univ Minnesota, Minneapolis, MN USA. [Loehr, Laura R.; Rosamond, Wayne D.; Chang, Patricia P.] Univ N Carolina, Chapel Hill, NC USA. [Fox, Ervin R.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Ni, Hanyu] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP73 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100120 ER PT J AU Rosenquist, KJ Massaro, JM Krieger, BE Murabito, JM Hoffmann, U Fox, CS AF Rosenquist, Klara J. Massaro, Joseph M. Krieger, Bernard E. Murabito, Joanne M. Hoffmann, Udo Fox, Caroline S. TI Fat Quality Estimated by Computed Tomography and Associations with Incident Cardiovascular Disease and All Cause Mortality SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Obesity; Outcomes C1 [Rosenquist, Klara J.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Rosenquist, Klara J.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Krieger, Bernard E.; Murabito, Joanne M.] Boston Med Cntr, Gen Internal Med Sect, Boston, MA USA. [Krieger, Bernard E.; Murabito, Joanne M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Div Intra Mural Rsch, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP63 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100111 ER PT J AU Shay, CM Colangelo, L Carnethon, MR Liu, K Allen, NB Lewis, CE Reis, JP Jacobs, DR Terry, JG Carr, JJ AF Shay, Christina M. Colangelo, Laura Carnethon, Mercedes R. Liu, Kiang Allen, Norrina B. Lewis, Cora E. Reis, Jared P. Jacobs, David R. Terry, J. G. Carr, J. J. TI Trajectories of Maintaining Recommended Amounts of Physical Activity in Young Adulthood and Associations with Abdominal Adiposity in Middle Age: The Cardia Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Physical activity; Obesity Longitudinal studies C1 [Shay, Christina M.] Univ Oklahoma, Hlth Sci Cntr, Oklahoma City, OK USA. [Colangelo, Laura; Carnethon, Mercedes R.; Liu, Kiang; Allen, Norrina B.] Northwestern Univ, Chicago, IL 60611 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. [Reis, Jared P.] NHLBI, NIH, Bethesda, MD 20892 USA. [Jacobs, David R.] Univ Minnesota, Minneapolis, MN USA. [Terry, J. G.; Carr, J. J.] Wake Forest Univ, Winston Salem, NC 27109 USA. RI Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA 047 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100039 ER PT J AU Siddique, J Colangelo, LA Reis, JP Spring, B Moller, AC Lloyd-Jones, D Liu, K AF Siddique, Juned Colangelo, Laura A. Reis, Jared P. Spring, Bonnie Moller, Arlen C. Lloyd-Jones, Donald Liu, Kiang TI Behavior Patterns over 20 Years and their Relationship to Subclinical Atherosclerosis SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Longitudinal studies; Risk factors; Subclinical atherosclerosis C1 [Siddique, Juned; Colangelo, Laura A.; Spring, Bonnie; Lloyd-Jones, Donald; Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Reis, Jared P.] NHLBI, NIH, Bethesda, MD 20892 USA. [Moller, Arlen C.] IIT, Chicago, IL 60616 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P378 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100496 ER PT J AU Sidney, S Liu, K Levine, DA Bibbins-Domingo, K Nguyen-Huynh, MN Lima, J Reis, JP Loria, C Lewis, CE AF Sidney, Stephen Liu, Kiang Levine, Deborah A. Bibbins-Domingo, Kirsten Nguyen-Huynh, Mai N. Lima, Joao Reis, Jared P. Loria, Catherine Lewis, Cora E. TI 24-Year Risk of Stroke in the Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Racial/ethnic disparities; Stroke; Blood pressure C1 [Sidney, Stephen; Nguyen-Huynh, Mai N.] Kaiser Permanente No Calif, Oakland, CA USA. [Liu, Kiang] Northwestern Univ, Chicago, IL 60611 USA. [Levine, Deborah A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lima, Joao] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Reis, Jared P.; Loria, Catherine] NHLBI, Bethesda, MD 20892 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP51 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100100 ER PT J AU Terry, JG Lovato, J Shay, CM Reis, I Gidding, SS Schreiner, PJ Goff, DC Jacobss, DR Carr, JJ AF Terry, James G. Lovato, James Shay, Christina M. Reis, Iared Gidding, Samuel S. Schreiner, Pamela J. Goff, David C. Jacobss, David R. Carr, J. J. TI Skeletal Muscle Adipose Tissue is Associated with Coronary Artery Calcification: The CARDIA Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Obesity; Subclinical atherosclerosis; Coronary vessels C1 [Terry, James G.; Lovato, James; Carr, J. J.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Shay, Christina M.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Reis, Iared] NIH, Bethesda, MD 20892 USA. [Gidding, Samuel S.] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Schreiner, Pamela J.; Jacobss, David R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Goff, David C.] Colorado Sch Publ Hlth, Aurora, CO USA. RI Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP66 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100114 ER PT J AU Tsao, CW Pencina, K Massaro, JM Levy, D Vasan, RS Hoffmann, U O'Donnell, CJ Mitchell, GF AF Tsao, Connie W. Pencina, Karol Massaro, Joseph M. Levy, Daniel Vasan, Ramachandran S. Hoffmann, Udo O'Donnell, Christopher J. Mitchell, Gary F. TI Relations of Subclinical Measures of Arterial Stiffness and Pulsatility with Arterial Calcification in Men and Women SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Aortic diseases; Calcification; Subclinical atherosclerosis C1 [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Tsao, Connie W.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Boston, MA USA. [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Framingham, MA USA. [Tsao, Connie W.; Levy, Daniel; Vasan, Ramachandran S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pencina, Karol; Massaro, Joseph M.; Vasan, Ramachandran S.] Boston Univ, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc F, Norwood, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P381 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100499 ER PT J AU Weinberg, I Gona, P O'Donnell, CJ Jaff, MR Murabito, J AF Weinberg, Ido Gona, Philimon O'Donnell, Christopher J. Jaff, Michael R. Murabito, Joanne TI Inter-arm Blood Pressure Difference and Cardiovascular Disease Risk in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Subclinical atherosclerosis; Cardiovascular disease; Risk factors C1 [Weinberg, Ido; Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gona, Philimon] Univ Massachusetts, Sch Med, Boston, MA 02125 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Boston, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Murabito, Joanne] Framingham Heart Dis Epidemiol Study, Boston, MA USA. [Murabito, Joanne] Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P075 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100216 ER PT J AU Zhu, N Jacobs, DR Meyer, KA He, K Launer, LJ Reis, JP Yaffe, K Sidney, S Whitmer, R Steffen, LM AF Zhu, Na Jacobs, David R. Meyer, Kate A. He, Ka Launer, Lenore J. Reis, Jared P. Yaffe, Kristine Sidney, Stephen Whitmer, Rachel Steffen, Lyn M. TI Dietary Pattern is Associated with Better Cognitive Function: The CARDIA Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Diet; Aging; Prevention C1 [Zhu, Na; Jacobs, David R.; Steffen, Lyn M.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Meyer, Kate A.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [He, Ka] Indiana Univ, Sch Publ Hlth, Bloomington, IN USA. [Launer, Lenore J.] NIA, Bethesda, MD 20892 USA. [Reis, Jared P.] NHLBI, Bethesda, MD 20892 USA. [Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Sidney, Stephen; Whitmer, Rachel] Kaiser Permanente Div Rsch, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P400 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100517 ER PT J AU Wang, HY Ma, CA Zhao, YG Fan, XY Zhou, Q Edmonds, P Uzel, G Oliveira, JB Orange, J Jain, A AF Wang, Hong-Ying Ma, Chi A. Zhao, Yongge Fan, Xiying Zhou, Qing Edmonds, Pamela Uzel, Gulbu Oliveira, Joao Bosco Orange, Jordan Jain, Ashish TI Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE apoptosis; B cell lymphopenia; cysteine mutation; heteromers ID COMMON VARIABLE IMMUNODEFICIENCY; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; KAPPA-B PATHWAY; MOLECULAR-BASIS; CELL; RECEPTOR; APOPTOSIS; APRIL; BAFF; TNF AB Mutations in the TNF family of proteins have been associated with inherited forms of immune deficiency. Using an array-based sequencing assay, we identified an autosomal-dominant deficiency in TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. This mutation occurs in the sixth exon of TWEAK and results in the amino acid substitution R145C within the conserved TNF-homology domain of the full-length protein. TWEAK mutant protein formed high molecular weight aggregates under nonreducing conditions, suggesting an increased propensity for intermolecular interactions. As a result, mutant TWEAK associated with B-cell-activating factor (BAFF) protein and down-regulated the BAFF-mediated activation of the noncanonical NF-kappa B pathway through inhibition of p100 processing to p52, resulting in inhibition of BAFF-dependent B-cell survival and proliferation. As BAFF mediates T-cell-independent isotype switching and B-cell survival, our data implicate TWEAK as a disease-susceptibility gene for a humoral immunodeficiency. C1 [Wang, Hong-Ying; Ma, Chi A.; Zhao, Yongge; Fan, Xiying; Edmonds, Pamela; Jain, Ashish] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Zhou, Qing] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA. [Uzel, Gulbu] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Oliveira, Joao Bosco] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Orange, Jordan] Univ Penn, Dept Pediat, Sch Med, Philadelphia, PA 19104 USA. RP Jain, A (reprint author), NIAID, Host Def Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ajain@niaid.nih.gov RI Yu, Xiaomin/I-6407-2016; OI orange, jordan/0000-0001-7117-7725; Oliveira, Joao/0000-0001-9388-8173; Fan, Xiying/0000-0003-3090-381X FU NIH/NIAID FX We thank the patients' families for their participation in this study; Ron Hornung and Margaret Brown for immunologic evaluations; Mary Derry for editoral assistance; and Ivona Aksentijevich, Linda Burkly, and Warren Strober for helpful discussions. This research was supported by the Intramural Research Program of the NIH/NIAID. NR 35 TC 15 Z9 16 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 26 PY 2013 VL 110 IS 13 BP 5127 EP 5132 DI 10.1073/pnas.1221211110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131XN UT WOS:000318031900060 PM 23493554 ER PT J AU Bukalo, O Campanac, E Hoffman, DA Fields, RD AF Bukalo, Olena Campanac, Emilie Hoffman, Dax A. Fields, R. Douglas TI Synaptic plasticity by antidromic firing during hippocampal network oscillations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE long-term depression; long-term potentiation; network plasticity; excitability ID LONG-TERM DEPRESSION; TIMING-DEPENDENT PLASTICITY; HIGH-FREQUENCY OSCILLATIONS; WAVE-RIPPLE COMPLEXES; IN-VITRO; SLEEP HOMEOSTASIS; ACTION-POTENTIALS; PYRAMIDAL CELLS; DOWN-REGULATION; MEMORY AB Learning and other cognitive tasks require integrating new experiences into context. In contrast to sensory-evoked synaptic plasticity, comparatively little is known of how synaptic plasticity may be regulated by intrinsic activity in the brain, much of which can involve nonclassical modes of neuronal firing and integration. Coherent high-frequency oscillations of electrical activity in CA1 hippocampal neurons [sharp-wave ripple complexes (SPW-Rs)] functionally couple neurons into transient ensembles. These oscillations occur during slow-wave sleep or at rest. Neurons that participate in SPW-Rs are distinguished from adjacent nonparticipating neurons by firing action potentials that are initiated ectopically in the distal region of axons and propagate antidromically to the cell body. This activity is facilitated by GABA(A)-mediated depolarization of axons and electrotonic coupling. The possible effects of antidromic firing on synaptic strength are unknown. We find that facilitation of spontaneous SPW-Rs in hippocampal slices by increasing gap-junction coupling or by GABAA-mediated axon depolarization resulted in a reduction of synaptic strength, and electrical stimulation of axons evoked a widespread, long-lasting synaptic depression. Unlike other forms of synaptic plasticity, this synaptic depression is not dependent upon synaptic input or glutamate receptor activation, but rather requires L-type calcium channel activation and functional gap junctions. Synaptic stimulation delivered after antidromic firing, which was otherwise too weak to induce synaptic potentiation, triggered a long-lasting increase in synaptic strength. Rescaling synaptic weights in subsets of neurons firing antidromically during SPW-Rs might contribute to memory consolidation by sharpening specificity of subsequent synaptic input and promoting incorporation of novel information. C1 [Bukalo, Olena; Fields, R. Douglas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Campanac, Emilie; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU National Institute of Child Health and Human Development FX We thank K. A. Pelkey, A. Dityatev, H. Wake, A. Morozov, and T. Coate for critically reading the manuscript and National Institute of Child Health and Human Development intramural funding for support. NR 55 TC 15 Z9 15 U1 1 U2 18 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 MAR 26 PY 2013 VL 110 IS 13 BP 5175 EP 5180 DI 10.1073/pnas.1210735110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131XN UT WOS:000318031900068 PM 23479613 ER PT J AU Miranda, P Contreras, JE Plested, AJR Sigworth, FJ Holmgren, M Giraldez, T AF Miranda, Pablo Contreras, Jorge E. Plested, Andrew J. R. Sigworth, Fred J. Holmgren, Miguel Giraldez, Teresa TI State-dependent FRET reports calcium- and voltage-dependent gating-ring motions in BK channels SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE allosteric regulation; SLO1 channel; fluorescence ID GREEN FLUORESCENT PROTEIN; K+ CHANNEL; POTASSIUM CHANNEL; CA2+-DEPENDENT ACTIVATION; STRUCTURAL DYNAMICS; ENERGY-TRANSFER; CA2+ BINDING; SENSITIVITY; DOMAIN; SITES AB Large-conductance voltage-and calcium-dependent potassium channels (BK, "Big K+") are important controllers of cell excitability. In the BK channel, a large C-terminal intracellular region containing a "gating-ring" structure has been proposed to transduce Ca2+ binding into channel opening. Using patch-clamp fluorometry, we have investigated the calcium and voltage dependence of conformational changes of the gating-ring region of BK channels, while simultaneously monitoring channel conductance. Fluorescence resonance energy transfer (FRET) between fluorescent protein inserts indicates that Ca2+ binding produces structural changes of the gating ring that are much larger than those predicted by current X-ray crystal structures of isolated gating rings. C1 [Miranda, Pablo; Giraldez, Teresa] Univ Hosp Nuestra Senora de Candelaria, Div Res, Tenerife 38010, Spain. [Miranda, Pablo] Univ La Laguna, Dept Physiol, Tenerife 38071, Spain. [Contreras, Jorge E.; Holmgren, Miguel] NINDS, NIH, Bethesda, MD 20892 USA. [Plested, Andrew J. R.] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany. [Plested, Andrew J. R.] Charite, NeuroCure, D-10117 Berlin, Germany. [Sigworth, Fred J.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. RP Giraldez, T (reprint author), Univ Hosp Nuestra Senora de Candelaria, Div Res, Tenerife 38010, Spain. EM giraldez@ull.es RI Giraldez, Teresa/G-8970-2015; OI Giraldez, Teresa/0000-0002-4096-810X; Plested, Andrew/0000-0001-6062-0832 FU Instituto de Salud Carlos III-Subdirectorate General for Evaluation and Promotion of Research Grants [MS07/00034, PI09/00406, PI12/00428]; Spanish Ministry of Economy Grant Consolider-Ingenio [CSD 2008-0005]; European Regional Development Funds from the European Union; National Institutes of Health (NIH)-National Institute of Neurological Disorders and Stroke; Deutsche Forschungsgemeinschaft [EXC257]; NIH [NS21501] FX We thank Diana Wesch for performing preliminary experiments at early stages of the project, which were not included in this manuscript; Diego Alvarez de la Rosa, Barbara Ehrlich, and Patricio Rojas for helpful comments on the manuscript; Deepa Srikumar for technical assistance; and Jie Zheng for providing the CFP24YFP tandem plasmid. This work was funded by Instituto de Salud Carlos III-Subdirectorate General for Evaluation and Promotion of Research Grants MS07/00034, PI09/00406, and PI12/00428, and Spanish Ministry of Economy Grant Consolider-Ingenio CSD 2008-0005; and cofinanced by the European Regional Development Funds, "A Way of Making Europe," from the European Union (to T.G). Additional support was from the intramural section of the National Institutes of Health (NIH)-National Institute of Neurological Disorders and Stroke (M.H.), Deutsche Forschungsgemeinschaft Grant EXC257 (to A.J.R.P.), and NIH Grant NS21501 (to F.J.S.). NR 41 TC 17 Z9 18 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 MAR 26 PY 2013 VL 110 IS 13 BP 5217 EP 5222 DI 10.1073/pnas.1219611110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131XN UT WOS:000318031900075 PM 23479636 ER PT J AU Sigurjonsdottir, K Bjorgulfsson, TM Aspelund, T Eiriksdottir, G Sigurdsson, S Ingvarsson, T Harris, TB Launer, L Gudnason, V Jonsson, H AF Sigurjonsdottir, Kristin Bjorgulfsson, Thorir M. Aspelund, Thor Eiriksdottir, Gudny Sigurdsson, Sigurdur Ingvarsson, Thorvaldur Harris, Tamara B. Launer, Lenore Gudnason, Vilmundur Jonsson, Helgi TI Type 3 finger length pattern is associated with total knee replacements due to osteoarthritis but not with hip replacements or hand osteoarthritis in the elderly: The AGES-Reykjavik study SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE Osteoarthritis; Finger length ratio; Epidemiology ID 4TH DIGIT RATIO; SEX-HORMONES; 2ND; 2D/4D; PREDICTOR; TESTOSTERONE; PERFORMANCE; ABILITY; SUCCESS; INDEX AB Background: Recent case-control studies have shown an association between type 3 finger length pattern (longer ring finger than index finger) and knee osteoarthritis. This large cross-sectional study tests the hypothesis that the type 3 pattern is associated with total joint replacements due to osteoarthritis in a large population based study. Methods: Finger length ratios were assessed visually on 5170 hand photographs (2975 females, 2195 males, mean age 76). In this population-based multidisciplinary study of aging in Reykjavik, Iceland, the prevalence of osteoarthritis associated total knee replacements was 223(4.3%) and total hip replacements 316(6.1%). We then performed a binary logistic regression analysis for total knee replacements and total hip replacements, including finger length patterns, osteoarthritis at other sites and other variables with possible association to osteoarthritis such as age, BMI and bone mineral density of the spine. Results: The prevalence of the type 3 pattern was 50% (43% in females, 58% in males). The regression analysis revealed an odds ratio for total knee replacements of 1.65 (1.24-2.2) p = 0.0007, in the type 3 finger pattern group, similar in both genders. This association was independent of the associations we have previously reported between total knee replacements and BMI and the presence of hand osteoarthritis. No association was seen between finger length patterns and total hip replacements. Conclusion: Finger length patterns read from digital photographs in this large study confirm previous radiographic observations with significant associations between the type 3 pattern and total knee replacements but not total hip replacements in both genders in this elderly group. C1 [Sigurjonsdottir, Kristin; Bjorgulfsson, Thorir M.; Aspelund, Thor; Gudnason, Vilmundur; Jonsson, Helgi] Univ Iceland, Reykjavik, Iceland. [Aspelund, Thor; Eiriksdottir, Gudny; Sigurdsson, Sigurdur; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Ingvarsson, Thorvaldur] Akureyri Cent Hosp, Akureyri, Iceland. [Harris, Tamara B.; Launer, Lenore] NIA, Bethesda, MD 20892 USA. [Sigurjonsdottir, Kristin; Jonsson, Helgi] Landspitalinn Univ Hosp ICELAND, Reykjavik, Iceland. RP Sigurjonsdottir, K (reprint author), Univ Iceland, Reykjavik, Iceland. EM krs2@hi.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 NIH [N01-AG-12100]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Icelandic Osteoarthritis Fund; University of Iceland Research Fund FX Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), the Icelandic Osteoarthritis Fund and the University of Iceland Research Fund. The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. NR 31 TC 5 Z9 5 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD MAR 26 PY 2013 VL 14 AR 112 DI 10.1186/1471-2474-14-112 PG 5 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 124QP UT WOS:000317480800002 PM 23530906 ER PT J AU Adamson, A Ghoreschi, K Rittler, M Chen, Q Sun, HW Vahedi, G Kanno, Y Stetler-Stevenson, WG O'Shea, JJ Laurence, A AF Adamson, Adewole Ghoreschi, Kamran Rittler, Matthew Chen, Qian Sun, Hong-Wei Vahedi, Golnaz Kanno, Yuka Stetler-Stevenson, William G. O'Shea, John J. Laurence, Arian TI Tissue Inhibitor of Metalloproteinase 1 Is Preferentially Expressed in Th1 and Th17 T-Helper Cell Subsets and Is a Direct Stat Target Gene SO PLOS ONE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INFLAMMATORY-BOWEL-DISEASE; MATRIX METALLOPROTEINASES; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; TGF-BETA; DIFFERENTIATION; CYTOKINE; T(H)17; TIMP-1 AB CD4(+) T helper (Th) cells differentiate into distinct effector subsets that are critical for host defense, but are also implicated in the pathogenesis of autoimmune disorders. Thelper17 (Th17) cells in particular are emerging as important drivers of multiple diseases including psoriasis, spondyloarthropathy and multiple sclerosis. To gain insight into the function of Th17 cells, we performed transcriptional profiling in hopes of elucidating products not previously recognized as being functionally relevant in these T cells. Herein, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted protein with pleiotropic effects on cellular growth, survival and integrity of the extracellular matrix, is preferentially produced by Th17 and Th1 cells. We further show that Th1 and Th17 cell TIMP1 regulation follows separate mechanisms with a requirement for STAT4 in the former and STAT3 in the latter. Finally, we demonstrate that when restricted to T cells, expression of TIMP1 promotes neuropathology in experimental allergic encephalomyelitis. C1 [Adamson, Adewole; Ghoreschi, Kamran; Sun, Hong-Wei; Vahedi, Golnaz; Kanno, Yuka; O'Shea, John J.; Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Rittler, Matthew; Stetler-Stevenson, William G.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Chen, Qian] Huazhong Univ Sci & Technol, Tongji Med Coll, Div Gastroenterol, Dept Internal Med, Wuhan, Hubei Province, Peoples R China. [Adamson, Adewole] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Boston, MA USA. [Ghoreschi, Kamran] Univ Tubingen, Dept Dermatol, Univ Med Ctr, Tubingen, Germany. RP Laurence, A (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM laurencea@mail.nih.gov RI Kanno, Yuka/B-5802-2013; Stetler-Stevenson, William/H-6956-2012; Laurence, Arian/A-8770-2009; OI Stetler-Stevenson, William/0000-0002-5500-5808; Laurence, Arian/0000-0003-0942-8292; Kanno, Yuka/0000-0001-5668-9319 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health FX This research was supported by intramural funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. AA was supported by the National Institutes of Health Clinical Research Training Program, a public-private partnership between the Foundation for the National Institutes of Health and Pfizer Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 3 Z9 3 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 MAR 26 PY 2013 VL 8 IS 3 AR e59367 DI 10.1371/journal.pone.0059367 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 123VE UT WOS:000317418500036 PM 23555662 ER PT J AU Lan, Q Cawthon, R Gao, YT Hu, W Hosgood, HD Barone-Adesi, F Ji, BT Bassig, B Chow, WH Shu, XO Cai, QY Xiang, YB Berndt, S Kim, C Chanock, S Zheng, W Rothman, N AF Lan, Qing Cawthon, Richard Gao, Yutang Hu, Wei Hosgood, H. Dean, III Barone-Adesi, Francesco Ji, Bu-Tian Bassig, Bryan Chow, Wong-Ho Shu, Xiaoou Cai, Qiuyin Xiang, Yongbin Berndt, Sonja Kim, Christopher Chanock, Stephen Zheng, Wei Rothman, Nathaniel TI Longer Telomere Length in Peripheral White Blood Cells Is Associated with Risk of Lung Cancer and the rs2736100 (CLPTM1L-TERT) Polymorphism in a Prospective Cohort Study among Women in China SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; MULTIPLEX QUANTITATIVE PCR; SUSCEPTIBILITY LOCI; DNA-REPAIR; VARIANTS; 5P15.33; CHEMOTHERAPY; LYMPHOMA; BIOLOGY; HEALTH AB A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations. C1 [Lan, Qing; Hu, Wei; Hosgood, H. Dean, III; Barone-Adesi, Francesco; Ji, Bu-Tian; Bassig, Bryan; Chow, Wong-Ho; Berndt, Sonja; Kim, Christopher; Chanock, Stephen; Rothman, Nathaniel] NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cawthon, Richard] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. [Gao, Yutang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Shu, Xiaoou; Cai, Qiuyin; Xiang, Yongbin; Zheng, Wei] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, Nashville, TN USA. [Shu, Xiaoou; Cai, Qiuyin; Xiang, Yongbin; Zheng, Wei] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Lan, Q (reprint author), NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM qingl@mail.nih.gov RI Hu, Wei/M-3524-2013 FU National Cancer Institute (Bethesda, MD) FX This work was supported by intramural funds from the National Cancer Institute (Bethesda, MD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 36 Z9 36 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 MAR 26 PY 2013 VL 8 IS 3 AR e59230 DI 10.1371/journal.pone.0059230 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 123VE UT WOS:000317418500027 PM 23555636 ER PT J AU Miao, M Wang, ZL Yang, ZQ Yuan, LL Parker, DM Putaporntip, C Jongwutiwes, S Xangsayarath, P Pongvongsa, T Moji, H Tuong, TD Abe, T Nakazawa, S Kyaw, MP Yan, GY Sirichaisinthop, J Sattabongkot, J Mu, JB Su, XZ Kaneko, O Cui, LW AF Miao, Miao Wang, Zenglei Yang, Zhaoqing Yuan, Lili Parker, Daniel M. Putaporntip, Chaturong Jongwutiwes, Somchai Xangsayarath, Phonepadith Pongvongsa, Tiengkham Moji, Hazuhiko Trinh Dinh Tuong Abe, Tomoko Nakazawa, Shusuke Kyaw, Myat Phone Yan, Guiyun Sirichaisinthop, Jeeraphat Sattabongkot, Jetsumon Mu, Jianbing Su, Xin-zhuan Kaneko, Osamu Cui, Liwang TI Genetic Diversity and Lack of Artemisinin Selection Signature on the Plasmodium falciparum ATP6 in the Greater Mekong Subregion SO PLOS ONE LA English DT Article ID SERCA-TYPE PFATPASE6; IN-VITRO; DNA POLYMORPHISM; POINT MUTATIONS; NUCLEOTIDE SUBSTITUTIONS; COMBINATION THERAPIES; MITOCHONDRIAL-DNA; RESISTANT MALARIA; S769N MUTATION; ARTESUNATE AB The recent detection of clinical Artemisinin (ART) resistance manifested as delayed parasite clearance in the Cambodia-Thailand border area raises a serious concern. The mechanism of ART resistance is not clear; but the P. falciparum sarco/endoplasmic reticulum Ca2+-ATPase (PfSERCA or PfATP6) has been speculated to be the target of ARTs and thus a potential marker for ART resistance. Here we amplified and sequenced pfatp6 gene (similar to 3.6 Kb) in 213 samples collected after 2005 from the Greater Mekong Subregion, where ART drugs have been used extensively in the past. A total of 24 single nucleotide polymorphisms (SNPs), including 8 newly found in this study and 13 nonsynonymous, were identified. However, these mutations were either uncommon or also present in other geographical regions with limited ART use. None of the mutations were suggestive of directional selection by ARTs. We further analyzed pfatp6 from a worldwide collection of 862 P. falciparum isolates in 19 populations from Asia, Africa, South America and Oceania, which include samples from regions prior to and after deployments ART drugs. A total of 71 SNPs were identified, resulting in 106 nucleotide haplotypes. Similarly, many of the mutations were continent-specific and present at frequencies below 5%. The most predominant and perhaps the ancestral haplotype occurred in 441 samples and was present in 16 populations from Asia, Africa, and Oceania. The 3D7 haplotype found in 54 samples was the second most common haplotype and present in nine populations from all four continents. Assessment of the selection strength on pfatp6 in the 19 parasite populations found that pfatp6 in most of these populations was under purifying selection with an average dN/dS ratio of 0.333. Molecular evolution analyses did not detect significant departures from neutrality in pfatp6 for most populations, challenging the suitability of this gene as a marker for monitoring ART resistance. C1 [Miao, Miao; Wang, Zenglei; Parker, Daniel M.; Cui, Liwang] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Yang, Zhaoqing; Yuan, Lili] Kunming Med Coll, Dept Parasitol, Kunming, Yunnan, Peoples R China. [Putaporntip, Chaturong; Jongwutiwes, Somchai] Chulalongkorn Univ, Dept Parasitol, Mol Biol Malaria & Opportunist Parasites Res Unit, Bangkok, Thailand. [Xangsayarath, Phonepadith; Abe, Tomoko; Nakazawa, Shusuke; Kaneko, Osamu] Nagasaki Univ, Dept Protozool, Inst Trop Med NEKKEN, Nagasaki, Japan. [Xangsayarath, Phonepadith; Abe, Tomoko; Nakazawa, Shusuke; Kaneko, Osamu] Nagasaki Univ, Global Ctr Excellence Program, Nagasaki, Japan. [Pongvongsa, Tiengkham] Stn Malariol Parasitol & Entomol, Kaysone Dist, Savannakhet Pro, Laos. [Moji, Hazuhiko] Res Inst Humanity & Nat, Kyoto, Japan. [Trinh Dinh Tuong] Natl Inst Malariol Parasitol & Entomol, Dept Epidemiol, Hanoi, Vietnam. [Kyaw, Myat Phone] Dept Med Res Lower Myanmar, Parasitol Res Div, Yangon, Myanmar. [Yan, Guiyun] Univ Calif Irvine, Program Publ Hlth, Irvine, CA USA. [Sirichaisinthop, Jeeraphat] Vector Borne Dis Training Ctr, Sara Buri, Thailand. [Sattabongkot, Jetsumon] Mahidol Univ, Fac Trop Med, Bangkok, Thailand. [Mu, Jianbing; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Cui, LW (reprint author), Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. EM luc2@psu.edu OI Parker, Daniel/0000-0002-5352-7338; Su, Xinzhuan/0000-0003-3246-3248 FU Divisions of Intramural Research, the National Institute of Allergy and Infectious Diseases, National Institutes of Health [U19 AI089672, 1R01AI075429] FX This project was supported by grants (U19 AI089672 and 1R01AI075429) and by the Divisions of Intramural Research, the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 6 Z9 8 U1 0 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 26 PY 2013 VL 8 IS 3 AR e59192 DI 10.1371/journal.pone.0059192 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 123VE UT WOS:000317418500024 PM 23555629 ER PT J AU Ronda, L Bettati, S Henry, ER Kashav, T Sanders, JM Royer, WE Mozzarelli, A AF Ronda, Luca Bettati, Stefano Henry, Eric R. Kashav, Tara Sanders, Jeffrey M. Royer, William E. Mozzarelli, Andrea TI Tertiary and Quaternary Allostery in Tetrameric Hemoglobin from Scapharca inaequivalvis SO BIOCHEMISTRY LA English DT Article ID COOPERATIVE DIMERIC HEMOGLOBIN; T-STATE HEMOGLOBIN; OXYGEN-BINDING; SILICA-GELS; FUNCTIONAL-CHARACTERIZATION; AFFINITY CONFORMATIONS; CRYSTAL-STRUCTURE; SINGLE-CRYSTALS; HEME-PROTEINS; RESOLUTION AB The clam Scapharca inaequivalvis possesses two cooperative oxygen binding hemoglobins in its red cells: a homodimeric HbI and a heterotetrameric A2B2 HbII, Each AB dimeric half of HbII is assembled in a manner very similar to that of the well-studied HbI. This study presents crystal structures of HbII along with oxygen binding data both in the crystalline state and in wet nanoporous silica gels. Despite very similar ligand-linked structural transitions observed in HbI and HbII crystals, HbII in the crystal or encapsulated in silica gels apparently exhibits minimal cooperativity in oxygen binding, in contrast with the full cooperativity exhibited by HbI crystals. However, oxygen binding curves in the crystal indicate the presence of a significant functional inequivalence of A and B chains. When this inequivalence is taken into account, both crystal and R state gel functional data are consistent with the conservation of a tertiary contribution to cooperative oxygen binding, quantitatively similar to that measured for HbI, and are in keeping with the structural information. Furthermore, our results indicate that to fully express cooperative ligand binding, HbII requires quaternary transitions hampered by crystal lattice and gel encapsulation, revealing greater complexity in cooperative function than the direct communication across a dimeric interface observed in HbI. C1 [Ronda, Luca; Mozzarelli, Andrea] Univ Parma, Dept Pharm, I-43124 Parma, Italy. [Bettati, Stefano] Univ Parma, Dept Neurosci, I-43125 Parma, Italy. [Bettati, Stefano; Mozzarelli, Andrea] Natl Inst Biostruct & Biosyst, I-00136 Rome, Italy. [Henry, Eric R.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Kashav, Tara; Sanders, Jeffrey M.; Royer, William E.] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. RP Royer, WE (reprint author), Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, 364 Plantat St,LRB921, Worcester, MA 01605 USA. EM andrea.mozzarelli@unipr.it RI Henry, Eric/J-3414-2013; Ronda, Luca/E-5214-2012; Mozzarelli, Andrea/C-3615-2014; OI Henry, Eric/0000-0002-5648-8696; Mozzarelli, Andrea/0000-0003-3762-0062; Ronda, Luca/0000-0002-5389-2669 FU U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; National Center for Research Resources [5P41RR007707]; National Institute of General Medical Sciences from the National Institutes of Health [8P41GM103543] FX We thank Drs. Gianni Colotti and Emilia Chiancone for the generous gift of purified HbII. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract DE-AC02-06CH11357. Use of BioCARS Sector 14 was also supported by grants from the National Center for Research Resources (5P41RR007707) and the National Institute of General Medical Sciences (8P41GM103543) from the National Institutes of Health. NR 53 TC 2 Z9 2 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 26 PY 2013 VL 52 IS 12 BP 2108 EP 2117 DI 10.1021/bi301620x PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 115YC UT WOS:000316846800010 PM 23458680 ER PT J AU Zhang, FM Walcott, B Zhou, DW Gustchina, A Lasanajak, Y Smith, DF Ferreira, RS Correia, MTS Paiva, PMG Bovin, NV Wlodawer, A Oliva, MLV Linhardt, RJ AF Zhang, Fuming Walcott, Benjamin Zhou, Dongwen Gustchina, Alla Lasanajak, Yi Smith, David F. Ferreira, Rodrigo S. Correia, Maria Tereza S. Paiva, Patricia M. G. Bovin, Nicolai V. Wlodawer, Alexander Oliva, Maria L. V. Linhardt, Robert J. TI Structural Studies of the Interaction of Crataeva tapia Bark Protein with Heparin and Other Glycosaminoglycans SO BIOCHEMISTRY LA English DT Article ID BINDING LECTIN; HEPARIN/HEPARAN SULFATE AB CrataBL, a protein isolated from Crataeva tapia bark, which is both a serine protease inhibitor and a lectin, has been previously shown to exhibit a number of interesting biological properties, including anti-inflammatory, analgesic, antitumor, and insecticidal activities. Using a glycan array, we have now shown that only sulfated carbohydrates are effectively bound by CrataBL. Because this protein was recently shown to delay clot formation by impairing the intrinsic pathway of the coagulation cascade, we considered that its natural ligand might be heparin. Heparin is a glycosaminoglycan (GAG) that interacts with a number of proteins, including thrombin and antithrombin III, which have a critical, essential pharmacological role in regulating blood coagulation. We have thus employed surface plasmon resonance to improve our understanding of the binding interaction between the heparin polysaccharide and CrataBL. Kinetic analysis shows that CrataBL displays strong heparin binding affinity (K-D = 49 nM). Competition studies using different size heparin-derived oligosaccharides showed that the binding of CrataBL to heparin is chain length-dependent. Full chain heparin with 40 saccharides or large oligosaccharides, having 16-18 saccharide residues, show strong binding affinity for CrataBL. Heparin-derived disaccharides through tetradecasaccharides show considerably lower binding affinity. Other highly sulfated GAGs, including chondroitin sulfate E and dermatan 4,6-disulfate, showed CrataBL binding affinity comparable to that of heparin. Less highly sulfated GAGs, heparan sulfate, chondroitin sulfate A and C, and dermatan sulfate displayed modest binding affinity as did chondroitin sulfate D. Studies using chemically modified heparin show that N-sulfo and 6-O-sulfo groups on heparin are essential for CrataBL-heparin interaction. C1 [Zhang, Fuming; Walcott, Benjamin; Linhardt, Robert J.] Rensselaer Polytech Inst, Dept Chem & Biol Engn, Dept Chem & Chem Biol, Ctr Biotechnol & Interdisciplinary Studies,Dept B, Troy, NY 12180 USA. [Zhou, Dongwen; Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Lasanajak, Yi; Smith, David F.] Emory Univ, Sch Med, Dept Biochem, Glyc Ctr, Atlanta, GA 30322 USA. [Ferreira, Rodrigo S.; Oliva, Maria L. V.] Univ Fed Sao Paulo, Dept Bioquim, BR-04044020 Sao Paulo, Brazil. [Correia, Maria Tereza S.; Paiva, Patricia M. G.] Univ Fed Pernambuco, Dept Bioquim, BR-50670901 Recife, PE, Brazil. [Bovin, Nicolai V.] Russian Acad Sci, Inst Bioorgan Chem, Lab Carbohydrate Chem, Moscow 117997, Russia. RP Zhang, FM (reprint author), Rensselaer Polytech Inst, Dept Chem & Biol Engn, Dept Chem & Chem Biol, Ctr Biotechnol & Interdisciplinary Studies, Troy, NY 12180 USA. EM zhangf2@rpi.edu; linhar@rpi.edu RI Ferreira, Rodrigo/C-1763-2013; Oliva, Maria Luiza/B-9537-2012; OI Ferreira, Rodrigo/0000-0003-4103-6870; Walcott, Benjamin/0000-0001-9374-9149; Paiva, Patricia/0000-0003-3467-708X FU National Institutes of Health (NIH) [GM-38060]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Molecular and Cell Biology grant (Presidium RAS); CAPES; CNPq; FAPESP [09/53766-5]; National Institute of General Medical Sciences [GM62116, GM98791] FX This work was supported in part by a grant from the National Institutes of Health (NIH) (GM-38060 to R.J.L.), in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part by a Molecular and Cell Biology grant (Presidium RAS) to N.V.B. We are also grateful to CAPES, CNPq, and FAPESP (Process 09/53766-5) for providing financial support.; We acknowledge The Consortium for Functional Glycomics funded by National Institute of General Medical Sciences Grants GM62116 and GM98791 for services provided by the Glycan Array Synthesis Core (The Scripps Research Institute, La Jolla, CA) that produced the mammalian glycan microarray and the Protein-Glycan Interaction Core (Emory University School of Medicine) that assisted with analysis of samples on the array. NR 30 TC 5 Z9 5 U1 2 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 26 PY 2013 VL 52 IS 12 BP 2148 EP 2156 DI 10.1021/bi400077b PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 115YC UT WOS:000316846800014 PM 23448527 ER PT J AU Budoff, MJ Young, R Lopez, VA Kronmal, RA Nasir, K Blumenthal, RS Detrano, RC Bild, DE Guerci, AD Liu, K Shea, S Szklo, M Post, W Lima, J Bertoni, A Wong, ND AF Budoff, Matthew J. Young, Rebekah Lopez, Victor A. Kronmal, Richard A. Nasir, Khurram Blumenthal, Roger S. Detrano, Robert C. Bild, Diane E. Guerci, Alan D. Liu, Kiang Shea, Steven Szklo, Moyses Post, Wendy Lima, Joao Bertoni, Alain Wong, Nathan D. TI Progression of Coronary Calcium and Incident Coronary Heart Disease Events MESA (Multi-Ethnic Study of Atherosclerosis) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE atherosclerosis; coronary calcification; coronary heart disease; imaging ID BEAM COMPUTED-TOMOGRAPHY; ARTERY CALCIUM; MULTIPLE IMPUTATION; MYOCARDIAL-INFARCTION; SURVIVAL ANALYSIS; LOWERING THERAPY; CALCIFICATION; RISK; PREDICTS; ADULTS AB Objectives The study examined whether progression of coronary artery calcium (CAC) is a predictor of future coronary heart disease (CHD) events. Background CAC predicts CHD events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. Methods We studied 6,778 persons (52.8% female) aged 45 to 84 years from the MESA (Multi-Ethnic Study of Atherosclerosis) study. A total of 5,682 persons had baseline and follow-up CAC scans approximately 2.5 +/- 0.8 years apart; multiple imputation was used to account for the remainder (n = 1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max = 9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HRs) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. Results A total of 343 and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 +/- 65.3 Agatston units. Among persons without CAC at baseline (n = 3,396), a 5-unit annual change in CAC was associated with an adjusted HR (95% Confidence Interval) of 1.4 (1.0 to 1.9) for total and 1.5 (1.1 to 2.1) for hard CHD. Among those with CAC >0 at baseline, HRs (per 100 unit annual change) were 1.2 (1.1 to 1.4) and 1.3 (1.1 to 1.5), respectively. Among participants with baseline CAC, those with annual progression of >= 300 units had adjusted HRs of 3.8 (1.5 to 9.6) for total and 6.3 (1.9 to 21.5) for hard CHD compared to those without progression. Conclusions Progression of CAC is associated with an increased risk for future hard and total CHD events. (J Am Coll Cardiol 2013;61:1231-9) (C) 2013 by the American College of Cardiology Foundation C1 [Budoff, Matthew J.; Nasir, Khurram] Harbor UCLA Med Ctr, Div Cardiol, LA Biomed Res Inst, Los Angeles, CA USA. [Young, Rebekah; Kronmal, Richard A.] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Lopez, Victor A.; Detrano, Robert C.; Wong, Nathan D.] Univ Calif Irvine, Dept Radiol, Irvine, CA 92697 USA. [Nasir, Khurram; Blumenthal, Roger S.; Post, Wendy; Lima, Joao] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Nasir, Khurram] Baptist Hlth Med Grp, Ctr Prevent & Wellness Res, Miami Beach, FL USA. [Nasir, Khurram] Florida Int Univ, Robert Stempel Coll Publ Hlth, Dept Epidemiol, Miami, FL 33199 USA. [Nasir, Khurram] Florida Int Univ, Dept Med, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Bild, Diane E.] NHLBI, Prevent & Populat Studies Program, Bethesda, MD 20892 USA. [Guerci, Alan D.] St Francis Hosp, Ctr Heart, Roslyn, NY USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Shea, Steven] Columbia Univ, Dept Med, New York, NY USA. [Szklo, Moyses] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Bertoni, Alain] Wake Forest Univ, Dept Med, Wake Forest, NC USA. RP Wong, ND (reprint author), Univ Calif Irvine, Dept Med, Heart Dis Prevent Program, Sprague Hall 112, Irvine, CA 92697 USA. EM ndwong@uci.edu FU NHLBI [N01-HC-95159, N01-HC-95169] FX This research was supported by NHLBI contracts N01-HC-95159 through N01-HC-95169. Dr. Budoff is a consultant for General Electric. Dr. Wong is a consultant for Re-Engineering Healthcare, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Paolo Raggi, MD, served as the Guest Editor for this article. NR 33 TC 72 Z9 73 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 26 PY 2013 VL 61 IS 12 BP 1231 EP 1239 DI 10.1016/j.jacc.2012.12.035 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 114OK UT WOS:000316751100004 PM 23500326 ER PT J AU Silman, I Roth, E Paz, A Triquigneaux, MM Ehrenshaft, M Xu, YC Shnyrov, VL Sussman, JL Deterding, LJ Ashani, Y Mason, RP Weiner, L AF Silman, Israel Roth, Esther Paz, Aviv Triquigneaux, Mathilde M. Ehrenshaft, Marilyn Xu, Yechun Shnyrov, Valery L. Sussman, Joel L. Deterding, Leesa J. Ashani, Yacov Mason, Ronald P. Weiner, Lev TI The specific interaction of the photosensitizer methylene blue with acetylcholinesterase provides a model system for studying the molecular consequences of photodynamic therapy SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT International Meeting on Cholinesterases CY JUN 04-09, 2012 CL Kazan, RUSSIA DE Acetylcholinesterase; Methylene blue; Photosensitizer; Photodynamic therapy; Mass spectroscopy; Singlet oxygen ID TORPEDO-CALIFORNICA ACETYLCHOLINESTERASE; ACTIVE-SITE GORGE; SINGLET OXYGEN; N-FORMYLKYNURENINE; TARGETED OXIDATION; LIGAND-BINDING; STATE; SUBSTRATE; PROTEINS; COMPLEX AB The photosensitizer, methylene blue (MB), generates singlet oxygen (O-1(2)) that irreversibly inhibits Torpedo californica acetylcholinesterase (TcAChE). In the dark MB inhibits reversibly, binding being accompanied by a bathochromic shift that can be used to show its displacement by other reversible inhibitors binding to the catalytic 'anionic' subsite (CAS), the peripheral 'anionic' subsite (PAS), or bridging them. Data concerning both reversible and irreversible inhibition are here reviewed. MB protects TcAChE from thermal denaturation, and differential scanning calorimetry reveals a similar to 8 degrees C increase in the denaturation temperature. The crystal structure of the MB/TcAChE complex reveals a single MB stacked against W279 in the PAS, pointing down the gorge towards the CAS. The intrinsic fluorescence of the irreversibly inhibited enzyme displays new emission bands that can be ascribed to N'-formylkynurenine (NFK); this was indeed confirmed using anti-NFK antibodies. Mass spectroscopy revealed that two Trp residues, Trp84 in the CAS, and Trp279 in the PAS, were the only Trp residues, out of a total of 14, significantly modified by photo-oxidation, both being converted to NFK. In the presence of competitive inhibitors that displace MB from the gorge, their modification is completely prevented. Thus, photo-oxidative damage caused by MB involves targeted release of O-1(2) by the bound photosensitizer within the aqueous milieu of the active-site gorge. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Silman, Israel; Roth, Esther; Paz, Aviv; Xu, Yechun; Ashani, Yacov] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. [Paz, Aviv; Xu, Yechun; Sussman, Joel L.] Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel. [Triquigneaux, Mathilde M.; Ehrenshaft, Marilyn; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Shnyrov, Valery L.] Univ Salamanca, Dept Biochem & Mol Biol, Salamanca 37007, Spain. [Deterding, Leesa J.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Weiner, Lev] Weizmann Inst Sci, Dept Chem Res Support, IL-76100 Rehovot, Israel. RP Silman, I (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. EM israel.silman@weizmann.ac.il OI Sussman, Joel/0000-0003-0306-3878 NR 32 TC 2 Z9 2 U1 1 U2 28 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD MAR 25 PY 2013 VL 203 IS 1 SI SI BP 63 EP 66 DI 10.1016/j.cbi.2012.10.021 PG 4 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 134HU UT WOS:000318201800014 PM 23159732 ER PT J AU Quick, V Wall, M Larson, N Haines, J Neumark-Sztainer, D AF Quick, Virginia Wall, Melanie Larson, Nicole Haines, Jess Neumark-Sztainer, Dianne TI Personal, behavioral and socio-environmental predictors of overweight incidence in young adults: 10-yr longitudinal findings SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Adolescents; Young adults; Overweight; Weight control ID FOOD FREQUENCY QUESTIONNAIRE; BODY-MASS INDEX; PROJECT EAT; ADOLESCENT OVERWEIGHT; PROTECTIVE FACTORS; WEIGHT CHANGE; SHARED RISK; OBESITY; CONSUMPTION; REPRODUCIBILITY AB Background: The objective of this study was to identify 10-year longitudinal predictors of overweight incidence during the transition from adolescence to young adulthood. Methods: Data were from Project EAT (Eating and Activity in Teens and Young Adults). A diverse, population-based cohort (N = 2,134) completed baseline surveys in 1998-1999 (mean age = 15.0 +/- 1.6, 'adolescence') and follow-up surveys in 2008-2009 (mean age = 25.4 +/- 1.7, 'young adulthood'). Surveys assessed personal, behavioral and socio-environmental factors hypothesized to be of relevance to obesity, in addition to height and weight. Multivariable logistic regression was used to estimate the adjusted odds for each personal, behavioral and socio-environmental factor at baseline, and 10-year changes for these factors, among non-overweight adolescents (n = 1,643) being predictive of the incidence of overweight (BMI >= 25) at 10-year follow-up. Results: At 10-year follow-up, 51% of young adults were overweight (26% increase from baseline). Among females and males, higher levels of body dissatisfaction, weight concerns, unhealthy weight control behaviors (e.g., fasting, purging), dieting, binge eating, weight-related teasing, and parental weight-related concerns and behaviors during adolescence and/or increases in these factors over the study period predicted the incidence of overweight at 10-year follow-up. Females with higher levels of whole grain intake and breakfast and dinner consumption frequency during adolescence were protected against becoming overweight. Among males, increases in vegetable intake protected against the incidence of overweight 10 years later. Conclusions: Findings suggest that obesity prevention interventions for adolescents should address weight-specific factors from within the domains of personal, behavioral, and socio-environmental factors such as promoting positive body image, decreasing unhealthy weight control behaviors, and limiting negative weight talk. C1 [Quick, Virginia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Bethesda, MD 20892 USA. [Larson, Nicole; Neumark-Sztainer, Dianne] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Wall, Melanie] Univ Minnesota, Div Biostat, Sch Publ Hlth, Minneapolis, MN 55454 USA. [Haines, Jess] Univ Guelph, Guelph, ON N1G 2W1, Canada. RP Quick, V (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Bethesda, MD 20892 USA. EM gingermquick@gmail.com OI Quick, Virginia/0000-0002-4338-963X; Neumark-Sztainer, Dianne/0000-0001-9435-1669 FU National Heart, Lung, and Blood Institute [R01HL084064]; National Research Service Award (NRSA) in Primary Medical Care [T32HP22239]; Bureau of Health Professions; Health Resources and Services Administration; Department of Health and Human Services FX This study was supported by Grant Number R01HL084064 from the National Heart, Lung, and Blood Institute (PI: Dianne Neumark-Sztainer). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. The first author's time was supported by a National Research Service Award (NRSA) in Primary Medical Care, Grant Number T32HP22239 (PI: Irene Borowsky), Bureau of Health Professions, Health Resources and Services Administration, Department of Health and Human Services. NR 48 TC 26 Z9 26 U1 4 U2 28 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 MAR 25 PY 2013 VL 10 AR 37 DI 10.1186/1479-5868-10-37 PG 13 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 126UA UT WOS:000317645500002 PM 23531253 ER PT J AU Rackoff, LA Bok, K Green, KY Kapikian, AZ AF Rackoff, Lauren A. Bok, Karin Green, Kim Y. Kapikian, Albert Z. TI Epidemiology and Evolution of Rotaviruses and Noroviruses from an Archival WHO Global Study in Children (1976-79) with Implications for Vaccine Design SO PLOS ONE LA English DT Article ID INFECTIOUS NONBACTERIAL GASTROENTERITIS; POLYMERASE CHAIN-REACTION; PHYLOGENETIC ANALYSIS; MAXIMUM-LIKELIHOOD; VP7 GENE; RT-PCR; VIRUS; GENOTYPE; NORWALK; STRAIN AB Prompted by the discovery of new gastrointestinal viruses, the NIH, NIAID and WHO investigated the etiology of acute diarrhea that occurred from 1976-1979 in a global cohort of infants and young children. Rotaviruses were found to be major pathogens worldwide, whereas the Norwalk virus could not be detected using a radioimmunoassay. The aim of this study is to re-evaluate the role and diversity of rotaviruses and noroviruses in the original cohort using more sensitive current technologies. Stools collected from Asia, Africa, and South America (n = 485) were evaluated for viral genotypes by RT-PCR and sequencing. Rotaviruses were detected in 28.9% and noroviruses in 9.7% of the specimens, with G1 rotaviruses and GII noroviruses accounting for the majority of each respective virus. Various strains in this study predated the currently assigned dates of discovery for their particular genotype, and in addition, two noroviruses (KL45 and T091) could not be assigned to current genotypes. Phylogenetic analyses demonstrated a relative constancy in circulating rotavirus genotypes over time, with several genotypes from this study becoming established in the current repertoire of viral species. Similarly, GII noroviruses have maintained dominance, with GII. 4 noroviruses continuing as a predominant genotype over time. Taken together, the complex molecular epidemiology of rotaviruses and noroviruses circulating in the 1970's is consistent with current patterns, an important consideration in the design of multivalent vaccines to control these viruses. C1 [Rackoff, Lauren A.; Bok, Karin; Green, Kim Y.; Kapikian, Albert Z.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Green, KY (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kgreen@niaid.nih.gov FU Division of Intramural Research (DIR) of NIAID, NIH FX The work was funded by the Division of Intramural Research (DIR) of NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 22 Z9 23 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 25 PY 2013 VL 8 IS 3 AR e59394 DI 10.1371/journal.pone.0059394 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 123NP UT WOS:000317397200023 PM 23536875 ER PT J AU Yang, ZH Grinchuk, V Urban, JF Bohl, J Sun, R Notari, L Yan, S Ramalingam, T Keegan, AD Wynn, TA Shea-Donohue, T Zhao, AP AF Yang, Zhonghan Grinchuk, Viktoriya Urban, Joseph F., Jr. Bohl, Jennifer Sun, Rex Notari, Luigi Yan, Shu Ramalingam, Thirumalai Keegan, Achsah D. Wynn, Thomas A. Shea-Donohue, Terez Zhao, Aiping TI Macrophages as IL-25/IL-33-Responsive Cells Play an Important Role in the Induction of Type 2 Immunity SO PLOS ONE LA English DT Article ID ALTERNATIVELY ACTIVATED MACROPHAGES; NIPPOSTRONGYLUS-BRASILIENSIS INFECTION; ADAPTIVE IMMUNITY; SMALL-INTESTINE; LYMPHOID-CELLS; IN-VIVO; CYTOKINE; EXPRESSION; RECEPTOR; DISEASE AB Type 2 immunity is essential for host protection against nematode infection but is detrimental in allergic inflammation or asthma. There is a major research focus on the effector molecules and specific cell types involved in the initiation of type 2 immunity. Recent work has implicated an important role of epithelial-derived cytokines, IL-25 and IL-33, acting on innate immune cells that are believed to be the initial sources of type 2 cytokines IL-4/IL-5/IL-13. The identities of the cell types that mediate the effects of IL-25/IL-33, however, remain to be fully elucidated. In the present study, we demonstrate that macrophages as IL-25/IL-33-responsive cells play an important role in inducing type 2 immunity using both in vitro and in vivo approaches. Macrophages produced type 2 cytokines IL-5 and IL-13 in response to the stimulation of IL-25/IL-33 in vitro, or were the IL-13-producing cells in mice administrated with exogenous IL-33 or infected with Heligmosomoides bakeri. In addition, IL-33 induced alternative activation of macrophages primarily through autocrine IL-13 activating the IL-4R alpha-STAT6 pathway. Moreover, depletion of macrophages attenuated the IL-25/IL-33-induced type 2 immunity in mice, while adoptive transfer of IL-33-activated macrophages into mice with a chronic Heligmosomoides bakeri infection induced worm expulsion accompanied by a potent type 2 protective immune response. Thus, macrophages represent a unique population of the innate immune cells pivotal to type 2 immunity and a potential therapeutic target in controlling type 2 immunity-mediated inflammatory pathologies. C1 [Yang, Zhonghan; Grinchuk, Viktoriya; Bohl, Jennifer; Sun, Rex; Notari, Luigi; Yan, Shu; Shea-Donohue, Terez; Zhao, Aiping] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Yang, Zhonghan; Grinchuk, Viktoriya; Bohl, Jennifer; Sun, Rex; Notari, Luigi; Yan, Shu; Shea-Donohue, Terez; Zhao, Aiping] Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA. [Yang, Zhonghan] Sun Yat Sen Univ, Dept Biochem, Zhongshan Med Sch, Guangzhou 510275, Guangdong, Peoples R China. [Urban, Joseph F., Jr.] ARS, USDA, Beltsville Human Nutr Res Ctr, Diet Genom & Immunol Lab, Beltsville, MD USA. [Keegan, Achsah D.] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA. [Ramalingam, Thirumalai; Wynn, Thomas A.] NIAID, Div Parasitol, NIH, Bethesda, MD 20892 USA. RP Zhao, AP (reprint author), Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. EM azhao@mbrc.umaryland.edu OI Urban, Joseph/0000-0002-1590-8869 FU NIH [R01-DK083418, R01-AI/DK49316, R01-AI038985]; USDA CRIS [1235-51000-055] FX This work was supported by NIH grants R01-DK083418 (AZ), R01-AI/DK49316 (T. S-D), R01-AI038985 (ADK), and USDA CRIS project #1235-51000-055 (JFU). The opinions and assertions in this article are those of the authors and do not necessarily represent those of the U. S. Department of Agriculture or the Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 36 Z9 38 U1 0 U2 13 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 MAR 25 PY 2013 VL 8 IS 3 AR e59441 DI 10.1371/journal.pone.0059441 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 123NP UT WOS:000317397200025 PM 23536877 ER PT J AU Mur, M Meys, M Bodurka, J Goebel, R Bandettini, PA Kriegeskorte, N AF Mur, Marieke Meys, Mirjam Bodurka, Jerzy Goebel, Rainer Bandettini, Peter A. Kriegeskorte, Nikolaus TI Human object-similarity judgments reflect and transcend the primate-IT object representation SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE object perception; vision; neuronal representation; fMRI; representational similarity analysis; human; primate ID INFERIOR TEMPORAL CORTEX; PREFRONTAL CORTEX; CORTICAL REPRESENTATION; INFEROTEMPORAL CORTEX; VISUAL-CORTEX; HUMAN BRAIN; SHAPES; CATEGORIZATION; ORGANIZATION; FEATURES AB Primate inferior temporal (IT) cortex is thought to contain a high-level representation of objects at the interface between vision and semantics. This suggests that the perceived similarity of real-world objects might be predicted from the IT representation. Here we show that objects that elicit similar activity patterns in human IT (hIT) tend to be judged as similar by humans. The IT representation explained the human judgments better than early visual cortex, other ventral-stream regions, and a range of computational models. Human similarity judgments exhibited category clusters that reflected several categorical divisions that are prevalent in the IT representation of both human and monkey, including the animate/inanimate and the face/body division. Human judgments also reflected the within-category representation of IT. However, the judgments transcended the IT representation in that they introduced additional categorical divisions. In particular, human judgments emphasized human-related additional divisions between human and non-human animals and between man-made and natural objects. hIT was more similar to monkey IT than to human judgments. One interpretation is that IT has evolved visual-feature detectors that distinguish between animates and inanimates and between faces and bodies because these divisions are fundamental to survival and reproduction for all primate species, and that other brain systems serve to more flexibly introduce species-dependent and evolutionarily more recent divisions. C1 [Mur, Marieke; Meys, Mirjam; Bandettini, Peter A.; Kriegeskorte, Nikolaus] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Mur, Marieke; Meys, Mirjam; Goebel, Rainer] Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, Maastricht, Netherlands. [Mur, Marieke; Kriegeskorte, Nikolaus] MRC, Cognit & Brain Sci Unit, Cambridge CB2 7EF, England. [Bodurka, Jerzy; Bandettini, Peter A.] NIMH, Funct Magnet Resonance Imaging Facil, NIH, Bethesda, MD 20892 USA. RP Kriegeskorte, N (reprint author), MRC, Cognit & Brain Sci Unit, 15 Chaucer Rd, Cambridge CB2 7EF, England. EM nikolaus.kriegeskorte@mrc-cbu.cam.ac.uk OI Kriegeskorte, Nikolaus/0000-0001-7433-9005 FU Medical Research Council [MC_U105597120] NR 56 TC 22 Z9 22 U1 1 U2 10 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD MAR 22 PY 2013 VL 4 AR 128 DI 10.3389/fpsyg.2013.00128 PG 22 WC Psychology, Multidisciplinary SC Psychology GA AA0TM UT WOS:000330810300001 PM 23525516 ER PT J AU Richardson, DB Volkow, ND Kwan, MP Kaplan, RM Goodchild, MF Croyle, RT AF Richardson, Douglas B. Volkow, Nora D. Kwan, Mei-Po Kaplan, Robert M. Goodchild, Michael F. Croyle, Robert T. TI Spatial Turn in Health Research SO SCIENCE LA English DT Editorial Material C1 [Richardson, Douglas B.] AAG, Washington, DC 20009 USA. [Volkow, Nora D.] NIDA, NIH, Rockville, MD 20852 USA. [Kwan, Mei-Po] Univ Illinois, Dept Geog & Geog Informat Sci, Urbana, IL 61801 USA. [Kaplan, Robert M.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Goodchild, Michael F.] Univ Calif Santa Barbara, Dept Geog, Santa Barbara, CA 93106 USA. [Croyle, Robert T.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Richardson, DB (reprint author), AAG, 1710 16th St NW, Washington, DC 20009 USA. EM drichardson@aag.org FU NCI NIH HHS [R13CA162823, R13 CA162823] NR 20 TC 48 Z9 51 U1 7 U2 75 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 MAR 22 PY 2013 VL 339 IS 6126 BP 1390 EP 1392 DI 10.1126/science.1232257 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 114KU UT WOS:000316740700028 PM 23520099 ER PT J AU Shnyrova, AV Bashkirov, PV Akimov, SA Pucadyil, TJ Zimmerberg, J Schmid, SL Frolov, VA AF Shnyrova, Anna V. Bashkirov, Pavel V. Akimov, Sergey A. Pucadyil, Thomas J. Zimmerberg, Joshua Schmid, Sandra L. Frolov, Vadim A. TI Geometric Catalysis of Membrane Fission Driven by Flexible Dynamin Rings SO SCIENCE LA English DT Article ID DEPENDENT CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; CONSTRICTION; REVEALS; FUSION; SHAPE AB Biological membrane fission requires protein-driven stress. The guanosine triphosphatase (GTPase) dynamin builds up membrane stress by polymerizing into a helical collar that constricts the neck of budding vesicles. How this curvature stress mediates nonleaky membrane remodeling is actively debated. Using lipid nanotubes as substrates to directly measure geometric intermediates of the fission pathway, we found that GTP hydrolysis limits dynamin polymerization into short, metastable collars that are optimal for fission. Collars as short as two rungs translated radial constriction to reversible hemifission via membrane wedging of the pleckstrin homology domains (PHDs) of dynamin. Modeling revealed that tilting of the PHDs to conform with membrane deformations creates the low-energy pathway for hemifission. This local coordination of dynamin and lipids suggests how membranes can be remodeled in cells. C1 [Shnyrova, Anna V.; Frolov, Vadim A.] Univ Basque Country, CSIC, Biophys Unit, Leioa, Spain. [Shnyrova, Anna V.; Frolov, Vadim A.] Univ Basque Country, Dept Biochem & Mol Biol, Leioa, Spain. [Bashkirov, Pavel V.; Akimov, Sergey A.] Russian Acad Sci, AN Frumkin Inst Phys Chem & Electrochem, Moscow 119071, Russia. [Akimov, Sergey A.] Natl Univ Sci & Technol MISiS, Moscow 119049, Russia. [Pucadyil, Thomas J.] Indian Inst Sci Educ & Res, Pune, Maharashtra, India. [Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Schmid, Sandra L.] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. [Frolov, Vadim A.] Basque Fdn Sci, IKERBASQUE, Bilbao, Spain. RP Frolov, VA (reprint author), Univ Basque Country, CSIC, Biophys Unit, Leioa, Spain. EM vadim.frolov@ehu.es RI Akimov, Sergey/L-2001-2013; Akimov, Sergey/I-6432-2015; OI Frolov, Vadim/0000-0002-0653-5669; Pucadyil, Thomas/0000-0002-2907-9889 FU Spanish Ministry of Economy and Competitiveness [BFU2012-34885]; Basque Government [IE12-332]; Russian Foundation for Basic Research [11-04-02087]; Russian Academy of Science; Ministry of Education and Science of the Russian Federation [14.740.11.1409]; National Institute of Child Health and Human Development; NIH [GM42455] FX We are grateful to J. Rizo-Rey and P. Kuzmin for critical reading of the manuscript. This work was in part supported by Spanish Ministry of Economy and Competitiveness grant BFU2012-34885 (V.A.F.); the Basque Government Program Etortek, grant IE12-332 (V.A.F); Russian Foundation for Basic Research grant 11-04-02087 (P.V.B.); the Russian Academy of Science program "Molecular and Cell Biology" (P.V.B. and S.A.A.); the Ministry of Education and Science of the Russian Federation, grant 14.740.11.1409 (P.V.B.); the Intramural Program of the National Institute of Child Health and Human Development (J.Z); and NIH grant GM42455 (S.L.S.). Additional data are presented in the supplementary materials. NR 28 TC 42 Z9 43 U1 4 U2 78 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 MAR 22 PY 2013 VL 339 IS 6126 BP 1433 EP 1436 DI 10.1126/science.1233920 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 114KU UT WOS:000316740700043 PM 23520112 ER PT J AU De Lay, N Schu, DJ Gottesman, S AF De Lay, Nicholas Schu, Daniel J. Gottesman, Susan TI Bacterial Small RNA-based Negative Regulation: Hfq and Its Accomplices SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ESCHERICHIA-COLI HFQ; TARGET MESSENGER-RNAS; BINDING SMALL RNAS; SM-LIKE PROTEIN; POLYNUCLEOTIDE PHOSPHORYLASE; TRANSLATIONAL INITIATION; NONCODING RNAS; SOLUBLE-RNAS; CRUCIAL ROLE; IN-VIVO AB A large group of bacterial small regulatory RNAs (sRNAs) use the Hfq chaperone to mediate pairing with and regulation of mRNAs. Recent findings help to clarify how Hfq acts and highlight the role of the endonuclease RNase E and its associated proteins (the degradosome) in negative regulation by these sRNAs. sRNAs frequently uncouple transcription and translation by blocking ribosome access to the mRNA, allowing other proteins access to the mRNA. As more examples of sRNA-mediated regulation are studied, more variations on how Hfq, RNase E, and other proteins collaborate to bring about sRNA-based regulation are being found. C1 [De Lay, Nicholas; Schu, Daniel J.; Gottesman, Susan] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM gottesms@helix.nih.gov FU National Cancer Institute Center for Cancer Research FX The preparation of this review was supported in whole by the National Institutes of Health Intramural Research Program of the National Cancer Institute Center for Cancer Research. NR 65 TC 96 Z9 96 U1 3 U2 45 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 MAR 22 PY 2013 VL 288 IS 12 BP 7996 EP 8003 DI 10.1074/jbc.R112.441386 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 112AS UT WOS:000316564500001 PM 23362267 ER PT J AU Weisfeld-Adams, JD Mehta, L Rucker, JC Dembitzer, FR Szporn, A Lublin, FD Introne, WJ Bhambhani, V Chicka, MC Cho, C AF Weisfeld-Adams, James D. Mehta, Lakshmi Rucker, Janet C. Dembitzer, Francine R. Szporn, Arnold Lublin, Fred D. Introne, Wendy J. Bhambhani, Vikas Chicka, Michael C. Cho, Catherine TI Atypical Chediak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE Chediak-Higashi syndrome; LYST; Lysosomal; Amyloid; Oxidative stress; Parkinsonism; Neurodegenerative disease ID BONE-MARROW-TRANSPLANTATION; PERIPHERAL NEUROPATHY; DEGENERATION; PARKINSONISM; AMYLOIDOSIS; GRISCELLI; GENOTYPE; MUTATION AB Background: Mutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chediak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction. Methods: In a consanguineous Pakistani kindred with clinical phenotypes consistent with attenuated CHS, we performed SNP array-based homozygosity mapping and whole gene sequencing of LYST. Results: We identified three individuals homozygous for a novel six base pair in-frame deletion in LYST (c.9827_9832ATACAA), predicting the loss of asparagine and threonine residues from the LYST transcript (p.Asn3276_Thr3277del), and segregating with the phenotype in this family. Conclusions: We further characterize the neurologic features of the attenuated form of CHS, and discuss pathophysiologic mechanisms underlying the neurodegenerative components of CHS. Attenuated CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease and have pigmentary abnormalities. We briefly discuss surveillance and management of patients with CHS-related neurodegeneration. C1 [Weisfeld-Adams, James D.; Mehta, Lakshmi] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Rucker, Janet C.; Lublin, Fred D.; Cho, Catherine] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Rucker, Janet C.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Dembitzer, Francine R.; Szporn, Arnold] Mt Sinai Sch Med, Dept Pathol, New York, NY USA. [Introne, Wendy J.; Bhambhani, Vikas] NICHHD, Sect Human Biochem Genet, NIH, Bethesda, MD 20892 USA. [Chicka, Michael C.] Prevent Genet, Marshfield, WI USA. RP Weisfeld-Adams, JD (reprint author), Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. EM james.weisfeld-adams@mssm.edu NR 26 TC 9 Z9 9 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD MAR 22 PY 2013 VL 8 AR 46 DI 10.1186/1750-1172-8-46 PG 7 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 114SQ UT WOS:000316763200001 PM 23521865 ER PT J AU Hwang, IY Hwang, KS Park, C Harrison, KA Kehrl, JH AF Hwang, Il-Young Hwang, Kyung-Sun Park, Chung Harrison, Kathleen A. Kehrl, John H. TI Rgs13 Constrains Early B Cell Responses and Limits Germinal Center Sizes SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; IMMUNE FUNCTION; LYMPH-NODES; PROTEINS; DIFFERENTIATION; LYMPHOCYTES; MIGRATION; DESENSITIZATION; RESPONSIVENESS; TRAFFICKING AB Germinal centers (GCs) are microanatomic structures that develop in secondary lymphoid organs in response to antigenic stimulation. Within GCs B cells clonally expand and their immunoglobulin genes undergo class switch recombination and somatic hypermutation. Transcriptional profiling has identified a number of genes that are prominently expressed in GC B cells. Among them is Rgs13, which encodes an RGS protein with a dual function. Its canonical function is to accelerate the intrinsic GTPase activity of heterotrimeric G-protein alpha subunits at the plasma membrane, thereby limiting heterotrimeric G-protein signaling. A unique, non-canonical function of RGS13 occurs following translocation to the nucleus, where it represses CREB transcriptional activity. The functional role of RGS13 in GC B cells is unknown. To create a surrogate marker for Rgs13 expression and a loss of function mutation, we inserted a GFP coding region into the Rgs13 genomic locus. Following immunization GFP expression rapidly increased in activated B cells, persisted in GC B cells, but declined in newly generated memory B and plasma cells. Intravital microscopy of the inguinal lymph node (LN) of immunized mice revealed the rapid appearance of GFP(+) cells at LN interfollicular regions and along the T/B cell borders, and eventually within GCs. Analysis of WT, knock-in, and mixed chimeric mice indicated that RGS13 constrains extra-follicular plasma cell generation, GC size, and GC B cell numbers. Analysis of select cell cycle and GC specific genes disclosed an aberrant gene expression profile in the Rgs13 deficient GC B cells. These results indicate that RGS13, likely acting at cell membranes and in nuclei, helps coordinate key decision points during the expansion and differentiation of naive B cells. C1 [Hwang, Il-Young; Hwang, Kyung-Sun; Park, Chung; Harrison, Kathleen A.; Kehrl, John H.] NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 8 Z9 8 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 22 PY 2013 VL 8 IS 3 AR e60139 DI 10.1371/journal.pone.0060139 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111VQ UT WOS:000316549400109 PM 23533672 ER PT J AU Schick, UM McDavid, A Crane, PK Weston, N Ehrlich, K Newton, KM Wallace, R Bookman, E Harrison, T Aragaki, A Crosslin, DR Wang, SS Reiner, AP Jackson, RD Peters, U Larson, EB Jarvik, GP Carlson, CS AF Schick, Ursula M. McDavid, Andrew Crane, Paul K. Weston, Noah Ehrlich, Kelly Newton, Katherine M. Wallace, Robert Bookman, Ebony Harrison, Tabitha Aragaki, Aaron Crosslin, David R. Wang, Sophia S. Reiner, Alex P. Jackson, Rebecca D. Peters, Ulrike Larson, Eric B. Jarvik, Gail P. Carlson, Christopher S. TI Confirmation of the Reported Association of Clonal Chromosomal Mosaicism with an Increased Risk of Incident Hematologic Cancer SO PLOS ONE LA English DT Article ID SPONTANEOUS-ABORTIONS; ABNORMALITIES; LEUKEMIA; MALIGNANCIES; MUTATIONS; GENOME; BIRTH; TET2 AB Chromosomal abnormalities provide clinical utility in the diagnosis and treatment of hematologic malignancies, and may be predictive of malignant transformation in individuals without apparent clinical presentation of a hematologic cancer. In an effort to confirm previous reports of an association between clonal mosaicism and incident hematologic cancer, we applied the anomDetectBAF algorithm to call chromosomal anomalies in genotype data from previously conducted Genome Wide Association Studies (GWAS). The genotypes were initially collected from DNA derived from peripheral blood of 12,176 participants in the Group Health electronic Medical Records and Genomics study (eMERGE) and the Women's Health Initiative (WHI). We detected clonal mosaicism in 169 individuals (1.4%) and large clonal mosaic events (>2 mb) in 117 (1.0%) individuals. Though only 9.5% of clonal mosaic carriers had an incident diagnosis of hematologic cancer (multiple myeloma, myelodysplastic syndrome, lymphoma, or leukemia), the carriers had a 5.5-fold increased risk (95% CI: 3.3-9.3; p-value = 7.5 x 10(-11)) of developing these cancers subsequently. Carriers of large mosaic anomalies showed particularly pronounced risk of subsequent leukemia (HR = 19.2, 95% CI: 8.9-41.6; p-value = 7.3x10(-14)). Thus we independently confirm the association between detectable clonal mosaicism and hematologic cancer found previously in two recent publications. C1 [Schick, Ursula M.; McDavid, Andrew; Harrison, Tabitha; Aragaki, Aaron; Reiner, Alex P.; Peters, Ulrike; Carlson, Christopher S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Crane, Paul K.; Larson, Eric B.] Univ Washington, Dept Med, Seattle, WA USA. [Weston, Noah; Ehrlich, Kelly; Newton, Katherine M.; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA. [Newton, Katherine M.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Wallace, Robert] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Bookman, Ebony] NHGRI, NIH, Bethesda, MD 20892 USA. [Crosslin, David R.; Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Crosslin, David R.; Jarvik, Gail P.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Reiner, Alex P.; Carlson, Christopher S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol, Columbus, OH 43210 USA. RP Carlson, CS (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM ccarlson@fhcrc.org RI Crane, Paul/C-8623-2014; Jarvik, Gail/N-6476-2014; OI Jarvik, Gail/0000-0002-6710-8708; Crane, Paul/0000-0003-4278-7465; McDavid, Andrew/0000-0002-6581-1213 FU National Institutes of Health (NIH) [HG004610, AG06781]; National Heart, Lung, and Blood Institute, NIH; U.S. 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]; GARNET Collaborative Research Group; NHGRI Genomics and Randomized Trials Network (GARNET) [U01 HG005152]; NIH Genes, Environment and Health Initiative [GEI] [U01 HG004424]; National Cancer Institute [R25CA094880]; [U01AG06781]; [U01HG004438]; [U01CKA137088]; [R01CKA059045] FX The initial ADPR was funded by U01AG06781 and the initial ACT study is also funded by U01AG06781. The eMERGE study was funded by National Institutes of Health (NIH) award HG004610, AG06781 (Group Health Cooperative). Genotyping of eMERGE samples was funded by grant U01HG004438. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. 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. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf. WHI GECCO colorectal cancer study was funded by U01CKA137088 and R01CKA059045. The authors wish to acknowledge the support of the GARNET Collaborative Research Group. Funding support for WHI-GARNET was provided through the NHGRI Genomics and Randomized Trials Network (GARNET) (Grant Number U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157). Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004424). Additional support for author UMS was provided by grant R25CA094880 from the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 9 Z9 9 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 22 PY 2013 VL 8 IS 3 AR e59823 DI 10.1371/journal.pone.0059823 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111VQ UT WOS:000316549400089 PM 23533652 ER PT J AU Kalia, J Swartz, KJ AF Kalia, Jeet Swartz, Kenton J. TI Exploring structure-function relationships between TRP and Kv channels SO SCIENTIFIC REPORTS LA English DT Article ID DEPENDENT K+ CHANNEL; VOLTAGE SENSOR; CAPSAICIN RECEPTOR; POTASSIUM CHANNELS; TARANTULA TOXINS; GATING-CHARGE; PORE DOMAIN; ION-CHANNEL; CRYSTAL-STRUCTURE; HEAT ACTIVATION AB The molecular mechanisms underlying the activation of Transient Receptor Potential (TRP) ion channels are poorly understood when compared to those of the voltage-activated potassium (Kv) channels. The architectural and pharmacological similarities between the members of these two families of channels suggest that their structure-function relationships may have common features. We explored this hypothesis by replacing previously identified domains and critical structural motifs of the membrane-spanning portions of Kv2.1 with corresponding regions of two TRP channels, TRPM8 and TRPV1. Our results show that the S3b-S4 paddle motif of Kv2.1, but not other domains, can be replaced by the analogous regions of both TRP channels without abolishing voltage-activation. In contrast, replacement of portions of TRP channels with those of Kv2.1 consistently yielded non-functional channels. Taken together, these results suggest that most structural elements within TRP channels and Kv channels are not sufficiently related to allow for the creation of hybrid channels. C1 [Kalia, Jeet; Swartz, Kenton J.] NINDS, Porter Neurosci Res Ctr, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), NINDS, Porter Neurosci Res Ctr, Mol Physiol & Biophys Sect, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov FU Intramural Research Program of the National Institutes of Health National Institute of Neurological Disorders and Stroke; National Institutes of Health National Institute of Neurological Disorders and Stroke competitive fellowship FX We thank Miguel Holmgren, Andres Jara-Oseguera, Dmitriy Krepkiy, Mark Mayer, Joe Mindell and members of the Swartz lab for helpful discussions. This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Neurological Disorders and Stroke (to K.J.S.), and by a National Institutes of Health National Institute of Neurological Disorders and Stroke competitive fellowship (to J.K.). NR 59 TC 17 Z9 17 U1 0 U2 13 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 MAR 22 PY 2013 VL 3 AR 1523 DI 10.1038/srep01523 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111TT UT WOS:000316544400006 PM 23519328 ER PT J AU Kubler-Kielb, J Vinogradov, E Ng, WI Maczynska, B Junka, A Bartoszewicz, M Zelazny, A Bennett, J Schneerson, R AF Kubler-Kielb, Joanna Vinogradov, Evgeny Ng, Weng-Ian Maczynska, Beata Junka, Adam Bartoszewicz, Marzenna Zelazny, Adrian Bennett, John Schneerson, Rachel TI The capsular polysaccharide and lipopolysaccharide structures of two carbapenem resistant Klebsiella pneumoniae outbreak isolates SO CARBOHYDRATE RESEARCH LA English DT Article DE Capsular polysaccharide; LPS; Structure; KPC; CRKP ID VACCINE; IMMUNOGENICITY; SEROTYPES; ANTIGENS; STRAINS AB Carbapenem resistant Klebsiella pneumoniae (CRKP) are isolated with increasing frequency, especially from immunocompromized patients. The capsular polysaccharide (CPS) types of CPKP were not determined. Investigation of two CRKP isolates from a 2011 outbreak at the Clinical Center, the National Institutes of Health, identified a new capsular type shared by the two isolates, similar to K. pneumonia K19 and K34 but structurally different than any published K. pneumoniae CPS repeating unit: -[-2-alpha-L-Rha-2-alpha-L-Rha-2-alpha-L-Rha-3-beta-D-Gal-3-alpha-D-GalA-](n)- vertical bar 4 alpha-L-Rha The LPS of the two isolates was found to have no O-specific polysaccharide and the chemical structure of the core oligosaccharides agreed with the published data. If this structure type will be prevalent among CPKP isolates, our findings could facilitate rapid diagnosis and help to develop new therapeutic solutions to this antibiotic resistant pathogen. Published by Elsevier Ltd. C1 [Kubler-Kielb, Joanna; Ng, Weng-Ian; Schneerson, Rachel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. [Vinogradov, Evgeny] Natl Res Council Canada, Ottawa, ON K1A 0R6, Canada. [Maczynska, Beata; Junka, Adam; Bartoszewicz, Marzenna] Med Acad Wroclaw, Dept Microbiol, Wroclaw, Poland. [Zelazny, Adrian] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Bennett, John] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Kubler-Kielb, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. EM kielbj@mail.nih.gov OI Vinogradov, Evgeny/0000-0002-5364-1376 FU NICHD; NIAID; Clinical Center, National Institutes of Health, Bethesda, MD FX Authors thank Prof. A. Przondo-Mordarska and Prof. A. Gamian for help in this project. This work was partially supported by the intramural programs of NICHD, NIAID and Clinical Center, National Institutes of Health, Bethesda, MD. NR 25 TC 6 Z9 6 U1 3 U2 24 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD MAR 22 PY 2013 VL 369 BP 6 EP 9 DI 10.1016/j.carres.2012.12.018 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 102CM UT WOS:000315821000003 PM 23360863 ER PT J AU Ladell, K Hashimoto, M Iglesias, MC Wilmann, PG McLaren, JE Gras, S Chikata, T Kuse, N Fastenackels, S Gostick, E Bridgeman, JS Venturi, V Arkoub, ZA Agut, H van Bockel, DJ Almeida, JR Douek, DC Meyer, L Venet, A Takiguchi, M Rossjohn, J Price, DA Appay, V AF Ladell, Kristin Hashimoto, Masao Iglesias, Maria Candela Wilmann, Pascal G. McLaren, James E. Gras, Stephanie Chikata, Takayuki Kuse, Nozomi Fastenackels, Solene Gostick, Emma Bridgeman, John S. Venturi, Vanessa Arkoub, Zaina Ait Agut, Henri van Bockel, David J. Almeida, Jorge R. Douek, Daniel C. Meyer, Laurence Venet, Alain Takiguchi, Masafumi Rossjohn, Jamie Price, David A. Appay, Victor TI A Molecular Basis for the Control of Preimmune Escape Variants by HIV-Specific CD8(+) T Cells SO IMMUNITY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-I; LYMPHOCYTE ESCAPE; ANTIGEN RECOGNITION; INFECTION; RESPONSES; TYPE-1; GAG; DIVERSITY; REPLICATION AB The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8(+) T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK(263-272)) presented by human leukocyte antigen (HLA)-B*2705. We found that cross-reactive CD8(+) T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B*2705(+) individuals. A protective CD8(+) T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation. C1 [Ladell, Kristin; McLaren, James E.; Gostick, Emma; Bridgeman, John S.; Rossjohn, Jamie; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Hashimoto, Masao; Chikata, Takayuki; Kuse, Nozomi; Takiguchi, Masafumi] Kumamoto Univ, Ctr AIDS Res, Kumamoto 8600811, Japan. [Iglesias, Maria Candela; Fastenackels, Solene; Almeida, Jorge R.; Appay, Victor] Univ Paris 06, Hop La Pitie Salpetriere, INSERM UMR S 945, F-75013 Paris, France. [Wilmann, Pascal G.; Gras, Stephanie; Rossjohn, Jamie] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Venturi, Vanessa] Univ New S Wales, Ctr Vasc Res, Computat Biol Grp, Sydney, NSW 2052, Australia. [Arkoub, Zaina Ait; Agut, Henri] Univ Paris 06, Hop La Pitie Salpetriere, DETIV UPMC ER1, Virol Lab, F-75013 Paris, France. [van Bockel, David J.] St Vincents Ctr Appl Med Res, Sydney, NSW 2010, Australia. [van Bockel, David J.] Univ New S Wales, Sydney, NSW 2010, Australia. [Almeida, Jorge R.; Douek, Daniel C.; Price, David A.] NIAID, Vaccine Res Ctr, Human Immunol Sect, NIH, Bethesda, MD 20892 USA. [Meyer, Laurence; Venet, Alain] Univ Paris 11, Hop Kremlin Bicetre, INSERM, F-94275 Le Kremlin Bicetre, France. [Appay, Victor] Grp Hosp Pitie Salpetriere, AP HP, Lab Immunol Cellulaire & Tissulaire, F-75013 Paris, France. RP Appay, V (reprint author), Univ Paris 06, Hop La Pitie Salpetriere, INSERM UMR S 945, F-75013 Paris, France. EM victor.appay@upmc.fr RI Rossjohn, Jamie/F-9032-2013; Ladell, Kristin/K-2475-2013; Price, David/C-7876-2013; Ladell, Kristin/C-8301-2013; Takiguchi, Masafumi/E-7468-2013; OI Rossjohn, Jamie/0000-0002-2020-7522; Price, David/0000-0001-9416-2737; Ladell, Kristin/0000-0002-9856-2938; Ramos de Almeida, Jorge/0000-0002-5009-8478 FU ANR, Sidaction [ANR-09-JCJC-0114-01]; French ANRS; National Institutes of Health via the Intramural Program of the Vaccine Research Center (National Institute of Allergy and Infectious Diseases); Australian Research Council (ARC); Australian National Health and Medical Research Council (NHMRC); UK Biotechnology and Biological Sciences Research Council [BB/H001085/1]; Japanese Ministry of Health [18390141]; Global COE program ("Global Education and Research Center Aiming at the Control of AIDS'') of the Japanese Ministry of Education, Science, Sports, and Culture; Sidaction Fellowship FX We thank all study participants, the French Agence Nationale de la Recherche sur le SIDA (ANRS) Cohorts ALT and PRIMO groups, and the staff at the MX2 beamline (Australian synchrotron). We are grateful to C. Blanc for sorting viable infected cells at the Pitie-Salpetriere Flow Cytometry Platform. This work was supported by the ANR (project ANR-09-JCJC-0114-01), Sidaction, the French ANRS, the National Institutes of Health via the Intramural Program of the Vaccine Research Center (National Institute of Allergy and Infectious Diseases), the Australian Research Council (ARC), the Australian National Health and Medical Research Council (NHMRC), the UK Biotechnology and Biological Sciences Research Council (grant BB/H001085/1), the Japanese Ministry of Health (grant 18390141), and the Global COE program ("Global Education and Research Center Aiming at the Control of AIDS'') of the Japanese Ministry of Education, Science, Sports, and Culture. M. C. I. is supported by a Sidaction Fellowship. V. V. and S. G. are ARC Future Fellows. P. G. W. is an NHMRC CJ Martin Fellow. J.R. is an NHMRC Australia Fellow. D. A. P. is a Wellcome Trust Senior Investigator. NR 48 TC 67 Z9 69 U1 2 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 21 PY 2013 VL 38 IS 3 BP 425 EP 436 DI 10.1016/j.immuni.2012.11.021 PG 12 WC Immunology SC Immunology GA AA2RJ UT WOS:000330941500009 PM 23521884 ER PT J AU Mattila, PK Feest, C Depoil, D Treanor, B Montaner, B Otipoby, KL Carter, R Justement, LB Bruckbauer, A Batista, FD AF Mattila, Pieta K. Feest, Christoph Depoil, David Treanor, Bebhinn Montaner, Beatriz Otipoby, Kevin L. Carter, Robert Justement, Louis B. Bruckbauer, Andreas Batista, Facundo D. TI The Actin and Tetraspanin Networks Organize Receptor Nanoclusters to Regulate B Cell Receptor-Mediated Signaling SO IMMUNITY LA English DT Article ID IMMUNE-SYNAPSE FORMATION; ANTIGEN RECEPTOR; MICROCLUSTER FORMATION; LYMPHOCYTE DEVELOPMENT; MEMBRANE; MICE; ACTIVATION; RESPONSES; TRANSDUCTION; EXPRESSION AB A key role is emerging for the cytoskeleton in coordinating receptor signaling, although the underlying molecular requirements remain unclear. Here we show that cytoskeleton disruption triggered signaling requiring not only the B cell receptor (BCR), but also the coreceptor CD19 and tetraspanin CD81, thus providing a mechanism for signal amplification upon surface-bound antigen stimulation. By using superresolution microscopy, we demonstrated that endogenous IgM, IgD, and CD19 exhibited distinct nanoscale organization within the plasma membrane of primary B cells. Upon stimulation, we detect a local convergence of receptors, although their global organization was not dramatically altered. Thus, we postulate that cytoskeleton reorganization releases BCR nanoclusters, which can interact with CD19 held in place by the tetraspanin network. These results not only suggest that receptor compartmentalization regulates antigen-induced activation but also imply a potential role for CD19 in mediating ligand-independent "tonic'' BCR signaling necessary for B cell survival. C1 [Mattila, Pieta K.; Feest, Christoph; Depoil, David; Treanor, Bebhinn; Montaner, Beatriz; Bruckbauer, Andreas; Batista, Facundo D.] Canc Res UK, London Res Inst, Lymphocyte Interact Lab, London WC2A 3LY, England. [Otipoby, Kevin L.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA. [Otipoby, Kevin L.] Immune Dis Inst, Boston, MA 02115 USA. [Carter, Robert] NIAMSD, NIH, Bethesda, MD 20892 USA. [Justement, Louis B.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. RP Batista, FD (reprint author), Canc Res UK, London Res Inst, Lymphocyte Interact Lab, 44 Lincolns Inn Fields, London WC2A 3LY, England. EM facundo.batista@cancer.org.uk RI Mattila, Pieta/G-6815-2013; Feest, Christoph/C-7874-2013; OI Mattila, Pieta/0000-0003-2805-0686; Feest, Christoph/0000-0002-0772-7267; Justement, Louis/0000-0001-7058-867X FU Cancer Research UK; Royal Society Wolfson Research Merit Award; Human Frontier Science Program FX We are extremely thankful to K. Rajewsky, K. Okkenhaug, and S. Levy for providing B1-8f Igh, Cd21-cre, E mu-Bcl2 transgenic, PI3K delta-mutant, and CD81-deficient mice, respectively. We would also like to thank D. Bray and members of the Lymphocyte Interaction Laboratory for critically reading the manuscript and for helpful discussions and comments. This work was supported by Cancer Research UK, Royal Society Wolfson Research Merit Award (F. D. B.), and Human Frontier Science Program (P.K.M.). NR 43 TC 97 Z9 99 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 21 PY 2013 VL 38 IS 3 BP 461 EP 474 DI 10.1016/j.immuni.2012.11.019 PG 14 WC Immunology SC Immunology GA AA2RJ UT WOS:000330941500012 PM 23499492 ER PT J AU Kastenmuller, W Brandes, M Wang, Z Herz, J Egen, JG Germain, RN AF Kastenmueller, Wolfgang Brandes, Marlene Wang, Ze Herz, Jasmin Egen, Jackson G. Germain, Ronald N. TI Peripheral Prepositioning and Local CXCL9 Chemokine-Mediated Guidance Orchestrate Rapid Memory CD8(+) T Cell Responses in the Lymph Node SO IMMUNITY LA English DT Article ID CLASSICAL DENDRITIC CELLS; ANTIGEN-PRESENTING CELL; HERPES-SIMPLEX-VIRUS; RECALL RESPONSES; COGNATE ANTIGEN; RECEPTOR CXCR3; CD8+T CELLS; IN-VIVO; B-CELLS; INFECTION AB After an infection, the immune system generates long-lived memory lymphocytes whose increased frequency and altered state of differentiation enhance host defense against reinfection. Recently, the spatial distribution of memory cells was found to contribute to their protective function. Effector memory CD8(+) T cells reside in peripheral tissue sites of initial pathogen encounter, in apparent anticipation of reinfection. Here we show that within lymph nodes (LNs), memory CD8(+) T cells were concentrated near peripheral entry portals of lymph-borne pathogens, promoting rapid engagement of infected sentinel macrophages. A feed-forward CXCL9-dependent circuit provided additional chemotactic cues that further increase local memory cell density. Memory CD8(+) T cells also produced effector responses to local cytokine triggers, but their dynamic behavior differed from that seen after antigen recognition. These data reveal the distinct localization and dynamic behavior of naive versus memory T cells within LNs and how these differences contribute to host defense. C1 [Kastenmueller, Wolfgang; Brandes, Marlene; Wang, Ze; Egen, Jackson G.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Herz, Jasmin] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Egen, Jackson G.] Genentech Res & Early Dev, Dept Immunol, San Francisco, CA 94080 USA. RP Kastenmuller, W (reprint author), Univ Bonn, Inst Mol Med, D-53105 Bonn, Germany. EM wkastenm@uni-bonn.de; rgermain@nih.gov OI Egen, Jackson/0000-0003-2053-0837 FU Intramural Research Program, NIAID, NIH; DFG [KA 3091/1-1, HE 6068/1-1] FX We would like to thank J. Farber and A. Luster for providing critical reagents, M. Gerner for help with imaging analysis, and G. Gasteiger, T. Lammermann, and N. van Panhuys for critically reading the manuscript. We are especially grateful to A. Luster and U. von Andrian for generously sharing unpublished data while this study was in progress or in revision. MVA NP-S-GFP was kindly provided by I. Drexler. This research was supported by the Intramural Research Program, NIAID, NIH, by DFG, KA 3091/1-1 to W. K., and HE 6068/1-1 to J.H. NR 58 TC 63 Z9 63 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 21 PY 2013 VL 38 IS 3 BP 502 EP 513 DI 10.1016/j.immuni.2012.11.012 PG 12 WC Immunology SC Immunology GA AA2RJ UT WOS:000330941500015 PM 23352234 ER PT J AU Wan, CK Oh, J Li, P West, EE Wong, EA Andraski, AB Spolski, R Yu, ZX He, JP Kelsall, BL Leonard, WJ AF Wan, Chi-Keung Oh, Jangsuk Li, Peng West, Erin E. Wong, Elizabeth A. Andraski, Allison B. Spolski, Rosanne Yu, Zu-Xi He, Jianping Kelsall, Brian L. Leonard, Warren J. TI The Cytokines IL-21 and GM-CSF Have Opposing Regulatory Roles in the Apoptosis of Conventional Dendritic Cells SO IMMUNITY LA English DT Article ID FOLLICULAR-HELPER-CELLS; HUMAN B-CELLS; T-CELLS; NEGATIVE REGULATOR; IMMUNE TOLERANCE; STEADY-STATE; NKT CELLS; INTERLEUKIN-21; DIFFERENTIATION; HOMEOSTASIS AB Interleukin-21 (IL-21) has broad actions on T and B cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive alpha-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive transfer of wild-type CD4(+) T cells caused more severe colitis with increased DCs and interferon-gamma (IFN-gamma)-producing CD4(+) T cells in Il21r(-/-)Rag2(-/-) mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2(-/-) mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response. C1 [Wan, Chi-Keung; Oh, Jangsuk; Li, Peng; West, Erin E.; Wong, Elizabeth A.; Andraski, Allison B.; Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Wan, Chi-Keung; Oh, Jangsuk; Li, Peng; West, Erin E.; Wong, Elizabeth A.; Andraski, Allison B.; Spolski, Rosanne; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core, NIH, Bethesda, MD 20892 USA. [He, Jianping; Kelsall, Brian L.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Intramural Research Program, National Heart, Lung, and Blood Institute, NIH FX We thank J.X. Lin, NHLBI and R. Schwartz, NIAID, for critical comments, H. Young for the Csf2 and control expression plasmids, L. Hennighausen and G. Robinson for Stat5a-/- mice, and NHLBI Flow Cytometry Core Facility for cell sorting and sample analysis. This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, NIH. R.S. and W.J.L. are inventors on patents related to IL-21. NR 59 TC 42 Z9 44 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 21 PY 2013 VL 38 IS 3 BP 514 EP 527 DI 10.1016/j.immuni.2013.02.011 PG 14 WC Immunology SC Immunology GA AA2RJ UT WOS:000330941500016 PM 23453633 ER PT J AU Blakey, DH Lafontaine, M Lavigne, J Sokolowski, D Philippe, JM Sapori, JM Biederbick, W Horre, R Marzi, WB Kondo, H Kuroki, Y Namera, A Okumura, T Yamamoto, M Yashiki, M Blain, PG Russell, DR Cibulsky, SM Jett, DA AF Blakey, David H. Lafontaine, Marc Lavigne, Jocelyn Sokolowski, Danny Philippe, Jean-Marc Sapori, Jean-Marc Biederbick, Walter Horre, Regine Marzi, Willi B. Kondo, Hisayoshi Kuroki, Yumiko Namera, Akira Okumura, Tetsu Yamamoto, Miyako Yashiki, Mikio Blain, Peter G. Russell, David R. Cibulsky, Susan M. Jett, David A. CA Global Hlth Security Initiative TI A screening tool to prioritize public health risk associated with accidental or deliberate release of chemicals into the atmosphere SO BMC PUBLIC HEALTH LA English DT Article DE Chemicals; Public health; Risk assessment; Atmospheric releases; Screening tool; Disaster management cycle AB The Chemical Events Working Group of the Global Health Security Initiative has developed a flexible screening tool for chemicals that present a risk when accidentally or deliberately released into the atmosphere. The tool is generic, semi-quantitative, independent of site, situation and scenario, encompasses all chemical hazards (toxicity, flammability and reactivity), and can be easily and quickly implemented by non-subject matter experts using freely available, authoritative information. Public health practitioners and planners can use the screening tool to assist them in directing their activities in each of the five stages of the disaster management cycle. C1 [Blakey, David H.; Lafontaine, Marc; Lavigne, Jocelyn; Sokolowski, Danny; Philippe, Jean-Marc; Sapori, Jean-Marc; Biederbick, Walter; Horre, Regine; Marzi, Willi B.; Kondo, Hisayoshi; Kuroki, Yumiko; Namera, Akira; Okumura, Tetsu; Yamamoto, Miyako; Yashiki, Mikio; Blain, Peter G.; Russell, David R.; Cibulsky, Susan M.; Jett, David A.] Global Hlth Secur Initiat, Chem Events Working Grp, Cardiff CF5 2YB, S Glam, Wales. [Blakey, David H.] Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. [Lafontaine, Marc; Lavigne, Jocelyn; Sokolowski, Danny] Hlth Canada, Chem Emergency Preparedness & Response Unit, Ottawa, ON K1A 0L2, Canada. [Philippe, Jean-Marc] Hosp Civils Lyon, Poison Control Ctr, Ctr Antipoison, Lyon, France. [Biederbick, Walter] Robert Koch Inst, Ctr Biol Secur, Berlin, Germany. [Biederbick, Walter; Horre, Regine] Fed Off Civil Protect & Disaster Assistance, Bonn, Germany. [Marzi, Willi B.] Fed Minist Interior, Bonn, Germany. [Kondo, Hisayoshi] Natl Disaster Med Ctr, MHLW DMAT Bur, Tokyo, Japan. [Kuroki, Yumiko] Japan Poison Informat Ctr, Tsukuba Off, Tsukuba, Ibaraki, Japan. [Namera, Akira; Yashiki, Mikio] Hiroshima Univ, Hiroshima, Japan. [Okumura, Tetsu] Govt Japan, Off Assistant Chief Cabinet Secretary Natl Secur, Cabinet Secretariat, Tokyo, Japan. [Yamamoto, Miyako] Natl Inst Hlth Sci, Div Safety Informat Drug Food & Chem, Setagaya Ku, Tokyo, Japan. [Blain, Peter G.] Newcastle Univ, Med Toxicol Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Russell, David R.] Cardiff Metropolitan Univ, WHO Collaborating Ctr Chem Incidents, Hlth Protect Agcy, Cardiff CF5 2YB, S Glam, Wales. [Cibulsky, Susan M.] Off Assistant Secretary Preparedness & Response, Hlth Serv, Washington, DC USA. [Cibulsky, Susan M.] Off Assistant Secretary Preparedness & Response, Human Serv, Washington, DC USA. [Jett, David A.] NINDS, NIH, Bethesda, MD 20892 USA. RP Russell, DR (reprint author), Global Hlth Secur Initiat, Chem Events Working Grp, Cardiff CF5 2YB, S Glam, Wales. EM david.russell@hpa.org.uk NR 36 TC 3 Z9 3 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAR 21 PY 2013 VL 13 AR 253 DI 10.1186/1471-2458-13-253 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 207AR UT WOS:000323569300001 PM 23517410 ER PT J AU Wu, SP Minter, A Costello, R Zingone, A Lee, CK Au, WY Landgren, O AF Wu, S. Peter Minter, Alex Costello, Rene Zingone, Adriana Lee, Cheuk-Kwong Au, Wing-Yan Landgren, Ola TI MGUS prevalence in an ethnically Chinese population in Hong Kong SO BLOOD LA English DT Letter ID UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; MULTIPLE-MYELOMA C1 [Wu, S. Peter; Minter, Alex; Costello, Rene; Zingone, Adriana; Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. [Lee, Cheuk-Kwong] Hong Kong Red Cross Blood Transfus Serv, Hong Kong, Hong Kong, Peoples R China. [Au, Wing-Yan] Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, NIH, 9000 Rockville Pike,Bldg 10 Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov FU Intramural NIH HHS NR 8 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 21 PY 2013 VL 121 IS 12 BP 2363 EP 2364 DI 10.1182/blood-2012-11-466011 PG 2 WC Hematology SC Hematology GA 182RI UT WOS:000321761100028 PM 23520330 ER PT J AU Klion, AD Mejia, R Cowen, EW Dowdell, KC Dunleavy, K Fahle, GA Holland-Thomas, N Maric, I Pittaluga, S Raffeld, M Santos, C Steller-Stevenson, M Krogmann, T Shatzer, AN Turk, SP Yin, YZ Xi, LQ Prussin, C Cohen, JI AF Klion, Amy D. Mejia, Rojelio Cowen, Edward W. Dowdell, Kennichi C. Dunleavy, Kieron Fahle, Gary A. Holland-Thomas, Nicole Maric, Irina Pittaluga, Stefania Raffeld, Mark Santos, Carlo Steller-Stevenson, Maryalice Krogmann, Tammy Shatzer, Amber N. Turk, Siu-Ping Yin, Yuzhi Xi, Liqiang Prussin, Calman Cohen, Jeffrey I. TI Chronic active Epstein-Barr virus infection: a novel cause of lymphocytic variant hypereosinophilic syndrome SO BLOOD LA English DT Letter C1 [Klion, Amy D.; Mejia, Rojelio; Santos, Carlo] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Dowdell, Kennichi C.; Krogmann, Tammy; Shatzer, Amber N.; Cohen, Jeffrey I.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Dunleavy, Kieron] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Fahle, Gary A.; Maric, Irina] NIH, Dept Lab Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Holland-Thomas, Nicole] NCI, Parasit Dis Lab, Clin Res Directorate, Clin Monitoring Res Program,SAIC Frederick Inc,Fr, Frederick, MD 21701 USA. [Pittaluga, Stefania; Raffeld, Mark; Steller-Stevenson, Maryalice; Xi, Liqiang] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Turk, Siu-Ping] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Yin, Yuzhi; Prussin, Calman] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Klion, AD (reprint author), NIH, Bldg 4,Room B1-28,4 Mem Dr, Bethesda, MD 20892 USA. EM aklion@nih.gov OI Prussin, Calman/0000-0002-3917-3326; Klion, Amy/0000-0002-4986-5326 FU Intramural NIH HHS NR 4 TC 7 Z9 9 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 21 PY 2013 VL 121 IS 12 BP 2364 EP 2366 DI 10.1182/blood-2012-12-472720 PG 5 WC Hematology SC Hematology GA 182RI UT WOS:000321761100029 PM 23520331 ER PT J AU Friboulet, L Olaussen, KA Pignon, JP Shepherd, FA Tsao, MS Graziano, S Kratzke, R Douillard, JY Seymour, L Pirker, R Filipits, M Andre, F Solary, E Ponsonnailles, F Robin, A Stoclin, A Dorvault, N Commo, F Adam, J Vanhecke, E Saulnier, P Thomale, J Le Chevalier, T Dunant, A Rousseau, V Le Teuff, G Brambilla, E Soria, JC AF Friboulet, Luc Olaussen, Ken Andre Pignon, Jean-Pierre Shepherd, Frances A. Tsao, Ming-Sound Graziano, Stephen Kratzke, Robert Douillard, Jean-Yves Seymour, Lesley Pirker, Robert Filipits, Martin Andre, Fabrice Solary, Eric Ponsonnailles, Florence Robin, Angelique Stoclin, Annabelle Dorvault, Nicolas Commo, Frederic Adam, Julien Vanhecke, Elsa Saulnier, Patrick Thomale, Juergen Le Chevalier, Thierry Dunant, Ariane Rousseau, Vanessa Le Teuff, Gwenael Brambilla, Elisabeth Soria, Jean-Charles TI ERCC1 Isoform Expression and DNA Repair in Non-Small-Cell Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID III BETA-TUBULIN; MESSENGER-RNA EXPRESSION; COMPLEMENTATION GROUP 1; ADJUVANT CHEMOTHERAPY; MONOCLONAL-ANTIBODIES; SURVIVAL; TRIAL; IMMUNODETECTION; VALIDATION; CARCINOMA AB Background The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. Methods We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR. 10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. Results We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. Conclusions Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.) C1 [Friboulet, Luc; Olaussen, Ken Andre; Andre, Fabrice; Ponsonnailles, Florence; Robin, Angelique; Stoclin, Annabelle; Dorvault, Nicolas; Commo, Frederic; Adam, Julien; Vanhecke, Elsa; Soria, Jean-Charles] Inst Gustave Roussy, INSERM, U981, F-94805 Villejuif, France. [Friboulet, Luc; Olaussen, Ken Andre; Ponsonnailles, Florence; Robin, Angelique; Stoclin, Annabelle; Dorvault, Nicolas; Commo, Frederic; Adam, Julien; Vanhecke, Elsa; Soria, Jean-Charles] Inst Gustave Roussy, Dept Hosp Univ Thorax Innovat, F-94805 Villejuif, France. [Andre, Fabrice; Le Chevalier, Thierry; Soria, Jean-Charles] Inst Gustave Roussy, Dept Canc Med, F-94805 Villejuif, France. [Pignon, Jean-Pierre; Dunant, Ariane; Rousseau, Vanessa; Le Teuff, Gwenael] Inst Gustave Roussy, Biostat & Epidemiol Unit, F-94805 Villejuif, France. [Solary, Eric] Inst Gustave Roussy, INSERM, UMR1009, F-94805 Villejuif, France. [Saulnier, Patrick] Inst Gustave Roussy, Translat Res Unit, F-94805 Villejuif, France. [Friboulet, Luc; Olaussen, Ken Andre; Andre, Fabrice; Solary, Eric; Ponsonnailles, Florence; Robin, Angelique; Stoclin, Annabelle; Dorvault, Nicolas; Commo, Frederic; Adam, Julien; Vanhecke, Elsa; Le Chevalier, Thierry; Soria, Jean-Charles] Univ Paris 11, Le Kremlin Bicetre, France. [Douillard, Jean-Yves] Inst Canc Ouest Rene Gauducheau, Nantes, France. [Brambilla, Elisabeth] Univ Grenoble 1, CHU Grenoble, Hop Albert Michallon, Inst Albert Bonniot,Dept Pathol,INSERM,U823, Grenoble, France. [Shepherd, Frances A.] Univ Hlth Network, Princess Margaret Hosp, Dept Med, Toronto, ON, Canada. [Tsao, Ming-Sound] Univ Hlth Network, Princess Margaret Hosp, Dept Pathol, Toronto, ON, Canada. [Graziano, Stephen] SUNY Upstate Med Univ, Dept Med, Syracuse, NY 13210 USA. [Kratzke, Robert] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Seymour, Lesley] Canada Clin Trials Grp, NCI, Kingston, ON, Canada. [Pirker, Robert; Filipits, Martin] Med Univ Vienna, Dept Med 1, Vienna, Austria. [Thomale, Juergen] Univ Duisburg Essen Med Sch, Inst Cell Biol, Essen, Germany. RP Soria, JC (reprint author), Inst Gustave Roussy, INSERM, U981, 114 Rue Edouard Vaillant, F-94805 Villejuif, France. EM soria@igr.fr RI Brambilla, Elisabeth/L-8796-2013; friboulet, luc/N-7276-2015 OI friboulet, luc/0000-0002-1129-4978 FU Eli Lilly; Institut National du Cancer Programme National d'Excellence Specialise and Programme Hospitalier de Recherche Clinique; La Ligue Nationale contre le Cancer; Sanofi-Aventis; European Union [HEALTH-F2-2010-258677-CURELUNG]; Roche FX Supported by an unrestricted grant from Eli Lilly and by grants from Institut National du Cancer Programme National d'Excellence Specialise and Programme Hospitalier de Recherche Clinique (to the International Adjuvant Lung Cancer Trial Biology); by La Ligue Nationale contre le Cancer and an unrestricted grant from Sanofi-Aventis (to the Lung Adjuvant Cisplatin Evaluation Biology project); by a contract (FP7-2007-13) from the European Union Seventh Framework Program under a grant agreement (HEALTH-F2-2010-258677-CURELUNG); and by a translational research fellowship from Roche (to Dr. Friboulet). NR 39 TC 148 Z9 161 U1 2 U2 38 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 MAR 21 PY 2013 VL 368 IS 12 BP 1101 EP 1110 DI 10.1056/oa1214271 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 108TH UT WOS:000316318600003 PM 23514287 ER PT J AU Freudlsperger, C Bian, Y Wise, SC Burnett, J Coupar, J Yang, X Chen, Z Van Waes, C AF Freudlsperger, C. Bian, Y. Wise, S. Contag Burnett, J. Coupar, J. Yang, X. Chen, Z. Van Waes, C. TI TGF-beta and NF-kappa B signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers SO ONCOGENE LA English DT Article DE TGF-beta TAK1; NF-kappa B; SMAD7; celastrol; head and neck cancer ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR-BETA; INDUCED APOPTOSIS; GENE-EXPRESSION; TUMOR-CELLS; KINASE TAK1; ACTIVATION; RECEPTOR; PROTEIN; MICE AB Transforming growth factor-beta (TGF-beta) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-beta signaling enhances de novo tumor development, whereas TGF-beta overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-beta-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-kappa B (NF-kappa B), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-beta and NF-kappa B pathways plays in altered activation of these pathways has not been established. Here, we show TGF-beta receptor II and TGF-beta-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-kappa B family member RELA (p65). Further, TGF-beta 1 treatment induced sequential phosphorylation of TAK1, IKK, I kappa B alpha and RELA in human HNSCC lines. TAK1 enhances TGF-beta-induced NF-kappa B activation, as TAK1 siRNA knockdown decreased TGF-beta 1-induced phosphorylation of IKK, I kappa B and RELA, degradation of I kappa B alpha, RELA nuclear translocation and DNA binding, and NF-kappa B-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. Celastrol, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-beta 1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-beta 1- and tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappa B reporter gene activity. Celastrol also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-beta and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-beta-induced SMAD and NF-kappa B reporters when compared with constitutive or TNF-alpha-induced NF-kappa B reporter gene activation. Thus, cross-talk by TGF-beta via TAK1 and NF-kappa B promotes the malignant phenotype of HNSCC. Moreover, NF-kappa B may contribute to the downstream attenuation of canonical TGF-beta signaling through increased SMAD7 expression. Celastrol highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-beta-NF-kappa B signal pathway. Oncogene (2013) 32, 1549-1559; doi:10.1038/onc.2012.171; published online 28 May 2012 C1 [Freudlsperger, C.; Bian, Y.; Wise, S. Contag; Burnett, J.; Coupar, J.; Yang, X.; Chen, Z.; Van Waes, C.] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [Freudlsperger, C.] Univ Hosp Tuebingen, Dept Oral & Maxillofacial Surg, Tubingen, Germany. RP Chen, Z (reprint author), Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, 10 Ctr Dr,MSC 1462,Bldg 10,Rm 4-2732, Bethesda, MD 20892 USA. EM chenz@nidcd.nih.gov; vanwaesc@nidcd.nih.gov FU National Institute on Deafness and Other Communication Disorders, NIH [ZIA-DC-000016, ZIA-DC-000073]; Clinical Research Training Program; NIH; Pfizer Inc. FX Supported by intramural projects ZIA-DC-000016 and ZIA-DC-000073 from the National Institute on Deafness and Other Communication Disorders, NIH. Dr Contag Wise was supported by the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc. The authors wish to thank Dr Ning T Yeh (NIDCD/NIH) and Chris Silvin (NHGRI/NIH) for their technical assistance. We would like to thank Drs Adam Glick and Ashok Kulkarni for review of the manuscript and helpful comments. NR 61 TC 46 Z9 52 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 21 PY 2013 VL 32 IS 12 BP 1549 EP 1559 DI 10.1038/onc.2012.171 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 110PC UT WOS:000316456000008 PM 22641218 ER PT J AU Braun, R Finney, R Yan, CH Chen, QR Hu, Y Edmonson, M Meerzaman, D Buetow, K AF Braun, Rosemary Finney, Richard Yan, Chunhua Chen, Qing-Rong Hu, Ying Edmonson, Michael Meerzaman, Daoud Buetow, Kenneth TI Discovery Analysis of TCGA Data Reveals Association between Germline Genotype and Survival in Ovarian Cancer Patients SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; PLATINUM COMPLEXES; TUMOR RESPONSE; BREAST-CANCER; CHEMOTHERAPY; CARCINOMA; SUSCEPTIBILITY; VARIANTS; POLYMORPHISMS; PREDICTION AB Background: Ovarian cancer remains a significant public health burden, with the highest mortality rate of all the gynecological cancers. This is attributable to the late stage at which the majority of ovarian cancers are diagnosed, coupled with the low and variable response of advanced tumors to standard chemotherapies. To date, clinically useful predictors of treatment response remain lacking. Identifying the genetic determinants of ovarian cancer survival and treatment response is crucial to the development of prognostic biomarkers and personalized therapies that may improve outcomes for the late-stage patients who comprise the majority of cases. Methods: To identify constitutional genetic variations contributing to ovarian cancer mortality, we systematically investigated associations between germline polymorphisms and ovarian cancer survival using data from The Cancer Genome Atlas Project (TCGA). Using stage-stratified Cox proportional hazards regression, we examined >650,000 SNP loci for association with survival. We additionally examined whether the association of significant SNPs with survival was modified by somatic alterations. Results: Germline polymorphisms at rs4934282 (AGAP11/C10orf116) and rs1857623 (DNAH14) were associated with stage-adjusted survival (p = 1.12e-07 and 1.80e-07, FDR q = 1.2e-04 and 2.4e-04, respectively). A third SNP, rs4869 (C10orf116), was additionally identified as significant in the exome sequencing data; it is in near-perfect LD with rs4934282. The associations with survival remained significant when somatic alterations. Conclusions: Discovery analysis of TCGA data reveals germline genetic variations that may play a role in ovarian cancer survival even among late-stage cases. The significant loci are located near genes previously reported as having a possible relationship to platinum and taxol response. Because the variant alleles at the significant loci are common (frequencies for rs4934282 A/C alleles = 0.54/0.46, respectively; rs1857623 A/G alleles = 0.55/0.45, respectively) and germline variants can be assayed noninvasively, our findings provide potential targets for further exploration as prognostic biomarkers and individualized therapies. C1 [Braun, Rosemary] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Braun, Rosemary; Finney, Richard; Yan, Chunhua; Chen, Qing-Rong; Hu, Ying; Edmonson, Michael; Meerzaman, Daoud; Buetow, Kenneth] NCI, Ctr Biomed Informat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Buetow, Kenneth] Arizona State Univ, Computat Sci & Informat Program, Complex Adapt Syst Initiat, Phoenix, AZ USA. RP Braun, R (reprint author), Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. EM rbraun@northwestern.edu OI Braun, Rosemary/0000-0001-9668-9866 FU National Cancer Institute, United States National Institutes of Health, Bethesda, MD FX The authors are supported by the Intramural Research Program of the National Cancer Institute, United States National Institutes of Health, Bethesda, MD. There were no external funding sources for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 15 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 MAR 21 PY 2013 VL 8 IS 3 AR e55037 DI 10.1371/journal.pone.0055037 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111UM UT WOS:000316546400001 PM 23555554 ER PT J AU Herman, JP Cloud, CP Wallman, J AF Herman, James P. Cloud, C. Phillip Wallman, Josh TI End-Point Variability Is Not Noise in Saccade Adaptation SO PLOS ONE LA English DT Article ID EYE-MOVEMENT; MOTOR ADAPTATION; ADAPTIVE-CONTROL; GAIN ADAPTATION; PLASTICITY; SIGNALS; ERROR; SEQUENCES; MEMORY; SYSTEM AB When each of many saccades is made to overshoot its target, amplitude gradually decreases in a form of motor learning called saccade adaptation. Overshoot is induced experimentally by a secondary, backwards intrasaccadic target step (ISS) triggered by the primary saccade. Surprisingly, however, no study has compared the effectiveness of different sizes of ISS in driving adaptation by systematically varying ISS amplitude across different sessions. Additionally, very few studies have examined the feasibility of adaptation with relatively small ISSs. In order to best understand saccade adaptation at a fundamental level, we addressed these two points in an experiment using a range of small, fixed ISS values (from 0 degrees to 1 degrees after a 10 degrees primary target step). We found that significant adaptation occurred across subjects with an ISS as small as 0.25 degrees. Interestingly, though only adaptation in response to 0.25 degrees ISSs appeared to be complete (the magnitude of change in saccade amplitude was comparable to size of the ISS), further analysis revealed that a comparable proportion of the ISS was compensated for across conditions. Finally, we found that ISS size alone was sufficient to explain the magnitude of adaptation we observed; additional factors did not significantly improve explanatory power. Overall, our findings suggest that current assumptions regarding the computation of saccadic error may need to be revisited. C1 [Herman, James P.; Cloud, C. Phillip; Wallman, Josh] CUNY City Coll, Dept Biol, New York, NY 10031 USA. [Herman, James P.; Wallman, Josh] CUNY, Grad Ctr, PhD Program Biol, New York, NY USA. [Cloud, C. Phillip] CUNY, Grad Ctr, PhD Program Psychol, New York, NY USA. RP Herman, JP (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM james.herman@nih.gov OI Herman, James/0000-0001-6916-2807 FU National Science Foundation [BCS-0842464]; National Institute of Health [1R01EY019508, RR-03060] FX This research was funded by grant BCS-0842464 from the National Science Foundation (www.nsf.gov), and grants 1R01EY019508 and RR-03060 from the National Institute of Health (www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 34 TC 7 Z9 7 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 MAR 21 PY 2013 VL 8 IS 3 AR e59731 DI 10.1371/journal.pone.0059731 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111UM UT WOS:000316546400058 PM 23555763 ER PT J AU Koreishi, M Gniadek, TJ Yu, S Masuda, J Honjo, Y Satoh, A AF Koreishi, Mayuko Gniadek, Thomas J. Yu, Sidney Masuda, Junko Honjo, Yasuko Satoh, Ayano TI The Golgin Tether Giantin Regulates the Secretory Pathway by Controlling Stack Organization within Golgi Apparatus SO PLOS ONE LA English DT Article ID ENDOPLASMIC-RETICULUM; TRYPANOSOMA-BRUCEI; TRANSPORT-VESICLE; PROTEIN GIANTIN; COPI VESICLES; MEMBRANE; ARCHITECTURE; INTERACTS; P115; DYNAMICS AB Golgins are coiled-coil proteins that play a key role in the regulation of Golgi architecture and function. Giantin, the largest golgin in mammals, forms a complex with p115, rab1, GM130, and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), thereby facilitating vesicle tethering and fusion processes around the Golgi apparatus. Treatment with the microtubule destabilizing drug nocodazole transforms the Golgi ribbon into individual Golgi stacks. Here we show that siRNA-mediated depletion of giantin resulted in more dispersed Golgi stacks after nocodazole treatment than by control treatment, without changing the average cisternal length. Furthermore, depletion of giantin caused an increase in cargo transport that was associated with altered cell surface protein glycosylation. Drosophila S2 cells are known to have dispersed Golgi stacks and no giantin homolog. The exogenous expression of mammalian giantin cDNA in S2 cells resulted in clustered Golgi stacks, similar to the Golgi ribbon in mammalian cells. These results suggest that the spatial organization of the Golgi ribbon is mediated by giantin, which also plays a role in cargo transport and sugar modifications. C1 [Koreishi, Mayuko; Satoh, Ayano] Okayama Univ, Grad Sch Nat Sci & Technol, Okayama, Japan. [Gniadek, Thomas J.