FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Heim, S Ihssen, N Hasselhorn, M Keil, A AF Heim, Sabine Ihssen, Niklas Hasselhorn, Marcus Keil, Andreas TI Early adolescents show sustained susceptibility to cognitive interference by emotional distractors SO COGNITION & EMOTION LA English DT Article DE Attention capture; Emotional distraction; Lexical decision ID ATTENTION-GRABBING POWER; VISUAL WORD RECOGNITION; SELECTIVE ATTENTION; READING FLUENCY; PICTURES; CHILDREN; INFORMATION; THREAT; PERSPECTIVE; PERCEPTION AB A child's ability to continuously pay attention to a cognitive task is often challenged by distracting events. Distraction is especially detrimental in a learning or classroom environment in which attended information is typically associated with establishing skills and knowledge. Here we report a study examining the effect of emotional distractors on performance in a subsequent visual lexical decision task in 11- to 13-year-old students (n=30). Lexical decisions about neutral verbs and verb-like pseudowords (i.e., targets) were analysed as a function of the preceding distractor type (pleasant, neutral, or unpleasant photos) and the picturetarget stimulus-onset asynchrony (SOA; 200 or 600 ms). Across distractor categories, emotionally arousing pictures prolonged decisions about word targets when compared to neutral pictures, irrespective of the SOA. The present results demonstrate that similar to adults, early adolescent students exhibit sustained susceptibility to cognitive interference by irrelevant emotional events. C1 [Heim, Sabine; Hasselhorn, Marcus] German Inst Int Educ Res, Ctr Res Individual Dev & Adapt Educ, Frankfurt, Germany. [Heim, Sabine] Univ Constance, Dept Psychol, Constance, Germany. [Ihssen, Niklas] Cardiff Univ, Sch Psychol, Cardiff CF10 3AX, S Glam, Wales. [Keil, Andreas] Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. [Keil, Andreas] Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL USA. RP Heim, S (reprint author), Rutgers State Univ, Infancy Studies Lab, Ctr Mol & Behav Neurosci, 197 Univ Ave, Newark, NJ 07102 USA. EM sabine.heim@rutgers.edu RI Keil, Andreas/F-9427-2011; Ihssen, Niklas/B-6324-2012 OI Keil, Andreas/0000-0002-4064-1924; Ihssen, Niklas/0000-0001-8386-1524 FU NIMH NIH HHS [R01 MH084932] NR 42 TC 1 Z9 1 U1 0 U2 5 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0269-9931 J9 COGNITION EMOTION JI Cogn. Emot. PD JUN 1 PY 2013 VL 27 IS 4 BP 696 EP 706 DI 10.1080/02699931.2012.736366 PG 11 WC Psychology, Experimental SC Psychology GA 146QV UT WOS:000319106500008 PM 23098096 ER PT J AU Matsuda, M Nogare, DD Somers, K Martin, K Wang, C Chitnis, AB AF Matsuda, Miho Nogare, Damian Dalle Somers, Katherine Martin, Kathleen Wang, Chongmin Chitnis, Ajay B. TI Lef1 regulates Dusp6 to influence neuromast formation and spacing in the zebrafish posterior lateral line primordium SO DEVELOPMENT LA English DT Article DE Lateral line; Wnt; FGF; Lef1; R-spondin; Dusp6; Zebrafish ID CELL-MIGRATION; WNT/BETA-CATENIN; TISSUE MIGRATION; LIMB DEVELOPMENT; WNT; EXPRESSION; ORGAN; DIFFERENTIATION; MORPHOGENESIS; RECEPTORS AB The posterior lateral line primordium (PLLp) migrates caudally and periodically deposits neuromasts. Coupled, but mutually inhibitory, Wnt-FGF signaling systems regulate proto-neuromast formation in the PLLp: FGF ligands expressed in response to Wnt signaling activate FGF receptors and initiate proto-neuromast formation. FGF receptor signaling, in turn, inhibits Wnt signaling. However, mechanisms that determine periodic neuromast formation and deposition in the PLLp remain poorly understood. Previous studies showed that neuromasts are deposited closer together and the PLLp terminates prematurely in lef1-deficient zebrafish embryos. It was suggested that this results from reduced proliferation in the leading domain of the PLLp and/or premature incorporation of progenitors into proto-neuromasts. We found that rspo3 knockdown reduces proliferation in a manner similar to that seen in lef1 morphants. However, it does not cause closer neuromast deposition or premature termination of the PLLp, suggesting that such changes in lef1-deficient embryos are not linked to changes in proliferation. Instead, we suggest that they are related to the role of Lef1 in regulating the balance of Wnt and FGF functions in the PLLp. Lef1 determines expression of the FGF signaling inhibitor Dusp6 in leading cells and regulates incorporation of cells into neuromasts; reduction of Dusp6 in leading cells in lef1-deficient embryos allows new proto-neuromasts to form closer to the leading edge. This is associated with progressively slower PLLp migration, reduced spacing between deposited neuromasts and premature termination of the PLLp system. C1 [Matsuda, Miho; Nogare, Damian Dalle; Somers, Katherine; Martin, Kathleen; Wang, Chongmin; Chitnis, Ajay B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Dev, NIH, Rockville, MD 20852 USA. [Matsuda, Miho] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA. RP Chitnis, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Dev, NIH, Rockville, MD 20852 USA. EM chitnisa@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) [HD001012-15]; NIH [HD062561] 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 (NIH) [HD001012-15]. M. M. was also supported by an NIH grant [HD062561]. Deposited in PMC for release after 12 months. NR 37 TC 17 Z9 17 U1 1 U2 11 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN 1 PY 2013 VL 140 IS 11 BP 2387 EP 2397 DI 10.1242/dev.091348 PG 11 WC Developmental Biology SC Developmental Biology GA 145UK UT WOS:000319043400014 PM 23637337 ER PT J AU Binder, AK Rodriguez, KF Hamilton, KJ Stockton, PS Reed, CE Korach, KS AF Binder, April K. Rodriguez, Karina F. Hamilton, Katherine J. Stockton, Patricia S. Reed, Casey E. Korach, Kenneth S. TI The Absence of ER-beta Results in Altered Gene Expression in Ovarian Granulosa Cells Isolated From In Vivo Preovulatory Follicles SO ENDOCRINOLOGY LA English DT Article ID ESTROGEN-RECEPTOR-BETA; TRANSCRIPTION FACTORS; OVULATORY RESPONSE; MESSENGER-RNA; MOUSE; OOCYTE; MICE; DIFFERENTIATION; HORMONE; GROWTH AB Determining the spatial and temporal expression of genes involved in the ovulatory pathway is critical for the understanding of the role of each estrogen receptor in the modulation of folliculogenesis and ovulation. Estrogen receptor (ER)-beta is highly expressed in ovarian granulosa cells, and mice lacking ER-beta are subfertile due to inefficient ovulation. Previous work has focused on isolated granulosa cells or cultured follicles and, although informative, provides confounding results due to the heterogeneous cell types present including granulosa and theca cells and oocytes and exposure to in vitro conditions. Herein we isolated preovulatory granulosa cells from wild-type (WT) and ER beta-null mice using laser capture microdissection to examine the genomic transcriptional response downstream of pregnant mare serum gonadotropin (mimicking FSH) and pregnant mare serum gonadotropin/human chorionic gonadotropin (mimicking LH) stimulation. This allows for a direct comparison of in vivo granulosa cells at the same stage of development from both WT and ER beta-null ovaries. ER beta-null granulosa cells showed altered expression of genes known to be regulated by FSH (Akap12 and Runx2) as well as not previously reported (Arnt2 and Pou5f1) inWT granulosa cells. Our analysis also identified 304 genes not previously associated with ER beta in granulosa cells. LH-responsive genes including Abcb1b and Fam110c show reduced expression in ER beta-null granulosa cells; however, novel genes including Rassf2 and Megf10 were also identified as being downstream of LH signaling in granulosa cells. Collectively, our data suggest that granulosa cells from ER beta-null ovaries may not be appropriately differentiated and are unable to respond properly to gonadotropin stimulation. C1 [Binder, April K.; Rodriguez, Karina F.; Hamilton, Katherine J.; Reed, Casey E.; Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. [Stockton, Patricia S.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, 111 TW Alexander Dr,MD B3-02, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU National Institutes of Health [Z01ES70065]; National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported by National Institutes of Health Grant Z01ES70065 and the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 49 TC 8 Z9 8 U1 1 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2013 VL 154 IS 6 BP 2174 EP 2187 DI 10.1210/en.2012-2256 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 147YO UT WOS:000319208200024 PM 23580569 ER PT J AU Kavarthapu, R Tsai-Morris, CH Fukushima, M Pickel, J Dufau, ML AF Kavarthapu, Raghuveer Tsai-Morris, Chon-Hwa Fukushima, Masato Pickel, James Dufau, Maria L. TI A 5 '-Flanking Region of Gonadotropin-Regulated Testicular RNA Helicase (GRTH/DDX25) Gene Directs Its Cell-Specific Androgen-Regulated Gene Expression in Testicular Germ Cells SO ENDOCRINOLOGY LA English DT Article ID MOUSE TESTIS; SPERMATOGENESIS; MICE; TRANSLATION; KNOCKOUT; RECEPTOR AB Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is a posttranscriptional regulator of genes that are essential for spermatid elongation and completion of spermatogenesis. It also prevents Leydig cells (LCs) from gonadotropin overstimulation of androgen production. In transgenic (Tg) mice carrying deletions of the GRTH 5'-flanking regions, we previously demonstrated that the -1085 bp to ATG contains the elements for basal and androgen-induced LC-specific expression. No expression in germ cells (GCs) was found with sequences extended up to -3.6 kb. To define regulatory regions of GRTH required for expression in GC, Tg mice were generated with 5'-flanking sequence 6.4 kb (6.4Kb-Tg) and/or deletion using green fluorescent protein (GFP) as reporter gene in the present study. GFP was expressed in all lines. Immunohistochemistry analysis showed that 6.4Kb-Tg directed GFP expression in both GCs and LCs. Deletion of the sequence -205 bp to -3.6 kb (6.4Kb/del-Tg) directs GFP expression only in meiotic and haploid GCs. This indicated that the distal region -6.4 kb/-3.6 kb is required for GRTH cell-specific expression in GC. Also, it inhibits the expression of GRTH in LC directed by the 205-bp promoter, an effect that is neutralized by the -3.6-kb/-205-bp sequence. Androgen receptor antagonist, flutamide treatment prevents GFP/GRTH expression in Tg lines, demonstrating in vivo direct and indirect effects of endogenous androgen on LCs and GCs, respectively. Our studies have generated and characterized Tg lines that can be used to define requirements for cell-specific expression of the GRTH gene and to further advance our knowledge on the regulation of GRTH by androgen in GCs. C1 [Kavarthapu, Raghuveer; Tsai-Morris, Chon-Hwa; Fukushima, Masato; Dufau, Maria L.] NIMH, Sect Mol Endocrinol, Program Dev Endocrinol & Genet,Transgen Core,NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Genet Lab, Transgen Core, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NIH, Bldg 49,6A36, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov OI kavarthapu, raghuveer/0000-0002-2198-2029 FU National Institutes of Health Intramural Research Program through the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the National Institutes of Health Intramural Research Program through the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 23 TC 4 Z9 5 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2013 VL 154 IS 6 BP 2200 EP 2207 DI 10.1210/en.2012-2230 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 147YO UT WOS:000319208200026 PM 23546600 ER PT J AU Lai, ME Origa, R Danjou, F Leoni, GB Vacquer, S Anni, F Corrias, C Farci, P Congiu, G Galanello, R AF Lai, Maria E. Origa, Raffaella Danjou, Fabrice Leoni, Gian B. Vacquer, Stefania Anni, Franco Corrias, Claudia Farci, Patrizia Congiu, Giovanna Galanello, Renzo TI Natural history of hepatitis C in thalassemia major: a long-term prospective study SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Article DE beta-thalassemia; hepatitis C virus infection; viral clearance; interleukin-28B; fibrosis progression; liver iron overload ID BETA-THALASSEMIA; VIRUS-INFECTION; POSTTRANSFUSION HEPATITIS; BLOOD-TRANSFUSION; LIVER FIBROSIS; IL28B; MULTICENTER; CLEARANCE; CHILDREN; GENOME AB Background Transfusion-acquired hepatitis C virus (HCV) remains an important problem among patients with thalassemia. In this study, we evaluated the natural history of post-transfusional hepatitis C in thalassemia major, paying special attention to spontaneous viral clearance, to factors influencing the chronicity rate and fibrosis progression. Design and Methods A prospective study to evaluate the incidence and etiology of transfusion-related hepatitis was started in 1980. In patients who developed hepatitis C, HCV RNA, ALT, and ferritin were measured over time. The correlation between interleukin-28B gene polymorphisms and viral clearance was also analyzed. Results Seventy-three of 135 patients (62.2%) acquired HCV. An extended follow-up (22 to 30yr) with HCV RNA assessment was available in 52 patients. Of them, 23 (44.2%) cleared the virus. The proportion of IL-28B genotypes was different between the subjects who cleared the virus and the subjects who did not. Fibrosis progression was similar in HCV RNApositive and HCV RNAnegative patients. Liver iron was the only factor associated with the fibrosis. Conclusions In thalassemia patients with HCV infection, liver iron does not play a major role in influencing the chronicity rate, whereas it is significantly associated with the fibrosis. C1 [Lai, Maria E.; Vacquer, Stefania; Corrias, Claudia] Osped Regionale Microcitemie, ASL8, I-09121 Cagliari, Italy. [Origa, Raffaella; Danjou, Fabrice; Leoni, Gian B.; Anni, Franco; Congiu, Giovanna; Galanello, Renzo] Clin Pediat 2A, Cagliari, Italy. [Farci, Patrizia] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Galanello, R (reprint author), Osped Regionale Microcitemie, DH Talassemia Eta Evolutiva, Clin Pediat 2A, Via Jenner Sn, I-09121 Cagliari, Italy. EM renzo.galanello@mcweb.unica.it RI Danjou, Fabrice/D-1563-2014; OI Danjou, Fabrice/0000-0002-4976-2327; Origa, Raffaella/0000-0002-2346-9616 FU Regione Autonoma della Sardegna [LR 11/90]; ApoPharma (Ontario, Canada) FX The authors thank Laura Placido for editorial assistance. This work was supported by LR 11/90 Regione Autonoma della Sardegna and by a research grant from ApoPharma (Ontario, Canada). NR 43 TC 10 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-4441 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD JUN PY 2013 VL 90 IS 6 BP 501 EP 507 DI 10.1111/ejh.12086 PG 7 WC Hematology SC Hematology GA 147CN UT WOS:000319143100006 PM 23414443 ER PT J AU Liu, CQ Lin, C Whitaker, DT Bakeri, H Bulgakov, OV Liu, PH Lei, JQ Dong, LJ Li, TS Swaroop, A AF Liu, Chunqiao Lin, Chen Whitaker, D. Thad Bakeri, Hirva Bulgakov, Oleg V. Liu, Pinghu Lei, Jingqi Dong, Lijin Li, Tiansen Swaroop, Anand TI Prickle1 is expressed in distinct cell populations of the central nervous system and contributes to neuronal morphogenesis SO HUMAN MOLECULAR GENETICS LA English DT Article ID PHOTORECEPTOR DEVELOPMENT; MOUSE PRICKLE1; POLARITY; RETINA; ORGANIZATION; ROD; POLARIZATION; STRABISMUS; MECHANISM; CORTEX AB Development of axons and dendrites constitutes a critical event in neuronal maturation and seems to require signaling through the planar cell polarity (PCP) pathway. Mutations in components of the PCP pathway lead to a spectrum of neurological phenotypes and disorders. For example, a missense mutation in Prickle 1 (Pk1) is associated with progressive myoclonus epilepsy (PME) in humans, and its reduced gene dosage increases sensitivity to induced seizure in mice. In an effort to unravel the role of the PCP pathway in mammalian neuronal development, we examined the expression of Pk1 in the central nervous system (CNS) using in situ hybridization (ISH) in combination with a genetic knock-in approach. We show that Pk1 transcripts are detected in the postmitotic cells of the subplate and cortical plate during mid- and late stages of cortical neurogenesis. In adult brain, Pk1 is expressed in distinct neuronal and glial cell populations, with dynamic formation of dendrites and glial processes during development. Of all the cell types in the mature retina, the highest expression of Pk1 is detected in cholinergic amacrine neurons. Knockdown of Pk1 by shRNA or dominant-negative constructs causes reduced axonal and dendritic extension in hippocampal neurons. Similarly, Pk1 knockdown in neonatal retina leads to defects in inner and outer segments and axon terminals of photoreceptors. Our studies implicate Pk1 function in axonal-dendritic development associated with the maturation of CNS neurons. C1 [Liu, Chunqiao; Lin, Chen; Whitaker, D. Thad; Bakeri, Hirva; Bulgakov, Oleg V.; Li, Tiansen; Swaroop, Anand] NEI, N NRL, Bethesda, MD 20892 USA. [Liu, Pinghu; Lei, Jingqi; Dong, Lijin] NEI, Genet Engn Facil, Bethesda, MD 20892 USA. RP Liu, CQ (reprint author), NEI, N NRL, MSC0610,6 Ctr Dr, Bethesda, MD 20892 USA. EM cqliu@nei.nih.gov; swaroopa@nei.nih.gov RI Liu, Chunqiao/O-3391-2013; OI Liu, Chunqiao/0000-0002-0299-7401; Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute FX This work is supported by the intramural research program of the National Eye Institute. NR 39 TC 10 Z9 10 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 1 PY 2013 VL 22 IS 11 BP 2234 EP 2246 DI 10.1093/hmg/ddt075 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 151AC UT WOS:000319432000010 PM 23420014 ER PT J AU Simeonov, DR Wang, XJ Wang, C Sergeev, Y Dolinska, M Bower, M Fischer, R Winer, D Dubrovsky, G Balog, JZ Huizing, M Hart, R Zein, WM Gahl, WA Brooks, BP Adams, DR AF Simeonov, Dimitre R. Wang, Xinjing Wang, Chen Sergeev, Yuri Dolinska, Monika Bower, Matthew Fischer, Roxanne Winer, David Dubrovsky, Genia Balog, Joan Z. Huizing, Marjan Hart, Rachel Zein, Wadih M. Gahl, William A. Brooks, Brian P. Adams, David R. TI DNA Variations in Oculocutaneous Albinism: An Updated Mutation List and Current Outstanding Issues in Molecular Diagnostics SO HUMAN MUTATION LA English DT Article DE albinism; OCA; TYR; OCA2; TYRP1; SLC45A2; TYRP2; SLC24A5 ID RECESSIVE OCULAR ALBINISM; PRADER-WILLI-SYNDROME; PINK LOCUS PROTEIN; P-GENE DELETION; TYROSINASE GENE; ANGELMAN-SYNDROME; INTRAGENIC DELETION; MELANOSOMAL PH; COMPREHENSIVE ANALYSIS; ENDOPLASMIC-RETICULUM AB Oculocutaneous albinism (OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are four types of OCA caused by mutations in TYR (OCA-1), OCA2 (OCA-2), TYRP1 (OCA-3), or SLC45A2 (OCA-4). Here we report 22 novel mutations in the OCA genes; 14 from a cohort of 61 patients seen as part of the NIH OCA Natural History Study and eight from a prior study at the University of Minnesota. We also include a comprehensive list of almost 600 previously reported OCA mutations along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions as a supplement. In addition to discussing the clinical and molecular features of OCA, we address the cases of apparent missing heritability. In our cohort, 26% of patients did not have two mutations in a single OCA gene. We demonstrate the utility of multiple detection methods to reveal mutations missed by Sanger sequencing. Finally, we review the TYR p.R402Q temperature-sensitive variant and confirm its association with cases of albinism with only one identifiable TYR mutation. C1 [Simeonov, Dimitre R.; Wang, Chen; Fischer, Roxanne; Winer, David; Dubrovsky, Genia; Balog, Joan Z.; Huizing, Marjan; Hart, Rachel; Gahl, William A.; Brooks, Brian P.; Adams, David R.] NHGRI, NIH, Bethesda, MD 20892 USA. [Wang, Xinjing; Wang, Chen; Sergeev, Yuri; Dolinska, Monika; Zein, Wadih M.; Brooks, Brian P.] NEI, NIH, Bethesda, MD 20892 USA. [Wang, Xinjing; Bower, Matthew] Univ Minnesota, Med Ctr, Div Genet & Metab, Minneapolis, MN 55455 USA. RP Adams, DR (reprint author), NIH, 10-10C103B,10 Ctr Dr, Bethesda, MD 20892 USA. EM dadams1@mail.nih.gov OI Simeonov, Dimitre/0000-0002-1693-8664 FU NIH FX Contract grant sponsor: NIH. NR 85 TC 28 Z9 34 U1 3 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD JUN PY 2013 VL 34 IS 6 BP 827 EP 835 DI 10.1002/humu.22315 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 148WH UT WOS:000319278500003 PM 23504663 ER PT J AU Hambridge, HL Mumford, SL Mattison, DR Ye, A Pollack, AZ Bloom, MS Mendola, P Lynch, KL Wactawski-Wende, J Schisterman, EF AF Hambridge, H. L. Mumford, S. L. Mattison, D. R. Ye, A. Pollack, A. Z. Bloom, M. S. Mendola, P. Lynch, K. L. Wactawski-Wende, J. Schisterman, E. F. TI The influence of sporadic anovulation on hormone levels in ovulatory cycles SO HUMAN REPRODUCTION LA English DT Article DE anovulation; sex hormones; menstrual cycle ID MENSTRUAL-CYCLE; WOMEN; PROGESTERONE; GONADOTROPIN; MENOPAUSE; BIOCYCLE; OBESITY AB Do ovulatory hormone profiles among healthy premenopausal women differ between women with and without sporadic anovulation? Women with one anovulatory cycle tended to have lower estradiol, progesterone and LH peak levels during their ovulatory cycle. Anovulation occurs sporadically in healthy premenopausal women, but the influence of hormones in a preceding cycle and the impact on a subsequent cycles hormone levels is unknown. The BioCycle Study was a prospective cohort including 250 healthy regularly menstruating women, 1844 years of age, from Western New York with no history of menstrual or ovulation disorders. The women were followed with up to eight study visits per cycle for two cycles, most of which were consecutive. All study visits were timed to menstrual cycle phase using fertility monitors and located at the University at Buffalo womens health research center from 2005 to 2007. The main outcomes measured were estradiol, progesterone, LH and follicle-stimulating hormone levels in serum at up to 16 visits over two cycles. Anovulation was defined as peak serum progesterone concentrations 5 ng/ml and no serum LH peak detected during the mid- or late-luteal phase visit. Reproductive hormone concentrations were lower during anovulatory cycles, but significant reductions were also observed in estradiol (25, P 0.003) and progesterone (22, P 0.001) during the ovulatory cycles of women with one anovulatory cycle compared with women with two ovulatory cycles. LH peak concentrations were decreased in the ovulatory cycle of women with an anovulatory cycle (significant amplitude effect, P 0.004; geometric mean levels 38 lower, P 0.05). Follow-up was limited to two menstrual cycles, and no ultrasound assessment of ovulation was available. Data were missing for a total of 168 of a possible 4072 cycle visits (4.1), though all women had at least five visits per cycle (94 had seven or more per cycle). These results suggest a possible underlying cause of anovulation, such as a longer-term subclinical follicular, ovarian or hypothalamic/pituitary dysfunction, even among healthy, regularly menstruating women. 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 (Contract no. HHSN275200403394C). The authors have no potential competing interests. C1 [Hambridge, H. L.; Mumford, S. L.; Mattison, D. R.; Ye, A.; Pollack, A. Z.; Mendola, P.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, Rockville, MD 20852 USA. [Hambridge, H. L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Hambridge, H. L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Mattison, D. R.] McLaughlin Ctr Populat Hlth Risk Anal & Risk Sci, Ottawa, ON, Canada. [Bloom, M. S.] SUNY Albany, Dept Environm Hlth Sci, Rensselaer, NY 12144 USA. [Bloom, M. S.] SUNY Albany, Dept Epidemiol & Biostat, Rensselaer, NY 12144 USA. [Lynch, K. L.] Univ Massachusetts, Div Biostat & Epidemiol, Sch Publ Hlth & Hlth Sci, Amherst, MA 01002 USA. [Wactawski-Wende, J.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, Rockville, MD 20852 USA. EM schistee@mail.nih.gov RI Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; Pollack, Anna/0000-0002-4313-3298; Mendola, Pauline/0000-0001-5330-2844; Schisterman, Enrique/0000-0003-3757-641X; Bloom, Michael/0000-0002-0028-5494 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275200403394C] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract no. HHSN275200403394C). NR 23 TC 17 Z9 17 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD JUN PY 2013 VL 28 IS 6 BP 1687 EP 1694 DI 10.1093/humrep/det090 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 151OI UT WOS:000319469500027 PM 23589536 ER PT J AU Carty, CL Spencer, KL Setiawan, VW Fernandez-Rhodes, L Malinowski, J Buyske, S Young, A Jorgensen, NW Cheng, I Carlson, CS Brown-Gentry, K Goodloe, R Park, A Parikh, NI Henderson, B Le Marchand, L Wactawski-Wende, J Fornage, M Matise, TC Hindorff, LA Arnold, AM Haiman, CA Franceschini, N Peters, U Crawford, DC AF Carty, C. L. Spencer, K. L. Setiawan, V. W. Fernandez-Rhodes, L. Malinowski, J. Buyske, S. Young, A. Jorgensen, N. W. Cheng, I. Carlson, C. S. Brown-Gentry, K. Goodloe, R. Park, A. Parikh, N. I. Henderson, B. Le Marchand, L. Wactawski-Wende, J. Fornage, M. Matise, T. C. Hindorff, L. A. Arnold, A. M. Haiman, C. A. Franceschini, N. Peters, U. Crawford, D. C. TI Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study SO HUMAN REPRODUCTION LA English DT Article DE menopause; menarche; genome-wide association study; race; ethnicity; single nucleotide polymorphism ID NATURAL MENOPAUSE; WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; PROSPECTIVE COHORT; SEQUENCE VARIANTS; AMERICAN-INDIANS; US GIRLS; RISK; METAANALYSIS; DESIGN AB Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study? We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry. Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations. A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM. SNPs previously associated with ANM (n 5 SNPs) and AM (n 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P 0.01 for ANM analyses and P 0.017 for AM analyses. We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends. Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings. The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research. The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The authors report no conflicts of interest. C1 [Carty, C. L.; Young, A.; Carlson, C. S.; Peters, U.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Spencer, K. L.] Heidelberg Univ, Tiffin, OH USA. [Setiawan, V. W.; Henderson, B.; Haiman, C. A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Fernandez-Rhodes, L.; Franceschini, N.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Malinowski, J.; Brown-Gentry, K.; Goodloe, R.; Crawford, D. C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Buyske, S.; Matise, T. C.] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Buyske, S.] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [Jorgensen, N. W.; Arnold, A. M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Cheng, I.] Canc Prevent Inst Calif, Fremont, CA USA. [Park, A.] Georgetown Univ, Sch Med, Dept Obstet & Gynecol, Washington Hosp Ctr, Washington, DC 20007 USA. [Parikh, N. I.] Univ Hawaii, John A Burns Sch Med, Queens Med Ctr, Honolulu, HI 96822 USA. [Parikh, N. I.] Univ Hawaii, Div Cardiovasc, Queens Med Ctr, Honolulu, HI 96822 USA. [Le Marchand, L.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Wactawski-Wende, J.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Fornage, M.] Univ Texas Houston, Hlth Sci Ctr, Houston, TX USA. [Hindorff, L. A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. RP Carty, CL (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. EM ccarty@fhcrc.org OI Buyske, Steven/0000-0001-8539-5416 FU National Human Genome Research Institute (NHGRI); [U01HG004803]; [U01HG004798]; [U01HG004802]; [U01HG004790]; [U01HG004801] FX The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The authors report no conflicts of interest. NR 68 TC 20 Z9 20 U1 3 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD JUN PY 2013 VL 28 IS 6 BP 1695 EP 1706 DI 10.1093/humrep/det071 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 151OI UT WOS:000319469500028 PM 23508249 ER PT J AU Da, DF Dixit, S Sattabonkot, J Mu, JB Abate, L Ramineni, B Ouedraogo, JB MacDonald, NJ Fay, MP Su, XZ Cohuet, A Wu, YM AF Da, Dari F. Dixit, Saurabh Sattabonkot, Jetsumon Mu, Jianbing Abate, Luc Ramineni, Bhanumati Ouedraogo, Jean Bosco MacDonald, Nicholas J. Fay, Michael P. Su, Xin-zhuan Cohuet, Anna Wu, Yimin TI Anti-Pfs25 Human Plasma Reduces Transmission of Plasmodium falciparum Isolates That Have Diverse Genetic Backgrounds SO INFECTION AND IMMUNITY LA English DT Article ID MALARIA TRANSMISSION; VACCINE CANDIDATE; BLOCKING VACCINE; SEXUAL STAGE; INFECTIONS; ANTIGENS; POPULATIONS; TESTS AB Pfs25 is a leading candidate for a malaria transmission-blocking vaccine whose potential has been demonstrated in a phase 1 trial with recombinant Pfs25 formulated with Montanide ISA51. Because of limited sequence polymorphism, the anti-Pfs25 antibodies induced by this vaccine are likely to have transmission-blocking or -reducing activity against most, if not all, field isolates. To test this hypothesis, we evaluated transmission-blocking activities by membrane feeding assay of anti-Pfs25 plasma from the Pfs25/ISA51 phase 1 trial against Plasmodium falciparum parasites from patients in two different geographical regions of the world, Thailand and Burkina Faso. In parallel, parasite isolates from these patients were sequenced for the Pfs25 gene and genotyped for seven microsatellites. The results indicate that despite different genetic backgrounds among parasite isolates, the Pfs25 sequences are highly conserved, with a single nonsynonymous nucleotide polymorphism detected in 1 of 41 patients in Thailand and Burkina Faso. The anti-Pfs25 immune plasma had significantly higher transmission-reducing activity against parasite isolates from the two geographical regions than the nonimmune controls (P < 0.0001). C1 [Da, Dari F.; Ouedraogo, Jean Bosco; Cohuet, Anna] IRSS, Bobo Dioulasso, Burkina Faso. [Da, Dari F.; Abate, Luc; Cohuet, Anna] UMR MIVEGEC UM1 UM2 CNRS 5290 IRD 224, IRD, Montpellier, France. [Dixit, Saurabh; Ramineni, Bhanumati; MacDonald, Nicholas J.; Wu, Yimin] NIAID, Lab Malaria Immunol & Vaccinol, Rockville, MD USA. [Sattabonkot, Jetsumon] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Mu, Jianbing; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, Rockville, MD USA. [Fay, Michael P.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Wu, YM (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, Rockville, MD USA. EM yiwu@niaid.nih.gov RI Cohuet, Anna/B-2745-2017; OI Cohuet, Anna/0000-0002-1876-5656; Fay, Michael P./0000-0002-8643-9625; Su, Xinzhuan/0000-0003-3246-3248 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States; European Community's Seventh Framework Program (FP7) [242095, 223736]; IRD FX This work was supported by funding from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States, and the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreements 242095 and 223736. Also, we thank IRD for financial support and for a fellowship to D.F.D. NR 23 TC 7 Z9 7 U1 1 U2 10 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 JUN PY 2013 VL 81 IS 6 BP 1984 EP 1989 DI 10.1128/IAI.00016-13 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 143GN UT WOS:000318855100012 PM 23509152 ER PT J AU Sultan, SZ Manne, A Stewart, PE Bestor, A Rosa, PA Charon, NW Motaleb, MA AF Sultan, Syed Z. Manne, Akarsh Stewart, Philip E. Bestor, Aaron Rosa, Patricia A. Charon, Nyles W. Motaleb, M. A. TI Motility Is Crucial for the Infectious Life Cycle of Borrelia burgdorferi SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; IXODES-SCAPULARIS TICKS; INNATE IMMUNE-RESPONSE; PERIPLASMIC FLAGELLA; HELICOBACTER-PYLORI; SURFACE PROTEIN; GENE-EXPRESSION; SERPULINA-HYODYSENTERIAE; CRYOELECTRON TOMOGRAPHY; LEPTOSPIRA-INTERROGANS AB The Lyme disease spirochete, Borrelia burgdorferi, exists in a zoonotic cycle involving an arthropod tick and mammalian host. Dissemination of the organism within and between these hosts depends upon the spirochete's ability to traverse through complex tissues. Additionally, the spirochete outruns the host immune cells while migrating through the dermis, suggesting the importance of B. burgdorferi motility in evading host clearance. B. burgdorferi's periplasmic flagellar filaments are composed primarily of a major protein, FlaB, and minor protein, FlaA. By constructing a flaB mutant that is nonmotile, we investigated for the first time the absolute requirement for motility in the mouse-tick life cycle of B. burgdorferi. We found that whereas wild-type cells are motile and have a flat-wave morphology, mutant cells were nonmotile and rod shaped. These mutants were unable to establish infection in C3H/HeN mice via either needle injection or tick bite. In addition, these mutants had decreased viability in fed ticks. Our studies provide substantial evidence that the periplasmic flagella, and consequently motility, are critical not only for optimal survival in ticks but also for infection of the mammalian host by the arthropod tick vector. C1 [Sultan, Syed Z.; Manne, Akarsh; Motaleb, M. A.] E Carolina Univ, Dept Microbiol & Immunol, Brody Sch Med, Greenville, NC 27858 USA. [Stewart, Philip E.; Bestor, Aaron; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, NIH, Rocky Mt Labs, Hamilton, MT USA. [Charon, Nyles W.; Motaleb, M. A.] W Virginia Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA. RP Motaleb, MA (reprint author), E Carolina Univ, Dept Microbiol & Immunol, Brody Sch Med, Greenville, NC 27858 USA. EM ncharon@hsc.wvu.edu; motalebm@ecu.edu FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; NIAID, NIH [AI29743]; National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH [AR060834] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (P.A.R.), and grants from the NIAID, NIH (AI29743 to N.W.C.), and National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH (AR060834 to M.A.M.). NR 117 TC 25 Z9 25 U1 2 U2 26 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 JUN PY 2013 VL 81 IS 6 BP 2012 EP 2021 DI 10.1128/IAI.01228-12 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 143GN UT WOS:000318855100016 PM 23529620 ER PT J AU Chen, Y Machner, MP AF Chen, Yang Machner, Matthias P. TI Targeting of the Small GTPase Rab6A ' by the Legionella pneumophila Effector LidA SO INFECTION AND IMMUNITY LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTOR; LEGIONNAIRES-DISEASE; TRANSLOCATED SUBSTRATE; ENDOPLASMIC-RETICULUM; GOLGI-COMPLEX; PROTEIN DRRA; RAB1; SYSTEM; BACTERIUM; TRANSPORT AB When the bacterium Legionella pneumophila, the causative agent of Legionnaires' disease, is phagocytosed by alveolar macrophages, it delivers a large number of effector proteins through its Dot/Icm type IV secretion system into the host cell cytosol. Among those proteins is LidA, an effector that interacts with several host GTPases of the Rab family, including Rab6A', a regulator of retrograde vesicle trafficking within eukaryotic cells. The effect of LidA on Rab6A' function and the role of Rab6A' for L. pneumophila growth within host cells has been unclear. Here, we show that LidA preferentially binds Rab6A' in the active GTP-bound conformation. Rab6 binding occurred through the central region of LidA and followed a stoichiometry for LidA and Rab6A' of 1:2. LidA maintained Rab6A' in the active conformation by efficiently blocking the hydrolysis of GTP by Rab6A', even in the presence of cellular GTPase-activating proteins, suggesting that the function of Rab6A' must be important for efficient intracellular replication of L. pneumophila. Accordingly, we found that production of constitutively inactive Rab6A'(T27N) but not constitutively active Rab6A'(Q72L) significantly reduced the ability of L. pneumophila to initiate intracellular replication in human macrophages. Thus, the presence of an active pool of Rab6 within host cells early during infection is required to support efficient intracellular growth of L. pneumophila. C1 [Chen, Yang; Machner, Matthias P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. [Chen, Yang] Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100871, Peoples R China. RP Machner, MP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. EM machnerm@mail.nih.gov RI Machner, Matthias/G-2758-2015; OI Machner, Matthias/0000-0002-6971-7451 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Work in the laboratory of M. Machner is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 40 TC 8 Z9 10 U1 0 U2 9 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 JUN PY 2013 VL 81 IS 6 BP 2226 EP 2235 DI 10.1128/IAI.00157-13 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 143GN UT WOS:000318855100039 PM 23569112 ER PT J AU Hwang, SK Chang, SH Minai-Tehrani, A Kim, YS Cho, MH AF Hwang, Soon-Kyung Chang, Seung-Hee Minai-Tehrani, Arash Kim, Yeon-Soo Cho, Myung-Haing TI Lentivirus-AIMP2-DX2 shRNA Suppresses Cell Proliferation by Regulating Akt1 Signaling Pathway in the Lungs of AIMP2(+/-) Mice SO JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY LA English DT Article DE aerosol gene delivery; shRNA AIMP2-DX2; angiogenesis; Akt1 signaling pathway ID TRANSFER-RNA SYNTHETASE; INITIATION-FACTOR 4E; GENE-THERAPY; BINDING-PROTEIN; TRANSLATION; CANCER; ANGIOGENESIS; TRANSFECTION; PROGRESSION; EXPRESSION AB Background: The long-term survival of lung cancer patients treated with conventional therapies remains poor and has changed little in decades. The need for novel approaches remains urgent. Aerosol-mediated delivery of genes has potential for the treatment of a broad spectrum of pulmonary disorders and may offer numerous advantages over invasive modes of delivery. Methods: The potential effects of aerosol-delivered lentiviral-based short hairpin AIMP2 lacking exon 2 (shDX2) on lung tumorigenesis were studied. Lentiviral-based shDX2 was delivered into AIMP2(+/-) mice through a nose-only inhalation system twice a week for 4 weeks. Results and Conclusions: The effects of shDX2 on lung cancer progression and the Akt1-mTOR-p70S6K signaling pathway were evaluated. Long-term repeated delivery of lentiviral-based shDX2 suppressed lung tumor progression significantly by inhibiting Akt1-related signals and decreasing both protein synthesis and angiogenesis. In vivo, the aerosol-mediated application of lentiviral-based short hairpin RNAs was successful in achieving potent and specific knockdown of the target. The collective results indicate the therapeutic potential of the repeated delivery of shDX2 for lung cancer treatment and prevention. C1 [Hwang, Soon-Kyung; Chang, Seung-Hee; Minai-Tehrani, Arash; Cho, Myung-Haing] Seoul Natl Univ, Coll Vet Med, Toxicol Lab, Seoul 151742, South Korea. [Hwang, Soon-Kyung] NCI, Gene Regulat Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA. [Kim, Yeon-Soo] Inje Univ, Dept Smart Foods & Drugs, Seoul, South Korea. [Kim, Yeon-Soo] Inje Univ, Indang Inst Mol Biol, Seoul, South Korea. [Cho, Myung-Haing] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Nanofus Technol, Suwon, South Korea. [Cho, Myung-Haing] Seoul Natl Univ, Grad Grp Tumor Biol, Seoul 151742, South Korea. [Cho, Myung-Haing] Seoul Natl Univ, Adv Inst Convergence Technol, Suwon, South Korea. RP Cho, MH (reprint author), Seoul Natl Univ, Coll Vet Med, Toxicol Lab, 1 Gwanak Ro, Seoul 151742, South Korea. EM mchotox@snu.ac.kr RI CHO, Myung-Haing/B-7362-2014 FU National Research Foundation from the Ministry of Education, Science and Technology (MEST) [NRF-2012-0001116, 2012M3A9C4048819]; Research Institute for Veterinary Science, Seoul National University FX This work was supported by National Research Foundation grants (NRF-2012-0001116 and 2012M3A9C4048819) from the Ministry of Education, Science and Technology (MEST). M. H. Cho was also partially supported by the Research Institute for Veterinary Science, Seoul National University. NR 32 TC 4 Z9 4 U1 2 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1941-2711 J9 J AEROSOL MED PULM D JI J. Aerosol Med. Pulm. Drug Deliv. PD JUN PY 2013 VL 26 IS 3 BP 165 EP 173 DI 10.1089/jamp.2011.0959 PG 9 WC Respiratory System SC Respiratory System GA 151KF UT WOS:000319458700006 PM 23517169 ER PT J AU Gupta, M Dixit, M Rao, KK AF Gupta, Monica Dixit, Madhulika Rao, K. Krishnamurthy TI Spo0A positively regulates epr expression by negating the repressive effect of co-repressors, SinR and ScoC, in Bacillus subtilis SO JOURNAL OF BIOSCIENCES LA English DT Article DE Anti-repressor; co-repressors; epr; ScoC (Hpr); SinR; Spo0A ID SWARMING MOTILITY; SERINE-PROTEASE; GENE; SPORULATION; ACTIVATION; PROMOTER; APRE AB Bacillus subtilis under nutritional deprivation exhibits several physiological responses such as synthesis of degradative enzymes, motility, competence, sporulation, etc. At the onset of post-exponential phase the global response regulator, Spo0A, directly or indirectly activates the expression of genes involved in the above processes. These genes are repressed during the exponential phase by a group of proteins called transition state regulators, e.g. AbrB, ScoC and SinR. One such post-exponentially expressed gene is epr, which encodes a minor extracellular serine protease and is involved in the swarming motility of B. subtilis. Deletion studies of the upstream region of epr promoter revealed that epr is co-repressed by transition state regulators, SinR and ScoC. Our study shows that Spo0A positively regulates epr expression by nullifying the repressive effect of co-repressors, SinR and ScoC. We demonstrate via in vitro mobility shift assays that Spo0A binds to the upstream region of epr promoter and in turn occludes the binding site of one of the co-repressor, SinR. This explains the mechanism behind the positive regulatory effect of Spo0A on epr expression. C1 [Gupta, Monica; Dixit, Madhulika; Rao, K. Krishnamurthy] Indian Inst Technol, Gene Regulat Lab, Dept Biosci & Bioengn, Bombay 400076, Maharashtra, India. RP Gupta, M (reprint author), Natl Inst Child Hlth & Human Dev NICHD, NIH, 6 Ctr Dr Room 2A09, Bethesda, MD 20892 USA. EM guptam3@mail.nih.gov FU Council for Scientific and Industrial Research, India FX MG acknowledges the Council for Scientific and Industrial Research, India, for the doctoral research fellowship. We thank M Ahuja and W Huynh for their valuable suggestions for the manuscript. NR 28 TC 2 Z9 2 U1 4 U2 20 PU INDIAN ACAD SCIENCES PI BANGALORE PA C V RAMAN AVENUE, SADASHIVANAGAR, P B #8005, BANGALORE 560 080, INDIA SN 0250-5991 J9 J BIOSCIENCES JI J. Biosci. PD JUN PY 2013 VL 38 IS 2 BP 291 EP 299 DI 10.1007/s12038-013-9309-8 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 147GG UT WOS:000319153600012 PM 23660663 ER PT J AU Chong, WH Andreopoulou, P Chen, CC Reynolds, J Guthrie, L Kelly, M Gafni, RI Bhattacharyya, N Boyce, AM El-Maouche, D Crespo, DO Sherry, R Chang, R Wodajo, FM Kletter, GB Dwyer, A Collins, MT AF Chong, William H. Andreopoulou, Panagiota Chen, Clara C. Reynolds, James Guthrie, Lori Kelly, Marilyn Gafni, Rachel I. Bhattacharyya, Nisan Boyce, Alison M. El-Maouche, Diala Crespo, Diana Ovejero Sherry, Richard Chang, Richard Wodajo, Felasfa M. Kletter, Gad B. Dwyer, Andrew Collins, Michael T. TI Tumor localization and biochemical response to cure in tumor-induced osteomalacia SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE FGF23; HYPOPHOSPHATEMIA; MINERAL METABOLISM; VITAMIN D; OSTEOMALACIA ID OF-THE-LITERATURE; ONCOGENIC-OSTEOMALACIA; HYPOPHOSPHATEMIC OSTEOMALACIA; MESENCHYMAL TUMORS; SCINTIGRAPHY; MANAGEMENT; FGF23 AB Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with 111Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and 18fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16 of 20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14 of 16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity=0.95, specificity=0.64, PPV=0.82, and NPV=0.88 for octreo-SPECT; sensitivity=0.88, specificity=0.36, PPV=0.62, and NPV=0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation. C1 [Chong, William H.; Andreopoulou, Panagiota; Guthrie, Lori; Kelly, Marilyn; Gafni, Rachel I.; Bhattacharyya, Nisan; Boyce, Alison M.; El-Maouche, Diala; Crespo, Diana Ovejero; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Andreopoulou, Panagiota] Montefiore Med Ctr, Einstein Coll Med, Dept Med, Div Endocrinol, Bronx, NY 10467 USA. [Chen, Clara C.; Reynolds, James; Chang, Richard; Dwyer, Andrew] NIH, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Bone Hlth Program, Div Orthopaed & Sports Med, Washington, DC 20010 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Sherry, Richard] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wodajo, Felasfa M.] Virginia Hosp Ctr, Arlington, VA USA. [Kletter, Gad B.] Swedish Med Ctr, Swedish Pediat Specialty Clin, Seattle, WA USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 218, Bethesda, MD 20892 USA. EM mc247k@nih.gov OI El-Maouche, Diala/0000-0002-0936-2249 FU Intramural Research Program of the NIH, NIDCR FX This research was supported by the Intramural Research Program of the NIH, NIDCR. NR 20 TC 20 Z9 23 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUN PY 2013 VL 28 IS 6 BP 1386 EP 1398 DI 10.1002/jbmr.1881 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 149VS UT WOS:000319350100017 PM 23362135 ER PT J AU Komatsu, Y Yu, PB Kamiya, N Pan, HC Fukuda, T Scott, GJ Ray, MK Yamamura, K Mishina, Y AF Komatsu, Yoshihiro Yu, Paul B. Kamiya, Nobuhiro Pan, Haichun Fukuda, Tomokazu Scott, Gregory J. Ray, Manas K. Yamamura, Ken-ichi Mishina, Yuji TI Augmentation of smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE BMP; CRANIOSYNOSTOSIS; NEURAL CREST CELLS; SMAD-SIGNALING; SUTURE ID FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; CALVARIAL BONE-DEVELOPMENT; SKULL VAULT; I RECEPTOR; OSTEOBLAST APOPTOSIS; SUTURE DEVELOPMENT; MOUSE MODEL; KAPPA-B; FGF; GROWTH AB Craniosynostosis describes conditions in which one or more sutures of the infant skull are prematurely fused, resulting in facial deformity and delayed brain development. Approximately 20% of human craniosynostoses are thought to result from gene mutations altering growth factor signaling; however, the molecular mechanisms by which these mutations cause craniosynostosis are incompletely characterized, and the causative genes for diverse types of syndromic craniosynostosis have yet to be identified. Here, we show that enhanced bone morphogenetic protein (BMP) signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells, but not in osteoblasts, causes premature suture fusion in mice. In support of a requirement for precisely regulated BMP signaling, this defect was rescued on a Bmpr1a haploinsufficient background, with corresponding normalization of Smad phosphorylation. Moreover, in vivo treatment with LDN-193189, a selective chemical inhibitor of BMP type I receptor kinases, resulted in partial rescue of craniosynostosis. Enhanced signaling of the fibroblast growth factor (FGF) pathway, which has been implicated in craniosynostosis, was observed in both mutant and rescued mice, suggesting that augmentation of FGF signaling is not the sole cause of premature fusion found in this model. The finding that relatively modest augmentation of Smad-dependent BMP signaling leads to premature cranial suture fusion suggests an important contribution of dysregulated BMP signaling to syndromic craniosynostoses and potential strategies for early intervention. C1 [Komatsu, Yoshihiro; Kamiya, Nobuhiro; Pan, Haichun; Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Komatsu, Yoshihiro; Kamiya, Nobuhiro; Fukuda, Tomokazu; Mishina, Yuji] NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Yu, Paul B.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Yu, Paul B.] Harvard Univ, Sch Med, Boston, MA USA. [Kamiya, Nobuhiro] Texas Scottish Rite Hosp Children, Ctr Excellence Hip Disorders, Dallas, TX 75219 USA. [Fukuda, Tomokazu] Tohoku Univ, Grad Sch Agr Sci, Sendai, Miyagi 980, Japan. [Scott, Gregory J.; Ray, Manas K.; Mishina, Yuji] NIEHS, Knock Out Core, NIH, Res Triangle Pk, NC 27709 USA. [Yamamura, Ken-ichi] Kumamoto Univ, Inst Mol Embryol & Genet, Kumamoto, Japan. RP Mishina, Y (reprint author), Univ Michigan, Sch Dent, Dept Biol & Mat Sci, 1011 North Univ Ave, Ann Arbor, MI 48109 USA. EM mishina@umich.edu OI Yu, Paul/0000-0003-2145-4944 FU National Institutes of Health [K99DE021054, K08HL079943, R01AR057374, R01DE020843, ES071003-11]; Japan Society for the Promotion of Science FX This study was supported by the National Institutes of Health (K99DE021054 to YK; K08HL079943 and R01AR057374 to PBY; and R01DE020843 and ES071003-11 to YM) and a fellowship from the Japan Society for the Promotion of Science (YK). NR 55 TC 16 Z9 16 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUN PY 2013 VL 28 IS 6 BP 1422 EP 1433 DI 10.1002/jbmr.1857 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 149VS UT WOS:000319350100020 PM 23281127 ER PT J AU Ishida, Y Nayak, S Mindell, JA Grabe, M AF Ishida, Yoichi Nayak, Smita Mindell, Joseph A. Grabe, Michael TI A model of lysosomal pH regulation SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID RAT-LIVER LYSOSOMES; PROTON PUMP; STORAGE DISEASE; REQUIRES OSTM1; CHLORIDE; CHANNEL; TRANSPORT; ACIDIFICATION; ENDOSOMES; PERMEABILITY AB Lysosomes must maintain an acidic luminal pH to activate hydrolytic enzymes and degrade internalized macromolecules. Acidification requires the vacuolar-type H+-ATPase to pump protons into the lumen and a counterion flux to neutralize the membrane potential created by proton accumulation. Early experiments suggested that the counterion was chloride, and more recently a pathway consistent with the ClC-7 Cl-/H+ antiporter was identified. However, reports that the steady-state luminal pH is unaffected in ClC-7 knockout mice raise questions regarding the identity of the carrier and the counterion. Here, we measure the current-voltage characteristics of a mammalian ClC-7 antiporter, and we use its transport properties, together with other key ion regulating elements, to construct a mathematical model of lysosomal pH regulation. We show that results of in vitro lysosome experiments can only be explained by the presence of ClC-7, and that ClC-7 promotes greater acidification than Cl-, K+, or Na+ channels. Our models predict strikingly different lysosomal K+ dynamics depending on the major counterion pathways. However, given the lack of experimental data concerning acidification in vivo, the model cannot definitively rule out any given mechanism, but the model does provide concrete predictions for additional experiments that would clarify the identity of the counterion and its carrier. C1 [Ishida, Yoichi] Univ Pittsburgh, Dept Hist & Philosophy Sci, Pittsburgh, PA 15260 USA. [Grabe, Michael] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Grabe, Michael] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. [Nayak, Smita] Swedish Ctr Res & Innovat, Swedish Hlth Serv, Seattle, WA 98122 USA. [Mindell, Joseph A.] NINDS, Membrane Transport Biophys Unit, NIH, Bethesda, MD 20892 USA. RP Grabe, M (reprint author), Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. EM mindellj@ninds.nih.gov; mdgrabe@pitt.edu OI Mindell, Joseph/0000-0002-6952-8247 FU National Institutes of Health [R21GM100224-01]; National Institute of Neurological Disorders and Stroke Intramural program FX We are grateful for financial support from National Institutes of Health grant R21GM100224-01 (to M. Grabe and S. Nayak) and the National Institute of Neurological Disorders and Stroke Intramural program (J.A. Mindell). NR 48 TC 26 Z9 26 U1 0 U2 17 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD JUN PY 2013 VL 141 IS 6 BP 705 EP 720 DI 10.1085/jgp.201210930 PG 16 WC Physiology SC Physiology GA 152BQ UT WOS:000319505000005 PM 23712550 ER PT J AU Levesque, S Taetzsch, T Lull, ME Johnson, JA McGraw, C Block, ML AF Levesque, Shannon Taetzsch, Thomas Lull, Melinda E. Johnson, Jo Anne McGraw, Constance Block, Michelle L. TI The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE air pollution; brain; inflammation-mediated neurodegeneration; microglia; neuroinflammation; oxidative stress ID PARTICULATE AIR-POLLUTION; ENGINE EXHAUST; PARKINSONS-DISEASE; BRAIN INFLAMMATION; PRENATAL EXPOSURE; ALPHA-SYNUCLEIN; YOUNG-ADULTS; RAT-BRAIN; IN-VIVO; NEUROINFLAMMATION AB Increasing reports support that air pollution causes neuroinflammation and is linked to central nervous system (CNS) disease/damage. Diesel exhaust particles (DEP) are a major component of urban air pollution, which has been linked to microglial activation and Parkinson's disease-like pathology. To begin to address how DEP may exert CNS effects, microglia and neuron-glia cultures were treated with either nanometer-sized DEP (<0.22M; 50g/mL), ultrafine carbon black (ufCB, 50g/mL), or DEP extracts (eDEP; from 50g/mL DEP), and the effect of microglial activation and dopaminergic (DA) neuron function was assessed. All three treatments showed enhanced ameboid microglia morphology, increased H2O2 production, and decreased DA uptake. Mechanistic inquiry revealed that the scavenger receptor inhibitor fucoidan blocked DEP internalization in microglia, but failed to alter DEP-induced H2O2 production in microglia. However, pre-treatment with the MAC1/CD11b inhibitor antibody blocked microglial H2O2 production in response to DEP. MAC1/ mesencephalic neuron-glia cultures were protected from DEP-induced loss of DA neuron function, as measured by DA uptake. These findings support that DEP may activate microglia through multiple mechanisms, where scavenger receptors regulate internalization of DEP and the MAC1 receptor is mandatory for both DEP-induced microglial H2O2 production and loss of DA neuron function. C1 [Levesque, Shannon; Taetzsch, Thomas; Lull, Melinda E.; McGraw, Constance; Block, Michelle L.] Virginia Commonwealth Univ Med Campus, Dept Anat & Neurobiol, Richmond, VA 23298 USA. [Johnson, Jo Anne] NIEHS, Cellular & Mol Pathol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Block, ML (reprint author), Virginia Commonwealth Univ Med Campus, Dept Anat & Neurobiol, Sanger Hall,Room 9-048,1101 E Marshall St,Box 980, Richmond, VA 23298 USA. EM mblock@vcu.edu FU National Institute of Environmental Health Sciences/the National Institute of health [1R01ES016951] FX This study was supported by the National Institute of Environmental Health Sciences/the National Institute of health (Grant number 1R01ES016951). The authors thank Thurn Sams and Maria Bright for their assistance with maintenance and breeding of timed-pregnant animals. The authors report no conflicts of interest. NR 66 TC 20 Z9 20 U1 4 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2013 VL 125 IS 5 BP 756 EP 765 DI 10.1111/jnc.12231 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 148CA UT WOS:000319218900013 PM 23470120 ER PT J AU Ye, DY Bakhtian, KD Asthagiri, AR Lonser, RR AF Ye, Donald Y. Bakhtian, Kamran D. Asthagiri, Ashok R. Lonser, Russell R. TI Pregnancy and von Hippel-Lindau disease RESPONSE SO JOURNAL OF NEUROSURGERY LA English DT Letter ID NATURAL-HISTORY; HEMANGIOBLASTOMAS; RESECTION C1 [Ye, Donald Y.; Bakhtian, Kamran D.; Asthagiri, Ashok R.; Lonser, Russell R.] NINDS, NIH, Bethesda, MD 20892 USA. [Lonser, Russell R.] Ohio State Univ, Columbus, OH 43210 USA. RP Ye, DY (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUN PY 2013 VL 118 IS 6 BP 1380 EP 1382 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 150BY UT WOS:000319366400043 PM 23875188 ER PT J AU Huser, V Cimino, JJ AF Huser, Vojtech Cimino, James J. TI Evaluating adherence to the International Committee of Medical Journal Editors' policy of mandatory, timely clinical trial registration SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID CLINICALTRIALS.GOV; UPDATE AB Objective To determine whether two specific criteria in Uniform Requirements for Manuscripts (URM) created by the International Committee of Medical Journal Editors (ICMJE)-namely, including the trial ID registration within manuscripts and timely registration of trials, are being followed. Materials and methods Observational study using computerized analysis of publicly available Medline article data and clinical trial registry data. We analyzed a purposive set of five ICMJE founding journals looking at all trial articles published in those journals during 20102011, and data from the ClinicalTrials.gov (CTG) trial registry. We measured adherence to trial ID inclusion policy as the percentage of trial journal articles that contained a valid trial ID within the article (journal-based sample). Adherence to timely registration was measured as the percentage of trials that registered the trial before enrolling the first participant within a 60-day grace period. We also examined timely registration rates by year of all phase II and higher interventional trials in CTG (registry-based sample). Results To determine trial ID inclusion, we analyzed 698 clinical trial articles in five journals. A total of 95.8% (661/690) of trial journal articles included the trial ID. In 88.3% the trial-article link is stored within a structured Medline field. To evaluate timely registration, we analyzed trials referenced by 451 articles from the selected five journals. A total of 60% (272/451) of articles were registered in a timely manner with an improving trend for trials initiated in later years (eg, 89% of trials that began in 2008 were registered in a timely manner). In the registry-based sample, the timely registration rates ranged from 56% for trials registered in 2006 to 72% for trials registered in 2011. Discussion Adherence to URM requirements for registration and trial ID inclusion increases the utility of PubMed and links it in an important way to clinical trial repositories. This new integrated knowledge source can facilitate research prioritization, clinical guidelines creation, and precision medicine. Conclusions The five selected journals adhere well to the policy of mandatory trial registration and also outperform the registry in adherence to timely registration. ICMJE's URM policy represents a unique international mandate that may be providing a powerful incentive for sponsors and investigators to document clinical trials and trial result publications and thus fulfill important obligations to trial participants and society. C1 [Huser, Vojtech; Cimino, James J.] NIH, Lab Informat Dev, Natl Lib Med, Ctr Clin, Bethesda, MD 20892 USA. RP Huser, V (reprint author), NIH, Lab Informat Dev, Ctr Clin, Natl Lib Med, 10 Ctr Dr, Bethesda, MD 20892 USA. EM vojtech.huser@nih.gov OI Cimino, James/0000-0003-4101-1622 FU Intramural Research Program of the National Institutes of Health Clinical Center; National Library of Medicine; NIH Clinical Center; NLM Intramural research program FX The authors are independent of any commercial funder. VH and JJC are supported by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Library of Medicine. The ideas and opinions expressed are those of the authors. The content of this publication does not necessarily reflect the views or policies of the US National Institutes of Health.; All authors have completed the unified competing interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: VH and JJC have support from NIH Clinical Center and NLM Intramural research program for the submitted work; authors have had no relationships in the previous 3 years with any commercial companies that might have an interest in the submitted work; their spouses, partners, or children have no financial relationships that might be relevant to the submitted work; and authors have no non-financial interests that might be relevant to the submitted work. NR 15 TC 23 Z9 23 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUN PY 2013 VL 20 IS E1 BP E169 EP E174 DI 10.1136/amiajnl-2012-001501 PG 6 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 147UD UT WOS:000319192100027 PM 23396544 ER PT J AU Newton, KM Peissig, PL Kho, AN Bielinski, SJ Berg, RL Choudhary, V Basford, M Chute, CG Kullo, IJ Li, RL Pacheco, JA Rasmussen, LV Spangler, L Denny, JC AF Newton, Katherine M. Peissig, Peggy L. Kho, Abel Ngo Bielinski, Suzette J. Berg, Richard L. Choudhary, Vidhu Basford, Melissa Chute, Christopher G. Kullo, Iftikhar J. Li, Rongling Pacheco, Jennifer A. Rasmussen, Luke V. Spangler, Leslie Denny, Joshua C. TI Validation of electronic medical record-based phenotyping algorithms: results and lessons learned from the eMERGE network SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID GENOME-WIDE ASSOCIATION; HEALTH RECORDS; VARIANTS; DEFINITION AB Background Genetic studies require precise phenotype definitions, but electronic medical record (EMR) phenotype data are recorded inconsistently and in a variety of formats. Objective To present lessons learned about validation of EMR-based phenotypes from the Electronic Medical Records and Genomics (eMERGE) studies. Materials and methods The eMERGE network created and validated 13 EMR-derived phenotype algorithms. Network sites are Group Health, Marshfield Clinic, Mayo Clinic, Northwestern University, and Vanderbilt University. Results By validating EMR-derived phenotypes we learned that: (1) multisite validation improves phenotype algorithm accuracy; (2) targets for validation should be carefully considered and defined; (3) specifying time frames for review of variables eases validation time and improves accuracy; (4) using repeated measures requires defining the relevant time period and specifying the most meaningful value to be studied; (5) patient movement in and out of the health plan (transience) can result in incomplete or fragmented data; (6) the review scope should be defined carefully; (7) particular care is required in combining EMR and research data; (8) medication data can be assessed using claims, medications dispensed, or medications prescribed; (9) algorithm development and validation work best as an iterative process; and (10) validation by content experts or structured chart review can provide accurate results. Conclusions Despite the diverse structure of the five EMRs of the eMERGE sites, we developed, validated, and successfully deployed 13 electronic phenotype algorithms. Validation is a worthwhile process that not only measures phenotype performance but also strengthens phenotype algorithm definitions and enhances their inter-institutional sharing. C1 [Newton, Katherine M.; Spangler, Leslie] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Peissig, Peggy L.; Berg, Richard L.; Choudhary, Vidhu] Marshfield Clin Res Fdn, Dept Biomed Informat, Marshfield, WI USA. [Kho, Abel Ngo; Pacheco, Jennifer A.; Rasmussen, Luke V.