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Yu, Sidney] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Yu, Sidney] Chinese Univ Hong Kong, Epithelial Cell Biol Res Ctr, Shatin, Hong Kong, Peoples R China. [Masuda, Junko] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Honjo, Yasuko] Okayama Univ, RCIS, Okayama, Japan. RP Satoh, A (reprint author), Okayama Univ, Grad Sch Nat Sci & Technol, Okayama, Japan. EM ayano113@cc.okayama-u.ac.jp OI SATOH, Ayano/0000-0003-3736-1283 FU Kurata Memorial Hitachi Science and Technology Foundation; special Coordination Fund for Promoting Science and Technology; JSPS KAKENHI of MEXT (Ministry of Education, Sport, Culture, Science and Technology in Japan) [23570167]; Hayashi Memorial Foundation for Female Natural Scientists; Ryobi Teien Memorial Foundation; Naito Foundation; Uehara Memorial Foundation; National Institutes of Health, USA [AG030101, GM060919] FX Funding sources The Kurata Memorial Hitachi Science and Technology Foundation, the special Coordination Fund for Promoting Science and Technology, and JSPS KAKENHI Grant Number23570167 of MEXT (Ministry of Education, Sport, Culture, Science and Technology in Japan), Hayashi Memorial Foundation for Female Natural Scientists, Ryobi Teien Memorial Foundation, the Naito Foundation, the Uehara Memorial Foundation, and the National Institutes of Health (AG030101 and GM060919, USA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 13 Z9 16 U1 1 U2 13 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 MAR 21 PY 2013 VL 8 IS 3 AR e59821 DI 10.1371/journal.pone.0059821 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111UM UT WOS:000316546400065 PM 23555793 ER PT J AU Rokic, MB Stojilkovic, SS Vavra, V Kuzyk, P Tvrdonova, V Zemkova, H AF Rokic, Milos B. Stojilkovic, Stanko S. Vavra, Vojtech Kuzyk, Pavlo Tvrdonova, Vendula Zemkova, Hana TI Multiple Roles of the Extracellular Vestibule Amino Acid Residues in the Function of the Rat P2X4 Receptor SO PLOS ONE LA English DT Article ID HUMAN P2X(1) RECEPTORS; GATED ION CHANNELS; ATP-BINDING-SITE; TRANSMEMBRANE SEGMENTS; AGONIST BINDING; LATERAL PORTALS; IDENTIFICATION; PORE; MODULATION; ACTIVATION AB The binding of ATP to trimeric P2X receptors (P2XR) causes an enlargement of the receptor extracellular vestibule, leading to opening of the cation-selective transmembrane pore, but specific roles of vestibule amino acid residues in receptor activation have not been evaluated systematically. In this study, alanine or cysteine scanning mutagenesis of V47-V61 and F324-N338 sequences of rat P2X4R revealed that V49, Y54, Q55, F324, and G325 mutants were poorly responsive to ATP and trafficking was only affected by the V49 mutation. The Y54F and Y54W mutations, but not the Y54L mutation, rescued receptor function, suggesting that an aromatic residue is important at this position. Furthermore, the Y54A and Y54C receptor function was partially rescued by ivermectin, a positive allosteric modulator of P2X4R, suggesting a rightward shift in the potency of ATP to activate P2X4R. The Q55T, Q55N, Q55E, and Q55K mutations resulted in non-responsive receptors and only the Q55E mutant was ivermectin-sensitive. The F324L, F324Y, and F324W mutations also rescued receptor function partially or completely, ivermectin action on channel gating was preserved in all mutants, and changes in ATP responsiveness correlated with the hydrophobicity and side chain volume of the substituent. The G325P mutant had a normal response to ATP, suggesting that G325 is a flexible hinge. A topological analysis revealed that the G325 and F324 residues disrupt a beta-sheet upon ATP binding. These results indicate multiple roles of the extracellular vestibule amino acid residues in the P2X4R function: the V49 residue is important for receptor trafficking to plasma membrane, the Y54 and Q55 residues play a critical role in channel gating and the F324 and G325 residues are critical for vestibule widening. C1 [Rokic, Milos B.; Vavra, Vojtech; Kuzyk, Pavlo; Tvrdonova, Vendula; Zemkova, Hana] Acad Sci Czech Republic, Inst Physiol, Dept Cellular & Mol Neuroendocrinol, Prague, Czech Republic. [Rokic, Milos B.; Tvrdonova, Vendula] Charles Univ Prague, Fac Sci, Dept Anim Physiol, Prague, Czech Republic. [Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Rokic, MB (reprint author), Acad Sci Czech Republic, Inst Physiol, Dept Cellular & Mol Neuroendocrinol, Prague, Czech Republic. EM rokic@biomed.cas.cz RI Zemkova, Hana/C-1844-2012; Vavra, Vojtech/C-1857-2012; Tvrdonova Stillerova, Vendula/G-3060-2014; ROKIC, MILOS/O-7204-2014 OI Tvrdonova Stillerova, Vendula/0000-0001-5295-2837; ROKIC, MILOS/0000-0002-9148-2716 FU Internal Grant Agency of Academy of Sciences [IAA500110910]; Grant Agency of the Czech Republic [P304/12/G069]; Grant Agency of Charles University [3446/2011]; Academy of Sciences of the Czech Republic [AVOZ 50110509, RVO 67985823]; Intramural Research Program of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) FX This work was supported by the Internal Grant Agency of Academy of Sciences (Grant No. IAA500110910), the Grant Agency of the Czech Republic (P304/12/G069), Grant Agency of Charles University (3446/2011), the Academy of Sciences of the Czech Republic (Research Project No. AVOZ 50110509 and RVO 67985823), and the Intramural Research Program of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 10 Z9 10 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 MAR 21 PY 2013 VL 8 IS 3 AR e59411 DI 10.1371/journal.pone.0059411 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111UM UT WOS:000316546400037 PM 23555667 ER PT J AU Chen, Q Swaminathan, S Yang, D Dai, L Sui, HY Yang, J Hornung, RL Wang, YM Huang, DW Hu, XJ Lempicki, RA Imamichi, T AF Chen, Qian Swaminathan, Sanjay Yang, De Dai, Lue Sui, Hongyan Yang, Jun Hornung, Ronald L. Wang, Yanmei Huang, Da Wei Hu, Xiaojun Lempicki, Richard A. Imamichi, Tomozumi TI Interleukin-27 Is a Potent Inhibitor of cis HIV-1 Replication in Monocyte-Derived Dendritic Cells via a Type I Interferon-Independent Pathway SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; GASTROINTESTINAL-TRACT; TRANS-INFECTION; CUTTING EDGE; IL-27; INDUCTION; DEPLETION; CYTOKINE; IMMATURE AB IL-27, a member of the IL-12 family of cytokines, plays an important and diverse role in the function of the immune system. Whilst generally recognized as an anti-inflammatory cytokine, in addition IL-27 has been found to have broad anti-viral effects. Recently, IL-27 has been shown to be a potent inhibitor of HIV-1 infection in CD4+ T cells and macrophages. The main objective of this study was to see whether IL-27 has a similar inhibitory effect on HIV-1 replication in dendritic cells (DCs). Monocytes were differentiated into immature DCs (iDCs) and mature DCs (mDCs) with standard techniques using a combination of GM-CSF, IL-4 and LPS. Following differentiation, iDCs were infected with HIV-1 and co-cultured in the presence or absence of IL-27. IL-27 treated DCs were shown to be highly potent inhibitors of cis HIV-1, particularly of CCR5 tropic strains. Of note, other IL-12 family members (IL-12, IL-23 and IL-35) had no effect on HIV-1 replication. Microarray studies of IL-27 treated DCs showed no up-regulation of Type I (IFN) gene expression. Neutralization of the Type-I IFN receptor had no impact on the HIV inhibition. Lastly, IL-27 mediated inhibition was shown to act post-viral entry and prior to completion of reverse transcription. These results show for the first time that IL-27 is a potent inhibitor of cis HIV-1 infection in DCs by a Type I IFN independent mechanism. IL-27 has previously been reported to inhibit HIV-1 replication in CD4+ T cells and macrophages, thus taken together, this cytokine is a potent anti-HIV agent against all major cell types targeted by the HIV-1 virus and may have a therapeutic role in the future. C1 [Chen, Qian; Swaminathan, Sanjay; Dai, Lue; Sui, Hongyan; Imamichi, Tomozumi] Sci Applicat Int Corp SAIC Frederick Inc, Appl & Dev Res Directorate ADD, Lab Human Retrovirol, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Yang, De] SAIC Frederick Inc, Basic Res Program Directorate, Mol Immunoregulat Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Yang, Jun; Huang, Da Wei; Hu, Xiaojun; Lempicki, Richard A.] SAIC Frederick Inc, Lab Immunopathogenesis & Bioinformat, ADD, Frederick Natl Lab Canc Res, Frederick, MD USA. [Hornung, Ronald L.; Wang, Yanmei] SAIC Frederick Inc, Immunol Monitoring Lab, ADD, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Imamichi, T (reprint author), Sci Applicat Int Corp SAIC Frederick Inc, Appl & Dev Res Directorate ADD, Lab Human Retrovirol, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM timamichi@mail.nih.gov RI Sui, Hongyan/M-1305-2013; Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Swaminathan, Sanjay/0000-0001-5315-6445 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Disease FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the National Institute of Allergy and Infectious Disease. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 10 Z9 11 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 MAR 20 PY 2013 VL 8 IS 3 AR e59194 DI 10.1371/journal.pone.0059194 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SW UT WOS:000317562600063 PM 23527130 ER PT J AU Fenichel, EP Kuminoff, NV Chowell, G AF Fenichel, Eli P. Kuminoff, Nicolai V. Chowell, Gerardo TI Skip the Trip: Air Travelers' Behavioral Responses to Pandemic Influenza SO PLOS ONE LA English DT Article ID INFECTIOUS-DISEASES; A H1N1; TRANSMISSION; IMPACT; SPREAD; MODELS; STRAIN; UK AB Theory suggests that human behavior has implications for disease spread. We examine the hypothesis that individuals engage in voluntary defensive behavior during an epidemic. We estimate the number of passengers missing previously purchased flights as a function of concern for swine flu or A/H1N1 influenza using 1.7 million detailed flight records, Google Trends, and the World Health Organization's FluNet data. We estimate that concern over "swine flu," as measured by Google Trends, accounted for 0.34% of missed flights during the epidemic. The Google Trends data correlates strongly with media attention, but poorly (at times negatively) with reported cases in FluNet. Passengers show no response to reported cases. Passengers skipping their purchased trips forwent at least $50 M in travel related benefits. Responding to actual cases would have cut this estimate in half. Thus, people appear to respond to an epidemic by voluntarily engaging in self-protection behavior, but this behavior may not be responsive to objective measures of risk. Clearer risk communication could substantially reduce epidemic costs. People undertaking costly risk reduction behavior, for example, forgoing nonrefundable flights, suggests they may also make less costly behavior adjustments to avoid infection. Accounting for defensive behaviors may be important for forecasting epidemics, but linking behavior with epidemics likely requires consideration of risk communication. C1 [Fenichel, Eli P.] Yale Univ, Sch Forestry & Environm Studies, New Haven, CT 06511 USA. [Kuminoff, Nicolai V.] Arizona State Univ, Dept Econ, Tempe, AZ 85287 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut, Tempe, AZ USA. [Chowell, Gerardo] Arizona State Univ, Sch Change, Tempe, AZ USA. [Chowell, Gerardo] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Fenichel, EP (reprint author), Yale Univ, Sch Forestry & Environm Studies, New Haven, CT 06511 USA. EM eli.fenichel@yale.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Fenichel, Eli/0000-0002-7649-8250 FU National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health [1R01GM100471-01] FX U.S. Airways Corporation generously provided data and background information on the airline industry. This publication was made possible by grant number 1R01GM100471-01 from the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health. Its contents are solely the responsibility of the authors and do not represent the official views of NIGMS or US Airways. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 14 Z9 14 U1 1 U2 32 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 MAR 20 PY 2013 VL 8 IS 3 AR e58249 DI 10.1371/journal.pone.0058249 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SW UT WOS:000317562600015 PM 23526970 ER PT J AU Toro, C Olive, M Dalakas, MC Sivakumar, K Bilbao, JM Tyndel, F Vidal, N Farrero, E Sambuughin, N Goldfarb, LG AF Toro, Camilo Olive, Montse Dalakas, Marinos C. Sivakumar, Kumaraswami Bilbao, Juan M. Tyndel, Felix Vidal, Noemi Farrero, Eva Sambuughin, Nyamkhishig Goldfarb, Lev G. TI Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins SO BMC NEUROLOGY LA English DT Article DE Myopathy; Respiratory failure; HMERF; Titin; Titin A-band mutation; Fibronectin type III ID PROTEIN AGGREGATE MYOPATHIES; AUTOSOMAL-DOMINANT MYOPATHY; CYCLIN-DEPENDENT KINASES; MYOFIBRILLAR MYOPATHY; MUSCULAR-DYSTROPHY; DILATED CARDIOMYOPATHY; TDP-43 ACCUMULATION; ONSET MYOPATHY; Z-LINE; MUSCLE AB Background: Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins. Methods: Whole exome sequencing analysis was carried out in a large U. S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy. Results: A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U. S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin. Conclusions: Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin. C1 [Toro, Camilo] NHGRI, Undiagnosed Dis Program, NIH, Bethesda, MD 20892 USA. [Olive, Montse; Vidal, Noemi] IDIBELL Hosp Univ Bellvitge, Dept Pathol, Inst Neuropathol, Barcelona, Spain. [Olive, Montse] IDIBELL Hosp Univ Bellvitge, Dept Neurol, Neuromuscular Unit, Barcelona, Spain. [Olive, Montse] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain. [Dalakas, Marinos C.] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Sivakumar, Kumaraswami] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Bilbao, Juan M.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Tyndel, Felix] Univ Toronto, Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. [Farrero, Eva] IDIBELL Hosp Univ Bellvitge, Pneumol Serv, Barcelona, Spain. [Sambuughin, Nyamkhishig] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Goldfarb, Lev G.] NINDS, NIH, Bethesda, MD 20892 USA. RP Goldfarb, LG (reprint author), NINDS, NIH, Room 4S06,5625 Fishers Lane,MSC 9404, Bethesda, MD 20892 USA. EM GoldfarbL@ninds.nih.gov OI Olive, Montse/0000-0001-5727-0165 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke; Spanish Instituto de Salud Carlos III [PI08-574]; USU [R080CD] FX We wish to thank D.O. Furst for providing the anti C-filamin antibody. The research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. Technical support was provided by the Bioinformatics core at the Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health and Biomedical Instrumentation Center of USU, Uniformed Services University. MO was supported by a grant from the Spanish Instituto de Salud Carlos III, PI08-574. NS was supported by USU grant R080CD. NR 51 TC 17 Z9 18 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD MAR 20 PY 2013 VL 13 AR 29 DI 10.1186/1471-2377-13-29 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA 113WW UT WOS:000316701100001 PM 23514108 ER PT J AU Brady, LS AF Brady, Linda S. TI Assessing biomarkers for brain diseases: progress and gaps SO GENOME MEDICINE LA English DT Editorial Material AB A report on the 2nd Wellcome Trust Scientific Conference on Biomarkers for Brain Disorders: Challenges and Opportunities, held at the Moller Centre, Cambridge, UK, February 3-5, 2013. C1 NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. RP Brady, LS (reprint author), NIMH, Div Neurosci & Basic Behav Sci, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM lbrady@mail.nih.gov 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 1756-994X J9 GENOME MED JI Genome Med. PD MAR 20 PY 2013 VL 5 AR 23 DI 10.1186/gm427 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 115FP UT WOS:000316798300001 PM 23673002 ER PT J AU Li, ZJ Herold, T He, CJ Valk, PJM Chen, P Jurinovic, V Mansmann, U Radmacher, MD Maharry, KS Sun, M Yang, XN Huang, H Jiang, X Sauerland, MC Buchner, T Hiddemann, W Elkahloun, A Neilly, MB Zhang, YM Larson, RA Le Beau, MM Caligiuri, MA Dohner, K Bullinger, L Liu, PP Delwel, R Marcucci, G Lowenberg, B Bloomfield, CD Rowley, JD Bohlander, SK Chen, JJ AF Li, Zejuan Herold, Tobias He, Chunjiang Valk, Peter J. M. Chen, Ping Jurinovic, Vindi Mansmann, Ulrich Radmacher, Michael D. Maharry, Kati S. Sun, Miao Yang, Xinan Huang, Hao Jiang, Xi Sauerland, Maria-Cristina Buechner, Thomas Hiddemann, Wolfgang Elkahloun, Abdel Neilly, Mary Beth Zhang, Yanming Larson, Richard A. Le Beau, Michelle M. Caligiuri, Michael A. Doehner, Konstanze Bullinger, Lars Liu, Paul P. Delwel, Ruud Marcucci, Guido Lowenberg, Bob Bloomfield, Clara D. Rowley, Janet D. Bohlander, Stefan K. Chen, Jianjun TI Identification of a 24-Gene Prognostic Signature That Improves the European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: An International Collaborative Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; GENE-EXPRESSION SIGNATURE; NORMAL CYTOGENETICS; GROUP-B; CEBPA MUTATIONS; POOR-PROGNOSIS; TANDEM DUPLICATION; NORMAL KARYOTYPE; YOUNGER ADULTS; FAVORABLE PROGNOSIS AB Purpose To identify a robust prognostic gene expression signature as an independent predictor of survival of patients with acute myeloid leukemia (AML) and use it to improve established risk classification. Patients and Methods Four independent sets totaling 499 patients with AML carrying various cytogenetic and molecular abnormalities were used as training sets. Two independent patient sets composed of 825 patients were used as validation sets. Notably, patients from different sets were treated with different protocols, and their gene expression profiles were derived using different microarray platforms. Cox regression and Kaplan-Meier methods were used for survival analyses. Results A prognostic signature composed of 24 genes was derived from a meta-analysis of Cox regression values of each gene across the four training sets. In multivariable models, a higher sum value of the 24-gene signature was an independent predictor of shorter overall (OS) and event-free survival (EFS) in both training and validation sets (P < .01). Moreover, this signature could substantially improve the European LeukemiaNet (ELN) risk classification of AML, and patients in three new risk groups classified by the integrated risk classification showed significantly (P < .001) distinct OS and EFS. Conclusion Despite different treatment protocols applied to patients and use of different microarray platforms for expression profiling, a common prognostic gene signature was identified as an independent predictor of survival of patients with AML. The integrated risk classification incorporating this gene signature provides a better framework for risk stratification and outcome prediction than the ELN classification. J Clin Oncol 31:1172-1181. (C) 2013 by American Society of Clinical Oncology C1 [Li, Zejuan; He, Chunjiang; Chen, Ping; Sun, Miao; Yang, Xinan; Huang, Hao; Jiang, Xi; Neilly, Mary Beth; Larson, Richard A.; Le Beau, Michelle M.; Rowley, Janet D.; Chen, Jianjun] Univ Chicago, Chicago, IL 60637 USA. [Zhang, Yanming] Northwestern Univ, Chicago, IL 60611 USA. [Herold, Tobias; Hiddemann, Wolfgang; Bohlander, Stefan K.] Univ Hosp Grosshadern, Munich, Germany. [Herold, Tobias; Jurinovic, Vindi; Mansmann, Ulrich; Hiddemann, Wolfgang; Bohlander, Stefan K.] Univ Munich, Munich, Germany. [Sauerland, Maria-Cristina; Buechner, Thomas] Univ Munster, D-48149 Munster, Germany. [Doehner, Konstanze; Bullinger, Lars] Univ Ulm, D-89069 Ulm, Germany. [Bohlander, Stefan K.] Univ Marburg, Marburg, Germany. [Valk, Peter J. M.; Delwel, Ruud; Lowenberg, Bob] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Radmacher, Michael D.; Maharry, Kati S.; Caligiuri, Michael A.; Marcucci, Guido; Bloomfield, Clara D.] Ohio State Univ, Columbus, OH 43210 USA. [Elkahloun, Abdel; Liu, Paul P.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Chen, JJ (reprint author), Univ Chicago, Dept Med, 900 E 57th St,Room 7134, Chicago, IL 60637 USA. EM jchen@medicine.bsd.uchicago.edu RI Liu, Paul/A-7976-2012; Sauerland , Maria Cristina /A-4154-2014; OI Liu, Paul/0000-0002-6779-025X; Bohlander, Stefan/0000-0002-2202-9088; He, Chunjiang/0000-0002-4868-331X; Herold, Tobias/0000-0002-9615-9432; Larson, Richard/0000-0001-9168-3203 FU Leukemia and Lymphoma Society (LLS) [6199-09]; Cancer and Leukemia Group B (CALGB) Pilot Grant [20801]; German Ministry of Education and Research National Genome Research Network [01G0876]; Dutch Cancer Foundation; National Institutes of Health (NIH) [R01 CA127277, P01 CA40046]; American Cancer Society [120993-RSG-11-156-01-LIB]; LLS Special Fellowship; G. Harold and Leila Y. Mathers Charitable Foundation; Gabrielle's Angel Foundation for Cancer Research; CALGB Leukemia Correlative Science Committee [U10 CA101140]; Ohio State University Leukemia Specialized Program of Research Excellence [P50CA140158]; Leukemia Clinical Research Foundation; NIH Intramural Research Program of the National Human Genome Research Institute; Department of Defense [W81XWH-10-1-0396]; National Natural Science Foundation of China [60971099]; Deutsche Jose Carreras Leukamie Stiftung [R 06/41v]; Deutsche Forschungsgemeinschaft Heisenberg-Stipendium [BU1339/3-1]; National Cancer Institute Cancer Center [P30 CA014599]; University of Chicago Committee on Cancer Biology Fellowship Program; Spastic Paralysis Foundation of the Illinois/Eastern Iowa Branch of Kiwanis International; Fidelity Foundation FX Supported in part by the Leukemia and Lymphoma Society (LLS) Translational Research Grant No. 6199-09 (J.D.R., J.C.), Cancer and Leukemia Group B (CALGB) Pilot Grant No. 20801 (J.D.R., J.C.), German Ministry of Education and Research National Genome Research Network Grant No. 01G0876 (S.K.B.), the Dutch Cancer Foundation Queen Wilhelmina Fund (P.J.M.V., R.D., B.L.), National Institutes of Health (NIH) Grant No. R01 CA127277 (J.C.), American Cancer Society Research Scholar Grant No. 120993-RSG-11-156-01-LIB (J.C.), an LLS Special Fellowship (Z.L.), the G. Harold and Leila Y. Mathers Charitable Foundation (J.C.), Gabrielle's Angel Foundation for Cancer Research (Z.L., X.J., H.H., J.C.), CALGB Leukemia Correlative Science Committee Grant No. U10 CA101140 (G.M.), Ohio State University Leukemia Specialized Program of Research Excellence Grant No. P50CA140158 Project 2 (G.M., C.D.B.), Leukemia Clinical Research Foundation grant (G.M., C.D.B.), the NIH Intramural Research Program of the National Human Genome Research Institute (A.E., P.P.L.), Department of Defense Predoctoral Traineeship Award No. W81XWH-10-1-0396 (M.S.), National Natural Science Foundation of China Grant No. 60971099 (X.Y.), Deutsche Jose Carreras Leukamie Stiftung Grant No. R 06/41v (L.B.), Deutsche Forschungsgemeinschaft Heisenberg-Stipendium Grant No. BU1339/3-1 (L.B.), NIH Grant No. P01 CA40046 (M.M.L.B.), National Cancer Institute Cancer Center Support Grant No. P30 CA014599 (M.M.L.B.), the University of Chicago Committee on Cancer Biology Fellowship Program (X.J.), the Spastic Paralysis Foundation of the Illinois/Eastern Iowa Branch of Kiwanis International (J.D.R.), and the Fidelity Foundation (J.D.R., J.C.). NR 59 TC 42 Z9 42 U1 0 U2 11 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 MAR 20 PY 2013 VL 31 IS 9 BP 1172 EP 1181 DI 10.1200/JCO.2012.44.3184 PG 10 WC Oncology SC Oncology GA 107AS UT WOS:000316187600017 PM 23382473 ER PT J AU Scimemi, A Meabon, JS Woltjer, RL Sullivan, JM Diamond, JS Cook, DG AF Scimemi, Annalisa Meabon, James S. Woltjer, Randall L. Sullivan, Jane M. Diamond, Jeffrey S. Cook, David G. TI Amyloid-beta(1-42) Slows Clearance of Synaptically Released Glutamate by Mislocalizing Astrocytic GLT-1 SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ALZHEIMERS-DISEASE; TRANSPORTER GLT-1; BRAIN; BETA; NEURODEGENERATION; EXPRESSION; MECHANISM; NEURONS; PATHWAY; PROTECT AB GLT-1, the major glutamate transporter in the adult brain, is abundantly expressed in astrocytic processes enveloping synapses. By limiting glutamate escape into the surrounding neuropil, GLT-1 preserves the spatial specificity of synaptic signaling. Here we show that the amyloid-beta peptide A beta(1-42) markedly prolongs the extracellular lifetime of synaptically released glutamate by reducing GLT-1 surface expression in mouse astrocytes and that this effect is prevented by the vitamin E derivative Trolox. These findings indicate that astrocytic glutamate transporter dysfunction may play an important role in the pathogenesis of Alzheimer's disease and suggest possible mechanisms by which several current treatment strategies could protect against the disease. C1 [Scimemi, Annalisa; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. [Meabon, James S.] Univ Washington, Dept Psychiat, Seattle, WA 98108 USA. [Cook, David G.] Univ Washington, Dept Med, Seattle, WA 98108 USA. [Cook, David G.] Univ Washington, Dept Pharmacol, Seattle, WA 98108 USA. [Sullivan, Jane M.] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Meabon, James S.; Cook, David G.] VA Puget Sound Hlth Care Syst, Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Woltjer, Randall L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97239 USA. RP Cook, DG (reprint author), VA Med Ctr, GRECC, 1660 S Columbian Way, Seattle, WA 98108 USA. EM dgcook@u.washington.edu RI Scimemi, Annalisa/O-5396-2014; Diamond, Jeffrey/C-1835-2015 OI Scimemi, Annalisa/0000-0003-4975-093X; Diamond, Jeffrey/0000-0002-1770-2629 FU Veteran's Affairs Office of Research and Development Medical Research Service; NIH [T32 AG000258, RO1 NS055804]; NINDS [NS002986] FX This work was supported by the Veteran's Affairs Office of Research and Development Medical Research Service (D. G. C.), NIH (Grants T32 AG000258, J.S.M.; and RO1 NS055804, J.M.S.), and NINDS Intramural Research Program (Grant NS002986, J.S.D.). We thank Mike Ahlquist, Ping Zhu, and Ning Li for excellent technical assistance. NR 28 TC 29 Z9 30 U1 1 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 20 PY 2013 VL 33 IS 12 BP 5312 EP 5318 DI 10.1523/JNEUROSCI.5274-12.2013 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 111XB UT WOS:000316553800023 PM 23516295 ER PT J AU Herring, BE Shi, Y Suh, YH Zheng, CY Blankenship, SM Roche, KW Nicoll, RA AF Herring, Bruce E. Shi, Yun Suh, Young Ho Zheng, Chan-Ying Blankenship, Sabine M. Roche, Katherine W. Nicoll, Roger A. TI Cornichon Proteins Determine the Subunit Composition of Synaptic AMPA Receptors SO NEURON LA English DT Article ID TRANSMEMBRANE AUXILIARY SUBUNITS; GLUTAMATE RECEPTORS; TARPS; PLASTICITY; TRAFFICKING; EXPRESSION; DROSOPHILA; NEURONS; NUMBER; MICE AB Cornichon-2 and cornichon-3 (CNIH-2/-3) are AMPA receptor (AMPAR) binding proteins that promote receptor trafficking and markedly slow AMPAR deactivation in heterologous cells, but their role in neurons is unclear. Using CNIH-2 and CNIH-3 conditional knockout mice, we find a profound reduction of AMPAR synaptic transmission in the hippocampus. This deficit is due to the selective loss of surface GluA1-containing AMPARs (GluA1A2 heteromers), leaving a small residual pool of synaptic GluA2A3 heteromers. The kinetics of AMPARs in neurons lacking CNIH-2/-3 are faster than those in WT neurons due to the fast kinetics of GluA2A3 heteromers. The remarkably selective effect of CNIHs on the GluA1 subunit is probably mediated by TARP gamma-8, Which prevents a functional association of CNIHs with non-GluA1 subunits. These results point to a sophisticated interplay between CNIHs and gamma-8 that dictates subunit-specific AMPAR trafficking and the strength and kinetics of synaptic AMPAR-mediated transmission. C1 [Herring, Bruce E.; Shi, Yun; Blankenship, Sabine M.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Herring, Bruce E.; Shi, Yun; Blankenship, Sabine M.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. [Suh, Young Ho] Ajou Univ, Sch Med, Chron Inflammatory Dis Res Ctr, Dept Pharmacol, Suwon 443721, South Korea. [Zheng, Chan-Ying; Roche, Katherine W.] NINDS, NIH, Bethesda, MD 20892 USA. RP Suh, YH (reprint author), Ajou Univ, Sch Med, Chron Inflammatory Dis Res Ctr, Dept Pharmacol, Suwon 443721, South Korea. EM suhy@ajou.ac.kr; roger.nicoll@ucsf.edu RI Shi, Yun/B-5623-2009; OI Roche, Katherine/0000-0001-7282-6539 FU US NIMH; NARSAD grant from the Brain and Behavior Research Fund; Intramural Research Program of NINDS; Basic Science Research Program [2011-0011694]; MRC through the National Research Foundation of Korea [2012048183] FX This work was funded by grants from the US NIMH to R.A.N. and a NARSAD grant from the Brain and Behavior Research Fund to B.E.H. C.-Y.Z. and K.W.R. were supported by the Intramural Research Program of NINDS. Y.H.S. was supported by the Basic Science Research Program (2011-0011694) and MRC (2012048183) through the National Research Foundation of Korea. NR 27 TC 41 Z9 41 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 20 PY 2013 VL 77 IS 6 BP 1083 EP 1096 DI 10.1016/j.neuron.2013.01.017 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 113CX UT WOS:000316645000010 PM 23522044 ER PT J AU Abraham, BJ Cui, KR Tang, QS Zhao, KJ AF Abraham, Brian J. Cui, Kairong Tang, Qingsong Zhao, Keji TI Dynamic regulation of epigenomic landscapes during hematopoiesis SO BMC GENOMICS LA English DT Article DE Epigenetics; Hematopoiesis; Gene expression; Histone modifications ID EMBRYONIC STEM-CELLS; HUMAN GENOME; HISTONE H3; GENE-EXPRESSION; CHROMATIN SIGNATURES; LYSINE-27 METHYLATION; ACTIVE PROMOTERS; EPIGENETIC MARK; T-CELLS; B-CELLS AB Background: Human blood develops from self-renewing hematopoietic stem cells to terminal lineages and necessitates regulator and effector gene expression changes; each cell type specifically expresses a subset of genes to carry out a specific function. Gene expression changes coincide with histone modification, histone variant deposition, and recruitment of transcription-related enzymes to specific genetic loci. Transcriptional regulation has been mostly studied using in vitro systems while epigenetic changes occurring during in vivo development remain poorly understood. Results: By integrating previously published and novel global expression profiles from human CD34+/CD133+ hematopoietic stem and progenitor cells (HSPCs), in vivo differentiated human CD4+ T-cells and CD19+ B-cells, and in vitro differentiated CD36+ erythrocyte precursors, we identified hundreds of transcripts specifically expressed in each cell type. To relate concurrent epigenomic changes to expression, we examined genome-wide distributions of H3K4me1, H3K4me3, H3K27me1, H3K27me3, histone variant H2A.Z, ATP-dependent chromatin remodeler BRG1, and RNA Polymerase II in these cell types, as well as embryonic stem cells. These datasets revealed that numerous differentiation genes are primed for subsequent downstream expression by BRG1 and PolII binding in HSPCs, as well as the bivalent H3K4me3 and H3K27me3 modifications in the HSPCs prior to their expression in downstream, differentiated cell types; much HSPC bivalency is retained from embryonic stem cells. After differentiation, bivalency resolves to active chromatin configuration in the specific lineage, while it remains in parallel differentiated lineages. PolII and BRG1 are lost in closer lineages; bivalency resolves to silent monovalency in more distant lineages. Correlation of expression with epigenomic changes predicts tens of thousands of potential common and tissue-specific enhancers, which may contribute to expression patterns and differentiation pathways. Conclusions: Several crucial lineage factors are bivalently prepared for their eventual expression or repression. Bivalency is not only resolved during differentiation but is also established in a step-wise manner in differentiated cell types. We note a progressive, specific silencing of alternate lineage genes in certain cell types coinciding with H3K27me3 enrichment, though expression silencing is maintained in its absence. Globally, the expression of type-specific genes across many cell types correlates strongly with their epigenetic profiles. These epigenomic data appear useful for further understanding mechanisms of differentiation and function of human blood lineages. C1 [Abraham, Brian J.; Cui, Kairong; Tang, Qingsong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Abraham, Brian J.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. RP Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov OI Abraham, Brian/0000-0001-8085-3027 FU Division of Intramural Research Program of the National Institute of Heart, Lung and Blood Institute, NIH FX We would like to thank Dr. Thomas Tullius at Boston University for critical reading of the manuscript and Dr. Weiqun Peng for helpful discussion. The DNA Sequencing Core and the Flow Cytometry Core of NHLBI assisted with this work. This work was supported by the Division of Intramural Research Program of the National Institute of Heart, Lung and Blood Institute, NIH. NR 77 TC 16 Z9 17 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAR 19 PY 2013 VL 14 AR 193 DI 10.1186/1471-2164-14-193 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 131YS UT WOS:000318035400001 PM 23510235 ER PT J AU Boonyaratanakornkit, J Schomacker, H Collins, P Schmidt, A AF Boonyaratanakornkit, Jim Schomacker, Henrick Collins, Peter Schmidt, Alexander TI Alix Serves as an Adaptor That Allows Human Parainfluenza Virus Type 1 to Interact with the Host Cell ESCRT System SO PLOS ONE LA English DT Article ID ALG-2-INTERACTING PROTEIN ALIX; SENDAI-VIRUS; C-PROTEIN; VACCINE CANDIDATES; BINDING PARTNER; P/C GENE; ATTENUATING MUTATIONS; REVERSE GENETICS; BRO1 DOMAIN; WILD-TYPE AB The cellular ESCRT (endosomal sorting complex required for transport) system functions in cargo-sorting, in the formation of intraluminal vesicles that comprise multivesicular bodies (MVB), and in cytokinesis, and this system can be hijacked by a number of enveloped viruses to promote budding. The respiratory pathogen human parainfluenza virus type I (HPIV1) encodes a nested set of accessory C proteins that play important roles in down-regulating viral transcription and replication, in suppressing the type I interferon (IFN) response, and in suppressing apoptosis. Deletion or mutation of the C proteins attenuates HPIV1 in vivo, and such mutants are being evaluated preclinically and clinically as vaccines. We show here that the C proteins interact and co-localize with the cellular protein Alix, which is a member of the class E vacuolar protein sorting (Vps) proteins that assemble at endosomal membranes into ESCRT complexes. The HPIV1 C proteins interact with the Bro1 domain of Alix at a site that is also required for the interaction between Alix and Chmp4b, a subunit of ESCRT-III. The C proteins are ubiquitinated and subjected to proteasome-mediated degradation, but the interaction with Alix(Bro1) protects the C proteins from degradation. Neither over-expression nor knock-down of Alix expression had an effect on HPIV1 replication, although this might be due to the large redundancy of Alix-like proteins. In contrast, knocking down the expression of Chmp4 led to an approximately 100-fold reduction in viral titer during infection with wild-type (WT) HPIV1. This level of reduction was similar to that observed for the viral mutant, P(C-) HPIV1, in which expression of the C proteins were knocked out. Chmp4 is capable of out-competing the HPIV1 C proteins for binding Alix. Together, this suggests a possible model in which Chmp4, through Alix, recruits the C proteins to a common site on intracellular membranes and facilitates budding. C1 [Boonyaratanakornkit, Jim; Schomacker, Henrick; Collins, Peter; Schmidt, Alexander] NIAID, Infect Dis Lab, RNA Viruses Sect, NIH, Bethesda, MD 20892 USA. RP Schmidt, A (reprint author), NIAID, Infect Dis Lab, RNA Viruses Sect, NIH, Bethesda, MD 20892 USA. EM as337y@gmail.com FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 4 Z9 4 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 MAR 19 PY 2013 VL 8 IS 3 AR e59462 DI 10.1371/journal.pone.0059462 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SR UT WOS:000317562100137 PM 23527201 ER PT J AU Roth, BL Gibbons, S Arunotayanun, W Huang, XP Setola, V Treble, R Iversen, L AF Roth, Bryan L. Gibbons, Simon Arunotayanun, Warunya Huang, Xi-Ping Setola, Vincent Treble, Ric Iversen, Les TI The Ketamine Analogue Methoxetamine and 3-and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor SO PLOS ONE LA English DT Article ID AGONIST AB In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl) cyclohexyl] piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects. C1 [Roth, Bryan L.; Huang, Xi-Ping; Setola, Vincent] Univ N Carolina, Chapel Hill Med Sch, Dept Pharmacol, NIMH Psychoact Drug Screening Program, Chapel Hill, NC USA. [Roth, Bryan L.; Huang, Xi-Ping; Setola, Vincent] Univ N Carolina, Chapel Hill Med Sch, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Gibbons, Simon; Arunotayanun, Warunya] UCL Sch Pharm, Dept Pharmaceut & Biol Chem, London, England. [Treble, Ric] LGC Forens, London, England. [Iversen, Les] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. RP Iversen, L (reprint author), Univ Oxford, Dept Pharmacol, S Parks Rd, Oxford OX1 3QT, England. EM les.iversen@pharm.ox.ac.uk RI Roth, Bryan/F-3928-2010 FU NIMH Psychoactive Drug Screening Program; UK's Forensic Early Warning System; NIMH-PDSP [HHSN-271-2008-00025-C] FX Supported by the NIMH Psychoactive Drug Screening Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Production of analytical reference standards for 3-methoxy-PCP and 3-methoxy-PCE was funded by the UK's Forensic Early Warning System and the authors thank the UK Home Office Centre for Applied Science and Technology for permission to use these materials in this study. The NIMH-PDSP is supported by Contract # HHSN-271-2008-00025-C. NR 26 TC 31 Z9 32 U1 0 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 MAR 19 PY 2013 VL 8 IS 3 AR e59334 DI 10.1371/journal.pone.0059334 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SR UT WOS:000317562100111 PM 23527166 ER PT J AU Weiger, MC Vedham, V Stuelten, CH Shou, KR Herrera, M Sato, M Losert, W Parent, CA AF Weiger, Michael C. Vedham, Vidya Stuelten, Christina H. Shou, Karen Herrera, Mark Sato, Misako Losert, Wolfgang Parent, Carole A. TI Real-Time Motion Analysis Reveals Cell Directionality as an Indicator of Breast Cancer Progression SO PLOS ONE LA English DT Article ID LYSOPHOSPHATIDIC ACID RECEPTORS; CARCINOMA-CELLS; MESENCHYMAL TRANSITION; KINASE INHIBITOR; TYROSINE KINASES; TUMOR-METASTASIS; BONE METASTASES; PARACRINE LOOP; IN-VITRO; MIGRATION AB Cancer cells alter their migratory properties during tumor progression to invade surrounding tissues and metastasize to distant sites. However, it remains unclear how migratory behaviors differ between tumor cells of different malignancy and whether these migratory behaviors can be utilized to assess the malignant potential of tumor cells. Here, we analyzed the migratory behaviors of cell lines representing different stages of breast cancer progression using conventional migration assays or time-lapse imaging and particle image velocimetry (PIV) to capture migration dynamics. We find that the number of migrating cells in transwell assays, and the distance and speed of migration in unconstrained 2D assays, show no correlation with malignant potential. However, the directionality of cell motion during 2D migration nicely distinguishes benign and tumorigenic cell lines, with tumorigenic cell lines harboring less directed, more random motion. Furthermore, the migratory behaviors of epithelial sheets observed under basal conditions and in response to stimulation with epidermal growth factor (EGF) or lysophosphatitic acid (LPA) are distinct for each cell line with regard to cell speed, directionality, and spatiotemporal motion patterns. Surprisingly, treatment with LPA promotes a more cohesive, directional sheet movement in lung colony forming MCF10CA1a cells compared to basal conditions or EGF stimulation, implying that the LPA signaling pathway may alter the invasive potential of MCF10CA1a cells. Together, our findings identify cell directionality as a promising indicator for assessing the tumorigenic potential of breast cancer cell lines and show that LPA induces more cohesive motility in a subset of metastatic breast cancer cells. C1 [Weiger, Michael C.; Vedham, Vidya; Stuelten, Christina H.; Shou, Karen; Parent, Carole A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Herrera, Mark; Losert, Wolfgang] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Sato, Misako] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Parent, CA (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov FU Center for Cancer Research, NCI, National Institutes of Health; NIH [R01GM085574] FX This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health. WL acknowledges support by NIH grant R01GM085574. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 12 Z9 12 U1 0 U2 21 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 MAR 19 PY 2013 VL 8 IS 3 AR e58859 DI 10.1371/journal.pone.0058859 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SR UT WOS:000317562100052 PM 23527039 ER PT J AU Harris, AK Meyerson, JR Matsuoka, Y Kuybeda, O Moran, A Bliss, D Das, SR Yewdell, JW Sapiro, G Subbarao, K Subramaniam, S AF Harris, Audray K. Meyerson, Joel R. Matsuoka, Yumiko Kuybeda, Oleg Moran, Amy Bliss, Donald Das, Suman R. Yewdell, Jonathan W. Sapiro, Guillermo Subbarao, Kanta Subramaniam, Sriram TI Structure and accessibility of HA trimers on intact 2009 H1N1 pandemic influenza virus to stem region-specific neutralizing antibodies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE envelope glycoproteins; subvolume averaging; virus structure; hemagglutunin; cryo-electron microscopy ID A VIRUS; CRYOELECTRON TOMOGRAPHY; MONOCLONAL-ANTIBODIES; ELECTRON TOMOGRAPHY; MEMBRANE-FUSION; HEMAGGLUTININ; EPITOPE; PH; SUBTYPES; BINDING AB Rapid antigenic variation of HA, the major virion surface protein of influenza A virus, remains the principal challenge to the development of broader and more effective vaccines. Some regions of HA, such as the stem region proximal to the viral membrane, are nevertheless highly conserved across strains and among most subtypes. A fundamental question in vaccine design is the extent to which HA stem regions on the surface of the virus are accessible to broadly neutralizing antibodies. Here we report 3D structures derived from cryoelectron tomography of HA on intact 2009 H1N1 pandemic virions in the presence and absence of the antibody C179, which neutralizes viruses expressing a broad range of HA subtypes, including H1, H2, H5, H6, and H9. By fitting previously derived crystallographic structures of trimeric HA into the density maps, we deduced the locations of the molecular surfaces of HA involved in interaction with C179. Using computational methods to distinguish individual unliganded HA trimers from those that have bound C179 antibody, we demonstrate that similar to 75% of HA trimers on the surface of the virus have C179 bound to the stem domain. Thus, despite their close packing on the viral membrane, the majority of HA trimers on intact virions are available to bind anti-stem antibodies that target conserved HA epitopes, establishing the feasibility of universal influenza vaccines that elicit such antibodies. C1 [Harris, Audray K.; Meyerson, Joel R.; Subramaniam, Sriram] NCI, Lab Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Matsuoka, Yumiko; Subbarao, Kanta] NIAID, Labs Infect Dis, NIH, Bethesda, MD 20892 USA. [Das, Suman R.; Yewdell, Jonathan W.] NIAID, Labs Viral Dis, NIH, Bethesda, MD 20892 USA. [Kuybeda, Oleg; Moran, Amy; Bliss, Donald] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Meyerson, Joel R.] MRC, Mitochondrial Biol Unit, Cambridge CB2 0XY, England. [Kuybeda, Oleg; Sapiro, Guillermo] Univ Minnesota, Dept Elect & Comp Engn, Minneapolis, MN 55455 USA. RP Subramaniam, S (reprint author), NCI, Lab Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU National Cancer Institute; National Institute of Allergy and Infectious Diseases; Department of Defense; NIH Intramural AIDS Research Fellowship FX We thank S. Fellini and S. Chacko and their colleagues for continued support of our use of the Biowulf computing cluster at the National Institutes of Health (NIH) (http://biowulf.nih.gov). This work was supported by funds from the intramural program of the National Cancer Institute (to S.S.), the intramural program of the National Institute of Allergy and Infectious Diseases (to K.S.), the Department of Defense (to G.S.), and an NIH Intramural AIDS Research Fellowship (to J.R.M.). NR 50 TC 29 Z9 31 U1 0 U2 24 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 MAR 19 PY 2013 VL 110 IS 12 BP 4592 EP 4597 DI 10.1073/pnas.1214913110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125EK UT WOS:000317521600045 PM 23460696 ER PT J AU Feng, MQ Gao, W Wang, RQ Chen, WZ Man, YG Figg, WD Wang, XW Dimitrov, DS Ho, M AF Feng, Mingqian Gao, Wei Wang, Ruoqi Chen, Weizao Man, Yan-Gao Figg, William Douglas Wang, Xin Wei Dimitrov, Dimiter S. Ho, Mitchell TI Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE heparan sulfate proteoglycans; liver cancer; monoclonal antibodies; phage display; cell growth ID LIVER-CANCER; KINASE MST2; IN-VIVO; GROWTH; PROTEIN; PATHWAY; MARKER; HIPPO; PROLIFERATION; COMBINATION AB Glypican-3 (GPC3) has emerged as a candidate therapeutic target in hepatocellular carcinoma (HCC), but the oncogenic role of GPC3 in HCC is poorly understood. Here, we report a human heavy-chain variable domain antibody, HN3, with high affinity (K-d = 0.6 nM) for cell-surface-associated GPC3 molecules. The human antibody recognized a conformational epitope that requires both the amino and carboxy terminal domains of GPC3. HN3 inhibited proliferation of GPC3-positive cells and exhibited significant inhibition of HCC xenograft tumor growth in nude mice. The underlying mechanism of HN3 action may involve cell-cycle arrest at G1 phase through Yes-associated protein signaling. This study suggests a previously unrecognized mechanism for GPC3-targeted cancer therapy. C1 [Feng, Mingqian; Gao, Wei; Wang, Ruoqi; Ho, Mitchell] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Figg, William Douglas] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Chen, Weizao; Dimitrov, Dimiter S.] NCI, Frederick Natl Lab, Frederick, MD 21702 USA. [Man, Yan-Gao] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD 20817 USA. RP Ho, M (reprint author), NCI, Mol Biol Lab, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Ho, Mitchell/F-5059-2015; Wang, Xin/B-6162-2009; Figg Sr, William/M-2411-2016 FU Intramural Research Program, Center for Cancer Research, NCI, NIH [Z01 BC 010891, ZIA BC 010891] FX We thank Shawn Spencer for calculating the HN3 half-life in vivo; our colleagues Yen Phung (National Cancer Institute; NCI) for generating the YP7 mAb and Heungnam Kim (NCI) for establishing the A431/G1 cell line used in the present project; and the National Institutes of Health (NIH) Fellows Editorial Board for editorial assistance. This work was supported by Grants Z01 BC 010891 and ZIA BC 010891 from the Intramural Research Program, Center for Cancer Research, NCI, NIH (to M.H.). NR 43 TC 33 Z9 35 U1 3 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 19 PY 2013 VL 110 IS 12 BP E1083 EP E1091 DI 10.1073/pnas.1217868110 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125EK UT WOS:000317521600004 PM 23471984 ER PT J AU Cozen, W Yu, G Gail, MH Ridaura, VK Nathwani, BN Hwang, AE Hamilton, AS Mack, TM Gordon, JI Goedert, JJ AF Cozen, W. Yu, G. Gail, M. H. Ridaura, V. K. Nathwani, B. N. Hwang, A. E. Hamilton, A. S. Mack, T. M. Gordon, J. I. Goedert, J. J. TI Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins SO BRITISH JOURNAL OF CANCER LA English DT Article DE Hodgkin lymphoma; twin study; survivorship; hygiene hypothesis; human fecal microbiome ID GUT MICROBIOME; EARLY-LIFE; DISEASE; CELLS; RISK; IGE AB Background: Adolescent/young adult Hodgkin lymphoma (AYAHL) survivors report fewer exposures to infections during childhood compared with controls, and they have functional lymphocyte aberrations. The gut microbiota plays a central role in immunity. Methods: We investigated whether fecal microbial diversity differed between 13 AYAHL survivors and their unaffected co-twin controls. Pyrosequencing of fecal bacterial 16S rRNA amplicons yielded 252 943 edited reads that were assigned to species-level operational taxonomic units (OTUs) and standardised for sequencing depth by random sampling. Microbial diversity was compared within vs between twin pairs and by case-control status. Results: The number of unique OTUs was more similar within twin pairs compared with randomly paired participants (P = 0.0004). The AYAHL cases had fewer unique OTUs compared with their co-twin controls (338 vs 369, P = 0.015); this difference was not significant (169 vs 183, P = 0.10) when restricted to abundant OTUs. Conclusion: In this small study, AYAHL survivors appear to have a deficit of rare gut microbes. Further work is needed to determine if reduced microbial diversity is a consequence of the disease, its treatment, or a particularly hygienic environment. C1 [Cozen, W.; Hwang, A. E.; Hamilton, A. S.; Mack, T. M.] USC Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Cozen, W.; Hamilton, A. S.; Mack, T. M.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Cozen, W.; Mack, T. M.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90089 USA. [Yu, G.; Gail, M. H.; Goedert, J. J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Ridaura, V. K.; Gordon, J. I.] Washington Univ, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA. [Nathwani, B. N.] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. RP Goedert, JJ (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov FU Intramural Research Program of the National Cancer Institute; National Cancer Institute [1R01CA58839, R03CA110836-01A2, HHSN261201000035C]; Leukemia Lymphoma Society [6137-07] FX We would like to thank Maureen Cairns for her assistance with data collection, and the twins for participating in the research. This work was supported by the Intramural Research Program of the National Cancer Institute, as well as by grants from the National Cancer Institute (1R01CA58839 TMM, R03CA110836-01A2 WC, and HHSN261201000035C WC) and the Leukemia Lymphoma Society (6137-07 WC). NR 38 TC 6 Z9 6 U1 0 U2 21 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 MAR 19 PY 2013 VL 108 IS 5 BP 1163 EP 1167 DI 10.1038/bjc.2013.60 PG 5 WC Oncology SC Oncology GA 118PQ UT WOS:000317038100022 PM 23443674 ER PT J AU Arem, H Bobe, G Sampson, J Subar, AF Park, Y Risch, H Hollenbeck, A Mayne, ST Stolzenberg-Solomon, RZ AF Arem, H. Bobe, G. Sampson, J. Subar, A. F. Park, Y. Risch, H. Hollenbeck, A. Mayne, S. T. Stolzenberg-Solomon, R. Z. TI Flavonoid intake and risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study Cohort SO BRITISH JOURNAL OF CANCER LA English DT Article DE pancreatic neoplasms; flavonoids; epidemiology; cohort studies ID RETIRED-PERSONS DIET; AMERICAN-ASSOCIATION; POLYPHENOLS; APOPTOSIS AB Background: Limited epidemiological studies show inverse associations between dietary flavonoid intake and pancreatic cancer risk, but results are inconsistent and are based on few cases. We examined the association between intake of flavonoids and pancreatic cancer risk in the large, prospective National Institutes of Health-AARP Diet and Health Study Cohort. Methods: During follow-up through 2006 (median follow-up 10.6 years), 2379 pancreatic cancer cases were identified. We used Cox proportional hazards modelling to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: We found no association between total flavonoid intake (Q5 vs Q1 HR = 1.09, 95% CI: 0.96-1.24) or any flavonoid subtypes and pancreatic cancer risk. Significant interactions were not observed by age, sex, smoking status, BMI or diabetes. Conclusion: Our results do not support the hypothesis that flavonoids have a protective role in pancreatic cancer carcinogenesis. C1 [Arem, H.; Risch, H.; Mayne, S. T.] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Arem, H.; Sampson, J.; Park, Y.; Stolzenberg-Solomon, R. Z.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bobe, G.] Univ Oregon, Linus Pauling Inst, Corvallis, OR USA. [Subar, A. F.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Risch, H.; Mayne, S. T.] Yale Canc Ctr, New Haven, CT USA. [Hollenbeck, A.] AARP, Washington, DC USA. RP Arem, H (reprint author), Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. EM Aremhe2@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; [T32 CA105666] FX This work was supported in part by the pre-doctoral training grant T32 CA105666. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract with the Florida Department of Health. The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or the Department of Health. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, 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, Center for Health Data and Research, Bureau of Health Planning and Statistics, State Health Division, State of Nevada Department of Health and Human Services. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for ascertainment and management of study outcomes, and Leslie Carroll at Information Management Services for data support and analysis. NR 20 TC 6 Z9 6 U1 0 U2 12 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 MAR 19 PY 2013 VL 108 IS 5 BP 1168 EP 1172 DI 10.1038/bjc.2012.584 PG 5 WC Oncology SC Oncology GA 118PQ UT WOS:000317038100023 PM 23299536 ER PT J AU Wilson, JC Murray, LJ Hughes, CM Black, A Anderson, LA AF Wilson, J. C. Murray, L. J. Hughes, C. M. Black, A. Anderson, L. A. TI Non-steroidal anti-inflammatory drug and aspirin use and the risk of head and neck cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE head and neck cancer; ibuprofen; aspirin; cohort study ID UPPER AERODIGESTIVE TRACT; ORAL-CANCER; CYCLOOXYGENASE-2; INHIBITION; PREVENTION; COHORT; COX-2 AB Background: Evidence for non-steroidal anti-inflammatory drugs (NSAIDs) preventing head and neck cancer (HNC) is inconclusive; however, there is some suggestion that aspirin may exert a protective effect. Methods: Using data from the United States National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we examined the association between aspirin and ibuprofen use and HNC. Results: Regular aspirin use was associated with a significant 22% reduction in HNC risk. No association was observed with regular ibuprofen use. Conclusion: Aspirin may have potential as a chemopreventive agent for HNC, but further investigation is warranted. C1 [Wilson, J. C.; Murray, L. J.; Anderson, L. A.] Queens Univ Belfast, Inst Clin Sci, Sch Med Dent & Biomed Sci, Ctr Publ Hlth,RVH, Belfast BT12 6BJ, Antrim, North Ireland. [Hughes, C. M.] Queens Univ Belfast, Sch Pharm, Ctr Med Biol, Belfast BT9 7BL, Antrim, North Ireland. [Black, A.] NCI, Rockville, MD 20852 USA. RP Wilson, JC (reprint author), Queens Univ Belfast, Inst Clin Sci, Sch Med Dent & Biomed Sci, Ctr Publ Hlth,RVH, Block B,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM wilsonj@uhbs.ch OI Anderson, Lesley/0000-0002-1000-3649 FU Division of Cancer Prevention, National Cancer Institute; NIH, DHHS FX This research was supported by contracts from the Division of Cancer Prevention, National Cancer Institute; NIH, DHHS. We thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Centre investigators and staff of the PLCO Cancer Screening Trial; Mr Tom Riley and staff, Information Management Services, Inc.; Ms Barbara O'Brien and staff, Westat, Inc. Most importantly, we acknowledge the study participants for their contributions to making this study possible. NR 22 TC 8 Z9 9 U1 0 U2 9 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 MAR 19 PY 2013 VL 108 IS 5 BP 1178 EP 1181 DI 10.1038/bjc.2013.73 PG 4 WC Oncology SC Oncology GA 118PQ UT WOS:000317038100025 PM 23449358 ER PT J AU Lubin, JH Caporaso, NE AF Lubin, J. H. Caporaso, N. E. TI Misunderstandings in the misconception on the use of pack-years in analysis of smoking SO BRITISH JOURNAL OF CANCER LA English DT Letter ID LUNG-CANCER MORTALITY; CIGARETTE-SMOKING; TOTAL EXPOSURE; ALCOHOL-CONSUMPTION; BLADDER-CANCER; ODDS RATIOS; INTENSITY; DNA; RISK; REPAIR C1 [Lubin, J. H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Caporaso, N. E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Lubin, JH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8105, Rockville, MD 20852 USA. EM lubinj@exchange.nih.gov NR 23 TC 4 Z9 4 U1 0 U2 5 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 MAR 19 PY 2013 VL 108 IS 5 BP 1218 EP 1220 DI 10.1038/bjc.2013.76 PG 3 WC Oncology SC Oncology GA 118PQ UT WOS:000317038100033 PM 23449359 ER PT J AU Sidorova, NY Scott, T Rau, DC AF Sidorova, Nina Y. Scott, Thomas Rau, Donald C. TI DNA Concentration-Dependent Dissociation of EcoRI: Direct Transfer or Reaction during Hopping SO BIOPHYSICAL JOURNAL LA English DT Article ID DIFFUSION-DRIVEN MECHANISMS; ONE-DIMENSIONAL DIFFUSION; RESTRICTION-ENDONUCLEASE; NONSPECIFIC DNA; PROTEIN TRANSLOCATION; INTERSEGMENT TRANSFER; NUCLEIC-ACIDS; COGNATE SITES; WATER RELEASE; BINDING AB Direct transfer of proteins between DNA helices is a recognized important feature of the recognition site search process. Direct transfer is characterized by a dissociation rate that depends on total DNA concentration. This is taken as evidence for the formation of an intermediate DNA-protein-DNA ternary complex. We find that the dissociation rate of EcoRI-DNA-specific complexes at 80 mM NaCl depends on the concentration of competitor oligonucleotide suggesting that direct transfer contributes to EcoRI dissociation. This dependence on competitor DNA concentration is not seen at 180 mM salt. A careful examination of the salt concentration dependence of the dissociation rate, however, shows that the predictions for the formation of a ternary complex are not observed experimentally. The findings can be rationalized by considering that just after dissociating from a DNA fragment the protein remains in close proximity to that fragment, can reassociate with it, and diffuse back to the recognition site rather than bind to an oligonucleotide in solution, a hopping excursion. The probability that a protein will bind to an oligonucleotide during a hop can be approximately calculated and shown to explain the data. A dependence of the dissociation rate of a DNA-protein complex on competitor DNA concentration does not necessarily mean direct transfer. C1 [Sidorova, Nina Y.; Scott, Thomas; Rau, Donald C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Rau, DC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM raud@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development) FX This work was supported by the Intramural Research Program of the National Institutes of Health, NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development). NR 40 TC 13 Z9 13 U1 2 U2 12 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 MAR 19 PY 2013 VL 104 IS 6 BP 1296 EP 1303 DI 10.1016/j.bpj.2013.01.041 PG 8 WC Biophysics SC Biophysics GA 111MO UT WOS:000316525600014 PM 23528089 ER PT J AU Ghuman, AS van den Honert, RN Martin, A AF Ghuman, Avniel Singh van den Honert, Rebecca N. Martin, Alex TI Interregional neural synchrony has similar dynamics during spontaneous and stimulus-driven states SO SCIENTIFIC REPORTS LA English DT Article ID RESTING HUMAN BRAIN; FUNCTIONAL ARCHITECTURE; CORTICAL ACTIVITY; AUDITORY-CORTEX; PHASE-LOCKING; MOTOR CORTEX; OSCILLATIONS; EEG; MEG; FLUCTUATIONS AB Assessing the correspondence between spontaneous and stimulus-driven neural activity can reveal intrinsic properties of the brain. Recent studies have demonstrated that many large-scale functional networks have a similar spatial structure during spontaneous and stimulus-driven states. However, it is unknown whether the temporal dynamics of network activity are also similar across these states. Here we demonstrate that, in the human brain, interhemispheric coupling of somatosensory regions is preferentially synchronized in the high beta frequency band (similar to 20-30 Hz) in response to somatosensory stimulation and interhemispheric coupling of auditory cortices is preferentially synchronized in the alpha frequency band (similar to 7-12 Hz) in response to auditory stimulation. Critically, these stimulus-driven synchronization frequencies were also selective to these interregional interactions during spontaneous activity. This similarity between stimulus-driven and spontaneous states suggests that frequency-specific oscillatory dynamics are intrinsic to the interactions between the nodes of these brain networks. C1 [Ghuman, Avniel Singh; van den Honert, Rebecca N.; Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Ghuman, AS (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM ghumana@upmc.edu OI Ghuman, Avniel/0000-0003-1746-4656 FU NIMH-DIRP FX We thank Jonathan McDaniel for assistance with data collection, Steve Gotts, Dale Stevens, David Leopold, and Alex Maier for insightful comments, and Tom Holroyd and the staff NIMH MEG core for assistance with data collection. This work was supported by the NIMH-DIRP. NR 58 TC 2 Z9 2 U1 0 U2 15 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 MAR 19 PY 2013 VL 3 AR 1481 DI 10.1038/srep01481 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WG UT WOS:000316250900002 PM 23512004 ER PT J AU Bhatt, S Lam, TT Lycett, SJ Brown, AJL Bowden, TA Holmes, EC Guan, Y Wood, JLN Brown, IH Kellam, P Pybus, OG AF Bhatt, S. Lam, T. T. Lycett, S. J. Brown, A. J. Leigh Bowden, T. A. Holmes, E. C. Guan, Y. Wood, J. L. N. Brown, I. H. Kellam, P. Pybus, O. G. CA Combating Swine Influenza TI The evolutionary dynamics of influenza A virus adaptation to mammalian hosts SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE influenza; swine; avian; adaptation; genomics; zoonosis ID MOLECULAR-BASIS; UNITED-STATES; SWINE VIRUS; PIGS; TRANSMISSION; H1N1; SEQUENCE; HEMAGGLUTININS; EMERGENCE; EPIDEMIC AB ew questions on infectious disease are more important than understanding how and why avian influenza A viruses successfully emerge in mammalian populations, yet little is known about the rate and nature of the virus' genetic adaptation in new hosts. Here, we measure, for the first time, the genomic rate of adaptive evolution of swine influenza viruses (SwIV) that originated in birds. By using a curated dataset of more than 24 000 human and swine influenza gene sequences, including 41 newly characterized genomes, we reconstructed the adaptive dynamics of three major SwIV lineages (Eurasian, EA; classical swine, CS; triple reassortant, TR). We found that, following the transfer of the EA lineage from birds to swine in the late 1970s, EA virus genes have undergone substantially faster adaptive evolution than those of the CS lineage, which had circulated among swine for decades. Further, the adaptation rates of the EA lineage antigenic haemagglutinin and neuraminidase genes were unexpectedly high and similar to those observed in human influenza A. We show that the successful establishment of avian influenza viruses in swine is associated with raised adaptive evolution across the entire genome for many years after zoonosis, reflecting the contribution of multiple mutations to the coordinated optimization of viral fitness in a new environment. This dynamics is replicated independently in the polymerase genes of the TR lineage, which established in swine following separate transmission from non-swine hosts. C1 [Bhatt, S.; Lam, T. T.; Pybus, O. G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Bhatt, S.; Kellam, P.] Wellcome Trust Sanger Inst, Hinxton, England. [Lycett, S. J.; Brown, A. J. Leigh] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Bowden, T. A.] Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Oxford, England. [Holmes, E. C.] Penn State Univ, Ctr Infect Dis Dynam, Mueller Lab, University Pk, PA 16802 USA. [Holmes, E. C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Guan, Y.] Univ Hong Kong, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Wood, J. L. N.] Univ Cambridge, Cambridge Infect Dis Consortium, Cambridge, England. [Brown, I. H.] Anim Hlth & Vet Labs Agcy, Weybridge, Surrey, England. RP Pybus, OG (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM oliver.pybus@zoo.ox.ac.uk RI Wood, James/A-1626-2008; Lam, Tommy Tsan-Yuk/D-4837-2012; Brown, Ian/E-1119-2011; APHA, Staff publications/E-6082-2010; OI Wood, James/0000-0002-0258-3188; Holmes, Edward/0000-0001-9596-3552; Bowden, Thomas/0000-0002-8066-8785; Pybus, Oliver/0000-0002-8797-2667; Nguyen-Van-Tam, Jonathan/0000-0003-2579-4655; Lycett, Samantha/0000-0003-3159-596X; Donnelly, Christl/0000-0002-0195-2463 FU UK COSI [BB/H014306/1]; BBSRC; MRC; Wellcome Trust; Defra [ED1204]; Royal Society; ESNIP3; COSI; Alborada Trust; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, NIH; European Union FX Combating Swine Influenza Consortium (COSI) members are listed in the electronic supplementary material. We thank the institutes named in Material and methods for providing isolates, contributors to ESNIP for depositing samples and Dr K. van Reeth for facilitating access. This work was supported by UK COSI (BB/H014306/1), co-funded by BBSRC, MRC, the Wellcome Trust and Defra. Surveillance in GB pigs was supported by Defra (ED1204). O.G.P. was supported by the Royal Society and ESNIP3; S.J.L. by the BBSRC, the Wellcome Trust and COSI; T. A. B. by the Wellcome Trust; J.L.N.W. by the Alborada Trust and the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center, NIH. ESNIP is funded by the European Union. NR 41 TC 13 Z9 13 U1 7 U2 97 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 19 PY 2013 VL 368 IS 1614 AR 20120382 DI 10.1098/rstb.2012.0382 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 088DH UT WOS:000314813500018 PM 23382435 ER PT J AU Duke-Sylvester, SM Biek, R Real, LA AF Duke-Sylvester, Scott M. Biek, Roman Real, Leslie A. TI Molecular evolutionary signatures reveal the role of host ecological dynamics in viral disease emergence and spread SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE disease ecology; evolution; phylodynamics; phylogeography; rabies; dispersal ID HUMAN-IMMUNODEFICIENCY-VIRUS; DEVELOPING-COUNTRIES; POPULATION-DYNAMICS; EPIZOOTIC RABIES; RACCOON RABIES; UNITED-STATES; SEQUENCES; EPIDEMIC; HISTORY; HEALTH AB RNA viruses account for numerous emerging and perennial infectious diseases, and are characterized by rapid rates of molecular evolution. The ecological dynamics of most emerging RNA viruses are still poorly understood and difficult to ascertain. The availability of genome sequence data for many RNA viruses, in principle, could be used to infer ecological dynamics if changes in population numbers produced a lasting signature within the pattern of genome evolution. As a result, the rapidly emerging phylogeographic structure of a pathogen, shaped by the rise and fall in the number of infections and their spatial distribution, could be used as a surrogate for direct ecological assessments. Based on rabies virus as our example, we use a model combining ecological and evolutionary processes to test whether variation in the rate of host movement results in predictive diagnostic patterns of pathogen genetic structure. We identify several linearizable relationships between host dispersal rate and measures of phylogenetic structure suggesting genetic information can be used to directly infer ecological process. We also find phylogenetic structure may be more revealing than demography for certain ecological processes. Our approach extends the reach of current analytic frameworks for infectious disease dynamics by linking phylogeography back to underlying ecological processes. C1 [Duke-Sylvester, Scott M.] Univ Louisiana Lafayette, Dept Biol, Lafayette, LA 70506 USA. [Duke-Sylvester, Scott M.; Real, Leslie A.] Emory Univ, Ctr Dis Ecol, Atlanta, GA 30322 USA. [Real, Leslie A.] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Biek, Roman] Univ Glasgow, MRC, Ctr Virus Res, Glasgow G12 8QQ, Lanark, Scotland. [Biek, Roman] Univ Glasgow, Inst Biodivers, Glasgow G12 8QQ, Lanark, Scotland. [Biek, Roman] Univ Glasgow, Coll Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland. [Real, Leslie A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Real, LA (reprint author), Emory Univ, Ctr Dis Ecol, Atlanta, GA 30322 USA. EM lreal@emory.edu OI Biek, Roman/0000-0003-3471-5357 FU NIH [RO1 AI047498]; RAPIDD Programme of the Science and Technology Directorate, The Department of Homeland Security and The Fogarty International Center; National Institutes of Health; Louisiana Board of Regents [LEQSF(2011-14-RD-A-27)] FX The authors thank Vijay Panjeti and Derek Johnson for their comments. This research was supported by NIH grant no. RO1 AI047498 to L. A. R., and the RAPIDD Programme of the Science and Technology Directorate, The Department of Homeland Security and The Fogarty International Center, National Institutes of Health and the Louisiana Board of Regents grant no. LEQSF(2011-14-RD-A-27) to S. M. D. Computer simulations were performed on the Emory High Performance Computer Cluster and the Louisiana Optical Network Initiative computers. NR 62 TC 3 Z9 3 U1 2 U2 62 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 19 PY 2013 VL 368 IS 1614 AR 20120194 DI 10.1098/rstb.2012.0194 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 088DH UT WOS:000314813500002 PM 23382419 ER PT J AU Faria, NR Suchard, MA Rambaut, A Streicker, DG Lemey, P AF Faria, Nuno Rodrigues Suchard, Marc A. Rambaut, Andrew Streicker, Daniel G. Lemey, Philippe TI Simultaneously reconstructing viral cross-species transmission history and identifying the underlying constraints SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE Bayesian diffusion models; branch partitioning; cross-species transmission; rabies virus ID RABIES VIRUS; STATISTICAL PHYLOGENETICS; POPULATION-DYNAMICS; INFECTIOUS-DISEASES; EMERGENCE; EVOLUTION; BATS; ORIGINS; INTERFACE; PATHOGENS AB The factors that determine the origin and fate of cross-species transmission events remain unclear for the majority of human pathogens, despite being central for the development of predictive models and assessing the efficacy of prevention strategies. Here, we describe a flexible Bayesian statistical framework to reconstruct virus transmission between different host species based on viral gene sequences, while simultaneously testing and estimating the contribution of several potential predictors of cross-species transmission. Specifically, we use a generalized linear model extension of phylogenetic diffusion to perform Bayesian model averaging over candidate predictors. By further extending this model with branch partitioning, we allow for distinct host transition processes on external and internal branches, thus discriminating between recent cross-species transmissions, many of which are likely to result in dead-end infections, and host shifts that reflect successful onwards transmission in the new host species. Our approach corroborates genetic distance between hosts as a key determinant of both host shifts and cross-species transmissions of rabies virus in North American bats. Furthermore, our results indicate that geographical range overlap is a modest predictor for cross-species transmission, but not for host shifts. Although our evolutionary framework focused on the multi-host reservoir dynamics of bat rabies virus, it is applicable to other pathogens and to other discrete state transition processes. C1 [Faria, Nuno Rodrigues; Lemey, Philippe] Katholieke Univ Leuven, Dept Microbiol & Immunol, Rega Inst, Louvain, Belgium. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Streicker, Daniel G.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. RP Faria, NR (reprint author), Katholieke Univ Leuven, Dept Microbiol & Immunol, Rega Inst, Louvain, Belgium. EM nuno.faria@rega.kuleuven.be RI Faria, Nuno/I-2975-2012; OI Faria, Nuno/0000-0001-8839-2798; Rodrigues Faria, Nuno/0000-0002-9747-8822; Rambaut, Andrew/0000-0003-4337-3707 FU European Union [278433-PREDEMICS]; ERC [260864]; US National Science Foundation [DMS 0856099]; US National Institutes of Health [R01 GM086887, R01 HG006139]; Fundacao para a Ciencia e Tecnologia [SFRH/BD/64530/2009]; National Evolutionary Synthesis Center (NESCent), NSF [EF-0423641]; Wellcome Trust [WT092807MA] FX We are grateful to two anonymous reviewers for their helpful comments. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 278433-PREDEMICS and ERC grant agreement no. 260864, the US National Science Foundation (DMS 0856099) and the US National Institutes of Health (R01 GM086887 and R01 HG006139). N.R.F. is supported by Fundacao para a Ciencia e Tecnologia under grant agreement no. SFRH/BD/64530/2009. This work was facilitated by the participation of D. G. S. and P. L. in the 2010 RAPIDD Workshop on Cross-species Transmission, hosted by the National Institutes of Health. Collaboration between M. A. S., A. R. and P. L. was supported by the National Evolutionary Synthesis Center (NESCent), NSF EF-0423641. A. R. is supported by the Wellcome Trust (WT092807MA). Further, research was partially completed while M. A. S. and P. L. were visiting the Institute for Mathematical Sciences, National University of Singapore in 2011. NR 44 TC 31 Z9 31 U1 0 U2 41 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 19 PY 2013 VL 368 IS 1614 AR 20120196 DI 10.1098/rstb.2012.0196 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 088DH UT WOS:000314813500003 PM 23382420 ER PT J AU Hay, SI Battle, KE Pigott, DM Smith, DL Moyes, CL Bhatt, S Brownstein, JS Collier, N Myers, MF George, DB Gething, PW AF Hay, Simon I. Battle, Katherine E. Pigott, David M. Smith, David L. Moyes, Catherine L. Bhatt, Samir Brownstein, John S. Collier, Nigel Myers, Monica F. George, Dylan B. Gething, Peter W. TI Global mapping of infectious disease SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE surveillance; biosurveillance; cartography; public health; atlas; crowdsourcing ID DOMINANT ANOPHELES VECTORS; MODEL-BASED GEOSTATISTICS; DISTRIBUTION MAPS; BIONOMIC PRECIS; HUMAN MALARIA; PLASMODIUM-FALCIPARUM; POPULATION BIOLOGY; HOST-RANGE; TRANSMISSION; HEALTH AB The primary aim of this review was to evaluate the state of knowledge of the geographical distribution of all infectious diseases of clinical significance to humans. A systematic review was conducted to enumerate cartographic progress, with respect to the data available for mapping and the methods currently applied. The results helped define the minimum information requirements for mapping infectious disease occurrence, and a quantitative framework for assessing the mapping opportunities for all infectious diseases. This revealed that of 355 infectious diseases identified, 174 (49%) have a strong rationale for mapping and of these only 7 (4%) had been comprehensively mapped. A variety of ambitions, such as the quantification of the global burden of infectious disease, international biosurveillance, assessing the likelihood of infectious disease outbreaks and exploring the propensity for infectious disease evolution and emergence, are limited by these omissions. An overview of the factors hindering progress in disease cartography is provided. It is argued that rapid improvement in the landscape of infectious diseases mapping can be made by embracing non-conventional data sources, automation of geo-positioning and mapping procedures enabled by machine learning and information technology, respectively, in addition to harnessing labour of the volunteer 'cognitive surplus' through crowdsourcing. C1 [Hay, Simon I.; Battle, Katherine E.; Pigott, David M.; Moyes, Catherine L.; Bhatt, Samir; Myers, Monica F.; Gething, Peter W.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Hay, Simon I.; Smith, David L.; George, Dylan B.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Smith, David L.] Johns Hopkins Bloomberg Sch Publ Hlth, Malaria Res Inst, Baltimore, MD USA. [Brownstein, John S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Brownstein, John S.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Collier, Nigel] Res Org Informat & Syst, Natl Inst Informat, Tokyo, Japan. RP Hay, SI (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, S Parks Rd, Oxford OX1 3PS, England. EM simon.hay@zoo.ox.ac.uk RI Smith, David/L-8850-2013; Hay, Simon/F-8967-2015; OI Moyes, Catherine/0000-0002-8028-4079; Smith, David/0000-0003-4367-3849; Hay, Simon/0000-0002-0611-7272; Pigott, David/0000-0002-6731-4034; Collier, Nigel/0000-0002-7230-4164; Gething, Peter/0000-0001-6759-5449; Battle, Katherine/0000-0003-2401-2615 FU Wellcome Trust [095066]; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Wellcome Trust, UK FX The catalyst for this review was a National Institute for Mathematical and Biological Synthesis (NIMBioS) and the US Department of Defense hosted meeting on infectious disease modelling (23-25 January 2011, Knoxville, TN, USA). NIMBioS also provided K. E. B. with resources to conduct the literature review. S. I. H. is financially supported by a Senior Research Fellowship from the Wellcome Trust (no. 095066) which also supports P. W. G., K. E. B. and D. M. P.; S. I. H., D. L. S. and D. B. G. also acknowledge support from the RAPIDD programme of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (http://www.fic.nih.gov). This work also forms part of the output of the Malaria Atlas Project (MAP, http://www.map.ox.ac.uk), principally financially supported by the Wellcome Trust, UK (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Thanks are extended to Dr Kevin Hanson and Prof. Louis Gross for insightful comments, to the Global Infectious Diseases and Epidemiology Network (GIDEON) for permission to reproduce their data within the 355 maps of the supplementary material. Finally, we are grateful to the editors Dr Oliver Pybus, Prof. Christophe Fraser and Prof. Andrew Rambaut for inviting us to participate in the scientific discussion meeting. NR 111 TC 42 Z9 44 U1 2 U2 127 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 19 PY 2013 VL 368 IS 1614 AR 20120250 DI 10.1098/rstb.2012.0250 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 088DH UT WOS:000314813500014 PM 23382431 ER PT J AU Park, M Loverdo, C Schreiber, SJ Lloyd-Smith, JO AF Park, Miran Loverdo, Claude Schreiber, Sebastian J. Lloyd-Smith, James O. TI Multiple scales of selection influence the evolutionary emergence of novel pathogens SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE emerging diseases; pathogen evolution; adaptation; branching processes ID IMMUNODEFICIENCY-VIRUS TYPE-1; CROSS-SPECIES TRANSMISSION; WITHIN-HOST; INFECTIOUS-DISEASES; MOLECULAR EVOLUTION; VIRAL LOAD; RNA VIRUS; DYNAMICS; ADAPTATION; VIRULENCE AB When pathogens encounter a novel environment, such as a new host species or treatment with an antimicrobial drug, their fitness may be reduced so that adaptation is necessary to avoid extinction. Evolutionary emergence is the process by which new pathogen strains arise in response to such selective pressures. Theoretical studies over the last decade have clarified some determinants of emergence risk, but have neglected the influence of fitness on evolutionary rates and have not accounted for the multiple scales at which pathogens must compete successfully. We present a cross-scale theory for evolutionary emergence, which embeds a mechanistic model of within-host selection into a stochastic model for emergence at the population scale. We explore how fitness landscapes at within-host and between-host scales can interact to influence the probability that a pathogen lineage will emerge successfully. Results show that positive correlations between fitnesses across scales can greatly facilitate emergence, while cross-scale conflicts in selection can lead to evolutionary dead ends. The local genotype space of the initial strain of a pathogen can have disproportionate influence on emergence probability. Our cross-scale model represents a step towards integrating laboratory experiments with field surveillance data to create a rational framework to assess emergence risk. C1 [Park, Miran; Loverdo, Claude; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Schreiber, Sebastian J.] Univ Calif Davis, Dept Evolut & Ecol, Davis, CA 95616 USA. [Schreiber, Sebastian J.] Univ Calif Davis, Grad Grp Appl Math, Davis, CA 95616 USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Park, M (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, 610 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM miran.park@ucla.edu RI Lloyd-Smith, James/K-4080-2012; OI Lloyd-Smith, James/0000-0001-7941-502X; Loverdo, Claude/0000-0002-0888-1717 FU NSF [EF-0928690, EF-0928987]; De Logi Chair in Biological Sciences; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIGMS [T32GM008185] FX The authors would like to thank John Novembre and members of the Lloyd-Smith laboratory for helpful suggestions and comments. The project was supported by the NSF grant nos EF-0928690 and EF-0928987. J.L.S. acknowledges the support of the De Logi Chair in Biological Sciences, and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. M. P. was also supported by NIGMS grant no. T32GM008185. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. NR 63 TC 16 Z9 16 U1 3 U2 57 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 19 PY 2013 VL 368 IS 1614 AR 20120333 DI 10.1098/rstb.2012.0333 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 088DH UT WOS:000314813500016 PM 23382433 ER PT J AU Viboud, C Nelson, MI Tan, Y Holmes, EC AF Viboud, Cecile Nelson, Martha I. Tan, Yi Holmes, Edward C. TI Contrasting the epidemiological and evolutionary dynamics of influenza spatial transmission SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE influenza; spatial diffusion; human mobility; phylogeography; source population; viral persistence ID WHOLE-GENOME ANALYSIS; UNITED-STATES; PANDEMIC INFLUENZA; A VIRUS; METAPOPULATION DYNAMICS; INTERNATIONAL SPREAD; GEOGRAPHIC SPREAD; H1N1 INFLUENZA; GLOBAL SPREAD; H3N2 VIRUSES AB In the past decade, rapid increases in the availability of high-resolution molecular and epidemiological data, combined with developments in statistical and computational methods to simulate and infer migration patterns, have provided key insights into the spatial dynamics of influenza A viruses in humans. In this review, we contrast findings from epidemiological and molecular studies of influenza virus transmission at different spatial scales. We show that findings are broadly consistent in large-scale studies of inter-regional or inter-hemispheric spread in temperate regions, revealing intense epidemics associated with multiple viral introductions, followed by deep troughs driven by seasonal bottlenecks. However, aspects of the global transmission dynamics of influenza viruses are still debated, especially with respect to the existence of tropical source populations experiencing high levels of genetic diversity and the extent of prolonged viral persistence between epidemics. At the scale of a country or community, epidemiological studies have revealed spatially structured diffusion patterns in seasonal and pandemic outbreaks, which were not identified in molecular studies. We discuss the role of sampling issues in generating these conflicting results, and suggest strategies for future research that may help to fully integrate the epidemiological and evolutionary dynamics of influenza virus over space and time. C1 [Viboud, Cecile; Nelson, Martha I.; Tan, Yi; Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. RP Viboud, C (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov OI Holmes, Edward/0000-0001-9596-3552 FU 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 FX This research was conducted in the context of the MISMS Study, an ongoing international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). This work was supported 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. All authors: no reported conflicts. NR 89 TC 17 Z9 17 U1 2 U2 50 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 19 PY 2013 VL 368 IS 1614 AR 20120199 DI 10.1098/rstb.2012.0199 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 088DH UT WOS:000314813500005 PM 23382422 ER PT J AU Yuan, HY Koelle, K AF Yuan, Hsiang-Yu Koelle, Katia TI The evolutionary dynamics of receptor binding avidity in influenza A: a mathematical model for a new antigenic drift hypothesis SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE influenza evolution; antigenic drift; binding avidity changes; disease dynamics ID IMMUNIZATION PRACTICES ACIP; HEMAGGLUTININ ANTIBODIES; ADVISORY-COMMITTEE; GENETIC EVOLUTION; CROSS-IMMUNITY; VIRUS; SELECTION; HA; RECOMMENDATIONS; DETERMINANTS AB The most salient feature of influenza evolution in humans is its antigenic drift. This process is characterized by structural changes in the virus's B-cell epitopes and ultimately results in the ability of the virus to evade immune recognition and thereby reinfect previously infected hosts. Until recently, amino acid substitutions in epitope regions of the viral haemagglutinin were thought to be positively selected for their ability to reduce antibody binding and therefore were thought to be responsible for driving antigenic drift. However, a recent hypothesis put forward by Hensley and co-workers posits that cellular receptor binding avidity is the dominant phenotype under selection, with antigenic drift being a side effect of these binding avidity changes. Here, we present a mathematical formulation of this new antigenic drift model and use it to show how rates of antigenic drift depend on epidemiological parameters. We further use the model to evaluate how two different vaccination strategies can impact antigenic drift rates and ultimately disease incidence levels. Finally, we discuss the assumptions present in the model formulation, predictions of the model, and future work that needs to be done to determine the consistency of this hypothesis with known patterns of influenza's genetic and antigenic evolution. C1 [Yuan, Hsiang-Yu] Duke Univ, Program Computat Biol & Bioinformat, Durham, NC 27708 USA. [Yuan, Hsiang-Yu; Koelle, Katia] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Yuan, HY (reprint author), Duke Univ, Program Computat Biol & Bioinformat, Durham, NC 27708 USA. EM hy.yuan@duke.edu; katia.koelle@duke.edu FU RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security [NSF-EF-08-27416]; Fogarty International Centre; James S. McDonnell Foundation FX We thank Christophe Fraser, Oliver Pybus and Andrew Rambaut for the opportunity to present this work at the 2012 Royal Society Meeting 'Next-generation molecular and evolutionary epidemiology of infectious disease'. We also thank the participants of this meeting, two anonymous referees, members of the Koelle research group, and Ben Bolker for helpful comments and useful discussions. This work was supported by grant no. NSF-EF-08-27416 to K. K., by the RAPIDD programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Centre, and by a Complex Systems grant to K. K. from the James S. McDonnell Foundation. NR 41 TC 5 Z9 5 U1 0 U2 26 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 19 PY 2013 VL 368 IS 1614 AR 20120204 DI 10.1098/rstb.2012.0204 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 088DH UT WOS:000314813500009 PM 23382426 ER PT J AU Sastalla, I Crown, D Masters, SL McKenzie, A Leppla, SH Moayeri, M AF Sastalla, Inka Crown, Devorah Masters, Seth L. McKenzie, Andrew Leppla, Stephen H. Moayeri, Mahtab TI Transcriptional analysis of the three Nlrp1 paralogs in mice SO BMC GENOMICS LA English DT Article DE Nlrp1; Inflammasome; Anthrax toxins; Lethal toxin; Bacillus anthracis; Splice variants ID ANTHRAX LETHAL TOXIN; INFLAMMASOME ACTIVATION; SUSCEPTIBILITY; MACROPHAGES; PYROPTOSIS; RECEPTORS; GENES; FLIP AB Background: Signals of danger and damage in the cytosol of cells are sensed by NOD-like receptors (NLRs), which are components of multiprotein complexes called inflammasomes. Inflammasomes activate caspase-1, resulting in IL-1-beta and IL-18 secretion and an inflammatory response. To date, the only known activator of rodent Nlrp1 is anthrax lethal toxin (LT), a protease secreted by the bacterial pathogen Bacillus anthracis. Although susceptibility of mouse macrophages to LT has been genetically linked to Nlrp1b, mice harbor two additional Nlrp1 paralogs in their genomes (Nlrp1a and Nlrp1c). However, little is known about their expression profile and sequence in different mouse strains. Furthermore, simultaneous expression of these paralogs may lead to competitional binding of Nlrp1b interaction partners needed for inflammasome activation, thus influencing macrophages susceptibility to LT. To more completely understand the role(s) of Nlrp1 paralogs in mice, we surveyed for their expression in a large set of LT-resistant and sensitive mouse macrophages. In addition, we provide sequence comparisons for Nlrp1a and report on previously unrecognized splice variants of Nlrp1b. Results: Our results show that macrophages from some inbred mouse strains simultaneously express different splice variants of Nlrp1b. In contrast to the highly polymorphic Nlrp1b splice variants, sequencing of expressed Nlrp1a showed the protein to be highly conserved across all mouse strains. We found that Nlrp1a was expressed only in toxin-resistant macrophages, with the sole exception of expression in LT-sensitive CAST/EiJ macrophages. Conclusions: Our data present a complex picture of Nlrp1 protein variations and provide a basis for elucidating their roles in murine macrophage function. Furthermore, the high conservation of Nlrp1a implies that it might be an important inflammasome sensor in mice. C1 [Sastalla, Inka; Crown, Devorah; McKenzie, Andrew; Leppla, Stephen H.; Moayeri, Mahtab] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Masters, Seth L.] Walter & Eliza Hall Inst Med Res, Inflammat Div, Parkville, Vic 3052, Australia. RP Sastalla, I (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 33 North Dr, Bethesda, MD 20892 USA. EM sastallai@niaid.nih.gov OI masters, seth/0000-0003-4763-576X FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 32 TC 14 Z9 21 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 MAR 18 PY 2013 VL 14 AR 188 DI 10.1186/1471-2164-14-188 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 138OH UT WOS:000318517400001 PM 23506131 ER PT J AU Tan, IS Ramamurthi, KS AF Tan, Irene S. Ramamurthi, Kumaran S. TI Membrane Remodeling: FisB Will Do In a Pinch SO CURRENT BIOLOGY LA English DT Editorial Material ID BACILLUS-SUBTILIS; FISSION; FUSION; SPORULATION AB Remodeling of membranes by fission or fusion has been extensively studied in eukaryotes, but proteins directly responsible for mediating such events in bacteria have not been discovered. A recent report identified a protein in Bacillus subtilis that exploits an affinity for a specific lipid to drive membrane fission during sporulation. C1 [Tan, Irene S.; Ramamurthi, Kumaran S.] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Tan, Irene S.] Johns Hopkins Univ, Grad Partnerships Program, NIH, Baltimore, MD 21218 USA. RP Tan, IS (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ramamurthiks@mail.nih.gov RI Ramamurthi, Kumaran/P-3516-2015 NR 13 TC 1 Z9 1 U1 0 U2 9 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 MAR 18 PY 2013 VL 23 IS 6 BP R251 EP R253 DI 10.1016/j.cub.2013.02.002 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 110GG UT WOS:000316430000018 PM 23518060 ER PT J AU Rusmini, M Griseri, P Lantieri, F Matera, I Hudspeth, KL Roberto, A Mikulak, J Avanzini, S Rossi, V Mattioli, G Jasonni, V Ravazzolo, R Pavan, WJ Pini-Prato, A Ceccherini, I Mavilio, D AF Rusmini, Marta Griseri, Paola Lantieri, Francesca Matera, Ivana Hudspeth, Kelly L. Roberto, Alessandra Mikulak, Joanna Avanzini, Stefano Rossi, Valentina Mattioli, Girolamo Jasonni, Vincenzo Ravazzolo, Roberto Pavan, William J. Pini-Prato, Alessio Ceccherini, Isabella Mavilio, Domenico TI Induction of RET Dependent and Independent ProInflammatory Programs in Human Peripheral Blood Mononuclear Cells from Hirschsprung Patients SO PLOS ONE LA English DT Article ID RECEPTOR TYROSINE KINASE; ENTERIC NERVOUS-SYSTEM; NEURAL CREST; INCREASED EXPRESSION; HEMATOPOIETIC-CELLS; GDNF GENE; TGF-BETA; DISEASE; PROTOONCOGENE; MUTATIONS AB Hirschsprung disease (HSCR) is a rare congenital anomaly characterized by the absence of enteric ganglia in the distal intestinal tract. While classified as a multigenic disorder, the altered function of the RET tyrosine kinase receptor is responsible for the majority of the pathogenesis of HSCR. Recent evidence demonstrate a strong association between RET and the homeostasis of immune system. Here, we utilize a unique cohort of fifty HSCR patients to fully characterize the expression of RET receptor on both innate (monocytes and Natural Killer lymphocytes) and adaptive (B and T lymphocytes) human peripheral blood mononuclear cells (PBMCs) and to explore the role of RET signaling in the immune system. We show that the increased expression of RET receptor on immune cell subsets from HSCR individuals correlates with the presence of loss-of-function RET mutations. Moreover, we demonstrate that the engagement of RET on PBMCs induces the modulation of several inflammatory genes. In particular, RET stimulation with glial-cell line derived neurotrophic factor family (GDNF) and glycosyl-phosphatidylinositol membrane anchored co-receptor alpha 1 (GFR alpha 1) trigger the up-modulation of genes encoding either for chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1) and cytokines (IL-1 beta, IL-6 and IL-8) and the down-regulation of chemokine/cytokine receptors (CCR2 and IL8-R alpha). Although at different levels, the modulation of these "RET-dependent genes'' occurs in both healthy donors and HSCR patients. We also describe another set of genes that, independently from RET stimulation, are differently regulated in healthy donors versus HSCR patients. Among these "RET-independent genes'', there are CSF-1R, IL1-R1, IL1-R2 and TGF beta-1, whose levels of transcripts were lower in HSCR patients compared to healthy donors, thus suggesting aberrancies of inflammatory responses at mucosal level. Overall our results demonstrate that immune system actively participates in the physiopathology of HSCR disease by modulating inflammatory programs that are either dependent or independent from RET signaling. C1 [Rusmini, Marta; Griseri, Paola; Matera, Ivana; Ravazzolo, Roberto; Ceccherini, Isabella] Ist Giannina Gaslini, Genet Mol Lab, IRCCS, I-16148 Genoa, Italy. [Rusmini, Marta; Lantieri, Francesca; Ravazzolo, Roberto] Univ Genoa, Dept Hlth Sci, Biostat Unit, Genoa, Italy. [Rusmini, Marta; Hudspeth, Kelly L.; Roberto, Alessandra; Mikulak, Joanna; Ravazzolo, Roberto; Mavilio, Domenico] Humanitas Clin & Res Ctr, Unit Clin & Expt Immunol, Milan, Italy. [Hudspeth, Kelly L.; Ravazzolo, Roberto; Mavilio, Domenico] Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy. [Avanzini, Stefano; Rossi, Valentina; Mattioli, Girolamo; Jasonni, Vincenzo; Ravazzolo, Roberto; Pini-Prato, Alessio] Giannina Gaslini Inst, Dept Pediat Surg, IRCCS, Genoa, Italy. [Ravazzolo, Roberto] Univ Genoa, DINOGMI Dept, Genoa, Italy. [Pavan, William J.] NHGRI, Mouse Embryol Sect, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Mavilio, D (reprint author), Humanitas Clin & Res Ctr, Unit Clin & Expt Immunol, Milan, Italy. EM domenico.mavilio@humanitas.it OI Roberto, Alessandra/0000-0001-6615-0026; Mavilio, Domenico/0000-0001-6147-0952 FU Fondazione Umberto Veronesi; Istituto Superiore di Sanita; Italian Ministry of Health (Bando Giovani Ricercatori) [GR-2008-1135082]; European Union [204188] FX MR is a recipient of a fellowship awarded by the Fondazione Umberto Veronesi. This work is supported by Istituto Superiore di Sanita (E-Rare grant, 2007 call awarded to IC), by Italian Ministry of Health (Bando Giovani Ricercatori GR-2008-1135082 awarded to DM) and by European Union (Marie Curie International Reintegration grant number 204188 awarded to DM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 7 Z9 8 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 MAR 18 PY 2013 VL 8 IS 3 AR e59066 DI 10.1371/journal.pone.0059066 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZS UT WOS:000316411600033 PM 23527089 ER PT J AU Yoshimura, T Howard, OMZ Ito, T Kuwabara, M Matsukawa, A Chen, KQ Liu, Y Liu, MY Oppenheim, JJ Wang, JM AF Yoshimura, Teizo Howard, O. M. Zack Ito, Toshihiro Kuwabara, Masaki Matsukawa, Akihiro Chen, Keqiang Liu, Ying Liu, Mingyong Oppenheim, Joost J. Wang, Ji Ming TI Monocyte Chemoattractant Protein-1/CCL2 Produced by Stromal Cells Promotes Lung Metastasis of 4T1 Murine Breast Cancer Cells SO PLOS ONE LA English DT Article ID TUMOR PROGRESSION; MAMMARY-TUMORS; MACROPHAGE INFILTRATION; INFLAMMATORY MONOCYTES; SUPPRESSOR-CELLS; IN-VIVO; ANGIOGENESIS; RECRUITMENT; EXPRESSION; MCP-1 AB MCP-1/CCL2 plays an important role in the initiation and progression of cancer. Since tumor cells produce MCP-1, they are considered to be the main source of this chemokine. Here, we examined whether MCP-1 produced by non-tumor cells affects the growth and lung metastasis of 4T1 breast cancer cells by transplanting them into the mammary pad of WT or MCP-1(-/-) mice. Primary tumors at the injected site grew similarly in both mice; however, lung metastases were markedly reduced in MCP-1(-/-) mice, with significantly longer mouse survival. High levels of MCP-1 mRNA were detected in tumors growing in WT, but not MCP-1(-/-) mice. Serum MCP-1 levels were increased in tumor-bearing WT, but not MCP-1(-/-) mice. Transplantation of MCP-1(-/-) bone marrow cells into WT mice did not alter the incidence of lung metastasis, whereas transplantation of WT bone marrow cells into MCP-1(-/-) mice increased lung metastasis. The primary tumors of MCP-1(-/-) mice consistently developed necrosis earlier than those of WT mice and showed decreased infiltration by macrophages and reduced angiogenesis. Interestingly, 4T1 cells that metastasized to the lung constitutively expressed elevated levels of MCP-1, and intravenous injection of 4T1 cells producing a high level of MCP-1 resulted in increased tumor foci in the lung of WT and MCP-1(-/-) mice. Thus, stromal cell-derived MCP-1 in the primary tumors promotes lung metastasis of 4T1 cells, but tumor cell-derived MCP-1 can also contribute once tumor cells enter the circulation. A greater understanding of the source and role of this chemokine may lead to novel strategies for cancer treatment. C1 [Yoshimura, Teizo; Howard, O. M. Zack; Chen, Keqiang; Liu, Ying; Liu, Mingyong; Oppenheim, Joost J.; Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Ito, Toshihiro; Kuwabara, Masaki; Matsukawa, Akihiro] Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. RP Yoshimura, T (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM yoshimut@mail.nih.gov RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 33 Z9 37 U1 0 U2 13 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 MAR 18 PY 2013 VL 8 IS 3 AR e58791 DI 10.1371/journal.pone.0058791 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZS UT WOS:000316411600011 PM 23527025 ER PT J AU Yu, PP Pisitkun, T Wang, GH Wang, R Katagiri, Y Gucek, M Knepper, MA Geller, HM AF Yu, Panpan Pisitkun, Trairak Wang, Guanghui Wang, Rong Katagiri, Yasuhiro Gucek, Marjan Knepper, Mark A. Geller, Herbert M. TI Global Analysis of Neuronal Phosphoproteome Regulation by Chondroitin Sulfate Proteoglycans SO PLOS ONE LA English DT Article ID SPINAL-CORD-INJURY; EXTRACELLULAR-MATRIX; NEURITE OUTGROWTH; INHIBITORY-ACTIVITY; CANCER-CELLS; AXON GROWTH; GLIAL SCAR; PHOSPHORYLATION; REGENERATION; GUIDANCE AB Chondroitin sulfate proteoglycans (CSPGs) are major components of the extracellular matrix which mediate inhibition of axonal regeneration after injury to the central nervous system (CNS). Several neuronal receptors for CSPGs have recently been identified; however, the signaling pathways by which CSPGs restrict axonal growth are still largely unknown. In this study, we applied quantitative phosphoproteomics to investigate the global changes in protein phosphorylation induced by CSPGs in primary neurons. In combination with isobaric Tags for Relative and Absolute Quantitation (iTRAQ) labeling, strong cation exchange chromatography (SCX) fractionation, immobilized metal affinity chromatography (IMAC) and LC-MS/MS, we identified and quantified 2214 unique phosphopeptides corresponding to 1118 phosphoproteins, with 118 changing significantly in abundance with CSPG treatment. The proteins that were regulated by CSPGs included key components of synaptic vesicle trafficking, axon guidance mediated by semaphorins, integrin signaling, cadherin signaling and EGF receptor signaling pathways. A significant number of the regulated proteins are cytoskeletal and related proteins that have been implicated in regulating neurite growth. Another highly represented protein category regulated by CSPGs is nucleic acid binding proteins involved in RNA post-transcriptional regulation. Together, by screening the overall phosphoproteome changes induced by CSPGs, this data expand our understanding of CSPG signaling, which provides new insights into development of strategies for overcoming CSPG inhibition and promoting axonal regeneration after CNS injury. C1 [Yu, Panpan; Katagiri, Yasuhiro; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Pisitkun, Trairak; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core Facil, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Wang, Rong] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Geller, HM (reprint author), NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, Div Intramural Res,NIH, Bldg 10, Bethesda, MD 20892 USA. EM geller@helix.nih.gov RI Yu, Panpan/A-4962-2013; OI Pisitkun, Trairak/0000-0001-6677-2271; Geller, Herbert/0000-0002-7048-6144 FU National Heart, Lung, and Blood Institute (NHLBI) Intramural Program FX This research was entirely funded through the National Heart, Lung, and Blood Institute (NHLBI) Intramural Program. There were no external funding sources for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 9 Z9 9 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2013 VL 8 IS 3 AR e59285 DI 10.1371/journal.pone.0059285 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZS UT WOS:000316411600054 PM 23527152 ER PT J AU Thompson, J Pikis, A Rich, J Hall, BG Withers, SG AF Thompson, John Pikis, Andreas Rich, Jamie Hall, Barry G. Withers, Stephen G. TI alpha-Galacturonidase(s): A new class of Family 4 glycoside hydrolases with strict specificity and a unique CHEV active site motif SO FEBS LETTERS LA English DT Article DE Glycoside hydrolase Family 4; alpha-Galacturonidase; LplD; CAZy database; Phylogenetic; pNP-alpha-D-galactopyranosiduronic acid; Bacillus subtilis ID PHOSPHO-ALPHA-GLUCOSIDASE; THERMOTOGA-MARITIMA; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; THERMOPHILIC BACTERIUM; GALACTOSIDASE; HYDROLYSIS; MECHANISM; 6-PHOSPHO-ALPHA-GLUCOSIDASE; ELIMINATION AB The catalytic activity of the Family 4 glycosidase LplD protein, whose active site motif is CHEV, is unknown despite its crystal structure having been determined in 2008. Here we identify that activity as being an alpha-galacturonidase whose natural substrate is probably alpha-1,4-di-galacturonate (GalUA(2)). Phylogenetic analysis shows that LplD belongs to a monophyletic clade of CHEV Family 4 enzymes, of which four other members are also shown to be galacturonidases. Family GH 4 enzymes catalyze the cleavage of the glycosidic bond, via a non-canonical redox-assisted mechanism that contrasts with Koshland's double-displacement mechanism. Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Thompson, John; Pikis, Andreas] NIDCR, Microbial Biochem & Genet Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Pikis, Andreas] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Rich, Jamie; Withers, Stephen G.] Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada. [Hall, Barry G.] Bellingham Res Inst, Bellingham, WA 98229 USA. RP Thompson, J (reprint author), NIDCR, Microbial Biochem & Genet Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM jthompson@dir.nidcr.nih.gov FU National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD; Natural Sciences and Engineering Research Council of Canada FX We thank Ricardo Dreyfuss for assistance with photography and computer graphics. This investigation was supported by the Intramural Research Program (IRP) of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD and by the Natural Sciences and Engineering Research Council of Canada. NR 33 TC 2 Z9 6 U1 0 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAR 18 PY 2013 VL 587 IS 6 BP 799 EP 803 DI 10.1016/j.febslet.2013.02.004 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 103VK UT WOS:000315947400041 PM 23416295 ER PT J AU Goldsmith, JC Wang, WC AF Goldsmith, Jonathan C. Wang, Winfred C. TI Preoperative transfusion in patients with sickle-cell disease SO LANCET LA English DT Editorial Material ID SURGERY C1 [Goldsmith, Jonathan C.] NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. [Wang, Winfred C.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. RP Goldsmith, JC (reprint author), NHLBI, Div Blood Dis & Resources, Bldg 10, Bethesda, MD 20892 USA. EM goldsmithjc@nhlbi.nih.gov NR 9 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAR 16 PY 2013 VL 381 IS 9870 BP 886 EP 888 DI 10.1016/S0140-6736(12)61995-3 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 105LB UT WOS:000316069700009 PM 23352053 ER PT J AU Galbraith, CG Keller, PJ Nogales, E AF Galbraith, Catherine G. Keller, Philipp J. Nogales, Eva TI New technologies in imaging SO MOLECULAR BIOLOGY OF THE CELL LA English DT Editorial Material C1 [Galbraith, Catherine G.] NIH, Bethesda, MD 20878 USA. [Keller, Philipp J.] Howard Hughes Med Inst, Janelia Farm Res Campus, Ashburn, VA 20147 USA. [Nogales, Eva] Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Nogales, E (reprint author), Univ Calif Berkeley, Berkeley, CA 94720 USA. EM enogales@lbl.gov FU Howard Hughes Medical Institute; NIGMS NIH HHS [P01 GM051487] NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 15 PY 2013 VL 24 IS 6 BP 669 EP 669 DI 10.1091/mbc.E12-12-0867 PG 1 WC Cell Biology SC Cell Biology GA 173YV UT WOS:000321120600001 PM 23486393 ER PT J AU Ohara, A Kasahara, Y Yamamoto, H Hata, H Kobayashi, H Numachi, Y Miyoshi, I Hall, FS Uhl, GR Ikeda, K Sora, I AF Ohara, Arihisa Kasahara, Yoshiyuki Yamamoto, Hideko Hata, Harumi Kobayashi, Hideaki Numachi, Yohtaro Miyoshi, Ichiro Hall, F. Scott Uhl, George R. Ikeda, Kazutaka Sora, Ichiro TI Exclusive expression of VMAT2 in noradrenergic neurons increases viability of homozygous VMAT2 knockout mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Transgenic; Locomotion; Dopamine; Monoamine ID VESICULAR MONOAMINE TRANSPORTER; DOPAMINE TRANSPORTER; MUTANT MICE; AMPHETAMINE; GENE; RAT; LOCALIZATION; DISRUPTION; ACTIVATION; LOCOMOTION AB The vesicular monoamine transporter 2 (VMAT2) translocates monoamine neurotransmitters from the neuronal cytoplasm into synaptic vesicles. Since VMAT2-/- mice die within a few days of birth, it is difficult to analyze the detailed VMAT2 functions using these mice. In this study, we generated human VMAT2 transgenic mice that expressed VMAT2 in noradrenergic neurons with the aim to rescue the lethality of VMAT2 deletion. The expression of human VMAT2 in noradrenergic neurons extended the life of VMAT2-/- mice for up to three weeks, and these mice showed severe growth deficiency compared with VMAT2+/+ mice. These results may indicate that VMAT2 expressed in noradrenergic neurons has crucial roles in survival during the first several weeks after birth, and VMAT2 functions in other monoaminergic systems could be required for further extended survival. Although VMAT2 rescue in noradrenergic neurons did not eliminate the increased morbidity and lethality associated with VMAT2 deletion, the extension of the lifespan in VMAT2 transgenic mice will enable behavioral, pharmacological and pathophysiological studies of VMAT2 function. (C) 2013 Elsevier Inc. All rights reserved. C1 [Ohara, Arihisa; Kasahara, Yoshiyuki; Hata, Harumi; Kobayashi, Hideaki; Numachi, Yohtaro; Sora, Ichiro] Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 9808574, Japan. [Yamamoto, Hideko; Ikeda, Kazutaka] Tokyo Metropolitan Inst Med Sci, Addict Subst Project, Tokyo 113, Japan. [Miyoshi, Ichiro] Tohoku Univ, Grad Sch Med, Inst Anim Experimentat, Sendai, Miyagi 9808574, Japan. [Hall, F. Scott; Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, Intramural Res Program, NIH DHHS, 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 Ikeda, Kazutaka/I-4694-2013; Kobayashi, Hideaki/C-8617-2009; Hall, Frank/C-3036-2013 OI Ikeda, Kazutaka/0000-0001-8342-0278; Kobayashi, Hideaki/0000-0003-3599-0465; Hall, Frank/0000-0002-0822-4063 FU MHLW of Japan; MEXT of Japan; National Institute on Drug Abuse, NIH/DHHS, USA (GRU); National Institute on Drug Abuse, NIH/DHHS, USA (FSH) FX We thank Dr. Kazuto Kobayashi for the kind gift of cDNA for DBH and Hiromi Suda for technical assistance. This study was supported by a Grant-in-Aid for Health and Labour Science Research (Research on Pharmaceutical and Medical Safety) from MHLW of Japan; by Grants-in-Aid for Core Research for Evolutional Science and Technology (CREST), Global COE Program (Basic 82 Translational Research Center for Global Brain Science) from MEXT of Japan and through funding from the Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS, USA (GRU and FSH). NR 24 TC 4 Z9 5 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 15 PY 2013 VL 432 IS 3 BP 526 EP 532 DI 10.1016/j.bbrc.2013.02.014 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 115WS UT WOS:000316843200023 PM 23410751 ER PT J AU Del Valle-Pinero, AY Van Deventer, HE Fourie, NH Martino, AC Patel, NS Remaley, AT Henderson, WA AF Del Valle-Pinero, Arseima Y. Van Deventer, Hendrick E. Fourie, Nicolaas H. Martino, Angela C. Patel, Nayan S. Remaley, Alan T. Henderson, Wendy A. TI Gastrointestinal permeability in patients with irritable assessed using a four probe permeability solution SO CLINICA CHIMICA ACTA LA English DT Article DE Intestinal permeability; Lactulose-to-mannitol ratio; Sucralose; Sucrose; Mass spectrometry; Multiple reaction monitoring ID BOWEL-SYNDROME PATIENTS; INTESTINAL PERMEABILITY; COLONIC PERMEABILITY; URINE; DISEASE; INFLAMMATION; DECREASES; SUGARS; SERUM; ASSAY AB Background: Abnormal gastrointestinal permeability has been linked to irritable bowel syndrome (IBS). The lactulose-to-mannitol ratio is traditionally used to assess small intestine permeability while sucralose and sucrose are used to assess colonic and gastric permeability respectively. We used a single 4-probe test solution to assess permeability throughout the gastrointestinal tract in IBS patients and healthy controls by measuring the recovery of the probes in urine after ingestion using a modified liquid chromatography mass spectrometry protocol. Methods: Fasting participants (N=59) drank a permeability test solution (100 ml: sucralose, sucrose, mannitol, and lactulose). Urine was collected over a 5-h period and kept frozen until analysis. Urinary sugar concentrations were measured using a liquid chromatography/triple quadruple mass spectrometer. Results: Colonic permeability was significantly lower in IBS patients when compared to healthy controls (p=0.011). Gastric and small intestinal permeability did not significantly differ between the groups. Conclusions: The study demonstrates the clinical potential of this non-invasive method for assessing alterations in gastrointestinal permeability in patients with IBS. Published by Elsevier B.V. C1 [Del Valle-Pinero, Arseima Y.; Fourie, Nicolaas H.; Martino, Angela C.; Patel, Nayan S.; Henderson, Wendy A.] NINR, Biobehav Branch, Intramural Res Program, NIH,DHHS, Bethesda, MD 20892 USA. [Van Deventer, Hendrick E.; Remaley, Alan T.] NIH, Dept Lab Med, DHHS, Bethesda, MD 20892 USA. [Van Deventer, Hendrick E.; Remaley, Alan T.] NIH, Warren Grant Magnuson Clin Ctr, DHHS, Bethesda, MD 20892 USA. RP Henderson, WA (reprint author), NINR, Biobehav Unit, NIH, DHHS, Bldg 10,2-1339, Bethesda, MD 20892 USA. EM hendersw@mail.nih.gov FU NINR's Intramural Research Training Awards; [1ZIANR000018-03] FX The authors thank the study participants, NIH Clinical Center and NIDDK Metabolic Program of Care (Dr. Kong Chen). We also thank Dr. Robert Shulman for the formulation of the test solution and Dr. Margaret Heitkemper for her mentorship. This study was funded by NINR's Intramural Research Training Awards (Del Valle-Pinero, Fourie, and Patel) and 1ZIANR000018-03 award (PI; Henderson). NR 31 TC 9 Z9 9 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD MAR 15 PY 2013 VL 418 BP 97 EP 101 DI 10.1016/j.cca.2012.12.032 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 111OL UT WOS:000316530500019 PM 23328210 ER PT J AU Lilja, AM Rojdner, J Mustafiz, T Thome, CM Storelli, E Gonzalez, D Unger-Lithner, C Greig, NH Nordberg, A Marutle, A AF Lilja, Anna M. Rojdner, Jennie Mustafiz, Tamanna Thome, Carina M. Storelli, Elisa Gonzalez, Daniel Unger-Lithner, Christina Greig, Nigel H. Nordberg, Agneta Marutle, Amelia TI Age-Dependent Neuroplasticity Mechanisms in Alzheimer Tg2576 Mice Following Modulation of Brain Amyloid-beta Levels SO PLOS ONE LA English DT Article ID NEURAL STEM-CELLS; TRANSGENIC MICE; A-BETA; HIPPOCAMPAL NEUROGENESIS; ADULT NEUROGENESIS; IMPAIRED NEUROGENESIS; NEUROTROPHIC-FACTOR; PRECURSOR PROTEIN; DENTATE GYRUS; MOUSE MODEL AB The objective of this study was to investigate the effects of modulating brain amyloid-beta (A beta) levels at different stages of amyloid pathology on synaptic function, inflammatory cell changes and hippocampal neurogenesis, i.e. processes perturbed in Alzheimer's disease (AD). Young (4- to 6-month-old) and older (15- to 18-month-old) APP(SWE) transgenic (Tg2576) mice were treated with the AD candidate drug (+)-phenserine for 16 consecutive days. We found significant reductions in insoluble A beta 1-42 levels in the cortices of both young and older transgenic mice, while significant reductions in soluble A beta 1-42 levels and insoluble A beta 1-40 levels were only found in animals aged 15-18 months. Autoradiography binding with the amyloid ligand Pittsburgh Compound B (H-3-PIB) revealed a trend for reduced fibrillar A beta deposition in the brains of older phenserine-treated Tg2576 mice. Phenserine treatment increased cortical synaptophysin levels in younger mice, while decreased interleukin-1 beta and increased monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels were detected in the cortices of older mice. The reduction in A beta 1-42 levels was associated with an increased number of bromodeoxyuridine-positive proliferating cells in the hippocampi of both young and older Tg2576 mice. To determine whether the increased cell proliferation was accompanied by increased neuronal production, the endogenous early neuronal marker doublecortin (DCX) was examined in the dentate gyrus (DG) using immunohistochemical detection. Although no changes in the total number of DCX+-expressing neurons were detected in the DG in Tg2576 mice at either age following (+)-phenserine treatment, dendritic arborization was increased in differentiating neurons in young Tg2576 mice. Collectively, these findings indicate that reducing A beta 1-42 levels in Tg2576 mice at an early pathological stage affects synaptic function by modulating the maturation and plasticity of newborn neurons in the brain. In contrast, lowering A beta levels in Tg2576 mice when Ab plaque pathology is prominent mainly alters the levels of proinflammatory cytokines and chemokines. C1 [Lilja, Anna M.; Rojdner, Jennie; Mustafiz, Tamanna; Thome, Carina M.; Storelli, Elisa; Gonzalez, Daniel; Unger-Lithner, Christina; Nordberg, Agneta; Marutle, Amelia] Karolinska Inst, Alzheimer Neurobiol Ctr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. [Rojdner, Jennie; Nordberg, Agneta] Karolinska Univ, Huddinge Hosp, Dept Geriatr Med, Stockholm, Sweden. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Marutle, A (reprint author), Karolinska Inst, Alzheimer Neurobiol Ctr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. EM amelia.marutle@ki.se OI Unger Lithner, Christina/0000-0001-9775-0411 FU Swedish Medical Research Council [05817]; Stockholm County Council-Karolinska Institutet; Karolinska Institutet Strategic Neuroscience Program; Swedish Brain Power; Brain Foundation; European Union; Gun and Bertil Stohne's Foundation; Foundation for Old Servants; Magnus Bergvall's Foundation; Dementia Association; Lars Hierta Memorial Foundation; Olle Engkvist Byggmastare Foundation; Karolinska Institutet Foundations; Johnson & Johnson administered through the Karolinska Institutet; Alzheimer Association Sweden; Karolinska Institutet for Funding for new doctoral students at Karolinska Institutet (KID); Erik and Edith Fernstrom's Foundation; Intramural Research Program, National Institute on Aging, National Institutes of Health; Torrey pines Therapeutics; GSK; Wyeth; Novartis; Pfizer; GE Healthcare; Johnson Johnson FX This work was supported by grants from the Swedish Medical Research Council (Project no. 05817), the Stockholm County Council-Karolinska Institutet (ALF grant), the Karolinska Institutet Strategic Neuroscience Program, Swedish Brain Power, the Brain Foundation, the INMiND consortium (Imaging of Neuroinflammation in Neurodegenerative Diseases) under the Seventh Research Framework Program of the European Union, Gun and Bertil Stohne's Foundation, the Foundation for Old Servants, Magnus Bergvall's Foundation, The Dementia Association, The Lars Hierta Memorial Foundation, the Olle Engkvist Byggmastare Foundation, Karolinska Institutet Foundations, an academic grant from Johnson & Johnson administered through the Karolinska Institutet, and the Alzheimer Association Sweden. AML was supported by a long-term scholarship from the Karolinska Institutet for Funding for new doctoral students at Karolinska Institutet (KID), a grant from Erik and Edith Fernstrom's Foundation, and a stipend from Gun and Bertil Stohne's Foundation. NHG was supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Agneta Nordberg is PI for clinical trials sponsored by Torrey pines Therapeutics, GSK, Wyeth, and has been a consultant for AstraZeneca, served on the advisory board for Elan, Pfizer, GSK, Novartis, Lundbeck AB, GE Health Care, and received honorarium for lectures from Novartis, Jansen-Cilag, Pfizer, Merck and received research grants from Novartis, Pfizer, GE Healthcare, Johnson & Johnson. The experimental Alzheimer drugs, (2)- phenserine and (+)phenserine, both derive from Nigel H. Greig's research and are covered in patents that have been assigned to the National Institutes of Health and Dr. Greig has no ownership of these patents. None of the other authors have any conflicts of interest and potential competing interests. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 65 TC 17 Z9 17 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 MAR 15 PY 2013 VL 8 IS 3 AR e58752 DI 10.1371/journal.pone.0058752 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZC UT WOS:000316409800027 PM 23554921 ER PT J AU Ou, JX Bharti, K Nodari, A Bertuzzi, S Arnheiter, H AF Ou, Jingxing Bharti, Kapil Nodari, Alessandro Bertuzzi, Stefano Arnheiter, Heinz TI Vax1/2 Genes Counteract Mitf-Induced Respecification of the Retinal Pigment Epithelium SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR MITF; EYE DEVELOPMENT; CELL-DIFFERENTIATION; ALAGILLE-SYNDROME; OPTIC VESICLE; NEURAL RETINA; HOMEOBOX GENE; BETA-CATENIN; EXPRESSION; TRANSDIFFERENTIATION AB During vertebrate eye development, the transcription factor MITF acts to promote the development of the retinal pigment epithelium (RPE). In embryos with Mitf mutations, the future RPE hyperproliferates and is respecified as retinal tissue but only in a small portion of the dorsal RPE. Using a series of genetic crosses, we show that this spatial restriction of RPE respecification is brought about by persistent expression of the anti-retinogenic ventral homeodomain gene Vax2 in the dorso-proximal and both Vax1 and Vax2 in the ventral RPE. We further show that dorso-proximal RPE respecification in Vax2/Mitf double mutants and dorso-proximal and ventral RPE respecification in Vax1/2/Mitf triple mutants result from increased FGF/MAP kinase signaling. In none of the mutants, however, does the distal RPE show signs of hyperproliferation or respecification, likely due to local JAGGED1/NOTCH signaling. Expression studies and optic vesicle culture experiments also suggest a role for NOTCH signaling within the mutant dorsal RPE domains, where ectopic JAGGED1 expression may partially counteract the effects of FGF/ERK1/2 signaling on RPE respecification. The results indicate the presence of complex interplays between distinct transcription factors and signaling molecules during eye development and show how RPE phenotypes associated with mutations in one gene are modulated by expression changes in other genes. C1 [Ou, Jingxing; Bharti, Kapil; Nodari, Alessandro; Bertuzzi, Stefano; Arnheiter, Heinz] NINDS, Mammalian Dev Sect, NIH, Bethesda, MD 20892 USA. RP Ou, JX (reprint author), NINDS, Mammalian Dev Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM ouj@nei.nih.gov OI Bertuzzi, Stefano/0000-0003-4562-3626 FU Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 4 Z9 4 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 15 PY 2013 VL 8 IS 3 AR e59247 DI 10.1371/journal.pone.0059247 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZC UT WOS:000316409800075 PM 23555005 ER PT J AU Rowzee, AM Perez-Riveros, PJ Zheng, CY Krygowski, S Baum, BJ Cawley, NX AF Rowzee, Anne M. Perez-Riveros, Paola J. Zheng, Changyu Krygowski, Sarah Baum, Bruce J. Cawley, Niamh X. TI Expression and Secretion of Human Proinsulin-B10 from Mouse Salivary Glands: Implications for the Treatment of Type I Diabetes Mellitus SO PLOS ONE LA English DT Article ID MEDIATED GENE-TRANSFER; INSULIN-RECEPTOR ISOFORM; CARBOXYPEPTIDASE-E; CELL LINE; MUTANT PROINSULIN; EPITHELIAL-CELLS; SKELETAL-MUSCLE; MICE; THERAPY; HYPERPROINSULINEMIA AB Adenovirus (Ad) mediated expression of therapeutic proteins from salivary glands can result in the delivery of biologically active proteins into the circulation where they impart their physiological function. In recent years, Ad vector delivery to salivary glands (SGs) has emerged as a viable option for gene therapy. Here, we engineered a variant of human proinsulin (hProinsulin-B10) into an Ad vector and demonstrated its ability to transduce cell lines, and express a bioactive protein that induces the phosphorylation of AKT, a key insulin signaling molecule. We also examined its expression in mice following delivery of the vector to the parotid gland (PTG), the submandibular gland (SMG) or to the liver via the tail vein and assessed transgenic protein expression and vector containment for each delivery method. In all cases, hProinsulin-B10 was expressed and secreted into the circulation. Lower levels of circulating hProinsulin-B10 were obtained from the PTG while higher levels were obtained from the tail vein and the SMG; however, vector particle containment was best when delivered to the SMG. Expression of hProinsulin-B10 in the SMG of chemically induced diabetic mice prevented excessive hyperglycemia observed in untreated mice. These results demonstrate that hProinsulin-B10 can be expressed and secreted into the circulation from SGs and can function physiologically in vivo. The ability to remediate a diabetic phenotype in a model of type 1 diabetes mellitus is the first step in an effort that may lead to a possible therapy for diabetes. C1 [Rowzee, Anne M.; Perez-Riveros, Paola J.; Zheng, Changyu; Krygowski, Sarah; Baum, Bruce J.