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Bielinski, Suzette J.] Mayo Clin, Dept Hlth Sci Res, Dept Epidemiol, Rochester, MN USA. [Basford, Melissa] Vanderbilt Univ, Off Personalized Med, Nashville, TN USA. [Chute, Christopher G.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Li, Rongling] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Denny, Joshua C.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN USA. [Denny, Joshua C.] Vanderbilt Univ, Dept Med, Nashville, TN USA. RP Newton, KM (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM newton.k@ghc.org RI Bielinski, Suzette/A-2238-2009; OI Bielinski, Suzette/0000-0002-2905-5430; Pacheco, Jennifer/0000-0001-8021-5818; Rasmussen, Luke/0000-0002-4497-8049 FU NHGRI; National Institute of General Medical Science [U01-HG-004610, U01-HG-004608, U01-HG-04599, U01HG004609, U01-HG-04603]; State of Washington Life Sciences Discovery Fund FX The eMERGE Network was initiated and funded by NHGRI, with additional funding from the National Institute of General Medical Science through the following grants: U01-HG-004610 (Group Health Cooperative); U01-HG-004608 (Marshfield Clinic); U01-HG-04599 (Mayo Clinic); U01HG004609 (Northwestern University); U01-HG-04603 (Vanderbilt University, also serving as the Coordinating Center), and the State of Washington Life Sciences Discovery Fund award to the Northwest Institute of Genetic Medicine. NR 24 TC 79 Z9 80 U1 2 U2 22 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUN PY 2013 VL 20 IS E1 BP E147 EP E154 DI 10.1136/amiajnl-2012-000896 PG 8 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 147UD UT WOS:000319192100024 PM 23531748 ER PT J AU Akhtar, A Kamal, AK AF Akhtar, Anjum Kamal, Ayeesha Kamran TI Benefit of neuroprotection in acute ischaemic stroke, shall we dare to hope? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 1 TC 0 Z9 0 U1 0 U2 1 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD JUN PY 2013 VL 63 IS 6 BP 792 EP 792 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 147ON UT WOS:000319177000031 PM 23901691 ER PT J AU Rahimi, Z Rahimi, Z Mozafari, H Parsian, A AF Rahimi, Zohreh Rahimi, Ziba Mozafari, Hadi Parsian, Abbas TI Preeclampsia and angiotensin converting enzyme (ACE) I/D and angiotensin II type-1 receptor (AT1R) A1166C polymorphisms: association with ACE I/D polymorphism SO JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM LA English DT Article DE Preeclampsia; ACE I/D; AT1R A1166C; MDA; TAC ID INSERTION/DELETION POLYMORPHISM; GENE POLYMORPHISMS; GESTATIONAL HYPERTENSION; OXIDATIVE STRESS; WESTERN IRAN; WOMEN; PREGNANCY; RISK; METAANALYSIS; POPULATION AB Background: The aim of the present study was to investigate the association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) and angiotensin II type-1 receptor (AT1R) A1166C polymorphisms with the risk of preeclampsia and lipid peroxidation in preeclamptic women from Western Iran. Methods: One hundred and ninety-eight preeclamptic women (128 women with mild and 70 with severe forms) and 100 age-and parity-matched controls were enrolled in this case-control study. Results: The presence of D allele of ACE was associated with a 1.8-fold increased risk of preeclampsia (p= 0.002) in total preeclamptic patients. The frequency of AT1R AC+ CC genotypes was higher in mild preeclamptic women (32%) compared to controls (27.2%) (p> 0.05). In mild preeclamptic women with ID genotype, the level of total antioxidant capacity (TAC) was significantly decreased compared to those with II genotype. Also, there was a trend toward increasing malondialdehyde (MDA) and decreasing TAC levels in mild and severe preeclamptic women with AT1R AA through CC genotypes. Conclusions: Our study indicates that lipid peroxidation and oxidative stress are involved in the development of preeclampsia that might be influenced by polymorphism in the renin-angiotensin-aldosterone system genes. C1 [Rahimi, Zohreh; Rahimi, Ziba; Mozafari, Hadi] Kermanshah Univ Med Sci, Med Biol Res Ctr, Kermanshah, Iran. [Rahimi, Zohreh] Kermanshah Univ Med Sci, Sch Med, Dept Biochem, Kermanshah, Iran. [Parsian, Abbas] NIAAA, Div Neurosci & Behav, NIH, Bethesda, MD USA. RP Rahimi, Z (reprint author), Med Biol Res Ctr, Sch Med, Daneshgah Ave,POB 67148-69914, Kermanshah, Iran. EM zrahimi@kums.ac.ir OI Rahimi, Zohreh/0000-0001-7589-3307 FU Kermanshah University of Medical Sciences, office of Vice Chancellor for Research, Kermanshah, Iran [89021] FX This work was supported by a grant from Kermanshah University of Medical Sciences, office of Vice Chancellor for Research, Kermanshah, Iran, (grant number 89021). NR 33 TC 9 Z9 10 U1 0 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1470-3203 J9 J RENIN-ANGIO-ALDO S JI J. Renin-Angiotensin-Aldosterone Syst. PD JUN PY 2013 VL 14 IS 2 BP 174 EP 180 DI 10.1177/1470320312448950 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 146VO UT WOS:000319123000010 PM 22719026 ER PT J AU Zhang, Y Ji, HF Liu, YX Shen, XD Gao, F Busuttil, RW Gao, B Kupiec-Weglinski, J AF Zhang, Yu Ji, Haofeng Liu, Yuanxing Shen, Xiu-da Gao, Feng Busuttil, Ronald W. Gao, Bin Kupiec-Weglinski, Jerzy TI Immunomodulation of IL-22 in Mouse Liver Ischemia-Reperfusion Injury IRI: Enhancement of Autophagy by STAT3-c-myc Signaling. SO LIVER TRANSPLANTATION LA English DT Meeting Abstract CT 19th Annual International Congress of the International-Liver-Transplantation-Society (ILTS) CY JUN 12-15, 2013 CL Sydney, AUSTRALIA SP Int Liver Transplantat Soc (ILTS) C1 [Zhang, Yu; Ji, Haofeng; Liu, Yuanxing; Shen, Xiu-da; Gao, Feng; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy] Dumont UCLA Transplant Ctr, Los Angeles, CA USA. [Gao, Bin] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD JUN PY 2013 VL 19 SU 1 BP S199 EP S200 PG 2 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 152HL UT WOS:000319522500389 ER PT J AU Hansen, MS Sorensen, TS AF Hansen, Michael Schacht Sorensen, Thomas Sangild TI Gadgetron: An open source framework for medical image reconstruction SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE image reconstruction; open source; GPU ID COMMODITY GRAPHICS HARDWARE; COIL ARRAYS; MRI; COMPRESSION; CHANNELS; SENSE AB This work presents a new open source framework for medical image reconstruction called the Gadgetron. The framework implements a flexible system for creating streaming data processing pipelines where data pass through a series of modules or Gadgets from raw data to reconstructed images. The data processing pipeline is configured dynamically at run-time based on an extensible markup language configuration description. The framework promotes reuse and sharing of reconstruction modules and new Gadgets can be added to the Gadgetron framework through a plugin-like architecture without recompiling the basic framework infrastructure. Gadgets are typically implemented in C/C++, but the framework includes wrapper Gadgets that allow the user to implement new modules in the Python scripting language for rapid prototyping. In addition to the streaming framework infrastructure, the Gadgetron comes with a set of dedicated toolboxes in shared libraries for medical image reconstruction. This includes generic toolboxes for data-parallel (e.g., GPU-based) execution of compute-intensive components. The basic framework architecture is independent of medical imaging modality, but this article focuses on its application to Cartesian and non-Cartesian parallel magnetic resonance imaging. Magn Reson Med, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Hansen, Michael Schacht] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Sorensen, Thomas Sangild] Aarhus Univ, Dept Comp Sci, DK-8000 Aarhus, Denmark. [Sorensen, Thomas Sangild] Aarhus Univ, Dept Clin Med, Aarhus, Denmark. RP Hansen, MS (reprint author), NHLBI, NIH, NIH Bldg 10-B1D-405,10 Ctr Dr, Bethesda, MD 20892 USA. EM michael.hansen@nih.gov RI Hansen, Michael/J-5391-2015; OI Hansen, Michael/0000-0002-8087-8731; Sorensen, Thomas Sangild/0000-0002-8482-7667 NR 24 TC 53 Z9 53 U1 4 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2013 VL 69 IS 6 BP 1768 EP 1776 DI 10.1002/mrm.24389 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 146FB UT WOS:000319074100030 PM 22791598 ER PT J AU Suhasini, AN Sommers, JA Muniandy, PA Coulombe, Y Cantor, SB Masson, JY Seidman, MM Brosh, RM AF Suhasini, Avvaru N. Sommers, Joshua A. Muniandy, Parameswary A. Coulombe, Yan Cantor, Sharon B. Masson, Jean-Yves Seidman, Michael M. Brosh, Robert M., Jr. TI Fanconi Anemia Group J Helicase and MRE11 Nuclease Interact To Facilitate the DNA Damage Response SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID REPAIR PATHWAY CHOICE; DOUBLE-STRAND BREAKS; CROSS-LINK REPAIR; GENOMIC STABILITY; END RESECTION; BINDING PROTEIN; BLOOMS SYNDROME; BACH1; COMPLEX; BRCA1 AB FANCJ mutations are linked to Fanconi anemia (FA) and increase breast cancer risk. FANCJ encodes a DNA helicase implicated in homologous recombination (HR) repair of double-strand breaks (DSBs) and interstrand cross-links (ICLs), but its mechanism of action is not well understood. Here we show with live-cell imaging that FANCJ recruitment to laser-induced DSBs but not psoralen-induced ICLs is dependent on nuclease-active MRE11. FANCJ interacts directly with MRE11 and inhibits its exonuclease activity in a specific manner, suggesting that FANCJ regulates the MRE11 nuclease to facilitate DSB processing and appropriate end resection. Cells deficient in FANCJ and MRE11 show increased ionizing radiation (IR) resistance, reduced numbers of gamma H2AX and RAD51 foci, and elevated numbers of DNA-dependent protein kinase catalytic subunit foci, suggesting that HR is compromised and the nonhomologous end-joining (NHEJ) pathway is elicited to help cells cope with IR-induced strand breaks. Interplay between FANCJ and MRE11 ensures a normal response to IR-induced DSBs, whereas FANCJ involvement in ICL repair is regulated by MLH1 and the FA pathway. Our findings are discussed in light of the current model for HR repair. C1 [Suhasini, Avvaru N.; Sommers, Joshua A.; Muniandy, Parameswary A.; Seidman, Michael M.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. [Coulombe, Yan; Masson, Jean-Yves] Univ Laval, Canc Res Ctr, Genome Stabil Lab, Quebec City, PQ, Canada. [Cantor, Sharon B.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; Fanconi Anemia Research Fund; Canadian Institute of Health Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and by the Fanconi Anemia Research Fund (R.M.B.). J.-Y.M. is an FRSQ senior investigator and is supported by the Canadian Institute of Health Research. NR 49 TC 19 Z9 19 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2013 VL 33 IS 11 BP 2212 EP 2227 DI 10.1128/MCB.01256-12 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 142BO UT WOS:000318771200010 PM 23530059 ER PT J AU Goedeke, L Vales-Lara, FM Fenstermaker, M Cirera-Salinas, D Chamorro-Jorganes, A Ramirez, CM Mattison, JA de Cabo, R Suarez, Y Fernandez-Hernando, C AF Goedeke, Leigh Vales-Lara, Frances M. Fenstermaker, Michael Cirera-Salinas, Daniel Chamorro-Jorganes, Aranzazu Ramirez, Cristina M. Mattison, Julie A. de Cabo, Rafael Suarez, Yajaira Fernandez-Hernando, Carlos TI A Regulatory Role for MicroRNA 33(star) in Controlling Lipid Metabolism Gene Expression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CHOLESTEROL HOMEOSTASIS; ENDOTHELIAL-CELLS; MIRNA-ASTERISK; MIR-33; DROSOPHILA; RECEPTOR; COMPLEX; BIOGENESIS; MECHANISMS; REPRESSION AB hsa-miR-33a and hsa-miR-33b, intronic microRNAs (miRNAs) located within the sterol regulatory element-binding protein 2 and 1 genes (Srebp-2 and -1), respectively, have recently been shown to regulate lipid homeostasis in concert with their host genes. Although the functional role of miR-33a and -b has been highly investigated, the role of their passenger strands, miR-33a(star) and -b(star), remains unclear. Here, we demonstrate that miR-33a(star) and -b(star) accumulate to steady-state levels in human, mouse, and nonhuman primate tissues and share a similar lipid metabolism target gene network as their sister strands. Analogous to miR33, miR-33(star) represses key enzymes involved in cholesterol efflux (ABCA1 and NPC1), fatty acid metabolism (CROT and CPT1a), and insulin signaling (IRS2). Moreover, miR-33(star) also targets key transcriptional regulators of lipid metabolism, including SRC1, SRC3, NFYC, and RIP140. Importantly, inhibition of either miR-33 or miR-33(star) rescues target gene expression in cells overexpressing pre-miR-33. Consistent with this, overexpression of miR-33(star) reduces fatty acid oxidation in human hepatic cells. Altogether, these data support a regulatory role for the miRNA(star) species and suggest that miR-33 regulates lipid metabolism through both arms of the miR-33/miR-33(star) duplex. C1 [Goedeke, Leigh; Vales-Lara, Frances M.; Fenstermaker, Michael; Cirera-Salinas, Daniel; Chamorro-Jorganes, Aranzazu; Ramirez, Cristina M.; Suarez, Yajaira; Fernandez-Hernando, Carlos] NYU, Sch Med, Dept Cell Biol, Dept Med,Leon H Charney Div Cardiol, New York, NY 10016 USA. [Goedeke, Leigh; Vales-Lara, Frances M.; Fenstermaker, Michael; Cirera-Salinas, Daniel; Chamorro-Jorganes, Aranzazu; Ramirez, Cristina M.; Suarez, Yajaira; Fernandez-Hernando, Carlos] NYU, Sch Med, Marc & Ruti Bell Vasc Biol & Dis Program, New York, NY USA. [Mattison, Julie A.; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Fernandez-Hernando, C (reprint author), NYU, Sch Med, Dept Cell Biol, Dept Med,Leon H Charney Div Cardiol, New York, NY 10016 USA. EM carlos.fernandez-hernando@nyumc.org RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Chamorro Jorganes, Aranzazu/0000-0003-2648-6945; Ramirez, Cristina M/0000-0003-2589-0786; , rafael/0000-0003-2830-5693; CIRERA SALINAS, DANIEL/0000-0003-2171-5032 FU National Institutes of Health [R01HL107953, R01HL106063, R01HL105945, 1F31AG043318-01]; American Heart Association [12POST9780016]; Deutsche Forschungsgemeinschaft; Intramural Research Program of the NIH, National Institute of Aging FX This work was supported by the National Institutes of Health (R01HL107953 and R01HL106063 to C.F.-H., R01HL105945 to Y.S., and 1F31AG043318-01 to L.G.), the American Heart Association (12POST9780016 to C.M.R.), and the Deutsche Forschungsgemeinschaft (to D.C.-S.). Rafael de Cabo and Julie A. Mattison are supported by the Intramural Research Program of the NIH, National Institute of Aging. NR 42 TC 53 Z9 56 U1 1 U2 21 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2013 VL 33 IS 11 BP 2339 EP 2352 DI 10.1128/MCB.01714-12 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 142BO UT WOS:000318771200020 PM 23547260 ER PT J AU Gold, PW Chrousos, GP AF Gold, P. W. Chrousos, G. P. TI Melancholic and atypical subtypes of depression represent distinct pathophysiological entities: CRH, neural circuits, and the diathesis for anxiety and depression SO MOLECULAR PSYCHIATRY LA English DT Editorial Material ID CORTICOTROPIN-RELEASING HORMONE; MAJOR DEPRESSION; BIOCHEMICAL MANIFESTATIONS; INDUCED ARTHRITIS; CUSHINGS-SYNDROME; NERVOUS-SYSTEM; LEWIS RATS; STRESS; GENE; RESPONSES C1 [Gold, P. W.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Chrousos, G. P.] Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Pediat 1,Div Endocrinol Metab & Diabet, GR-11527 Athens, Greece. [Chrousos, G. P.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Gold, PW (reprint author), NIMH, Intramural Res Program, Bethesda, MD 20892 USA. EM PhilipGold@mail.nih.gov FU Intramural NIH HHS NR 36 TC 24 Z9 24 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2013 VL 18 IS 6 BP 632 EP 634 DI 10.1038/mp.2013.5 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 151HP UT WOS:000319451600001 PM 23698316 ER PT J AU Lamers, F Vogelzangs, N Merikangas, KR de Jonge, P Beekman, ATF Penninx, BWJH AF Lamers, F. Vogelzangs, N. Merikangas, K. R. de Jonge, P. Beekman, A. T. F. Penninx, B. W. J. H. TI Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression SO MOLECULAR PSYCHIATRY LA English DT Article DE depression; inflammation; metabolic syndrome; salivary cortisol; subtypes ID MAJOR DEPRESSION; SALIVARY CORTISOL; ANTIDEPRESSANT USE; ANXIETY NESDA; GENETIC-LINKAGE; CYTOKINES; ASSOCIATIONS; DISORDER; FEATURES; METAANALYSIS AB The hypothalamic-pituitary-adrenal (HPA) axis and the inflammatory response system have been suggested as pathophysiological mechanisms implicated in the etiology of major depressive disorder (MDD). Although meta-analyses do confirm associations between depression and these biological systems, effect sizes vary greatly among individual studies. A potentially important factor explaining variability is heterogeneity of MDD. Aim of this study was to evaluate the association between depressive subtypes (based on latent class analysis) and biological measures. Data from 776 persons from the Netherlands Study of Depression and Anxiety, including 111 chronic depressed persons with melancholic depression, 122 with atypical depression and 543 controls were analyzed. Inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha), metabolic syndrome components, body mass index (BMI), saliva cortisol awakening curves (area under the curve with respect to the ground (AUCg) and with respect to the increase (AUCi)), and diurnal cortisol slope were compared among groups. Persons with melancholic depression had a higher AUCg and higher diurnal slope compared with persons with atypical depression and with controls. Persons with atypical depression had significantly higher levels of inflammatory markers, BMI, waist circumference and triglycerides, and lower high-density lipid cholesterol than persons with melancholic depression and controls. This study confirms that chronic forms of the two major subtypes of depression are associated with different biological correlates with inflammatory and metabolic dysregulation in atypical depression and HPA-axis hyperactivity in melancholic depression. The data provide further evidence that chronic forms of depressive subtypes differ not only in their symptom presentation, but also in their biological correlates. These findings have important implications for future research on pathophysiological pathways of depression and treatment. C1 [Lamers, F.; Merikangas, K. R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Vogelzangs, N.; Beekman, A. T. F.; Penninx, B. W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat EMGO, Inst Hlth & Care Res, Amsterdam, Netherlands. [de Jonge, P.; Penninx, B. W. J. H.] Univ Groningen, Univ Med Ctr Groningen, ICPE, Dept Psychiat, Groningen, Netherlands. [de Jonge, P.; Penninx, B. W. J. H.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Penninx, B. W. J. H.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. RP Lamers, F (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, 35 Convent Dr,Room 1A108, Bethesda, MD 20892 USA. EM lamersf@mail.nih.gov RI de Jonge, peter/L-6395-2013 OI de Jonge, peter/0000-0002-0866-6929 FU Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw) [10-000-1002]; VU University Medical Center; GGZ inGeest; Arkin; Leiden University Medical Center; GGZ Rivierduinen; University Medical Center Groningen; Lentis; GGZ Friesland; GGZ Drenthe; Scientific Institute for Quality of Healthcare (IQ healthcare); Netherlands Institute for Health Services Research (NIVEL); Netherlands Institute of Mental Health and Addiction (Trimbos); Neuroscience Campus Amsterdam; Netherlands Organisation for Scientific research (VIDI project); Rubicon fellowship from the Netherlands Organisation for Scientific research; National Institute of Mental Health, Genetic Epidemiology Research Branch; VICI grant from the Netherlands Organisation for Scientific research FX The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), Netherlands Institute for Health Services Research (NIVEL) and Netherlands Institute of Mental Health and Addiction (Trimbos). Biomarker funding was provided by the Neuroscience Campus Amsterdam and the Netherlands Organisation for Scientific research (VIDI project). BWJHP is supported by a VICI grant from the Netherlands Organisation for Scientific research. FL is supported by a Rubicon fellowship from the Netherlands Organisation for Scientific research and by a Supplemental Intramural Research Training Award from the National Institute of Mental Health, Genetic Epidemiology Research Branch. The views and opinions expressed in this article are ours and should not be construed to represent the views of any of the sponsoring organizations, agencies or US Government. NR 65 TC 134 Z9 138 U1 6 U2 51 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 JUN PY 2013 VL 18 IS 6 BP 692 EP 699 DI 10.1038/mp.2012.144 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 151HP UT WOS:000319451600011 PM 23089630 ER PT J AU Eisenberg, DP Ianni, AM Wei, SM Kohn, PD Kolachana, B Apud, J Weinberger, DR Berman, KF AF Eisenberg, D. P. Ianni, A. M. Wei, S-M Kohn, P. D. Kolachana, B. Apud, J. Weinberger, D. R. Berman, K. F. TI Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE schizophrenia; BDNF; hippocampus; PET; Val(66)Met; working memory ID POSITRON EMISSION TOMOGRAPHY; LONG-TERM POTENTIATION; CEREBRAL-BLOOD-FLOW; SYNAPTIC-TRANSMISSION; PREFRONTAL CORTEX; ANTIPSYCHOTIC-DRUGS; ADULT HIPPOCAMPUS; MESSENGER-RNA; DENTATE GYRUS; CONNECTIVITY AB A Val(66)Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val(66)Met SNP and [O-15]H2O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val(66)Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions. C1 [Eisenberg, D. P.; Ianni, A. M.; Wei, S-M; Kohn, P. D.; Berman, K. F.] NIMH, Sect Integrat Neuroimaging, NIH, DHHS, Bethesda, MD 20892 USA. [Eisenberg, D. P.; Ianni, A. M.; Wei, S-M; Kohn, P. D.; Kolachana, B.; Apud, J.; Berman, K. F.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,DHHS, Bethesda, MD 20892 USA. [Weinberger, D. R.] Lieber Inst Brain Dev, Baltimore, MD USA. RP Berman, KF (reprint author), NIMH, Sect Integrat Neuroimaging, NIH, 9000 Rockville Pike,Bldg 10,Room 3C209, Bethesda, MD 20892 USA. EM bermank@mail.nih.gov RI Eisenberg, Daniel/C-7432-2014; Eisenberg, Daniel/S-4342-2016 FU Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD FX This research was supported by the Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892. We would like to thank the staff of the NIH PET Center and the NIMH GCAP Inpatient Program for their assistance in data acquisition. NR 62 TC 11 Z9 12 U1 1 U2 8 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 JUN PY 2013 VL 18 IS 6 BP 713 EP 720 DI 10.1038/mp.2012.187 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 151HP UT WOS:000319451600014 PM 23319002 ER PT J AU Scharf, JM Yu, D Mathews, CA Neale, BM Stewart, SE Fagerness, JA Evans, P Gamazon, E Edlund, CK Service, SK Tikhomirov, A Osiecki, L Illmann, C Pluzhnikov, A Konkashbaev, A Davis, LK Han, B Crane, J Moorjani, P Crenshaw, AT Parkin, MA Reus, VI Lowe, TL Rangel-Lugo, M Chouinard, S Dion, Y Girard, S Cath, DC Smit, JH King, RA Fernandez, TV Leckman, JF Kidd, KK Kidd, JR Pakstis, AJ State, MW Herrera, LD Romero, R Fournier, E Sandor, P Barr, CL Phan, N Gross-Tsur, V Benarroch, F Pollak, Y Budman, CL Bruun, RD Erenberg, G Naarden, AL Lee, PC Weiss, N Kremeyer, B Berrio, GB Campbell, DD Silgado, JCC Ochoa, WC Restrepo, SCM Muller, H Duarte, AVV Lyon, GJ Leppert, M Morgan, J Weiss, R Grados, MA Anderson, K Davarya, S Singer, H Walkup, J Jankovic, J Tischfield, JA Heiman, GA Gilbert, DL Hoekstra, PJ Robertson, MM Kurlan, R Liu, C Gibbs, JR Singleton, A Hardy, J Strengman, E Ophoff, RA Wagner, M Moessner, R Mirel, DB Posthuma, D Sabatti, C Eskin, E Conti, DV Knowles, JA Ruiz-Linares, A Rouleau, GA Purcell, S Heutink, P Oostra, BA McMahon, WM Freimer, NB Cox, NJ Pauls, DL AF Scharf, J. M. Yu, D. Mathews, C. A. Neale, B. M. Stewart, S. E. Fagerness, J. A. Evans, P. Gamazon, E. Edlund, C. K. Service, S. K. Tikhomirov, A. Osiecki, L. Illmann, C. Pluzhnikov, A. Konkashbaev, A. Davis, L. K. Han, B. Crane, J. Moorjani, P. Crenshaw, A. T. Parkin, M. A. Reus, V. I. Lowe, T. L. Rangel-Lugo, M. Chouinard, S. Dion, Y. Girard, S. Cath, D. C. Smit, J. H. King, R. A. Fernandez, T. V. Leckman, J. F. Kidd, K. K. Kidd, J. R. Pakstis, A. J. State, M. W. Herrera, L. D. Romero, R. Fournier, E. Sandor, P. Barr, C. L. Phan, N. Gross-Tsur, V. Benarroch, F. Pollak, Y. Budman, C. L. Bruun, R. D. Erenberg, G. Naarden, A. L. Lee, P. C. Weiss, N. Kremeyer, B. Berrio, G. B. Campbell, D. D. Cardona Silgado, J. C. Ochoa, W. C. Mesa Restrepo, S. C. Muller, H. Valencia Duarte, A. V. Lyon, G. J. Leppert, M. Morgan, J. Weiss, R. Grados, M. A. Anderson, K. Davarya, S. Singer, H. Walkup, J. Jankovic, J. Tischfield, J. A. Heiman, G. A. Gilbert, D. L. Hoekstra, P. J. Robertson, M. M. Kurlan, R. Liu, C. Gibbs, J. R. Singleton, A. Hardy, J. Strengman, E. Ophoff, R. A. Wagner, M. Moessner, R. Mirel, D. B. Posthuma, D. Sabatti, C. Eskin, E. Conti, D. V. Knowles, J. A. Ruiz-Linares, A. Rouleau, G. A. Purcell, S. Heutink, P. Oostra, B. A. McMahon, W. M. Freimer, N. B. Cox, N. J. Pauls, D. L. CA North Amer Brain Expression UK Human Brain Expression Database TI Genome-wide association study of Tourette's syndrome SO MOLECULAR PSYCHIATRY LA English DT Article DE genetics; GWAS; neurodevelopmental disorder; tics; Tourette's syndrome ID COPY NUMBER VARIANTS; COMMON VARIANTS; SLITRK1 VAR321; SCHIZOPHRENIA; FAMILY; INDIVIDUALS; DEPENDENCE; MUTATIONS; DISORDER; POLR3B AB Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P < 5 x 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P = 1.85 x 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal ( P = 3.6 x 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder. C1 [Scharf, J. M.; Yu, D.; Neale, B. M.; Stewart, S. E.; Fagerness, J. A.; Osiecki, L.; Illmann, C.; Crane, J.; Purcell, S.; Pauls, D. L.] Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA USA. [Scharf, J. M.; Yu, D.; Neale, B. M.; Stewart, S. E.; Fagerness, J. A.; Osiecki, L.; Illmann, C.; Crane, J.; Purcell, S.; Pauls, D. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Scharf, J. M.] Massachusetts Gen Hosp, Dept Neurol, Movement Disorders Unit, Boston, MA 02114 USA. [Scharf, J. M.] Brigham & Womens Hosp, Div Cognit & Behav Neurol, Boston, MA 02115 USA. [Scharf, J. M.; Neale, B. M.; Purcell, S.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Mathews, C. A.; Reus, V. I.; Lowe, T. L.; Rangel-Lugo, M.; Lee, P. C.; Weiss, N.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Neale, B. M.; Moorjani, P.; Crenshaw, A. T.; Parkin, M. A.; Mirel, D. B.; Purcell, S.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Neale, B. M.; Purcell, S.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Stewart, S. E.] Univ British Columbia, British Columbia Mental Hlth & Addict Res Inst, Vancouver, BC V5Z 1M9, Canada. [Evans, P.; Gamazon, E.; Tikhomirov, A.; Pluzhnikov, A.; Konkashbaev, A.; Davis, L. K.; Cox, N. J.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Evans, P.; Gamazon, E.; Tikhomirov, A.; Pluzhnikov, A.; Konkashbaev, A.; Davis, L. K.; Cox, N. J.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Edlund, C. K.; Conti, D. V.] Univ So Calif, Dept Prevent Med, Div Biostat, Los Angeles, CA 90089 USA. [Edlund, C. K.] Univ So Calif, Keck Sch Med, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Service, S. K.; Strengman, E.; Ophoff, R. A.; Freimer, N. B.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA USA. [Han, B.; Eskin, E.] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90024 USA. [Moorjani, P.] Harvard Univ, Dept Genet, Cambridge, MA 02138 USA. [Chouinard, S.; Dion, Y.; Girard, S.; Rouleau, G. A.] Univ Montreal, Montreal, PQ, Canada. [Cath, D. C.; Smit, J. H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Cath, D. C.] Univ Utrecht, Dept Clin & Hlth Psychol, Utrecht, Netherlands. [King, R. A.; Fernandez, T. V.; Leckman, J. F.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Kidd, K. K.; Kidd, J. R.; Pakstis, A. J.; State, M. W.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Herrera, L. D.; Romero, R.; Fournier, E.] Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica. [Sandor, P.; Barr, C. L.; Phan, N.] Univ Hlth Network, Toronto Western Res Inst, Toronto, ON, Canada. [Sandor, P.] Univ Toronto, Dept Psychiat, Div Child Psychiat, Toronto, ON, Canada. [Barr, C. L.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Gross-Tsur, V.; Pollak, Y.] Shaare Zedek Med Ctr, Neuropediat Unit, Jerusalem, Israel. [Benarroch, F.] Hadassah Hebrew Univ, Med Ctr, Herman Dana Div Child & Adolescent Psychiat, Jerusalem, Israel. [Budman, C. L.; Bruun, R. D.] North Shore Long Isl Jewish Med Ctr, Manhasset, NY USA. [Budman, C. L.] Hofstra Univ, Sch Med, Hempstead, NY 11550 USA. [Bruun, R. D.] NYU, Med Ctr, New York, NY 10016 USA. [Erenberg, G.] Cleveland Clin, Cleveland, OH 44106 USA. [Naarden, A. L.] Med City Dallas Hosp, Dept Clin Res, Dallas, TX USA. [Kremeyer, B.; Campbell, D. D.; Muller, H.; Robertson, M. M.; Hardy, J.; Ruiz-Linares, A.] UCL, London, England. [Kremeyer, B.] Wellcome Trust Sanger Inst, Cambridge, England. [Berrio, G. B.; Cardona Silgado, J. C.; Ochoa, W. C.; Mesa Restrepo, S. C.; Valencia Duarte, A. V.] Univ Antioquia, Medellin, Colombia. [Campbell, D. D.] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China. [Campbell, D. D.] Univ Hong Kong, Ctr Genom Sci, Hong Kong, Hong Kong, Peoples R China. [Valencia Duarte, A. V.] Univ Pontificia Bolivariana, Medellin, Colombia. [Lyon, G. J.; Leppert, M.; Morgan, J.; Weiss, R.; McMahon, W. M.] Univ Utah, Salt Lake City, UT USA. [Lyon, G. J.] Cold Spring Harbor Lab, Stanley Inst Cognit Genom, Cold Spring Harbor, NY 11724 USA. [Grados, M. A.; Anderson, K.; Davarya, S.; Singer, H.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Walkup, J.] Weill Cornell Med Ctr, Dept Psychiat, Div Child & Adolescent Psychiat, New York, NY USA. [Jankovic, J.] Baylor Coll Med, Dept Neurol, Parkinsons Dis Ctr, Houston, TX 77030 USA. [Jankovic, J.] Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA. [Tischfield, J. A.; Heiman, G. A.] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Tischfield, J. A.; Heiman, G. A.] Rutgers State Univ, Human Genet Inst New Jersey, Piscataway, NJ USA. [Gilbert, D. L.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Gilbert, D. L.] Univ Cincinnati, Cincinnati, OH USA. [Hoekstra, P. J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Robertson, M. M.] St Georges Hosp & Med Sch, London, England. [Kurlan, R.] Overlook Hosp, Atlantic Neurosci Inst, Summit, NJ USA. [Liu, C.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Gibbs, J. R.; Singleton, A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Strengman, E.; Ophoff, R. A.] Univ Med Ctr, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands. [Wagner, M.; Moessner, R.] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany. [Posthuma, D.] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands. [Posthuma, D.; Heutink, P.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands. [Posthuma, D.] Erasmus Univ, Sophia Childrens Hosp, Med Ctr, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands. [Sabatti, C.] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Eskin, E.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Knowles, J. A.] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Purcell, S.] Mt Sinai Sch Med, Div Psychiat Genom, New York, NY USA. [Oostra, B. A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. RP Pauls, DL (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. EM jscharf@partners.org; dpauls@pngu.mgh.harvard.edu RI Hoekstra, Pieter/O-4396-2014; reus, victor/I-7923-2015; Gilbert, Donald/D-6443-2016; Wagner, Michael/E-2325-2011; Trabzuni, Daniah/C-4034-2012; Hardy, John/C-2451-2009; Traynor, Bryan/G-5690-2010; Lyon, Gholson/D-2765-2014; Singleton, Andrew/C-3010-2009; Weale, Michael/F-2587-2010; Stewart, Evelyn/K-6961-2014 OI Fernandez, Thomas V/0000-0003-0830-022X; Tischfield, Jay/0000-0003-3217-8287; Gamazon, Eric/0000-0003-4204-8734; Stewart, S. Evelyn/0000-0002-0994-6383; reus, victor/0000-0002-8193-5697; Gilbert, Donald/0000-0002-9245-6878; Wagner, Michael/0000-0003-2589-6440; Trabzuni, Daniah/0000-0003-4826-9570; Campbell, Desmond/0000-0003-1085-714X; Barr, Cathy/0000-0003-0361-0106; Lyon, Gholson/0000-0002-5869-0716; Weale, Michael/0000-0003-4593-1186; FU NIH; Tourette Syndrome Association (TSA); Psyadon; Shire; Solway; UCB Pharma; Janssen; Eli Lilly; Pfizer; Prestwick; Psyadon Pharmaceuticals; Otsuka Pharmaceuticals; NINDS; TSA; Talecris Biotherapeutics; Klingenstein Third Generation Foundation; John Wiley and Sons; McGraw Hill; Oxford University Press; Allergan; Allon Therapeutics; Ceregene; Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation; EMD Serono; Huntington's Disease Society of America; Huntington Study Group; Impax Pharmaceuticals; Ipsen Limited; Lundbeck; Medtronic; Merz Pharmaceuticals; Michael J Fox Foundation for Parkinson Research; National Institutes of Health; National Parkinson Foundation; Neurogen; St Jude Medical; Teva Pharmaceutical Industries; University of Rochester; Parkinson Study Group; Tourette Syndrome Association; Judah Foundation; NIH [NS40024, NS16648, NS037484, NS043538, MH079489, MH085057]; Tourette Syndrome Association International Consortium for Genetics; American Recovery and Re-investment Act (ARRA) [NS40024-07S1, NS16648-29S1]; American Academy of Neurology Foundation Grant; National Center for Research Resources [U54 RR020278]; New Jersey Center for Tourette Syndrome & Associated Disorders (through New Jersey Department of Health and Senior Services) [08-1827-FS-N-0, P01MH049351, R01MH061940, K05MH076273, T32MH018268]; UK Medical Research Council; Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project [Z01 AG000932-02]; NIH Genes, Environment and Health Initiative [GEI] [U01 HG004422]; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH contract [HHSN268200782096C]; NIMH; Guilford Press; Oxford Press FX Drs Pauls, Scharf, Mathews, Cox, Freimer, McMahon, Heutink, Oostra, Grados, King, Rouleau, Sandor and Budman have all received research support from the NIH and the Tourette Syndrome Association (TSA) on behalf of the TSA International Consortium for Genetics (TSAICG). Drs Scharf, Mathews and Grados have received honoraria and travel support from the TSA. Dr Mathews is a member of the TSA Medical Advisory Board. Dr Sandor has received support and consulting fees from Psyadon, Shire, Solway, UCB Pharma, Janssen, Eli Lilly, Pfizer and Prestwick. Dr Budman has been funded by Psyadon Pharmaceuticals, Otsuka Pharmaceuticals and NINDS and is a member of the National TSA Medical Advisory Board, LI TSA and LI CHADD Medical Advisory Boards. Dr Hoekstra has received honoraria for advice through Desitin, Eli Lilly and Shire. Dr Dion has received honoraria from Biovail Pharma, Pfizer and Eli Lilly. Dr Leckman has been funded by the NIH, the TSA, Talecris Biotherapeutics, Klingenstein Third Generation Foundation, John Wiley and Sons, McGraw Hill and Oxford University Press. Dr Walkup receives research support, travel support for paid and unpaid activities, serves in an unpaid position on the Medical Advisory Board and receives an honorarium for an Educational Meeting from the TSA. He receives royalties from Guilford Press and Oxford Press. He received free medication and placebo from Lilly, Pfizer and Abbott for NIH-funded studies. Dr Jankovic has received research grants from the following: Allergan, Allon Therapeutics, Ceregene, Chelsea Therapeutics, Diana Helis Henry Medical Research Foundation, EMD Serono, Huntington's Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck, Medtronic, Merz Pharmaceuticals, Michael J Fox Foundation for Parkinson Research, National Institutes of Health, National Parkinson Foundation, Neurogen, St Jude Medical, Teva Pharmaceutical Industries, University of Rochester and Parkinson Study Group. He has served as a consultant or advisory committee member for Allergan, Chelsea Therapeutics, EMD Serono, Lundbeck, Merz Pharmaceuticals, Michael J Fox Foundation for Parkinson Research and Teva Pharmaceutical Industries. He also serves on the editorial boards for Elsevier, Medlink: Neurology, Neurology in Clinical Practice, Neurotoxin Institute, Scientiae and UpToDate. Dr Knowles is on the Scientific Advisory Committee for Next-Generation Sequencing of Life Technologies, and is a technical advisor to SoftGenetics. Ms Anderson, Dr Barr, Dr Benarroch, Mr Berrio, Dr Bruun, Mr Campbell, Dr Cath, Dr Chouinard, Dr Conti, Ms Crane, Mr Crenshaw, Ms Davarya, Dr Davis, Ms Duarte, Mr Edlund, Dr Erenberg, Dr Eskin, Dr Evans, Mr Fagerness, Dr Fernandez, Mr Fournier, Mr Gamazon, Mr Gibbs, Dr Gilbert, Dr Girard, Dr Gross-Tsur, Dr Han, Dr Hardy, Dr Heiman, Dr Herrera, Dr Heutink, Dr Illmann, Dr J Kidd, Dr K Kidd, Mr. Konkashbaev, Dr Kremeyer, Dr Kurlan, Dr Lee, Dr Leppert, Dr Liu, Dr Lowe, Dr Lyon, Dr Mirel, Dr Moessner, Ms Moorjani, Mr Morgan, Mr Muller, Dr Naarden, Dr Neale, Dr Ochoa, Dr Ophoff, Ms Osiecki, Dr Pakstis, Ms Parkin, Mr Phan, Dr Pluzhnikov, Dr Pollak, Dr Posthuma, Dr Purcell, Dr Rangel-Lugo, Dr Restrepo, Dr Reus, Ms Rivas, Dr Robertson, Ms Romero, Dr Ruiz-Linares, Dr Sabatti, Ms Service, Mr Silgado, Dr Singer, Dr Singleton, Dr Smit, Dr State, Dr Stewart, Mr. Strengman, Dr Tikhomirov, Dr Tischfield, Dr Wagner, Dr N Weiss, Dr R Weiss and Ms Yu declare no conflict of interest.; We are grateful to all the patients with Tourette's syndrome who generously agreed to participate in this study. Furthermore, the members of the Tourette Syndrome Association International Consortium for Genetics are deeply indebted to the Tourette Syndrome Association for their guidance and support. We also thank Libby Bernier and Janelle Alabiso for their assistance in manuscript preparation and Stephan Ripke for help with meta-analysis figures. This work was supported by a grant from the Judah Foundation, NIH Grants NS40024 to DLP and the Tourette Syndrome Association International Consortium for Genetics, NIH Grant NS16648 and a grant from the Tourette Syndrome Association to DLP, NIH Grant NS037484 to NBF, NIH Grant NS043538 to AR-L, American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 to DLP, NIH Grant MH079489, and an American Academy of Neurology Foundation Grant and NIH Grant MH085057 to JMS. The Broad Institute Center for Genotyping and Analysis was supported by Grant U54 RR020278 from the National Center for Research Resources. Support was also provided by the New Jersey Center for Tourette Syndrome & Associated Disorders (through New Jersey Department of Health and Senior Services: 08-1827-FS-N-0) to GAH and JAT and P01MH049351, R01MH061940, K05MH076273 and T32MH018268 to JFL. Funding support for generation of the eQTL data was provided by the UK Medical Research Council and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project Z01 AG000932-02. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). The data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs0 00092.v1.p1 through dbGaP accession number phs000092.v1.p. None of the funding agencies for this project (NINDS, NIMH, the Tourette Syndrome Association and the Judah Foundation) had any influence or played any role in (1) the design or conduct of the study; (2) management, analysis or interpretation of the data; and (3) preparation, review or approval of the manuscript. NR 55 TC 56 Z9 56 U1 3 U2 42 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 JUN PY 2013 VL 18 IS 6 BP 721 EP 728 DI 10.1038/mp.2012.69 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 151HP UT WOS:000319451600015 PM 22889924 ER PT J AU Roediger, B Kyle, R Yip, KH Sumaria, N Guy, TV Kim, BS Mitchell, AJ Tay, SS Jain, R Forbes-Blom, E Chen, X Tong, PL Bolton, HA Artis, D Paul, WE de St Groth, BF Grimbaldeston, MA Le Gros, G Weninger, W AF Roediger, Ben Kyle, Ryan Yip, Kwok Ho Sumaria, Nital Guy, Thomas V. Kim, Brian S. Mitchell, Andrew J. Tay, Szun S. Jain, Rohit Forbes-Blom, Elizabeth Chen, Xi Tong, Philip L. Bolton, Holly A. Artis, David Paul, William E. de St Groth, Barbara Fazekas Grimbaldeston, Michele A. Le Gros, Graham Weninger, Wolfgang TI Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells SO NATURE IMMUNOLOGY LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; TRANSCRIPTION FACTOR GATA3; ATOPIC-DERMATITIS; TYPE-2 IMMUNITY; LUNG INFLAMMATION; INFLUENZA-VIRUS; MAST-CELLS; IN-VIVO; EXPRESSION; MICE AB Type 2 immunity is critical for defense against cutaneous infections but also underlies the development of allergic skin diseases. We report the identification in normal mouse dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depended on interleukin 7 (IL-7) and constitutively produced IL-13. Intravital multiphoton microscopy showed that dermal ILC2 cells specifically interacted with mast cells, whose function was suppressed by IL-13. Treatment of mice deficient in recombination-activating gene 1 (Rag1(-/-)) with IL-2 resulted in the population expansion of activated, IL-5-producing dermal ILC2 cells, which led to spontaneous dermatitis characterized by eosinophil infiltrates and activated mast cells. Our data show that ILC2 cells have both pro-and anti-inflammatory properties and identify a previously unknown interactive pathway between two innate populations of cells of the immune system linked to type 2 immunity and allergic diseases. C1 [Roediger, Ben; Sumaria, Nital; Guy, Thomas V.; Mitchell, Andrew J.; Tay, Szun S.; Jain, Rohit; Tong, Philip L.; Bolton, Holly A.; de St Groth, Barbara Fazekas; Weninger, Wolfgang] Centenary Inst, Newtown, Tas, Australia. [Kyle, Ryan; Forbes-Blom, Elizabeth; Le Gros, Graham] Malaghan Inst Med Res, Wellington, New Zealand. [Yip, Kwok Ho; Grimbaldeston, Michele A.] SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia. [Kim, Brian S.; Artis, David] Perelman Sch Med Philadelphia, Dept Microbiol, Philadelphia, PA USA. [Kim, Brian S.; Artis, David] Perelman Sch Med Philadelphia, Inst Immunol, Philadelphia, PA USA. [Kim, Brian S.] Perelman Sch Med Philadelphia, Dept Dermatol, Philadelphia, PA USA. [Chen, Xi; Paul, William E.] Natl Inst Allerg Dis, NIH, Bethesda, MD USA. [Tong, Philip L.; de St Groth, Barbara Fazekas; Weninger, Wolfgang] Univ Sydney, Discipline Dermatol, Camperdown, NSW, Australia. [Tong, Philip L.; Weninger, Wolfgang] Royal Prince Alfred Hosp, Dept Dermatol, Camperdown, NSW 2050, Australia. [Artis, David] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. RP Weninger, W (reprint author), Centenary Inst, Newtown, Tas, Australia. EM glegros@malaghan.org.nz; w.weninger@centenary.org.au RI Forbes-Blom, Elizabeth/I-3648-2013; Mitchell, Andrew/C-2714-2009; Le Gros, Graham/C-6725-2011; OI Mitchell, Andrew/0000-0003-4454-853X; Bolton, Holly/0000-0003-4628-7708; Weninger, Wolfgang/0000-0003-3133-8699; /0000-0002-4905-462X FU Australian National Health; Medical Research Council; Health Research Council of New Zealand; Marjorie Barclay Trust; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (US National Institutes of Health); Cancer Institute New South Wales FX We thank J. Ho Cho and J. Sprent (Garvan Institute) for mice deficient in IL-7, IL-15 or Jak3; M. Kleinschek (DNAX) for Il25-/- mice; P. Besmer (Sloan Kettering Institute) for c-Kit-eGFP mice; Z. Eshar (Weizmann Institute of Science) for mouse SPE-7 hybridoma cells that produce IgE monoclonal antibody specific for 2,4-dinitrophenyl; A. Smith, S. Allen, S. Dervish, C. Zhu, A. Terry, Y. Wen Loh, K. Price and M. Camberis for technical assistance; M. Rizk and J. Qin for animal husbandry; L. Feigenbaum for help in preparing mice with transgenic expression of a bacterial artificial chromosome; N. Kolesnikoff and H. Taing for help with culturing bone marrow-derived mast cells; and L. Cavanagh for administrative assistance. Supported by the Australian National Health and Medical Research Council (M.A.G.), the Health Research Council of New Zealand, the Marjorie Barclay Trust, the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (US National Institutes of Health) and the Cancer Institute New South Wales (W.W.). NR 50 TC 147 Z9 152 U1 3 U2 48 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 JUN PY 2013 VL 14 IS 6 BP 564 EP + DI 10.1038/ni.2584 PG 13 WC Immunology SC Immunology GA 146RG UT WOS:000319107600009 PM 23603794 ER PT J AU Latz, E Xiao, TS Stutz, A AF Latz, Eicke Xiao, T. Sam Stutz, Andrea TI Activation and regulation of the inflammasomes SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID NF-KAPPA-B; CHRONIC GRANULOMATOUS-DISEASE; INNATE IMMUNE-RESPONSES; NOD-LIKE RECEPTOR; NLRP3 INFLAMMASOME; NALP3 INFLAMMASOME; CASPASE-1 ACTIVATION; IL-1-BETA PRODUCTION; CYTOCHROME-C; HOST-DEFENSE AB Inflammasomes are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-18. In this Review, we discuss the complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response, and we highlight the similarities to another molecular signalling platform - the apoptosome - that monitors cellular health. Extracellular regulatory mechanisms are discussed, as well as the intracellular control of inflammasome assembly, for example, via ion fluxes, free radicals and autophagy. C1 [Latz, Eicke; Stutz, Andrea] Univ Bonn, Univ Hosp, Inst Innate Immun, D-53127 Bonn, Germany. [Latz, Eicke] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. [Latz, Eicke] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01655 USA. [Latz, Eicke] DZNE, D-53175 Bonn, Germany. [Latz, Eicke] Norwegian Univ Sci & Technol, Ctr Mol Inflammat Res, NO-7491 Trondheim, Norway. [Xiao, T. Sam] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Latz, E (reprint author), Univ Bonn, Univ Hosp, Inst Innate Immun, D-53127 Bonn, Germany. EM eicke.latz@uni-bonn.de RI Xiao, Tsan/I-7616-2013; Xiao, Tsan/A-8590-2010; Latz, Eicke/H-3951-2014 OI Xiao, Tsan/0000-0001-9688-475X; Latz, Eicke/0000-0003-1488-5666 FU US National Institutes of Health (NIH); Deutsche Forschungsgemeinschaft (DFG), Germany; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, USA FX The authors would like to thank C. M. De Nardo and B. G. Monks for critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (NIH) and the Deutsche Forschungsgemeinschaft (DFG), Germany (to E.L.), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, USA (to T.S.X.). E.L. is a member of the excellence cluster ImmunoSensation in Bonn, Germany. NR 153 TC 556 Z9 576 U1 19 U2 215 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD JUN PY 2013 VL 13 IS 6 BP 397 EP 411 DI 10.1038/nri3452 PG 15 WC Immunology SC Immunology GA 151FE UT WOS:000319445300008 PM 23702978 ER PT J AU Pastor, WA Aravind, L Rao, A AF Pastor, William A. Aravind, L. Rao, Anjana TI TETonic shift: biological roles of TET proteins in DNA demethylation and transcription SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID EMBRYONIC STEM-CELLS; GENOME-WIDE ANALYSIS; CPG-BINDING-PROTEIN; ZYGOTIC PATERNAL GENOME; ACUTE MYELOID-LEUKEMIA; BASE EXCISION-REPAIR; THYMINE DNA; 5-METHYLCYTOSINE OXIDATION; GENE-EXPRESSION; PROMOTER DNA AB In many organisms, the methylation of cytosine in DNA has a key role in silencing 'parasitic' DNA elements, regulating transcription and establishing cellular identity. The recent discovery that ten-eleven translocation (TET) proteins are 5-methylcytosine oxidases has provided several chemically plausible pathways for the reversal of DNA methylation, thus triggering a paradigm shift in our understanding of how changes in DNA methylation are coupled to cell differentiation, embryonic development and cancer. C1 [Pastor, William A.; Rao, Anjana] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA. [Pastor, William A.; Rao, Anjana] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Aravind, L.] US NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. RP Pastor, WA (reprint author), Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. EM wpastor@ucla.edu; arao@liai.org FU US National Institutes of health (NIH) [AI44432, HD065812, CA151535]; California Institute of Regenerative Medicine [RM-01729]; Leukemia and Lymphoma Society [TRP 6187- 12]; National Library of Medicine, NIH; National Science Foundation; Jane Coffin Childs Memorial Fund for Medical Research FX The authors thank S. Evans and A. Clark for comments on the manuscript. This work was supported by US National Institutes of health (NIH) R01 grants AI44432, HD065812 and CA151535, grant RM-01729 from the California Institute of Regenerative Medicine, and Translational Research grant TRP 6187- 12 from the Leukemia and Lymphoma Society (to A.R). Work in the laboratory of L.A. is supported by intramural funds of the National Library of Medicine, NIH. W.A.P. was supported by a predoctoral graduate research fellowship from the National Science Foundation and is currently supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. NR 186 TC 259 Z9 267 U1 7 U2 102 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD JUN PY 2013 VL 14 IS 6 BP 341 EP 356 DI 10.1038/nrm3589 PG 16 WC Cell Biology SC Cell Biology GA 151LO UT WOS:000319462200011 PM 23698584 ER PT J AU Grobman, WA Gilbert, SA Iams, JD Spong, CY Saade, G Mercer, BM Tita, ATN Rouse, DJ Sorokin, Y Leveno, KJ Tolosa, JE Thorp, JM Caritis, SN Van Dorsten, JP AF Grobman, William A. Gilbert, Sharon A. Iams, Jay D. Spong, Catherine Y. Saade, George Mercer, Brian M. Tita, Alan T. N. Rouse, Dwight J. Sorokin, Yoram Leveno, Kenneth J. Tolosa, Jorge E. Thorp, John M. Caritis, Steve N. Van