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Cawley, Niamh X.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Cawley, NX (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM cawleyn@mail.nih.gov FU Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Dental and Craniofacial Research, National Institutes of Health (Bethesda, MD) FX This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Dental and Craniofacial Research, National Institutes of Health (Bethesda, MD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 4 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 MAR 15 PY 2013 VL 8 IS 3 AR e59222 DI 10.1371/journal.pone.0059222 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZC UT WOS:000316409800072 PM 23554999 ER PT J AU Bosire, C Stampfer, MJ Subar, AF Park, Y Kirkpatrick, SI Chiuve, SE Hollenbeck, AR Reedy, J AF Bosire, Claire Stampfer, Meir J. Subar, Amy F. Park, Yikyung Kirkpatrick, Sharon I. Chiuve, Stephanie E. Hollenbeck, Albert R. Reedy, Jill TI Index-based Dietary Patterns and the Risk of Prostate Cancer in the NIH-AARP Diet and Health Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diet; food habits; prostatic neoplasms ID RETIRED-PERSONS DIET; FATTY-ACIDS; AMERICAN-ASSOCIATION; NATIONAL-INSTITUTES; EATING INDEX-2005; CHRONIC DISEASE; QUALITY SCORES; BREAST; WOMEN; FISH AB Few studies have investigated the relationship between overall diet and the risk of prostate cancer. We examined the association between 3 diet quality indices the Healthy Eating Index-2005 (HEI-2005), Alternate Healthy Eating Index-2010 (AHEI-2010), and alternate Mediterranean diet score (aMED) and prostate cancer risk. At baseline, dietary intake was assessed in a cohort of 293,464 US men in the National Institutes of Health (NIH)-AARP Diet and Health Study. Cox proportional hazards regression was used to estimate hazard ratios. Between 1995 and 2006, we ascertained 23,453 incident cases of prostate cancer, including 2,251 advanced cases and 428 fatal cases. Among men who reported a history of prostate-specific antigen testing, high HEI-2005 and AHEI-2010 scores were associated with lower risk of total prostate cancer (for the highest quintile compared with the lowest, hazard ratio (HR) = 0.92, 95% confidence interval (Cl): 0.86, 0.98, P for trend = 0.01; and HR = 0.93, 95% Cl: 0.88, 0.99, P for trend = 0.05, respectively). No significant association was observed between aMED score and total prostate cancer or between any of the indices and advanced or fatal prostate cancer, regardless of prostate-specific antigen testing status. In individual component analyses, the fish component of aMED and (0-3 fatty acids component of AHEI-2010 were inversely associated with fatal prostate cancer (HR = 0.79, 95% CI: 0.65, 0.96, and HR = 0.94, 95% Cl: 0.90, 0.98, respectively). C1 [Bosire, Claire; Stampfer, Meir J.; Chiuve, Stephanie E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Stampfer, Meir J.; Chiuve, Stephanie E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Subar, Amy F.; Kirkpatrick, Sharon I.; Reedy, Jill] NCI, Risk Factor Monitoring & Methods Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chiuve, Stephanie E.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Bosire, C (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM cbosire@hsph.harvard.edu OI Kirkpatrick, Sharon/0000-0001-9896-5975; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, National Institutes of Health [R25 CA098566] FX This research was supported in part by the Intermural Research Program of the National Cancer Institute, National Institutes of Health. C. Bosire was supported in part by the National Cancer Institute at the National Institutes of Health (training grant R25 CA098566). NR 43 TC 29 Z9 30 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2013 VL 177 IS 6 BP 504 EP 513 DI 10.1093/aje/kws261 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 109NE UT WOS:000316374500004 PM 23408548 ER PT J AU McDonald, PG O'Connell, M Lutgendorf, SK AF McDonald, Paige Green O'Connell, Mary Lutgendorf, Susan K. TI Psychoneuroimmunology and cancer: A decade of discovery, paradigm shifts, and methodological innovations SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Editorial Material DE Biobehavioral; Psycho-oncology; Tumor biology; Cancer treatment; Cancer outcomes ID INDUCED SICKNESS BEHAVIOR; PRIMARY BREAST-CANCER; KILLER-CELL-ACTIVITY; TUMOR MICROENVIRONMENT; SOCIOECONOMIC-STATUS; OVARIAN-CARCINOMA; CHILDHOOD-CANCER; BIOBEHAVIORAL FACTORS; HEALTH DISPARITIES; SOCIAL SUPPORT AB This article introduces the supplement Advances in Cancer and Brain, Behavior, and Immunity and outlines important discoveries, paradigm shifts, and methodological innovations that have emerged in the past decade to advance mechanistic and translational understanding of biobehavioral influences on tumor biology, cancer treatment-related sequelae, and cancer outcomes. We offer a heuristic framework for research on biobehavioral pathways in cancer. The shifting survivorship landscape is highlighted, and we propose that the changing demographics suggest prudent adoption of a life course perspective of cancer and cancer survivorship. We note opportunities for psychoneuroimmunology (PNI) research to ameliorate the long-term, unintended consequences of aggressive curative intent and call attention to the critical role of reciprocal translational pathways between animal and human studies. Lastly, we briefly summarize the articles included in this compilation and offer our perspectives on future research directions. Published by Elsevier Inc. C1 [McDonald, Paige Green] NCI, Basic Biobehav & Psychol Sci Branch, BRP, DCCPS,NIH,DHHS, Bethesda, MD 20892 USA. [O'Connell, Mary] NCI, BRP, DCCPS, NIH,DHHS, Bethesda, MD 20892 USA. [Lutgendorf, Susan K.] Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. [Lutgendorf, Susan K.] Univ Iowa, Dept Urol, Iowa City, IA 52242 USA. [Lutgendorf, Susan K.] Univ Iowa, Dept Obstet & Gynecol, Iowa City, IA 52242 USA. [Lutgendorf, Susan K.] Univ Iowa, Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. RP McDonald, PG (reprint author), 6130 Execut Blvd,MSC 7363, Bethesda, MD 20892 USA. EM mcdonald.paige@mail.nih.gov OI Green, Paige/0000-0001-7886-8924 NR 152 TC 10 Z9 10 U1 2 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAR 15 PY 2013 VL 30 SI SI BP S1 EP S9 DI 10.1016/j.bbi.2013.01.003 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 111GW UT WOS:000316510800001 ER PT J AU Camps, J Pitt, JJ Emons, G Hummon, AB Case, CM Grade, M Jones, TL Nguyen, QT Ghadimi, BM Beissbarth, T Difilippantonio, MJ Caplen, NJ Ried, T AF Camps, Jordi Pitt, Jason J. Emons, Georg Hummon, Amanda B. Case, Chanelle M. Grade, Marian Jones, Tamara L. Nguyen, Quang T. Ghadimi, B. Michael Beissbarth, Tim Difilippantonio, Michael J. Caplen, Natasha J. Ried, Thomas TI Genetic Amplification of the NOTCH Modulator LNX2 Upregulates the WNT/beta-Catenin Pathway in Colorectal Cancer SO CANCER RESEARCH LA English DT Article ID LINEAGE-SURVIVAL ONCOGENE; COPY-NUMBER ALTERATION; TRANSCRIPTIONAL DEREGULATION; COLON-CANCER; WNT SIGNALS; STEM-CELLS; TUMORS; EXPRESSION; REVEALS; TUMORIGENESIS AB Chromosomal copy number alterations (aneuploidy) define the genomic landscape of most cancer cells, but identification of the oncogenic drivers behind these imbalances remains an unfinished task. In this study, we conducted a systematic analysis of colorectal carcinomas that integrated genomic copy number changes and gene expression profiles. This analysis revealed 44 highly overexpressed genes mapping to localized amplicons on chromosome 13, gains of which occur often in colorectal cancers (CRC). RNA interference (RNAi)-mediated silencing identified eight candidates whose loss-of-function reduced cell viability 20% or more in CRC cell lines. The functional space of the genes NUPL1, LNX2, POLR1D, POMP, SLC7A1, DIS3, KLF5, and GPR180 was established by global expression profiling after RNAi exposure. One candidate, LNX2, not previously known as an oncogene, was involved in regulating NOTCH signaling. Silencing LNX2 reduced NOTCH levels but also downregulated the transcription factor TCF7L2 and markedly reduced WNT signaling. LNX2 overexpression and chromosome 13 amplification therefore constitutively activates the WNT pathway, offering evidence of an aberrant NOTCH-WNT axis in CRC. Cancer Res; 73(6); 2003-13. (C)2012 AACR. C1 [Camps, Jordi; Emons, Georg; Hummon, Amanda B.; Case, Chanelle M.; Grade, Marian; Nguyen, Quang T.; Difilippantonio, Michael J.; Ried, Thomas] NCI, Canc Genom Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20893 USA. [Pitt, Jason J.; Jones, Tamara L.; Caplen, Natasha J.] NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20893 USA. [Emons, Georg; Grade, Marian; Ghadimi, B. Michael; Beissbarth, Tim] Univ Med Gottingen, Dept Gen & Visceral Surg, Gottingen, Germany. RP Camps, J (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, 50 South Dr,Bldg 50,Rm 1408, Bethesda, MD 20893 USA. EM campsj@mail.nih.gov; riedt@mail.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU Intramural Research Program of the NIH, National Cancer Institute; Deutsche Forschungsgemeinschaft [KFO 179] FX This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, and through the KFO 179 from the Deutsche Forschungsgemeinschaft. NR 49 TC 23 Z9 23 U1 1 U2 19 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 MAR 15 PY 2013 VL 73 IS 6 BP 2003 EP 2013 DI 10.1158/0008-5472.CAN-12-3159 PG 11 WC Oncology SC Oncology GA 107AR UT WOS:000316187500035 PM 23319804 ER PT J AU Lygate, CA Aksentijevic, D Dawson, D ten Hove, M Phillips, D de Bono, JP Medway, DJ Sebag-Montefiore, L Hunyor, I Channon, KM Clarke, K Zervou, S Watkins, H Balaban, RS Neubauer, S AF Lygate, Craig A. Aksentijevic, Dunja Dawson, Dana ten Hove, Michiel Phillips, Darci de Bono, Joseph P. Medway, Debra J. Sebag-Montefiore, Liam Hunyor, Imre Channon, Keith M. Clarke, Kieran Zervou, Sevasti Watkins, Hugh Balaban, Robert S. Neubauer, Stefan TI Living Without Creatine Unchanged Exercise Capacity and Response to Chronic Myocardial Infarction in Creatine-Deficient Mice SO CIRCULATION RESEARCH LA English DT Article DE cardiovascular physiological phenomena; heart contractility; heart failure; metabolism; mice, transgenic ID LEFT-VENTRICULAR FUNCTION; ENERGY-METABOLISM; HEART-FAILURE; KNOCKOUT MICE; MOUSE HEART; RAT-HEART; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; BETA-GUANIDINOPROPIONATE; INCREASED SUSCEPTIBILITY; UNCOUPLING PROTEINS AB Rationale: Creatine is thought to be involved in the spatial and temporal buffering of ATP in energetic organs such as heart and skeletal muscle. Creatine depletion affects force generation during maximal stimulation, while reduced levels of myocardial creatine are a hallmark of the failing heart, leading to the widely held view that creatine is important at high workloads and under conditions of pathological stress. Objective: We therefore hypothesised that the consequences of creatine-deficiency in mice would be impaired running capacity, and exacerbation of heart failure following myocardial infarction. Methods and Results: Surprisingly, mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase [GAMT]) voluntarily ran just as fast and as far as controls (>10 km/night) and performed the same level of work when tested to exhaustion on a treadmill. Furthermore, survival following myocardial infarction was not altered, nor was subsequent left ventricular (LV) remodelling and development of chronic heart failure exacerbated, as measured by 3D-echocardiography and invasive hemodynamics. These findings could not be accounted for by compensatory adaptations, with no differences detected between WT and GAMT(-/-) proteomes. Alternative phosphotransfer mechanisms were explored; adenylate kinase activity was unaltered, and although GAMT(-/-) hearts accumulated the creatine precursor guanidinoacetate, this had negligible energy-transfer activity, while mitochondria retained near normal function. Conclusions: Creatine-deficient mice show unaltered maximal exercise capacity and response to chronic myocardial infarction, and no obvious metabolic adaptations. Our results question the paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle. (Circ Res. 2013;112:945-955.) C1 [Lygate, Craig A.; Aksentijevic, Dunja; Dawson, Dana; ten Hove, Michiel; de Bono, Joseph P.; Medway, Debra J.; Sebag-Montefiore, Liam; Hunyor, Imre; Channon, Keith M.; Zervou, Sevasti; Watkins, Hugh; Neubauer, Stefan] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. [Lygate, Craig A.; Aksentijevic, Dunja; ten Hove, Michiel; Medway, Debra J.; Sebag-Montefiore, Liam; Hunyor, Imre; Channon, Keith M.; Zervou, Sevasti; Watkins, Hugh; Neubauer, Stefan] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Phillips, Darci; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Clarke, Kieran] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Lygate, Craig A.; Aksentijevic, Dunja; Medway, Debra J.; Sebag-Montefiore, Liam; Channon, Keith M.; Clarke, Kieran; Zervou, Sevasti; Watkins, Hugh; Neubauer, Stefan] British Heart Fdn Ctr Res Excellence, Oxford, England. RP Lygate, CA (reprint author), Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Roosevelt Dr, Oxford OX3 7BN, England. EM clygate@well.ox.ac.uk RI Dawson, Dana/H-3616-2012; OI Lygate, Craig/0000-0001-6079-0284; Watkins, Hugh/0000-0002-5287-9016 FU British Heart Foundation [RG/10/002/28187]; Wellcome Trust [090532/Z/09/Z] FX This work was supported by British Heart Foundation grant RG/10/002/28187 and Wellcome Trust Core Award, Grant 090532/Z/09/Z. NR 66 TC 42 Z9 43 U1 0 U2 10 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 MAR 15 PY 2013 VL 112 IS 6 BP 945 EP U218 DI 10.1161/CIRCRESAHA.112.300725 PG 32 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 107BO UT WOS:000316189900011 PM 23325497 ER PT J AU Freidlin, B Korn, EL AF Freidlin, Boris Korn, Edward L. TI Borrowing Information across Subgroups in Phase II Trials: Is It Useful? SO CLINICAL CANCER RESEARCH LA English DT Article ID BAYESIAN CLINICAL-TRIALS; DESIGN; CANCER; SUBTYPES; MODEL; DRUG AB Because of the heterogeneity of human tumors, cancer patient populations are usually composed of multiple subgroups with different molecular and/or histologic characteristics. In screening new anticancer agents, there might be a scientific rationale to expect some degree of similarity in clinical activity across the subgroups. This poses a challenge to the design of phase II trials assessing clinical activity: Conducting an independent evaluation in each subgroup requires considerable time and resources, whereas a pooled evaluation that completely ignores patient heterogeneity can miss treatments that are only active in some subgroups. It has been suggested that approaches that borrow information across subgroups can improve efficiency in this setting. In particular, the hierarchical Bayesian approach putatively uses the outcome data to decide whether borrowing of information is appropriate. We evaluated potential benefits of the hierarchical Bayesian approach (using models suggested previously) and a simpler pooling approach by simulations. In the phase II setting, the hierarchical Bayesian approach is shown not to work well in the simulations considered, as there appears to be insufficient information in the outcome data to determine whether borrowing across subgroups is appropriate. When there is strong rationale for expecting a uniform level of activity across the subgroups, approaches using simple pooling of information across subgroups may be useful. Clin Cancer Res; 19(6); 1326-34. (C) 2012 AACR. C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, EPN 8122, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 19 TC 4 Z9 4 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2013 VL 19 IS 6 BP 1326 EP 1334 DI 10.1158/1078-0432.CCR-12-1223 PG 9 WC Oncology SC Oncology GA 107BE UT WOS:000316188900004 PM 23303215 ER PT J AU Ridnour, LA Cheng, RYS Switzer, CH Heinecke, JL Ambs, S Glynn, S Young, HA Trinchieri, G Wink, DA AF Ridnour, Lisa A. Cheng, Robert Y. S. Switzer, Christopher H. Heinecke, Julie L. Ambs, Stefan Glynn, Sharon Young, Howard A. Trinchieri, Giorgio Wink, David A. TI Molecular Pathways: Toll-like Receptors in the Tumor Microenvironment-Poor Prognosis or New Therapeutic Opportunity SO CLINICAL CANCER RESEARCH LA English DT Article ID APOPTOSIS-INDUCING LIGAND; NITRIC-OXIDE SYNTHASE; BREAST-CANCER; UP-REGULATION; METASTATIC MELANOMA; COLORECTAL-CANCER; TOPICAL IMIQUIMOD; SUPPRESSOR-CELLS; BLADDER-CANCER; LUNG-CANCER AB Numerous reports have described Toll-like receptor (TLR) expression in the tumor microenvironment as it relates to cancer progression, as well as their involvement in inflammation. While TLRs mediate immune surveillance, clinical studies have associated TLR expression in the tumor with poor patient survival, indicating that TLR expression may affect cancer treatment and survival. This review will examine mechanisms in which TLR activation upregulates protumorigenic pathways, including the induction of inducible nitric oxide synthase (iNOS2) and COX2, which in turn increase TLR expression and promote a feed-forward loop leading to tumor progression and the development of more aggressive tumor phenotypes. These propagating loops involve cancer cell, stroma, and/or immune cell TLR expression. Because of abundant TLR expression in many human tumors, several TLR agonists are now in clinical and preclinical trials and some have shown enhanced efficacy when used as adjuvant with radiation, chemotherapy, or cancer vaccines. These findings suggest that TLR expression influences cancer biology and therapeutic response, which may involve specific interactions within the tumor microenvironment, including mediators of inflammation such as nitric oxide and the arachidonic acid signaling pathways. Clin Cancer Res; 19(6); 1340-6. (C) 2012 AACR. C1 [Ridnour, Lisa A.; Cheng, Robert Y. S.; Switzer, Christopher H.; Heinecke, Julie L.; Wink, David A.] NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. [Ambs, Stefan] NCI, Lab Human Carcinogenesis, Bethesda, MD 20892 USA. [Young, Howard A.; Trinchieri, Giorgio] NCI, Lab Expt Immunol, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Glynn, Sharon] Natl Univ Ireland NUI Galway, Prostate Canc Inst, Galway, Ireland. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, 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 Intramural Program, Center for Cancer Research, National Cancer Institute, NIH FX This work was funded by the Intramural Program, Center for Cancer Research, National Cancer Institute, NIH. NR 66 TC 45 Z9 48 U1 1 U2 22 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 MAR 15 PY 2013 VL 19 IS 6 BP 1340 EP 1346 DI 10.1158/1078-0432.CCR-12-0408 PG 7 WC Oncology SC Oncology GA 107BE UT WOS:000316188900006 PM 23271799 ER PT J AU Thomas, A Mena, E Kurdziel, K Venzon, D Khozin, S Berman, AW Choyke, P Szabo, E Rajan, A Giaccone, G AF Thomas, Anish Mena, Esther Kurdziel, Karen Venzon, David Khozin, Sean Berman, Arlene W. Choyke, Peter Szabo, Eva Rajan, Arun Giaccone, Giuseppe TI F-18-Fluorodeoxyglucose Positron Emission Tomography in the Management of Patients with Thymic Epithelial Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID PREOPERATIVE CHEMOTHERAPY; HISTOLOGIC CLASSIFICATION; FDG-PET; THYMOMA; MALIGNANCIES; CANCER; PREDICTION; MASSES; GRADE AB Purpose: There are limited data regarding the role of F-18-fluorodeoxyglucose positron emission tomography ([F-18]-FDG PET) imaging in management of patients with thymic epithelial tumors (TET). The primary objective of this study was to assess the usefulness of early [F-18]-FDG PET to monitor treatment efficacy and its correlation with Response Evaluation Criteria in Solid Tumors (RECIST) in patients with TETs. Experimental Design: [F-18]-FDG PET/computed tomographic (CT) scans were conducted at baseline and after 6 weeks of treatment in patients enrolled in two phase II and one phase I/II clinical trials. On the basis of data from other solid tumors, metabolic response was defined as a reduction of [F-18]-FDG uptake by more than 30% as assessed by average standardized uptake values (SUV) of up to five most metabolically active lesions. Results: Fifty-six patients with unresectable Masaoka stage III or IV TETs were included. There was a close correlation between early metabolic response and subsequent best response using RECIST (P < 0.0001-0.0003): sensitivity and specificity for prediction of best response were 95% and 100%, respectively. Metabolic responders had significantly longer progression-free survival (median, 11.5 vs. 4.6 months; P = 0.044) and a trend toward longer overall survival (median, 31.8 vs. 18.4 months; P = 0.14) than nonresponders. [F-18]-FDG uptake was significantly higher in thymic carcinoma than in thymoma (P = 0.0004-0.0010). Conclusion: In patients with advanced TETs, early metabolic response closely correlates with outcome of therapy. [F-18]-FDG PET may be used to monitor treatment efficacy and assess histologic differences in patients with advanced TETs. Clin Cancer Res; 19(6); 1487-93. (C) 2013 AACR. C1 [Thomas, Anish; Khozin, Sean; Berman, Arlene W.; Rajan, Arun; Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Mena, Esther; Kurdziel, Karen; Choyke, Peter] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Szabo, Eva] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU National Cancer Institute, NIH FX The study was supported by Intramural Program, National Cancer Institute, NIH. NR 34 TC 6 Z9 6 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 MAR 15 PY 2013 VL 19 IS 6 BP 1487 EP 1493 DI 10.1158/1078-0432.CCR-12-2929 PG 7 WC Oncology SC Oncology GA 107BE UT WOS:000316188900020 PM 23382114 ER PT J AU Sohl, CD Kasiviswanathan, R Copeland, WC Anderson, KS AF Sohl, Christal D. Kasiviswanathan, Rajesh Copeland, William C. Anderson, Karen S. TI Mutations in human DNA polymerase gamma confer unique mechanisms of catalytic deficiency that mirror the disease severity in mitochondrial disorder patients SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; REVERSE-TRANSCRIPTASE; AUTOSOMAL-DOMINANT; POLG1 MUTATIONS; TOXICITY; REPLICATION; DEFECTS; SUBUNIT; DISCRIMINATION; PARKINSONISM AB Human mitochondrial DNA polymerase gamma (pol gamma) is solely responsible for the replication and repair of the mitochondrial genome. Unsurprisingly, alterations in pol gamma activity have been associated with mitochondrial diseases such as Alpers syndrome and progressive external ophthalmoplegia. Thus far, predicting the severity of mitochondrial disease based the magnitude of deficiency in pol gamma activity has been difficult. In order to understand the relationship between disease severity in patients and enzymatic defects in vitro, we characterized the molecular mechanisms of four pol gamma mutations, A957P, A957S, R1096C and R1096H, which have been found in patients suffering from aggressive Alpers syndrome to mild progressive external ophthalmoplegia. The A957P mutant showed the most striking deficiencies in the incorporation efficiency of a correct deoxyribonucleotide triphosphate (dNTP) relative to wild-type pol gamma, with less, but still significant incorporation efficiency defects seen in R1096H and R1096C, and only a small decrease in incorporation efficiency observed for A957S. Importantly, this trend matches the disease severity observed in patients very well (approximated as A957P >> R1096C >= R1096H >> A957S, from most severe disease to least severe). Further, the A957P mutation conferred a two orders of magnitude loss of fidelity relative to wild-type pol gamma, indicating that a buildup of mitochondrial genomic mutations may contribute to the death in infancy seen with these patients. We conclude that characterizing the unique molecular mechanisms of pol gamma deficiency for physiologically important mutant enzymes is important for understanding mitochondrial disease and for predicting disease severity. C1 [Sohl, Christal D.; Anderson, Karen S.] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. [Kasiviswanathan, Rajesh; Copeland, William C.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Anderson, KS (reprint author), Yale Univ, Sch Med, Dept Pharmacol, 333 Cedar St, New Haven, CT 06520 USA. EM karen.anderson@yale.edu FU National Institutes of Health [GM049551, GM099289, ES 065080] FX This work was supported by the National Institutes of Health (GM049551 to K.S.A., GM099289 to C.D.S., ES 065080 to W.C.C.). NR 46 TC 5 Z9 5 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 15 PY 2013 VL 22 IS 6 BP 1074 EP 1085 DI 10.1093/hmg/dds509 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 108MD UT WOS:000316296600002 PM 23208208 ER PT J AU Iliff, AJ Renoux, AJ Krans, A Usdin, K Sutton, MA Todd, PK AF Iliff, Adam J. Renoux, Abigail J. Krans, Amy Usdin, Karen Sutton, Michael A. Todd, Peter K. TI Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID MENTAL-RETARDATION PROTEIN; LONG-TERM DEPRESSION; SPATIAL PROCESSING DEFICITS; ROBUST PEDIGREE ANALYSIS; GROUP-I MGLUR; MESSENGER-RNA; TREMOR/ATAXIA SYNDROME; MOUSE MODEL; FULL MUTATION; CGG-REPEAT AB Fragile X premutation-associated disorders, including Fragile X-associated Tremor Ataxia Syndrome, result from unmethylated CGG repeat expansions in the 5' untranslated region (UTR) of the FMR1 gene. Premutation-sized repeats increase FMR1 transcription but impair rapid translation of the Fragile X mental retardation protein (FMRP), which is absent in Fragile X Syndrome (FXS). Normally, FMRP binds to RNA and regulates metabotropic glutamate receptor (mGluR)-mediated synaptic translation, allowing for dendritic synthesis of several proteins. FMRP itself is also synthesized at synapses in response to mGluR activation. However, the role of activity-dependent translation of FMRP in synaptic plasticity and Fragile X-premutation-associated disorders is unknown. To investigate this question, we utilized a CGG knock-in mouse model of the Fragile X premutation with 120-150 CGG repeats in the mouse Fmr1 5' UTR. These mice exhibit increased Fmr1 mRNA production but impaired FMRP translational efficiency, leading to a modest reduction in basal FMRP expression. Cultured hippocampal neurons and synaptoneurosomes derived from CGG KI mice demonstrate impaired FMRP translation in response to the group I mGluR agonist 3,5-dihydroxyphenylglycine. Electrophysiological analysis reveals enhanced mGluR-mediated long-term depression (mGluR-LTD) at CA3-CA1 synapses in acute hippocampal slices prepared from CGG KI mice relative to wild-type littermates, similar to Fmr1 knockout mice. However, unlike mGluR-LTD in mice completely lacking FMRP, mGluR-LTD in CGG knock-in mice remains dependent on new protein synthesis. These studies demonstrate partially overlapping synaptic plasticity phenotypes in mouse models of FXS and Fragile X premutation disorders and support a role for activity-dependent synthesis of FMRP in enduring forms of synaptic plasticity. C1 [Iliff, Adam J.] Univ Michigan, Neurosci Grad Program, Ann Arbor, MI 48109 USA. [Renoux, Abigail J.; Sutton, Michael A.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Renoux, Abigail J.; Krans, Amy; Todd, Peter K.] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Sutton, Michael A.] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Usdin, Karen] NIDDK, NIH, Bethesda, MD 20892 USA. RP Sutton, MA (reprint author), Univ Michigan, Mol & Behav Neurosci Inst, Dept Mol & Integrat Physiol, 5067 BSRB,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM masutton@umich.edu; petertod@med.umich.edu FU National Institutes of Mental Health [RO1MH085798]; National Institutes of Neurological Disorders and Stroke [F31NS073372]; National Institutes of Health [T32GM008322, K08NS069809]; PEW Biomedical Scholars Program; Harris Professorship FX This work was supported by the National Institutes of Mental Health (grant number RO1MH085798 to M.A.S.); the National Institutes of Neurological Disorders and Stroke (grant number F31NS073372 to A.J.I.); the National Institutes of Health (grant number T32GM008322 to A.J.R., K08NS069809 to P.K.T.); the PEW Biomedical Scholars Program to M.A.S.; and the Harris Professorship to P.K.T. NR 91 TC 20 Z9 21 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 15 PY 2013 VL 22 IS 6 BP 1180 EP 1192 DI 10.1093/hmg/dds525 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 108MD UT WOS:000316296600010 PM 23250915 ER PT J AU Hur, C Miller, M Kong, CY Dowling, EC Nattinger, KJ Dunn, M Feuer, EJ AF Hur, Chin Miller, Melecia Kong, Chung Yin Dowling, Emily C. Nattinger, Kevin J. Dunn, Michelle Feuer, Eric J. TI Trends in esophageal adenocarcinoma incidence and mortality SO CANCER LA English DT Article DE esophageal neoplasms; adenocarcinoma; incidence; mortality; epidemiology; SEER program ID BARRETTS-ESOPHAGUS; UNITED-STATES; RISING INCIDENCE; GASTRIC CARDIA; CANCER; SURVEILLANCE; SURVIVAL; EPIDEMIOLOGY; DIAGNOSIS; RATES AB BACKGROUND: Over the past several decades, the incidence of esophageal adenocarcinoma (EAC) has rapidly increased. The purpose of this analysis was to examine temporal trends in EAC incidence and mortality within the US population and, in addition, to explore these trends within subgroups of the population. METHODS: The National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER 9) data were used to examine incidence and incidence-based (IB) mortality in EAC from 1975 to 2009. Secular trends in incidence and IB mortality by cancer stage, sex, and race were further characterized using the NCI's Joinpoint Regression program. RESULTS: Based on SEER 9 data, EAC incidence and IB mortality continues to increase in the United States. However, since the mid-1990s, the overall rate of increase in both EAC incidence and IB mortality appears to be slowing. In addition, in early-stage cancers, there is a noticeable leveling off of IB mortality rates and divergence from incidence starting in the late 1990s. Over the study period, the average annual percentage increase in incidence was 6.1% in men and 5.9% in women. CONCLUSIONS: EAC incidence and IB mortality rates continue to rise in the United States, although at a slower rate in more recent years. In early-stage cancers, IB mortality and incidence rates have diverged primarily because IB mortality rates have plateaued beginning in the late 1990s. Although EAC continues to be less common in women, the rate of increase in EAC incidence is similar in both sexes. Cancer 2013. (c) 2012 American Cancer Society. C1 [Hur, Chin; Miller, Melecia; Kong, Chung Yin; Dowling, Emily C.; Nattinger, Kevin J.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Hur, Chin; Nattinger, Kevin J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Hur, Chin; Kong, Chung Yin] Harvard Univ, Sch Med, Boston, MA USA. [Dunn, Michelle; Feuer, Eric J.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Hur, C (reprint author), ITA, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM chur@partners.org OI Hur, Chin/0000-0002-2819-7576 FU National Institutes of Health [R01CA140574, U01CA152926, K25CA133141] FX This work was supported by the National Institutes of Health (grants R01CA140574 and U01CA152926 to Dr. Hur and grant K25CA133141 to Dr. Kong). NR 22 TC 102 Z9 103 U1 2 U2 23 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 MAR 15 PY 2013 VL 119 IS 6 BP 1149 EP 1158 DI 10.1002/cncr.27834 PG 10 WC Oncology SC Oncology GA 100JW UT WOS:000315696600008 PM 23303625 ER PT J AU Liu, J Li, Q Kuehn, MR Ying, LTT Vokes, SA Chiang, C AF Liu, Jiang Li, Qiang Kuehn, Michael R. Ying Litingtung Vokes, Steven A. Chiang, Chin TI Sonic hedgehog signaling directly targets Hyaluronic Acid Synthase 2, an essential regulator of phalangeal joint patterning SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Sonic hedgehog; Limb; Joint patterning; Hyaluronic acid synthase; Gil factors; Aggrecan ID CHONDROCYTE PERICELLULAR MATRIX; ARTICULAR-CARTILAGE FORMATION; HYALURONAN-BINDING PROTEINS; PROMOTES TUMOR PROGRESSION; LIMB BUD MESENCHYME; VERTEBRATE LIMB; SYNOVIAL JOINT; BREAST-CANCER; LINK-PROTEIN; CHICK LIMB AB Sonic hedgehog (Shh) signal, mediated by the Gli family of transcription factors, plays an essential role in the growth and patterning of the limb. Through analysis of the early limb bud transcriptome, we identified a posteriorly-enriched gene, Hyaluronic Acid Synthase 2 (Has2), which encodes a key enzyme for the synthesis of hyaluronan (HA), as a direct target of Gli transcriptional regulation during early mouse limb development. Has2 expression in the limb bud is lost in Shh null and expanded anteriorly in Gli3 mutants. We identified an similar to 3 kb Has2 promoter fragment that contains two strong Gli-binding consensus sequences, and mutation of either site abrogated the ability of Gli1 to activate Has2 promoter in a cell-based assay. Additionally, this promoter fragment is sufficient to direct expression of a reporter gene in the posterior limb mesenchyme. Chromatin immunoprecipitation of DNA-Gli3 protein complexes from limb buds indicated that Gli3 strongly binds to the Has2 promoter region, suggesting that Has2 is a direct transcriptional target of the Shh signaling pathway. We also showed that Has2 conditional mutant (Has2(cko)) hindlimbs display digit-specific patterning defects with longitudinally shifted phalangeal joints and impaired chondrogenesis. Has2(cko) limbs show less capacity for mesenchymal condensation with mislocalized distributions of chondroitin sulfate proteoglycans (CSPGs), aggrecan and link protein. Has2(cko) limb phenotype displays striking resemblance to mutants with defective chondroitin sulfation suggesting tight developmental control of HA on CSPG function. Together, our study identifies Has2 as a novel downstream target of Shh signaling required for joint patterning and chondrogenesis. (C) 2013 Elsevier Inc. All rights reserved. C1 [Liu, Jiang; Ying Litingtung; Chiang, Chin] Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN 37232 USA. [Li, Qiang; Vokes, Steven A.] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Kuehn, Michael R.] NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. RP Chiang, C (reprint author), Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN 37232 USA. EM chin.chiang@vanderbilt.edu RI Kuehn, Michael/A-4573-2014; Xia, Bo/P-9380-2016; OI Kuehn, Michael/0000-0002-7703-9160; Vokes, Steven/0000-0002-1724-0102 FU [NIHRO1 HD49667] FX Thanks to all Chiang lab members for suggestions throughout this study. The hypoxia marker EF5 was made available by the NCI and obtained through Dr. Cameron Koch at the University of Pennsylvania; we thank them for this valuable reagent. The Vanderbilt Transgenic Mouse/Embryonic Stem Cell Shared Resource helped with the injection of targeted ES cells. This work was funded by NIHRO1 HD49667 to C.C. NR 102 TC 5 Z9 5 U1 0 U2 11 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 MAR 15 PY 2013 VL 375 IS 2 BP 160 EP 171 DI 10.1016/j.ydbio.2012.12.018 PG 12 WC Developmental Biology SC Developmental Biology GA 102JQ UT WOS:000315841300006 PM 23313125 ER PT J AU Silver, DL Leeds, KE Hwang, HW Miller, EE Pavan, WJ AF Silver, Debra L. Leeds, Karen E. Hwang, Hun-Way Miller, Emily E. Pavan, William J. TI The EJC component Magoh regulates proliferation and expansion of neural crest-derived melanocytes SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Melanoblast development; Mitosis; Magoh; Sox10 ID EXON JUNCTION COMPLEX; CELL-DIVISION; MOUSE EMBRYO; SOX10; PATTERNS; TRANSCRIPTION; PIGMENTATION; EXPRESSION; MIGRATION; PROTEINS AB Melanoblasts are a population of neural crest-derived cells that generate the pigment-producing cells of our body. Defective melanoblast development and function underlies many disorders including Waardenburg syndrome and melanoma. Understanding the genetic regulation of melanoblast development will help elucidate the etiology of these and other neurocristopathies. Here we demonstrate that Magoh, a component of the exon junction complex, is required for normal melanoblast development. Magoh haploinsufficient mice are hypopigmented and exhibit robust genetic interactions with the transcription factor, Sox10. These phenotypes are caused by a marked reduction in melanoblast number beginning at mid-embryogenesis. Strikingly, while Magoh haploinsufficiency severely reduces epidermal melanoblasts, it does not significantly affect the number of dermal melanoblasts. These data indicate Magoh impacts melanoblast development by disproportionately affecting expansion of epidermal melanoblast populations. We probed the cellular basis for melanoblast reduction and discovered that Magoh mutant melanoblasts do not undergo increased apoptosis, but instead are arrested in mitosis. Mitotic arrest is evident in both Magoh haploinsufficient embryos and in Magoh siRNA treated melanoma cell lines. Together our findings indicate that Magoh-regulated proliferation of melanoblasts in the dermis may be critical for production of epidermally-bound melanoblasts. Our results point to a central role for Magoh in melanocyte development. (C) 2013 Elsevier Inc. All rights reserved. C1 [Silver, Debra L.; Leeds, Karen E.; Hwang, Hun-Way; Pavan, William J.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Silver, Debra L.; Miller, Emily E.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. RP Silver, DL (reprint author), Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. EM debra.silver@duke.edu; bpavan@nhgri.nih.gov OI Hwang, Hun-Way/0000-0003-0522-1577 FU National Institute for General Medical Sciences PRAT fellowship; Intramural Research program of NIH/NHGRI; National Institutes of Health [R00NS064197] FX The authors thank Laura Baxter for careful reading of the manuscript. The authors also thank Arturo Incao for mouse husbandry, S. Anderson for FACs analysis, and Aditi Senthilnathan for analysis of melanocyte phenotypes. This work was funded in part by a National Institute for General Medical Sciences PRAT fellowship (to D.L.S.) and by the Intramural Research program of NIH/NHGRI (to W.J.P.) and by a National Institutes of Health grant to DLS (R00NS064197). NR 33 TC 15 Z9 15 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAR 15 PY 2013 VL 375 IS 2 BP 172 EP 181 DI 10.1016/j.ydbio.2013.01.004 PG 10 WC Developmental Biology SC Developmental Biology GA 102JQ UT WOS:000315841300007 PM 23333945 ER PT J AU Yong, KJ Milenic, DE Baidoo, KE Brechbiel, MW AF Yong, Kwon Joong Milenic, Diane E. Baidoo, Kwamena E. Brechbiel, Martin W. TI Sensitization of Tumor to Pb-212 Radioimmunotherapy by Gemcitabine Involves Initial Abrogation of G2 Arrest and Blocked DNA Damage Repair by Interference With Rad51 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID DISSEMINATED PERITONEAL DISEASE; CELL-CYCLE; TARGETING HER2; CHECKPOINT; CHK1; RADIATION; APOPTOSIS; MECHANISM; KINASE AB Purpose: To elucidate the mechanism of the therapeutic efficacy of targeted a-particle radiation therapy using Pb-212-TCMC-trastuzumab together with gemcitabine for treatment of disseminated peritoneal cancers. Methods and Materials: Mice bearing human colon cancer LS-174T intraperitoneal xenografts were pretreated with gemcitabine, followed by Pb-212-TCMC-trastuzumab and compared with controls. Results: Treatment with Pb-212-TCMC-trastuzumab increased the apoptotic rate in the S-phase-arrested tumors induced by gemcitabine at earlier time points (6 to 24 hours). Pb-212-TCMC-trastuzumab after gemcitabine pretreatment abrogated G2/M arrest at the same time points, which may be associated with the inhibition of Chk1 phosphorylation and, in turn, cell cycle perturbation, resulting in apoptosis. Pb-212-TCMC-trastuzumab treatment after gemcitabine pretreatment caused depression of DNA synthesis, DNA double-strand breaks, accumulation of unrepaired DNA, and down-regulation of Rad51 protein, indicating that DNA damage repair was blocked. In addition, modification in the chromatin structure of p21 may be associated with transcriptionally repressed chromatin states, indicating that the open structure was delayed at earlier time points. Conclusion: These findings suggest that the cell-killing efficacy of Pb-212-TCMC-trastuzumab after gemcitabine pretreatment may be associated with abrogation of the G2/M checkpoint, inhibition of DNA damage repair, and chromatin remodeling. (C) 2013 Elsevier Inc. C1 [Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; 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,MSC 1002,Room B3B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 20 TC 8 Z9 9 U1 0 U2 11 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 MAR 15 PY 2013 VL 85 IS 4 BP 1119 EP 1126 DI 10.1016/j.ijrobp.2012.09.015 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 101YC UT WOS:000315809300051 PM 23200172 ER PT J AU Strbo, N Vaccari, M Pahwa, S Kolber, MA Doster, MN Fisher, E Gonzalez, L Stablein, D Franchini, G Podack, ER AF Strbo, Natasa Vaccari, Monica Pahwa, Savita Kolber, Michael A. Doster, Melvin N. Fisher, Eva Gonzalez, Louis Stablein, Donald Franchini, Genoveffa Podack, Eckhard R. TI Cutting Edge: Novel Vaccination Modality Provides Significant Protection against Mucosal Infection by Highly Pathogenic Simian Immunodeficiency Virus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SHOCK-PROTEIN GP96; RHESUS-MONKEYS; IMMUNE-RESPONSES; DENDRITIC CELLS; CHALLENGE; RECEPTOR; SIV; EFFICACY; VACCINES AB Vaccine-induced protection against infection by HIV or highly pathogenic and virulent SIV strains has been limited. In a proof-of-concept study, we show that a novel vaccine approach significantly protects rhesus macaques from mucosal infection by the highly pathogenic strain SIVmac251. We vaccinated three cohorts of 12 macaques each with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp(96)-Ig. Cohort 1 was vaccinated with cells secreting gp96(SIV)Ig carrying SIV peptides. In addition, Cohort 2 received recombinant envelope protein SIV-gp120. Cohort 3 was injected with cells secreting gp(96)-Ig (no SIV Ags) vaccines. Cohort 2 was protected from infection. After seven rectal challenges with highly pathogenic SIVmac251, the hazard ratio was 0.27, corresponding to a highly significant, 73% reduced risk for viral acquisition. The apparent success of the novel vaccine modality recommends further study. The Journal of Immunology, 2013, 190: 2495-2499. C1 [Strbo, Natasa; Pahwa, Savita; Fisher, Eva; Gonzalez, Louis; Podack, Eckhard R.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. [Strbo, Natasa; Pahwa, Savita; Kolber, Michael A.; Gonzalez, Louis; Podack, Eckhard R.] Univ Miami, Miller Sch Med, Ctr AIDS Res, Miami, FL 33136 USA. [Vaccari, Monica; Doster, Melvin N.; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20817 USA. [Kolber, Michael A.; Podack, Eckhard R.] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Stablein, Donald] EMMES Corp, Rockville, MD 20850 USA. RP Podack, ER (reprint author), Univ Miami, Miller Sch Med, 1600 NW 10th Ave,RMSB 3045, Miami, FL 33136 USA. EM epodack@miami.edu FU University of Miami; National Institutes of Health [NIAID R33 AI 073234]; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research; Alliance for Cancer Gene Therapy, Stamford, CT FX The work was supported by the National Institutes of Health (Grant NIAID R33 AI 073234 to E.R.P.), the Intramural Research Program of the National Institutes of Health (to G.F.), the National Cancer Institute, the Center for Cancer Research, and the Alliance for Cancer Gene Therapy, Stamford, CT (to E.R.P.). E.R.P. and the University of Miami have a financial interest in the commercial development of gp96-Ig-based vaccines. The other authors have no financial conflicts of interest. NR 22 TC 19 Z9 19 U1 1 U2 12 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2013 VL 190 IS 6 BP 2495 EP 2499 DI 10.4049/jimmunol.1202655 PG 5 WC Immunology SC Immunology GA 099XG UT WOS:000315657200006 PM 23401588 ER PT J AU Sun, XZ Wiedeman, A Agrawal, N Teal, TH Tanaka, L Hudkins, KL Alpers, CE Bolland, S Buechler, MB Hamerman, JA Ledbetter, JA Liggitt, D Elkon, KB AF Sun, Xizhang Wiedeman, Alice Agrawal, Nalini Teal, Thomas H. Tanaka, Lena Hudkins, Kelly L. Alpers, Charles E. Bolland, Silvia Buechler, Matthew B. Hamerman, Jessica A. Ledbetter, Jeffrey A. Liggitt, Denny Elkon, Keith B. TI Increased Ribonuclease Expression Reduces Inflammation and Prolongs Survival in TLR7 Transgenic Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; NECROSIS-FACTOR-ALPHA; T-CELLS; AUTOANTIBODY SPECIFICITY; IN-VIVO; B-CELLS; ANTIGEN; LIVER; RNA; AUTOIMMUNITY AB TLR7 activation is implicated in the pathogenesis of systemic lupus erythematosus. Mice that overexpress TLR7 develop a lupus-like disease with autoantibodies and glomerulonephritis and early death. To determine whether degradation of the TLR7 ligand RNA would alter the course of disease, we created RNase A transgenic (Tg) mice. We then crossed the RNase Tg to TLR7 Tg mice to create TLR7 3 RNase double Tg (DTg) mice. DTg mice had a significantly increased survival associated with reduced activation of T and B lymphocytes and reduced kidney deposition of IgG and C3. We observed massive hepatic inflammation and cell death in TLR7 Tg mice. In contrast, hepatic inflammation and necrosis were strikingly reduced in DTg mice. These findings indicate that high concentrations of serum RNase protect against immune activation and inflammation associated with TLR7 stimulation and that RNase may be a useful therapeutic strategy in the prevention or treatment of inflammation in systemic lupus erythematosus and, possibly, liver diseases. The Journal of Immunology, 2013, 190: 2536-2543. C1 [Sun, Xizhang; Agrawal, Nalini; Teal, Thomas H.; Tanaka, Lena; Ledbetter, Jeffrey A.; Elkon, Keith B.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Wiedeman, Alice; Buechler, Matthew B.; Hamerman, Jessica A.; Elkon, Keith B.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Hudkins, Kelly L.; Alpers, Charles E.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Buechler, Matthew B.; Hamerman, Jessica A.] Virginia Mason, Benaroya Res Inst, Program Immunol, Seattle, WA 98101 USA. [Liggitt, Denny] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. RP Elkon, KB (reprint author), Univ Washington, Div Rheumatol, 1959 Northeast Pacific St,Box 356428, Seattle, WA 98195 USA. EM elkon@u.washington.edu FU Alliance for Lupus Research FX This work was supported by a grant from the Alliance for Lupus Research (to K.B.E.). NR 38 TC 25 Z9 25 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 MAR 15 PY 2013 VL 190 IS 6 BP 2536 EP 2543 DI 10.4049/jimmunol.1202689 PG 8 WC Immunology SC Immunology GA 099XG UT WOS:000315657200011 PM 23382559 ER PT J AU Wejksza, K Lee-Chang, C Bodogai, M Bonzo, J Gonzalez, FJ Lehrmann, E Becker, K Biragyn, A AF Wejksza, Katarzyna Lee-Chang, Catalina Bodogai, Monica Bonzo, Jessica Gonzalez, Frank J. Lehrmann, Elin Becker, Kevin Biragyn, Arya TI Cancer-Produced Metabolites of 5-Lipoxygenase Induce Tumor-Evoked Regulatory B Cells via Peroxisome Proliferator-Activated Receptor alpha SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELLS; INFLAMMATORY DISEASES; ACID-METABOLISM; LEUKOTRIENE B-4; EXPRESSION; INHIBITORS; MICE; METASTASIS; RESPONSES; CYCLOOXYGENASE-2 AB Breast cancer cells facilitate distant metastasis through the induction of immunosuppressive regulatory B cells, designated tBregs. We report in this study that, to do this, breast cancer cells produce metabolites of the 5-lipoxygenase pathway such as leukotriene B-4 to activate the peroxisome proliferator-activated receptor alpha (PPAR alpha) in B cells. Inactivation of leukotriene B-4 signaling or genetic deficiency of PPAR alpha in B cells blocks the generation of tBregs and thereby abrogates lung metastasis in mice with established breast cancer. Thus, in addition to eliciting fatty acid oxidation and metabolic signals, PPAR alpha initiates programs required for differentiation of tBregs. We propose that PPAR alpha in B cells and/or tumor 5-lipoxygenase pathways represents new targets for pharmacological control of tBreg-mediated cancer escape. The Journal of Immunology, 2013, 190: 2575-2584. C1 [Wejksza, Katarzyna; Lee-Chang, Catalina; Bodogai, Monica; Biragyn, Arya] NIA, Immunoregulat Sect, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Bonzo, Jessica; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Lehrmann, Elin; Becker, Kevin] NIA, Res Resources Branch, Baltimore, MD 21224 USA. RP Biragyn, A (reprint author), NIA, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov RI Lee-Chang, Catalina/A-5580-2015; OI Lee-Chang, Catalina/0000-0002-7675-2124; Lehrmann, Elin/0000-0002-9869-9475 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 51 TC 17 Z9 17 U1 0 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2013 VL 190 IS 6 BP 2575 EP 2584 DI 10.4049/jimmunol.1201920 PG 10 WC Immunology SC Immunology GA 099XG UT WOS:000315657200015 PM 23408836 ER PT J AU Quinn, KM Da Costa, A Yamamoto, A Berry, D Lindsay, RWB Darrah, PA Wang, LS Cheng, C Kong, WP Gall, JGD Nicosia, A Folgori, A Colloca, S Cortese, R Gostick, E Price, DA Gomez, CE Esteban, M Wyatt, LS Moss, B Morgan, C Roederer, M Bailer, RT Nabel, GJ Koup, RA Seder, RA AF Quinn, Kylie M. Da Costa, Andreia Yamamoto, Ayako Berry, Dana Lindsay, Ross W. B. Darrah, Patricia A. Wang, Lingshu Cheng, Cheng Kong, Wing-Pui Gall, Jason G. D. Nicosia, Alfredo Folgori, Antonella Colloca, Stefano Cortese, Riccardo Gostick, Emma Price, David A. Gomez, Carmen E. Esteban, Mariano Wyatt, Linda S. Moss, Bernard Morgan, Cecilia Roederer, Mario Bailer, Robert T. Nabel, Gary J. Koup, Richard A. Seder, Robert A. TI Comparative Analysis of the Magnitude, Quality, Phenotype, and Protective Capacity of Simian Immunodeficiency Virus Gag-Specific CD8(+) T Cells following Human-, Simian-, and Chimpanzee-Derived Recombinant Adenoviral Vector Immunization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REPLICATION-DEFECTIVE ADENOVIRUS; CHRONIC VIRAL-INFECTION; LONG-TERM IMMUNITY; VACCINE VECTORS; RHESUS-MONKEYS; CELLULAR-IMMUNITY; DENDRITIC CELLS; IN-VIVO; RESPONSES; IMMUNOGENICITY AB Recombinant adenoviral vectors (rAds) are the most potent recombinant vaccines for eliciting CD8(+) T cell-mediated immunity in humans; however, prior exposure from natural adenoviral infection can decrease such responses. In this study we show low seroreactivity in humans against simian-(sAd11, sAd16) or chimpanzee-derived (chAd3, chAd63) compared with human-derived (rAd5, rAd28, rAd35) vectors across multiple geographic regions. We then compared the magnitude, quality, phenotype, and protective capacity of CD8(+) T cell responses in mice vaccinated with rAds encoding SIV Gag. Using a dose range (1 x 10(7)-10(9) particle units), we defined a hierarchy among rAd vectors based on the magnitude and protective capacity of CD8(+) T cell responses, from most to least, as: rAd5 and chAd3, rAd28 and sAd11, chAd63, sAd16, and rAd35. Selection of rAd vector or dose could modulate the proportion and/or frequency of IFN-gamma+TNF-alpha+IL-2(+) and KLRG1(+)CD127(-)CD8(+) T cells, but strikingly similar to 30-80% of memory CD8(+) T cells coexpressed CD127 and KLRG1. To further optimize CD8(+) T cell responses, we assessed rAds as part of prime-boost regimens. Mice primed with rAds and boosted with NYVAC generated Gag-specific responses that approached similar to 60% of total CD8(+) T cells at peak. Alternatively, priming with DNA or rAd28 and boosting with rAd5 or chAd3 induced robust and equivalent CD8(+) T cell responses compared with prime or boost alone. Collectively, these data provide the immunologic basis for using specific rAd vectors alone or as part of prime-boost regimens to induce CD8(+) T cells for rapid effector function or robust long-term memory, respectively. The Journal of Immunology, 2013, 190: 2720-2735. C1 [Quinn, Kylie M.; Da Costa, Andreia; Yamamoto, Ayako; Berry, Dana; Lindsay, Ross W. B.; Darrah, Patricia A.; Wang, Lingshu; Cheng, Cheng; Kong, Wing-Pui; Roederer, Mario; Bailer, Robert T.; Nabel, Gary J.; Koup, Richard A.; Seder, Robert A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gall, Jason G. D.] GenVec Inc, Gaithersburg, MD 20878 USA. [Nicosia, Alfredo; Folgori, Antonella; Colloca, Stefano; Cortese, Riccardo] Okairos Srl, I-00144 Rome, Italy. [Nicosia, Alfredo; Cortese, Riccardo] CEINGE, I-80145 Naples, Italy. [Nicosia, Alfredo] Univ Naples Federico II, Dept Biochem & Med Biotechnol, I-80131 Naples, Italy. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Gomez, Carmen E.; Esteban, Mariano] CSIC, Ctr Nacl Biotecnol, E-28049 Madrid, Spain. [Wyatt, Linda S.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Morgan, Cecilia] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. RP Seder, RA (reprint author), NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr MSC 3025,Bldg 40,Room 3512, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov RI Price, David/C-7876-2013; Gomez, Carmen/K-1940-2014 OI Price, David/0000-0001-9416-2737; Gomez, Carmen/0000-0002-5414-7935 FU Foundation for the National Institutes of Health; Collaboration for AIDS Vaccine Discovery Award rom the Bill and Melinda Gates Foundation [OPP1039775] FX This work was supported in part by a grant from the Foundation for the National Institutes of Health with support from Collaboration for AIDS Vaccine Discovery Award OPP1039775 from the Bill and Melinda Gates Foundation. NR 83 TC 39 Z9 39 U1 2 U2 14 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2013 VL 190 IS 6 BP 2720 EP 2735 DI 10.4049/jimmunol.1202861 PG 16 WC Immunology SC Immunology GA 099XG UT WOS:000315657200030 PM 23390298 ER PT J AU Crane, DD Griffin, AJ Wehrly, TD Bosio, CM AF Crane, Deborah D. Griffin, Amanda J. Wehrly, Tara D. Bosio, Catharine M. TI B1a Cells Enhance Susceptibility to Infection with Virulent Francisella tularensis via Modulation of NK/NKT Cell Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID VACCINE STRAIN INFECTION; B-CELLS; TYROSINE KINASE; XID DEFECT; INTRACELLULAR BACTERIUM; RESPIRATORY-INFECTION; MEDIATED IMMUNITY; HUMAN NEUTROPHILS; IL-10 PRODUCTION; MICE AB B1a cells are an important source of natural Abs, Abs directed against T-independent Ags, and are a primary source of IL-10. Bruton's tyrosine kinase (btk) is a cytoplasmic kinase that is essential for mediating signals from the BCR and is critical for development of B1a cells. Consequentially, animals lacking btk have few B1a cells, minimal Ab responses, and can preferentially generate Th1-type immune responses following infection. B1a cells have been shown to aid in protection against infection with attenuated Francisella tularensis, but their role in infection mediated by fully virulent F. tularensis is not known. Therefore, we used mice with defective btk (CBA/CaHN-Btk(XID)/J [XID mice]) to determine the contribution of B1a cells in defense against the virulent F. tularensis ssp. tularensis strain SchuS4. Surprisingly, XID mice displayed increased resistance to pulmonary infection with F. tularensis. Specifically, XID mice had enhanced clearance of bacteria from the lung and spleen and significantly greater survival of infection compared with wild-type controls. We revealed that resistance to infection in XID mice was associated with decreased numbers of IL-10-producing B1a cells and concomitant increased numbers of IL-12-producing macrophages and IFN-gamma-producing NK/NKT cells. Adoptive transfer of wild-type B1a cells into XID mice reversed the control of bacterial replication. Similarly, depletion of NK/NKT cells also increased bacterial burdens in XID mice. Together, our data suggest B cell-NK/NKT cell cross-talk is a critical pivot controlling survival of infection with virulent F. tularensis. The Journal of Immunology, 2013, 190: 2756-2766. C1 [Crane, Deborah D.; Griffin, Amanda J.; Wehrly, Tara D.; Bosio, Catharine M.] NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Bosio, CM (reprint author), NIAID, Immun Pulm Pathogens Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 63 TC 15 Z9 15 U1 0 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2013 VL 190 IS 6 BP 2756 EP 2766 DI 10.4049/jimmunol.1202697 PG 11 WC Immunology SC Immunology GA 099XG UT WOS:000315657200033 PM 23378429 ER PT J AU Canary, LA Vinton, CL Morcock, DR Pierce, JB Estes, JD Brenchley, JM Klatt, NR AF Canary, Lauren A. Vinton, Carol L. Morcock, David R. Pierce, Jordan B. Estes, Jacob D. Brenchley, Jason M. Klatt, Nichole R. TI Rate of AIDS Progression Is Associated with Gastrointestinal Dysfunction in Simian Immunodeficiency Virus-Infected Pigtail Macaques SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; IMMUNE ACTIVATION; HIV-INFECTION; SIV INFECTION; MICROBIAL TRANSLOCATION; COAGULATION BIOMARKERS; ANTIRETROVIRAL THERAPY; IL-17 PRODUCTION; SOOTY MANGABEYS; PLASMA-LEVELS AB During HIV/SIV infection, mucosal immune system dysfunction and systemic immune activation are associated with progression to AIDS; however, it is unclear to what extent pre-existing gastrointestinal damage relates to disease progression postinfection. Pigtail macaques (PTM) are an excellent model in which to assess mucosal dysfunction in relation to HIV/SIV pathogenesis, as the majority of these animals have high levels of gastrointestinal damage, immune activation, and microbial translocation prior to infection, and rapidly progress to AIDS upon SIV infection. In this study, we characterized the mucosal immune environment prior to and throughout SIV infection in 13 uninfected PTM and 9 SIV-infected PTM, of which 3 were slow progressors. This small subset of slow progressors had limited innate immune activation in mucosal tissues in the periphery, which was associated with a more intact colonic epithelial barrier. Furthermore, we found that preinfection levels of microbial translocation, as measured by LP-Sbinding protein, in PTM correlated with the rate of progression to AIDS. These data suggest that pre-existing levels of microbial translocation and gastrointestinal tract dysfunction may influence the rate of HIV disease progression. The Journal of Immunology, 2013, 190: 2959-2965. C1 [Canary, Lauren A.; Vinton, Carol L.; Pierce, Jordan B.; Brenchley, Jason M.; Klatt, Nichole R.] NIAID, Mol Microbiol Lab, Program Barrier Immun & Repair, NIH, Bethesda, MD 20892 USA. [Morcock, David R.; Estes, Jacob D.] Frederick Natl Lab Canc Res, Sci Applicat Int Corp Frederick, AIDS & Canc & Virus Program, Frederick, MD 21702 USA. [Klatt, Nichole R.] Univ Washington, Dept Pharmaceut, Washington Natl Primate Res Ctr, Seattle, WA 98121 USA. RP Brenchley, JM (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 301, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov; klattnr@uw.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part by Contract HHSN261200800001E from the National Cancer Institute, National Institutes of Health. NR 42 TC 22 Z9 22 U1 1 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2013 VL 190 IS 6 BP 2959 EP 2965 DI 10.4049/jimmunol.1202319 PG 7 WC Immunology SC Immunology GA 099XG UT WOS:000315657200053 PM 23401593 ER PT J AU Carr, GV Jenkins, KA Weinberger, DR Papaleo, F AF Carr, Gregory V. Jenkins, Kimberly A. Weinberger, Daniel R. Papaleo, Francesco TI Loss of dysbindin-1 in mice impairs reward-based operant learning by increasing impulsive and compulsive behavior SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Dysbindin; Impulsivity; Compulsivity; Timing; Schizophrenia; Operant learning ID SCHIZOPHRENIA SUSCEPTIBILITY GENE; PREFRONTAL CORTEX; WORKING-MEMORY; HIPPOCAMPAL-FORMATION; MESSENGER-RNA; 6P22.3 GENE; DOPAMINE; DTNBP1; BRAIN; OVEREXPRESSION AB The dystrobrevin-binding protein 1 (DTNBP1)gene, which encodes the dysbindin-1 protein, is a potential schizophrenia susceptibility gene. Polymorphisms in the DTNBP1 gene have been associated with altered cognitive abilities. In the present study, dysbindin-1 null mutant (dys-/-), heterozygous (dys+/-), and wild-type (dys+/+) mice, on a C57BL/6J genetic background, were tested in either a match to sample or nonmatch to sample visual discrimination task. This visual discrimination task was designed to measure rule learning and detect any changes in response timing over the course of testing. Dys-/- mice displayed significant learning deficits and required more trials to acquire this task. However, once criterion was reached, there were no differences between the genotypes on any behavioral measures. Dys-/- mice exhibited increased compulsive and impulsive behaviors compared to control littermates suggesting the inability to suppress incorrectly-timed responses underlies their increased time to acquisition. Indeed, group comparisons of behavior differences between the first and last day of testing showed that only dys-/- mice consistently decreased measures of perseverative, premature, timeout, and total responses. These findings illustrate how some aspects of altered cognitive performance in dys-/- mice might be related to increased impulsive and compulsive behaviors, analogous to cognitive deficits in some individuals with psychiatric disorders: Published by Elsevier B.V. C1 [Carr, Gregory V.; Jenkins, Kimberly A.; Weinberger, Daniel R.; Papaleo, Francesco] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Baltimore, MD USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Psychiat Neurol & Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. [Papaleo, Francesco] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. [Papaleo, Francesco] Univ Padua, Dipartimento Sci Farmaco, I-35131 Padua, Italy. RP Papaleo, F (reprint author), Ist Italiano Tecnol, Dept Neurosci & Brain Technol, Via Morego 30, I-16163 Genoa, Italy. EM francesco.papaleo@iit.it RI Carr, Gregory/M-8821-2016; OI Carr, Gregory/0000-0002-6091-6729; Papaleo, Francesco/0000-0002-6326-0657 FU National Institute of Mental Health Intramural Research Program; NIMH Julius Axelrod Memorial Fellowship Training Award; Marie Curie FP7 Reintegration Grant [268247] FX We thank Qingjun Tian and Jingshan Chen for technical assistance and Audrey Bebensee, Randy Xun, and Omoye Akhile for critical review of the manuscript. This research was supported by the National Institute of Mental Health Intramural Research Program, by the NIMH Julius Axelrod Memorial Fellowship Training Award, and by the Marie Curie FP7 Reintegration Grant No. 268247. The authors declare that they have no financial conflicts of interest. NR 51 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 15 PY 2013 VL 241 BP 173 EP 184 DI 10.1016/j.bbr.2012.12.021 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 095BE UT WOS:000315308700023 PM 23261874 ER PT J AU Smith, RM Papp, AC Webb, A Ruble, CL Munsie, LM Nisenbaum, LK Kleinman, JE Lipska, BK Sadee, W AF Smith, Ryan M. Papp, Audrey C. Webb, Amy Ruble, Cara L. Munsie, Leanne M. Nisenbaum, Laura K. Kleinman, Joel E. Lipska, Barbara K. Sadee, Wolfgang TI Multiple Regulatory Variants Modulate Expression of 5-Hydroxytryptamine 2A Receptors in Human Cortex SO BIOLOGICAL PSYCHIATRY LA English DT Article DE 5-HT2A; depression; HTR2A; mRNA expression; schizophrenia; serotonin ID MESSENGER-RNA EXPRESSION; 5-HT2A RECEPTOR; T102C POLYMORPHISM; GENETIC-VARIATION; DIFFERENTIAL EXPRESSION; SEROTONIN TRANSPORTER; SUICIDAL-BEHAVIOR; PROMOTER ACTIVITY; HUMAN BRAIN; HTR2A GENE AB Background: The 5-hydroxytryptamine 2A receptor, encoded by HTR2A, is a major postsynaptic target for serotonin in the human brain and a therapeutic drug target. Despite hundreds of genetic associations investigating HTR2A polymorphisms in neuropsychiatric disorders and therapies, the role of genetic HTR2A variability in health and disease remains uncertain. Methods: To discover and characterize regulatory HTR2A variants, we sequenced whole transcriptomes from 10 human brain regions with massively parallel RNA sequencing and measured allelic expression of multiple HTR2A messenger (m) RNA transcript variants. Following discovery of functional variants, we further characterized their impact on genetic expression in vitro. Results: Three polymorphisms modulate the use of novel alternative exons and untranslated regions (UTRs), changing expression of RNA and protein. The frequent promoter variant rs6311, widely implicated in human neuropsychiatric disorders, decreases usage of an upstream transcription start site encoding a longer 5'UTR with greater translation efficiency. rs76665058, located in an extended 3'UTR and unique to individuals of African descent, modulates allelic HTR2A mRNA expression. The third single nucleotide polymorphism, unannotated and present in only a single subject, directs alternative splicing of exon 2. Targeted analysis of HTR2A in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study reveals associations between functional variants and depression severity or citalopram response. Conclusions: Regulatory polymorphisms modulate HTR2A mRNA expression in an isoform-specific manner, directing the usage of novel untranslated regions and alternative exons. These results provide a foundation for delineating the role of HTR2A and serotonin signaling in central nervous system disorders. C1 [Smith, Ryan M.; Papp, Audrey C.; Sadee, Wolfgang] Ohio State Univ, Coll Med, Dept Pharmacol, Program Pharmacogen, Columbus, OH 43210 USA. [Webb, Amy] Ohio State Univ, Dept Biomed Informat, Columbus, OH 43210 USA. [Ruble, Cara L.; Munsie, Leanne M.; Nisenbaum, Laura K.] Eli Lilly & Co, Lilly Corp Ctr, Translat Med & Tailored Therapeut, Indianapolis, IN 46285 USA. [Kleinman, Joel E.; Lipska, Barbara K.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Sadee, Wolfgang] Ohio State Univ, Dept Pharm, Columbus, OH 43210 USA. [Sadee, Wolfgang] Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. [Sadee, Wolfgang] Ohio State Univ, Dept Human Genet Internal Med, Columbus, OH 43210 USA. [Sadee, Wolfgang] Ohio State Univ, Dept Environm Hlth Sci, Columbus, OH 43210 USA. RP Smith, RM (reprint author), 5168 Graves Hall,333 W 10th Ave, Columbus, OH 43210 USA. EM Ryan.Smith2@osumc.edu RI Smith, Ryan/H-6898-2012; Lipska, Barbara/E-4569-2017 FU National Institute of General Medical Sciences [U01GM092655]; National Center for Research Resources [UL1RR025755]; Eli Lilly Collaborative Research Grant; U.S. Air Force Department of Defense [FA7014-09-2-0004]; National Institute of Mental Health [N01MH90003] FX This work was supported by the National Institute of General Medical Sciences (Grant No. U01GM092655 to WS), the National Center for Research Resources (Grant No. UL1RR025755 to Rebecca D. Jackson), an Eli Lilly Collaborative Research Grant (to WS), and the U.S. Air Force Department of Defense (Grant No. FA7014-09-2-0004 to Gail E. Herman).; Data and biomaterials for the clinical analysis were obtained from the limited access data sets distributed from the National Institutes of Health-supported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. STAR*D focused on nonpsychotic major depressive disorder in adults seen in outpatient settings. The primary purpose of this research study was to determine which treatments work best if the first treatment with medication does not produce an acceptable response. The study was supported by National Institute of Mental Health Contract Grant No. N01MH90003 to the University of Texas Southwestern Medical Center. NR 53 TC 16 Z9 16 U1 1 U2 11 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 MAR 15 PY 2013 VL 73 IS 6 BP 546 EP 554 DI 10.1016/j.biopsych.2012.09.028 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 093JA UT WOS:000315186700010 PM 23158458 ER PT J AU Tabb, B Morcock, DR Trubey, CM Quinones, OA Hao, XP Smedley, J Macallister, R Piatak, M Harris, LD Paiardini, M Silvestri, G Brenchley, JM Alvord, WG Lifson, JD Estes, JD AF Tabb, Brian Morcock, David R. Trubey, Charles M. Quinones, Octavio A. Hao, Xing Pei Smedley, Jeremy Macallister, Rhonda Piatak, Michael, Jr. Harris, Levelle D. Paiardini, Mirko Silvestri, Guido Brenchley, Jason M. Alvord, W. Gregory Lifson, Jeffrey D. Estes, Jacob D. TI Reduced Inflammation and Lymphoid Tissue Immunopathology in Rhesus Macaques Receiving Anti-Tumor Necrosis Factor Treatment During Primary Simian Immunodeficiency Virus Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE SIV; rhesus macaque; Sooty mangabey; lymph node; inflammation; adalimumab; TNF; macrophage; fibrosis; collagen; TGFb ID AFRICAN-GREEN MONKEYS; NF-KAPPA-B; TNF-ALPHA; IMMUNE ACTIVATION; SIV INFECTION; TYPE-1 INFECTION; RHEUMATOID-ARTHRITIS; HIV-1 INFECTION; SOOTY MANGABEYS; NATURAL HOSTS AB Background. Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections induce robust, generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation, fibrotic damage of lymphoid tissues, and CD4(+) T-cell loss, pathogenic processes that contribute to disease progression. Methods. To better understand the contribution of tumor necrosis factor (TNF), a key regulator of acute inflammation, to lentiviral pathogenesis, rhesus macaques newly infected with SIVmac239 were treated for 12 weeks in a pilot study with adalimumab (Humira), a human anti-TNF monoclonal antibody. Results. Adalimumab did not affect plasma SIV RNA levels or measures of T-cell immune activation (CD38 or Ki67) in peripheral blood or lymph node T cells. However, compared with untreated rhesus macaques, adalimumab-treated rhesus macaques showed attenuated expression of proinflammatory genes, decreased infiltration of polymorphonuclear cells into the T-cell zone of lymphoid tissues, and weaker antiinflammatory regulatory responses to SIV infection (ie, fewer presumed alternatively activated [ ie, CD163(+)] macrophages, interleukin 10-producing cells, and transforming growth factor beta-producing cells), along with reduced lymphoid tissue fibrosis and better preservation of CD4+ T cells. Conclusions. While HIV/SIV replication drives pathogenesis, these data emphasize the contribution of the inflammatory response to lentiviral infection to overall pathogenesis, and they suggest that early modulation of the inflammatory response may help attenuate disease progression. C1 [Tabb, Brian; Morcock, David R.; Trubey, Charles M.; Piatak, Michael, Jr.; Lifson, Jeffrey D.; Estes, Jacob D.] SAIC Frederick, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Hao, Xing Pei] SAIC Frederick, Frederick Natl Lab Canc Res, Data Management Serv, Frederick, MD USA. [Smedley, Jeremy; Macallister, Rhonda] SAIC Frederick, Frederick Natl Lab Canc Res, Frederick, MD USA. [Quinones, Octavio A.; Alvord, W. Gregory] SAIC Frederick, Frederick Natl Lab Canc Res, Lab Anim Sci Program, Frederick, MD USA. [Harris, Levelle D.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. [Paiardini, Mirko; Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. RP Estes, JD (reprint author), Frederick Natl Lab SAIC Frederick, Retroviral Immunopathol Sect ACVP, Ft Detrick Campus,Bldg 535,Rm 411, Frederick, MD 21702 USA. EM estesj@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). NR 50 TC 26 Z9 30 U1 0 U2 7 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 MAR 15 PY 2013 VL 207 IS 6 BP 880 EP 892 DI 10.1093/infdis/jis643 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 092XO UT WOS:000315156500003 PM 23087435 ER PT J AU Durbin, AP Kirkpatrick, BD Pierce, KK Elwood, D Larsson, CJ Lindow, JC Tibery, C Sabundayo, BP Shaffer, D Talaat, KR Hynes, NA Wanionek, K Carmolli, MP Luke, CJ Murphy, BR Subbarao, K Whitehead, SS AF Durbin, Anna P. Kirkpatrick, Beth D. Pierce, Kristen K. Elwood, Daniel Larsson, Catherine J. Lindow, Janet C. Tibery, Cecilia Sabundayo, Beulah P. Shaffer, Donna Talaat, Kawsar R. Hynes, Noreen A. Wanionek, Kimberli Carmolli, Marya P. Luke, Catherine J. Murphy, Brian R. Subbarao, Kanta Whitehead, Stephen S. TI A Single Dose of Any of Four Different Live Attenuated Tetravalent Dengue Vaccines Is Safe and Immunogenic in Flavivirus-naive Adults: A Randomized, Double-blind Clinical Trial SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE dengue vaccine; live attenuated tetravalent; clinical trial ID PHASE-I TRIAL; HEMORRHAGIC-FEVER; ANTIBODY-RESPONSES; SHOCK SYNDROME; CANDIDATE; INFECTION; SEROTYPES; CHILDREN; FORMULATIONS; ADOLESCENTS AB Background. Dengue virus (DENV) causes hundreds of millions of infections annually. Four dengue sero-types exist, and previous infection with one serotype increases the likelihood of severe disease with a second, heterotypic DENV infection. Methods. In a randomized, placebo-controlled study, the safety and immunogenicity of 4 different admixtures of a live attenuated tetravalent (LATV) dengue vaccine were evaluated in 113 flavivirus-naive adults. Serum neutralizing antibody levels to all 4 dengue viruses were measured on days 0, 28, 42, and 180. Results. A single dose of each LATV admixture induced a trivalent or better neutralizing antibody response in 75%-90% of vaccinees. There was no significant difference in the incidence of adverse events between vaccinees and placebo-recipients other than rash. A trivalent or better response correlated with rash and with non-black race (P < .0001). Black race was significantly associated with a reduced incidence of vaccine viremia. Conclusions. TV003 induced a trivalent or greater antibody response in 90% of flavivirus-naive vaccinees and is a promising candidate for the prevention of dengue. Race was identified as a factor influencing the infectivity of the LATV viruses, reflecting observations of the effect of race on disease severity in natural dengue infection. C1 [Durbin, Anna P.; Elwood, Daniel; Tibery, Cecilia; Sabundayo, Beulah P.; Shaffer, Donna; Talaat, Kawsar R.; Hynes, Noreen A.; Wanionek, Kimberli] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kirkpatrick, Beth D.; Pierce, Kristen K.; Larsson, Catherine J.; Lindow, Janet C.; Carmolli, Marya P.] Univ Vermont, Coll Med, Burlington, VT 05405 USA. [Luke, Catherine J.; Murphy, Brian R.; Subbarao, Kanta; Whitehead, Stephen S.] NIAID, NIH, Bethesda, MD 20892 USA. [Hynes, Noreen A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Durbin, AP (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, 624 N Broadway,Rm 217, Baltimore, MD 21205 USA. EM adurbin@jhsph.edu OI Lindow, Janet/0000-0003-3235-3698 FU National Institute of Allergy and Infectious Diseases (NIAID) Intramural Research Program, National Institutes of Health [HHSN272200900010C] FX This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) Intramural Research Program, National Institutes of Health (contract HHSN272200900010C). NR 40 TC 55 Z9 58 U1 0 U2 17 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 MAR 15 PY 2013 VL 207 IS 6 BP 957 EP 965 DI 10.1093/infdis/jis936 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 092XO UT WOS:000315156500012 PM 23329850 ER PT J AU Amornphimoltham, P Rechache, K Thompson, J Masedunskas, A Leelahavanichkul, K Patel, V Molinolo, A Gutkind, JS Weigert, R AF Amornphimoltham, Panomwat Rechache, Kamil Thompson, Jamie Masedunskas, Andrius Leelahavanichkul, Kantima Patel, Vyomesh Molinolo, Alfredo Gutkind, J. Silvio Weigert, Roberto TI Rab25 Regulates Invasion and Metastasis in Head and Neck Cancer SO CLINICAL CANCER RESEARCH LA English DT Article AB Purpose: Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common cancers with a 50% five-year survival rate, which has remained unchanged for the past three decades. One of the major reasons for the aggressiveness of this cancer is that HNSCCs readily metastasize to cervical lymph nodes that are abundant in the head and neck region. Hence, discovering new molecules controlling the metastatic process as well as understanding their regulation at the molecular level are essential for effective therapeutic strategies. Experimental Design: Rab25 expression level was analyzed in HNSCC tissue microarray. We used a combination of intravital microscopy in live animals and immunofluorescence in an in vitro invasion assay to study the role of Rab25 in tumor cell migration and invasion. Results: In this study, we identified the small GTPase Rab25 as a key regulator of HNSCC metastasis. We observed that Rab25 is downregulated in HNSCC patients. Next, we determined that reexpression of Rab25 in a metastatic cell line is sufficient to block invasion in a three-dimensional collagen matrix and metastasis to cervical lymph nodes in a mouse model for oral cancer. Specifically, Rab25 affects the organization of F-actin at the cell surface, rather than cell proliferation, apoptosis, or tumor angiogenesis. Conclusion: These findings suggest that Rab25 plays an important role in tumor migration and metastasis, and that understanding its function may lead to the development of new strategies to prevent metastasis in oral cancer patients. (C) 2013 AACR. C1 [Amornphimoltham, Panomwat; Rechache, Kamil; Thompson, Jamie; Masedunskas, Andrius; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Intracellular Membrane Trafficking Unit, Bethesda, MD 20892 USA. [Leelahavanichkul, Kantima; Patel, Vyomesh; Molinolo, Alfredo; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Mol Carcinogenesis Unit, Bethesda, MD 20892 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 30 Convent Dr, Bethesda, MD 20892 USA. EM weigertr@mail.nih.gov OI Masedunskas, Andrius/0000-0002-4533-5467 FU Intramural Research Program of National Institute of Dental and Craniofacial Research, NIH FX This research was supported by the Intramural Research Program of National Institute of Dental and Craniofacial Research, NIH. NR 50 TC 22 Z9 23 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 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2013 VL 19 IS 6 BP 1375 EP 1388 DI 10.1158/1078-0432.CCR-12-2858 PG 14 WC Oncology SC Oncology GA V38FY UT WOS:000209330500001 PM 23340300 ER PT J AU Ryan, PB Madigan, D Stang, PE Overhage, JM Racoosin, JA Hartzema, AG AF Ryan, Patrick B. Madigan, David Stang, Paul E. Overhage, J. Marc Racoosin, Judith A. Hartzema, Abraham G. TI Response to Comment on 'Empirical assessment of methods for risk identification in healthcare data' SO STATISTICS IN MEDICINE LA English DT Article C1 [Ryan, Patrick B.; Stang, Paul E.] Janssen Res & Dev, Titusville, NJ 08560 USA. [Ryan, Patrick B.; Madigan, David; Stang, Paul E.; Overhage, J. Marc; Racoosin, Judith A.; Hartzema, Abraham G.] NIH, Observat Med Outcomes Partnership Fdn, Bethesda, MD 20892 USA. [Ryan, Patrick B.] Univ N Carolina, UNC Eshelman Sch Pharm, Chapel Hill, NC USA. [Madigan, David] Columbia Univ, Dept Stat, New York, NY USA. [Overhage, J. Marc] Regenstrief Inst Hlth Care, Indianapolis, IN USA. [Overhage, J. Marc] Indiana Univ Sch Med, Indianapolis, IN USA. [Racoosin, Judith A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Hartzema, Abraham G.] Univ Florida, Coll Pharm, Gainesville, FL USA. RP Ryan, PB (reprint author), Janssen Res & Dev, 1125 Trenton Harbourton Rd,POB 200,MS K304, Titusville, NJ 08560 USA. EM ryan@omop.org NR 3 TC 0 Z9 0 U1 0 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 MAR 15 PY 2013 VL 32 IS 6 BP 1075 EP 1077 DI 10.1002/sim.5725 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 092BT UT WOS:000315094500015 PM 23413215 ER PT J AU Mirabello, L Schiffman, M Ghosh, A Rodriguez, AC Vasiljevic, N Wentzensen, N Herrero, R Hildesheim, A Wacholder, S Scibior-Bentkowska, D Burk, RD Lorincz, AT AF Mirabello, Lisa Schiffman, Mark Ghosh, Arpita Rodriguez, Ana C. Vasiljevic, Natasa Wentzensen, Nicolas Herrero, Rolando Hildesheim, Allan Wacholder, Sholom Scibior-Bentkowska, Dorota Burk, Robert D. Lorincz, Attila T. TI Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HPV16; methylation; epidemiology; receiver operating curve; biomarker ID PAPILLOMAVIRUS TYPE-16 DNA; ATYPICAL SQUAMOUS-CELLS; 16 E6 GENE; UNDETERMINED SIGNIFICANCE; NATURAL-HISTORY; CPG METHYLATION; YOUNG-WOMEN; CANCER; INFECTION; CYTOLOGY AB We explored the association of human papillomavirus type 16 (HPV16) DNA methylation with age, viral load, viral persistence and risk of incident and prevalent high grade CIN (CIN2+) in serially collected specimens from the Guanacaste, Costa Rica cohort. 273 exfoliated cervical cell specimens (diagnostic and pre-diagnostic) were selected: (1) 92 with HPV16 DNA clearance (controls), (2) 72 with HPV16 DNA persistence (without CIN2+) and (3) 109 with CIN2+. DNA was extracted, bisulfite converted and methylation was quantified using pyrosequencing assays at 66 CpGs across the HPV genome. The Kruskal-Wallis test was used to determine significant differences among groups, and receiver operating characteristic curve analyses were used to evaluate how well methylation identified women with CIN2+. In diagnostic specimens, 88% of CpG sites had significantly higher methylation levels in CIN2+ after correction for multiple tests compared with controls. The highest area under the ROC curve (AUC) was 0.82 for CpG site 6457 in L1, and a diagnostic sensitivity of 91% corresponded to a specificity of 60% for CIN2+. Prospectively, 17% of CpG sites had significantly higher methylation in pre-diagnostic CIN2+ specimens (median time of 3 years before diagnosis) versus controls. The strongest pre-diagnostic CpG site was 6367 in L1 with an AUC of 0.76. Age-stratified analyses suggested that women older than the median age of 28 years have an increased risk of precancer associated with high methylation. Higher methylation in CIN2+ cases was not explained by higher viral load. We conclude that elevated levels of HPV16 DNA methylation may be useful to predict concurrently diagnosed as well as future CIN2+. C1 [Mirabello, Lisa] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Rodriguez, Ana C.; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Vasiljevic, Natasa; Scibior-Bentkowska, Dorota; Lorincz, Attila T.] Univ London, Ctr Canc Prevent, Wolfson Inst Prevent Med, London, England. [Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet Gynecol & Womens Hlth, Bronx, NY 10467 USA. RP Mirabello, L (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS-7101, Bethesda, MD 20892 USA. EM mirabellol@mail.nih.gov; a.lorincz@qmul.ac.uk RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Cancer Research UK [C569/A10404] FX Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics and Cancer Research UK; Grant number: C569/A10404 NR 28 TC 48 Z9 49 U1 3 U2 30 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 MAR 15 PY 2013 VL 132 IS 6 BP 1412 EP 1422 DI 10.1002/ijc.27750 PG 11 WC Oncology SC Oncology GA 078BG UT WOS:000314072500019 PM 22847263 ER PT J AU Rao, VK AF Rao, V. Koneti TI ITP: hematology's Cosette from Les Miserables SO BLOOD LA English DT Editorial Material ID IMMUNE THROMBOCYTOPENIA; MONOCLONAL-ANTIBODY; RITUXIMAB C1 NIH, Bethesda, MD 20892 USA. RP Rao, VK (reprint author), NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 11 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 14 PY 2013 VL 121 IS 11 BP 1928 EP 1930 DI 10.1182/blood-2013-01-477729 PG 5 WC Hematology SC Hematology GA 182PR UT WOS:000321756700004 PM 23493768 ER PT J AU Chen, J Pise-Masison, CA Shih, JH Morris, JC Janik, JE Conlon, KC Keating, A Waldmann, TA AF Chen, Jing Pise-Masison, Cynthia A. Shih, Joanna H. Morris, John C. Janik, John E. Conlon, Kevin C. Keating, Anne Waldmann, Thomas A. TI Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia SO BLOOD LA English DT Article ID MONOCLONAL-ANTIBODY; MURINE MODEL; PHASE-II; EFFECTIVE THERAPY; COMPLETE RESPONSE; INTERFERON-ALPHA; CANCER CELLS; LYMPHOMA; EXPRESSION; LEUKEMIA/LYMPHOMA AB Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2R alpha (sIL-2R alpha) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2R alpha levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. #NCT00061048. C1 [Chen, Jing; Morris, John C.; Janik, John E.; Conlon, Kevin C.; Waldmann, Thomas A.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Pise-Masison, Cynthia A.] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Keating, Anne] Astellas Pharma US Inc, Deerfield, IL USA. RP Waldmann, TA (reprint author), NIH, Bldg 10,Room 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 49 TC 24 Z9 25 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 14 PY 2013 VL 121 IS 11 BP 2029 EP 2037 DI 10.1182/blood-2012-05-427773 PG 9 WC Hematology SC Hematology GA 182PR UT WOS:000321756700020 PM 23321252 ER PT J AU Adams, MA Ding, D Sallis, JF Bowles, HR Ainsworth, BE Bergman, P Bull, FC Carr, H Craig, CL De Bourdeaudhuij, I Gomez, LF Hagstromer, M Klasson-Heggebo, L Inoue, S Lefevre, J Macfarlane, DJ Matsudo, S Matsudo, V McLean, G Murase, N Sjostrom, M Tomten, H Volbekiene, V Bauman, A AF Adams, Marc A. Ding, Ding Sallis, James F. Bowles, Heather R. Ainsworth, Barbara E. Bergman, Patrick Bull, Fiona C. Carr, Harriette Craig, Cora L. De Bourdeaudhuij, Ilse Fernando Gomez, Luis Hagstromer, Maria Klasson-Heggebo, Lena Inoue, Shigeru Lefevre, Johan Macfarlane, Duncan J. Matsudo, Sandra Matsudo, Victor McLean, Grant Murase, Norio Sjostrom, Michael Tomten, Heidi Volbekiene, Vida Bauman, Adrian TI Patterns of neighborhood environment attributes related to physical activity across 11 countries: a latent class analysis SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Built environment; International; Recreation; Surveillance; Exercise ID BUILT ENVIRONMENT; WALKABILITY SCALE; OBESITY; WALKING; RECREATION; ADULTS; DETERMINANTS; RELIABILITY; VALIDITY; TRANSIT AB Background: Neighborhood environment studies of physical activity (PA) have been mainly single-country focused. The International Prevalence Study (IPS) presented a rare opportunity to examine neighborhood features across countries. The purpose of this analysis was to: 1) detect international neighborhood typologies based on participants' response patterns to an environment survey and 2) to estimate associations between neighborhood environment patterns and PA. Methods: A Latent Class Analysis (LCA) was conducted on pooled IPS adults (N=11,541) aged 18 to 64 years old (mean=37.5 +/- 12.8 yrs; 55.6% women) from 11 countries including Belgium, Brazil, Canada, Colombia, Hong Kong, Japan, Lithuania, New Zealand, Norway, Sweden, and the U. S. This subset used the Physical Activity Neighborhood Environment Survey (PANES) that briefly assessed 7 attributes within 10-15 minutes walk of participants' residences, including residential density, access to shops/services, recreational facilities, public transit facilities, presence of sidewalks and bike paths, and personal safety. LCA derived meaningful subgroups from participants' response patterns to PANES items, and participants were assigned to neighborhood types. The validated short-form International Physical Activity Questionnaire (IPAQ) measured likelihood of meeting the 150 minutes/week PA guideline. To validate derived classes, meeting the guideline either by walking or total PA was regressed on neighborhood types using a weighted generalized linear regression model, adjusting for gender, age and country. Results: A 5-subgroup solution fitted the dataset and was interpretable. Neighborhood types were labeled, "Overall Activity Supportive (52% of sample)", "High Walkable and Unsafe with Few Recreation Facilities (16%)", "Safe with Active Transport Facilities (12%)", "Transit and Shops Dense with Few Amenities (15%)", and "Safe but Activity Unsupportive (5%)". Country representation differed by type (e. g., U. S. disproportionally represented "Safe but Activity Unsupportive"). Compared to the Safe but Activity Unsupportive, two types showed greater odds of meeting PA guideline for walking outcome (High Walkable and Unsafe with Few Recreation Facilities, OR=2.26 (95% CI 1.18-4.31); Overall Activity Supportive, OR=1.90 (95% CI 1.13-3.21). Significant but smaller odds ratios were also found for total PA. Conclusions: Meaningful neighborhood patterns generalized across countries and explained practical differences in PA. These observational results support WHO/UN recommendations for programs and policies targeted to improve features of the neighborhood environment for PA. C1 [Adams, Marc A.; Ainsworth, Barbara E.] Arizona State Univ, Sch Nutr & Hlth Promot, Phoenix, AZ USA. [Sallis, James F.] Univ Calif San Diego, San Diego, CA 92103 USA. [Bowles, Heather R.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, NIH, Bethesda, MD 20892 USA. [Hagstromer, Maria; Sjostrom, Michael] Karolinska Inst, Unit Prevent Nutr, Dept Biosci & Nutr, Stockholm, Sweden. [Bergman, Patrick] Linnaeus Univ, Sch Educ Psychol & Sports Sci, Kalmar, Sweden. [Bull, Fiona C.] Univ Western Australia, Sch Populat Hlth, Crawley, WA, Australia. [Craig, Cora L.] Canadian Fitness & Lifestyle Res Inst, Sch Publ Hlth, Ottawa, ON, Canada. [Klasson-Heggebo, Lena] Valnesfjord Rehabil Ctr, Valnesfjord, Norway. [Carr, Harriette; McLean, Grant] Sport New Zealand, Minist Hlth, Wellington, New Zealand. [De Bourdeaudhuij, Ilse] Univ Ghent, Dept Movement & Sport Sci, B-9000 Ghent, Belgium. [Fernando Gomez, Luis] Pontificia Univ Javeriana, Bogota, Colombia. [Inoue, Shigeru; Murase, Norio] Tokyo Med Univ, Dept Prevent Med & Publ Hlth, Tokyo 1608402, Japan. [Lefevre, Johan] Katholic Univ, Dept Kinesiol, Leuven, Belgium. [Macfarlane, Duncan J.] Univ Hong Kong, Inst Human Performance, Hong Kong, Hong Kong, Peoples R China. [Matsudo, Sandra; Matsudo, Victor] CELAFISCS, Ctr Studies, Phys Fitness Res Ctr Sao Caetano do Sul, Sao Paulo, Brazil. [Tomten, Heidi] Oppegard Municipal, Oppegard Cty, Norway. [Volbekiene, Vida] Lithuanian Acad Phys Educ, Dept Sport Sci, Kaunas, Lithuania. [Ding, Ding; Bauman, Adrian] Univ Sydney, Prevent Res Collaborat, Sydney, NSW 2006, Australia. RP Adams, MA (reprint author), Arizona State Univ, Sch Nutr & Hlth Promot, Phoenix, AZ USA. EM marc.adams@asu.edu RI Bull, Fiona/G-4148-2012; Bergman, Patrick/B-5906-2012; Adams, Marc/C-3513-2013; Matsudo, Sandra/E-7309-2013; Matsudo, Victor/E-8122-2013 OI Bergman, Patrick/0000-0003-4934-8684; Adams, Marc/0000-0001-6310-1472; Matsudo, Sandra/0000-0002-3705-9458; Hagstromer, Maria/0000-0002-4607-8677; Matsudo, Victor/0000-0003-3552-486X FU National Heart, Lung and Blood Institute [T32HL079891]; American Heart Association [12BGIA9280017] FX This manuscript was supported in part by grants from National Heart, Lung and Blood Institute (T32HL079891) and the American Heart Association (12BGIA9280017). NR 49 TC 19 Z9 19 U1 6 U2 73 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 MAR 14 PY 2013 VL 10 AR 34 DI 10.1186/1479-5868-10-34 PG 11 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 118OK UT WOS:000317034600001 PM 23497187 ER PT J AU Prustel, T Meier-Schellersheim, M AF Pruestel, Thorsten Meier-Schellersheim, Martin TI Theory of reversible diffusion-influenced reactions with non-Markovian dissociation in two space dimensions SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID PROTON-TRANSFER REACTIONS; GEMINATE RECOMBINATION; DYNAMICS AB We investigate the reversible diffusion-influenced reaction of an isolated pair in the presence of a non-Markovian generalization of the backreaction boundary condition in two space dimensions. Following earlier work by Agmon and Weiss, we consider residence time probability densities that decay slower than an exponential and that are characterized by a single parameter 0 < sigma <= 1. We calculate an exact expression for a Green's function of the two-dimensional diffusion equation subject to a non-Markovian backreaction boundary condition that is valid for arbitrary sigma and for all times. We use the obtained expression to derive the survival probability for the initially unbound pair and we calculate an exact expression for the probability S(t vertical bar*) that the initially bound particle is unbound. Finally, we obtain an approximate solution for long times. In particular, we show that the ultimate fate of the bound state is complete dissociation, as in the Markovian case. However, the limiting value is approached quite differently: Instead of a similar to t(-1) decay, we obtain 1 - S(t vertical bar*) similar to t(-sigma) ln t. The derived expressions should be relevant for a better understanding of reversible membrane-bound reactions in cell biology. [http://dx.doi.org/10.1063/1.4794311] C1 [Pruestel, Thorsten; Meier-Schellersheim, Martin] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. RP Prustel, T (reprint author), NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. EM prustelt@niaid.nih.gov; mms@niaid.nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. We would like to thank Bastian R. Angermann and Frederick Klauschen for helpful discussions. NR 24 TC 3 Z9 3 U1 0 U2 10 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 MAR 14 PY 2013 VL 138 IS 10 AR 104112 DI 10.1063/1.4794311 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 111TK UT WOS:000316543400013 PM 23514470 ER PT J AU Shah, MA Wainberg, ZA Catenacci, DVT Hochster, HS Ford, J Kunz, P Lee, FC Kallender, H Cecchi, F Rabe, DC Keer, H Martin, AM Liu, Y Gagnon, R Bonate, P Liu, L Gilmer, T Bottaro, DP AF Shah, Manish A. Wainberg, Zev A. Catenacci, Daniel V. T. Hochster, Howard S. Ford, James Kunz, Pamela Lee, Fa-Chyi Kallender, Howard Cecchi, Fabiola Rabe, Daniel C. Keer, Harold Martin, Anne-Marie Liu, Yuan Gagnon, Robert Bonate, Peter Liu, Li Gilmer, Tona Bottaro, Donald P. TI Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric Cancer SO PLOS ONE LA English DT Article ID VASCULAR ENDOTHELIAL GROWTH; C-MET; ACQUIRED-RESISTANCE; THERAPEUTIC TARGET; CLINICAL-FEATURES; PROGNOSTIC MARKER; AMPLIFICATION; CARCINOMA; GENE; ADENOCARCINOMA AB Purpose: The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. Patients and Methods: Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of >= 25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity. Results: From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25-88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9-7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET: total MET protein ratio decreased with foretinib treatment. Conclusion: These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer. C1 [Shah, Manish A.] New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. [Wainberg, Zev A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Catenacci, Daniel V. T.] Univ Chicago, Chicago, IL 60637 USA. [Hochster, Howard S.] Yale Univ, New Haven, CT USA. [Ford, James; Kunz, Pamela] Stanford Univ, Stanford, CA 94305 USA. [Lee, Fa-Chyi] Univ New Mexico, Albuquerque, NM 87131 USA. [Kallender, Howard; Martin, Anne-Marie; Liu, Yuan; Gagnon, Robert; Liu, Li] GlaxoSmithKline, Collegeville, PA USA. [Cecchi, Fabiola; Rabe, Daniel C.; Bottaro, Donald P.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Keer, Harold] Exelixis, San Francisco, CA USA. [Bonate, Peter; Gilmer, Tona] GlaxoSmithKline, Res Triangle Pk, NC USA. RP Shah, MA (reprint author), New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. EM mas9313@med.cornell.edu RI Bottaro, Donald/F-8550-2010; OI Bottaro, Donald/0000-0002-5057-5334; Cecchi, Franco/0000-0002-2035-5621 FU GlaxoSmithKline FX Funding for this study was provided by GlaxoSmithKline. The funders were intimately involved in study design, data collection, and analysis. They had no role in the decision to publish, but they were involved in manuscript preparation. NR 36 TC 76 Z9 81 U1 2 U2 10 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 MAR 14 PY 2013 VL 8 IS 3 AR e54014 DI 10.1371/journal.pone.0054014 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109YM UT WOS:000316407400003 PM 23516391 ER PT J AU Misteli, T AF Misteli, Tom TI The Cell Biology of Genomes: Bringing the Double Helix to Life SO CELL LA English DT Article ID STOCHASTIC GENE-EXPRESSION; ORGANIZATION; CHROMATIN AB The recent ability to routinely probe genome function at a global scale has revolutionized our view of genomes. One of the most important realizations from these approaches is that the functional output of genomes is affected by the nuclear environment in which they exist. Integration of sequence information with molecular and cellular features of the genome promises a fuller understanding of genome function. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research FX Due to space limitations, mostly review articles were cited. Work in the author's laboratory is supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. NR 13 TC 31 Z9 31 U1 2 U2 26 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 MAR 14 PY 2013 VL 152 IS 6 BP 1209 EP 1212 DI 10.1016/j.cell.2013.02.048 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 107CO UT WOS:000316192500002 PM 23498929 ER PT J AU Lenoir-Wijnkoop, I Jones, PJ Uauy, R Segal, L Milner, J AF Lenoir-Wijnkoop, I. Jones, P. J. Uauy, R. Segal, L. Milner, J. TI Nutrition economics - food as an ally of public health SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Nutrition economics; Health economics; Public health; Cost-effectiveness ID DAIRY CONSUMPTION; MYOCARDIAL-INFARCTION; CHILD UNDERNUTRITION; MEDITERRANEAN DIET; COLORECTAL-CANCER; MEAT CONSUMPTION; RISK; TRENDS; INTERVENTIONS; CONSEQUENCES AB Non-communicable diseases (NCD) are a major and increasing contributor to morbidity and mortality in developed and developing countries. Much of the chronic disease burden is preventable through modification of lifestyle behaviours, and increased attention is being focused on identifying and implementing effective preventative health strategies. Nutrition has been identified as a major modifiable determinant of NCD. The recent merging of health economics and nutritional sciences to form the nascent discipline of nutrition economics aims to assess the impact of diet on health and disease prevention, and to evaluate options for changing dietary choices, while incorporating an understanding of the immediate impacts and downstream consequences. In short, nutrition economics allows for generation of policy-relevant evidence, and as such the discipline is a crucial partner in achieving better population nutritional status and improvements in public health and wellness. The objective of the present paper is to summarise presentations made at a satellite symposium held during the 11th European Nutrition Conference, 28 October 2011, where the role of nutrition and its potential to reduce the public health burden through alleviating undernutrition and nutrition deficiencies, promoting better-quality diets and incorporating a role for functional foods were discussed. C1 [Lenoir-Wijnkoop, I.] Danone Res, Sci Affairs, RD 128, F-91767 Palaiseau, France. [Lenoir-Wijnkoop, I.] Univ Utrecht, Dept Pharmaceut Sci, Utrecht, Netherlands. [Jones, P. J.] Univ Manitoba, Richardson Ctr Funct Foods & Nutraceut, Winnipeg, MB, Canada. [Uauy, R.] Univ Chile, INTA, Inst Nutr, Santiago, Chile. [Segal, L.] Univ S Australia, Sansom Inst Hlth Res, Hlth Econ & Social Policy Grp, Adelaide, SA 5001, Australia. [Milner, J.] NCI, Nutr Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Lenoir-Wijnkoop, I (reprint author), Danone Res, Sci Affairs, RD 128, F-91767 Palaiseau, France. EM irene.lenoir@danone.com RI Segal, Leonie/B-2357-2009; OI Segal, Leonie/0000-0002-6391-6791; Jones, Peter/0000-0001-5887-2846 FU Danone Institute International; Danone Research FX The present paper summarises presentations made at a satellite symposium held at the 11th European Nutrition Conference, 28 October 2011, which was made possible by an unrestricted grant from Danone Institute International. Writing and editorial assistance were provided by Lisa Buttle, of Chill Pill Media. This was contracted and funded by Danone Research. The authors have declared that they have no conflicting interests. I. L.-W. is an employee of Danone Research. NR 39 TC 10 Z9 11 U1 6 U2 63 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD MAR 14 PY 2013 VL 109 IS 5 BP 777 EP 784 DI 10.1017/S0007114512005107 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 097EL UT WOS:000315456700001 PM 23339933 ER PT J AU Wang, PY Ma, WZ Park, JY Celi, FS Arena, R Choi, JW Ali, QA Tripodi, DJ Zhuang, J Lago, CU Strong, LC Talagala, SL Balaban, RS Kang, JG Hwang, PM AF Wang, Ping-yuan Ma, Wenzhe Park, Joon-Young Celi, Francesco S. Arena, Ross Choi, Jeong W. Ali, Qais A. Tripodi, Dotti J. Zhuang, Jie Lago, Cory U. Strong, Louise C. Talagala, S. Lalith Balaban, Robert S. Kang, Ju-Gyeong Hwang, Paul M. TI Increased Oxidative Metabolism in the Li-Fraumeni Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MITOCHONDRIAL METABOLISM; MUSCLE; CANCER; APOPTOSIS; EXERCISE AB There is growing evidence that alterations in metabolism may contribute to tumorigenesis. Here, we report on members of families with the Li-Fraumeni syndrome who carry germline mutations in TP53, the gene encoding the tumor-suppressor protein p53. As compared with family members who are not carriers and with healthy volunteers, family members with these mutations have increased oxidative phosphorylation of skeletal muscle. Basic experimental studies of tissue samples from patients with the Li-Fraumeni syndrome and a mouse model of the syndrome support this in vivo finding of increased mitochondrial function. These results suggest that p53 regulates bioenergetic homeostasis in humans. (Funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; ClinicalTrials.govnumber, NCT00406445.) C1 [Wang, Ping-yuan; Ma, Wenzhe; Choi, Jeong W.; Ali, Qais A.; Tripodi, Dotti J.; Zhuang, Jie; Lago, Cory U.; Balaban, Robert S.; Kang, Ju-Gyeong; Hwang, Paul M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Celi, Francesco S.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Talagala, S. Lalith] NINDS, NIH, Bethesda, MD 20892 USA. [Park, Joon-Young] Temple Univ, Philadelphia, PA 19122 USA. [Arena, Ross] Univ New Mexico, Albuquerque, NM 87131 USA. [Strong, Louise C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10CRC 5-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM hwangp@nhlbi.nih.gov RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 FU Division of Intramural Research, National Heart, Lung, and Blood Institute; National Institutes of Health Bench-to-Bedside Award; National Heart, Lung, and Blood Institute; National Institutes of Health FX Supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute and by a National Institutes of Health Bench-to-Bedside Award (to Drs. Hwang and Strong).; Funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health. NR 26 TC 34 Z9 34 U1 1 U2 14 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 MAR 14 PY 2013 VL 368 IS 11 BP 1027 EP 1032 DI 10.1056/NEJMoa1214091 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 104HF UT WOS:000315982100009 PM 23484829 ER PT J AU Das, SR Hensley, SE Ince, WL Brooke, CB Subba, A Delboy, MG Russ, G Gibbs, JS Bennink, JR Yewdell, JW AF Das, Suman R. Hensley, Scott E. Ince, William L. Brooke, Christopher B. Subba, Anju Delboy, Mark G. Russ, Gustav Gibbs, James S. Bennink, Jack R. Yewdell, Jonathan W. TI Defining Influenza A Virus Hemagglutinin Antigenic Drift by Sequential Monoclonal Antibody Selection SO CELL HOST & MICROBE LA English DT Article ID RECEPTOR SPECIFICITY; GLYCOPROTEIN; EVOLUTION; REPERTOIRE; DYNAMICS; MUTANTS; DISEASE; MICE AB Human influenza A virus (IAV) vaccination is limited by "antigenic drift," rapid antibody-driven escape reflecting amino acid substitutions in the globular domain of hemagglutinin (HA), the viral attachment protein. To better understand drift, we used anti-hemagglutinin monoclonal Abs (mAbs) to sequentially select IAV escape mutants. Twelve selection steps, each resulting in a single amino acid substitution in the hemagglutinin globular domain, were required to eliminate antigenicity defined by monoclonal or polyclonal Abs. Sequential mutants grow robustly, showing the structural plasticity of HA, although several hemagglutinin substitutions required an epistatic substitution in the neuraminidase glycoprotein to maximize growth. Selecting escape mutants from parental versus sequential variants with the same mAb revealed distinct escape repertoires, attributed to contextual changes in antigenicity and the mutation landscape. Since each hemagglutinin mutation potentially sculpts future mutation space, drift can follow many stochastic paths, undermining its unpredictability and underscoring the need for drift-insensitive vaccines. C1 [Das, Suman R.; Hensley, Scott E.; Ince, William L.; Brooke, Christopher B.; Gibbs, James S.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Das, Suman R.; Subba, Anju; Delboy, Mark G.] J Craig Venter Inst, Infect Dis Grp, Rockville, MD 20850 USA. [Das, Suman R.] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Russ, Gustav] Slovak Acad Sci, Inst Virol, Bratislava 84505, Slovakia. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU NIAID; Department of Health and Human Services [HHSN272200900007C]; NIH; JCVI internal start-up fund; Division of Intramural Research, NIAID FX We thank Glennys Reynoso for providing outstanding technical assistance. We thank Dr. Walter Gerhard for his generous gift of the large panel of mAbs and viruses. We thank Dr. Adolfo Garcia-Sastre and Dr. David Wentworth for kindly providing eight-plasmid reverse-genetics plasmid to rescue WT and mutant viruses. We thank Dr. Zhiping Ye for providing ferret anti-sera to PR8 virus. The sequencing of the whole genome of the SEQ-variants was done at JCVI, which is one of the Genomic Sequencing Center of Infectious Diseases (GSCID) and has been funded with federal funds from the NIAID, NIH, and Department of Health and Human Services under contract number HHSN272200900007C. S. R. D. is supported by JCVI internal start-up fund. J. W. Y. and J. R. B. are generously supported by the Division of Intramural Research, NIAID. S. R. D., S. E. H., W. L. I., G. R., J. R. B., and J. W. Y. conceived of and designed experiments. S. R. D., S. E. H., W. L. I., C. B. B., A. S., M. G. D., G. R., and J. S. G. performed experiments. S. R. D., S. E. H., W. L. I., C. B. B., A. S., M. G. D., G. R., J. R. B., and J. W. Y. analyzed data. S. R. D. and J. W. Y. wrote the manuscript. NR 37 TC 25 Z9 26 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAR 13 PY 2013 VL 13 IS 3 BP 314 EP 323 DI 10.1016/j.chom.2013.02.008 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AA1IS UT WOS:000330850400012 PM 23498956 ER PT J AU Lewis, NS Javakhishvili, Z Russell, CA Machablishvili, A Lexmond, P Verhagen, JH Vuong, O Onashvili, T Donduashvili, M Smith, DJ Fouchier, RAM AF Lewis, Nicola S. Javakhishvili, Zurab Russell, Colin A. Machablishvili, Ann Lexmond, Pascal Verhagen, Josanne H. Oanh Vuong Onashvili, Tinatin Donduashvili, Marina Smith, Derek J. Fouchier, Ron A. M. TI Avian Influenza Virus Surveillance in Wild Birds in Georgia: 2009-2011 SO PLOS ONE LA English DT Article ID BLACK-HEADED GULLS; A VIRUS; HEMAGGLUTININ AB The Caucasus, at the border of Europe and Asia, is important for migration and over-wintering of wild waterbirds. Three flyways, the Central Asian, East Africa-West Asia, and Mediterranean/Black Sea flyways, converge in the Caucasus region. Thus, the Caucasus region might act as a migratory bridge for influenza virus transmission when birds aggregate in high concentrations in the post-breeding, migrating and overwintering periods. Since August 2009, we have established a surveillance network for influenza viruses in wild birds, using five sample areas geographically spread throughout suitable habitats in both eastern and western Georgia. We took paired tracheal and cloacal swabs and fresh feces samples. We collected 8343 swabs from 76 species belonging to 17 families in 11 orders of birds, of which 84 were real-time RT-PCR positive for avian influenza virus (AIV). No highly pathogenic AIV (HPAIV) H5 or H7 viruses were detected. The overall AIV prevalence was 1.6%. We observed peak prevalence in large gulls during the autumn migration (5.3-9.8%), but peak prevalence in Black-headed Gulls in spring (4.2-13%). In ducks, we observed increased AIV prevalence during the autumn post-moult aggregations and migration stop-over period (6.3%) but at lower levels to those observed in other more northerly post-moult areas in Eurasia. We observed another prevalence peak in the overwintering period (0.14-5.9%). Serological and virological monitoring of a breeding colony of Armenian Gulls showed that adult birds were seropositive on arrival at the breeding colony, but juveniles remained serologically and virologically negative for AIV throughout their time on the breeding grounds, in contrast to gull AIV data from other geographic regions. We show that close phylogenetic relatives of viruses isolated in Georgia are sourced from a wide geographic area throughout Western and Central Eurasia, and from areas that are represented by multiple different flyways, likely linking different host sub-populations. C1 [Lewis, Nicola S.; Russell, Colin A.; Smith, Derek J.] Univ Cambridge, Dept Zool, Cambridge, England. [Lexmond, Pascal; Verhagen, Josanne H.; Oanh Vuong; Smith, Derek J.; Fouchier, Ron A. M.] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Lexmond, Pascal; Verhagen, Josanne H.; Oanh Vuong; Smith, Derek J.; Fouchier, Ron A. M.] Erasmus MC, Natl Influenza Ctr, Rotterdam, Netherlands. [Russell, Colin A.; Smith, Derek J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Javakhishvili, Zurab] Ilia State Univ, Inst Ecol, Tbilisi, Rep of Georgia. [Machablishvili, Ann] Ivane Javakhishvili Tbilisi State Univ, Tbilisi, Rep of Georgia. [Machablishvili, Ann] Natl Ctr Dis Control, Influenza Sect, Tbilisi, Rep of Georgia. [Onashvili, Tinatin; Donduashvili, Marina] Lab Minist Agr, Tbilisi, Rep of Georgia. RP Lewis, NS (reprint author), Univ Cambridge, Dept Zool, Cambridge, England. EM nsl25@cam.ac.uk RI Fouchier, Ron/A-1911-2014; OI Fouchier, Ron/0000-0001-8095-2869; Russell, Colin/0000-0002-2113-162X; Tripp, Ralph/0000-0002-2924-9956 FU Wellcome Trust Fellowship [WT089235MF]; NIAID-NIH "NIAID Centres of Excellence for Influenza Research and Surveillance'' [HHSN266200700010C] FX This work was supported by a Wellcome Trust Fellowship WT089235MF http://www.wellcome.ac.uk/index.htm and by NIAID-NIH contract No. HHSN266200700010C "NIAID Centres of Excellence for Influenza Research and Surveillance'' http://www.niaid.nih.gov/LabsAndResources/resources/ceirs/Pages/crip.asp x. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 16 Z9 16 U1 1 U2 38 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 MAR 13 PY 2013 VL 8 IS 3 AR e58534 DI 10.1371/journal.pone.0058534 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 115YY UT WOS:000316849200081 PM 23516501 ER PT J AU Mahnke, YD Song, KM Sauer, MM Nason, MC Giret, MTM Carvalho, KI Costa, PR Roederer, M Kallas, EG AF Mahnke, Yolanda D. Song, Kaimei Sauer, Mariana M. Nason, Martha C. Giret, Maria Teresa M. Carvalho, Karina I. Costa, Priscilla R. Roederer, Mario Kallas, Esper G. TI Early immunologic and virologic predictors of clinical HIV-1 disease progression SO AIDS LA English DT Article DE CD38; cell-associated viral load; immunophenotyping; prognosis; progression; T-cell activation ID CD8(+) T-CELLS; VIRAL LOAD; TYPE-1 INFECTION; FOLLOW-UP; SET-POINT; CD4(+); RESPONSES; ACTIVATION; SURVIVAL; VIREMIA AB Objective: To identify early determinants of HIV-1 disease progression, which could potentially enable individualized patient treatment, and provide correlates of progression applicable as reference phenotypes to evaluate breakthrough infections in vaccine development. Design: High-throughput technologies were employed to interrogate multiple parameters on cryopreserved, retrospective peripheral blood mononuclear cell (PBMC) samples from 51 individuals from Sao Paulo, Brazil, obtained within 1 year of diagnosing early Clade B HIV-1 infection. Fast Progressors, Slow Progressors, and Controllers were identified based on a 2-year clinical follow-up. Methods: Phenotypic and functional T-cell parameters were tested by flow cytometry and qPCR to identify potential early determinants of subsequent HIV-1 disease progression. Results: Major differences were observed between Controllers and Progressors, especially in cell-associated viral load (CAVL), the differentiation pattern and CD38 expression of CD8(+) T cells, and the cytokine pattern and activation phenotype of HIV-1-specific CD8(+) T cells. Despite remarkably few other differences between the two Progressor groups, the CAVL had predictive power independent of plasma viral load. Conclusion: Analysis of three parameters (% CD38(+)CD8(+) T cells, total CAVL,% CCR5(+) CD8(+) T cells) was sufficient to predict subsequent disease progression (P < 0.001). Use of such prognostic correlates may be crucial when early CD4(+) T-cell counts and plasma viral load levels fail to discriminate among groups with differing subsequent clinical progression. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins AIDS 2013, 27:697-706 C1 [Mahnke, Yolanda D.; Song, Kaimei; Roederer, Mario] NIAID, ImmunoTechnol Sect, VRC, NIH, Bethesda, MD 20892 USA. [Sauer, Mariana M.; Giret, Maria Teresa M.; Carvalho, Karina I.; Costa, Priscilla R.; Kallas, Esper G.] Univ Sao Paulo, Sch Med, Div Clin Immunol & Allergy, Sao Paulo, Brazil. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Giret, Maria Teresa M.] Univ Florida, Miller Sch Med, Story Lab 2, Miami, FL USA. RP Mahnke, YD (reprint author), 40 Convent Dr,Rm 5608, Bethesda, MD 20892 USA. EM mahnkey@mail.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Brazilian Program for STD and AIDS, Ministry of Health [914/BRA/3014-UNESCO/Kallas]; Sao Paulo City Health Department [2004-0.168.922-7/Kallas]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2004/15856-9, 2006/50096-0] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; the Brazilian Program for STD and AIDS, Ministry of Health (grant number 914/BRA/3014-UNESCO/Kallas); the Sao Paulo City Health Department (grant number 2004-0.168.922-7/Kallas); and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (grant numbers 2004/15856-9 and 2006/50096-0). The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 6 Z9 6 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 13 PY 2013 VL 27 IS 5 BP 697 EP 706 DI 10.1097/QAD.0b013e32835ce2e9 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 098CY UT WOS:000315524700003 PM 23211771 ER PT J AU Wong, WT AF Wong, Wai T. TI Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE microglia; aging; priming; neurodegeneration; rejuvenation; inflammation; activation; senescence ID LONG-TERM POTENTIATION; ADULT HIPPOCAMPAL NEUROGENESIS; CENTRAL-NERVOUS-SYSTEM; AMYOTROPHIC-LATERAL-SCLEROSIS; ALZHEIMERS-DISEASE BRAIN; NEURAL PRECURSOR CELLS; TRANSCRIPTION FACTOR-A; AGE-RELATED DECLINE; ACTIVATION IN-VIVO; RAT-BRAIN AB Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and age-related macular degeneration (AMD), share two characteristics in common: (1) a disease prevalence that increases markedly with advancing age, and (2) neuroinflammatory changes in which microglia, the primary resident immune cell of the CNS, feature prominently. These characteristics have led to the hypothesis that pathogenic mechanisms underlying age-related neurodegenerative disease involve aging changes in microglia. If correct, targeting features of microglial senescence may constitute a feasible therapeutic strategy. This review explores this hypothesis and its implications by considering the current knowledge on how microglia undergo change during aging and how the emergence of these aging phenotypes relate to significant alterations in microglial function. Evidence and theories on cellular mechanisms implicated in driving senescence in microglia are reviewed, as are rejuvenative measures and strategies that aim to reverse or ameliorate the aging microglial phenotype. Understanding and controlling microglial aging may represent an opportunity for elucidating disease mechanisms and for formulating novel therapies. C1 NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, NIH, 6 Ctr Dr,6-217, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute Intramural Research Program; Macular Degeneration Research (MDR); BrightFocus Foundation FX Research in our laboratory is supported by the National Eye Institute Intramural Research Program. Acknowledgment is made for grant support to the donors of Macular Degeneration Research (MDR), a program of the American Health Assistance Foundation (AHAF, now the BrightFocus Foundation). NR 194 TC 53 Z9 54 U1 2 U2 27 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD MAR 13 PY 2013 VL 7 AR 22 DI 10.3389/fncel.2013.00022 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 111TQ UT WOS:000316544100001 PM 23493481 ER PT J AU He, BJ AF He, Biyu J. TI Spontaneous and Task-Evoked Brain Activity Negatively Interact SO JOURNAL OF NEUROSCIENCE LA English DT Article ID EVENT-RELATED RESPONSES; TO-TRIAL VARIABILITY; CAT VISUAL-CORTEX; CORTICAL-NEURONS; ACTIVITY FLUCTUATIONS; NEURAL VARIABILITY; SENSORY RESPONSES; DECISION-MAKING; BARREL CORTEX; BALLOON MODEL AB A widely held assumption is that spontaneous and task-evoked brain activity sum linearly, such that the recorded brain response in each single trial is the algebraic sum of the constantly changing ongoing activity and the stereotypical evoked activity. Using functional magnetic resonance imaging signals acquired from normal humans, we show that this assumption is invalid. Across widespread cortices, evoked activity interacts negatively with ongoing activity, such that higher prestimulus baseline results in less activation or more deactivation. As a consequence of this negative interaction, trial-to-trial variability of cortical activity decreases following stimulus onset. We further show that variability reduction follows overlapping but distinct spatial pattern from that of task-activation/deactivation and it contains behaviorally relevant information. These results favor an alternative perspective to the traditional dichotomous framework of ongoing and evoked activity. That is, to view the brain as a nonlinear dynamical system whose trajectory is tighter when performing a task. Further, incoming sensory stimuli modulate the brain's activity in a manner that depends on its initial state. We propose that across-trial variability may provide a new approach to brain mapping in the context of cognitive experiments. C1 [He, Biyu J.] NINDS, NIH, Bethesda, MD 20892 USA. RP He, BJ (reprint author), 10 Ctr Dr,Bldg 10,Room B1D728, Bethesda, MD 20892 USA. EM biyu.he@nih.gov OI He, Biyu/0000-0003-1549-1351 FU Intramural Research Program of the National Institutes of Health/National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Neurological Disorders and Stroke. I thank Marc Raichle for sharing the data used in this study; Michael Berry, Alan Koretsky, and Afonso Silva for discussions; and David Leopold, Alex Martin, and Peter Bandettini for comments on a previous draft of the manuscript. NR 74 TC 48 Z9 48 U1 0 U2 23 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 MAR 13 PY 2013 VL 33 IS 11 BP 4672 EP 4682 DI 10.1523/JNEUROSCI.2922-12.2013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 106CO UT WOS:000316119200005 PM 23486941 ER PT J AU Cimino, JJ AF Cimino, James J. TI Improving the Electronic Health Record-Are Clinicians Getting What They Wished For? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID MEDICAL RECORDS; TEACH; GUIDE C1 [Cimino, James J.] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20852 USA. RP Cimino, JJ (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20852 USA. EM james.cimino@nih.gov OI Cimino, James/0000-0003-4101-1622 FU Intramural NIH HHS [Z99 CL999999] NR 9 TC 27 Z9 27 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 MAR 13 PY 2013 VL 309 IS 10 BP 991 EP 992 DI 10.1001/jama.2013.890 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 103SH UT WOS:000315938700025 PM 23483171 ER PT J AU Clair, C Rigotti, NA Porneala, B Fox, CS D'Agostino, RB Pencina, MJ Meigs, JB AF Clair, Carole Rigotti, Nancy A. Porneala, Bianca Fox, Caroline S. D'Agostino, Ralph B., Sr. Pencina, Michael J. Meigs, James B. TI Association of Smoking Cessation and Weight Change With Cardiovascular Disease Among Adults With and Without Diabetes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; CORONARY-HEART-DISEASE; CIGARETTE-SMOKING; UNITED-STATES; RISK-FACTORS; MORTALITY; MELLITUS; WOMEN; POPULATION; OUTCOMES AB Importance Smoking cessation reduces the risks of cardiovascular disease (CVD), but weight gain that follows quitting smoking may weaken the CVD benefit of quitting. Objective To test the hypothesis that weight gain following smoking cessation does not attenuate the benefits of smoking cessation among adults with and without diabetes. Design, Setting, and Participants Prospective community-based cohort study using data from the Framingham Offspring Study collected from 1984 through 2011. At each 4-year examination, self-reported smoking status was assessed and categorized as smoker, recent quitter (-4 years), long-term quitter (-4 years), and nonsmoker. Pooled Cox proportional hazards models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events. Main Outcome Measure Incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure. Results After a mean follow-up of 25 (SD, 9.6) years, 631 CVD events occurred among 3251 participants. Median 4-year weight gain was greater for recent quitters without diabetes (2.7 kg [interquartile range {IQR}, -0.5 to 6.4]) and with diabetes (3.6 kg [IQR, -1.4 to 8.2]) than for long-term quitters (0.9 kg [IQR, -1.4 to 3.2] and 0.0 kg [IQR, -3.2 to 3.2], respectively, P < .001). Among participants without diabetes, age-and sex-adjusted incidence rate of CVD was 5.9 per 100 person-examinations (95% CI, 4.9-7.1) in smokers, 3.2 per 100 person-examinations (95% CI, 2.1-4.5) in recent quitters, 3.1 per 100 person-examinations (95% CI, 2.6-3.7) in long-term quitters, and 2.4 per 100 person-examinations (95% CI, 2.0-3.0) in nonsmokers. After adjustment for CVD risk factors, compared with smokers, recent quitters had a hazard ratio (HR) for CVD of 0.47 (95% CI, 0.23-0.94) and long-term quitters had an HR of 0.46 (95% CI, 0.34-0.63); these associations had only a minimal change after further adjustment for weight change. Among participants with diabetes, there were similar point estimates that did not reach statistical significance. Conclusions and Relevance In this community-based cohort, smoking cessation was associated with a lower risk of CVD events among participants without diabetes, and weight gain that occurred following smoking cessation did not modify this association. This supports a net cardiovascular benefit of smoking cessation, despite subsequent weight gain. JAMA. 2013;309(10):1014-1021 www.jama.com C1 [Clair, Carole; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Clair, Carole; Rigotti, Nancy A.; Porneala, Bianca; Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA USA. [Fox, Caroline S.] NHLBI, NIH, Framingham Heart Study, Framingham, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Pencina, Michael J.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Pencina, Michael J.] Harvard Clin Res Inst, Boston, MA USA. RP Clair, C (reprint author), Univ Lausanne, Dept Ambulatory Care & Community Med, 44 Bugnon Ave, CH-1011 Lausanne, Switzerland. EM carole.willi@gmail.com RI Clair, Carole/D-9786-2014 OI Clair, Carole/0000-0001-5281-0943 FU UpToDate Inc; Swiss National Science Foundation [PBLAP3-127728/1]; SICPA Foundation; National Heart, Lung, and Blood Institute (NHLBI) [5K24HL4440-10]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K24 DK080140]; Swiss National Science Foundation; NHLBI Framingham Heart Study [N01-HC-25195] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rigotti reported serving as an unpaid consultant to Pfizer and Allere Wellbeing Inc; conducting research projects sponsored by Pfizer and Nabi Biopharmaceuticals; and receiving royalties from UpToDate Inc for chapters related to smoking cessation. Dr Pencina reported serving as a data and safety monitoring board member for Thoracos. No other authors reported disclosures.; Dr Clair was supported by a grant from the Swiss National Science Foundation (PBLAP3-127728/1) and by a grant from the SICPA Foundation. Dr Rigotti was supported by National Heart, Lung, and Blood Institute (NHLBI) grant 5K24HL4440-10. Dr Meigs was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant K24 DK080140.; The Swiss National Science Foundation, SICPA Foundation, and NIDDK had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. The Framingham Heart Study is supported by the NHLBI Framingham Heart Study (contract N01-HC-25195 [Drs D'Agostino and Pencina]). The NHLBI approved the manuscript. NR 26 TC 71 Z9 73 U1 3 U2 26 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 MAR 13 PY 2013 VL 309 IS 10 BP 1014 EP 1021 DI 10.1001/jama.2013.1644 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 103SH UT WOS:000315938700030 PM 23483176 ER PT J AU Purcell, RH Engle, RE Govindarajan, S Herbert, R St Claire, M Elkins, WR Cook, A Shaver, C Beauregard, M Swerczek, J Emerson, SU AF Purcell, Robert H. Engle, Ronald E. Govindarajan, Sugantha Herbert, Richard St Claire, Marisa Elkins, William R. Cook, Anthony Shaver, Charlene Beauregard, Michelle Swerczek, Joanne Emerson, Suzanne U. TI Pathobiology of hepatitis E: lessons learned from primate models SO EMERGING MICROBES & INFECTIONS LA English DT Article DE HEV; host range; nonhuman primates; virulence; genotypes ID NON-B-HEPATITIS; E VIRUS; IGG SEROPREVALENCE; UNITED-STATES; ANTI-HEV; NON-A; INFECTION; TRANSMISSION; STRAINS; DISEASE AB Like the other hepatitis viruses, hepatitis E virus (HEV) has been difficult to study because of limitations in cell culture systems and small animal models. Much of what we know has come from epidemiological studies in developing countries and, more recently, in industrialized countries. However, the epidemiology is very different in these two settings: hepatitis E in developing countries is epidemic as well as sporadic, principally water-borne, most likely to cause disease in older children and young adults and relatively severe, especially in pregnant women; in industrialized countries the disease is sporadic, principally food-borne, most common in the elderly and probably associated with mostly inapparent infections. These differences are believed to be genotypically determined. To examine the biological parameters of hepatitis E, we have studied HEV infections in nonhuman primates, which are surrogates of man. Infections with HEV genotypes 1-3 were compared in rhesus and cynomolgus macaques and chimpanzees. In general, the biological characteristics of the different HEV genotypes mirrored their epidemiological characteristics. C1 [Purcell, Robert H.; Engle, Ronald E.; Herbert, Richard; St Claire, Marisa; Elkins, William R.; Beauregard, Michelle; Swerczek, Joanne; Emerson, Suzanne U.] NIAID, NIH, Bethesda, MD 20892 USA. [Govindarajan, Sugantha] Univ So Calif, Rancho Los Amigos Hosp, Downey, CA 90242 USA. [Cook, Anthony; Shaver, Charlene] Bioqual Inc, Rockville, MD 20850 USA. RP Emerson, SU (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM semerson@niaid.nih.gov FU intramural research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors are grateful for the excellent statistical support of Jing Qin, Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This study was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The authors have nothing to declare. NR 27 TC 4 Z9 5 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2222-1751 J9 EMERG MICROBES INFEC JI Emerg. Microbes Infect. PD MAR 13 PY 2013 VL 2 AR e9 DI 10.1038/emi2013.9 PG 6 WC Immunology; Microbiology SC Immunology; Microbiology GA AL5MO UT WOS:000339178100001 PM 26038457 ER PT J AU Ferguson, JF Patel, PN Shah, RY Mulvey, CK Gadi, R Nijjar, PS Usman, HM Mehta, NN Shah, R Master, SR Propert, KJ Reilly, MP AF Ferguson, Jane F. Patel, Parth N. Shah, Rhia Y. Mulvey, Claire K. Gadi, Ram Nijjar, Prabhjot S. Usman, Haris M. Mehta, Nehal N. Shah, Rachana Master, Stephen R. Propert, Kathleen J. Reilly, Muredach P. TI Race and gender variation in response to evoked inflammation SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; TOLL-LIKE RECEPTOR-4; INSULIN-RESISTANCE; METABOLIC ENDOTOXEMIA; SEVERE SEPSIS; IN-VIVO; ATHEROSCLEROSIS; LIPOPROTEINS; BIOMARKERS AB Background: Race- and gender-variation in innate immunity may contribute to demographic differences in inflammatory and cardiometabolic disease; yet their influence on dynamic responses during inflammatory stress is poorly understood. Our objective was to examine race and gender influence on the response to experimental endotoxemia. Methods: The Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) study was designed to investigate regulation of inflammatory and metabolic responses during low-grade endotoxemia (LPS 1 ng/kg intravenously) in healthy individuals (median age 24, IQR=7) of European (EA; n=193, 47% female) and African ancestry (AA; n=101, 59% female). Results: Baseline clinical, metabolic, and inflammatory biomarkers by race and gender were consistent with epidemiological literature; pre-LPS cytokines (e.g. median (IQR) IL-6, 2.7 (2) vs. 2.1 (2) pg/ml, P=0.001) were higher in AA than EA. In contrast, acute cytokine responses during endotoxemia were lower in AA than EA (e.g. median (IQR) peak IL-1RA, 30 (38) vs. 43 (45) ng/ml P=0.002) as was the induction of hepatic acute-phase proteins (e.g. median (IQR) peak CRP 12.9 (9) vs. 17.4 (12) mg/L P=0.005). Further, baseline levels of cytokines were only weakly correlated with peak inflammatory responses (all r(s) <0.2) both in AA and in EA. There were less pronounced and less consistent differences in the response by gender, with males having a higher AUC for CRP response compared to females (median (IQR) AUC: 185 (112) vs. 155 (118), P=0.02). Conclusions: We observed lower levels of evoked inflammation in response to endotoxin in AA compared with EA, despite similar or higher baseline levels of inflammatory markers in AA. Our data also suggest that levels of inflammatory biomarkers measured in epidemiological settings might not predict the degree of acute stress-response or risk of diseases characterized by activation of innate immunity. C1 [Ferguson, Jane F.; Patel, Parth N.; Shah, Rhia Y.; Mulvey, Claire K.; Gadi, Ram; Usman, Haris M.; Mehta, Nehal N.; Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Perelman Sch Med, Smilow Ctr Translat Res 11 136, Philadelphia, PA 19104 USA. [Nijjar, Prabhjot S.] Univ Minnesota, Sch Med, Div Cardiol, Minneapolis, MN 55455 USA. [Mehta, Nehal N.] NHLBI, Bethesda, MD 20892 USA. [Shah, Rachana] Childrens Hosp, Div Pediat Endocrinol, Philadelphia, PA 19104 USA. [Master, Stephen R.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Propert, Kathleen J.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Ferguson, JF (reprint author), Univ Penn, Cardiovasc Inst, Perelman Sch Med, Smilow Ctr Translat Res 11 136, Bldg 421,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM jfer@mail.med.upenn.edu; muredach@mail.med.upenn.edu RI Ferguson, Jane/C-7154-2011; OI Ferguson, Jane/0000-0001-6896-1025; Shah, Rachana/0000-0001-7866-557X FU National Center for Research Resources, National Institutes of Health [UL1TR000003]; National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR000003]; NIH-NHLBI SCCOR Project [P50-HL-083799]; American Heart Association [12POST11840017]; [RO1-HL-111694]; [RO1-HL-113147]; [RO1-DK-090505]; [UO1-HL-108636]; [K24-HL-107643] FX The project described was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000003 as well as a NIH-NHLBI SCCOR Project grant (P50-HL-083799) to MPR. JFF is supported by a postdoctoral fellowship grant from the American Heart Association (12POST11840017). MPR is also supported by RO1-HL-111694, RO1-HL-113147, RO1-DK-090505, UO1-HL-108636 and K24-HL-107643. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 43 TC 30 Z9 30 U1 1 U2 5 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 MAR 12 PY 2013 VL 11 AR 63 DI 10.1186/1479-5876-11-63 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 133CU UT WOS:000318115800001 PM 23497455 ER PT J AU Akrawinthawong, K Park, J Piknova, B Sibmooh, N Fucharoen, S Schechter, AN AF Akrawinthawong, Krittapoom Park, Jiwon Piknova, Barbora Sibmooh, Nathawut Fucharoen, Suthat Schechter, Alan N. TI A FLOW-CYTOMETRIC ANALYSIS OF THE INHIBITION OF PLATELET REACTIVITY WITH NITRITE REDUCTION BY DEOXYGENATED ERYTHROCYTES SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. Mahidol Univ, Fac Med, Siriraj Hosp, Bangkok 10700, Thailand. NR 0 TC 0 Z9 0 U1 0 U2 4 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 MAR 12 PY 2013 VL 61 IS 10 SU S BP E2067 EP E2067 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202271 ER PT J AU AlGhatrif, M Strait, J Morrell, C Canepa, M Wright, J Najjar, S Ferrucci, L Lakatta, E AF AlGhatrif, Majd Strait, James Morrell, Christopher Canepa, Marco Wright, Jeanette Najjar, Samer Ferrucci, Luigi Lakatta, Edward TI AGE-ASSOCIATED LONGITUDINAL CHANGES IN ARTERIAL STIFFNESS TRAJECTORIES AND BLOOD PRESSURE WITHIN INDIVIDUALS OF COMMUNITY DWELLING POPULATION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 NIA, Baltimore, MD 21224 USA. Johns Hopkins Sch Med, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1381 EP E1381 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201486 ER PT J AU Donekal, S Venkatesh, BA Kihei, Y Liu, C Nacif, M Armstrong, A Wu, C Gomes, AS Hundley, WG McClelland, R Bluemke, D Lima, JAC AF Donekal, Sirisha Venkatesh, Bharath Ambale Kihei, Yoneyama Liu, Chia Nacif, Marcelo Armstrong, Anderson Wu, Colin Gomes, Antoinette S. Hundley, W. Gregory McClelland, Robyn Bluemke, David Lima, Joao A. C. TI DETERMINANTS OF TEMPORAL CHANGE IN REGIONAL MYOCARDIAL FUNCTION: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Johns Hopkins Univ, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. RI Armstrong, Anderson/G-8407-2012; Ambale Venkatesh, Bharath/F-4941-2016 OI Armstrong, Anderson/0000-0003-3161-8922; Ambale Venkatesh, Bharath/0000-0002-2330-2373 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E939 EP E939 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201044 ER PT J AU Karikkineth, AC Canepa, M Elango, P Strait, JB Lakatta, EG Ferrucci, L AF Karikkineth, Ajoy C. Canepa, Marco Elango, Palchamy Strait, James B. Lakatta, Edward G. Ferrucci, Luigi TI C-REACTIVE PROTEIN AS A PREDICTOR OF INTIMAL MEDIA THICKNESS IN A HEALTHY COMMUNITY DWELLING POPULATION OF A BROAD AGE RANGE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Karikkineth, Ajoy C.; Canepa, Marco; Elango, Palchamy; Strait, James B.; Lakatta, Edward G.; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E2030 EP E2030 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202234 ER PT J AU Mehta, NN Sheth, NH Baker, J Ogdie, A Raper, A Saboury, B Werner, TJ Thomas, P VanVoorhees, A Alavi, A Torigian, D Gelfand, J AF Mehta, Nehal N. Sheth, Nikhil H. Baker, Joshua Ogdie, Alexis Raper, Anna Saboury, Babak Werner, Thomas J. Thomas, Preethi VanVoorhees, Abby Alavi, Abass Torigian, Drew Gelfand, Joel TI A COMPARISON OF VASCULAR INFLAMMATION IN RHEUMATOID ARTHRITIS, PSORIASIS AND HEALTHY CONTROLS BY FDG-PET/CT: A PILOT STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 NHLBI, Bethesda, MD 20892 USA. Univ Penn, Philadelphia, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1056 EP E1056 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201161 ER PT J AU Baez, A Shiloach, J AF Baez, Antonino Shiloach, Joseph TI Escherichia coli avoids high dissolved oxygen stress by activation of SoxRS and manganese-superoxide dismutase SO MICROBIAL CELL FACTORIES LA English DT Article DE Oxidative stress; ROS; SoxS; Catalase activity; SOD activity ID HIGH CELL-DENSITY; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; ANTIOXIDANT DEFENSES; REGULON; SITE; ACONITASE; GENE; BIOSYNTHESIS; INACTIVATION AB Background: High concentrations of reactive oxygen species (ROS) were reported to cause oxidative stress to E. coli cells associated with reduced or inhibited growth. The high ROS concentrations described in these reports were generated by exposing the bacteria to H2O2 and superoxide-generating chemicals which are non-physiological growth conditions. However, the effect of molecular oxygen on oxidative stress response has not been evaluated. Since the use of oxygen-enriched air is a common strategy to support high density growth of E. coli, it was important to investigate the effect of high dissolved oxygen concentrations on the physiology and growth of E. coli and the way it responds to oxidative stress. Results: To determine the effect of elevated oxygen concentrations on the growth characteristics, specific gene expression and enzyme activity in E. coli, the parental and SOD-deficient strain were evaluated when the dissolved oxygen (dO(2)) level was increased from 30% to 300%. No significant differences in the growth parameters were observed in the parental strain except for a temporary decrease of the respiration and acetate accumulation profile. By performing transcriptional analysis, it was determined that the parental strain responded to the oxidative stress by activating the SoxRS regulon. However, following the dO(2) switch, the SOD-deficient strain activated both the SoxRS and OxyR regulons but it was unable to resume its initial growth rate. Conclusion: The transcriptional analysis and enzyme activity results indicated that when E. coli is exposed to dO(2) shift, the superoxide stress regulator SoxRS is activated and causes the stimulation of the superoxide dismutase system. This enables the E. coli to protect itself from the poisoning effects of oxygen. The OxyR protecting system was not activated, indicating that H2O2 did not increase to stressing levels. C1 [Baez, Antonino; Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. EM yossi@nih.gov FU intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Funding was provided by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The authors would like to thank James Imlay (University of Illinois) for providing the AB1157 and PN134 strains, N. Majdalani (NCI, NIH) for the scientific advice and Mrs. D. Livnat for critical editorial assistance. NR 37 TC 8 Z9 8 U1 1 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2859 J9 MICROB CELL FACT JI Microb. Cell. Fact. PD MAR 12 PY 2013 VL 12 AR 23 DI 10.1186/1475-2859-12-23 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 115DL UT WOS:000316792700001 PM 23497217 ER PT J AU Yeo, M Berglund, K Hanna, M Guo, JU Kittur, J Torres, MD Abramowitz, J Busciglio, J Gao, Y Birnbaumer, L Liedtke, WB AF Yeo, Michele Berglund, Ken Hanna, Michael Guo, Junjie U. Kittur, Jaya Torres, Maria D. Abramowitz, Joel Busciglio, Jorge Gao, Yuan Birnbaumer, Lutz Liedtke, Wolfgang B. TI Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DEVELOPMENTAL SWITCH; PRENATAL EXPOSURE; BRAIN-DEVELOPMENT; GENOME; MECP2; GABA; NEUROTOXICITY; TRANSCRIPTION; ISCHEMIA; US AB Bisphenol A (BPA) is a ubiquitous compound that is emerging as a possible toxicant during embryonic development. BPA has been shown to epigenetically affect the developing nervous system, but the molecular mechanisms are not clear. Here we demonstrate that BPA exposure in culture led to delay in the perinatal chloride shift caused by significant decrease in potassium chloride cotransporter 2 (Kcc2) mRNA expression in developing rat, mouse, and human cortical neurons. Neuronal chloride increased correspondingly. Treatment with epigenetic compounds decitabine and trichostatin A rescued the BPA effects as did knockdown of histone deacetylase 1 and combined knockdown histone deacetylase 1 and 2. Furthermore, BPA evoked increase in tangential interneuron migration and increased chloride in migrating neurons. Interestingly. BPA exerted its effect in a sexually dimorphic manner, with a more accentuated effect in females than males. By chromatin immunoprecipitation, we found a significant increase in binding of methyl-CpG binding protein 2 to the "cytosine-phosphate-guanine shores" of the Kcc2 promoter, and decrease in binding of acetylated histone H3K9 surrounding the transcriptional start site. Methyl-CpG binding protein 2-expressing neurons were more abundant resulting from BPA exposure. The sexually dimorphic effect of BPA on Kcc2 expression was also demonstrated in cortical neurons cultured from the offspring of BPA-fed mouse dams. In these neurons and in cortical slices, decitabine was found to rescue the effect of BPA on Kcc2 expression. Overall, our results indicate that BPA can disrupt Kcc2 gene expression through epigenetic mechanisms. Beyond increase in basic understanding, our findings have relevance for identifying unique neurodevelopmental toxicity mechanisms of BPA, which could possibly play a role in pathogenesis of human neurodevelopmental disorders. C1 [Yeo, Michele; Berglund, Ken; Liedtke, Wolfgang B.] Duke Univ, Dept Med Neurol, Durham, NC 27710 USA. [Liedtke, Wolfgang B.] Duke Univ, Dept Neurobiol, Durham, NC 27710 USA. [Hanna, Michael; Torres, Maria D.; Busciglio, Jorge] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92617 USA. [Guo, Junjie U.; Gao, Yuan] Johns Hopkins Univ, Lieber Inst Brain Dev & Neuroregenerat, Baltimore, MD 21205 USA. [Guo, Junjie U.; Gao, Yuan] Johns Hopkins Univ, Stem Cell Program, Inst Cell Engn, Baltimore, MD 21205 USA. [Kittur, Jaya; Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Liedtke, Wolfgang B.] Duke Univ, Clin Pain, Durham, NC 27705 USA. [Liedtke, Wolfgang B.] Duke Univ, Clin Palliat Care, Durham, NC 27705 USA. RP Birnbaumer, L (reprint author), NIEHS, Neurobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM bimbaul@niehs.nih.gov; wolfgang@neuro.duke.edu RI Abramowitz, Joel/A-2620-2015 FU Duke University; National Institutes of Health [R21NS066307, HD38466, AG16573]; intramural funds from the National Institute of Environmental Health Sciences; Klingenstein Fund FX This study was supported by funding from Duke University, the Klingenstein Fund, the National Institutes of Health [R21NS066307 (to W.B.L) and HD38466 and AG16573 (to J.B.)], and intramural funds from the National Institute of Environmental Health Sciences (to L.B.). NR 38 TC 28 Z9 28 U1 6 U2 30 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 MAR 12 PY 2013 VL 110 IS 11 BP 4315 EP 4320 DI 10.1073/pnas.1300959110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107RK UT WOS:000316238300039 PM 23440186 ER PT J AU Liu, X Duyn, JH AF Liu, Xiao Duyn, Jeff H. TI Time-varying functional network information extracted from brief instances of spontaneous brain activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE instantaneous coactivation; network dynamics; nonstationary connectivity; resting-state network; clustering analysis ID RESTING-STATE; DEFAULT NETWORK; SENSORY STIMULATION; CLUSTER-ANALYSIS; GLOBAL SIGNAL; MOTOR CORTEX; CONNECTIVITY; FLUCTUATIONS; ARCHITECTURE; DYNAMICS AB Recent functional magnetic resonance imaging studies have shown that the brain is remarkably active even in the absence of overt behavior, and this activity occurs in spatial patterns that are reproducible across subjects and follow the brain's established functional subdivision. Investigating the distribution of these spatial patterns is an active area of research with the goal of obtaining a better understanding of the neural networks underlying brain function. One intriguing aspect of spontaneous activity is an apparent nonstationarity, or variability of interaction between brain regions. It was recently proposed that spontaneous brain activity may be dominated by brief traces of activity, possibly originating from a neuronal avalanching phenomenon. Such traces may involve different subregions in a network at different times, potentially reflecting functionally relevant relationships that are not captured with conventional data analysis. To investigate this, we examined publicly available functional magnetic resonance imaging data with a dedicated analysis method and found indications that functional networks inferred from conventional correlation analysis may indeed be driven by activity at only a few critical time points. Subsequent analysis of the activity at these critical time points revealed multiple spatial patterns, each distinctly different from the established functional networks. The spatial distribution of these patterns suggests a potential functional relevance. C1 [Liu, Xiao; Duyn, Jeff H.] NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Liu, X (reprint author), NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. EM liux15@ninds.nih.gov RI Liu, Xiao/C-5943-2016 FU Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 47 TC 86 Z9 88 U1 3 U2 24 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 MAR 12 PY 2013 VL 110 IS 11 BP 4392 EP 4397 DI 10.1073/pnas.1216856110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107RK UT WOS:000316238300052 PM 23440216 ER PT J AU Innes, CL Hesse, JE Palii, SS Helmink, BA Holub, AJ Sleckman, BP Paules, RS AF Innes, Cynthia L. Hesse, Jill E. Palii, Stela S. Helmink, Beth A. Holub, Abigail J. Sleckman, Barry P. Paules, Richard S. TI DNA damage activates a complex transcriptional response in murine lymphocytes that includes both physiological and cancer-predisposition programs SO BMC GENOMICS LA English DT Article DE miR-155; B cells; Ionizing radiation; DNA damage; Double strand breaks; Transcriptome profiles ID DOUBLE-STRAND BREAKS; IONIZING-RADIATION; EXPRESSION; GENE; MICRORNA-155; MIR-155; PROLIFERATION; INFLAMMATION; REQUIREMENT; PATHWAY AB Background: Double strand (ds) DNA breaks are a form of DNA damage that can be generated from both genotoxic exposures and physiologic processes, can disrupt cellular functions and can be lethal if not repaired properly. Physiologic dsDNA breaks are generated in a variety of normal cellular functions, including the RAG endonuclease-mediated rearrangement of antigen receptor genes during the normal development of lymphocytes. We previously showed that physiologic breaks initiate lymphocyte development-specific transcriptional programs. Here we compare transcriptional responses to physiological DNA breaks with responses to genotoxic DNA damage induced by ionizing radiation. Results: We identified a central lymphocyte-specific transcriptional response common to both physiologic and genotoxic breaks, which includes many lymphocyte developmental processes. Genotoxic damage causes robust alterations to pathways associated with B cell activation and increased proliferation, suggesting that genotoxic damage initiates not only the normal B cell maturation processes but also mimics activated B cell response to antigenic agents. Notably, changes including elevated levels of expression of Kras and mmu-miR-155 and the repression of Socs1 were observed following genotoxic damage, reflecting induction of a cancer-prone phenotype. Conclusions: Comparing these transcriptional responses provides a greater understanding of the mechanisms cells use in the differentiation between types of DNA damage and the potential consequences of different sources of damage. These results suggest genotoxic damage may induce a unique cancer-prone phenotype and processes mimicking activated B cell response to antigenic agents, as well as the normal B cell maturation processes. C1 [Innes, Cynthia L.; Hesse, Jill E.; Palii, Stela S.; Paules, Richard S.] NIEHS, Environm Stress & Canc Grp, Res Triangle Pk, NC 27709 USA. [Helmink, Beth A.; Holub, Abigail J.; Sleckman, Barry P.] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA. RP Paules, RS (reprint author), NIEHS, Environm Stress & Canc Grp, POB 12233, Res Triangle Pk, NC 27709 USA. EM paules@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences; NIH/NIAID [R01 AI047829] FX The authors would like to thank the members of the NIEHS Microarray Core facility and the NIEHS Flow Cytometry Core facility for their helpful service and technical expertise, and the members of the Environmental Genetics Group at NIEHS for helpful discussions concerning Nrf2 pathways. The authors would also like to thank Drs. Michael Fessler, Anton Jetten, and Kymberly Gowdy for their helpful comments and suggestions. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences and by a grant to BPS from NIH/NIAID (R01 AI047829). NR 29 TC 0 Z9 0 U1 0 U2 7 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 MAR 12 PY 2013 VL 14 AR 163 DI 10.1186/1471-2164-14-163 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 109XE UT WOS:000316403000001 PM 23496831 ER PT J AU Walsh, MP Duncan, B Larabee, S Krauss, A Davis, JPE Cui, YZ Kim, SY Guimond, M Bachovchin, W Fry, TJ AF Walsh, Meghaan P. Duncan, Brynn Larabee, Shannon Krauss, Aviva Davis, Jessica P. E. Cui, Yongzhi Kim, Su Young Guimond, Martin Bachovchin, William Fry, Terry J. TI Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors SO PLOS ONE LA English DT Article ID FIBROBLAST ACTIVATION PROTEIN; DIPEPTIDYL PEPTIDASE-IV; PHASE-II TRIAL; CANCER-IMMUNOTHERAPY; ANTITUMOR IMMUNITY; ADAPTIVE IMMUNITY; SMALL-MOLECULE; LYMPH-NODES; TALABOSTAT; IMMUNOSURVEILLANCE AB Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have antitumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine. C1 [Walsh, Meghaan P.; Duncan, Brynn; Larabee, Shannon; Krauss, Aviva; Davis, Jessica P. E.; Cui, Yongzhi; Kim, Su Young; Fry, Terry J.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Guimond, Martin] Univ Montreal, Maisonneuve Rosemont Hosp, Montreal, PQ, Canada. [Bachovchin, William] Tufts Univ, Sackler Sch Grad Biomed Sci, Dept Biochem, Boston, MA 02111 USA. RP Fry, TJ (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM fryt@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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 8 Z9 8 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 MAR 12 PY 2013 VL 8 IS 3 AR e58860 DI 10.1371/journal.pone.0058860 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WV UT WOS:000316252500050 PM 23554941 ER PT J AU Yang, BK Ma, CC Chen, ZS Yi, WN McNutt, MA Wang, Y Korteweg, C Gu, J AF Yang, Baokai Ma, Changchun Chen, Zhengshan Yi, Weining McNutt, Michael A. Wang, Yun Korteweg, Christine Gu, Jiang TI Correlation of Immunoglobulin G Expression and Histological Subtype and Stage in Breast Cancer SO PLOS ONE LA English DT Article ID CHAIN CONSTANT-REGION; KAPPA-LIGHT-CHAIN; DUCTAL CARCINOMA; CELL-LINES; JAPANESE WOMEN; RISK-FACTORS; PLASMA IGA; IN-SITU; TUMORS; PREVENTION AB Introduction: Recently, growing evidence indicates that immunoglobulins (Igs) are not only produced by mature B lymphocytes or plasma cells, but also by various normal cells types at immune privileged sites and neoplasm, including breast cancer. However, the association of breast cancer derived IgG with genesis and development of the disease has not yet been established. Methods: In this study we examined the expression of IgG in 186 breast cancers, 20 benign breast lesions and 30 normal breast tissues. Both immunohistochemistry with antibodies to Ig kappa (immunoglobulin G kappa light chain) and Ig gamma (immunoglobulin G heavy chain) and in situ hybridization with an antisense probe to IgG1 heavy chain constant region gene were performed. Various clinicopathological features were also analyzed. Results: We found that IgG is specifically expressed in human breast cancer cells. Both infiltrating ductal carcinoma and infiltrating lobular carcinoma had significantly greater numbers of Ig kappa and Ig gamma positive cancer cells as compared with medullary carcinoma, carcinoma in situ, and benign lesions (all p<0.05). In addition, IgG expression was correlated with breast cancer histological subtypes (p<0.01) and AJCC stages (p<0.05), with more abundance of IgG expression in more malignant histological subtypes or in more advanced stage of the disease. Conclusions: IgG expression in breast cancer cells is correlated with malignancy and AJCC stages of the cancers. This suggests that breast cancer derived IgG may be associated with genesis, development and prognosis of the cancer. C1 [Yang, Baokai; Chen, Zhengshan; McNutt, Michael A.; Wang, Yun; Gu, Jiang] Peking Beijing Univ, Dept Pathol, Sch Basic Med Sci, Hlth Sci Ctr, Beijing, Peoples R China. [Ma, Changchun; Chen, Zhengshan; Korteweg, Christine; Gu, Jiang] Shantou Univ, Guangdong Prov Key Lab Infect Dis & Mol Immunopat, Dept Pathol & Pathophysiol, Coll Med, Shantou, Peoples R China. [Ma, Changchun] Shantou Univ, Dept Radiat Oncol, Canc Hosp, Coll Med, Shantou, Peoples R China. [Yi, Weining] Peking Beijing Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Hlth Sci Ctr, Beijing, Peoples R China. [Wang, Yun] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Gu, J (reprint author), Peking Beijing Univ, Dept Pathol, Sch Basic Med Sci, Hlth Sci Ctr, Beijing, Peoples R China. EM jguemailbox@gmail.com RI Chen, Zhengshan/J-7499-2014 FU Li Fu Educational Foundation; 111 project of the Ministry of Education, China [B07001]; National Natural Science Foundation of China [81030033, 30971150]; Science and Technology Funding of Shantou [186] FX This work was supported by the Li Fu Educational Foundation, 111 project of the Ministry of Education, China (No. B07001), the National Natural Science Foundation of China (Nos. 81030033 and 30971150 to J.G.) and the Science and Technology Funding of Shantou (No. 186 to C. M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 2 Z9 2 U1 0 U2 10 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 MAR 12 PY 2013 VL 8 IS 3 AR e58706 DI 10.1371/journal.pone.0058706 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WV UT WOS:000316252500040 PM 23554916 ER PT J AU Sabino, EC Ribeiro, AL Salemi, VMC Oliveira, CD Antunes, AP Menezes, MM Ianni, BM Nastari, L Fernandes, F Patavino, GM Sachdev, V Capuani, L de Almeida-Neto, C Carrick, DM Wright, D Kavounis, K Goncalez, TT Carneiro-Proietti, AB Custer, B Busch, MP Murphy, EL AF Sabino, Ester C. Ribeiro, Antonio L. Salemi, Vera M. C. Oliveira, Claudia Di Lorenzo Antunes, Andre P. Menezes, Marcia M. Ianni, Barbara M. Nastari, Luciano Fernandes, Fabio Patavino, Giuseppina M. Sachdev, Vandana Capuani, Ligia de Almeida-Neto, Cesar Carrick, Danielle M. Wright, David Kavounis, Katherine Goncalez, Thelma T. Carneiro-Proietti, Anna Barbara Custer, Brian Busch, Michael P. Murphy, Edward L. CA Natl Heart Lung Blood Inst TI Ten-Year Incidence of Chagas Cardiomyopathy Among Asymptomatic Trypanosoma cruzi-Seropositive Former Blood Donors SO CIRCULATION LA English DT Article DE blood donors; Brazil; Chagas cardiomyopathy; Chagas disease; incidence ID HEART-DISEASE; UNITED-STATES; MORTALITY; RISK; PREDICTORS; ECHOCARDIOGRAPHY; RECOMMENDATIONS; TRANSMISSION; MORBIDITY; INFECTION AB Background-Very few studies have measured disease penetrance and prognostic factors of Chagas cardiomyopathy among asymptomatic Trypanosoma cruzi-infected persons. Methods and Results-We performed a retrospective cohort study among initially healthy blood donors with an index T cruzi-seropositive donation and age-, sex-, and period-matched seronegatives in 1996 to 2002 in the Brazilian cities of Sao Paulo and Montes Claros. In 2008 to 2010, all subjects underwent medical history, physical examination, ECGs, and echocardiograms. ECG and echocardiogram results were classified by blinded core laboratories, and records with abnormal results were reviewed by a blinded panel of 3 cardiologists who adjudicated the outcome of Chagas cardiomyopathy. Associations with Chagas cardiomyopathy were tested with multivariate logistic regression. Mean follow-up time between index donation and outcome assessment was 10.5 years for the seropositives and 11.1 years for the seronegatives. Among 499 T cruzi seropositives, 120 (24%) had definite Chagas cardiomyopathy, and among 488 T cruzi seronegatives, 24 (5%) had cardiomyopathy, for an incidence difference of 1.85 per 100 person-years attributable to T cruzi infection. Of the 120 seropositives classified as having Chagas cardiomyopathy, only 31 (26%) presented with ejection fraction <50%, and only 11 (9%) were classified as New York Heart Association class II or higher. Chagas cardiomyopathy was associated (P<0.01) with male sex, a history of abnormal ECG, and the presence of an S-3 heart sound. Conclusions-There is a substantial annual incidence of Chagas cardiomyopathy among initially asymptomatic T cruzi-seropositive blood donors, although disease was mild at diagnosis. (Circulation. 2013;127:1105-1115.) C1 [Sabino, Ester C.] Univ Sao Paulo, Dept Infect Dis, Sao Paulo, Brazil. [Sabino, Ester C.] Univ Sao Paulo, Inst Trop Med, Sao Paulo, Brazil. [Ribeiro, Antonio L.] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG, Brazil. [Ribeiro, Antonio L.] Univ Fed Minas Gerais, Fac Med, Belo Horizonte, MG, Brazil. [Salemi, Vera M. C.; Ianni, Barbara M.; Nastari, Luciano; Fernandes, Fabio] Univ Sao Paulo, Fac Med, Heart Inst InCor, Cardiomyopathy Unit, Sao Paulo, Brazil. [Oliveira, Claudia Di Lorenzo] Univ Fed Sao Joao del Rei, Divinopolis, Brazil. [Antunes, Andre P.; Menezes, Marcia M.] Ctr Ciencias Biol & Saude, Prontosocor De Montes Cl, MG, Brazil. [Patavino, Giuseppina M.; Capuani, Ligia; de Almeida-Neto, Cesar] Fundacao Prosangue Hemoctr Sao Paulo, Sao Paulo, Brazil. [Sachdev, Vandana] NHLBI, Bethesda, MD 20892 USA. [Carrick, Danielle M.; Wright, David; Kavounis, Katherine] Westat Corp, Rockville, MD USA. [Goncalez, Thelma T.; Custer, Brian; Busch, Michael P.; Murphy, Edward L.] Blood Syst Res Inst, San Francisco, CA USA. [Carneiro-Proietti, Anna Barbara] Hemominas, Belo Horizonte, MG, Brazil. [Carneiro-Proietti, Anna Barbara; Busch, Michael P.] Fac Saude & Ecol Humana, Vespasiano, Brazil. [Murphy, Edward L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Murphy, EL (reprint author), UCSF, BSRI, 270 Masonic Ave, San Francisco, CA 94118 USA. EM murphy@ucsf.edu RI Fernandes, Fabio/D-5994-2012; Ribeiro, Antonio/C-2707-2009; Nastari, Luciano/C-8528-2012; de Almeida-Neto, Cesar/O-9224-2014; Sabino, Ester/F-7750-2010; Salemi, Vera/C-9104-2013; Ianni, Barbara/C-7689-2012; OI Ribeiro, Antonio/0000-0002-2740-0042; Nastari, Luciano/0000-0002-7959-3827; Sabino, Ester/0000-0003-2623-5126; Salemi, Vera/0000-0002-7152-1810; Ianni, Barbara/0000-0002-1588-5492; Capuani, Ligia/0000-0002-3467-6805 FU National Institutes of Health, REDS-II International Component [HHSN-268200417175-C]; Intramural Research Program of the NHLBI; NHLBI FX This study was supported by the NHLBI, National Institutes of Health, REDS-II International Component (contract HHSN-268200417175-C) and by the Intramural Research Program of the NHLBI. NR 27 TC 38 Z9 39 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 12 PY 2013 VL 127 IS 10 BP 1105 EP + DI 10.1161/CIRCULATIONAHA.112.123612 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 104NH UT WOS:000316000300010 PM 23393012 ER PT J AU Bailey, RL Gahche, JJ Miller, PE Thomas, PR Dwyer, JT AF Bailey, Regan L. Gahche, Jaime J. Miller, Paige E. Thomas, Paul R. Dwyer, Johanna T. TI Why US Adults Use Dietary Supplements SO JAMA INTERNAL MEDICINE LA English DT Article ID CARDIOVASCULAR-DISEASE; ALTERNATIVE MEDICINE; NATIONAL-HEALTH; UNITED-STATES; CANCER; VITAMIN; WOMEN; METAANALYSIS; PREVENTION; PATTERNS AB Background: Dietary supplements are used by more than half of adults, although to our knowledge, the reasons motivating use have not been previously examined in US adults using nationally representative data. The purpose of this analysis was to examine motivations for dietary supplement use, characterize the types of products used for the most commonly reported motivations, and to examine the role of physicians and health care practitioners in guiding choices about dietary supplements. Methods: Data from adults (>= 20 years; n = 11 956) were examined in the 2007-2010 National Health and Nutrition Examination Survey, a nationally representative, cross-sectional, population-based survey. Results: The most commonly reported reasons for using supplements were to "improve" (45%) or "maintain" (33%) overall health. Women used calcium products for "bone health" (36%), whereas men were more likely to report supplement use for "heart health or to lower cholesterol" (18%). Older adults (>= 60 years) were more likely than younger individuals to report motivations related to site-specific reasons like heart, bone and joint, and eye health. Only 23% of products were used based on recommendations of a health care provider. Multivitaminmineral products were the most frequently reported type of supplement taken, followed by calcium and omega-3 or fish oil supplements. Supplement users are more likely to report very good or excellent health, have health insurance, use alcohol moderately, eschew cigarette smoking, and exercise more frequently than nonusers. Conclusions: Supplement users reported motivations related to overall health more commonly than for supplementing nutrients from food intakes. Use of supplements was related to more favorable health and lifestyle choices. Less than a quarter of supplements used by adults were recommended by a physician or health care provider. C1 [Bailey, Regan L.; Thomas, Paul R.; Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Miller, Paige E.] NCI, NIH, Bethesda, MD 20892 USA. [Gahche, Jaime J.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Dwyer, Johanna T.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. RP Bailey, RL (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,3B01, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU NIH, Office of Dietary Supplements FX This work was supported by the NIH, Office of Dietary Supplements. NR 36 TC 124 Z9 125 U1 4 U2 53 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 11 PY 2013 VL 173 IS 5 BP 355 EP 361 DI 10.1001/jamainternmed.2013.2299 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 153OY UT WOS:000319613100007 PM 23381623 ER PT J AU Barthwal, MK Anzinger, JJ Xu, Q Bohnacker, T Wymann, MP Kruth, HS AF Barthwal, Manoj K. Anzinger, Joshua J. Xu, Qing Bohnacker, Thomas Wymann, Matthias P. Kruth, Howard S. TI Fluid-Phase Pinocytosis of Native Low Density Lipoprotein Promotes Murine M-CSF Differentiated Macrophage Foam Cell Formation SO PLOS ONE LA English DT Article ID COLONY-STIMULATING FACTOR; RECEPTOR-MEDIATED ENDOCYTOSIS; ATHEROSCLEROTIC LESIONS; APOLIPOPROTEIN-E; MICE DEFICIENT; PHOSPHOINOSITIDE 3-KINASE; HYPERLIPIDEMIC MICE; CULTURED-CELLS; FACTOR OP; MACROPINOCYTOSIS AB During atherosclerosis, low-density lipoprotein (LDL)-derived cholesterol accumulates in macrophages to form foam cells. Macrophage uptake of LDL promotes foam cell formation but the mechanism mediating this process is not clear. The present study investigates the mechanism of LDL uptake for macrophage colony-stimulating factor (M-CSF)-differentiated murine bone marrow-derived macrophages. LDL receptor-null (LDLR-/-) macrophages incubated with LDL showed non-saturable accumulation of cholesterol that did not down-regulate for the 24 h examined. Incubation of LDLR-/- macrophages with increasing concentrations of I-125-LDL showed non-saturable macrophage LDL uptake. A 20-fold excess of unlabeled LDL had no effect on I-125-LDL uptake by wild-type macrophages and genetic deletion of the macrophage scavenger receptors CD36 and SRA did not affect I-125-LDL uptake, showing that LDL uptake occurred by fluid-phase pinocytosis independently of receptors. Cholesterol accumulation was inhibited approximately 50% in wild-type and LDLR-/- mice treated with LY294002 or wortmannin, inhibitors of all classes of phosphoinositide 3-kinases (PI3K). Time-lapse, phase-contrast microscopy showed that macropinocytosis, an important fluid-phase uptake pathway in macrophages, was blocked almost completely by PI3K inhibition with wortmannin. Pharmacological inhibition of the class I PI3K isoforms alpha, beta, gamma or delta did not affect macrophage LDL-derived cholesterol accumulation or macropinocytosis. Furthermore, macrophages from mice expressing kinase-dead class I PI3K beta, gamma or delta isoforms showed no decrease in cholesterol accumulation or macropinocytosis when compared with wild-type macrophages. Thus, non-class I PI3K isoforms mediated macropinocytosis in these macrophages. Further characterization of the components necessary for LDL uptake, cholesterol accumulation, and macropinocytosis identified dynamin, microtubules, actin, and vacuolar type H(+)-ATPase as contributing to uptake. However, Pak1, Rac1, and Src-family kinases, which mediate fluid-phase pinocytosis in certain other cell types, were unnecessary. In conclusion, our findings provide evidence that targeting those components mediating macrophage macropinocytosis with inhibitors may be an effective strategy to limit macrophage accumulation of LDL-derived cholesterol in arteries. C1 [Barthwal, Manoj K.; Anzinger, Joshua J.; Xu, Qing; Kruth, Howard S.] NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. [Bohnacker, Thomas; Wymann, Matthias P.] Univ Basel, Dept Biomed, Basel, Switzerland. RP Kruth, HS (reprint author), NHLBI, Sect Expt Atherosclerosis, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kruthh@nhlbi.nih.gov RI Wymann, Matthias/C-3227-2008 FU Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health; Indo-US Science and Technology Forum; International Atherosclerosis Society FX This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. M. K. B. was supported by a fellowship from the Indo-US Science and Technology Forum and received additional support from the International Atherosclerosis Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 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 MAR 11 PY 2013 VL 8 IS 3 AR e58054 DI 10.1371/journal.pone.0058054 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WI UT WOS:000316251100027 PM 23536783 ER PT J AU Polackwich, RJ Koch, D Arevalo, R Miermont, AM Jee, KJ Lazar, J Urbach, J Mueller, SC McAllister, RG AF Polackwich, Robert J. Koch, Daniel Arevalo, Richard Miermont, Anne M. Jee, Kathleen J. Lazar, John Urbach, Jeffrey Mueller, Susette C. McAllister, Ryan G. TI A Novel 3D Fibril Force Assay Implicates Src in Tumor Cell Force Generation in Collagen Networks SO PLOS ONE LA English DT Article ID FAMILY KINASES; TRACTION FORCE; CANCER-CELLS; EXTRACELLULAR PROTEOLYSIS; SIGNAL-TRANSDUCTION; MECHANICAL FORCE; FOCAL ADHESIONS; BREAST-CANCER; LEADING-EDGE; RPTP-ALPHA AB New insight into the biomechanics of cancer cell motility in 3D extracellular matrix (ECM) environments would significantly enhance our understanding of aggressive cancers and help identify new targets for intervention. While several methods for measuring the forces involved in cell-matrix interactions have been developed, previous to this study none have been able to measure forces in a fibrillar environment. We have developed a novel assay for simultaneously measuring cell mechanotransduction and motility in 3D fibrillar environments. The assay consists of a controlled-density fibrillar collagen gel atop a controlled-stiffness polyacrylamide (PAA) surface. Forces generated by living cells and their migration in the 3D collagen gel were measured with the 3D motion of tracer beads within the PAA layer. Here, this 3D fibril force assay is used to study the role of the invasion-associated protein kinase Src in mechanotransduction and motility. Src expression and activation are linked with proliferation, invasion, and metastasis, and have been shown to be required in 2D for invadopodia membranes to direct and mediate invasion. Breast cancer cell line MDA-MD-231 was stably transfected with GFP-tagged constitutively active Src or wild-type Src. In 3D fibrillar collagen matrices we found that, relative to wild-type Src, constitutively active Src: 1) increased the strength of cell-induced forces on the ECM, 2) did not significantly change migration speed, and 3) increased both the duration and the length, but not the number, of long membrane protrusions. Taken together, these results support the hypothesis that Src controls invasion by controlling the ability of the cell to form long lasting cellular protrusions to enable penetration through tissue barriers, in addition to its role in promoting invadopodia matrix-degrading activity. C1 [Polackwich, Robert J.; Koch, Daniel; Arevalo, Richard; Urbach, Jeffrey; McAllister, Ryan G.] Georgetown Univ, Dept Phys, Washington, DC 20057 USA. [Miermont, Anne M.; Jee, Kathleen J.; Lazar, John; Mueller, Susette C.; McAllister, Ryan G.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20057 USA. [Miermont, Anne M.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP McAllister, RG (reprint author), Georgetown Univ, Dept Phys, Washington, DC 20057 USA. EM rmca@physics.georgetown.edu OI Urbach, Jeffrey/0000-0002-1593-520X FU National Cancer Institute [5K25CA126836]; National Science Foundation [DMR-0804782]; Lombardi Comprehensive Cancer Center Microscopy and Imaging Shared Resource; U.S. Public Health Service [2P30-CA-51008, 1S10 RR15768-01, 1 S10 RR019291-01A2]; [9R01 CA112673] FX This project was supported in part by Award Number 5K25CA126836 from the National Cancer Institute to RM and supported in part by Award number DMR-0804782 from the National Science Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. This work was further supported in part by the Lombardi Comprehensive Cancer Center Microscopy and Imaging Shared Resource funded by U.S. Public Health Service Grants 2P30-CA-51008, 1S10 RR15768-01, and 1 S10 RR019291-01A2 and by 9R01 CA112673 to SCM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 5 Z9 5 U1 1 U2 36 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 MAR 11 PY 2013 VL 8 IS 3 AR e58138 DI 10.1371/journal.pone.0058138 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WI UT WOS:000316251100028 PM 23536784 ER PT J AU Yao, XH Ping, YF Liu, Y Chen, KQ Yoshimura, T Liu, MY Gong, WH Chen, C Niu, Q Guo, DY Zhang, X Wang, JM Bian, XW AF Yao, Xiaohong Ping, Yifang Liu, Ying Chen, Kequiang Yoshimura, Teizo Liu, Mingyong Gong, Wanghua Chen, Chong Niu, Qin Guo, Deyu Zhang, Xia Wang, Ji Ming Bian, Xiuwu TI Plays a Key Role in Vasculogenic Mimicry Formation, Neovascularization and Tumor Initiation by Glioma Stem-like Cells SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; FORMYLPEPTIDE RECEPTOR FPR; BEVACIZUMAB PLUS IRINOTECAN; CANCER-CELLS; RECURRENT GLIOBLASTOMA; PROGENITOR CELLS; PRECURSOR CELLS; BLOOD-VESSELS; ANGIOGENESIS; IDENTIFICATION AB Human glioblastomas (GBM) are thought to be initiated by glioma stem-like cells (GSLCs). GSLCs also participate in tumor neovascularization by transdifferentiating into vascular endothelial cells. Here, we report a critical role of GSLCs in the formation of vasculogenic mimicry (VM), which defines channels lined by tumor cells to supply nutrients to early growing tumors and tumor initiation. GSLCs preferentially expressed vascular endothelial growth factor receptor-2 (VEGFR-2) that upon activation by VEGF, mediated chemotaxis, tubule formation and increased expression of critical VM markers by GSLCs. Knockdown of VEGFR-2 in GSLCs by shRNA markedly reduced their capacity of self-renewal, forming tubules, initiating xenograft tumors, promoting vascularization and the establishment of VM. Our study demonstrates VEGFR-2 as an essential molecule to sustain the "stemness" of GSLCs, their capacity to initiate tumor vasculature, and direct initiation of tumor. C1 [Yao, Xiaohong; Ping, Yifang; Chen, Chong; Niu, Qin; Guo, Deyu; Zhang, Xia; Bian, Xiuwu] Third Mil Med Univ, Inst Pathol, Chongqing, Peoples R China. [Yao, Xiaohong; Ping, Yifang; Chen, Chong; Niu, Qin; Guo, Deyu; Zhang, Xia; Bian, Xiuwu] Third Mil Med Univ, Southwest Canc Ctr, Chongqing, Peoples R China. [Yao, Xiaohong; Liu, Ying; Chen, Kequiang; Yoshimura, Teizo; Liu, Mingyong; Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Liu, Mingyong] Third Mil Med Univ, Daping Hosp, Dept Spinal Surg, Chongqing, Peoples R China. [Gong, Wanghua] SAIC Frederick, Basic Res Program, Frederick, MD USA. RP Wang, JM (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM wangji@mail.nih.gov; bianxiuwu@263.net RI Zhang, Xia/B-8152-2008; Bian, Xiu-wu/D-4736-2017 OI Zhang, Xia/0000-0002-9040-1486; Bian, Xiu-wu/0000-0003-4383-0197 FU National Basic Research Program of China (973 Program) [2010CB529403]; National Natural Science Foundation of China (NSFC) [30800421, 30870965]; Natural Science Foundation Project of CQ (CSTC) [2008BB5136]; National Cancer Institute (NCI), National Institutes of Health (NIH) [HHSN261200800001E]; NCI, NIH, United States of America FX This project was supported in part by the National Basic Research Program of China (973 Program, No. 2010CB529403), the National Natural Science Foundation of China (NSFC, No. 30800421 and 30870965) and the Natural Science Foundation Project of CQ (CSTC, 2008BB5136). This project was also funded in part with Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Contract No. HHSN261200800001E and was supported in part by the Intramural Research Program of the NCI, NIH, United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 37 Z9 42 U1 0 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 MAR 11 PY 2013 VL 8 IS 3 AR e57188 DI 10.1371/journal.pone.0057188 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WI UT WOS:000316251100009 PM 23536763 ER PT J AU Kotlarz, D Zietara, N Uzel, G Weidemann, T Braun, CJ Diestelhorst, J Krawitz, PM Robinson, PN Hecht, J Puchalka, J Gertz, EM Schaffer, AA Lawrence, MG Kardava, L Pfeifer, D Baumann, U Pfister, ED Hanson, EP Schambach, A Jacobs, R Kreipe, H Moir, S Milner, JD Schwille, P Mundlos, S Klein, C AF Kotlarz, Daniel Zietara, Natalia Uzel, Gulbu Weidemann, Thomas Braun, Christian J. Diestelhorst, Jana Krawitz, Peter M. Robinson, Peter N. Hecht, Jochen Puchalka, Jacek Gertz, E. Michael Schaeffer, Alejandro A. Lawrence, Monica G. Kardava, Lela Pfeifer, Dietmar Baumann, Ulrich Pfister, Eva-Doreen Hanson, Eric P. Schambach, Axel Jacobs, Roland Kreipe, Hans Moir, Susan Milner, Joshua D. Schwille, Petra Mundlos, Stefan Klein, Christoph TI Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CELL RESPONSES; WSXWS MOTIF; T-CELLS; DIFFERENTIATION; INTERLEUKIN-21; CHAIN; DEFICIENCY; ACTIVATION; GENERATION; INFECTION AB Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children. C1 [Kotlarz, Daniel; Zietara, Natalia; Braun, Christian J.; Diestelhorst, Jana; Klein, Christoph] Hannover Med Sch, Dept Pediat Hematol Oncol, D-30625 Hannover, Germany. [Baumann, Ulrich; Pfister, Eva-Doreen] Hannover Med Sch, Dept Pediat Kidney Liver & Metab Dis, D-30625 Hannover, Germany. [Schambach, Axel] Hannover Med Sch, Dept Expt Hematol, D-30625 Hannover, Germany. [Jacobs, Roland] Hannover Med Sch, Dept Clin Immunol & Rheumatol, D-30625 Hannover, Germany. [Kreipe, Hans] Hannover Med Sch, Dept Pathol, D-30625 Hannover, Germany. [Kotlarz, Daniel; Zietara, Natalia; Braun, Christian J.; Diestelhorst, Jana; Puchalka, Jacek; Klein, Christoph] Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat, D-80539 Munich, Germany. [Uzel, Gulbu] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, Bethesda, MD USA. [Lawrence, Monica G.; Milner, Joshua D.] NIAID, Lab Allerg Dis, Bethesda, MD USA. [Kardava, Lela; Moir, Susan] NIAID, Lab Immunoregulat, Bethesda, MD USA. [Hanson, Eric P.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Weidemann, Thomas; Schwille, Petra] Tech Univ Dresden, Biophys Res Grp, D-01062 Dresden, Germany. [Krawitz, Peter M.; Robinson, Peter N.; Hecht, Jochen; Mundlos, Stefan] Max Planck Inst Mol Genet, D-14195 Berlin, Germany. [Krawitz, Peter M.; Robinson, Peter N.; Hecht, Jochen; Mundlos, Stefan] Charite, Inst Med Genet & Human Genet, D-10117 Berlin, Germany. [Krawitz, Peter M.; Robinson, Peter N.; Hecht, Jochen; Mundlos, Stefan] Charite, Berlin Brandenburg Ctr Regenerat Therapies BCRT, D-10117 Berlin, Germany. [Pfeifer, Dietmar] Univ Med Ctr Freiburg, Genom Core Lab, Dept Hematol Oncol, D-79095 Freiburg, Germany. RP Klein, C (reprint author), Hannover Med Sch, Dept Pediat Hematol Oncol, D-30625 Hannover, Germany. EM christoph.klein@med.uni-muenchen.de RI Krawitz, Peter/F-3142-2012; OI Krawitz, Peter/0000-0002-3194-8625; Gertz, E. Michael/0000-0001-8390-4387; Robinson, Peter/0000-0002-0736-9199 FU DFG [KF0250, SFB900]; BMBF (PID-NET); E-RARE; DAAD; REBIRTH [EXC62/1]; Care-for-Rare Foundation; Deutsche Jose Carreras Leukamie-Stiftung; Intramural Research Program of the NIH; NIAID; NIAMS; NLM FX The study is supported by grants from DFG (KF0250, SFB900, Gottfried-Wilhelm-Leibniz Program), BMBF (PID-NET), E-RARE, DAAD, REBIRTH (EXC62/1), Care-for-Rare Foundation, and Deutsche Jose Carreras Leukamie-Stiftung (fellowship to D. Kotlarz). This research is supported in part by the Intramural Research Program of the NIH, NIAID, NIAMS, and NLM. NR 35 TC 69 Z9 72 U1 0 U2 20 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 MAR 11 PY 2013 VL 210 IS 3 BP 433 EP 443 DI 10.1084/jem.20111229 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 104MH UT WOS:000315997000001 PM 23440042 ER PT J AU Ben-Sasson, SZ Hogg, A Hu-Li, J Wingfield, P Chen, X Crank, M Caucheteux, S Ratner-Hurevich, M Berzofsky, JA Nir-Paz, R Paul, WE AF Ben-Sasson, Shlomo Z. Hogg, Alison Hu-Li, Jane Wingfield, Paul Chen, Xi Crank, Michelle Caucheteux, Stephane Ratner-Hurevich, Maya Berzofsky, Jay A. Nir-Paz, Ran Paul, William E. TI IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ADAPTIVE IMMUNE-RESPONSES; TUMOR-NECROSIS-FACTOR; TRANSENDOTHELIAL MIGRATION; ENDOTHELIAL-CELLS; DIFFERENTIAL EXPRESSION; ENVELOPE GLYCOPROTEIN; CYTOKINE PRODUCTION; DENDRITIC CELLS; VACCINIA VIRUS; CD11C(+) CELLS AB Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1(-/-) OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon gamma (IFN-gamma). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-gamma when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory. C1 [Ben-Sasson, Shlomo Z.; Hu-Li, Jane; Chen, Xi; Crank, Michelle; Caucheteux, Stephane; Paul, William E.] NIAID, Lab Immunol, Bethesda, MD USA. [Hogg, Alison; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wingfield, Paul] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Ben-Sasson, Shlomo Z.; Ratner-Hurevich, Maya] Hebrew Univ Jerusalem, Lautenberg Ctr Tumor Immunol, Hadassah Med Ctr, IL-91120 Jerusalem, Israel. [Nir-Paz, Ran] Hebrew Univ Jerusalem, Dept Clin Microbiol & Infect Dis, Hadassah Med Ctr, IL-91120 Jerusalem, Israel. RP Paul, WE (reprint author), NIAID, Lab Immunol, Bethesda, MD USA. EM wpaul@niaid.nih.gov OI Nir-Paz, Ran/0000-0002-1567-2550 FU Intramural Research Program of the National Institute for Allergy and Infectious Disease; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute for Allergy and Infectious Disease, National Institutes of Health. NR 48 TC 36 Z9 38 U1 0 U2 18 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 MAR 11 PY 2013 VL 210 IS 3 BP 491 EP 502 DI 10.1084/jem.20122006 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 104MH UT WOS:000315997000006 PM 23460726 ER PT J AU Dai, L Lidie, KB Chen, Q Adelsberger, JW Zheng, X Huang, DW Yang, J Lempicki, RA Rehman, T Dewar, RL Wang, YM Hornung, RL Canizales, KA Lockett, SJ Lane, HC Imamichi, T AF Dai, Lue Lidie, Kristy B. Chen, Qian Adelsberger, Joseph W. Zheng, Xin Huang, DaWei Yang, Jun Lempicki, Richard A. Rehman, Tauseef Dewar, Robin L. Wang, Yanmei Hornung, Ronald L. Canizales, Kelsey A. Lockett, Stephen J. Lane, H. Clifford Imamichi, Tomozumi TI IL-27 inhibits HIV-1 infection in human macrophages by down-regulating host factor SPTBN1 during monocyte to macrophage differentiation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; REVERSE TRANSCRIPTION; MONONUCLEAR PHAGOCYTES; SAMHD1 RESTRICTS; REPLICATION FITNESS; DRUG-RESISTANCE; IN-VITRO; EXPRESSION AB The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down-regulating spectrin beta nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1-mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27-treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir. C1 [Dai, Lue; Lidie, Kristy B.; Chen, Qian; Adelsberger, Joseph W.; Zheng, Xin; Huang, DaWei; Yang, Jun; Lempicki, Richard A.; Rehman, Tauseef; Dewar, Robin L.; Wang, Yanmei; Hornung, Ronald L.; Canizales, Kelsey A.; Imamichi, Tomozumi] Sci Applicat Int Corp Frederick Inc, Frederick Natl Lab Canc Res, Appl & Dev Directorate, Ft Detrick, MD 21702 USA. [Lockett, Stephen J.] Sci Applicat Int Corp Frederick Inc, Frederick Natl Lab Canc Res, Adv Technol Program Directorate, Ft Detrick, MD 21702 USA. [Lane, H. Clifford] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Imamichi, T (reprint author), Sci Applicat Int Corp Frederick Inc, Frederick Natl Lab Canc Res, Appl & Dev Directorate, Ft Detrick, MD 21702 USA. EM timamichi@mail.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU NCI, NIH [HHSN261200800001E]; NIAID FX This project has been funded in whole or in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by NIAID. NR 83 TC 15 Z9 16 U1 0 U2 17 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 MAR 11 PY 2013 VL 210 IS 3 BP 517 EP 534 DI 10.1084/jem.20120572 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 104MH UT WOS:000315997000008 PM 23460728 ER PT J AU Ramos-Alvarez, I Martin-Duce, A Moreno-Villegas, Z Sanz, R Aparicio, C Portal-Nunez, S Mantey, SA Jensen, RT Gonzalez, N AF Ramos-Alvarez, Irene Martin-Duce, Antonio Moreno-Villegas, Zaida Sanz, Raul Aparicio, Cesar Portal-Nunez, Sergio Mantey, Samuel A. Jensen, Robert T. Gonzalez, Nieves TI Bombesin receptor subtype-3 (BRS-3), a novel candidate as therapeutic molecular target in obesity and diabetes SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE BRS-3; Human-muscle; GLUT-4; Glucose-metabolism; Diabetes; Obesity ID RAT SKELETAL-MUSCLE; GLUCAGON-LIKE PEPTIDE-1; HUMAN ORPHAN RECEPTOR; GLUCOSE-TRANSPORT; GENE-EXPRESSION; HIGH-AFFINITY; GLP-1; INSULIN; METABOLISM; AGONIST AB BRS-3 KO-mice developed obesity and unbalanced glucose metabolism, suggesting an important role of BRS-3 receptor in glucose homeostasis. We explored BRS-3 expression in skeletal muscle from normal, obese or type-2 diabetic (T2D) patients, and the effect of [D-Phe(6), beta-Ala(11), Phe(13), Nle(14)]bombesin(6-14) - BRS-3-agonist-peptide (BRS-3-AP) - on glucose-related effects, before or after BRS-3 gene silencing. In muscle tissue and primary cultured myocytes from altered metabolic states, BRS-3 gene/protein expressions were down-regulated. In normal, obese and T2D cells: A) BRS-3-AP as insulin enhanced BRS-3 and GLUT-4 mRNA/protein levels; improving glucotransporter translocation to plasma membrane, and B) BRS-3-AP caused a concentration-related-stimulation of glucose transport, being obese and T2D myocytes more sensitive to the ligand than normal. Wortmannin and PD98059, but not rapamycin, abolished the stimulatory action of BRS-3-AP on glucose transport. BRS-3 plays an important role in glucose metabolism, and could be use as a molecular target, and/or its ligand, as a therapeutic agent for obesity and diabetes treatments. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Ramos-Alvarez, Irene; Moreno-Villegas, Zaida; Gonzalez, Nieves] IIS Fdn Jimenez Diaz, Dept Metab Nutr & Hormonas, Madrid 28040, Spain. [Ramos-Alvarez, Irene; Gonzalez, Nieves] CIBERDEM, Madrid, Spain. [Martin-Duce, Antonio] Univ Alcala de Henares, Dept Nursery, Surg Unit, Madrid, Spain. [Sanz, Raul] IIS Fdn Jimenez Diaz, Dept Neurol, Madrid 28040, Spain. [Aparicio, Cesar] Fdn Jimenez Diaz, Dept Vasc Surg, Madrid, Spain. [Portal-Nunez, Sergio] IIS Fdn Jimenez Diaz, RETICEF, Dept Bone & Mineral Metab, Madrid 28040, Spain. [Mantey, Samuel A.; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP Gonzalez, N (reprint author), IIS Fdn Jimenez Diaz, Dept Metab Nutr & Hormonas, Avda Reyes Catolicos 2, Madrid 28040, Spain. EM ngonzalezg@fjd.es RI Portal-Nunez, Sergio/L-7391-2014; Gonzalez, Nieves/N-2199-2014 OI Portal-Nunez, Sergio/0000-0003-0659-1545; Gonzalez, Nieves/0000-0002-1551-2872 FU Instituto de Salud CarlosIII [CP08/00158]; Fundacion Eugenio Rodriguez Pascual, Spain [12224/001]; RETICEF [RD06/0013/1002] FX This study was supported by a grant from the Instituto de Salud CarlosIII (CP08/00158), (ENDODIAB, CIBERDEM) and Fundacion Eugenio Rodriguez Pascual (12224/001), Spain. I.R.A. and Z.M.V. are Research Fellow from the Fundacion Conchita Rabago de Jimenez Diaz; S.P.N. is recipient of a research contract from RETICEF (RD06/0013/1002). The authors declare that there is not conflict of interest that would prejudice the impartiality of the reported research. We thank Estrella Martin-Crespo (Dpt. of Metabolism, Nutrition and Hormones, IIS-Fundacion Jimenez Diaz) for excellent technical assistance and Felicidad Lopez (Dpt. of Surgery, Fundacion Jimenez Diaz) for outstanding sample-coordination. NR 32 TC 6 Z9 7 U1 0 U2 14 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 MAR 10 PY 2013 VL 367 IS 1-2 BP 109 EP 115 DI 10.1016/j.mce.2012.12.025 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 099HH UT WOS:000315611600012 PM 23291341 ER PT J AU Bissler, JJ Kingswood, JC Radzikowska, E Zonnenberg, BA Frost, M Belousova, E Sauter, M Nonomura, N Brakemeier, S de Vries, PJ Whittemore, VH Chen, D Sahmoud, T Shah, G Lincy, J Lebwohl, D Budde, K AF Bissler, John J. Kingswood, J. Christopher Radzikowska, Elzbieta Zonnenberg, Bernard A. Frost, Michael Belousova, Elena Sauter, Matthias Nonomura, Norio Brakemeier, Susanne de Vries, Petrus J. Whittemore, Vicky H. Chen, David Sahmoud, Tarek Shah, Gaurav Lincy, Jeremie Lebwohl, David Budde, Klemens TI Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial SO LANCET LA English DT Article ID T-CELL LYMPHOMA; RENAL ANGIOMYOLIPOMATA; CONSENSUS CONFERENCE; CLINICAL-TRIAL; SIROLIMUS; DISEASE; EFFICACY; THERAPY; PHASE-2; WOMEN AB Background Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata. Methods In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2: 1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400. Results 118 patients (median age 31.0 years; IQR 18.0-61.0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31-53%]) for everolimus and 0% (0 of 39 [0-9%]) for placebo (response rate difference 42% [24-58%]; one-sided Cochran-Mantel-Haenszel test p<0.0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]). Interpretation Everolimus reduced angiomyolipoma volume with an acceptable safety profi le, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. C1 [Bissler, John J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Kingswood, J. Christopher] Royal Sussex Cty Hosp, Brighton BN2 5BE, E Sussex, England. [Radzikowska, Elzbieta] Natl TB & Lung Dis Res Inst, Warsaw, Poland. [Zonnenberg, Bernard A.] Univ Med Ctr, Utrecht, Netherlands. [Frost, Michael] Minnesota Epilepsy Grp, St Paul, MN USA. [Belousova, Elena] Moscow Res Inst Pediat & Pediat Surg, Moscow, Russia. [Sauter, Matthias] Klinikum Univ Munchen, Med Klin & Poliklin 4, Munich, Germany. [Nonomura, Norio] Osaka Univ Hosp, Osaka 553, Japan. [Brakemeier, Susanne; Budde, Klemens] Charite, D-13353 Berlin, Germany. [de Vries, Petrus J.] Univ Cape Town, Div Child & Adolescent Psychiat, ZA-7700 Rondebosch, South Africa. [Whittemore, Vicky H.] NINDS, NIH, Bethesda, MD 20892 USA. [Chen, David; Sahmoud, Tarek; Shah, Gaurav; Lebwohl, David] Novartis Pharmaceut, Florham Pk, NJ USA. [Lincy, Jeremie] Novartis Pharmaceut, Basel, Switzerland. RP Bissler, JJ (reprint author), Cincinnati Childrens Hosp Med Ctr, 240 Albert Sabin Way, Cincinnati, OH 45229 USA. EM john.bissler@cchmc.org RI Chiang, Vincent, Ming-Hsien/D-4312-2016; OI Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863; Belousova, Elena Dmitrievna/0000-0003-3594-6974 FU Novartis Pharmaceuticals; Novartis FX Funding Novartis Pharmaceuticals.; DC, TS, GS, JL, and DL are employees of Novartis. DC, GS, and DL own Novartis stock. DL has Novartis stock options. JJB, JCK, ER, BAZ, MF, EB, MS, PJdV, and KB are Novartis consultants (including advisory boards), and have had travel paid, research funded, or speaker honoraria/speakers bureau by or for Novartis. MF is a member of speakers bureaus and advisory boards for Lundbeck and UCB. NN, SB, and VHW declare that they have no conflicts of interest. NR 30 TC 222 Z9 239 U1 2 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAR 9 PY 2013 VL 381 IS 9869 BP 817 EP 824 DI 10.1016/S0140-6736(12)61767-X PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 105IL UT WOS:000316060600031 PM 23312829 ER PT J AU Carrington, LB Armijos, MV Lambrechts, L Barker, CM Scott, TW AF Carrington, Lauren B. Armijos, M. Veronica Lambrechts, Louis Barker, Christopher M. Scott, Thomas W. TI Effects of Fluctuating Daily Temperatures at Critical Thermal Extremes on Aedes aegypti Life-History Traits SO PLOS ONE LA English DT Article ID DENGUE VIRUS TRANSMISSION; CLIMATE-CHANGE; CULICIDAE; DIPTERA; MOSQUITOS; SURVIVAL; VECTOR; AUSTRALIA; MICROCLIMATE; CALIFORNIA AB Background: The effect of temperature on insect biology is well understood under constant temperature conditions, but less so under more natural, fluctuating conditions. A fluctuating temperature profile around a mean of 26 degrees C can alter Aedes aegypti vector competence for dengue viruses as well as numerous life-history traits, however, the effect of fluctuations on mosquitoes at critical thermal limits is unknown. Methodology/Principal Findings: We investigated the effects of large and small daily temperature fluctuations at low (16 degrees C) and high (35-37 degrees C) mean temperatures, after we identified these temperatures as being thresholds for immature development and/or adult reproduction under constant temperature conditions. We found that temperature effects on larval development time, larval survival and adult reproduction depend on the combination of mean temperature and magnitude of fluctuations. Importantly, observed degree-day estimates for mosquito development under fluctuating temperature profiles depart significantly (around 10-20%) from that predicted by constant temperatures of the same mean. At low mean temperatures, fluctuations reduce the thermal energy required to reach pupation relative to constant temperature, whereas at high mean temperatures additional thermal energy is required to complete development. A stage-structured model based on these empirical data predicts that fluctuations can significantly affect the intrinsic growth rate of mosquito populations. Conclusions/Significance: Our results indicate that by using constant temperatures, one could under- or over-estimate values for numerous life-history traits compared to more natural field conditions dependent upon the mean temperature. This complexity may in turn reduce the accuracy of population dynamics modeling and downstream applications for mosquito surveillance and disease prevention. C1 [Carrington, Lauren B.; Armijos, M. Veronica; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Carrington, Lauren B.; Armijos, M. Veronica; Barker, Christopher M.; Scott, Thomas W.] Univ Calif Davis, Ctr Vectorborne Dis, Davis, CA 95616 USA. [Lambrechts, Louis] Inst Pasteur, CNRS URA 3012, Paris, France. [Barker, Christopher M.] Univ Calif Davis, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Barker, Christopher M.; Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Carrington, LB (reprint author), Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. EM lbcarrington@gmail.com RI Lambrechts, Louis/A-2057-2010; OI Lambrechts, Louis/0000-0001-5958-2138; Carrington, Lauren Bree/0000-0001-9273-7912 FU Ecology of Infectious Disease program of the National Science Foundation [EF-0914384]; CDC, Climate Change: Environmental Impact on Human Health [U01 EH000418] FX The work was funded by grant EF-0914384 from the Ecology of Infectious Disease program of the National Science Foundation. CMB also acknowledges financial support from grant U01 EH000418 from CDC, Climate Change: Environmental Impact on Human Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 33 Z9 36 U1 1 U2 35 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 MAR 8 PY 2013 VL 8 IS 3 AR e58824 DI 10.1371/journal.pone.0058824 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140TZ UT WOS:000318679900094 PM 23520534 ER PT J AU Brenner, AV Neta, G Sturgis, EM Pfeiffer, RM Hutchinson, A Yeager, M Xu, L Zhou, C Wheeler, W Tucker, MA Chanock, SJ Sigurdson, AJ AF Brenner, Alina V. Neta, Gila Sturgis, Erich M. Pfeiffer, Ruth M. Hutchinson, Amy Yeager, Meredith Xu, Li Zhou, Cindy Wheeler, William Tucker, Margaret A. Chanock, Stephen J. Sigurdson, Alice J. TI Common Single Nucleotide Polymorphisms in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer SO PLOS ONE LA English DT Article ID PROTEIN-C INHIBITOR; US RADIOLOGIC TECHNOLOGISTS; LINKAGE DISEQUILIBRIUM; AUTOIMMUNE-DISEASE; FAMILY-HISTORY; UNITED-STATES; CARCINOMA; INFLAMMATION; ASSOCIATION; RADIATION AB Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kappa B pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (PSNP-trend) for the association between genotype (common homozygous, heterozygous, variant homozygous) and risk of PTC. To correct for multiple comparisons, we applied the false discovery rate method (FDR). Gene region-and pathway-level associations (P-Region and P-Pathway) were assessed by combining individual PSNP-trend values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (PSNP-FDR/PSNP-trend = 0.02/6x10(-6) and PSNP-FDR/PSNP-trend = 0.04/2x10(-5), respectively). These associations were independent of a history of autoimmune thyroiditis (OR = 6.4; 95% confidence interval: 3.0-13.4). At the gene region level, SERPINA5 was suggestively associated with risk of PTC (PRegion-FDR/P-Region = 0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (PPathway = 0.02) associated with PTC risk largely due to the strong effect of SERPINA5. Our results require replication but suggest that the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC. C1 [Brenner, Alina V.; Neta, Gila; Sigurdson, Alice J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Sturgis, Erich M.; Xu, Li] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Hutchinson, Amy; Yeager, Meredith] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Zhou, Cindy] George Washington Univ, Dept Epidemiol & Biostat, Washington, DC USA. [Wheeler, William] Informat Management Syst, Silver Spring, MD USA. [Tucker, Margaret A.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Gaithersburg, MD USA. RP Brenner, AV (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. EM brennera@mail.nih.gov RI Xu, Li/B-9535-2012; Tucker, Margaret/B-4297-2015; Zhou, Cindy /H-2165-2015 OI Zhou, Cindy /0000-0003-4814-4305 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; American Thyroid Association FX This project was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, and by a grant from the American Thyroid Association (PI: E. M. Sturgis). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 13 Z9 13 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 MAR 8 PY 2013 VL 8 IS 3 AR e57243 DI 10.1371/journal.pone.0057243 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140TZ UT WOS:000318679900023 PM 23520464 ER PT J AU Lizunov, VA Stenkula, K Troy, A Cushman, SW Zimmerberg, J AF Lizunov, Vladimir A. Stenkula, Karin Troy, Aaron Cushman, Samuel W. Zimmerberg, Joshua TI Insulin Regulates Glut4 Confinement in Plasma Membrane Clusters in Adipose Cells SO PLOS ONE LA English DT Article ID GLUCOSE-TRANSPORT; ANCHORED PROTEINS; LIPID RAFTS; TRANSLOCATION; VESICLES; FUSION; RAT; TRAFFICKING; MICROSCOPY; DIFFUSION AB Insulin-stimulated delivery of glucose transporter-4 (GLUT4) to the plasma membrane (PM) is the hallmark of glucose metabolism. In this study we examined insulin's effects on GLUT4 organization in PM of adipose cells by direct microscopic observation of single monomers tagged with photoswitchable fluorescent protein. In the basal state, after exocytotic delivery only a fraction of GLUT4 is dispersed into the PM as monomers, while most of the GLUT4 stays at the site of fusion and forms elongated clusters (60-240 nm). GLUT4 monomers outside clusters diffuse freely and do not aggregate with other monomers. In contrast, GLUT4 molecule collision with an existing cluster can lead to immediate confinement and association with that cluster. Insulin has three effects: it shifts the fraction of dispersed GLUT4 upon delivery, it augments the dissociation of GLUT4 monomers from clusters similar to 3-fold and it decreases the rate of endocytic uptake. All together these three effects of insulin shift most of the PM GLUT4 from clustered to dispersed states. GLUT4 confinement in clusters represents a novel kinetic mechanism for insulin regulation of glucose homeostasis. C1 [Lizunov, Vladimir A.; Troy, Aaron; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Stenkula, Karin; Cushman, Samuel W.] NIDDKD, Expt Diabet Metab & Nutr Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM joshz@mail.nih.gov FU Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Diabetes and Digestive and Kidney Diseases FX This work was funded by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 8 Z9 8 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 MAR 8 PY 2013 VL 8 IS 3 AR e57559 DI 10.1371/journal.pone.0057559 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140TZ UT WOS:000318679900031 PM 23520472 ER PT J AU Tran, DT Ten Hagen, KG AF Tran, Duy T. Ten Hagen, Kelly G. TI Mucin-type O-Glycosylation during Development SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; FAMILIAL TUMORAL CALCINOSIS; CORONARY-ARTERY-DISEASE; UDP-GALNAC; DROSOPHILA-MELANOGASTER; MICE LACKING; CORE-1 BETA-1,3-GALACTOSYLTRANSFERASE; CAENORHABDITIS-ELEGANS; MOLECULAR CHAPERONE; NERVOUS-SYSTEM AB Mucin-type O-glycosylation is an evolutionarily conserved protein modification present on membrane-bound and secreted proteins. Aberrations in O-glycosylation are responsible for certain human diseases and are associated with disease risk factors. Recent studies have demonstrated essential roles for mucin-type O-glycosylation in protein secretion, stability, processing, and function. Here, we summarize our current understanding of the diverse roles of mucin-type O-glycosylation during eukaryotic development. Appreciating how this conserved modification operates in developmental processes will provide insight into its roles in human disease and disease susceptibilities. C1 [Tran, Duy T.; Ten Hagen, Kelly G.] NIDCR, Dev Glycobiol Sect, NIH, Bethesda, MD 20892 USA. RP Ten Hagen, KG (reprint author), NIDCR, Dev Glycobiol Sect, NIH, Bethesda, MD 20892 USA. EM kelly.tenhagen@nih.gov FU Intramural Research Program of the NIDCR, National Institutes of Health FX This work was supported by the Intramural Research Program of the NIDCR, National Institutes of Health. This is the third article in the Thematic Minireview Series on Glycobiology and Extracellular Matrices: Glycan Functions Pervade Biology at All Levels. NR 76 TC 49 Z9 50 U1 1 U2 15 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 MAR 8 PY 2013 VL 288 IS 10 BP 6921 EP 6929 DI 10.1074/jbc.R112.418558 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 104NY UT WOS:000316002400014 PM 23329828 ER PT J AU Meitzler, JL Hinde, S Banfi, B Nauseef, WM de Montellano, PRO AF Meitzler, Jennifer L. Hinde, Sara Banfi, Botond Nauseef, William M. de Montellano, Paul R. Ortiz TI Conserved Cysteine Residues Provide a Protein-Protein Interaction Surface in Dual Oxidase (DUOX) Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN MYELOPEROXIDASE; ANGSTROM RESOLUTION; FUNCTIONAL-ANALYSIS; CATALYTIC-ACTIVITY; CONGENITAL GOITER; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; PLASMA-MEMBRANE; NADPH OXIDASES; DOMAIN AB Intramolecular disulfide bond formation is promoted in oxidizing extracellular and endoplasmic reticulum compartments and often contributes to protein stability and function. DUOX1 and DUOX2 are distinguished from other members of the NOX protein family by the presence of a unique extracellular N-terminal region. These peroxidase-like domains lack the conserved cysteines that confer structural stability to mammalian peroxidases. Sequence-based structure predictions suggest that the thiol groups present are solvent-exposed on a single protein surface and are too distant to support intramolecular disulfide bond formation. To investigate the role of these thiol residues, we introduced four individual cysteine to glycine mutations in the peroxidase-like domains of both human DUOXs and purified the recombinant proteins. The mutations caused little change in the stabilities of the monomeric proteins, supporting the hypothesis that the thiol residues are solvent-exposed and not involved in disulfide bonds that are critical for structural integrity. However, the ability of the isolated hDUOX1 peroxidase-like domain to dimerize was altered, suggesting a role for these cysteines in protein-protein interactions that could facilitate homodimerization of the peroxidase-like domain or, in the full-length protein, heterodimeric interactions with a maturation protein. When full-length hDUOX1 was expressed in HEK293 cells, the mutations resulted in decreased H2O2 production that correlated with a decreased amount of the enzyme localized to the membrane surface rather than with a loss of activity or with a failure to synthesize the mutant proteins. These results support a role for the cysteine residues in intermolecular disulfide bond formation with the DUOX maturation factor DUOXA1. C1 [Meitzler, Jennifer L.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hinde, Sara; Banfi, Botond; Nauseef, William M.] Univ Iowa, Inflammat Program, Dept Med, Iowa City, IA 52240 USA. [Banfi, Botond] Univ Iowa, Dept Anat & Cell Biol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52240 USA. [Banfi, Botond] Vet Adm Med Ctr, Iowa City, IA 52240 USA. [de Montellano, Paul R. Ortiz] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. RP de Montellano, PRO (reprint author), Univ Calif San Francisco, Genentech Hall GH N572D,600 16th St, San Francisco, CA 94158 USA. EM ortiz@cgl.ucsf.edu FU National Institutes of Health [DK 30297, HL 090830, AI 70958, AI 044642]; National Center for Research Resources Grant [P41RR001614] FX This work was supported by National Institutes of Health Grants DK 30297 (to P. R. O. M.), HL 090830 (to B. B.), and AI 70958 and AI 044642 (to W. M. N.). This work was also supported by the resources and use of facilities at the Iowa City Department of Veterans Affairs Medical Center, Iowa City, IA (to W. M. N.).; We thank Karine Reiter and the Narum laboratory for the use of their JASCO J-815 spectropolarimeter. Mass spectrometric proteomic analyses were carried out by Bio-Organic Bio-medical Mass Spectrometry Resource at the University of California (director, A. L. Burlingame) supported by National Center for Research Resources Grant P41RR001614. NR 42 TC 12 Z9 12 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 8 PY 2013 VL 288 IS 10 BP 7147 EP 7157 DI 10.1074/jbc.M112.414797 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 104NY UT WOS:000316002400036 PM 23362256 ER PT J AU Hubbard, BP Gomes, AP Dai, H Li, J Case, AW Considine, T Riera, TV Lee, JE Yen, ES Lamming, DW Pentelute, BL Schuman, ER Stevens, LA Ling, AJY Armour, SM Michan, S Zhao, HZ Jiang, Y Sweitzer, SM Blum, CA Disch, JS Ng, PY Howitz, KT Rolo, AP Hamuro, Y Moss, J Perni, RB Ellis, JL Vlasuk, GP Sinclair, DA AF Hubbard, Basil P. Gomes, Ana P. Dai, Han Li, Jun Case, April W. Considine, Thomas Riera, Thomas V. Lee, Jessica E. Yen, Sook E. Lamming, Dudley W. Pentelute, Bradley L. Schuman, Eli R. Stevens, Linda A. Ling, Alvin J. Y. Armour, Sean M. Michan, Shaday Zhao, Huizhen Jiang, Yong Sweitzer, Sharon M. Blum, Charles A. Disch, Jeremy S. Ng, Pui Yee Howitz, Konrad T. Rolo, Anabela P. Hamuro, Yoshitomo Moss, Joel Perni, Robert B. Ellis, James L. Vlasuk, George P. Sinclair, David A. TI Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators SO SCIENCE LA English DT Article ID SMALL-MOLECULE ACTIVATORS; MITOCHONDRIAL-FUNCTION; DEACETYLASE ACTIVITY; RESVERATROL; SIRTUINS; SURVIVAL; TRANSCRIPTION; ACETYLATION; MODULATION; SRT1720 AB A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1 alpha and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs. C1 [Hubbard, Basil P.; Gomes, Ana P.; Li, Jun; Lamming, Dudley W.; Ling, Alvin J. Y.; Armour, Sean M.; Michan, Shaday; Sinclair, David A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Gomes, Ana P.; Rolo, Anabela P.] Univ Coimbra, Dept Life Sci, Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal. [Dai, Han; Case, April W.; Considine, Thomas; Riera, Thomas V.; Schuman, Eli R.; Blum, Charles A.; Disch, Jeremy S.; Ng, Pui Yee; Perni, Robert B.; Ellis, James L.; Vlasuk, George P.] Sirtris, Cambridge, MA 02139 USA. [Lee, Jessica E.; Yen, Sook E.; Hamuro, Yoshitomo] ExSAR Corp, Monmouth Jct, NJ 08852 USA. [Pentelute, Bradley L.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Stevens, Linda A.; Moss, Joel] NHLBI, NIH, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Zhao, Huizhen; Jiang, Yong; Sweitzer, Sharon M.] GlaxoSmithKline, Collegeville, PA 19426 USA. [Howitz, Konrad T.] BIOMOL Res Labs Inc, Plymouth Meeting, PA 19462 USA. [Rolo, Anabela P.] Univ Aveiro, Dept Biol, P-3810193 Aveiro, Portugal. [Sinclair, David A.] Univ New S Wales, Dept Pharmacol, Sydney, NSW 2052, Australia. RP Sinclair, DA (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM david_sinclair@hms.harvard.edu RI Li, Jun/B-8055-2014; OI Lee, Jessica/0000-0002-8567-1633; Sinclair, David/0000-0002-9936-436X; Rolo, Anabela/0000-0003-3535-9630; Lamming, Dudley/0000-0002-0079-4467 FU Glenn Foundation for Medical Research; Ellison Medical Foundation; Juvenile Diabetes Research Foundation; United Mitochondrial Disease Foundation; NIH; NIAID; NSERC fellowship; Portuguese Science and Technology Foundation; Intramural Research Program; NIH/NHLBI FX Supported by the Glenn Foundation for Medical Research, the Ellison Medical Foundation, the Juvenile Diabetes Research Foundation, the United Mitochondrial Disease Foundation, NIH and NIAID grants, an NSERC fellowship (B. P. H.), the Portuguese Science and Technology Foundation (A. P. G.), the Intramural Research Program, and NIH/NHLBI (L. A. S. and J.M.). D. A. S. is a consultant and inventor on patents licensed to Sirtris, a GSK company. H. D., A. W. C., T. C., T. V. R., E. R. S., H.Z., Y.J., S. M. S., C. A. B., J.S.D., P.Y.N., R. B. P., J.L.E., and G. P. V. are employees of Sirtris, a GSK company. Dedicated to the memories of Jana Perni and Harmon Rasnow. A patent application on the PNC1-OPT sirtuin assay has been filed by Harvard Medical School with D. A. S. and B. P. H. as inventors. Patent applications related to sirtuin activators have been filed by Sirtris and Biomol. Natural Sirt1 activators will be provided upon request. Synthetic STACs are provided under a material transfer agreement from Sirtris. NR 29 TC 249 Z9 256 U1 9 U2 127 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 MAR 8 PY 2013 VL 339 IS 6124 BP 1216 EP 1219 DI 10.1126/science.1231097 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 100OG UT WOS:000315709900051 PM 23471411 ER PT J AU Cibelli, J Emborg, ME Prockop, DJ Roberts, M Schatten, G Rao, M Harding, J Mirochnitchenko, O AF Cibelli, Jose Emborg, Marina E. Prockop, Darwin J. Roberts, Michael Schatten, Gerald Rao, Mahendra Harding, John Mirochnitchenko, Oleg TI Strategies for Improving Animal Models for Regenerative Medicine SO CELL STEM CELL LA English DT Editorial Material ID MYOCARDIAL-INFARCTION; CELLS AB The field of regenerative medicine is moving toward translation to clinical practice. However, there are still knowledge gaps and safety concerns regarding stem cell-based therapies. Improving large animal models and methods for transplantation, engraftment, and imaging should help address these issues, facilitating eventual use of stem cells in the clinic. C1 [Cibelli, Jose] Michigan State Univ, Cellular Reprogramming Lab, Dept Anim Sci, E Lansing, MI 48824 USA. [Emborg, Marina E.] Univ Wisconsin, Dept Med Phys, Madison, WI 53715 USA. [Emborg, Marina E.] Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Prockop, Darwin J.] Texas A&M Hlth Sci Ctr, Coll Med, Temple, TX 76502 USA. [Prockop, Darwin J.] Inst Regenerat Med Scott & White, Dept Med, Temple, TX 76502 USA. [Roberts, Michael] Univ Missouri, CS Bond Life Sci Ctr 240B, Columbia, MO 65211 USA. [Schatten, Gerald] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA. [Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Harding, John; Mirochnitchenko, Oleg] NIH, Div Comparat Med ORIP DPCPSI OD, Bethesda, MD 20892 USA. RP Mirochnitchenko, O (reprint author), NIH, Div Comparat Med ORIP DPCPSI OD, 6701 Democracy Blvd,Suite 943-950, Bethesda, MD 20892 USA. EM oleg.mirochnitchenko@nih.gov OI Schatten, Gerald/0000-0001-5206-7782 FU NICHD NIH HHS [P01 HD047675, R01 HD069979]; NIH HHS [P40 OD011050, P51 OD011106] NR 10 TC 12 Z9 13 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD MAR 7 PY 2013 VL 12 IS 3 BP 271 EP 274 DI 10.1016/j.stem.2013.01.004 PG 4 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VC UT WOS:000329569400004 PM 23472868 ER PT J AU Venkataraman, G Song, JY Tzankov, A Dirnhofer, S Heinze, G Kohl, M Traverse-Glehen, A Eberle, FC Hanson, JC Raffeld, MA Pittaluga, S Jaffe, ES AF Venkataraman, Girish Song, Joo Y. Tzankov, Alexandar Dirnhofer, Stephan Heinze, Georg Kohl, Maria Traverse-Glehen, Alexandra Eberle, Franziska C. Hanson, Jeffrey C. Raffeld, Mark A. Pittaluga, Stefania Jaffe, Elaine S. TI Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival SO BLOOD LA English DT Article ID REED-STERNBERG CELLS; CENTER B-CELL; IMMUNOGLOBULIN GENE REARRANGEMENTS; PROGNOSTIC-SIGNIFICANCE; CLONAL IMMUNOGLOBULIN; RARE EXPRESSION; DISEASE; RECEPTOR; PHENOTYPE; TRANSCRIPTION AB Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens (TCA), but the clinical significance of this finding is uncertain. Fifty cHLs expressing any TCA on the HRS cells (TCA-cHL) were identified in two cohorts (National Cancer Institute, n = 38; Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor gamma rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for TCA (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the TCA-cHL group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the TCA, CD4 and CD2 were most commonly expressed, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. During a median follow up of 113 months, TCA expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84]; P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001). TCA-cHL often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with TCA-negative cHLs. C1 [Venkataraman, Girish; Song, Joo Y.; Eberle, Franziska C.; Hanson, Jeffrey C.; Raffeld, Mark A.; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Tzankov, Alexandar; Dirnhofer, Stephan] Univ Basel Hosp, Inst Pathol, CH-4031 Basel, Switzerland. [Heinze, Georg; Kohl, Maria] Med Univ Vienna, Ctr Med Stat Informat & Intelligent Syst, Sect Clin Biometr, Vienna, Austria. [Traverse-Glehen, Alexandra] Ctr Hosp Lyon Sud, Hosp Civils Lyon, Hematopathol Dept, F-69310 Pierre Benite, France. RP Venkataraman, G (reprint author), Loyola Univ, Med Ctr, Dept Pathol, Bldg 110,Room 2222,2160 S 1st Ave, Maywood, IL 60153 USA. EM elainejaffe@nih.gov; elainejaffe@nih.gov RI Song, Joo/E-5356-2016; OI Song, Joo/0000-0003-3497-2513; Venkataraman, Girish/0000-0002-8674-2608; Jaffe, Elaine/0000-0003-4632-0301; Tzankov, Alexandar/0000-0002-1100-3819 FU Center for Cancer Research, NCI FX This study was supported by the intramural budget of the Center for Cancer Research, NCI. NR 51 TC 15 Z9 15 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 7 PY 2013 VL 121 IS 10 BP 1795 EP 1804 DI 10.1182/blood-2012-06-439455 PG 10 WC Hematology SC Hematology GA 182NZ UT WOS:000321751800016 PM 23305738 ER PT J AU Kurotaki, D Osato, N Nishiyama, A Yamamoto, M Ban, T Sato, H Nakabayashi, J Umehara, M Miyake, N Matsumoto, N Nakazawa, M Ozato, K Tamura, T AF Kurotaki, Daisuke Osato, Naoki Nishiyama, Akira Yamamoto, Michio Ban, Tatsuma Sato, Hideaki Nakabayashi, Jun Umehara, Marina Miyake, Noriko Matsumoto, Naomichi Nakazawa, Masatoshi Ozato, Keiko Tamura, Tomohiko TI Essential role of the IRF8-KLF4 transcription factor cascade in murine monocyte differentiation SO BLOOD LA English DT Article ID DENDRITIC CELLS; MYELOID PROGENITORS; GENE-EXPRESSION; TARGET GENES; MACROPHAGES; IDENTIFICATION; LINEAGE; ICSBP; MICE; IMMUNODEFICIENCY AB Monocytes regulate host defenses, inflammation, and tissue homeostasis. The transcription factor interferon regulatory factor-8 (IRF8) stimulates monocyte/macrophage differentiation, yet genome-wide understanding of the differentiation program initiated by IRF8 is lacking. By combining chromatin immunoprecipitation sequencing with gene expression profiling, we show that during IRF8-dependent monocyte differentiation, IRF8 binding occurs at both promoter-proximal and promotor-distal regions together with the transcription factor PU.1 and is associated with gene induction. Many of the promoter-distal IRF8 binding sites show an increase in histone H3 lysine 4 monomethylation, a signature for enhancers. However, about half the IRF8-induced genes were not bound by IRF8, suggesting the involvement of downstream transcription factors. Analysis of DNA motifs in cis-regulatory elements of these indirect IRF8 target genes predicted that Kruppel-like factor-4 (KLF4)-essential for Ly6C(+) monocyte development-is one such factor. Indeed, monocyte development in Irf8(-/-) mice is as defective as that in Klf4(-/-) chimeric mice. Moreover, Irf8(-/-) monocyte-dendritic cell progenitors do not express Klf4 messenger RNA. Introduction of KLF4 into an Irf8(-/-) myeloid progenitor cell line induced a subset of IRF8 target genes and caused partial monocyte differentiation. Taken together, our present results uncover genome-wide behavior of IRF8 and identify an IRF8-KLF4 axis that operates during monocyte differentiation. C1 [Kurotaki, Daisuke; Osato, Naoki; Nishiyama, Akira; Yamamoto, Michio; Ban, Tatsuma; Sato, Hideaki; Nakabayashi, Jun; Umehara, Marina; Tamura, Tomohiko] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa 2360004, Japan. [Miyake, Noriko; Matsumoto, Naomichi] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Yokohama, Kanagawa 2360004, Japan. [Nakazawa, Masatoshi] Yokohama City Univ, Grad Sch Med, Dept Expt Anim Sci, Yokohama, Kanagawa 2360004, Japan. [Ozato, Keiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Tamura, T (reprint author), Yokohama City Univ, Grad Sch Med, Dept Immunol, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan. EM tamurat@yokohama-cu.ac.jp FU Japan Society for the Promotion of Science [24390246, 23659492, 24118002, 24790322, 23590343]; MEXT; Yokohama City University; Yokohama Foundation for Advancement of Medical Science FX This work was supported by KAKENHI grants-in-aid 24390246, 23659492, and 24118002 (T. T.), 24790322 (D. K.), and 23590343 (A.N.) from the Japan Society for the Promotion of Science, a Special Coordination Fund for Promoting Science and Technology "Creation of Innovation Centers for Advanced Interdisciplinary Research Areas" from MEXT (T. T.), a grant for Strategic Research Promotion from Yokohama City University (T. T.), and a grant from the Yokohama Foundation for Advancement of Medical Science (T. T.). The supercomputing resource was provided by Human Genome Center of the Institute of Medical Science at the University of Tokyo. NR 45 TC 60 Z9 60 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 7 PY 2013 VL 121 IS 10 BP 1839 EP 1849 DI 10.1182/blood-2012-06-437863 PG 11 WC Hematology SC Hematology GA 182NZ UT WOS:000321751800021 PM 23319570 ER PT J AU Kang, HS Liao, G DeGraff, LM Gerrish, K Bortner, CD Garantziotis, S Jetten, AM AF Kang, Hong Soon Liao, Grace DeGraff, Laura M. Gerrish, Kevin Bortner, Carl D. Garantziotis, Stavros Jetten, Anton M. TI CD44 Plays a Critical Role in Regulating Diet-Induced Adipose Inflammation, Hepatic Steatosis, and Insulin Resistance SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; MACROPHAGE ACCUMULATION; METABOLIC-DISORDERS; PROFILING REVEALS; LIVER STEATOSIS; ROR-ALPHA; OBESITY; OSTEOPONTIN; DISEASE; TISSUE AB CD44 is a multifunctional membrane receptor implicated in the regulation of several biological processes, including inflammation. CD44 expression is elevated in liver and white adipose tissue (WAT) during obesity suggesting a possible regulatory role for CD44 in metabolic syndrome. To study this hypothesis, we examined the effect of the loss of CD44 expression on the development of various features of metabolic syndrome using CD44 null mice. Our study demonstrates that CD44-deficient mice (CD44KO) exhibit a significantly reduced susceptibility to the development of high fat-diet (HFD)-induced hepatic steatosis, WAT-associated inflammation, and insulin resistance. The decreased expression of genes involved in fatty acid synthesis and transport (Fasn and Cd36), de novo triglyceride synthesis (Mogat1), and triglyceride accumulation (Cidea, Cidec) appears in part responsible for the reduced hepatic lipid accumulation in CD44KO(HFD) mice. In addition, the expression of various inflammatory and cell matrix genes, including several chemokines and its receptors, osteopontin, and several matrix metalloproteinases and collagen genes was greatly diminished in CD44KO(HFD) liver consistent with reduced inflammation and fibrogenesis. In contrast, lipid accumulation was significantly increased in CD44KO(HFD) WAT, whereas inflammation as indicated by the reduced infiltration of macrophages and expression of macrophage marker genes, was significantly diminished in WAT of CD44KO(HFD) mice compared to WT(HFD) mice. CD44KO(HFD) mice remained considerably more insulin sensitive and glucose tolerant than WT(HFD) mice and exhibited lower blood insulin levels. Our study indicates that CD44 plays a critical role in regulating several aspects of metabolic syndrome and may provide a new therapeutic target in the management of insulin resistance. C1 [Kang, Hong Soon; Liao, Grace; DeGraff, Laura M.; Jetten, Anton M.] NIH, Cell Biol Sect, Res Triangle Pk, NC USA. [Gerrish, Kevin] NIH, Microarray Grp, Res Triangle Pk, NC USA. [Bortner, Carl D.] NIEHS, Lab Signal Transduct, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Garantziotis, Stavros] NIH, Matrix Biol Sect, LRB, Res Triangle Pk, NC USA. RP Jetten, AM (reprint author), NIH, Cell Biol Sect, Res Triangle Pk, NC USA. EM jetten@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009; OI Garantziotis, Stavros/0000-0003-4007-375X; Jetten, Anton/0000-0003-0954-4445 FU Intramural Research Program of the NIEHS, NIH [Z01-ES-101586] FX This research was supported by the Intramural Research Program of the NIEHS, NIH (Z01-ES-101586). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 17 Z9 17 U1 4 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 7 PY 2013 VL 8 IS 3 AR e58417 DI 10.1371/journal.pone.0058417 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500081 PM 23505504 ER PT J AU Dranchak, P MacArthur, R Guha, R Zuercher, WJ Drewry, DH Auld, DS Inglese, J AF Dranchak, Patricia MacArthur, Ryan Guha, Rajarshi Zuercher, William J. Drewry, David H. Auld, Douglas S. Inglese, James TI Profile of the GSK Published Protein Kinase Inhibitor Set Across ATP-Dependent and-Independent Luciferases: Implications for Reporter-Gene Assays SO PLOS ONE LA English DT Article ID FIREFLY LUCIFERASE; CHEMICAL LIBRARIES; RENILLA LUCIFERASE; POTENT INHIBITORS; TYROSINE KINASE; ENERGY-TRANSFER; IN-VITRO; DISCOVERY; IDENTIFICATION; BIOLUMINESCENCE AB A library of 367 protein kinase inhibitors, the GSK Published Kinase Inhibitor Set (PKIS), which has been annotated for protein kinase family activity and is available for public screening efforts, was assayed against the commonly used luciferase reporter enzymes from the firefly, Photinus pyralis (FLuc) and marine sea pansy, Renilla reniformis (RLuc). A total of 22 compounds (similar to 6% of the library) were found to inhibit FLuc with 10 compounds showing potencies <= 1 mu M. Only two compounds were found to inhibit RLuc, and these showed relatively weak potency values (similar to 10 mu M). An inhibitor series of the VEGFR2/TIE2 protein kinase family containing either an aryl oxazole or benzimidazole-urea core illustrate the different structure activity relationship profiles FLuc inhibitors can display for kinase inhibitor chemotypes. Several FLuc inhibitors were broadly active toward the tyrosine kinase and CDK families. These data should aid in interpreting the results derived from screens employing the GSK PKIS in cell-based assays using the FLuc reporter. The study also underscores the general need for strategies such as the use of orthogonal reporters to identify kinase or non-kinase mediated cellular responses. C1 [Dranchak, Patricia; MacArthur, Ryan; Guha, Rajarshi; Auld, Douglas S.; Inglese, James] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Inglese, James] NHGRI, NIH, Bethesda, MD 20892 USA. [Zuercher, William J.; Drewry, David H.] GlaxoSmithKline, Dept Biol Chem, Res Triangle Pk, NC USA. RP Inglese, J (reprint author), NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. EM jinglese@mail.nih.gov FU NIH Roadmap for Medical Research FX This work was supported by the NIH Roadmap for Medical Research (J.I. and D.S.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 20 Z9 20 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 MAR 7 PY 2013 VL 8 IS 3 AR e57888 DI 10.1371/journal.pone.0057888 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500037 PM 23505445 ER PT J AU Hagglund, MGA Roshanbin, S Lofqvist, E Hellsten, SV Nilsson, VCO Todkar, A Zhu, YN Stephansson, O Drgonova, J Uhl, GR Schioth, HB Fredriksson, R AF Hagglund, Maria G. A. Roshanbin, Sahar Lofqvist, Erik Hellsten, Sofie V. Nilsson, Victor C. O. Todkar, Aniruddha Zhu, Yinan Stephansson, Olga Drgonova, Jana Uhl, George R. Schioth, Helgi B. Fredriksson, Robert TI B(0)AT2 (SLC6A15) Is Localized to Neurons and Astrocytes, and Is Involved in Mediating the Effect of Leucine in the Brain SO PLOS ONE LA English DT Article ID AMINO-ACID TRANSPORTER; CENTRAL-NERVOUS-SYSTEM; BINDING INHIBITOR DBI; REGULATES FOOD-INTAKE; ORPHAN TRANSPORTER; EXPRESSION PATTERN; V7-3 SLC6A15; PROTEIN; RAT; CHAIN AB The B(0)AT2 protein is a product of the SLC6A15 gene belonging to the SLC6 subfamily and has been shown to be a transporter of essential branched-chain amino acids. We aimed to further characterize the B(0)AT2 transporter in CNS, and to use Slc6a15 knock out (KO) mice to investigate whether B(0)AT2 is important for mediating the anorexigenic effect of leucine. We used the Slc6a15 KO mice to investigate the role of B(0)AT2 in brain in response to leucine and in particular the effect on food intake. Slc6a15 KO mice show lower reduction of food intake as well as lower neuronal activation in the ventromedial hypothalamic nucleus (VMH) in response to leucine injections compared to wild type mice. We also used RT-PCR on rat tissues, in situ hybridization and immunohistochemistry on mouse CNS tissues to document in detail the distribution of SLC6A15 on gene and protein levels. We showed that B(0)AT2 immunoreactivity is mainly neuronal, including localization in many GABAergic neurons and spinal cord motor neurons. B(0)AT2 immunoreactivity was also found in astrocytes close to ventricles, and co-localized with cytokeratin and diazepam binding inhibitor (DBI) in epithelial cells of the choroid plexus. The data suggest that B(0)AT2 play a role in leucine homeostasis in the brain. C1 [Hagglund, Maria G. A.; Roshanbin, Sahar; Lofqvist, Erik; Hellsten, Sofie V.; Nilsson, Victor C. O.; Todkar, Aniruddha; Zhu, Yinan; Stephansson, Olga; Schioth, Helgi B.; Fredriksson, Robert] Uppsala Univ, Dept Neurosci, Uppsala, Sweden. [Drgonova, Jana; Uhl, George R.] NIDA, Mol Neurobiol Branch, NIH, Baltimore, MD USA. RP Fredriksson, R (reprint author), Uppsala Univ, Dept Neurosci, Uppsala, Sweden. EM Robert.Fredriksson@neuro.uu.se OI Drgonova, Jana/0000-0002-4623-8466 FU Swedish Research Council; Ahlens Foundation; Novo Nordisk Foundation; Goran Gustafsson Foundation; Engkvist Foundation; Magnus Bergvall Foundation; National Institutes of Health Intramural Research Program (NIDA) FX This study was supported by the Swedish Research Council as well as the Ahlens Foundation, the Novo Nordisk Foundation, the Goran Gustafsson Foundation, Engkvist Foundation and Magnus Bergvall Foundation, and the National Institutes of Health Intramural Research Program (NIDA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 6 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 MAR 7 PY 2013 VL 8 IS 3 AR e58651 DI 10.1371/journal.pone.0058651 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500110 PM 23505546 ER PT J AU Rajadas, J Sun, WC Li, H Inayathullah, M Cereghetti, D Tan, A Coelho, VD Chrest, FJ Kusiak, JW Smith, WW Taub, D Wu, JC Rifkind, JM AF Rajadas, Jayakumar Sun, Wenchao Li, Hai Inayathullah, Mohammed Cereghetti, Damiano Tan, Aaron Coelho, Valeria de Mello Chrest, Francis J. Kusiak, John W. Smith, Wanli Wei Taub, Dennis Wu, Joseph C. Rifkind, Joseph M. TI Enhanced A beta(1-40) Production in Endothelial Cells Stimulated with Fibrillar A beta(1-42) SO PLOS ONE LA English DT Article ID AMYLOID-BETA PEPTIDE; BLOOD-BRAIN-BARRIER; NITRIC-OXIDE SYNTHASE; SMOOTH-MUSCLE-CELLS; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; POSSIBLE INVOLVEMENT; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; IN-VITRO AB Amyloid accumulation in the brain of Alzheimer's patients results from altered processing of the 39- to 43-amino acid amyloid beta protein (A beta). The mechanisms for the elevated amyloid (A beta(1-42)) are considered to be over-expression of the amyloid precursor protein (APP), enhanced cleavage of APP to A beta, and decreased clearance of A beta from the central nervous system (CNS). We report herein studies of A beta stimulated effects on endothelial cells. We observe an interesting and as yet unprecedented feedback effect involving A beta(1-42) fibril-induced synthesis of APP by Western blot analysis in the endothelial cell line Hep-1. We further observe an increase in the expression of A beta(1-40) by flow cytometry and fluorescence microscopy. This phenomenon is reproducible for cultures grown both in the presence and absence of serum. In the former case, flow cytometry reveals that A beta(1-40) accumulation is less pronounced than under serum-free conditions. Immunofluorescence staining further corroborates these observations. Cellular responses to fibrillar A beta(1-42) treatment involving eNOS upregulation and increased autophagy are also reported. C1 [Rifkind, Joseph M.] NIA, Mol Dynam Sect, Baltimore, MD 21224 USA. [Coelho, Valeria de Mello; Taub, Dennis] NIA, Immunol Lab, Baltimore, MD 21224 USA. [Chrest, Francis J.; Kusiak, John W.; Smith, Wanli Wei] NIA, Res Resources Branch, Baltimore, MD 21224 USA. [Rajadas, Jayakumar; Sun, Wenchao; Li, Hai; Inayathullah, Mohammed; Cereghetti, Damiano] Stanford Univ, Sch Med, Biomat & Adv Drug Delivery Lab, Stanford, CA 94305 USA. [Tan, Aaron] UCL, UCL Med Sch, UCL Div Surg & Intervent Sci, Ctr Nanotechnol & Regenerat Med, London WC1E 6BT, England. [Wu, Joseph C.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Wu, Joseph C.] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. RP Rajadas, J (reprint author), Stanford Univ, Sch Med, Biomat & Adv Drug Delivery Lab, Stanford, CA 94305 USA. EM jayraja@stanford.edu; rifkindj@mail.nih.gov RI Inayathullah, Mohammed/C-6953-2015 OI Inayathullah, Mohammed/0000-0001-7646-1709 FU Intramural Research Program the National Institute of Health; National Institute on Aging; National Institute of Health [HL095571] FX This research was in part supported by the Intramural Research Program the National Institute of Health, National Institute on Aging and National Institute of Health HL095571. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 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 MAR 7 PY 2013 VL 8 IS 3 AR e58194 DI 10.1371/journal.pone.0058194 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500058 PM 23505467 ER PT J AU Sproull, M Avondoglio, D Kramp, T Shankavaram, U Camphausen, K AF Sproull, Mary Avondoglio, Dane Kramp, Tamalee Shankavaram, Uma Camphausen, Kevin TI Correlation of Plasma FL Expression with Bone Marrow Irradiation Dose SO PLOS ONE LA English DT Article ID TOTAL-BODY IRRADIATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE-RADIATION-SYNDROME; LIGAND CONCENTRATION; URINE BIOSPECIMENS; HEMATOPOIESIS; MICE; TRANSPLANTATION; CHEMOTHERAPY; BIODOSIMETRY AB Purpose: Ablative bone marrow irradiation is an integral part of hematopoietic stem cell transplantation. These treatment regimens are based on classically held models of radiation dose and the bone marrow response. Flt-3 ligand (FL) has been suggested as a marker of hematopoiesis and bone marrow status but the kinetics of its response to bone marrow irradiation has yet to be fully characterized. In the current study, we examine plasma FL response to total body and partial body irradiation in mice and its relationship with irradiation dose, time of collection and pattern of bone marrow exposure. Materials/Methods: C57BL6 mice received a single whole body or partial body irradiation dose of 1-8 Gy. Plasma was collected by mandibular or cardiac puncture at 24, 48 and 72 hr post-irradiation as well as 1-3 weeks post-irradiation. FL levels were determined via ELISA assay and used to generate two models: a linear regression model and a gated values model correlating plasma FL levels with radiation dose. Results: At all doses between 1-8 Gy, plasma FL levels were greater than control and the level of FL increased proportionally to the total body irradiation dose. Differences in FL levels were statistically significant at each dose and at all time points. Partial body irradiation of the trunk areas, encompassing the bulk of the hematopoietically active bone marrow, resulted in significantly increased FL levels over control but irradiation of only the head or extremities did not. FL levels were used to generate a dose prediction model for total body irradiation. In a blinded study, the model differentiated mice into dose received cohorts of 1, 4 or 8 Gy based on plasma FL levels at 24 or 72 hrs post-irradiation. Conclusion: Our findings indicate that plasma FL levels might be used as a marker of hematopoietically active bone marrow and radiation exposure in mice. C1 [Sproull, Mary; Avondoglio, Dane; Kramp, Tamalee; Shankavaram, Uma; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov NR 50 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 7 PY 2013 VL 8 IS 3 AR e58558 DI 10.1371/journal.pone.0058558 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500101 PM 23505536 ER PT J AU Yuan, JM Jin, CH Qin, HD Wang, JD Sha, WW Wang, MZ Zhang, YB Zhang, FQ Li, JJ Li, JF Yu, S Qi, SG Shugart, YY AF Yuan, Jianmin Jin, Chunhui Qin, Hai-De Wang, Jidong Sha, Weiwei Wang, Mingzhong Zhang, Yunbiao Zhang, Fuquan Li, Jijiang Li, Jianfeng Yu, Shui Qi, Shuguang Shugart, Yin Yao TI Replication Study Confirms Link between TSPAN18 Mutation and Schizophrenia in Han Chinese SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; MENTAL-RETARDATION; BIPOLAR DISORDER; RISK AB Schizophrenia (SCZ) is a severe psychiatric disorder associated with many different risk factors, both genetic and environmental. A recent genome-wide association study (GWAS) of Han Chinese identified three single-nucleotide polymorphisms (SNPs rs11038167, rs11038172, and rs835784) in the tetraspanins gene TSPAN18 as possible susceptibility loci for schizophrenia. Hoping to validate these findings, we conducted a case-control study of Han Chinese with 1093 schizophrenia cases and 1022 healthy controls. Using the LDR-PCR method to genotype polymorphisms in TSPAN18, we found no significant differences (P>0.05) between patients and controls in either the allele or genotype frequency of the SNPs rs11038167 and rs11038172. We did find, however, that the frequency of the 'A' allele of SNP rs835784 is significantly higher in patients than in controls. We further observed a significant association (OR = 1.197, 95% CI = 1.047-1.369) between risk for SCZ and this 'A' allele. These results confirm the significant association, in Han Chinese populations, of increased SCZ risk and the variant of the TSPAN18 gene containing the 'A' allele of SNP rs835784. C1 [Yuan, Jianmin; Jin, Chunhui; Wang, Jidong; Zhang, Yunbiao; Zhang, Fuquan; Yu, Shui; Qi, Shuguang] Wuxi Mental Hlth Ctr, Wuxi, Jiangsu, Peoples R China. [Jin, Chunhui] Jiangsu Inst Psychol, Wuxi, Jiangsu, Peoples R China. [Qin, Hai-De; Shugart, Yin Yao] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Sha, Weiwei; Li, Jijiang] Yangzhou Wutaishan Hosp, Yangzhou, Jiangsu, Peoples R China. [Wang, Mingzhong; Li, Jianfeng] Nanjing Qinglongshan Mental Hosp, Nanjing, Jiangsu, Peoples R China. RP Qi, SG (reprint author), Wuxi Mental Hlth Ctr, Wuxi, Jiangsu, Peoples R China. EM shuguangqi0208@126.com; kay1yao@mail.nih.gov FU Key Characteristic Specialty/Discipline of Wuxi Hospital Management Center; Wuxi Municipal Health Bureau [Q201208]; Intramural Research Program at the National Institute of Mental Health (NIMH) FX This work was supported by a grant from the Key Characteristic Specialty/Discipline of Wuxi Hospital Management Center, from the Research Project of the Wuxi Municipal Health Bureau (Q201208). HDQ and YYS are supported by supported by the Intramural Research Program at the National Institute of Mental Health (NIMH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this presentation do not necessarily represent the views of the NIMH, National Institutes of Health, Health and Human Services, or the United States Government. NR 19 TC 13 Z9 14 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 7 PY 2013 VL 8 IS 3 AR e58785 DI 10.1371/journal.pone.0058785 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500127 PM 23505562 ER PT J AU Gonzalez-Caballero, N Valenzuela, JG Mc Ribeiro, J Cuervo, P Brazil, RP AF Gonzalez-Caballero, Natalia Valenzuela, Jesus G. Mc Ribeiro, Jose Cuervo, Patricia Brazil, Reginaldo P. TI Transcriptome exploration of the sex pheromone gland of Lutzomyia longipalpis (Diptera: Psychodidae: Phlebotominae) SO PARASITES & VECTORS LA English DT Article DE Lutzomyia longipalpis; Male pheromone gland; Transcriptome; Mevalonate pathway ID FARNESYL-DIPHOSPHATE-SYNTHASE; COTTON BOLL-WEEVIL; HMG-COA REDUCTASE; GREEN PEACH APHID; MEVALONATE PATHWAY; JUVENILE-HORMONE; IPS-PINI; VISCERAL LEISHMANIASIS; BINDING-PROTEINS; SPECIES COMPLEX AB Background: Molecules involved in pheromone biosynthesis may represent alternative targets for insect population control. This may be particularly useful in managing the reproduction of Lutzomyia longipalpis, the main vector of the protozoan parasite Leishmania infantum in Latin America. Besides the chemical identity of the major components of the L. longipalpis sex pheromone, there is no information regarding the molecular biology behind its production. To understand this process, obtaining information on which genes are expressed in the pheromone gland is essential. Methods: In this study we used a transcriptomic approach to explore the pheromone gland and adjacent abdominal tergites in order to obtain substantial general sequence information. We used a laboratory-reared L. longipalpis (one spot, 9-Methyl GermacreneB) population, captured in Lapinha Cave, state of Minas Gerais, Brazil for this analysis. Results: From a total of 3,547 cDNA clones, 2,502 high quality sequences from the pheromone gland and adjacent tissues were obtained and assembled into 1,387 contigs. Through blast searches of public databases, a group of transcripts encoding proteins potentially involved in the production of terpenoid precursors were identified in the 4th abdominal tergite, the segment containing the pheromone gland. Among them, protein-coding transcripts for four enzymes of the mevalonate pathway such as 3-hydroxyl-3-methyl glutaryl CoA reductase, phosphomevalonate kinase, diphosphomevalonate descarboxylase, and isopentenyl pyrophosphate isomerase were identified. Moreover, transcripts coding for farnesyl diphosphate synthase and NADP+ dependent farnesol dehydrogenase were also found in the same tergite. Additionally, genes potentially involved in pheromone transportation were identified from the three abdominal tergites analyzed. Conclusion: This study constitutes the first transcriptomic analysis exploring the repertoire of genes expressed in the tissue containing the L. longipalpis pheromone gland as well as the flanking tissues. Using a comparative approach, a set of molecules potentially present in the mevalonate pathway emerge as interesting subjects for further study regarding their association to pheromone biosynthesis. The sequences presented here may be used as a reference set for future research on pheromone production or other characteristics of pheromone communication in this insect. Moreover, some matches for transcripts of unknown function may provide fertile ground of an in-depth study of pheromone-gland specific molecules. C1 [Gonzalez-Caballero, Natalia; Brazil, Reginaldo P.] Fiocruz MS, IOC, Lab Bioquim & Fisiol Insetos, BR-21040360 Rio De Janeiro, RJ, Brazil. [Valenzuela, Jesus G.; Mc Ribeiro, Jose] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Cuervo, Patricia] Fiocruz MS, IOC, Lab Pesquisa Leishmaniose, BR-21040360 Rio De Janeiro, RJ, Brazil. RP Brazil, RP (reprint author), Fiocruz MS, IOC, Lab Bioquim & Fisiol Insetos, Av Brasil 4365,Sala 213, BR-21040360 Rio De Janeiro, RJ, Brazil. EM rpbrazil@ioc.fiocruz.br RI Cuervo, Patricia/F-9896-2012; OI Ribeiro, Jose/0000-0002-9107-0818 FU Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ); Division of Intramural Research, the National Institute of Allergy and Infectious Disease FX This work was supported by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) and the Division of Intramural Research, the National Institute of Allergy and Infectious Disease. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 108 TC 5 Z9 5 U1 4 U2 33 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD MAR 7 PY 2013 VL 6 AR 56 DI 10.1186/1756-3305-6-56 PG 16 WC Parasitology SC Parasitology GA 129GC UT WOS:000317826000001 PM 23497448 ER PT J AU Robinson, OJ Krimsky, M Grillon, C AF Robinson, Oliver J. Krimsky, Marissa Grillon, Christian TI The impact of induced anxiety on response inhibition SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE anxiety; threat; threat of shock; response inhibition; mind-wandering ID SUSTAINED ATTENTION; PREPULSE INHIBITION; SHOCK; COGNITION; THREAT; MIND; STARTLE; VIGILANCE; EMOTION; TASK AB Anxiety has wide reaching effects on cognition; evidenced most prominently by the "difficulties concentrating" seen in anxiety disorders, and by adaptive harm-avoidant behaviors adopted under threatening circumstances. Despite having critical implications for daily-living, the precise impact of anxiety on cognition is as yet poorly quantified. Here we attempt to clarify the impact of anxiety on sustained attention and response inhibition via a translational anxiety induction in healthy individuals (N = 22). Specifically, in a within-subjects design, participants completed the Sustained Attention to Response Task (SART) in which subjects withhold responses to infrequent no-go stimuli under threat of unpredictable electrical shock (anxious) and safe (non-anxious) conditions. Different studies have argued that this task measures either (1) attention lapses due to off-task thinking or (2) response inhibition; two cognitive functions which are likely impacted by anxiety. We show that threat of shock significantly reduces errors of commission on the no-go trials relative to the safe condition whilst having no effect on go trials or overall reaction time (RT). We suggest that this is because threat of shock during SART promotes response inhibition. In particular we argue that, by virtue of frequency, subjects acquire a habitual bias toward a go response which impairs no-go performance and that threat of shock improves the ability to withhold these prepotent responses. This improved response inhibition likely falls within the range of adaptive cognitive functions which promote cautious harm avoidance under threatening conditions, although a range of alternative explanations for this effect is discussed. C1 [Robinson, Oliver J.; Krimsky, Marissa; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA. RP Robinson, OJ (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, 15K North Dr, Bethesda, MD 20892 USA. EM oliver.j.robinson@gmail.com OI Robinson, Oliver/0000-0002-3100-1132 FU National Institutes of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health. NR 39 TC 15 Z9 15 U1 6 U2 40 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD MAR 7 PY 2013 VL 7 AR 69 DI 10.3389/fnhum.2013.00069 PG 5 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 107XC UT WOS:000316253200001 PM 23471118 ER PT J AU Wang, YC Leung, JW Jiang, YJ Lowery, MG Do, H Vasquez, KM Chen, JJ Wang, WD Li, L AF Wang, Yucai Leung, Justin W. Jiang, Yingjun Lowery, Megan G. Do, Huong Vasquez, Karen M. Chen, Junjie Wang, Weidong Li, Lei TI FANCM and FAAP24 Maintain Genome Stability via Cooperative as Well as Unique Functions SO MOLECULAR CELL LA English DT Article ID ANEMIA CORE COMPLEX; CROSS-LINK REPAIR; COMPLEMENTATION GROUP-M; NUCLEOTIDE EXCISION-REPAIR; DNA-DAMAGE; MONOUBIQUITINATED FANCD2; BINDING-PROTEIN; BLOOM-SYNDROME; REPLICATION; PATHWAY AB The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess nonoverlapping functions such that FAAP24 promotes ATR-mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent interstrand crosslink repair by facilitating recruitment of lesion incision activities, which requires its translocase activity. Our data suggest that FANCM and FAAP24 play multiple, while not fully epistatic, roles in maintaining genomic integrity. C1 [Wang, Yucai; Leung, Justin W.; Jiang, Yingjun; Do, Huong; Chen, Junjie; Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. [Lowery, Megan G.; Vasquez, Karen M.] Univ Texas MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Houston, TX 77030 USA. [Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Wang, Yucai; Chen, Junjie; Li, Lei] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA. [Wang, Weidong] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Li, L (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM leili@mdanderson.org RI Jiang, Yingjun/I-8919-2014 FU Intramural Research Program of the National Institute on Aging [AG000688-07]; National Institute of Health; CPRIT (Multi-Investigator Award) [RP110465-P2]; National Cancer Institute [CA127945, CA097175]; Department of Defense [W81XWH-05-1-0470] FX The authors wish to thank Dr. Zhenghe Wang for providing reagents and technical advice on rAAV-based targeting and Drs. Lee Zou and Junran Zhang for technical advices on RPA2 immunostaining. This work was supported in part by the Intramural Research Program of the National Institute on Aging (AG000688-07), National Institute of Health (W.W.) and by grants from CPRIT (Multi-Investigator Award; RP110465-P2 to J.C.) and the National Cancer Institute (CA127945 and CA097175 Project 3 to L.L). eChIP substrates preparation and clonogenic survivals were assisted respectively by Core C and Core B (CA097175). J.C. is a recipient of an Era of Hope Scholar award from the Department of Defense (W81XWH-05-1-0470). NR 50 TC 27 Z9 28 U1 0 U2 7 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 MAR 7 PY 2013 VL 49 IS 5 BP 997 EP 1009 DI 10.1016/j.molcel.2012.12.010 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 106TQ UT WOS:000316168000020 PM 23333308 ER PT J AU Williams, JS Smith, DJ Marjavaara, L Lujan, SA Chabes, A Kunkel, TA AF Williams, Jessica S. Smith, Dana J. Marjavaara, Lisette Lujan, Scott A. Chabes, Andrei Kunkel, Thomas A. TI Topoisomerase 1-Mediated Removal of Ribonucleotides from Nascent Leading-Strand DNA SO MOLECULAR CELL LA English DT Article ID BASE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; MISMATCH REPAIR; SUBSTRATE-SPECIFICITY; POLYMERASE-EPSILON; DNTP POOLS; RNASE-H; REPLICATION; YEAST; TRANSCRIPTION AB RNase H2-dependent ribonucleotide excision repair (RER) removes ribonucleotides incorporated during DNA replication. When RER is defective, ribonucleotides in the nascent leading strand of the yeast genome are associated with replication stress and genome instability. Here, we provide evidence that topoisomerase 1 (Top1) initiates an independent form of repair to remove ribonucleotides from genomic DNA. This Top1-dependent process activates the S phase checkpoint. Deleting TOP1 reverses this checkpoint activation and also relieves replication stress and genome instability in RER-defective cells. The results reveal an additional removal pathway for a very common lesion in DNA, and they imply that the "dirty" DNA ends created when Top1 incises ribonucleotides in DNA are responsible for the adverse consequences of ribonucleotides in RNase H2-defective cells. C1 [Williams, Jessica S.; Smith, Dana J.; Lujan, Scott A.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Williams, Jessica S.; Smith, Dana J.; Lujan, Scott A.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Marjavaara, Lisette; Chabes, Andrei] Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden. [Chabes, Andrei] Umea Univ, Lab Mol Infect Med Sweden, S-90187 Umea, Sweden. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Chabes, Andrei/0000-0003-1708-8259 FU Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065070]; Swedish Foundation for Strategic Research; Swedish Research Council; Swedish Cancer Society FX We thank Michelle Heacock and Scott Williams for helpful comments on the manuscript and Kunkel lab members for data previously generated in the lab and useful discussions. We are grateful to Grace Kiss ling for statistical advice and Carl Bortner for expert assistance with flow cytometry analysis. We also acknowledge the National Institute of Environmental Health Sciences Molecular Genetics Core Facility for sequence analysis of 5-FOA-resistant mutants and the Flow Cytometry Center for FACS analysis. This work was supported by Project Z01 ES065070 (to T.A.K.) from the Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences, and by the Swedish Foundation for Strategic Research, the Swedish Research Council, and the Swedish Cancer Society (to A.G.). NR 32 TC 51 Z9 51 U1 1 U2 18 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 MAR 7 PY 2013 VL 49 IS 5 BP 1010 EP 1015 DI 10.1016/j.molcel.2012.12.021 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 106TQ UT WOS:000316168000021 PM 23375499 ER PT J AU Sakakibara, S Espigol-Frigole, G Gasperini, P Uldrick, TS Yarchoan, R Tosato, G AF Sakakibara, S. Espigol-Frigole, G. Gasperini, P. Uldrick, T. S. Yarchoan, R. Tosato, G. TI A20/TNFAIP3 inhibits NF-kappa B activation induced by the Kaposi's sarcoma-associated herpesvirus vFLIP oncoprotein SO ONCOGENE LA English DT Article DE KSHV; NF-kappa B; vFLIP/K13; endothelial cells; Kaposi's sarcoma; AIDS ID ZINC-FINGER PROTEIN; DEPENDENT GENE-EXPRESSION; KINASE COMPLEX; IKK-GAMMA; ENDOTHELIAL-CELLS; TRANSCRIPTION FACTOR; UBIQUITIN CHAINS; A20 INTERACTS; KSHV VFLIP; ENZYME A20 AB Kaposi's sarcoma-associated herpesvirus (KSHV) K13/vFLIP (viral Flice-inhibitory protein) induces transcription of numerous genes through NF-kappa B activation, including pro-inflammatory cytokines, which contribute to the pathogenesis of Kaposi's sarcoma (KS). In this study, we report that KSHV vFLIP induces the expression of the NF-kappa B regulatory proteins A20, ABIN-1 and ABIN-3 (A20-binding NF-kappa B inhibitors) in primary human endothelial cells, and that KS spindle cells express A20 in KS tissue. In reporter assays, A20 strongly impaired vFLIP-induced NF-kappa B activation in 293T cells, but ABIN-1 and ABIN-3 did not. Mutational analysis established that the C-terminal domain (residues 427-790) is critical for A20 modulation of NF-kappa B, but the ubiquitin-editing OTU (ovarian tumor) domain is not. In functional assays, A20 inhibited vFLIP-induced expression of the chemokine IP-10, reduced vFLIP-induced cell proliferation and increased IKK1 protein levels. Thus, we demonstrate that A20 negatively regulates NF-kappa B activation directly induced by KSHV vFLIP. By attenuating excessive and prolonged vFLIP-induced NF-kappa B activation that could be harmful to KSHV-infected cells, A20 likely has an important role in the pathogenesis of KSHV-associated diseases, in which vFLIP is expressed. Oncogene (2013) 32, 1223-1232; doi:10.1038/onc.2012.145; published online 23 April 2012 C1 [Sakakibara, S.; Espigol-Frigole, G.; Gasperini, P.; Tosato, G.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Uldrick, T. S.; Yarchoan, R.] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Espigol-Frigole, G (reprint author), NCI, Cellular Oncol Lab, CCR, NIH, Bldg 37,Room 4134, Bethesda, MD 20892 USA. EM GESPIGOL@clinic.ub.es FU intramural research program in Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA FX We thank G Nolan (Stanford University), BK Weaver (Missouri State University), J-M Peloponese Jr, K-T Jeang (NIAID, NIH), DB Conze, JD Ashwell (NCI, NIH), AV Grishin (University of Southern California), A Leonardi (University of Naples, Italy), R Lin (Jewish General Hospital, Canada) for reagents; the patients who volunteered for this study; Dr MN Polizzotto (NCI, NIH), K Aleman and K Wyvill for patient care; the Confocal Microscopy Core Facility (Laboratory of Experimental Carcinogenesis, CCR, NCI) for providing LSM510 and the DNA Minicore Facility (Laboratory of Experimental Carcinogenesis, CCR, NCI) for DNA sequencing, and K Sakakibara (NCI, NIH) for her help in reporter assay. We also thank Drs D Lowy, O Salvucci, H Ohnuki and all members of Laboratory of Cellular Oncology Branch for their advice and help on this work. This study was supported by the intramural research program in Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD20892, USA. NR 65 TC 5 Z9 9 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 7 PY 2013 VL 32 IS 10 BP 1223 EP 1232 DI 10.1038/onc.2012.145 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 110OP UT WOS:000316454500003 PM 22525270 ER PT J AU Wagner, KU Booth, BW Boulanger, CA Smith, GH AF Wagner, K-U Booth, B. W. Boulanger, C. A. Smith, G. H. TI Multipotent PI-MECs are the true targets of MMTV-neu tumorigenesis SO ONCOGENE LA English DT Letter ID MAMMARY EPITHELIAL-CELLS; STEM C1 [Wagner, K-U] Univ Nebraska Med Ctr, Omaha, NE 68198 USA. [Booth, B. W.] Clemson Univ, Clemson, NC USA. [Boulanger, C. A.; Smith, G. H.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wagner, KU (reprint author), Univ Nebraska Med Ctr, Omaha, NE 68198 USA. EM gs4d@nih.gov RI Wagner, Kay-Uwe/B-6044-2009 NR 6 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 7 PY 2013 VL 32 IS 10 BP 1338 EP 1338 DI 10.1038/onc.2012.452 PG 1 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 110OP UT WOS:000316454500014 PM 23045277 ER PT J AU Broderick, JP Palesch, YY Demchuk, AM Yeatts, SD Khatri, P Hill, MD Jauch, EC Jovin, TG Yan, B Silver, FL von Kummer, R Molina, CA Demaerschalk, BM Budzik, R Clark, WM Zaidat, OO Malisch, TW Goyal, M Schonewille, WJ Mazighi, M Engelter, ST Anderson, C Spilker, J Carrozzella, J Ryckborst, KJ Janis, LS Martin, RH Foster, LD Tomsick, TA AF Broderick, Joseph P. Palesch, Yuko Y. Demchuk, Andrew M. Yeatts, Sharon D. Khatri, Pooja Hill, Michael D. Jauch, Edward C. Jovin, Tudor G. Yan, Bernard Silver, Frank L. von Kummer, Ruediger Molina, Carlos A. Demaerschalk, Bart M. Budzik, Ronald Clark, Wayne M. Zaidat, Osama O. Malisch, Tim W. Goyal, Mayank Schonewille, Wouter J. Mazighi, Mikael Engelter, Stefan T. Anderson, Craig Spilker, Judith Carrozzella, Janice Ryckborst, Karla J. Janis, L. Scott Martin, Renee H. Foster, Lydia D. Tomsick, Thomas A. CA Interventional Management Stroke TI Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE ISCHEMIC-STROKE; PERCUTANEOUS CORONARY INTERVENTION; TISSUE-PLASMINOGEN ACTIVATOR; MYOCARDIAL-INFARCTION; CLINICAL-TRIALS; POOLED ANALYSIS; MERCI TRIAL; III TRIAL; MANAGEMENT; TIME AB BACKGROUND Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain. METHODS We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2: 1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). RESULTS The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or >= 20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P = 0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P = 0.83). CONCLUSIONS The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.) C1 [Broderick, Joseph P.; Khatri, Pooja; Spilker, Judith; Carrozzella, Janice; Tomsick, Thomas A.] Univ Cincinnati, Acad Hlth Ctr, Inst Neurosci, Dept Neurol, Cincinnati, OH 45267 USA. [Broderick, Joseph P.; Khatri, Pooja; Spilker, Judith; Carrozzella, Janice; Tomsick, Thomas A.] Univ Cincinnati, Acad Hlth Ctr, Inst Neurosci, Dept Rehabil Med & Radiol, Cincinnati, OH 45267 USA. [Palesch, Yuko Y.; Yeatts, Sharon D.; Foster, Lydia D.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Jauch, Edward C.] Med Univ S Carolina, Div Emergency Med, Charleston, SC USA. [Demchuk, Andrew M.; Hill, Michael D.; Goyal, Mayank; Ryckborst, Karla J.] Univ Calgary, Hotchkiss Brain Inst, Seaman Family Magnet Resonance Res Ctr, Dept Clin Neurosci, Calgary, AB, Canada. [Demchuk, Andrew M.; Hill, Michael D.; Goyal, Mayank; Ryckborst, Karla J.] Univ Calgary, Hotchkiss Brain Inst, Seaman Family Magnet Resonance Res Ctr, Dept Radiol, Calgary, AB, Canada. [Jovin, Tudor G.] Univ Pittsburgh, Med Ctr, Stroke Inst, Pittsburgh, PA USA. [Yan, Bernard] Univ Melbourne, Royal Melbourne Hosp, Melbourne Brain Ctr, Melbourne, Vic 3050, Australia. [Silver, Frank L.] Univ Toronto, Dept Med, Div Neurol, Toronto, ON, Canada. [Silver, Frank L.] Univ Hlth Network, Toronto, ON, Canada. [von Kummer, Ruediger] Dresden Univ, Stroke Ctr, Univ Hosp, Dept Neuroradiol, Dresden, Germany. [Molina, Carlos A.] Hosp Univ Vall dHebron, Dept Neurol, Neurovasc Unit, Barcelona, Spain. [Demaerschalk, Bart M.] Mayo Clin, Dept Neurol, Phoenix, AZ USA. [Budzik, Ronald] Riverside Methodist Hosp, OhioHlth Neurosci Inst, Columbus, OH 43214 USA. [Clark, Wayne M.] Oregon Hlth & Sci Univ, Oregon Stroke Ctr, Portland, OR 97201 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. [Malisch, Tim W.] Alexian Bros Med Ctr, Elk Grove Village, IL USA. [Schonewille, Wouter J.] Univ Med Ctr Utrecht, Dept Neurol, Utrecht, Netherlands. [Schonewille, Wouter J.] St Antonius Hosp, Nieuwegein, Netherlands. [Mazighi, Mikael] Hop Xavier Bichat, Dept Neurol, Paris, France. [Mazighi, Mikael] Hop Xavier Bichat, Stroke Ctr, Paris, France. [Engelter, Stefan T.] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Anderson, Craig] Univ Sydney, Royal Prince Alfred Hosp, George Inst Global Hlth, Sydney, NSW 2006, Australia. [Janis, L. Scott] NINDS, NIH, Bethesda, MD 20892 USA. RP Broderick, JP (reprint author), Univ Cincinnati, Dept Neurol, Inst Neurosci, 260 Stetson St,Suite 2300,POB 670525, Cincinnati, OH 45267 USA. EM joseph.broderick@uc.edu RI Demchuk, Andrew/E-1103-2012; OI Demchuk, Andrew/0000-0002-4930-7789; Yan, Bernard/0000-0001-8802-9606; Hill, Michael/0000-0002-6269-1543 FU National Institutes of Health; National Institute of Neurological Disorders and Stroke [UC U01NS052220, MUSC U01NS054630, U01NS077304]; Genentech; EKOS; Concentric Medical; Cordis Neurovascular; Boehringer Ingelheim; Oakstone Publishing; BrainsGate; Edge Therapeutics; Covidien; Penumbra; Janssen Pharmaceuticals; Medical Dialogues; Vernalis Group; Hoffmann-La Roche Canada; Servier Canada; Bristol-Myers Squibb Canada; Heart and Stroke Foundation of Alberta, Northwest Territories, and Nunavut; Alberta Innovates-Health Solutions; Silk Road Medical; Boehringer Ingelheim Canada; Lundbeck; GE Healthcare; Photo-Thera FX Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.); Supported by grants from the National Institutes of Health and the National Institute of Neurological Disorders and Stroke (UC U01NS052220, MUSC U01NS054630, and U01NS077304) and by Genentech, EKOS, Concentric Medical, Cordis Neurovascular, and Boehringer Ingelheim.; Dr. Broderick reports receiving consulting fees from Photo-Thera, receiving lecture fees from Oakstone Publishing, and receiving a drug from Schering-Plough for use in a study funded by the National Institutes of Health. Dr. Palesch reports receiving consulting fees from BrainsGate and Edge Therapeutics. Dr. Demchuk reports receiving grant support and lecture fees from Covidien. Dr. Khatri reports receiving consulting fees from Penumbra, Genentech, and Janssen Pharmaceuticals; providing expert testimony for Medico-Legal Consulting; receiving lecture fees from Medical Dialogues; receiving royalties from Informa, and receiving travel support from Genentech. Dr. Hill reports receiving consulting fees from Vernalis Group; receiving grant support from Hoffmann-La Roche Canada; receiving lecture fees from Hoffmann-La Roche Canada, Servier Canada, and Bristol-Myers Squibb Canada; receiving stock options from Calgary Scientific; receiving support from the Heart and Stroke Foundation of Alberta, Northwest Territories, and Nunavut and Alberta Innovates-Health Solutions; and serving as an unpaid board member for the Heart and Stroke Foundation of Alberta, Northwest Territories, and Nunavut and the Institute of Circulatory and Respiratory Health of the Canadian Institutes of Health Research. Dr. Jovin reports receiving consulting fees and stock options from Silk Road Medical. Dr. Silver reports serving as an unpaid board member for Boehringer Ingelheim Canada, Bayer Canada, and Bristol-Myers Squibb and Pfizer Canada; receiving lecture fees from Boehringer Ingelheim Canada and Servier Canada; and receiving travel support from Boehringer Ingelheim Canada. Dr. von Kummer reports serving as a board member for Lundbeck and Boehringer Ingelheim; receiving consulting fees from Lundbeck; and receiving lecture fees from Penumbra, Boehringer Ingelheim, and Lundbeck. Dr. Demaerschalk reports receiving grant support and consultant fees from Genentech. Dr. Budzik reports receiving consulting and lecture fees from Concentric Medical. Dr. Goyal reports receiving consulting and lecture fees from Covidien; receiving grant support from Covidien; and owning stock options in Calgary Scientific and NoNO. Dr. Engelter reports serving as a board member for Boehringer Ingelheim and receiving travel support from Boehringer Ingelheim. Dr. Anderson reports receiving lecture fees and travel support from GE Healthcare. Ms. Spilker reports receiving payment for the development of educational presentations from The Stroke Group and serving as a board member for The Stroke Interventionalist: The Clinical Journal of Acute Stroke Treatment. Dr. Tomsick reports receiving grant support from Covidien. No other potential conflict of interest relevant to this article was reported. NR 34 TC 779 Z9 804 U1 6 U2 55 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 MAR 7 PY 2013 VL 368 IS 10 BP 893 EP 903 DI 10.1056/NEJMoa1214300 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 100BG UT WOS:000315669100005 PM 23390923 ER PT J AU Lee, C Lamart, S Moroz, BE AF Lee, Choonsik Lamart, Stephanie Moroz, Brian E. TI Computational lymphatic node models in pediatric and adult hybrid phantoms for radiation dosimetry SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID HUMAN ANATOMY; FEMALE; SIZE; NUMBER; PROTECTION; CT AB We developed models of lymphatic nodes for six pediatric and two adult hybrid computational phantoms to calculate the lymphatic node dose estimates from external and internal radiation exposures. We derived the number of lymphatic nodes from the recommendations in International Commission on Radiological Protection (ICRP) Publications 23 and 89 at 16 cluster locations for the lymphatic nodes: extrathoracic, cervical, thoracic (upper and lower), breast (left and right), mesentery (left and right), axillary (left and right), cubital (left and right), inguinal (left and right) and popliteal (left and right), for different ages (newborn, 1-, 5-, 10-, 15-year-old and adult). We modeled each lymphatic node within the voxel format of the hybrid phantoms by assuming that all nodes have identical size derived from published data except narrow cluster sites. The lymph nodes were generated by the following algorithm: (1) selection of the lymph node site among the 16 cluster sites; (2) random sampling of the location of the lymph node within a spherical space centered at the chosen cluster site; (3) creation of the sphere or ovoid of tissue representing the node based on lymphatic node characteristics defined in ICRP Publications 23 and 89. We created lymph nodes until the pre-defined number of lymphatic nodes at the selected cluster site was reached. This algorithm was applied to pediatric (newborn, 1-, 5-and 10-year-old male, and 15-year-old males) and adult male and female ICRP-compliant hybrid phantoms after voxelization. To assess the performance of our models for internal dosimetry, we calculated dose conversion coefficients, called S values, for selected organs and tissues with Iodine-131 distributed in six lymphatic node cluster sites using MCNPX2.6, a well validated Monte Carlo radiation transport code. Our analysis of the calculations indicates that the S values were significantly affected by the location of the lymph node clusters and that the values increased for smaller phantoms due to the shorter inter-organ distances compared to the bigger phantoms. By testing sensitivity of S values to random sampling and voxel resolution, we confirmed that the lymph node model is reasonably stable and consistent for different random samplings and voxel resolutions. C1 [Lee, Choonsik; Lamart, Stephanie; Moroz, Brian E.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Lee, C (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM leechoonsik@mail.nih.gov RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU Intramural NIH HHS [ZIA CP010132-17] NR 32 TC 4 Z9 5 U1 0 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD MAR 7 PY 2013 VL 58 IS 5 BP N59 EP N82 DI 10.1088/0031-9155/58/5/N59 PG 24 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 093KS UT WOS:000315191400002 PM 23391692 ER PT J AU Warner, ET Glasgow, RE Emmons, KM Bennett, GG Askew, S Rosner, B Colditz, GA AF Warner, Erica T. Glasgow, Russell E. Emmons, Karen M. Bennett, Gary G. Askew, Sandy Rosner, Bernard Colditz, Graham A. TI Recruitment and retention of participants in a pragmatic randomized intervention trial at three community health clinics: Results and lessons learned SO BMC PUBLIC HEALTH LA English DT Article DE Health disparities; Weight-loss; Obesity; Hypertension; Pragmatic trial; Recruitment; Retention ID TERM WEIGHT-LOSS; AFRICAN-AMERICANS; MEDICAL-RESEARCH; FOLLOW-UP; OBESITY; PROGRAM; COHORT; WOMEN; HYPERTENSION; PREVALENCE AB Background: Obesity and hypertension and their associated health complications disproportionately affect communities of color and people of lower socioeconomic status. Recruitment and retention of these populations in research trials, and retention in weight loss trials has been an ongoing challenge. Methods: Be Fit, Be Well was a pragmatic randomized weight loss and hypertension management trial of patients attending one of three community health centers in Boston, Massachusetts. Participants were asked to complete follow-up assessments every 6-months for two years. We describe challenges encountered and strategies implemented to recruit and retain trial participants over the 24-month intervention. We also identify baseline participant characteristics associated with retention status. Retention strategies included financial incentives, contact between assessment visits, building relationships with health center primary care providers (PCPs) and staff, and putting participant convenience first. Results: Active refusal rates were low with 130 of 2,631 patients refusing participation (4.9%). Of 474 eligible persons completing telephone screening, 365 (77.0%) completed their baseline visit and were randomized into the study. The study population was predominantly non-Hispanic Black (71.2%), female (68.5%) and reported annual household income of less than $35,000 (70.1%). Recruitment strategies included use of passive approval of potential participants by PCPs, use of part-time staff, and outsourcing calls to a call center. A total of 314 (86.0%) people completed the 24-month visit. Retention levels varied across study visits and intervention condition. Most participants completed three or more visits (69.6%), with 205 (56.2%) completing all four. At 24-months, lower retention was observed for males and the intervention condition. Retention strategies included building strong relationships with clinic staff, flexibility in overcoming participant barriers through use of taxi vouchers, night and weekend appointments, and keeping participants engaged via newsletters and social gatherings. Conclusion: We were able to retain 86.0% of participants at 24-months. Recruitment and retention of high percentages of racial/ethnic minorities and lower income samples is possible with planning, coordination with a trusted community setting and staff (e.g. community health centers and RAs), adaptability and building strong relationships. C1 [Warner, Erica T.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Warner, Erica T.; Emmons, Karen M.; Bennett, Gary G.] Dana Farber Canc Inst, Ctr Community Based Res, Div Populat Sci, Boston, MA 02115 USA. [Warner, Erica T.; Rosner, Bernard] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Bennett, Gary G.; Askew, Sandy] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Rosner, Bernard] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. RP Warner, ET (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM ewarner@hsph.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU National Heart, Lung, and Blood Institute [U01-HL087071, K22CA126992, K05CA124415-04, 5T32CA009001-36, 5R25GM055353-14] FX This work was supported in part by grant U01-HL087071 from the National Heart, Lung, and Blood Institute and grants K22CA126992 (Dr. Bennett), K05CA124415-04 (Dr. Emmons), 5T32CA009001-36 (Dr. Warner), and 5R25GM055353-14 (Dr. Warner). NR 36 TC 13 Z9 13 U1 3 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAR 6 PY 2013 VL 13 AR 192 DI 10.1186/1471-2458-13-192 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 119UH UT WOS:000317123500002 PM 23496916 ER PT J AU Lucassen, EA Zhao, XC Rother, KI Mattingly, MS Courville, AB de Jonge, L Csako, G Cizza, G AF Lucassen, Eliane A. Zhao, Xiongce Rother, Kristina I. Mattingly, Megan S. Courville, Amber B. de Jonge, Lilian Csako, Gyorgy Cizza, Giovanni CA Sleep Extension Study Grp TI Evening Chronotype Is Associated with Changes in Eating Behavior, More Sleep Apnea, and Increased Stress Hormones in Short Sleeping Obese Individuals SO PLOS ONE LA English DT Article ID MORNINGNESS-EVENINGNESS; FOOD-INTAKE; FREQUENCY; VALIDATION; EPIDEMIC; ADULTS; MORNINGNESS/EVENINGNESS; CONTRIBUTORS; POPULATION; METABOLISM AB Background: Short sleep duration and decreased sleep quality are emerging risk factors for obesity and its associated morbidities. Chronotype, an attribute that reflects individual preferences in the timing of sleep and other behaviors, is a continuum from morningness to eveningness. The importance of chronotype in relation to obesity is mostly unknown. Evening types tend to have unhealthy eating habits and suffer from psychological problems more frequently than Morning types, thus we hypothesized that eveningness may affect health parameters in a cohort of obese individuals reporting sleeping less than 6.5 hours per night. Methodology and Principal Findings: Baseline data from obese (BMI: 38.5+/-6.4 kg/m(2)) and short sleeping (5.8+/-0.8 h/night by actigraphy) participants (n = 119) of the Sleep Extension Study were analyzed (www.ClinicalTrials.gov, identifier NCT00261898). Assessments included the Horne and Ostberg Morningness-Eveningness questionnaire, a three-day dietary intake diary, a 14-day sleep diary, 14 days of actigraphy, and measurements of sleep apnea. Twenty-four hour urinary free cortisol, 24 h urinary norepinephrine and epinephrine levels, morning plasma ACTH and serum cortisol, fasting glucose and insulin, and lipid parameters were determined. Eveningness was associated with eating later in the day on both working and non-working days. Progression towards eveningness was associated with an increase in BMI, resting heart rate, food portion size, and a decrease in the number of eating occasions and HDL-cholesterol. Evening types had overtly higher 24 h urinary epinephrine and morning plasma ACTH levels, and higher morning resting heart rate than Morning types. In addition, Evening types more often had sleep apnea, independent of BMI or neck circumference. Conclusions: Eveningness was associated with eating later and a tendency towards fewer and larger meals and lower HDL-cholesterol levels. In addition, Evening types had more sleep apnea and higher stress hormones. Thus, eveningness in obese, chronically sleep-deprived individuals compounds the cardiovascular risk associated with obesity. C1 [Lucassen, Eliane A.; Courville, Amber B.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Intramural Res Program, NIH, Bethesda, MD USA. [Rother, Kristina I.] NIH, Sect Pediat Diabet & Metab, Bethesda, MD 20892 USA. [Mattingly, Megan S.; de Jonge, Lilian; Cizza, Giovanni] NIDDK, Sect Neuroendocrinol Obes, NIH, Bethesda, MD 20892 USA. [Csako, Gyorgy] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), NIDDK, Sect Neuroendocrinol Obes, NIH, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov OI de Jonge, Lilian/0000-0001-5900-0695 FU National Institutes of Health, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases; Fulbright; VSBfonds; Leiden University Fund FX This study was supported by the National Institutes of Health, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases. EAL received scholarships from Fulbright, VSBfonds and the Leiden University Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors had a conflict of interest. NR 49 TC 40 Z9 40 U1 1 U2 31 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 MAR 6 PY 2013 VL 8 IS 3 AR e56519 DI 10.1371/journal.pone.0056519 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 117EP UT WOS:000316936100004 PM 23483886 ER PT J AU Mikolas, P Kollarova, J Sebkova, K Saudek, V Yilma, P Kostrouchova, M Krause, MW Kostrouch, Z Kostrouchova, M AF Mikolas, Pavol Kollarova, Johana Sebkova, Katerina Saudek, Vladimir Yilma, Petr Kostrouchova, Marketa Krause, Michael W. Kostrouch, Zdenek Kostrouchova, Marta TI GEI-8, a Homologue of Vertebrate Nuclear Receptor Corepressor NCoR/SMRT, Regulates Gonad Development and Neuronal Functions in Caenorhabditis elegans SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE COMPLEXES; C-ELEGANS; HORMONE-RECEPTORS; MEDIATED REPRESSION; NERVOUS-SYSTEM; PROTEIN; SMRT; GENE; PROGRESSION; EXPRESSION AB NCoR and SMRT are two paralogous vertebrate proteins that function as corepressors with unliganded nuclear receptors. Although C. elegans has a large number of nuclear receptors, orthologues of the corepressors NCoR and SMRT have not unambiguously been identified in Drosophila or C. elegans. Here, we identify GEI-8 as the closest homologue of NCoR and SMRT in C. elegans and demonstrate that GEI-8 is expressed as at least two isoforms throughout development in multiple tissues, including neurons, muscle and intestinal cells. We demonstrate that a homozygous deletion within the gei-8 coding region, which is predicted to encode a truncated protein lacking the predicted NR domain, results in severe mutant phenotypes with developmental defects, slow movement and growth, arrested gonadogenesis and defects in cholinergic neurotransmission. Whole genome expression analysis by microarrays identified sets of de-regulated genes consistent with both the observed mutant phenotypes and a role of GEI-8 in regulating transcription. Interestingly, the upregulated transcripts included a predicted mitochondrial sulfide: quinine reductase encoded by Y9C9A.16. This locus also contains non-coding, 21-U RNAs of the piRNA class. Inhibition of the expression of the region coding for 21-U RNAs leads to irregular gonadogenesis in the homozygous gei-8 mutants, but not in an otherwise wild-type background, suggesting that GEI-8 may function in concert with the 21-U RNAs to regulate gonadogenesis. Our results confirm that GEI-8 is the orthologue of the vertebrate NCoR/SMRT corepressors and demonstrate important roles for this putative transcriptional corepressor in development and neuronal function. C1 [Mikolas, Pavol; Sebkova, Katerina; Kostrouchova, Marta] Charles Univ Prague, Fac Med 1, Inst Cellular Biol & Pathol, Lab Mol Biol & Genet, Prague, Czech Republic. [Kollarova, Johana; Saudek, Vladimir; Yilma, Petr; Kostrouchova, Marketa; Kostrouch, Zdenek] Charles Univ Prague, Fac Med 1, Inst Cellular Biol & Pathol, Lab Mol Pathol, Prague, Czech Republic. [Krause, Michael W.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kostrouchova, M (reprint author), Charles Univ Prague, Fac Med 1, Inst Cellular Biol & Pathol, Lab Mol Biol & Genet, Prague, Czech Republic. EM marta.kostrouchova@lf1.cuni.cz OI Krause, Michael/0000-0001-6127-3940 FU Czech Science Foundation [304/08/0970]; Ministry of Education, Youth and Sports of the Czech Republic [0021620806]; Charles University in Prague [SVV 2012 264514, 579612]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, USA FX The work was supported by the following grants: grant 304/08/0970 from the Czech Science Foundation (http://www.gacr.cz/international.htm), grant 0021620806 from the Ministry of Education, Youth and Sports of the Czech Republic (http://www.msmt.cz), Prvouk/1LF/1 and UNCE 204022 from the Charles University in Prague ( http://www.cuni.cz). PM, JK and KS were partially supported by the grant SVV 2012 264514 from the Charles University in Prague (http:// www.cuni.cz). KS was partially supported by the Grant 579612 from the Charles University in Prague. MWK is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, USA (http://www2.niddk.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 68 TC 4 Z9 8 U1 1 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 MAR 6 PY 2013 VL 8 IS 3 AR e58462 DI 10.1371/journal.pone.0058462 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 117EP UT WOS:000316936100119 PM 23484030 ER PT J AU Miura, K Deng, BB Tullo, G Diouf, A Moretz, SE Locke, E Morin, M Fay, MP Long, CA AF Miura, Kazutoyo Deng, Bingbing Tullo, Gregory Diouf, Ababacar Moretz, Samuel E. Locke, Emily Morin, Merribeth Fay, Michael P. Long, Carole A. TI Qualification of Standard Membrane-Feeding Assay with Plasmodium falciparum Malaria and Potential Improvements for Future Assays SO PLOS ONE LA English DT Article ID TRANSMISSION-BLOCKING IMMUNITY; GAMETOCYTE INFECTIVITY; VACCINE; ANTIBODIES; AREA; MOSQUITOS; PFS25; PARASITEMIA; POPULATIONS; VALIDATION AB Vaccines that interrupt malaria transmission are of increasing interest and a robust functional assay to measure this activity would promote their development by providing a biologically relevant means of evaluating potential vaccine candidates. Therefore, we aimed to qualify the standard membrane-feeding assay (SMFA). The assay measures the transmission-blocking activity of antibodies by feeding cultured P. falciparum gametocytes to Anopheles mosquitoes in the presence of the test antibodies and measuring subsequent mosquito infection. The International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline Q2(R1) details characteristics considered in assay validation. Of these characteristics, we decided to qualify the SMFA for Precision, Linearity, Range and Specificity. The transmission-blocking 4B7 monoclonal antibody was tested over 6 feeding experiments at several concentrations to determine four suitable concentrations that were tested in triplicate in the qualification experiments (3 additional feeds) to evaluate Precision, Linearity and Range. For Specificity, 4B7 was tested in the presence of normal mouse IgG. We determined intra-and inter-assay variability of % inhibition of mean oocyst intensity at each concentration of 4B7 (lower concentrations showed higher variability). We also showed that % inhibition was dependent on 4B7 concentration and the activity is specific to 4B7. Since obtaining empirical data is time-consuming, we generated a model using data from all 9 feeds and simulated the effects of different parameters on final readouts to improve the assay procedure and analytical methods for future studies. For example, we estimated the effect of number of mosquitoes dissected on variability of % inhibition, and simulated the relationship between % inhibition in oocyst intensity and % inhibition of prevalence of infected mosquitos at different mean oocysts in the control. SMFA is one of the few biological assays used in preclinical and early clinical development of transmission-blocking vaccines, and this study strongly supports its further development and application. C1 [Miura, Kazutoyo; Deng, Bingbing; Tullo, Gregory; Diouf, Ababacar; Moretz, Samuel E.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Locke, Emily; Morin, Merribeth] PATH Malaria Vaccine Initiat, Washington, DC USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Miura, K (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM kmiura@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU National Institute of Allergy and Infectious Diseases/National Institutes of Health; PATH Malaria Vaccine Initiative FX The study was supported by the intramural program of the National Institute of Allergy and Infectious Diseases/National Institutes of Health and by the PATH Malaria Vaccine Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 29 Z9 29 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 MAR 6 PY 2013 VL 8 IS 3 AR e57909 DI 10.1371/journal.pone.0057909 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 117EP UT WOS:000316936100053 PM 23483940 ER PT J AU Mota-Miranda, ACA Barreto, FK Amarante, MFC Batista, E Monteiro-Cunha, JP Farre, L Galvao-Castro, B Alcantara, LCJ AF Mota-Miranda, Aline C. A. Barreto, Fernanda K. Amarante, Maria F. C. Batista, Everton Monteiro-Cunha, Joana P. Farre, Lourdes Galvao-Castro, Bernardo Alcantara, Luiz C. J. TI Molecular characterization of HTLV-1 gp46 glycoprotein from health carriers and HAM/TSP infected individuals SO VIROLOGY JOURNAL LA English DT Article DE HTLV-1; HAM/TSP; Gp46; Mutation ID LYMPHOTROPIC VIRUS TYPE-1; I-ASSOCIATED MYELOPATHY; TROPICAL SPASTIC PARAPARESIS; PROVIRAL LOAD; VACCINE DESIGN; CELL; PROTEINS; SELECTION; ENTRY; SITES AB Background: Human T-cell Leukemia Virus type 1 (HTLV-1) is the etiological agent of tropical spastic paraparesis/ HTLV-associated myelopathy (HAM/TSP) that can be identified in around 0.25%-3.8% of the infected population. Disease progression can be monitored by the proviral load and may depend on genetic factors, however, it is not well understood why some HTLV-1 infected people develop the disease while others do not. The present study attempts to assess the molecular diversity of gp46 glycoprotein in HAM/TSP patients and Health Carrier (HC) individuals. Methods: Blood samples were collected from 10 individuals, and DNA was extracted from PBMCs to measure the HTLV-1 proviral load. The gp46 coding sequences were amplified PCR, cloned and sequenced. The molecular characterization was performed using bioinformatics tools. Results: The median HTLV-1 proviral load of HC (n = 5) and HAM/TSP (n = 5) patients was similar (average 316,227 copies/106 PBMCs). The gp46 molecular characterization of 146 clones (70 HC and 76 HAM/TSP) revealed an overall diversity, within HC and HAM/TSP clones, of 0.4% and 0.6%, respectively. Five frequent mutations were detected among groups (HAM/TSP and HC clone sequences). A single amino acid (aa) substitution (S35L) was exclusive for the HC group, and three gp46 substitutions (F14S, N42H, G72S) were exclusive for the HAM/TSP group. The remaining frequent mutation (V247I) was present in both groups (p = 0.0014). The in silico protein analysis revealed that the mutated alleles F14S and N42H represent more hydrophilic and flexible protein domains that are likely to be less antigenic. The Receptor Binding Domain is quite variable in the HAM/TSP group. Two other domains (aa 53-75 and 175-209) that contain multiple linear T-cell epitopes showed genetic diversity in both HAM/TSP and HC groups. Further analysis revealed 27 and 13 T-cell epitopes for class I HLA alleles and class II HLA alleles, when analyzing the entire gp46. Conclusions: The most common gp46 mutations were not associated clinical status because they were found in only one individual, except for the V247I mutation, that was found at viral clones from HAM/TSP ad HC individuals. Because of this, we cannot associate any of the gp46 found mutations with the clinical profile. C1 [Mota-Miranda, Aline C. A.; Barreto, Fernanda K.; Galvao-Castro, Bernardo; Alcantara, Luiz C. J.] Fiocruz MS, CPqGM, Fundacao Oswaldo Cruz, Ctr Pesquisa Goncalo Moniz, BR-40295001 Salvador, BA, Brazil. [Mota-Miranda, Aline C. A.; Monteiro-Cunha, Joana P.; Galvao-Castro, Bernardo] Escola Bahiana Med & Saude Publ, Salvador, BA, Brazil. [Mota-Miranda, Aline C. A.; Monteiro-Cunha, Joana P.] Univ Fed Bahia, Inst Ciencias Saude, Salvador, BA, Brazil. [Batista, Everton; Farre, Lourdes] Fundacao Oswaldo Cruz, Ctr Pesquisa Goncalo Moniz, Lab Patol Expt, Salvador, BA, Brazil. [Amarante, Maria F. C.] NCI, NIH, Bethesda, MD 20892 USA. RP Alcantara, LCJ (reprint author), Fiocruz MS, CPqGM, Fundacao Oswaldo Cruz, Ctr Pesquisa Goncalo Moniz, Rua Waldemar Falcao 121, BR-40295001 Salvador, BA, Brazil. EM lalcan@bahia.fiocruz.br OI Farre, Lourdes/0000-0002-3168-1940 FU FAPESB; CNPq FX We would like to thank the FAPESB and CNPq financial support. NR 44 TC 1 Z9 1 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD MAR 6 PY 2013 VL 10 AR 75 DI 10.1186/1743-422X-10-75 PG 10 WC Virology SC Virology GA 108NL UT WOS:000316300400001 PM 23510700 ER PT J AU Volkow, ND Tomasi, D Wang, GJ Telang, F Fowler, JS Logan, J Maynard, LJ Wong, CT AF Volkow, Nora D. Tomasi, Dardo Wang, Gene-Jack Telang, Frank Fowler, Joanna S. Logan, Jean Maynard, L. Jayne Wong, Christopher T. TI Predominance of D2 Receptors in Mediating Dopamine's Effects in Brain Metabolism: Effects of Alcoholism SO JOURNAL OF NEUROSCIENCE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ORAL METHYLPHENIDATE; HUNTINGTONS-DISEASE; F-18 FALLYPRIDE; COCAINE ABUSERS; MESSENGER-RNA; PET; HUMANS; RELEASE; BINDING AB Dopamine signals through D1-like and D2-like receptors, which can stimulate or inhibit, respectively, neuronal activity. Here we assessed the balance between D1 or D2 receptor signaling in the human brain and how it is affected in alcoholism. Using PET, we measured the relationship between changes in dopamine and brain glucose metabolism induced by methylphenidate in controls and alcoholics. We show that methylphenidate induced significant DA increases in striatum, amygdala, and medial orbitofrontal cortex, whereas it decreased metabolism in these brain regions. Methylphenidate-induced dopamine increases were greater in controls than in alcoholics, whereas methylphenidate-induced metabolic decreases were greater in alcoholics. For both groups, methylphenidate-induced dopamine increases were associated with decreases in regional brain metabolism, and the correlations were strongest in subthalamic nuclei, anterior cingulate, and medial orbitofrontal cortex. These correlations were more extensive and robust and the slopes steeper in alcoholics than in controls despite their attenuated dopamine responses to methylphenidate, which suggests an impaired modulation of dopamine signals in the brain of alcoholic subjects. These findings are consistent with a predominant inhibitory effect of dopamine in the human brain that is likely mediated by the prominence of dopamine D2/D3 receptors. C1 [Volkow, Nora D.; Telang, Frank; Maynard, L. Jayne; Wong, Christopher T.] NIDA, Rockville, MD 20857 USA. [Volkow, Nora D.; Tomasi, Dardo] NIAAA, Rockville, MD 20857 USA. [Wang, Gene-Jack; Fowler, Joanna S.; Logan, Jean] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Wang, Gene-Jack; Fowler, Joanna S.; Logan, Jean] Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. RP Volkow, ND (reprint author), NIDA, Execut Blvd 6001,Room 5274, Rockville, MD 20857 USA. EM nvolkow@nida.nih.gov RI Tomasi, Dardo/J-2127-2015; OI Logan, Jean/0000-0002-6993-9994 FU National Institutes of Health FX This research was supported by the National Institutes of Health intramural program. NR 56 TC 9 Z9 10 U1 0 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 6 PY 2013 VL 33 IS 10 BP 4527 EP 4535 DI 10.1523/JNEUROSCI.5261-12.2013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 103OB UT WOS:000315926300030 PM 23467368 ER PT J AU Varmus, H Kumar, HS AF Varmus, Harold Kumar, Harpal S. TI Addressing the Growing International Challenge of Cancer: A Multinational Perspective SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID VACCINATION; COUNTRIES; MORTALITY; BENEFITS; BURDEN; DEATH AB Leaders in cancer research and policy from 15 economically diverse countries met at the U.S. National Institutes of Health in November 2012 to discuss opportunities to reduce cancer incidence and mortality, improve cancer care, and increase our understanding of disease pathophysiology. Here, we present recommendations that the participants believe will enable faster progress in addressing the growing international challenge of cancer. C1 [Varmus, Harold] NCI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kumar, Harpal S.] Canc Res UK, London EC1V 4AD, England. RP Varmus, H (reprint author), NCI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM harold.varmus@nih.gov; harpal.kumar@cancer.org.uk NR 26 TC 12 Z9 14 U1 2 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAR 6 PY 2013 VL 5 IS 175 AR 175cm2 DI 10.1126/scitranslmed.3005899 PG 5 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 103MY UT WOS:000315922500001 PM 23467558 ER PT J AU Nishiyama, A Sharov, AA Piao, Y Amano, M Amano, T Hoang, HG Binder, BY Tapnio, R Bassey, U Malinou, JN Correa-Cerro, LS Yu, H Xin, L Meyers, E Zalzman, M Nakatake, Y Stagg, C Sharova, L Qian, Y Dudekula, D Sheer, S Cadet, JS Hirata, T Yang, HT Goldberg, I Evans, MK Longo, DL Schlessinger, D Ko, MSH AF Nishiyama, Akira Sharov, Alexei A. Piao, Yulan Amano, Misa Amano, Tomokazu Hoang, Hien G. Binder, Bernard Y. Tapnio, Richard Bassey, Uwem Malinou, Justin N. Correa-Cerro, Lina S. Yu, Hong Xin, Li Meyers, Emily Zalzman, Michal Nakatake, Yuhki Stagg, Carole Sharova, Lioudmila Qian, Yong Dudekula, Dawood Sheer, Sarah Cadet, Jean S. Hirata, Tetsuya Yang, Hsih-Te Goldberg, Ilya Evans, Michele K. Longo, Dan L. Schlessinger, David Ko, Minoru S. H. TI Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells SO SCIENTIFIC REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; SELF-RENEWAL; MICROARRAY DATA; PLURIPOTENCY; NETWORK; CIRCUITRY; NANOG; DIFFERENTIATION; LINES; OCT4 AB Networks of transcription factors (TFs) are thought to determine and maintain the identity of cells. Here we systematically repressed each of 100 TFs with shRNA and carried out global gene expression profiling in mouse embryonic stem (ES) cells. Unexpectedly, only the repression of a handful of TFs significantly affected transcriptomes, which changed in two directions/trajectories: one trajectory by the repression of either Pou5f1 or Sox2; the other trajectory by the repression of either Esrrb, Sall4, Nanog, or Tcfap4. The data suggest that the trajectories of gene expression change are already preconfigured by the gene regulatory network and roughly correspond to extraembryonic and embryonic fates of cell differentiation, respectively. These data also indicate the robustness of the pluripotency gene network, as the transient repression of most TFs did not alter the transcriptomes. C1 [Nishiyama, Akira; Sharov, Alexei A.; Piao, Yulan; Amano, Misa; Amano, Tomokazu; Hoang, Hien G.; Binder, Bernard Y.; Tapnio, Richard; Bassey, Uwem; Malinou, Justin N.; Correa-Cerro, Lina S.; Yu, Hong; Xin, Li; Meyers, Emily; Zalzman, Michal; Nakatake, Yuhki; Stagg, Carole; Sharova, Lioudmila; Qian, Yong; Dudekula, Dawood; Sheer, Sarah; Cadet, Jean S.; Hirata, Tetsuya; Yang, Hsih-Te; Goldberg, Ilya; Evans, Michele K.; Longo, Dan L.; Schlessinger, David; Ko, Minoru S. H.] NIA, NIH, Baltimore, MD 21224 USA. [Nakatake, Yuhki; Ko, Minoru S. H.] Keio Univ, Sch Med, Sakaguchi Lab, Dept Syst Med, Tokyo 1608582, Japan. RP Ko, MSH (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM kom@z7.keio.jp RI Ko, Minoru/B-7969-2009; Amano, Tomokazu/F-9720-2013; Nakatake, Yuhki/K-5405-2013; Goldberg, Ilya/H-5307-2011; OI Ko, Minoru/0000-0002-3530-3015; Goldberg, Ilya/0000-0001-8514-6110; Dudekula, Dawood/0000-0002-4054-1827 FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 27 TC 28 Z9 28 U1 1 U2 10 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 MAR 6 PY 2013 VL 3 AR 1390 DI 10.1038/srep01390 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 100JR UT WOS:000315695900001 PM 23462645 ER PT J AU Chapman, JW O'Callaghan, CJ Hu, N Ding, K Yothers, GA Catalano, PJ Shi, Q Gray, RG O'Connell, MJ Sargent, DJ AF Chapman, J. W. O'Callaghan, C. J. Hu, N. Ding, K. Yothers, G. A. Catalano, P. J. Shi, Q. Gray, R. G. O'Connell, M. J. Sargent, D. J. CA ACCENT Collaborative Grp TI Innovative estimation of survival using log-normal survival modelling on ACCENT database SO BRITISH JOURNAL OF CANCER LA English DT Article DE colon cancer; survival; log-normal; Cox; Kaplan-Meier; ACCENT database ID INDIVIDUAL PATIENT DATA; 18 RANDOMIZED-TRIALS; COLORECTAL-CANCER; COLON-CANCER; PROPORTIONAL-HAZARDS; BREAST-CANCER; CETUXIMAB; THERAPY AB Background: The ACCENT database, with individual patient data for 20 898 patients from 18 colon cancer clinical trials, was used to support Food and Drug Administration (FDA) approval of 3-year disease-free survival as a surrogate for 5-year overall survival. We hypothesised substantive differences in survival estimation with log-normal modelling rather than standard Kaplan-Meier or Cox approaches. Methods: Time to relapse, disease-free survival, and overall survival were estimated using Kaplan-Meier, Cox, and log-normal approaches for male subjects aged 60-65 years, with stage III colon cancer, treated with 5-fluorouracil-based chemotherapy regimens (with 5FU), or with surgery alone (without 5FU). Results: Absolute differences between Cox and log-normal estimates with (without) 5FU varied by end point. The log-normal model had 5.8 (6.3)% higher estimated 3-year time to relapse than the Cox model; 4.8 (5.1)% higher 3-year disease-free survival; and 3.2 (2.2)% higher 5-year overall survival. Model checking indicated greater data support for the log-normal than the Cox model, with Cox and Kaplan Meier estimates being more similar. All three model types indicate consistent evidence of treatment benefit on both 3-year disease-free survival and 5-year overall survival; patients allocated to 5FU had 5.0-6.7% higher 3-year disease-free survival and 5.3-6.8% higher 5-year overall survival. Conclusion: Substantive absolute differences between estimates of 3-year disease-free survival and 5-year overall survival with log-normal and Cox models were large enough to be clinically relevant, and warrant further consideration. C1 [Chapman, J. W.; O'Callaghan, C. J.; Hu, N.; Ding, K.] Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. [Yothers, G. A.] Univ Pittsburgh, NSABP Biostat Ctr, Pittsburgh, PA USA. [Yothers, G. A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Catalano, P. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shi, Q.; Sargent, D. J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Gray, R. G.] Univ Birmingham, Birmingham, W Midlands, England. [Yothers, G. A.; O'Connell, M. J.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RP Chapman, JW (reprint author), Queens Univ, NCIC Clin Trials Grp, 10 Stuart St, Kingston, ON, Canada. EM jchapman@ctg.queensu.ca OI Sargent, Daniel/0000-0002-2684-4741; Yothers, Greg/0000-0002-7965-7333 FU Canadian Cancer Society Research Institute; NCCTG grant from the National Cancer Institute at the National Institutes of Health [CA25224]; Canadian National Sciences and Engineering Research Council; Queen's University Department of Community Health and Epidemiology FX This work was supported by a Canadian Cancer Society Research Institute grant to the NCIC Clinical Trials Group (CTG) for NCIC CTG Faculty; the ACCENT group is supported by the NCCTG grant from the National Cancer Institute at the National Institutes of Health (Grant CA25224); and N Hu was supported by a Canadian National Sciences and Engineering Research Council grant to K Ding and by Queen's University Department of Community Health and Epidemiology graduate student support. NR 19 TC 3 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 5 PY 2013 VL 108 IS 4 BP 784 EP 790 DI 10.1038/bjc.2013.34 PG 7 WC Oncology SC Oncology GA 114XI UT WOS:000316775900008 PM 23385733 ER PT J AU Naing, A LoRusso, P Fu, S Hong, D Chen, HX Doyle, LA Phan, AT Habra, MA Kurzrock, R AF Naing, A. LoRusso, P. Fu, S. Hong, D. Chen, H. X. Doyle, L. A. Phan, A. T. Habra, M. A. Kurzrock, R. TI Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE phase I clinical trials; IGF-1R pathway; mTOR pathway; adrenocortical carcinoma; cixutumumab ID ADRENAL-CORTICAL CARCINOMA; TUMORS; MITOTANE; CANCER; CELLS; AKT; UPSTREAM; KINASE; TRIAL AB Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy without an available effective systemic chemotherapy. Insulin growth factor 2 (IGF-2) overexpression leading to the activation of the IGF-1 receptor (IGF-1R)/mammalian target of rapamycin (mTOR) pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at IGF-1R was combined with temsirolimus on the basis of preclinical data. Methods: Patients received cixutumumab, 3-6 mg kg(-1) intravenously (IV) weekly, and temsirolimus, 25-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Results: Twenty-six patients were enrolled (13 (50%) men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolaemia (31%), hypertriglyceridemia (35%), and hyperglycaemia (31%). In all, 11 of 26 patients (42%) achieved stable disease (SD) >6 months (duration range = 6-21 months) with 3 of the 11 having received a prior IGF-1R inhibitor. Conclusion: Cixutumumab combined with temsirolimus was well tolerated and >40% of patients achieved prolonged SD. C1 [Naing, A.; Fu, S.; Hong, D.; Kurzrock, R.] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Clin Trials Program 1, Houston, TX 77030 USA. [LoRusso, P.] Wayne State Univ, Barbara Ann Karmanos Canc Inst, Res Adm, Detroit, MI 48201 USA. [Chen, H. X.; Doyle, L. A.] NCI, Canc Therapy Evaluat Program, NIH, Rockville, MD 20852 USA. [Phan, A. T.] Univ Texas MD Anderson Canc Ctr, Dept GI Med Oncol, Houston, TX 77030 USA. [Habra, M. A.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia, Houston, TX 77030 USA. RP Naing, A (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Phase Clin Trials Program 1, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM anaing@mdanderson.org FU [R21CA13763301A1]; [U01CA62461]; [U01CA62487] FX We acknowledge Kristie Lawhorn, RN, for coordinating and data collection, and Joann Aaron, MA, for scientific review of and editing the paper. This study was supported by R21CA13763301A1 (AN), U01CA62461 (RK), and U01CA62487 (PL). NR 27 TC 43 Z9 45 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 5 PY 2013 VL 108 IS 4 BP 826 EP 830 DI 10.1038/bjc.2013.46 PG 5 WC Oncology SC Oncology GA 114XI UT WOS:000316775900013 PM 23412108 ER PT J AU Sirur, A Best, RB AF Sirur, Anshul Best, Robert B. TI Effects of Interactions with the GroEL Cavity on Protein Folding Rates SO BIOPHYSICAL JOURNAL LA English DT Article ID MOLECULAR CHAPERONES; MACROMOLECULAR STRUCTURE; ESCHERICHIA-COLI; CONFINED SPACES; CAGE; SIMULATIONS; BINDING; LANDSCAPE; RHODANESE; THERMODYNAMICS AB Encapsulation of proteins in chaperonins is an important mechanism by which the cell prevents the accumulation of misfolded species in the cytosol. However, results from theory and simulation for repulsive cavities appear to be inconsistent with recent experimental results showing, if anything, a slowdown in folding rate for encapsulated Rhodanese. We study the folding of Rhodanese in GroEL, using coarse-grained molecular simulations of the complete system including chaperonin and substrate protein. We find that, by approximating the substrate:GroEL interactions as repulsive, we obtain a strong acceleration in rate of between one and two orders of magnitude; a similar result is obtained by representing the chaperonin as a simple spherical cavity. Remarkably, however, we find that using a carefully parameterized, sequence-based potential to capture specific residue-residue interactions between Rhodanese and the GroEL cavity walls induces a very strong reduction of the folding rates. The effect of the interactions is large enough to completely offset the effects of confinement, such that folding in some cases can be even slower than that of the unconfined protein. The origin of the slowdown appears to be stabilization-relative to repulsive confinement-of the unfolded state through binding to the cavity walls, rather than a reduction of the diffusion coefficient along the folding coordinate. C1 [Sirur, Anshul; Best, Robert B.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI Best, Robert/H-7588-2016 OI Best, Robert/0000-0002-7893-3543 FU Biotechnology and Biological Sciences Research Council studentship; Royal Society University Research Fellowship FX A.S. was supported by a Biotechnology and Biological Sciences Research Council studentship and R.B.B. was supported by a Royal Society University Research Fellowship. NR 58 TC 15 Z9 15 U1 1 U2 30 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 MAR 5 PY 2013 VL 104 IS 5 BP 1098 EP 1106 DI 10.1016/j.bpj.2013.01.034 PG 9 WC Biophysics SC Biophysics GA 101AY UT WOS:000315748800019 PM 23473493 ER PT J AU Li, YJ Periwal, V AF Li, Yanjun Periwal, Vipul TI Synergy in Free Radical Generation is Blunted by High-Fat Diet Induced Alterations in Skeletal Muscle Mitochondrial Metabolism SO BIOPHYSICAL JOURNAL LA English DT Article ID OXYGEN SPECIES GENERATION; BETA-CELL MITOCHONDRIA; INSULIN-RESISTANCE; OXIDATIVE-PHOSPHORYLATION; ACID CYCLE; 3-NITROPROPIONIC ACID; UNCOUPLING PROTEINS; COMPUTATIONAL MODEL; COMPLEX-II; MECHANISMS AB Due to their role in cellular energetics and metabolism, skeletal muscle mitochondria appear to play a key role in the development of insulin resistance and type II diabetes. High-fat diet can induce higher levels of reactive oxygen species (ROS), evidenced by hydrogen peroxide (H2O2) emission from mitochondria, which may be causal for insulin resistance in skeletal muscle. The underlying mechanisms are unclear. Recent published data on single substrate (pyruvate, succinate, fat) metabolism in both normal diet (CON) and high-fat diet (HFD) states of skeletal muscle allowed us to develop an integrated mathematical model of skeletal muscle mitochondrial metabolism. Model simulations suggested that long-term HFD may affect specific metabolic reaction/pathways by altering enzyme activities. Our model allows us to predict oxygen consumption and ROS generation for any combination of substrates. In particular, we predict a synergy between (iso-membrane potential) combinations of pyruvate and fat in ROS production compared to the sum of ROS production with each substrate singly in both CON and HFD states. This synergy is blunted in the HFD state. C1 [Li, Yanjun; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Periwal, V (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. EM vipulp@mail.nih.gov RI Periwal, Vipul/I-1728-2012 FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. NR 57 TC 2 Z9 2 U1 1 U2 6 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 MAR 5 PY 2013 VL 104 IS 5 BP 1127 EP 1141 DI 10.1016/j.bpj.2013.01.025 PG 15 WC Biophysics SC Biophysics GA 101AY UT WOS:000315748800022 PM 23473496 ER PT J AU Wang, E Kawaoka, S Yu, M Shi, JW Ni, T Yang, WJ Zhu, J Roeder, RG Vakoc, CR AF Wang, Eric Kawaoka, Shinpei Yu, Ming Shi, Junwei Ni, Ting Yang, Wenjing Zhu, Jun Roeder, Robert G. Vakoc, Christopher R. TI Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epigenetics; cancer ID RNA-POLYMERASE-II; ACUTE MYELOID-LEUKEMIA; H3K79 METHYLATION; TUMOR-SUPPRESSOR; HUMAN-CELLS; GENE; TRANSCRIPTION; MONOUBIQUITINATION; LEUKEMOGENESIS; UBIQUITYLATION AB Mixed-lineage leukemia (MLL) fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here, we identify the histone H2B E3 ubiquitin ligase ring finger protein 20 (RNF20) as an additional chromatin regulator that is necessary for MLL-fusion-mediated leukemo-genesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation, under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, effects resembling Dot1l inhibition. Using ChIP-seq, we found that H2B ubiquitination is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, Rnf20 is required to maintain local levels of H3K79 methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby cotranscriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program. C1 [Wang, Eric; Kawaoka, Shinpei; Shi, Junwei; Vakoc, Christopher R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Yu, Ming; Roeder, Robert G.] Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10065 USA. [Shi, Junwei] SUNY Stony Brook, Mol & Cellular Biol Program, Stony Brook, NY 11794 USA. [Ni, Ting; Yang, Wenjing; Zhu, Jun] NHLBI, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Roeder, RG (reprint author), Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10065 USA. EM roeder@rockefeller.edu; vakoc@cshl.edu OI Vakoc, Christopher/0000-0002-1158-7180 FU Starr Cancer Foundation Grant [I4-A430]; Edward P. Evans Foundation; Martin Sass Foundation; F. M. Kirby Foundation; Leukemia and Lymphoma Society Specialized Center of Research (SCOR) Grant [7132-08]; Burroughs-Wellcome Career Awards for Medical Scientists award; National Cancer Institute Cancer Center Support Grant Development Funds [CA45508] FX We thank M. Taylor, E. Earl, and L. Bianco for support with mouse work; F. Karginov for assistance with RNA-seq analysis; and G. Blobel and C. Hammell for comments on the manuscript. This work was supported by Starr Cancer Foundation Grant I4-A430 (to C.R.V. and R.G.R), and additional funding was provided by the Edward P. Evans Foundation, the Martin Sass Foundation, and the F. M. Kirby Foundation. R.G.R. was also supported by Leukemia and Lymphoma Society Specialized Center of Research (SCOR) Grant 7132-08. C.R.V. is also supported by a Burroughs-Wellcome Career Awards for Medical Scientists award and National Cancer Institute Cancer Center Support Grant Development Funds (Grant CA45508). NR 50 TC 26 Z9 27 U1 0 U2 23 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 5 PY 2013 VL 110 IS 10 BP 3901 EP 3906 DI 10.1073/pnas.1301045110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109OH UT WOS:000316377400054 PM 23412334 ER PT J AU Chiorazzi, M Rui, LX Yang, YD Ceribelli, M Tishbi, N Maurer, CW Ranuncolo, SM Zhao, H Xu, WH Chan, WCC Jaffe, ES Gascoyne, RD Campo, E Rosenwald, A Ott, G Delabie, J Rimsza, LM Shaham, S Staudt, LM AF Chiorazzi, Michael Rui, Lixin Yang, Yandan Ceribelli, Michele Tishbi, Nima Maurer, Carine W. Ranuncolo, Stella M. Zhao, Hong Xu, Weihong Chan, Wing-Chung C. Jaffe, Elaine S. Gascoyne, Randy D. Campo, Elias Rosenwald, Andreas Ott, German Delabie, Jan Rimsza, Lisa M. Shaham, Shai Staudt, Louis M. TI Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; ubiquitin ID PROTEASOME-DEPENDENT DEGRADATION; C-ELEGANS; SIGNALING PATHWAY; B-CELLS; BCL-2; GENE; PHOSPHORYLATION; INDUCTION; APOPTOSIS; EXPRESSION AB Cell death is a common metazoan cell fate, and its inactivation is central to human malignancy. In Caenorhabditis elegans, apoptotic cell death occurs via the activation of the caspase CED-3 following binding of the EGL-1/BH3-only protein to the antiapoptotic CED-9/BCL2 protein. Here we report a major alternative mechanism for caspase activation in vivo involving the F-box protein DRE-1. DRE-1 functions in parallel to EGL-1, requires CED-9 for activity, and binds to CED-9, suggesting that DRE-1 promotes apoptosis by inactivating CED-9. FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death. Moreover, some human diffuse large B-cell lymphomas have inactivating mutations in FBXO10 or express FBXO10 at low levels. Our results suggest that DRE-1/FBXO10 is a conserved regulator of apoptosis. C1 [Chiorazzi, Michael; Tishbi, Nima; Maurer, Carine W.; Shaham, Shai] Rockefeller Univ, Lab Dev Genet, New York, NY 10065 USA. [Rui, Lixin; Yang, Yandan; Ceribelli, Michele; Ranuncolo, Stella M.; Zhao, Hong; Xu, Weihong; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Chan, Wing-Chung C.] Univ Nebraska, Dept Pathol, Omaha, NE 68198 USA. [Chan, Wing-Chung C.] Univ Nebraska, Dept Microbiol, Omaha, NE 68198 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Campo, Elias] Univ Barcelona, Hosp Clin, E-08036 Barcelona, Spain. [Rosenwald, Andreas] Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, D-70376 Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Delabie, Jan] Oslo Univ Hosp, Pathol Clin, N-0424 Oslo, Norway. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. [Rimsza, Lisa M.] SW Oncol Grp, Ann Arbor, MI 48106 USA. RP Shaham, S (reprint author), Rockefeller Univ, Lab Dev Genet, New York, NY 10065 USA. EM shaham@rockefeller.edu; lstaudt@mail.nih.gov OI Campo, elias/0000-0001-9850-9793; Delabie, Jan/0000-0001-5023-0689; Jaffe, Elaine/0000-0003-4632-0301 FU National Research Service [F30AG035484]; National Institutes of Health (NIH)/National Institute on Aging (NIA); NIH [GM07739]; National Health and Medical Research Council of Australia [R01HD042680, R01NS081490]; National Cancer Institute (NCI) Strategic Partnerships to Evaluate Cancer Signatures [UO1-CA 114778]; Intramural Research Program of the NIH; NCI; Center for Cancer Research FX We thank members of the S. S. and L. M. S. laboratories for comments and the Shohei Mitani for strain C05C8.6(tm3719). Some nematode strains used were provided by the Caenorhabditis Genetics Center. This work was supported by National Research Service Award F30AG035484 from the National Institutes of Health (NIH)/National Institute on Aging (NIA) (to M. Chiorazzi); NIH Medical Scientist Training Program Grant GM07739 (to M. Chiorazzi); a C. J. Martin Fellowship from the National Health and Medical Research Council of Australia (to L.R.); NIH Grants R01HD042680 and R01NS081490 (to S.S.); National Cancer Institute (NCI) Strategic Partnerships to Evaluate Cancer Signatures Grant UO1-CA 114778; and the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 34 TC 22 Z9 37 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 5 PY 2013 VL 110 IS 10 BP 3943 EP 3948 DI 10.1073/pnas.1217271110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109OH UT WOS:000316377400061 PM 23431138 ER PT J AU Welsbie, DS Yang, ZY Ge, Y Mitchell, KL Zhou, XR Martin, SE Berlinicke, CA Hackler, L Fuller, J Fu, J Cao, LH Han, B Auld, D Xue, T Hirai, S Germain, L Simard-Bisson, C Blouin, R Nguyen, JV Davis, CHO Enke, RA Boye, SL Merbs, SL Marsh-Armstrong, N Hauswirth, WW DiAntonio, A Nickells, RW Inglese, J Hanes, J Yau, KW Quigley, HA Zack, DJ AF Welsbie, Derek S. Yang, Zhiyong Ge, Yan Mitchell, Katherine L. Zhou, Xinrong Martin, Scott E. Berlinicke, Cynthia A. Hackler, Laszlo, Jr. Fuller, John Fu, Jie Cao, Li-hui Han, Bing Auld, Douglas Xue, Tian Hirai, Syu-ichi Germain, Lucie Simard-Bisson, Caroline Blouin, Richard Nguyen, Judy V. Davis, Chung-ha O. Enke, Raymond A. Boye, Sanford L. Merbs, Shannath L. Marsh-Armstrong, Nicholas Hauswirth, William W. DiAntonio, Aaron Nickells, Robert W. Inglese, James Hanes, Justin Yau, King-Wai Quigley, Harry A. Zack, Donald J. TI Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neuroprotection; MAP3K12; drug discovery ID INHIBITOR SELECTIVITY; AXONAL REGENERATION; MOUSE RETINA; IN-VIVO; DEGENERATION; GLAUCOMA; PATHWAY; NEURONS; INJURY; ELECTROPORATION AB Glaucoma, a major cause of blindness worldwide, is a neurodegenerative optic neuropathy in which vision loss is caused by loss of retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for the development of neuroprotective drugs, we developed a high-throughput RNA interference screen with primary RGCs and used it to screen the full mouse kinome. The screen identified dual leucine zipper kinase (DLK) as a key neuroprotective target in RGCs. In cultured RGCs, DLK signaling is both necessary and sufficient for cell death. DLK undergoes robust posttranscriptional up-regulation in response to axonal injury in vitro and in vivo. Using a conditional knockout approach, we confirmed that DLK is required for RGC JNK activation and cell death in a rodent model of optic neuropathy. In addition, tozasertib, a small molecule protein kinase inhibitor with activity against DLK, protects RGCs from cell death in rodent glaucoma and traumatic optic neuropathy models. Together, our results establish a previously undescribed drug/drug target combination in glaucoma, identify an early marker of RGC injury, and provide a starting point for the development of more specific neuroprotective DLK inhibitors for the treatment of glaucoma, non-glaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations. C1 [Welsbie, Derek S.; Yang, Zhiyong; Ge, Yan; Mitchell, Katherine L.; Zhou, Xinrong; Berlinicke, Cynthia A.; Hackler, Laszlo, Jr.; Fuller, John; Fu, Jie; Han, Bing; Enke, Raymond A.; Merbs, Shannath L.; Hanes, Justin; Yau, King-Wai; Quigley, Harry A.; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. [Welsbie, Derek S.; Quigley, Harry A.; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Glaucoma Ctr Excellence, Baltimore, MD 21287 USA. [Ge, Yan] Minist Educ, Key Lab Pathobiol, Changchun 130000, Peoples R China. [Zhou, Xinrong] Harbin Med Univ, Affiliated Hosp 2, Dept Ophthalmol, Harbin 150086, Heilongjiang, Peoples R China. [Martin, Scott E.; Auld, Douglas; Inglese, James] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Fu, Jie; Han, Bing; Hanes, Justin] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Ctr Nanomed, Baltimore, MD 21231 USA. [Cao, Li-hui; Xue, Tian; Nguyen, Judy V.; Marsh-Armstrong, Nicholas; Yau, King-Wai; Zack, Donald J.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Hirai, Syu-ichi] Wakayama Med Univ, Sch Med, Dept Biol, Wakayama 6410011, Japan. [Germain, Lucie; Simard-Bisson, Caroline; Marsh-Armstrong, Nicholas] Univ Laval, Ctr Hosp Affilie Univ Quebec, Ctr Rech Fonds Rech Quebec Sante, Ctr Lab Organogenese Expt,Lab Organogenese Expt, Quebec City, PQ G1J 1Z4, Canada. [Germain, Lucie; Simard-Bisson, Caroline] Univ Laval, Fac Med, Dept Chirurg, Quebec City, PQ G1J 1Z4, Canada. [Blouin, Richard] Univ Sherbrooke, Fac Sci, Dept Biol, Sherbrooke, PQ J1K 2R1, Canada. [Davis, Chung-ha O.] Kennedy Krieger Inst, Hugo W Moser Res Inst, Baltimore, MD 21205 USA. [Boye, Sanford L.; Hauswirth, William W.] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. [DiAntonio, Aaron] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Nickells, Robert W.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA. [Inglese, James] NHGRI, NIH, Bethesda, MD 20892 USA. [Zack, Donald J.] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Zack, Donald J.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. [Zack, Donald J.] Inst Vis, F-75012 Paris, France. RP Zack, DJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. EM dzack@jhmi.edu OI Fuller, John/0000-0002-6587-146X; Zack, Don/0000-0002-7966-1973 FU National Eye Institute; NIH; American Health Assistance Foundation; Glaucoma Research Foundation; Research to Prevent Blindness, Inc; Macula Vision Research Foundation; Eldon Family Foundation; Vision for Children FX We thank Noriko Esumi, Akrit Sodhi, Ted Dawson, and Valina Dawson for reviewing the manuscript and/or scientific advice; Mary Ellen Pease and Matthew Steinhart for help with the rat glaucoma experiment; and Jiangxia Wang and John McGready for assistance with the statistics. This study was supported, in part, by grants from the National Eye Institute; NIH; the American Health Assistance Foundation; Glaucoma Research Foundation; Research to Prevent Blindness, Inc.; the Macula Vision Research Foundation; the Eldon Family Foundation; Vision for Children; and generous gifts from the Guerrieri Family Foundation and from Mr. and Mrs. Robert and Clarice Smith. NR 51 TC 56 Z9 56 U1 1 U2 27 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 MAR 5 PY 2013 VL 110 IS 10 BP 4045 EP 4050 DI 10.1073/pnas.1211284110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109OH UT WOS:000316377400078 PM 23431148 ER PT J AU Liu, HS Chefer, S Lu, HB Guillem, K Rea, W Kurup, P Yang, YH Peoples, L Stein, EA AF Liu, Hua-Shan Chefer, Svetlana Lu, Hanbing Guillem, Karine Rea, William Kurup, Pradeep Yang, Yihong Peoples, Laura Stein, Elliot A. TI Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE context cues; neuroplasticity; drug addiction ID SEEKING BEHAVIOR; ORBITOFRONTAL CORTEX; ACCUMBENS NEURONS; FUNCTIONAL MRI; INSULAR CORTEX; NEURAL SYSTEMS; BASOLATERAL AMYGDALA; PREFRONTAL CORTEX; EXTENDED AMYGDALA; DECISION-MAKING AB Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experience-induced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S-) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S- was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S-). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions. C1 [Liu, Hua-Shan; Chefer, Svetlana; Lu, Hanbing; Rea, William; Kurup, Pradeep; Yang, Yihong; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Liu, Hua-Shan] Univ Penn, Dept Neurol, Ctr Funct Neuroimaging, Philadelphia, PA 19104 USA. [Chefer, Svetlana] NIAID, NIH, Frederick, MD 21072 USA. [Guillem, Karine] Univ Bordeaux, Inst Malad Neurodegenerat, F-33076 Bordeaux, France. [Guillem, Karine] Univ Bordeaux 2, Neurophysiol Lab, CNRS, F-33076 Bordeaux, France. [Guillem, Karine; Peoples, Laura] Univ Penn, Sch Med, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Peoples, Laura] Drexel Univ, Coll Med, Dept Physiol & Pharmacol, Philadelphia, PA 19129 USA. RP Stein, EA (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM estein@mail.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH); NIH; Institute for Translational Medicine and Therapeutics of the University of Pennsylvania; National Center for Research Resources [UL155024134] FX We thank Dr. Anna Rose Childress for her helpful comments and insights on the study. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), and by an NIH Director's Bench-to-Bedside grant (to L.P. and E.A.S.). The project was also partially supported by the Institute for Translational Medicine and Therapeutics of the University of Pennsylvania and National Center for Research Resources Grant UL155024134. NR 62 TC 6 Z9 6 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 5 PY 2013 VL 110 IS 10 BP 4093 EP 4098 DI 10.1073/pnas.1207531110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109OH UT WOS:000316377400086 PM 23431137 ER PT J AU Hong, JH Yang, D Shcheynikov, N Ohana, E Shin, DM Muallem, S AF Hong, Jeong Hee Yang, Dongki Shcheynikov, Nikolay Ohana, Ehud Shin, Dong Min Muallem, Shmuel TI Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3- cotransporters family SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RECEPTOR-BINDING PROTEIN; HCO3-SALVAGE; ROBETTA SERVER; IP3 RECEPTOR; TRANSPORTERS; PREDICTION; CALCIUM; CLONING; DOMAIN; PNBC1 AB Fluid and HCO3- secretion is a vital function of secretory epithelia, involving basolateral HCO3- entry through the Na+-HCO3- cotransporter (NBC) NBCe1-B, and luminal HCO3- exit mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 26 (SLC26) Cl-/HCO3- exchangers. HCO3- secretion is highly regulated, with the WNK/SPAK kinase pathway setting the resting state and the IRBIT/PP1 pathway setting the stimulated state. However, we know little about the relationships between the WNK/SPAK and IRBIT/PP1 sites in the regulation of the transporters. The first 85 N-terminal amino acids of NBCe1-B function as an auto-inhibitory domain. Here we have identified a positively charged module within NBCe1-B(37-65) that is conserved in NBCn1-A and all 20 members of the NBC superfamily except NBCe1-A. This module is required for the interaction and activation of NBCe1-B and NBCn1-A by IRBIT and their regulation by phosphatidylinositol 4,5-bisphosphate (PIP2). Activation of the transporters by IRBIT and PIP2 is nonadditive but complementary. Phosphorylation of Ser65 mediates regulation of NBCe1-B by SPAK, and phosphorylation of Thr49 is required for regulation by IRBIT and SPAK. Sequence searches using the NBCe1-B regulatory module as a template identified a homologous sequence in the CFTR R domain and Slc26a6 sulfat transporter and antisigma factor antagonist (STAS) domain. Accordingly, the R and STAS domains bind IRBIT, and the R domain is required for activation of CFTR by IRBIT. These findings reveal convergence of regulatory modalities in a conserved domain of the NBC that may be present in other HCO3- transporters and thus in the regulation of epithelial fluid and HCO3- secretion. C1 [Hong, Jeong Hee; Shcheynikov, Nikolay; Ohana, Ehud; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Yang, Dongki] Gachon Univ Med & Sci, Dept Physiol, Grad Sch Med, Inchon 406799, South Korea. [Shin, Dong Min] Yonsei Univ, Coll Dent, Brain Korea Project 21, Dept Oral Biol, Seoul 120752, South Korea. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM Shmuel.Muallem@nih.gov FU National Institutes of Health, National Institute of Dental and Cranial Research Intramural Research Program [Z1A-DE000735]; National Research Foundation of Korea [NRF-2009-352-E00046]; Korean Government; National Research Foundation of Korea's Basic Science Research Program; Ministry of Education, Science and Technology [2012-0003965, 2012R1A2A1A01003487] FX This work was funded by the National Institutes of Health, National Institute of Dental and Cranial Research Intramural Research Program (Grant Z1A-DE000735); the National Research Foundation of Korea (Grant NRF-2009-352-E00046, funded by the Korean Government); and the National Research Foundation of Korea's Basic Science Research Program funded by the Ministry of Education, Science and Technology (Grants 2012-0003965 and 2012R1A2A1A01003487). NR 26 TC 28 Z9 28 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 MAR 5 PY 2013 VL 110 IS 10 BP 4105 EP 4110 DI 10.1073/pnas.1221410110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109OH UT WOS:000316377400088 PM 23431199 ER PT J AU Robinson, OJ Overstreet, C Charney, DR Vytal, K Grillon, C AF Robinson, Oliver J. Overstreet, Cassie Charney, Danielle R. Vytal, Katherine Grillon, Christian TI Stress increases aversive prediction error signal in the ventral striatum SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE threat of shock; punishment; anxiety; face perception ID PUNISHMENT PREDICTION; TRYPTOPHAN DEPLETION; MISMATCH NEGATIVITY; REWARD PREDICTION; ANXIETY; THREAT; RESPONSES; HUMANS; ROLES; FEAR AB From job interviews to the heat of battle, it is evident that people think and learn differently when stressed. In fact, learning under stress may have long-term consequences; stress facilitates aversive conditioning and associations learned during extreme stress may result in debilitating emotional responses in posttraumatic stress disorder. The mechanisms underpinning such stress-related associations, however, are unknown. Computational neuroscience has successfully characterized several mechanisms critical for associative learning under normative conditions. One such mechanism, the detection of a mismatch between expected and observed outcomes within the ventral striatum (i.e., "prediction errors"), is thought to be a critical precursor to the formation of new stimulus-outcome associations. An untested possibility, therefore, is that stress may affect learning via modulation of this mechanism. Here we combine a translational model of stress with a cognitive neuro-imaging paradigm to demonstrate that stress significantly increases ventral striatum aversive (but not appetitive) prediction error signal. This provides a unique account of the propensity to form threat-related associations under stress with direct implications for our understanding of both normal stress and stress-related disorders. C1 [Robinson, Oliver J.; Overstreet, Cassie; Charney, Danielle R.; Vytal, Katherine; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. RP Robinson, OJ (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. EM oliver.j.robinson@gmail.com OI Robinson, Oliver/0000-0002-3100-1132 FU Intramural Research Program of the National Institute of Mental Health FX We thank Angie Wu for help with subject scheduling and support and Stuart White for indispensable help setting up PE models. This research was supported by the Intramural Research Program of the National Institute of Mental Health. NR 34 TC 27 Z9 27 U1 4 U2 22 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 MAR 5 PY 2013 VL 110 IS 10 BP 4129 EP 4133 DI 10.1073/pnas.1213923110 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109OH UT WOS:000316377400092 PM 23401511 ER PT J AU Pavlova, O Peterson, JH Ieva, R Bernstein, HD AF Pavlova, Olga Peterson, Janine H. Ieva, Raffaele Bernstein, Harris D. TI Mechanistic link between beta barrel assembly and the initiation of autotransporter secretion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE membrane protein assembly; outer membrane proteins; protein translocation ID BACTERIAL AUTOTRANSPORTER; OUTER-MEMBRANE; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; PROTEIN-TRANSPORT; VIRULENCE FACTOR; DOMAIN; BIOGENESIS; TRANSLOCATION; ARCHITECTURE AB Autotransporters are bacterial virulence factors that contain an N-terminal extracellular ("passenger") domain and a C-terminal beta barrel ("beta") domain that anchors the protein to the outer membrane. The beta domain is required for passenger domain secretion, but its exact role in autotransporter biogenesis is unclear. Here we describe insights into the function of the beta domain that emerged from an analysis of mutations in the Escherichia coli O157:H7 autotransporter EspP. We found that the G1066A and G1081D mutations slightly distort the structure of the beta domain and delay the initiation of passenger domain translocation. Site-specific photocrosslinking experiments revealed that the mutations slow the insertion of the beta domain into the outer membrane, but do not delay the binding of the beta domain to the factor that mediates the insertion reaction (the Bam complex). Our results demonstrate that the beta domain does not simply target the passenger domain to the outer membrane, but promotes translocation when it reaches a specific stage of assembly. Furthermore, our results provide evidence that the Bam complex catalyzes the membrane integration of beta barrel proteins in a multistep process that can be perturbed by minor structural defects in client proteins. C1 [Pavlova, Olga; Peterson, Janine H.; Ieva, Raffaele; Bernstein, Harris D.] NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov RI Ieva, Raffaele/J-9207-2014 OI Ieva, Raffaele/0000-0002-3405-0650 FU National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program FX We thank Travis Barnard for helping to construct Fig. 1 and Yihong Ye for providing valuable comments on the manuscript. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program. NR 41 TC 23 Z9 24 U1 0 U2 28 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 5 PY 2013 VL 110 IS 10 BP E938 EP E947 DI 10.1073/pnas.1219076110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109OH UT WOS:000316377400011 PM 23431155 ER PT J AU Doubeni, CA Weinmann, S Adams, K Kamineni, A Buist, DSM Ash, AS Rutter, CM Doria-Rose, VP Corley, DA Greenlee, RT Chubak, J Williams, A Kroll-Desrosiers, AR Johnson, E Webster, J Richert-Boe, K Levin, TR Fletcher, RH Weiss, NS AF Doubeni, Chyke A. Weinmann, Sheila Adams, Kenneth Kamineni, Aruna Buist, Diana S. M. Ash, Arlene S. Rutter, Carolyn M. Doria-Rose, V. Paul Corley, Douglas A. Greenlee, Robert T. Chubak, Jessica Williams, Andrew Kroll-Desrosiers, Aimee R. Johnson, Eric Webster, Joseph Richert-Boe, Kathryn Levin, Theodore R. Fletcher, Robert H. Weiss, Noel S. TI Screening Colonoscopy and Risk for Incident Late-Stage Colorectal Cancer Diagnosis in Average-Risk Adults A Nested Case-Control Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SERVICES TASK-FORCE; FECAL-OCCULT-BLOOD; RANDOMIZED CONTROLLED TRIAL; NATIONAL-INSTITUTES; BETHESDA GUIDELINES; MORTALITY; HEALTH; SIGMOIDOSCOPY; POPULATION; STATEMENT AB Background: The effectiveness of screening colonoscopy in average-risk adults is uncertain, particularly for right colon cancer. Objective: To examine the association between screening colonoscopy and risk for incident late-stage colorectal cancer (CRC). Design: Nested case-control study. Setting: Four U.S. health plans. Patients: 1039 average-risk adults enrolled for at least 5 years in one of the health plans. Case patients were aged 55 to 85 years on their diagnosis date (reference date) of stage IIB or higher (late-stage) CRC during 2006 to 2008. One or 2 control patients were selected for each case patient, matched on birth year, sex, health plan, and prior enrollment duration. Measurements: Receipt of CRC screening 3 months to 10 years before the reference date, ascertained through medical record audits. Case patients and control patients were compared on receipt of screening colonoscopy or sigmoidoscopy by using conditional logistic regression that accounted for health history, socioeconomic status, and other screening exposures. Results: In analyses restricted to 471 eligible case patients and their 509 matched control patients, 13 case patients (2.8%) and 46 control patients (9.0%) had undergone screening colonoscopy, which corresponded to an adjusted odds ratio (AOR) of 0.29 (95% CI, 0.15 to 0.58) for any late-stage CRC, 0.36 (CI, 0.16 to 0.80) for right colon cancer, and 0.26 (CI, 0.06 to 1.11; P = 0.069) for left colon/rectum cancer. Ninety-two case patients (19.5%) and 173 control patients (34.0%) had screening sigmoidoscopy, corresponding to an AOR of 0.50 (CI, 0.36 to 0.70) overall, 0.79 (CI, 0.51 to 1.23) for right colon late-stage cancer, and 0.26 (CI, 0.14 to 0.48) for left colon cancer. Limitation: The small number of screening colonoscopies affected the precision of the estimates. Conclusion: Screening with colonoscopy in average-risk persons was associated with reduced risk for diagnosis of incident late-stage CRC, including right-sided colon cancer. For sigmoidoscopy, this association was seen for left CRC, but the association for right colon late-stage cancer was not statistically significant. C1 Univ Penn, Philadelphia, PA 19104 USA. Meyers Primary Care Inst, Reliant Med Grp, Worcester, MA USA. Univ Massachusetts, Sch Med, Worcester, MA USA. Kaiser Permanente Northwest, Portland, OR USA. HealthPartners Hlth Syst, Minneapolis, MN USA. Grp Hlth Res Inst, Seattle, WA USA. Univ Washington, Seattle, WA 98195 USA. NCI, NIH, Bethesda, MD 20892 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Marshfield Clin Res Fdn, Marshfield, WI USA. Kaiser Permanente, Honolulu, HI USA. Harvard Univ, Sch Med, Boston, MA USA. RP Doubeni, CA (reprint author), Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, 3400 Spruce St,Gates 2, Philadelphia, PA 19104 USA. EM chyke.doubeni@uphs.upenn.edu OI Doubeni, Chyke/0000-0001-7495-0285; Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute of the National Institutes of Health [UC2CA148576]; National Institutes of Health [K01-CA127118, K01-CA127118-S1, U01-CA151736]; Surveillance, Epidemiology and End Results Program of the National Cancer Institute [N01-CN-67009, N01-PC-35142]; State of Washington FX Grant Support: By grant UC2CA148576 from the National Cancer Institute of the National Institutes of Health. Additional support was provided to Dr. Doubeni through awards K01-CA127118, K01-CA127118-S1, and U01-CA151736, also from the National Institutes of Health. Data collection on cancer incidence for this study was supported in part by data infrastructure developed by the HMO Cancer Research Network at participating sites. Group Health Research Institute's Cancer Surveillance System is funded in part by contracts N01-CN-67009 and N01-PC-35142 from the Surveillance, Epidemiology and End Results Program of the National Cancer Institute, with additional support from the State of Washington. NR 35 TC 52 Z9 52 U1 0 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAR 5 PY 2013 VL 158 IS 5 BP 312 EP + DI 10.7326/0003-4819-158-5-201303050-00003 PN 1 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 105HP UT WOS:000316057700002 PM 23460054 ER PT J AU Wickner, RB Edskes, HK Bateman, DA Kelly, AC Gorkovskiy, A Dayani, Y Zhou, A AF Wickner, Reed B. Edskes, Herman K. Bateman, David A. Kelly, Amy C. Gorkovskiy, Anton Dayani, Yaron Zhou, Albert TI Amyloids and Yeast Prion Biology SO BIOCHEMISTRY LA English DT Article ID HET-S PRION; BETA-SHEET STRUCTURE; SOLID-STATE NMR; TRANSMISSION ELECTRON-MICROSCOPY; TRANSCRIPTIONAL REGULATOR SFP1; DISEASE-RELATED PROTEIN; 2-MU-M CIRCLE PLASMID; SACCHAROMYCES-CEREVISIAE; PSI+ PRION; BATTEN-DISEASE AB The prions (infectious proteins) of Saccharomyces cerevisiae are proteins acting as genes, by templating their conformation from one molecule to another in analogy to DNA templating its sequence. Most yeast prions are amyloid forms of normally soluble proteins, and a single protein sequence can have any of several self-propagating forms (called prion strains or variants), analogous to the different possible alleles of a DNA gene. A central issue in prion biology is the structural basis of this conformational templating process. The in-register parallel beta sheet structure found for several infectious yeast prion amyloids naturally suggests an explanation for this conformational templating. While most prions are plainly diseases, the [Het-s] prion of Podospora anserina may be a functional amyloid, with important structural implications. Yeast prions are important models for human amyloid diseases in general, particularly because new evidence is showing infectious aspects of several human amyloidoses previously classified as prions. We also review studies of the roles of chaperones, aggregate-collecting proteins, and other cellular components using yeast that have led the way in improving the understanding of similar processes that must be operating in many human amyloidoses. C1 [Wickner, Reed B.; Edskes, Herman K.; Bateman, David A.; Kelly, Amy C.; Gorkovskiy, Anton; Dayani, Yaron; Zhou, Albert] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov RI Gorkovskiy, Anton/J-8930-2016 OI Gorkovskiy, Anton/0000-0003-4811-2282 FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 187 TC 28 Z9 28 U1 1 U2 28 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 5 PY 2013 VL 52 IS 9 BP 1514 EP 1527 DI 10.1021/bi301686a PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 102KW UT WOS:000315844500002 PM 23379365 ER PT J AU Lomash, S Chittori, S Brown, P Mayer, ML AF Lomash, Suvendu Chittori, Sagar Brown, Patrick Mayer, Mark L. TI Anions Mediate Ligand Binding in Adineta vaga Glutamate Receptor Ion Channels SO STRUCTURE LA English DT Article ID CRYSTAL-STRUCTURES; KAINATE RECEPTORS; TERMINAL DOMAIN; AMPA; DESENSITIZATION; SELECTIVITY; MECHANISMS; ASSOCIATION; MODULATION; ACTIVATION AB AvGluR1, a glutamate receptor ion channel from the primitive eukaryote Adineta vaga, is activated by alanine, cysteine, methionine, and phenylalanine, which produce lectin-sensitive desensitizing responses like those to glutamate, aspartate, and serine. AvGluR1 LBD crystal structures reveal an unusual scheme for binding dissimilar ligands that may be utilized by distantly related odorant/chemo-sensory receptors. Arginine residues in domain 2 coordinate the gamma-carboxyl group of glutamate, whereas in the alanine, methionine, and serine complexes a chloride ion acts as a surrogate ligand, replacing the gamma-carboxyl group. Removal of Cl- lowers affinity for these ligands but not for glutamate or aspartate nor for phenylalanine, which occludes the anion binding site and binds with low affinity. AvGluR1 LBD crystal structures and sedimentation analysis also provide insights into the evolutionary link between prokaryotic and eukaryotic iGluRs and reveal features unique to both classes, emphasizing the need for additional structure-based studies on iGluR-ligand interactions. C1 [Lomash, Suvendu; Chittori, Sagar; Mayer, Mark L.] NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. [Brown, Patrick] NIBIB, NIH, DHHS, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov RI Mayer, Mark/H-5500-2013; OI Chittori, Sagar/0000-0003-1417-6552 FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NICHD, NIH, DHHS FX We thank Dr. E. Isacoff for the AvGluR1 cDNA, the Swartz lab (NINDS) for oocytes, and Andi Balbo and Carla Glasser for technical assistance. Synchrotron diffraction data was collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source (APS), Argonne National Laboratory. Use of APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. This work was supported by the intramural research program of NICHD, NIH, DHHS. NR 44 TC 6 Z9 6 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAR 5 PY 2013 VL 21 IS 3 BP 414 EP 425 DI 10.1016/j.str.2013.01.006 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 104ER UT WOS:000315975100013 PM 23434404 ER PT J AU Brew, BJ McLean, CA Major, EO AF Brew, Bruce J. McLean, Catriona A. Major, Eugene O. TI Progressive multifocal leukoencephalopathy caused by BK virus? SO MEDICAL JOURNAL OF AUSTRALIA LA English DT Editorial Material ID DISEASE C1 [Brew, Bruce J.] St Vincents Hosp, Dept Neurol, Sydney, NSW 2010, Australia. [McLean, Catriona A.] Alfred Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Brew, BJ (reprint author), St Vincents Hosp, Dept Neurol, Sydney, NSW 2010, Australia. EM b.brew@unsw.edu.au RI Brew, Bruce/J-6513-2012 NR 8 TC 0 Z9 0 U1 1 U2 2 PU AUSTRALASIAN MED PUBL CO LTD PI PYRMONT PA LEVEL 2, 26-32 PYRMONT BRIDGE RD, PYRMONT, NSW 2009, AUSTRALIA SN 0025-729X J9 MED J AUSTRALIA JI Med. J. Aust. PD MAR 4 PY 2013 VL 198 IS 4 BP 179 EP 180 DI 10.5694/mja12.11798 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 106PI UT WOS:000316156600003 PM 23451948 ER PT J AU Vasilakis, N Widen, S da Rosa, APAT Wood, TG Walker, PJ Holmes, EC Tesh, RB AF Vasilakis, Nikos Widen, Steven da Rosa, Amelia P. A. Travassos Wood, Thomas G. Walker, Peter J. Holmes, Edward C. Tesh, Robert B. TI Malpais spring virus is a new species in the genus vesiculovirus SO VIROLOGY JOURNAL LA English DT Article DE Malpais spring virus (MSPV); Family rhabdoviridae; Genus vesiculovirus; Genome sequence; Phylogeny ID VESICULAR STOMATITIS-VIRUS; P-GENE; PHYLOGENIES; PROTEIN AB Background: Malpais Spring virus (MSPV) is a mosquito-borne rhabdovirus that infects a variety of wild and feral ungulates in New Mexico, including horses and deer. Although, initial serologic tests and electron microscopy at the time of isolation nearly 25 years ago provided evidence that MSPV is a novel virus, possibly related to vesiculoviruses, the virus still has not been approved as a new species. Findings: Use of the illumina platform allowed us to obtain the complete genome of MSPV. Analysis of the complete 11019 nt genome sequence of the prototype 85-488NM strain of MSPV indicates that it encodes the five common rhabdovirus structural proteins (N, P, M, G and L) with alternative ORFs (> 180 nt) in the N, M and G genes, including a 249 nt ORF in the G gene predicted to encode a 9.26 kDa highly basic transmembrane protein. Although antigenically very distant, phylogenetic analysis of the L gene indicates that MSPV is most closely related to Jurona virus, also isolated from mosquitoes in Brazil, as well as a number of other vesiculoviruses. Conclusions: In sum, our analysis indicates MSPV should be classified as a member of the genus Vesiculovirus, family Rhabdoviridae. The complete genome sequence of MSPV will be helpful in the development of a reverse genetics system to study the unique aspects of this vesiculovirus in vivo and in vitro, and will assist development of specific diagnostic tests to study the epidemiology of MSPV infection. C1 [Vasilakis, Nikos; da Rosa, Amelia P. A. Travassos; Tesh, Robert B.] Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. [Vasilakis, Nikos; da Rosa, Amelia P. A. Travassos; Tesh, Robert B.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Vasilakis, Nikos; Tesh, Robert B.] Univ Texas Med Branch, Ctr Trop Dis, Galveston, TX 77555 USA. [Vasilakis, Nikos; Tesh, Robert B.] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Widen, Steven; Wood, Thomas G.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Walker, Peter J.] CSIRO Anim Food & Hlth Sci, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Emerging Infect & Biosecur Inst, Sch Biol Sci, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Vasilakis, N (reprint author), Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. EM nivasila@utmb.edu RI Walker, Peter/H-6059-2013; OI Walker, Peter/0000-0003-1851-642X; Holmes, Edward/0000-0001-9596-3552 FU Department of Pathology start up funds; Institute for Human Infections and Immunity, University of Texas Medical Branch, NIH [HHSN272201000040I/HHSN27200004/D04] FX This work is supported in part by the Department of Pathology start up funds and a grant from the Institute for Human Infections and Immunity, University of Texas Medical Branch (NV), NIH contract HHSN272201000040I/HHSN27200004/D04 (RBT). NR 13 TC 6 Z9 6 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD MAR 4 PY 2013 VL 10 AR 69 DI 10.1186/1743-422X-10-69 PG 5 WC Virology SC Virology GA 108MY UT WOS:000316298900001 PM 23497016 ER PT J AU Gallagher, JJ Zhang, XW Hall, FS Uhl, GR Bearer, EL Jacobs, RE AF Gallagher, Joseph J. Zhang, Xiaowei Hall, F. Scott Uhl, George R. Bearer, Elaine L. Jacobs, Russell E. TI Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse SO PLOS ONE LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; TENSOR-BASED MORPHOMETRY; VIVO H-1-NMR SPECTROSCOPY; MANGANESE-ENHANCED MRI; DOPAMINE-TRANSPORTER; IN-VIVO; SEROTONIN TRANSPORTER; ALZHEIMERS-DISEASE; N-ACETYLASPARTATE; EXTRACELLULAR DOPAMINE AB Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of more robust connectivity in the frontal portion of the reward circuit of the DAT and NET knockout mice compared to the SERT knockout mice. C1 [Gallagher, Joseph J.; Zhang, Xiaowei; Bearer, Elaine L.; Jacobs, Russell E.] CALTECH, Beckman Inst, Biol Imaging Ctr, Pasadena, CA 91125 USA. [Bearer, Elaine L.] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD USA. RP Jacobs, RE (reprint author), CALTECH, Beckman Inst, Biol Imaging Ctr, Pasadena, CA 91125 USA. EM rjacobs@caltech.edu RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Beckman Institute; NIH NINDS [NS062184]; NIMH [MH087660]; NIMGS [P5OGM08273]; NIDA [R01DA18184]; National Institute on Drug Abuse; Harvey Family endowment FX The project was funded in part by the Beckman Institute, NIH NINDS NS062184, NIMH MH087660, NIMGS P5OGM08273 (ELB), and NIDA R01DA18184 (REJ) and, in part, by the National Institute on Drug Abuse, Intramural Research Program (GRU and FSH), and by the Harvey Family endowment (ELB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 117 TC 7 Z9 9 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 4 PY 2013 VL 8 IS 3 AR e57597 DI 10.1371/journal.pone.0057597 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099PY UT WOS:000315634900030 PM 23469209 ER PT J AU Epstein-Lubow, G Khachaturian, AS Ryan, LM Baumgart, M AF Epstein-Lubow, Gary Khachaturian, Ara S. Ryan, Laurie M. Baumgart, Matthew TI THE NATIONAL ALZHEIMER'S PROJECT ACT AND THE NATIONAL PLAN TO ADDRESS ALZHEIMER'S DISEASE: AN UPDATE AND FUTURE DIRECTIONS SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Khachaturian, Ara S.] Journal Alzheimers Assoc, Alzheimers & Dementia, Rockville, MD USA. [Ryan, Laurie M.] NIA, Bethesda, MD 20892 USA. [Baumgart, Matthew] Alzheimers Assoc, Chicago, IL USA. [Epstein-Lubow, Gary] Brown Univ, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S36 EP S37 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400049 ER PT J AU Evans, JD Lavretsky, H O'Hara, R Gildengers, A AF Evans, Jovier D. Lavretsky, Helen O'Hara, Ruth Gildengers, Ariel TI COGNITION AND MOOD DISORDER: IS THERE A CONNECTION TO NEURODEGENERATION AND COGNITIVE DECLINE? SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Evans, Jovier D.] NIMH, Bethesda, MD 20892 USA. [Lavretsky, Helen] Univ Calif Los Angeles, Los Angeles, CA USA. [O'Hara, Ruth] Stanford Univ, Palo Alto, CA 94304 USA. [Gildengers, Ariel] Univ Pittsburgh, Pittsburgh, PA USA. RI Lavretsky, Helen/M-5711-2015 OI Lavretsky, Helen/0000-0001-9990-5085 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S8 EP S9 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400007 ER PT J AU Kellner, CH Liebman, LS Nazarian, R Knapp, RG McCall, WV Husain, MM Petrides, G Young, RC Greenberg, RM Weiner, RD Prudic, J Rudorfer, MV Lisanby, SH AF Kellner, Charles H. Liebman, Lauren S. Nazarian, Roya Knapp, Rebecca G. McCall, W. Vaughn Husain, Mustafa M. Petrides, Georgios Young, Robert C. Greenberg, Robert M. Weiner, Richard D. Prudic, Joan Rudorfer, Matthew V. Lisanby, Sarah H. TI Efficacy of Right Unilateral Ultrabrief Pulse Electroconvulsive Therapy (ECT): Data from Phase 1 of the PRIDE Study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Kellner, Charles H.; Liebman, Lauren S.; Nazarian, Roya] Mt Sinai, New York, NY USA. [Knapp, Rebecca G.] Med Univ S Carolina, Charleston, SC 29425 USA. [McCall, W. Vaughn] Georgia Hlth Sci Univ, Augusta, GA USA. [Husain, Mustafa M.] Univ Texas SW, Dallas, TX USA. [Petrides, Georgios] Zucker Hillside Hosp, Glen Oaks, NY USA. [Young, Robert C.] Cornell Univ, Weill Med Coll, White Plains, NY USA. [Young, Robert C.] Lutheran Med Ctr, Brooklyn, NY USA. [Weiner, Richard D.; Lisanby, Sarah H.] Duke Univ, Durham, NC USA. [Prudic, Joan] Columbia Univ, New York, NY USA. [Rudorfer, Matthew V.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S131 EP S131 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400145 ER PT J AU Niederehe, G Gallagher-Thompson, DE Cook, IA Wittink, MN AF Niederehe, George Gallagher-Thompson, Dolores E. Cook, Ian A. Wittink, Marsha N. TI PERSONALIZING TREATMENT FOR LATE-LIFE DEPRESSION: RESEARCH APPROACHES SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Niederehe, George] NIMH, Bethesda, MD 20892 USA. [Gallagher-Thompson, Dolores E.] Stanford Univ, Stanford, CA 94305 USA. [Cook, Ian A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Wittink, Marsha N.] Univ Rochester, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S27 EP S28 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400036 ER PT J AU Smith, JC Abdala, APL Borgmann, A Rybak, IA Paton, JFR AF Smith, Jeffrey C. Abdala, Ana P.L. Borgmann, Anke Rybak, Ilya A. Paton, Julian F.R. TI Brainstem respiratory networks: building blocks and microcircuits SO TRENDS IN NEUROSCIENCES LA English DT Review DE breathing; brainstem; respiratory central pattern generator; breathing disorders ID PRE-BOTZINGER COMPLEX; CENTRAL HYPOVENTILATION SYNDROME; MOUSE PREBOTZINGER COMPLEX; NONSPECIFIC CATION CURRENT; PERSISTENT SODIUM CURRENT; CENTRAL PATTERN GENERATOR; RHYTHM GENERATION; RETROTRAPEZOID NUCLEUS; IN-VITRO; SEROTONERGIC NEURONS AB Breathing movements in mammals are driven by rhythmic neural activity generated within spatially and functionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial-functional organization of key neural microcircuits of this CPG from recent multidisciplinary experimental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site- and mechanism-specific interventions to treat various disorders of the neural control of breathing. C1 NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Univ Bristol, Bristol Heart Inst, Sch Physiol & Pharmacol, Bristol, Avon, England. Drexel Univ, Coll Med, Dept Anat & Neurobiol, Philadelphia, PA 19104 USA. RP Smith, JC (reprint author), NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM smithj2@heliz.nih.gov RI Abdala, Ana Paula/G-9104-2014 OI Abdala, Ana Paula/0000-0001-6051-2591 FU Intramural NIH HHS; NHLBI NIH HHS [R33 HL087379]; NINDS NIH HHS [R01 NS057815, R01 NS069220] NR 113 TC 84 Z9 85 U1 1 U2 34 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD MAR PY 2013 VL 36 IS 3 BP 152 EP 162 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 113ZY UT WOS:000316710400006 PM 23254296 ER PT J AU Merino, JG Latour, LL Tso, A Lee, KY Kang, DW Davis, LA Lazar, RM Horvath, KA Corso, PJ Warach, S AF Merino, J. G. Latour, L. L. Tso, A. Lee, K. Y. Kang, D. W. Davis, L. A. Lazar, R. M. Horvath, K. A. Corso, P. J. Warach, S. TI Blood-Brain Barrier Disruption after Cardiac Surgery SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID BYPASS GRAFT-SURGERY; RECOVERY MR-IMAGES; CEREBROSPINAL-FLUID; CARDIOPULMONARY BYPASS; MATRIX METALLOPROTEINASES; EXPERIMENTAL STROKE; REPERFUSION INJURY; RAT-BRAIN; OFF-PUMP; ARTERY AB To shed light on brain complications occurring after heart surgery, the authors assessed BBB disruption and DWI findings in half of their patients by imaging at 24 hours after surgery and 24-48 hours later. Additionally, postcontrast T1 images were obtained postoperatively at 2-4 days in the other half of the patients. Almost half the patients undergoing cardiac surgery had evidence of BBB abnormalities and three-quarters showed acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MR can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery. BACKGROUND AND PURPOSE: CNS complications are often seen after heart surgery, and postsurgical disruption of the BBB may play an etiologic role. The objective of this study was to determine the prevalence of MR imaging-detected BBB disruption (HARM) and DWI lesions after cardiac surgery. MATERIALS AND METHODS: All patients had an MRI after cardiac surgery. For half the patients (group 1), we administered gadolinium 24 hours after surgery and obtained high-resolution DWI and FLAIR images 24-48 hours later. We administered gadolinium to the other half (group 2) at the time of the postoperative scan, 2-4 days after surgery. Two stroke neurologists evaluated the images. RESULTS: Of the 19 patients we studied, none had clinical evidence of a stroke or delirium at the time of the gadolinium administration or the scan, but 9 patients (47%) had HARM (67% in group 1; 30% in group 2; P = .18) and 14 patients (74%) had DWI lesions (70% in group 1; 78% in group 2; P = 1.0). Not all patients with DWI lesions had HARM, and not all patients with HARM had DWI lesions (P = .56). CONCLUSIONS: Almost half the patients undergoing cardiac surgery have evidence of HARM, and three-quarters have acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MR imaging can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery. C1 [Merino, J. G.; Latour, L. L.; Davis, L. A.; Warach, S.] NINDS, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. [Merino, J. G.; Horvath, K. A.] Johns Hopkins Community Phys, Bethesda, MD USA. [Tso, A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Lee, K. Y.] Yonsei Univ, Coll Med, Dept Neurol, Seoul, South Korea. [Kang, D. W.] Asan Med Ctr, Seoul, South Korea. [Lazar, R. M.] Columbia Univ, Dept Neurol, Coll Phys & Surg, New York, NY USA. [Horvath, K. A.] NHLBI, Bethesda, MD 20892 USA. [Corso, P. J.] Washington Hosp Ctr, Dept Cardiac Surg, Washington, DC 20010 USA. RP Merino, JG (reprint author), Suburban Hosp Stroke Program, 8600 Old Georgetown Rd, Bethesda, MD 20814 USA. EM merinoj@ninds.nih.gov OI Lee, Kyung-Yul/0000-0001-5585-7739; Merino, Jose/0000-0002-6676-0008 FU Division of Intramural Research of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health FX This research was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. NR 41 TC 16 Z9 17 U1 1 U2 5 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD MAR PY 2013 VL 34 IS 3 BP 518 EP 523 DI 10.3174/ajnr.A3251 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 291RN UT WOS:000329846900013 PM 22918429 ER PT J AU Ferzli, M Roberson, R Kuddo, T Abebe, D Spong, CY AF Ferzli, Myriam Roberson, Robin Kuddo, Thea Abebe, Daniel Spong, Catherine Y. TI Prenatal Alcohol Exposure Alters Acute Phosphorylation of Cellular Signaling Pathways SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Roberson, Robin; Kuddo, Thea; Abebe, Daniel; Spong, Catherine Y.] NICHD, UPDN, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 65A EP 65A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100008 ER PT J AU Johnson, J Hoffman, GE Le, WW Kurus, M Usdin, K AF Johnson, Joshua Hoffman, Gloria E. Le, Wei Wei Kurus, Meltem Usdin, Karen TI Increased Immature Follicle Involution in the Fragile X Premutation Mouse SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Johnson, Joshua; Kurus, Meltem] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Hoffman, Gloria E.; Le, Wei Wei] Morgan State Univ, Dept Biol, Baltimore, MD 21239 USA. [Usdin, Karen] NIDDK, LCMB Gene Express & Regulat Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 77A EP 77A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100053 ER PT J AU Rosenblatt, KP Nicolaides, KH Romero, R Bryant-Greenwood, PK Syngelaki, A Menon, R Galen, RS Evans, MI AF Rosenblatt, Kevin P. Nicolaides, Kypros H. Romero, Roberto Bryant-Greenwood, Peter K. Syngelaki, Argyro Menon, Ramkumar Galen, Robert S. Evans, Mark I. TI Proteomic Derived Biomarker Panel for First Trimester Identification of Patients at Risk for Pre-Term Delivery SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Rosenblatt, Kevin P.] Univ Texas Houston, IMM, Houston, TX USA. [Nicolaides, Kypros H.; Syngelaki, Argyro] Fetal Med Fdn, Harris Birthright Ctr, London, England. [Romero, Roberto] NICHD, Pregnancy Res Branch, Detroit, MI USA. [Bryant-Greenwood, Peter K.] UTMB, Galveston, TX USA. [Menon, Ramkumar] Univ Hawaii, Honolulu, HI 96822 USA. [Galen, Robert S.] U Georgia Publ Hlth, Athens, GA USA. [Evans, Mark I.] Comprehens Genet, Prenatal Diag, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 80A EP 80A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100063 ER PT J AU Hill, MJ Segars, JH Kino, T AF Hill, Micah J. Segars, James H. Kino, Tomoshige TI CREB-Regulated Transcription Coactivator 2 (CRTC2) Is a Coregulator of the Progesterone and Glucocorticoid Receptor SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Hill, Micah J.; Segars, James H.; Kino, Tomoshige] NIH, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 101A EP 102A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100135 ER PT J AU Muneyyirci-Delale, O Charles, C Sinaii, N Anopa, J Dalloul, M Stratton, P AF Muneyyirci-Delale, Ozgul Charles, Cassandra Sinaii, Ninet Anopa, Jenny Dalloul, Mudar Stratton, Pamela TI Sustained Improvement in Endometriosis-Related Pelvic Pain with Leuprolide or Norethindrone Treatment SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Muneyyirci-Delale, Ozgul; Charles, Cassandra; Anopa, Jenny; Dalloul, Mudar] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Muneyyirci-Delale, Ozgul] Kings Cty Hosp Ctr, Brooklyn, NY USA. [Sinaii, Ninet] NIH Clin Ctr, Biostat & Clin Epidemiol Serv, Bethesda, MD USA. [Stratton, Pamela] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 147A EP 148A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100288 ER PT J AU Stratton, P Sinaii, N Khachikyan, I Ortiz, R Gemmill, J Shah, J AF Stratton, Pamela Sinaii, Ninet Khachikyan, Izabella Ortiz, Robin Gemmill, Julie Shah, Jay TI Interrelationship among Levator Spasm, Sensitization, Myofascial Dysfunction, Anxiety and Depression in Patients with Endometriosis and Chronic Pelvic Pain SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Stratton, Pamela; Khachikyan, Izabella; Gemmill, Julie] NICHD, PRAE, Bethesda, MD USA. [Sinaii, Ninet] CC, BCES, Bethesda, MD USA. [Ortiz, Robin; Shah, Jay] NIH, RM, CC, Bethesda, MD 20892 USA. [Ortiz, Robin] Loyola SOM, Maywood, IL USA. [Gemmill, Julie] NYCOM, Old Westbury, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 148A EP 149A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100292 ER PT J AU Devine, K Egbuniwe, M Mumford, S Armstrong, AY AF Devine, Kate Egbuniwe, Mary Mumford, Sunni Armstrong, Alicia Y. TI Is Pre-ART Myomectomy Cost-Effective in Women with Intramural (IM) Fibroids? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Devine, Kate; Mumford, Sunni; Armstrong, Alicia Y.] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 150A EP 150A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100296 ER PT J AU Fru, KN Levy, G Wesley, R Neiman, L Venkatesan, A Armstrong, A AF Fru, Karenne N. Levy, Gary Wesley, Robert Neiman, Lynnette Venkatesan, Aradhana Armstrong, Alicia TI Prolactin as a Biomarker for Tumor Burden and Response to UPA Therapy in African American Women with Symptomatic Leiomyoma SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Fru, Karenne N.; Levy, Gary; Neiman, Lynnette; Armstrong, Alicia] Eunice Kennedy Shriver Natl Inst Child & Human De, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Wesley, Robert] NIH, Dept Biostat, Bethesda, MD 20892 USA. [Venkatesan, Aradhana] NIH, Dept Radiol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 150A EP 150A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100297 ER PT J AU Levy, G Malik, M Britten, J Segars, JH Catherino, WH AF Levy, Gary Malik, Minnie Britten, Joy Segars, James H. Catherino, William H. TI Ulipristal Acetate Decreases TGF-beta 3 Expression and Dissolves Extracellular Matrix in Leiomyoma Cells SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Levy, Gary; Malik, Minnie; Britten, Joy; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Levy, Gary; Segars, James H.; Catherino, William H.] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 151A EP 151A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100300 ER PT J AU Zarek, SM Driggers, PH Malik, M Segars, JH AF Zarek, Shvetha M. Driggers, Paul H. Malik, Minnie Segars, James H. TI Characterization of AKAP13, Progesterone Receptor and Estrogen Receptor Gene Expression in Breast Cancer Cells SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Zarek, Shvetha M.; Driggers, Paul H.; Malik, Minnie; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Driggers, Paul H.; Segars, James H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 168A EP 168A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100359 ER PT J AU Salafia, C Girardi, T Newschaffer, C Miller, R Walker, C Misra, D Katzman, P Moye, J Fallin, M Herz-Picciotto, I Croen, L AF Salafia, C. Girardi, T. Newschaffer, C. Miller, R. Walker, C. Misra, D. Katzman, P. Moye, J. Fallin, M. Herz-Picciotto, I. Croen, L. TI Placental Angiogenesis and ASD: Measurable Differences in Placental Vascular Structure SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Salafia, C.] New York State Off Mental Retardat & Dev Disabil, Inst Basic Res, Staten Isl, NY USA. [Girardi, T.] Placental Analyt, R&D, Larchmont, NY USA. [Newschaffer, C.] Drexel Univ, Drexel Autism Ctr, Philadelphia, PA 19104 USA. [Miller, R.] URSM, Rochester, NY USA. [Walker, C.] UC Davis SOM, Sacramento, CA USA. [Misra, D.] Wayne State Univ SOM, Detroit, MI USA. [Katzman, P.] URSOM, Rochester, NY USA. [Moye, J.] NICHD, Natl Childrens Study, Rockville, MD USA. [Fallin, M.] JHU Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Herz-Picciotto, I.] UC, Sch Med, MIND Insitute, Sacramento, CA USA. [Croen, L.] Kaiser Permanente, Res, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 204A EP 204A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100482 ER PT J AU Hill, MJ Eltoukhi, H Richter, KS Widra, E Wolff, EF AF Hill, Micah J. Eltoukhi, Heba Richter, Kevin S. Widra, Eric Wolff, Erin F. TI Endometrial Thickness on the Day of hCG Trigger Positively Correlates with ART Outcomes and Differs by Racial Group SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Hill, Micah J.; Eltoukhi, Heba; Wolff, Erin F.] NIH, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Richter, Kevin S.; Widra, Eric] Shady Grove Reprod Sci Ctr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 225A EP 225A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100552 ER PT J AU McDonnold, MA AF McDonnold, Mollie A. TI Waist to Hip Ratio Versus BMI as Predictor of Obesity Related Pregnancy Outcomes SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [McDonnold, Mollie A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 247A EP 247A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100624 ER PT J AU Cantu, J AF Cantu, Jessica TI Lab Abnormalities in Pregnancy-Associated Hypertension: Frequency and Impact on Pregnancy Outcomes SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Cantu, Jessica] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 260A EP 260A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100669 ER PT J AU Myatt, L AF Myatt, Leslie TI Identification of Different Phenotypes of Preeclampsia by Clustering Analysis of Biomarker Profiles SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Myatt, Leslie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 266A EP 266A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100691 ER PT J AU Myatt, L AF Myatt, Leslie TI Relationship of Inflammatory Biomarkers in Preeclampsia to BMI SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Myatt, Leslie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 266A EP 267A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100692 ER PT J AU Cox, J Egbuniwe, M Levy, G Armstrong, A Drieling, J Neiman, L AF Cox, Jeris Egbuniwe, Mary Levy, Gary Armstrong, Alicia Drieling, Jennifer Neiman, Lynnette TI Ulipristal Acetate Does Not Predispose the Fallopian Tube Epithelium to Neoplastic Changes. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Cox, Jeris; Levy, Gary; Armstrong, Alicia; Neiman, Lynnette] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Egbuniwe, Mary] Mt Sinai Hosp, Dept Ob GYN, New York, NY 10029 USA. [Drieling, Jennifer] NCI, Dept Pathol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 271A EP 271A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100709 ER PT J AU Yu, B Haymes, S Zhou, YL Levy, G Segars, J Armstrong, A AF Yu, Bo Haymes, Snezana Zhou, Yaling Levy, Gary Segars, James Armstrong, Alicia TI Investigating the Role of Apoptosis in the Chemoprotection Effect of GnRH Antagonist SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Yu, Bo; Levy, Gary; Segars, James; Armstrong, Alicia] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Haymes, Snezana; Zhou, Yaling] Walter Reed Natl Mil Med Ctr, Dept Res Programs, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 282A EP 282A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100747 ER PT J AU Silver, R AF Silver, Robert CA Stillbirth Collaborative Res Netwo TI 7-Dehydrocholesterol Reductase Gene Mutations and Stillbirth SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Silver, Robert] Univ Utah, Salt Lake City, UT USA. [Stillbirth Collaborative Res Netwo] NICHD, Stillbirth Collaborat Res Network, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 284A EP 285A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100756 ER PT J AU Bolnick, JM Kilburn, BA Diamond, MP Jeelani, R Armant, DR AF Bolnick, Jay M. Kilburn, Brian A. Diamond, Michael P. Jeelani, Roohi Armant, D. Randall TI Trophoblast Cells Obtained by Noninvasive Transcervical Sampling during Early Pregnancy Have an Extravillous Phenotype. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Bolnick, Jay M.; Kilburn, Brian A.; Diamond, Michael P.; Jeelani, Roohi; Armant, D. Randall] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Armant, D. Randall] Wayne State Univ, Detroit, MI USA. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 300A EP 301A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100812 ER PT J AU Bolnick, JM Namo, R Chiang, PJ Kilburn, BA Diamond, MP Smith, SM Armant, RD AF Bolnick, Jay M. Namo, Rita Chiang, Po Jen Kilburn, Brian A. Diamond, Michael P. Smith, Susan M. Armant, Randall D. TI Apoptosis of Alcohol-Exposed Human Placental Cytotrophoblast Cells Occurs Downstream of Intracellular Calcium Signaling. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Bolnick, Jay M.; Namo, Rita; Chiang, Po Jen; Kilburn, Brian A.; Diamond, Michael P.; Armant, Randall D.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Smith, Susan M.] Univ Wisconsin, Madison, WI USA. [Armant, Randall D.] Wayne State Univ, Detroit, MI USA. [Armant, Randall D.] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 301A EP 301A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100813 ER PT J AU Myatt, L AF Myatt, Leslie TI Association of Maternal Biomarkers with Obstetric Outcomes. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 60th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 20-23, 2013 CL Orlando, FL SP Soc Gynecol Invest C1 [Myatt, Leslie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2013 VL 20 IS S3 SU 3 BP 330A EP 330A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LK UT WOS:000329543100912 ER PT J AU Boyington, JEA Czajkowski, S AF Boyington, Josephine E. A. Czajkowski, Susan TI Enrollment and Retention Challenges in Early-Phase Intervention Development Studies: The Obesity-Related Behavioral Intervention Trials (ORBIT) SO PREVENTING CHRONIC DISEASE LA English DT Editorial Material ID US ADULTS; PREVALENCE; TRENDS C1 [Boyington, Josephine E. A.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Boyington, JEA (reprint author), NHLBI, NIH, 6701 Rockledge Dr,Ste 10224, Bethesda, MD 20892 USA. EM boyingtonje@mail.nih.gov NR 12 TC 0 Z9 0 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD MAR PY 2013 VL 10 AR UNSP 130040 DI 10.5888/pcd10.130040 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 285JK UT WOS:000329389800003 ER PT J AU Sutin, AR Terracciano, A Milaneschi, Y An, Y Ferrucci, L Zonderman, AB AF Sutin, Angelina R. Terracciano, Antonio Milaneschi, Yuri An, Yang Ferrucci, Luigi Zonderman, Alan B. TI The Effect of Birth Cohort on Well-Being: The Legacy of Economic Hard Times SO PSYCHOLOGICAL SCIENCE LA English DT Article DE aging; well-being ID LONGITUDINAL CHANGE; LIFE SATISFACTION; NEGATIVE AFFECT; UNITED-STATES; AGE; HAPPINESS; PANEL AB In the present research, we examined the effects of age, cohort, and time of measurement on well-being across adulthood. Cross-sectional and longitudinal analyses of two independent samples-one with more than 10,000 repeated assessments across 30 years (mean assessments per participant = 4.44, SD = 3.47) and one with nationally representative data-suggested that well-being declines with age. This decline, however, reversed when we controlled for birth cohort. That is, once we accounted for the fact that older cohorts had lower levels of well-being, all cohorts increased in well-being with age relative to their own baseline. Participants tested more recently had higher well-being, but time of measurement, unlike cohort, did not change the shape of the trajectory. Although well-being increased with age for everyone, cohorts that lived through the economic challenges of the early 20th century had lower well-being than those born during more prosperous times. C1 [Sutin, Angelina R.; Terracciano, Antonio; Milaneschi, Yuri; An, Yang; Ferrucci, Luigi; Zonderman, Alan B.] NIA, Baltimore, MD 21224 USA. [Sutin, Angelina R.; Terracciano, Antonio] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Milaneschi, Yuri] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. RP Sutin, AR (reprint author), Florida State Univ, Coll Med, 1115 W Call St, Tallahassee, FL 32306 USA. EM angelina.sutin@med.fsu.edu RI terracciano, antonio/B-1884-2008; OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000183-22, ZIA AG000183-23] NR 30 TC 14 Z9 14 U1 0 U2 22 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 EI 1467-9280 J9 PSYCHOL SCI JI Psychol. Sci. PD MAR PY 2013 VL 24 IS 3 BP 379 EP 385 DI 10.1177/0956797612459658 PG 7 WC Psychology, Multidisciplinary SC Psychology GA 113BN UT WOS:000316640900019 PM 23349030 ER PT J AU de Mello, KGC Mello, FCQ Borga, L Rolla, V Duarte, RS Sampaio, EP Holland, SM Prevots, DR Dalcolmo, MP AF Couto de Mello, Karla Gripp Queiroz Mello, Fernanda C. Borga, Liamar Rolla, Valeria Duarte, Rafael S. Sampaio, Elizabeth P. Holland, Steven M. Prevots, D. Rebecca Dalcolmo, Margareth P. TI Clinical and Therapeutic Features of Pulmonary Nontuberculous Mycobacterial Disease, Brazil, 1993-2011 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID KANSASII INFECTION; LUNG-DISEASE; EPIDEMIOLOGY; TUBERCULOSIS; PREVALENCE; SYSTEMS AB To identify clinical and therapeutic features of pulmonary nontuberculous mycobacterial (PNTM) disease, we conducted a retrospective analysis of patients referred to the Brazilian reference center, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, who received a diagnosis of PNTM during 1993-2011 with at least 1 respiratory culture positive for NTM. Associated conditions included bronchiectasis (21.8%), chronic obstructive pulmonary disease (20.7%), cardiovascular disease (15.5%), AIDS (9.8%), diabetes (9.8%), and hepatitis C (4.6%).Two patients had Hansen disease; 1 had Marfan syndrome. Four mycobacterial species comprised 85.6% of NTM infections: Mycobacterium kansasii, 59 cases (33.9%); M. avium complex, 53 (30.4%); M. abscessus, 23 (13.2%); and M. fortuitum, 14 (8.0%). A total of 42 (24.1%) cases were associated with rapidly growing mycobacteria. In countries with a high prevalence of tuberculosis, PNTM is likely misdiagnosed as tuberculosis, thus showing the need for improved capacity to diagnose mycobacterial disease as well as greater awareness of PNTM disease prevalence. C1 [Couto de Mello, Karla Gripp; Borga, Liamar; Dalcolmo, Margareth P.] Fundacao Oswaldo Cruz, Natl Sch Publ Heath, Rio De Janeiro, Brazil. [Queiroz Mello, Fernanda C.] Univ Fed Rio de Janeiro, Sch Med, Rio De Janeiro, Brazil. [Rolla, Valeria; Sampaio, Elizabeth P.] Inst Oswaldo Cruz, BR-20001 Rio De Janeiro, Brazil. [Duarte, Rafael S.] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. [Holland, Steven M.; Prevots, D. Rebecca] NIH, Bethesda, MD 20892 USA. RP Dalcolmo, MP (reprint author), Estr Curicica 2000, BR-21045900 Curicica Rio de Janeiro, RJ, Brazil. EM margarethdalcolmo@terra.com.br FU Oswaldo Cruz Foundation; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [303777/2010-9]; Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro [E-26/111.497/2008, E-26/103.225/2011] FX This study was supported in part by funds from the Oswaldo Cruz Foundation and in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. F.C.Q.M. was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (project no. 303777/2010-9) and by Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (project nos. E-26/111.497/2008 and E-26/103.225/2011). NR 27 TC 14 Z9 14 U1 0 U2 4 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 MAR PY 2013 VL 19 IS 3 BP 393 EP 399 DI 10.3201/eid1903.120735 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 268LU UT WOS:000328173000006 PM 23745217 ER PT J AU Bemmels, H Biesecker, B Schmidt, JL Krokosky, A Guidotti, R Sutton, EJ AF Bemmels, Heather Biesecker, Barbara Schmidt, Johanna L. Krokosky, Alyson Guidotti, Rick Sutton, Erica J. TI Psychological and Social Factors in Undergoing Reconstructive Surgery Among Individuals With Craniofacial Conditions: An Exploratory Study SO CLEFT PALATE-CRANIOFACIAL JOURNAL LA English DT Article DE craniofacial conditions; decision making; parental role; pediatrics; psychological and social implications; reconstructive surgery ID TREACHER-COLLINS-SYNDROME; PORT-WINE STAINS; POSITIVE EXPOSURE; NOONAN SYNDROME; CLEFT-LIP; CHILDREN; ADOLESCENTS; DIFFERENCE; MANAGEMENT; ANOMALIES AB Objective: Reconstructive surgery to improve psychological well-being is commonly offered to children with craniofacial conditions. Few studies have explored the challenges of reconstructive surgery beyond the physical risks: poor treatment outcomes, infection, brain damage, and death. This qualitative study aims to understand the psychological and social implications such interventions can have for individuals with craniofacial conditions. Design: A total of 38 individuals between the ages of 12 and 61 with such craniofacial conditions as Sturge-Weber syndrome, Treacher Collins syndrome, Mobius syndrome, cleft lip and palate, Noonan syndrome, Crouzon syndrome, and amniotic band syndrome participated in semistructured video-recorded interviews. Participants were recruited at conferences, through study flyers, and by word of mouth. Descriptive, thematic analysis was used to identify themes related to reconstructive surgery. Results: Dominant themes included undergoing surgery to reduce stigmatization, the psychological and social implications of the interventions, outcome satisfaction, parental involvement in decision making about surgery, and recommendations for parents considering surgery for their children with craniofacial conditions. Experiences with reconstructive surgery varied, with some participants expressing surgical benefits and others, disillusionment. Conclusions: The range of participant attitudes and experiences reflect the complexity of reconstructive surgery. Pediatric health care teams involved in the care of children with craniofacial conditions play an important role in advising patients (and their parents) about existing treatment options. The psychological and social implications of reconstructive surgery should be relayed to help families weigh the risks and benefits of surgery in an informed and meaningful way. C1 [Bemmels, Heather] Univ Minnesota, Dept Educ Psychol, Minneapolis, MN 55455 USA. [Biesecker, Barbara] Johns Hopkins Univ, NHGRI, Genet Counseling Training Program, Bethesda, MD USA. [Biesecker, Barbara] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Schmidt, Johanna L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Krokosky, Alyson] Genet Alliance, Washington, DC USA. [Guidotti, Rick] Posit Exposure, New York, NY USA. [Sutton, Erica J.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 1P8, Canada. [Sutton, Erica J.] Univ Toronto, Joint Ctr Bioeth, Toronto, ON M5T 1P8, Canada. RP Sutton, EJ (reprint author), Univ Toronto, Dalla Lana Sch Publ Hlth, 155 Coll St,Suite 754, Toronto, ON M5T 1P8, Canada. EM erica.sutton@utoronto.ca OI Bemmels, Heather/0000-0003-4110-3906 FU Intramural Research Program at the National Human Genome Research Institute, National Institutes of Health FX This research was supported in part by the Intramural Research Program at the National Human Genome Research Institute, National Institutes of Health. NR 36 TC 3 Z9 3 U1 2 U2 9 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1545-1569 EI 1055-6656 J9 CLEFT PALATE-CRAN J JI Cleft Palate-Craniofac. J. PD MAR PY 2013 VL 50 IS 2 BP 158 EP 167 DI 10.1597/11-127 PG 10 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA 259NS UT WOS:000327534200008 PM 22315960 ER PT J AU Banerjee, AA Shen, H Hautman, M Anwer, J Hong, S Kapetanovic, IM Liu, Y Lyubimov, AV AF Banerjee, Aryamitra A. Shen, Hao Hautman, Mathew Anwer, Jaseem Hong, Seungpyo Kapetanovic, Izet M. Liu, Ying Lyubimov, Alexander V. TI Enhanced Oral Bioavailability of The Hydrophobic Chemopreventive Agent (Sr13668) in Beagle Dogs SO CURRENT PHARMACEUTICAL BIOTECHNOLOGY LA English DT Article DE Polymeric nanoparticles; Bioavailability; Chemoprevention; Nanoprecipitation; Oral drug delivery; Pharmacokinetics; Size distribution; Surface charges ID POLYMERIC NANOPARTICLES; FORMULATION; DELIVERY AB Potency and activity of SR13668 in cancer prevention have been proven in several in vitro and in vivo cancer models. However, the compound is highly hydrophobic and its limited oral bioavailability has hindered its clinical translation. In this study, we encapsulated SR13668 into polymeric nanoparticles to increase compound aqueous solubility and therefore bioavailability. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (100-200nm) encapsulating SR13668 with narrow size distribution and high drug loading were generated by a continuous and scalable process of flash nanoprecipitation integrated with spray dry. A single gavage dose of SR13668-PLGA nanoparticles at 2.8 mg/kg was administered in eight beagle dogs. Drug levels in animal whole blood and plasma were measured over 24 hours. Enhanced bioavailability of SR13668 using nanoparticles compared with formulations of Labrasol (R) and neat drug in 0.5% methylcellulose is reported. This is the first attempt to study pharmacokinetics of SR13668 in large animals with orally administrated nanoparticle suspension. C1 [Banerjee, Aryamitra A.; Lyubimov, Alexander V.] Univ Illinois, Toxicol Res Lab, Chicago, IL 60612 USA. [Shen, Hao; Liu, Ying] Univ Illinois, Dept Chem Engn, Chicago, IL 60607 USA. [Hautman, Mathew; Anwer, Jaseem] Ctr Biomed Testing, Chicago, IL 60612 USA. [Hong, Seungpyo; Liu, Ying] Univ Illinois, Dept Biopharmaceut Sci, Chicago, IL 60612 USA. [Kapetanovic, Izet M.] NCI, Bethesda, MD 20892 USA. RP Lyubimov, AV (reprint author), Univ Illinois, Toxicol Res Lab, 808 S Wood St,Rm 1306, Chicago, IL 60612 USA. EM liuying@uic.edu; lyubimov@uic.edu FU National Cancer Institute, Department of Health and Human Services [N01-CN-43306] FX This study was financially supported by National Cancer Institute, Department of Health and Human Services (contract number N01-CN-43306). The authors are thankful to Dr. Yoon Yeo, Department of Industrial and Physical Pharmacy and Weldon School of Biomedical Engineering at Purdue University, for assisting us to use the spray drier in her laboratory for preparing the nanoparticles. NR 17 TC 3 Z9 3 U1 1 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2010 EI 1873-4316 J9 CURR PHARM BIOTECHNO JI Curr. Pharm. Biotechnol. PD MAR PY 2013 VL 14 IS 4 BP 464 EP 469 PG 6 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 252DU UT WOS:000326986000012 PM 23590143 ER PT J AU Peterson, EJR Kireev, D Moon, AF Midon, M Janzen, WP Pingoud, A Pedersen, LC Singleton, SF AF Peterson, Eliza J. R. Kireev, Dmitri Moon, Andrea F. Midon, Marika Janzen, William P. Pingoud, Alfred Pedersen, Lars C. Singleton, Scott F. TI Inhibitors of Streptococcus pneumoniae Surface Endonuclease EndA Discovered by High-Throughput Screening Using a PicoGreen Fluorescence Assay SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE Streptococcus pneumoniae; EndA; endonuclease; virulence factor; high-throughput screening (HTS); PicoGreen ID NEUTROPHIL EXTRACELLULAR TRAPS; GENETIC-TRANSFORMATION; DIPLOCOCCUS-PNEUMONIAE; PROMISCUOUS INHIBITORS; NUCLEASE; ESCAPE; DNA; DEOXYRIBONUCLEASE; EXPRESSION; MECHANISM AB The human commensal pathogen Streptococcus pneumoniae expresses a number of virulence factors that promote serious pneumococcal diseases, resulting in significant morbidity and mortality worldwide. These virulence factors may give S. pneumoniae the capacity to escape immune defenses, resist antimicrobial agents, or a combination of both. Virulence factors also present possible points of therapeutic intervention. The activities of the surface endonuclease, EndA, allow S. pneumoniae to establish invasive pneumococcal infection. EndA's role in DNA uptake during transformation contributes to gene transfer and genetic diversification. Moreover, EndA's nuclease activity degrades the DNA backbone of neutrophil extracellular traps (NETs), allowing pneumococcus to escape host immune responses. Given its potential impact on pneumococcal pathogenicity, EndA is an attractive target for novel antimicrobial therapy. Herein, we describe the development of a high-throughput screening assay for the discovery of nuclease inhibitors. Nuclease-mediated digestion of double-stranded DNA was assessed using fluorescence changes of the DNA dye ligand, PicoGreen. Under optimized conditions, the assay provided robust and reproducible activity data (Z'= 0.87) and was used to screen 4727 small molecules against an imidazole-rescued variant of EndA. In total, six small molecules were confirmed as novel EndA inhibitors, some of which may have utility as research tools for understanding pneumococcal pathogenesis and for drug discovery. C1 [Peterson, Eliza J. R.; Singleton, Scott F.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Kireev, Dmitri; Janzen, William P.; Singleton, Scott F.] Univ N Carolina, UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Moon, Andrea F.; Pedersen, Lars C.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Midon, Marika; Pingoud, Alfred] Univ Giessen, D-35390 Giessen, Germany. RP Singleton, SF (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. EM scott_singleton@unc.edu FU National Institutes of Health; National Institute of General Medical Sciences [GM058114]; Division of Intramural Research of the National Institute of Environmental Health Sciences [1 ZIA ES102645-03]; Deutsche Forschungsgemeinschaft; National Center for Research Resources; National Center for Advancing Translational Sciences [UL1TR000083] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institutes of Health, including a grant to S. F. S. from the National Institute of General Medical Sciences (grant number GM058114), a grant to L. C. P. from the Division of Intramural Research of the National Institute of Environmental Health Sciences (grant number 1 ZIA ES102645-03), a grant (ECCPS) to M. M. from the Deutsche Forschungsgemeinschaft, and support from the National Center for Research Resources and the National Center for Advancing Translational Sciences (grant number UL1TR000083). NR 34 TC 5 Z9 6 U1 0 U2 24 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD MAR PY 2013 VL 18 IS 3 BP 247 EP 257 DI 10.1177/1087057112461153 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 087OM UT WOS:000314771500002 PM 23015019 ER PT J AU Naujokas, MF Anderson, B Ahsan, H Aposhian, HV Graziano, JH Thompson, C Suk, WA AF Naujokas, Marisa F. Anderson, Beth Ahsan, Habibul Aposhian, H. Vasken Graziano, Joseph H. Thompson, Claudia Suk, William A. TI The Broad Scope of Health Effects from Chronic Arsenic Exposure: Update on a Worldwide Public Health Problem SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE arsenic; arsenic health effects; cancer; chronic arsenic exposure; development; drinking water; skin lesions ID LONGITUDINAL-STUDY HEALS; INDUCED SKIN-LESIONS; DRINKING-WATER; CANCER-MORTALITY; LUNG-CANCER; OXIDATIVE STRESS; DNA METHYLATION; BLADDER-CANCER; NORTHERN CHILE; WEST-BENGAL AB BACKGROUND: Concerns for arsenic exposure are not limited to toxic waste sites and massive poisoning events. Chronic exposure continues to be a major public health problem worldwide, affecting hundreds of millions of persons. OBJECTIVES: We reviewed recent information on worldwide concerns for arsenic exposures and public health to heighten awareness of the current scope of arsenic exposure and health outcomes and the importance of reducing exposure, particularly during pregnancy and early life. METHODS: We synthesized the large body of current research pertaining to arsenic exposure and health outcomes with an emphasis on recent publications. DISCUSSION: Locations of high arsenic exposure via drinking water span from Bangladesh, Chile, and Taiwan to the United States. The U. S. Environmental Protection Agency maximum contaminant level (MCL) in drinking water is 10 mu g/L; however, concentrations of > 3,000 mu g/L have been found in wells in the United States. In addition, exposure through diet is of growing concern. Knowledge of the scope of arsenic-associated health effects has broadened; arsenic leaves essentially no bodily system untouched. Arsenic is a known carcinogen associated with skin, lung, bladder, kidney, and liver cancer. Dermatological, developmental, neurological, respiratory, cardiovascular, immunological, and endocrine effects are also evident. Most remarkably, early-life exposure may be related to increased risks for several types of cancer and other diseases during adulthood. CONCLUSIONS: These data call for heightened awareness of arsenic-related pathologies in broader contexts than previously perceived. Testing foods and drinking water for arsenic, including individual private wells, should be a top priority to reduce exposure, particularly for pregnant women and children, given the potential for life-long effects of developmental exposure. C1 [Naujokas, Marisa F.] MDB Inc, Durham, NC 27713 USA. [Anderson, Beth; Suk, William A.] NIEHS, Superfund Res Program, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Ahsan, Habibul] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Aposhian, H. Vasken] Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85721 USA. [Graziano, Joseph H.] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA. [Thompson, Claudia] NIEHS, Susceptibil & Populat Hlth Branch, Superfund Res Program, NIH,DHHS, Res Triangle Pk, NC 27709 USA. RP Naujokas, MF (reprint author), MDB Inc, Meridian Corp Ctr 2525, Suite 50, Durham, NC 27713 USA. EM naujokasmf@niehs.nih.gov RI Calderon, Jaqueline/B-5841-2014 OI Calderon, Jaqueline/0000-0002-7865-3357 FU National Institute of Environmental Health Sciences (NIEHS) [GS-OOF-0001S]; National Institute of Environmental Health Sciences (NIEHS) (Health and Human Services) [CR700013]; National Institutes of Health; NIEHS SRP [P42ES10349, RO1CA107431, RO1CA102484] FX M.F.N. is supported through a contract with the National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program (SRP) (contract GS-OOF-0001S, Health and Human Services order CR700013). H. A. is supported by National Institutes of Health and NIEHS SRP grants P42ES10349, RO1CA107431, and RO1CA102484. J.G. is supported by NIEHS SRP grant P42ES10349. NR 140 TC 173 Z9 179 U1 24 U2 165 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 MAR PY 2013 VL 121 IS 3 BP 295 EP 302 DI 10.1289/ehp.1205875 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208TU UT WOS:000323703500019 PM 23458756 ER PT J AU Snijder, CA Heederik, D Pierik, FH Hofman, A Jaddoe, VW Koch, HM Longnecker, MP Burdorf, A AF Snijder, Claudia A. Heederik, Dick Pierik, Frank H. Hofman, Albert Jaddoe, Vincent W. Koch, Holger M. Longnecker, Matthew P. Burdorf, Alex TI Fetal Growth and Prenatal Exposure to Bisphenol A: The Generation R Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE birth weight; bisphenol A; fetal growth; head circumference; pregnancy; urine ID IN-UTERO EXPOSURE; BIRTH OUTCOMES; ENDOCRINE DISRUPTERS; PREGNANT-WOMEN; ULTRASOUND; CHEMICALS; ESTROGEN; WEIGHT; HEALTH; PHYTOESTROGENS AB BACKGROUND: Prenatal exposure to bisphenol A (BPA) has been associated with adverse birth outcomes, but findings of previous studies have been inconsistent. OBJECTIVE: We investigated the relation of prenatal BPA exposure with intrauterine growth and evaluated the effect of the number of measurements per subject on observed associations. METHODS: This study was embedded in a Dutch population-based prospective cohort study, with urine samples collected during early, mid-, and late pregnancy. The study comprised 219 women, of whom 99 had one measurement, 40 had two measurements, and 80 had three measurements of urinary BPA. Fetal growth characteristics were repeatedly measured by ultrasound during pregnancy and combined with measurements at birth. Linear regression models for repeated measurements of both BPA and fetal growth were used to estimate associations between urinary concentrations of creatinine-based BPA (BPA(CB)) and intrauterine growth. RESULTS: The relationship between BPA(CB) and fetal growth was sensitive to the number of BPA measurements per woman. Among 80 women with three BPA measurements, women with BPA(CB) > 4.22 mu g/g crea (creatinine) had lower growth rates for fetal weight and head circumference than did women with BPA(CB) < 1.54 mu g/g crea, with estimated differences in mean values at birth of -683 g (20.3% of mean) and -3.9 cm (11.5% of mean), respectively. When fewer measurements were available per woman, the exposure-response relationship became progressively attenuated and statistically nonsignificant. CONCLUSION: Our findings suggest that maternal urinary BPA may impair fetal growth. Because previous studies have shown contradictory findings, further evidence is needed to corroborate these findings in the general population. C1 [Snijder, Claudia A.; Hofman, Albert; Jaddoe, Vincent W.] Erasmus MC, Generat Study Grp R, NL-3000 CA Rotterdam, Netherlands. [Snijder, Claudia A.; Burdorf, Alex] Erasmus MC, Dept Publ Hlth, NL-3000 CA Rotterdam, Netherlands. [Heederik, Dick] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Pierik, Frank H.] TNO Netherlands Org Appl Sci Res, Dept Urban Environm & Safety, Utrecht, Netherlands. [Hofman, Albert; Jaddoe, Vincent W.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Jaddoe, Vincent W.] Erasmus MC, Dept Pediat, NL-3000 CA Rotterdam, Netherlands. [Koch, Holger M.] Inst Ruhr Univ, German Social Accid Insurance, Inst Prevent & Occupat Med, Bochum, Germany. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Burdorf, A (reprint author), Erasmus MC, Dept Publ Hlth, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM a.burdorf@erasmusmc.nl RI Koch, Holger/B-3277-2011; OI Koch, Holger/0000-0002-8328-2837; Longnecker, Matthew/0000-0001-6073-5322 FU European project CONTAMED; European Union [212502]; U.S. National Institutes of Health, National Institute of Environmental Health Sciences FX The present study was conducted in commission of the European project CONTAMED with funding from the European Union's Seventh Framework Programme (FP7) for Research and Technology Development (EU grant agreement 212502). This research was supported in part by the intramural research program of the U.S. National Institutes of Health, National Institute of Environmental Health Sciences. NR 42 TC 42 Z9 42 U1 2 U2 31 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 MAR PY 2013 VL 121 IS 3 BP 393 EP 398 DI 10.1289/ehp.1205296 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208TU UT WOS:000323703500033 PM 23459363 ER PT J AU Navas-Acien, A Maull, EA Thayer, KA AF Navas-Acien, Ana Maull, Elizabeth A. Thayer, Kristina A. TI Arsenic and Diabetes: Navas-Acien et al. Respond SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID PREVALENCE; EXPOSURE C1 [Navas-Acien, Ana] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Maull, Elizabeth A.; Thayer, Kristina A.] NIH, Natl Inst Environm Hlth Sci, Dept Hlth & Human Serv, Div Natl Toxicol Program, Res Triangle Pk, NC USA. RP Navas-Acien, A (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. EM maull@niehs.nih.gov NR 8 TC 3 Z9 3 U1 1 U2 3 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 MAR PY 2013 VL 121 IS 3 BP A71 EP A72 DI 10.1289/ehp.1206100R PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208TU UT WOS:000323703500005 PM 23455044 ER PT J AU LaLonde, JM Le-Khac, M Jones, DM Courter, JR Park, J Schon, A Princiotto, AM Wu, XL Mascola, JR Freire, E Sodroski, J Madani, N Hendrickson, WA Smith, AB AF LaLonde, Judith M. Le-Khac, Matthew Jones, David M. Courter, Joel R. Park, Jongwoo Schoen, Arne Princiotto, Amy M. Wu, Xueling Mascola, John R. Freire, Ernesto Sodroski, Joseph Madani, Navid Hendrickson, Wayne A. Smith, Amos B., III TI Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-ray and Thermodynamic Characterization SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE HIV; gp120; CD4; entry inhibitor; structure-based drug design; thermodynamics; X-ray crystallography; viral inhibition; protein-protein interactions ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEINS; GP120; CD4; BINDING; RECEPTOR; ANTIBODY; COMPLEX; MIMICS AB The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a submicromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 mu M, respectively), without promoting CD4-independent viral entry. The thermodynamic signatures indicate a binding preference for the (R,R)- over the (S,S)-enantiomer. The crystal structure of the small-molecule/gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4-gp120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 entry inhibitors. C1 [LaLonde, Judith M.] Bryn Mawr Coll, Dept Chem, Bryn Mawr, PA 19010 USA. [Le-Khac, Matthew] Columbia Univ, Dept Pharmacol, New York, NY 10032 USA. [Le-Khac, Matthew; Hendrickson, Wayne A.] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Jones, David M.; Courter, Joel R.; Park, Jongwoo; Smith, Amos B., III] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Schoen, Arne; Freire, Ernesto] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Princiotto, Amy M.; Sodroski, Joseph; Madani, Navid] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Wu, Xueling; Mascola, John R.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Sodroski, Joseph] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Sodroski, Joseph] Ragon Inst MGH MIT & Harvard, Boston, MA 02115 USA. [Hendrickson, Wayne A.] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. RP LaLonde, JM (reprint author), Bryn Mawr Coll, Dept Chem, Bryn Mawr, PA 19010 USA. EM jlalonde@brynmawr.edu; wayne@xtl.cumc.columbia.edu; smithab@sas.upenn.edu FU NIH [GM 56550, AI090682-01]; NIH Intramural IATAP; NIAID programs; Ragon Institute of MGH; Ragon Institute of MIT; Ragon Institute of Harvard FX Funding was provided by NIH GM 56550 to J.M.L., E.F., WA.H., A.B.S., and J.S. and by NIH Intramural IATAP and NIAID programs to J.R.M. and J.S. Funding to N.M. was provided by NIH AI090682-01. N.M. and J.S. were also supported by Ragon Institute of MGH, MIT, and Harvard. NR 27 TC 27 Z9 27 U1 4 U2 12 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 MAR PY 2013 VL 4 IS 3 BP 338 EP 343 DI 10.1021/ml300407y PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 207JD UT WOS:000323593800006 PM 23667716 ER PT J AU Miller, FG AF Miller, Franklin G. TI TWO PHILOSOPHICAL DEATHS Hume and Hitchens SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article AB This essay describes the deaths of David Hume (1711-1776) and Christopher Hitchens (1949-2012). Both distinguished thinkers and writers, who shared much in their world views, died around the same age after a similarly prolonged course of terminal illness. However, the great difference in the power of medicine to intervene with the goal of cure or preserving life made their lives while facing death dramatically different. The narratives of these two deaths help shed light on some of the key features that make particular deaths and the processes of dying good or bad, as well as highlight the difficulty in achieving a good death in the world of contemporary medicine. C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov FU Intramural Research Program of the Clinical Center, NIH FX This research was supported by the Intramural Research Program of the Clinical Center, NIH. NR 12 TC 0 Z9 0 U1 1 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD SPR PY 2013 VL 56 IS 2 BP 251 EP 258 PG 8 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 203ND UT WOS:000323299000007 PM 23974505 ER PT J AU Crane, NJ Huffman, SW Alemozaffar, M Gage, FA Levin, IW Elster, EA AF Crane, Nicole J. Huffman, Scott W. Alemozaffar, Mehrdad Gage, Frederick A. Levin, Ira W. Elster, Eric A. TI Evidence of a heterogeneous tissue oxygenation: renal ischemia/reperfusion injury in a large animal model SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE visible reflectance spectroscopy; oxygenation; kidney; swine ID VISIBLE-LIGHT SPECTROSCOPY; LEAST-SQUARES METHODS; PARTIAL NEPHRECTOMY; INFRARED-SPECTROSCOPY; ISCHEMIA; KIDNEY; ARTERY; FLOW AB Renal ischemia that occurs intraoperatively during procedures requiring clamping of the renal artery (such as renal procurement for transplantation and partial nephrectomy for renal cancer) is known to have a significant impact on the viability of that kidney. To better understand the dynamics of intraoperative renal ischemia and recovery of renal oxygenation during reperfusion, a visible reflectance imaging system (VRIS) was developed to measure renal oxygenation during renal artery clamping in both cooled and warm porcine kidneys. For all kidneys, normothermic and hypothermic, visible reflectance imaging demonstrated a spatially distinct decrease in the relative oxy-hemoglobin concentration (%HbO(2)) of the superior pole of the kidney compared to the middle or inferior pole. Mean relative oxy-hemoglobin concentrations decrease more significantly during ischemia for normothermic kidneys compared to hypothermic kidneys. VRIS may be broadly applicable to provide an indicator of organ ischemia during open and laparoscopic procedures. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI. C1 [Crane, Nicole J.; Gage, Frederick A.; Elster, Eric A.] Naval Med Res Ctr, Dept Regenerat Med, Silver Spring, MD 20910 USA. [Huffman, Scott W.] Western Carolina Univ, Dept Chem & Phys, Cullowhee, NC 28723 USA. [Alemozaffar, Mehrdad] Univ So Calif, Inst Urol, Norris Canc Ctr, Los Angeles, CA 90089 USA. [Gage, Frederick A.; Elster, Eric A.] Walter Reed Natl Mil Med Ctr, Dept Surg, Bethesda, MD 20814 USA. [Levin, Ira W.] NIDDK, Chem Phys Lab, Natl Inst Hlth, Bethesda, MD USA. [Crane, Nicole J.; Elster, Eric A.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. RP Elster, EA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Surg, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM eric.elster@usuhs.edu FU Department of Defense [602227D.0483.01.A0518]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX The authors thank Drs. Nadeem Dhanani, Marie McHenry, Ben McHone, and Peter Pinto for their surgical assistance during the experiments. This effort was supported (in part) by the Department of Defense (work unit no. 602227D.0483.01.A0518, Medical Free Electron Laser Program). We also acknowledge support from the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The experiments reported herein were conducted in compliance with the Animal Welfare Act and in accordance with the principles set forth in the "Guide for the Care and Use of Laboratory Animals," Institute of Laboratory Animals Resources, National Research Council, National Academy Press, 1996. The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of the Army, Department of the Navy, the Department of Defense, or the U.S. government. This work was prepared as part of official government duties. Title 17 U.S.C. 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 U. S. government work as a work prepared by a military service member or employee of the U. S. government as part of that person's official duties. We certify that all individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the analysis of data (when applicable), the writing of the document, and the approval of the submission of this version; that the document represents valid work; that if we used information derived from another source, we obtained all necessary approvals to use it and made appropriate acknowledgements in the document; and that each author takes public responsibility for it. NR 28 TC 4 Z9 4 U1 1 U2 5 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD MAR PY 2013 VL 18 IS 3 AR 035001 DI 10.1117/1JBO.18.3.035001 PG 7 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 190JV UT WOS:000322336700016 PM 23456040 ER PT J AU Liu, JK Hickson, DA Musani, SK Talegawkar, SA Carithers, TC Tucker, KL Fox, CS Taylor, HA AF Liu, Jiankang Hickson, DeMarc A. Musani, Solomon K. Talegawkar, Sameera A. Carithers, Teresa C. Tucker, Katherine L. Fox, Caroline S. Taylor, Herman A. TI Dietary Patterns, Abdominal Visceral Adipose Tissue, and Cardiometabolic Risk Factors in African Americans: The Jackson Heart Study SO OBESITY LA English DT Article ID METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; FAT; ADULTS; WOMEN; LIVER AB Objective: To examine the relative association of abdominal visceral adipose tissue (VAT) with cardiometabolic risk factors between African and European Americans. Design and Methods: We conducted a cross-sectional study of 2035 African Americans from Jackson Heart Study (JHS) and 3170 European Americans from Framingham Heart Study (FHS) who underwent computed tomography assessment of VAT and subcutaneous adipose tissue (SAT). The FHS participants were weighted to match the age distribution of the JHS participants and the metabolic risk factors were examined by study groups in relation to VAT. Results: JHS participants had higher rates of obesity, hypertension, diabetes and metabolic syndrome than FHS participants (all p = 0.001). The associations were weaker in JHS women for VAT with blood pressure, triglycerides, HDL-C, and total cholesterol (p(interaction) = 0.03 to 0.001) than FHS women. In contrast, JHS men had stronger associations for VAT with high triglycerides, low HDL, and metabolic syndrome (all p(interaction) = 0.001) compared to FHS men. Similar associations and gender patterns existed for SAT with most metabolic risk factors. Conclusions: The relative association between VAT and cardiometabolic risk factors is weaker in JHS women compared to FHS women, whereas stronger association with triglycerides and HDL were observed in JHS men. C1 [Liu, Jiankang; Hickson, DeMarc A.; Musani, Solomon K.; Taylor, Herman A.] Jackson State Univ, Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS USA. [Talegawkar, Sameera A.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Carithers, Teresa C.] Univ Mississippi, Dept Family & Consumer Sci, Oxford, MS USA. [Tucker, Katherine L.] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Liu, JK (reprint author), Jackson State Univ, Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS USA. EM jliu@umc.edu OI Tucker, Katherine/0000-0001-7640-662X FU National Heart, Lung, and Blood Institute [N01-HC-95170, N01-HC-95171, N01-C-95172]; National Center on Minority Health and Health Disparities FX The authors thank the staff, interns, and participants in Jackson Heart Study for their long-term commitment and important contributions to the study. The Jackson Heart Study is supported by the National Heart, Lung, and Blood Institute and the National Center on Minority Health and Health Disparities. Funding for H.A.T. was provided under contracts N01-HC-95170, N01-HC-95171, and N01-C-95172 from the National Heart, Lung, and Blood Institute and the National Center on Minority Health and Health Disparities. NR 28 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 J9 OBESITY JI Obesity PD MAR PY 2013 VL 21 IS 3 BP 644 EP 651 DI 10.1038/oby.2012.145 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 187AK UT WOS:000322087600057 PM 23592674 ER PT J AU Sanz-Clemente, A Gray, JA Ogilvie, KA Nicoll, RA Roche, KW AF Sanz-Clemente, Antonio Gray, John A. Ogilvie, Kyle A. Nicoll, Roger A. Roche, Katherine W. TI Activated CaMKII Couples GluN2B and Casein Kinase 2 to Control Synaptic NMDA Receptors SO CELL REPORTS LA English DT Article ID D-ASPARTATE RECEPTOR; LONG-TERM POTENTIATION; SUBUNIT COMPOSITION; DENDRITIC SPINES; NR2B SUBUNIT; VISUAL-CORTEX; PHOSPHORYLATION; TRAFFICKING; PLASTICITY; BINDING AB Synaptic activity triggers a profound reorganization of the molecular composition of excitatory synapses. For example, NMDA receptors are removed from synapses in an activity- and calcium-dependent manner, via casein kinase 2 (CK2) phosphorylation of the PDZ ligand of the GluN2B subunit (S1480). However, how synaptic activity drives this process remains unclear because CK2 is a constitutively active kinase, which is not directly regulated by calcium. We show here that activated CaMKII couples GluN2B and CK2 to form a trimolecular complex and increases CK2-mediated phosphorylation of GluN2B S1480. In addition, a GluN2B mutant, which contains an insert to mimic the GluN2A sequence and cannot bind to CaMKII, displays reduced S1480 phosphorylation and increased surface expression. We find that although disrupting GluN2B/CaMKII binding reduces synapse number, it increases synaptic-GluN2B content. Therefore, the GluN2B/CaMKII association controls synapse density and PSD composition in an activity-dependent manner, including recruitment of CK2 for the removal of GluN2B from synapses. C1 [Sanz-Clemente, Antonio; Ogilvie, Kyle A.; Roche, Katherine W.] NINDS, Natl Inst Hlth, Receptor Biol Sect, Bethesda, MD 20892 USA. [Gray, John A.; Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. RP Roche, KW (reprint author), NINDS, Natl Inst Hlth, Receptor Biol Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM rochek@ninds.nih.gov OI Roche, Katherine/0000-0001-7282-6539 FU NINDS Intramural Research Program; NIMH; NARSAD Young Investigator Award; NARSAD Hammerschlag Family Investigator FX We thank John D. Badger II for technical assistance. We also thank the NINDS sequencing facility and light imaging facility for expertise and advice. This research was supported by the NINDS Intramural Research Program (A.S.-C., K.A.O., and K.W.R.) and grants from the NIMH (J.A.G. and R.A.N.). J.A.G. is funded by a NARSAD Young Investigator Award and is the NARSAD Hammerschlag Family Investigator. NR 40 TC 20 Z9 21 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAR PY 2013 VL 3 IS 3 BP 607 EP 614 DI 10.1016/j.celrep.2013.02.011 PG 8 WC Cell Biology SC Cell Biology GA 184MZ UT WOS:000321896000003 PM 23478024 ER PT J AU Bravo, PE Zimmerman, SL Luo, HC Pozios, I Rajaram, M Pinheiro, A Steenbergen, C Kamel, IR Wahl, RL Bluemke, DA Bengel, FM Abraham, MR Abraham, TP AF Bravo, Paco E. Zimmerman, Stefan L. Luo, Hong-Chang Pozios, Iraklis Rajaram, Mahadevan Pinheiro, Aurelio Steenbergen, Charles Kamel, Ihab R. Wahl, Richard L. Bluemke, David A. Bengel, Frank M. Abraham, M. Roselle Abraham, Theodore P. TI Relationship of Delayed Enhancement by Magnetic Resonance to Myocardial Perfusion by Positron Emission Tomography in Hypertrophic Cardiomyopathy SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE cardiac MRI; fibrosis; HCM; ischemia; PET ID CORONARY MICROVASCULAR DYSFUNCTION; LATE GADOLINIUM ENHANCEMENT; FLOW RESERVE; CONTRAST ENHANCEMENT; RISK-ASSESSMENT; QUANTIFICATION; ARRHYTHMIAS; ISCHEMIA; FIBROSIS; ARTERIES AB Background Presence of delayed enhancement (DE) on cardiac magnetic resonance (CMR) is associated with worse clinical outcomes in hypertrophic cardiomyopathy. We investigated the relationship between DE on CMR and myocardial ischemia in hypertrophic cardiomyopathy. Methods and Results Hypertrophic cardiomyopathy patients (n=47) underwent CMR for assessment of DE and vasodilator stress ammonia positron emission tomography to quantify myocardial blood flow and coronary flow reserve. The summed difference score for regional myocardial perfusion was also assessed. Patients in the DE group (n=35) had greater left ventricular wall thickness (2.09 +/- 0.44 versus 1.78 +/- 0.34 cm; P=0.03). Stress myocardial blood flow (2.25 +/- 0.46 versus 1.78 +/- 0.43 mL/min per gram; P=0.01) and coronary flow reserve (2.78 +/- 0.32 versus 2.01 +/- 0.52; P<0.001) were significantly lower in DE-positive patients. Summed difference score (median, 5 versus 0; P<0.0001) was significantly higher in patients with DE. A coronary flow reserve <2.00 was seen in 18 patients (51%) with DE but in none of the DE-negative patients (P<0.0001). CMR and positron emission tomography showed visually concordant DE and regional myocardial perfusion abnormalities in 31 patients and absence of DE and perfusion defects in 9 patients. Four DE-positive patients demonstrated normal regional myocardial perfusion, and 3 DE-negative patients had (apical) regional myocardial perfusion abnormalities. Conclusions We found a close relationship between DE by CMR and microvascular function in most of the patients studied. However, a small proportion of patients had DE in the absence of perfusion abnormalities, suggesting that microvascular dysfunction and ischemia are not the sole causes of DE in hypertrophic cardiomyopathy patients. C1 [Bravo, Paco E.; Zimmerman, Stefan L.; Rajaram, Mahadevan; Kamel, Ihab R.; Wahl, Richard L.; Bluemke, David A.] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21205 USA. [Luo, Hong-Chang; Pozios, Iraklis; Pinheiro, Aurelio; Abraham, M. Roselle; Abraham, Theodore P.] Johns Hopkins Med Inst, Div Cardiol, Baltimore, MD 21205 USA. [Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. [Luo, Hong-Chang] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Med Ultrasound, Wuhan 430074, Peoples R China. [Bengel, Frank M.] Hannover Med Sch, Dept Nucl Med, Hannover, Germany. RP Abraham, TP (reprint author), Johns Hopkins Univ, Sch Med, CARNEGIE 568B,600 N Wolfe St,Blalock 910F, Baltimore, MD 21287 USA. EM tabraha3@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [HL098046] FX This work was supported in part by a grant from the National Institutes of Health (HL098046). NR 38 TC 14 Z9 14 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD MAR PY 2013 VL 6 IS 2 BP 210 EP 217 DI 10.1161/CIRCIMAGING.112.000110 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 167XM UT WOS:000320668800012 PM 23418294 ER PT J AU Lai, C Wilson, W AF Lai, Catherine Wilson, Wyndham TI T-cell lymphoma Preface SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Editorial Material C1 [Lai, Catherine; Wilson, Wyndham] NCI, NIH, Bethesda, MD 20892 USA. RP Lai, C (reprint author), NCI, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM Catherine.lai@nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD MAR PY 2013 VL 26 IS 1 BP 1 EP 1 DI 10.1016/j.beha.2013.05.001 PG 1 WC Hematology SC Hematology GA 174RR UT WOS:000321173600001 PM 23768635 ER PT J AU Lai, C Dunleavy, K AF Lai, Catherine Dunleavy, Kieron TI NK/T-cell lymphomas in children SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE T-lymphoblastic lymphoma; T-LBL; anaplastic large cell lymphoma; ALCL; ALK; PTCL-NOS; angioimmunoblastic T-cell lymphoma; AITL; NOTCH1; mTOR; CD30 ID PERIPHERAL T-CELL; ACUTE-LYMPHOBLASTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; BONE-MARROW-TRANSPLANTATION; FRANKFURT-MUNSTER GROUP; ONCOLOGY-GROUP; PEDIATRIC-ONCOLOGY; BFM-GROUP; CLINICAL-FEATURES; DOSE METHOTREXATE AB In children, T and NK-cell lymphomas are uncommon in Western Countries. While there has been significant experience treating T-cell lymphoblastic lymphoma (T-LBL) and anaplastic large cell lymphoma (ALCL), other subtypes are very rarely encountered and there are no standard approaches to their management. There are many challenges in defining optimal therapy for many of these diseases but recent progress in elucidating their biology has led to new molecular insights and identified interesting targets for novel drug discovery. In this review, we discuss these disorders in children, how they are approached therapeutically and what lies on the horizon with respect to novel treatment approaches. Published by Elsevier Ltd. C1 [Lai, Catherine; Dunleavy, Kieron] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), NCI, Bldg 10,Rm 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 72 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD MAR PY 2013 VL 26 IS 1 BP 33 EP 41 DI 10.1016/j.beha.2013.04.004 PG 9 WC Hematology SC Hematology GA 174RR UT WOS:000321173600005 PM 23768639 ER PT J AU Bajor-Dattilo, EB Pittaluga, S Jaffe, ES AF Bajor-Dattilo, Ewa B. Pittaluga, Stefania Jaffe, Elaine S. TI Pathobiology of T-cell and NK-cell lymphomas SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE pathobiology; pathogenesis; anaplastic large cell lymphoma; peripheral T-cell lymphoma; extranodal NK/T-cell lymphoma; enteropathy associated T-cell lymphoma; hepatosplenic T-cell lymphoma; subcutaneous panniculitis-like T-cell lymphoma; primary cutaneous gamma delta T-cell lymphoma; cellular origin; nodal; extranodal; innate immune system; adaptive immune system; T-follicular helper cells; alpha beta T-cell receptor; gamma delta T-cell receptor ID EPSTEIN-BARR-VIRUS; CLASSICAL HODGKIN LYMPHOMA; FOLLICULAR-GROWTH PATTERN; GAMMA-DELTA; B-CELL; LYMPHOPROLIFERATIVE DISORDERS; ANGIOIMMUNOBLASTIC LYMPHADENOPATHY; CLINICOPATHOLOGICAL ENTITY; GENE-EXPRESSION; CELIAC-DISEASE AB T-cell and NK-cell lymphomas are uncommon lymphomas with an aggressive clinical course. The causes and precise cellular origins of most T-cell lymphomas are still not well defined. The WHO classification utilizes morphologic and immunophenotypic features in conjunction with clinical aspects and in some instances genetics to delineate a prognostically and therapeutically meaningful categorization. The anatomic localization of neoplastic T-cells and NK-cells parallels in part their proposed normal cellular counterparts and functions. T-cells of the adaptive immune system are mainly based in lymph nodes and peripheral blood, whereas lymphomas derived from T-cells and NK-cells of the innate immune system are mainly extranodal. This approach allows for better understanding of some of the manifestations of the T-cell and NK-cell lymphomas, including their cellular distribution, some aspects of morphology and even associated clinical findings. Published by Elsevier Ltd. C1 [Bajor-Dattilo, Ewa B.; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Pathol Lab, Bldg 10,Room 2B42, Bethesda, MD 20892 USA. EM ewa.bajor-dattilo@nih.gov; stefpitt@mail.nih.gov; ejaffe@mail.nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 FU Intramural NIH HHS [ZIA BC011070-05] NR 94 TC 8 Z9 8 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD MAR PY 2013 VL 26 IS 1 BP 75 EP 87 DI 10.1016/j.beha.2013.04.007 PG 13 WC Hematology SC Hematology GA 174RR UT WOS:000321173600008 PM 23768642 ER PT J AU Moraitis, AG Hewison, M Collins, M Anaya, C Holick, MF AF Moraitis, Andreas G. Hewison, Martin Collins, Michael Anaya, Candido Holick, Michael F. TI HYPERCALCEMIA ASSOCIATED WITH MINERAL OIL-INDUCED SCLEROSING PARAFFINOMAS SO ENDOCRINE PRACTICE LA English DT Article ID ANGIOTENSIN-CONVERTING ENZYME; SUBCUTANEOUS FAT NECROSIS; D-MEDIATED HYPERCALCEMIA; VITAMIN-D; 25-HYDROXYVITAMIN D-3-1-ALPHA-HYDROXYLASE; SARCOIDOSIS; NEWBORN; 1-ALPHA-HYDROXYLASE; EXPRESSION; GRANULOMAS AB Objective: Granuloma-forming diseases such as sarcoidosis are associated with extrarenal synthesis of 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. We describe a case of extensive skin lesions associated with mineral oil injections in which we provide evidence for cutaneous granuloma synthesis of 1,25(OH)(2)D in the pathogenesis of the patient's hypercalcemia. Methods: Analysis of expression of the 25(OH) D-1a-hydroxylase (1-a OHase [CYP27b1]) was carried out by immunohistochemical analysis of involved skin. Results: In involved skin, expression of CYP27b1 was found in the dermis, where it is not normally expressed. Successful management of hypercalcemia was achieved with glucocorticoids. Conclusions: Hypercalcemia associated with mineral oil induced skin lesions is likely driven by unregulated expression of CYP27b1 by inflammatory monocytes and macrophages infiltrating the dermis. C1 [Moraitis, Andreas G.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Hewison, Martin] Univ Calif Los Angeles, David Geffen Sch Med, Orthopaed Hosp, Res Ctr, Los Angeles, CA 90095 USA. [Hewison, Martin] Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, New York, NY USA. [Collins, Michael] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, New York, NY USA. [Anaya, Candido] New York Downtown Hosp Weill Cornell, New York, NY USA. [Holick, Michael F.] Boston Univ, Sch Med, Dept Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. RP Moraitis, AG (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM moraitia@mail.nih.gov OI Holick, Michael/0000-0001-6023-9062 FU New York Downtown Hospital; UCLA Orthopaedic Hospital Research Center FX The authors have no multiplicity of interest to disclose. This work was funded by the New York Downtown Hospital and the UCLA Orthopaedic Hospital Research Center. NR 25 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X J9 ENDOCR PRACT JI Endocr. Pract. PD MAR-APR PY 2013 VL 19 IS 2 BP E50 EP E56 DI 10.4158/EP12092.CR PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 154JX UT WOS:000319672400003 PM 23337133 ER PT J AU Romling, U Galperin, MY Gomelsky, M AF Romling, Ute Galperin, Michael Y. Gomelsky, Mark TI Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger SO MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS LA English DT Review ID ENTERICA SEROVAR TYPHIMURIUM; 3',5'-CYCLIC DIGUANYLIC ACID; PILZ DOMAIN PROTEINS; HD-GYP DOMAIN; REGULATES BIOFILM FORMATION; DIMERIC GUANOSINE-MONOPHOSPHATE; PSEUDOMONAS-FLUORESCENS PF0-1; SIGNAL-TRANSDUCTION SYSTEMS; GENERAL STRESS-RESPONSE; PRIME TRANSCRIPTION INITIATION AB Twenty-five years have passed since the discovery of cyclic dimeric (3'-> 5') GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger. C1 [Romling, Ute] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Galperin, Michael Y.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Gomelsky, Mark] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. RP Romling, U (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. EM ute.romling@ki.se OI Romling, Ute/0000-0003-3812-6621; Galperin, Michael/0000-0002-2265-5572 FU European Commission; Swedish Research Council of Natural Sciences; Petrus and Augusta Hedlund Foundation; Carl Trygger Foundation; Swedish Research Council of Medicine and Health; Karolinska Institutet; Intramural Research Program of the National Institutes of Health at the National Library of Medicine; NSF [MCB 1052575]; USDA [AFRI 2010-65201-20599]; University of Wyoming Agricultural Experiment Station FX The work of our groups has been supported by the European Commission, the Swedish Research Council of Natural Sciences, the Petrus and Augusta Hedlund Foundation, the Carl Trygger Foundation, the Swedish Research Council of Medicine and Health, and the Karolinska Institutet (U. R.); by the Intramural Research Program of the National Institutes of Health at the National Library of Medicine (M.Y.G.); and by grants from the NSF (MCB 1052575), the USDA (AFRI 2010-65201-20599), and the University of Wyoming Agricultural Experiment Station (M.G.). NR 487 TC 389 Z9 397 U1 12 U2 169 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1092-2172 J9 MICROBIOL MOL BIOL R JI Microbiol. Mol. Biol. Rev. PD MAR PY 2013 VL 77 IS 1 BP 1 EP 52 DI 10.1128/MMBR.00043-12 PG 52 WC Microbiology SC Microbiology GA 157NF UT WOS:000319903400001 PM 23471616 ER PT J AU Kim, H Stotts, NA Froelicher, ES Engler, MM Porter, C AF Kim, Hyunjung Stotts, Nancy A. Froelicher, Erika S. Engler, Marguerite M. Porter, Carol TI ENTERAL NUTRITIONAL INTAKE IN ADULT KOREAN INTENSIVE CARE PATIENTS SO AMERICAN JOURNAL OF CRITICAL CARE LA English DT Article ID CRITICALLY-ILL PATIENTS; RECEIVING MECHANICAL VENTILATION; UNIT PATIENTS; ICU PATIENTS; ENERGY-EXPENDITURE; CONTROLLED-TRIAL; CALORIC-INTAKE; DELIVERY; SUPPORT; OUTCOMES AB Background Nutritional support is important for maximizing clinical outcomes in critically ill patients, but enteral nutritional intake is often inadequate. Objectives To assess the nutritional intake of energy and protein during the first 4 days after initiation of enteral feeding and to examine the relationship between intake and interruptions of enteral feeding in Korean patients in intensive care. Methods A cohort of 34 critically ill adults who had a primary medical diagnosis and received bolus enteral feeding were studied prospectively. Energy and protein requirements were determined by using the Harris-Benedict equation and the American Dietetic Association equation. Energy and protein intake prescribed and received and the reasons for and lengths of feeding interruptions were recorded for 4 consecutive days immediately after enteral feeding began. Results Although the differences between requirements and intakes of energy and protein decreased significantly, patients did not receive required energy and protein intake during the 4 days of the study. Energy intake prescribed was consistently less than required on each of the 4 days. Enteral nutrition was withheld for a mean of 6 hours per patient for the 4 days. Prolonged feeding interruptions due to gastrointestinal intolerance (r = -0.874; P < .001) and procedures (r = -0.839; P = .005) were negatively associated with the percentage of prescribed energy received. Conclusion Enteral nutritional intake was insufficient in bolusfed Korean intensive care patients because of prolonged feeding interruptions and underprescription of enteral nutrition. Feeding interruptions due to gastrointestinal intolerance and procedures were the main contributors to inadequate energy intake. (American Journal of Critical Care. 2013; 22: 126-135) C1 [Kim, Hyunjung] Hallym Univ, Div Nursing, Chunchon, Gangwon, South Korea. [Stotts, Nancy A.; Froelicher, Erika S.] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Froelicher, Erika S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Engler, Marguerite M.] NINR, NIH, Bethesda, MD 20892 USA. [Porter, Carol] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Stotts, NA (reprint author), Univ Calif San Francisco, 2 Koret Way 631Y, San Francisco, CA 94143 USA. EM nancy.stotts@nursing.ucsf.edu FU Alpha Eta Chapter Research Award of Sigma Theta Tau International Honor Society of Nursing; University of California San Francisco Graduate Student Research Award; University of California San Francisco School of Nursing Century Club Award FX This study was supported by the Alpha Eta Chapter Research Award of Sigma Theta Tau International Honor Society of Nursing, the University of California San Francisco Graduate Student Research Award, and the University of California San Francisco School of Nursing Century Club Award. NR 43 TC 5 Z9 5 U1 0 U2 5 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1062-3264 EI 1937-710X J9 AM J CRIT CARE JI Am. J. Crit. Care PD MAR 1 PY 2013 VL 22 IS 2 BP 126 EP 135 DI 10.4037/ajcc2013629 PG 10 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA 153QL UT WOS:000319617400007 PM 23455862 ER PT J AU Cook, NL Bonds, DE Kiefe, CI Curtis, JP Krumholz, HM Kressin, NR Peterson, ED AF Cook, Nakela L. Bonds, Denise E. Kiefe, Catarina I. Curtis, Jeptha P. Krumholz, Harlan M. Kressin, Nancy R. Peterson, Eric D. CA Natl Heart Lung Blood Inst Ctr Car TI Centers for Cardiovascular Outcomes Research Defining a Collaborative Vision SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE cross-collaboration; outcomes research; translation of knowledge ID ACUTE MYOCARDIAL-INFARCTION; ACUTE CORONARY SYNDROMES; PULMONARY-EMBOLISM; SECONDARY PREVENTION; INSURANCE STATUS; UNSTABLE ANGINA; WHITE PATIENTS; DISEASE; HEART; RISK AB Background-Recognizing the value of outcomes research to understand and bridge translational gaps, to establish evidence in clinical practice and delivery of medicine, and to generate new hypotheses on ongoing questions of treatment and care, the National Heart, Lung, and Blood Institute of the National Institutes of Health established the Centers for Cardiovascular Outcomes Research program in 2010. Methods and Results-The National Heart, Lung, and Blood Institute funded 3 centers and a research coordinating unit. Each center has an independent project focus, including (1) characterizing care transition and predicting clinical events and quality of life for patients discharged after an acute coronary syndrome; (2) identifying center and regional factors associated with better patient outcomes across several cardiovascular conditions and procedures; and (3) examining the impact of healthcare reform in Massachusetts on overall and disparate care and outcomes for several cardiovascular conditions and venous thromboembolism. Cross-program collaborations seek to advance the field methodologically and to develop early-stage investigators committed to careers in outcomes research. Conclusions-The Centers for Cardiovascular Outcomes Research program represents a significant investment in cardiovascular outcomes research by the National Heart, Lung, and Blood Institute. The vision of this program is to leverage scientific rigor and cross-program collaboration to advance the science of healthcare delivery and outcomes beyond what any individual unit could achieve alone. C1 [Cook, Nakela L.] NHLBI, Bethesda, MD 20892 USA. [Kiefe, Catarina I.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Curtis, Jeptha P.; Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Sect Cardiovasc Med, New Haven, CT 06510 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Robert Wood Johnson Clin Scholars Program, New Haven, CT 06510 USA. [Krumholz, Harlan M.] Yale Univ, Sch Publ Hlth, Dept Hlth Policy & Management, New Haven, CT USA. [Curtis, Jeptha P.; Krumholz, Harlan M.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. [Kressin, Nancy R.] Dept Vet Affairs, Boston, MA USA. [Kressin, Nancy R.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Peterson, Eric D.] Duke Univ, Sch Med, Duke Clin Res Inst, Duke Outcomes Res Ctr, Durham, NC USA. RP Cook, NL (reprint author), 31 Ctr Dr,Bldg 31,Room 5A48, Bethesda, MD 20814 USA. EM nakela.cook@nih.gov OI Kressin, Nancy/0000-0003-2767-4286 FU NHLBI [U01HL 105268, U01HL105270, U01HL105342, U01HL107023]; University of Massachusetts' Clinical and Translational Science Award [U54 RR 026088]; Research Career Scientist award from the Department of Veterans Affairs, Health Services Research & Development Service [RCS 02-066-1] FX TRACE-CORE is supported through a cooperative agreement with NHLBI, U01HL 105268; work on this article is also partially supported through the University of Massachusetts' Clinical and Translational Science Award, U54 RR 026088. CCOR at Yale University is supported through a cooperative agreement with NHLBI, U01HL105270. Center for Health Insurance Reform, Cardiovascular Outcomes and Disparities is supported through a cooperative agreement with NHLBI, U01HL105342. Dr Kressin is supported in part by a Research Career Scientist award from the Department of Veterans Affairs, Health Services Research & Development Service (RCS 02-066-1). RCU is supported through a cooperative agreement with NHLBI, U01HL107023. NR 23 TC 4 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD MAR PY 2013 VL 6 IS 2 BP 223 EP 228 DI 10.1161/CIRCOUTCOMES.0b013e31828e8d5c PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 150LO UT WOS:000319392100015 PM 23481526 ER PT J AU Summers, FA Mason, RP Ehrenshaft, M AF Summers, Fiona A. Mason, Ronald P. Ehrenshaft, Marilyn TI Development of immunoblotting techniques for DNA radical detection SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Free radicals; Oxidatively generated damage; DNA; ELISA; Immuno-spin trapping; Immunoblotting ID HYDROGEN-PEROXIDE; PVDF MEMBRANE; GENOMIC DNA; DAMAGE; ION; OXIDATION; COPPER; BINDING; REQUIREMENT; GLUTATHIONE AB Radical damage to DNA has been implicated in cell death, cellular dysfunction, and cancer. A recently developed method for detecting DNA radicals uses the nitrone spin trap DMPO (5,5-dimethyl-1-pyrroline N-oxide) to trap radicals. The trapped radicals then decay into stable nitrone adducts detectable with anti-DMPO antibodies and quantifiable by ELISA or dot-blot assay. However, the sequences of DNA that are damaged are likely to be as important as the total level of damage. Therefore, we have developed immunoblotting methods for detection of DNA nitrone adducts on electrophoretically separated DNA, comparable to Western blotting for proteins. These new techniques not only allow the assessment of relative radical adduct levels, but can reveal specific DNA fragments, and ultimately nucleotides, as radical targets. Moreover, we have determined that denaturation of samples into single-stranded DNA enhances the detection of DNA-DMPO adducts in our new blotting methods and also in ELISA. Published by Elsevier Inc. C1 [Summers, Fiona A.; Mason, Ronald P.; Ehrenshaft, Marilyn] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Summers, FA (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM summersfa@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences 52 [Z01 ES050139-13]; National Institute of Environmental Health Sciences FX We are grateful to A.G. Motten, J. Corbett, and M. Mason for valuable help in the preparation of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences 52 (Z01 ES050139-13). Funding for open access charge was from the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 48 TC 5 Z9 5 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 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAR PY 2013 VL 56 BP 64 EP 71 DI 10.1016/j.freeradbiomed.2012.10.550 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 154BY UT WOS:000319647700007 PM 23142572 ER PT J AU Wehr, NB Levine, RL AF Wehr, Nancy B. Levine, Rodney L. TI Antibodies against methionine sulfoxide of proteins Response SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Letter C1 [Wehr, Nancy B.; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NIH, Bldg 50,Room 2351, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural NIH HHS [ZIA HL000225-35] NR 3 TC 1 Z9 2 U1 1 U2 3 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 MAR PY 2013 VL 56 BP 236 EP 236 DI 10.1016/j.freeradbiomed.2012.12.018 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 154BY UT WOS:000319647700021 PM 23277145 ER PT J AU Kapoor, A Simmonds, P Scheel, TKH Hjelle, B Cullen, JM Burbelo, PD Chauhan, LV Duraisamy, R Leon, MS Jain, K Vandegrift, KJ Calisher, CH Rice, CM Lipkin, WI AF Kapoor, Amit Simmonds, Peter Scheel, Troels K. H. Hjelle, Brian Cullen, John M. Burbelo, Peter D. Chauhan, Lokendra V. Duraisamy, Raja Leon, Maria Sanchez Jain, Komal Vandegrift, Kurt Jason Calisher, Charles H. Rice, Charles M. Lipkin, W. Ian TI Identification of Rodent Homologs of Hepatitis C Virus and Pegiviruses SO MBIO LA English DT Article ID SURROGATE MODEL; CELL-CULTURE; INFECTION; REPLICATION; GENOMES; AGENT; HOST; PATHOGENESIS; NUCLEOTIDE; FLAVIVIRUS AB Hepatitis C virus (HCV) and human pegivirus (HPgV or GB virus C) are globally distributed and infect 2 to 5% of the human population. The lack of tractable-animal models for these viruses, in particular for HCV, has hampered the study of infection, transmission, virulence, immunity, and pathogenesis. To address this challenge, we searched for homologous viruses in small mammals, including wild rodents. Here we report the discovery of several new hepaciviruses (HCV-like viruses) and pegiviruses (GB virus-like viruses) that infect wild rodents. Complete genome sequences were acquired for a rodent hepacivirus (RHV) found in Peromyscus maniculatus and a rodent pegivirus (RPgV) found in Neotoma albigula. Unique genomic features and phylogenetic analyses confirmed that these RHV and RPgV variants represent several novel virus species in the Hepacivirus and Pegivirus genera within the family Flaviviridae. The genetic diversity of the rodent hepaciviruses exceeded that observed for hepaciviruses infecting either humans or non-primates, leading to new insights into the origin, evolution, and host range of hepaciviruses. The presence of genes, encoded proteins, and translation elements homologous to those found in human hepaciviruses and pegiviruses suggests the potential for the development of new animal systems with which to model HCV pathogenesis, vaccine design, and treatment. IMPORTANCE The genetic and biological characterization of animal homologs of human viruses provides insights into the origins of human infections and enhances our ability to study their pathogenesis and explore preventive and therapeutic interventions. Horses are the only reported host of nonprimate homologs of hepatitis C virus (HCV). Here, we report the discovery of HCV-like viruses in wild rodents. The majority of HCV-like viruses were found in deer mice (Peromyscus maniculatus), a small rodent used in laboratories to study viruses, including hantaviruses. We also identified pegiviruses in rodents that are distinct from the pegiviruses found in primates, bats, and horses. These novel viruses may enable the development of small-animal models for HCV, the most common infectious cause of liver failure and hepatocellular carcinoma after hepatitis B virus, and help to explore the health relevance of the highly prevalent human pegiviruses. C1 [Kapoor, Amit; Chauhan, Lokendra V.; Duraisamy, Raja; Leon, Maria Sanchez; Jain, Komal; Calisher, Charles H.; Lipkin, W. Ian] Columbia Univ, Ctr Infect & Immun, New York, NY 10027 USA. [Simmonds, Peter] Univ Edinburgh, Roslin Inst, Edinburgh, Midlothian, Scotland. [Scheel, Troels K. H.; Rice, Charles M.] Rockefeller Univ, Ctr Study Hepatitis C, Lab Virol & Infect Dis, New York, NY 10021 USA. [Scheel, Troels K. H.] Copenhagen Univ Hosp, Copenhagen Hepatitis C Program CO HEP, Dept Infect Dis, Hvidovre, Denmark. [Scheel, Troels K. H.] Copenhagen Univ Hosp, Clin Res Ctr, Hvidovre, Denmark. [Scheel, Troels K. H.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Int Hlth Immunol & Microbiol, Copenhagen, Denmark. [Hjelle, Brian] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Cullen, John M.] North Carolina Coll Vet Med, Raleigh, NC USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Clin Dent Res Core, NIH, Bethesda, MD USA. [Vandegrift, Kurt Jason] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. RP Kapoor, A (reprint author), Columbia Univ, Ctr Infect & Immun, New York, NY 10027 USA. EM ak3117@columbia.edu FU National Institutes of Health [AI081132, AI079231, AI57158, AI070411, AI090055, AI072613, CA057973, EY017404]; intramural research program, National Institute of Dental and Craniofacial Research, NIH; Greenberg Medical Research Institute; Starr Foundation; Danish Council for Independent Research FX This work was supported by awards from the National Institutes of Health (grants AI081132, AI079231, AI57158, AI070411, AI090055, AI072613, CA057973, and EY017404) and in part from the intramural research program, National Institute of Dental and Craniofacial Research, NIH, the Greenberg Medical Research Institute, the Starr Foundation, and the Danish Council for Independent Research. NR 39 TC 48 Z9 52 U1 2 U2 27 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2013 VL 4 IS 2 AR e00216-13 DI 10.1128/mBio.00216-13 PG 10 WC Microbiology SC Microbiology GA 137JI UT WOS:000318431500033 PM 23572554 ER PT J AU Tanaka, TQ Dehdashti, SJ Nguyen, DT Mckew, JC Zheng, W Williamson, KC AF Tanaka, Takeshi Q. Dehdashti, Seameen J. Dac-Trung Nguyen McKew, John C. Zheng, Wei Williamson, Kim C. TI A quantitative high throughput assay for identifying gametocytocidal compounds SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Malaria; Gametocytes; AlamarBlue; High throughput screening; Malaria drug discovery ID PLASMODIUM-FALCIPARUM GAMETOCYTES; IN-VITRO; MALARIA; CLOTRIMAZOLE; MEFLOQUINE; REVEALS; DRUGS AB Current antimalarial drug treatment does not effectively kill mature Plasmodium falciparum gametocytes, the parasite stage responsible for malaria transmission from human to human via a mosquito. Consequently, following standard therapy malaria can still be transmitted for over a week after the clearance of asexual parasites. A new generation of malaria drugs with gametocytocidal properties, or a gametocytocidal drug that could be used in combinational therapy with currently available antimalarials, is needed to control the spread of the disease and facilitate eradication efforts. We have developed a 1536-well gametocyte viability assay for the high throughput screening of large compound collections to identify novel compounds with gametocytocidal activity. The signal-to-basal ratio and Z'-factor for this assay were 3.2-fold and 0.68, respectively. The IC50 value of epoxomicin, the positive control compound, was 1.42 +/- 0.09 nM that is comparable to previously reported values. This miniaturized assay significantly reduces the number of gametocytes required for the AlamarBlue viability assay, and enables high throughput screening for lead discovery efforts. Additionally, the screen does not require a specialized parasite line, gametocytes from any strain, including field isolates, can be tested. A pilot screen utilizing the commercially available LOPAC library, consisting of 1280 known compounds, revealed two selective gametocytocidal compounds having 54- and 7.8-fold gametocytocidal selectivity in comparison to their cell cytotoxicity effect against the mammalian SH-SY5Y cell line. Published by Elsevier B.V. C1 [Tanaka, Takeshi Q.; Williamson, Kim C.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Dehdashti, Seameen J.; Dac-Trung Nguyen; McKew, John C.; Zheng, Wei] NIH, Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA. [Williamson, Kim C.] Loyola Univ, Dept Biol, Chicago, IL 60660 USA. RP Zheng, W (reprint author), NIH, Natl Ctr Advancing Translat Sci, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov; kwilli4@luc.edu RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Programs of the Therapeutics for Rare and Neglected Diseases (TRND), National Center for Advancing Translational Sciences (NCATS); National Institute of Allergy and Infectious Diseases (NIAID); Public Health Service from the NIAID, National Institutes of Health (NIH) [AI10139601] FX This work was supported by the Intramural Research Programs of the Therapeutics for Rare and Neglected Diseases (TRND), National Center for Advancing Translational Sciences (NCATS) and the National Institute of Allergy and Infectious Diseases (NIAID), and Public Health Service grant AI10139601 from the NIAID, National Institutes of Health (NIH). The authors thank Paul Shinn for assistance in compound management. TQT is a JSPS Research Fellow in Biomedical and Behavioral Research at NIH. NR 23 TC 24 Z9 24 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD MAR PY 2013 VL 188 IS 1 BP 20 EP 25 DI 10.1016/j.molbiopara.2013.02.005 PG 6 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 148LN UT WOS:000319246200003 PM 23454872 ER PT J AU Lee, JG Baek, K Soetandyo, N Ye, YH AF Lee, Jin-Gu Baek, Kheewoong Soetandyo, Nia Ye, Yihong TI Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells SO NATURE COMMUNICATIONS LA English DT Article ID TYROSINE-PHOSPHATASE 1B; FANCONI-ANEMIA PATHWAY; OXIDATIVE STRESS; MONOUBIQUITINATED PCNA; REDOX REGULATION; DNA-DAMAGE; UBIQUITIN; ENZYMES; ROLES; ACTIVATION AB In eukaryotes, deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates, altering their stabilities, localizations or activities. Here we show that many DUBs of the USP and UCH subfamilies can be reversibly inactivated upon oxidation by reactive oxygen species in vitro and in cells. Oxidation occurs preferentially on the catalytic cysteine, abrogating the isopeptide-cleaving activity without affecting these enzymes' affinity to ubiquitin. Sensitivity to oxidative inhibition is associated with DUB activation wherein the active site cysteine is converted to a deprotonated state prone to oxidation. We demonstrate that this redox regulation is essential for mono-ubiquitination of proliferating-cell nuclear antigen in response to oxidative DNA damage, which initiates a DNA damage-tolerance programme. These findings establish a novel mechanism of DUB regulation that may be integrated with other redox-dependent signalling circuits to govern cellular adaptation to oxidative stress, a process intimately linked to aging and cancer. C1 [Lee, Jin-Gu; Baek, Kheewoong; Soetandyo, Nia; Ye, Yihong] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU NIDDK FX We thank W. Kim and S. Gygi (Harvard Taplin Mass Spectrometry Center) for assistance in mass spectrometry analyses, J.W. Harper (Harvard Medical School) and K. Lindsten (Karolinska Institute) for DUB constructs, K.-Y. Lee (NHGRI) for the USP1 and UAF1 plasmids, J. Kwon and T. Leto (NIAID) for helpful discussions, M. Krause, M. Gellert (NIDDK) and Q. Ran (University of Texas Health Science Centre at San Antonio), and J. Wang (Johns Hopkins University) for critical reading of the manuscript. The research is supported by the Intramural Research Program of the NIDDK. NR 55 TC 52 Z9 54 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2013 VL 4 AR 1568 DI 10.1038/ncomms2532 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143NJ UT WOS:000318873900022 PM 23463011 ER PT J AU Permuth-Wey, J Lawrenson, K Shen, HC Velkova, A Tyrer, JP Chen, ZH Lin, HY Chen, YA Tsai, YY Qu, XT Ramus, SJ Karevan, R Lee, J Lee, N Larson, MC Aben, KK Anton-Culver, H Antonenkova, N Antoniou, AC Armasu, SM Bacot, F Baglietto, L Bandera, EV Barnholtz-Sloan, J Beckmann, MW Birrer, MJ Bloom, G Bogdanova, N Brinton, LA Brooks-Wilson, A Brown, R Butzow, R Cai, QY Campbell, I Chang-Claude, J Chanock, S Chenevix-Trench, G Cheng, JQ Cicek, MS Coetzee, GA Cook, LS Couch, FJ Cramer, DW Cunningham, JM Dansonka-Mieszkowska, A Despierre, E Doherty, JA Dork, T du Bois, A Durst, M Easton, DF Eccles, D Edwards, R Ekici, AB Fasching, PA Fenstermacher, DA Flanagan, JM Garcia-Closas, M Gentry-Maharaj, A Giles, GG Glasspool, RM Gonzalez-Bosquet, J Goodman, MT Gore, M Gorski, B Gronwald, J Hall, P Halle, MK Harter, P Heitz, F Hillemanns, P Hoatlin, M Hogdall, CK Hogdall, E Hosono, S Jakubowska, A Jensen, A Jim, H Kalli, KR Karlan, BY Kaye, SB Kelemen, LE Kiemeney, LA Kikkawa, F Konecny, GE Krakstad, C Kjaer, SK Kupryjanczyk, J Lambrechts, D Lambrechts, S Lancaster, JM Le, ND Leminen, A Levine, DA Liang, D Lim, BK Lin, J Lissowska, J Lu, KH Lubinski, J Lurie, G Massuger, LFAG Matsuo, K McGuire, V McLaughlin, JR Menon, U Modugno, F Moysich, KB Nakanishi, T Narod, SA Nedergaard, L Ness, RB Nevanlinna, H Nickels, S Noushmehr, H Odunsi, K Olson, SH Orlow, I Paul, J Pearce, CL Pejovic, T Pelttari, LM Pike, MC Poole, EM Raska, P Renner, SP Risch, HA Rodriguez-Rodriguez, L Rossing, MA Rudolph, A Runnebaum, IB Rzepecka, IK Salvesen, HB Schwaab, I Severi, G Shridhar, V Shu, XO Shvetsov, YB Sieh, W Song, HL Southey, MC Spiewankiewicz, B Stram, D Sutphen, R Teo, SH Terry, KL Tessier, DC Thompson, PJ Tworoger, SS van Altena, AM Vergote, I Vierkant, RA Vincent, D Vitonis, AF Wang-Gohrke, S Weber, RP Wentzensen, N Whittemore, AS Wik, E Wilkens, LR Winterhoff, B Woo, YL Wu, AH Xiang, YB Yang, HP Zheng, W Ziogas, A Zulkifli, F Phelan, CM Iversen, E Schildkraut, JM Berchuck, A Fridley, BL Goode, EL Pharoah, PDP Monteiro, ANA Sellers, TA Gayther, SA AF Permuth-Wey, Jennifer Lawrenson, Kate Shen, Howard C. Velkova, Aneliya Tyrer, Jonathan P. Chen, Zhihua Lin, Hui-Yi Chen, Y. Ann Tsai, Ya-Yu Qu, Xiaotao Ramus, Susan J. Karevan, Rod Lee, Janet Lee, Nathan Larson, Melissa C. Aben, Katja K. Anton-Culver, Hoda Antonenkova, Natalia Antoniou, Antonis C. Armasu, Sebastian M. Bacot, Francois Baglietto, Laura Bandera, Elisa V. Barnholtz-Sloan, Jill Beckmann, Matthias W. Birrer, Michael J. Bloom, Greg Bogdanova, Natalia Brinton, Louise A. Brooks-Wilson, Angela Brown, Robert Butzow, Ralf Cai, Qiuyin Campbell, Ian Chang-Claude, Jenny Chanock, Stephen Chenevix-Trench, Georgia Cheng, Jin Q. Cicek, Mine S. Coetzee, Gerhard A. Cook, Linda S. Couch, Fergus J. Cramer, Daniel W. Cunningham, Julie M. Dansonka-Mieszkowska, Agnieszka Despierre, Evelyn Doherty, Jennifer A. Doerk, Thilo du Bois, Andreas Duerst, Matthias Easton, Douglas F. Eccles, Diana Edwards, Robert Ekici, Arif B. Fasching, Peter A. Fenstermacher, David A. Flanagan, James M. Garcia-Closas, Montserrat Gentry-Maharaj, Aleksandra Giles, Graham G. Glasspool, Rosalind M. Gonzalez-Bosquet, Jesus Goodman, Marc T. Gore, Martin Gorski, Bohdan Gronwald, Jacek Hall, Per Halle, Mari K. Harter, Philipp Heitz, Florian Hillemanns, Peter Hoatlin, Maureen Hogdall, Claus K. Hogdall, Estrid Hosono, Satoyo Jakubowska, Anna Jensen, Allan Jim, Heather Kalli, Kimberly R. Karlan, Beth Y. Kaye, Stanley B. Kelemen, Linda E. Kiemeney, Lambertus A. Kikkawa, Fumitaka Konecny, Gottfried E. Krakstad, Camilla Kjaer, Susanne Kruger Kupryjanczyk, Jolanta Lambrechts, Diether Lambrechts, Sandrina Lancaster, Johnathan M. Le, Nhu D. Leminen, Arto Levine, Douglas A. Liang, Dong Lim, Boon Kiong Lin, Jie Lissowska, Jolanta Lu, Karen H. Lubinski, Jan Lurie, Galina Massuger, Leon F. A. G. Matsuo, Keitaro McGuire, Valerie McLaughlin, John R. Menon, Usha Modugno, Francesmary Moysich, Kirsten B. Nakanishi, Toru Narod, Steven A. Nedergaard, Lotte Ness, Roberta B. Nevanlinna, Heli Nickels, Stefan Noushmehr, Houtan Odunsi, Kunle Olson, Sara H. Orlow, Irene Paul, James Pearce, Celeste L. Pejovic, Tanja Pelttari, Liisa M. Pike, Malcolm C. Poole, Elizabeth M. Raska, Paola Renner, Stefan P. Risch, Harvey A. Rodriguez-Rodriguez, Lorna Rossing, Mary Anne Rudolph, Anja Runnebaum, Ingo B. Rzepecka, Iwona K. Salvesen, Helga B. Schwaab, Ira Severi, Gianluca Shridhar, Viji Shu, Xiao-Ou Shvetsov, Yurii B. Sieh, Weiva Song, Honglin Southey, Melissa C. Spiewankiewicz, Beata Stram, Daniel Sutphen, Rebecca Teo, Soo-Hwang Terry, Kathryn L. Tessier, Daniel C. Thompson, Pamela J. Tworoger, Shelley S. van Altena, Anne M. Vergote, Ignace Vierkant, Robert A. Vincent, Daniel Vitonis, Allison F. Wang-Gohrke, Shan Weber, Rachel Palmieri Wentzensen, Nicolas Whittemore, Alice S. Wik, Elisabeth Wilkens, Lynne R. Winterhoff, Boris Woo, Yin Ling Wu, Anna H. Xiang, Yong-Bing Yang, Hannah P. Zheng, Wei Ziogas, Argyrios Zulkifli, Famida Phelan, Catherine M. Iversen, Edwin Schildkraut, Joellen M. Berchuck, Andrew Fridley, Brooke L. Goode, Ellen L. Pharoah, Paul D. P. Monteiro, Alvaro N. A. Sellers, Thomas A. Gayther, Simon A. CA Australian Canc Study Australian Ovarian Canc Study Consortium Investigators Modifiers TI Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31 SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; MICRORNA EXPRESSION; GENETIC-VARIANTS; FUNCTIONAL ANNOTATION; SITE POLYMORPHISMS; PARKINSON-DISEASE; COMMON INVERSION; BINDING-SITES; MAPT REGION; RISK AB Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio 1.12, P 10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P 10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARH-GAP27 and PLEKHM1 as candidate EOC susceptibility genes. C1 [Permuth-Wey, Jennifer; Velkova, Aneliya; Tsai, Ya-Yu; Phelan, Catherine M.; Monteiro, Alvaro N. A.; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Div Populat Sci, Tampa, FL 33612 USA. [Lawrenson, Kate; Shen, Howard C.; Ramus, Susan J.; Karevan, Rod; Lee, Janet; Lee, Nathan; Pearce, Celeste L.; Pike, Malcolm C.; Stram, Daniel; Wu, Anna H.; Gayther, Simon A.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Tyrer, Jonathan P.; Song, Honglin] Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England. [Chen, Zhihua; Qu, Xiaotao; Bloom, Greg; Fenstermacher, David A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Biomed Informat, Tampa, FL 33612 USA. [Lin, Hui-Yi; Chen, Y. Ann] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Biostat, Tampa, FL 33612 USA. [Larson, Melissa C.; Armasu, Sebastian M.; Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Aben, Katja K.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & HTA, NL-6500 HB Nijmegen, Netherlands. [Aben, Katja K.; Kiemeney, Lambertus A.] Comprehens Canc Ctr Netherlands, NL-1066 CX Amsterdam, Netherlands. [Anton-Culver, Hoda] Univ Calif Irvine, UCI Ctr Med, Genet Epidemiol Res Inst, Dept Epidemiol, Irvine, CA 92697 USA. [Antonenkova, Natalia] Byelorussian Inst Oncol & Med Radiol Aleksandrov, Minsk 223040, Byelarus. [Antoniou, Antonis C.; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Canc Genet Lab, Brisbane, Qld 4006, Australia. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Melbourne, Vic 3002, Australia. [Bacot, Francois; Tessier, Daniel C.; Vincent, Daniel] McGill Univ, Montreal, PQ H3A 0G1, Canada. [Bacot, Francois; Tessier, Daniel C.; Vincent, Daniel] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic 3053, Australia. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Bandera, Elisa V.; Rodriguez-Rodriguez, Lorna] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ 08901 USA. [Barnholtz-Sloan, Jill; Raska, Paola] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Beckmann, Matthias W.; Fasching, Peter A.; Renner, Stefan P.] Univ Erlangen Nurnberg, Ctr Comprehens Canc, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Birrer, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bogdanova, Natalia; Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, D-30625 Hannover, Germany. [Brinton, Louise A.; Chanock, Stephen; Wentzensen, Nicolas; Yang, Hannah P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Brown, Robert; Flanagan, James M.] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London SW7 2AZ, England. [Butzow, Ralf; Leminen, Arto] Univ Helsinki, Dept Obstet & Gynecol, HUS, FIN-00290 Helsinki, Finland. [Butzow, Ralf; Leminen, Arto] Univ Helsinki, Cent Hosp, HUS, FIN-00290 Helsinki, Finland. [Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Cent Hosp, HUS, Dept Pathol, FIN-00290 Helsinki, Finland. [Cai, Qiuyin; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37232 USA. [Cai, Qiuyin; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Campbell, Ian] Univ Melbourne, Dept Pathol, Melbourne, Vic 3053, Australia. [Chang-Claude, Jenny; Nickels, Stefan; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Cheng, Jin Q.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Interdisciplinary Oncol, Tampa, FL 33612 USA. [Cicek, Mine S.; Goode, Ellen L.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA. [Coetzee, Gerhard A.; Noushmehr, Houtan] Univ So Calif, Norris Comprehens Canc Ctr, Dept Urol Microbiol & Prevent Med, Los Angeles, CA 90089 USA. [Cook, Linda S.] Univ New Mexico, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Cunningham, Julie M.; Shridhar, Viji] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN 55905 USA. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr, Dept Mol Pathol, PL-02781 Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.; Spiewankiewicz, Beata] Inst Oncol, PL-02781 Warsaw, Poland. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Univ Hosp Leuven, Dept Obstet & Gynaecol, Div Gynecol Oncol, B-3000 Louvain, Belgium. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Univ Hosp Leuven, Leuven Canc Inst, B-3000 Louvain, Belgium. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Epidemiol & Biostat Sect, Lebanon, NH 03755 USA. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Dr Horst Schmidt Klin, Dept Gynecol & Gynecol Oncol, D-65199 Wiesbaden, Germany. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, D-45136 Essen, Germany. [Duerst, Matthias; Runnebaum, Ingo B.; Pharoah, Paul D. P.] Jena Univ Hosp, Dept Gynecol & Obstet, D-07743 Jena, Germany. [Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England. [Eccles, Diana] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO17 1BJ, Hants, England. [Edwards, Robert] Maggee Womens Hosp, Pittsburgh, PA 15213 USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. [Fasching, Peter A.; Konecny, Gottfried E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Epidemiol Sect, London SW7 3RP, England. [Garcia-Closas, Montserrat] Inst Canc Res, Genet Sect, London SW7 3RP, England. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, London SW7 3RP, England. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Gynaecol Canc Res Ctr, London W1T 7DN, England. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3806, Australia. [Glasspool, Rosalind M.; Paul, James] Beatson West Scotland Canc Ctr, Glasgow G12 0YN, Lanark, Scotland. [Gonzalez-Bosquet, Jesus; Lancaster, Johnathan M.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Womens Oncol, Tampa, FL 33612 USA. [Goodman, Marc T.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Gore, Martin] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Gorski, Bohdan; Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, PL-70115 Szczecin, Poland. [Hall, Per] Karolinska Ist, Dept Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Halle, Mari K.; Krakstad, Camilla; Salvesen, Helga B.; Wik, Elisabeth] Haukeland Hosp, Dept Gynecol & Obstet, N-5006 Bergen, Norway. [Halle, Mari K.; Krakstad, Camilla; Salvesen, Helga B.; Wik, Elisabeth] Univ Bergen, Dept Clin Sci, N-5006 Bergen, Norway. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, D-30625 Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, D-30625 Hannover, Germany. [Hoatlin, Maureen] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Hogdall, Claus K.; Kjaer, Susanne Kruger] Rigshosp, Juliane Marie Ctr, Dept Obstet & Gynecol, DK-2100 Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Mol Unit, Dept Pathol, DK-2730 Herlev, Denmark. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne Kruger] Danish Canc Soc, Res Ctr, DK-2100 Copenhagen, Denmark. [Hosono, Satoyo; Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 4648681, Japan. [Jim, Heather] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Hlth Outcomes & Behav, Tampa, FL 33612 USA. [Kalli, Kimberly R.] Mayo Clin, Dept Med Oncol, Rochester, MN 55905 USA. [Karlan, Beth Y.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kaye, Stanley B.] Inst Canc Res, Med Sect, Sutton SM2 5NG, Surrey, England. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Popluat Hlth Res, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet, Calgary, AB T2S 3C3, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Oncol, Calgary, AB T2S 3C3, Canada. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6500 HB Nijmegen, Netherlands. [Kikkawa, Fumitaka] Nagoya Univ, Grad Sch Med, Dept Obster & Gynecol, Nagoya, Aichi 4668550, Japan. [Lambrechts, Diether] VIB, Vesalius Res Ctr, B-3000 Louvain, Belgium. [Lambrechts, Diether] Univ Louvain, Dept Oncol, Lab Translat Genet, B-3000 Louvain, Belgium. [Le, Nhu D.] BC Canc Agcy, Vancouver, BC G12 0YN, Canada. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Lim, Boon Kiong; Woo, Yin Ling] Univ Malaya, Fac Med, UM Canc Res Inst, Dept Obstet & Gynaecol, Kuala Lumpur 59100, Malaysia. [Lin, Jie] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Lurie, Galina; Shvetsov, Yurii B.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96813 USA. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Dept Gynaecol, Med Ctr, NL-6500 HB Nijmegen, Netherlands. [McGuire, Valerie; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [McLaughlin, John R.] Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. [McLaughlin, John R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA 15213 USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Nakanishi, Toru] Aichi Canc Ctr, Cent Hosp, Dept Gynecol Oncol, Nagoya, Aichi 4648681, Japan. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON M5G 1N8, Canada. [Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Noushmehr, Houtan] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, USC Epigenome Ctr, Los Angeles, CA 90089 USA. [Noushmehr, Houtan] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Genet, BR-14049900 Ribeirao Preto, SP, Brazil. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97239 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06520 USA. [Risch, Harvey A.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98109 USA. [Schwaab, Ira] Inst Human Genet Wiesbaden, D-65187 Wiesbaden, Germany. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3053, Australia. [Spiewankiewicz, Beata] Maria Sklodowska Curie Mem Canc Ctr, Dept Gynecol Oncol, PL-02781 Warsaw, Poland. [Sutphen, Rebecca] Univ S Florida, Coll Med, Pediat Epidemiol Ctr, Tampa, FL 33612 USA. [Teo, Soo-Hwang; Zulkifli, Famida] Sime Darby Med Ctr, Canc Res Initiat Fdn, Selangor 47500, Malaysia. [Teo, Soo-Hwang; Zulkifli, Famida] Univ Malaya, Fac Med, Dept Surg, Kuala Lumpur 59100, Malaysia. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89081 Ulm, Germany. [Weber, Rachel Palmieri; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27708 USA. [Winterhoff, Boris] Mayo Clin, Dept Obstet & Gynecol, Rochester, MN 55905 USA. [Xiang, Yong-Bing] Shanghai Canc Inst, Shanghai 220025, Peoples R China. [Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Ctr Canc Genet Res & Prevent, Dept Epidemiol, Irvine, CA 92697 USA. [Iversen, Edwin] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC 27708 USA. [Berchuck, Andrew] Duke Canc Inst, Dept Obstet & Gynecol, Durham, NC 27708 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66160 USA. RP Permuth-Wey, J (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Div Populat Sci, Tampa, FL 33612 USA. EM Jenny.Wey@moffitt.org; Thomas.Sellers@moffitt.org; gayther@usc.edu RI Whittemore, Alice/F-9925-2014; Brooks-Wilson, Angela/E-9399-2012; Teo, Soo-hwang/H-2353-2014; Bandera, Elisa/M-4169-2014; Massuger, Leon/H-8072-2014; friedlander, michael/G-3490-2013; Noushmehr, Houtan/C-9692-2013; McLaughlin, John/E-4577-2013; Kiemeney, Lambertus/D-3357-2009; Tang, Macy/B-9798-2014; Blanco, Ignacio/D-2565-2013; Renner, Stefan/F-1158-2014; Dork, Thilo/J-8620-2012; salvesen, Helga/C-1187-2017; Osorio, Ana/I-4324-2014; Wyld, David/B-8893-2015; Jakubowska, Anna/O-8050-2014; campbell, Ian/F-6006-2011; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; montagna, marco/E-2225-2012; Woo, Yin Ling/B-5198-2010; KIKKAWA, Fumitaka/I-7341-2014; Nicklin, James/F-8035-2013; van Altena, Anne/B-9824-2016; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Gronwald, Jacek/A-4576-2017 OI Brooks-Wilson, Angela/0000-0003-1009-6408; Bandera, Elisa/0000-0002-8789-2755; friedlander, michael/0000-0002-6488-0604; Noushmehr, Houtan/0000-0003-4051-8114; Kiemeney, Lambertus/0000-0002-2368-1326; Blanco, Ignacio/0000-0002-7414-7481; Renner, Stefan/0000-0003-2057-1268; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799; Nevanlinna, Heli/0000-0002-0916-2976; Halle, Mari/0000-0002-2660-8271; Orlow, Irene/0000-0001-6234-6961; Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; salvesen, Helga/0000-0002-4438-8831; Tworoger, Shelley/0000-0002-6986-7046; Osorio, Ana/0000-0001-8124-3984; Nathanson, Katherine/0000-0002-6740-0901; Rudolph, Anja/0000-0001-7520-2035; Kjaer, Susanne/0000-0002-8347-1398; Glasspool, Rosalind/0000-0002-5000-1680; Wyld, David/0000-0001-9523-4333; Monteiro, Alvaro/0000-0002-8448-4801; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; montagna, marco/0000-0002-4929-2150; Woo, Yin Ling/0000-0003-1742-1066; Nicklin, James/0000-0001-5378-496X; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Gronwald, Jacek/0000-0002-3643-2871 FU European Commission [223175-HEALTH-F2-2009-223175]; Ovarian Cancer Research Fund; US National Cancer Institute [R01-CA-114343, R01-CA114343-S1]; Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113]; National Health and Medical Research Council; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; Canadian Institutes of Health Research [MSH-87734]; NHS; American Cancer Society [CRTG-00-196-01-CCE]; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]; Canadian Institutes for Health Research [MOP-86727]; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Cancer Research UK [C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689]; Celma Mastry Ovarian Cancer Foundation; Danish Cancer Society [94-222-52]; Norwegian Cancer Society, Helse Vest, the Norwegian Research Council; ELAN Funds of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Imperial Experimental Cancer Research Centre [C1312/A15589]; Nationaal Kankerplan of Belgium; Ministry of Health Labour and Welfare of Japan; L & S Milken Foundation; Radboud University Nijmegen Medical Centre; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Roswell Park Cancer Institute Alliance Foundation; US National Cancer Institutes [K07-CA80668, K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067001, N01-PC035137, P01-CA017054, P01-CA087696, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419]; NIH/National Center for Research Resources/General Clinical Research Grant [M01-RR000056]; US Army Medical Research and Materiel Command [DAMD17-98-18659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-101-02802]; Department of Defense Ovarian Cancer Research Program [W81XWH-07-1-0449]; National Health and Medical Research Council of Australia [199600, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]; German Cancer Research Center; Pomeranian Medical University; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Malaysian Ministry of Higher Education [UM. C/HlR/MOHE/06]; Cancer Research Initiatives Foundation; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital 'Womens Health Theme'; Royal Marsden Hospital; WorkSafeBC; U.S. Natl Canc Inst [R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA136924, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R01-CA83918, U01-CA069417, U01-CA071966, P30-CA15083, PSA 042205] FX We thank all the individuals who participated in this research and all the researchers, clinicians and administrative staff who have made possible the many studies contributing to this work. In particular, we thank D. Bowtell, P. Webb, A. deFazio, D. Gertig, A. Green, P. Parsons, N. Hayward and D. Whiteman (AUS); D. L. Wachter, S. Oeser, S. Landrith (BAV); G. Peuteman, T. Van Brussel and D. Smeets (BEL); the staff of the genotyping unit, S LaBoissiere and F Robidoux (McGill University and Genome Quebec Innovation Centre); U. Eilber and T. Koehler (GER); L. Gacucova (HMO); P. Schuermann, F. Kramer, T.-W. Park-Simon, K. Beer-Grondke and D. Schmidt (HJO); G. L. Keeney, C. Hilker and J. Vollenweider (MAY); the state cancer registries of AL, AZ, AR, CA, CO, CT, DE, FL, GA, HI, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WYL (NHS); L. Paddock, M. King, U. Chandran, A. Samoila and Y. Bensman (NJO); M. Insua and R. Evey (Moffitt); The Sherie Hildredth Ovarian Cancer Foundation (ORE); M. Sherman, A. Hutchinson, N. Szeszenia-Dabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner (POL); C. Luccarini, P. Harrington the SEARCH team and ECRIC (SEA); the Scottish Gynaecological Clinical Trails group and SCOTROC1 investigators (SRO); W-H. Chow, Y.-T. Gao, G. Yang, B.-T. Ji (SWH); I. Jacobs, M. Widschwendter, E. Wozniak, N. Balogun, A. Ryan and J. Ford (UKO); M. Notaridou (USC); C. Pye (UKR); and V. Slusher (U19). The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175-HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund, thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07).; The scientific development and funding for this project were in part supported by the US National Cancer Institute (R01-CA-114343 and R01-CA114343-S1) and the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112). This study made use of the data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute. Information about TCGA, and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov/. D. F. E. is a Principal Research Fellow of Cancer Research UK, G.C.-T. and P. M. W. are supported by the National Health and Medical Research Council. B. K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). L. E. K. is supported by a Canadian Institutes of Health Research Investigator award (MSH-87734). M. G. acknowledges NHS funding to the NIHR Biomedical Research Centre. A. C. A. is Cancer Research UK Senior Cancer Research Fellow.; Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the Norwegian Cancer Society, Helse Vest, the Norwegian Research Council; ELAN Funds of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Imperial Experimental Cancer Research Centre (C1312/A15589); the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; the L & S Milken Foundation; the Radboud University Nijmegen Medical Centre; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA80668, K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067001, N01-PC035137, P01-CA017054, P01-CA087696, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA136924, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R03-CA113148, R03-CA115195, R37-CA070867, R01-CA83918, U01-CA069417, U01-CA071966, P30-CA15083, PSA 042205, and Intramural research funds); the NIH/National Center for Research Resources/General Clinical Research Grant (M01-RR000056); the US Army Medical Research and Materiel Command (DAMD17-98-18659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-101- 02802); the Department of Defense Ovarian Cancer Research Program (W81XWH-07-1-0449); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P. 685); the German Cancer Research Center; Pomeranian Medical University; the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Malaysian Ministry of Higher Education (UM. C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital 'Womens Health Theme' and the Royal Marsden Hospital; WorkSafeBC. NR 53 TC 49 Z9 49 U1 2 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2013 VL 4 AR 1627 DI 10.1038/ncomms2613 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143NJ UT WOS:000318873900080 PM 23535648 ER PT J AU Rickhag, M Hansen, FH Sorensen, G Strandfelt, KN Andresen, B Gotfryd, K Madsen, KL Vestergaard-Klewe, I Ammendrup-Johnsen, I Eriksen, J Newman, AH Fuchtbauer, EM Gomeza, J Woldbye, DPD Wortwein, G Gether, U AF Rickhag, Mattias Hansen, Freja Herborg Sorensen, Gunnar Strandfelt, Kristine Norgaard Andresen, Bjorn Gotfryd, Kamil Madsen, Kenneth L. Vestergaard-Klewe, Ib Ammendrup-Johnsen, Ina Eriksen, Jacob Newman, Amy H. Fuchtbauer, Ernst-Martin Gomeza, Jesus Woldbye, David P. D. Wortwein, Gitta Gether, Ulrik TI A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter SO NATURE COMMUNICATIONS LA English DT Article ID MICE LACKING; MONOAMINE TRANSPORTERS; LIGAND MOTIF; LOCALIZATION; TRAFFICKING; SURFACE; INTERNALIZATION; GLUTAMATE; CELLS; PICK1 AB The dopamine transporter mediates reuptake of dopamine from the synaptic cleft. The cellular mechanisms controlling dopamine transporter levels in striatal nerve terminals remain poorly understood. The dopamine transporters contain a C-terminal PDZ (PSD-95/Discs-large/ZO-1) domain-binding sequence believed to bind synaptic scaffolding proteins, but its functional significance is uncertain. Here we demonstrate that two different dopamine transporter knock-in mice with disrupted PDZ-binding motifs (dopamine transporter-AAA and dopamine transporter + Ala) are characterized by dramatic loss of dopamine transporter expression in the striatum, causing hyperlocomotion and attenuated response to amphetamine. In cultured dopaminergic neurons and striatal slices from dopamine transporter-AAA mice, we find markedly reduced dopamine transporter surface levels and evidence for enhanced constitutive internalization. In dopamine transporter-AAA neurons, but not in wildtype neurons, surface levels are rescued in part by expression of a dominant-negative dynamin mutation (K44A). Our findings suggest that PDZ-domain interactions are critical for synaptic distribution of dopamine transporter in vivo and thereby for proper maintenance of dopamine homoeostasis. C1 [Rickhag, Mattias; Hansen, Freja Herborg; Sorensen, Gunnar; Strandfelt, Kristine Norgaard; Andresen, Bjorn; Gotfryd, Kamil; Madsen, Kenneth L.; Vestergaard-Klewe, Ib; Ammendrup-Johnsen, Ina; Eriksen, Jacob; Gether, Ulrik] Univ Copenhagen, Fac Hlth & Med Sci, Lundbeck Fdn Ctr Biomembranes Nanomed, Dept Neurosci & Pharmacol,Mol Neuropharmacol Lab, Copenhagen, Denmark. [Sorensen, Gunnar; Woldbye, David P. D.; Wortwein, Gitta] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Lab Neuropsychiat, Copenhagen, Denmark. [Newman, Amy H.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Fuchtbauer, Ernst-Martin] Aarhus Univ, Dept Mol Biol, DK-8000 Aarhus, Denmark. [Gomeza, Jesus] Univ Bonn, Inst Pharmaceut Biol, Bonn, Germany. [Wortwein, Gitta] Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Copenhagen, Denmark. RP Gether, U (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Lundbeck Fdn Ctr Biomembranes Nanomed, Dept Neurosci & Pharmacol,Mol Neuropharmacol Lab, Copenhagen, Denmark. EM gether@sund.ku.dk RI Madsen, Kenneth/C-7778-2012; OI Madsen, Kenneth/0000-0001-9274-6691; Eriksen, Jacob/0000-0003-0726-9769; Gether, Ulrik/0000-0002-0020-3807; Wortwein, Gitta/0000-0001-6981-7885 FU National Institute of Health [P01 DA 12408]; Danish Medical Research Council; University of Copenhagen BioScaRT Program of Excellence; Lundbeck Foundation Center for Biomembranes in Nanomedicine; Lundbeck Foundation; Novo Nordisk Foundation; Fabrikant Vilhelm Pedersen og Hustrus Mindelegat FX We thank P. Elsman, P. Clausen and L. A. Hansen for excellent technical assistance and A. Fuchtbauer for ES cell culture. We thank Professor M. Moller for comments on the manuscript. The work was supported by the National Institute of Health Grants P01 DA 12408 (U. G.), the Danish Medical Research Council (M. R., K. L. M., B. A. and U. G.), University of Copenhagen BioScaRT Program of Excellence (G. S., I.A.J., D. P. D. W., G. W. and U. G.), Lundbeck Foundation Center for Biomembranes in Nanomedicine (U. G. and J.E.), the Lundbeck Foundation (M. R.) the Novo Nordisk Foundation (U. G.) and Fabrikant Vilhelm Pedersen og Hustrus Mindelegat (U.G.). NR 46 TC 18 Z9 18 U1 4 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2013 VL 4 AR 1580 DI 10.1038/ncomms2568 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143NJ UT WOS:000318873900034 PM 23481388 ER PT J AU Shen, H Fridley, BL Song, HL Lawrenson, K Cunningham, JM Ramus, SJ Cicek, MS Tyrer, J Stram, D Larson, MC Kobel, M Ziogas, A Zheng, W Yang, HP Wu, AH Wozniak, EL Woo, YL Winterhoff, B Wik, E Whittemore, AS Wentzensen, N Weber, RP Vitonis, AF Vincent, D Vierkant, RA Vergote, I Van Den Berg, D Van Altena, AM Tworoger, SS Thompson, PJ Tessier, DC Terry, KL Teo, SH Templeman, C Stram, DO Southey, MC Sieh, W Siddiqui, N Shvetsov, YB Shu, XO Shridhar, V Wang-Gohrke, S Severi, G Schwaab, I Salvesen, HB Rzepecka, IK Runnebaum, IB Rossing, MA Rodriguez-Rodriguez, L Risch, HA Renner, SP Poole, EM Pike, MC Phelan, CM Pelttari, LM Pejovic, T Paul, J Orlow, I Omar, SZ Olson, SH Odunsi, K Nickels, S Nevanlinna, H Ness, RB Narod, SA Nakanishi, T Moysich, KB Monteiro, ANA Moes-Sosnowska, J Modugno, F Menon, U McLaughlin, JR McGuire, V Matsuo, K Adenan, NAM Massuger, LFAG Lurie, G Lundvall, L Lubinski, J Lissowska, J Levine, DA Leminen, A Lee, AW Le, ND Lambrechts, S Lambrechts, D Kupryjanczyk, J Krakstad, C Konecny, GE Kjaer, SK Kiemeney, LA Kelemen, LE Keeney, GL Karlan, BY Karevan, R Kalli, KR Kajiyama, H Ji, BT Jensen, A Jakubowska, A Iversen, E Hosono, S Hogdall, CK Hogdall, E Hoatlin, M Hillemanns, P Heitz, F Hein, R Harter, P Halle, MK Hall, P Gronwald, J Gore, M Goodman, MT Giles, GG Gentry-Maharaj, A Garcia-Closas, M Flanagan, JM Fasching, PA Ekici, AB Edwards, R Eccles, D Easton, DF Durst, M du Bois, A Dork, T Doherty, JA Despierre, E Dansonka-Mieszkowska, A Cybulski, C Cramer, DW Cook, LS Chen, XQ Charbonneau, B Chang-Claude, J Campbell, I Butzow, R Bunker, CH Brueggmann, D Brown, R Brooks-Wilson, A Brinton, LA Bogdanova, N Block, MS Benjamin, E Beesley, J Beckmann, MW Bandera, EV Baglietto, L Bacot, F Armasu, SM Antonenkova, N Anton-Culver, H Aben, KK Liang, D Wu, XF Lu, KR Hildebrandt, MAT Schildkraut, JM Sellers, TA Huntsman, D Berchuck, A Chenevix-Trench, G Gayther, SA Pharoah, PDP Laird, PW Goode, EL Pearce, CL AF Shen, Hui Fridley, Brooke L. Song, Honglin Lawrenson, Kate Cunningham, Julie M. Ramus, Susan J. Cicek, Mine S. Tyrer, Jonathan Stram, Douglas Larson, Melissa C. Koebel, Martin Ziogas, Argyrios Zheng, Wei Yang, Hannah P. Wu, Anna H. Wozniak, Eva L. Woo, Yin Ling Winterhoff, Boris Wik, Elisabeth Whittemore, Alice S. Wentzensen, Nicolas Weber, Rachel Palmieri Vitonis, Allison F. Vincent, Daniel Vierkant, Robert A. Vergote, Ignace Van Den Berg, David Van Altena, Anne M. Tworoger, Shelley S. Thompson, Pamela J. Tessier, Daniel C. Terry, Kathryn L. Teo, Soo-Hwang Templeman, Claire Stram, Daniel O. Southey, Melissa C. Sieh, Weiva Siddiqui, Nadeem Shvetsov, Yurii B. Shu, Xiao-Ou Shridhar, Viji Wang-Gohrke, Shan Severi, Gianluca Schwaab, Ira Salvesen, Helga B. Rzepecka, Iwona K. Runnebaum, Ingo B. Rossing, Mary Anne Rodriguez-Rodriguez, Lorna Risch, Harvey A. Renner, Stefan P. Poole, Elizabeth M. Pike, Malcolm C. Phelan, Catherine M. Pelttari, Liisa M. Pejovic, Tanja Paul, James Orlow, Irene Omar, Siti Zawiah Olson, Sara H. Odunsi, Kunle Nickels, Stefan Nevanlinna, Heli Ness, Roberta B. Narod, Steven A. Nakanishi, Toru Moysich, Kirsten B. Monteiro, Alvaro N. A. Moes-Sosnowska, Joanna Modugno, Francesmary Menon, Usha McLaughlin, John R. McGuire, Valerie Matsuo, Keitaro Adenan, Noor Azmi Mat Massuger, Leon F. A. G. Lurie, Galina Lundvall, Lene Lubinski, Jan Lissowska, Jolanta Levine, Douglas A. Leminen, Arto Lee, Alice W. Le, Nhu D. Lambrechts, Sandrina Lambrechts, Diether Kupryjanczyk, Jolanta Krakstad, Camilla Konecny, Gottfried E. Kjaer, Susanne Krueger Kiemeney, Lambertus A. Kelemen, Linda E. Keeney, Gary L. Karlan, Beth Y. Karevan, Rod Kalli, Kimberly R. Kajiyama, Hiroaki Ji, Bu-Tian Jensen, Allan Jakubowska, Anna Iversen, Edwin Hosono, Satoyo Hogdall, Claus K. Hogdall, Estrid Hoatlin, Maureen Hillemanns, Peter Heitz, Florian Hein, Rebecca Harter, Philipp Halle, Mari K. Hall, Per Gronwald, Jacek Gore, Martin Goodman, Marc T. Giles, Graham G. Gentry-Maharaj, Aleksandra Garcia-Closas, Montserrat Flanagan, James M. Fasching, Peter A. Ekici, Arif B. Edwards, Robert Eccles, Diana Easton, Douglas F. Duerst, Matthias du Bois, Andreas Doerk, Thilo Doherty, Jennifer A. Despierre, Evelyn Dansonka-Mieszkowska, Agnieszka Cybulski, Cezary Cramer, Daniel W. Cook, Linda S. Chen, Xiaoqing Charbonneau, Bridget Chang-Claude, Jenny Campbell, Ian Butzow, Ralf Bunker, Clareann H. Brueggmann, Doerthe Brown, Robert Brooks-Wilson, Angela Brinton, Louise A. Bogdanova, Natalia Block, Matthew S. Benjamin, Elizabeth Beesley, Jonathan Beckmann, Matthias W. Bandera, Elisa V. Baglietto, Laura Bacot, Francois Armasu, Sebastian M. Antonenkova, Natalia Anton-Culver, Hoda Aben, Katja K. Liang, Dong Wu, Xifeng Lu, Karen Hildebrandt, Michelle A. T. Schildkraut, Joellen M. Sellers, Thomas A. Huntsman, David Berchuck, Andrew Chenevix-Trench, Georgia Gayther, Simon A. Pharoah, Paul D. P. Laird, Peter W. Goode, Ellen L. Pearce, Celeste Leigh CA PRACTICAL Consortium Australian Ovarian Canc Study Grp Australian Canc Study TI Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; CLEAR-CELL CARCINOMA; PROSTATE-CANCER; COMMON VARIANTS; RISK; LOCI; MODY AB HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 x 10(-10)) and clear cell (rs11651755 OR = 0.77, P = 1.6 x 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes. C1 [Shen, Hui; Laird, Peter W.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66160 USA. [Song, Honglin; Tyrer, Jonathan; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England. [Lawrenson, Kate; Ramus, Susan J.; Stram, Douglas; Wu, Anna H.; Van Den Berg, David; Stram, Daniel O.; Pike, Malcolm C.; Lee, Alice W.; Karevan, Rod; Gayther, Simon A.; Pearce, Celeste Leigh] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cunningham, Julie M.; Shridhar, Viji] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN 55905 USA. [Cicek, Mine S.; Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA. [Larson, Melissa C.; Vierkant, Robert A.; Armasu, Sebastian M.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Koebel, Martin] Univ Calgary, Calgary Lab Serv, Dept Pathol & Lab Med, Calgary, AB T2N 2T9, Canada. [Ziogas, Argyrios; Shu, Xiao-Ou; Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Ctr Canc Genet Res & Prevent, Dept Epidemiol, Irvine, CA 92697 USA. [Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr, Nashville, TN 37232 USA. [Yang, Hannah P.; Wentzensen, Nicolas; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wozniak, Eva L.; Menon, Usha; Gentry-Maharaj, Aleksandra] UCL EGA Inst Womens Hlth, Gynaecol Canc Res Ctr, London NW1 2BU, England. [Woo, Yin Ling; Omar, Siti Zawiah; Adenan, Noor Azmi Mat] Univ Malaya, UM Canc Res Inst, Fac Med, Dept Obstet & Gynaecol, Kuala Lumpur 59100, Malaysia. [Winterhoff, Boris] Mayo Clin, Dept Obstet & Gynecol, Rochester, MN 55905 USA. [Wik, Elisabeth; Salvesen, Helga B.; Krakstad, Camilla; Halle, Mari K.] Haukeland Hosp, Dept Gynecol & Obstet, N-5006 Bergen, Norway. [Wik, Elisabeth; Salvesen, Helga B.; Krakstad, Camilla; Halle, Mari K.] Univ Bergen, Dept Clin Sci, N-5006 Bergen, Norway. [Whittemore, Alice S.; Sieh, Weiva; McGuire, Valerie] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Whittemore, Alice S.; Sieh, Weiva; McGuire, Valerie] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27708 USA. [Vitonis, Allison F.; Terry, Kathryn L.; Cramer, Daniel W.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Vincent, Daniel; Tessier, Daniel C.; Bacot, Francois] Genome Quebec, Montreal, PQ H3A 0G1, Canada. [Vergote, Ignace; Lambrechts, Sandrina; Lambrechts, Diether; Despierre, Evelyn] VIB, Vesalius Res Ctr, B-3000 Louvain, Belgium. [Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn] Univ Hosp Leuven, Dept Obstet & Gynaecol, Div Gynecol Oncol, B-3000 Louvain, Belgium. [Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn] Univ Hosp Leuven, Leuven Canc Inst, B-3000 Louvain, Belgium. [Van Altena, Anne M.; Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, NL-6500 HB Nijmegen, Netherlands. [Tworoger, Shelley S.; Poole, Elizabeth M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Tworoger, Shelley S.; Terry, Kathryn L.; Poole, Elizabeth M.; Cramer, Daniel W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Thompson, Pamela J.; Shvetsov, Yurii B.; Lurie, Galina] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96813 USA. [Teo, Soo-Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya 47500, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Med Ctr, Canc Res Inst, Kuala Lumpur 59100, Malaysia. [Templeman, Claire; Brueggmann, Doerthe] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3053, Australia. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89091 Ulm, Germany. [Severi, Gianluca; Giles, Graham G.; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3053, Australia. [Severi, Gianluca; Giles, Graham G.; Baglietto, Laura] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Schwaab, Ira] Inst Human Genet Wiesbaden, D-65187 Wiesbaden, Germany. [Rzepecka, Iwona K.; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka] Maria Sklodowska Curie Mem Canc Ctr, Inst Oncol, Dept Mol Pathol, PL-02781 Warsaw, Poland. [Runnebaum, Ingo B.; Duerst, Matthias] Jena Univ Hosp, Dept Gynecol & Obstet, D-07743 Jena, Germany. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98109 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98109 USA. [Rodriguez-Rodriguez, Lorna; Bandera, Elisa V.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ 08901 USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06520 USA. [Renner, Stefan P.; Fasching, Peter A.; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Ctr Comprehens Canc, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Pike, Malcolm C.; Orlow, Irene; Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Phelan, Catherine M.; Monteiro, Alvaro N. A.; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Div Populat Sci, Tampa, FL 33612 USA. [Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto; Butzow, Ralf] Univ Helsinki, Dept Obstet & Gynecol, Helsinki 00029, Hus, Finland. [Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto; Butzow, Ralf] Univ Helsinki, Cent Hosp, Helsinki 00029, Hus, Finland. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97239 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Paul, James] Beatson West Scotland Canc Ctr, Glasgow G12 0YN, Lanark, Scotland. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Nickels, Stefan; Hein, Rebecca; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON M5G IN8, Canada. [Nakanishi, Toru] Aichi Canc Ctr Cent Hosp, Dept Gynecol Oncol, Nagoya, Aichi 4648681, Japan. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Modugno, Francesmary] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA. [Modugno, Francesmary; Bunker, Clareann H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA 15213 USA. [McLaughlin, John R.] Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. [McLaughlin, John R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G IX5, Canada. [Matsuo, Keitaro; Hosono, Satoyo] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 4648681, Japan. [Lundvall, Lene; Kjaer, Susanne Krueger; Hogdall, Claus K.] Copenhagen Univ Hosp, Juliane Marie Ctr, Gynecol Clin, DK-2100 Copenhagen, Denmark. [Lubinski, Jan; Jakubowska, Anna; Gronwald, Jacek; Cybulski, Cezary] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, PL-70115 Szczecin, Poland. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Le, Nhu D.] BC Canc Agcy, Vancouver, BC G12 0YN, Canada. [Lambrechts, Sandrina; Lambrechts, Diether; Despierre, Evelyn] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Louvain, Belgium. [Konecny, Gottfried E.; Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Kjaer, Susanne Krueger; Jensen, Allan; Hogdall, Estrid] Danish Canc Soc, Res Ctr, DK-2100 Copenhagen, Denmark. [Kiemeney, Lambertus A.; Aben, Katja K.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & HTA, NL-6500 HB Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6500 HB Nijmegen, Netherlands. [Kiemeney, Lambertus A.; Aben, Katja K.] Ctr Comprehens Canc, NL-1066 CX Utrecht, Netherlands. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB T2N 2T9, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet & Oncol, Calgary, AB T2N 2T9, Canada. [Keeney, Gary L.] Mayo Clin, Dept Lab Med & Pathol, Div Anat Pathol, Rochester, MN 55905 USA. [Karlan, Beth Y.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kalli, Kimberly R.; Block, Matthew S.] Mayo Clin, Dept Med Oncol, Rochester, MN 55905 USA. [Kajiyama, Hiroaki] Nagoya Univ, Grad Sch Med, Dept Obstet & Gynecol, Nagoya, Aichi 4648601, Japan. [Ji, Bu-Tian] NCI, Div Canc Etiol & Genet, Bethesda, MD 20892 USA. [Iversen, Edwin] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. [Hogdall, Estrid] Univ Copenhagen, Mol Unit, Dept Pathol, Herlev Hosp, DK-2730 Copenhagen, Denmark. [Hoatlin, Maureen] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, D-30625 Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, D-30625 Hannover, Germany. [Heitz, Florian; Harter, Philipp; du Bois, Andreas] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, D-45136 Essen, Germany. [Heitz, Florian; Harter, Philipp; du Bois, Andreas] Dr Horst Schmidt Klin, Dept Gynecol & Gynecol Oncol, D-65199 Wiesbaden, Germany. [Hein, Rebecca] Univ Cologne, Dept Child & Adolescent Psychiat & Psychotherapy, PMV Res Grp, D-50931 Cologne, Germany. [Hall, Per] Karolinska Inst, Dept Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Gore, Martin] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Ctr Inst, Los Angeles, CA 90048 USA. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3806, Australia. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Breakthrough Breast Canc Res Ctr, London SW7 3RP, England. [Flanagan, James M.; Brown, Robert] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London SW7 2AZ, England. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. [Edwards, Robert] Magee Womens Hosp, Pittsburgh, PA 15213 USA. [Eccles, Diana] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton S017 1BJ, Hants, England. [Doerk, Thilo; Bogdanova, Natalia] Hannover Med Sch, Gynaecol Res Unit, D-30625 Hannover, Germany. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Epidemiol & Biostat Sect, Lebanon, NH 03755 USA. [Cook, Linda S.; Charbonneau, Bridget] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Chen, Xiaoqing; Beesley, Jonathan; Chenevix-Trench, Georgia; Australian Canc Study] Queensland Inst Med Res, Dept Genet, Herston, Qld 4006, Australia. [Campbell, Ian] Peter MacCallum Canc Inst, Div Res, Canc Genet Lab, Melbourne, Vic 3002, Australia. [Butzow, Ralf] Univ Melbourne, Dept Pathol, Melbourne, Vic 3053, Australia. [Campbell, Ian] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3002, Australia. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki 00029, Hus, Finland. [Brooks-Wilson, Angela] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC V52 1L3, Canada. [Benjamin, Elizabeth] UCL, Inst Canc, Dept Pathol, London WC1E 6JJ, England. [Antonenkova, Natalia] Belarusian Inst Oncol & Med Radiol Aleksandrov NN, Minsk 223040, Byelarus. [Liang, Dong] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77044 USA. [Wu, Xifeng; Hildebrandt, Michelle A. T.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC 27708 USA. [Huntsman, David] Vancouver Gen Hosp, BC Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Berchuck, Andrew] Duke Canc Inst, Gynecol Canc Program, Durham, NC 27708 USA. [Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. RP Goode, EL (reprint author), Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA. EM egoode@mayo.edu RI campbell, Ian/F-6006-2011; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Woo, Yin Ling/B-5198-2010; Nicklin, James/F-8035-2013; van Altena, Anne/B-9824-2016; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; salvesen, Helga/C-1187-2017; Wyld, David/B-8893-2015; friedlander, michael/G-3490-2013; Kiemeney, Lambertus/D-3357-2009; Tang, Macy/B-9798-2014; Batra, Jyotsna/B-4130-2011; Renner, Stefan/F-1158-2014; Dork, Thilo/J-8620-2012; Whittemore, Alice/F-9925-2014; Brooks-Wilson, Angela/E-9399-2012; Teo, Soo-hwang/H-2353-2014; Bandera, Elisa/M-4169-2014; Laird, Peter/G-8683-2012; Massuger, Leon/H-8072-2014; Jakubowska, Anna/O-8050-2014 OI Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Eeles, Rosalind/0000-0002-3698-6241; Tworoger, Shelley/0000-0002-6986-7046; Kjaer, Susanne/0000-0002-8347-1398; Monteiro, Alvaro/0000-0002-8448-4801; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799; Kobel, Martin/0000-0002-6615-2037; Nevanlinna, Heli/0000-0002-0916-2976; Halle, Mari/0000-0002-2660-8271; Orlow, Irene/0000-0001-6234-6961; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Woo, Yin Ling/0000-0003-1742-1066; Nicklin, James/0000-0001-5378-496X; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; salvesen, Helga/0000-0002-4438-8831; Wyld, David/0000-0001-9523-4333; friedlander, michael/0000-0002-6488-0604; Kiemeney, Lambertus/0000-0002-2368-1326; Renner, Stefan/0000-0003-2057-1268; Brooks-Wilson, Angela/0000-0003-1009-6408; Bandera, Elisa/0000-0002-8789-2755; FU European Commission [223175-HEALTH-F2-2009-223175]; Ovarian Cancer Research Fund; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network: a NCI Cancer Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113]; Deutsche Krebshilfe; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; Canadian Institutes of Health Research [MSH-87734]; National Institutes of Health [T32GM067587]; American Cancer Society [CRTG-00-196-01-CCE]; California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]; Canadian Institutes for Health Research [MOP-86727]; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Cancer Research UK [C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689]; Celma Mastry Ovarian Cancer Foundation; Danish Cancer Society [94-222-52]; Norwegian Cancer Society, Helse Vest; Norwegian Research Council; University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Imperial Experimental Cancer Research Centre [C1312/A15589]; Ovarian Cancer Research Fund [PPD/USC.06]; Nationaal Kankerplan of Belgium; Ministry of Health Labour and Welfare of Japan; L & S Milken Foundation; Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]; Roswell Park Cancer Institute Alliance Foundation; US National Cancer Institute [K07-CA095666, K07-CA143047, K07-CA80668, K22-CA138563, N01-CN55424, N01-PC067001, N01-PC035137, P01-CA017054, P01-CA087696, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449]; US Army Medical Research and Material Command [DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280]; National Health and Medical Research Council of Australia [199600, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Phi Beta Psi Sorority; Lon V. Smith Foundation [LVS-39420]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital 'Womens Health Theme'; Royal Marsden Hospital; WorkSafeBC; U.S. Natl Canc Inst [R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443]; US Natl Canc Inst [R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R01-CA141154, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, P30-CA15083, R01CA83918, U24 CA143882] FX We thank all the individuals who took part in this study and all the researchers, clinicians and administrative staff who have made possible the many studies contributing to this work. In particular, we thank: D. Bowtell, P. M. Webb, A. deFazio, D. Gertig, A. Green, P. Parsons, N. Hayward and D. Whiteman (AUS); G. Peuteman, T. Van Brussel and D. Smeets (BEL); the staff of the genotyping unit, S LaBoissie` re and F Robidoux (Genome Quebec); U. Eilber and T. Koehler (GER); L. Gacucova (HMO); P. Schurmann, F. Kramer, W. Zheng, T.-W. Park-Simon, K. Beer-Grondke and D. Schmidt (HJO); S. Windebank, C. Hilker and J. Vollenweider (MAY); the state cancer registries of AL, AZ, AR, CA, CO, CT, DE, FL, GA, HI, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY (NHS); L. Paddock, M. King, U. Chandran, A. Samoila and Y. Bensman (NJO); M. Sherman, A. Hutchinson, N. Szeszenia-Dabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner (POL); C. Luccarini, P. Harrington, the SEARCH team and ECRIC (SEA); the Scottish Gynaecological Clinical Trials group and SCOTROC1 investigators (SRO); W.-H. Chow and Y.-T. Gao (SWH); I. Jacobs, M. Widschwendter, N. Balogun, A. Ryan and J. Ford (UKO); and Carole Pye (UKR). The Collaborative Oncological Gene-Environment Study (COGS) project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175-HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund, thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding of this project were (in part) supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network: a NCI Cancer Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium.; A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute. Information about TCGA, and the investigators and institutions who constitute the TCGA research network, can be found at http://cancergenome.nih.gov/. G. C. T. is a Senior Principal Research Fellow of the National Health and Medical Research Council, Australia. D. F. E. is a Principal Research Fellow of Cancer Research UK. P. A. F. is supported by the Deutsche Krebshilfe. B. K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN). L. E. K. is supported by a Canadian Institutes of Health Research Investigator award (MSH-87734). H. S. 1 is supported by a National Institutes of Health training grant (T32GM067587), 'Training in Cellular, Biochemical and Molecular Sciences'. Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research (MOP-86727); Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086 and C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the Norwegian Cancer Society, Helse Vest, the Norwegian Research Council, ELAN Funds of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Imperial Experimental Cancer Research Centre (C1312/A15589); the Ovarian Cancer Research Fund (PPD/USC.06); Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; the L & S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K07-CA80668, K22-CA138563, N01-CN55424, N01-PC067001, N01-PC035137, P01-CA017054, P01-CA087696, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA149429, R01-CA141154, R03-CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, P30-CA15083, R01CA83918, U24 CA143882 and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669 and W81XWH-10-1-0280); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-Wurttemberg through Medical Faculty of the University of Ulm (P.; 685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Phi Beta Psi Sorority; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital 'Womens Health Theme' and the Royal Marsden Hospital; and WorkSafeBC. We acknowledge the contributions of Kyriaki Michailidou, Ali Amin Al Olama and Karoline Kuchenbaecker to the iCOGS statistical analyses and Shahana Ahmed, Melanie J. Maranian and Catherine S Healey for their contributions to the iCOGS genotyping quality-control process. US National Health Institute/National Center for Research Resources/General Clinical Research Center M01-RR000056. NR 33 TC 66 Z9 66 U1 2 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2013 VL 4 AR 1628 DI 10.1038/ncomms2629 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143NJ UT WOS:000318873900081 PM 23535649 ER PT J AU Valapala, M Hose, S Gongora, C Dong, LJ Wawrousek, EF Zigler, JS Sinha, D AF Valapala, Mallika Hose, Stacey Gongora, Celine Dong, Lijin Wawrousek, Eric F. Zigler, J. Samuel, Jr. Sinha, Debasish TI Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes SO NATURE COMMUNICATIONS LA English DT Article ID LYSOSOMAL ACIDIFICATION; SPONTANEOUS MUTATION; GAMMA-SECRETASE; MOUSE RETINA; CELL-DEATH; ACTIVATION; ENDOCYTOSIS; BETA-A3/A1-CRYSTALLIN; DROSOPHILA; RECEPTOR AB Astrocytes migrate from the optic nerve into the inner retina, forming a template upon which retinal vessels develop. In the Nuc1 rat, mutation in the gene encoding beta A3/A1-crystallin disrupts both Notch signalling in astrocytes and formation of the astrocyte template. Here we show that loss of beta A3/A1-crystallin in astrocytes does not impede Notch ligand binding or extracellular cleavages. However, it affects vacuolar-type proton ATPase (V-ATPase) activity, thereby compromising acidification of the endolysosomal compartments, leading to reduced gamma-secretase-mediated processing and release of the Notch intracellular domain (NICD). Lysosomal-mediated degradation of Notch is also impaired. These defects decrease the level of NICD in the nucleus, inhibiting the expression of Notch target genes. Overexpression of beta A3/A1-crystallin in those same astrocytes restored V-ATPase activity and normal endolysosomal acidification, thereby increasing the levels of gamma-secretase to facilitate optimal Notch signalling. We postulate that beta A3/A1-crystallin is essential for normal endolysosomal acidification, and thereby, normal activation of Notch signalling in astrocytes. C1 [Valapala, Mallika; Hose, Stacey; Zigler, J. Samuel, Jr.; Sinha, Debasish] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Gongora, Celine] INSERM, IRCM, U896, F-34298 Montpellier, France. [Dong, Lijin; Wawrousek, Eric F.] NEI, NIH, Bethesda, MD 20892 USA. RP Sinha, D (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. EM Debasish@jhmi.edu FU National Institutes of Health [EY018636, EY019037, EY01765]; Research to Prevent Blindness FX This work was supported by grants from the National Institutes of Health, EY018636 (D. S.), EY019037 (D. S.) and EY01765 (Wilmer Imaging Core) and Research to Prevent Blindness (an unrestricted grant to The Wilmer Eye Institute). D. S. is a recipient of the Sybil B. Harrington Special Scholar award for Macular Degeneration from Research to Prevent Blindness. We thank Drs Akrit Sodhi and Xiaoban Xin for providing the adenoviral vectors and Dr Raphael Kopan for N delta E plasmids. We also thank Morton F Goldberg, Bidyut Ghosh and Seth Greenbaum for critically reading the manuscript. NR 60 TC 18 Z9 18 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2013 VL 4 AR 1629 DI 10.1038/ncomms2624 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143NJ UT WOS:000318873900082 PM 23535650 ER PT J AU Wu, SD Zhu, WH Nhan, T Toth, JI Petroski, MD Wolf, DA AF Wu, Shuangding Zhu, Wenhong Tina Nhan Toth, Julia I. Petroski, Matthew D. Wolf, Dieter A. TI CAND1 controls in vivo dynamics of the cullin 1-RING ubiquitin ligase repertoire SO NATURE COMMUNICATIONS LA English DT Article ID F-BOX PROTEIN; COP9 SIGNALOSOME; SUBSTRATE-ADAPTERS; NEDDYLATION; NEDD8; CUL1; SCF; ACTIVATION; TIP120A; CONJUGATION AB The combinatorial architecture of cullin 1-RING ubiquitin ligases, in which multiple F-box containing substrate receptors compete for access to CUL1, poses special challenges to assembling cullin 1-RING ubiquitin ligase complexes through high affinity protein interactions while maintaining the flexibility to dynamically sample the entire F-box containing substrate receptor repertoire. Here, using highly quantitative mass spectrometry, we demonstrate that this problem is addressed by CAND1, a factor that controls the dynamics of the global cullin 1-RING ubiquitin ligase network by promoting the assembly of newly synthesized F-box containing substrate receptors with CUL1-RBX1 core complexes. Our studies of in vivo cullin 1-RING ubiquitin ligase dynamics and in vitro biochemical findings showing that CAND1 can displace F-box containing substrate receptors from Cul1p suggest that CAND1 functions in a cycle that serves to exchange F-box containing substrate receptors on CUL1 cores. We propose that this cycle assures comprehensive sampling of the entire F-box containing substrate receptor repertoire in order to maintain the cullin 1-RING ubiquitin ligase landscape, a function that we show to be critical for substrate degradation and normal physiology. C1 [Wu, Shuangding; Tina Nhan; Toth, Julia I.; Petroski, Matthew D.; Wolf, Dieter A.] Sanford Burnham Med Res Inst, Signal Transduct Program, La Jolla, CA 92037 USA. [Zhu, Wenhong; Wolf, Dieter A.] Sanford Burnham Med Res Inst, NCI, Canc Ctr Prote Facil, La Jolla, CA 92037 USA. [Wolf, Dieter A.] Sanford Burnham Med Res Inst, San Diego Ctr Syst Biol, La Jolla, CA 92037 USA. RP Wolf, DA (reprint author), Sanford Burnham Med Res Inst, Signal Transduct Program, La Jolla, CA 92037 USA. EM dwolf@sanfordburnham.org OI Wolf, Dieter/0000-0002-3761-1070 FU NIH [GM59780, P20 CA132386-03, P50 GM085764-03] FX We thank Y. Takayama for Ams2p antibodies and Z. Ronai for review of the manuscript. We also thank R. Deshaies and T. Kurz for sharing results prior to publication. This work was supported by NIH grants GM59780, P20 CA132386-03 and P50 GM085764-03. NR 39 TC 35 Z9 35 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2013 VL 4 AR 1642 DI 10.1038/ncomms2636 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143NJ UT WOS:000318873900095 PM 23535663 ER PT J AU White, SF Frick, PJ Lawing, K Bauer, D AF White, Stuart F. Frick, Paul J. Lawing, Kathryn Bauer, Daliah TI CallousUnemotional Traits and Response to Functional Family Therapy in Adolescent Offenders SO BEHAVIORAL SCIENCES & THE LAW LA English DT Article ID CALLOUS-UNEMOTIONAL TRAITS; DISRUPTIVE BEHAVIOR DISORDERS; PSYCHOPATHIC FEATURES; ANTISOCIAL-BEHAVIOR; CONDUCT PROBLEMS; SEX OFFENDERS; RECIDIVISM; CHILDREN; METAANALYSIS; VIOLENCE AB OBJECTIVE The current study examined whether callousunemotional (CU) traits moderated the effectiveness of Functional Family Therapy for juvenile justice involved adolescents. METHOD Participants were all youths (n=134) who had been arrested and participated in an FFT program provided in a community mental health center over a 20-month period (mean age 15.34, 71.6% males, 59% African-American). Parent and self-report ratings of emotional, behavioral, and social functioning, multi-informant ratings of treatment progress, and probation/arrest records were used as outcome indicators. RESULTS CU traits were associated with poorer behavioral, emotional, and social adjustment prior to treatment but they were also associated with greater improvements in adjustment over the course of treatment. CU traits were not associated with significantly lower rates of participation or higher rates of treatment dropout, and the association between CU traits and risk for violent charges decreased after treatment at 6- and 12-month follow-ups. However, CU traits were still correlated with poorer levels of adjustment post-treatment, less perceived change over treatment by youth and their parents, and increased likelihood of violent offending during treatment. CONCLUSIONS The results of this study indicate that FFT can lead to improvements in youth with CU traits; however, they enter treatment with a greater number of symptoms and are at higher risk for committing violence during treatment than other youth. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [White, Stuart F.] NIMH, Bethesda, MD 20892 USA. [Frick, Paul J.; Lawing, Kathryn] Univ New Orleans, New Orleans, LA 70148 USA. RP White, SF (reprint author), NIMH, 9000 Rockville Pike,Bldg 15k,Room 300-C, Bethesda, MD 20892 USA. EM whitesf@mail.nih.gov NR 43 TC 15 Z9 15 U1 2 U2 38 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0735-3936 J9 BEHAV SCI LAW JI Behav. Sci. Law PD MAR-APR PY 2013 VL 31 IS 2 BP 271 EP 285 DI 10.1002/bsl.2041 PG 15 WC Psychology, Applied; Law SC Psychology; Government & Law GA 139ZA UT WOS:000318622600008 PM 23172768 ER PT J AU Morens, DM Folkers, GK Fauci, AS AF Morens, David M. Folkers, Gregory K. Fauci, Anthony S. TI Dengue: The Continual Re-Emergence of a Centuries-Old Disease SO ECOHEALTH LA English DT Editorial Material C1 [Morens, David M.; Folkers, Gregory K.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dmorens@niaid.nih.gov NR 8 TC 2 Z9 2 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1612-9202 J9 ECOHEALTH JI EcoHealth PD MAR PY 2013 VL 10 IS 1 BP 104 EP 106 DI 10.1007/s10393-013-0825-7 PG 3 WC Biodiversity Conservation; Ecology; Environmental Sciences SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 143CM UT WOS:000318843900013 PM 23456289 ER PT J AU Yan, S Li, ZJ Thiele, CJ AF Yan, Shuang Li, Zhijie Thiele, Carol J. TI Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in Neuroblastoma and Pediatric Sarcomas In vitro and In vivo SO ONCOTARGET LA English DT Article DE neuroblastoma; Ewing sarcoma; rhabdomyosarcoma; JAK inhibitor; STAT3 ID SIGNAL TRANSDUCER; CONSTITUTIVE ACTIVATION; PROGNOSTIC-FACTORS; EWING SARCOMA; SOLID TUMORS; CELL-GROWTH; CANCER; RHABDOMYOSARCOMA; RESISTANCE; TRANSCRIPTION-3 AB The IL-6/JAK/STAT pathway is a key signal transduction pathway implicated in the pathogenesis of many human cancers, suggesting that kinase inhibitors targeting JAK/STAT3 may have a broad spectrum of antitumor activity. AZD1480, a pharmacological JAK1/2 inhibitor, exhibits anti-tumor potency in multiple adult malignancies. To evaluate the efficacy of inhibition of JAK/STAT3 signal transduction pathway we assessed the activity of AZD1480 in pediatric malignancies using preclinical models of three highly malignant pediatric solid tumors: neuroblastoma (NB), rhabdomyosarcoma (RMS) and the Ewing Sarcoma Family Tumors (ESFT). In this study, we employed panels of biomedical and biological experiments to evaluate the in vitro and in vivo activity of AZD1480 in NB, RMS and ESFT. Our data indicate that AZD1480 blocks endogenous as well as IL-6 induced STAT3 activation. AZD1480 decreases cell viability in 7/7NB, 7/7RMS and 2/2 ESFT cell lines (median EC50 is 1.5 mu M, ranging from 0.36-5.37 mu M). AZD1480 induces cell growth inhibition and caspase-dependent apoptosis in vitro and decreases expression of STAT3 target genes, including cell cycle regulators CyclinD1, 3 and CDC25A, anti-apoptotic genes Bcl-2 and survivin, the metastasis-related factor TIMP-1 and c-Myc. In vivo studies showed AZD1480 significantly decreased tumor growth and prolonged overall survival in tumor-bearing mice. Tumors from AZD1480-treated mice showed inhibition of activated STAT3 as well as decreased expression of STAT3 downstream targets. Our study provides strong evidence of the anti-tumor growth potency of JAK inhibitor AZD1480 in pediatric solid tumors, providing proof-of principle that inhibition of the JAK/STAT3 signal transduction could be a promising therapeutic target for high-risk pediatric solid tumors. C1 [Yan, Shuang; Li, Zhijie; Thiele, Carol J.] NCI, Ctr Canc Res, Pediat Oncol Branch, Cell & Mol Biol Sect, Bethesda, MD 20892 USA. RP Thiele, CJ (reprint author), NCI, Ctr Canc Res, Pediat Oncol Branch, Cell & Mol Biol Sect, Bethesda, MD 20892 USA. EM ct47a@nih.gov RI Yan, Shuang/N-7131-2013 FU NIH, National Cancer Institute; Center for Cancer Research FX We would like to thank: Dr. Choh Yeung (Pediatric Oncology Branch, National Cancer Institute) for his kind assistance with the orthotropic mice models; AstraZeneca (Boston) for provide AZD1480; Dr. Dennis Huszar (Cancer Bioscience, AstraZeneca) for coordinating the supply of AZD1480 and suggesting on the dose of AZD1480 on animal models; Dr. Stanley He (Pediatric Oncology Branch, National Cancer Institute) for editing the manuscript; Dr. Lee Helman (Pediatric Oncology Branch, National Cancer Institute) for critical review and discussion on the manuscript. All xenograft studies were approved by the Animal Care and Use Committee of the National Cancer Institute in accordance with the institutional guidelines (Protocol Number: PB-023). This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research. NR 35 TC 30 Z9 34 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR PY 2013 VL 4 IS 3 BP 433 EP 445 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 142FW UT WOS:000318783400007 PM 23531921 ER PT J AU Zhurkin, VB Olson, WK AF Zhurkin, Victor B. Olson, Wilma K. TI Can nucleosomal DNA be described by an elastic model? Comment on "Sequence-dependent collective properties of DNAs and their role in biological systems" by Pasquale De Santis and Anita Scipioni SO PHYSICS OF LIFE REVIEWS LA English DT Editorial Material ID DEFORMATIONS; MECHANICS; CHROMATIN; HISTONE C1 [Zhurkin, Victor B.] NCI, NIH, Bethesda, MD 20892 USA. [Olson, Wilma K.] Rutgers State Univ, Wright Rieman Labs, Piscataway, NJ 08854 USA. RP Zhurkin, VB (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM zhurkin@nih.gov; wilma.olson@rutgers.edu FU NIGMS NIH HHS [R01 GM034809] NR 17 TC 1 Z9 1 U1 3 U2 12 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 MAR PY 2013 VL 10 IS 1 BP 70 EP 72 DI 10.1016/j.plrev.2013.01.009 PG 3 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA 139MR UT WOS:000318587300011 PM 23587120 ER PT J AU Wilcox, AJ Bonde, JPE AF Wilcox, Allen J. Bonde, Jens Peter E. TI On environmental threats to male infertility SO ASIAN JOURNAL OF ANDROLOGY LA English DT Editorial Material ID TESTICULAR DYSGENESIS SYNDROME; IN-UTERO EXPOSURE; SPERM COUNTS; SEMEN QUALITY; ENDOCRINE DISRUPTION; REPRODUCTIVE-TRACT; FERTILITY; PREGNANCY; PHTHALATE; SMOKING C1 [Wilcox, Allen J.] NIEHS, Epidemiol Branch, Durham, NC 27709 USA. [Bonde, Jens Peter E.] Univ Copenhagen Hosp, Dept Occupat & Environm Med, DK-2400 Copenhagen NV, Denmark. RP Wilcox, AJ (reprint author), NIEHS, Epidemiol Branch, Durham, NC 27709 USA. EM wilcox@niehs.nih.gov OI Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS NR 37 TC 6 Z9 9 U1 0 U2 22 PU ACTA PHARMACOLOGICA SINICA PI SHANGHAI PA 294 TAI-YUAN RD, SHANGHAI, 200031, PEOPLES R CHINA SN 1008-682X J9 ASIAN J ANDROL JI Asian J. Androl. PD MAR PY 2013 VL 15 IS 2 SI SI BP 199 EP 200 DI 10.1038/aja.2012.153 PG 2 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 140XV UT WOS:000318690700011 PM 23334202 ER PT J AU Liaudet, L Rosenblatt-Velin, N Pacher, P AF Liaudet, Lucas Rosenblatt-Velin, Nathalie Pacher, Pal TI Role of Peroxynitrite in the Cardiovascular Dysfunction of Septic Shock SO CURRENT VASCULAR PHARMACOLOGY LA English DT Article DE Septic shock; cardiovascular dysfunction; nitric oxide; superoxide; peroxynitrite; oxidative stress; nitration; poly(ADP-ribose) polymerase; animal models ID PROTEIN-TYROSINE NITRATION; NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; POLY(ADP-RIBOSE) POLYMERASE ACTIVATION; MANGANESE SUPEROXIDE-DISMUTASE; SPLANCHNIC ARTERY-OCCLUSION; OXIDATIVE STRESS; HEART-FAILURE; IN-VIVO; MATRIX METALLOPROTEINASES AB The intense systemic inflammatory response characterizing septic shock is associated with an increased generation of free radicals by multiple cell types in cardiovascular and non cardiovascular tissues. The oxygen-centered radical superoxide anion (O-2(center dot-)) rapidly reacts with the nitrogen-centered radical nitric oxide (NO center dot) to form the potent oxidant species peroxynitrite. Peroxynitrite oxidizes multiple targets molecules, either directly or via the secondary generation of highly reactive radicals, resulting in significant alterations in lipids, proteins and nucleic acids, with significant cytotoxic consequences. The formation of peroxynitrite is a key pathophysiological mechanism contributing to the cardiovascular collapse of septic shock, promoting vascular contractile failure, endothelial and myocardial dysfunction, and is also implicated in the occurrence of multiple organ dysfunction in this setting. The recent development of various porphyrin-based pharmacological compounds accelerating the degradation of peroxynitrite has allowed to specifically address these pathophysiological roles of peroxynitrite in experimental septic shock. Such agents, including 5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrinato iron III chloride (FeTTPs), manganese tetrakis(4-N-methylpyridyl) porphyrin (MnTMPyP), Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin) (FP-15) and WW-85, have been shown to improve the cardiovascular and multiple organ failure in small and large animal models of septic shock. Therefore, these findings support the development of peroxynitrite decomposition catalysts as potentially useful novel therapeutic agents to restore cardiovascular function in sepsis. C1 [Liaudet, Lucas] Fac Biol & Med, Dept Intens Care Med, CH-1010 Lausanne, Switzerland. [Liaudet, Lucas; Rosenblatt-Velin, Nathalie] Fac Biol & Med, Div Clin Pathophysiol, CH-1010 Lausanne, Switzerland. [Liaudet, Lucas; Rosenblatt-Velin, Nathalie] Fac Biol & Med, Dept Physiol, CH-1010 Lausanne, Switzerland. Univ Hosp Med Ctr, CH-1011 Lausanne, Switzerland. [Pacher, Pal] NIAAA, Sect Oxidat Stress & Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Liaudet, L (reprint author), BH 08 621 Univ Hosp Med, Dept Intens Care Med, CH-1011 Lausanne, Switzerland. EM lucas.liaudet@chuv.ch RI Pacher, Pal/B-6378-2008; Liaudet, Lucas/E-1322-2017 OI Pacher, Pal/0000-0001-7036-8108; Liaudet, Lucas/0000-0003-2670-4930 FU Swiss National Foundation for Scientific Research [Nr 310030_135394/1, 310030_132491]; Intramural Program of National Institutes of Health/NIAAA FX Supported by grants from the Swiss National Foundation for Scientific Research (Nr 310030_135394/1 to LL and 310030_132491 to NRV) and Intramural Program of National Institutes of Health/NIAAA (to PP). NR 150 TC 12 Z9 15 U1 1 U2 22 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1611 J9 CURR VASC PHARMACOL JI Current Vascular Pharmacology PD MAR PY 2013 VL 11 IS 2 BP 196 EP 207 PG 12 WC Pharmacology & Pharmacy; Peripheral Vascular Disease SC Pharmacology & Pharmacy; Cardiovascular System & Cardiology GA 139RV UT WOS:000318602600009 PM 23506498 ER PT J AU Tsao, CW O'Donnell, CJ AF Tsao, Connie W. O'Donnell, Christopher J. TI Lipid profiles and coronary artery plaque by CT angiography: Promise for translation of biology to imaging SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Editorial Material ID MULTISLICE COMPUTED-TOMOGRAPHY; ACUTE CHEST-PAIN; CARDIOVASCULAR-DISEASE; MAGNETIC-RESONANCE; PROGNOSTIC VALUE; RISK; CALCIUM; SUBFRACTIONATION; APOLIPOPROTEINS; CHOLESTEROL C1 [Tsao, Connie W.] Framingham Heart Dis Epidemiol Study, Natl Heart Lung & Blood Inst, Framingham, MA 01702 USA. Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Tsao, CW (reprint author), Framingham Heart Dis Epidemiol Study, Natl Heart Lung & Blood Inst, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. FU Intramural NIH HHS [ZIA HL006002-06, Z99 HL999999, ZIA HL006002-05] NR 28 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD MAR-APR PY 2013 VL 7 IS 2 BP 91 EP 93 DI 10.1016/j.jcct.2013.02.001 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 137WV UT WOS:000318469800004 PM 23622504 ER PT J AU Robledo, R Lorenz, J Beck, J Else, J Bender, P AF Robledo, Renato Lorenz, Joseph Beck, Jeanne Else, James Bender, Patrick TI Genetic Analysis of Putative Familial Relationships in a Captive Chimpanzee (Pan troglodytes) Population SO COLLEGIUM ANTROPOLOGICUM LA English DT Article DE nonhuman primates; microsatellite; genotyping; pedigree; heterozygosity ID HUMAN GENOME; LINKAGE MAP; MICROSATELLITES; APES AB Twelve autosomal dinucleotide repeat loci were analyzed in chimpanzees genomes by DNA amplification using primers designed for analysis of human loci. The markers span the entire length of human chromosomes 21 and 22. Nine markers were polymorphic in chimpanzee as well, with a somewhat comparable level of polymorphism and allele size range. Even in the presence of very limited information and in spite of missing samples, it was possible to reconstruct a complex pedigree and to provide molecular data that corroborate family relationships that were deduced from cage history and behavioral data. The conclusions were further supported by mitochondrial DNA analysis. The data presented in this report show that the extremely abundant source of human markers may be exploited to validate, with molecular evidence, hypotheses on individual relationship or alleged pedigrees, based upon behavioral observations. C1 [Robledo, Renato] Univ Cagliari, Dept Biomed Sci, I-09042 Cagliari, Italy. [Lorenz, Joseph] Cent Washington Univ, Dept Anthropol & Museum Studies, Ellensburg, WA USA. [Beck, Jeanne] Coriell Inst Med Res, Camden, NJ USA. [Else, James] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Bender, Patrick] NIMH, Rockville, MD 20857 USA. RP Robledo, R (reprint author), Univ Cagliari, Dept Biomed Sci, SS 554 Km 4,500, I-09042 Cagliari, Italy. EM rrobledo@unica.it NR 12 TC 0 Z9 0 U1 0 U2 7 PU COLLEGIUM ANTROPOLOGICUM PI ZAGREB PA INST ANTHROPOLOGICAL RESEARCH, GAJEVA 32, PO BOX 290, HR-10000 ZAGREB, CROATIA SN 0350-6134 J9 COLLEGIUM ANTROPOL JI Coll. Anthropol. PD MAR PY 2013 VL 37 IS 1 BP 245 EP 250 PG 6 WC Anthropology SC Anthropology GA 134HI UT WOS:000318200600038 PM 23697280 ER PT J AU Turner, MR Hardiman, O Benatar, M Brooks, BR Chio, A de Carvalho, M Ince, PG Lin, C Miller, RG Mitsumoto, H Nicholson, G Ravits, J Shaw, PJ Swash, M Talbot, K Traynor, BJ Van den Berg, LH Veldink, JH Vucic, S Kiernan, MC AF Turner, Martin R. Hardiman, Orla Benatar, Michael Brooks, Benjamin R. Chio, Adriano de Carvalho, Mamede Ince, Paul G. Lin, Cindy Miller, Robert G. Mitsumoto, Hiroshi Nicholson, Garth Ravits, John Shaw, Pamela J. Swash, Michael Talbot, Kevin Traynor, Bryan J. Van den Berg, Leonard H. Veldink, Jan H. Vucic, Steve Kiernan, Matthew C. TI Controversies and priorities in amyotrophic lateral sclerosis SO LANCET NEUROLOGY LA English DT Review ID MOTOR-NEURON DISEASE; GENOME-WIDE ASSOCIATION; PROGRESSIVE MUSCULAR-ATROPHY; DIAGNOSTIC-CRITERIA; CLINICAL-FEATURES; SPORADIC ALS; NEURODEGENERATIVE DISEASES; NEUROPHYSIOLOGICAL INDEX; HEXANUCLEOTIDE REPEAT; PREDICTS SURVIVAL AB Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events. C1 [Turner, Martin R.; Talbot, Kevin] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England. [Hardiman, Orla] Univ Dublin Trinity Coll, Acad Neurol Unit, Trinity Biomed Sci Inst, Dublin 2, Ireland. [Hardiman, Orla] Beaumont Hosp, Natl Neurosci Ctr, Dublin 9, Ireland. [Benatar, Michael] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Brooks, Benjamin R.] Univ N Carolina, Dept Neurol, Sch Med, Charlotte, NC 28223 USA. [Chio, Adriano] Univ Turin, Dept Neurosci, I-10124 Turin, Italy. [de Carvalho, Mamede] Univ Lisbon, Translat Physiol & Clin Unit, Inst Mol Med, P-1699 Lisbon, Portugal. [de Carvalho, Mamede] Univ Lisbon, Fac Med, P-1699 Lisbon, Portugal. [Ince, Paul G.; Shaw, Pamela J.] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield, S Yorkshire, England. [Lin, Cindy] Univ New S Wales, Fac Med, Sch Med Sci, Sydney, NSW, Australia. [Miller, Robert G.] Calif Pacific Med Ctr, San Francisco, CA USA. [Mitsumoto, Hiroshi] New York Presbyterian Columbia Univ Med Ctr, New York, NY USA. [Nicholson, Garth] ANZAC Res Inst, Northcott Neurosci Lab, Concord, NSW, Australia. [Ravits, John] Univ Calif San Diego, San Diego, CA 92103 USA. [Swash, Michael] Queen Mary Sch Med, London, England. [Swash, Michael] Royal London Hosp, London E1 1BB, England. [Swash, Michael] Univ Lisbon, Inst Neurosci, P-1699 Lisbon, Portugal. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, Bethesda, MD 20892 USA. [Van den Berg, Leonard H.; Veldink, Jan H.] Univ Med Ctr Utrecht, Dept Neurol, Utrecht, Netherlands. [Vucic, Steve] Univ Sydney, Sydney Med Sch Westmead, Sydney, NSW 2006, Australia. [Kiernan, Matthew C.] Neurosci Res Australia, Sydney, NSW 2031, Australia. RP Kiernan, MC (reprint author), Neurosci Res Australia, Sydney, NSW 2031, Australia. EM M.kiernan@unsw.edu.au RI Traynor, Bryan/G-5690-2010; Kiernan, Matthew/E-4460-2011; OI de Carvalho, Mamede/0000-0001-7556-0158; Chio, Adriano/0000-0001-9579-5341; Turner, Martin/0000-0003-0267-3180 FU MDA; ALSA; FDA; NIH; Carolina ALS Research Fund; NINDS; Biogen Idec; Cytokinetics; Neuraltus; GlaxoSmithKline; National Health and Medical Research Council; Medical Research Council; Motor Neuron Disease UK Lady Edith Wolfson Clinician Scientist Fellowship; Health Seventh Framework Programme [259867]; ALSA (the ALS Association); HRB (the Health Research Board) Clinical Scientist Award; Research Motor Neuron; NIH, National Institute on Aging [Z01-AG000949-02] FX MB receives research funding from MDA, ALSA, FDA, and NIH and provides consulting services for Cytokinetics and Asublo. OH has received honoraria for consulting work for Biogen Idec and Cytokinetics. AC serves on scientific advisory boards for Cytokinetics and Biogen Idec. BRB receives research funding from Carolina ALS Research Fund, MDA, ALSA, NINDS, Biogen Idec, Cytokinetics, Neuraltus, and GlaxoSmithKline. MRT received payment from Biogen Idec for a consultancy on ALS staging. RGM provided consulting services for Cytokinetics, Asubio, Biogen, and Knopp and received research support as principal investigator for Neuraltus, and was on speakers' bureau for Avanir. MCK, MS, KT, BJT, LHVdB, JHV, SV, MdC, PGI, CL, HM, GN, JR, and PJS declare that they have no conflicts of interest.; The Fort Denison consensus meeting was supported by Neuroscience Research Australia and the University of New South Wales. MCK receives funding support from the National Health and Medical Research Council. MRT is supported by the Medical Research Council & Motor Neuron Disease UK Lady Edith Wolfson Clinician Scientist Fellowship. OH received funding from the Health Seventh Framework Programme (FP7/2007-2013) under grant agreement No 259867, ALSA (the ALS Association), HRB (the Health Research Board) Clinical Scientist Award, and Research Motor Neuron (previously named Motor Neuron Disease Research Foundation). BJT is supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02). We are grateful to Olaf Ansorge for his expert advice on table 1. Helpful discussion with Linda Greensmith and Denise Figlewicz regarding the SOD1 mouse model of ALS is gratefully acknowledged. NR 123 TC 185 Z9 187 U1 6 U2 95 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2013 VL 12 IS 3 BP 310 EP 322 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 138SW UT WOS:000318531300016 PM 23415570 ER PT J AU Litton, P AF Litton, Paul TI Physician Participation in Executions, the Morality of Capital Punishment, and the Practical Implications of Their Relationship SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Review ID CLINICAL-RESEARCH; LETHAL INJECTION; FORENSIC PSYCHIATRY; ETHICAL DILEMMAS; MEDICINE; CARE AB Evidence that some executed prisoners suffered excruciating pain has reinvigorated the ethical debate about physician participation in executions. In widely publicized litigation, death row inmates argue that participation of anesthesiologists in their execution is constitutionally required to minimize the risk of unnecessary suffering. For many years, commentators supported the ethical ban on physician participation reflected in codes of professional medical organizations. However, a recent wave of scholarship concurs with inmate advocates, urging the law to require or permit physician participation. Both the anti- and pro-physician-participation literature share a common premise: the ethics of physician participation should be analyzed independently from the moral status of capital punishment. This considerable literature implausibly divorces the ethics of physician participation from the moral status of the death penalty. Any ethical position on physician involvement requires some judgment about the moral status of capital punishment. The article examines anti- and pro-participation arguments to show that each one either is unpersuasive without discussion of the death penalty's moral status or implicitly assumes a view on the social worth of the death penalty. The article then articulates the practical implications of its arguments for both lawmakers and professional medical organizations. C1 [Litton, Paul] Univ Missouri, Sch Law, Columbia, MO 65211 USA. [Litton, Paul] NIH, Dept Clin Bioeth, Bethesda, MD USA. RP Litton, P (reprint author), Univ Missouri, Sch Law, Columbia, MO 65211 USA. FU American Society for Law, Medicine, Ethics; SLU's Center for Health Law Studies FX An abstract for this article was chosen for presentation at the Health Law Scholars Workshop, sponsored by the American Society for Law, Medicine, & Ethics and SLU's Center for Health Law Studies. I am very thankful for excellent comments from workshop participants. I am especially grateful to Kathy Cerminara, Annette Clark, Kelly Dineen, Rebecca Dresser, Jim DuBois, Phil Peters, Christina Wells, and Robin Fretwell Wilson for providing extensive and helpful feedback. For many helpful conversations and medical knowledge, I thank Y. Bernard Su and Christopher Bruno. I also thank my colleagues participating in a workshop at the University of Missouri. NR 73 TC 4 Z9 4 U1 3 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-1105 EI 1748-720X J9 J LAW MED ETHICS JI J. Law Med. Ethics PD SPR PY 2013 VL 41 IS 1 SI SI BP 333 EP 352 DI 10.1111/jlme.12024 PG 20 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 130IY UT WOS:000317909200024 PM 23581676 ER PT J AU George, SM Alfano, CM Smith, AW Irwin, ML McTiernan, A Bernstein, L Baumgartner, KB Ballard-Barbash, R AF George, Stephanie M. Alfano, Catherine M. Smith, Ashley Wilder Irwin, Melinda L. McTiernan, Anne Bernstein, Leslie Baumgartner, Kathy B. Ballard-Barbash, Rachel TI Sedentary Behavior, Health-Related Quality of Life, and Fatigue Among Breast Cancer Survivors SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE health behavior; survivorship; epidemiology ID TELEVISION VIEWING TIME; PHYSICAL-ACTIVITY; EATING INDEX-2005; LEISURE-TIME; MORTALITY; ADULTS; DIAGNOSIS; ADIPOSITY; CARCINOMA; EXERCISE AB Background: Many cancer survivors experience declines in health-related quality of life (HRQOL) and increases in fatigue as a result of cancer and its treatment. Exercise is linked to improvements in these outcomes, but little is known about the role of sedentary behavior. In a large, ethnically-diverse cohort of breast cancer survivors, we examined the relationship between sedentary time, HRQOL, and fatigue, and examined if that relationship differed by recreational moderate-vigorous physical activity (MVPA) level. Methods: Participants were 710 women diagnosed with stage 0-IIIA breast cancer in the Health, Eating, Activity, and Lifestyle Study. Women completed questionnaires at approximately 30-months postdiagnosis (sedentary time; recreational MVPA) and 41-months postdiagnosis (HRQOL; fatigue). In multivariate models, we regressed these outcomes linearly on quartiles of daily sedentary time, and a variable jointly reflecting sedentary time quartiles and MVPA categories (0; >0 to <9; >= 9 MET-hrs/wk). Results: Sedentary time was not independently related to subscales or summary scores of HRQOL or fatigue. In addition, comparisons of women with high vs. low (Q4:Q1) sedentary time by MVPA level did not result in significant differences in HRQOL or fatigue. Conclusion: In this breast cancer survivor cohort, self-reported sedentary time was not associated with HRQOL or fatigue, 3.5 years postdiagnosis. C1 [George, Stephanie M.; Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Smith, Ashley Wilder] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Irwin, Melinda L.] Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth, Seattle, WA 98104 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Populat Sci, Duarte, CA 91010 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Baumgartner, Kathy B.] Univ Louisville, Dept Epidemiol & Publ Hlth, Louisville, KY 40292 USA. RP George, SM (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01 PC067010, N01-CN-75036-20, N01 CN005228, K05 CA136967, N01-CN-05228] NR 52 TC 9 Z9 9 U1 3 U2 13 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD MAR PY 2013 VL 10 IS 3 BP 350 EP 358 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 135BP UT WOS:000318261300006 PM 22820125 ER PT J AU Ozturk, A Aygun, N Smith, SA Caffo, B Calabresi, PA Reich, DS AF Ozturk, Arzu Aygun, Nafi Smith, Seth A. Caffo, Brian Calabresi, Peter A. Reich, Daniel S. TI Axial 3D gradient-echo imaging for improved multiple sclerosis lesion detection in the cervical spinal cord at 3T SO NEURORADIOLOGY LA English DT Article DE Multiple sclerosis; Diagnostic imaging; Magnetic resonance imaging; Spinal cord; Magnetization transfer contrast imaging ID INVERSION-RECOVERY MR; MAGNETIZATION-TRANSFER; MULTIARRAY COILS; WHITE-MATTER; 1.5 T; ARTIFACTS; BRAIN; SEQUENCES; DISEASE; ABNORMALITIES AB In multiple sclerosis (MS), spinal cord imaging can help in diagnosis and follow-up evaluation. However, spinal cord magnetic resonance imaging (MRI) is technically challenging, and image quality, particularly in the axial plane, is typically poor compared to brain MRI. Because gradient-recalled echo (GRE) images might offer improved contrast resolution within the spinal cord at high magnetic field strength, both without and with a magnetization transfer prepulse, we compared them to T2-weighted fast-spin-echo (T2-FSE) images for the detection of MS lesions in the cervical cord at 3T. On a clinical 3T MRI scanner, we studied 62 MS cases and 19 healthy volunteers. Axial 3D GRE sequences were performed without and with off-resonance radiofrequency irradiation. To mimic clinical practice, all images were evaluated in conjunction with linked images from a sagittal short tau inversion recovery scan, which is considered the gold standard for lesion detection in MS. Two experienced observers recorded image quality, location and size of focal lesions, atrophy, swelling, and diffuse signal abnormality independently at first and then in consensus. The number and volume of lesions detected with high confidence was more than three times as high on both GRE sequences compared to T2-FSE (p < 0.0001). Approximately 5 % of GRE scans were affected by artifacts that interfered with image interpretation, not significantly different from T2W-FSE. Axial 3D GRE sequences are useful for MS lesion detection when compared to 2D T2-FSE sequences in the cervical spinal cord at 3T and should be considered when examining intramedullary spinal cord lesions. C1 [Ozturk, Arzu; Aygun, Nafi; Reich, Daniel S.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21287 USA. [Smith, Seth A.] Kennedy Krieger Inst, FM Kirby Res Ctr Funct Brain Imaging, Baltimore, MD 21205 USA. [Caffo, Brian; Reich, Daniel S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Calabresi, Peter A.; Reich, Daniel S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, NIH, Bethesda, MD 20892 USA. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Unit, NIH, Bldg 10,Rm 5C103,10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. EM daniel.reich@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU NIH [P41RR015241, K99NS064098]; National Multiple Sclerosis Society [CA1029A2, TR3760A3]; Nancy Davis Center without Walls; NINDS FX We thank Terri Brawner, Jonathan Farrell, Eliza Gordon-Lipkin, Kathleen Kahl, Ivana Kusevic, and Peter van Zijl for assistance with data collection, and Govind Nair and Jiwon Oh for critical comments on the manuscript. Funding sources include NIH grants P41RR015241 and K99NS064098; National Multiple Sclerosis Society grants CA1029A2 and TR3760A3; and the Nancy Davis Center without Walls. Dr. Reich is supported by the Intramural Research Program of NINDS. NR 48 TC 10 Z9 10 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-3940 J9 NEURORADIOLOGY JI Neuroradiology PD MAR PY 2013 VL 55 IS 4 BP 431 EP 439 DI 10.1007/s00234-012-1118-5 PG 9 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 132CI UT WOS:000318045000007 PM 23208410 ER PT J AU Tachiwana, H Miya, Y Shono, N Ohzeki, JI Osakabe, A Otake, K Larionov, V Earnshaw, WC Kimura, H Masumoto, H Kurumizaka, H AF Tachiwana, Hiroaki Miya, Yuta Shono, Nobuaki Ohzeki, Jun-ichirou Osakabe, Akihisa Otake, Koichiro Larionov, Vladimir Earnshaw, William C. Kimura, Hiroshi Masumoto, Hiroshi Kurumizaka, Hitoshi TI Nap1 regulates proper CENP-B binding to nucleosomes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN CENTROMERE PROTEIN; HISTONE CHAPERONE NAP1; OUTER KINETOCHORE; CHROMOSOME SEGREGATION; CRYSTAL-STRUCTURE; BUDDING YEAST; A NUCLEOSOME; ALPHOID DNA; IN-VITRO; COMPLEX AB CENP-B is a widely conserved centromeric satellite DNA-binding protein, which specifically binds to a 17-bp DNA sequence known as the CENP-B box. CENP-B functions positively in the de novo assembly of centromeric nucleosomes, containing the centromere-specific histone H3 variant, CENP-A. At the same time, CENP-B also prevents undesired assembly of the CENP-A nucleosome through heterochromatin formation on satellite DNA integrated into ectopic sites. Therefore, improper CENP-B binding to chromosomes could be harmful. However, no CENP-B eviction mechanism has yet been reported. In the present study, we found that human Nap1, an acidic histone chaperone, inhibited the non-specific binding of CENP-B to nucleosomes and apparently stimulated CENP-B binding to its cognate CENP-B box DNA in nucleosomes. In human cells, the CENP-B eviction activity of Nap1 was confirmed in model experiments, in which the CENP-B binding to a human artificial chromosome or an ectopic chromosome locus bearing CENP-B boxes was significantly decreased when Nap1 was tethered near the CENP-B box sequence. In contrast, another acidic histone chaperone, sNASP, did not promote CENP-B eviction in vitro and in vivo and did not stimulate specific CENP-B binding to CENP-A nucleosomes in vitro. We therefore propose a novel mechanism of CENP-B regulation by Nap1. C1 [Tachiwana, Hiroaki; Miya, Yuta; Osakabe, Akihisa; Kurumizaka, Hitoshi] Waseda Univ, Grad Sch Adv Sci & Engn, Struct Biol Lab, Shinjuku Ku, Tokyo 1628480, Japan. [Shono, Nobuaki; Ohzeki, Jun-ichirou; Otake, Koichiro; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Human Genome Res, Lab Cell Engn, Kisarazu, Chiba 2920818, Japan. [Shono, Nobuaki; Otake, Koichiro] Nagoya Univ, Grad Sch Sci, Div Biol Sci, Chikusa Ku, Nagoya, Aichi 4648602, Japan. [Larionov, Vladimir] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [Kimura, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. RP Kurumizaka, H (reprint author), Waseda Univ, Grad Sch Adv Sci & Engn, Struct Biol Lab, Shinjuku Ku, 2-2 Wakamatsu Cho, Tokyo 1628480, Japan. EM masumoto@kazusa.or.jp; kurumizaka@waseda.jp RI Shono, Nobuaki/C-4130-2017; OI Shono, Nobuaki/0000-0002-9060-1074; Kimura, Hiroshi/0000-0003-0854-083X FU Japanese Society for the Promotion of Science (JSPS); Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; Waseda Research Institute for Science and Engineering; Sagawa Foundation for Promotion of Cancer Research; NOVARTIS Foundation (Japan) for the Promotion of Science; Kazusa DNA Research Institute Foundation; NIH, NCI, CCR; Wellcome Trust [073915]; Wellcome Trust Centre for Cell Biology [077707, 092076]; Waseda University FX Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS); Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (in part); Waseda Research Institute for Science and Engineering, the Sagawa Foundation for Promotion of Cancer Research, and NOVARTIS Foundation (Japan) for the Promotion of Science (to H. K.); Kazusa DNA Research Institute Foundation (to H. M.); Intramural Research Program of the NIH, NCI, CCR (to V. L.). Work in the WCE lab is funded by The Wellcome Trust, of which WCE is a Principal Research Fellow [073915]; Wellcome Trust Centre for Cell Biology [077707 and 092076]. Funding for open access charge: Waseda University. NR 69 TC 6 Z9 6 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR PY 2013 VL 41 IS 5 BP 2869 EP 2880 DI 10.1093/nar/gks1464 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 132JB UT WOS:000318062600015 PM 23325853 ER PT J AU Lim, SJ Boyle, PJ Chinen, M Dale, RK Lei, EP AF Lim, Su Jun Boyle, Patrick J. Chinen, Madoka Dale, Ryan K. Lei, Elissa P. TI Genome-wide localization of exosome components to active promoters and chromatin insulators in Drosophila SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; CRYPTIC UNSTABLE TRANSCRIPTS; LARGE GENE LISTS; MESSENGER-RNA; BIDIRECTIONAL PROMOTERS; NUCLEAR-ORGANIZATION; ENHANCER BLOCKING; BITHORAX COMPLEX; BINDING PROTEINS; QUALITY-CONTROL AB Chromatin insulators are functionally conserved DNA-protein complexes situated throughout the genome that organize independent transcriptional domains. Previous work implicated RNA as an important cofactor in chromatin insulator activity, although the precise mechanisms are not yet understood. Here we identify the exosome, the highly conserved major cellular 3' to 5' RNA degradation machinery, as a physical interactor of CP190-dependent chromatin insulator complexes in Drosophila. Genome-wide profiling of exosome by ChIP-seq in two different embryonic cell lines reveals extensive and specific overlap with the CP190, BEAF-32 and CTCF insulator proteins. Colocalization occurs mainly at promoters but also boundary elements such as Mcp, Fab-8, scs and scs', which overlaps with a promoter. Surprisingly, exosome associates primarily with promoters but not gene bodies of active genes, arguing against simple cotranscriptional recruitment to RNA substrates. Similar to insulator proteins, exosome is also significantly enriched at divergently transcribed promoters. Directed ChIP of exosome in cell lines depleted of insulator proteins shows that CTCF is required specifically for exosome association at Mcp and Fab-8 but not other sites, suggesting that alternate mechanisms must also contribute to exosome chromatin recruitment. Taken together, our results reveal a novel positive relationship between exosome and chromatin insulators throughout the genome. C1 [Lim, Su Jun; Boyle, Patrick J.; Chinen, Madoka; Dale, Ryan K.; Lei, Elissa P.] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lei, EP (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM leielissa@niddk.nih.gov OI Dale, Ryan/0000-0003-2664-3744 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK015602-05] FX Funding for open access charge: Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases [DK015602-05 to E.L.]. NR 78 TC 15 Z9 15 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR PY 2013 VL 41 IS 5 BP 2963 EP 2980 DI 10.1093/nar/gkt037 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 132JB UT WOS:000318062600022 PM 23358822 ER PT J AU Chon, H Sparks, JL Rychlik, M Nowotny, M Burgers, PM Crouch, RJ Cerritelli, SM AF Chon, Hyongi Sparks, Justin L. Rychlik, Monika Nowotny, Marcin Burgers, Peter M. Crouch, Robert J. Cerritelli, Susana M. TI RNase H2 roles in genome integrity revealed by unlinking its activities SO NUCLEIC ACIDS RESEARCH LA English DT Article ID AICARDI-GOUTIERES-SYNDROME; SUBSTRATE-SPECIFICITY; TOPOISOMERASE-I; RIBONUCLEASE H; MACROMOLECULAR CRYSTALLOGRAPHY; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURES; DNA-REPLICATION; EXCISION-REPAIR; INSTABILITY AB Ribonuclease H2 (RNase H2) protects genome integrity by its dual roles of resolving transcription-related R-loops and ribonucleotides incorporated in DNA during replication. To unlink these two functions, we generated a Saccharomyces cerevisiae RNase H2 mutant that can resolve R-loops but cannot cleave single ribonucleotides in DNA. This mutant definitively correlates the 2-5 bp deletions observed in rnh201 Delta strains with single rNMPs in DNA. It also establishes a connection between R-loops and Sgs1-mediated replication reinitiation at stalled forks and identifies R-loops uniquely processed by RNase H2. In mouse, deletion of any of the genes coding for RNase H2 results in embryonic lethality, and in humans, RNase H2 hypomorphic mutations cause Aicardi-Goutieres syndrome (AGS), a neuroinflammatory disorder. To determine the contribution of R-loops and rNMP in DNA to the defects observed in AGS, we characterized in yeast an AGS-related mutation, which is impaired in processing both substrates, but has sufficient R-loop degradation activity to complement the defects of rnh201 Delta sgs1 Delta strains. However, this AGS-related mutation accumulates 2-5 bp deletions at a very similar rate as the deletion strain. C1 [Chon, Hyongi; Crouch, Robert J.; Cerritelli, Susana M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. [Sparks, Justin L.; Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Rychlik, Monika; Nowotny, Marcin] Int Inst Mol & Cell Biol, Lab Prot Struct, PL-02109 Warsaw, Poland. RP Crouch, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Bethesda, MD 20892 USA. EM Robert_crouch@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Institutes of Health [GM032431]; Wellcome Trust [081760] FX Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (in part); National Institutes of Health [GM032431, in part] to P. M. B.; Wellcome Trust International Senior Research Fellowship [081760 to M.N.]. M.N. is an HHMI International Early Career Scholar. Funding for open access charge: Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 54 TC 38 Z9 38 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR PY 2013 VL 41 IS 5 BP 3130 EP 3143 DI 10.1093/nar/gkt027 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 132JB UT WOS:000318062600035 PM 23355612 ER PT J AU He, SS Guynet, C Siguier, P Hickman, AB Dyda, F Chandler, M Bao, TH AF He, Susu Guynet, Catherine Siguier, Patricia Hickman, Alison B. Dyda, Fred Chandler, Mick Bao Ton-Hoang TI IS200/IS605 family single-strand transposition: mechanism of IS608 strand transfer SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA TRANSPOSITION; SEQUENCE; RECONSTITUTION; TRANSPOSASES; RECOGNITION AB Transposase, TnpA, of the IS200/IS605 family member IS608, catalyses single-strand DNA transposition and is dimeric with hybrid catalytic sites composed of an HUH motif from one monomer and a catalytic Y127 present in an alpha-helix (alpha D) from the other (trans configuration). alpha D is attached to the main body by a flexible loop. Although the reactions leading to excision of a transposition intermediate are well characterized, little is known about the dynamic behaviour of the transpososome that drives this process. We provide evidence strongly supporting a strand transfer model involving rotation of both alpha D helices from the trans to the cis configuration (HUH and Y residues from the same monomer). Studies with TnpA heterodimers suggest that TnpA cleaves DNA in the trans configuration, and that the catalytic tyrosines linked to the 5'-phosphates exchange positions to allow rejoining of the cleaved strands (strand transfer) in the cis configuration. They further imply that, after excision of the transposon junction, TnpA should be reset to a trans configuration before the cleavage required for integration. Analysis also suggests that this mechanism is conserved among members of the IS200/IS605 family. C1 [He, Susu; Guynet, Catherine; Siguier, Patricia; Chandler, Mick; Bao Ton-Hoang] CNRS, Unite Mixte Rech 5100, Lab Microbiol & Genet Mol, F-31062 Toulouse, France. [Hickman, Alison B.; Dyda, Fred] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bao, TH (reprint author), CNRS, Unite Mixte Rech 5100, Lab Microbiol & Genet Mol, 118 Rte Narbonne, F-31062 Toulouse, France. EM Michael.Chandler@ibcg.biotoul.fr; Tonhoang@ibcg.biotoul.fr OI Chandler, Michael/0000-0002-0292-6662 FU Centre National de Recherche Scientifique (CNRS, France); ANR [ANR08 Blanc-0336 Mobigen]; National Institute of Diabetes and Digestive and Kidney Diseases; CNRS FX Centre National de Recherche Scientifique (CNRS, France); by ANR [ANR08 Blanc-0336 Mobigen to M. C]; intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (to F. D). Funding for open access charge: CNRS intramural funding. NR 15 TC 11 Z9 11 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR PY 2013 VL 41 IS 5 BP 3302 EP 3313 DI 10.1093/nar/gkt014 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 132JB UT WOS:000318062600047 PM 23345619 ER PT J AU Lublin, FD Cofield, SS Cutter, GR Conwit, R Narayana, PA Nelson, F Salter, AR Gustafson, T Wolinsky, JS AF Lublin, Fred D. Cofield, Stacey S. Cutter, Gary R. Conwit, Robin Narayana, Ponnada A. Nelson, Flavia Salter, Amber R. Gustafson, Tarah Wolinsky, Jerry S. CA CombiRx Investigators TI Randomized study combining interferon and glatiramer acetate in multiple sclerosis SO ANNALS OF NEUROLOGY LA English DT Article ID BRAIN ATROPHY; MS; TRIAL; MRI; SEGMENTATION; MECHANISMS; THERAPIES; DISEASE; VOLUME AB Objective A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon -1a (IFN) 30g intramuscularly weekly and glatiramer acetate (GA) 20mg daily is more efficacious than either agent alone in relapsingremitting multiple sclerosis. Methods A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics. Results Combination IFN+GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results. Interpretation Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences. ANN NEUROL 2013;73:327340 C1 [Lublin, Fred D.; Gustafson, Tarah] Icahn Sch Med Mt Sinai, Corinne Goldsmith Dickinson Ctr Multiple Sclerosi, Dept Neurol, New York, NY USA. [Lublin, Fred D.; Gustafson, Tarah] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY USA. [Cofield, Stacey S.; Cutter, Gary R.; Salter, Amber R.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Conwit, Robin] NINDS, NIH, Bethesda, MD 20892 USA. [Narayana, Ponnada A.] Univ Texas Hlth Sci Ctr Houston, Dept Diagnost & Intervent Imaging, Houston, TX USA. [Nelson, Flavia; Wolinsky, Jerry S.] Univ Texas Hlth Sci Ctr Houston, Dept Neurol, Houston, TX USA. RP Lublin, FD (reprint author), 5 East 98th St, New York, NY 10029 USA. EM fred.lublin@mssm.edu FU NIH National Institute of Neurological Disorders and Stroke [UO1NS045719, R21NS41986]; Celgene; Sanofi-Aventis; Acorda; Novartis; EMD Serono; Pfizer; Teva; Teva Neuroscience; National Multiple Sclerosis Society; CMSC; MS Monitor; Biogen Idec; Bayer HealthCare; Mesdcape Radiology, Projects in Knowledge; Clayton Foundation for Research; NIH/NINDS; NIH/NIBIB; Consortium MS Centers; USF; Texas Neurological Society; Teva Pharmaceuticals; Medscape CME; University of Buffalo; Serono Symposia International Foundation; University of Utah; NINDS; Prime FX This study was funded by the NIH National Institute of Neurological Disorders and Stroke (phase III study grant UO1NS045719, planning grant R21NS41986) and is listed on www.clinicaltrials.gov as NCT00211887. Study agents and matched placebo were kindly provided by their manufacturers, Biogen Idec and Teva Pharmaceutical.; F.D.L.: consultancy, Biogen Idec, Teva Neuroscience, Bayer HealthCare, EMD Serono, Novartis, Pfizer, Actelion, Sanofi-Aventis, Acorda, Questcor, Roche, Genentech, Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, MedImmune, Abbott, Bristol-Myers Squibb, Xenoport, Medicinova, Genmab, Morphosys, Avanir, Kyowa Hakko Kirin, Receptos; grants/grants pending, Celgene, Sanofi-Aventis, Acorda, Novartis; speaking fees, EMD Serono, Pfizer, Teva. S.S.C.: consultancy, Teva Neuroscience, American Shoulder and Elbow Society, MedImmune, Manitoba Health Research Council, Centocor Ortho Biotech; paid educational presentations, Teva Neuroscience. G.R.C.: grants/grants pending, National Multiple Sclerosis Society; board membership, Pythagoras; consultancy, Biogen Idec, Teva Neuroscience, Bayer HealthCare, EMD Serono, Novartis, Pfizer, Sanofi-Aventis, Questcor, Celgene, Revalesio, Coronado Bioscience, Genzyme, MedImmune, Abbott, Receptos, Gilead, Neuren, Apotex/Modigenetec, NHLBI, NICHD, Ono/Merck, Merck, Nuron Biotech, Somnus, Spinifex, United Bioscience, Cleveland Clinic, Vivus, GlaxoSmithKlein; speaking fees, CMSC, Novartis, Teva; paid educational presentations, MS Monitor. F.N.: consultancy, Bayer HealthCare, Biogen Idec, MS Society, Genentech, Sanofi-Aventis, Teva Neuroscience, Novartis; grants/grants pending, Novartis; speaking fees, Biogen Idec, Bayer HealthCare; paid educational presentations, Mesdcape Radiology, Projects in Knowledge. J.S.W.: board membership, Novartis Pharmaceuticals, Sanofi-Aventis, Teva Pharmaceuticals, Eli Lilly, BC Decker; consultancy, Genentech, Novartis Pharmaceuticals, Teva Neuroscience, Teva Pharmaceuticals, Acorda, Acetilon, Bayer HealthCare, Celgene, Astellas, Hoffman LaRoche, Janssen R & D; grants/grants pending, Sanofi-Aventis, Clayton Foundation for Research, National Multiple Sclerosis Society, NIH/NINDS, NIH/NIBIB; speaking fees, Consortium MS Centers, USF Health Professionals, Texas Neurological Society, Teva Pharmaceuticals, Medscape CME, University of Buffalo, Serono Symposia International Foundation, University of Utah, Biogen Idec, NINDS, Prime; royalties, Millipore (Chemicon International) Corp. NR 22 TC 74 Z9 75 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2013 VL 73 IS 3 BP 327 EP 340 DI 10.1002/ana.23863 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 131KW UT WOS:000317992900004 PM 23424159 ER PT J AU Liu, DP Zhou, XH AF Liu, Danping Zhou, Xiao-Hua TI Covariate Adjustment in Estimating the Area Under ROC Curve with Partially Missing Gold Standard SO BIOMETRICS LA English DT Article DE Alzheimer's disease; Area under ROC curve; Covariate adjustment; U statistics; Verification bias; Weighted estimating equations ID OPERATING CHARACTERISTIC CURVE; NONIGNORABLE VERIFICATION BIAS; DIAGNOSTIC-TESTS; DISEASE; ACCURACY AB In ROC analysis, covariate adjustment is advocated when the covariates impact the magnitude or accuracy of the test under study. Meanwhile, for many large scale screening tests, the true condition status may be subject to missingness because it is expensive and/or invasive to ascertain the disease status. The complete-case analysis may end up with a biased inference, also known as verification bias. To address the issue of covariate adjustment with verification bias in ROC analysis, we propose several estimators for the area under the covariate-specific and covariate-adjusted ROC curves (AUCx and AAUC). The AUCx is directly modeled in the form of binary regression, and the estimating equations are based on the U statistics. The AAUC is estimated from the weighted average of AUCx over the covariate distribution of the diseased subjects. We employ reweighting and imputation techniques to overcome the verification bias problem. Our proposed estimators are initially derived assuming that the true disease status is missing at random (MAR), and then with some modification, the estimators can be extended to the not missing at random (NMAR) situation. The asymptotic distributions are derived for the proposed estimators. The finite sample performance is evaluated by a series of simulation studies. Our method is applied to a data set in Alzheimer's disease research. C1 [Liu, Danping] Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA. [Zhou, Xiao-Hua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Liu, DP (reprint author), Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA. EM azhou@uw.edu; danping.liu@nih.gov FU NIH/NIA [U01AG016976]; National Institute of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX The authors would like to thank National Alzheimer's Coordinating Center (NACC) for providing the data for analysis. The authors are grateful to the associate editor and two anonymous referees for their insightful comments, which greatly improved the quality of this paper. The work was supported in part by NIH/NIA grant U01AG016976. The research of Dr. Danping Liu is supported in part by the Intramural Research Program of the National Institute of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). This article does not necessarily represent the findings and conclusions of VA HSR&D. Dr. Xiao-Hua Zhou is presently a Core Investigator and Biostatistics Unit Director at HSR&D Center of Excellence, Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA. NR 16 TC 3 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2013 VL 69 IS 1 BP 91 EP 100 DI 10.1111/biom.12001 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 122FM UT WOS:000317303500010 PM 23410529 ER PT J AU Kinsella, K Beard, J Suzman, R AF Kinsella, Kevin Beard, John Suzman, Richard TI Can Populations Age Better, Not Just Live Longer? SO GENERATIONS-JOURNAL OF THE AMERICAN SOCIETY ON AGING LA English DT Article ID LAST YEAR; LIFE; COSTS; DISADVANTAGE; DISABILITY; DISEASE; HEALTH; TRENDS C1 [Kinsella, Kevin] CNR, Comm Populat, Washington, DC 20418 USA. [Beard, John] WHO, Dept Ageing & Life Course, CH-1211 Geneva, Switzerland. [Suzman, Richard] NIA, Div Behav & Social Res, NIH, Washington, DC USA. RP Kinsella, K (reprint author), CNR, Comm Populat, Washington, DC 20418 USA. RI Beard, John/K-9621-2014 OI Beard, John/0000-0002-8557-0242 NR 26 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC AGING PI SAN FRANCISCO PA 833 MARKET ST, STE 511, SAN FRANCISCO, CA 94103-1824 USA SN 0738-7806 J9 GENERATIONS JI Generations-J. Am. Soc. Aging PD SPR PY 2013 VL 37 IS 1 BP 19 EP 26 PG 8 WC Gerontology SC Geriatrics & Gerontology GA 125US UT WOS:000317567500004 ER PT J AU McIver, Z Melenhorst, JJ Wu, C Grim, A Ito, S Cho, I Hensel, N Battiwalla, M Barrett, AJ AF McIver, Zachariah Melenhorst, Jan Joseph Wu, Colin Grim, Andrew Ito, Sawa Cho, Irene Hensel, Nancy Battiwalla, Minoo Barrett, Austin John TI Donor lymphocyte count and thymic activity predict lymphocyte recovery and outcomes after matched-sibling hematopoietic stem cell transplant SO HAEMATOLOGICA LA English DT Article ID REGULATORY T-CELLS; VERSUS-HOST-DISEASE; SUPPRESSIVE FUNCTION; IMMUNE RECONSTITUTION; PERIPHERAL-BLOOD; RISK-FACTORS; BONE-MARROW; RECIPIENTS; ANTIGEN; EXPRESSION AB Delayed immune recovery is a characteristic feature of allogeneic hematopoietic stem cell transplantation in adult recipients. Although recipient thymic T-cell neogenesis contributes to T-cell regeneration after transplantation, thymic recovery in the transplant recipient decreases with increasing age, and is diminished by intensive preconditioning regimens and graft-versus-host disease. In adult recipients, most events that determine transplant success or failure occur during the period when the majority of circulating T cells is derived from the donor's post thymic T-cell repertoire. As a result, the make-up of the donor lymphocyte compartment may strongly influence immune recovery and transplant outcomes. The aim of this study was to examine donor lymphocyte counts in a series of patients undergoing an allogeneic hematopoietic stem cell transplant to identify the potential contribution of donor regulatory and conventional T lymphocyte populations to immune recovery and transplant outcomes. We examined donor lymphocyte subset counts in relation to post-transplant lymphocyte recovery and transplant events in 220 consecutive myeloablative, T-cell-depleted, HLA-identical sibling hematopoietic stem cell transplant recipients with hematologic malignancies. In a multivariate analysis, absolute numbers of donor CD4(+) recent thymic emigrants were associated with overall survival (P=0.032). The donors' absolute lymphocyte count and thymic production of regulatory T cells were both associated with extensive chronic graft-versus-host disease (P=0.002 and P=0.022, respectively). In conclusion, these results identify donor immune characteristics that are associated with lymphocyte recovery, extensive chronic graft-versus-host disease, and survival in the recipient following allogeneic hematopoietic stem cell transplantation. The study reported here was performed using peripheral blood samples drawn from donors and patients enrolled in the ClinicalTrials.gov-registered trials NCT00001623, NCT00001873, NCT00353860, NCT00066300, NCT00079391, and NCT00398346. C1 [McIver, Zachariah; Melenhorst, Jan Joseph; Grim, Andrew; Ito, Sawa; Cho, Irene; Hensel, Nancy; Battiwalla, Minoo; Barrett, Austin John] NHLBI, Allogene Stem Cell Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wu, Colin] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP McIver, Z (reprint author), NHLBI, Allogene Stem Cell Transplantat Sect, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mej@mail.med.upenn.edu NR 37 TC 7 Z9 7 U1 0 U2 10 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2013 VL 98 IS 3 BP 346 EP 352 DI 10.3324/haematol.2012.072991 PG 7 WC Hematology SC Hematology GA 125HJ UT WOS:000317530600005 PM 23065508 ER PT J AU Nekhai, S Xu, M Foster, A Kasvosve, I Diaz, S Machado, RF Castro, OL Kato, GJ Taylor, JG Gordeuk, VR AF Nekhai, Sergei Xu, Min Foster, Altreisha Kasvosve, Ishmael Diaz, Sharmin Machado, Roberto F. Castro, Oswaldo L. Kato, Gregory J. Taylor, James G. Gordeuk, Victor R. TI Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin SO HAEMATOLOGICA LA English DT Article ID SICKLE-CELL-DISEASE; REGULATORY PEPTIDE HEPCIDIN; PRIMARY IRON OVERLOAD; NECROSIS-FACTOR-ALPHA; HUMAN SERUM HEPCIDIN; PULMONARY-HYPERTENSION; AFRICAN-AMERICANS; HEREDITARY HEMOCHROMATOSIS; J774 MACROPHAGES; RISK-FACTOR AB Ferroportin Q248H mutation has an allele frequency of 2.2-13.4% in African populations and is associated with a mild tendency to increased serum ferritin in the general population. Some investigators have reported that ferroportin Q248H is degraded after exposure to hepcidin in exactly the same manner as wild-type ferroportin, but supraphysiological concentrations of hepcidin were used. The aim of our study was to determine whether ferroportin Q248H may have reduced sensitivity to physiological concentrations of hepcidin. The sensitivity of ferroportin Q248H to hepcidin was determined in 293T cells transiently expressing ferroportin using immunoblotting and fluorescence analysis. Ferritin concentrations were measured in these cells and also in human primary monocytes derived from humans with different ferroportin genotypes. The effect of Q248H on serum iron measures was examined in patients with sickle cell anemia. Immunoblotting and fluorescence analysis showed decreased sensitivity of ferroportin Q248H to physiological concentrations of hepcidin. Lower ferritin concentrations were observed after incubation with iron and hepcidin in 293T cells expressing ferroportin Q248H and in primary monocytes from ferroportin Q248H subjects. In sickle cell anemia, ferroportin Q248H heterozygotes had lower serum ferritin concentrations than wild-type subjects, consistent with enhanced iron release by macrophage ferroportin Q248H. A clinical benefit of ferroportin Q248H was suggested by lower echocardiographic estimates of pulmonary artery pressure in patients carrying mutant alleles. In conclusion, our results suggest that ferroportin Q248H protein is resistant to physiological concentrations of hepcidin and that this mutation has discernible effects on iron metabolism-related clinical complications of sickle cell anemia. They provide a mechanistic explanation for the effect of ferroportin Q248H on iron status in individuals of African descent and suggest that these changes in iron metabolism may be beneficial under certain disease-specific circumstances. (ClinicalTrials.gov Identifier:NCT00011648). C1 [Nekhai, Sergei; Xu, Min; Foster, Altreisha; Diaz, Sharmin; Castro, Oswaldo L.; Gordeuk, Victor R.] Howard Univ, Ctr Sickle Cell Dis, Dept Med, Washington, DC 20059 USA. [Kasvosve, Ishmael] Univ Botswana, Dept Med Lab Sci, Gaborone, Botswana. [Machado, Roberto F.; Gordeuk, Victor R.] Univ Illinois, Sickle Cell Ctr, Chicago, IL USA. [Kato, Gregory J.; Taylor, James G.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Nekhai, S (reprint author), Howard Univ, Ctr Sickle Cell Dis, Dept Med, Washington, DC 20059 USA. EM snekhai@howard.edu; vgordeuk@uic.edu RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Taylor, James/0000-0002-4421-1809 FU NIH [1SC1GM082325, R25 HL003679, RCMI-NIH 2G12RR003048, P30HL107253, R01 HL079912, 2MOI RR10284]; District of Columbia Developmental Center for AIDS Research Grant [P30AI087714]; NHLBI Division of Intramural Research [1ZIAHL006012-03] FX This work was supported by NIH Research Grants (1SC1GM082325, R25 HL003679, RCMI-NIH 2G12RR003048, P30HL107253, R01 HL079912, 2MOI RR10284) District of Columbia Developmental Center for AIDS Research Grant (P30AI087714), and by the NHLBI Division of Intramural Research (1ZIAHL006012-03). NR 68 TC 10 Z9 10 U1 0 U2 4 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2013 VL 98 IS 3 BP 455 EP 463 DI 10.3324/haematol.2012.066530 PG 9 WC Hematology SC Hematology GA 125HJ UT WOS:000317530600025 PM 23065513 ER PT J AU Nourale, M Lee, JS Zhang, YZ Kanias, T Zhao, XJ Xiong, ZY Oriss, TB Zeng, QL Kato, GJ Gibbs, JSR Hildesheim, ME Sachdev, V Barst, RJ Machado, RF Hassell, KL Little, JA Schraufnagel, DE Krishnamurti, L Novelli, E Girgis, RE Morris, CR Rosenzweig, EB Badesch, DB Lanzkron, S Castro, OL Goldsmith, JC Gordeuk, VR Gladwin, MT AF Nourale, Mehdi Lee, Janet S. Zhang, Yingze Kanias, Tamir Zhao, Xuejun Xiong, Zeyu Oriss, Timothy B. Zeng, Qilu Kato, Gregory J. Gibbs, J. Simon R. Hildesheim, Mariana E. Sachdev, Vandana Barst, Robyn J. Machado, Roberto F. Hassell, Kathryn L. Little, Jane A. Schraufnagel, Dean E. Krishnamurti, Lakshmanan Novelli, Enrico Girgis, Reda E. Morris, Claudia R. Rosenzweig, Erika Berman Badesch, David B. Lanzkron, Sophie Castro, Oswaldo L. Goldsmith, Jonathan C. Gordeuk, Victor R. Gladwin, Mark T. CA Walk-PHASST Investigators Patients TI The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe SO HAEMATOLOGICA LA English DT Article ID HEMOGLOBIN OXYGEN DESATURATION; NITRIC-OXIDE BIOAVAILABILITY; PULMONARY-HYPERTENSION; PULSE OXIMETRY; MICROPARTICLE ENUMERATION; EXERCISE CAPACITY; CHEST SYNDROME; DISEASE; CHILDREN; ASSOCIATION AB The intensity of hemolytic anemia has been proposed as an independent risk factor for the development of certain clinical complications of sickle cell disease, such as pulmonary hypertension, hypoxemia and cutaneous leg ulceration. A composite variable derived from several individual markers of hemolysis could facilitate studies of the underlying mechanisms of hemolysis. In this study, we assessed the association of hemolysis with outcomes in sickle cell anemia. A hemolytic component was calculated by principal component analysis from reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and total bilirubin concentrations in 415 hemoglobin SS patients. Association of this component with direct markers of hemolysis and clinical outcomes was assessed. As primary validation, both plasma red blood cell microparticles and cell-free hemoglobin concentration were higher in the highest hemolytic component quartile compared to the lowest quartile (P <= 0.0001 for both analyses). The hemolytic component was lower with hydroxyurea therapy, higher hemoglobin F, and alpha-thalassemia (P <= 0.0005); it was higher with higher systemic pulse pressure, lower oxygen saturation, and greater values for tricuspid regurgitation velocity, left ventricular diastolic dimension and left ventricular mass (all P<0.0001). Two-year follow-up analysis showed that a high hemolytic component was associated with an increased risk of death (hazard ratio, HR 3.44; 95% confidence interval, CI: 1.2-9.5; P=0.02). The hemolytic component reflects direct markers of intravascular hemolysis in patients with sickle cell disease and allows for adjusted analysis of associations between hemolytic severity and clinical outcomes. These results confirm associations between hemolytic rate and pulse pressure, oxygen saturation, increases in Doppler-estimated pulmonary systolic pressures and mortality C1 [Nourale, Mehdi; Castro, Oswaldo L.] Howard Univ, Washington, DC 20059 USA. [Lee, Janet S.; Zhang, Yingze; Kanias, Tamir; Xiong, Zeyu; Zeng, Qilu; Novelli, Enrico; Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15260 USA. [Lee, Janet S.; Kanias, Tamir; Oriss, Timothy B.; Hildesheim, Mariana E.; Gladwin, Mark T.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA. [Zhao, Xuejun; Kato, Gregory J.; Sachdev, Vandana] NHLBI, Cardiovasc & Pulm Med Branch, Bethesda, MD 20892 USA. [Gibbs, J. Simon R.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England. [Barst, Robyn J.; Rosenzweig, Erika Berman] Columbia Univ, New York, NY USA. [Machado, Roberto F.; Schraufnagel, Dean E.; Gordeuk, Victor R.] Univ Illinois, Chicago, IL USA. [Hassell, Kathryn L.; Badesch, David B.] Univ Colorado HSC, Denver, CO USA. [Little, Jane A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Girgis, Reda E.; Lanzkron, Sophie] Johns Hopkins Univ, Baltimore, MD USA. [Morris, Claudia R.] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Goldsmith, Jonathan C.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15260 USA. EM gladwinmt@upmc.edu RI Kato, Gregory/I-7615-2014; Kanias, Tamir/K-2384-2016; OI Kato, Gregory/0000-0003-4465-3217; Kanias, Tamir/0000-0001-6558-0913; Schraufnagel, Dean/0000-0003-0063-7223 FU National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [HHSN268200617182C]; NIH CTSA from NHLBI [UL1 RR024131, 2 R25 HL003679-08, 1 R01 HL079912-02]; Howard University GCRC from NCRR, NIH, Bethesda, MD [2MOI RR10284-10]; NIH [R01HL098032, RO1HL096973]; Institute for Transfusion Medicine; Hemophilia Center of Western Pennsylvania; National Institutes of Health; [R01HL086884]; [R01HL086884 03S1] FX This work was supported by funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contract HHSN268200617182C. This work was also supported in part by NIH CTSA grant UL1 RR024131 (to CRM), grant ns. 2 R25 HL003679-08 and 1 R01 HL079912-02 from NHLBI (to VRG), by Howard University GCRC grant n. 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, by R01HL086884 and R01HL086884 03S1 (to JSL), by NIH grants R01HL098032 and RO1HL096973 (to MTG), by the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania and by the intramural research program of the National Institutes of Health. NR 46 TC 45 Z9 46 U1 0 U2 14 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2013 VL 98 IS 3 BP 464 EP 472 DI 10.3324/haematol.2012.068965 PG 9 WC Hematology SC Hematology GA 125HJ UT WOS:000317530600026 PM 22983573 ER PT J AU Yang, WZ Ye, G Meng, AH Sabir, G Qiao, X Guo, DA Ye, M AF Yang, Wen-zhi Ye, Guan Meng, A-hui Sabir, Gulnar Qiao, Xue Guo, De-an Ye, Min TI Rapid characterisation of flavonoids from Sophora alopecuroides L. by HPLC/DAD/ESI-MS (n) SO NATURAL PRODUCT RESEARCH LA English DT Article DE Sophora alopecuroides L; HPLC; DAD; ESI-MS; (n); characterisation; flavonoids ID IONIZATION MASS-SPECTROMETRY; PHENOLIC-COMPOUNDS; AGLYCONES AB An HPLC/DAD/ESI-MS (n) method was established to characterise flavonoids in the seeds of Sophora alopecuroides L. All the flavonoids exhibited abundant [MH] ions, which triggered data-dependent multistage mass spectrometry fragmentations. Characteristic UV spectra were used to confirm flavonoid subtypes. In total, 22 flavonoids and two phenolic compounds were detected and identified. Five of them were identified by comparing with reference standards, and the others were characterised based on the retention behaviour, multistage fragmentation feature and UV absorption. A total of 19 compounds were reported from S. alopecuroides for the first time. This method accomplished rapid profiling of flavonoid constituents in S. alopecuroides L. C1 [Yang, Wen-zhi; Qiao, Xue; Guo, De-an; Ye, Min] Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. [Ye, Guan] NIH, Bethesda, MD 20892 USA. [Meng, A-hui] Beijing Forestry Univ, Coll Biol Sci & Biotechnol, Beijing 100083, Peoples R China. [Sabir, Gulnar] Xinjiang Inst Chinese Mat Med & Eth, Urumqi 830002, Peoples R China. RP Ye, M (reprint author), Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, 38 Xueyuan Rd, Beijing 100191, Peoples R China. EM yemin@bjmu.edu.cn FU Peking University Health Science Center [985-2-119-121] FX This study was supported by the 985 Project of Peking University Health Science Center (No. 985-2-119-121). NR 11 TC 2 Z9 2 U1 3 U2 25 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1478-6419 J9 NAT PROD RES JI Nat. Prod. Res. PD MAR 1 PY 2013 VL 27 IS 4-5 BP 323 EP 330 DI 10.1080/14786419.2012.688052 PG 8 WC Chemistry, Applied; Chemistry, Medicinal SC Chemistry; Pharmacology & Pharmacy GA 101SB UT WOS:000315793600006 PM 22625220 ER PT J AU Shariff-Marco, S Breen, N Stinchcomb, DG Klabunde, CN AF Shariff-Marco, Salma Breen, Nancy Stinchcomb, David G. Klabunde, Carrie N. TI Multilevel Predictors of Colorectal Cancer Screening Use in California SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID CARE HEALTH PLAN; BRIEF CONCEPTUAL TUTORIAL; MANAGED CARE; UNITED-STATES; LOGISTIC-REGRESSION; SOCIAL EPIDEMIOLOGY; SOCIOECONOMIC-STATUS; CONTEXTUAL PHENOMENA; INTERVIEW SURVEY; POVERTY RATE AB Background: Screening can detect colorectal cancer (CRC) early, yet its uptake needs to be improved. Social determinants of health (SDOH) may be linked to CRC screening use but are not well understood. Objectives: To examine geographic variation in CRC screening and the extent to which multilevel SDOH explain its use in California, the most populous and racially/ethnically diverse state in the United States. Study Design: Analysis of individual and neighborhood data on 20,626 adult respondents aged years from the 2005 California Health Interview Survey. Methods: We used multilevel logistic regression models to estimate the effects of individual characteristics and area-level segregation, socioeconomic status (SES), and healthcare resources at 2 different geographic levels on CRC screening use. Results: We confirmed that individual-level factors (eg, race/ethnicity, income, insurance) were strong predictors and found that area-level healthcare resources were associated with CRC screening. Primary care shortage in the Medical Service Study Area was associated with CRC screening for any modality (odds ratio [OR] = 0.89; 95% confidence interval [Cl], 0.80-1.00). County-level HMO penetration (OR = 1.85; 95% Cl, 1.47-2.33) and primary care shortage (OR = 0.73; 95% CI, 0.53-0.99) were associated with CRC screening with flexible sigmoidoscopy. Conclusions: Contextual factors including locality, primary care resources, and HMO membership are important determinants of CRC screening uptake; SES and segregation did not explain variation in screening behavior. More studies of contextual factors and varying geographic scales are needed to further elucidate their impact on CRC screening uptake. Am J Manag Care. 2013;19(3):205-216 C1 [Shariff-Marco, Salma] Canc Prevent Inst Calif, Fremont, CA USA. [Breen, Nancy; Klabunde, Carrie N.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Stinchcomb, David G.] Westat Corp, Rockville, MD USA. RP Shariff-Marco, S (reprint author), Canc Prevent Inst Calif, 2201 Walnut Ave,Ste 300, Fremont, CA 94538 USA. EM salma.shariff-marco@cpic.org FU Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute FX We would like to acknowledge the Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute for providing financial support for Salma Shariff-Marco in her postdoctoral fellowship. We would also like to acknowledge Tim McNeel, William Waldron, and Jeremy Lyman at Information Management Services, Inc, for their support in merging our data sets, developing programs for the descriptive analysis, and generating the maps for the Figure; and Penny Randall-Levy of the Scientific Consulting. Group, Inc, for her help with the references. Finally, we would like to acknowledge Drs Martin L. Brown and Rachel Ballard-Barbash for their thoughtful reviews. NR 66 TC 9 Z9 9 U1 3 U2 4 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD MAR PY 2013 VL 19 IS 3 BP 205 EP 216 PG 12 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 123GI UT WOS:000317376000004 PM 23544762 ER PT J AU Weyemi, U Redon, CE Parekh, PR Dupuy, C Bonner, WM AF Weyemi, Urbain Redon, Christophe E. Parekh, Palak R. Dupuy, Corinne Bonner, William M. TI NADPH Oxidases NOXs and DUOXs as Putative Targets for Cancer Therapy SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE NADPH oxidases; ROS; Cancer; Cancer therapy; Tumors; NOXs inhibitors ID SMOOTH-MUSCLE-CELLS; OXYGEN SPECIES PRODUCTION; ENDOTHELIAL GROWTH-FACTOR; COLON EPITHELIAL-CELLS; REACTIVE OXYGEN; NAD(P)H OXIDASE; ESOPHAGEAL ADENOCARCINOMA; DIPHENYLENE IODONIUM; PROSTATE-CANCER; MELANOMA-CELLS AB Reactive oxygen species (ROS) form a class of molecules with both positive and negative impacts on cellular health. Negatively, ROS may react with cellular constituents including proteins, lipids, and DNA to generate an array of oxidative lesions. These lesions may compromise genome stability which is critical for long-term cellular homeostasis and healthy progeny. Paradoxically, ROS also function as strong signalling molecules that mediate various growth-related responses, so their presence is also essential for cellular metabolism. While ROS are generated in an unregulated manner by physical stresses such as exposure to ionizing radiation and biochemical malfunctions such as mitochondrial leakage, cells also contain the NADPH oxidases NOXs and DUOXs, which specifically generate ROS in a wide variety of tissues. While the NOXs/DUOXs may be involved in maintaining optimal cellular redox levels, there is also accumulating evidence that NADPH oxidases-derived ROS may elevate the risk for genomic instability and cancer. Cancer cells may produce high levels of ROS, and in some cases, the source of these ROS has been linked to NOX/DUOX deregulation as reported for prostate cancer (NOX1 and NOX5), melanoma and glioblastoma (NOX4) among others. In addition, recent studies reveal that targeting NADPH oxidases with NOXs inhibitors may impair tumor growth in vivo; indicating that these proteins may be useful targets in future clinical strategies to fight cancer. This review provides an overview of the current knowledge concerning these enzymes, their roles in cancer, and their potential as targets in future cancer therapies. C1 [Weyemi, Urbain; Redon, Christophe E.; Parekh, Palak R.; Bonner, William M.] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Dupuy, Corinne] Univ Paris 11, Inst Gustave Roussy, CNRS, UMR 8200, F-94805 Villejuif, France. RP Weyemi, U (reprint author), NCI, Bldg 37,Room 5050,9000 Rockville Pike, Bethesda, MD 20892 USA. EM urbain.weyemi@nih.gov RI Parekh, Palak/B-7042-2015; Weyemi, Urbain/E-2083-2016 OI Parekh, Palak/0000-0001-9201-5194; FU NIAID Radiation/Nuclear Countermeasures Program; National Cancer Institute, Center for Cancer Research, NIH FX We thank Dr. Thomas L. Leto (National Institutes of Health, NIH) for the critical reading of the manuscript. This research was supported by the NIAID Radiation/Nuclear Countermeasures Program and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH. NR 108 TC 22 Z9 24 U1 2 U2 21 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD MAR PY 2013 VL 13 IS 3 BP 502 EP 514 PG 13 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 129OB UT WOS:000317849500013 PM 22931418 ER PT J AU Garcia-Crespo, KE Chan, CC Gabryszewski, SJ Percopo, CM Rigaux, P Dyer, KD Domachowske, JB Rosenberg, HF AF Garcia-Crespo, Katia E. Chan, Calvin C. Gabryszewski, Stanislaw J. Percopo, Caroline M. Rigaux, Peter Dyer, Kimberly D. Domachowske, Joseph B. Rosenberg, Helene F. TI Lactobacillus priming of the respiratory tract: Heterologous immunity and protection against lethal pneumovirus infection SO ANTIVIRAL RESEARCH LA English DT Article DE Cytokines; Neutrophils; Peptidoglycan; Genomic DNA; Heterologous immunity ID INFLUENZA-VIRUS INFECTION; NONTYPABLE HAEMOPHILUS-INFLUENZAE; SYNCYTIAL VIRUS; BACTERIAL PNEUMONIA; MONOCLONAL-ANTIBODY; VIRAL-INFECTIONS; MICE; INNATE; NOD2; PEPTIDOGLYCAN AB We showed previously that wild-type mice primed via intranasal inoculation with live or heat-inactivated Lactobacillus species were fully (100%) protected against the lethal sequelae of infection with the virulent pathogen, pneumonia virus of mice (PVM), a response that is associated with diminished expression of proinflammatory cytokines and diminished virus recovery. We show here that 40% of the mice primed with live Lactobacillus survived when PVM challenge was delayed for 5 months. This robust and sustained resistance to PVM infection resulting from prior interaction with an otherwise unrelated microbe is a profound example of heterologous immunity. We undertook the present study in order to understand the nature and unique features of this response. We found that intranasal inoculation with L. reuteri elicited rapid, transient neutrophil recruitment in association with proinflammatory mediators (CXCL1, CCL3, CCL2, CXCL10, TNF-alpha and IL-17A) but not Th1 cytokines. IFN gamma does not contribute to survival promoted by Lactobacillus-priming. Live L reuteri detected in lung tissue underwent rapid clearance, and was undetectable at 24 h after inoculation. In contrast, L reuteri peptidoglycan (PGN) and L. reuteri genomic DNA (gDNA) were detected at 24 and 48 h after inoculation, respectively. In contrast to live bacteria, intranasal inoculation with isolated L. reuteri gDNA elicited no neutrophil recruitment, had minimal impact on virus recovery and virus-associated production of CCL3, and provided no protection against the negative sequelae of virus infection. Isolated PGN elicited neutrophil recruitment and proinflammatory cytokines but did not promote sustained survival in response to subsequent PVM infection. Overall, further evaluation of the responses leading to. Lactobacillus-mediated heterologous immunity may provide insight into novel antiviral preventive modalities. Published by Elsevier B.V. C1 [Garcia-Crespo, Katia E.; Chan, Calvin C.; Gabryszewski, Stanislaw J.; Percopo, Caroline M.; Rigaux, Peter; Dyer, Kimberly D.; Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Domachowske, Joseph B.] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. RP Rosenberg, HF (reprint author), NIAID, Inflammat Immunobiol Sect, Lab Allerg Dis, NIH, Bldg 10,Room 11C215,MSC 1883, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU NIAID Division of Intramural Research (DIR) [AI000943]; Children's Miracle Network of New York FX The authors are grateful for the assistance of Dr. Alfonso Gonzalo and the staff of National Institute of Allergy and Infectious Diseases 14BS animal facility for care of mice used in these studies, Mr. Ricardo Dreyfuss of Medical Arts who prepared the photomicrographs for publication, and Dr. Stephanie Glineur for performing the studies to detect serum antibodies to PVM. HFR would also like to thank Dr. Peter J. Openshaw who brought the concept of innate imprinting to our attention. This work is funded by NIAID Division of Intramural Research (DIR) AI000943 to HFR and Children's Miracle Network of New York to JBD. NR 55 TC 16 Z9 16 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAR PY 2013 VL 97 IS 3 BP 270 EP 279 DI 10.1016/j.antiviral.2012.12.022 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 127OX UT WOS:000317709400008 PM 23274789 ER PT J AU Lu, J Bian, ZY Zhang, R Zhang, Y Liu, C Yan, L Zhang, SM Jiang, DS Wei, X Zhu, XH Chen, MY Wang, AB Chen, YJ Yang, QL Liu, PP Li, HL AF Lu, Jing Bian, Zhou-Yan Zhang, Ran Zhang, Yan Liu, Chen Yan, Ling Zhang, Shu-Min Jiang, Ding-Sheng Wei, Xiang Zhu, Xue Hai Chen, Manyin Wang, Ai-Bing Chen, Yingjie Yang, Qinglin Liu, Peter P. Li, Hongliang TI Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy SO BASIC RESEARCH IN CARDIOLOGY LA English DT Article DE IRF3; Hypertrophy; Remodeling; Signal transduction; ERK1/2 ID TRANSCRIPTION FACTORS; HEART-FAILURE; SIGNALING PATHWAYS; CALCINEURIN-NFAT; PROTEIN-KINASE; IN-VIVO; ACTIVATION; EXPRESSION; GROWTH; CELLS AB Interferon regulatory factor (IRF) 3, a member of the highly conserved IRF family transcription factors, plays a pivotal role in innate immune response, apoptosis, and oncogenesis. Recent studies have implicated IRF3 in a wide range of host defense. However, whether IRF3 induces defensive responses to hypertrophic stresses such as biomechanical stress and neurohumoral factors remains unclear. Herein, we employed an IRF3-deficient mouse model, cardiac-specific IRF3-overexpression mouse model and isolated cardiomyocytes to investigate the role of IRF3 in cardiac hypertrophy induced by aortic banding (AB) or isoproterenol (ISO). The extent of cardiac hypertrophy was quantitated by echocardiography as well as by pathological and molecular analysis. Our results demonstrate that IRF3 deficiency profoundly exacerbated cardiac hypertrophy, whereas overexpression of IRF3 in the heart significantly blunted pathological cardiac remodeling induced by pressure overload. Similar results were also observed in cultured cardiomyocytes upon the treatment with ISO. Mechanistically, we discovered that IRF3 interacted with ERK2 and thereby inhibited the ERK1/2 signaling. Furthermore, inactivation of ERK1/2 by U0126 offset the IRF3-deficient-mediated hypertrophic response induced by aortic banding. Altogether, these data demonstrate that IRF3 plays a protective role in AB-induced hypertrophic response by inactivating ERK1/2 in the heart. Therefore, IRF3 could be a new target for the prevention and therapy of cardiac hypertrophy and failure. C1 [Lu, Jing; Bian, Zhou-Yan; Zhang, Yan; Yan, Ling; Zhang, Shu-Min; Jiang, Ding-Sheng; Li, Hongliang] Wuhan Univ, Cardiovasc Res Inst, Renmin Hosp, Dept Cardiol, Wuhan 430060, Peoples R China. [Zhang, Ran] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100005, Peoples R China. [Zhang, Ran] Peking Union Med Coll, Beijing 100005, Peoples R China. [Liu, Chen] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Cardiol, Guangzhou 510275, Guangdong, Peoples R China. [Wei, Xiang; Zhu, Xue Hai] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Thorac & Cardiovasc Surg, Wuhan 430030, Peoples R China. [Chen, Manyin; Liu, Peter P.] Univ Toronto, Richard Lewar Ctr Excellence, Div Cardiol Heart & Stroke, Toronto, ON, Canada. [Wang, Ai-Bing] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Chen, Yingjie] Univ Minnesota, Div Cardiovasc, Minneapolis, MN 55455 USA. [Yang, Qinglin] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. RP Li, HL (reprint author), Wuhan Univ, Cardiovasc Res Inst, Renmin Hosp, Dept Cardiol, Jiefang Rd 238, Wuhan 430060, Peoples R China. EM lihl@whu.edu.cn FU Funds for Distinguished Young Scientists of Hubei [2010CDA092]; National Natural Science Foundation of China [30900524, 81170086, 3087451, 30801351]; National Science and Technology Support Project [2011BAI15B02, 2012BAI39B05]; National Basic Research Program of China [2011CB503902] FX We thank Dr. Tadatsugu Taniguchi for providing IRF3-knockout mice and Dr. Kensuke Tsushima for discussion by Email. This study was supported Funds for Distinguished Young Scientists of Hubei (2010CDA092) and by the National Natural Science Foundation of China (Grants 30900524 and 81170086, 3087451 and 30801351), and National Science and Technology Support Project (NO. 2011BAI15B02 and No. 2012BAI39B05), National Basic Research Program of China (No. 2011CB503902). NR 53 TC 44 Z9 45 U1 0 U2 21 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0300-8428 J9 BASIC RES CARDIOL JI Basic Res. Cardiol. PD MAR PY 2013 VL 108 IS 2 AR 326 DI 10.1007/s00395-012-0326-9 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 121JK UT WOS:000317239300002 PM 23307144 ER PT J AU Mamounas, EP Tang, G Paik, S Baehner, FL Jeong, J Sing, A Butler, SM Sing, AP Shak, S Wolmark, N AF Mamounas, E. P. Tang, G. Paik, S. Baehner, F. L. Jeong, J. Sing, A. Butler, S. M. Sing, A. P. Shak, S. Wolmark, N. TI RECURRENCE SCORE FOR PROGNOSIS AND PREDICTION OF PACLITAXEL BENEFIT IN NODE(+)/ER(+) BREAST CANCER SO BREAST LA English DT Meeting Abstract C1 [Mamounas, E. P.; Jeong, J.; Wolmark, N.] NSABP Operat & Biostat Ctr, Pittsburgh, PA USA. [Tang, G.; Paik, S.] NSABP, Pittsburgh, PA USA. [Baehner, F. L.] Genom Hlth Inc, Pathol, Redwood City, CA USA. [Sing, A.; Sing, A. P.; Shak, S.] Genom Hlth Inc, Pathol, Biostat, Med Affairs, Redwood City, CA USA. [Butler, S. M.] Genom Hlth Inc, Pathol, Biostat, Redwood City, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD MAR PY 2013 VL 22 SU 1 BP S89 EP S90 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 126PZ UT WOS:000317634800234 ER PT J AU Estey, MP Diamandis, EP Eisenhofer, G Pacak, K Maher, ER Young, WF de Krijger, RR AF Estey, Mathew P. Diamandis, Eleftherios P. Eisenhofer, Graeme Pacak, Karel Maher, Eamonn R. Young, William F. de Krijger, Ronald R. TI Pheochromocytoma SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Estey, Mathew P.; Diamandis, Eleftherios P.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Diamandis, Eleftherios P.] Univ Hlth Network, Dept Clin Biochem, Toronto, ON, Canada. [Diamandis, Eleftherios P.] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5T 3L9, Canada. [Eisenhofer, Graeme] Tech Univ Dresden, Inst Clin Chem & Lab Med, D-01062 Dresden, Germany. [Eisenhofer, Graeme] Tech Univ Dresden, Dept Med, Univ Hosp, D-01062 Dresden, Germany. [Pacak, Karel] Eunice Kennedy Shriver NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Maher, Eamonn R.] Univ Birmingham, Sch Med, Ctr Rare Dis & Personalised Med, Inst Biomed Res West, Birmingham, W Midlands, England. [Young, William F.] Mayo Clin, Div Endocrinol, Rochester, MN USA. [de Krijger, Ronald R.] Erasmus MC Univ, Med Ctr Rotterdam, Dept Pathol, Josephine Nefkens Inst, Rotterdam, Netherlands. RP Diamandis, EP (reprint author), Mt Sinai Hosp, Joseph & Wolf Lebov Ctr, 60 Murray St Box 32,Flr 6,Rm L6-201, Toronto, ON M5T 3L9, Canada. EM ediamandis@mtsinai.on.ca RI MAHER, EAMONN/A-9507-2008; OI MAHER, EAMONN/0000-0002-6226-6918; Diamandis, Eleftherios/0000-0002-1589-820X FU Intramural NIH HHS [ZIA HD008735-11, ZIA HD008735-13] NR 0 TC 8 Z9 8 U1 0 U2 4 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD MAR PY 2013 VL 59 IS 3 BP 466 EP 472 DI 10.1373/clinchem.2012.182246 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 122SE UT WOS:000317337600004 PM 23209036 ER PT J AU Hartman, RL Huestis, MA AF Hartman, Rebecca L. Huestis, Marilyn A. TI Cannabis Effects on Driving Skills SO CLINICAL CHEMISTRY LA English DT Review CT Society-of-Forensic-Toxicologists Conference CY 2012 CL Boston, MA SP Soc Forens Toxicologists ID VEHICLE COLLISION RISK; ORAL FLUID; BLOOD CANNABINOIDS; TRAFFIC INJURIES; MOTOR CONTROL; MARIJUANA USE; ALCOHOL; PERFORMANCE; DRIVERS; THC AB BACKGROUND: Cannabis is the most prevalent illicit drug identified in impaired drivers. The effects of cannabis on driving continue to be debated, making prosecution and legislation difficult. Historically, delays in sample collection, evaluating the inactive Delta(9)-tetrahydrocannabinol (THC) metabolite 11-nor-9-carboxy-THC, and polydrug use have complicated epidemiologic evaluations of driver impairment after cannabis use. CONTENT: We review and evaluate the current literature on cannabis' effects on driving, highlighting the epidemiologic and experimental data. Epidemiologic data show that the risk of involvement in a motor vehicle accident (MVA) increases approximately 2-fold after cannabis smoking. The adjusted risk of driver culpability also increases substantially, particularly with increased blood THC concentrations. Studies that have used urine as the biological matrix have not shown an association between cannabis and crash risk. Experimental data show that drivers attempt to compensate by driving more slowly after smoking cannabis, but control deteriorates with increasing task complexity. Cannabis smoking increases lane weaving and impaired cognitive function. Critical-tracking tests, reaction times, divided-attention tasks, and lane-position variability all show cannabis-induced impairment. Despite purported tolerance in frequent smokers, complex tasks still show impairment. Combining cannabis with alcohol enhances impairment, especially lane weaving. SUMMARY: Differences in study designs frequently account for inconsistencies in results between studies. Participant-selection bias and confounding factors attenuate ostensible cannabis effects, but the association with MVA often retains significance. Evidence suggests recent smoking and/or blood THC concentrations 2-5 ng/mL are associated with substantial driving impairment, particularly in occasional smokers. Future cannabis-and-driving research should emphasize challenging tasks, such as divided attention, and include occasional and chronic daily cannabis smokers. (C) 2012 American Association for Clinical Chemistry C1 [Hartman, Rebecca L.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Hartman, Rebecca L.] Univ Maryland, Toxicol Program, Grad Program Life Sci, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Rm 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [ZIA DA000413-12] NR 74 TC 90 Z9 91 U1 6 U2 70 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD MAR PY 2013 VL 59 IS 3 BP 478 EP 492 DI 10.1373/clinchem.2012.194381 PG 15 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 122SE UT WOS:000317337600008 PM 23220273 ER PT J AU Bergamaschi, MM Karschner, EL Goodwin, RS Scheidweiler, KB Hirvonen, J Queiroz, RHC Huestis, MA AF Bergamaschi, Mateus M. Karschner, Erin L. Goodwin, Robert S. Scheidweiler, Karl B. Hirvonen, Jussi Queiroz, Regina H. C. Huestis, Marilyn A. TI Impact of Prolonged Cannabinoid Excretion in Chronic Daily Cannabis Smokers' Blood on Per Se Drugged Driving Laws SO CLINICAL CHEMISTRY LA English DT Article ID MARIJUANA USE; NEUROPSYCHOLOGICAL PERFORMANCE; GAS-CHROMATOGRAPHY; MASS-SPECTROMETRY; USERS; HEAVY; THC; DELTA-1-TETRAHYDROCANNABINOL; PLASMA; BRAIN AB BACKGROUND: Cannabis is the illicit drug most frequently reported with impaired driving and motor vehicle accidents. Some "per se" laws make it illegal to drive with any amount of drug in the body, while others establish blood, saliva, or urine concentrations above which it is illegal to drive. The persistence of Delta(9)-tetrahydrocannabinol (THC) in chronic daily cannabis smokers' blood is unknown. METHODS: Thirty male chronic daily cannabis smokers resided on a secure research unit for up to 33 days, with daily blood collection. Samples were processed in an ice bath during sample preparation to minimize cannabinoid adsorption onto precipitant material. We quantified THC by 2-dimensional GC-MS. RESULTS: Of the 30 participants, 27 were THC-positive on admission, with a median (range) concentration of 1.4 mu g/L (0.3-6.3). THC decreased gradually; only 1 of 11 participants was negative at 26 days, 2 of 5 remained THC-positive (0.3 mu g/L) for 30 days, and 5.0% of participants had THC >= 1.0 mu g/L for 12 days. Median 11-hydroxy-THC concentrations were 1.1 mu g/L on admission, with no results >= 1.0 mu g/L 24 h later. 11-Nor-9-carboxy-THC (THCCOOH) detection rates were 96.7% on admission, decreasing slowly to 95.7% and 85.7% on days 8 and 22, respectively; 4 of 5 participants remained THCCOOH positive (0.6-2.7 mu g/L) after 30 days, and 1 remained positive on discharge at 33 days. CONCLUSIONS: Cannabinoids can be detected in blood of chronic daily cannabis smokers during a month of sustained abstinence. This is consistent with the time course of persisting neurocognitive impairment reported in recent studies. (C) 2012 American Association for Clinical Chemistry C1 [Bergamaschi, Mateus M.; Karschner, Erin L.; Goodwin, Robert S.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Bergamaschi, Mateus M.; Queiroz, Regina H. C.] Univ Sao Paulo, Sch Pharmaceut Sci, BR-14049 Ribeirao Preto, Brazil. [Hirvonen, Jussi] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, 251 Bayview Blvd,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU CAPES (Brazilian Federal Agency for the Support and Evaluation of Graduate Education); Intramural Research Program, National Institute on Drug Abuse and National Institute of Mental Health, NIH FX M.M. Bergamaschi, CAPES (Brazilian Federal Agency for the Support and Evaluation of Graduate Education); M.A. Huestis, Intramural Research Program, National Institute on Drug Abuse and National Institute of Mental Health, NIH. NR 42 TC 45 Z9 45 U1 3 U2 36 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD MAR PY 2013 VL 59 IS 3 BP 519 EP 526 DI 10.1373/clinchem.2012.195503 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 122SE UT WOS:000317337600012 PM 23449702 ER PT J AU Weymar, M Bradley, MM Hamm, AO Lang, PJ AF Weymar, Mathias Bradley, Margaret M. Hamm, Alfons O. Lang, Peter J. TI When fear forms memories: Threat of shock and brain potentials during encoding and recognition SO CORTEX LA English DT Article DE Emotion; Memory; Stress; Threat; ERPs ID EVENT-RELATED POTENTIALS; ANXIETY DISORDERS; ANTICIPATORY ANXIETY; STRESS; STARTLE; INFORMATION; HUMANS; EMOTION; AROUSAL; REFLEX AB The anticipation of highly aversive events is associated with measurable defensive activation, and both animal and human research suggests that stress-inducing contexts can facilitate memory. Here, we investigated whether encoding stimuli in the context of anticipating an aversive shock affects recognition memory. Event-related potentials (ERPs) were measured during a recognition test for words that were encoded in a font color that signaled threat or safety. At encoding, cues signaling threat of shock, compared to safety, prompted enhanced P2 and P3 components. Correct recognition of words encoded in the context of threat, compared to safety, was associated with an enhanced old-new ERP difference (500-700 msec; centro-parietal), and this difference was most reliable for emotional words. Moreover, larger old new ERP differences when recognizing emotional words encoded in a threatening context were associated with better recognition, compared to words encoded in safety. Taken together; the data indicate enhanced memory for stimuli encoded in a context in which an aversive event is merely anticipated, which could assist in understanding effects of anxiety and stress on memory processes. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Weymar, Mathias; Bradley, Margaret M.; Lang, Peter J.] Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL 32611 USA. [Hamm, Alfons O.] Ernst Moritz Arndt Univ Greifswald, Dept Biol & Clin Psychol, Greifswald, Germany. RP Weymar, M (reprint author), Univ Florida, NIMH Ctr Study Emot & Attent, POB 112766, Gainesville, FL 32611 USA. EM mweymar@ufl.edu; bradley@ufl.edu; hamm@uni-greifswald.de; langp@phhp.ufl.edu FU NIMH [P50-MH072850, MH082702]; German Research Society (Deutsche Forschungsgemeinschaft, DFG) [WE 4801/1-1] FX This research was supported in part by NIMH grants P50-MH072850 and MH082702 to Peter Lang and Margaret Bradley at the University of Florida Center for the Study of Emotion and Attention and by a post-doctoral stipend from the German Research Society (Deutsche Forschungsgemeinschaft, DFG) to Mathias Weymar (Forschungsstipendium, WE 4801/1-1). NR 47 TC 15 Z9 17 U1 5 U2 25 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD MAR PY 2013 VL 49 IS 3 BP 819 EP 826 DI 10.1016/j.cortex.2012.02.012 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 122MT UT WOS:000317322900020 PM 22483973 ER PT J AU Pecina, M Mickey, BJ Love, T Wang, H Langenecker, SA Hodgkinson, C Shen, PH Villafuerte, S Hsu, D Weisenbach, SL Stohler, CS Goldman, D Zubieta, JK AF Pecina, Marta Mickey, Brian J. Love, Tiffany Wang, Heng Langenecker, Scott A. Hodgkinson, Colin Shen, Pei-Hong Villafuerte, Sandra Hsu, David Weisenbach, Sara L. Stohler, Christian S. Goldman, David Zubieta, Jon-Kar TI DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience SO CORTEX LA English DT Article DE Imaging; Dopamine; DLPFC; Reward; Emotion ID DORSOLATERAL PREFRONTAL CORTEX; TREATMENT-RESISTANT DEPRESSION; DEEP BRAIN-STIMULATION; VENTRAL TEGMENTAL AREA; RECEPTOR GENE; MAJOR DEPRESSION; MOOD DISORDERS; SCHIZOPHRENIA; FMRI; ACTIVATION AB Dopamine (DA) neurotransmission through D2 receptors (DRD2) has been implicated in the regulation of reward processing, cognition and the effects of drugs of abuse, and also has significant effects in responses to stressors and salient aversive stimuli. An examination of the influence of genetic variation across multiple psychophysical measures therefore appears critical to understand the neurobiology of DA-modulated complex personality traits and psychiatric illnesses. To examine inter-individual variation in the function of DRD2 modulated mechanisms in healthy humans, we used a haplotype-based and single nucleotide polymorphism (SNP) investigation. Their effects were interrogated with functional magnetic resonance imaging during reward and emotional processing. We found that a haplotype block composed by two SNPs, rs4274224 and rs4581480, affected the hemodynamic responses of the dorsolateral prefrontal cortex (DLPFC) during reward expectation and the subgenual anterior cingulate cortices (sgACC) during implicit emotional processing. Exploratory analysis within the significant haplotype block revealed the same functional effects only for the SNP rs4274224. Further analysis on rs4274224 using functional connectivity and positron emission tomography (PET) measures of DA D-2/3 receptor mediated neurotransmission confirmed a gene effect on the functional connectivity of the DLPFC during reward anticipation and subcortical stress induced DA release. At a phenotypic trait level, significant effects of genotype were obtained for the NEO PI-R "Openness to Experience" and further correlated with neuroimaging data. Overall, these results show significant neurobiological effects of genotype variation in DRD2 on multiple functional domains, such as emotional, stress and reward processing. As such, it contributes to normal variation and potentially to vulnerability to psychopathology associated with those functions, such as risk for mood and substance use disorders. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Pecina, Marta; Wang, Heng; Villafuerte, Sandra; Zubieta, Jon-Kar] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Hodgkinson, Colin; Shen, Pei-Hong; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Mickey, Brian J.; Love, Tiffany; Langenecker, Scott A.; Villafuerte, Sandra; Hsu, David; Weisenbach, Sara L.; Zubieta, Jon-Kar] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Zubieta, Jon-Kar] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Stohler, Christian S.] Univ Maryland, Sch Dent, College Pk, MD 20742 USA. RP Zubieta, JK (reprint author), Univ Michigan, 205 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM zubieta@umich.edu RI Mickey, Brian/J-1756-2014; Hsu, David/J-5814-2014; Goldman, David/F-9772-2010; Weisenbach, Sara/M-2384-2016; OI Mickey, Brian/0000-0002-7847-7680; Goldman, David/0000-0002-1724-5405; Weisenbach, Sara/0000-0002-5330-4038; Love, Tiffany/0000-0001-9299-3190 FU Phil F. Jenkins Foundation; Alicia Koplowitz Foundation; [R01 DA 016423]; [R01 DA 022520]; [K01 MH 074459]; [K01 MH 085035] FX Work was supported by R01 DA 016423, R01 DA 022520 (JKZ), a career development award, K01 MH 074459 (SAL), K01 MH 085035 (DTH), the Phil F. Jenkins Foundation and the Alicia Koplowitz Foundation. We would also like to acknowledge the contribution of the technologists of the functional MRI laboratory and the PET Center at the University of Michigan. NR 99 TC 25 Z9 27 U1 2 U2 23 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD MAR PY 2013 VL 49 IS 3 BP 877 EP 890 DI 10.1016/j.cortex.2012.01.010 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 122MT UT WOS:000317322900025 PM 22424959 ER PT J AU Ma, C Wang, Y Zhang, G Chen, Z Qiu, Y Li, J Luo, J Huang, B Jiang, C Huang, G Wan, X Korteweg, C Gu, J AF Ma, C. Wang, Y. Zhang, G. Chen, Z. Qiu, Y. Li, J. Luo, J. Huang, B. Jiang, C. Huang, G. Wan, X. Korteweg, C. Gu, J. TI Immunoglobulin G Expression and its Potential Role in Primary and Metastatic Breast Cancers SO CURRENT MOLECULAR MEDICINE LA English DT Article DE Breast cancer; complement; immune escape; immunoglobulin G; metastasis ID CELL-LINES; GENE TRANSCRIPTS; CA215; ACTIVATION; COMPLEXES; BIOMARKER; SURVIVAL; RECEPTOR; GROWTH; LUNGS AB Recently immunoglobulin G (IgG) was found to be produced by neoplasms and promote tumor growth in cancer cell lines and animal models. To investigate the pathophysiological significance of cancer-produced IgG in breast cancer, we examined the expressions of IgG in 68 breast cancers including 40 primary cancers without metastasis and 28 cancers with axillary lymph node metastases. IgG gene expression was detected in all these samples. We found that IgG-expressing cancer cells were predominantly located in the periphery of the primary cancer nest and that these cells showed more cellular atypia and nuclear pleomorphism. We also found that the abundance of IgG-expressing cancer cells was higher and the cells were more evenly distributed in the metastatic cancer cells than that in the primary lesion. These findings suggest that IgG-expressing breast cancer cells have a more aggressive biological behavior than the IgG negative cancer cells and it could be an indicator for progression and metastasis of the disease. Co-localization of IgG and C1q complement was detected in both primary and metastatic lesions implying that immune complexes might be formed in situ. We speculate that such immune complexes might facilitate immune escape of cancer cells. Our findings suggest that locally produced IgG plays important roles in breast cancer, and may serve as a potential therapeutic target. C1 [Ma, C.; Wang, Y.; Chen, Z.; Qiu, Y.; Li, J.; Luo, J.; Huang, B.; Jiang, C.; Huang, G.; Wan, X.; Korteweg, C.; Gu, J.] Shantou Univ, Coll Med, Guangdong Prov Key Lab Infect Dis & Mol Immunopat, Dept Pathol & Pathophysiol, Shantou 515041, Guangdong, Peoples R China. [Ma, C.] Shantou Univ, Coll Med, Canc Hosp, Dept Radiat Oncol, Shantou 515041, Guangdong, Peoples R China. [Wang, Y.] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Zhang, G.] Shantou Univ, Coll Med, Breast Ctr, Canc Hosp, Shantou 515041, Guangdong, Peoples R China. [Gu, J.] Beijing Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100871, Peoples R China. RP Gu, J (reprint author), Shantou Univ, Coll Med, Guangdong Prov Key Lab Infect Dis & Mol Immunopat, 22 Xinling Rd, Shantou 515041, Guangdong, Peoples R China. EM jguemailbox@gmail.com RI Chen, Zhengshan/J-7499-2014; Zhang, Guo-Jun/H-3890-2015 OI Zhang, Guo-Jun/0000-0001-5182-5887 FU National Nature Science Foundation of China [81030033, 30971150, 81001199, 30950110335]; Natural Science Foundation of Guangdong Province [8451503102001823]; Guangdong Provincial Key Laboratory; Science and Technology Foundation of Shantou [186]; Breast Center in Cancer Hospital of Shantou University Medical College FX This work was supported by grants from the National Nature Science Foundation of China (No. 81030033, 30971150 to J.G., No. 81001199 to Z.C. and No. 30950110335 to C. K.), the Natural Science Foundation of Guangdong Province (No. 8451503102001823), the Guangdong Provincial Key Laboratory, and the Science and Technology Foundation of Shantou (No. 186 to C. M.) and by the Breast Center in Cancer Hospital of Shantou University Medical College. We also gratefully acknowledge Prof. Min Su and his colleagues (Department of Pathology, Shantou University Medical College) for their help in providing tissue samples. NR 29 TC 11 Z9 14 U1 2 U2 14 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD MAR PY 2013 VL 13 IS 3 BP 429 EP 437 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 119RV UT WOS:000317116100012 PM 23331015 ER PT J AU Wu, DC Zhuang, DM Liu, XF Lu, LH Wang, H Li, C Lai, CC Li, JY He, YP AF Wu, Dao-Chun Zhuang, Dao-Ming Liu, Xiao-Feng Lu, Li-He Wang, Hua Li, Cong Lai, Christopher Cong Li, Jing-Yun He, Yan-Ping TI Synthesis and Biological Evaluation of Novel Hydroxylphenethyl-S-DACOs as High Active Anti-HIV Agents SO LETTERS IN DRUG DESIGN & DISCOVERY LA English DT Article DE Anti HIV-1 activity; Water-solubility; Molecular Docking; NNRTIs; Pyrimidone; S-DACOs ID REVERSE-TRANSCRIPTASE INHIBITORS; DABO SERIES; PYRIMIDIN-4(3H)-ONES; DERIVATIVES; NNRTIS AB A novel 5-alky-6-(cyclohexylmethyl)-2-((2-hydroxy-2-phenylethyl)thio)-pyrimidin-4(3H)-one derivatives were synthesized and their ability to inhibit HIV evaluated. The screening results revealed that compounds 2a-g had a favorable property in inhibiting HIV. The compounds 2b, in particular, showed a special potent anti-HIV activities with EC50 values of 0.003 mu M and CC50 values of 200 mu M. Preliminary structure-activity relationship (SAR) and molecular modeling analyses of these newly synthesized hydroxylphenethyl-S-DACOs are also discussed. C1 [Wu, Dao-Chun; Liu, Xiao-Feng; Lu, Li-He; Wang, Hua; Li, Cong; He, Yan-Ping] Yunnan Univ, Key Lab Med Chem Nat Resources, Minist Educ, Sch Chem Sci & Technol, Kunming 650091, Peoples R China. [Zhuang, Dao-Ming; Li, Jing-Yun] Acad Mil Med Sci, Inst Microbiol & Epidemiol, Beijing 100071, Peoples R China. [Lai, Christopher Cong] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Li, JY (reprint author), Yunnan Univ, Key Lab Med Chem Nat Resources, Minist Educ, Sch Chem Sci & Technol, Kunming 650091, Peoples R China. EM lijy@nic.bmi.an.cn; yphe@ynu.edu.cn FU National Natural Science-Foundation of China [30560179, 30960459]; Science Foundation of Chinese academy science [W8090303]; Science Foundation of Yunnan province [2010CI019] FX Financial support from the National Natural Science-Foundation of China (Grant No. 30560179 and 30960459), the Science Foundation of Chinese academy science (Grant No.W8090303) and the Science Foundation of Yunnan province (Grant No. 2010CI019) are gratefully acknowledged. NR 14 TC 2 Z9 2 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1808 J9 LETT DRUG DES DISCOV JI Lett. Drug Des. Discov. PD MAR PY 2013 VL 10 IS 3 BP 271 EP 276 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 130NW UT WOS:000317926100010 ER PT J AU Domingos-Pereira, S Decrausaz, L Derre, L Bobst, M Romero, P Schiller, JT Jichlinski, P Nardelli-Haefliger, D AF Domingos-Pereira, S. Decrausaz, L. Derre, L. Bobst, M. Romero, P. Schiller, J. T. Jichlinski, P. Nardelli-Haefliger, D. TI Intravaginal TLR agonists increase local vaccine-specific CD8 T cells and human papillomavirus-associated genital-tumor regression in mice SO MUCOSAL IMMUNOLOGY LA English DT Article ID SIMPLEX-VIRUS TYPE-2; CERVICAL-CANCER; BACTERIAL-DNA; CPG; RESPONSES; MUCOSA; OLIGODEOXYNUCLEOTIDES; IMMUNOTHERAPY; EXPRESSION; INDUCTION AB Human ppillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic vaccines have had limited clinical efficacy to date. Here, we report that intravaginal (IVAG) instillation of CpG-ODN (TLR9 agonist) or poly-(I:C) (TLR3 agonist) after subcutaneous E7 vaccination increased similar to fivefold the number of vaccine-specific interferon-gamma-secreting CD8 T cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The IVAG treatment locally increased both E7-specific and total CD8 T cells, but not CD4 T cells. This previously unreported selective recruitment of CD8 T cells from the periphery by IVAG CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/ melanoma differentiation-associated gene 5 signaling pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, IVAG CpG-ODN following vaccination led to complete regression of large genital HPV tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines. C1 [Domingos-Pereira, S.; Decrausaz, L.; Derre, L.; Bobst, M.; Jichlinski, P.; Nardelli-Haefliger, D.] CHU Vaudois, Dept Urol, CH-1011 Lausanne, Switzerland. [Domingos-Pereira, S.; Decrausaz, L.; Derre, L.; Bobst, M.; Jichlinski, P.; Nardelli-Haefliger, D.] Univ Lausanne, Lausanne, Switzerland. [Romero, P.] Univ Lausanne, Ludwig Ctr Canc Res, Lausanne, Switzerland. [Schiller, J. T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Nardelli-Haefliger, D (reprint author), CHU Vaudois, Dept Urol, CH-1011 Lausanne, Switzerland. EM dnardell@hospvd.ch OI nardelli-haefliger, denise/0000-0003-1812-9905 FU Oncosuisse [OCS 02304-082008]; Swiss National Science Foundation [310000-112406, 31003A-135109]; Fondation Emma Muschamp FX This work was supported by Oncosuisse (OCS 02304-082008), the Swiss National Science Foundation (#310000-112406 and 31003A-135109), and the Fondation Emma Muschamp. We thank Dr Roland Sahli for his help in handling the array data and Virginie Martin for her technical help. NR 49 TC 24 Z9 24 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD MAR PY 2013 VL 6 IS 2 BP 393 EP 404 DI 10.1038/mi.2012.83 PG 12 WC Immunology SC Immunology GA 127TJ UT WOS:000317721400017 PM 22968420 ER PT J AU Kim, H Gordon, S Dionne, R AF Kim, H. Gordon, S. Dionne, R. TI Genome-wide approaches (GWA) in oral and craniofacial diseases research SO ORAL DISEASES LA English DT Review DE genome-wide; genomics; craniofacial; microarray ID SQUAMOUS-CELL CARCINOMA; NONSYNDROMIC CLEFT-LIP; DIFFERENTIAL GENE-EXPRESSION; SUBGINGIVAL MICROBIAL PROFILES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CASE-PARENT TRIOS; SALIVARY-GLAND; SJOGRENS-SYNDROME; CHRONIC PERIODONTITIS; SUSCEPTIBILITY LOCUS AB Underlying molecular genetic mechanisms of diseases can be deciphered with unbiased strategies using recently developed technologies enabling genome-wide scale investigations. These technologies have been applied in scanning for genetic variations, gene expression profiles, and epigenetic changes for oral and craniofacial diseases. However, these approaches as applied to oral and craniofacial conditions are in the initial stages, and challenges remain to be overcome, including analysis of high throughput data and their interpretation. Here, we review methodology and studies using genome-wide approaches in oral and craniofacial diseases and suggest future directions. Oral Diseases (2013) 19, 111-120 C1 [Kim, H.; Dionne, R.] NINR, NIH, Bethesda, MD 20892 USA. [Gordon, S.] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. RP Dionne, R (reprint author), NINR, NIH, 3 Mem Dr B3 Rm5E28, Bethesda, MD 20892 USA. EM dionner@mail.nih.gov FU Intramural NIH HHS [ZIA NR000015-07] NR 103 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD MAR PY 2013 VL 19 IS 2 BP 111 EP 120 DI 10.1111/j.1601-0825.2012.01962.x PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 124TG UT WOS:000317489000001 PM 22913301 ER PT J AU Bornholdt, R Helgen, K Koepfli, KP Oliveira, L Lucherini, M Eizirik, E AF Bornholdt, Renata Helgen, Kristofer Koepfli, Klaus-Peter Oliveira, Larissa Lucherini, Mauro Eizirik, Eduardo TI Taxonomic revision of the genus Galictis (Carnivora: Mustelidae): species delimitation, morphological diagnosis, and refined mapping of geographical distribution SO ZOOLOGICAL JOURNAL OF THE LINNEAN SOCIETY LA English DT Review DE America; greater grison; lesser grison; morphometrics; Neotropical region; phylogeny; skin variation; skull variation; taxonomy ID CHARACTER DISPLACEMENT; BIOGEOGRAPHIC HISTORY; SEXUAL-DIMORPHISM; AMERICAN MINK; SYSTEMATICS; DIVERSITY; EVOLUTIONARY; PROCYONIDAE; RADIATION; MAMMALS AB Although critical for enabling in-depth evolutionary, ecological, or conservation-orientated studies, taxonomic knowledge is still scarce for many groups of organisms, including mammals of the order Carnivora. For some of these taxa, even basic aspects such as species limits and geographical distribution are still uncertain. This is the case for the Neotropical mustelid genus Galictis, considered one of the least studied carnivoran genera in the Americas. To address this issue, we performed a comprehensive assessment of morphological and molecular characters to test the number of species within Galictis, and to characterize their distinctiveness and evolutionary history. In addition, we reviewed and consolidated the available information on the taxonomy of this genus, so as to provide a historical framework upon which we could interpret our data. Our analyses demonstrated that two Galictis species can be clearly delimited and diagnosed using metric and nonmetric morphological characters as well as DNA sequences from mitochondrial and nuclear gene segments. On the basis of this clarified species-level delimitation, we reassessed the geographical range of each Galictis taxon, identifying possible areas of sympatry between them. These results provide a solid taxonomic framework for Galictis, enabling the development of additional studies focusing on this poorly known taxon. (c) 2013 The Linnean Society of London, Zoological Journal of the Linnean Society, 2013, 167, 449-472. doi: 10.1111/j.1096-3642.2012.00859.x C1 [Bornholdt, Renata; Eizirik, Eduardo] Fac Biociencias PUCRS, BR-90619900 Porto Alegre, RS, Brazil. [Helgen, Kristofer] Natl Museum Nat Hist, Smithsonian Inst, Div Mammals, Washington, DC 20560 USA. [Koepfli, Klaus-Peter] NIH, Lab Genom Divers, Frederick, MD 21702 USA. [Lucherini, Mauro] Univ Nacl Sur, Dept Biol Bioquim & Farm, Grp Ecol Comportamental Mamiferos, RA-8000 Bahia Blanca, Buenos Aires, Argentina. [Eizirik, Eduardo] Inst Procarnivoros, BR-12945010 Atibaia, SP, Brazil. RP Eizirik, E (reprint author), Fac Biociencias PUCRS, Av Ipiranga,6681 Predio 12, BR-90619900 Porto Alegre, RS, Brazil. EM eduardo.eizirik@pucrs.br RI Eizirik, Eduardo/K-8034-2012 OI Eizirik, Eduardo/0000-0002-9658-0999 FU Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS, Brazil); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brazil); Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Brazil); Smithsonian Institution (USA) FX The authors wish to thank the people in charge of the mammalian collections analysed in this study, who made this research project possible: Carla S. Fontana (MCT-PUCRS), Marcia A. Jardim (FZB/RS), Felipe Peters (ULBRA), Mauricio Graipel (LAMAq-UFSC), Mario de Vivo (MZUSP), Joao A. Oliveira (MNHN), Diego A. de Moraes (UFPE), Joao Alberto de Queiroz (MPEG), Enrique Gonzalez (MNHNA), David Flores (MACN), Hugo Lopez (MLP), Linda Gordon (USNM), Eileen Westwig (AMNH), Ned Gilmore (ANSP), Catherine Weisel (MCZ), Bill Stanley and Tracy Damitz (FMNH), Kristof Zyskowski (YPM), Robert Timm (NHMKU), Chris Conroy (MVZ), Mark Hafner (LSUMNS), Louise Tomsett and Paula Jenkins (BMNH), and Clara Stefen (SMT). We also gratefully acknowledge Cladinara Sarturi and Priscilla Mena Zamberlan (PUCRS, Brazil), as well as Jessica Tomlin and Hannah Zinnert (both supported through the Werner H. Kirsten Student Intern Program at the NCI, Frederick, Maryland, USA) for excellent laboratory assistance. We also thank all members from the Grupo de Ecologia Comportamental de Mamiferos (GECM) who participated in sample collection in Argentina, especially Estela Luengos Vidal, Diego Castillo, Claudia Manfredi, and Emma B. Casanave. Finally, we are especially grateful to Cristine S. Trinca, Andrea T. Thomaz, Joao Feliz, Henrique V. Figueiro, Lucas G. da Silva, and Tiago F. da Silva for support at various stages of this research. This project was supported by the Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS, Brazil), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brazil), Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Brazil), and the Smithsonian Institution (USA). NR 101 TC 7 Z9 12 U1 2 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0024-4082 J9 ZOOL J LINN SOC-LOND JI Zool. J. Linn. Soc. PD MAR PY 2013 VL 167 IS 3 BP 449 EP 472 DI 10.1111/j.1096-3642.2012.00859.x PG 24 WC Zoology SC Zoology GA 114NX UT WOS:000316749600005 ER PT J AU Boxer, AL Gold, M Huey, E Gao, FB Burton, EA Chow, T Kao, A Leavitt, BR Lamb, B Grether, M Knopman, D Cairns, NJ Mackenzie, IR Mitic, L Roberson, ED Van Kammen, D Cantillon, M Zahs, K Salloway, S Morris, J Tong, G Feldman, H Fillitt, H Dickinson, S Khachaturian, Z Sutherland, M Farese, R Miller, BL Cummings, J AF Boxer, Adam L. Gold, Michael Huey, Edward Gao, Fen-Biao Burton, Edward A. Chow, Tiffany Kao, Aimee Leavitt, Blair R. Lamb, Bruce Grether, Megan Knopman, David Cairns, Nigel J. Mackenzie, Ian R. Mitic, Laura Roberson, Erik D. Van Kammen, Daniel Cantillon, Marc Zahs, Kathleen Salloway, Stephen Morris, John Tong, Gary Feldman, Howard Fillitt, Howard Dickinson, Susan Khachaturian, Zaven Sutherland, Margaret Farese, Robert Miller, Bruce L. Cummings, Jeffrey TI Frontotemporal degeneration, the next therapeutic frontier: Molecules and animal models for frontotemporal degeneration drug development SO ALZHEIMERS & DEMENTIA LA English DT Review DE Frontotemporal degeneration; Treatment; Tau; Progranulin; TDP-43 ID AMYOTROPHIC-LATERAL-SCLEROSIS; CAENORHABDITIS-ELEGANS MODEL; TRANSGENIC ZEBRAFISH MODEL; HUMAN SOMATIC-CELLS; MOUSE MODEL; LOBAR DEGENERATION; ALZHEIMERS-DISEASE; IN-VIVO; NEURODEGENERATIVE DISEASES; PATHOLOGICAL PHENOTYPES AB Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases. (c) 2013 The Alzheimer's Association. All rights reserved. C1 [Boxer, Adam L.; Kao, Aimee; Miller, Bruce L.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Gold, Michael] Allon Therapeut, Vancouver, BC, Canada. [Huey, Edward] Columbia Univ, Dept Neurol, Taub Inst, New York, NY USA. [Gao, Fen-Biao] Univ Massachusetts, Dept Neurol, Worcester, MA 01605 USA. [Burton, Edward A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Chow, Tiffany] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Leavitt, Blair R.] Univ British Columbia, Dept Med, Div Neurol, Ctr Mol Med & Therapeut, Vancouver, BC, Canada. [Lamb, Bruce] Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA. [Grether, Megan; Mitic, Laura] Bluefield Project Cure Frontotemporal Dementia, San Francisco, CA USA. [Knopman, David] Mayo Clin, Dept Neurol, Rochester, MN USA. [Cairns, Nigel J.; Morris, John] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Mackenzie, Ian R.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Roberson, Erik D.] Univ Alabama Birmingham, Dept Neurol, Sch Med, Birmingham, AL 35294 USA. [Van Kammen, Daniel] CNS Drug Dev Consultant, Princeton, NJ USA. [Cantillon, Marc] Crit Path Inst, Rockville, MD USA. [Zahs, Kathleen] Univ Minnesota, Sch Med, Grossman Ctr Memory Res & Care, Minneapolis, MN 55455 USA. [Salloway, Stephen] Brown Univ, Sch Med, Dept Neurol, Providence, RI 02912 USA. [Tong, Gary] Bristol Myers Squibb Co, Princeton, NJ USA. [Feldman, Howard] Univ British Columbia, Dept Med, Div Neurol, Vancouver, BC V6T 1W5, Canada. [Fillitt, Howard] Alzheimers Drug Discovery Fdn, New York, NY USA. [Dickinson, Susan] Assoc Frontotemporal Degenerat, Radnor, PA USA. [Khachaturian, Zaven] KRA Associates, Potomac, MD USA. [Sutherland, Margaret] NINDS, NIH, Bethesda, MD 20892 USA. [Farese, Robert] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA. [Cummings, Jeffrey] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Las Vegas, NV USA. RP Boxer, AL (reprint author), Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. EM aboxer@memory.ucsf.edu OI Roberson, Erik/0000-0002-1810-9763; Feldman, Howard/0000-0002-9258-4538; Burton, Edward/0000-0002-8072-4636 NR 74 TC 25 Z9 25 U1 0 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAR PY 2013 VL 9 IS 2 BP 176 EP 188 DI 10.1016/j.jalz.2012.03.002 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 119JD UT WOS:000317092700010 PM 23043900 ER PT J AU Adam, L Gold, M Huey, E Hu, WT Rosen, H Kramer, J Gao, FB Burton, EA Chow, T Kao, A Leavitt, BR Lamb, B Grether, M Knopman, D Cairns, NJ Mackenzie, IR Mitic, L Roberson, ED Van Kammen, D Cantillon, M Zahs, K Jackson, G Salloway, S Morris, J Tong, G Feldman, H Fillit, H Dickinson, S Khachaturian, ZS Sutherland, M Abushakra, S Lewcock, J Farese, R Kenet, RO LaFerla, F Perrin, S Whitaker, S Honig, L Mesulam, MM Boeve, B Grossman, M Miller, BL Cummings, JL AF Boxer, Adam L. Gold, Michael Huey, Edward Hu, William T. Rosen, Howard Kramer, Joel Gao, Fen-Biao Burton, Edward A. Chow, Tiffany Kao, Aimee Leavitt, Blair R. Lamb, Bruce Grether, Megan Knopman, David Cairns, Nigel J. Mackenzie, Ian R. Mitic, Laura Roberson, Erik D. Van Kammen, Daniel Cantillon, Marc Zahs, Kathleen Jackson, George Salloway, Stephen Morris, John Tong, Gary Feldman, Howard Fillit, Howard Dickinson, Susan Khachaturian, Zaven S. Sutherland, Margaret Abushakra, Susan Lewcock, Joseph Farese, Robert Kenet, Robert O. LaFerla, Frank Perrin, Steve Whitaker, Steve Honig, Lawrence Mesulam, Marsel M. Boeve, Brad Grossman, Murray Miller, Bruce L. Cummings, Jeffrey L. TI The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: The next therapeutic frontier) SO ALZHEIMERS & DEMENTIA LA English DT Review DE Frontotemporal degeneration; FTD; Alzheimer's disease; AD; Progressive supranuclear palsy; Corticobasal degeneration; Treatment; Clinical trial; Biomarker; Drug development ID PROGRESSIVE SUPRANUCLEAR PALSY; ADDENBROOKES COGNITIVE EXAMINATION; RICHARDSON-OLSZEWSKI-SYNDROME; PLACEBO-CONTROLLED TRIAL; LOBAR DEGENERATION; ALZHEIMERS-DISEASE; DIAGNOSTIC-CRITERIA; BEHAVIORAL VARIANT; TEST BATTERY; DEMENTIA AB Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies. (C) 2013 The Alzheimer's Association. All rights reserved. C1 [Boxer, Adam L.; Rosen, Howard; Kramer, Joel; Kao, Aimee; Miller, Bruce L.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Gold, Michael] Allon Therapeut, Vancouver, BC, Canada. [Huey, Edward; Honig, Lawrence] Columbia Univ, Dept Neurol, Taub Inst, New York, NY USA. [Hu, William T.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Gao, Fen-Biao] Univ Massachusetts, Dept Neurol, Worcester, MA 01605 USA. [Burton, Edward A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Chow, Tiffany] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Leavitt, Blair R.] Univ British Columbia, Dept Med, Div Neurol, Ctr Mol Med & Therapeut, Vancouver, BC V6T 1W5, Canada. [Lamb, Bruce] Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA. [Grether, Megan; Mitic, Laura] Bluefield Project Cure Frontotemporal Dementia, San Francisco, CA USA. [Knopman, David; Boeve, Brad] Mayo Clin, Dept Neurol, Rochester, MN USA. [Cairns, Nigel J.; Morris, John] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Mackenzie, Ian R.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Roberson, Erik D.] Univ Alabama Birmingham, Dept Neurol, Sch Med, Birmingham, AL 35294 USA. [Van Kammen, Daniel] CNS Drug Dev Consultant, Princeton, NJ USA. [Cantillon, Marc] Crit Path Inst, Rockville, MD USA. [Zahs, Kathleen] Univ Minnesota, Sch Med, Grossman Ctr Memory Res & Care, Minneapolis, MN 55455 USA. [Cantillon, Marc] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA. [Chow, Tiffany] Brown Univ, Sch Med, Dept Neurol, Providence, RI 02912 USA. [Tong, Gary] Bristol Myers Squibb Co, Princeton, NJ USA. [Feldman, Howard] Univ British Columbia, Dept Med, Div Neurol, Vancouver, BC V6T 1W5, Canada. [Fillit, Howard] Alzheimers Drug Discovery Fdn, New York, NY USA. [Dickinson, Susan] Assoc Frontotemporal Degenerat, Radnor, PA USA. [Khachaturian, Zaven S.] KRA Associates, Potomac, MD USA. [Sutherland, Margaret] NINDS, NIH, Bethesda, MD 20892 USA. [Abushakra, Susan] Elan Pharmaceut, San Francisco, CA USA. [Lewcock, Joseph] Genentech Inc, San Francisco, CA 94080 USA. [Farese, Robert] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA. [Kenet, Robert O.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [LaFerla, Frank] Univ Calif Irvine, MIND Inst, Irvine, CA USA. [Perrin, Steve] ALS Therapy Dev Inst, Cambridge, MA USA. [Whitaker, Steve] Omeros Corp, Seattle, WA USA. [Mesulam, Marsel M.] Northwestern Univ, Feinberg Sch Med, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL 60611 USA. [Grossman, Murray] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Cummings, Jeffrey L.] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Las Vegas, NV USA. RP Boxer, AL (reprint author), Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. EM aboxer@memory.ucsf.edu OI Roberson, Erik/0000-0002-1810-9763; Feldman, Howard/0000-0002-9258-4538; Burton, Edward/0000-0002-8072-4636 NR 67 TC 0 Z9 0 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAR PY 2013 VL 9 IS 2 BP 189 EP 198 DI 10.1016/j.jalz.2012.03.003 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 119JD UT WOS:000317092700011 ER PT J AU Sabatinelli, D Keil, A Frank, DW Lang, PJ AF Sabatinelli, Dean Keil, Andreas Frank, David W. Lang, Peter J. TI Emotional perception: Correspondence of early and late event-related potentials with cortical and subcortical functional MRI SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Emotion; Attention; Perception; fMRI; ERP ID VISUAL-CORTEX; HUMAN AMYGDALA; MOTIVATIONAL RELEVANCE; FACIAL EXPRESSIONS; BRAIN POTENTIALS; SOCIAL ANXIETY; EEG-FMRI; ATTENTION; PICTURES; AROUSAL AB This research examines the relationship between brain activity recorded with functional magnetic resonance imaging (fMRI) and event related potentials (ERP) as these responses varied over a series of emotionally evocative and neutral pictures. We investigate the relationship of early occipitotemporal and later centroparietal emotion-modulated ERPs in one sample to fMRI estimates of neural activity in another sample in a replicated experiment. Using this approach, we aimed to link effects found in time-resolved electrocortical measures to specific neural structures across individual emotional and nonemotional picture stimuli. The centroparietal late positive potential (LPP) showed covariation with emotion-modulated regions of hemodynamic activation across multiple dorsal and ventral visual cortical structures, while the early occipitotemporal potential was not reliably associated. Subcortical and corticolimbic structures involved in the perception of motivationally relevant stimuli also related to modulation of the LPP, and were modestly associated to the amplitude of the early occipitotemporal potential. These data suggest that early occipitotemporal potentials may reflect multiple sources of modulation including motivational relevance, and supports the perspective that the slow-wave LPP represents aggregate cortical and subcortical structures involved in emotional discrimination. (c) 2012 Elsevier B.V. All rights reserved. C1 [Sabatinelli, Dean; Frank, David W.] Univ Georgia, Dept Psychol, Athens, GA 30601 USA. [Sabatinelli, Dean; Frank, David W.] Univ Georgia, Bioimaging Res Ctr, Athens, GA 30601 USA. [Keil, Andreas; Lang, Peter J.] Univ Florida, NIMH Ctr, Study Emot & Attent, Gainesville, FL 32601 USA. RP Sabatinelli, D (reprint author), Univ Georgia, 523 Psychology Bldg, Athens, GA 30601 USA. EM sabat@uga.edu RI Keil, Andreas/F-9427-2011; OI Keil, Andreas/0000-0002-4064-1924; sabatinelli, dean/0000-0001-7409-8504 FU NIMH NIH HHS [R01 MH084932, P50 MH072850] NR 60 TC 56 Z9 56 U1 3 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD MAR PY 2013 VL 92 IS 3 SI SI BP 513 EP 519 DI 10.1016/j.biopsycho.2012.04.005 PG 7 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 120JI UT WOS:000317166200009 PM 22560889 ER PT J AU Sinha, BK Bhattacharjee, S Chatterjee, S Jiang, JJ Motten, AG Kumar, A Espey, MG Mason, RP AF Sinha, Birandra K. Bhattacharjee, Suchandra Chatterjee, Saurabh Jiang, JinJie Motten, Ann G. Kumar, Ashutosh Espey, Michael Graham Mason, Ronald P. TI Role of Nitric Oxide in the Chemistry and Anticancer Activity of Etoposide (VP-16,213) SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID PROSTATE-CANCER CELLS; BREAST-CANCER; DNA-DAMAGE; RIBONUCLEOTIDE REDUCTASE; CATALYZED METABOLISM; SYNTHASE EXPRESSION; RADICAL FORMATION; ALPHA-TOCOPHEROL; NITROGEN-OXIDES; O-DEMETHYLATION AB Originally identified as an innate cytotoxin, nitric oxide ((NO)-N-center dot) formation in tumors can influence chemotherapy and exacerbate cancer progression. Here, we examined the hypothesis that (NO)-N-center dot generation contributes to cancer cell drug resistance toward the widely used anticancer drug Etoposide (VP-16). The UV-vis spectrum of VP-16 was not changed by exposure of VP-16 to (NO)-N-center dot in aqueous buffer. In contrast, reddish-orange compound(s) characteristic of o-quinone- and nitroso-VP-16 were readily generated in a hydrophobic medium (chloroform) in an oxygen-dependent manner. Similar products were also formed when the VP-16 radical, generated from VP-16 and horseradish peroxidase/H2O2, was exposed directly to (NO)-N-center dot in chloroform in the presence of oxygen. Separation and spectral analysis of VP-16 reaction extracts by electron spin resonance and UV-vis indicated the generation of the phenoxy radical and the o-quinone of VP-16, as well as putative nitroxide, iminoxyl, and other nitrogen oxide intermediates. Nitric oxide products of VP-16 displayed significantly diminished topoisomerase II-dependent cleavage of DNA and cytotoxicity to human HL-60 leukemia cells. LPS-mediated induction of nitric oxide synthase in murine macrophages resulted in VP-16 resistance compared to Raw cells. Furthermore, (NO)-N-center dot products derived from iNOS rapidly reacted with VP-16 leading to decreased DNA damage and cytotoxicity. Together, these observations suggest that the formation of (NO)-N-center dot in tumors (associated macrophages) can contribute to VP-16 resistance via the detoxification of VP-16. C1 [Sinha, Birandra K.; Bhattacharjee, Suchandra; Chatterjee, Saurabh; Jiang, JinJie; Motten, Ann G.; Kumar, Ashutosh; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Espey, Michael Graham] NIDDK, Off Sci Director, NIH, Bethesda, MD USA. RP Sinha, BK (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM sinha1@niehs.nih.gov FU Intramural Research Program of the NIH; NIH/NIEHS; NIH; Pathway to Independence Award [ES01-19875A]; [K99-R00] FX This research was supported by the Intramural Research Program of the NIH, and NIH/NIEHS. S.C. is also supported by a K99-R00, NIH, and Pathway to Independence Award (ES01-19875A). NR 64 TC 4 Z9 4 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAR PY 2013 VL 26 IS 3 BP 379 EP 387 DI 10.1021/tx300480q PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 110JU UT WOS:000316439200008 PM 23402364 ER PT J AU Jacobs, SR Weiner, BJ Minasian, LM Good, MJ AF Jacobs, Sara R. Weiner, Bryan J. Minasian, Lori M. Good, Marjorie J. TI Achieving high cancer control trial enrollment in the community setting: An analysis of the Community Clinical Oncology Program SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Cancer; Clinical trial enrollment; Cancer symptom control; Community Clinical Oncology Program ID SYMPTOMS; CARE AB Determining the factors that lead to successful enrollment of patients in cancer control clinical trials is essential as cancer patients are often burdened with side effects such as pain, nausea, and fatigue. One promising intervention for increasing enrollment in cancer control trials is the National Cancer Institute's Community Clinical Oncology Program (CCOP). In this article, we examined CCOP staffing, policies, and procedures associated with enrollment in control trials. Data were obtained from three sources: the online CCOP, MB-CCOP, and Research Base Management System, CCOP Annual Progress Reports, and a survey of CCOP Administrators conducted in 2011. We analyzed cancer control trial accrual in 2011 among 46 CCOPs using multivariate regression. Three factors were significant predictors of accrual. First, having a team of staff dedicated to enrolling patients in control and prevention trials, compared to having no dedicated staff, was associated on average with an additional 30 patients enrolled in control trials (p<0.05). Second, CCOPs that recognized physicians for enrolling a large number of patients compared to CCOPs that did not recognize high enrolling physicians enrolled on average an additional 25 patients in control trials (p<0.05). Lastly, the number of cancer control trials available was also associated with enrollment (beta=5.50, p<0.00). Our results indicate that CCOPs looking to increase enrollment in control trials should consider dedicating a team of staff to enroll patients in these types of trials. In addition, CCOPs or other volunteer research systems looking to increase physician participation should consider recognizing high enrolling physicians. (C) 2013 Elsevier Inc. All rights reserved. C1 [Jacobs, Sara R.; Weiner, Bryan J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC 27599 USA. [Weiner, Bryan J.] Univ N Carolina, Cecil G Sheps Ctr Hlth Serv Res, Chapel Hill, NC 27599 USA. [Minasian, Lori M.; Good, Marjorie J.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Jacobs, SR (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, 1101 McGavran Greenberg Hall,CB 7411, Chapel Hill, NC 27599 USA. EM jacobssr@live.unc.edu FU National Cancer Institute at the National Institutes of Health [R25CA116339, R01CA124402] FX This work was supported by the National Cancer Institute at the National Institutes of Health (R25CA116339 and R01CA124402). NR 15 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2013 VL 34 IS 2 BP 320 EP 325 DI 10.1016/j.cct.2012.12.008 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 120KL UT WOS:000317169100017 PM 23295315 ER PT J AU Murray, DM Katz, ML Post, DM Pennell, ML Young, GS Tatum, CM Paskett, ED AF Murray, David M. Katz, Mira L. Post, Doug M. Pennell, Michael L. Young, Gregory S. Tatum, Cathy M. Paskett, Electra D. TI Enhancing cancer screening in primary care: Rationale, design, analysis plan, and recruitment results SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Colorectal cancer; Screening; Group-randomized trial ID RANDOM-EFFECTS MODELS; LINEAR MIXED MODELS; COLORECTAL-CANCER; MAXIMUM-LIKELIHOOD; RANDOMIZED-TRIALS; HEALTH; GUIDELINES; INFERENCE; RESPONSES; SERVICES AB Colorectal cancer (CRC) is the third leading type of cancer and the third leading cause of cancer death in the United States. National policy-making organizations recognize and support a variety of CRC screening strategies among average-risk adults aged 50 and older based on strong evidence showing that screening decreases mortality from CRC and can also reduce the incidence of the disease. The goal of this study was to test a multi-level stepped intervention to increase CRC screening rates. We used a group-randomized trial design where the units of assignment were clinics and the units of observation were eligible patients receiving care at those clinics, with stratified random assignment of clinics to study conditions. The primary analysis was planned as a mixed-model logistic regression to account for the expected positive intraclass correlation associated with clinics. Our recruitment experience reflected the difficulties of conducting research in the real world where changes in economic conditions, staff turnover/layoff, inadequate medical records, and poor acceptance of research can significantly impact study plans. It demonstrated the problems that can emerge when procedures used in the study depart from those used in the pilot work to generate parameter estimates for power analysis. It also demonstrated the importance of allowing for attrition at the group and patient levels so that if recruitment falls short, it is possible to maintain adequate power with only a slight increase in the detectable difference. This experience should assist others planning group-randomized trials, whether in cancer screening or in other areas. Published by Elsevier Inc. C1 [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Biostat & Bioinformat Branch, NIH, Bethesda, MD 20892 USA. [Katz, Mira L.] Ohio State Univ, Coll Publ Hlth, Div Hlth Behav & Hlth Promot, Columbus, OH 43210 USA. [Pennell, Michael L.] Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA. [Paskett, Electra D.] Ohio State Univ, Coll Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Young, Gregory S.] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Post, Doug M.] Ohio State Univ, Coll Med, Dept Family Med, Columbus, OH 43210 USA. [Katz, Mira L.; Tatum, Cathy M.; Paskett, Electra D.] Ohio State Univ, Coll Med, Dept Internal Med, Div Canc Prevent & Control, Columbus, OH 43210 USA. [Katz, Mira L.; Post, Doug M.; Tatum, Cathy M.; Paskett, Electra D.] Ohio State Univ, Ctr Comprehens Canc, Div Populat Sci, Columbus, OH 43210 USA. RP Murray, DM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Biostat & Bioinformat Branch, NIH, 6100 Execut Blvd,Room 2B03, Bethesda, MD 20892 USA. EM david.murray2@nih.gov FU National Cancer Institute [R01 CA116487, P30 CA016058, K07 CA107079] FX This study was supported by Research Grants R01 CA116487 and P30 CA016058 (to E.D. Paskett), and K07 CA107079 (to M.L. Katz) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 45 TC 1 Z9 1 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2013 VL 34 IS 2 BP 356 EP 363 DI 10.1016/j.cct.2013.01.003 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 120KL UT WOS:000317169100021 PM 23357561 ER PT J AU Levy, G Hill, MJ Plowden, TC Catherino, WH Armstrong, AY AF Levy, Gary Hill, Micah J. Plowden, Torie C. Catherino, William H. Armstrong, Alicia Y. TI Biomarkers in uterine leiomyoma SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 1st Reproductive Biomarker Meeting CY MAR 30-31, 2012 CL Valencia, SPAIN DE Leiomyoma; fibroids; biomarker ID EPITHELIAL OVARIAN-CANCER; SERUM CA 125; TRANSVAGINAL SONOGRAPHY; DIFFERENTIAL-DIAGNOSIS; PELVIC MASS; HLA-G; GROWTH; FIBROIDS; MYOMAS; RECEPTOR AB Biomarkers are biologic compounds that are easily accessible and reflect normal physiology or pathology. They are useful in a variety of clinical situations that involve detection of subclinical disease, risk stratification, preoperative planning, and monitoring treatment. A useful intervention needs to exist for a biomarker to be an effective tool. Many compounds have been investigated as potential biomarkers for the diagnosis and surveillance of uterine leiomyomas. Most of these compounds demonstrate subtle differences among patients when leiomyomas are compared with controls. The compounds investigated lack the diagnostic accuracy necessary to add any benefit to the current available modalities used to diagnose and monitor uterine leiomyomas. (Fertil Steril (R) 2013;99:1146-52. (C) 2013 by American Society for Reproductive Medicine.) C1 [Levy, Gary; Hill, Micah J.; Catherino, William H.; Armstrong, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Plowden, Torie C.] Bayne Jones Army Community Hosp, Ft Polk, LA USA. [Catherino, William H.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Armstrong, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 Ctr Dr,Room 1-3140,MSC 1109, Bethesda, MD 20892 USA. EM aa257w@nih.gov FU National Institutes of Health, Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, Bethesda, Maryland FX Supported in part by the National Institutes of Health, Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, Bethesda, Maryland. NR 72 TC 6 Z9 7 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD MAR PY 2013 VL 99 IS 4 BP 1146 EP 1152 DI 10.1016/j.fertnstert.2012.10.048 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 113JP UT WOS:000316663300024 PM 23200685 ER PT J AU Cong, M Hu, CM Cao, YF Fang, ZZ Tang, SH Wang, JR Luo, JS AF Cong, Ming Hu, Cui-Min Cao, Yun-Feng Fang, Zhong-Ze Tang, Shu-Hong Wang, Jia-Rui Luo, Jun-Sheng TI Cryptotanshinone and dihydrotanshinone I exhibit strong inhibition towards human liver microsome (HLM)-catalyzed propofol glucuronidation SO FITOTERAPIA LA English DT Article DE Danshen; UDP-glucuronosyltransferases (UGTs); Herb-drug interaction ID UDP-GLUCURONOSYLTRANSFERASE ISOFORMS; SALVIA-MILTIORRHIZA; SUPRAVENTRICULAR TACHYCARDIA; TANSHINONE IIA; IDENTIFICATION; CONSTITUENTS; CHEMISTRY AB Danshen is one of the most famous herbs in the world, and more and more danshen-prescribed drugs interactions have been reported in recent years. Evaluation of inhibition potential of danshen's major ingredients towards UDP-glucuronosyltransferases (UGTs) will be helpful for understanding detailed mechanisms for danshen-drugs interaction. Therefore, the aim of the present study is to investigate the inhibitory situation of cryptotanshinone and dihydrotanshinone I towards UGT enzyme-catalyzed propofol glucuronidation. In vitro the human liver microsome (HLM) incubation system was used, and the results showed that cryptotanshinone and dihydrotanshinone I exhibited dose-dependent inhibition towards HLM-catalyzed propofol glucuronidation. Dixon plot and Lineweaver-Burk plot showed that the inhibition type was best fit to competitive inhibition type for both cryptotanshinone and dihydrotanshinone I. The second plot using the slopes from the Lineweaver-Burk plot versus the concentrations of cryptotanshinone or dihydrotanshinone I was employed to calculate the inhibition parameters (K-1) to be 0.4 and 1.7 mu M, respectively. Using the reported maximum plasma concentration (C-max), the altered in vivo exposure of propofol increased by 10% and 8.2% for the co-administration of dihydrotanshinone I and cryptotanshinone, respectively. All these results indicated the possible danshen-propofol interaction due to the inhibition of dihydrotanshinone I and cryptotanshinone towards the glucuronidation reaction of propofol. (C) 2013 Elsevier B.V. All rights reserved. C1 [Cong, Ming; Luo, Jun-Sheng] Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. [Cao, Yun-Feng; Fang, Zhong-Ze] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China. [Cao, Yun-Feng; Fang, Zhong-Ze] Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China. [Tang, Shu-Hong; Wang, Jia-Rui] Fifth Hosp Dalian, Dept Oncol, Dalian 116021, Peoples R China. [Hu, Cui-Min; Fang, Zhong-Ze] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Luo, JS (reprint author), Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. EM luojunshengljs@sina.com NR 30 TC 15 Z9 16 U1 3 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0367-326X J9 FITOTERAPIA JI Fitoterapia PD MAR PY 2013 VL 85 BP 109 EP 113 DI 10.1016/j.fitote.2013.01.002 PG 5 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 120LO UT WOS:000317172000016 PM 23333907 ER PT J AU He, B Baird, R Butera, R Datta, A George, S Hecht, B Hero, A Lazzi, G Lee, RC Liang, J Neuman, M Peng, GCY Perreault, EJ Ramasubramanian, M Wang, MD Wikswo, J Yang, GZ Zhang, YT AF He, Bin Baird, Richard Butera, Robert Datta, Aniruddha George, Steven Hecht, Bruce Hero, Alfred Lazzi, Gianluca Lee, Raphael C. Liang, Jie Neuman, Michael Peng, Grace C. Y. Perreault, Eric J. Ramasubramanian, Melur Wang, May D. Wikswo, John Yang, Guang-Zhong Zhang, Yuan-Ting TI Grand Challenges in Interfacing Engineering With Life Sciences and Medicine SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Bioengineering; biomedical engineering; engineering; grand challenges; healthcare; life science; medicine ID BIOLOGY AB This paper summarizes the discussions held during the First IEEE Life Sciences Grand Challenges Conference, held on October 4-5, 2012, at the National Academy of Sciences, Washington, DC, and the grand challenges identified by the conference participants. Despite tremendous efforts to develop the knowledge and ability that are essential in addressing biomedical and health problems using engineering methodologies, the optimization of this approach toward engineering the life sciences and healthcare remains a grand challenge. The conference was aimed at high-level discussions by participants representing various sectors, including academia, government, and industry. Grand challenges were identified by the conference participants in five areas including engineering the brain and nervous system; engineering the cardiovascular system; engineering of cancer diagnostics, therapeutics, and prevention; translation of discoveries to clinical applications; and education and training. A number of these challenges are identified and summarized in this paper. C1 [He, Bin] Univ Minnesota, Inst Engn Med, Minneapolis, MN 55455 USA. [Baird, Richard; Peng, Grace C. Y.] NIBIB, NIH, Bethesda, MD 20892 USA. [Butera, Robert] Georgia Inst Technol, Sch Elect & Comp Engn, Atlanta, GA 30332 USA. [Datta, Aniruddha] Texas A&M Univ, College Stn, TX 77840 USA. [George, Steven] Univ Calif Irvine, Irvine, CA 92697 USA. [Hecht, Bruce] Analog Devices Inc, Norwood, MA 02062 USA. [Hero, Alfred] Univ Michigan, Ann Arbor, MI 48109 USA. [Lazzi, Gianluca] Univ Utah, Salt Lake City, UT 84112 USA. [Lee, Raphael C.] Univ Chicago, Chicago, IL 60637 USA. [Liang, Jie] Univ Illinois, Chicago, IL 60607 USA. [Neuman, Michael] Michigan Technol Univ, Houghton, MI 49931 USA. [Perreault, Eric J.] Northwestern Univ, Chicago, IL 60611 USA. [Ramasubramanian, Melur] Clemson Univ, Clemson, SC 29634 USA. [Wang, May D.] Georgia Inst Technol, Atlanta, GA 30332 USA. [Wang, May D.] Emory Univ, Atlanta, GA 30332 USA. [Wikswo, John] Vanderbilt Univ, Nashville, TN 37235 USA. [Yang, Guang-Zhong] Univ London Imperial Coll Sci Technol & Med, Hamlyn Ctr, London SW7 2AZ, England. [Zhang, Yuan-Ting] Chinese Univ Hong Kong, Joint Res Ctr Biomed Engn, Shatin, Hong Kong, Peoples R China. [Zhang, Yuan-Ting] SIAT, Key Lab Hlth Informat, Chinese Acad Sci, Shenzhen, Peoples R China. RP He, B (reprint author), Univ Minnesota, Inst Engn Med, Minneapolis, MN 55455 USA. EM binhe@umn.edu; bairdri@mail.nih.gov; rbutera@gatech.edu; datta@ece.tamu.edu; scgeorge@uci.edu; Bruce.Hecht@analog.com; hero@umich.edu; lazzi@utah.edu; rlee@surgery.bsd.uchicago.edu; jliang@uic.edu; mneuman@mtu.edu; penggr@mail.nih.gov; e-perreault@northwestern.edu; rammk@clemson.edu; maywang@bme.gatech.edu; john.wikswo@vanderbilt.edu; g.z.yang@imperial.ac.uk; ytzhang@ee.cuhk.edu.hk RI Perreault, Eric/B-7632-2009; OI Butera, Robert/0000-0002-1806-0621 FU National Science Foundation [CBET-1206695]; Institute for Engineering in Medicine of the University of Minnesota FX This work was organized by the IEEE and was supported in part by the National Science Foundation under Grant CBET-1206695 and in part by the Institute for Engineering in Medicine of the University of Minnesota. NR 14 TC 20 Z9 21 U1 4 U2 42 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD MAR PY 2013 VL 60 IS 3 BP 589 EP 598 DI 10.1109/TBME.2013.2244886 PG 10 WC Engineering, Biomedical SC Engineering GA 115KL UT WOS:000316810900002 PM 23380847 ER PT J AU Karasek, D Shah, U Frysak, Z Stratakis, C Pacak, K AF Karasek, D. Shah, U. Frysak, Z. Stratakis, C. Pacak, K. TI An update on the genetics of pheochromocytoma SO JOURNAL OF HUMAN HYPERTENSION LA English DT Review DE pheochromocytoma; paraganglioma; genes; catecholamines; metanephrines ID HIPPEL-LINDAU-DISEASE; SUCCINATE-DEHYDROGENASE; GERMLINE MUTATIONS; NEUROFIBROMATOSIS TYPE-1; TUMOR-SUPPRESSOR; FAMILIAL PHEOCHROMOCYTOMA; CLINICAL-FEATURES; PARAGANGLIOMAS; SDHB; DIAGNOSIS AB Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors. About 30% or more of them are thought to be of inherited origin due to germ-line mutations in at least 10 well-characterized genes. There are data linking specific genotypes of these tumors to specific locations, typical biochemical phenotypes or future clinical behaviors. Conversely, clinical features, catecholamine production and immunohistochemistry evaluation can help with the proper order of genetic testing for PHEO and PGL. The identification of a germ-line mutation can lead to an early diagnosis, appropriate treatment, regular surveillance and better prognosis not only for the patient but also for their family members. Moreover, the latest discoveries in molecular pathogenesis of these tumors will provide an important basis for future personalized therapy. Journal of Human Hypertension (2013) 27, 141-147; doi: 10.1038/jhh.2012.20; published online 31 May 2012 C1 [Karasek, D.; Frysak, Z.] Univ Hosp Olomouc, Dept Internal Med 3, Olomouc, Czech Republic. [Shah, U.; Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Stratakis, C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC-1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. NR 60 TC 19 Z9 22 U1 0 U2 14 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 MAR PY 2013 VL 27 IS 3 BP 141 EP 147 DI 10.1038/jhh.2012.20 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 119SI UT WOS:000317117500001 PM 22648268 ER PT J AU Jacob, KD Noren Hooten, N Trzeciak, AR Evans, MK AF Jacob, Kimberly D. Noren Hooten, Nicole Trzeciak, Andrzej R. Evans, Michele K. TI Markers of oxidant stress that are clinically relevant in aging and age-related disease SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Review DE DNA oxidation; RNA oxidation; Protein oxidation; Single strand breaks; CRP ID OXIDATIVE DNA-DAMAGE; C-REACTIVE PROTEIN; ALKALINE COMET ASSAY; DOUBLE-STRAND BREAKS; CEREBROSPINAL-FLUID F-2-ISOPROSTANES; DEPENDENT DIABETES-MELLITUS; HEME DEGRADATION-PRODUCTS; TANDEM MASS-SPECTROMETRY; NEURONAL RNA OXIDATION; HUMAN SKELETAL-MUSCLE AB Despite the long held hypothesis that oxidant stress results in accumulated oxidative damage to cellular macromolecules and subsequently to aging and age-related chronic disease, it has been difficult to consistently define and specifically identify markers of oxidant stress that are consistently and directly linked to age and disease status. Inflammation because it is also linked to oxidant stress, aging, and chronic disease also plays an important role in understanding the clinical implications of oxidant stress and relevant markers. Much attention has focused on identifying specific markers of oxidative stress and inflammation that could be measured in easily accessible tissues and fluids (lymphocytes, plasma, serum). The purpose of this review is to discuss markers of oxidant stress used in the field as biomarkers of aging and age-related diseases, highlighting differences observed by race when data is available. We highlight DNA, RNA, protein, and lipid oxidation as measures of oxidative stress, as well as other well-characterized markers of oxidative damage and inflammation and discuss their strengths and limitations. We present the current state of the literature reporting use of these markers in studies of human cohorts in relation to age and age-related disease and also with a special emphasis on differences observed by race when relevant. Published by Elsevier Ireland Ltd. C1 [Jacob, Kimberly D.; Noren Hooten, Nicole; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Trzeciak, Andrzej R.] NIDA, Mol Neurobiol Res Branch, NIH, Baltimore, MD USA. RP Evans, MK (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. EM me42v@nih.gov OI Noren Hooten, Nicole/0000-0002-1683-3838 FU Intramural Research Program of the NIH, National Institute on Aging FX We thank Dr. David Wilson III and Dr. Joseph Rifkind for critical reading of the manuscript. Research in this laboratory is supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 275 TC 68 Z9 69 U1 3 U2 44 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD MAR-APR PY 2013 VL 134 IS 3-4 BP 139 EP 157 DI 10.1016/j.mad.2013.02.008 PG 19 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 120DH UT WOS:000317150500009 PM 23428415 ER PT J AU Bertola, A Mathews, S Ki, SH Wang, H Gao, B AF Bertola, Adeline Mathews, Stephanie Ki, Sung Hwan Wang, Hua Gao, Bin TI Mouse model of chronic and binge ethanol feeding (the NIAAA model) SO NATURE PROTOCOLS LA English DT Article ID ALCOHOLIC LIVER-DISEASE; OXIDATIVE STRESS; INTRAGASTRIC INFUSION; HEPATIC STEATOSIS; FATTY LIVER; TNF-ALPHA; FED MICE; INJURY; PATHOGENESIS; STEATOHEPATITIS AB Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4-6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption. C1 [Bertola, Adeline; Mathews, Stephanie; Ki, Sung Hwan; Wang, Hua; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. EM bgao@mail.nih.gov OI Bertola, Adeline/0000-0002-4885-8423 FU NIAAA at the NIH FX We greatly appreciate all current and previous lab members for their technical support and helpful discussions. We also thank L. Chedester, A. Barnes and R. Kechrid from the Office of Laboratory Animal Science for their technical and engineering support, and for their critical reading of the manuscript. This work is supported by the intramural program of NIAAA at the NIH. NR 44 TC 107 Z9 114 U1 6 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 J9 NAT PROTOC JI Nat. Protoc. PD MAR PY 2013 VL 8 IS 3 BP 627 EP 637 DI 10.1038/nprot.2013.032 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 119PU UT WOS:000317110600015 PM 23449255 ER PT J AU Knutson, KM Rakowsky, ST Solomon, J Krueger, F Raymont, V Tierney, MC Wassermann, EM Grafman, J AF Knutson, Kristine M. Rakowsky, Shana T. Solomon, Jeffrey Krueger, Frank Raymont, Vanessa Tierney, Michael C. Wassermann, Eric M. Grafman, Jordan TI Injured brain regions associated with anxiety in Vietnam veterans SO NEUROPSYCHOLOGIA LA English DT Article DE Anxiety; Traumatic brain injury; Voxel-based lesion symptom mapping ID POSTTRAUMATIC-STRESS-DISORDER; PENETRATING HEAD-INJURY; AVERSIVE VISUAL-STIMULI; BED NUCLEUS; ORBITOFRONTAL CORTEX; BASOLATERAL AMYGDALA; HIPPOCAMPAL-LESIONS; PREFRONTAL CORTEX; STRIA TERMINALIS; FUNCTIONAL NEUROANATOMY AB Anxiety negatively affects quality of life and psychosocial functioning. Previous research has shown that anxiety symptoms in healthy individuals are associated with variations in the volume of brain regions, such as the amygdala, hippocampus, and the bed nucleus of the stria terminalis. Brain lesion data also suggests the hemisphere damaged may affect levels of anxiety. We studied a sample of 182 male Vietnam War veterans with penetrating brain injuries, using a semi-automated voxel-based lesion-symptom mapping (VLSM) approach. VLSM reveals significant associations between a symptom such as anxiety and the location of brain lesions, and does not require a broad, subjective assignment of patients into categories based on lesion location. We found that lesioned brain regions in cortical and limbic areas of the left hemisphere, including middle, inferior and superior temporal lobe, hippocampus, and fusiform regions, along with smaller areas in the inferior occipital lobe, parahippocampus, amygdala, and insula, were associated with increased anxiety symptoms as measured by the Neurobehavioral Rating Scale (NRS). These results were corroborated by similar findings using Neuropsychiatric Inventory (NPI) anxiety scores, which supports these regions' role in regulating anxiety. In summary, using a semi-automated analysis tool, we detected an effect of focal brain damage on the presentation of anxiety. We also separated the effects of brain injury and war experience by including a control group of combat veterans without brain injury. We compared this control group against veterans with brain lesions in areas associated with anxiety, and against veterans with lesions only in other brain areas. Published by Elsevier Ltd. C1 [Knutson, Kristine M.; Tierney, Michael C.; Wassermann, Eric M.] NINDS, Behav Neurol Unit, NIH, Bethesda, MD 20892 USA. [Rakowsky, Shana T.] Georgetown Univ, Georgetown Coll, Washington, DC USA. [Solomon, Jeffrey] Expert Image Anal LLC, Potomac, MD USA. [Krueger, Frank] George Mason Univ, Dept Mol Neurosci, Fairfax, VA 22030 USA. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Raymont, Vanessa] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Raymont, Vanessa] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Grafman, Jordan] Rehabil Inst Chicago, Brain Injury Res Program, Chicago, IL 60611 USA. RP Knutson, KM (reprint author), NINDS, Behav Neurol Unit, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM knutsonk@ninds.nih.gov; jgrafman@ric.org OI Knutson, Kristine/0000-0003-4626-4514; Grafman, Jordan H./0000-0001-8645-4457 FU United States National Institutes of Health, National Institute of Neurological Disorders and Stroke, intramural research program; United States Army Medical Research and Material Command [DAMD17-01-1-0675] FX We especially thank the Vietnam War veterans who participated in this study. We thank the National Naval Medical Center for their support and provision of their facilities and S. Bonifant, B. Cheon, C. Ngo, A. Greathouse, K. Reding, and G. Tasick for their invaluable help with the testing of participants and organization of this study. The work was supported by the United States National Institutes of Health, National Institute of Neurological Disorders and Stroke, intramural research program, and a project grant from the United States Army Medical Research and Material Command administrated by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year post-injury follow-up study, Grant DAMD17-01-1-0675). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, nor the United States Government. NR 120 TC 7 Z9 7 U1 4 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD MAR PY 2013 VL 51 IS 4 BP 686 EP 694 DI 10.1016/j.neuropsychologia.2013.01.003 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 121PV UT WOS:000317257600012 PM 23328629 ER PT J AU Damiano, DL Prosser, LA Curatalo, LA Alter, KE AF Damiano, Diane L. Prosser, Laura A. Curatalo, Lindsey A. Alter, Katharine E. TI Muscle Plasticity and Ankle Control After Repetitive Use of a Functional Electrical Stimulation Device for Foot Drop in Cerebral Palsy SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE cerebral palsy; electrical stimulation; gait; ankle; ultrasound; muscle thickness; cross-sectional area ID STRENGTH; CHILDREN; GAIT; ARCHITECTURE; FES AB Background/Objectives. The primary goal was to determine whether repetitive functional electrical stimulation (FES) for unilateral foot drop increases tibialis anterior (TA) muscle size compared with an untreated baseline and the contralateral side in cerebral palsy (CP). Secondary goals were to determine whether positive changes in muscle size and gait, if found, accumulated during the 3 intervals during which participants used the device. FES devices differ from traditional orthoses that often restrict muscle activation and may exacerbate weakness, promote continued dependence on orthoses, or precipitate functional decline. Methods. Participants were 14 independent ambulators with inadequate dorsiflexion in swing, with a mean age of 13.1 years, evaluated before and after the 3-month baseline, 1-month device accommodation, 3-month primary intervention, and 3-month follow-up phases. The FES device (WalkAide) stimulated the common fibular nerve to dorsiflex the ankle and evert the foot while monitoring use. TA muscle ultrasound, gait velocity, and ankle kinematic data for barefoot and device conditions are reported. Results. Ultrasound measures of TA anatomic cross-sectional area and muscle thickness increased in the intervention compared with baseline and with the contralateral side and were maintained at follow-up. Maximum ankle dorsiflexion decreased at baseline but improved or was maintained during the intervention phase with and without the device, respectively. Muscle size gains were preserved at follow-up, but barefoot ankle motion returned to baseline values. Conclusions. This FES device produced evidence of use-dependent muscle plasticity in CP. Permanent improvements in voluntary ankle control after repetitive stimulation were not demonstrated. C1 [Damiano, Diane L.; Curatalo, Lindsey A.; Alter, Katharine E.] NIH, Bethesda, MD 20814 USA. [Prosser, Laura A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Alter, Katharine E.] Mt Washington Pediat Hosp, Baltimore, MD USA. RP Damiano, DL (reprint author), NIH, 10 Ctr Dr,MSC 1604, Bethesda, MD 20814 USA. EM damianod@cc.nih.gov RI Prosser, Laura/C-1242-2009; Van Mulders, Benjamin/P-1241-2014; Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU Intramural Research Program at the NIH Clinical Center FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Intramural Research Program at the NIH Clinical Center. Innovative Neurotronics provided the devices to all participants. NR 20 TC 14 Z9 15 U1 0 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD MAR-APR PY 2013 VL 27 IS 3 BP 200 EP 207 DI 10.1177/1545968312461716 PG 8 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 118WY UT WOS:000317058600002 PM 23042834 ER PT J AU Starks, AM Martin, DN Dorsey, TH Boersma, BJ Wallace, TA Ambs, S AF Starks, Adrienne M. Martin, Damali N. Dorsey, Tiffany H. Boersma, Brenda J. Wallace, Tiffany A. Ambs, Stefan TI Household Income Is Associated with the p53 Mutation Frequency in Human Breast Tumors SO PLOS ONE LA English DT Article ID NITRIC-OXIDE SYNTHASE; TP53 GENE-MUTATIONS; AFRICAN-AMERICAN; CANCER PATIENTS; MOLECULAR PATHOGENESIS; SOCIOECONOMIC-STATUS; RACIAL DISPARITIES; EPITHELIAL-CELLS; SUPPRESSOR GENE; POOR-PROGNOSIS AB Background: A study from Scotland reported that the p53 mutation frequency in breast tumors is associated with socioeconomic deprivation. Methods: We analyzed the association of the tumor p53 mutational status with tumor characteristics, education, and self-reported annual household income (HI) among 173 breast cancer patients from the greater Baltimore area, United States. Results: p53 mutational frequency was significantly associated with HI. Patients with < $15,000 HI had the highest p53 mutation frequency (21%), followed by the income group between $15,000 and $60,000 (18%), while those above $60,000 HI had the fewest mutations (5%). When dichotomized at $60,000, 26 out of 135 patients in the low income category had acquired a p53 mutation, while only 2 out of 38 with a high income carried a mutation (P<0.05). In the adjusted logistic regression analysis with 3 income categories (trend test), the association between HI and p53 mutational status was independent of tumor characteristics, age, race/ethnicity, tobacco smoking and body mass. Further analyses revealed that HI may impact the p53 mutational frequency preferentially in patients who develop an estrogen receptor (ER)-negative disease. Within this group, 42% of the low income patients (<$15,000 HI) carried a mutation, followed by the middle income group (21%), while those above $60,000 HI did not carry mutations (P-trend < 0.05). Conclusions: HI is associated with the p53 mutational frequency in patients who develop an ER-negative disease. Furthermore, high income patients may acquire fewer p53 mutations than other patients, suggesting that lifetime exposures associated with socio-economic status may impact breast cancer biology. C1 [Starks, Adrienne M.; Dorsey, Tiffany H.; Boersma, Brenda J.; Wallace, Tiffany A.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Martin, Damali N.] NCI, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov RI Boersma, Brenda/A-9270-2009 OI Boersma, Brenda/0000-0002-8992-2735 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, United States of America FX The research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 5 Z9 5 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 MAR 1 PY 2013 VL 8 IS 3 AR e57361 DI 10.1371/journal.pone.0057361 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 103EI UT WOS:000315897100019 PM 23469190 ER PT J AU Alivisatos, AP Andrews, AM Boyden, ES Chun, M Church, GM Deisseroth, K Donoghue, JP Fraser, SE Lippincott-Schwartz, J Looger, LL Masmanidis, S McEuen, PL Nurmikko, AV Park, H Peterka, DS Reid, C Roukes, ML Scherer, A Schnitzer, M Sejnowski, TJ Shepard, KL Tsao, D Turrigiano, G Weiss, PS Xu, C Yuste, R Zhuang, XW AF Alivisatos, A. Paul Andrews, Anne M. Boyden, Edward S. Chun, Miyoung Church, George M. Deisseroth, Karl Donoghue, John P. Fraser, Scott E. Lippincott-Schwartz, Jennifer Looger, Loren L. Masmanidis, Sotiris McEuen, Paul L. Nurmikko, Arto V. Park, Hongkun Peterka, Darcy S. Reid, Clay Roukes, Michael L. Scherer, Axel Schnitzer, Mark Sejnowski, Terrence J. Shepard, Kenneth L. Tsao, Doris Turrigiano, Gina Weiss, Paul S. Xu, Chris Yuste, Rafael Zhuang, Xiaowei TI Nanotools for Neuroscience and Brain Activity Mapping SO ACS NANO LA English DT Article ID SELF-ASSEMBLED MONOLAYERS; REDUCED SEROTONIN TRANSPORTER; VENTRAL TEGMENTAL AREA; IMAGING-DEPTH LIMIT; IN-VIVO; NEURAL CIRCUITS; MICROELECTRODE ARRAYS; ACTION-POTENTIALS; ELECTRODE ARRAYS; TEMPORAL RESOLUTION AB Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations In current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there Is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and In the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function. C1 [Alivisatos, A. Paul] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Alivisatos, A. Paul] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [Andrews, Anne M.; Masmanidis, Sotiris; Weiss, Paul S.] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA. [Andrews, Anne M.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90095 USA. [Andrews, Anne M.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Boyden, Edward S.] MIT, Dept Biol Engn Brain & Cognit Sci, Media Lab, Cambridge, MA 02139 USA. [Boyden, Edward S.] MIT, McGovern Inst, Cambridge, MA 02139 USA. [Chun, Miyoung] Kavli Fdn, Oxnard, CA 93030 USA. [Church, George M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Church, George M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Church, George M.] Harvard Univ, Biophys Program, Boston, MA 02115 USA. [Deisseroth, Karl; Schnitzer, Mark] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Deisseroth, Karl] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Deisseroth, Karl] Stanford Univ, Dept Psychiat, Stanford, CA 94305 USA. [Donoghue, John P.] Brown Univ, Dept Comp Sci, Div Engn, Dept Neurosci, Providence, RI 02912 USA. [Fraser, Scott E.; Park, Hongkun] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Fraser, Scott E.; Park, Hongkun] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Fraser, Scott E.; Park, Hongkun] Univ So Calif, Dept Physiol & Biophys, Los Angeles, CA 90089 USA. [Fraser, Scott E.; Park, Hongkun] Univ So Calif, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90089 USA. [Fraser, Scott E.; Park, Hongkun] Univ So Calif, Dept Pediat Radiol & Ophthalmol, Los Angeles, CA 90089 USA. [Lippincott-Schwartz, Jennifer; Peterka, Darcy S.; Yuste, Rafael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Looger, Loren L.] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Masmanidis, Sotiris] Univ Calif Los Angeles, Dept Neurobiol, Los Angeles, CA 90095 USA. [McEuen, Paul L.] Cornell Univ, Dept Phys, Lab Atom & Solid State Phys, Ithaca, NY 14853 USA. [McEuen, Paul L.] Cornell Univ, Kavli Inst Cornell Nanoscale Sci, Ithaca, NY 14853 USA. [Nurmikko, Arto V.] Brown Univ, Dept Phys, Providence, RI 02912 USA. [Nurmikko, Arto V.] Brown Univ, Div Engn, Providence, RI 02912 USA. [Fraser, Scott E.; Park, Hongkun] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Fraser, Scott E.; Park, Hongkun] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Lippincott-Schwartz, Jennifer; Peterka, Darcy S.; Yuste, Rafael] Columbia Univ, Howard Hughes Med Inst, New York, NY 10027 USA. [Lippincott-Schwartz, Jennifer; Peterka, Darcy S.; Yuste, Rafael] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Reid, Clay] Allen Inst Brain Sci, Seattle, WA 98103 USA. [Roukes, Michael L.; Scherer, Axel] CALTECH, Kavli Nanosci Inst, Pasadena, CA 91125 USA. [Roukes, Michael L.; Scherer, Axel] CALTECH, Dept Phys, Pasadena, CA 91125 USA. [Roukes, Michael L.; Scherer, Axel] CALTECH, Dept Appl Phys, Pasadena, CA 91125 USA. [Roukes, Michael L.] CALTECH, Dept Bioengn, Pasadena, CA 91125 USA. [Scherer, Axel] CALTECH, Dept Elect Engn, Pasadena, CA 91125 USA. [Schnitzer, Mark] Stanford Univ, James H Clark Ctr, Dept Appl Phys, Stanford, CA 94305 USA. [Schnitzer, Mark] Stanford Univ, James H Clark Ctr, Dept Biol, Stanford, CA 94305 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Howard Hughes Med Inst, Computat Neurobiol Lab, La Jolla, CA 92037 USA. [Sejnowski, Terrence J.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Shepard, Kenneth L.] Columbia Univ, Dept Elect Engn, New York, NY 10027 USA. [Tsao, Doris] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Turrigiano, Gina] Brandeis Univ, Dept Biol, Waltham, MA 02254 USA. [Turrigiano, Gina] Brandeis Univ, Ctr Complex Syst, Waltham, MA 02254 USA. [Weiss, Paul S.] Univ Calif Los Angeles, Dept Mat Sci & Engn, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Xu, Chris] Cornell Univ, Sch Appl & Engn Phys, Ithaca, NY 14853 USA. [Yuste, Rafael] Columbia Univ, Kavli Inst Brain Sci, New York, NY 10027 USA. [Zhuang, Xiaowei] Harvard Univ, Howard Hughes Med Inst, Dept Chem, Cambridge, MA 02138 USA. [Zhuang, Xiaowei] Harvard Univ, Howard Hughes Med Inst, Dept Biol Chem, Cambridge, MA 02138 USA. [Zhuang, Xiaowei] Harvard Univ, Howard Hughes Med Inst, Dept Phys, Cambridge, MA 02138 USA. RP Masmanidis, S (reprint author), Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA. EM smasmanidis@ucla.edu; etcher@caltech.edu; psw@cnsl.ucla.edu; rmy5@columbia.edu RI Andrews, Anne/B-4442-2011; Weiss, Paul/A-2575-2011; Alivisatos , Paul /N-8863-2015 OI Andrews, Anne/0000-0002-1961-4833; Weiss, Paul/0000-0001-5527-6248; Alivisatos , Paul /0000-0001-6895-9048 FU Kavli Foundation FX We gratefully acknowledge the Kavli Foundation for support and encouragement of this initiative and the discussions that led up to it. The authors acknowledge helpful discussions with Prof. Adam Cohen, Dr. Tim Harris, Prof. John Rogers, and Dr. Alan Rudolph, as well as many of our colleagues. We thank Ms. Holly Bunje for help in preparing the manuscript. NR 179 TC 121 Z9 122 U1 13 U2 308 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD MAR PY 2013 VL 7 IS 3 BP 1850 EP 1866 DI 10.1021/nn4012847 PG 17 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 115YB UT WOS:000316846700005 PM 23514423 ER PT J AU Scheibye-Knudsen, M Scheibye-Alsing, K Canugovi, C Croteau, DL Bohr, VA AF Scheibye-Knudsen, Morten Scheibye-Alsing, Karsten Canugovi, Chandrika Croteau, Deborah L. Bohr, Vilhelm A. TI A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging SO AGING-US LA English DT Article DE aging; mitochondria; progeria; bioenergetics; diagnostics; bioinformatics ID DNA-DAMAGE; DYSFUNCTION; AGE; PREVALENCE; RESISTANCE; ATROPHY; CANCER; BRAIN AB The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a clustering algorithm, a disease network, a mitochondrial barcode and two scoring algorithms. Using these tools we detected mitochondrial involvement in a number of diseases not previously recorded as mitochondrial. As a proof of principle Cockayne syndrome, ataxia with oculomotor apraxia 1 (AOA1), spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-telangiectasia have recently been shown to have mitochondrial dysfunction and those diseases showed strong association with mitochondrial disorders. We next evaluated mitochondrial involvement in aging and detected two distinct categories of accelerated aging disorders, one of them being associated with mitochondrial dysfunction. Normal aging seemed to associate stronger with the mitochondrial diseases than the non-mitochondrial partially supporting a mitochondrial theory of aging. C1 [Scheibye-Knudsen, Morten; Canugovi, Chandrika; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Bethesda, MD 20892 USA. [Scheibye-Alsing, Karsten] Univ Copenhagen, Fac Hlth & Med Sci, IBHV, Sect Genet & Bioinformat, DK-1168 Copenhagen, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Bethesda, MD 20892 USA. EM vbohr@nih.gov OI Scheibye-Knudsen, Morten/0000-0002-6637-1280 FU intramural program of the National Institutes of Health FX We would like to thank Dr. Peter Sykora for critically reading the manuscript. This work was supported by funds from the intramural program of the National Institutes of Health. NR 39 TC 19 Z9 19 U1 0 U2 6 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 MAR PY 2013 VL 5 IS 3 BP 192 EP 208 PG 17 WC Cell Biology SC Cell Biology GA 116DO UT WOS:000316863000007 PM 23524341 ER PT J AU Gourh, PR Tan, FK Rueda, B Arnett, FC Assassi, S Reveille, JD Radstake, TRD Agarwal, SK Martin, J Mayes, MD AF Gourh, Pravitt R. Tan, Filemon K. Rueda, Blanca Arnett, Frank C. Assassi, Shervin Reveille, John D. Radstake, Timothy R. D. Agarwal, Sandeep K. Martin, Javier Mayes, Maureen D. TI GENE-GENE INTERACTIONS IN INTERFERON PATHWAY GENE POLYMORPHISMS IN EUROPEAN AND AMERICAN SCLERODERMA COHORTS SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT 33rd European Workshop for Rheumatology Research (EWRR) CY FEB 28-MAR 02, 2013 CL Prague, CZECH REPUBLIC SP UCB, Abbott, GlaxoSmithKline (GSK), MSD, AMGEN, MD Biosciences, Novo Nordisk C1 [Gourh, Pravitt R.] NIH, Bethesda, MD 20892 USA. [Tan, Filemon K.; Arnett, Frank C.; Assassi, Shervin; Reveille, John D.; Agarwal, Sandeep K.; Mayes, Maureen D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Rueda, Blanca] Univ Granada, Fac Ciencias Salud, Granada, Spain. [Radstake, Timothy R. D.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Martin, Javier] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain. 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 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR PY 2013 VL 72 SU 1 BP A56 EP A57 PG 3 WC Rheumatology SC Rheumatology GA 115JM UT WOS:000316808400144 ER PT J AU Mizesko, MC Banerjee, PP Monaco-Shawver, L Mace, EM Bernal, W Sawalle-Belohradsky, J Belohradsky, B Heinz, V Freeman, AF Sullivan, KE Holland, SM Torgerson, TR Al-Herz, W Chou, J Hanson, IC Albert, MH Geha, RS Renner, ED Orange, JS AF Mizesko, M. C. Banerjee, P. P. Monaco-Shawver, L. Mace, E. M. Bernal, W. Sawalle-Belohradsky, J. Belohradsky, B. Heinz, V. Freeman, A. F. Sullivan, K. E. Holland, S. M. Torgerson, T. R. Al-Herz, W. Chou, J. Hanson, I. C. Albert, M. H. Geha, R. S. Renner, E. D. Orange, J. S. TI IMPAIRED NATURAL KILLER CELL FUNCTION IN DOCK8 DEFICIENCY SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT 33rd European Workshop for Rheumatology Research (EWRR) CY FEB 28-MAR 02, 2013 CL Prague, CZECH REPUBLIC SP UCB, Abbott, GlaxoSmithKline (GSK), MSD, AMGEN, MD Biosciences, Novo Nordisk C1 [Mizesko, M. C.; Banerjee, P. P.; Mace, E. M.; Hanson, I. C.; Orange, J. S.] Baylor Coll Med, Houston, TX 77030 USA. [Mizesko, M. C.; Banerjee, P. P.; Mace, E. M.; Hanson, I. C.; Orange, J. S.] Texas Childrens Hosp, Houston, TX 77030 USA. [Monaco-Shawver, L.; Bernal, W.; Sullivan, K. E.] Childrens Hosp Philadelphia, Res Inst, Philadelphia, PA 19104 USA. [Sawalle-Belohradsky, J.; Belohradsky, B.; Heinz, V.; Albert, M. H.; Renner, E. D.] Univ Munich, Univ Childrens Hosp, Munich, Germany. [Freeman, A. F.; Holland, S. M.] NIAID, NIH, Bethesda, MD 20892 USA. [Torgerson, T. R.] Univ Washington, Seattle, WA 98195 USA. [Torgerson, T. R.] Seattle Childrens Hosp, Seattle, WA USA. [Al-Herz, W.] Kuwait Univ, Kuwait, Kuwait. [Al-Herz, W.] Allergy & Clin Immunol Unit, Kuwait, Kuwait. [Chou, J.; Geha, R. S.] Boston Childrens Hosp, Boston, MA USA. 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 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR PY 2013 VL 72 SU 1 BP A12 EP A13 DI 10.1136/annrheumdis-2013-203215.23 PG 3 WC Rheumatology SC Rheumatology GA 115JM UT WOS:000316808400033 ER PT J AU Zou, BB Li, QQ Zhao, JS Li, JM Cuff, CF Reed, E AF Zou, Baobo Li, Q. Quentin Zhao, Jinshun Li, Jueli M. Cuff, Christopher F. Reed, Eddie TI beta-Elemene and Taxanes Synergistically Induce Cytotoxicity and Inhibit Proliferation in Ovarian Cancer and Other Tumor Cells SO ANTICANCER RESEARCH LA English DT Article DE Chinese medicine; beta-elemene; taxanes; synergism; ovarian cancer; prostate cancer; apoptosis; cell cycle arrest ID IN-VITRO; PROSTATE-CANCER; BREAST-CANCER; ANTITUMOR-ACTIVITY; CARCINOMA CELLS; STAGE-III; TAXOL; CHEMOTHERAPY; PACLITAXEL; APOPTOSIS AB beta-Elemene, originally derived from plants, has been recently investigated as a new anticancer agent. The purpose of this study was to explore the efficacy and mechanisms of action of the combined use of beta-elemene plus a taxane as an antitumor therapeutic strategy for ovarian cancer and other carcinomas. The interaction of beta-elemene with paclitaxel or docetaxel produced additive to moderately synergistic effects against the platinum-resistant ovarian cancer cell line A2780/CP70 and its parental cell line A2780, and showed moderately synergistic activity against PC-3 prostate cancer cells. In addition, the co-administration of beta-elemene and a taxane at low-micromolar concentrations dramatically increased the rate of micronucleus formation and the percentage of mitotic arrest in both ovarian cancer cell lines, as compared with treatment with either agent alone. The highest synergy towards the ovarian cancer cells was observed with beta-elemene plus docetaxel. Consistent with these data, treatment of A2780/CP70 cells with 16-elemene plus a taxane strikingly reduced cell viability and increased cell apoptosis, as assessed by annexin V binding. Moreover, beta-elemene plus docetaxel induced elevated levels of caspase-9 and p53 proteins in A2780/CP70 cells, and the combination of beta-elemene plus a taxane caused marked cell-cycle arrest at the G(2)/M phase in these cells. One possible mechanism to account for the enhanced cytotoxic efficacy of this combination treatment is a beta-elemene-induced increase in taxane influx into cancer cells. These observations indicate that combination therapy with beta-elemene and taxanes has synergistic antitumor activity against ovarian and prostate carcinomas in vitro. This promising new therapeutic combination warrants further pre-clinical exploration for the treatment of chemoresistant ovarian cancer and other types of tumors. C1 [Zou, Baobo; Zhao, Jinshun] Ningbo Univ, Sch Med, Dept Publ Hlth, Zhejiang Prov Key Lab Pathol & Physiol Technol, Ningbo 315211, Zhejiang, Peoples R China. [Zou, Baobo; Li, Q. Quentin; Zhao, Jinshun; Cuff, Christopher F.; Reed, Eddie] W Virginia Univ, Sch Med, Morgantown, WV 26506 USA. [Li, Jueli M.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Li, Q. Quentin; Reed, Eddie] NCI, NIH, Bethesda, MD 20892 USA. RP Li, QQ (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov FU National Nature Science Foundation of China [81273111]; Foundation of Innovative Research Team of Educational Commission of Zhejiang Province [T200907]; Nature Science Foundation of Ningbo City [2012A610185]; Ningbo Scientific Projects [2012C5019, SZX11073]; Scientific Innovation Team Project of Ningbo [2011B82014]; Innovative Research Team of Ningbo [2009B21002]; Ningbo University; U.S. National Institutes of Health [P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003]; West Virginia University School of Medicine Research Grant FX This publication was made possible by grants from the National Nature Science Foundation of China (no. 81273111), the Foundation of Innovative Research Team of Educational Commission of Zhejiang Province (T200907), the Nature Science Foundation of Ningbo City (no. 2012A610185), the Ningbo Scientific Projects (2012C5019 and SZX11073), the Scientific Innovation Team Project of Ningbo (no. 2011B82014), Innovative Research Team of Ningbo (2009B21002) and K.C. Wong Magna Fund in Ningbo University, and by grants from the U.S. National Institutes of Health (nos. P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003) and a West Virginia University School of Medicine Research Grant (to QQL). NR 59 TC 8 Z9 8 U1 1 U2 6 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAR PY 2013 VL 33 IS 3 BP 929 EP 940 PG 12 WC Oncology SC Oncology GA 114VH UT WOS:000316770400024 PM 23482764 ER PT J AU Mastelic, B Lewis, DJM Golding, H Gust, I Sheets, R Lambert, PH AF Mastelic, Beatris Lewis, David J. M. Golding, Hana Gust, Ian Sheets, Rebecca Lambert, Paul-Henri TI Potential use of inflammation and early immunological event biomarkers in assessing vaccine safety SO BIOLOGICALS LA English DT Article DE Vaccine; Biomarkers; Vaccine safety ID MONOCYTE ACTIVATION TEST; HUMAN SERUM-ALBUMIN; WHOLE-BLOOD ASSAY; IN-WATER EMULSION; CD4(+) T-CELLS; NALP3 INFLAMMASOME; DENDRITIC CELLS; INTERNATIONAL VALIDATION; BYSTANDER ACTIVATION; AUTOIMMUNE-DISEASES AB Highly effective vaccines have traditionally been designed in a rather empirical way, often with incomplete understanding of their mode of action. Full assessment of efficacy and reactogenicity takes time and, as a result, vaccine introduction to the market is usually slow and expensive. In addition, in rare cases, unacceptable reactogenicity may only become apparent after years of development or even widespread use. However, recent advances in cell biology and immunology offer a range of new technologies and systems for identifying biological responses or "biomarkers" that could possibly be used to evaluate and predict efficacy and safety during vaccine development and post-marketing surveillance. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the potential use of biomarkers to assess vaccine safety which was held in Baltimore, Maryland, USA, from 10 to 11 May 2012 and organized by the International Association for Biologicals (JABS). The conference focused particularly on determining which biomarkers might relate to vaccine efficacy and reactogenicity and whether our knowledge base was sufficiently robust at this time for the data to be used for decision-making. More information on the conference output can be found on the JABS website, http://www.iabs.org/. C1 [Mastelic, Beatris; Lambert, Paul-Henri] Univ Geneva, WHO, Ctr Vaccinol & Neonatal Immunol, CMU, CH-1211 Geneva 4, Switzerland. [Lewis, David J. M.] Univ Surrey, Clin Res Ctr, Guildford GU2 7XP, Surrey, England. [Golding, Hana] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA. [Gust, Ian] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. [Sheets, Rebecca] NIAID, CAPT, US PHS, NIH, Bethesda, MD 20892 USA. RP Lambert, PH (reprint author), Univ Geneva, WHO, Ctr Vaccinol & Neonatal Immunol, CMU, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. EM paul.lambert@unige.ch OI Lewis, David JM/0000-0003-3105-9075 FU GlaxoSmithKline Biologicals; Sanofi Pasteur; Novartis; IMI; Pfizer; CSL FX We thank Betty Dodet (Dodet Bioscience) for her skillful help in the preparation of this report. This workshop was made possible by unrestricted educational grants from GlaxoSmithKline Biologicals, Sanofi Pasteur, Novartis, IMI, Pfizer and CSL. NR 72 TC 8 Z9 8 U1 1 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 J9 BIOLOGICALS JI Biologicals PD MAR PY 2013 VL 41 IS 2 BP 115 EP 124 DI 10.1016/j.biologicals.2012.10.005 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 115WX UT WOS:000316843700010 PM 23194656 ER PT J AU Reina, SA Shomaker, LB Mooreville, M Courville, AB Brady, SM Olsen, C Yanovski, SZ Tanofsky-Kraff, M Yanovski, JA AF Reina, Samantha A. Shomaker, Lauren B. Mooreville, Mira Courville, Amber B. Brady, Sheila M. Olsen, Cara Yanovski, Susan Z. Tanofsky-Kraff, Marian Yanovski, Jack A. TI Sociocultural pressures and adolescent eating in the absence of hunger SO BODY IMAGE LA English DT Article DE Body image; Adolescence; Eating in the absence of hunger; Pressure to be thin; Obesity ID CHILD-FEEDING QUESTIONNAIRE; BODY-IMAGE; ENERGY-INTAKE; DIETARY RESTRAINT; PUBERTAL CHANGES; COLLEGE-WOMEN; RISK-FACTORS; ACUTE STRESS; WEIGHT-GAIN; OVERWEIGHT AB Parental feeding practices and sociocultural pressures theoretically influence eating behavior. Yet, whether these factors relate to eating in the absence of hunger (EAH) is unknown. We assessed if sociocultural pressures were associated with EAH among 90 adolescents (M-age = 15.27, SD = 1.39; 48% female). Parents completed the Child Feeding Questionnaire. Adolescents completed the Perceived Sociocultural Pressures Scale, Sociocultural Attitudes Towards Appearance Questionnaire-3, and Multidimensional Body Self-Relations Questionnaire-Appearance Scales. On two occasions, EAH was assessed as snack food intake after adolescents ate to satiety. Controlling for body composition and demographics, parental restriction and family pressure to be thin were associated with greater EAH. Media pressure was related to more EAH in girls. Appearance orientation and preoccupation with becoming overweight mediated links between sociocultural pressures and EAH. Findings support the notion that sociocultural pressures and their links to body image may contribute to the course of disinhibited eating behaviors during adolescence. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Reina, Samantha A.; Shomaker, Lauren B.; Mooreville, Mira; Brady, Sheila M.; Yanovski, Susan Z.; Tanofsky-Kraff, Marian; Yanovski, Jack A.] Natl Inst Child Hlth & Human Dev NICHD, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Shomaker, Lauren B.; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol MPS, Bethesda, MD 20814 USA. [Courville, Amber B.] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Olsen, Cara] USUHS, Dept Prevent Med & Biometr, Bethesda, MD USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, Bethesda, MD USA. RP Shomaker, LB (reprint author), NICHHD, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH CRC, 10 Ctr Dr,MSC 1103,Room 1-3330, Bethesda, MD 20892 USA. EM shomakel@mail.nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [Z99 HD999999, ZIA HD000641-17]; NICHD NIH HHS [1F32HD056762, 1K99HD069516, F32 HD056762, K99 HD069516, Z01 HD000641, Z01HD00641] NR 81 TC 2 Z9 2 U1 4 U2 36 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1740-1445 J9 BODY IMAGE JI Body Image PD MAR PY 2013 VL 10 IS 2 BP 182 EP 190 DI 10.1016/j.bodyim.2012.12.004 PG 9 WC Psychology, Clinical; Psychiatry; Psychology, Multidisciplinary SC Psychology; Psychiatry GA 118LM UT WOS:000317027000005 PM 23394966 ER PT J AU Zamarin, D Giralt, S Landau, H Lendvai, N Lesokhin, A Chung, D Koehne, G Chimento, D Devlin, SM Riedel, E Bhutani, M Babu, D Hassoun, H AF Zamarin, D. Giralt, S. Landau, H. Lendvai, N. Lesokhin, A. Chung, D. Koehne, G. Chimento, D. Devlin, S. M. Riedel, E. Bhutani, M. Babu, D. Hassoun, H. TI Patterns of relapse and progression in multiple myeloma patients after auto-SCT: implications for patients' monitoring after transplantation SO BONE MARROW TRANSPLANTATION LA English DT Article DE multiple myeloma; autologous transplantation; relapse; free light chain assay ID FREE LIGHT-CHAIN; STEM-CELL TRANSPLANTATION; MONOCLONAL GAMMOPATHIES; SERUM; IMMUNOGLOBULIN; URINE; IMMUNOFIXATION AB Auto-SCT (ASCT) is widely used in first-line treatment of multiple myeloma (MM). However, most patients eventually relapse or have progression of disease (R/POD). Although precise knowledge of R/POD patterns would be important to generate evidence-based surveillance recommendations after ASCT, such data is limited in the literature, especially after introduction of the free light chain assay (FLCA). This retrospective study examined the patterns of R/POD after first-line ASCT in 273 patients, using established criteria. At the time of R/POD, only 2% of patients had no associated serological evidence of R/POD. A total of 85% had asymptomatic R/POD, first detected by serological testing, whereas 15% had symptomatic R/POD with aggressive disease, early R/POD and short survival, with poor cytogenetics and younger age identified as risk factors. Although occult skeletal lesions were found in 40% of asymptomatic patients tested following serological R/POD, yearly skeletal surveys and urine testing were poor at heralding R/POD. We found a consistent association between paraprotein types at diagnosis and R/POD, allowing informed recommendations for appropriate serological monitoring and propose a new needed criterion using FLCA for patients relapsing by FLC only. Our findings provide important evidence-based recommendations that strengthen current monitoring guidelines after first-line ASCT in MM. Bone Marrow Transplantation (2013) 48, 419-424; doi:10.1038/bmt.2012.151; published online 13 August 2012 C1 [Zamarin, D.; Giralt, S.; Landau, H.; Lendvai, N.; Lesokhin, A.; Chung, D.; Koehne, G.; Chimento, D.; Hassoun, H.] Mem Sloan Kettering Canc Ctr, Dept Med, Div Hematol Malignancies, New York, NY 10065 USA. [Devlin, S. M.; Riedel, E.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY USA. [Bhutani, M.] NCI, Dept Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Babu, D.] Columbia Univ Coll Phys & Surg, St Lukes Roosevelt Hosp Ctr, Mem Sloan Kettering Canc Ctr, Dept Internal Med, New York, NY 10032 USA. [Babu, D.] Weil Cornell Med Sch, New York, NY USA. RP Hassoun, H (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Div Hematol Malignancies, 1275 York Ave,Room H709, New York, NY 10065 USA. EM hassounh@mskcc.org FU NCI NIH HHS [T32 CA009207] NR 27 TC 12 Z9 12 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2013 VL 48 IS 3 BP 419 EP 424 DI 10.1038/bmt.2012.151 PG 6 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 116YU UT WOS:000316920100016 PM 22890289 ER PT J AU Liu, W Liu, Y Guo, T Hu, C Luo, H Zhang, L Shi, S Cai, T Ding, Y Jin, Y AF Liu, W. Liu, Y. Guo, T. Hu, C. Luo, H. Zhang, L. Shi, S. Cai, T. Ding, Y. Jin, Y. TI TCF3, a novel positive regulator of osteogenesis, plays a crucial role in miR-17 modulating the diverse effect of canonical Wnt signaling in different microenvironments SO CELL DEATH & DISEASE LA English DT Article DE transcription factor 3; miR-17; canonical Wnt signaling; osteogenesis; microenvironment ID MESENCHYMAL STEM-CELLS; BONE-MARROW MICROENVIRONMENT; HUMAN PERIODONTAL-LIGAMENT; GENE-EXPRESSION; LINEAGE COMMITMENT; SELF-RENEWAL; IN-VIVO; RUNX2; PROLIFERATION; OSTEOBLASTS AB Wnt signaling pathways are a highly conserved pathway, which plays an important role from the embryonic development to bone formation. The effect of Wnt pathway on osteogenesis relies on their cellular environment and the expression of target genes. However, the molecular mechanism of that remains unclear. On the basis of the preliminary results, we observed the contrary effect of canonical Wnt signaling on osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in the different culture environment. Furthermore, we found that the expression level of miR-17 was also varied with the change in the culture environment. Therefore, we hypothesized that miR-17 and canonical Wnt signaling may have potential interactions, particularly the inner regulation relationship in different microenvironments. In this paper, we observed that canonical Wnt signaling promoted osteogenesis of PDLSCs in the fully culture medium, while inhibited it in the osteogenic differentiation medium. Interestingly, alteration in the expression level of endogenous miR-17 could partially reverse the different effect of canonical Wnt signaling. Furthermore, the role of miR-17 was because of its target gene TCF3 (transcription factor 3), a key transcription factor of canonical Wnt pathway. Overexpression of TCF3 attenuated the effect of miR-17 on modulating canonical Wnt signaling. Finally, we elucidated that TCF3 enhanced osteogenesis both in vitro and in vivo. In brief, the different level of miR-17 was the main cause of the different effect of canonical Wnt signaling, and TCF3 was the crucial node of miR-17-canonial Wnt signaling regulation loop. This understanding of microRNAs regulating signaling pathways in different microenvironments may pave the way for fine-tuning the process of osteogenesis in bone-related disorders. Cell Death and Disease (2013) 4, e539; doi:10.1038/cddis.2013.65; published online 14 March 2013 C1 [Liu, W.; Liu, Y.; Guo, T.; Ding, Y.] Fourth Mil Med Univ, Sch Stomatol, Dept Orthodont, Xian 710032, Shaanxi, Peoples R China. [Liu, W.; Liu, Y.; Hu, C.; Luo, H.; Zhang, L.; Jin, Y.] Fourth Mil Med Univ, Res & Dev Ctr Tissue Engn, Xian 710032, Shaanxi, Peoples R China. [Shi, S.] Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90089 USA. [Cai, T.] NIDCR, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. [Jin, Y.] Fourth Mil Med Univ, Dept Oral Histol & Pathol, Sch Stomatol, Xian 710032, Shaanxi, Peoples R China. RP Jin, Y (reprint author), 145 West Changle Rd, Xian 710032, Shaanxi, Peoples R China. EM Dingyin@fmmu.edu.cn; yanjin@fmmu.edu.cn RI Hu, Cheng-Hu/I-4210-2013; Jin, Yan/I-4204-2013 FU National Basic Research Program (973 Program) [2011CB964700, 2010CB944802]; Nature Science Foundation of China [81020108019, 31030033, 31200972]; National Institute of Dental and Craniofacial Research, National Institutes of Health; Department of Health and Human Services [R01DE019932] FX This work was supported by grants from the National Basic Research Program (973 Program) (2011CB964700 and 2010CB944802), the Nature Science Foundation of China (81020108019, 31030033 and 31200972) and a grant from the National Institute of Dental and Craniofacial Research, National Institutes of Health and Department of Health and Human Services (R01DE019932 to SS). NR 47 TC 15 Z9 17 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD MAR PY 2013 VL 4 AR e539 DI 10.1038/cddis.2013.65 PG 11 WC Cell Biology SC Cell Biology GA 116FR UT WOS:000316868700018 PM 23492770 ER PT J AU Liu, J Nussinov, R AF Liu, Jin Nussinov, Ruth TI The role of allostery in the ubiquitin-proteasome system SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Allosteric; allostery; degradation; molecular machine; ubiquitin ID END RULE PATHWAY; CONJUGATING ENZYME; STRUCTURAL BASIS; DRUG DISCOVERY; SACCHAROMYCES-CEREVISIAE; MULTIUBIQUITIN CHAIN; MECHANISTIC INSIGHTS; SUMO CONJUGATION; BINDING CASCADES; FOLDING FUNNELS AB The ubiquitin-proteasome system (UPS) is involved in many cellular processes including protein degradation. Degradation of a protein via this system involves two successive steps: ubiquitination and degradation. Ubiquitination tags the target protein with ubiquitin-like proteins (UBLs), such as ubiquitin, small ubiquitin-like modifier (SUMO) and NEDD8, via a cascade involving three enzymes: activating enzyme E1, conjugating enzyme E2 and E3 ubiquitin ligases. The proteasomes recognize the UBL-tagged substrate proteins and degrade them. Accumulating evidence indicates that allostery is a central player in the regulation of ubiquitination, as well as deubiquitination and degradation. Here, we provide an overview of the key mechanistic roles played by allostery in all steps of these processes, and highlight allosteric drugs targeting them. Throughout the review, we emphasize the crucial mechanistic role played by linkers in allosterically controlling the UPS action by biasing the sampling of the conformational space, which facilitate the catalytic reactions of the ubiquitination and degradation. Finally, we propose that allostery may similarly play key roles in the regulation of molecular machines in the cell, and as such allosteric drugs can be expected to be increasingly exploited in therapeutic regimes. C1 [Liu, Jin; Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program,Frederick Natl Lab, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. EM NussinoR@helix.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract 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 the 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 89 TC 16 Z9 18 U1 0 U2 15 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-9238 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD MAR-APR PY 2013 VL 48 IS 2 BP 89 EP 97 DI 10.3109/10409238.2012.742856 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 117LN UT WOS:000316955000001 PM 23234564 ER PT J AU Marullo, L Dupuis, J Scapoli, C Meigs, JB Morris, A Prokopenko, I AF Marullo, L. Dupuis, J. Scapoli, C. Meigs, J. B. Morris, A. Prokopenko, I. TI Impact of Type 2 diabetes susceptibility loci on variation in multiple cardio-metabolic traits SO DIABETIC MEDICINE LA English DT Meeting Abstract C1 [Marullo, L.; Scapoli, C.] Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy. [Marullo, L.; Morris, A.; Prokopenko, I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Dupuis, J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Meigs, J. B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, J. B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Prokopenko, I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. RI Scapoli, Chiara/E-2268-2015 OI Scapoli, Chiara/0000-0003-4058-4787 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 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD MAR PY 2013 VL 30 SU 1 SI SI BP 51 EP 51 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 108AQ UT WOS:000316263400161 ER PT J AU Fliedner, SM Shankavaram, U Elkahloun, AG Huynh, TT Linehan, WM Timmers, HJ Tischler, AS Powers, J de Krijger, R Baysal, B David, G Lehnert, H Camphausen, K Pacak, K AF Fliedner, S. M. Shankavaram, U. Elkahloun, A. G. Huynh, T. T. Linehan, W. M. Timmers, H. J. Tischler, A. S. Powers, J. de Krijger, R. Baysal, B. David, G. Lehnert, H. Camphausen, K. Pacak, K. TI Genotype and tumor location determine gene expression signatures in pseudohypoxic pheochromocytomas and paragangliomas SO EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES LA English DT Meeting Abstract C1 [Fliedner, S. M.; Lehnert, H.] Univ Hosp Schleswig Holstein, Dept Med 1, Lubeck, Germany. [Fliedner, S. M.; Huynh, T. T.; Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Shankavaram, U.; David, G.; Camphausen, K.] NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Elkahloun, A. G.] NHGRI, NIH, Canc Genet Branch, Bethesda, MD 20892 USA. [Linehan, W. M.] NCI, NIH, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Timmers, H. J.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands. [Tischler, A. S.; Powers, J.] Tufts Med Ctr, Dept Pathol, Boston, MA USA. [de Krijger, R.] Erasmus MC Univ, Med Ctr, Dept Pathol, Josephine Nefkens Inst, Rotterdam, Netherlands. [Baysal, B.] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA. [David, G.] Feinberg Northwestern Med Sch, Dept Radiat Oncol, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH PI STUTTGART PA RUEDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0947-7349 J9 EXP CLIN ENDOCR DIAB JI Exp. Clin. Endocrinol. Diabet. PD MAR PY 2013 VL 121 IS 3 MA P27 DI 10.1055/s-0033-1336697 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 113IE UT WOS:000316659000092 ER PT J AU Pamporaki, C Darr, R Bursztyn, M Krinner, A Glokner, S Bornstein, S Pacak, K Lenders, JWM Eisenhofer, G AF Pamporaki, C. Daerr, R. Bursztyn, M. Krinner, A. Gloekner, S. Bornstein, S. Pacak, K. Lenders, J. W. M. Eisenhofer, G. TI Plasma free versus deconjugated metanephrines for diagnosis of pheochromocytoma SO EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES LA English DT Meeting Abstract C1 [Pamporaki, C.; Daerr, R.; Gloekner, S.; Eisenhofer, G.] Uniklinikum Dresden, Inst Clin Chem & Lab Med, Dresden, Germany. [Bursztyn, M.; Bornstein, S.] Uniklinikum Dresden, Dresden, Germany. [Krinner, A.] Tech Univ Dresden, Inst Med Informat & Biometry, Dresden, Germany. [Pacak, K.] NICHHD, NIH, Bethesda, MD 20892 USA. [Lenders, J. W. M.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. RI Lenders, J.W.M./L-4487-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH PI STUTTGART PA RUEDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0947-7349 J9 EXP CLIN ENDOCR DIAB JI Exp. Clin. Endocrinol. Diabet. PD MAR PY 2013 VL 121 IS 3 MA OP2_13 DI 10.1055/s-0033-1336621 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 113IE UT WOS:000316659000014 ER PT J AU Yamane, H Paul, WE AF Yamane, Hidehiro Paul, William E. TI Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets SO IMMUNOLOGICAL REVIEWS LA English DT Review DE T-helper cells; TCR signals; cytokines; transcription factors; Notch pathway ID NF-KAPPA-B; TGF-BETA; IN-VIVO; GATA3 EXPRESSION; MICE LACKING; T(H)2 DIFFERENTIATION; TH2 DIFFERENTIATION; MEDIATED ACTIVATION; CYTOKINE PRODUCTION; KINASE ACTIVATION AB CD4(+) T-helper (Th) cells are a major cell population that play an important role in governing acquired immune responses to a variety of foreign antigens as well as inducing some types of autoimmune diseases. There are at least four distinct Th cell subsets (Th1, Th2, Th17, and inducible T-regulatory cells), each of which has specialized functions to control immune responses. Each of these cell types emerge from naive CD4(+) T cells after encounter with foreign antigens presented by dendritic cells (DCs). Each Th cell subset expresses a unique set of transcription factors and produces hallmark cytokines. Both T-cell receptor (TCR)-mediated stimulation and the cytokine environment created by activated CD4(+) T cells themselves, by 'partner' DCs, and/or other cell types during the course of differentiation, play an important role in the fate decisions toward distinct Th subsets. Here, we review how TCR-mediated signals in collaboration with the cytokine environment influence the fate decisions of naive CD4(+) T cells toward distinct Th subsets at the early stages of activation. We also discuss the roles of TCR-proximal signaling intermediates and of the Notch pathway in regulating the differentiation to distinct Th phenotypes. C1 [Yamane, Hidehiro; Paul, William E.] NIAID, Cytokine Biol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Yamane, H (reprint author), Bldg 10,Room 11N314,10 Ctr Dr, Bethesda, MD 20892 USA. EM hyamane@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. The authors declare no competing financial interests. NR 99 TC 119 Z9 119 U1 3 U2 47 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD MAR PY 2013 VL 252 SI SI BP 12 EP 23 DI 10.1111/imr.12032 PG 12 WC Immunology SC Immunology GA 119DT UT WOS:000317078300002 PM 23405892 ER PT J AU Vahedi, G Poholek, AC Hand, TW Laurence, A Kanno, Y O'Shea, JJ Hirahara, K AF Vahedi, Golnaz Poholek, Amanda C. Hand, Timothy W. Laurence, Arian Kanno, Yuka O'Shea, John J. Hirahara, Kiyoshi TI Helper T-cell identity and evolution of differential transcriptomes and epigenomes SO IMMUNOLOGICAL REVIEWS LA English DT Review DE T-cell plasticity; STAT; epigenetics; histone modification; T-cell differentiation; enhancers; master regulator ID DE-NOVO DIFFERENTIATION; IFN-GAMMA PROMOTER; HYPER-IGE SYNDROME; IN-VIVO; GENE-EXPRESSION; TH17 CELLS; MOLECULAR-MECHANISMS; TH2 DIFFERENTIATION; LINEAGE COMMITMENT; EPIGENETIC CONTROL AB CD4(+) T cells are critical for the elimination of an immense array of microbial pathogens. Among the ways they accomplish this task is to generate progeny with specialized, characteristic patterns of gene expression. From this perspective, helper cells can be viewed as pluripotent precursors that adopt distinct cell fates. Although there are aspects of helper cell differentiation that can be modeled as a classic cell fate commitment, CD4(+) T cells also maintain considerable flexibility in their transcriptional program. This makes sense in terms of host defense, but raises the question of how these remarkable cells balance both these requirements, a high degree of specific gene expression and the capacity for plasticity. In this review, we discuss recent advances in our understanding of CD4(+) T-cell specification, focusing on how genomic perspectives have influenced our views of these processes. The relative contributions of sensors of the cytokine milieu, especially the signal transducer and activator of transcription family transcription factors, 'master regulators', and other transcription factors are considered as they relate to the helper cell transcriptome and epigenome. C1 [Vahedi, Golnaz; Poholek, Amanda C.; Laurence, Arian; Kanno, Yuka; O'Shea, John J.; Hirahara, Kiyoshi] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Hand, Timothy W.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), 10 Ctr Dr,Bldg10,Room 13C103, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Kanno, Yuka/B-5802-2013; Laurence, Arian/A-8770-2009; Hirahara, Kiyoshi/E-2460-2017; OI Laurence, Arian/0000-0003-0942-8292; Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319 FU NIH/NIAMS Intramural Research Program (IRP); JSPS; PRAT FX This work was supported by NIH/NIAMS Intramural Research Program (IRP), the JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH (K. H.) and PRAT (A. P.). The authors have no conflicts of interest to declare. NR 218 TC 46 Z9 48 U1 1 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD MAR PY 2013 VL 252 SI SI BP 24 EP 40 DI 10.1111/imr.12037 PG 17 WC Immunology SC Immunology GA 119DT UT WOS:000317078300003 PM 23405893 ER PT J AU Boyer, CB Hightow-Weidman, L Bethel, J Li, SX Henry-Reid, L Futterman, D Maturo, D Straub, DM Howell, K Reid, S Lowe, J Kapogiannis, BG Ellen, JM AF Boyer, Cherrie B. Hightow-Weidman, Lisa Bethel, James Li, Su X. Henry-Reid, Lisa Futterman, Donna Maturo, Donna Straub, Diane M. Howell, Kourtney Reid, Shirleta Lowe, Jaime Kapogiannis, Bill G. Ellen, Jonathan M. TI An Assessment of the Feasibility and Acceptability of a Friendship-Based Social Network Recruitment Strategy to Screen At-Risk African American and Hispanic/Latina Young Women for HIV Infection SO JAMA PEDIATRICS LA English DT Article ID UNITED-STATES; PROJECT ORE; ADOLESCENTS; YOUTH; INTERVENTION; POPULATIONS; HIV/STI; RATES; MEN AB Objectives: To examine the feasibility and acceptability of a friendship-based network recruitment strategy for identifying undiagnosed human immunodeficiency virus (HIV) infection within young women's same-sex friendship networks and to determine factors that facilitated and hindered index recruiters (IRs) in recruiting female friendship network members (FNMs) as well as factors that facilitated and hindered FNMs in undergoing HIV screening. Design: A cross-sectional study design that incorporated dual incentives for IRs and their female FNMs. Setting: The IRs were recruited through 3 Adolescent Trials Network for HIV/AIDS Interventions sites within their Adolescent Medicine Trials Units. Data were collected from January 1, 2009, through June 30, 2010. Participants: The IRs self-identifying as HIV positive, negative, or status unknown were enrolled to recruit FNMs to undergo HIV screening. Main Outcome Measures: Self-reports of HIV risk and facilitators and barriers to network recruitment and HIV screening were assessed using an audio-computer-assisted self-interview. Participants were identified as HIV negative or positive on the basis of an OraQuick HIV test with confirmatory enzyme-linked immunosorbent assay and/or Western blot tests. Results: Nearly all (156 [98.1%]) eligible IRs agreed to participate and most (78.4%) recruited 1 or more FNMs. Of the 381 FNMs, most (342 [89.8%]) agreed to HIV screening. Although a high acceptance of HIV screening was achieved, the HIV prevalence was low (0.26%). Conclusion: Our findings provide compelling evidence to suggest that use of a female friendship network approach is a feasible and acceptable means for engaging at-risk young women in HIV screening, as shown by their high rates of agreement to undergo HIV screening. JAMA Pediatr.2013;167(3):289-296. Published online January 21, 2013. doi:10.1001/2013.jamapediatrics.398 C1 [Boyer, Cherrie B.] Univ Calif San Francisco, Div Adolescent & Young Adult Med, Dept Pediat, San Francisco, CA 94118 USA. [Hightow-Weidman, Lisa] Univ N Carolina, Dept Med, Div Infect Dis, Chapel Hill, NC USA. [Bethel, James; Li, Su X.] WESTAT Corp, Rockville, MD 20850 USA. [Henry-Reid, Lisa; Lowe, Jaime] John H Stroger Jr Hosp Cook Cty, Div Adolescent & Young Adult Med, Dept Pediat, Chicago, IL USA. [Futterman, Donna; Howell, Kourtney] Montefiore Med Ctr, Div Adolescent Med, Dept Pediat, Bronx, NY 10467 USA. [Maturo, Donna; Reid, Shirleta] Univ Miami, Sch Med, Div Adolescent Med, Miami, FL USA. [Straub, Diane M.] Univ S Florida, Div Gen Pediat & Adolescent Med, Tampa, FL USA. [Kapogiannis, Bill G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat & Adolescent Med Branch, NIH, Bethesda, MD USA. [Ellen, Jonathan M.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Boyer, CB (reprint author), Univ Calif San Francisco, Div Adolescent & Young Adult Med, Dept Pediat, 3333 Calif St,Ste 245, San Francisco, CA 94118 USA. EM boyerc@peds.ucsf.edu FU National Institutes of Health through the National Institute of Child Health and Human Development [U01 HD40533]; National Institute on Drug Abuse; National Institute on Mental Health FX The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) is funded by grant U01 HD40533 from the National Institutes of Health through the National Institute of Child Health and Human Development with supplemental funding from the National Institute on Drug Abuse and the National Institute on Mental Health. NR 26 TC 3 Z9 3 U1 1 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 J9 JAMA PEDIATR JI JAMA Pediatr. PD MAR PY 2013 VL 167 IS 3 BP 289 EP 296 DI 10.1001/2013.jamapediatrics.398 PG 8 WC Pediatrics SC Pediatrics GA 115GB UT WOS:000316799500012 PM 23338776 ER PT J AU Guha, S Rees, E Darvasi, A Ivanov, D Ikeda, M Bergen, SE Magnusson, PK Cormican, P Morris, D Gill, M Cichon, S Rosenfeld, JA Lee, A Gregersen, PK Kane, JM Malhotra, AK Rietschel, M Nothen, MM Degenhardt, F Priebe, L Breuer, R Strohmaier, J Ruderfer, DM Moran, JL Chambert, KD Sanders, AR Shi, JX Kendler, K Riley, B O'Neill, T Walsh, D Malhotra, D Corvin, A Purcell, S Sklar, P Iwata, N Hultman, CM Sullivan, PF Sebat, J McCarthy, S Gejman, PV Levinson, DF Owen, MJ O'Donovan, MC Lencz, T Kirov, G AF Guha, Saurav Rees, Elliott Darvasi, Ariel Ivanov, Dobril Ikeda, Masashi Bergen, Sarah E. Magnusson, Patrik K. Cormican, Paul Morris, Derek Gill, Michael Cichon, Sven Rosenfeld, Jeffrey A. Lee, Annette Gregersen, Peter K. Kane, John M. Malhotra, Anil K. Rietschel, Marcella Noethen, Markus M. Degenhardt, Franziska Priebe, Lutz Breuer, Rene Strohmaier, Jana Ruderfer, Douglas M. Moran, Jennifer L. Chambert, Kimberly D. Sanders, Alan R. Shi, Jianxin Kendler, Kenneth Riley, Brien O'Neill, Tony Walsh, Dermot Malhotra, Dheeraj Corvin, Aiden Purcell, Shaun Sklar, Pamela Iwata, Nakao Hultman, Christina M. Sullivan, Patrick F. Sebat, Jonathan McCarthy, Shane Gejman, Pablo V. Levinson, Douglas F. Owen, Michael J. O'Donovan, Michael C. Lencz, Todd Kirov, George CA Mol Genetics Schizophrenia Wellcome Trust Case Control TI Implication of a Rare Deletion at Distal 16p11.2 in Schizophrenia SO JAMA PSYCHIATRY LA English DT Article ID COPY-NUMBER VARIATION; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; DE-NOVO; DEVELOPMENTAL DELAY; DISEASE; GENE; POPULATION; MUTATIONS; PHENOTYPE AB Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. Design: Genetic association study of microarray data. Setting: Samples of DNA were collected at 9 sites from different countries. Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parent-offspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls. Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls. Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094%) and 3 of 19 954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P=.001, Fisher exact test). Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia. JAMA Psychiatry. 2013; 70(3): 253-260. Published online January 16, 2013. doi:10.1001/2013.jamapsychiatry.71 C1 [Guha, Saurav; Kane, John M.; Malhotra, Anil K.; Lencz, Todd] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY 11004 USA. [Rees, Elliott; Ivanov, Dobril; Owen, Michael J.; O'Donovan, Michael C.; Kirov, George] Cardiff Univ, Med Res Council, Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Rees, Elliott; Ivanov, Dobril; Owen, Michael J.; O'Donovan, Michael C.; Kirov, George] Cardiff Univ, Neurosci & Mental Hlth Res Inst, Cardiff CF10 3AX, S Glam, Wales. [Darvasi, Ariel] Hebrew Univ Jerusalem, Inst Life Sci, Dept Genet, IL-91904 Jerusalem, Israel. [Ikeda, Masashi; Iwata, Nakao] Fujita Hlth Univ, Sch Med, Toyoake, Aichi 47011, Japan. [Bergen, Sarah E.; Purcell, Shaun] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Bergen, Sarah E.; Purcell, Shaun] Harvard Univ, Sch Med, Boston, MA USA. [Bergen, Sarah E.; Purcell, Shaun] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Bergen, Sarah E.; Moran, Jennifer L.; Chambert, Kimberly D.; Purcell, Shaun] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Magnusson, Patrik K.; Hultman, Christina M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Cormican, Paul; Morris, Derek; Gill, Michael; Corvin, Aiden] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland. [Walsh, Dermot] Hlth Res Board, Dublin, Ireland. [Cichon, Sven; Noethen, Markus M.; Degenhardt, Franziska; Priebe, Lutz] Univ Bonn, Inst Human Genet, Bonn, Germany. [Cichon, Sven; Degenhardt, Franziska; Priebe, Lutz] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Noethen, Markus M.] Ctr Neurodegenerat Dis, Bonn, Germany. [Cichon, Sven] Res Ctr Juelich, Inst Neurosci & Med, Julich, Germany. [Rosenfeld, Jeffrey A.] Univ Med & Dent New Jersey, IST High Performance & Res Comp, Newark, NJ 07103 USA. [Lee, Annette; Gregersen, Peter K.] Feinstein Inst Med Res, Robert S Boas Ctr Human Genet & Genom, Manhasset, NY USA. [Kane, John M.; Malhotra, Anil K.; Lencz, Todd] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA. [Kane, John M.; Malhotra, Anil K.; Lencz, Todd] Hofstra Univ, Sch Med, Dept Psychiat, Long Isl City, NY USA. [Rietschel, Marcella; Breuer, Rene; Strohmaier, Jana] Heidelberg Univ, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany. [Ruderfer, Douglas M.; Purcell, Shaun; Sklar, Pamela] Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY USA. [Sanders, Alan R.; Gejman, Pablo V.] NorthShore Univ, HealthSyst Res Inst, Dept Psychiat & Behav Sci, Evanston, IL USA. [Sanders, Alan R.; Gejman, Pablo V.] Univ Chicago, Dept Psychiat & Behav Sci, Chicago, IL 60637 USA. [Shi, Jianxin] NCI, Bethesda, MD 20892 USA. [Kendler, Kenneth] Virginia Commonwealth Univ, Sch Med, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. [Riley, Brien] Virginia Commonwealth Univ, Sch Med, Dept Psychiat, Richmond, VA 23284 USA. [O'Neill, Tony] Queens Univ, Dept Psychiat, Belfast, Ireland. [Malhotra, Dheeraj; Sebat, Jonathan] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, La Jolla, CA 92093 USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [McCarthy, Shane] Woodbury Genome Ctr, Cold Spring Harbor Lab, Stanley Inst Cognit Genom, Cold Spring on Hudson, NY USA. [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Lencz, T (reprint author), Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd st, Glen Oaks, NY 11004 USA. EM tlencz@NSHS.edu; Kirov@cardiff.ac.uk RI Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Ruderfer, Douglas/M-5795-2016; Lencz, Todd/J-3418-2014; Magnusson, Patrik/C-4458-2017; OI Gill, Michael/0000-0003-0206-5337; Ivanov, Dobril/0000-0001-6271-6301; Moran, Jennifer/0000-0002-5664-4716; Nothen, Markus/0000-0002-8770-2464; Cichon, Sven/0000-0002-9475-086X; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Guha, Saurav/0000-0002-0620-5408; Morris, Derek/0000-0002-3413-570X; Cichon, Sven/0000-0002-9475-086X; Ruderfer, Douglas/0000-0002-2365-386X; Lencz, Todd/0000-0001-8586-338X; Bergen, Sarah/0000-0002-5888-0034; Sebat, Jonathan/0000-0002-9087-526X FU Medical Research Council [G0800509]; National Institute of Mental Health (NIMH) [2 P50 MH066392-05A1]; EU-GEI from the European Union; Stanley Medical Research Institute; Merck Genome Research Foundation; Herman Foundation; North Shore-Long Island Jewish Health System Foundation; National Institutes of Health [RC2 MH089964, R01 MH084098, P50 MH080173, P30 MH090590]; NIMH [MH67257, H59588, MH59571, MH59565, MH59587, MH60870, MH59566, MH59586, MH61675, MH60879, MH81800, MH46276, MH46289, MH46318, MH79469, MH79470]; National Alliance for Research on Schizophrenia and Depression; Genetic Association Information Network; Paul Michael Donovan Charitable Foundation; Walter E. Nichols, MD, and Eleanor Nichols endowments (Stanford University); National Center for Research Resources [U54 RR020278]; German Federal Ministry of Education and Research (BMBF) [01GS08144, 01GS08147]; Wellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 068545/Z/02]; UK Medical Research Council [G0000934]; UK National Blood Service; Japan Ministry of Education, Culture, Sports, Science and Technology; Ministry of Health, Labor and Welfare; Core Research for Evolutional Science and Technology; Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation) FX Work at Cardiff University was supported by grant G0800509 from the Medical Research Council Programme and Centre Grants, grant 2 P50 MH066392-05A1 from the National Institute of Mental Health (NIMH), and grant EU-GEI from the European Union. Genotyping was funded by multiple grants to the Stanley Center for Psychiatric Research at the Broad Institute from the Stanley Medical Research Institute, the Merck Genome Research Foundation, and the Herman Foundation. The Zucker Hillside Hospital work was supported by the North Shore-Long Island Jewish Health System Foundation and grants RC2 MH089964 (Dr Lencz), R01 MH084098 (Dr Lencz), P50 MH080173 (Dr A. K. Malhotra), and P30 MH090590 (Dr Kane) from the National Institutes of Health. Molecular Genetics of Schizophrenia Consortium data collection was supported by R01 grants MH67257, H59588, MH59571, MH59565, MH59587, MH60870, MH59566, MH59586, MH61675, MH60879, and MH81800 and U01 grants MH46276, MH46289, MH46318, MH79469, and MH79470 from the NIMH. We acknowledge support through Young Investigator Awards (Dr Sanders and Jubao Duan, PhD) from the National Alliance for Research on Schizophrenia and Depression and from the Genetic Association Information Network, the Paul Michael Donovan Charitable Foundation, and the Walter E. Nichols, MD, and Eleanor Nichols endowments (Stanford University). Genotyping performed by the Center for Genotyping and Analysis at the Broad Institute of Harvard and Massachusetts Institute of Technology was supported by grant U54 RR020278 from the National Center for Research Resources. The German study was supported by grants 01GS08144 and 01GS08147 from the German Federal Ministry of Education and Research (BMBF), within the context of the Integrated Genome Research Network MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia). Control data were provided by the community-based studies of PopGen (Population-based Recruitment of Patients and Controls for the Analysis of Complex Genotype-Phenotype Relationships), Cooperative Health Research in the Region Augsburg, the Heinz Nixdorf Recall study, and MooDS. Genotyping of Wellcome Trust Case Control Consortium 2 samples was funded by grants 085475/B/08/Z and 085475/Z/08/Z from the Wellcome Trust. The British 1958 Birth Cohort DNA collection was funded by grant G0000934 from the UK Medical Research Council and grant 068545/Z/02 from the Wellcome Trust, and the UK National Blood Service controls by the Wellcome Trust. The Japanese cohort was supported in part by research grants from the Japan Ministry of Education, Culture, Sports, Science and Technology; the Ministry of Health, Labor and Welfare; the Core Research for Evolutional Science and Technology; and the Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation). NR 28 TC 23 Z9 23 U1 2 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-622X J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAR PY 2013 VL 70 IS 3 BP 253 EP 260 DI 10.1001/2013.jamapsychiatry.71 PG 8 WC Psychiatry SC Psychiatry GA 114GY UT WOS:000316730300002 PM 23325106 ER PT J AU Furey, ML Drevets, WC Hoffman, EM Frankel, E Speer, AM Zarate, CA AF Furey, Maura L. Drevets, Wayne C. Hoffman, Elana M. Frankel, Erica Speer, Andrew M. Zarate, Carlos A., Jr. TI Potential of Pretreatment Neural Activity in the Visual Cortex During Emotional Processing to Predict Treatment Response to Scopolamine in Major Depressive Disorder SO JAMA PSYCHIATRY LA English DT Article ID RAPID ANTIDEPRESSANT RESPONSE; CEREBRAL-BLOOD-FLOW; WORKING-MEMORY; CHOLINERGIC ENHANCEMENT; FUNCTIONAL CONNECTIVITY; SELECTIVE ATTENTION; FACIAL EXPRESSIONS; PREFRONTAL CORTEX; MOOD-STATE; MODULATION AB Context: The need for improved treatment options for patients with major depressive disorder (MDD) is critical. Faster-acting antidepressants and biomarkers that predict clinical response will facilitate treatment. Scopolamine produces rapid antidepressant effects and thus offers the opportunity to characterize potential biomarkers of treatment response within short periods. Objective: To determine if baseline brain activity when processing emotional information can predict treatment response to scopolamine in MDD. Design: A double-blind, placebo-controlled, crossover study together with repeated functional magnetic resonance imaging, acquired as participants performed face-identity and face-emotion working memory tasks. Setting: National Institute of Mental Health Division of Intramural Research Programs. Participants: Fifteen currently depressed outpatients meeting DSM-IV criteria for recurrent MDD and 21 healthy participants, between 18 and 55 years of age. Main Outcome Measure: The magnitude of treatment response to scopolamine (percentage of change in the Montgomery-Asberg Depression Rating Scale score between study end and baseline) was correlated with blood oxygenlevel-dependent(BOLD) signal associated with each working memory component (encode, maintenance, and test) for both identity and emotion tasks. Treatment response also was correlated with change in BOLD response (scopolamine vs baseline). Baseline activity was compared between healthy and MDD groups. Results: Baseline BOLD response in the bilateral middle occipital cortex, selectively during the stimulus-processing components of the emotion working memory task (no correlation during the identity task), correlated with treatment response magnitude. Change in BOLD response following scopolamine administration in overlapping areas in the middle occipital cortex while performing the same task conditions also correlated with clinical response. Healthy controls showed higher activity in the same visual regions than patients with MDD during baseline. Conclusion: These results implicate cholinergic and visual processing dysfunction in the pathophysiology of MDD and suggest that neural response in the visual cortex, selectively to emotional stimuli, may provide a useful biomarker for identifying patients who will respond favorably to scopolamine. Trial Registration: clinicaltrials.gov Identifier: NCT00055575 JAMA Psychiatry. 2013; 70(3): 280-290. Published online January 30, 2013. doi:10.1001/2013.jamapsychiatry.60 C1 [Furey, Maura L.; Frankel, Erica; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Speer, Andrew M.] NIMH, Lab Brain & Cognit, 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. [Hoffman, Elana M.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. RP Furey, ML (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 15K North Dr,Bldg 15K,Room 115B, Bethesda, MD 20892 USA. EM mfurey@mail.nih.gov RI Furey, Maura/H-5273-2013 FU National Institutes of Health National Institute of Mental Health Division of Intramural Research Programs FX This research was supported by the National Institutes of Health National Institute of Mental Health Division of Intramural Research Programs. NR 58 TC 29 Z9 30 U1 4 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-622X J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAR PY 2013 VL 70 IS 3 BP 280 EP 290 DI 10.1001/2013.jamapsychiatry.60 PG 11 WC Psychiatry SC Psychiatry GA 114GY UT WOS:000316730300005 PM 23364679 ER PT J AU Gabay, O Gabay, C AF Gabay, Odile Gabay, Cem TI Hand osteoarthritis: New insights SO JOINT BONE SPINE LA English DT Review DE Hand OA; Biology; Genetic ID KNEE OSTEOARTHRITIS; EROSIVE OSTEOARTHRITIS; GENERAL-POPULATION; OBESE-PATIENTS; DOUBLE-BLIND; WEIGHT-LOSS; ASSOCIATION; HIP; LEPTIN; TRIAL AB Hand osteoarthritis (OA) is one of the most common localization of OA affecting predominantly women. The etiology seems to be multifactorial and the disease heterogeneous, comprising several clinical and radiological subsets. Hand OA includes thumb base (trapeziometarcarpal joint), metacarpophalangeal joints, distal and proximal interphalangeal joints OA. We reviewed below the prevalence, diagnosis, imaging, epidemiology, risk factors, but mostly the last discoveries in the biology and pathophysiology with particular attention to the potential role of adipokines and genetic factors. Finally, we also reviewed the different treatments currently available as well as potential future therapies. (C) 2012 Societe francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. C1 [Gabay, Odile] NIAMSD, Cartilage Biol & Orthoped Branch, NIH, Bethesda, MD 20892 USA. [Gabay, Cem] Univ Hosp Geneva, Div Rheumatol, CH-1211 Geneva 14, Switzerland. RP Gabay, C (reprint author), Univ Hosp Geneva, Div Rheumatol, 26 Ave Beau Sejour, CH-1211 Geneva 14, Switzerland. EM Cem.Gabay@hcuge.ch FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health; Swiss National Science Foundation [310030-135195]; Rheumasearch Foundation; Institute of arthritis Research FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health (OG). CG is supported by a Swiss National Science Foundation grant(310030-135195), the Rheumasearch Foundation, and the Institute of arthritis Research. NR 59 TC 3 Z9 3 U1 2 U2 11 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1297-319X J9 JOINT BONE SPINE JI Joint Bone Spine PD MAR PY 2013 VL 80 IS 2 BP 130 EP 134 DI 10.1016/j.jbspin.2012.06.011 PG 5 WC Rheumatology SC Rheumatology GA 115ED UT WOS:000316794500004 PM 22871418 ER PT J AU Kristensen, DM Waller, AS Yamada, T Bork, P Mushegian, AR Koonin, EV AF Kristensen, David M. Waller, Alison S. Yamada, Takuji Bork, Peer Mushegian, Arcady R. Koonin, Eugene V. TI Orthologous Gene Clusters and Taxon Signature Genes for Viruses of Prokaryotes SO JOURNAL OF BACTERIOLOGY LA English DT Article ID STRAND RNA VIRUSES; EVOLUTIONARY GENOMICS; PROTEIN FAMILIES; BACTERIOPHAGES; IDENTIFICATION; ARCHAEA; GENERATION; SIMILARITY; DIVERSITY; ALGORITHM AB Viruses are the most abundant biological entities on earth and encompass a vast amount of genetic diversity. The recent rapid increase in the number of sequenced viral genomes has created unprecedented opportunities for gaining new insight into the structure and evolution of the virosphere. Here, we present an update of the phage orthologous groups (POGs), a collection of 4,542 clusters of orthologous genes from bacteriophages that now also includes viruses infecting archaea and encompasses more than 1,000 distinct virus genomes. Analysis of this expanded data set shows that the number of POGs keeps growing without saturation and that a substantial majority of the POGs remain specific to viruses, lacking homologues in prokaryotic cells, outside known proviruses. Thus, the great majority of virus genes apparently remains to be discovered. A complementary observation is that numerous viral genomes remain poorly, if at all, covered by POGs. The genome coverage by POGs is expected to increase as more genomes are sequenced. Taxon-specific, single-copy signature genes that are not observed in prokaryotic genomes outside detected proviruses were identified for two-thirds of the 57 taxa (those with genomes available from at least 3 distinct viruses), with half of these present in all members of the respective taxon. These signatures can be used to specifically identify the presence and quantify the abundance of viruses from particular taxa in metagenomic samples and thus gain new insights into the ecology and evolution of viruses in relation to their hosts. C1 [Kristensen, David M.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Waller, Alison S.; Bork, Peer] European Mol Biol Lab, D-69012 Heidelberg, Germany. [Yamada, Takuji] Tokyo Inst Technol, Midori Ku, Yokohama, Kanagawa 227, Japan. [Mushegian, Arcady R.] Stowers Inst Med Res, Kansas City, MO USA. [Mushegian, Arcady R.] Univ Kansas, Med Ctr, Dept Microbiol, Kansas City, KS 66103 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov RI Bork, Peer/F-1813-2013; OI Bork, Peer/0000-0002-2627-833X; Mushegian, Arcady/0000-0002-6809-9225 FU U.S. Department of Health and Human Services; Stowers Institute for Medical Research FX D.M.K. and E.V.K. are supported by intramural funds of the U.S. Department of Health and Human Services (to the National Library of Medicine). A.R.M. was supported by the Stowers Institute for Medical Research. NR 47 TC 35 Z9 35 U1 1 U2 30 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAR PY 2013 VL 195 IS 5 BP 941 EP 950 DI 10.1128/JB.01801-12 PG 10 WC Microbiology SC Microbiology GA 117NY UT WOS:000316961400004 PM 23222723 ER EF