Dorsten, J. Peter CA Eunice Kennedy Shriver Natl Inst TI Activity Restriction Among Women With a Short Cervix SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 33rd Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM) CY FEB 11-16, 2013 CL San Francisco, CA SP Soc Maternal Fetal Med (SMFM) ID PRETERM BIRTH; PROGESTERONE; DELIVERY; RISK; PREVENTION AB OBJECTIVE: To estimate determinants of and outcomes associated with activity restriction among women with a short cervix. METHODS: This was a secondary analysis of a randomized trial of 17-alpha hydroxyprogesterone caproate for prevention of preterm birth among nulliparous women with singleton gestations and cervices less than 30 mm by midtrimester ultrasonography. Women were asked weekly whether they had been placed on pelvic, work, or nonwork rest. "Any activity restriction" was defined as being placed on any type of rest. Factors associated with any activity restriction were determined and the association between preterm birth and activity restriction was estimated with multivariable logistic regression. RESULTS: Of the 657 women in the trial, 646 ( 98%) responded to questions regarding activity restriction. Two hundred fifty-two (39.0%) were placed on any activity restriction at a median of 23.9 weeks (interquartile range 22.6-27.9 weeks). Women on activity restriction were older, more likely to have private insurance, less likely to be Hispanic, had a shorter cervical length, and were more likely to have funneling and intra-amniotic debris. Preterm birth at less than 37 weeks of gestation was more common among women placed on activity restriction (37% compared with 17%, P<.001). After controlling for potential confounding factors, preterm birth remained more common among those placed on activity restriction ( adjusted odds ratio 2.37, 95% confidence interval 1.60-3.53). Results were similar for preterm birth at less than 34 weeks of gestation. CONCLUSION: Activity restriction did not reduce the rate of preterm birth in asymptomatic nulliparous women with a short cervix. C1 Northwestern Univ, Dept Obstet, Chicago, IL 60611 USA. Northwestern Univ, Dept Gynecol, Chicago, IL 60611 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Univ Alabama Birmingham, Birmingham, AL USA. Brown Univ, Providence, RI 02912 USA. Wayne State Univ, Detroit, MI USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ N Carolina, Chapel Hill, NC USA. Univ Pittsburgh, Pittsburgh, PA USA. Med Univ S Carolina, Charleston, SC 29425 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Grobman, WA (reprint author), 250 East Super St,Suite 05-2175, Chicago, IL 60611 USA. EM w-grobman@northwestern.edu OI caritis, steve/0000-0002-2169-0712 FU NCATS NIH HHS [UL1 TR000005, UL1 TR000150]; NCRR NIH HHS [5UL1RR025764, M01 RR000080, M01 RR00080, UL1 RR024153, UL1 RR024989, UL1 RR025764]; NICHD NIH HHS [U10 HD021410, HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, R24 HD050924, U01 HD036801, U10 HD027869, U10 HD027915, U10 HD027917, U10 HD034116, U10 HD034208, U10 HD036801, U10 HD040485, U10 HD040500, U10 HD040512, U10 HD040544, U10 HD040545, U10 HD040560, U10 HD053097, U10 HD053118, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560, UG1 HD053097] NR 19 TC 15 Z9 16 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2013 VL 121 IS 6 BP 1181 EP 1186 DI 10.1097/AOG.0b013e3182917529 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 151BR UT WOS:000319436100007 PM 23812450 ER PT J AU Figueroa, D Landon, MB Mele, L Spong, CY Ramin, SM Casey, B Wapner, RJ Varner, MW Thorp, JM Sciscione, A Catalano, P Harper, M Saade, G Caritis, SN Sorokin, Y Peaceman, AM Tolosa, JE AF Figueroa, Dana Landon, Mark B. Mele, Lisa Spong, Catherine Y. Ramin, Susan M. Casey, Brian Wapner, Ronald J. Varner, Michael W. Thorp, John M., Jr. Sciscione, Anthony Catalano, Patrick Harper, Margaret Saade, George Caritis, Steve N. Sorokin, Yoram Peaceman, Alan M. Tolosa, Jorge E. CA Eunice Kennedy Shriver Natl Inst TI Relationship Between 1-Hour Glucose Challenge Test Results and Perinatal Outcomes SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID GESTATIONAL DIABETES-MELLITUS; INTERNATIONAL WORKSHOP; PREGNANCY; WOMEN; RISK AB OBJECTIVE: To estimate the relationship between 1-hour 50 g glucose challenge test values and perinatal outcomes. METHODS: This was a secondary analysis of data from a multicenter treatment trial of mild gestational diabetes mellitus. Women with glucose challenge test values of 135-199 mg/dL completed a 3-hour oral glucose tolerance test. Mild gestational diabetes mellitus was defined as fasting glucose less than 95 mg/dL and two or more abnormal oral glucose tolerance test values: 1-hour 180 mg/dL or more; 2-hour 155 mg/dL or more; and 3-hour 140 mg/dL or more. Our study included untreated women with glucose challenge test values of 135-139 mg/dL and 140-199 mg/dL and a comparison group with values less than 120 mg/dL. Primary outcomes included a perinatal composite (stillbirth, neonatal death, hypoglycemia, hyperbilirubinemia, neonatal hyperinsulinemia, and birth trauma), large for gestational age (LGA, birth weight above the 90th percentile based on sex-specific and race-specific norms), and macrosomia (greater than 4,000 g). RESULTS: There were 436 women with glucose challenge test values less than 120 mg/dL and 1,403 with values of 135 mg/dL or more (135-139, n=135; 140-199, n=1,268). The composite perinatal outcome occurred in 25.6% of those with glucose challenge test values less than 120 mg/dL compared with 21.1% for values of 135-139 mg/dL and 35.3% for values of 140-199 mg/dL. Rates of LGA by group were 6.6%, 6.8%, and 12.4%, respectively. Rates of macrosomia by group were 7.8%, 6.1%, and 12.1%, respectively. Compared with glucose challenge test values less than 120 mg/dL, the adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for values of 140-199 mg/dL were 1.48 (1.14-1.93) for the composite outcome, 1.97 (1.29-3.11) for LGA, and 1.61 (1.07-2.49) for macrosomia. For glucose challenge test values of 135-139 mg/dL, adjusted ORs and 95% CIs were 0.75 (0.45-1.21), 1.04 (0.44-2.24), and 0.75 (0.30-1.66), respectively. The subcategories with glucose challenge test values of 140-144 mg/dL and 145-149 mg/dL also were associated with an increase in selected outcomes when compared with those with values less than 120 mg/dL. CONCLUSIONS: Glucose challenge test values of 135139 mg/dL were not associated with adverse outcomes compared with values less than 120 mg/dL; however, glucose challenge test values of 140 mg/dL or more were associated with an increase in odds of the composite perinatal outcome, LGA, and macrosomia. C1 Univ Alabama Birmingham, Dept Obstet, Birmingham, AL USA. Univ Alabama Birmingham, Dept Gynecol, Birmingham, AL USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Columbia Univ, New York, NY USA. Univ Utah, Salt Lake City, UT USA. Univ N Carolina, Chapel Hill, NC USA. Drexel Univ, Philadelphia, PA 19104 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Wake Forest Univ Hlth Sci, Winston Salem, NC USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Univ Pittsburgh, Pittsburgh, PA USA. Wayne State Univ, Detroit, MI USA. Northwestern Univ, Chicago, IL 60611 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Figueroa, D (reprint author), 176F 10270C,619 19th St S, Birmingham, AL 35249 USA. EM gcampbel@uabmc.edu RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD27915, HD34116, HD40485, HD34208, HD27869, HD40500, HD40560, HD34136, HD40544, HD27860, HD40545, HD53097, HD21410, HD27917, HD40512, HD53118, HD36801]; General Clinical Research Centers Grant [M01-RR00034]; National Center for Research Resources [UL1-RR024989, M01-RR00080, UL1-RR025764, C06-RR11234] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD27915, HD34116, HD40485, HD34208, HD27869, HD40500, HD40560, HD34136, HD40544, HD27860, HD40545, HD53097, HD21410, HD27917, HD40512, HD53118, HD36801), a General Clinical Research Centers Grant (M01-RR00034), and the National Center for Research Resources (UL1-RR024989, M01-RR00080, UL1-RR025764, C06-RR11234) and does not necessarily represent the official views of the NICHD or the National Institutes of Health. NR 20 TC 11 Z9 11 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2013 VL 121 IS 6 BP 1241 EP 1247 DI 10.1097/AOG.0b013e31829277f5 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 151BR UT WOS:000319436100015 PM 23812458 ER PT J AU Johnson, EO Calogero, AE Konstandi, M Kamilaris, TC La Vignera, S Chrousos, GP AF Johnson, Elizabeth O. Calogero, Aldo E. Konstandi, Maria Kamilaris, Themis C. La Vignera, Sandro Chrousos, George P. TI Effects of experimentally induced hyperthyroidism on central hypothalamic-pituitary-adrenal axis function in rats: in vitro and in situ studies SO PITUITARY LA English DT Article DE Thyroid hormone; ACTH; Corticosterone; Corticotrophs; mRNA; Hypothalamic-pituitary-adrenal axis; Stress ID CORTICOTROPIN-RELEASING-FACTOR; VASOPRESSIN MESSENGER-RNA; THYROID STORM; PARAVENTRICULAR NUCLEUS; STRESS; PROOPIOMELANOCORTIN; THYROXINE; CORTICOSTERONE; RESPONSES; HORMONE AB Hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally responsible for the hypercorticosteronism remains unclear. The purpose of this study was to assess the effects of hyperthyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis, to identify the locus in the HPA axis that is principally affected, and address the time-dependent effects of alterations in thyroid status. The functional integrity of each component of the HPA axis was examined in vitro and in situ in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given pharmacological dose (50 mu g) of thyroxin for 7 or 60 days. Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days. Basal plasma ACTH levels were similar to controls. Both hypothalamic CRH content and the magnitude of KCL- and arginine vasopressin (AVP)-induced CRH release from hypothalamic culture were increased in long-term hyperthyroid rats. There was a significant increase in the content of both ACTH and beta-endorphin in the anterior pituitaries of both short- and long-term hyperthyroid animals. Short-term hyperthyroid rats showed a significant increase in basal POMC mRNA expression in the anterior pituitary, and chronically hyperthyroid animals showed increased stress-induced POMC mRNA expression. Adrenal cultures taken from short-term hyperthyroid rats responded to exogenous ACTH with an exaggerated corticosterone response, while those taken from 60-day hyperthyroid animals showed responses similar to controls. The findings show that hyperthyroidism is associated with hypercorticosteronemia and HPA axis dysfunction that becomes more pronounced as the duration of hyperthyroidism increases. The evidence suggests that experimentally induced hyperthyroidism is associated with central hyperactivity of the HPA axis. C1 [Johnson, Elizabeth O.] Univ Athens, Sch Med, Dept Anat, GR-11527 Athens, Greece. [Calogero, Aldo E.] Univ Catania, Osped Garibaldi, Dept Biomed Sci, Sect Endocrinol Androl & Internal Med, Catania, Italy. [Konstandi, Maria] Univ Ioannina, Sch Med, Dept Pharmacol, GR-45110 Ioannina, Greece. [Kamilaris, Themis C.] NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. [La Vignera, Sandro] Univ Catania, Dept Internal Med & Syst Dis, Sect Endocrinol Androl & Internal Med, Catania, Italy. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Johnson, EO (reprint author), Univ Athens, Sch Med, Dept Anat, 75 Mikras Asias Str, GR-11527 Athens, Greece. EM elizabethojohnson@gmail.com NR 35 TC 7 Z9 7 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X EI 1573-7403 J9 PITUITARY JI Pituitary PD JUN PY 2013 VL 16 IS 2 BP 275 EP 286 DI 10.1007/s11102-012-0417-5 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 149CL UT WOS:000319295500020 PM 22975847 ER PT J AU Nelson, PG Nelson, KB AF Nelson, P. G. Nelson, K. B. TI Innervation of the placenta and uterus: Competition between cytotrophoblasts and nerves? SO PLACENTA LA English DT Article DE Denervation; Vascular smooth muscle; Spiral artery remodeling ID SINOAORTIC-DENERVATED RATS; TROPHOBLAST INVASION; UMBILICAL-CORD; IN-VITRO; PREGNANCY; PREECLAMPSIA; MYOMETRIUM; ABSENCE; GROWTH; MODEL AB In normal pregnancy, invasion of the uterus by trophoblasts is followed by dramatic elimination of the rich uterine innervation present in the non-pregnant state, and by remodeling of maternal spiral arteries. In general, the healthy survival of vascular smooth muscle requires innervation, but whether denervation plays a role in stripping of vascular smooth muscle from spiral arteries in normal pregnancy has not been explored. We propose that the temporal and spatial association of trophoblast invasion with denervation in pregnancy may involve competitive interaction between the invading trophoblast and persisting neurons. We suggest feasible experiments to explore the possible effects of such trophoblast-nerve competition on spiral artery remodeling. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Nelson, P. G.] NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Nelson, K. B.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC USA. [Nelson, K. B.] NINDS, NIH, Bethesda, MD 20892 USA. RP Nelson, PG (reprint author), NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. EM nelsonp@mail.nih.gov; nelsonk@ninds.nih.gov NR 43 TC 1 Z9 1 U1 1 U2 6 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD JUN PY 2013 VL 34 IS 6 BP 463 EP 466 DI 10.1016/j.placenta.2013.03.004 PG 4 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 146LO UT WOS:000319092800001 PM 23602335 ER PT J AU Anthis, NJ Clore, GM AF Anthis, Nicholas J. Clore, G. Marius TI Sequence-specific determination of protein and peptide concentrations by absorbance at 205 nm SO PROTEIN SCIENCE LA English DT Article DE protein; absorbance; UV; concentration; molecular biology; absorptivity; extinction coefficient ID COMPLEX; APO AB Quantitative studies in molecular and structural biology generally require accurate and precise determination of protein concentrations, preferably via a method that is both quick and straightforward to perform. The measurement of ultraviolet absorbance at 280 nm has proven especially useful, since the molar absorptivity (extinction coefficient) at 280 nm can be predicted directly from a protein sequence. This method, however, is only applicable to proteins that contain tryptophan or tyrosine residues. Absorbance at 205 nm, among other wavelengths, has been used as an alternative, although generally using absorptivity values that have to be uniquely calibrated for each protein, or otherwise only roughly estimated. Here, we propose and validate a method for predicting the molar absorptivity of a protein or peptide at 205 nm directly from its amino acid sequence, allowing one to accurately determine the concentrations of proteins that do not contain tyrosine or tryptophan residues. This method is simple to implement, requires no calibration, and should be suitable for a wide range of proteins and peptides. C1 [Anthis, Nicholas J.; Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Program of the NIH, NIDDK; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX Grant sponsors: Intramural Program of the NIH, NIDDK, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to GMC). NR 20 TC 27 Z9 27 U1 5 U2 33 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUN PY 2013 VL 22 IS 6 BP 851 EP 858 DI 10.1002/pro.2253 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 150WP UT WOS:000319422500016 PM 23526461 ER PT J AU Master, Z Resnik, DB AF Master, Zubin Resnik, David B. TI Hype and Public Trust in Science SO SCIENCE AND ENGINEERING ETHICS LA English DT Article DE Public trust; Hype; Biotechnology; Public support/enthusiasm; Responsible conduct of research ID STEM-CELL RESEARCH; GENE-THERAPY; AFRICAN-AMERICANS; TUSKEGEE SYPHILIS; MEDIA HYPE; BIOTECHNOLOGY; COMMUNICATION; TOURISM; NEWS; PERCEPTIONS AB Social scientists have begun elucidating the variables that influence public trust in science, yet little is known about hype in biotechnology and its effects on public trust. Many scholars claim that hyping biotechnology results in a loss of public trust, and possibly public enthusiasm or support for science, because public expectations of the biotechnological promises will be unmet. We argue for the need for empirical research that examines the relationships between hype, public trust, and public enthusiasm/support. We discuss the complexities in designing empirical studies that provide evidence for a causal link between hype, public trust, and public enthusiasm/support, but also illustrate how this may be remedied. Further empirical research on hype and public trust is needed in order to improve public communication of science and to design evidence-based education on the responsible conduct of research for scientists. We conclude that conceptual arguments made on hype and public trust must be nuanced to reflect our current understanding of this relationship. C1 [Master, Zubin] Univ Alberta, Hlth Law & Sci Policy Grp, Ctr Law, Edmonton, AB T6G 2H5, Canada. [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Master, Z (reprint author), Univ Alberta, Hlth Law & Sci Policy Grp, Ctr Law, Rm 462,89 Ave & 111 St, Edmonton, AB T6G 2H5, Canada. EM zubin@zubsplace.com; resnikd@niehs.nih.gov FU Cancer Stem Cell Consortium; Stem Cell Network FX We are grateful to Professor Timothy Caulfield for the insightful comments on several iterations of this manuscript. We would also like to thank Dr. Bruce Androphy and the reviewers of this manuscript for providing helpful feedback. This research was supported, in part, by a generous grant from the Cancer Stem Cell Consortium and the Stem Cell Network. The work presented here does not represent the views of Health Canada or the Canadian government. This research is also the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. NR 81 TC 16 Z9 17 U1 5 U2 51 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1353-3452 J9 SCI ENG ETHICS JI Sci. Eng. Ethics PD JUN PY 2013 VL 19 IS 2 BP 321 EP 335 DI 10.1007/s11948-011-9327-6 PG 15 WC Ethics; Engineering, Multidisciplinary; History & Philosophy Of Science; Multidisciplinary Sciences; Philosophy SC Social Sciences - Other Topics; Engineering; History & Philosophy of Science; Science & Technology - Other Topics; Philosophy GA 149XS UT WOS:000319355300004 PM 22045550 ER PT J AU Homma, K Okamoto, S Mandai, M Gotoh, N Rajasimha, HK Chang, YS Chen, S Li, W Cogliati, T Swaroop, A Takahashi, M AF Homma, Kohei Okamoto, Satoshi Mandai, Michiko Gotoh, Norimoto Rajasimha, Harsha K. Chang, Yi-Sheng Chen, Shan Li, Wei Cogliati, Tiziana Swaroop, Anand Takahashi, Masayo TI Developing Rods Transplanted into the Degenerating Retina of Crx-Knockout Mice Exhibit Neural Activity Similar to Native Photoreceptors SO STEM CELLS LA English DT Article DE Retinal photoreceptors; Induced pluripotent stem cells; Cell transplantation; Calcium flux ID EMBRYONIC STEM-CELLS; INFRARED FLUORESCENT PROTEINS; LEBERS CONGENITAL AMAUROSIS; AGE-RELATED MACULOPATHY; NA+ ACTION-POTENTIALS; PHASE-I TRIAL; MACULAR DEGENERATION; CONE PHOTORECEPTORS; VISUAL FUNCTION; DEFICIENT MICE AB Replacement of dysfunctional or dying photoreceptors offers a promising approach for retinal neurodegenerative diseases, including age-related macular degeneration and retinitis pigmentosa. Several studies have demonstrated the integration and differentiation of developing rod photoreceptors when transplanted in wild-type or degenerating retina; however, the physiology and function of the donor cells are not adequately defined. Here, we describe the physiological properties of developing rod photoreceptors that are tagged with green fluorescent protein (GFP) driven by the promoter of rod differentiation factor, Nrl. GFP-tagged developing rods show Ca2+ responses and rectifier outward currents that are smaller than those observed in fully developed photoreceptors, suggesting their immature developmental state. These immature rods also exhibit hyperpolarization-activated current (I-h) induced by the activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. When trans-planted into the subretinal space of wild-type or retinal degeneration mice, GFP-tagged developing rods can integrate into the photoreceptor outer nuclear layer in wildtype mouse retina and exhibit Ca2+ responses and membrane current comparable to native rod photoreceptors. A proportion of grafted rods develop rhodopsin-positive outer segment-like structures within 2 weeks after transplantation into the retina of Crx-knockout mice and produce rectifier outward current and Ih upon membrane depolarization and hyperpolarization. GFP-positive rods derived from induced pluripotent stem (iPS) cells also display similar membrane current Ih as native developing rod photoreceptors, express rod-specific phototransduction genes, and HCN-1 channels. We conclude that Nrl-promoter-driven GFP-tagged donor photoreceptors exhibit physiological characteristics of rods and that iPS cell-derived rods in vitro may provide a renewable source for cell-replacement therapy. C1 [Homma, Kohei; Okamoto, Satoshi; Mandai, Michiko; Takahashi, Masayo] RIKEN, Ctr Dev Biol, Lab Retinal Regenerat, Kobe, Hyogo, Japan. [Homma, Kohei; Gotoh, Norimoto; Rajasimha, Harsha K.; Chang, Yi-Sheng; Cogliati, Tiziana; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Chen, Shan; Li, Wei] NEI, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Chang, Yi-Sheng] Natl Cheng Kung Univ & Hosp, Dept Ophthalmol, Tainan, Taiwan. RP Homma, K (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. EM kohei.homma@nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU Ministry of Education, Culture, Sports, Science, and Technology (MEXT); Ministry of Health Labor and Welfare; Japan Society for the Promotion of Science (JSPS); JSPS Postdoctoral Fellowships for Research Abroad (Kaitoku-NIH); National Eye Institute, National Institutes of Health, Bethesda, MD, USA FX We thank Itaru Arai and Masao Tachibana (University of Tokyo) for help in patch-clamp recording, Robert Farris (Biological Imaging Core, National Eye Institute) for Ca2+ imaging, Linn Gieser for Affymetrix Chip analysis, Juthaporn Assawachananont for retinal differentiation culture, Kyoko Iseki, Chie Ishigami, and Chikako Yamada for technical support, and lab colleagues for helpful discussions. We are grateful to Takahisa Furukawa (Osaka Bioscience Institute) for providing Crx-knockout mice. This work was supported by Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Ministry of Health Labor and Welfare, a grant-in-aid for Young Scientists (B) from Japan Society for the Promotion of Science (JSPS) (to KH), JSPS Postdoctoral Fellowships for Research Abroad (Kaitoku-NIH) (to KH), and by intramural research program of the National Eye Institute, National Institutes of Health, Bethesda, MD, USA. NR 63 TC 33 Z9 33 U1 3 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUN PY 2013 VL 31 IS 6 BP 1149 EP 1159 DI 10.1002/stem.1372 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 149QD UT WOS:000319335200012 PM 23495178 ER PT J AU Derdeyn, CP Fiorella, D Lynn, MJ Turan, TN Lane, BF Janis, LS Chimowitz, MI AF Derdeyn, Colin P. Fiorella, David Lynn, Michael J. Turan, Tanya N. Lane, Bethany F. Janis, L. Scott Chimowitz, Marc I. TI Intracranial Stenting SAMMPRIS SO STROKE LA English DT Article; Proceedings Paper CT 28th Princeton Conference CY MAY 17-19, 2012 CL Cincinnati, OH DE angioplasty; clinical trial; risk factor management; stenting; stroke ID AGGRESSIVE MEDICAL-MANAGEMENT; PREVENTING RECURRENT STROKE; TRANSIENT ISCHEMIC ATTACK; ARTERIAL-STENOSIS; ANTITHROMBOTIC THERAPY; BLOOD-PRESSURE; ASPIRIN; CLOPIDOGREL; TRIAL; WARFARIN C1 [Derdeyn, Colin P.] Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Neurosurg, St Louis, MO USA. [Fiorella, David] SUNY Stony Brook, Dept Neurosurg, Stony Brook, NY 11794 USA. [Lynn, Michael J.; Lane, Bethany F.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Turan, Tanya N.; Chimowitz, Marc I.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Janis, L. Scott] NINDS, NIH, Bethesda, MD 20892 USA. RP Derdeyn, CP (reprint author), Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, Campus Box 8131,510 S Kingshighway Blvd, St Louis, MO 63110 USA. EM derdeync@mir.wustl.edu OI Turan, Tanya/0000-0001-5399-8845; Derdeyn, Colin/0000-0002-5932-2683 FU NCRR NIH HHS [UL1 RR024131, TL1 RR029889, UL1 RR029882, UL1 RR029890, UL1RR024131, UL1RR029882, UL1RR029889, UL1RR029890]; NEI NIH HHS [P30 EY006360, U10 EY013287, UG1 EY013287]; NINDS NIH HHS [K23 NS069668, K24 NS050307, P50 NS055977, R01 NS036643, R01 NS051631, R01 NS051688, U01 NS058728] NR 24 TC 2 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUN PY 2013 VL 44 IS 6 SU 1 BP S41 EP S44 DI 10.1161/STROKEAHA.111.000370 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 151KI UT WOS:000319459000017 PM 23709726 ER PT J AU Lendoiro, E Gonzalez-Colmenero, E Concheiro-Guisan, A de Castro, A Cruz, A Lopez-Rivadulla, M Concheiro, M AF Lendoiro, Elena Gonzalez-Colmenero, Eva Concheiro-Guisan, Ana de Castro, Ana Cruz, Angelines Lopez-Rivadulla, Manuel Concheiro, Marta TI Maternal Hair Analysis for the Detection of Illicit Drugs, Medicines, and Alcohol Exposure During Pregnancy SO THERAPEUTIC DRUG MONITORING LA English DT Article; Proceedings Paper CT 17th Congress of the Society-of-Hair-Testing (SoHT) CY JUN, 2012 CL Toronto, CANADA SP Soc Hair Testing (SoHT) DE hair; pregnancy; drugs of abuse; alcohol; tobacco ID CHROMATOGRAPHY-MASS SPECTROMETRY; NEONATAL HAIR; LIQUID-CHROMATOGRAPHY; BIOANALYTICAL PROCEDURES; FETAL TOXICOLOGY; COCAINE; MECONIUM; OPIATES; METABOLITES; TOBACCO AB Background/objectives: Drug of abuse consumption throughout pregnancy is a serious public health problem and an important economic cost to the health system. The aim of this work was to compare maternal interview and hair analysis to determine drug consumption throughout pregnancy and to study relations among maternal interview, hair results, and neonatal outcomes. Methods: Two hundred nine mothers agreed to participate. After delivery, they were interviewed and a hair sample collected. Hair samples were segmented in trimesters and analyzed for 35 drugs [opioids, cocaine, amphetamines, Delta(9)-tetrahydrocannabinol (THC), ketamine, methadone, antidepressants, benzodiazepines, and hypnotics; limits of quantification 5-100 pg/mg] and for ethyl glucuronide (limit of quantification 10 pg/mg) by liquid chromatography-tandem mass spectrometry. Statistical analysis was performed with chi(2) test and t test. Results: In the interview, 4.3% mothers declared using illicit drugs during pregnancy (cocaine 1.4%, THC 2.9%, and opiates 1%), 3.3% medicines (methadone 1.9%, benzodiazepines 1.9%, and antidepressants 0.5%), 21.5% tobacco, and 13.7% alcohol. Hair analysis showed 15.4% prevalence in illicit drugs (cocaine 12.4%, THC 3.8%, opiates 1%, and ketamine 1%), 22.5% in medicines (methadone 3.3%, benzodiazepines 11%, antidepressants 9.1%, zopiclone 1%, and fentanyl 1.4%), and 3.9% in alcohol. Neonatal abstinence syndrome was developed in 8.1% newborns, all of them from mothers with high methadone-positive hair results (>926.2 pg/mg). Statistically significant lower newborn weight and length were found in neonates from declared smokers compared with nonsmokers (P < 0.05). Conclusions: Maternal hair analysis showed to be more sensitive than maternal interview to detect drug use during pregnancy, except for alcohol. In this preliminary study, no statistically significant differences were found between exposed and nonexposed newborns to drugs, except for tobacco consumption. C1 [Lendoiro, Elena; de Castro, Ana; Cruz, Angelines; Lopez-Rivadulla, Manuel; Concheiro, Marta] Univ Santiago de Compostela, Inst Ciencias Forenses, Secc Toxicol, Santiago De Compostela, Spain. [Gonzalez-Colmenero, Eva; Concheiro-Guisan, Ana] Complejo Hosp Univ Vigo, Secc Neonatol, Vigo, Spain. [de Castro, Ana] Cienytech SL, Dept Desarrollo & Validac Metodos Cromatograf, Santiago De Compostela, Spain. [Concheiro, Marta] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Concheiro, M (reprint author), NIDA, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 200,Room 05A729, Baltimore, MD 21224 USA. EM marta.concheiro-guisan@nih.gov RI DE CASTRO, ANA/M-5159-2015; OI DE CASTRO, ANA/0000-0002-9832-012X; CRUZ LANDEIRA, ANGELINES/0000-0003-1382-4546 NR 38 TC 15 Z9 15 U1 4 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD JUN PY 2013 VL 35 IS 3 BP 296 EP 304 DI 10.1097/FTD.0b013e318288453f PG 9 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 146CO UT WOS:000319066700004 PM 23666580 ER PT J AU Scott, JR Courter, JD Saldaa, SN Widemann, BC Fisher, M Weiss, B Perentesis, J Vinks, AA AF Scott, Jeffrey R. Courter, Joshua D. Saldaa, Shannon N. Widemann, Brigitte C. Fisher, Michael Weiss, Brian Perentesis, John Vinks, Alexander A. TI Population Pharmacokinetics of Sirolimus in Pediatric Patients With Neurofibromatosis Type 1 SO THERAPEUTIC DRUG MONITORING LA English DT Article DE sirolimus; neurofibromatosis; pharmacokinetics; pediatric ID RENAL-TRANSPLANT RECIPIENTS; MAMMALIAN TARGET; RAPAMYCIN; MTOR; THERAPY; PATHWAY; GROWTH; REQUIREMENTS; CLEARANCE; BRAIN AB Purpose: The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of treatment duration on clearance and dose requirements, and to evaluate the association of sirolimus clearance with patient-specific factors, including age, weight, body surface area (BSA), race, and sex. Methods: Sirolimus concentration-time data were collected from an ongoing prospective trial in children with NF1. An iterative 2-stage Bayesian method was used for the PK parameter analyses. Results: Data from 44 patients with NF1 were included in the analyses. Mean age was 8.4 years (SD 4.5, range 3-18), and mean weight was 29.8 kg (SD 16.7, range 12-85.8). Mean sirolimus clearance was 11.8 L/h (SD 4.6, range 2.2-24.1), and the mean dose to obtain a target trough concentration of 10-15 ng/mL was 2.0 mg/m(2) administered twice daily (SD 0.72, range 0.77-3.85). A nonlinear relationship between age and clearance was observed. Total body weight and BSA were strong predictors of sirolimus clearance (r(2) = 0.67 and 0.65, respectively). Conclusions: Sirolimus clearance in children with NF1 is comparable with that in pediatric transplant patients. Clearance was most associated with body size parameters (BSA and total body weight) in children with NF1. When normalized for size, an age effect on clearance was observed in the youngest patients, most likely because of the maturational changes in drug absorption and metabolism. A mean dose of 2.0 mg/m(2) twice a day was required for attainment of target trough concentrations of 10-15 ng/mL in children greater than 3 years of age who have NF1. The updated model will allow PK-guided individualized dosing of sirolimus in patients with NF1. C1 [Scott, Jeffrey R.; Courter, Joshua D.; Saldaa, Shannon N.] Cincinnati Childrens Hosp Med Ctr, Div Pharma, Cincinnati, OH 45229 USA. [Saldaa, Shannon N.; Vinks, Alexander A.] Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, Cincinnati, OH 45229 USA. [Saldaa, Shannon N.; Weiss, Brian; Perentesis, John; Vinks, Alexander A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Fisher, Michael] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Weiss, Brian; Perentesis, John] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Div Oncol, Cincinnati, OH 45229 USA. RP Vinks, AA (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Clin Pharmacol, 3333 Burnet Ave,MLC 6018, Cincinnati, OH 45229 USA. EM sander.vinks@cchmc.org FU Department of Defense [W81XWH-05-615]; Neurofibromatosis Clinical Trials Consortium; National Institutes of Health [5K24HD050387] FX Supported by Department of Defense grant W81XWH-05-615, Neurofibromatosis Clinical Trials Consortium (B. C. Widemann, M. Fisher, B. Weiss, J. Perentesis, and A. A. Vinks), and National Institutes of Health grant 5K24HD050387 (A. A. Vinks). NR 35 TC 9 Z9 9 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD JUN PY 2013 VL 35 IS 3 BP 332 EP 337 DI 10.1097/FTD.0b013e318286dd3f PG 6 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 146CO UT WOS:000319066700009 PM 23666574 ER PT J AU Abbracchio, MP Boeynaems, JM Cattaneo, M Di Virgilio, F Illes, P Inoue, K Jacobson, KA Miras-Portugal, MT Ralevic, V Robson, SC Verkhratsky, A Zimmermann, H AF Abbracchio, M. P. Boeynaems, J. -M. Cattaneo, M. Di Virgilio, F. Illes, P. Inoue, K. Jacobson, K. A. Teresa Miras-Portugal, M. Ralevic, V. Robson, S. C. Verkhratsky, A. Zimmermann, H. TI Reply to: "The discovery of a new class of synaptic transmitters in smooth muscle fifty years ago and amelioration of coronary artery thrombosis' SO ACTA PHYSIOLOGICA LA English DT Editorial Material ID TAENIA-COLI; GUINEA-PIG; ACETYLCHOLINE; EXCITABILITY; CONDUCTION; RECEPTOR; DRUGS C1 [Abbracchio, M. P.] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy. [Boeynaems, J. -M.] Univ Libre Brussels, Brussels, Belgium. [Cattaneo, M.] Univ Milan, Dipartimento Sci Salute, Milan, Italy. [Di Virgilio, F.] Univ Ferrara, Dept Morphol Surg & Expt Med, I-44100 Ferrara, Italy. [Illes, P.] Univ Leipzig, Dept Pharmacol & Toxicol, D-04109 Leipzig, Germany. [Inoue, K.] Kiushu Univ, Fukuoka, Japan. [Jacobson, K. A.] NIDDK, Mol Recognit Sect, NIH, Bethesda, MD USA. [Jacobson, K. A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Teresa Miras-Portugal, M.] Univ Complutense Madrid, Dept Biochem & Mol Biol, Madrid, Spain. [Ralevic, V.] Univ Nottingham, Sch Biomed Sci, Nottingham NG7 2RD, England. [Robson, S. C.] Harvard Univ, Dept Med, Boston, MA 02115 USA. [Verkhratsky, A.] Univ Manchester, Manchester, Lancs, England. [Zimmermann, H.] Goethe Univ Frankfurt, Inst Cell Biol & Neurosci, D-60054 Frankfurt, Germany. RP Abbracchio, MP (reprint author), Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy. EM mariapia.abbracchio@unimi.it RI Jacobson, Kenneth/A-1530-2009; Verkhratsky, Alexei/J-4527-2013; Miras-Portugal, Maria Teresa/L-7137-2014; Abbracchio, Maria Pia/B-9342-2014; OI Jacobson, Kenneth/0000-0001-8104-1493; Verkhratsky, Alexei/0000-0003-2592-9898; Abbracchio, Maria Pia/0000-0002-7833-3388; Cattaneo, Marco/0000-0002-7343-4534 FU Intramural NIH HHS [Z99 DK999999, ZIA DK031116-25, ZIA DK031116-26] NR 10 TC 1 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1748-1708 J9 ACTA PHYSIOL JI Acta Physiol. PD JUN PY 2013 VL 208 IS 2 BP 139 EP 140 DI 10.1111/apha.12101 PG 2 WC Physiology SC Physiology GA 142RB UT WOS:000318813700003 PM 23551801 ER PT J AU Fontana, L Addante, F Copetti, M Paroni, G Fontana, A Sancarlo, D Pellegrini, F Ferrucci, L Pilotto, A AF Fontana, Luigi Addante, Filomena Copetti, Massimiliano Paroni, Giulia Fontana, Andrea Sancarlo, Daniele Pellegrini, Fabio Ferrucci, Luigi Pilotto, Alberto TI Identification of a metabolic signature for multidimensional impairment and mortality risk in hospitalized older patients SO AGING CELL LA English DT Article DE comprehensive geriatric assessment; IGF-1; inflammation; mortality; multidimensional prognostic index; testosterone ID COMPREHENSIVE GERIATRIC ASSESSMENT; TERM CALORIE RESTRICTION; PROGNOSTIC INDEX; ELDERLY PATIENTS; FRAILTY; PROTEIN; ATHEROSCLEROSIS; INFLAMMATION; VALIDATION; HUMANS AB A combination of several metabolic and hormonal adaptations has been proposed to control aging. Little is known regarding the effects of multiple deregulations of these metabolic and hormonal systems in modulating frailty and mortality in hospitalized elderly patients. We measured 17 biological serum parameters from different metabolic/hormonal pathways in 594 hospitalized elderly patients followed up to 1year who were stratified into three groups according to their multidimensional impairment, evaluated by a Comprehensive Geriatric Assessment (CGA)-based Multidimensional Prognostic Index (MPI). The mortality incidence rates were 7% at 1 month and 21% at 1 year. Our data show that frailty and mortality rate were positively associated with chronic inflammation and with a down-regulation of multiple endocrine factors. Of the 17 biomarkers examined, blood levels of IGF-1, triiodothyronine, C-reactive protein, erythrocyte sedimentation rate, white blood cell and lymphocyte counts, iron, albumin, total cholesterol, and LDL-c were significantly associated with both MPI severity grade and mortality. In multivariate Cox proportional hazard model, the following biomarkers most strongly predicted the risk of mortality (adjusted hazard ratio (HR) per 1 quintile increment in predictor distribution): IGF-1 HR=0.71 (95% CI: 0.630.80), CRP HR=1.48 (95% CI: 1.321.65), hemoglobin HR=0.82 (95% CI: 0.730.92), and glucose HR=1.17 (95% CI: 1.041.30). Multidimensional impairment assessed by MPI is associated with a distinctive metabolic signature'. The concomitant elevation of markers of inflammation, associated with a simultaneous reduction in multiple metabolic and hormonal factors, predicts mortality in hospitalized elderly patients. C1 [Fontana, Luigi] Univ Salerno, Dept Med, Sch Med, I-84100 Salerno, Italy. [Fontana, Luigi] Washington Univ, Div Geriatr & Nutr Sci, St Louis, MO 63110 USA. [Fontana, Luigi] CEINGE Biotecnol Avanzate, Naples, Italy. [Addante, Filomena; Paroni, Giulia; Sancarlo, Daniele; Pilotto, Alberto] IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Gerontol Geriatr Res Lab, San Giovanni Rotondo, Italy. [Copetti, Massimiliano; Fontana, Andrea; Pellegrini, Fabio] IRCCS Casa Sollievo Sofferenza, Unit Biostat, San Giovanni Rotondo, Italy. [Pellegrini, Fabio] Consorzio Mario Negri Sud, Unit Biostat, DCPE, Chieti, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Harbor Hosp Ctr, Baltimore, MD 21224 USA. [Pilotto, Alberto] S Antonio Hosp, Geriatr Unit, Azienda ULSS Padova 16, Padua, Italy. RP Fontana, L (reprint author), Washington Univ, Sch Med, Div Geriatr & Nutr Sci, 4566 Scott Ave,Campus Box 8113, St Louis, MO 63110 USA. EM lfontana@dom.wustl.edu; alberto.pilotto@sanita.padova.it RI Fontana, Luigi/K-4773-2013; Fontana, Andrea/J-8584-2016; Copetti, Massimiliano/K-3186-2016; Sancarlo, Daniele/C-1056-2017; Paroni, Giulia/C-3768-2017 OI Fontana, Andrea/0000-0002-6660-5315; Copetti, Massimiliano/0000-0002-7960-5947; Sancarlo, Daniele/0000-0001-9541-6364; Paroni, Giulia/0000-0003-0240-8475 FU 'Ministero della Salute', IRCCS FX This work is fully supported by 'Ministero della Salute', IRCCS Research Program, Ricerca Corrente 2009-2011, Linea n. 2 'Malattie complesse'. NR 49 TC 17 Z9 17 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD JUN PY 2013 VL 12 IS 3 BP 459 EP 466 DI 10.1111/acel.12068 PG 8 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 142ON UT WOS:000318806900013 PM 23496093 ER PT J AU Singh, A Warren, J Schultz, A Hackett, CJ Sharma, O AF Singh, Anjali Warren, Jon Schultz, Alan Hackett, Charles J. Sharma, Opendra TI Working Group Consultation: Alloimmunity as a Vaccine Approach Against HIV/AIDS: National Institutes of Health Meeting Report, May 24, 2012 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS TYPE-1; COMPLEX CLASS-I; CCR5 ANTIBODIES; AIDS VACCINE; MACAQUES; INFECTION; TRANSMISSION; RESPONSES; HIV-1; DETERMINANTS AB Alloimmunization vaccine strategies propose to avoid the problem of the extreme antigenic variability of human immunodeficiency virus (HIV) by instead focusing on the cellular antigens incorporated into HIV virions as they bud from infected cells. This report summarizes a Consultation meeting convened by the National Institute of Allergy and Infectious Diseases, National Institutes of Health on May 24, 2012. The objectives of the meeting were to (1) reach a consensus on the essential questions surrounding alloimmunization as a strategy for vaccine design against HIV, and (2) determine the experimental elements that might be needed for addressing these questions in an optimized pilot framework nonhuman primate (NHP) protocol for allogeneic immunization. The Consultation revisited the rationale and concerns of vaccination to induce allogeneic immunity, one of the most potent natural immune responses. The panelists' consensus was that a carefully designed skin graft transplant pilot experiment, in major histocompatibility complex (MHC) disparate male Mauritian cynomolgus macaques (MCM; Macaca fascicularis), would be useful for initially evaluating if alloimmunization results in an effective or even a partially effective safe AIDS vaccine. A successful NHP study for allogeneic immunization would provide further opportunities to explore vaccine-elicited immune and genetic correlates of protection against the acquisition of viral infection. C1 [Singh, Anjali; Warren, Jon; Schultz, Alan; Sharma, Opendra] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Hackett, Charles J.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. RP Sharma, O (reprint author), NIH, 6700-B Rockledge Dr,Room 4151, Bethesda, MD 20892 USA. EM anjalisingh@niaid.nih.gov; os4g@nih.gov NR 31 TC 0 Z9 0 U1 1 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN PY 2013 VL 29 IS 6 BP 851 EP 858 DI 10.1089/aid.2013.0041 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 144ZT UT WOS:000318983000002 PM 23530996 ER PT J AU Miller, FG Gelinas, L AF Miller, Franklin G. Gelinas, Luke TI Nudging, Autonomy, and Valid Consent: Context Matters SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Miller, Franklin G.; Gelinas, Luke] NIH, Bethesda, MD 20892 USA. RP Gelinas, L (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM luke.gelinas@nih.gov NR 5 TC 5 Z9 5 U1 1 U2 8 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD JUN 1 PY 2013 VL 13 IS 6 BP 12 EP 13 DI 10.1080/15265161.2013.781866 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 136IN UT WOS:000318355700003 ER PT J AU Lempert, KD Kopp, JB AF Lempert, Kenneth D. Kopp, Jeffrey B. TI Hurricane Sandy as a Kidney Failure Disaster SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID PATIENT-CARE; APRIL 2009; LESSONS; EARTHQUAKE; AFTERMATH; HEMODIALYSIS; EXPERIENCES; FACILITIES; LAQUILA; RELIEF C1 [Lempert, Kenneth D.] Nephrol Consultants Northwest Ohio, Toledo, OH USA. [Kopp, Jeffrey B.] NIH, Bethesda, MD 20892 USA. RP Lempert, KD (reprint author), 2109 Hughes Dr,Ste 920, Toledo, OH 43606 USA. EM kenneth.lempertmd@promedica.org OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS NR 22 TC 6 Z9 6 U1 0 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2013 VL 61 IS 6 BP 865 EP 868 DI 10.1053/j.ajkd.2013.03.017 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 145FC UT WOS:000318999200006 PM 23684492 ER PT J AU Olden, M Teumer, A Bochud, M Pattaro, C Kottgen, A Turner, ST Rettig, R Chen, MH Dehghan, A Bastardot, F Schmidt, R Vollenweider, P Schunkert, H Reilly, MP Fornage, M Launer, LJ Verwoert, GC Mitchell, GF Bis, JC O'Donnell, CJ Cheng, CY Sim, X Siscovick, DS Coresh, J Kao, WHL Fox, CS O'Seaghdha, CM AF Olden, Matthias Teumer, Alexander Bochud, Murielle Pattaro, Cristian Koettgen, Anna Turner, Stephen T. Rettig, Rainer Chen, Ming-Huei Dehghan, Abbas Bastardot, Francois Schmidt, Reinhold Vollenweider, Peter Schunkert, Heribert Reilly, Muredach P. Fornage, Myriam Launer, Lenore J. Verwoert, Germaine C. Mitchell, Gary F. Bis, Joshua C. O'Donnell, Christopher J. Cheng, Ching-Yu Sim, Xueling Siscovick, David S. Coresh, Josef Kao, W. H. Linda Fox, Caroline S. O'Seaghdha, Conall M. CA AortaGen CARDIoGRAM CHARGE Eye CHARGE IMT ICBP NeuroCHARGE CKDGen Consortia TI Overlap Between Common Genetic Polymorphisms Underpinning Kidney Traits and Cardiovascular Disease Phenotypes: The CKDGen Consortium SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Cardiovascular disease; chronic kidney disease; genomics; single-nucleotide polymorphism (SNP) ID GENOME-WIDE ASSOCIATION; GLOMERULAR-FILTRATION-RATE; CORONARY-HEART-DISEASE; UNITED-STATES; RISK-FACTORS; CYSTATIN-C; METAANALYSIS; MORTALITY; LOCI; ALBUMINURIA AB Background: Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits. Study Design: We conducted 2 targeted analyses. First, we examined whether known single-nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5 x 10(-4) (0.05/325 tests). Setting & Participants: Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395), and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium. Predictor: We used 19 kidney SNPs and 64 vascular SNPs. Outcomes & Measurements: Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber, and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria. Results: In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were nonsignificant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (P = 9.3 x 10(-10)) and diastolic (P = 1.6 x 10(-14)) blood pressure and coronary artery disease (P = 2.2 x 10(-6)), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were nonsignificant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (P = 1.06 x 10(-07) and P = 7.05 x 10(-08)). Limitations: The combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations. Conclusions: Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself. (c) 2013 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Olden, Matthias; Chen, Ming-Huei; O'Donnell, Christopher J.; Fox, Caroline S.; O'Seaghdha, Conall M.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Bochud, Murielle] CHU Vaudois, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland. [Bochud, Murielle; Bastardot, Francois] Fac Biol & Med, Lausanne, Switzerland. [Pattaro, Cristian] European Acad Bolzano Bozen EURAC, Inst Med Genet, Bolzano, Italy. [Pattaro, Cristian] Med Univ Lubeck, D-23538 Lubeck, Germany. [Koettgen, Anna; Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Koettgen, Anna] Univ Hosp Freiburg, Div Renal, Freiburg, Germany. [Turner, Stephen T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, Greifswald, Germany. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Dehghan, Abbas] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Dehghan, Abbas] NCHA, Leiden, Netherlands. [Bastardot, Francois] CHU Vaudois, Dept Med, Lausanne, Switzerland. [Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Vollenweider, Peter] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Div Epidemiol, Sch Publ Hlth, Houston, TX USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Verwoert, Germaine C.] Erasmus MC, Dept Internal Med, Dept Epidemiol, Rotterdam, Netherlands. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Bis, Joshua C.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Cheng, Ching-Yu] Singapore Eye Res Inst, Singapore, Singapore. [Cheng, Ching-Yu] Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Cheng, Ching-Yu] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore 117595, Singapore. [Cheng, Ching-Yu] Duke NUS Grad Med Sch, Off Clin Sci, Ctr Quantitat Med, Singapore, Singapore. [Sim, Xueling] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Mol Epidemiol, Singapore 117595, Singapore. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Fox, Caroline S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP O'Seaghdha, CM (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM conall.o'seaghdha@nih.gov RI Cheng, Ching-Yu/K-7017-2013; Bochud, Murielle/A-3981-2010; Colaus, PsyColaus/K-6607-2013 OI Cheng, Ching-Yu/0000-0003-0655-885X; Bochud, Murielle/0000-0002-5727-0218; Dehghan, Abbas/0000-0001-6403-016X; FU NHLBI's Framingham Heart Study [N01-HC-25195] FX This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health and Boston University School of Medicine. This work was supported in part by the NHLBI's Framingham Heart Study (contract N01-HC-25195). Full information on funding of the GWAS performed by the involved consortia is available in the consortia's previously published articles. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 15 Z9 15 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2013 VL 61 IS 6 BP 889 EP 898 DI 10.1053/j.ajkd.2012.12.024 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 145FC UT WOS:000318999200009 PM 23474010 ER PT J AU Shahinian, VB Hedgeman, E Gillespie, BW Young, EW Robinson, B Hsu, CY Plantinga, LC Burrows, NR Eggers, P Saydah, S Powe, NR Saran, R AF Shahinian, Vahakn B. Hedgeman, Elizabeth Gillespie, Brenda W. Young, Eric W. Robinson, Bruce Hsu, Chi-yuan Plantinga, Laura C. Burrows, Nilka Rios Eggers, Paul Saydah, Sharon Powe, Neil R. Saran, Rajiv CA CDC CKD Surveillance Syst TI Estimating Prevalence of CKD Stages 3-5 Using Health System Data SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; surveillance; prevalence; epidemiology ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; UNITED-STATES; RISK; POPULATION; RECORD; DEATH; CARE AB Background: The feasibility of using health system data to estimate prevalence of chronic kidney disease (CKD) stages 3-5 was explored. Study Design: Cohort study. Setting & Participants: A 5% national random sample of patients from the Veterans Affairs (VA) health care system, enrollees in a managed care plan in Michigan (M-CARE), and participants from the 2005-2006 National Health and Nutrition Examination Survey (NHANES). Predictor: Observed CKD prevalence estimates in the health system population were calculated as patients with an available outpatient serum creatinine measurement with estimated glomerular filtration rate <60 mL/min/1.73 m(2), among those with at least one outpatient visit during the year. Outcomes & Measurements: A logistic regression model was fitted using data from the 2005-2006 NHANES to predict CKD prevalence in those untested for serum creatinine in the health system population, adjusted for demographics and comorbid conditions. Model results then were combined with the observed prevalence in tested patients to derive an overall predicted prevalence of CKD within the health systems. Results: Patients in the VA system were older, had more comorbid conditions, and were more likely to be tested for serum creatinine than those in the M-CARE system. Observed prevalences of CKD stages 3-5 were 15.6% and 0.9% in the VA and M-CARE systems, respectively. Using data from NHANES, the overall predicted prevalences of CKD were 20.4% and 1.6% in the VA and M-CARE systems, respectively. Limitations: Health system data quality was limited by missing data for laboratory results and race. A single estimated glomerular filtration rate value was used to define CKD, rather than persistence over 3 months. Conclusions: Estimation of CKD prevalence within health care systems is feasible, but discrepancies between observed and predicted prevalences suggest that this approach is dependent on data availability and quality of information for comorbid conditions, as well as the frequency of testing for CKD in the health care system. (c) 2013 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Shahinian, Vahakn B.; Hedgeman, Elizabeth; Young, Eric W.; Saran, Rajiv] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Shahinian, Vahakn B.; Hedgeman, Elizabeth; Saran, Rajiv] Univ Michigan, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA. [Gillespie, Brenda W.] Univ Michigan, Ctr Stat Consultat & Res, Ann Arbor, MI 48109 USA. [Gillespie, Brenda W.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Young, Eric W.] Vet Adm Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Robinson, Bruce] Arbor Res Collaborat Hlth, Ann Arbor, MI USA. [Hsu, Chi-yuan] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Plantinga, Laura C.; Powe, Neil R.] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Plantinga, Laura C.; Powe, Neil R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Burrows, Nilka Rios; Saydah, Sharon] Ctr Dis Control & Prevent, Atlanta, GA USA. [Saydah, Sharon] NIDDK, Bethesda, MD USA. RP Saran, R (reprint author), Univ Michigan, Kidney Epidemiol & Cost Ctr, Div Nephrol, Dept Internal Med, 1415 Washington Hts,Ste 3645, Ann Arbor, MI 48109 USA. EM rsaran@umich.edu FU Centers for Disease Control and Prevention (CDC) [1U58DP003836] FX This work is funded by the Centers for Disease Control and Prevention (CDC), grant 1U58DP003836 for the project titled "Establishing a Surveillance System for Chronic Kidney Disease." This material is the result of work partially supported with resources and the use of facilities at the VA Ann Arbor Healthcare System. Publication and report contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC, the VA, or the US Government. NR 18 TC 10 Z9 11 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2013 VL 61 IS 6 BP 930 EP 938 DI 10.1053/j.ajkd.2013.01.018 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 145FC UT WOS:000318999200014 PM 23489675 ER PT J AU Balow, JE Ryan, JG Chae, JJ Booty, MG Bulua, A Stone, D Sun, HW Greene, J Barham, B Goldbach-Mansky, R Kastner, DL Aksentijevich, I AF Balow, James E., Jr. Ryan, John G. Chae, Jae Jin Booty, Matthew G. Bulua, Ariel Stone, Deborah Sun, Hong-Wei Greene, James Barham, Beverly Goldbach-Mansky, Raphaela Kastner, Daniel L. Aksentijevich, Ivona TI Microarray-based gene expression profiling in patients with cryopyrin-associated periodic syndromes defines a disease-related signature and IL-1-responsive transcripts SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID JUVENILE IDIOPATHIC ARTHRITIS; NLRP3 INFLAMMASOME ACTIVATION; AUTOINFLAMMATORY DISEASES; OXIDATIVE STRESS; CIAS1 MUTATIONS; IL-1 BLOCKADE; INTERLEUKIN-1; SECRETION; FAMILY; LIPOPOLYSACCHARIDE AB Objective To analyse gene expression patterns and to define a specific gene expression signature in patients with the severe end of the spectrum of cryopyrin-associated periodic syndromes (CAPS). The molecular consequences of interleukin 1 inhibition were examined by comparing gene expression patterns in 16 CAPS patients before and after treatment with anakinra. Methods We collected peripheral blood mononuclear cells from 22 CAPS patients with active disease and from 14 healthy children. Transcripts that passed stringent filtering criteria (p values <= false discovery rate 1%) were considered as differentially expressed genes (DEG). A set of DEG was validated by quantitative reverse transcription PCR and functional studies with primary cells from CAPS patients and healthy controls. We used 17 CAPS and 66 non-CAPS patient samples to create a set of gene expression models that differentiates CAPS patients from controls and from patients with other autoinflammatory conditions. Results Many DEG include transcripts related to the regulation of innate and adaptive immune responses, oxidative stress, cell death, cell adhesion and motility. A set of gene expression-based models comprising the CAPS-specific gene expression signature correctly classified all 17 samples from an independent dataset. This classifier also correctly identified 15 of 16 post-anakinra CAPS samples despite the fact that these CAPS patients were in clinical remission. Conclusions We identified a gene expression signature that clearly distinguished CAPS patients from controls. A number of DEG were in common with other systemic inflammatory diseases such as systemic onset juvenile idiopathic arthritis. The CAPS-specific gene expression classifiers also suggest incomplete suppression of inflammation at low doses of anakinra. C1 [Balow, James E., Jr.; Ryan, John G.; Chae, Jae Jin; Booty, Matthew G.; Stone, Deborah; Barham, Beverly; Kastner, Daniel L.; Aksentijevich, Ivona] NHGRI, Bethesda, MD 20892 USA. [Bulua, Ariel] NIAMSD, Autoimmun Branch, Immunoregulat Unit, Bethesda, MD 20892 USA. [Sun, Hong-Wei] NIAMSD, Office Sci & Technol, Bethesda, MD 20892 USA. [Greene, James] Catholic Univ Amer, Washington, DC 20064 USA. [Goldbach-Mansky, Raphaela] NIAMSD, Translat Autoinflammatory Dis Sect, Bethesda, MD 20892 USA. RP Aksentijevich, I (reprint author), NHGRI, 9000 Rockville Pike,Bldg 10-B2-5235, Bethesda, MD 20892 USA. EM aksentii@exchange.nih.gov OI Booty, Matthew/0000-0002-0835-3439 FU NIAMS; NHGRI at the NIH FX This study was supported by the intramural research programme of the NIAMS and NHGRI at the NIH. NR 32 TC 9 Z9 10 U1 0 U2 5 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 JUN PY 2013 VL 72 IS 6 BP 1064 EP 1070 DI 10.1136/annrheumdis-2012-202082 PG 7 WC Rheumatology SC Rheumatology GA 143ZB UT WOS:000318907100050 PM 23223423 ER PT J AU Banerjee, A Horwitz, B AF Banerjee, Arpan Horwitz, Barry TI Can quantum probability help analyze the behavior of functional brain networks? SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID SPATIOTEMPORAL REORGANIZATION; COORDINATION; DEGENERACY; SYSTEMS; OBJECT AB Pothos & Busemeyer (P&B) argue how key concepts of quantum probability, for example, order/context, interference, superposition, and entanglement, can be used in cognitive modeling. Here, we suggest that these concepts can be extended to analyze neurophysiological measurements of cognitive tasks in humans, especially in functional neuroimaging investigations of large-scale brain networks. C1 [Banerjee, Arpan; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. RP Banerjee, A (reprint author), Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. EM Arpan.Banerjee@nih.gov; horwitzb@mail.nih.gov FU Intramural NIH HHS [ZIA DC000057-12] NR 17 TC 1 Z9 1 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0140-525X EI 1469-1825 J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD JUN PY 2013 VL 36 IS 3 BP 278 EP 279 DI 10.1017/S0140525X12002877 PG 2 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 143ZT UT WOS:000318909200037 PM 23673025 ER PT J AU Enoch, MA AF Enoch, Mary-Anne TI The First Steps on the Path Toward Genomic Predictors of Behavioral Therapy for Posttraumatic Stress Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID NEUROTROPHIC FACTOR; FEAR EXTINCTION; POLYMORPHISMS; ASSOCIATION; FKBP5 C1 [Enoch, Mary-Anne] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Enoch, MA (reprint author), NIAAA, NIH, DICBR, LNG, 5625 Fishers Lane,Suite 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov FU Intramural NIH HHS [ZIA AA000306-08] NR 10 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2013 VL 73 IS 11 BP 1039 EP 1040 DI 10.1016/j.biopsych.2013.04.005 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 145EJ UT WOS:000318997000001 PM 23647733 ER PT J AU Arunotayanun, W Dalley, JW Huang, XP Setola, V Treble, R Iversen, L Roth, BL Gibbons, S AF Arunotayanun, Warunya Dalley, Jeffrey W. Huang, Xi-Ping Setola, Vincent Treble, Ric Iversen, Leslie Roth, Bryan L. Gibbons, Simon TI An analysis of the synthetic tryptamines AMT and 5-MeO-DALT: Emerging 'Novel Psychoactive Drugs' SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Tryptamines; Alpha-methyl-tryptamine; 5-Methoxy-N,N-diallyl-tryptamine; LSD; Novel Psychoactive Drugs (NPD) ID LEGAL HIGHS; HALLUCINOGENS; INTERNET AB Novel Psychoactive Drugs (NPD) can be sold without restriction and are often synthetic analogues of controlled drugs. The tryptamines are an important class of NPD as they bind to the various serotonin (5-HT) receptor subtypes and cause psychosis and hallucinations that can lead to injury or death through misadventure. Here we report on the structure elucidation and receptor binding profiles of two widely marketed tryptamine-derived NPDs, namely alpha-methyl-tryptamine and 5-methoxy-N,N-diallyl-tryptamine. (C) 2013 Published by Elsevier Ltd. C1 [Arunotayanun, Warunya; Gibbons, Simon] UCL Sch Pharm, Dept Pharmaceut & Biol Chem, London WC1N 1AX, England. [Dalley, Jeffrey W.] Univ Cambridge, Dept Psychol, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Huang, Xi-Ping; Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Dept Pharmacol, Program Neurosci, Chapel Hill, NC 27514 USA. [Huang, Xi-Ping; Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Div Chem Biol & Med Chem, Chapel Hill, NC 27514 USA. [Huang, Xi-Ping; Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27514 USA. [Treble, Ric] LGC Forens, London TW11 0LY, England. [Iversen, Leslie] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. RP Gibbons, S (reprint author), UCL Sch Pharm, Dept Pharmaceut & Biol Chem, 29-39 Brunswick Sq, London WC1N 1AX, England. EM simon.gibbons@ucl.ac.uk RI Roth, Bryan/F-3928-2010 FU NIMH; Praboromarajchanok Institute, Thai Ministry of Health FX We are grateful to Praboromarajchanok Institute, Thai Ministry of Health for a doctoral Scholarship to Warunya Arunotayanun and the NIMH for supporting the research at PDSP. NR 26 TC 12 Z9 12 U1 0 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 1 PY 2013 VL 23 IS 11 BP 3411 EP 3415 DI 10.1016/j.bmcl.2013.03.066 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 144XR UT WOS:000318976100059 PM 23602445 ER PT J AU Perrotta, C Kleefeld, S Staines, A Tewari, P De Roos, AJ Baris, D Birmann, B Chiu, B Cozen, W Becker, N Foretova, L Maynadie, M Nieters, A de Sanjose, S Miligi, L Costantini, AS Purdue, M Spinelli, J Cocco, P AF Perrotta, Carla Kleefeld, Silke Staines, Anthony Tewari, Prerna De Roos, Anneclaire J. Baris, Dalsu Birmann, Brenda Chiu, Brian Cozen, Wendy Becker, Nikolaus Foretova, Lenka Maynadie, Marc Nieters, Alexandra de Sanjose, Silvia Miligi, Lucia Costantini, Adele Seniori Purdue, Mark Spinelli, John Cocco, Pierluigi TI Multiple myeloma and occupation: A pooled analysis by the International Multiple Myeloma Consortium SO CANCER EPIDEMIOLOGY LA English DT Article DE Multiple myeloma; Case-control study; Agriculture; Farmers; Solvents ID MULTICENTER CASE-CONTROL; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; PESTICIDE EXPOSURE; RISK; LYMPHOMA; SOLVENTS; BENZENE; DISEASE; HEALTH AB Objective: We investigated occupational risk of multiple myeloma (MM) in a pooled analysis of five international case-control studies. Methods: We calculated the odds ratio and its 95% confidence interval for selected occupations with unconditional regression analysis in 1959 MM cases and 6192 controls, by pooling study-specific risks using random-effects meta-analysis. Exposure to organic solvents was assessed with a job-exposure matrix (JEM). Results: Gardeners and nursery workers combined, most likely exposed to pesticides, showed a 50% increase in risk (OR = 1.50, 95% CI 0.9-2.3), while other farming jobs did not. Metal processors (OR = 1.55, 95% CI 0.9-2.3), female cleaners (OR = 1.32, 95% CI 1.0-1.8), and high level exposure to organic solvents (OR = 1.38, 95% CI 0.96-1.8) also showed moderately increased risks. Conclusions: Additional case-control studies of MM aetiology are warranted to further investigate the nature of the repeatedly reported increase in MM risk in several occupational groups. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Perrotta, Carla] Hosp Italiano Buenos Aires, Family & Community Med Dept, Buenos Aires, DF, Argentina. [Kleefeld, Silke] Natl Univ Ireland, Dept Phys, Galway, Ireland. [Staines, Anthony] Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland. [Tewari, Prerna] Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin, Ireland. [Tewari, Prerna] Trinity Coll Dublin, Inst Mol Med, Dublin, Ireland. [De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Baris, Dalsu; Purdue, Mark] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Birmann, Brenda] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Birmann, Brenda] Harvard Univ, Sch Med, Boston, MA USA. [Chiu, Brian] Univ Chicago, Dept Hlth Studies, Div Biol Sci, Chicago, IL 60637 USA. [Cozen, Wendy] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Becker, Nikolaus] German Canc Res Ctr, Heidelberg, Germany. [Foretova, Lenka] Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Maynadie, Marc] Dijon Univ Hosp, Dijon, France. [Nieters, Alexandra] Univ Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [de Sanjose, Silvia] Catalan Inst Oncol, Barcelona, Spain. [de Sanjose, Silvia] CIBERESP, Barcelona, Spain. [Miligi, Lucia; Costantini, Adele Seniori] Inst Study & Prevent Canc, Occupat & Environm Epidemiol Unit, Florence, Italy. [Spinelli, John] BC Canc Agcy, Canc Control Res Program, Vancouver, BC, Canada. [Cocco, Pierluigi] Univ Cagliari, Dept Publ Hlth, Occupat Hlth Sect, I-09042 Cagliari, Italy. RP Cocco, P (reprint author), Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Occupat Hlth Sect, Asse Didattico Policlin Univ, SS 554,Km 4,500, I-09042 Cagliari, Italy. EM coccop@medicina.unica.it RI Spinelli, John/B-6210-2013; de Sanjose Llongueras, Silvia/H-6339-2014; OI Staines, Anthony/0000-0001-9161-1357 FU Irish Health Research Board; Italian Ministry of University, Education and Research [prot. 2007WEJLZB, prot. 20092ZELR2]; Italian Association for Cancer Research [2012/IG11855] FX Funding was provided by the Irish Health Research Board; the Italian Ministry of University, Education and Research (prot. 2007WEJLZB; prot. 20092ZELR2); the Italian Association for Cancer Research (Investigator Grant 2012/IG11855). NR 25 TC 5 Z9 5 U1 1 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD JUN PY 2013 VL 37 IS 3 BP 300 EP 305 DI 10.1016/j.canep.2013.01.008 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 140TH UT WOS:000318677600015 PM 23403129 ER PT J AU Gara, N Ghany, MG AF Gara, Naveen Ghany, Marc G. TI What the Infectious Disease Physician Needs to Know About Pegylated Interferon and Ribavirin SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE peginterferon; ribavirin; chronic hepatitis C treatment; adverse events ID CHRONIC HEPATITIS-C; SUSTAINED VIROLOGICAL RESPONSE; PLACEBO-CONTROLLED TRIAL; ALPHA-2A PLUS RIBAVIRIN; CHRONIC HCV INFECTION; GENOTYPE 1 INFECTION; COMBINATION THERAPY; DOUBLE-BLIND; PEGINTERFERON ALPHA-2A; COINFECTED PATIENTS AB The treatment of chronic hepatitis C is rapidly evolving from triple therapy to regimens that do not require interferon or even ribavirin. However, pegylated interferon and ribavirin will remain the backbone of hepatitis C therapy for the time being. This review summarizes the pharmacokinetics of peginterferon and ribavirin with a particular emphasis on their side-effect profile and management. Finally, the continued role of peginterferon and ribavirin in future therapies will be discussed. C1 [Gara, Naveen; Ghany, Marc G.] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov FU Intramural Divisions of the National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute of the National Institutes of Health FX This work was supported by the Intramural Divisions of the National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute of the National Institutes of Health. NR 50 TC 9 Z9 9 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2013 VL 56 IS 11 BP 1629 EP 1636 DI 10.1093/cid/cit074 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 140GB UT WOS:000318641300019 PM 23429551 ER PT J AU Bowers, K Laughon, SK Kiely, M Brite, J Chen, Z Zhang, C AF Bowers, K. Laughon, S. K. Kiely, M. Brite, J. Chen, Z. Zhang, C. TI Gestational diabetes, pre-pregnancy obesity and pregnancy weight gain in relation to excess fetal growth: variations by race/ethnicity SO DIABETOLOGIA LA English DT Article DE Adiposity; Fetal macrosomia; Gestational diabetes; Pregnancy; Weight gain ID BODY-MASS INDEX; RISK-FACTORS; CHILDHOOD OBESITY; UNITED-STATES; MACROSOMIA; MELLITUS; OVERWEIGHT; PREVALENCE; ETHNICITY; OUTCOMES AB The escalating rate of childhood obesity is a public health concern worldwide, with children in certain ethnic groups being disproportionately affected. Our objective was to examine the joint effects of pre-pregnancy adiposity, pregnancy weight gain and gestational diabetes (GDM) in relation to excess fetal growth and to identify susceptible races or ethnic populations. The risk for delivery of a large-for-gestational-age (LGA) infant, specific to race and fetal sex, was evaluated in 105,985 pregnancies in the Consortium on Safe Labor from 2002-2008. Generalised estimating equations were used to estimate the risk for delivery of LGA infants. Joint effects were employed to evaluate the interplay of three risk factors. Models were stratified by racial group considering one, two or three factors (i.e. pre-pregnancy adiposity, pregnancy weight gain and GDM, with 0 factors as the reference group). Greater pre-pregnancy adiposity, pregnancy weight gain and GDM were independently associated with increased risk of giving birth to an LGA infant across all races (except GDM among non-Hispanic whites), in both underweight and normal-weight women. Among non-Hispanic white, non-Hispanic black and Hispanic women, the three-factor joint effect was associated with substantially increased odds of LGA (OR [95% CI] 11.27 [8.40, 15.11], 7.09 [4.81, 10.45] and 10.19 [6.84, 15.19], respectively). However, for Asian women the joint effect of all three factors (OR [95% CI] 5.14 [2.11, 12.50]) was approximately the same as any of the two factors. GDM, pre-pregnancy obesity and excessive pregnancy weight gain were jointly associated with elevated risk of giving birth to an LGA infant and the effects varied by race. This suggests that those involved in public health efforts aimed at preventing LGA deliveries should consider variations in racial groups when devising effective strategies. C1 [Bowers, K.; Laughon, S. K.; Kiely, M.; Zhang, C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Brite, J.] CUNY Hunter Coll, CUNY Inst Demog Res, New York, NY 10021 USA. [Brite, J.] CUNY Hunter Coll, CUNY Sch Publ Hlth, New York, NY 10021 USA. [Chen, Z.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Zhang, C (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Rockville, MD 20852 USA. EM katherine.bowers@cchmc.org; zhangcu@mail.nih.gov RI Bowers, Katherine/N-5226-2015; OI Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX The data included in this paper were obtained from the CSL, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through Contract No. HHSN267200603425C. Institutions involved in the CSL include, in alphabetical order: Baystate Medical Center, Springfield, MA, USA; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, CA, USA; Christiana Care Health System, Newark, DE, USA; Georgetown University Hospital, MedStar Health, Washington, DC, USA; Indiana University Clarian Health, Indianapolis, IN, USA; Intermountain Healthcare and the University of Utah, Salt Lake City, UT, USA; Maimonides Medical Center, Brooklyn, NY, USA; MetroHealth Medical Center, Cleveland, OH, USA; Summa Health System, Akron City Hospital, Akron, OH, USA; The EMMES Corporation, Rockville MD, USA (data coordinating centre); University of Illinois at Chicago, Chicago, IL, USA; University of Miami, Miami, FL, USA; and University of Texas Health Science Center at Houston, Houston, TX, USA. The named authors alone are responsible for the views expressed in this manuscript, which do not necessarily represent the decisions or the stated policy of the National Institute of Child Health and Human Development. NR 26 TC 29 Z9 31 U1 2 U2 24 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JUN PY 2013 VL 56 IS 6 BP 1263 EP 1271 DI 10.1007/s00125-013-2881-5 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 142HI UT WOS:000318787600009 PM 23571827 ER PT J AU Saito, K Moore, R Negishi, M AF Saito, Kosuke Moore, Rick Negishi, Masahiko TI p38 Mitogen-Activated Protein Kinase Regulates Nuclear Receptor CAR that Activates the CYP2B6 Gene SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CONSTITUTIVE ANDROSTANE RECEPTOR; INDUCED EXPRESSION; ENHANCER MODULE; INDUCTION; HEPATOCYTES; MOUSE; IDENTIFICATION; TRANSLOCATION; ALPHA; CELLS AB The constitutive active/androstane receptor (CAR) regulates hepatic drug metabolism by activating genes, such as cytochrome P450, and certain transferases. p38 Mitogen-activated protein kinase (MAPK) is highly activated in human primary hepatocytes but barely in human hepatoma cell lines including HepG2 cells. Liganded-CAR induced CYP2B6 mRNA in human primary hepatocytes far more effectively than in HepG2 cells ectopically expressing CAR. In the present study, we found that activation of p38 MAPK by anisomycin potentiated induction of CYP2B6 mRNA by CAR ligand in HepG2 cells to levels observed in ligand-treated human primary hepatocytes. siRNA knockdown of p38 MAPK abrogated the ability of anisomycin to synergistically induce CYP2B6 mRNA. In addition to CYP2B6, anisomycin cotreatment potentiated an increase in CYP2A7 and CYP2C9 mRNAs but not CYP3A4 or UDP-glucuronosyltransferase 1A1 mRNAs. Thus, activated p38 MAPK is required for liganded-CAR to selectively activate a set of genes that encode drug-metabolizing enzymes. Our present results suggest that CAR-mediated induction of these enzymes cannot be understood by ligand binding alone because the specificity and magnitude of induction are codetermined by a given cell signaling, such as p38 MAPK; both physiologic and pathophysiological states of cell signaling may have a strong impact in hepatic drug-metabolizing capability during treatments. C1 [Saito, Kosuke; Moore, Rick; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU National Institutes of Health National Institute of Environmental Health Sciences Intramural Research Program [Z01ES1005-01] FX This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences Intramural Research Program [Grant Z01ES1005-01]. NR 20 TC 8 Z9 9 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUN PY 2013 VL 41 IS 6 BP 1170 EP 1173 DI 10.1124/dmd.113.051623 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 144WD UT WOS:000318971400001 PM 23539296 ER PT J AU White, AJ Sandler, DP Bolick, SCE Xu, ZL Taylor, JA DeRoo, LA AF White, Alexandra J. Sandler, Dale P. Bolick, Sophia C. E. Xu, Zongli Taylor, Jack A. DeRoo, Lisa A. TI Recreational and household physical activity at different time points and DNA global methylation SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE DNA methylation; LINE-1; Physical activity; Pyrosequencing; Sister Study ID MODERATE FOLATE-DEPLETION; BREAST-CANCER; POSTMENOPAUSAL WOMEN; GENE; HYPOMETHYLATION; INFLAMMATION; ASSOCIATION; EPIGENETICS; MECHANISMS; PREVENTION AB Background: DNA methylation patterns are heritable but can change over time and in response to exposures. Lower global DNA methylation, which may result in increased genomic and chromosomal instability, has been associated with increased cancer risk. Physical activity is a modifiable factor that has been inversely related to the risk of cancer. Changes in DNA methylation may be a mechanism by which lifestyle and environment factors influence disease. We investigated the relationship between DNA methylation and physical activity in a sample of women enroled in The Sister Study, a large United States (U.S.) cohort study of women aged 35-74 years with a family history of breast cancer. Methods: Global DNA methylation was measured using bisulphite-converted DNA and pyrosequencing of a LINE-1 repetitive sequence in the peripheral blood of 647 non-Hispanic white women. Physical activity (average hours per week) was retrospectively assessed for three time periods: childhood (ages 5-12), teenage years (ages 13-19) and the previous 12 months. Findings: Compared with women with physical activity levels below the median for all three time periods, those at or above the median physical activity for one (beta = 0.20, 95% confidence interval (CI): -0.10, 0.49), two (beta = 0.22, 95% CI: - 0.08, 0.52) or all three (beta = 0.33, 95% CI: 0.01, 0.66) time periods had increased global methylation. Interpretation: Maintaining higher levels of physical activity over these three time periods was associated with increased global DNA methylation, consistent with reported associations between exercise and decreased cancer risk. Published by Elsevier Ltd. C1 [White, Alexandra J.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Sandler, Dale P.; Xu, Zongli; Taylor, Jack A.; DeRoo, Lisa A.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Bolick, Sophia C. E.; Taylor, Jack A.] NIEHS, Mol Carcinogenesis Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP DeRoo, LA (reprint author), NIEHS, Epidemiol Branch, POB 12233,Mail Drop A3-05 111,TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM DeRooL@niehs.nih.gov OI xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES044005]; NIEHS [ES07018] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, (Z01 ES044005). Alexandra J. White was also supported in part by NIEHS training Grant ES07018. We thank Ms. Karen Baldwin for assisting with the laboratory assays and Drs. Anne Marie Jukic and Abee Boyles for helpful comments on an earlier draft of this paper. NR 39 TC 16 Z9 17 U1 3 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUN PY 2013 VL 49 IS 9 BP 2199 EP 2206 DI 10.1016/j.ejca.2013.02.013 PG 8 WC Oncology SC Oncology GA 144YG UT WOS:000318978000015 PM 23473616 ER PT J AU Muller, YL Hanson, RL Knowler, WC Fleming, J Goswami, J Huang, K Traurig, M Sutherland, J Wiedrich, C Wiedrich, K Mahkee, D Ossowski, V Kobes, S Bogardus, C Baier, LJ AF Muller, Yunhua L. Hanson, Robert L. Knowler, William C. Fleming, Jamie Goswami, Jayita Huang, Ke Traurig, Michael Sutherland, Jeff Wiedrich, Chris Wiedrich, Kim Mahkee, Darin Ossowski, Vicky Kobes, Sayuko Bogardus, Clifton Baier, Leslie J. TI Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; TRAIT LINKAGE ANALYSIS; BODY-MASS INDEX; PIMA-INDIANS; AMERICAN-INDIANS; FINELY MAP; MELLITUS; ADIPONECTIN; COMPONENTS; LOCUS AB A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 x 10(-11)-1.4 x 10(-23)), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 x 10(-7)). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 "mixed" heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 x 10(-4), n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus. C1 [Muller, Yunhua L.; Hanson, Robert L.; Knowler, William C.; Fleming, Jamie; Goswami, Jayita; Huang, Ke; Traurig, Michael; Sutherland, Jeff; Wiedrich, Chris; Wiedrich, Kim; Mahkee, Darin; Ossowski, Vicky; Kobes, Sayuko; Bogardus, Clifton; Baier, Leslie J.] NIDDKD, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85004 USA. RP Baier, LJ (reprint author), NIDDKD, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 455 North 5th St, Phoenix, AZ 85004 USA. EM ymuller@mail.nih.gov; lbaier@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Intramural Research Program of the National Institute of Diabetes and Kidney Diseases (NIDDK) FX We thank the participants from the Gila River Indian Community for their cooperation and Jill Loebel and Glenn Nishimoto for technical assistance. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Kidney Diseases (NIDDK). NR 40 TC 4 Z9 4 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD JUN PY 2013 VL 132 IS 6 BP 697 EP 707 DI 10.1007/s00439-013-1278-3 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 145MY UT WOS:000319021500010 PM 23468175 ER PT J AU Matyi, SA Dupre, JM Johnson, WL Hoyt, PR White, DG Brody, T Odenwald, WF Gustafson, JE AF Matyi, S. A. Dupre, J. M. Johnson, W. L. Hoyt, P. R. White, D. G. Brody, T. Odenwald, W. F. Gustafson, J. E. TI Isolation and characterization of Staphylococcus aureus strains from a Paso del Norte dairy SO JOURNAL OF DAIRY SCIENCE LA English DT Article DE Staphylococcus aureus; methicillin-resistant; mastitis; genomics ID CASSETTE CHROMOSOME MEC; FIELD GEL-ELECTROPHORESIS; POLYMERASE-CHAIN-REACTION; METHICILLIN-RESISTANT; GENETIC ELEMENT; IN-VIVO; IDENTIFICATION; HOSPITALS; EVOLUTION; HUMANS AB The primary purpose of this study was to determine if methicillin-resistant Staphylococcus aureus (MRSA) strains could be identified in the milk of dairy cattle in a Paso del Norte region dairy of the United States. Using physiological and PCR-based identification schemes, a total of 40 Staph. aureus strains were isolated from 29 raw milk samples of 133 total samples analyzed. Pulsed-field gel electrophoresis after digestion with the SmaI enzyme revealed that the 40 confirmed strains were represented by 5 pulsed-field types, which each contained 3 or more strains. Of 7 hospital strains isolated from cows undergoing antibiotic therapy, 3 demonstrated resistance to 3 or more antimicrobial classes and displayed similar pulsed-field gel electrophoresis patterns. A secondary purpose of this study was to elucidate the evolutionary relationships of strains isolated in this study to genomically characterized Staph. aureus strains. Therefore, Roche 454 GS (Roche Diagnostics Corp., Dallas, TX) pyrosequencing was used to produce draft genome sequences of an MRSA raw milk isolate (H29) and a methicillin-susceptible Staph. aureus (PB32). Analysis using the BLASTn database (http://blast.ncbi.nlm.nih.gov/) demonstrated that the H29 draft genome was highly homologous to the human MRSA strain JH1, yet the beta-lactamase plasmid carried by H29 was different from that carried by JH1. Genomic analysis of H29 also clearly explained the multidrug resistance phenotype of this raw milk isolate. Analysis of the PB32 draft genome (using BLASTn) demonstrated that this raw milk isolate was most related to human MRSA strain 04-02981. Although PB32 is not a MRSA, the PB32 draft genome did reveal the presence of a unique staphylococcal cassette mec (SCCmec) remnant In addition, the PB32 draft genome revealed the presence of a novel bovine staphylococcal pathogenicity island, SaPIbovPB32. This study demonstrates the presence of clones closely related to human and (or) bovine Staph. aureus strains circulating in a dairy herd. C1 [Matyi, S. A.; Dupre, J. M.; Johnson, W. L.; Hoyt, P. R.; Gustafson, J. E.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. [Matyi, S. A.; Hoyt, P. R.; Gustafson, J. E.] Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. [White, D. G.] US FDA, Ctr Vet Med, Laurel, MD 20708 USA. [Brody, T.; Odenwald, W. F.] NIH, Neural Cell Fate Determinants Sect, Bethesda, MD 20892 USA. RP Gustafson, JE (reprint author), New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. EM john.gustafson@okstate.edu FU NSF [DBI-0821806]; National Institutes of Health [R25 GM07667-30, S06-GM61222-05]; National Institute of General Medical Sciences [8P20GM103451] FX All authors acknowledge the participation of the Roadrunner Genomics Facility at New Mexico State University (NMSU; Las Cruces) and NSF award no. DBI-0821806. All authors also acknowledge prior support from the National Institutes of Health: SC-1GM083882-01 (J. E. Gustafson), R25 GM07667-30 [NMSU Minority Access to Research Careers (MARC) program], S06-GM61222-05 [NMSU Minority Biomedical Research Support-Research Initiative for Scientific Enhancement (MBRS-RISE) program], the National Center for Research Resources (5P20RR016480-12), and the National Institute of General Medical Sciences [8P20GM103451; New Mexico Idea Network of Biomedical Research Excellence (INBRE) program]. NR 48 TC 1 Z9 1 U1 2 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-0302 J9 J DAIRY SCI JI J. Dairy Sci. PD JUN PY 2013 VL 96 IS 6 BP 3535 EP 3542 DI 10.3168/jds.2013-6590 PG 8 WC Agriculture, Dairy & Animal Science; Food Science & Technology SC Agriculture; Food Science & Technology GA 145OX UT WOS:000319027600014 PM 23608491 ER PT J AU Palys, KE Berger, VW AF Palys, Kaitlin E. Berger, Vance W. TI A Note on the Jadad Score as an Efficient Tool for Measuring Trial Quality SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Letter C1 [Palys, Kaitlin E.] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. RP Palys, KE (reprint author), Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. EM palysk@vt.edu; vb78c@nih.gov NR 3 TC 7 Z9 8 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD JUN PY 2013 VL 17 IS 6 BP 1170 EP 1171 DI 10.1007/s11605-012-2106-0 PG 2 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 143XF UT WOS:000318901800021 PM 23233271 ER PT J AU Maltsev, VA Lakatta, EG AF Maltsev, Victor A. Lakatta, Edward G. TI Numerical models based on a minimal set of sarcolemmal electrogenic proteins and an intracellular Ca2+ clock generate robust, flexible, and energy-efficient cardiac pacemaking SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Numerical modeling; Biological pacemakers; Pacemaker cells; Ca2+ cycling; Ion channels; Na+/Ca2+ exchanger ID SINOATRIAL NODE CELLS; MATHEMATICAL-MODEL; I-F; CURRENTS; ELECTROPHYSIOLOGY; AUTOMATICITY; STIMULATION; VARIABILITY; EXPRESSION; MECHANISM AB Recent evidence supports the idea that robust and, importantly, FLEXIBLE automaticity of cardiac pacemaker cells is conferred by a coupled system of membrane ion currents (an "M-clock") and a sarcoplasmic reticulum (SR)-based Ca2+ oscillator ("Ca(2+)clock") that generates spontaneous diastolic Ca2+ releases. This study identified numerical models of a human biological pacemaker that features robust and flexible automaticity generated by a minimal set of electrogenic proteins and a Ca(2+)clock. Following the Occam's razor principle (principle of parsimony), M-clock components of unknown molecular origin were excluded from Maltsev-Lakatta pacemaker cell model and thirteen different model types of only 4 or 5 components were derived and explored by a parametric sensitivity analysis. The extended ranges of SR Ca2+ pumping (i.e. Ca(2+)clock performance) and conductance of ion currents were sampled, yielding a large variety of parameter combination, i.e. specific model sets. We tested each set's ability to simulate autonomic modulation of human heart rate (minimum rate of 50 to 70 bpm; maximum rate of 140 to 210 bpm) in response to stimulation of cholinergic and p-adrenergic receptors. We found that only those models that include a Ca(2+)clock (including the minimal 4-parameter model "I-caL + I-Kr + I-Ncx + Ca(2+)clock") were able to reproduce the full range of autonomic modulation. Inclusion of I-f or I-caT decreased the flexibility, but increased the robustness of the models (a relatively larger number of sets did not fail during testing). The new models comprised of components with clear molecular identity (i.e. lacking I-bNa & I-st) portray a more realistic pacemaking: A smaller Na+ influx is expected to demand less energy for Na+ extrusion. The new large database of the reduced coupled-clock numerical models may serve as a useful tool for the design of biological pacemakers. It will also provide a conceptual basis for a general theory of robust, flexible, and energy-efficient pacemaking based on realistic components. (C) 2013 Published by Elsevier Ltd. C1 [Maltsev, Victor A.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Lab Cardiovasc Sci, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM maltsevvi@mail.nih.gov; LakattaE@grc.nia.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. We thank Dr. Michael Rosen of Columbia University for helpful discussions on the topic of the paper. NR 35 TC 13 Z9 13 U1 0 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2013 VL 59 BP 181 EP 195 DI 10.1016/j.yjmcc.2013.03.004 PG 15 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 144SF UT WOS:000318960000021 PM 23507256 ER PT J AU Klebe, S Golmard, JL Nalls, MA Saad, M Singleton, AB Bras, JM Hardy, J Simon-Sanchez, J Heutink, P Kuhlenbaumer, G Charfi, R Klein, C Hagenah, J Gasser, T Wurster, I Lesage, S Lorenz, D Deuschl, G Durif, F Pollak, P Damier, P Tison, F Durr, A Amouyel, P Lambert, JC Tzourio, C Maubaret, C Charbonnier-Beaupel, F Tahiri, K Vidailhet, M Martinez, M Brice, A Corvol, JC AF Klebe, Stephan Golmard, Jean-Louis Nalls, Michael A. Saad, Mohamad Singleton, Andrew B. Bras, Jose M. Hardy, John Simon-Sanchez, Javier Heutink, Peter Kuhlenbaeumer, Gregor Charfi, Rim Klein, Christine Hagenah, Johann Gasser, Thomas Wurster, Isabel Lesage, Suzanne Lorenz, Delia Deuschl, Guenther Durif, Franck Pollak, Pierre Damier, Philippe Tison, Francois Durr, Alexandra Amouyel, Philippe Lambert, Jean-Charles Tzourio, Christophe Maubaret, Cecilia Charbonnier-Beaupel, Fanny Tahiri, Khadija Vidailhet, Marie Martinez, Maria Brice, Alexis Corvol, Jean-Christophe CA IPDGC TI The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID CATECHOL-O-METHYLTRANSFERASE; OBSESSIVE-COMPULSIVE DISORDER; GENOME-WIDE ASSOCIATION; MONOAMINE OXIDASE-B; VAL(158)MET POLYMORPHISM; ENZYME-ACTIVITY; NO ASSOCIATION; HUMAN BRAIN; POPULATION; GENOTYPE AB The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1 +/- 13.9, p=0.03) than the Val/Met (57.4 +/- 13.9) and the Met/Met genotypes (58.3 +/- 13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD. C1 [Klebe, Stephan; Lesage, Suzanne; Durr, Alexandra; Charbonnier-Beaupel, Fanny; Tahiri, Khadija; Brice, Alexis; Corvol, Jean-Christophe] INSERM, UMR S975, CR ICM, Paris, France. [Klebe, Stephan; Lesage, Suzanne; Durr, Alexandra; Charbonnier-Beaupel, Fanny; Tahiri, Khadija; Vidailhet, Marie; Brice, Alexis; Corvol, Jean-Christophe] UPMC Univ Paris 06, UMR S975, CR ICM, Pitie Salpetriere Hosp, Paris, France. [Klebe, Stephan; Lesage, Suzanne; Durr, Alexandra; Charbonnier-Beaupel, Fanny; Tahiri, Khadija; Vidailhet, Marie; Brice, Alexis; Corvol, Jean-Christophe] Hop La Pitie Salpetriere, CR ICM, CNRS, UMR 7225, Paris, France. [Klebe, Stephan; Durr, Alexandra; Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, F-75651 Paris 13, France. [Klebe, Stephan; Corvol, Jean-Christophe] Hop La Pitie Salpetriere, INSERM, CIC 9503, F-75651 Paris 13, France. [Klebe, Stephan; Vidailhet, Marie; Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Neurol, F-75651 Paris 13, France. [Klebe, Stephan] Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany. [Golmard, Jean-Louis] Hop La Pitie Salpetriere, AP HP, Dept Biostat, F-75651 Paris 13, France. [Nalls, Michael A.; Singleton, Andrew B.; Simon-Sanchez, Javier] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Saad, Mohamad; Martinez, Maria] CPTP, INSERM U1043, Toulouse, France. [Saad, Mohamad; Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Bras, Jose M.; Hardy, John] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Simon-Sanchez, Javier; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Gen, Amsterdam, Netherlands. [Kuhlenbaeumer, Gregor] Univ Kiel, Inst Expt Med, Kiel, Germany. [Charfi, Rim; Durr, Alexandra; Corvol, Jean-Christophe] Hop La Pitie Salpetriere, AP HP, Dept Pharmacol, F-75651 Paris 13, France. [Charfi, Rim] Univ Tunis El Manar, Fac Med Tunis, Ctr Natl Pharmacovigilance Tunis, Serv Pharmacol Clin, Tunis, Tunisia. [Klein, Christine; Hagenah, Johann] Univ Lubeck, Inst Neurogenet, Lubeck, Germany. [Gasser, Thomas; Wurster, Isabel] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Gasser, Thomas; Wurster, Isabel] German Ctr Neurodegenerat Dis DZNE, Dept Neurodegenerat Dis, Tubingen, Germany. [Lorenz, Delia; Deuschl, Guenther] Univ Kiel, UKS H, Dept Neurol, Kiel, Germany. [Durif, Franck] CHU Grenoble, Hop Gabriel Montpied, Dept Neurol, Clermont Ferrand, France. [Pollak, Pierre] CHU Grenoble, Dept Neurol, Grenoble, France. [Damier, Philippe] CHU Nantes, Ctr Invest Clin, F-44035 Nantes 01, France. [Tison, Francois] Hop Haut Leveque, Dept Neurol, Pessac, France. [Amouyel, Philippe; Lambert, Jean-Charles] INSERM, U744, F-59045 Lille, France. [Amouyel, Philippe; Lambert, Jean-Charles] Inst Pasteur, Lille, France. [Amouyel, Philippe; Lambert, Jean-Charles] Univ Lille Nord France, Lille, France. [Tzourio, Christophe] Univ Paris 06, Hop Pitie Salpetriere, Modelisat Rech Clin ER4 UPMC, CNRS CRICM 7225, Paris, France. [Tzourio, Christophe] INSERM UMR S708, Paris, France. [Maubaret, Cecilia] Univ Bordeaux Segalen, INSERM U897, Bordeaux, France. [Vidailhet, Marie] INSERM, UMR S975, Paris, France. RP Corvol, JC (reprint author), Hop La Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, Ctr Invest Clin, 47 Blvd Hop, F-75651 Paris 13, France. EM jean-christophe.corvol@psl.aphp.fr RI de Silva, Rohan/C-1734-2008; Martinez, Maria/B-3111-2013; Guerreiro, Rita/A-1327-2011; corvol, jean-christophe/I-6387-2012; Revesz, Tamas/A-8732-2010; Trabzuni, Daniah/C-4034-2012; lambert, jean-charles/F-8787-2013; van de Warrenburg, Bart/D-1935-2010; Hardy, John/C-2451-2009; Traynor, Bryan/G-5690-2010; Lambert, jean-charles/A-9553-2014; Singleton, Andrew/C-3010-2009; O'Sullivan, Sean/C-9333-2012; Cooper, J Mark/D-5826-2013; Weale, Michael/F-2587-2010; Bras, Jose/A-1428-2011; Deloukas, Panos/B-2922-2013; Tzourio, christophe/B-4015-2009; Deuschl, Gunther/A-7986-2010; Scheffer, Hans/E-4644-2012 OI Bhatia, Kailash/0000-0001-8185-286X; Wood, Nicholas/0000-0002-9500-3348; Chen, Honglei/0000-0003-3446-7779; Pirinen, Matti/0000-0002-1664-1350; de Silva, Rohan/0000-0002-5052-5775; Martinez, Maria/0000-0003-2180-4537; corvol, jean-christophe/0000-0001-7325-0199; Revesz, Tamas/0000-0003-2501-0259; Trabzuni, Daniah/0000-0003-4826-9570; Bras, Jose/0000-0001-8186-0333; Schulte, Claudia/0000-0003-4006-1265; Stefansson, Hreinn/0000-0002-9331-6666; Rivadeneira, Fernando/0000-0001-9435-9441; Lambert, jean-charles/0000-0003-0829-7817; O'Sullivan, Sean/0000-0002-0583-7956; Cooper, J Mark/0000-0002-3007-3054; Weale, Michael/0000-0003-4593-1186; Deloukas, Panos/0000-0001-9251-070X; Tzourio, christophe/0000-0002-6517-2984; Scheffer, Hans/0000-0002-2986-0915 FU Intramural NIH HHS; Medical Research Council [G0701075, G0802462, G0901254, G1100479, MC_G1000735, MR/J006742/1]; NCATS NIH HHS [UL1 TR000448]; NCRR NIH HHS [RR024992, UL1 RR024992]; NIA NIH HHS [Z01 AG000949, Z01 AG000949-02]; NIEHS NIH HHS [Z01 ES101986]; NINDS NIH HHS [NS057105, P30 NS057105, R01 NS058714, R01 NS075321]; Parkinson's UK [F-1202, G-0907, G-0909, G-1107, K-1212]; Wellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 089698, 090532, WT089698] NR 46 TC 14 Z9 15 U1 3 U2 32 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JUN PY 2013 VL 84 IS 6 BP 666 EP 673 DI 10.1136/jnnp-2012-304475 PG 8 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 142CM UT WOS:000318773800015 PM 23408064 ER PT J AU Kornik, RI Naik, HB Lee, CCR Estrada-Veras, J Gahl, WA Cowen, EW AF Kornik, Rachel I. Naik, Haley B. Lee, Chyi-Chia Richard Estrada-Veras, Juvianee Gahl, William A. Cowen, Edward W. TI Diabetes insipidus, bone lesions, and new-onset red-brown papules in a 42-year-old man SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material DE BRAF; diabetes insipidus; Erdheim-Chester; histiocytosis; pituitary; vemurafenib ID ERDHEIM-CHESTER-DISEASE; LANGERHANS CELL HISTIOCYTOSES C1 [Kornik, Rachel I.; Naik, Haley B.; Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Estrada-Veras, Juvianee; Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1908,Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 FU Intramural NIH HHS [ZID BC011317-01] NR 13 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUN PY 2013 VL 68 IS 6 BP 1034 EP 1038 DI 10.1016/j.jaad.2013.01.013 PG 5 WC Dermatology SC Dermatology GA 143ZW UT WOS:000318909600038 PM 23466246 ER PT J AU Fernandez, KH Bream, M Ali, MA Krogmann, T Zhao, H Li, Y Cohen, JI Damon, I Liu, V AF Fernandez, Kristen Heins Bream, Matthew Ali, Mir A. Krogmann, Tammy Zhao, Hui Li, Yu Cohen, Jeffrey I. Damon, Inger Liu, Vincent TI Investigation of molluscum contagiosum virus, orf and other parapoxviruses in lymphomatoid papulosis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter ID T-CELL LYMPHOMA C1 [Fernandez, Kristen Heins] Univ Missouri, Dept Dermatol, Columbia, MO 65211 USA. [Bream, Matthew; Liu, Vincent] Univ Iowa, Dept Dermatol, Iowa City, IA USA. [Bream, Matthew; Liu, Vincent] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. [Ali, Mir A.; Krogmann, Tammy; Cohen, Jeffrey I.] NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Ali, Mir A.; Krogmann, Tammy; Cohen, Jeffrey I.] NIH, Med Virol Sect, Bethesda, MD 20892 USA. [Zhao, Hui; Li, Yu; Damon, Inger] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. RP Fernandez, KH (reprint author), Univ Missouri, Dept Dermatol, Columbia, MO 65211 USA. EM Fernandezk@health.missouri.edu OI Fernandez, Kristen/0000-0002-3267-825X FU Intramural NIH HHS [Z01 AI000058-34] NR 5 TC 2 Z9 2 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUN PY 2013 VL 68 IS 6 BP 1046 EP 1047 DI 10.1016/j.jaad.2012.12.972 PG 3 WC Dermatology SC Dermatology GA 143ZW UT WOS:000318909600046 PM 23680202 ER PT J AU Jagu, S Kwak, K Schiller, JT Lowy, DR Kleanthous, H Kalnin, K Wang, CG Wang, HK Chow, LT Huh, WK Jaganathan, KS Chivukula, SV Roden, RBS AF Jagu, Subhashini Kwak, Kihyuck Schiller, John T. Lowy, Douglas R. Kleanthous, Harold Kalnin, Kirill Wang, Chenguang Wang, Hsu-Kun Chow, Louise T. Huh, Warner K. Jaganathan, Kilvani S. Chivukula, Sudha V. Roden, Richard B. S. TI Phylogenetic Considerations in Designing a Broadly Protective Multimeric L2 Vaccine SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS HPV; VIRUS-LIKE PARTICLES; CROSS-NEUTRALIZING EPITOPE; MINOR CAPSID PROTEIN; GENITAL WARTS; N-TERMINUS; BOVINE PAPILLOMAVIRUS-4; HEALTHY-VOLUNTEERS; TA-GW; INFECTION AB While the oncogenic human papillomavirus (HPV) types with the greatest medical impact are clustered within the alpha 9 and alpha 7 species, a significant fraction of cervical cancers are caused by alpha 5, alpha 6, and alpha 11 viruses. Benign genital warts are caused principally by the alpha 10 viruses HPV6 and HPV11. In an effort to achieve broad protection against both cervical cancer-and genital wart-associated types, we produced at high levels in bacteria a multimeric protein (alpha 11-88x8) fusing eight polypeptides corresponding to a protective domain comprising L2 residues alpha 11 to 88 derived from HPV6 (alpha 10), HPV16 (alpha 9), HPV18 (alpha 7), HPV31 (alpha 9), HPV39 (alpha 7), HPV51 (alpha 5), HPV56 (alpha 6), and HPV73 (alpha 11) and a truncated derivative with the last three units deleted (alpha 11-88x5). Mice were immunized three times with alpha 11-88x8 or alpha 11-88x5 adjuvanted with alum or the licensed HPV vaccines and challenged intravaginally with HPV6, HPV16, HPV26, HPV31, HPV33, HPV35, HPV45, HPV51, HPV56, HPV58, or HPV59 pseudovirions. The alpha 11-88x5 and alpha 11-88x8 vaccines induced similarly robust protection against each HPV type tested and indistinguishable HPV16-neutralizing antibody titers. Passive transfer of alpha 11-88x8 antisera was protective. Further, rabbit antisera to alpha 11-88x8 and alpha 11-88x5 similarly neutralized native HPV18 virions. These findings suggest that immunologic competition between units is not a significant issue and that it is not necessary to include a unit of L2 derived from each species to achieve broader protection against diverse medically significant HPV types than is achieved with the licensed HPV vaccines. C1 [Jagu, Subhashini; Kwak, Kihyuck; Roden, Richard B. S.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21218 USA. [Wang, Chenguang] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Schiller, John T.; Lowy, Douglas R.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Kleanthous, Harold; Kalnin, Kirill] Sanofi Pasteur, Boston, MA USA. [Wang, Hsu-Kun; Chow, Louise T.] Univ Alabama Birmingham, Dept Biochem & Mol Genet, Birmingham, AL USA. [Huh, Warner K.] Univ Alabama Birmingham, Dept Gynecol Oncol, Birmingham, AL USA. [Jaganathan, Kilvani S.; Chivukula, Sudha V.] Shantha Biotech Ltd, Hyderabad, AP, India. RP Roden, RBS (reprint author), Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21218 USA. EM roden@jhmi.edu FU Public Health Service [CA133749, CA118790, CA83679, P50 CA098252]; American Cancer Society [RSG 116279]; intramural program of the National Cancer Institute; Sanofi Pasteur/Shantha Biotechnics FX This study was funded by Public Health Service grants CA133749, CA118790, CA83679, and P50 CA098252 and by American Cancer Society grant RSG 116279, the intramural program of the National Cancer Institute, and Sanofi Pasteur/Shantha Biotechnics. NR 45 TC 15 Z9 15 U1 1 U2 11 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 JUN PY 2013 VL 87 IS 11 BP 6127 EP 6136 DI 10.1128/JVI.03218-12 PG 10 WC Virology SC Virology GA 143ZF UT WOS:000318907500007 PM 23536682 ER PT J AU Navarro, A Trask, SD Patton, JT AF Navarro, Aitor Trask, Shane D. Patton, John T. TI Generation of Genetically Stable Recombinant Rotaviruses Containing Novel Genome Rearrangements and Heterologous Sequences by Reverse Genetics SO JOURNAL OF VIROLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; SEGMENTED DSRNA VIRUSES; HEPATITIS-C VIRUS; REPLICATION; MECHANISM; PROTEIN; CHILDREN; CODON; DIVERSITY; INFECTION AB The rotavirus (RV) genome consists of 11 segments of double-stranded RNA (dsRNA). Typically, each segment contains 5' and 3' untranslated regions (UTRs) that flank an open reading frame (ORF) encoding a single protein. RV variants with segments of atypical size owing to sequence rearrangements have been described. In many cases, the rearrangement originates from a partial head-to-tail sequence duplication that initiates after the stop codon of the ORF, leaving the protein product of the segment unaffected. To probe the limits of the RV genome to accommodate additional genetic sequence, we used reverse genetics to insert duplications (analogous to synthetic rearrangements) and heterologous sequences into the 3' UTR of the segment encoding NSP2 (gene 8). The approach allowed the recovery of recombinant RVs that contained sequence duplications (up to 200 bp) and heterologous sequences, including those for FLAG, the hepatitis C virus E2 epitope, and the internal ribosome entry site of cricket paralysis virus. The recombinant RVs grew to high titer (> 10(7) PFU/ml) and remained genetically stable during serial passage. Despite their longer 3' UTRs, rearranged RNAs of recombinant RVs expressed wild-type levels of protein in vivo. Competitive growth experiments indicated that, unlike RV segments with naturally occurring sequence duplications, genetically engineered segments were less efficiently packaged into progeny viruses. Thus, features of naturally occurring rearranged segments, other than their increased length, contribute to their enhanced packaging phenotype. Our results define strategies for developing recombinant RVs as expression vectors, potentially leading to next-generation RV vaccines that induce protection against other infectious agents. C1 [Navarro, Aitor; Trask, Shane D.; Patton, John T.] NIAID, Rotavirus Mol Biol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Rotavirus Mol Biol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 63 TC 9 Z9 11 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2013 VL 87 IS 11 BP 6211 EP 6220 DI 10.1128/JVI.00413-13 PG 10 WC Virology SC Virology GA 143ZF UT WOS:000318907500015 PM 23536662 ER PT J AU Ferenczy, MW Johnson, KR Marshall, LJ Monaco, MC Major, EO AF Ferenczy, Michael W. Johnson, Kory R. Marshall, Leslie J. Monaco, Maria Chiara Major, Eugene O. TI Differentiation of Human Fetal Multipotential Neural Progenitor Cells to Astrocytes Reveals Susceptibility Factors for JC Virus SO JOURNAL OF VIROLOGY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; PLURIPOTENT STEM-CELLS; CENTRAL-NERVOUS-SYSTEM; TRANSCRIPTION FACTOR; SPI-B; HUMAN BRAIN; C-JUN; ASTROGLIAL SUBTYPES; GENE-EXPRESSION; BINDING SITES AB Viral infections of the central nervous system (CNS) are of increasing concern, especially among immunocompromised populations. Rodent models are often inappropriate for studies of CNS infection, as many viruses, including JC virus (JCV) and HIV, cannot replicate in rodent cells. Consequently, human fetal brain-derived multipotential CNS progenitor cells (NPCs) that can be differentiated into neurons, oligodendrocytes, or astrocytes have served as a model in CNS studies. NPCs can be nonproductively infected by JCV, while infection of progenitor-derived astrocytes (PDAs) is robust. We profiled cellular gene expression at multiple times during differentiation of NPCs to PDAs. Several activated transcription factors show commonality between cells of the brain, in which JCV replicates, and lymphocytes, in which JCV is likely latent. Bioinformatic analysis determined transcription factors that may influence the favorable transcriptional environment for JCV in PDAs. This study attempts to provide a framework for understanding the functional transcriptional profile necessary for productive JCV infection. C1 [Ferenczy, Michael W.; Marshall, Leslie J.; Monaco, Maria Chiara; Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Johnson, Kory R.] NINDS, Bioinformat Sect, NIH, Bethesda, MD 20892 USA. RP Ferenczy, MW (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM michael.ferenczy@nih.gov; majorg@ninds.nih.gov FU Intramural AIDS Research Fellowship from the NIH Office of AIDS Research; Division of Intramural Research of the NINDS FX M.W.F. was supported in part by the Intramural AIDS Research Fellowship from the NIH Office of AIDS Research. The Laboratory of Molecular Medicine and Neuroscience and Bioinformatics Section are supported by the Division of Intramural Research of the NINDS. NR 51 TC 6 Z9 7 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2013 VL 87 IS 11 BP 6221 EP 6231 DI 10.1128/JVI.00396-13 PG 11 WC Virology SC Virology GA 143ZF UT WOS:000318907500016 PM 23536657 ER PT J AU Manzke, N Akhmetzyanova, I Hasenkrug, KJ Trilling, M Zelinskyy, G Dittmer, U AF Manzke, Nora Akhmetzyanova, Ilseyar Hasenkrug, Kim J. Trilling, Mirko Zelinskyy, Gennadiy Dittmer, Ulf TI CD4(+) T Cells Develop Antiretroviral Cytotoxic Activity in the Absence of Regulatory T Cells and CD8(+) T Cells SO JOURNAL OF VIROLOGY LA English DT Article ID FRIEND RETROVIRUS INFECTION; HUMAN-IMMUNODEFICIENCY-VIRUS; FUNCTIONAL IMPAIRMENT; IMMUNE-RESPONSES; VIRAL-INFECTION; CUTTING EDGE; IN-VITRO; PROTECTION; MICE; REPLICATION AB Conventional CD4(+) T cells play an important role in viral immunity. In most virus infections, they provide essential help for antiviral B and T cell responses. In chronic infections, including HIV infection, an expansion of regulatory T cells (Tregs) has been demonstrated, which can suppress virus- specific CD4(+) T cell responses in vitro. However, the suppressive activity of Tregs on effector CD4(+) T cells in retroviral infection is less well documented in vivo. We took advantage of a transgenic mouse in which Tregs can be selectively depleted to determine the influence of such cells on retrovirus- specific CD4(+) T cell responses during an ongoing infection. Mice were infected with Friend retrovirus (FV), and Tregs were depleted during the acute phase of the infection. In nondepleted mice, activated CD4(+) T cells produced Th1- type cytokines but did not exhibit any antiviral cytotoxicity as determined in a major histocompatibility complex (MHC) class II- restricted in vivo cytotoxic T lymphocyte (CTL) assay. Depletion of Tregs significantly increased the numbers of virus- specific CD4(+) T cells and improved their cytokine production, whereas it induced only very little CD4(+) T cell cytotoxicity. However, after dual depletion of Tregs and CD8(+) T cells, conventional CD4(+) T cells developed significant cytotoxic activity against FV epitope- labeled target cells in vivo and contributed to the control of virus replication. Thus, both Tregs and CD8(+) T cells influence the cytotoxic activity of conventional CD4(+) T cells during an acute retroviral infection. C1 [Manzke, Nora; Akhmetzyanova, Ilseyar; Trilling, Mirko; Zelinskyy, Gennadiy; Dittmer, Ulf] Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany. [Hasenkrug, Kim J.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Dittmer, U (reprint author), Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany. EM ulf.dittmer@uni-due.de OI Trilling, Mirko/0000-0003-3659-3541 FU Deutsche Forschungsgesellschaft [TRR60 Project B4]; [Di714/11-1] FX This work was supported by a grant to U.D. and G.Z. from the Deutsche Forschungsgesellschaft (TRR60 Project B4) and by a grant to U.D. and I.A. (Di714/11-1). NR 56 TC 9 Z9 9 U1 0 U2 11 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 JUN PY 2013 VL 87 IS 11 BP 6306 EP 6313 DI 10.1128/JVI.00432-13 PG 8 WC Virology SC Virology GA 143ZF UT WOS:000318907500023 PM 23536666 ER PT J AU Manasanch, EE Freeman, AF Pittaluga, S Costello, R Holland, SM Landgren, O AF Manasanch, Elisabet E. Freeman, Alexandra F. Pittaluga, Stefania Costello, Rene Holland, Steven M. Landgren, Ola TI Serum free light chains as predictors of lymphomagenesis in patients with autosomal dominant hyper-immunoglobulin E syndrome (Job's syndrome) SO LEUKEMIA & LYMPHOMA LA English DT Letter ID IGE SYNDROME; DISORDER C1 [Manasanch, Elisabet E.; Costello, Rene; Landgren, Ola] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Hematopathol Sect, NIH, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, 9000 Rockville Pike,Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov NR 8 TC 3 Z9 3 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 2013 VL 54 IS 6 BP 1316 EP 1317 DI 10.3109/10428194.2012.736984 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 142OI UT WOS:000318806400032 PM 23039380 ER PT J AU Osgood, K Krakoff, J Thearle, M AF Osgood, Kristy Krakoff, Jonathan Thearle, Marie TI Serum Uric Acid Predicts Both Current and Future Components of the Metabolic Syndrome SO METABOLIC SYNDROME AND RELATED DISORDERS LA English DT Article ID INSULIN-RESISTANCE; PIMA-INDIANS; FRUCTOSE; OBESITY; HYPERURICEMIA; GLUCOSE; HYPERTENSION; INDIVIDUALS; IMMUNOASSAY; RISK AB Background: Uric acid (UA) is known to be associated with excess adiposity and insulin resistance. Our aim was to investigate the relationship between UA and the factors associated with the metabolic syndrome and type 2 diabetes mellitus (T2DM), both initially and longitudinally. Methods: Serum UA was assessed as a potential determinant of concurrent blood pressure, serum lipids, glucose regulation measured via an oral glucose tolerance test (OGTT), acute insulin response (AIR), and insulin action (M) measured with hyperinsulinemic-euglycemic clamps in 245 participants (72% Native American, 56% male). UA was also assessed as a predictor of the above variables in 60 participants with follow-up data available (median follow-up time = 11.2 years [interquartile range (IQR) = 8.1, 13.6 years]. The impact of UA on the risk of T2DM was determined as 36 of the 245 participants developed T2DM after the baseline visit. Results: UA was negatively associated with both concurrent and future M, such that for every 1 mg/dL increase in serum UA, M decreased 7.6% (P < 0.001) and future M decreased 6.3% (P = 0.02). However, UA was not associated with AIR (P = 0.7). UA concentrations were a predictor of T2DM [hazard risk ratio (HRR) = 1.5; P = 0.02]. UA was positively associated with both concurrent blood pressure and lipids and also predicted future increases in blood pressure and total cholesterol. Conclusions: Not only did UA associate with concomitant insulin action, blood pressure, and lipids, it also predicted future declines in insulin action and T2DM. UA is a potential target for preventing decreases in insulin sensitivity and rises in blood pressure and cholesterol. C1 [Osgood, Kristy; Krakoff, Jonathan; Thearle, Marie] NIDDKD, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH,Dept Hlth & Human Serv, Phoenix, AZ USA. RP Thearle, M (reprint author), NIH, Dept Hlth & Human Serv, 4212 N 16th St, Phoenix, AZ 85016 USA. EM thearlem@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; American Podiatric Medical Association/American Diabetes Association (APMA/ADA) FX We would like to thank the volunteers who participated in this study as well as the clinical research staff of the Phoenix Epidemiology and Clinical Research Branch. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. K.O. is supported by an American Podiatric Medical Association/American Diabetes Association (APMA/ADA) joint fellowship grant. NR 28 TC 19 Z9 21 U1 2 U2 9 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-4196 J9 METAB SYNDR RELAT D JI Metab. Syndr. Relat. Disord. PD JUN PY 2013 VL 11 IS 3 BP 157 EP 162 DI 10.1089/met.2012.0151 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 145WZ UT WOS:000319051400004 PM 23360433 ER PT J AU Rath, MF Rohde, K Klein, DC Moller, M AF Rath, Martin F. Rohde, Kristian Klein, David C. Moller, Morten TI Homeobox Genes in the Rodent Pineal Gland: Roles in Development and Phenotype Maintenance SO NEUROCHEMICAL RESEARCH LA English DT Review DE Pineal gland; Homeobox gene; Rodent; Brain development; Circadian rhythm ID ARYLALKYLAMINE-N-ACETYLTRANSFERASE; HYDROXYINDOLE-O-METHYLTRANSFERASE; IN-SITU HYBRIDIZATION; VERTEBRATE EYE DEVELOPMENT; PHOTORECEPTOR CELL FATE; RAT PINEAL; MESSENGER-RNA; CIRCADIAN EXPRESSION; TRANSCRIPTION FACTOR; MELATONIN SYNTHESIS AB The pineal gland is a neuroendocrine gland responsible for nocturnal synthesis of melatonin. During early development of the rodent pineal gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential for normal pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the pineal gland appears to be unusual because strong homeobox gene expression persists in the pineal gland of the adult brain. Accordingly, in addition to developmental functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of pineal development and recent progress in understanding the involvement of homebox genes in rodent pineal development and adult function. A working model is proposed for understanding the sequential action of homeobox genes in controlling development and mature circadian function of the mammalian pinealocyte based on knowledge from detailed developmental and daily gene expression analyses in rats, the pineal phenotypes of homebox gene-deficient mice and studies on development of the retinal photoreceptor; the pinealocyte and retinal photoreceptor share features not seen in other tissues and are likely to have evolved from the same ancestral photodetector cell. C1 [Rath, Martin F.; Rohde, Kristian; Moller, Morten] Univ Copenhagen, Dept Neurosci & Pharmacol, Panum Inst 24 2, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark. [Rath, Martin F.; Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. RP Rath, MF (reprint author), Univ Copenhagen, Dept Neurosci & Pharmacol, Panum Inst 24 2, Fac Hlth & Med Sci, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. EM mrath@sund.ku.dk RI chen, zhu/K-5923-2013; OI Rath, Martin/0000-0002-4047-6324 FU Danish Medical Research Council; Lundbeck Foundation; Novo Nordisk Foundation; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This work was supported by the Danish Medical Research Council, the Lundbeck Foundation, the Novo Nordisk Foundation and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 126 TC 9 Z9 9 U1 0 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUN PY 2013 VL 38 IS 6 SI SI BP 1100 EP 1112 DI 10.1007/s11064-012-0906-y PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 145KE UT WOS:000319013700003 PM 23076630 ER PT J AU Barak, B Okun, E Ben-Simon, Y Lavi, A Shapira, R Madar, R Wang, Y Norman, E Sheinin, A Pita, MA Yizhar, O Mughal, MR Stuenkel, E van Praag, H Mattson, MP Ashery, U AF Barak, Boaz Okun, Eitan Ben-Simon, Yoav Lavi, Ayal Shapira, Ronit Madar, Ravit Wang, Yue Norman, Eric Sheinin, Anton Pita, Mario A. Yizhar, Ofer Mughal, Mohamed R. Stuenkel, Edward van Praag, Henriette Mattson, Mark P. Ashery, Uri TI Neuron-Specific Expression of Tomosyn1 in the Mouse Hippocampal Dentate Gyrus Impairs Spatial Learning and Memory SO NEUROMOLECULAR MEDICINE LA English DT Article DE Synaptic plasticity; Synaptic transmission; Behavior; Tomosyn; Short-term plasticity; Hippocampus; Lentivirus; Dentate gyrus ID LONG-TERM POTENTIATION; SYNAPTIC VESICLE CYCLE; SNARE CORE COMPLEXES; NEUROTRANSMITTER RELEASE; PRESYNAPTIC PROTEINS; NMDA RECEPTORS; WORKING-MEMORY; MOSSY FIBER; WATER MAZE; EXOCYTOSIS AB Tomosyn, a syntaxin-binding protein, is known to inhibit vesicle priming and synaptic transmission via interference with the formation of SNARE complexes. Using a lentiviral vector, we specifically overexpressed tomosyn1 in hippocampal dentate gyrus neurons in adult mice. Mice were then subjected to spatial learning and memory tasks and electrophysiological measurements from hippocampal slices. Tomosyn1-overexpression significantly impaired hippocampus-dependent spatial memory while tested in the Morris water maze. Further, tomosyn1-overexpressing mice utilize swimming strategies of lesser cognitive ability in the Morris water maze compared with control mice. Electrophysiological measurements at mossy fiber-CA3 synapses revealed impaired paired-pulse facilitation in the mossy fiber of tomosyn1-overexpressing mice. This study provides evidence for novel roles for tomosyn1 in hippocampus-dependent spatial learning and memory, potentially via decreased synaptic transmission in mossy fiber-CA3 synapses. Moreover, it provides new insight regarding the role of the hippocampal dentate gyrus and mossy fiber-CA3 synapses in swimming strategy preference, and in learning and memory. C1 [Barak, Boaz; Ben-Simon, Yoav; Lavi, Ayal; Shapira, Ronit; Sheinin, Anton; Ashery, Uri] Tel Aviv Univ, Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. [Barak, Boaz; Ben-Simon, Yoav; Lavi, Ayal; Ashery, Uri] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Okun, Eitan; Madar, Ravit] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Okun, Eitan; Madar, Ravit] Bar Ilan Univ, Gonda Goldschmidt Multidisciplinary Brain Res Ctr, IL-52900 Ramat Gan, Israel. [Wang, Yue; Norman, Eric; Pita, Mario A.; Mughal, Mohamed R.; van Praag, Henriette; Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Yizhar, Ofer] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. [Stuenkel, Edward] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. RP Ashery, U (reprint author), Tel Aviv Univ, Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. EM uria@post.tau.ac.il RI van Praag, Henriette/F-3939-2015; okun, eitan/K-1314-2016; OI van Praag, Henriette/0000-0002-5727-434X; okun, eitan/0000-0001-8474-1487; Madar, Ravit/0000-0002-2025-8178; Ben-Simon, Yoav/0000-0002-7075-097X; Yizhar, Ofer/0000-0003-4228-1448 FU National Institute on Aging, NIH; Israel Science Foundation [1211/07, 730/11]; BSF [2009279]; National Institutes of Health [RO1 NS053978]; Boehringer Ingelheim Fonds FX We would like to thank Prof. Pablo Castillo for comments on the manuscript, Dr. Peisu Zhang for technical help, and Dr. Sarah Rothman for editing the manuscript. This research was supported, in part, by the Intramural Research Program of the National Institute on Aging, NIH, the Israel Science Foundation (Grant no. 1211/07 and 730/11; U.A.) and the BSF (Grant no. 2009279; U.A.), the National Institutes of Health (RO1 NS053978; E. S. and U. A.) and by travel grant from Boehringer Ingelheim Fonds (awarded to Boaz Barak). NR 55 TC 8 Z9 8 U1 0 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD JUN PY 2013 VL 15 IS 2 BP 351 EP 363 DI 10.1007/s12017-013-8223-4 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 143CS UT WOS:000318844500011 PM 23519441 ER PT J AU Panlilio, LV Zanettini, C Barnes, C Solinas, M Goldberg, SR AF Panlilio, Leigh V. Zanettini, Claudio Barnes, Chanel Solinas, Marcelo Goldberg, Steven R. TI Prior Exposure to THC Increases the Addictive Effects of Nicotine in Rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE self-administration; gateway drug hypothesis; behavioral economics; open field; light-dark test; cannabis ID ILLICIT DRUG-USE; GATEWAY HYPOTHESIS; CANNABIS USE; MARIJUANA USE; BEHAVIORAL SENSITIZATION; REINFORCING EFFICACY; RECEPTOR ANTAGONIST; AMERICAN YOUTH; RHESUS-MONKEYS; ADULT RATS AB Although it is more common for drug abuse to progress from tobacco to cannabis, in many cases cannabis use develops before tobacco use. Epidemiological evidence indicates that prior cannabis use increases the likelihood of becoming dependent on tobacco. To determine whether this effect might be due to cannabis exposure per se, in addition to any genetic, social, or environmental factors that might contribute, we extended our series of studies on 'gateway drug' effects in animal models of drug abuse. Rats were exposed to THC, the main psychoactive constituent of cannabis, for 3 days (two intraperitoneal injections/day). Then, starting 1 week later, they were allowed to self-administer nicotine intravenously. THC exposure increased the likelihood of acquiring the nicotine self-administration response from 65% in vehicle-exposed rats to 94% in THC-exposed rats. When the price of nicotine was manipulated by increasing the response requirement, THC-exposed rats maintained higher levels of intake than vehicle-exposed rats, indicating that THC exposure increased the value of nicotine reward. These results contrast sharply with our earlier findings that prior THC exposure did not increase the likelihood of rats acquiring either heroin or cocaine self-administration, nor did it increase the reward value of these drugs. The findings obtained here suggest that a history of cannabis exposure might have lasting effects that increase the risk of becoming addicted to nicotine. C1 [Panlilio, Leigh V.; Zanettini, Claudio; Barnes, Chanel; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. [Zanettini, Claudio] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Solinas, Marcelo] INSERM, U1084, Expt & Clin Neurosci Lab, Poitiers, France. [Solinas, Marcelo] Univ Poitiers, Poitiers, France. 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 Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 FU Intramural Research Program of the NIH; National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse. Thanks to Syrena Bracey for assistance in conducting the experiments. NR 80 TC 18 Z9 18 U1 6 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2013 VL 38 IS 7 BP 1198 EP 1208 DI 10.1038/npp.2013.16 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 146UV UT WOS:000319120000006 PM 23314220 ER PT J AU Hatsukami, DK Heishman, SJ Vogel, RI Denlinger, RL Roper-Batker, AN Mackowick, KM Jensen, J Murphy, SE Thomas, BF Donny, E AF Hatsukami, Dorothy K. Heishman, Stephen J. Vogel, Rachel Isaksson Denlinger, Rachel L. Roper-Batker, Astia N. Mackowick, Kristen M. Jensen, Joni Murphy, Sharon E. Thomas, Brian F. Donny, Eric TI DoseResponse Effects of Spectrum Research Cigarettes SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE CONTENT CIGARETTES; CARCINOGEN EXPOSURE; SMOKING; TOBACCO; BIOMARKERS; MORTALITY; SMOKERS AB Experimental cigarettes are needed to conduct studies examining the effects of varying doses of nicotine content on smoking behavior. The National Institute on Drug Abuse contracted with Research Triangle Institute to make such cigarettes available to researchers. The goal of this study was to determine whether cigarettes that vary in nicotine content produce an expected doseresponse effect. Two studies were conducted. The first study recruited subjects from 3 sites and consisted of a single, within-subject laboratory session. Subjects first smoked 4 puffs on their usual-brand cigarette and then in double-blind, random-order, smoked 4 puffs on each experimental cigarette that contained either low nicotine (LN, 0.4mg/g), intermediate nicotine (IN, 5.75.8mg/g), or high nicotine (HN, 11.412.8mg/g). Each puffing bout was separated by a 30-min interval. Subjects completed questionnaires and were assessed for vital signs after each cigarette. The second study involved 1 site and used a between-subject design in which subjects were assigned to 1 of the 3 experimental cigarettes for 1 week. Subjective responses and biomarkers of exposure were assessed. In the first study, significant doseresponse effects were observed, particularly between the LN and HN cigarettes. The second study showed decreases in cigarette smoking and exposure biomarkers predominantly in the LN group, with no changes in the HN cigarette group. These results are similar to those observed in prior literature, confirming that these experimental cigarettes can be used safely and with the expected pharmacological effects. C1 [Hatsukami, Dorothy K.; Roper-Batker, Astia N.; Jensen, Joni] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55414 USA. [Heishman, Stephen J.; Mackowick, Kristen M.] NIDA, Intramural Res Program, Baltimore, MD USA. [Vogel, Rachel Isaksson; Murphy, Sharon E.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55414 USA. [Denlinger, Rachel L.; Donny, Eric] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Thomas, Brian F.] Res Triangle Inst, Res Triangle Pk, NC 27709 USA. RP Hatsukami, DK (reprint author), Univ Minnesota, 717 Delaware St SE, Minneapolis, MN 55414 USA. EM hatsu001@umn.edu OI Thomas, Brian/0000-0002-0097-4804; Donny, Eric/0000-0003-3288-9652; Vogel, Rachel/0000-0003-0149-8464 FU National Institute on Drug Abuse at the National Institutes of Health Intramural Research Program [HHSN271201000003C, U54DA031659]; University of Minnesota, Forster Family Professor in Cancer Prevention Endowment; Nabi Biopharmaceuticals; NIDA FX This work was supported by the National Institute on Drug Abuse at the National Institutes of Health Intramural Research Program and under contract no. HHSN271201000003C, U54DA031659, and the University of Minnesota, Forster Family Professor in Cancer Prevention Endowment.; Dorothy Hatsukami was funded by Nabi Biopharmaceuticals and NIDA to be a site for a nicotine immunotherapy trial. There are no other declarations. NR 17 TC 17 Z9 17 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUN PY 2013 VL 15 IS 6 BP 1113 EP 1121 DI 10.1093/ntr/nts247 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 142PW UT WOS:000318810500013 PM 23178320 ER PT J AU Rao, JS Kim, HW Harry, GJ Rapoport, SI Reese, EA AF Rao, Jagadeesh Sridhara Kim, Hyung-Wook Harry, Gaylia Jean Rapoport, Stanley Isaac Reese, Edmund Arthur TI Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Arachidonic acid cascade; Cytokines; Inflammation; Synaptophysin; Drebrin; Brain; Synapse ID CYTOSOLIC PHOSPHOLIPASE A(2); NECROSIS-FACTOR-ALPHA; KAPPA-B ACTIVITY; ALZHEIMERS-DISEASE; RAT-BRAIN; 1ST-EPISODE PSYCHOSIS; POSTSYNAPTIC DENSITY; COX-2 TRANSCRIPTION; PREFRONTAL CORTEX; NITRIC-OXIDE AB Schizophrenia (SZ) is a progressive, neuropsychiatric disorder associated with cognitive impairment. A number of brain alterations have been linked to cognitive impairment, including neuroinflammation, excitotoxicity, increased arachidonic acid (AA) signaling and reduced synaptic protein. On this basis, we tested the hypothesis that SZ pathology is associated with these pathological brain changes. To do this, we examined postmortem frontal cortex from 10 SZ patients and 10 controls and measured protein and mRNA levels of cytokines, and astroglial, microglial, neuroinflammatory, excitotoxic, AA cascade, apoptotic and synaptic markers. Mean protein and mRNA levels of interleukin-1 beta, tumor necrosis factor-alpha, glial acidic fibrillary protein (GFAP), a microglial marker CD11b, and nuclear factor kappa B subunits were significantly increased in SZ compared with control brain. Protein and mRNA levels of cytosolic and secretory phospholipase A(2) and cyclooxygenase also were significantly elevated. N-methyl-D-aspartate receptor subunits 1 and 2B, inducible nitric oxide synthase and c-Fos were not significantly different. In addition, reduced protein and mRNA levels of brain-derived neurotrophic factor, synaptophysin and drebrin were found in SZ compared with control frontal cortex. Increased neuroinflammation and AA cascade enzyme markers with synaptic protein loss could promote disease progression and cognitive defects in SZ patients. Drugs that downregulate these changes might be considered for new therapies in SZ. Published by Elsevier B.V. C1 [Rao, Jagadeesh Sridhara; Kim, Hyung-Wook; Rapoport, Stanley Isaac; Reese, Edmund Arthur] NIA, BPMS, NIH, Bethesda, MD 20892 USA. [Harry, Gaylia Jean] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Rao, JS (reprint author), NIA, BPMS, NIH, 9000 Rockville Pike,Bldg 9,1S-126, Bethesda, MD 20892 USA. EM jrao@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health; PHS grant [R24MH068855]; Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.; We thank the NIH Fellows Editorial Board and Ms. Mairi Stevens for editing our manuscript. We thank the Harvard Brain Bank, Boston, MA for providing the post-mortem brain samples under PHS grant number R24MH068855. This research was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. NR 71 TC 48 Z9 48 U1 7 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUN PY 2013 VL 147 IS 1 BP 24 EP 31 DI 10.1016/j.schres.2013.02.017 PG 8 WC Psychiatry SC Psychiatry GA 145VN UT WOS:000319047100003 PM 23566496 ER PT J AU Murk, AJ Rijntjes, E Blaauboer, BJ Clewell, R Crofton, KM Dingemans, MML Furlow, JD Kavlock, R Kohrle, J Opitz, R Traas, T Visser, TJ Xia, MH Gutleb, AC AF Murk, AlberTinka J. Rijntjes, Eddy Blaauboer, Bas J. Clewell, Rebecca Crofton, Kevin M. Dingemans, Milou M. L. Furlow, J. David Kavlock, Robert Koehrle, Josef Opitz, Robert Traas, Theo Visser, Theo J. Xia, Menghang Gutleb, Arno C. TI Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals SO TOXICOLOGY IN VITRO LA English DT Review DE Endocrine disruption; Thyroid hormone; Alternatives to animal testing; In vitro assays; Toxicokinetics; Testing strategy; Battery; Functional assay; Metabolism ID SODIUM-IODIDE SYMPORTER; POLYBROMINATED DIPHENYL ETHERS; THYROTROPIN-RELEASING-HORMONE; MICROSOMAL-ENZYME INDUCERS; HYDROXYLATED POLYCHLORINATED-BIPHENYLS; CONSTITUTIVE ANDROSTANE RECEPTOR; BROMINATED FLAME RETARDANTS; THYROXINE-BINDING GLOBULIN; BEARS URSUS-MARITIMUS; PREGNANE-X-RECEPTOR AB The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endocrine systems, sexual behaviour and fertility and cardiovascular function. Therefore, concern about TH disruption (THD) has resulted in strategies being developed to identify THD chemicals (THDCs), Information on potential of chemicals causing THD is typically derived from animal studies. For the majority of chemicals, however, this information is either limited or unavailable. It is also unlikely that animal experiments will be performed for all THD relevant chemicals in the near future for ethical, financial and practical reasons. In addition, typical animal experiments often do not provide information on the mechanism of action of THDC, making it harder to extrapolate results across species. Relevant effects may not be identified in animal studies when the effects are delayed, life stage specific, not assessed by the experimental paradigm (e.g., behaviour) or only occur when an organism has to adapt to environmental factors by modulating TH levels. Therefore, in vitro and in silico alternatives to identify THDC and quantify their potency are needed. THDC have many potential mechanisms of action, including altered hormone production, transport, metabolism, receptor activation and disruption of several feed-back mechanisms. In vitro assays are available for many of these endpoints, and the application of modern '-omics' technologies, applicable for in vivo studies can help to reveal relevant and possibly new endpoints for inclusion in a targeted THDC in vitro test battery. Within the framework of the ASAT initiative (Assuring Safety without Animal Testing), an international group consisting of experts in the areas of thyroid endocrinology, toxicology of endocrine disruption, neurotoxicology, high-throughput screening, computational biology, and regulatory affairs has reviewed the state of science for (1) known mechanisms for THD plus examples of THDC; (2) in vitro THD tests currently available or under development related to these mechanisms; and (3) in silico methods for estimating the blood levels of THDC. Based on this scientific review, the panel has recommended a battery of test methods to be able to classify chemicals as of less or high concern for further hazard and risk assessment for THD. In addition, research gaps and needs are identified to be able to optimize and validate the targeted THD in vitro test battery for a mechanism-based strategy for a decision to opt out or to proceed with further testing for THD. Published by Elsevier Ltd. C1 [Murk, AlberTinka J.] Wageningen Univ, Subdept Toxicol, NL-6703 HE Wageningen, Netherlands. [Rijntjes, Eddy; Koehrle, Josef] Charite, Inst Expt Endokrinol, D-13353 Berlin, Germany. [Blaauboer, Bas J.] Univ Utrecht, Inst Risk Assessment Sci, Doerenkamp Zbinden Chair, NL-3508 TC Utrecht, Netherlands. [Clewell, Rebecca] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Crofton, Kevin M.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Dingemans, Milou M. L.] Univ Utrecht, Fac Vet Med, Inst Risk Assessment Sci, Neurotoxicol Res Grp,Toxicol Div, Utrecht, Netherlands. [Furlow, J. David] Univ Calif Davis, Dept Neurobiol Physiol & Behav, Davis, CA USA. [Kavlock, Robert] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Opitz, Robert] Univ Libre Brussels, Inst Interdisciplinary Res Mol Human Biol, B-1070 Brussels, Belgium. [Visser, Theo J.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Traas, Theo] Natl Inst Publ Hlth & Environm, Bur REACH, NL-3720 BA Bilthoven, Netherlands. [Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Gutleb, Arno C.] Ctr Rech Publ Gabriel Lippmann, Dept Environm & Agrobiotechnol, Belvaux, Luxembourg. RP Murk, AJ (reprint author), Wageningen Univ, Subdept Toxicol, Tuinlaan 5, NL-6703 HE Wageningen, Netherlands. EM Tinka.Murk@wur.nl RI Crofton, Kevin/J-4798-2015; OI Crofton, Kevin/0000-0003-1749-9971; Kohrle, Josef/0000-0002-9187-9078 FU "Proefdiervrij" (the Dutch Society for the Replacement of Animal Testing (dsRAT)); ASAT Foundation FX This paper is based on the results of a workshop organized by the Institute for Risk Assessment Sciences, Utrecht University, for which financial support was kindly provided by "Proefdiervrij" (the Dutch Society for the Replacement of Animal Testing (dsRAT) www.proefdiervrij.nl/english) and the ASAT Foundation (www.asat-initiative.eu/). We want to thank Mania, Montano for the nicer version he made of Fig. 1. NR 410 TC 51 Z9 52 U1 11 U2 133 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD JUN PY 2013 VL 27 IS 4 SI SI BP 1320 EP 1346 DI 10.1016/j.tiv.2013.02.012 PG 27 WC Toxicology SC Toxicology GA 143AF UT WOS:000318838000015 PM 23453986 ER PT J AU Marshall, SJ Hayn, MH Stegemann, AP Agarwal, PK Badani, KK Balbay, MD Dasgupta, P Hemal, AK Hollenbeck, BK Kibel, AS Menon, M Mottrie, A Nepple, K Pattaras, JG Peabody, JO Poulakis, V Pruthi, RS Redorta, JP Rha, KH Richstone, L Schanne, F Scherr, DS Siemer, S Stockle, M Wallen, EM Weizer, AZ Wiklund, P Wilson, T Woods, M Guru, KA AF Marshall, Susan J. Hayn, Matthew H. Stegemann, Andrew P. Agarwal, Piyush K. Badani, Ketan K. Balbay, M. Derya Dasgupta, Prokar Hemal, Ashok K. Hollenbeck, Brent K. Kibel, Adam S. Menon, Mani Mottrie, Alex Nepple, Kenneth Pattaras, John G. Peabody, James O. Poulakis, Vassilis Pruthi, Raj S. Palou Redorta, Joan Rha, Koon-Ho Richstone, Lee Schanne, Francis Scherr, Douglas S. Siemer, Stefan Stoeckle, Michael Wallen, Eric M. Weizer, Alon Z. Wiklund, Peter Wilson, Timothy Woods, Michael Guru, Khurshid A. TI Impact of surgeon and volume on extended lymphadenectomy at the time of robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium (IRCC) SO BJU INTERNATIONAL LA English DT Article DE lymphadenectomy; bladder cancer; cystectomy; robotics ID INVASIVE BLADDER-CANCER; LYMPH-NODE DISSECTION; OUTCOMES; ASSOCIATION; EXPERIENCE; CARCINOMA; SURVIVAL; YIELD AB Objective To evaluate the incidence of, and predictors for, extended lymph node dissection (LND) in patients undergoing robot-assisted radical cystectomy (RARC) for bladder cancer, as extendedLND is critical for the treatment of bladder cancer but the role of minimally invasive surgery for extended LND has not been well-defined in a multi-institutional setting. Patients and Methods Used the International Robotic Cystectomy Consortium (IRCC) database. In all, 765 patients who underwent RARC at 17 institutions from 2003 to 2010 were evaluated for receipt of extended LND. Patients were stratified by age, sex, clinical stage, institutional volume, sequential case number, and surgeon volume. Logistic regression analyses were used to correlate variables to the likelihood of undergoing extended LND. Results In all, 445 (58%) patients underwent extended LND. Among all patients, a median (range) of 18 (0-74) LNs were examined. High-volume institutions (>= 100 cases) had a higher mean LN yield (23 vs 15, P < 0.001). On univariable analysis, surgeon volume, institutional volume, and sequential case number were associated with likelihood of undergoing extended LND. On multivariable analysis, surgeon volume [odds ratio (OR) 3.46, 95% confidence interval (CI) 2.37-5.06, P < 0.001] and institution volume [OR 2.65, 95% CI 1.47-4.78, P = 0.001) were associated with undergoing extended LND. Conclusions Robot-assisted LND can achieve similar LN yields to those of open LND after RC. High-volume surgeons are more likely to perform extended LND, reflecting a correlation between their growing experience and increased comfort with advanced vascular dissection. C1 [Marshall, Susan J.; Stegemann, Andrew P.; Guru, Khurshid A.] Roswell Pk Canc Inst, Dept Urol, Buffalo, NY 14263 USA. [Hayn, Matthew H.] Maine Med Ctr, Dept Urol, Portland, ME 04102 USA. [Agarwal, Piyush K.] NCI, Dept Urol, Bethesda, MD 20892 USA. [Badani, Ketan K.] Columbia Univ, Dept Urol, Med Ctr, New York, NY USA. [Balbay, M. Derya] Mem Sisli Hosp, Dept Urol, Istanbul, Turkey. [Dasgupta, Prokar] Guys Hosp, Dept Urol, London SE1 9RT, England. [Dasgupta, Prokar] Kings Coll London, Sch Med, London WC2R 2LS, England. [Hemal, Ashok K.] Wake Forest Univ, Dept Urol, Baptist Med Ctr, Winston Salem, NC 27109 USA. [Hollenbeck, Brent K.; Weizer, Alon Z.] Univ Michigan Hlth Syst, Dept Urol, Ann Arbor, MI USA. [Kibel, Adam S.; Nepple, Kenneth] Washington Univ, Sch Med, Dept Urol, St Louis, MO USA. [Menon, Mani; Peabody, James O.] Henry Ford Hlth Syst, Dept Urol, Detroit, MI USA. [Mottrie, Alex] Onze Lieve Vrouw Hosp, Dept Urol, Aalast, Belgium. [Pattaras, John G.] Emory Univ, Sch Med, Dept Urol, Atlanta, GA USA. [Poulakis, Vassilis] Doctors Hosp, Dept Urol, Athens, Greece. [Pruthi, Raj S.; Wallen, Eric M.] Univ N Carolina, Dept Urol, Chapel Hill, NC USA. [Palou Redorta, Joan] Fundacio Puigvert, Barcelona, Spain. [Rha, Koon-Ho] Yonsei Univ, Hlth Syst Severance Hosp, Dept Urol, Seoul 120749, South Korea. [Richstone, Lee] Arthur Smith Inst Urol, Dept Urol, New York, NY USA. [Schanne, Francis] Urol Surg Associates Delaware, Dept Urol, Newark, DE USA. [Scherr, Douglas S.] Weill Cornell Med Ctr, Dept Urol, New York, NY USA. [Siemer, Stefan; Stoeckle, Michael] Univ Clin Saarland, Dept Urol, Homburg, Germany. [Wiklund, Peter] Karolinska Univ Hosp, Dept Urol, Stockholm, Sweden. [Wilson, Timothy] City Hope Natl Med Ctr, Dept Urol, Duarte, CA USA. [Wilson, Timothy] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Woods, Michael] Loyola Univ, Med Ctr, Dept Urol, Maywood, IL 60153 USA. RP Guru, KA (reprint author), Roswell Pk Canc Inst, Dept Urol Oncol, Elm & Carlton St, Buffalo, NY 14263 USA. EM khurshid.guru@roswellpark.org RI Petersen, Ninni/B-8346-2014; OI Agarwal, Piyush/0000-0002-6042-6834; Rha, Koon Ho/0000-0001-8588-7584 FU Medical Research Council [MR/J006742/1] NR 24 TC 26 Z9 26 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD JUN PY 2013 VL 111 IS 7 BP 1075 EP 1080 DI 10.1111/j.1464-410X.2012.11583.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 142PQ UT WOS:000318809900017 PM 23442001 ER PT J AU Bensen, JT Tse, CK Nyante, SJ Barnholtz-Sloan, JS Cole, SR Millikan, RC AF Bensen, Jeannette T. Tse, Chiu Kit Nyante, Sarah J. Barnholtz-Sloan, Jill S. Cole, Stephen R. Millikan, Robert C. TI Association of germline microRNA SNPs in pre-miRNA flanking region and breast cancer risk and survival: the Carolina Breast Cancer Study SO CANCER CAUSES & CONTROL LA English DT Article DE MicroRNA; Breast cancer; Germline; Single nucleotide polymorphism; Risk; Survival ID SINGLE-NUCLEOTIDE POLYMORPHISMS; BINDING-SITES; CELL-LINES; ENVIRONMENT INTERACTIONS; AFRICAN-AMERICAN; GENETIC-VARIANTS; MESSENGER-RNA; EXPRESSION; POPULATION; APOPTOSIS AB Common germline variation in the 5' region proximal to precursor (pre-) miRNA gene sequences is evaluated for association with breast cancer risk and survival among African Americans and Caucasians. We genotyped nine single nucleotide polymorphisms (SNPs) within six miRNA gene regions previously associated with breast cancer, in 1,972 cases and 1,776 controls. In a race-stratified analysis using unconditional logistic regression, odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to evaluate SNP association with breast cancer risk. Additionally, hazard ratios (HRs) for breast cancer-specific mortality were estimated. Two miR-185 SNPs provided suggestive evidence of an inverse association with breast cancer risk (rs2008591, OR = 0.72 (95 % CI = 0.53-0.98, p value = 0.04) and rs887205, OR = 0.71 (95 % CI = 0.52-0.96, p value = 0.03), respectively) among African Americans. Two SNPs, miR-34b/34c (rs4938723, HR = 0.57 (95 % CI = 0.37-0.89, p value = 0.01)) and miR-206 (rs6920648, HR = 0.77 (95 % CI = 0.61-0.97, p value = 0.02)), provided evidence of association with breast cancer survival. Further adjustment for stage resulted in more modest associations with survival (HR = 0.65 [95 % CI = 0.42-1.02, p value = 0.06] and HR = 0.79 [95 % CI = 0.62-1.00, p value = 0.05, respectively]). Our results suggest that germline variation in the 5' region proximal to pre-miRNA gene sequences may be associated with breast cancer risk among African Americans and breast cancer-specific survival generally; however, further validation is needed to confirm these findings. C1 [Bensen, Jeannette T.; Tse, Chiu Kit; Cole, Stephen R.; Millikan, Robert C.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Bensen, Jeannette T.; Millikan, Robert C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Nyante, Sarah J.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Barnholtz-Sloan, Jill S.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. RP Bensen, JT (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM jbensen@med.unc.edu FU Specialized Program of Research Excellence (SPORE) in Breast Cancer at UNC; National Institute of Health/National Cancer Institute [P50-CA58223, P30-CA16086]; Lineberger Comprehensive Cancer Center [R25 CA57726] FX The authors would like to acknowledge the UNC BioSpecimen Processing Facility for our DNA extractions, blood processing, storage, and sample disbursement (https://genome.unc.edu/bsp) and the UNC Mammalian Genotyping Core for CBCS sample genotyping (http://mgc.unc.edu). The authors would also like to thank Amy Otto for her thorough review and editing. This work was supported by the Specialized Program of Research Excellence (SPORE) in Breast Cancer at UNC funded by National Institute of Health/National Cancer Institute [P50-CA58223] (supports JTB, CKT, and RCM); the Lineberger Comprehensive Cancer Center Core Grant funded by the National Institute of Health/National Cancer Institute [P30-CA16086] (funded manuscript preparation and submission), and by the Lineberger Comprehensive Cancer Center Cancer Control Education Program Predoctoral Fellowship [R25 CA57726] (supported SJN). NR 62 TC 32 Z9 32 U1 1 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2013 VL 24 IS 6 BP 1099 EP 1109 DI 10.1007/s10552-013-0187-z PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 136OY UT WOS:000318372400005 PM 23526039 ER PT J AU Nicastro, HL Mondul, AM Rohrmann, S Platz, EA AF Nicastro, Holly L. Mondul, Alison M. Rohrmann, Sabine Platz, Elizabeth A. TI Associations between urinary soy isoflavonoids and two inflammatory markers in adults in the United States in 2005-2008 SO CANCER CAUSES & CONTROL LA English DT Article DE Soy isoflavonoids; Inflammation; C-reactive protein; White blood cell count; Cross-sectional studies ID C-REACTIVE PROTEIN; BLOOD-CELL COUNT; HORMONE-REPLACEMENT THERAPY; COLORECTAL-CANCER RISK; CORONARY-HEART-DISEASE; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; NATIONAL-HEALTH; BREAST-CANCER AB The aim of this study was to determine the association between urinary isoflavonoid (genistein, daidzein, and the daidzein metabolites O-desmethylangolensin (O-DMA) and equol) excretion and markers of inflammation in adults in the United States in National Health and Nutrition Examination Survey (NHANES) 2005-2008. The NHANES is a cross-sectional study conducted by the National Center for Health Statistics to study the health and nutritional status of people living in the United States. The analysis included 1,683 participants from study years 2005-2008 for whom urinary isoflavonoids were measured and who met inclusion criteria. Urinary isoflavonoids were measured by HPLC-APPI-MS/MS. Serum C-reactive protein (CRP) was measured by latex-based nephelometry. White blood cell (WBC) count was measured by Coulter counting. Multivariable linear regression was used to calculate the geometric mean values of the markers, and multivariable logistic regression was used to estimate the odds of high CRP (a parts per thousand yen3 mg/L) and of high WBC count (a parts per thousand yen7,900/mu L) by quartile of urinary isoflavonoid (nmol/mg creatinine). The highest quartile of genistein (OR = 0.62; 95 % CI 0.39-0.99) was associated with significantly decreased odds of high CRP compared with the lowest quartile. The sum of daidzein and its metabolites was significantly inversely associated with serum CRP concentration (p-trend = 0.017). Equol was inversely associated with WBC count (p-trend < 0.0001). O-DMA was the only isoflavonoid whose excretion was significantly associated with a decrease in both CRP (p-trend = 0.024) and WBC count (p-trend < 0.0001). Though no clear pattern emerged, higher excretion of certain soy isoflavonoids was associated with decreased CRP concentration and WBC counts, suggesting a possible inverse association between soy intake and inflammation. C1 [Nicastro, Holly L.] NCI, Canc Prevent Fellowship Program, Nutr Sci Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Mondul, Alison M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Rohrmann, Sabine] Univ Zurich, Inst Social & Prevent Med, Div Canc Epidemiol & Prevent, CH-8006 Zurich, Switzerland. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Nicastro, HL (reprint author), NCI, Canc Prevent Fellowship Program, Nutr Sci Res Grp, Canc Prevent Div, 9609 Med Ctr Dr 5E-572, Bethesda, MD 20892 USA. EM holly.nicastro@nih.gov OI Mondul, Alison/0000-0002-8843-1416 FU Intramural NIH HHS [Z99 CA999999] NR 55 TC 5 Z9 5 U1 0 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2013 VL 24 IS 6 BP 1185 EP 1196 DI 10.1007/s10552-013-0198-9 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 136OY UT WOS:000318372400014 PM 23558443 ER PT J AU Atz, AM Travison, TG McCrindle, BW Mahony, L Glatz, AC Kaza, AK Breitbart, RE Colan, SD Kaltman, JR Margossian, R Pasquali, SK Wang, YL Gersony, WM AF Atz, Andrew M. Travison, Thomas G. McCrindle, Brian W. Mahony, Lynn Glatz, Andrew C. Kaza, Aditya K. Breitbart, Roger E. Colan, Steven D. Kaltman, Jonathan R. Margossian, Renee Pasquali, Sara K. Wang, Yanli Gersony, Welton M. CA Pediat Heart Network Investigators TI Cardiac performance and quality of life in patients who have undergone the Fontan procedure with and without prior superior cavopulmonary connection SO CARDIOLOGY IN THE YOUNG LA English DT Article DE Congenital heart disease; Fontan; functionally univentricular heart; quality of life ID EXERCISE PERFORMANCE; OPERATION; HEART; ANASTOMOSIS; PALLIATION; VENTRICLE; OUTCOMES; CHILDREN AB Background: A superior cavopulmonary connection is commonly performed before the Fontan procedure in patients with a functionally univentricular heart. Data are limited regarding associations between a prior superior cavopulmonary connection and functional and ventricular performance late after the Fontan procedure. Methods: We compared characteristics of those with and without prior superior cavopulmonary connection among 546 subjects enrolled in the Pediatric Heart Network Fontan Cross-Sectional Study. We further compared different superior cavopulmonary connection techniques: bidirectional cavopulmonary anastomosis (n equals 229), bilateral bidirectional cavopulmonary anastomosis (n equals 39), and hemi-Fontan (n equals 114). Results: A prior superior cavopulmonary connection was performed in 408 subjects (75%); the proportion differed by year of Fontan surgery and centre (p-value less than 0.0001 for each). The average age at Fontan was similar, 3.5 years in those with superior cavopulmonary connection versus 3.2 years in those without (p-value equals 0.4). The type of superior cavopulmonary connection varied by site (p-value less than 0.001) and was related to the type of Fontan procedure. Exercise performance, echocardiographic variables, and predominant rhythm did not differ by superior cavopulmonary connection status or among superior cavopulmonary connection types. Using a test of interaction, findings did not vary according to an underlying diagnosis of hypoplastic left heart syndrome. Conclusions: After controlling for subject and era factors, most long-term outcomes in subjects with a prior superior cavopulmonary connection did not differ substantially from those without this procedure. The type of superior cavopulmonary connection varied significantly by centre, but late outcomes were similar. C1 [Atz, Andrew M.] Med Univ S Carolina, Dept Pediat, Div Cardiol, Charleston, SC 29425 USA. [Travison, Thomas G.; Wang, Yanli] New England Res Inst, Watertown, MA 02172 USA. [McCrindle, Brian W.] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Cardiol, Toronto, ON M5G 1X8, Canada. [Mahony, Lynn] Univ Texas Southwestern, Dept Pediat, Dallas, TX USA. [Glatz, Andrew C.] Childrens Hosp Philadelphia, Div Cardiol, Philadelphia, PA 19104 USA. [Kaza, Aditya K.] Univ Utah, Dept Surg, Salt Lake City, UT USA. [Breitbart, Roger E.; Colan, Steven D.; Margossian, Renee] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Kaltman, Jonathan R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Pasquali, Sara K.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Gersony, Welton M.] Columbia Univ, Div Pediat, Med Ctr, New York, NY USA. RP Atz, AM (reprint author), Med Univ S Carolina, Dept Pediat, Div Cardiol, Childrens Hosp, MSC 915,Room 601, Charleston, SC 29425 USA. EM atzam@musc.edu FU National Heart, Lung, and Blood Institute [U01, HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288] FX Supported by U01 grants from the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288) This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health/ National Heart, Lung, and Blood Institute. NR 20 TC 5 Z9 5 U1 0 U2 5 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1047-9511 J9 CARDIOL YOUNG JI Cardiol. Young PD JUN PY 2013 VL 23 IS 3 BP 335 EP 343 DI 10.1017/S1047951112001175 PG 9 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA 139ZQ UT WOS:000318624200003 PM 22824161 ER PT J AU Mortazavi, A Ling, YH Martin, LK Wei, L Phelps, MA Liu, ZF Harper, EJ Ivy, SP Wu, X Zhou, BS Liu, XY Deam, D Monk, JP Hicks, WJ Yen, Y Otterson, GA Grever, MR Bekaii-Saab, T AF Mortazavi, Amir Ling, Yonghua Martin, Ludmila Katherine Wei, Lai Phelps, Mitch A. Liu, Zhongfa Harper, Erica J. Ivy, S. Percy Wu, Xin Zhou, Bing-Sen Liu, Xiyong Deam, Deidre Monk, J. Paul Hicks, William J. Yen, Yun Otterson, Gregory A. Grever, Michael R. Bekaii-Saab, Tanios TI A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Triapine; Gemcitabine; Phase I; Clinical Trial ID RIBONUCLEOTIDE REDUCTASE INHIBITOR; 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE 3-AP; CELL LUNG-CANCER; PANCREATIC ADENOCARCINOMA; 30-MINUTE INFUSION; 2ND-LINE TREATMENT; M2 SUBUNIT; KB CELLS; TRIAL; LEUKEMIA AB Purpose Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Experimental Design Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m(2) over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Results Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m(2) (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. Conclusions This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure. C1 [Mortazavi, Amir; Martin, Ludmila Katherine; Harper, Erica J.; Wu, Xin; Deam, Deidre; Monk, J. Paul; Hicks, William J.; Otterson, Gregory A.; Bekaii-Saab, Tanios] Ohio State Univ, Div Med Oncol, Dept Internal Med, Coll Med, Columbus, OH 43210 USA. [Mortazavi, Amir; Ling, Yonghua; Martin, Ludmila Katherine; Wei, Lai; Phelps, Mitch A.; Liu, Zhongfa; Harper, Erica J.; Wu, Xin; Deam, Deidre; Monk, J. Paul; Hicks, William J.; Otterson, Gregory A.; Grever, Michael R.; Bekaii-Saab, Tanios] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Ling, Yonghua; Phelps, Mitch A.; Liu, Zhongfa] Ohio State Univ, Columbus, OH 43210 USA. [Wei, Lai] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Phelps, Mitch A.; Liu, Zhongfa] Ohio State Univ, Div Pharmaceut, Coll Pharm, Columbus, OH 43210 USA. [Ivy, S. Percy] NCI, Canc Therapeut Evaluat Program, Rockville, MD 20852 USA. [Zhou, Bing-Sen; Liu, Xiyong; Yen, Yun] City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA. [Grever, Michael R.] Ohio State Univ, Div Hematol, Dept Internal Med, Columbus, OH 43210 USA. RP Bekaii-Saab, T (reprint author), Ohio State Univ, Div Med Oncol, Dept Internal Med, Coll Med, A454 Starling Loving Hall,320 West 10th Ave, Columbus, OH 43210 USA. EM Tanios.Saab@osumc.edu RI Liu, Zhongfa/G-8549-2013; Bekaii-Saab, Tanios/E-2733-2011; Phelps, Mitch/H-3941-2013 OI Liu, Xiyong/0000-0002-0259-3669; Phelps, Mitch/0000-0002-1615-5280 FU National Institutes of Health, National Cancer Institute, Bethesda, U.S.A. (NCI Protocol) [7043]; National Institutes of Health [U01 CA076576] FX We thank all the patients who participated in this trial, as well as the Clinical Trials Office personnel, James Cancer Hospital inpatient nurses and enrolling physicians, for their help in completion of this study. This study was supported by the National Institutes of Health, National Cancer Institute, Bethesda, U.S.A. (NCI Protocol #7043).; This study was supported by the U01 Grant through National Institutes of Health (Grant #U01 CA076576). NR 47 TC 8 Z9 9 U1 0 U2 13 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD JUN PY 2013 VL 31 IS 3 BP 685 EP 695 DI 10.1007/s10637-012-9863-1 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 140MA UT WOS:000318657000021 PM 22847785 ER PT J AU Gordon, MS Rosen, LS Mendelson, D Ramanathan, RK Goldman, J Liu, LL Xu, Y Gerson, SL Anthony, SP Figg, WD Spencer, S Adams, BJ Theuer, CP Leigh, BR Weiss, GJ AF Gordon, Michael S. Rosen, Lee S. Mendelson, David Ramanathan, Ramesh K. Goldman, Jonathan Liu, Lili Xu, Yan Gerson, Stanton L. Anthony, Stephen P. Figg, William D. Spencer, Shawn Adams, Bonne J. Theuer, Charles P. Leigh, Bryan R. Weiss, Glen J. TI A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE TRC102; Base excision repair; Methoxyamine; Pemetrexed; First-in-human; Phase 1 ID CELL LUNG-CANCER; COLON-CANCER; MASS-SPECTROMETRY; METHOXYAMINE; TEMOZOLOMIDE; EFFICACY; PLASMA AB Introduction TRC102 potentiates the activity of cancer therapies that induce base excision repair (BER) including antimetabolite and alkylating agents. TRC102 rapidly and covalently binds to apurinic/apyrimidinic (AP) sites generated during BER, and TRC102-bound DNA causes topoisomerase II-dependent irreversible strand breaks and apoptosis. This study assessed the safety, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of TRC102 alone and in combination with pemetrexed. Purpose Patients with advanced solid tumors received oral TRC102 daily for 4 days. Two weeks later, patients began standard-dose pemetrexed on day 1 in combination with oral TRC102 on days 1 to 4. The pemetrexed-TRC102 combination was repeated every 3 weeks until disease progression. Methods Twenty-eight patients were treated with TRC102 at 15, 30, 60 or 100 mg/m(2)/d. The MTD was exceeded at 100 mg/m(2)/d due to grade 3 anemia in 50 % of patients. TRC102 exposure increased in proportion to dose with a mean t(1/2) of 28 h. A pharmacodynamic assay confirmed that TRC102 binds to pemetrexed-induced AP sites at all doses studied. Stable disease or better was achieved in 15 of 25 patients evaluable for response (60 %), including one patient with recurrent metastatic oropharyngeal carcinoma that expressed high levels of thymidylate synthase, who achieved a partial response and was progression free for 14 months. Conclusions When administered with pemetrexed, the maximum tolerated dose of oral TRC102 is 60 mg/m(2)/d for 4 days. Randomized controlled studies are planned to evaluate the clinical benefit of adding TRC102 to pemetrexed and other agents that induce BER. C1 [Gordon, Michael S.; Mendelson, David] Pinnacle Oncol Hematol, Scottsdale, AZ 85258 USA. [Rosen, Lee S.; Goldman, Jonathan] Univ Calif, Los Angeles Div Hematol Oncol, Santa Monica, CA USA. [Ramanathan, Ramesh K.; Weiss, Glen J.] Scottsdale Healthcare VGPCC TGen, Virginia G Piper Canc Ctr Clin Trials, Scottsdale, AZ USA. [Liu, Lili; Xu, Yan; Gerson, Stanton L.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Liu, Lili; Xu, Yan; Gerson, Stanton L.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Anthony, Stephen P.] Evergreen Hematol & Oncol, Spokane, WA USA. [Figg, William D.; Spencer, Shawn] NCI, SAIC Frederick Inc, Ctr Canc Res, Frederick Natl Lab Canc Res,NIH, Frederick, MD 21701 USA. [Figg, William D.; Spencer, Shawn] NCI, NIH, Frederick, MD 21701 USA. [Adams, Bonne J.; Theuer, Charles P.; Leigh, Bryan R.] TRACON Pharmaceut, San Diego, CA USA. RP Gordon, MS (reprint author), Pinnacle Oncol Hematol, 9055 E Del Camino,Suite 100, Scottsdale, AZ 85258 USA. EM mgordon@azpoh.com RI Figg Sr, William/M-2411-2016 FU TRACON Pharmaceuticals Inc San Diego CA FX This Research was supported by TRACON Pharmaceuticals Inc San Diego CA NR 24 TC 8 Z9 9 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD JUN PY 2013 VL 31 IS 3 BP 714 EP 723 DI 10.1007/s10637-012-9876-9 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 140MA UT WOS:000318657000024 PM 23054206 ER PT J AU Handen, BL Johnson, CR Butter, EM Lecavalier, L Scahill, L Aman, MG McDougle, CJ Arnold, LE Swiezy, NB Sukhodolsky, DG Mulick, JA White, SW Bearss, K Hollway, JA Stigler, KA Dziura, J Yu, S Sacco, K Vitiello, B AF Handen, Benjamin L. Johnson, Cynthia R. Butter, Eric M. Lecavalier, Luc Scahill, Lawrence Aman, Michael G. McDougle, Christopher J. Arnold, L. Eugene Swiezy, Naomi B. Sukhodolsky, Denis G. Mulick, James A. White, Susan W. Bearss, Karen Hollway, Jill A. Stigler, Kimberly A. Dziura, James Yu, Sunkyung Sacco, Kelley Vitiello, Benedetto TI Use of a Direct Observational Measure in a Trial of Risperidone and Parent Training in Children with Pervasive Developmental Disorders SO JOURNAL OF DEVELOPMENTAL AND PHYSICAL DISABILITIES LA English DT Article DE Autism spectrum disorder; Autism; Observational measures; Behavioral interventions; Parent training; Clinical trials ID ABERRANT BEHAVIOR CHECKLIST; RANDOMIZED CLINICAL-TRIAL; HYPERACTIVE-CHILDREN; FUNCTIONAL-ANALYSIS; METHYLPHENIDATE; AUTISM; ADHD; MEDICATION; ATTENTION; CROSSOVER AB A Structured Observational Analog Procedure (SOAP), an analogue measure of parent-child interactions, was used to assess treatment outcome in children with Autism Spectrum Disorder and serious behavior problems. It served as a secondary outcome measure in a 24-week, randomized trial of risperidone (MED; N = 49) versus risperidone plus parent training (COMB; n = 75) (ages 4-13 years). At 24-weeks, there was 28 % reduction in child inappropriate behavior during a Demand Condition (p = .0002) and 12 % increase in compliance to parental requests (p = .004) for the two treatment conditions combined. Parents displayed 64 % greater use of positive reinforcement (p = .001) and fewer repeated requests for compliance (p < .0001). In the analysis of covariance (ANCOVA), COMB parents used significantly more positive reinforcement (p = .01) and fewer restrictive statements (p < .05) than MED parents. The SOAP is sensitive to change in child and parent behavior as a function of risperidone alone and in combination with PMT and can serve as a valuable complement to parent and clinician-based measures. C1 [Handen, Benjamin L.; Johnson, Cynthia R.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Butter, Eric M.; Lecavalier, Luc; Aman, Michael G.; Arnold, L. Eugene; Mulick, James A.; Hollway, Jill A.] Ohio State Univ, Columbus, OH 43210 USA. [Scahill, Lawrence; Bearss, Karen; Dziura, James] Emory Univ, Sch Med, Atlanta, GA USA. [McDougle, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. [Swiezy, Naomi B.; Stigler, Kimberly A.] Indiana Univ Sch Med, Indianapolis, IN USA. [Sukhodolsky, Denis G.] Yale Univ, New Haven, CT USA. [White, Susan W.] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Yu, Sunkyung] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Sacco, Kelley] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Handen, Benjamin L.] Western Psychiat Inst & Clin, Merck Program, Pittsburgh, PA 15203 USA. RP Handen, BL (reprint author), Western Psychiat Inst & Clin, Merck Program, 1011 Bingham St, Pittsburgh, PA 15203 USA. EM handenbl@upmc.edu OI Scahill, Lawrence/0000-0001-5073-1707; Sukhodolsky, Denis/0000-0002-5401-792X FU NIMH NIH HHS [U10 MH066768, U10 MH066764, U10 MH066766] NR 36 TC 4 Z9 4 U1 1 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1056-263X J9 J DEV PHYS DISABIL JI J. Dev. Phys. Disabil. PD JUN PY 2013 VL 25 IS 3 BP 355 EP 371 DI 10.1007/s10882-012-9316-y PG 17 WC Rehabilitation SC Rehabilitation GA 142JP UT WOS:000318793800007 PM 23730123 ER PT J AU Semba, RD Crasto, C Strait, J Sun, K Schaumberg, DA Ferrucci, L AF Semba, R. D. Crasto, C. Strait, J. Sun, K. Schaumberg, D. A. Ferrucci, L. TI Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults SO JOURNAL OF HUMAN HYPERTENSION LA English DT Article ID ARTERIAL STIFFNESS AB Fibroblast growth factor 21 (FGF21), a recently discovered endocrine factor, has an important role in glucose and lipid metabolism and may contribute to the development of atherosclerosis and coronary heart disease. The present cross-sectional study examined the relationship of FGF21 with hypertension in 744 community-dwelling adults who participated in the Baltimore Longitudinal Study of Aging (BLSA). C1 [Semba, R. D.; Crasto, C.; Sun, K.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Strait, J.; Ferrucci, L.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Schaumberg, D. A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. EM rdsemba@jhmi.edu FU NHLBI NIH HHS [R01 HL094507]; NIA NIH HHS [R01 AG027012] NR 12 TC 14 Z9 16 U1 0 U2 9 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 JUN PY 2013 VL 27 IS 6 BP 397 EP 399 DI 10.1038/jhh.2012.52 PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 140XI UT WOS:000318689400011 PM 23190795 ER PT J AU Lopera-Mesa, TM Doumbia, S Chiang, S Zeituni, AE Konate, DS Doumbouya, M Keita, AS Stepniewska, K Traore, K Diakite, SAS Ndiaye, D Sa, JM Anderson, JM Fay, MP Long, CA Diakite, M Fairhurst, RM AF Lopera-Mesa, Tatiana M. Doumbia, Saibou Chiang, Serena Zeituni, Amir E. Konate, Drissa S. Doumbouya, Mory Keita, Abdoul S. Stepniewska, Kasia Traore, Karim Diakite, Seidina A. S. Ndiaye, Daouda Sa, Juliana M. Anderson, Jennifer M. Fay, Michael P. Long, Carole A. Diakite, Mahamadou Fairhurst, Rick M. TI Plasmodium falciparum Clearance Rates in Response to Artesunate in Malian Children With Malaria: Effect of Acquired Immunity SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Plasmodium falciparum; malaria; artemisinin; parasite clearance; antimalarial immunity; Mali ID PARASITE CLEARANCE; ARTEMISININ RESISTANCE; INFECTED ERYTHROCYTES; MICROVASCULAR SEQUESTRATION; AFRICAN CHILDREN; WESTERN CAMBODIA; RANDOMIZED-TRIAL; SURFACE; SUSCEPTIBILITY; CHLOROQUINE AB Background. Artemisinin resistance, a long parasite clearance half-life in response to artemisinin, has been described in patients with Plasmodium falciparum malaria in southeast Asia. Few baseline half-lives have been reported from Africa, where artemisinins were recently introduced. Methods. We treated P. falciparum malaria in 215 Malian children aged 0.5-15 years with artesunate (0, 24, 48 hours) and amodiaquine (72, 96, 120 hours). We estimated half-life by measuring parasite density every 6 hours until undetectable and evaluated the effects of age, sex, ethnicity, and red blood cell (RBC) polymorphisms on half-life. We quantified the proportion of parasitized RBCs recognized by autologous immunoglobulin G (IgG). Results. The geometric mean half-life was 1.9 hours (95% confidence interval, 1.8-2.0) and did not correlate with parasite ex vivo susceptibility to artemisinins. In a linear model accounting for host factors, half-life decreased by 4.1 minutes for every 1-year increase in age. The proportion of parasitized RBCs recognized by IgG correlated inversely with half-life (r = -0.475; P = .0006). Conclusions. Parasite clearance in response to artesunate is faster in Mali than in southeast Asia. IgG responses to parasitized RBCs shorten half-life and may influence this parameter in areas where age is not an adequate surrogate of immunity and correlates of parasite-clearing immunity have not been identified. Clinical Trials Registration. NCT00669084. C1 [Lopera-Mesa, Tatiana M.; Chiang, Serena; Zeituni, Amir E.; Sa, Juliana M.; Anderson, Jennifer M.; Long, Carole A.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Doumbia, Saibou; Konate, Drissa S.; Doumbouya, Mory; Keita, Abdoul S.; Traore, Karim; Diakite, Seidina A. S.; Diakite, Mahamadou] Univ Bamako, Fac Med Pharm & Odontostomatol, Malaria Res & Training Ctr, Bamako, Mali. [Stepniewska, Kasia] Univ Oxford, Nuffield Dept Clin Med, Worldwide Antimalarial Resistance Network, Oxford OX1 2JD, England. [Stepniewska, Kasia] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford OX1 2JD, England. [Ndiaye, Daouda] Cheikh Anta Diop Univ, Fac Med & Pharm, Parasitol Lab, Dakar, Senegal. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Rm 3E-10A, Rockville, MD 20852 USA. EM rfairhurst@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 43 TC 28 Z9 28 U1 0 U2 9 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 JUN 1 PY 2013 VL 207 IS 11 BP 1655 EP 1663 DI 10.1093/infdis/jit082 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 139EA UT WOS:000318563200006 PM 23448727 ER PT J AU Tobian, AAR Grabowski, MK Kigozi, G Redd, AD Eaton, KP Serwadda, D Cornish, TC Nalugoda, F Watya, S Buwembo, D Nkale, J Wawer, MJ Quinn, TC Gray, RH AF Tobian, Aaron A. R. Grabowski, Mary K. Kigozi, Godfrey Redd, Andrew D. Eaton, Kevin P. Serwadda, David Cornish, Toby C. Nalugoda, Fred Watya, Stephen Buwembo, Denis Nkale, James Wawer, Maria J. Quinn, Thomas C. Gray, Ronald H. TI Human Papillomavirus Clearance Among Males Is Associated With HIV Acquisition and Increased Dendritic Cell Density in the Foreskin SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human papillomavirus (HPV); male circumcision; HIV; AIDS; Uganda; penile cancer; cervical cancer; sexually transmitted infections ID SIMPLEX-VIRUS TYPE-2; RISK HUMAN-PAPILLOMAVIRUS; MALE CIRCUMCISION; RANDOMIZED-TRIAL; NEGATIVE MEN; HETEROSEXUAL COUPLES; NATURAL-HISTORY; FEMALE PARTNERS; INFECTED MEN; UGANDA AB Methods. A case-control analysis nested within a male circumcision trial was conducted. Cases consisted of 44 male HIV seroconverters, and controls were 787 males who were persistently negative for HIV. The Roche HPV Linear Array Genotype Test detected high-risk HPV (HR-HPV) and low-risk HPV (LR-HPV) genotypes. Generalized estimating equations logistic regression was used to estimate adjusted odds ratios (aORs) of HIV seroconversion. In addition, densities of CD1a(+) dendritic cells, CD4(+) T cells, and CD8(+) T cells were measured using immunohistochemistry analysis in foreskins of 79 males randomly selected from participants in the circumcision trial. Results. HR-HPV or LR-HPV acquisition was not significantly associated with HIV seroconversion, after adjustment for sexual behaviors. However, HR-HPV and LR-HPV clearance was significantly associated with HIV seroconversion (aOR, 3.25 [95% confidence interval {CI}, 1.11-9.55] and 3.18 [95% CI, 1.14-8.90], respectively). The odds of HIV seroconversion increased with increasing number of HPV genotypes cleared (P < .001, by the test for trend). The median CD1a(+) dendritic cell density in the foreskin epidermis was significantly higher among males who cleared HPV (72.0 cells/mm(2) [interquartile range {IQR}, 29.4-138.3 cells/mm(2)]), compared with males who were persistently negative for HPV (32.1 cells/mm(2) [IQR, 3.1-96.2 cells/mm(2)]; P = .047), and increased progressively with the number of HPV genotypes cleared (P = .05). Conclusions. HPV clearance was associated with subsequent HIV seroconversion and also with increased epidermal dendritic cell density, which potentially mediates HIV seroconversion. C1 [Tobian, Aaron A. R.; Cornish, Toby C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Eaton, Kevin P.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Grabowski, Mary K.; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Redd, Andrew D.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Tobian, Aaron A. R.; Kigozi, Godfrey; Serwadda, David; Nalugoda, Fred; Buwembo, Denis; Nkale, James; Wawer, Maria J.; Gray, Ronald H.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Watya, Stephen] Makerere Univ, Dept Urol, Kampala, Uganda. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu RI Cornish, Toby/A-4394-2015 OI Cornish, Toby/0000-0002-1902-2109 FU National Institute of Allergy and Infectious Diseases (NIAID), NIH [U1AI5117I, 1K23AI093152-01A1, U01-AI-068613, 3U01-AI075115-03S1]; Fogarty International Center [5D43TW001508, 2D43TW000010-19-AITRP]; NIH [1K23AI093152-01A1, R01AI087409-01A1]; Doris Duke Charitable Foundation [22006.02]; Johns Hopkins University FX This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID), NIH (grants U1AI5117I, 1K23AI093152-01A1, U01-AI-068613, and 3U01-AI075115-03S1); the Division of Intramural Research, NIAID, NIH (for laboratory support); and The Fogarty International Center (grants 5D43TW001508 and 2D43TW000010-19-AITRP for training staff to collect specimens and perform interviews). A. A. R. T. was supported by the NIH (grants 1K23AI093152-01A1 and R01AI087409-01A1), a Doris Duke Charitable Foundation Clinician Scientist Development Award (22006.02), and a Johns Hopkins University Clinician Scientist Award. NR 38 TC 9 Z9 9 U1 0 U2 11 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 JUN 1 PY 2013 VL 207 IS 11 BP 1713 EP 1722 DI 10.1093/infdis/jit035 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 139EA UT WOS:000318563200012 PM 23345339 ER PT J AU Karron, RA Thumar, B Schappell, E Buchholz, UJ Collins, PL AF Karron, Ruth A. Thumar, Bhagvanji Schappell, Elizabeth Buchholz, Ursula J. Collins, Peter L. TI Attenuation of Live Respiratory Syncytial Virus Vaccines Is Associated With Reductions in Levels of Nasal Cytokines SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE respiratory syncytial virus; live-attenuated vaccine; cytokine ID MONOCLONAL-ANTIBODY; PRIMARY INFECTION; REVERSE GENETICS; BRONCHIOLITIS; CHILDREN; INFANTS; PATHOGENESIS; CANDIDATE; RESPONSES; PROTEIN AB Background. Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract illness (LRTI) in children. Several promising live-attenuated RSV vaccines are in development. Defining additional markers of attenuation could enhance clinical trials. Methods. We used clinical data, virologic data, and nasal wash (NW) specimens from 20 RSV-naive children enrolled in studies of 4 live-attenuated RSV vaccines. Seven received minimally attenuated cpts248/955 or cpts530/1009 (group 1), 6 received moderately attenuated cpts248/404 (group 2), and 7 received highly attenuated rA2cp248/404/1030/delta SH (group 3). NW specimens were tested for cytokines and chemokines via an electrochemiluminescence biosensor assay. Results. Group 1 exhibited 1 instance of LRTI and significantly higher rates of fever than groups 2 or 3; there were no significant differences in peak titers of vaccine virus in NW specimens. In contrast, levels of interferon gamma, interleukin 1 beta, interleukin 2, interleukin 6, and interleukin 13 were significantly greater in NW specimens from group 1, compared with those from group 3. Maximum increases in levels of most cytokines occurred after peak viral replication but coincided with clinical illness. Conclusions. Substantial increases in proinflammatory, antiinflammatory, T-helper 1, T-helper 2, and regulatory cytokines were detected in children who received minimally attenuated live RSV vaccines but not in children who received highly attenuated vaccines. Levels of cytokines in NW specimens may be useful biomarkers of attenuation for live RSV vaccines. C1 [Karron, Ruth A.; Thumar, Bhagvanji; Schappell, Elizabeth] NIAID, Ctr Immunizat Res, Dept Int Hlth, Johns Hopkins Bloomberg Sch Publ Hlth,NIH, Baltimore, MD USA. [Buchholz, Ursula J.; Collins, Peter L.] NIAID, Lab Infect Dis, NIH, Baltimore, MD USA. RP Karron, RA (reprint author), 624 N Broadway 217, Baltimore, MD 21205 USA. EM rkarron@jhsph.edu OI Schappell, Elizaeth/0000-0003-2142-5318 FU National Institutes of Health (NIH) [N01-AI-15444, HHSN272200900010C]; Intramural Research Program, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the National Institutes of Health (NIH; contracts N01-AI-15444 and HHSN272200900010C). U. J. B. and P. L. C. were supported by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, NIH. NR 27 TC 7 Z9 7 U1 1 U2 6 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 JUN 1 PY 2013 VL 207 IS 11 BP 1773 EP 1779 DI 10.1093/infdis/jit089 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 139EA UT WOS:000318563200018 PM 23482643 ER PT J AU Simon-Loriere, E Holmes, EC AF Simon-Loriere, Etienne Holmes, Edward C. TI Gene Duplication Is Infrequent in the Recent Evolutionary History of RNA Viruses SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE RNA virus; gene duplication; genome size; genetic redundancy ID COMPLETE NUCLEOTIDE-SEQUENCE; EPHEMERAL FEVER RHABDOVIRUS; MOUTH-DISEASE VIRUS; OPEN READING FRAMES; FAMILY CLOSTEROVIRIDAE; GENOME ORGANIZATION; GLYCOPROTEIN GENES; MOLECULAR ANALYSIS; SUBGENOMIC RNAS; YELLOWS-VIRUS AB Gene duplication generates genetic novelty and redundancy and is a major mechanism of evolutionary change in bacteria and eukaryotes. To date, however, gene duplication has been reported only rarely in RNA viruses. Using a conservative BLAST approach we systematically screened for the presence of duplicated (i.e., paralogous) proteins in all RNA viruses for which full genome sequences are publicly available. Strikingly, we found only nine significantly supported cases of gene duplication, two of which are newly described here-in the 25 and 26 kDa proteins of Beet necrotic yellow vein virus (genus Benyvirus) and in the U1 and U2 proteins of Wongabel virus (family Rhabdoviridae). Hence, gene duplication has occurred at a far lower frequency in the recent evolutionary history of RNA viruses than in other organisms. Although the rapidity of RNA virus evolution means that older gene duplication events will be difficult to detect through sequence-based analyses alone, it is likely that specific features of RNA virus biology, and particularly intrinsic constraints on genome size, reduce the likelihood of the fixation and maintenance of duplicated genes. C1 [Simon-Loriere, Etienne] Inst Pasteur, Unite Genet Fonct Malad Infect, Paris, France. [Simon-Loriere, Etienne] CNRS, URA CNRS3012, Paris, France. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, 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 Holmes, EC (reprint author), Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. EM edward.holmes@sydney.edu.au OI Holmes, Edward/0000-0001-9596-3552; , Etienne/0000-0001-8420-7743 FU NHMRC Australia Fellowship FX E.C.H. acknowledges support from an NHMRC Australia Fellowship. NR 60 TC 7 Z9 7 U1 0 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD JUN PY 2013 VL 30 IS 6 BP 1263 EP 1269 DI 10.1093/molbev/mst044 PG 7 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 142QL UT WOS:000318812000004 PM 23486612 ER PT J AU Jayasekara, PS Phan, K Tosh, DK Kumar, TS Moss, SM Zhang, GF Barchi, JJ Gao, ZG Jacobson, KA AF Jayasekara, P. Suresh Khai Phan Tosh, Dilip K. Kumar, T. Santhosh Moss, Steven M. Zhang, Guofeng Barchi, Joseph J., Jr. Gao, Zhan-Guo Jacobson, Kenneth A. TI Modulation of G protein-coupled adenosine receptors by strategically functionalized agonists and antagonists immobilized on gold nanoparticles SO PURINERGIC SIGNALLING LA English DT Article DE G protein-coupled receptor; Nanoparticle; Nucleoside; Adenosine; Radioligand binding ID QUANTUM DOTS; TUMOR-GROWTH; CANCER; TARGETS; CELLS; LIGANDS; DELIVERY; SIZE AB Gold nanoparticles (AuNPs) allow the tuning of pharmacokinetic and pharmacodynamic properties by active or passive targeting of drugs for cancer and other diseases. We have functionalized gold nanoparticles by tethering specific ligands, agonists and antagonists, of adenosine receptors (ARs) to the gold surface as models for cell surface interactions with G protein-coupled receptors (GPCRs). The AuNP conjugates with chain-extended AR ligands alone (PEGylated nucleosides and nonnucleosides, anchored to the Au via thioctic acid) were found to be insoluble in water due to hydrophobic entities in the ligand. Therefore, we added a second, biologically inactive pendant moiety to increase the water solubility, consisting of a PEGylated chain terminating in a carboxylic or phosphate group. The purity and stability of the immobilized biologically active ligand were examined by ultrafiltration and HPLC. Pharmacological receptor binding studies on these GPCR ligand-derivatized AuNPs (2-5 nm in diameter), performed using membranes of mammalian cells stably expressing human A(1), A(2A), and A(3)ARs, showed that the desired selectivity was retained with K (i) values (nanomolar) of A(3)AR agonist 21b and A(2A)AR antagonists 24 and 26a of 14 (A(3)), 34 (A(2A)), and 69 (A(2A)), respectively. The corresponding monomers displayed K (i) values of 37, 61, and 1,420 nM, respectively. In conclusion, we have synthesized stable, water-soluble AuNP derivatives of tethered A(3) and A(2A)AR ligands that retain the biological properties of their monomeric ligands and are intended for therapeutic and imaging applications. This is the first prototypical application to gold carriers of small molecule (nonpeptide) GPCR ligands, which are under investigation for treatment of cancer and inflammatory diseases. C1 [Jayasekara, P. Suresh; Khai Phan; Tosh, Dilip K.; Kumar, T. Santhosh; Moss, Steven M.; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Zhang, Guofeng] NIBIB, Biomed Engn & Phys Sci Shared Resource, NIH, Bethesda, MD 20892 USA. [Barchi, Joseph J., Jr.] Frederick Natl Lab Canc Res, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Barchi Jr., Joseph/N-3784-2014 OI Jacobson, Kenneth/0000-0001-8104-1493; FU NIDDK; NCI, National Institutes of Health FX We thank Dr. Noel Whittaker (NIDDK) for MS measurements. This research was supported by the Intramural Research Programs of NIDDK and NCI, National Institutes of Health. NR 43 TC 2 Z9 2 U1 3 U2 49 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD JUN PY 2013 VL 9 IS 2 BP 183 EP 198 DI 10.1007/s11302-012-9338-z PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 139CT UT WOS:000318559800006 PM 23179047 ER PT J AU Wei, Q Costanzi, S Balasubramanian, R Gao, ZG Jacobson, KA AF Wei, Qiang Costanzi, Stefano Balasubramanian, Ramachandran Gao, Zhan-Guo Jacobson, Kenneth A. TI A(2B) adenosine receptor blockade inhibits growth of prostate cancer cells SO PURINERGIC SIGNALLING LA English DT Article DE Prostate cancer; Cancer; Adenosine receptor; A(2B); G protein-coupled receptor (GPCR); Cell proliferation ID PROTEIN-COUPLED RECEPTORS; EXPRESSION; THERAPY; INVOLVEMENT; APOPTOSIS; TARGETS; TUMORS AB The role of the A(2B) adenosine receptor (AR) in prostate cell death and growth was studied. The A(2B) AR gene expression quantified by real-time quantitative RT-PCR and Western blot analysis was the highest among four AR subtypes (A(1), A(2A), A(2B), and A(3)) in all three commonly used prostate cancer cell lines, PC-3, DU145, and LNCaP. We explored the function of the A(2B) AR using PC-3 cells as a model. The A(2B) AR was visualized in PC-3 cells by laser confocal microscopy. The nonselective A(2B) AR agonist NECA and the selective A(2B) AR agonist BAY60-6583, but not the A(2A) AR agonist CGS21680, concentration-dependently induced adenosine 3',5'-cyclic monophosphate (cyclic AMP) accumulation. NECA diminished lactate dehydrogenase (LDH) release, TNF-alpha-induced increase of caspase-3 activity, and cycloheximide (CHX)-induced morphological changes typical of apoptosis in PC-3 cells, which were blocked by a selective A(2B) AR antagonist PSB603. NECA-induced proliferation of PC-3 cells was diminished by siRNA specific for the A(2B) AR. The selective A(2B) AR antagonist PSB603 was shown to inhibit cell growth in all three cell lines. Thus, A(2B) AR blockade inhibits growth of prostate cancer cells, suggesting selective A(2B) AR antagonists as potential novel therapeutics. C1 [Wei, Qiang; Balasubramanian, Ramachandran; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Wei, Qiang] Southern Med Univ, Nan Fang Hosp, Dept Urol, Guangzhou 510515, Guangdong, Peoples R China. [Costanzi, Stefano] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Costanzi, Stefano/G-8990-2013; Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Costanzi, Stefano/0000-0003-3183-7332 FU NIDDK Intramural Research Program, National Institutes of Health, Bethesda, MD, USA; National Natural Science Foundation of China [30940072]; Guangdong Province Science and Technology Program [2012B031800263]; Nanfang Hospital, Southern Medical University, Guangzhou, China FX This study was supported by the NIDDK Intramural Research Program, National Institutes of Health, Bethesda, MD, USA; the National Natural Science Foundation of China (no.: 30940072); Guangdong Province Science and Technology Program (2012B031800263); and Nanfang Hospital, Southern Medical University, Guangzhou, China. The authors thank Dr. Yafang Hu (Children's National Medical Center, Washington, DC, USA) for assistance in confocal microscopy experiments. We thank Prof. Ad IJzerman (Leiden University, The Netherlands) for providing LUF6210 (BAY60-6583). NR 21 TC 24 Z9 25 U1 0 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD JUN PY 2013 VL 9 IS 2 BP 271 EP 280 DI 10.1007/s11302-012-9350-3 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 139CT UT WOS:000318559800014 PM 23315335 ER PT J AU Kane, AM DeFrancesco, TC Boyle, MC Malarkey, DE Ritchey, JW Atkins, CE Cullen, JM Kornegay, JN Keene, BW AF Kane, A. M. DeFrancesco, T. C. Boyle, M. C. Malarkey, D. E. Ritchey, J. W. Atkins, C. E. Cullen, J. M. Kornegay, J. N. Keene, B. W. TI Cardiac structure and function in female carrier's of a canine model of Duchenne muscular dystrophy SO RESEARCH IN VETERINARY SCIENCE LA English DT Article DE Cardiomyopathy; Carrier; GRMD; Duchenne muscular dystrophy ID CARDIOMYOPATHY; ABNORMALITIES; DOGS; ELECTROCARDIOGRAM; ECHOCARDIOGRAPHY; MUSCLE; VECTORCARDIOGRAM; CONDUCTION; CHILDREN; SKELETAL AB This investigation tested the hypothesis that carriers of golden retriever muscular dystrophy (GRMD), a genetically homologous condition of Duchenne muscular dystrophy (DMD), have quantifiable abnormalities in myocardial function, structure, or cardiac rhythm. Eleven GRMD carriers and four matched controls had cardiac evaluations and postmortem examinations. 24-h ECG Holter monitoring disclosed ventricular ectopy in 10 of 11 carriers and 2 of 4 controls. Conventional echocardiography failed to demonstrate significant differences between carriers and controls in systolic function. All carriers had multi-focal, minimal to marked myofiber necrosis, fibrosis, mineralization, inflammation, and/or fatty change in their hearts. Immunohistochemistry revealed a mosaic dystrophin deficiency in scattered cardiac myofibers in all carriers. No controls had cardiac histologic lesions; all had uniform dystrophin staining. Despite cardiac mosaic dystrophin expression and degenerative cardiac lesions, GRMD carriers at up to 3 years of age could not be distinguished statistically from normal controls by echocardiography or 24-h Holter monitoring. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Kane, A. M.] Angell Anim Med Ctr, Jamaica Plain, MA 02130 USA. [Kane, A. M.; DeFrancesco, T. C.; Atkins, C. E.; Keene, B. W.] N Carolina State Univ, Dept Clin Sci, Coll Vet Med, Raleigh, NC 27607 USA. [Cullen, J. M.] N Carolina State Univ, Coll Vet Med, Dept Populat Hlth & Pathobiol, Raleigh, NC 27607 USA. [Boyle, M. C.; Malarkey, D. E.] Natl Inst Environm Hlth Sci, Cellular & Mol Pathol Branch, Res Triangle Pk, NC USA. [Ritchey, J. W.] Oklahoma State Univ, Coll Vet Med, Dept Vet Pathobiol, Stillwater, OK 74078 USA. [Kornegay, J. N.] Texas A&M Univ, Coll Vet Med, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. RP DeFrancesco, TC (reprint author), N Carolina State Univ, Dept Clin Sci, Coll Vet Med, 1052 William Moore Dr, Raleigh, NC 27607 USA. EM teresa_defrancesco@ncsu.edu NR 46 TC 4 Z9 4 U1 2 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0034-5288 J9 RES VET SCI JI Res. Vet. Sci. PD JUN PY 2013 VL 94 IS 3 BP 610 EP 617 DI 10.1016/j.rvsc.2012.09.027 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 136RH UT WOS:000318380600041 PM 23231955 ER PT J AU Reilly, CM Bruner, DW Mitchell, SA Minasian, LM Basch, E Dueck, AC Cella, D Reeve, BB AF Reilly, Carolyn Miller Bruner, Deborah Watkins Mitchell, Sandra A. Minasian, Lori M. Basch, Ethan Dueck, Amylou C. Cella, David Reeve, Bryce B. TI A literature synthesis of symptom prevalence and severity in persons receiving active cancer treatment SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Cancer; Symptoms; Systematic review ID STEM-CELL TRANSPLANTATION; QUALITY-OF-LIFE; MULTIPLE SYMPTOMS; BREAST-CANCER; LUNG-CANCER; DISTRESSING SYMPTOMS; COLORECTAL-CANCER; JAPANESE VERSION; PROSTATE-CANCER; VALIDATION AB Patients with cancer experience acute and chronic symptoms caused by their underlying disease or by the treatment. While numerous studies have examined the impact of various treatments on symptoms experienced by cancer patients, there are inconsistencies regarding the symptoms measured and reported in treatment trials. This article presents a systematic review of the research literature of the prevalence and severity of symptoms in patients undergoing cancer treatment. A systematic search for studies of persons receiving active cancer treatment was performed with the search terms of "multiple symptoms" and "cancer" for studies involving patients over the age of 18 years and published in English during the years 2001 to 2011. Search outputs were reviewed independently by seven authors, resulting in the synthesis of 21 studies meeting criteria for generation of an Evidence Table reporting symptom prevalence and severity ratings. Data were extracted from 21 multi-national studies to develop a pooled sample of 4,067 cancer patients in whom the prevalence and severity of individual symptoms was reported. In total, the pooled sample across the 21 studies was comprised of 62 % female, with a mean age of 58 years (range 18 to 97 years). A majority (62 %) of these studies assessed symptoms in homogeneous samples with respect to tumor site (predominantly breast and lung cancer), while 38 % of the included studies utilized samples with mixed diagnoses and treatment regimens. Eighteen instruments and structured interviews were including those measuring single symptoms, multi-symptom inventories, and single symptom items drawn from HRQOL or health status measures. The MD Anderson Symptom Inventory was the most commonly used instrument in the studies analyzed (n = 9 studies; 43 %), while the Functional Assessment of Cancer Therapy, Hospital Anxiety and Depression Subscale, Medical Outcomes Survey Short Form-36, and Symptom Distress Scale were each employed in two studies. Forty-seven symptoms were identified across the 21 studies which were then categorized into 17 logical groupings. Symptom prevalence and severity were calculated across the entire cohort and also based upon sample sizes in which the symptoms were measured providing the ability to rank symptoms. Symptoms are prevalent and severe among patients with cancer. Therefore, any clinical study seeking to evaluate the impact of treatment on patients should consider including measurement of symptoms. This study demonstrates that a discrete set of symptoms is common across cancer types. This set may serve as the basis for defining a "core" set of symptoms to be recommended for elicitation across cancer clinical trials, particularly among patients with advanced disease. C1 [Reilly, Carolyn Miller; Bruner, Deborah Watkins] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Atlanta, GA 30322 USA. [Mitchell, Sandra A.; Minasian, Lori M.] NCI, Bethesda, MD 20892 USA. [Basch, Ethan; Reeve, Bryce B.] Univ N Carolina, Chapel Hill, NC USA. [Dueck, Amylou C.] Mayo Clin, Scottsdale, AZ USA. [Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Reilly, CM (reprint author), Emory Univ, Nell Hodgson Woodruff Sch Nursing, 1520 Clifton Rd,NE 254, Atlanta, GA 30322 USA. EM carolyn.reilly@emory.edu OI Reilly, Carolyn/0000-0003-1641-1747 FU National Cancer Institute FX The analyses reported in this paper were conducted in conjunction with preparations for an NCI Clinical Trials Planning Meeting Building Bridges: The Identification of Core Symptom and Health-Related Quality of Life Domains for Use in Cancer Research, convened by the National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee. Support from the National Cancer Institute is gratefully acknowledged. The authors have no conflicts to declare, had full control of all primary data, and agree to allow the journal to review the data if requested. NR 61 TC 37 Z9 38 U1 0 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD JUN PY 2013 VL 21 IS 6 BP 1525 EP 1550 DI 10.1007/s00520-012-1688-0 PG 26 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 138OA UT WOS:000318516700003 PM 23314601 ER PT J AU Persky, S Kaphingst, KA Allen, VC Senay, I AF Persky, Susan Kaphingst, Kimberly A. Allen, Vincent C., Jr. Senay, Ibrahim TI Effects of Patient-Provider Race Concordance and Smoking Status on Lung Cancer Risk Perception Accuracy Among African-Americans SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Lung cancer; Risk perception; Race concordance; Smoking; Virtual reality ID VIRTUAL ENVIRONMENT TECHNOLOGY; MEDICAL DECISION-MAKING; PHYSICIAN COMMUNICATION; RACIAL DISPARITIES; HEALTH-CARE; CIGARETTE SMOKERS; BIAS; TRUST; PREVENTION; TOOL AB Communication of lung cancer risk information between providers and African-American patients occurs in a context marked by race-based health disparities. A controlled experiment assessed whether perceived physician race influenced African-American patients' (n = 127) risk perception accuracy following the provision of objective lung cancer risk information. Participants interacted with a virtual reality-based, simulated physician who provided personalized cancer risk information. Participants who interacted with a racially discordant virtual doctor were less accurate in their risk perceptions at post-test than those who interacted with a concordant virtual doctor, F(1,94) = 4.02, p = .048. This effect was amplified among current smokers. Effects were not mediated by trust in the provider, engagement with the health care system, or attention during the encounter. The current study demonstrates that African-American patients' perceptions of a doctor's race are sufficient to independently impact their processing of lung cancer risk information. C1 [Persky, Susan] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Kaphingst, Kimberly A.] Washington Univ, St Louis, MO USA. [Allen, Vincent C., Jr.] Univ Calif Los Angeles, Los Angeles, CA USA. [Senay, Ibrahim] Zirve Univ, Gaziantep, Turkey. RP Persky, S (reprint author), NHGRI, Social & Behav Res Branch, 31 Ctr Dr,Rm B1B36, Bethesda, MD 20892 USA. EM perskys@mail.nih.gov FU Intramural NIH HHS [ZIA HG200383-01, ZID HG200384-01] NR 62 TC 5 Z9 5 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD JUN PY 2013 VL 45 IS 3 BP 308 EP 317 DI 10.1007/s12160-013-9475-9 PG 10 WC Psychology, Multidisciplinary SC Psychology GA 137OM UT WOS:000318445300008 PM 23389688 ER PT J AU Edwards, FL Yedjou, CG Tchounwou, PB AF Edwards, Falicia L. Yedjou, Clement G. Tchounwou, Paul B. TI Involvement of oxidative stress in methyl parathion and parathion-induced toxicity and genotoxicity to human liver carcinoma (HepG2) cells SO ENVIRONMENTAL TOXICOLOGY LA English DT Article DE methyl parathion; parathion; cytotoxicity; oxidative stress; DNA damage; HepG2 cells ID PESTICIDE-MANUFACTURING WORKERS; DNA-DAMAGE; ARSENIC TRIOXIDE; VITAMIN-E; LIPID-PEROXIDATION; COMET ASSAY; DIAZINON; ORGANOPHOSPHORUS; RATS; MALATHION AB Methyl parathion (C8H10NO5PS) and parathion (C10H14NO5PS) are both organophosphate insecticides (OPI) widely used for household and agricultural applications. They are known for their ability to irreversibly inhibit acetylcholinesterase which often leads to a profound effect on the nervous system of exposed organisms. Many recently published studies have indicated that human exposure to OPI may be associated with neurologic, hematopoietic, cardiovascular, and reproductive adverse effects. Studies have also linked OPI exposure to a number of degenerative diseases including Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. Also, oxidative stress (OS) has been reported as a possible mechanism of OPI toxicity in humans. Hence, the aim of the present investigation was to use human liver carcinoma (HepG2) cells as a test model to evaluate the role of OS in methyl parathion- and parathion-induced toxicity. To achieve this goal, we performed the MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay for cell viability, lipid peroxidation assay for malondialdehyde (MDA) production, and Comet assay for DNA damage, respectively. Results from MTT assay indicated that methyl parathion and parathion gradually reduce the viability of HepG2 cells in a dose-dependent manner, showing 48 h-LD50 values of 26.20 mM and 23.58 mM, respectively. Lipid peroxidation assay resulted in a significant increase (P < 0.05) of MDA level in methyl parathion- and parathion-treated HepG2 cells compared with controls, suggesting that OS plays a key role in OPI-induced toxicity. Comet assay indicated a significant increase in genotoxicity at higher concentrations of OPI exposure. Overall, we found that methyl-parathion is slightly less toxic than parathion to HepG2 cells. The cytotoxic effect of these OPI was found to be associated, at least in part, with oxidative cell/tissue damage. (c) 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013. C1 [Edwards, Falicia L.] Texas A&M Univ, Dept Biol & Environm Sci, Commerce, TX 75429 USA. [Edwards, Falicia L.; Yedjou, Clement G.; Tchounwou, Paul B.] Jackson State Univ, Mol Toxicol Res Lab, NIH Ctr Environm Hlth, Coll Sci Engn & Technol, Jackson, MS 39217 USA. RP Tchounwou, PB (reprint author), Jackson State Univ, Mol Toxicol Res Lab, NIH Ctr Environm Hlth, Coll Sci Engn & Technol, 14000 Lynch St,POB 18540, Jackson, MS 39217 USA. EM paul.b.tchounwou@jsums.edu FU National Institutes of Health (through the RCMI Center for Environmental Health) [5G12RR013459-13]; Department of the Army Cooperative Agreement (at Jackson State University) [W912HZ-04-2-0002] FX Contract grant sponsor: National Institutes of Health (through the RCMI Center for Environmental Health); Contract grant number: 5G12RR013459-13; Contract grant sponsor: Department of the Army Cooperative Agreement (at Jackson State University); Contract grant number: W912HZ-04-2-0002 NR 44 TC 10 Z9 11 U1 4 U2 42 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-4081 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD JUN PY 2013 VL 28 IS 6 BP 342 EP 348 DI 10.1002/tox.20725 PG 7 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA 139ZL UT WOS:000318623700006 PM 21544925 ER PT J AU Weisbrod, AB Zhang, LS Jain, M Barak, S Quezado, MM Kebebew, E AF Weisbrod, Allison B. Zhang, Lisa Jain, Meenu Barak, Stephanie Quezado, Martha M. Kebebew, Electron TI Altered PTEN, ATRX, CHGA, CHGB, and TP53 Expression Are Associated with Aggressive VHL-Associated Pancreatic Neuroendocrine Tumors SO HORMONES & CANCER LA English DT Article ID RENAL-CELL CARCINOMA; REGION-SPECIFIC ANTIBODIES; CHROMOGRANIN-A; ENDOCRINE-TUMORS; SECRETOGRANIN-II; MTOR PATHWAY; GENE-EXPRESSION; BREAST-CANCER; ISLET CELLS; P53 PROTEIN AB Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which 8-17 % of germline mutation carriers develop pancreatic neuroendocrine tumors (PNETs). There is limited data on prognostic markers for PNETs other than Ki-67, which is included in the World Health Organization classification system. Recently, specific genes and pathways have been identified by whole exome sequencing which may be involved in the tumorigenesis of PNETs and may be markers of disease aggressiveness. The objective of this study was to identify molecular markers of aggressive disease in VHL-associated PNETs. The protein expression of eight genes (PTEN, CHGA, CHGB, ATRX, DAXX, CC-3, VEGF, and TP53) was analyzed in PNETs by immunohistochemistry and compared to clinical data, VHL genotype, functional imaging results, and pathologic findings. Subcellular distribution of phosphatase and tensin (PTEN), chromogranin A (CHGA), and alpha thalassemia/mental retardation syndrome X-linked (ATRX) were significantly different by WHO classifications (p a parts per thousand currency signaEuro parts per thousand 0.05). There was decreased PTEN nuclear to cytoplasmic ratio (p < 0.01) and decreased CHGA nuclear expression (p = 0.03) in malignant samples as compared to benign. Lower cytoplasmic chromogranin B (CHGB) expression (p = 0.03) was associated with malignant tumors and metastasis. Higher nuclear expression of PTEN was associated with VHL mutations in exon 3 (p = 0.04). Higher PTEN and CHGB expression was associated with higher FDG-PET avidity (p < 0.05). Cytoplasmic expression of CC-3 was associated with higher serum chromogranin A levels (rho = 0.72, p = 0.02). Lastly, greater cytoplasmic expression of p53 was associated with metastasis. Our findings suggest that altered PTEN, ATRX, CHGA, and CHGB expression are associated with aggressive PNET phenotype in VHL and may serve as useful adjunct prognostic markers to Ki-67 in PNETs. C1 [Weisbrod, Allison B.; Zhang, Lisa; Jain, Meenu; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Barak, Stephanie; Quezado, Martha M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 67 TC 7 Z9 7 U1 1 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 J9 HORM CANCER-US JI Horm. Cancer PD JUN PY 2013 VL 4 IS 3 BP 165 EP 175 DI 10.1007/s12672-013-0134-1 PG 11 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 138NB UT WOS:000318514200005 PM 23361940 ER PT J AU Schneider, L Houdayer, E Bai, O Hallett, M AF Schneider, Logan Houdayer, Elise Bai, Ou Hallett, Mark TI What We Think before a Voluntary Movement SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID ELECTRICAL-STIMULATION; CONSCIOUS INTENTION; CORTICAL-NEURONS; FREE WILL; TIME; PREDICTION; BRAIN; ARM; EXPERIENCE; ENSEMBLES AB A central feature of voluntary movement is the sense of volition, but when this sense arises in the course of movement formulation and execution is not clear. Many studies have explored how the brain might be actively preparing movement before the sense of volition; however, because the timing of the sense of volition has depended on subjective and retrospective judgments, these findings are still regarded with a degree of scepticism. EEG events such as beta event-related desynchronization and movement-related cortical potentials are associated with the brain's programming of movement. Using an optimized EEG signal derived from multiple variables, we were able to make real-time predictions of movements in advance of their occurrence with a low false-positive rate. We asked participants what they were thinking at the time of prediction: Sometimes they were thinking about movement, and other times they were not. Our results indicate that the brain can be preparing to make voluntary movements while participants are thinking about something else. C1 [Schneider, Logan; Houdayer, Elise; Bai, Ou; Hallett, Mark] NIH, Bethesda, MD 20892 USA. [Bai, Ou] Virginia Commonwealth Univ, Richmond, VA 23284 USA. RP Schneider, L (reprint author), NIH, Bethesda, MD 20892 USA. FU National Institute of Neurological Disorders Intramural Research Program; Howard Hughes Medical Institute-National Institutes of Health Medical Research Scholars Fellowship; Fyssen Foundation FX The work was supported by the National Institute of Neurological Disorders Intramural Research Program. L. Schneider was funded by the Howard Hughes Medical Institute-National Institutes of Health Medical Research Scholars Fellowship, Chevy Chase, MD. E. Houdayer was funded by the Fyssen Foundation. NR 35 TC 8 Z9 8 U1 1 U2 19 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD JUN PY 2013 VL 25 IS 6 BP 822 EP 829 DI 10.1162/jocn_a_00360 PG 8 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 136IG UT WOS:000318355000001 PM 23363409 ER PT J AU Wilson-Mendenhall, CD Simmons, WK Martin, A Barsalou, LW AF Wilson-Mendenhall, Christine D. Simmons, W. Kyle Martin, Alex Barsalou, Lawrence W. TI Contextual Processing of Abstract Concepts Reveals Neural Representations of Nonlinguistic Semantic Content SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID PERCEPTUAL SYMBOL SYSTEMS; ANTERIOR TEMPORAL-LOBES; SOCIAL COGNITION; FMRI EVIDENCE; SEPARATING PROCESSES; SITUATED SIMULATION; FUNCTIONAL MRI; KNOWLEDGE; BRAIN; METAANALYSIS AB Concepts develop for many aspects of experience, including abstract internal states and abstract social activities that do not refer to concrete entities in the world. The current study assessed the hypothesis that, like concrete concepts, distributed neural patterns of relevant nonlinguistic semantic content represent the meanings of abstract concepts. In a novel neuroimaging paradigm, participants processed two abstract concepts (convince, arithmetic) and two concrete concepts (rolling, red) deeply and repeatedly during a concept-scene matching task that grounded each concept in typical contexts. Using a catch trial design, neural activity associated with each concept word was separated from neural activity associated with subsequent visual scenes to assess activations underlying the detailed semantics of each concept. We predicted that brain regions underlying mentalizing and social cognition (e. g., medial prefrontal cortex, superior temporal sulcus) would become active to represent semantic content central to convince, whereas brain regions underlying numerical cognition (e. g., bilateral intraparietal sulcus) would become active to represent semantic content central to arithmetic. The results supported these predictions, suggesting that the meanings of abstract concepts arise from distributed neural systems that represent concept-specific content. C1 [Wilson-Mendenhall, Christine D.] Northeastern Univ, Boston, MA 02115 USA. [Simmons, W. Kyle] Laureate Inst Brain Res, Tulsa, OK USA. [Martin, Alex] NIMH, Bethesda, MD 20892 USA. [Barsalou, Lawrence W.] Emory Univ, Atlanta, GA 30322 USA. RP Barsalou, LW (reprint author), Emory Univ, Dept Psychol, 483 Psychol & Interdisciplinary Sci Bldg,36 Eagle, Atlanta, GA 30322 USA. EM barsalou@emory.edu RI Simmons, William/K-8925-2015 OI Simmons, William/0000-0002-0399-9003 FU NSF; DARPA [FA8650-05-C-7256] FX We are grateful to Robert Smith and to the Emory Biomedical Imaging Technology Center staff for their help with data collection. This work was supported by an NSF Graduate Research Fellowship to Christine D. Wilson-Mendenhall and by DARPA contract FA8650-05-C-7256 to Lawrence W. Barsalou. NR 62 TC 24 Z9 24 U1 4 U2 30 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD JUN PY 2013 VL 25 IS 6 BP 920 EP 935 DI 10.1162/jocn_a_00361 PG 16 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 136IG UT WOS:000318355000010 PM 23363408 ER PT J AU Godwin, KM Ostwald, SK Cron, SG Wasserman, J AF Godwin, Kyler M. Ostwald, Sharon K. Cron, Stanley G. Wasserman, Joan TI Long-Term Health-Related Quality of Life of Stroke Survivors and Their Spousal Caregivers SO JOURNAL OF NEUROSCIENCE NURSING LA English DT Article DE health-related quality of life; long-term survivors of stroke; spousal caregivers; stroke ID EAST MELBOURNE STROKE; INPATIENT REHABILITATION; PHYSICAL HEALTH; BYPASS-SURGERY; DEPRESSION; MUTUALITY; PREDICTORS; BURDEN; DETERMINANTS; SATISFACTION AB Because treatment for stroke has improved, individuals are living longer with the effects of a stroke. The resulting long-term impairment can affect both stroke survivors' and their caregivers' health-related quality of life (HRQOL). Few studies have examined the HRQOL of stroke survivors and their caregivers greater than 2 years poststroke. The stroke survivors and their spousal caregivers (n = 30 dyads) who had previously completed a 12-month study after discharge from inpatient rehabilitation were assessed at 3-5 years poststroke. The HRQOL and related outcomes were measured for stroke survivors and caregivers. Data from baseline to 12 months were used in conjunction with data from this study. Linear mixed models were used to analyze the change in repeated measures over time. Multiple linear regression was used to analyze the relationship of generic HRQOL to related psychosocial outcomes. The stroke survivors were an average of 4.68 years poststroke. The mean age for stroke survivors and caregivers was 70.8 and 64.9 years, respectively. Most stroke survivors were men (80%) and non-Hispanic White (70%). Among stroke survivors, depression decreased from baseline to 12 months (p = .04) but increased from 12 months to the end of follow-up (p = .003). The caregivers' depression decreased from baseline to all time points (p = .015). Stroke-specific HRQOL showed statistically significant (p < .03) decreases between 12 months and end of follow-up. Increased number of illnesses and older age were associated with caregivers' lower physical HRQOL score (p = .004). Higher depression was associated with lower mental HRQOL score for both caregivers and stroke survivors (p = .003 and p = .011, respectively). Both stroke survivors and caregivers continue to experience negative stroke-related health outcomes for many years after the initial stroke; some of these outcomes even worsen over time. These findings illustrate the need for ongoing psychological and medical evaluation for both long-term stroke survivors and caregivers. Development and testing of targeted behavioral interventions are also warranted. C1 [Godwin, Kyler M.] Baylor Coll Med, Houston, TX 77030 USA. [Godwin, Kyler M.] Michael E DeBakey VA Med Ctr, Houston VA HSR&D Ctr Excellence, Houston, TX USA. [Ostwald, Sharon K.; Cron, Stanley G.] Univ Texas Hlth Sci Ctr Houston, Sch Nursing, Houston, TX USA. [Wasserman, Joan] NINR, Off Extramural Programs, NIH, Washington, DC USA. RP Godwin, KM (reprint author), Baylor Coll Med, Houston, TX 77030 USA. EM godwin@bcm.edu FU Rehabilitation Nursing Foundation; National Institutes of Nursing Research, National Institutes of Health [NR035316] FX This study was supported by grants from the Rehabilitation Nursing Foundation (J. Wasserman, PI) and the National Institutes of Nursing Research, National Institutes of Health (S. K. Ostwald, PI, NR035316). NR 43 TC 23 Z9 23 U1 2 U2 26 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0888-0395 J9 J NEUROSCI NURS JI J. Neurosci. Nurs. PD JUN PY 2013 VL 45 IS 3 BP 147 EP 154 DI 10.1097/JNN.0b013e31828a410b PG 8 WC Clinical Neurology; Nursing SC Neurosciences & Neurology; Nursing GA 138BO UT WOS:000318483500007 PM 23558977 ER PT J AU Xia, JX Varudkar, N Baker, CN Abukenda, I Martinez, C Natarajan, A Grinberg, A Pfeifer, K Ebert, SN AF Xia, Jixiang Varudkar, Namita Baker, Candice N. Abukenda, Ibrahim Martinez, Celines Natarajan, Aruna Grinberg, Alexander Pfeifer, Karl Ebert, Steven N. TI Targeting of the Enhanced Green Fluorescent Protein Reporter to Adrenergic Cells in Mice SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE Phenylethanolamine-N-methyltransferase; Adrenal medulla; Chromaffin cells; Green fluorescent protein; Knock-in ID PHENYLETHANOLAMINE-N-METHYLTRANSFERASE; MOUSE FETAL-DEVELOPMENT; EMBRYONIC STEM-CELLS; MESSENGER-RNA; RAT-HEART; CATECHOLAMINES; EPINEPHRINE; EXPRESSION; GENE; LYMPHOCYTES AB Adrenaline and noradrenaline are important neurotransmitter hormones that mediate physiological stress responses in adult mammals, and are essential for cardiovascular function during a critical period of embryonic/fetal development. In this study, we describe a novel mouse model system for identifying and characterizing adrenergic cells. Specifically, we generated a reporter mouse strain in which a nuclear-localized enhanced green fluorescent protein gene (nEGFP) was inserted into exon 1 of the gene encoding Phenylethanolamine n-methyltransferase (Pnmt), the enzyme responsible for production of adrenaline from noradrenaline. Our analysis demonstrates that this knock-in mutation effectively marks adrenergic cells in embryonic and adult mice. We see expression of nEGFP in Pnmt-expressing cells of the adrenal medulla in adult animals. We also note that nEGFP expression recapitulates the restricted expression of Pnmt in the embryonic heart. Finally, we show that nEGFP and Pnmt expressions are each induced in parallel during the in vitro differentiation of pluripotent mouse embryonic stem cells into beating cardiomyocytes. Thus, this new mouse genetic model should be useful for the identification and functional characterization of adrenergic cells in vitro and in vivo. C1 [Xia, Jixiang; Varudkar, Namita; Baker, Candice N.; Abukenda, Ibrahim; Martinez, Celines; Ebert, Steven N.] Univ Cent Florida, Coll Med, Burnett Sch Biomed Sci, Orlando, FL 32827 USA. [Natarajan, Aruna] Medstar Georgetown Univ Hosp, Dept Pediat, Washington, DC USA. [Grinberg, Alexander; Pfeifer, Karl] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Ebert, SN (reprint author), Univ Cent Florida, Coll Med, Burnett Sch Biomed Sci, 6900 Lake Nona Blvd, Orlando, FL 32827 USA. EM steven.ebert@ucf.edu OI Pfeifer, Karl/0000-0002-0254-682X FU NIH [HL78716]; NICHD FX This study was supported by funding from the NIH (HL78716) to S.N.E., and intramural NICHD funds to K.P. NR 26 TC 0 Z9 0 U1 0 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD JUN PY 2013 VL 54 IS 2 BP 350 EP 360 DI 10.1007/s12033-012-9570-3 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 135SI UT WOS:000318308400026 PM 22706789 ER PT J AU McCleese, JK Bear, MD Kulp, SK Mazcko, C Khanna, C London, CA AF McCleese, J. K. Bear, M. D. Kulp, S. K. Mazcko, C. Khanna, C. London, C. A. TI Met interacts with EGFR and Ron in canine osteosarcoma SO VETERINARY AND COMPARATIVE ONCOLOGY LA English DT Article DE cross-talk; EGFR; Met; osteosarcoma; Ron ID GROWTH-FACTOR RECEPTOR; BREAST-CANCER CELLS; C-MET; LUNG-CANCER; PROGNOSTIC-SIGNIFICANCE; CROSS-TALK; ACQUIRED-RESISTANCE; INHIBITOR ACTIVITY; TYROSINE KINASES; CARCINOMA CELLS AB The receptor tyrosine kinase (RTK) Met is known to be over-expressed in canine osteosarcoma (OSA). In human cancers, the RTKs Met, epidermal growth factor receptor (EGFR) and Ron are frequently co-expressed and engage in heterodimerization, altering signal transduction and promoting resistance to targeted therapeutics. We found that EGFR and Ron are expressed in canine OSA cell lines and primary tissues, EGFR and Ron are frequently phosphorylated in OSA tumour samples, and Met is co-associated with EGFR and Ron in canine OSA cell lines. Transforming growth factor alpha (TGF) and hepatocyte growth factor (HGF) stimulation induced amplification of ERK1/2 and STAT3 phosphorylation in OSA cells and Met was phosphorylated following TGF stimulation providing evidence for receptor cross-talk. Lastly, treatment of OSA cells with combined gefitinib and crizotinib inhibited cell proliferation in an additive manner. Together, these data support the notion that Met, EGFR and Ron interact in OSA cells and as such, may represent viable targets for therapeutic intervention. C1 [McCleese, J. K.; Bear, M. D.; London, C. A.] Ohio State Univ, Dept Vet Biosci, Coll Vet Med, Columbus, OH 43210 USA. [Kulp, S. K.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Mazcko, C.; Khanna, C.] NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP London, CA (reprint author), Ohio State Univ, Dept Vet Biosci, 454 VMAB,1925 Coffey Rd, Columbus, OH 43210 USA. EM london.20@osu.edu RI London, Cheryl/E-6561-2012 FU Morris Animal Foundation FX The authors thank Mahmoud Abdel-Rasoul and Soledad Fernandez from the Center for Biostatistics, The Ohio State University for statistical analysis. We thank Mr Tim Vojt from The Ohio State University, Department of Veterinary Medicine, Biomedical Media Services, for his assistance. We would like to thank Pfizer for kindly providing crizotinib. Funds for this study was provided by the Morris Animal Foundation. NR 55 TC 8 Z9 8 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1476-5810 J9 VET COMP ONCOL JI Vet. Comp. Oncol. PD JUN PY 2013 VL 11 IS 2 BP 124 EP 139 DI 10.1111/j.1476-5829.2011.00309.x PG 16 WC Veterinary Sciences SC Veterinary Sciences GA 137NR UT WOS:000318443100004 PM 22235915 ER PT J AU Boyce, AM Bhattacharyya, N Collins, MT AF Boyce, Alison M. Bhattacharyya, Nisan Collins, Michael T. TI Fibrous Dysplasia and Fibroblast Growth Factor-23 Regulation SO CURRENT OSTEOPOROSIS REPORTS LA English DT Article DE FGF23; Fibrous dysplasia; Phosphorus; Vitamin D; Mineral metabolism; Bone AB Fibrous dysplasia (FD) is a skeletal disorder caused by activating mutations in G(s)alpha that result in elevations in cAMP. A feature of FD is elevated blood levels of the bone cell-derived phosphaturic hormone, fibroblast growth factor-23 (FGF23). FGF23 regulates serum phosphorus and active vitamin D levels by action on proximal renal tubule cells. An essential step in the production of biologically active FGF23 is glycosylation by the UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase (ppGalNAc-T3). In the absence of glycosylation, FGF23 is processed into inactive Nand C-terminal proteins by a subtilisin proprotein convertase, probably furin. Normally, most if not all circulating FGF23 is intact. In FD, C-terminal levels are elevated, suggesting altered FGF23 processing. Altered processing in FD is the result of a cAMP-dependent, coordinated decrease in ppGalNAc-T3 and an increase in furin enzyme activity. These findings, and emerging data from other diseases, suggest regulation of FGF23 processing may be a physiologically important process. C1 [Boyce, Alison M.] Childrens Natl Med Ctr, Div Orthopaed & Sports Med, Bone Hlth Program, Washington, DC 20010 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Bhattacharyya, Nisan; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Boyce, AM (reprint author), Childrens Natl Med Ctr, Div Endocrinol & Diabet, 111 Michigan Ave NW, Washington, DC 20010 USA. EM aboyce@childrensnational.org; mc247k@nih.gov FU Division of Intramural Research of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human services; Bone Health Program at Children's National Medical Center FX This manuscript was supported by Division of Intramural Research of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human services (A.M. B., N.B., and M.T.C.), and the Bone Health Program at Children's National Medical Center (A.M.B.). NR 73 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA EI 1544-2241 J9 CURR OSTEOPOROS REP JI Curr. Osteoporos. Rep. PD JUN PY 2013 VL 11 IS 2 BP 65 EP 71 DI 10.1007/s11914-013-0144-5 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V35YX UT WOS:000209182000001 PM 23532406 ER PT J AU Shuch, B Linehan, WM Srinivasan, R AF Shuch, Brian Linehan, W. Marston Srinivasan, Ramaprasad TI Aerobic glycolysis: a novel target in kidney cancer SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review DE glycolysis; kidney cancer; Krebs cycle; metabolism; Warburg effect ID RENAL-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; PYRUVATE-KINASE M2; INDUCIBLE FACTOR-I; FUMARATE-HYDRATASE; HEREDITARY LEIOMYOMATOSIS; CUTANEOUS LEIOMYOMATA; ENERGY-METABOLISM; BINDING-PROTEIN; C-MYC AB Renal cell carcinoma (RCC) is a heterogenous group of cancers that arise from the nephron. While there are distinct histologic subtypes associated with common genetic alterations, most forms of RCC are linked by a common pathway of dysregulated metabolism. Reliance on aerobic glycolysis, a feature of cancer first hypothesized by Warburg, is a common feature in sporadic and hereditary forms of kidney cancer. Two hereditary forms of RCC, succinate dehydrogenase (SDH) and hereditary leiomyomatosis and RCC (HLRCC), are characterized by mutations in Krebs cycle enzymes, rendering them dependent on glycolysis for energy requirements. The reliance on these pathways may make them vulnerable to novel metabolic strategies, including inhibition of glycolysis, glucose uptake and macromolecule biosynthesis. C1 [Shuch, Brian; Linehan, W. Marston; Srinivasan, Ramaprasad] NCI, Urol Oncol Branch, CRC, Bethesda, MD 20892 USA. RP Srinivasan, R (reprint author), NCI, Urol Oncol Branch, CRC, 10 Ctr Dr,Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM ramasrin@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors are supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 82 TC 16 Z9 17 U1 0 U2 5 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 EI 1744-8328 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD JUN PY 2013 VL 13 IS 6 BP 711 EP 719 DI 10.1586/ERA.13.57 PG 9 WC Oncology SC Oncology GA AH3UY UT WOS:000336052500012 PM 23773105 ER PT J AU Kent, EE Smith, AW Keegan, THM Lynch, CF Wu, XC Hamilton, AS Kato, I Schwartz, SM Harlan, LC AF Kent, Erin E. Smith, Ashley Wilder Keegan, Theresa H. M. Lynch, Charles F. Wu, Xiao-Cheng Hamilton, Ann S. Kato, Ikuko Schwartz, Stephen M. Harlan, Linda C. CA AYA HOPE Study Grp TI Talking About Cancer and Meeting Peer Survivors: Social Information Needs of Adolescents and Young Adults Diagnosed with Cancer SO JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY LA English DT Article DE survivorship; social support; information needs; support group; peer support; communication AB Purpose: Limited research exists on the social information needs of adolescents and young adults (AYAs, aged 15-39 at diagnosis) with cancer. Methods: The Adolescent and Young Adult Health Outcomes and Patient Experiences (AYA HOPE) Study recruited 523 patients to complete surveys 6-14 months after cancer diagnosis. Participants reported information needs for talking about their cancer experience with family and friends (TAC) and meeting peer survivors (MPS). Multiple logistic regression was used to examine factors associated with each need. Results: Approximately 25% (118/477) and 43% (199/462) of participants reported a TAC or MPS need respectively. Participants in their 20s (vs. teenagers) were more likely to report a MPS need (p = 0.03). Hispanics (vs. non-Hispanic whites) were more likely to report a TAC need (p = 0.01). Individuals who did not receive but reported needing support groups were about 4 and 13 times as likely to report TAC and MPS needs respectively (p < 0.05). Participants reporting high symptom burden were more likely to report TAC and MPS needs (p < 0.01), and those reporting fair/poor quality of care were more likely to report a TAC need (p < 0.01). Those reporting that cancer had an impact on several key relationships with family and friends were more likely to report social information needs. Conclusion: Social information needs are higher in AYAs diagnosed in their 20s, in Hispanics, among those reporting high symptom burden and/or lower quality of care, and in individuals not in support groups. Efforts should be made to develop interventions for AYAs in most need of social information and support. C1 [Kent, Erin E.] NCI, Canc Prevent Fellowship, Bethesda, MD 20852 USA. [Kent, Erin E.] NCI, Off Canc Survivorship, Bethesda, MD 20852 USA. [Kent, Erin E.; Smith, Ashley Wilder] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20852 USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Wu, Xiao-Cheng] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, Louisiana Tumor Registry,Program Epidemiol, New Orleans, LA USA. [Hamilton, Ann S.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Kato, Ikuko] Wayne State Univ, Sch Med, Dept Pathol & Oncol, Detroit, MI USA. [Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Harlan, Linda C.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20852 USA. RP Kent, EE (reprint author), NCI, Outcomes Res Branch, 6130 Executive Blvd,Room 4020, Bethesda, MD 20852 USA. EM erin.kent@nih.gov OI Schwartz, Stephen/0000-0001-7499-8502 FU [N01-PC-35136]; [N01-PC-35139]; [N01-PC-35142]; [N01-PC-35143]; [N01-PC-35145]; [N01-PC-54402]; [N01-PC-54404] FX The study authors would like to thank Gretchen Keel for her assistance with data analysis for this project. Supported by contracts N01-PC-35136, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, and N01-PC-54404. NR 36 TC 13 Z9 13 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2156-5333 EI 2156-535X J9 J ADOLESC YOUNG ADUL JI J. Adolesc. Young Adult Oncol. PD JUN PY 2013 VL 2 IS 2 BP 44 EP 52 DI 10.1089/jayao.2012.0029 PG 9 WC Oncology SC Oncology GA V39IJ UT WOS:000209404400002 PM 23781400 ER PT J AU Beddar, S Deye, J Romeijn, E Mackie, T Paganetti, H Jin, J McGuire, S AF Beddar, S. Deye, J. Romeijn, E. Mackie, T. Paganetti, H. Jin, J. McGuire, S. TI Grantsmanship and Funding SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 [Beddar, S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Deye, J.] NCI, Bethesda, MD 20892 USA. [Romeijn, E.] Univ Michigan, Ann Arbor, MI 48109 USA. [Mackie, T.] Univ Wisconsin, Madison, WI USA. [Paganetti, H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jin, J.] Henry Ford Hosp Syst, Detroit, MI USA. [McGuire, S.] Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2013 VL 40 IS 6 DI 10.1118/1.4815615 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI4QM UT WOS:000336849900027 ER PT J AU Lamart, S Lee, C Lee, C AF Lamart, S. Lee, C. Lee, C. TI Conversion of Computational Phantom to DICOM CT Images to Be Used in a Treatment Planning System for Epidemiologic Dose Reconstruction Studies SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 [Lamart, S.; Lee, C.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lee, C.] Univ Michigan Hosp, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2013 VL 40 IS 6 DI 10.1118/1.4814718 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI4QM UT WOS:000336849901567 ER PT J AU Lee, C Lee, C Lamart, S Simon, SL Curtis, RE Inskip, P AF Lee, C. Lee, C. Lamart, S. Simon, S. L. Curtis, R. E. Inskip, P. TI Use of Computational Human Phantoms Combined with a Treatment Planning System to Study the Sensitivity of Reconstructed Normal Tissue Dose to Patient Size and Assumptions On Second Tumor Location SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 [Lee, C.; Lamart, S.; Simon, S. L.; Curtis, R. E.; Inskip, P.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lee, C.] Univ Michigan Hosp, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2013 VL 40 IS 6 DI 10.1118/1.4814719 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI4QM UT WOS:000336849901568 ER PT J AU Glasgow, RE Askew, S Purcell, P Levine, E Warner, ET Stange, KC Colditz, GA Bennett, GG AF Glasgow, Russell E. Askew, Sandy Purcell, Peyton Levine, Erica Warner, Erica T. Stange, Kurt C. Colditz, Graham A. Bennett, Gary G. TI Use of RE-AIM to address health inequities: Application in a low-income community health center-based weight loss and hypertension self-management program SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Weight loss; Health disparities; Low income; RE-AIM; Pragmatic trial; Implementation science AB While health inequities are well documented, and there are helpful frameworks to understand health disparities, implementation frameworks are also needed to focus the design, evaluation, and reporting on interventions targeting populations at increased risk. This study aims to describe how the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework can be used for these purposes and illustrate its application in the context of a randomized, pragmatic weight loss and hypertension self-management intervention. RE-AIM was used to both plan and evaluate the Be Fit Be Well program for urban community health center patients. The RE-AIM framework helped to focus attention on and produce high rates of adoption and reach. Implementation rates varied across components. Weight losses were statistically significant, but not clinically significant. They were robust across a variety of patient characteristics, and the program was relatively of low cost. Individual weight losses and blood pressure reductions were maintained throughout the 24-month period, but the program was not sustained at any of the three settings. Implementation frameworks such as REAIM can help design pragmatic interventions that focus on both the context for disparities reduction and the ultimate goal of public health impact. C1 [Glasgow, Russell E.; Purcell, Peyton] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Askew, Sandy; Levine, Erica; Bennett, Gary G.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Warner, Erica T.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stange, Kurt C.] Case Western, Ctr Comprehens Canc, Dept Family Med, Cleveland, OH USA. [Stange, Kurt C.] Case Western, Ctr Comprehens Canc, Dept Community Hlth, Cleveland, OH USA. [Stange, Kurt C.] Case Western, Ctr Comprehens Canc, Dept Epidemiol & Biostat, Cleveland, OH USA. [Stange, Kurt C.] Case Western, Ctr Comprehens Canc, Dept Sociol, Cleveland, OH USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci,Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 6144, Bethesda, MD 20892 USA. EM glasgowre@mail.nih.gov RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU National Institutes of Health (NIH) [5 U01 HL087071]; National Cancer Institute [5T32CA009001-36]; National Institute of General Medical Sciences [5R25GM055353-14] FX The findings and conclusions in this publication are those of the authors and do not necessarily represent the views of the National Cancer Institute, National Institutes of Health. This research was supported by the National Institutes of Health (NIH) Grant 5 U01 HL087071. Erica T. Warner was supported by the National Cancer Institute grant number 5T32CA009001-36 and by the National Institute of General Medical Sciences grant number 5R25GM055353-14. NR 29 TC 15 Z9 15 U1 5 U2 11 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD JUN PY 2013 VL 3 IS 2 BP 200 EP 210 DI 10.1007/s13142-013-0201-8 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V39LP UT WOS:000209412800008 PM 23750180 ER PT J AU Gao, F Taha, AY Ma, KZ Chang, LS Kiesewetter, D Rapoport, SI AF Gao, Fei Taha, Ameer Y. Ma, Kaizong Chang, Lisa Kiesewetter, Dale Rapoport, Stanley I. TI Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified alpha-linolenic acid by rat liver (Retracted article. See vol. 36, pg. 1565, 2014) SO AGE LA English DT Article; Retracted Publication DE Liver; Synthesis-secretion rate; Conversion; Aging; Age; Metabolism; Alpha-linolenic acid; n-3 Polyunsaturated fatty acids (n-3 PUFAs); Docosahexaenoic acid (DHA); Lipid ID N-3 PUFA DEPRIVATION; AGE-RELATED-CHANGES; POLYUNSATURATED FATTY-ACIDS; HORMONE-SENSITIVE LIPASE; BRAIN PHOSPHOLIPIDS; LIPOPROTEIN-LIPASE; DELTA-6-DESATURASE ACTIVITY; DELTA-6 DESATURASE; FISCHER-344 RATS; NERVOUS-SYSTEM AB Docosahexaenoic acid (DHA, 22:6n-3), an n-3 polyunsaturated fatty acid (PUFA) found at high concentrations in brain and retina and critical to their function, can be obtained from fish products or be synthesized from circulating alpha-linolenic acid (alpha-LNA, 18:3n-3) mainly in the liver. With aging, liver synthetic enzymes are reported reduced or unchanged in the rat. To test whether liver synthesis-secretion of DHA from alpha-LNA changes with age, we measured whole-body DHA conversion coefficients and rates in unanesthetized adult male Fischer-344 rats aged 10, 20, or 30 months, fed an eicosapentaenoic acid (EPA, 20:5n-3)- and DHA-containing diet. Unesterified [U- (13) C]alpha-LNA bound to albumin was infused intravenously for 2 h, while [(13) C]-esterified n-3 PUFAs were measured in arterial plasma, as were unlabeled unesterified and esterified PUFA concentrations. Plasma unesterified n-3 PUFA concentrations declined with age, but esterified n-3 PUFA concentrations did not change significantly. Calculated conversion coefficients were not changed significantly with age, whereas synthesis-secretion rates (product of conversion coefficient and unesterified plasma alpha-LNA concentration) of esterified DHA and n-3 DPA were reduced. Turnovers of esterified n-3 PUFAs in plasma decreased with age, whereas half-lives increased. The results suggest that hepatic capacity to synthesize DHA and other n-3 PUFAs from circulating alpha-LNA is maintained with age in the rat, but that reduced plasma alpha-LNA availability reduces net synthesis-secretion. As unesterified plasma DHA is the form that is incorporated preferentially into brain phospholipid, its reduced synthesis may be deleterious to brain function in aged rats. C1 [Gao, Fei; Taha, Ameer Y.; Ma, Kaizong; Chang, Lisa; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Kiesewetter, Dale] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Gao, Fei] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Expt Therapeut & Reperfus Injury, Boston, MA 02115 USA. RP Gao, F (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Expt Therapeut & Reperfus Injury, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM fgao1@partners.org FU National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute on Aging, and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 65 TC 5 Z9 5 U1 1 U2 22 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD JUN PY 2013 VL 35 IS 3 BP 597 EP 608 DI 10.1007/s11357-012-9390-1 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 133XL UT WOS:000318174100007 PM 22388930 ER PT J AU Eckley, DM Rahimi, S Mantilla, S Orlov, NV Coletta, CE Wilson, MA Iser, WB Delaney, JD Zhang, YQ Wood, W Becker, KG Wolkow, CA Goldberg, IG AF Eckley, D. Mark Rahimi, Salim Mantilla, Sandra Orlov, Nikita V. Coletta, Christopher E. Wilson, Mark A. Iser, Wendy B. Delaney, John D. Zhang, Yongqing Wood, William, III Becker, Kevin G. Wolkow, Catherine A. Goldberg, Ilya G. TI Molecular characterization of the transition to mid-life in Caenorhabditis elegans SO AGE LA English DT Article DE Machine classifier; Biomarker of aging; Metastable aging state; Microarray analysis ID LARGE GENE LISTS; C-ELEGANS; LIFE-SPAN; CIRCADIAN-RHYTHMS; MITOCHONDRIAL-FUNCTION; ISOGENIC POPULATIONS; LONGEVITY ASSURANCE; ELECTRON-TRANSPORT; UBIQUITIN LIGASE; AGE-1 GENE AB We present an initial molecular characterization of a morphological transition between two early aging states. In previous work, an age score reflecting physiological age was developed using a machine classifier trained on images of worm populations at fixed chronological ages throughout their lifespan. The distribution of age scores identified three stable post-developmental states and transitions. The first transition occurs at day 5 post-hatching, where a significant percentage of the population exists in both state I and state II. The temperature dependence of the timing of this transition (Q (10) similar to 1.17) is too low to be explained by a stepwise process with an enzymatic or chemical rate-limiting step, potentially implicating a more complex mechanism. Individual animals at day 5 were sorted into state I and state II groups using the machine classifier and analyzed by microarray expression profiling. Despite being isogenic, grown for the same amount of time, and indistinguishable by eye, these two morphological states were confirmed to be molecularly distinct by hierarchical clustering and principal component analysis of the microarray results. These molecular differences suggest that pharynx morphology reflects the aging state of the whole organism. Our expression profiling yielded a gene set that showed significant overlap with those from three previous age-related studies and identified several genes not previously implicated in aging. A highly represented group of genes unique to this study is involved in targeted ubiquitin-mediated proteolysis, including Skp1-related (SKR), F-box-containing, and BTB motif adaptors. C1 [Eckley, D. Mark; Rahimi, Salim; Mantilla, Sandra; Orlov, Nikita V.; Coletta, Christopher E.; Delaney, John D.; Goldberg, Ilya G.] NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. [Wilson, Mark A.; Iser, Wendy B.; Wolkow, Catherine A.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Zhang, Yongqing; Wood, William, III; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Cent Lab, Serv Sect,NIH, Baltimore, MD 21224 USA. RP Goldberg, IG (reprint author), NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. EM igg@nih.gov RI Eckley, Mark/M-3526-2014; Goldberg, Ilya/H-5307-2011; OI Eckley, Mark/0000-0003-2296-5164; Goldberg, Ilya/0000-0001-8514-6110; Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health, National Institute on Aging FX This work was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 52 TC 5 Z9 17 U1 1 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 J9 AGE JI Age PD JUN PY 2013 VL 35 IS 3 BP 689 EP 703 DI 10.1007/s11357-012-9401-2 PG 15 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 133XL UT WOS:000318174100014 PM 22610697 ER PT J AU Zhao, HY Ghirlando, R Piszczek, G Curth, U Brautigam, CA Schuck, P AF Zhao, Huaying Ghirlando, Rodolfo Piszczek, Grzegorz Curth, Ute Brautigam, Chad A. Schuck, Peter TI Recorded scan times can limit the accuracy of sedimentation coefficients in analytical ultracentrifugation SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Sedimentation velocity; Hydrodynamic modeling ID VELOCITY ANALYTICAL ULTRACENTRIFUGATION; SIZE-DISTRIBUTION ANALYSIS; ESCHERICHIA-COLI; PROTEIN; MACROMOLECULES; CONFORMATION; ASSOCIATION; ALGORITHMS; SYSTEMS; MODEL AB We report systematic and large inaccuracies in the recorded elapsed time in data files from the analytical ultracentrifuge, leading to overestimates of the sedimentation coefficients of up to 10%. This far exceeds previously considered factors contributing to the uncertainty in this parameter and has significant ramifications for derived parameters such as hydrodynamic shape and molar mass estimates. The source of this error is currently unknown, but we found it to be quantitatively consistent across different instruments, increasing with rotor speed. Furthermore, its occurrence appears to correlate with the use of the latest data acquisition software from the manufacturer, in use in some of our laboratories for nearly 2 years. Many of the recently published sedimentation coefficients may need to be reexamined. The problem can be easily recognized by comparing the file timestamps provided by the operating system with the elapsed scan times recorded within the data files. Therefore, we implemented a routine in SEDFIT that can automatically examine the data files, alert the user to significant discrepancies, and correct the scan times accordingly. This eliminates errors in the recorded scan times. Published by Elsevier Inc. C1 [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Curth, Ute] Hannover Med Sch, Inst Biophys Chem, D-30625 Hannover, Germany. [Brautigam, Chad A.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Biomedical Imaging and Bioengineering, National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering, National Institute of Diabetes and Digestive and Kidney Diseases, and National Heart, Lung, and Blood Institute, National Institutes of Health. NR 30 TC 34 Z9 34 U1 0 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 1 PY 2013 VL 437 IS 1 BP 104 EP 108 DI 10.1016/j.ab.2013.02.011 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 132GG UT WOS:000318055300019 PM 23458356 ER PT J AU Mollan, TL Alayash, AI AF Mollan, Todd L. Alayash, Abdu I. TI Redox Reactions of Hemoglobin: Mechanisms of Toxicity and Control SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Editorial Material ID MYOGLOBIN; HEME AB In the last several years, significant work has been done studying hemoglobin (Hb) oxidative reactions and clearance mechanisms using both in vitro and in vivo model systems. One active research area involves the study of molecular chaperones and other proteins that are thought to mitigate the toxicity of acellular Hb. For example, the plasma protein haptoglobin (Hp) and the pre-erythroid protein alpha-hemoglobin-stabilizing protein (AHSP) bind to acellular Hb and alpha-subunits of Hb, respectively, to reduce these adverse effects. Moreover, there has been significant work studying hemopexin and alpha-1 microglobulin, both of which are thought to be involved with hemin degradation. These studies have coincided with the timely publication of the first crystal structure of the Hb-Hp complex. In constructing this Forum, we have invited a number of researchers in the area of Hb and myoglobin (Mb) redox biochemistry, as well as those who have contributed fundamentally to our knowledge of Hp function. Our goal has been to update this critically important research area, because we believe that it will ultimately impact the practice of transfusion medicine in a number of important ways. Antioxid. Redox Signal. 18, 2251-2253. C1 [Mollan, Todd L.; Alayash, Abdu I.] US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), US FDA, Lab Biochem & Vasc Biol, Ctr Biol Evaluat & Res, NIH Bldg 29,Rm 112 8800 Rockville Pike, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov FU NHLBI NIH HHS [HL110900, P01 HL110900] NR 14 TC 7 Z9 7 U1 0 U2 19 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2013 VL 18 IS 17 BP 2251 EP 2253 DI 10.1089/ars.2013.5195 PG 3 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 133QF UT WOS:000318153400002 PM 23330885 ER PT J AU Rifkind, JM Nagababu, E AF Rifkind, Joseph M. Nagababu, Enika TI Hemoglobin Redox Reactions and Red Blood Cell Aging SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID HEME DEGRADATION-PRODUCTS; NITRIC-OXIDE SYNTHASE; OXIDATIVE-STRESS; ERYTHROCYTE-MEMBRANE; HYDROGEN-PEROXIDE; HYPOXIC CONDITIONS; TYROSINE PHOSPHORYLATION; RETICULOCYTE MATURATION; HEMORHEOLOGICAL CHANGES; GLUTATHIONE METABOLISM AB Significance: The physiological mechanism(s) for recognition and removal of red blood cells (RBCs) from circulation after 120 days of its lifespan is not fully understood. Many of the processes thought to be associated with the removal of RBCs involve oxidative stress. We have focused on hemoglobin (Hb) redox reactions, which is the major source of RBC oxidative stress. Recent Advances: The importance of Hb redox reactions have been shown to originate in large parts from the continuous slow autoxidation of Hb producing superoxide and its dramatic increase under hypoxic conditions. In addition, oxidative stress has been shown to be associated with redox reactions that originate from Hb reactions with nitrite and nitric oxide (NO) and the resultant formation of highly toxic peroxynitrite when NO reacts with superoxide released during Hb autoxidation. Critical Issues: The interaction of Hb, particularly under hypoxic conditions with band 3 of the RBC membrane is critical for the generating the RBC membrane changes that trigger the removal of cells from circulation. These changes include exposure of antigenic sites, increased calcium leakage into the RBC, and the resultant leakage of potassium out of the RBC causing cell shrinkage and impaired deformability. Future Directions: The need to understand the oxidative damage to specific membrane proteins that result from redox reactions occurring when Hb is bound to the membrane. Proteomic studies that can pinpoint the specific proteins damaged under different conditions will help elucidate the cellular aging processes that result in cells being removed from circulation. Antioxid. Redox Signal. 18, 2274-2283. C1 [Rifkind, Joseph M.; Nagababu, Enika] NIA, Mol Dynam Sect, Baltimore, MD 21224 USA. RP Rifkind, JM (reprint author), NIA, Mol Dynam Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rifkindj@mail.nih.gov FU Intramural Research Program of National Institute on Aging, National Institutes of Health FX This research was supported by the Intramural Research Program of National Institute on Aging, National Institutes of Health. NR 105 TC 27 Z9 28 U1 4 U2 27 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2013 VL 18 IS 17 BP 2274 EP 2283 DI 10.1089/ars.2012.4867 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 133QF UT WOS:000318153400005 PM 23025272 ER PT J AU Huang, P Lin, J Wang, SJ Zhou, ZJ Li, ZM Wang, Z Zhang, CL Yue, XY Niu, G Yang, M Cui, DX Chen, XY AF Huang, Peng Lin, Jing Wang, Shouju Zhou, Zhijun Li, Zhiming Wang, Zhe Zhang, Chunlei Yue, Xuyi Niu, Gang Yang, Min Cui, Daxiang Chen, Xiaoyuan TI Photosensitizer-conjugated silica-coated gold nanoclusters for fluorescence imaging-guided photodynamic therapy SO BIOMATERIALS LA English DT Article DE Theranostics; Silica; Gold nanocluster; Chlorin e6 (Ce6); Fluorescence imaging; Photodynamic therapy ID SEMICONDUCTOR QUANTUM DOTS; WALLED CARBON NANOTUBES; PHOTOTHERMAL THERAPY; MULTIFUNCTIONAL NANOPARTICLES; NANORODS; CANCER; THERANOSTICS; GENERATION; DELIVERY; SYSTEM AB Multifunctional theranostics have recently been intensively explored to optimize the efficacy and safety of therapeutic regimens. In this work, a photo-theranostic agent based on chlorin e6 (Ce6) photosensitizer-conjugated silica-coated gold nanoclusters (AuNC5@SiO2 Ce6) is strategically designed and prepared for fluorescence imaging-guided photodynamic therapy (PDT). The AuNCs@SiO2 Ce6 shows the following features: i) high Ce6 photosensitizer loading; ii) no non-specific release of Ce6 during its circulation; iii) significantly enhanced cellular uptake efficiency of Ce6, offering a remarkably improved photodynamic therapeutic efficacy compared to free Ce6; iv) subcellular characterization of the nanoformula via both the fluorescence of Ce6 and plasmon luminescence of AuNCs; v) fluorescence imaging-guided photodynamic therapy (PDT). This photo-theranostics owns good stability, high water dispersibility and solubility, non-cytotoxicity, and good biocompatibility, thus facilitating its biomedical applications, particularly for multi-modal optical, CT and photoacoustic (PA) imaging-guided PDT or sonodynamic therapy. Published by Elsevier Ltd. C1 [Huang, Peng; Yang, Min] Jiangsu Inst Nucl Med, Key Lab Nucl Med, Jiangsu Key Lab Mol Nucl Med, Minist Hlth, Wuxi 214063, Peoples R China. [Huang, Peng; Lin, Jing; Zhou, Zhijun; Li, Zhiming; Zhang, Chunlei; Cui, Daxiang] Shanghai Jiao Tong Univ, Inst Micronano Sci & Technol, Shanghai 200240, Peoples R China. [Huang, Peng; Lin, Jing; Wang, Shouju; Wang, Zhe; Yue, Xuyi; Niu, Gang; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Wang, Zhe; Yue, Xuyi] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Yang, M (reprint author), Jiangsu Inst Nucl Med, Key Lab Nucl Med, Jiangsu Key Lab Mol Nucl Med, Minist Hlth, Wuxi 214063, Peoples R China. EM yangmin@jsinm.org; dxcui@sjtu.edu.cn; Shawn.Chen@nih.gov RI Huang, Peng/H-9985-2013; Huang, Peng/R-2480-2016 OI Huang, Peng/0000-0003-3651-7813 FU National Key Basic Research Program (973 Project) [2010CB933901, 2013CB733802]; National Science Foundation of China [81171399, 81272987, 51102258, 31170961, 81101101, 81230033, 81101077]; Jiangsu Province Foundation [BK2011166, BE2012622, BL2012031, RC2011095]; Zhejiang Province Foundation [LY12H11011]; Chinese Academy of Sciences professorship for Senior International Scientists [2011T2J06]; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported in part, by National Key Basic Research Program (973 Project) (2010CB933901 and 2013CB733802), National Science Foundation of China (81171399, 81272987, 51102258, 31170961, 81101101, 81171399, 81230033 and 81101077), Jiangsu Province Foundation (BK2011166, BE2012622, BL2012031 and RC2011095), Zhejiang Province Foundation (LY12H11011), the Chinese Academy of Sciences professorship for Senior International Scientists (2011T2J06), and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 64 TC 77 Z9 77 U1 29 U2 424 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD JUN PY 2013 VL 34 IS 19 BP 4643 EP 4654 DI 10.1016/j.biomaterials.2013.02.063 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 135CE UT WOS:000318262800010 PM 23523428 ER PT J AU Vicha, A Musil, Z Pacak, K AF Vicha, Ales Musil, Zdenek Pacak, Karel TI Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE gene; mutation; paraganglioma; pheochromocytoma; succinate dehydrogenase ID GERMLINE MUTATIONS; CANCER-THERAPY; MAX MUTATIONS; HYPOXIA; TMEM127; HEREDITARY; DEGRADATION; INHIBITOR; PATHWAY; HSP90 AB Purpose of review To summarize the recent advances in the genetics of pheochromocytoma and paraganglioma (PHEO/PGL), focusing on the new susceptibility genes and dividing PHEOs/PGLs into two groups based on their transcription profile. Recent findings Recently, TMEM127, MYC-associated factor X, and hypoxia-inducible factor (HIF) 2 alpha have been described in the pathogenesis of PHEOs/PGLs. Thus, now about 30-40% of these tumors are linked to the germline mutations, which also include mutations in the VHL, RET, NF1, SDHx, and SDHAF2 genes. Furthermore, PHEOs/PGLs have been divided into two groups, cluster 1 (SDHx/VHL) and cluster 2 (RET/NF1), based on the transcription profile revealed by genome-wide expression microarray analysis. Summary PHEOs/PGLs are the most inherited tumors among (neuro) endocrine tumors. Future approaches in genetics, including whole-genome sequencing, will allow the discovery of additional PHEO/PGL susceptibility genes. The current division of PHEOs/PGLs into cluster 1 and 2 provides us with additional knowledge related to the pathogenesis of these tumors, including the introduction of new treatment options for patients with metastatic PHEOs/PGLs. New discoveries related to the role of the HIF-1/HIF-2 alpha genes in the pathogenesis of almost all inherited PHEOs/PGLs may call for a new regrouping of these tumors and discoveries of new treatment targets. C1 [Vicha, Ales; Musil, Zdenek] Charles Univ Prague, Dept Pediat Hematol & Oncol, Fac Med 2, Univ Hosp Motol, Prague, Czech Republic. [Musil, Zdenek] Charles Univ Prague, Gen Teaching Hosp, Inst Biol & Med Genet, Fac Med 1, Prague, Czech Republic. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Pacak, K (reprint author), NICHD, Sect Med Neuroendocrinol, NIH, CRC, Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke at the National Institutes of Health; project for the conceptual development of research organization [00064203] FX The authors thank Victoria Martucci and Ankita Reddy for their technical assistance. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, and the project for the conceptual development of research organization 00064203. NR 57 TC 18 Z9 20 U1 0 U2 15 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 JUN PY 2013 VL 20 IS 3 BP 186 EP 191 DI 10.1097/MED.0b013e32835fcc45 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 131VE UT WOS:000318024200005 PM 23481210 ER PT J AU Qin, LY Liu, YX Hong, JS Crews, FT AF Qin, Liya Liu, Yuxin Hong, Jau-Shyong Crews, Fulton T. TI NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration SO GLIA LA English DT Article DE neuroimmune; senescence; Parkinson's disease; substantia nigra; endotoxin ID PARKINSONS-DISEASE; SUPEROXIDE-PRODUCTION; NEUROINFLAMMATION; MODEL; INFLAMMATION; MICE; DEXTROMETHORPHAN; NEUROTOXICITY; MECHANISMS; NEURONS AB Parkinson's disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (TH+IR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2+/+) mice with NOX subunit gp91phox-deficient (NOX2/) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (P < 0.01) loss of TH+IR neurons in NOX2+/+ mice, whereas NOX2/ mice did not show a significant decrease. Microglia (Iba1+IR) showed morphological activation in NOX2+/+ mice, but not in NOX2/ mice at 1 hr. Treatment of NOX2+/+ mice with LPS resulted in a 12-fold increase in NOX2 mRNA in midbrain and 5.56.5-fold increases in NOX2 protein (+IR) in SN compared with the saline controls. Brain reactive oxygen species (ROS), determined using diphenyliodonium histochemistry, was increased by LPS in SN between 1 hr and 20 months. Diphenyliodonium (DPI), an NOX inhibitor, blocked LPS-induced activation of microglia and production of ROS, TNF, IL-1, and MCP-1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2+/+ mice showed age-related increases in microglial activation, NOX, and ROS levels at 12 and 22 months of age. Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age. (c) 147. C1 [Qin, Liya; Crews, Fulton T.] Univ N Carolina, Bowles Ctr Alcohol Studies, Sch Med, Chapel Hill, NC 27599 USA. [Liu, Yuxin] Hebei Univ, Sch Pharmaceut Sci, Lab Cell Pharmacol, Baoding, Peoples R China. [Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. [Crews, Fulton T.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA. [Crews, Fulton T.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Crews, FT (reprint author), Univ N Carolina, Bowles Ctr Alcohol Studies, 1021 Thurston Bowles Bldg,CB 7178, Chapel Hill, NC 27599 USA. EM ftcrews@med.unc.edu FU National Institute of Health, National Institute of Environmental Health Sciences; National Institute on Alcohol Abuse and Alcoholism [AA020023, AA020024, AA020022, AA019767, AA11605, AA007573]; Bowles Center for Alcohol Studies; NIH/NIEHS FX This work was supported by grants from National Institute of Health, National Institute of Environmental Health Sciences and the National Institute on Alcohol Abuse and Alcoholism [AA020023, AA020024, AA020022, AA019767, AA11605, and AA007573] and the Bowles Center for Alcohol Studies. This work was also supported in part by the Intramural Research Program of the NIH/NIEHS. The authors thank Michelle L. Block and Belinda Wilson for their technical support and thank Diana Lotito for assisting with the manuscript preparation. NR 28 TC 66 Z9 69 U1 3 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUN PY 2013 VL 61 IS 6 BP 855 EP 868 DI 10.1002/glia.22479 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 131KS UT WOS:000317992500003 PM 23536230 ER PT J AU Ahsan, MJ Khalilullah, H Yasmin, S Jadav, SS Stables, JP Govindasamy, J AF Ahsan, Mohamed Jawed Khalilullah, Habibullah Yasmin, Sabina Jadav, Surender Singh Stables, James P. Govindasamy, Jeyabalan TI Synthesis and anticonvulsant evaluation of 2-(substituted benzylidene/ethylidene)-N-(substituted phenyl)hydrazinecarboxamide analogues SO MEDICINAL CHEMISTRY RESEARCH LA English DT Article DE Anticonvulsant agents; 6 Hz psychomotor seizure test; Maximal electroshock seizure; Molecular properties prediction; Neurotoxicity; Semicarbazones ID ANTIEPILEPTIC DRUGS; SEMICARBAZONES; EPILEPSY AB In the present investigation, we described herein the molecular properties prediction by Molinspiration (2008) and synthesized a series of 17 2-(substituted benzylidene/ethylidene)-N-(substituted phenyl)hydrazinecarboxamide analogues. All the title compounds (4a-q) followed the Lipinski "Rule of Five." The synthesized compounds were characterised by elemental analyses and spectral data followed by anticonvulsant activity according to the Antiepileptic Drug Development Programme Protocol. 2-(4-Hydroxybenzylidene)-N-(2-chlorophenyl)hydrazinecarboxamide (4j) was found to be the most active compound of the series showing protection at 4.0 h at a dose of 100 mg/kg against maximal electroshock seizure test and 50 % (2/4, 0.25, 1-2 h) and 100 % (4/4, 0.5 h) protection in 6 Hz psychomotor seizure test without showing any neurotoxicity. N-(2-chlorophenyl)hydrazine carboxamide (3b) showed 100 % (4/4, 0.25-2 h) and 66.6 % (2/3, 4 h) protection in 6 Hz psychomotor seizure test. C1 [Ahsan, Mohamed Jawed; Khalilullah, Habibullah; Govindasamy, Jeyabalan] Alwar Pharm Coll, Dept Pharmaceut Chem, Alwar 301030, Rajasthan, India. [Ahsan, Mohamed Jawed] Nims Univ, Dept Pharmaceut Sci, Jaipur 303121, Rajasthan, India. [Yasmin, Sabina; Jadav, Surender Singh] Birla Inst Technol, Dept Pharmaceut Chem, Ranchi 835215, Jharkhand, India. [Stables, James P.] NIH, Preclin Pharmacol Sect, Epilepsy Branch, Bethesda, MD 20892 USA. RP Ahsan, MJ (reprint author), Alwar Pharm Coll, Dept Pharmaceut Chem, Alwar 301030, Rajasthan, India. EM jawedpharma@gmail.com RI Jadav, Surender Singh/D-1205-2013; OI Jadav, Surender Singh/0000-0002-5397-8956; Ahsan, Mohamed Jawed/0000-0002-6919-5489; Khalilullah, Habibullah/0000-0002-7401-6254; yasmin, sabina/0000-0001-8399-1230 NR 22 TC 1 Z9 4 U1 0 U2 2 PU SPRINGER BIRKHAUSER PI NEW YORK PA 233 SPRING STREET, 6TH FLOOR, NEW YORK, NY 10013 USA SN 1054-2523 J9 MED CHEM RES JI Med. Chem. Res. PD JUN PY 2013 VL 22 IS 6 BP 2746 EP 2754 DI 10.1007/s00044-012-0271-z PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 131JB UT WOS:000317988100019 ER PT J AU Tweedie, D Rachmany, L Rubovitch, V Zhang, YQ Becker, KG Perez, E Hoffer, BJ Pick, CG Greig, NH AF Tweedie, David Rachmany, Lital Rubovitch, Vardit Zhang, Yongqing Becker, Kevin G. Perez, Evelyn Hoffer, Barry J. Pick, Chaim G. Greig, Nigel H. TI Changes in mouse cognition and hippocampal gene expression observed in a mild physical- and blast-traumatic brain injury SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; Alzheimer's disease ID IMPAIRED RECOGNITION MEMORY; DIFFUSE AXONAL INJURY; ELEVATED PLUS-MAZE; ALPHA SYNTHESIS INHIBITOR; FLUID-PERCUSSION INJURY; OBJECT-RECOGNITION; HEAD-INJURY; BARRIER PERMEABILITY; SPATIAL MEMORY; CORTEX DAMAGE AB Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to Alzheimer's disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. (C) 2013 Elsevier Inc. All rights reserved. C1 [Tweedie, David; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Rachmany, Lital; Rubovitch, Vardit; Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Perez, Evelyn] NIA, Lab Expt Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Hoffer, Barry J.] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH 44106 USA. RP Tweedie, D (reprint author), NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program, BRC Room 05B121,251 Bayview Blvd, Baltimore, MD 21224 USA. EM tweedieda@grc.nia.nih.gov; litalrac@post.tau.ac.il; rubovitc@post.tau.ac.il; zhangyon@grc.nia.nih.gov; BeckerK@grc.nia.nih.gov; perezev@grc.nia.nih.gov; bjh82@case.edu; pickc@post.tau.ac.il; greign@grc.nia.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU National Institute on Aging; National Institute on Drug Abuse, National Institutes of Health; Sackler School of Medicine, Tel-Aviv University; Israeli science foundation [108/09] FX The authors wish to acknowledge Dr. Henriette van Pragg as well as William Wood III and Elin Lehrmann for their help in the preparation of this manuscript. This research was supported in part by the Intramural Research Programs of both the National Institute on Aging and National Institute on Drug Abuse, National Institutes of Health, and by the Sackler School of Medicine, Tel-Aviv University, and in part by a grant from the Israeli science foundation, grant no. 108/09. NR 99 TC 27 Z9 27 U1 1 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUN PY 2013 VL 54 BP 1 EP 11 DI 10.1016/j.nbd.2013.02.006 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 132EZ UT WOS:000318052000001 PM 23454194 ER PT J AU Ringer, C Buning, LS Schafer, MKH Eiden, LE Weihe, E Schutz, B AF Ringer, Cornelia Buening, Luisa-Sybille Schaefer, Martin K. H. Eiden, Lee E. Weihe, Eberhard Schuetz, Burkhard TI PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Amyotrophic lateral sclerosis; Microglia; Neuroinflammation; Neuroprotection; Neuropeptide; Parasympathetic; Sympathetic ID CYCLASE-ACTIVATING POLYPEPTIDE; VASOACTIVE-INTESTINAL-PEPTIDE; MOTOR-NEURON DEGENERATION; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ADENYLATE-CYCLASE; GENE-EXPRESSION; TRANSGENIC MICE; SPINAL-CORD; AUTONOMIC IMPAIRMENT; PARKINSONS-DISEASE AB Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous PACAP in the superoxide dismutase 1, SOD1(G93A), mouse model of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the PACAP specific receptor PAC1, but only visceromotor neurons expressed PACAP as a potential autocrine source of regulation of these receptors. In SOD1(G93A) mice, only a small subset of the surviving somatomotor neurons showed induction of PACAP mRNA, and somatomotor neuron degeneration was unchanged in PACAP-deficient SOD1(G93A) mice. Pre-ganglionic sympathetic visceromotor neurons were found to be resistant in SOD1(G93A) mice, while pre-ganglionic parasympathetic neurons degenerated during ALS disease progression in this mouse model. PACAP-deficient SOD1(G93A) mice showed even greater preganglionic parasympathetic neuron loss compared to SOD1(G93A) mice, and additional degeneration of preganglionic sympathetic neurons. Thus, constitutive expression of PACAP and PAC1 may confer neuroprotection to central visceromotor neurons in SOD1(G93A) mice via autocrine pathways. Regarding the progression of neuroinflammation, the switch from amoeboid to hypertrophic microglial phenotype observed in SOD1(G93A) mice was absent in PACAP-deficient SOD1(G93A) mice. Thus, endogenous PACAP may promote microglial cytodestructive functions thought to drive ALS disease progression. This hypothesis was consistent with prolongation of life expectancy and preserved tongue motor function in PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment if stage of disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered. (C) 2013 Elsevier Inc. All rights reserved. C1 [Ringer, Cornelia; Buening, Luisa-Sybille; Schaefer, Martin K. H.; Weihe, Eberhard; Schuetz, Burkhard] Univ Marburg, Inst Anat & Cell Biol, D-35037 Marburg, Germany. [Eiden, Lee E.] NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Weihe, E (reprint author), Univ Marburg, Inst Anat & Cell Biol, Mol Neurosci Dept, Robert Koch Str 8, D-35037 Marburg, Germany. EM weihe@staff.uni-marburg.de; schuetzb@staff.uni-marburg.de OI Eiden, Lee/0000-0001-7524-944X FU Intramural NIH HHS [ZIA MH002386-26, ZIA MH002386-27] NR 73 TC 4 Z9 4 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUN PY 2013 VL 54 BP 32 EP 42 DI 10.1016/j.nbd.2013.02.010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 132EZ UT WOS:000318052000004 PM 23466699 ER PT J AU Van Panhuys, N Camberis, M Yamada, M Tegoshi, T Arizono, N Le Gros, G AF Van Panhuys, Nicholas Camberis, Mali Yamada, Minoru Tegoshi, Tatsuya Arizono, Naoki Le Gros, Graham TI Mucosal trapping and degradation of Nippostrongylus brasiliensis occurs in the absence of STAT6 SO PARASITOLOGY LA English DT Article DE Nippostrongylus brasiliensis; STAT6; TH2; mucosal trapping ID ALTERNATIVELY ACTIVATED MACROPHAGES; EPITHELIAL-CELL FUNCTION; TRICHINELLA-SPIRALIS; PROTECTIVE IMMUNITY; NEMATODE PARASITES; STRONGYLOIDES-RATTI; IMMATURE PARASITES; MIGRATION ROUTES; HOST PROTECTION; ADULT WORMS AB Hookworms represent a major infectious burden globally, especially in developing countries. The murine hookworm Nippostrongylus brasiliensis is normally cleared in a manner dependent on IL-13, IL4-R and STAT6 signalling. Here we have used STAT6-deficient animals to model a non-resistant population and describe 2 novel STAT6-independent processes for the clearance of N. brasiliensis. During primary infection STAT6(-/-) animals are able to clear gut-dwelling N. brasiliensis by a mechanism involving the trapping and degradation of worms in the gut mucosa. Here, a previously undescribed STAT6-independent up-regulation of Relm-beta was observed which correlated with the mucosal trapping and degradation of worms. Previous studies have indicated that during secondary infection STAT6 deficient animals fail to expel adult worms and remain susceptible to re-infection and long-term colonization of the gut. We report here that an initial partially protective response occurs early upon re-infection in the absence of STAT6, and that a late-phase protective secondary response arises in the gut of STAT6-deficient mice leading to the clearance of the majority of N. brasiliensis, through their trapping and death in the mucosal layer of the lower region of the small intestine. These findings show that there are a number of redundant effector pathways which act to reduce worm burden in the gut which can be activated by mechanisms that do not work through the dominant STAT6 signalling pathway and may be useful as targets for future vaccination strategies against resistant hookworm strains. C1 [Van Panhuys, Nicholas] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Camberis, Mali; Le Gros, Graham] Victoria Univ, Malaghan Inst Med Res, Wellington 6242, New Zealand. [Yamada, Minoru; Tegoshi, Tatsuya; Arizono, Naoki] Kyoto Prefectural Univ Med, Dept Med Zool, Kyoto 6020841, Japan. RP Van Panhuys, N (reprint author), NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike Bldg 4,Room 128,MSC 0421, Bethesda, MD 20892 USA. EM vanpanhuysn@niaid.nih.gov RI Le Gros, Graham/C-6725-2011; van Panhuys, Nicholas/E-1812-2011; OI van Panhuys, Nicholas/0000-0003-2199-852X FU New Zealand Foundation for Research Science and Technology FX N.V.P. was funded by the New Zealand Foundation for Research Science and Technology. NR 45 TC 3 Z9 3 U1 0 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 J9 PARASITOLOGY JI Parasitology PD JUN PY 2013 VL 140 IS 7 BP 833 EP 843 DI 10.1017/S0031182012002260 PG 11 WC Parasitology SC Parasitology GA 136MJ UT WOS:000318365700005 PM 23442551 ER PT J AU O'Leary, MC Smith, FO Seibel, NL AF O'Leary, Maura C. Smith, Franklin O. Seibel, Nita L. TI The American society of pediatric hematology/oncology (ASPHO) 2013 distinguished career award goes to Dr. Gregory H. Reaman SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material C1 [Smith, Franklin O.] Univ Cincinnati, Inst Canc, Cincinnati, OH USA. [Seibel, Nita L.] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP O'Leary, MC (reprint author), W East 2510 Virginia Ave NW, Washington, DC 20037 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2013 VL 60 IS 6 BP 897 EP 898 DI 10.1002/pbc.24528 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 130QV UT WOS:000317934800010 PM 23553980 ER PT J AU Eldreth, D Hardin, MG Pavletic, N Ernst, M AF Eldreth, Dana Hardin, Michael G. Pavletic, Nevia Ernst, Monique TI Adolescent Transformations of Behavioral and Neural Processes as Potential Targets for Prevention SO PREVENTION SCIENCE LA English DT Article DE Development; Adolescent; Child; Neuroimaging ID MESIAL PREFRONTAL CORTEX; EYE-MOVEMENT CONTROL; EVENT-RELATED FMRI; RESPONSE-INHIBITION; COGNITIVE CONTROL; ORBITOFRONTAL CORTEX; AGE-DIFFERENCES; UNITED-STATES; DEPRESSED ADOLESCENTS; AMYGDALA ACTIVATION AB Adolescence is a transitional period in development that is marked by a distinct, typical behavioral profile of high rates of exploration, novelty-seeking, and emotional lability. While these behaviors generally assist the adolescent transition to independence, they can also confer vulnerability for excessive risk-taking and psychopathology, particularly in the context of specific environmental or genetic influences. As prevention research depends on the identification of targets of vulnerability, the following review will discuss the interplay among motivational systems including reward-related, avoidance-related, and regulatory processes in typical and atypical adolescent development. Each set of processes will be discussed in relation to their underlying neural correlates and distinct developmental trajectories. Evidence suggests that typical adolescent behavior and the risk for atypical development are mediated by heightened adolescent responsiveness of reward-related and avoidance-related systems under specific conditions, concurrent with poor modulation by immature regulatory processes. Finally, we will propose strategies to exploit heightened reward processing to reinforce inhibitory control, which is an essential component of regulatory processes in prevention interventions. C1 [Hardin, Michael G.; Pavletic, Nevia; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Eldreth, Dana] RTI Int, Mol Epidemiol Gen Environm & Hlth, Baltimore, MD USA. RP Ernst, M (reprint author), NIMH, Sect Dev & Affect Neurosci, 15K North Dr, Bethesda, MD 20892 USA. EM Ernstm@mail.nih.gov NR 108 TC 6 Z9 7 U1 4 U2 17 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD JUN PY 2013 VL 14 IS 3 SI SI BP 257 EP 266 DI 10.1007/s11121-012-0322-1 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 131GE UT WOS:000317979900007 PM 23404658 ER PT J AU Lich, KH Ginexi, EM Osgood, ND Mabry, PL AF Lich, Kristen Hassmiller Ginexi, Elizabeth M. Osgood, Nathaniel D. Mabry, Patricia L. TI A Call to Address Complexity in Prevention Science Research SO PREVENTION SCIENCE LA English DT Article DE Systems science; Complex systems; Prevention science methodology ID SUBSTANCE-ABUSE PREVENTION; SOCIAL NETWORK INFLUENCES; NO DRUG-ABUSE; PUBLIC-HEALTH; SYSTEMS SCIENCE; MENTAL-HEALTH; MODEL; ADOLESCENTS; DYNAMICS; PROGRAM AB The problems targeted by preventive interventions are often complex, embedded in multiple levels of social and environmental context, and span the developmental lifespan. Despite this appreciation for multiple levels and systems of influence, prevention science has yet to apply analytic approaches that can satisfactorily address the complexities with which it is faced. In this article, we introduce a systems science approach to problem solving and methods especially equipped to handle complex relationships and their evolution over time. Progress in prevention science may be significantly enhanced by applying approaches that can examine a wide array of complex systems interactions among biology, behavior, and environment that jointly yield unique combinations of developmental risk and protective factors and outcomes. To illustrate the potential utility of a systems science approach, we present examples of current prevention research challenges, and propose how to complement traditional methods and augment research objectives by applying systems science methodologies. C1 [Lich, Kristen Hassmiller] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC 27599 USA. [Ginexi, Elizabeth M.] NCI, NIH, Bethesda, MD 20892 USA. [Osgood, Nathaniel D.] Univ Saskatchewan, Saskatoon, SK, Canada. [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Lich, KH (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC 27599 USA. EM klich@unc.edu RI Osgood, Nathaniel/L-1805-2016 FU NCRR NIH HHS [KL2RR025746] NR 55 TC 16 Z9 16 U1 3 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD JUN PY 2013 VL 14 IS 3 SI SI BP 279 EP 289 DI 10.1007/s11121-012-0285-2 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 131GE UT WOS:000317979900009 PM 22983746 ER PT J AU Pescatori, M Bedognetti, D Venturelli, E Menard-Moyon, C Bernardini, C Muresu, E Piana, A Maida, G Manetti, R Sgarrella, F Bianco, A Delogu, LG AF Pescatori, Mario Bedognetti, Davide Venturelli, Enrica Menard-Moyon, Cecilia Bernardini, Camilla Muresu, Elena Piana, Andrea Maida, Giorgio Manetti, Roberto Sgarrella, Francesco Bianco, Alberto Delogu, Lucia Gemma TI Functionalized carbon nanotubes as immunomodulator systems SO BIOMATERIALS LA English DT Article DE Nanomedicine; Carbon nanomaterials; Immune system; Gene expression; Microarrays; Cytokines ID GENE-EXPRESSION; PARIETAL PLEURA; IMMUNE CELLS; IFN-GAMMA; DELIVERY; IMMUNOTHERAPY; ACTIVATION; REJECTION; TOXICITY; CANCER AB In view of the broad potential biomedical applications of carbon nanotubes (CNTs) different studies were performed to assess their effect on the immune system. However, the work performed to date was able to give a restricted view looking only at some activation markers and cytokine expression. The immune system is rarely limited to few molecule interactions being instead always a balance of switching several genes on and off. Whole genome expression (microarray) is a technology able to give the full picture on genome expression. Here we describe a microarray genome-wide study on Jurkat cells, a T lymphocyte cell line, and THP1, a monocytic cell line, representative of both types of immune response, the adaptive and innate, respectively. Since any structure or molecule modification may lead to very different immune reactions, we treated the two cell lines with four types of functionalized multi-walled CNTs that differ in terms of functionalization and diameter. After having assessed the internalization and the lack of toxicity of CNTs in both cell types, we used the Affymetrix technology to analyze the expression of about 32,000 transcripts. Three of the tested nanotubes (i.e., ox-MWCNT-1, ox-MWCNT-NH3+-1, and ox-MWCNT-NH3+-2) activated immune-related pathways in monocytes but not in T cells. In view of these charateristics they were named as monocyte activating CNTs (MA-CNTs). Molecular pathways upregulated by MA-CNTs included IL6, CD40, dendritic cell maturation, tumor necrosis factor-(TNF)-alpha/TNFR1-2, NFKB signaling and T helper 1 chemokine pathways (CXCR3 and CCR5 ligand pathways). These pathways are commonly activated during acute inflammatory processes as those associated with immune-mediated tumor rejection and pathogen clearance. One of them (i.e., ox-MWCNT-2) downregulated genes associated with ribosomal proteins in both monocytes and T cells. We validated our findings at gene expression level by performing real-time PCR assessing the most highly modulated genes in monocytes. To confirm the results at protein level, the secretion of IL1 beta, INF alpha, IL6 and IL10 by THP1 and primary monocytes was assessed by ELISA, corroborating gene-expression data. Our results provide new insights into the whole gene expression modulation by different CNTs on immune cells. Considering the well known drug carrier ability of CNTs, our findings demonstrate that MA-CNTs here behave as cell specific immunostimulatory systems, giving very interesting future perspectives for their application also as immunotherapeutic agents and/or vaccine adjuvants. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Pescatori, Mario] Erasmus MC, Lab Expt Surg Oncol, Sect Surg Oncol, Dept Surg, Rotterdam, Netherlands. [Pescatori, Mario] Crosslinks BV, Rotterdam, Netherlands. [Bedognetti, Davide] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Bedognetti, Davide] NIH, Trans Natl Inst Hlth Ctr Human Immunol, Bethesda, MD 20892 USA. [Venturelli, Enrica; Menard-Moyon, Cecilia; Bianco, Alberto] CNRS, Inst Biol Mol & Cellulaire, Lab Immunopathol & Chim Therapeut, F-67000 Strasbourg, France. [Bernardini, Camilla] Univ Cattolica Sacro Cuore, Inst Anat & Cell Biol, Rome, Italy. [Muresu, Elena; Piana, Andrea; Maida, Giorgio] Univ Sassari, Dipartimento Sci Biocmed, I-07100 Sassari, Italy. [Manetti, Roberto] Univ Sassari, Dipartimento Med Clin Sperimentale & Oncol, I-07100 Sassari, Italy. [Sgarrella, Francesco; Delogu, Lucia Gemma] Univ Sassari, Dipartimento Chim & Farm, I-07100 Sassari, Italy. RP Bianco, A (reprint author), CNRS, Inst Biol Mol & Cellulaire, Lab Immunopathol & Chim Therapeut, F-67000 Strasbourg, France. EM a.bianco@ibmc-cnrs.unistra.fr; lgdelogu@uniss.it OI Bedognetti, Davide/0000-0002-5857-773X FU Gianfranco Del Prete award for Medicine, Biology and Nanotechnology; Conquer Cancer Foundation of the American Society of Clinical Oncology Young Investigator Award; Fondazione Banco di Sardegna [994/2010.0410, 186/2011.0484]; University of Sassari; Centre National de la Recherche Scientifique; European Union [HEALTH-2007-201587]; Sardinia Region FX We thank Alessia Lamolinara (Unita operativa di immunooncologia, Universita degli Studi di Chieti) for technical assistance. We thank the laboratories of Prof. Pippia and Prof. Fiori (UNISS) for the kind gift of Jurkat and THP1 cell lines. L.G.D. was supported by "Gianfranco Del Prete award 2012 for Medicine, Biology and Nanotechnology". D.B. was supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology 2011 Young Investigator Award. This work was supported in part by Fondazione Banco di Sardegna Grants 994/2010.0410 and 186/2011.0484 (to L.G.D.), the University of Sassari, the Centre National de la Recherche Scientifique, and the European Union Seventh Framework Programme FP7 (HEALTH-2007-201587, ANTICARB) program. L.G.D. wishes to thank Sardinia Region for supporting an Invited Professorship to A.B. NR 54 TC 50 Z9 50 U1 2 U2 123 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD JUN PY 2013 VL 34 IS 18 BP 4395 EP 4403 DI 10.1016/j.biomaterials.2013.02.052 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 130AJ UT WOS:000317884800001 PM 23507086 ER PT J AU George, SM Smith, AW Alfano, CM Bowles, HR Irwin, ML McTiernan, A Bernstein, L Baumgartner, KB Ballard-Barbash, R AF George, Stephanie M. Smith, Ashley W. Alfano, Catherine M. Bowles, Heather R. Irwin, Melinda L. McTiernan, Anne Bernstein, Leslie Baumgartner, Kathy B. Ballard-Barbash, Rachel TI The association between television watching time and all-cause mortality after breast cancer SO JOURNAL OF CANCER SURVIVORSHIP-RESEARCH AND PRACTICE LA English DT Article DE Sedentary behavior; Exercise; Breast neoplasm; Mortality; Physical activity ID PHYSICAL-ACTIVITY; SEDENTARY BEHAVIORS; VIEWING TIME; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; POOLING PROJECT; SITTING TIME; LIFE-STYLE; US ADULTS; SURVIVORS AB Sedentary time is a rapidly emerging independent risk factor for mortality in the general population, but its prognostic effect among cancer survivors is unknown. In a multiethnic, prospective cohort of breast cancer survivors, we hypothesized that television watching time would be independently associated with an increased risk of death from any cause. The Health, Eating, Activity, and Lifestyle Study cohort included 687 women diagnosed with local or regional breast cancer. On average 30 (+/- 4) months postdiagnosis, women completed self-report assessments on time spent sitting watching television/videos in a typical day in the previous year. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for death from any cause (n = 89) during the 7 years of follow-up. Television time (top tertile vs. bottom tertile) was positively related to risk of death (HR, 1.94; 95 % CI, 1.02, 3.66, p (trend) = 0.024), but the association was attenuated and not statistically significant after adjustment for aerobic moderate-vigorous intensity physical activity (HR, 1.70; 95 % CI, 0.89, 3.22, p (trend) = 0.14) and all covariates (HR, 1.39; 95 % CI, 0.69, 2.82, p (trend) = 0.48). In this first published investigation on this topic, we did not observe a statistically significant multivariate-adjusted association between television watching time and risk of death among women diagnosed with breast cancer. These results begin an evidence base on this topic that can be built upon to inform lifestyle recommendations for this expanding, aging population. C1 [George, Stephanie M.; Smith, Ashley W.; Bowles, Heather R.; Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Irwin, Melinda L.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Populat Sci, Duarte, CA 91010 USA. [Bernstein, Leslie] Beckman Res Ctr, Duarte, CA USA. [Baumgartner, Kathy B.] Univ Louisville, Dept Epidemiol & Populat Hlth, Louisville, KY 40292 USA. RP George, SM (reprint author), 6130 Execut Blvd,EPN 4017A, Bethesda, MD USA. EM stephanie.george@nih.gov FU National Cancer Institute [N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010] FX We would like to thank Dr. Charles L. Wiggins, HEAL Study managers, Todd Gibson of Information Management Systems, and the HEAL Study participants. This study was funded by National Cancer Institute Grants N01-CN-75036-20, NO1-CN-05228, and NO1-PC-67010. NR 28 TC 7 Z9 7 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD JUN PY 2013 VL 7 IS 2 BP 247 EP 252 DI 10.1007/s11764-013-0265-y PG 6 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 129SP UT WOS:000317862900009 PM 23378061 ER PT J AU Weaver, KE Foraker, RE Alfano, CM Rowland, JH Arora, NK Bellizzi, KM Hamilton, AS Oakley-Girvan, I Keel, G Aziz, NM AF Weaver, Kathryn E. Foraker, Randi E. Alfano, Catherine M. Rowland, Julia H. Arora, Neeraj K. Bellizzi, Keith M. Hamilton, Ann S. Oakley-Girvan, Ingrid Keel, Gretchen Aziz, Noreen M. TI Cardiovascular risk factors among long-term survivors of breast, prostate, colorectal, and gynecologic cancers: a gap in survivorship care? SO JOURNAL OF CANCER SURVIVORSHIP-RESEARCH AND PRACTICE LA English DT Article DE Cancer survivorship; Cardiovascular diseases; Risk factors; Health behaviors; Epidemiology; Cancer ID NUTRITION EXAMINATION SURVEYS; AMERICAN-HEART-ASSOCIATION; QUALITY-OF-LIFE; PHYSICAL-ACTIVITY; FOLLOW-UP; TESTICULAR CANCER; NATIONAL-HEALTH; UNITED-STATES; DISEASE; POPULATION AB Individuals diagnosed with high survival cancers will often die of cardiovascular disease (CVD) rather than a recurrence of their cancer, yet CVD risk factors may be overlooked during survivorship care. We assess the prevalence of CVD risk factors among long-term cancer survivors and compare results to survey data from the general population in the same geographic region. We also characterize how often at-risk survivors discuss CVD-related health behaviors with their health care providers. Survivors (n = 1,582) of breast, prostate, colorectal, and gynecologic cancers, 4-14 years after diagnosis, were recruited from two California cancer registries for a cross-sectional mail survey. We assessed CVD risk factors, including smoking, body mass index, physical inactivity, hypercholesterolemia, hypertension, and diabetes, as well as report of discussions with health care providers about diet, exercise, smoking, and lifestyle change assistance. With the exception of current smoking, CVD risk factors were more common among survivors than the general adult population. Of survivors, 62.0 % were overweight or obese, 55.0 % reported hypertension, 20.7 % reported diabetes, 18.1 % were inactive, and 5.1 % were current smokers. Compared to white, non-Hispanic survivors, Hispanic (b = 0.37, p = 0.007) and African-American (b = 0.66, p < 0.0001), but not Asian, survivors reported significantly more risk factors. One in three survivors with one or more risk factors for CVD did not report a health promotion discussion with their health care providers. CVD risk factors are common among long-term survivors, but many at-risk survivors may not discuss lifestyle prevention with their health care team. Primary care and oncology should work together to deliver optimal survivorship care that addresses CVD risk factors, as well as prevalent disease. Cardiovascular disease may compromise cancer survivors' long-term health and well-being, yet cardiovascular risk factors may be overlooked during survivorship care. We document that CVD risk factors are common among cancers survivors, yet nearly a third of survivors do not report health promotion discussions with their medical teams. Survivors should be aware of their cardiovascular risk factors and initiate discussions with their medical teams about health promotion topics, if appropriate. C1 [Weaver, Kathryn E.] Wake Forest Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC 27157 USA. [Foraker, Randi E.] Ohio State Univ, Div Epidemiol, Coll Publ Hlth, Columbus, OH 43210 USA. [Alfano, Catherine M.; Rowland, Julia H.; Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Bellizzi, Keith M.] Univ Connecticut, Dept Human Dev & Family Studies, Storrs, CT USA. [Hamilton, Ann S.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Oakley-Girvan, Ingrid] Canc Prevent Inst Calif, Fremont, CA USA. [Keel, Gretchen] Informat Management Serv Inc, Silver Spring, MD USA. [Aziz, Noreen M.] NINR, NIH, Bethesda, MD 20892 USA. RP Weaver, KE (reprint author), Wake Forest Sch Med, Dept Social Sci & Hlth Policy, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM keweaver@wakehealth.edu OI Keel, Gretchen/0000-0003-1042-9612 FU National Cancer Institute at the National Institutes of Health [N01-PC-35136, HHSN 261201100189P] FX This work was supported by the National Cancer Institute at the National Institutes of Health. Contracts No. N01-PC-35136 and HHSN 261201100189P. The ideas and opinions expressed herein are those of the authors and endorsement by the NCI, and/or their contractors and subcontractors is not intended nor should be inferred. NR 36 TC 44 Z9 45 U1 1 U2 35 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD JUN PY 2013 VL 7 IS 2 BP 253 EP 261 DI 10.1007/s11764-013-0267-9 PG 9 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 129SP UT WOS:000317862900010 PM 23417882 ER PT J AU Katsounas, A Hubbard, JJ Wang, CH Zhang, XZ Dou, D Shivakumar, B Winter, S Schlaak, JF Lempicki, RA Masur, H Polis, M Kottilil, S Osinusi, A AF Katsounas, Antonios Hubbard, Jonathan J. Wang, Crystal H. Zhang, Xiaozhen Dou, Diana Shivakumar, Bhavana Winter, Sophie Schlaak, Joerg F. Lempicki, Richard A. Masur, Henry Polis, Michael Kottilil, Shyam Osinusi, Anu TI High interferon-stimulated gene ISG-15 expression affects HCV treatment outcome in patients co-infected with HIV and HCV SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HCV; HIV; ISG-15; ISG; interferon response ID VIRUS; EVASION AB Increased baseline expression and lack of induction of interferon-stimulated genes (ISG) are strong negative predictors of therapeutic response to PegIFN/RBV in patients co-infected with HIV and hepatitis C virus (HCV). This study specifically addressed whether ISG-15 expression influences therapeutic responses in 20 HIV/HCV genotype-1 subjects undergoing HCV treatment. Non-responders had significantly higher baseline expression and selective induction of ISG-15 after IFN- treatment relative to participants with sustained virological response. High baseline levels of ISG-15 were also associated with less induction of ISG with treatment. These results support a role for ISG-15 as a prognostic indicator and resistance factor to IFN-. J. Med. Virol. 85: 959963, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Katsounas, Antonios; Winter, Sophie; Schlaak, Joerg F.] Univ Hosp, Dept Gastroenterol & Hepatol, Essen, Germany. [Hubbard, Jonathan J.; Wang, Crystal H.; Zhang, Xiaozhen; Dou, Diana; Shivakumar, Bhavana; Polis, Michael; Kottilil, Shyam; Osinusi, Anu] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Lempicki, Richard A.; Osinusi, Anu] CMRPSAIC Frederick Inc, Clin Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA. [Masur, Henry] NIH, CCMD, CC, Bethesda, MD 20892 USA. RP Osinusi, A (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 8C-434, Bethesda, MD 20892 USA. EM osinusia@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Polis, Michael/0000-0002-9151-2268; Schlaak, Joerg/0000-0002-9499-1014 FU NIH (National Institute of Allergy and Infectious Diseases); National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH; Pfizer Inc FX Grant sponsor: Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases); Grant sponsor: National Cancer Institute, National Institutes of Health; Grant number: HHSN261200800001E; Grant sponsor: NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). NR 12 TC 4 Z9 4 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD JUN PY 2013 VL 85 IS 6 BP 959 EP 963 DI 10.1002/jmv.23576 PG 5 WC Virology SC Virology GA 130IE UT WOS:000317906300004 PM 23588721 ER PT J AU Akshintala, S Jones, E Dombi, E Fox, E Lodish, M Whitcomb, P Balis, F Widemann, B AF Akshintala, Srivandana Jones, Elizabeth Dombi, Eva Fox, Elizabeth Lodish, Maya Whitcomb, Patricia Balis, Frank Widemann, Brigitte TI CHARACTERISTICS OF PEDIATRIC PATIENTS WITH ADVANCED MEDULLARY THYROID CARCINOMA (MTC) ASSOCIATED WITH MULTIPLE ENDOCRINE NEOPLASIA (MEN) 2B DUE TO M918T MUTATION SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Akshintala, Srivandana; Jones, Elizabeth; Dombi, Eva; Fox, Elizabeth; Lodish, Maya; Whitcomb, Patricia; Balis, Frank; Widemann, Brigitte] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2013 VL 60 SU 2 BP S68 EP S68 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 131HY UT WOS:000317984800231 ER PT J AU Khincha, P Mai, P Peters, J Hoskins, L Walcott, F Bremer, R Savage, S AF Khincha, Payal Phuong Mai Peters, June Hoskins, Lindsey Walcott, Farzana Bremer, Renee Savage, Sharon TI LI-FRAUMENI SYNDROME: A CLINICAL, GENETIC AND EPIDEMIOLOGIC COHORT STUDY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Khincha, Payal; Phuong Mai; Peters, June; Hoskins, Lindsey; Walcott, Farzana; Bremer, Renee; Savage, Sharon] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2013 VL 60 SU 2 BP S71 EP S72 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 131HY UT WOS:000317984800243 ER PT J AU Mamcarz, E Berg, M Peled, T Frei, G Reger, R Tian, X Childs, R AF Mamcarz, Ewelina Berg, Maria Peled, Tony Frei, Gabi Reger, Robert Tian, Xin Childs, Richard TI NICOTINAMIDE (NAM) INCREASES SURFACE EXPRESSION OF CD62L ON IN VITRO EXPANDED NK CELLS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Mamcarz, Ewelina; Berg, Maria; Peled, Tony; Frei, Gabi; Reger, Robert; Tian, Xin; Childs, Richard] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2013 VL 60 SU 2 BP S11 EP S11 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 131HY UT WOS:000317984800035 ER PT J AU Shah, N Borowitz, M Robey, N Gamper, C Symons, H Loeb, D Wayne, A Chen, A AF Shah, Nirali Borowitz, Michael Robey, Nancy Gamper, Christopher Symons, Heather Loeb, David Wayne, Alan Chen, Allen TI OUTCOMES OF CHILDREN WITH HEMATOLOGIC MALIGNANCIES WHO RELAPSE AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION AND POST-HCT MINIMAL RESIDUAL DISEASE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Shah, Nirali; Borowitz, Michael; Robey, Nancy; Gamper, Christopher; Symons, Heather; Loeb, David; Wayne, Alan; Chen, Allen] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2013 VL 60 SU 2 BP S98 EP S98 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 131HY UT WOS:000317984800335 ER PT J AU Shah, N Borowitz, M Steinberg, S Robey, N Gamper, C Loeb, D Symons, H Wayne, A Chen, A AF Shah, Nirali Borowitz, Michael Steinberg, Seth Robey, Nancy Gamper, Christopher Loeb, David Symons, Heather Wayne, Alan Chen, Allen TI FACTORS PREDICTIVE OF RELAPSE OF HEMATOLOGIC MALIGNANCIES IN PEDIATRIC PATIENTS AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION (ALLOHCT) SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Shah, Nirali; Borowitz, Michael; Steinberg, Seth; Robey, Nancy; Gamper, Christopher; Loeb, David; Symons, Heather; Wayne, Alan; Chen, Allen] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2013 VL 60 SU 2 BP S96 EP S96 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 131HY UT WOS:000317984800328 ER PT J AU Colegate, SM Gardner, DR Davis, TZ Welsh, SL Betz, JM Panter, KE AF Colegate, Steven M. Gardner, Dale R. Davis, T. Zane Welsh, Stanley L. Betz, Joseph M. Panter, Kip E. TI Identification of a lycopsamine-N-oxide chemotype of Amsinckia intermedia SO BIOCHEMICAL SYSTEMATICS AND ECOLOGY LA English DT Article DE Dehydropyrrolizidine alkaloids; Amsinckia intermedia; Lycopsamine; N-oxide; HPLC-esiMS ID PYRROLIZIDINE ALKALOIDS; MS C1 [Colegate, Steven M.; Gardner, Dale R.; Davis, T. Zane; Panter, Kip E.] ARS, Poisonous Plant Res Lab, USDA, Logan, UT 84341 USA. [Welsh, Stanley L.] Brigham Young Univ, Stanley L Welsh Herbarium, Provo, UT 84602 USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Colegate, SM (reprint author), ARS, Poisonous Plant Res Lab, USDA, 1150 East 1400 North, Logan, UT 84341 USA. EM steven.colegate@ars.usda.gov NR 13 TC 1 Z9 1 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0305-1978 J9 BIOCHEM SYST ECOL JI Biochem. Syst. Ecol. PD JUN PY 2013 VL 48 BP 132 EP 135 DI 10.1016/j.bse.2012.11.006 PG 4 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 124ER UT WOS:000317447100022 ER PT J AU Kashiwaya, Y Bergman, C Lee, JH Wan, RQ King, MT Mughal, MR Okun, E Clarke, K Mattson, MP Veech, RL AF Kashiwaya, Yoshihiro Bergman, Christian Lee, Jong-Hwan Wan, Ruiqian King, M. Todd Mughal, Mohamed R. Okun, Eitan Clarke, Kieran Mattson, Mark P. Veech, Richard L. TI A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Cognitive deficits; Hippocampus; Amygdala; 3xTgAD; Frontotemporal lobe dementia; Energy Metabolism; Anxiety ID A-BETA-DEPOSITION; OXIDATIVE STRESS; CALORIE RESTRICTION; BEHAVIORAL DEFICITS; INSULIN-RESISTANCE; BRAIN; IMPAIRMENT; MEMORY; INFLAMMATION; DYSFUNCTION AB Alzheimer's disease (AD) involves progressive accumulation of amyloid beta-peptide (A beta) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory. The 3xTgAD mouse model was used to test the hypothesis that a ketone esterebased diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased A beta deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the same regions of the hippocampus, amygdala, and cortex. Thus, a novel ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model. Published by Elsevier Inc. C1 [Kashiwaya, Yoshihiro; Bergman, Christian; King, M. Todd; Veech, Richard L.] NIAAA, Lab Metab Control, NIH, Bethesda, MD 20892 USA. [Lee, Jong-Hwan] Konkuk Univ, Coll Vet Med, Dept Vet Anat, Seoul 143701, South Korea. [Wan, Ruiqian; Mughal, Mohamed R.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Okun, Eitan] Bar Ilan Univ, Gonda Multidisciplinary Brain Res Ctr, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Clarke, Kieran] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov FU National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism FX The authors thank Andrew Holmes, Elizabeth Gratton, and Shireesh Srivastava for scientific advice and technical assistance. This research was supported by the Intramural Research Programs of the National Institute on Aging and the National Institute on Alcohol Abuse and Alcoholism. NR 52 TC 55 Z9 55 U1 6 U2 67 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 JUN PY 2013 VL 34 IS 6 BP 1530 EP 1539 DI 10.1016/j.neurobiolaging.2012.11.023 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 123UQ UT WOS:000317417100003 PM 23276384 ER PT J AU Liu, D Pitta, M Jiang, HY Lee, JH Zhang, GF Chen, XZ Kawamoto, EM Mattson, MP AF Liu, Dong Pitta, Michael Jiang, Haiyang Lee, Jong-Hwan Zhang, Guofeng Chen, Xinzhi Kawamoto, Elisa M. Mattson, Mark P. TI Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession SO NEUROBIOLOGY OF AGING LA English DT Article DE NAD(+); Nicotinamide; Mitochondria; DLP1; Autophagy; Lysosome; 3xTgAD; p-Akt; CREB; Learning and memory ID ABNORMAL MITOCHONDRIAL DYNAMICS; AMYLOID-BETA; MOUSE MODEL; OXIDATIVE STRESS; NAD(+) DEPLETION; TRANSGENIC MICE; IN-VIVO; A-BETA; NEURODEGENERATIVE DISEASE; SIGNALING PATHWAYS AB Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathologic accumulations of amyloid beta-peptide (A beta) and hyperphosphorylated tau in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the beta-nicotinamide adenine dinucleotide precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling, and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration, and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and A beta toxicity. beta-Nicotinamide adenine dinucleotide biosynthesis, autophagy, and phosphatidylinositol-3-kinase signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced A beta and hyperphosphorylated tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (protein kinase B [Akt] and extracellular signal-regulated kinases) and the transcription factor cyclic adenosine monophosphate (AMP) response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system. Published by Elsevier Inc. C1 [Liu, Dong; Pitta, Michael; Jiang, Haiyang; Chen, Xinzhi; Kawamoto, Elisa M.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Lee, Jong-Hwan] Konkuk Univ, Coll Vet Med, Dept Anat, Seoul, South Korea. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Biomed Res Ctr Room 05C214,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Kawamoto, Elisa/E-3485-2012 OI Kawamoto, Elisa/0000-0001-8637-414X FU National Institute on Aging FX The authors thank M. Mughal for assistance with management of the 3xTgAD mouse colony, R. Leapman for supporting our EM studies, and P. Ghosh and S. L. Chan for helpful discussion and providing antibodies. This research was supported by the Intramural Research Program of the National Institute on Aging. NR 100 TC 28 Z9 29 U1 1 U2 34 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 JUN PY 2013 VL 34 IS 6 BP 1564 EP 1580 DI 10.1016/j.neurobiolaging.2012.11.020 PG 17 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 123UQ UT WOS:000317417100007 PM 23273573 ER PT J AU Cui, ZZ Gerfen, CR Young, WS AF Cui, Zhenzhong Gerfen, Charles R. Young, W. Scott, III TI Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE hippocampal CA2; entorhinal cortex; paraventricular nucleus; supramammillary nucleus; median raphe nucleus; septum; anterograde tracer; Fluorogold; Green Beads; AAV-GFP; AAV-tdTomato; cre recombinase; adeno-associated virus; vasopressin ID MEDIAN RAPHE NUCLEUS; VASOPRESSIN 1B RECEPTOR; SUPRAMAMMILLARY NUCLEUS; THETA-RHYTHM; ENTORHINAL CORTEX; DENTATE GYRUS; SEPTAL AREA; HORSERADISH-PEROXIDASE; PARAHIPPOCAMPAL REGION; ANTEROGRADE TRANSPORT AB The CA2 area is an important, although relatively unexplored, component of the hippocampus. We used various tracers to provide a comprehensive analysis of CA2 connections in C57BL/6J mice. Using various adeno-associated viruses that express fluorescent proteins, we found a vasopressinergic projection from the paraventricular nuclei of the hypothalamus (PVN) to the CA2 as well as a projection from pyramidal neurons of the CA2 to the supramammillary nuclei. These projections were confirmed by retrograde tracing. As expected, we observed CA2 afferent projections from neurons in ipsilateral entorhinal cortical layer II as well as from bilateral dorsal CA2 and CA3 using retrograde tracers. Additionally, we saw CA2 neuronal input from bilateral medial septal nuclei, vertical and horizontal limbs of the nucleus of diagonal band of Broca, supramammillary nuclei (SUM), and median raphe nucleus. Dorsal CA2 injections of adeno-associated virus expressing green fluorescent protein revealed axonal projections primarily to dorsal CA1, CA2, and CA3 bilaterally. No projection was detected to the entorhinal cortex from the dorsal CA2. These results are consistent with recent observations that the dorsal CA2 forms disynaptic connections with the entorhinal cortex to influence dynamic memory processing. Mouse dorsal CA2 neurons send bilateral projections to the medial and lateral septal nuclei, vertical and horizontal limbs of the diagonal band of Broca, and SUM. Novel connections from the PVN and to the SUM suggest important regulatory roles for CA2 in mediating social and emotional input for memory processing. J. Comp. Neurol. 521:18441866, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Cui, Zhenzhong; Young, W. Scott, III] NIMH, Sect Neural Gene Express, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Young, WS (reprint author), NIMH, NIH, 9000 Rockville Pike,MSC 4483,Bldg 49,Room 5A56, Bethesda, MD 20892 USA. EM wsy@mail.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU National Institute of Mental Health Intramural Research Program [Z01-MH-002498-23, Z01-MH-002947-23] FX Grant sponsor: National Institute of Mental Health Intramural Research Program; Grant number: Z01-MH-002498-23 (to W.S.Y.); Grant number: Z01-MH-002947-23 (to C. R. G.). NR 103 TC 33 Z9 34 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUN 1 PY 2013 VL 521 IS 8 BP 1844 EP 1866 DI 10.1002/cne.23263 PG 23 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 122AF UT WOS:000317286500010 PM 23172108 ER PT J AU Pesatori, AC Carugno, M Consonni, D Caporaso, NE Wacholder, S Tucker, M Landi, MT AF Pesatori, Angela Cecilia Carugno, Michele Consonni, Dario Caporaso, Neil E. Wacholder, Sholom Tucker, Margaret Landi, Maria Teresa TI Reproductive and hormonal factors and the risk of lung cancer: The EAGLE study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE casecontrol study; lung cancer; reproductive factors ID PRACTITIONERS ORAL-CONTRACEPTION; REPLACEMENT THERAPY; CHINESE-WOMEN; ESTROGEN-RECEPTOR; POSTMENOPAUSAL WOMEN; ROYAL-COLLEGE; COHORT; ASSOCIATION; HEALTH; EXPRESSION AB Evidence about the role for reproductive and hormonal factors in the etiology of lung cancer in women is conflicting. To clarify this question, we examined 407 female cases and 499 female controls from the Environment And Genetics in Lung cancer Etiology population-based casecontrol study. Subjects were interviewed in person using a computer-assisted personal interview to assess demographics, education, smoking history, medical history, occupational history, reproductive and hormonal factors. Associations of interest were investigated using logistic regression models, adjusted for catchment area and age (matching variables), cigarette smoking (status, pack-years and time since quitting). Additional confounding variables were investigated but did not substantially affect the results. We observed a reduced risk of lung cancer among women with later age at first live birth [31 years: odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.311.06, p-trend = 0.05], later age at menopause (51 years: OR = 0.49, 95%CI = 0.310.79, p-trend = 0.003) and longer reproductive periods (41 years: OR = 0.44, 95%CI = 0.250.79, p-trend = 0.01). A reduced risk was also observed for hormone replacement therapy (OR = 0.63, 95%CI = 0.420.95, p = 0.03) and oral contraceptive use (OR = 0.67, 95%CI = 0.451.00, p = 0.05) but no trend with duration of use was detected. Menopausal status (both natural and induced) was associated with an augmented risk. No additional associations were identified for other reproductive variables. This study suggests that women who continue to produce estrogens have a lower lung cancer risk. Large studies with great number of never smoking women, biomarkers of estrogen and molecular classification of lung cancer are needed for a more comprehensive view of the association between reproductive factors and lung cancer risk. C1 [Pesatori, Angela Cecilia; Carugno, Michele] Univ Milan, Dept Clin Sci & Community Hlth, Epidemiol Res Ctr, EPOCA, I-20122 Milan, Italy. [Pesatori, Angela Cecilia; Consonni, Dario] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Prevent Med, Epidemiol Unit, Milan, Italy. [Caporaso, Neil E.; Wacholder, Sholom; Tucker, Margaret; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Pesatori, AC (reprint author), Univ Milan, Dept Clin Sci & Community Hlth, Epidemiol Res Ctr, EPOCA, Via San Barnaba 8, I-20122 Milan, Italy. EM angela.pesatori@unimi.it RI Tucker, Margaret/B-4297-2015; Consonni, Dario/K-7943-2016; OI Consonni, Dario/0000-0002-8935-3843; pesatori, angela/0000-0002-0261-3252 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Lombardy Region (Environmental Epidemiology Program); CARIPLO Foundation, Milan, Italy FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Lombardy Region (Environmental Epidemiology Program) and CARIPLO Foundation, Milan, Italy NR 50 TC 18 Z9 18 U1 0 U2 49 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JUN 1 PY 2013 VL 132 IS 11 BP 2630 EP 2639 DI 10.1002/ijc.27926 PG 10 WC Oncology SC Oncology GA 115PI UT WOS:000316824000019 PM 23129166 ER PT J AU Purdue, MP Moore, LE Merino, MJ Boffetta, P Colt, JS Schwartz, KL Bencko, V Davis, FG Graubard, BI Janout, V Ruterbusch, JJ Beebe-Dimmer, J Cote, ML Shuch, B Mates, D Hofmann, JN Foretova, L Rothman, N Szeszenia-Dabrowska, N Matveev, V Wacholder, S Zaridze, D Linehan, WM Brennan, P Chow, WH AF Purdue, Mark P. Moore, Lee E. Merino, Maria J. Boffetta, Paolo Colt, Joanne S. Schwartz, Kendra L. Bencko, Vladimir Davis, Faith G. Graubard, Barry I. Janout, Vladimir Ruterbusch, Julie J. Beebe-Dimmer, Jennifer Cote, Michele L. Shuch, Brian Mates, Dana Hofmann, Jonathan N. Foretova, Lenka Rothman, Nathaniel Szeszenia-Dabrowska, Neonilia Matveev, Vsevolod Wacholder, Sholom Zaridze, David Linehan, W. Marston Brennan, Paul Chow, Wong-Ho TI An investigation of risk factors for renal cell carcinoma by histologic subtype in two case-control studies SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE renal cell carcinoma; histology; case-control studies; body mass index ID BODY-MASS INDEX; CLEAR-CELL; KIDNEY CANCER; FAMILY-HISTORY; GENETIC-BASIS; YOUNG-ADULTS; PAPILLARY; FEATURES; TUMORS; HYPERTENSION AB To investigate whether renal cell carcinoma (RCC) histologic subtypes possess different etiologies, we conducted analyses of established RCC risk factors by subtype (clear cell, papillary and chromophobe) in two case-control studies conducted in the United States (1,217 cases, 1,235 controls) and Europe (1,097 cases, 1,476 controls). Histology was ascertained for 706 U.S. cases (58% of total) and 917 European cases (84%) through a central slide review conducted by a single pathologist. For the remaining cases, histology was abstracted from the original diagnostic pathology report. Case-only analyses were performed to compute odds ratios (ORs) and 95% confidence intervals (CI) summarizing subtype differences by age, sex and race. Case-control analyses were performed to compute subtype-specific ORs for other risk factors using polytomous regression. In case-only analyses, papillary cases (N = 237) were older (OR = 1.2, 95% CI = 1.11.4 per 10-year increase), less likely to be female (OR = 0.5, 95% CI = 0.40.8) and more likely to be black (OR = 2.6, 95% CI = 1.83.9) as compared to clear cell cases (N = 1,524). In case-control analyses, BMI was associated with clear cell (OR = 1.2, 95% CI = 1.11.3 per 5 kg/m2 increase) and chromophobe RCC (N = 80; OR = 1.2, 95% CI = 1.11.4), but not papillary RCC (OR = 1.1, 95% CI = 1.01.2; test versus clear cell, p = 0.006). No subtype differences were observed for associations with smoking, hypertension or family history of kidney cancer. Our findings support the existence of distinct age, sex and racial distributions for RCC subtypes, and suggest that the obesity-RCC association differs by histology. C1 [Purdue, Mark P.; Moore, Lee E.; Colt, Joanne S.; Graubard, Barry I.; Hofmann, Jonathan N.; Rothman, Nathaniel; Wacholder, Sholom; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Merino, Maria J.; Shuch, Brian; Linehan, W. Marston] NCI, Ctr Canc Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Schwartz, Kendra L.; Ruterbusch, Julie J.] Wayne State Univ, Sch Med, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Schwartz, Kendra L.; Ruterbusch, Julie J.] Wayne State Univ, Sch Med, Barbara Ann Karmanos Inst, Detroit, MI USA. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Davis, Faith G.] Univ Illinois, Sch Publ Hlth, Dept Epidemiol, Chicago, IL USA. [Janout, Vladimir] Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. [Beebe-Dimmer, Jennifer; Cote, Michele L.] Wayne State Univ, Sch Med, Barbara Ann Karmanos Inst, Dept Oncol, Detroit, MI 48202 USA. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Lodz, Poland. [Matveev, Vsevolod; Zaridze, David] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8114, Bethesda, MD 20892 USA. EM purduem@mail.nih.gov RI Zaridze, David/K-5605-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; mates, dana/0000-0002-6219-9807 FU NIH (Intramural Research Program), the National Cancer Institute FX Grant sponsors: NIH (Intramural Research Program), the National Cancer Institute NR 39 TC 26 Z9 27 U1 1 U2 25 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 JUN 1 PY 2013 VL 132 IS 11 BP 2640 EP 2647 DI 10.1002/ijc.27934 PG 8 WC Oncology SC Oncology GA 115PI UT WOS:000316824000020 PM 23150424 ER PT J AU Ahsan, MJ Khalilullah, H Stables, JP Govindasamy, J AF Ahsan, Mohamed Jawed Khalilullah, Habibullah Stables, James P. Govindasamy, Jeyabalan TI Synthesis and anticonvulsant activity of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues SO JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY LA English DT Article DE Pyrazolines; 6 Hz psychomotor seizure test; maximal electroshock seizure test; subcutaneous metrazole seizure test; neurotoxicity ID ANTIMYCOBACTERIAL EVALUATION; PYRAZOLINE DERIVATIVES; ANTIEPILEPTIC DRUGS; SEMICARBAZONES; AGENTS AB A series of fourteen 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues were synthesized and evaluated for anticonvulsant activity according to the Antiepileptic Drug Development Programme (ADD) protocol. Some of the synthesized compounds showed significant activity in minimal clonic seizure model (6 Hz psychomotor seizure test). 3-(4-Fluorophenyl)-N-(4-bromophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c] pyrazole-2-carboxamide (4c) was found to be the most active compound of the series showing 75% (3/4, 0.25-2.0 h) and 50% (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity. 3-(Pyridin-4-yl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a, 4-dihydro-3H-indeno[1,2-c] pyrazole-2-carboxamide (4f) showed protection in maximal electroshock (MES) seizure and subcutaneous metrazol (scMET) seizure at 300 mg/kg. C1 [Ahsan, Mohamed Jawed; Khalilullah, Habibullah; Govindasamy, Jeyabalan] Alwar Pharm Coll, Dept Pharmaceut Chem, New Drug Discovery Res, Alwar 301030, Rajasthan, India. [Ahsan, Mohamed Jawed] Nims Univ, Dept Pharmaceut Sci, Jaipur, Rajasthan, India. [Stables, James P.] NIH, Preclin Pharmacol Sect, Epilepsy Branch, Bethesda, MD 20892 USA. RP Govindasamy, J (reprint author), Alwar Pharm Coll, Dept Pharmaceut Chem, New Drug Discovery Res, Alwar 301030, Rajasthan, India. EM jeyabalan2001@gmail.com OI Ahsan, Mohamed Jawed/0000-0002-6919-5489; Khalilullah, Habibullah/0000-0002-7401-6254 NR 25 TC 3 Z9 4 U1 0 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1475-6366 J9 J ENZYM INHIB MED CH JI J. Enzym. Inhib. Med. Chem. PD JUN PY 2013 VL 28 IS 3 BP 644 EP 650 DI 10.3109/14756366.2012.663364 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 110CJ UT WOS:000316419400029 PM 22397394 ER PT J AU Chen, G Saad, ZS Britton, JC Pine, DS Cox, RW AF Chen, Gang Saad, Ziad S. Britton, Jennifer C. Pine, Daniel S. Cox, Robert W. TI Linear mixed-effects modeling approach to FMRI group analysis SO NEUROIMAGE LA English DT Article DE FMRI group analysis; GLM; AN(C)OVA; LME; ICC; AFNI; R ID BOLD HEMODYNAMIC-RESPONSES; NEUROIMAGING DATA; INFERENCE; VARIABILITY; REGIONS; HUMANS; AFNI AB Conventional group analysis is usually performed with Student-type t-test, regression, or standard AN(C)OVA in which the variance-covariance matrix is presumed to have a simple structure. Some correction approaches are adopted when assumptions about the covariance structure is violated. However, as experiments are designed with different degrees of sophistication, these traditional methods can become cumbersome, or even be unable to handle the situation at hand. For example, most current FMRI software packages have difficulty analyzing the following scenarios at group level: (1) taking within-subject variability into account when there are effect estimates from multiple runs or sessions; (2) continuous explanatory variables (covariates) modeling in the presence of a within-subject (repeated measures) factor, multiple subject-grouping (between-subjects) factors, or the mixture of both; (3) subject-specific adjustments in covariate modeling; (4) group analysis with estimation of hemodynamic response (HDR) function by multiple basis functions; (5) various cases of missing data in longitudinal studies; and (6) group studies involving family members or twins. Here we present a linear mixed-effects modeling (LME) methodology that extends the conventional group analysis approach to analyze many complicated cases, including the six prototypes delineated above, whose analyses would be otherwise either difficult or unfeasible under traditional frameworks such as AN(C)OVA and general linear model (GLM). In addition, the strength of the LME framework lies in its flexibility to model and estimate the variance-covariance structures for both random effects and residuals. The intradass correlation (ICC) values can be easily obtained with an LME model with crossed random effects, even at the presence of confounding fixed effects. The simulations of one prototypical scenario indicate that the LME modeling keeps a balance between the control for false positives and the sensitivity for activation detection. The importance of hypothesis formulation is also illustrated in the simulations. Comparisons with alternative group analysis approaches and the limitations of LME are discussed in details. Published by Elsevier Inc. C1 [Chen, Gang; Saad, Ziad S.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, HHS, Bethesda, MD 20892 USA. [Britton, Jennifer C.; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, NIH, HHS, Bethesda, MD 20892 USA. RP Chen, G (reprint author), NIMH, Sci & Stat Comp Core, NIH, HHS, Bethesda, MD 20892 USA. EM gangchen@mail.nih.gov RI Britton, Jennifer/J-4501-2013 FU NIMH; NINDS Intramural Research Programs of the NIH FX Special thanks are due to Donald G. McLaren for his help in clarifying some technical details of GLM Flex, and to Thomas Nichols and anonymous reviewers for their suggestions to improve our manuscript. The research and writing of this paper were supported by the NIMH and NINDS Intramural Research Programs of the NIH. NR 54 TC 52 Z9 53 U1 1 U2 27 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2013 VL 73 BP 176 EP 190 DI 10.1016/j.neuroimage.2013.01.047 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 119FZ UT WOS:000317084500017 PM 23376789 ER PT J AU Thomas, C Baker, CI AF Thomas, Cibu Baker, Chris I. TI Teaching an adult brain new tricks: A critical review of evidence for training-dependent structural plasticity in humans SO NEUROIMAGE LA English DT Editorial Material DE VBM; DTI; Structural plasticity; Training; MRI ID VOXEL-BASED MORPHOMETRY; FUNCTIONAL NEUROIMAGING DATA; CLUSTER-SIZE INFERENCE; DIFFUSION-TENSOR MRI; PRIMARY MOTOR CORTEX; RAT VISUAL-CORTEX; IN-VIVO; SYNAPTIC PLASTICITY; GRAY-MATTER; PERMUTATION METHODS AB A growing number of structural neuroimaging studies have reported significant changes in gray matter density or volume and white matter microstructure in the adult human brain following training. Such reports appear consistent with animal studies of training-dependent structural plasticity showing changes in, for example, dendritic spines. However, given the microscopic nature of these changes in animals and the relatively low spatial resolution of MRI, it is unclear that such changes can be reliably detected in humans. Here, we critically evaluate the robustness of the current evidence in humans, focusing on the specificity, replicability, and the relationship of the reported changes with behavior. We find that limitations of experimental design, statistical methods, and methodological artifacts may underlie many of the reported effects, seriously undermining the evidence for training-dependent structural changes in adult humans. The most robust evidence, showing specificity of structural changes to training, task and brain region, shows changes in anterior hippocampal volume with exercise in elderly participants. We conclude that more compelling evidence and converging data from animal studies is required to substantiate structural changes in the adult human brain with training, especially in the neocortex. (C) 2012 Elsevier Inc. All rights reserved. C1 [Thomas, Cibu] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Thomas, C (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM cibu.thomas@nih.gov OI Baker, Chris/0000-0001-6861-8964 FU Intramural NIH HHS NR 114 TC 60 Z9 61 U1 5 U2 88 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 JUN PY 2013 VL 73 BP 225 EP 236 DI 10.1016/j.neuroimage.2012.03.069 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 119FZ UT WOS:000317084500022 PM 22484409 ER PT J AU Fields, RD AF Fields, R. Douglas TI Changes in brain structure during learning: Fact or artifact? Reply to Thomas and Baker SO NEUROIMAGE LA English DT Review DE White matter plasticity; Learning and memory; Environmental enrichment; MRI; DTI; Activity-dependent myelination; Neuroimaging; Plasticity ID ADULT HUMAN BRAIN; PLASTICITY AB In their review in this issue, Thomas and Baker question the validity of longitudinal human neuroimaging studies that have claimed to demonstrate structural plasticity. This commentary identifies problems with some of the arguments raised in their review and suggests that there is strong evidence, from both animal and human studies, that experience can alter brain structure. (C) 2012 Published by Elsevier Inc. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, 35 Lincoln Dr,Bldg 35,Room 2A211, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU NICHD FX This work was supported by funds for intramural research at NICHD. NR 16 TC 9 Z9 9 U1 0 U2 21 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 JUN PY 2013 VL 73 BP 260 EP 264 DI 10.1016/j.neuroimage.2012.08.085 PG 5 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 119FZ UT WOS:000317084500026 PM 22982725 ER PT J AU Thomas, C Baker, CI AF Thomas, Cibu Baker, Chris I. TI On evidence, biases and confounding factors: Response to commentaries SO NEUROIMAGE LA English DT Review DE VBM; DTI; Structural plasticity; Training; MRI ID WHITE-MATTER CHANGES; STRUCTURAL-CHANGES; TAXI DRIVERS; MRI; MEDITATION AB In a critical review (Thomas and Baker, 2012), we argued for caution in evaluating reports of training-dependent adult structural plasticity measured with MRI. Here, we respond to the commentaries on our review, clarifying our position and addressing some of the specific criticisms raised. (C) 2012 Elsevier Inc. All rights reserved. C1 [Thomas, Cibu; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Thomas, Cibu] NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. [Thomas, Cibu; Baker, Chris I.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Thomas, C (reprint author), NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. EM cibu.thomas@nih.gov OI Baker, Chris/0000-0001-6861-8964 FU Intramural Research Program of NIMH; Department of Defense in the Center for Neuroscience and Regenerative Medicine FX This work was supported by the Intramural Research Program of NIMH. Support for this work also included funding from Department of Defense in the Center for Neuroscience and Regenerative Medicine. We thank Dr. Carlo Pierpaoli for helpful comments and discussion. NR 42 TC 5 Z9 5 U1 0 U2 21 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 JUN PY 2013 VL 73 BP 265 EP 267 DI 10.1016/j.neuroimage.2012.11.009 PG 3 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 119FZ UT WOS:000317084500027 PM 23160116 ER PT J AU Bianco, C Castro, NP Baraty, C Rollman, K Held, N Rangel, MC Karasawa, H Gonzales, M Strizzi, L Salomon, DS AF Bianco, Caterina Castro, Nadia P. Baraty, Christina Rollman, Kelly Held, Natalie Rangel, Maria Cristina Karasawa, Hideaki Gonzales, Monica Strizzi, Luigi Salomon, David S. TI Regulation of human Cripto-1 expression by nuclear receptors and DNA promoter methylation in human embryonal and breast cancer cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID PLURIPOTENT STEM-CELLS; MAMMARY EPITHELIAL-CELLS; DIFFERENTIAL RECRUITMENT; OCT4 EXPRESSION; COLON-CANCER; LRH-1; REPRESSION; LIVER; GENE; GCNF AB Human Cripto-1 (CR-1) plays an important role in regulating embryonic development while also regulating various stages of tumor progression. However, mechanisms that regulate CR-1 expression during embryogenesis and tumorigenesis are still not well defined. In the present study, we investigated the effects of two nuclear receptors, liver receptor homolog (LRH)-1 and germ cell nuclear factor receptor (GCNF) and epigenetic modifications on CR-1 gene expression in NTERA-2 human embryonal carcinoma cells and in breast cancer cells. CR-1 expression in NTERA-2 cells was positively regulated by LRH-1 through direct binding to a DR0 element within the CR-1 promoter, while GCNF strongly suppressed CR-1 expression in these cells. In addition, the CR-1 promoter was unmethylated in NTERA-2 cells, while T47D, ZR75-1, and MCF7 breast cancer cells showed high levels of CR-1 promoter methylation and low CR-1 mRNA and protein expression. Treatment of breast cancer cells with a demethylating agent and histone deacetylase inhibitors reduced methylation of the CR-1 promoter and reactivated CR-1 mRNA and protein expression in these cells, promoting migration and invasion of breast cancer cells. Analysis of a breast cancer tissue array revealed that CR-1 was highly expressed in the majority of human breast tumors, suggesting that CR-1 expression in breast cancer cell lines might not be representative of in vivo expression. Collectively, these findings offer some insight into the transcriptional regulation of CR-1 gene expression and its critical role in the pathogenesis of human cancer. J. Cell. Physiol. 228: 11741188, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Bianco, Caterina; Castro, Nadia P.; Baraty, Christina; Rollman, Kelly; Held, Natalie; Rangel, Maria Cristina; Karasawa, Hideaki; Gonzales, Monica; Salomon, David S.] Frederick Natl Lab Canc Res, Lab Canc Prevent, Frederick, MD USA. [Strizzi, Luigi] Northwestern Univ, Childrens Mem Res Ctr, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. RP Salomon, DS (reprint author), Lab Canc Prevent, 1050 Boyles Dr,Bldg 560 Room 1246, Frederick, MD 21701 USA. EM biancoc@mail.nih.gov; salomond@mail.nih.gov RI Rangel, Maria Cristina/P-7216-2014 OI Rangel, Maria Cristina/0000-0002-8002-9617 FU NIH, National Cancer Institute, Center for Cancer Research; Eisenberg Research Scholar Fund FX Contract grant sponsor: Intramural Research Program, NIH, National Cancer Institute, Center for Cancer Research.; Contract grant sponsor: Eisenberg Research Scholar Fund. NR 41 TC 13 Z9 16 U1 0 U2 101 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUN PY 2013 VL 228 IS 6 BP 1174 EP 1188 DI 10.1002/jcp.24271 PG 15 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 096OL UT WOS:000315414000007 PM 23129342 ER PT J AU Jimeno-Yepes, AJ Sticco, JC Mork, JG Aronson, AR AF Jimeno-Yepes, Antonio J. Sticco, J. Caitlin Mork, James G. Aronson, Alan R. TI GeneRIF indexing: sentence selection based on machine learning SO BMC BIOINFORMATICS LA English DT Article ID BIOMEDICAL ARTICLES AB Background: A Gene Reference Into Function (GeneRIF) describes novel functionality of genes. GeneRIFs are available from the National Center for Biotechnology Information (NCBI) Gene database. GeneRIF indexing is performed manually, and the intention of our work is to provide methods to support creating the GeneRIF entries. The creation of GeneRIF entries involves the identification of the genes mentioned in MEDLINE (R) citations and the sentences describing a novel function. Results: We have compared several learning algorithms and several features extracted or derived from MEDLINE sentences to determine if a sentence should be selected for GeneRIF indexing. Features are derived from the sentences or using mechanisms to augment the information provided by them: assigning a discourse label using a previously trained model, for example. We show that machine learning approaches with specific feature combinations achieve results close to one of the annotators. We have evaluated different feature sets and learning algorithms. In particular, Naive Bayes achieves better performance with a selection of features similar to one used in related work, which considers the location of the sentence, the discourse of the sentence and the functional terminology in it. Conclusions: The current performance is at a level similar to human annotation and it shows that machine learning can be used to automate the task of sentence selection for GeneRIF annotation. The current experiments are limited to the human species. We would like to see how the methodology can be extended to other species, specifically the normalization of gene mentions in other species. C1 [Jimeno-Yepes, Antonio J.; Sticco, J. Caitlin; Mork, James G.; Aronson, Alan R.] Natl Lib Med, Bethesda, MD 20894 USA. [Jimeno-Yepes, Antonio J.] NICTA Victoria Res Lab, Melbourne, Vic 3010, Australia. RP Jimeno-Yepes, AJ (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM antonio.jimeno@gmail.com OI Jimeno Yepes, Antonio Jose/0000-0002-6581-094X FU Intramural Research Program of the NIH, National Library of Medicine; National Library of Medicine; Australian Government; Australian Research Council through the ICT Centre of Excellence program FX This work was supported in part by the Intramural Research Program of the NIH, National Library of Medicine and by an appointment of A. Jimeno-Yepes to the NLM Research Participation Program sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education.; NICTA is funded by the Australian Government as represented by the Department of Broadband, Communications and the Digital Economy and the Australian Research Council through the ICT Centre of Excellence program. NR 32 TC 9 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAY 31 PY 2013 VL 14 AR 171 DI 10.1186/1471-2105-14-171 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 167SE UT WOS:000320653700001 PM 23725347 ER PT J AU Bonzheim, I Irmler, M Klier-Richter, M Steinhilber, J Anastasov, N Schafer, S Adam, P Beckers, J Raffeld, M Fend, F Quintanilla-Martinez, L AF Bonzheim, Irina Irmler, Martin Klier-Richter, Margit Steinhilber, Julia Anastasov, Natasa Schaefer, Sabine Adam, Patrick Beckers, Johannes Raffeld, Mark Fend, Falko Quintanilla-Martinez, Leticia TI Identification of C/EBP beta Target Genes in ALK plus Anaplastic Large Cell Lymphoma (ALCL) by Gene Expression Profiling and Chromatin Immunoprecipitation SO PLOS ONE LA English DT Article ID NF-KAPPA-B; BINDING-PROTEIN-BETA; RNA HELICASE-II/GU; SIGNALING PATHWAY; CYCLIN D1; II GU; TRANSCRIPTION; KINASE; SURVIVAL; DOMAINS AB C/EBP beta (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBP beta responsible for ALK-mediated oncogenesis. C/EBP beta was knocked down in ALK+ ALCL cell lines with a C/EBP beta-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBP beta. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBP beta was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBP beta-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBP beta in ALK-mediated oncogenesis. C1 [Bonzheim, Irina; Klier-Richter, Margit; Steinhilber, Julia; Schaefer, Sabine; Adam, Patrick; Fend, Falko; Quintanilla-Martinez, Leticia] Univ Tubingen Hosp, Inst Pathol & Neuropathol, Tubingen, Germany. [Bonzheim, Irina; Klier-Richter, Margit; Steinhilber, Julia; Schaefer, Sabine; Adam, Patrick; Fend, Falko; Quintanilla-Martinez, Leticia] Univ Tubingen, Ctr Comprehens Canc, Tubingen, Germany. [Bonzheim, Irina; Klier-Richter, Margit; Anastasov, Natasa; Quintanilla-Martinez, Leticia] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen GmbH, Inst Pathol, Neuherberg, Germany. [Irmler, Martin; Beckers, Johannes] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen GmbH, Inst Expt Genet, Neuherberg, Germany. [Raffeld, Mark] NCI, Natl Inst Hlth, Bethesda, MD 20892 USA. [Beckers, Johannes] Tech Univ Munich, Chair Expt Genet, Freising Weihenstephan, Germany. RP Quintanilla-Martinez, L (reprint author), Univ Tubingen Hosp, Inst Pathol & Neuropathol, Tubingen, Germany. EM Leticia.Quintanilla-Fend@med.uni-tuebingen.de RI Beckers, Johannes/K-7237-2012; Irmler, Martin/B-3317-2013; Anastasov, Natasa/M-9848-2014 OI Beckers, Johannes/0000-0001-7874-3822; Irmler, Martin/0000-0003-3169-479X; Anastasov, Natasa/0000-0002-4088-1119 FU University of Tubingen [SFB 685, TP B8]; IZKF fortune program, University of Tubingen FX This work was supported by the SFB 685 "Immunotherapy" of the University of Tubingen, TP B8 (LQM and FF) and by the IZKF fortune program, University of Tubingen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 10 Z9 10 U1 1 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 MAY 31 PY 2013 VL 8 IS 5 AR e64544 DI 10.1371/journal.pone.0064544 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 156DC UT WOS:000319799900050 PM 23741337 ER PT J AU Hesse, JE Liu, LW Innes, CL Cui, YX Palii, SS Paules, RS AF Hesse, Jill E. Liu, Liwen Innes, Cynthia L. Cui, Yuxia Palii, Stela S. Paules, Richard S. TI Genome-Wide Small RNA Sequencing and Gene Expression Analysis Reveals a microRNA Profile of Cancer Susceptibility in ATM-Deficient Human Mammary Epithelial Cells SO PLOS ONE LA English DT Article ID PERIPHERAL-BLOOD DNA; BREAST-CANCER; ATAXIA-TELANGIECTASIA; DAMAGE RESPONSE; PROTEIN-KINASE; BIOGENESIS; ENRICHMENT; REGULATORS; APOPTOSIS; VARIANTS AB Deficiencies in the ATM gene are the underlying cause for ataxia telangiectasia, a syndrome characterized by neurological, motor and immunological defects, and a predisposition to cancer. MicroRNAs (miRNAs) are useful tools for cancer profiling and prediction of therapeutic responses to clinical regimens. We investigated the consequences of ATM deficiency on miRNA expression and associated gene expression in normal human mammary epithelial cells (HME-CCs). We identified 81 significantly differentially expressed miRNAs in ATM-deficient HME-CCs using small RNA sequencing. Many of these have been implicated in tumorigenesis and proliferation and include down-regulated tumor suppressor miRNAs, such as hsa-miR-29c and hsa-miR-16, as well as over-expressed pro-oncogenic miRNAs, such as hsa-miR-93 and hsa-miR-221. MicroRNA changes were integrated with genome wide gene expression profiles to investigate possible miRNA targets. Predicted mRNA targets of the miRNAs significantly regulated after ATM depletion included many genes associated with cancer formation and progression, such as SOCS1 and the proto-oncogene MAF. While a number of miRNAs have been reported as altered in cancerous cells, there is little understanding as to how these small RNAs might be driving cancer formation or how they might be used as biomarkers for cancer susceptibility. This study provides preliminary data for defining miRNA profiles that may be used as prognostic or predictive biomarkers for breast cancer. Our integrated analysis of miRNA and mRNA expression allows us to gain a better understanding of the signaling involved in breast cancer predisposition and suggests a mechanism for the breast cancer-prone phenotype seen in ATM-deficient patients. C1 [Hesse, Jill E.; Innes, Cynthia L.; Cui, Yuxia; Palii, Stela S.; Paules, Richard S.] NIEHS, Environm Stress & Canc Grp, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Liu, Liwen; Paules, Richard S.] NIEHS, NIEHS Microarray Core, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Paules, RS (reprint author), NIEHS, Environm Stress & Canc Grp, Lab Toxicol & Pharmacol, POB 12233, Res Triangle Pk, NC 27709 USA. EM paules@niehs.nih.gov FU Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES021157] FX This research was supported by the Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES021157). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 2 Z9 3 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 31 PY 2013 VL 8 IS 5 AR UNSP e64779 DI 10.1371/journal.pone.0064779 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 156DC UT WOS:000319799900105 PM 23741392 ER PT J AU Zilversmit, MM Chase, EK Chen, DS Awadalla, P Day, KP McVean, G AF Zilversmit, Martine M. Chase, Ella K. Chen, Donald S. Awadalla, Philip Day, Karen P. McVean, Gil TI Hypervariable antigen genes in malaria have ancient roots SO BMC EVOLUTIONARY BIOLOGY LA English DT Article DE Non-allelic homologous recombination; Hidden Markov-model; var genes; Malaria; PfEMP1; Gene family evolution; Balancing selection ID LOW-COMPLEXITY REGIONS; PLASMODIUM-FALCIPARUM; RECOMBINATION; DIVERSITY; EVOLUTION; POLYMORPHISM; PROTEINS; ORIGIN; FAMILY AB Background: The var genes of the human malaria parasite Plasmodium falciparum are highly polymorphic loci coding for the erythrocyte membrane proteins 1 (PfEMP1), which are responsible for the cytoaherence of P. falciparum infected red blood cells to the human vasculature. Cytoadhesion, coupled with differential expression of var genes, contributes to virulence and allows the parasite to establish chronic infections by evading detection from the host's immune system. Although studying genetic diversity is a major focus of recent work on the var genes, little is known about the gene family's origin and evolutionary history. Results: Using a novel hidden Markov model-based approach and var sequences assembled from additional isolates and species, we are able to reveal elements of both the early evolution of the var genes as well as recent diversifying events. We compare sequences of the var gene DBL alpha domains from divergent isolates of P. falciparum (3D7 and HB3), and a closely-related species, Plasmodium reichenowi. We find that the gene family is equally large in P. reichenowi and P. falciparum - with a minimum of 51 var genes in the P. reichenowi genome (compared to 61 in 3D7 and a minimum of 48 in HB3). In addition, we are able to define large, continuous blocks of homologous sequence among P. falciparum and P. reichenowi var gene DBL alpha domains. These results reveal that the contemporary structure of the var gene family was present before the divergence of P. falciparum and P. reichenowi, estimated to be between 2.5 to 6 million years ago. We also reveal that recombination has played an important and traceable role in both the establishment, and the maintenance, of diversity in the sequences. Conclusions: Despite the remarkable diversity and rapid evolution found in these loci within and among P. falciparum populations, the basic structure of these domains and the gene family is surprisingly old and stable. Revealing a common structure as well as conserved sequence among two species also has implications for developing new primate-parasite models for studying the pathology and immunology of falciparum malaria, and for studying the population genetics of var genes and associated virulence phenotypes. C1 [Zilversmit, Martine M.] NIAID, NIH, Rockville, MD 20852 USA. [Zilversmit, Martine M.; Chen, Donald S.; Day, Karen P.] NYU, Langone Med Ctr, Dept Microbiol, New York, NY 10010 USA. [Zilversmit, Martine M.; Chase, Ella K.; McVean, Gil] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Zilversmit, Martine M.; Awadalla, Philip] Univ Montral, CHU St Justine Ctr Rech, Montreal, PQ H3T 1C5, Canada. [McVean, Gil] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. RP Zilversmit, MM (reprint author), NIAID, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM martine.zilversmit@nih.gov RI Day, Karen/F-3697-2015; OI Day, Karen/0000-0002-6115-6135; McVean, Gil/0000-0002-5012-4162 FU Royal Society North American Visiting Scholar Fellowship; National Institutes of Health Ruth L. Kirschstein National Research Service Award [F32AI071765]; EPSRC; Human Frontiers in Science Research Grant; Wellcome Trust Program Grant Award [WT041354]; NIH NIAID [1R01AI084156] FX The work in this paper would not be possible without the free availability of unpublished data from the Wellcome Trust Sanger Institute. Additionally, we would like to thank Dr. Sue Kyes for access to HB3 var gene sequences, to Dr. James Cotton for helpful discussion on the var gene DBL alpha phylogeny, Dr. Jane Carlton for helpful discussion on gene family evolution, to Dr. Sebastian Gurevich for aid in manuscript preparation, and two anonymous reviewers for helpful comments. This work was supported by a Royal Society North American Visiting Scholar Fellowship (MMZ and GM), a National Institutes of Health Ruth L. Kirschstein National Research Service Award (F32AI071765, DSC), an EPSRC studentship (EKC), a Human Frontiers in Science Research Grant (PA and GM) and a Wellcome Trust Program Grant Award WT041354 (KD) to and NIH NIAID 1R01AI084156 (KD and DSC). NR 35 TC 13 Z9 13 U1 0 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD MAY 31 PY 2013 VL 13 AR UNSP 110 DI 10.1186/1471-2148-13-110 PG 11 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 159RA UT WOS:000320062100001 PM 23725540 ER PT J AU Liu, YC Miles, JJ Neller, MA Gostick, E Price, DA Purcell, AW McCluskey, J Burrows, SR Rossjohn, J Gras, S AF Liu, Yu Chih Miles, John J. Neller, Michelle A. Gostick, Emma Price, David A. Purcell, Anthony W. McCluskey, James Burrows, Scott R. Rossjohn, Jamie Gras, Stephanie TI Highly Divergent T-cell Receptor Binding Modes Underlie Specific Recognition of a Bulged Viral Peptide bound to a Human Leukocyte Antigen Class I Molecule SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; SELF-PEPTIDE; HLA MICROPOLYMORPHISM; STRUCTURAL BASIS; MHC RESTRICTION; EPITOPE; ALLORECOGNITION; IMPACT; REPERTOIRE; MECHANISM AB Human leukocyte antigen (HLA)-I molecules can present long peptides, yet the mechanisms by which T-cell receptors (TCRs) recognize featured pHLA-I landscapes are unclear. We compared the binding modes of three distinct human TCRs, CA5, SB27, and SB47, complexed with a "super-bulged" viral peptide (LPEPLPQGQLTAY) restricted by HLA-B*35:08. The CA5and SB27 TCRs engaged HLA-B*35:08LPEP similarly, straddling the central region of the peptide but making limited contacts with HLA-B* 35: 08. Remarkably, the the CA5TCR did not contact the alpha 1-helix of HLA-B* 35: 08. Differences in the CDR3 beta loop between the CA5 and SB27 TCRs caused altered fine specificities. Surprisingly, the SB47 TCR engaged HLA-B* 35: 08LPEP using a completely distinct binding mechanism, namely "bypassing" the bulged peptide and making extensive contacts with the extreme N-terminal end of HLA-B* 35: 08. This docking footprint included HLA-I residues not observed previously as TCR contact sites. The three TCRs exhibited differing patterns of alloreactivity toward closely related or distinct HLA-I allo-types. Thus, the human T-cell repertoire comprises a range of TCRs that can interact with "bulged" pHLA-I epitopes using unpredictable strategies, including the adoption of atypical footprints on the MHC-I. C1 [Liu, Yu Chih; Purcell, Anthony W.; Rossjohn, Jamie; Gras, Stephanie] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Miles, John J.; Neller, Michelle A.; Burrows, Scott R.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Miles, John J.; Neller, Michelle A.; Burrows, Scott R.] Australian Ctr Vaccine Dev, Brisbane, Qld 4006, Australia. [Miles, John J.; Gostick, Emma; Price, David A.; Rossjohn, Jamie] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Price, David A.] NIADD, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [McCluskey, James] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. RP Gras, S (reprint author), Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. EM stephanie.gras@monash.edu RI Burrows, Scott/G-2050-2011; Price, David/C-7876-2013; McCluskey, James/A-1291-2007; OI Price, David/0000-0001-9416-2737; McCluskey, James/0000-0002-8597-815X; Purcell, Anthony/0000-0003-0532-8331; Rossjohn, Jamie/0000-0002-2020-7522 FU Australian Research Council (ARC) [DP110102078]; National Health and Medical Research Council of Australia (NHMRC) [APP1009326] FX This work was supported by the Australian Research Council (ARC) Grant DP110102078 and the National Health and Medical Research Council of Australia (NHMRC) Grant APP1009326. NR 49 TC 16 Z9 16 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 31 PY 2013 VL 288 IS 22 BP 15442 EP 15454 DI 10.1074/jbc.M112.447185 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 156LA UT WOS:000319822300003 PM 23569211 ER PT J AU Chung, S Miller, JT Lapkouski, M Tian, L Yang, W Le Grice, SFJ AF Chung, Suhman Miller, Jennifer T. Lapkouski, Mikalai Tian, Lan Yang, Wei Le Grice, Stuart F. J. TI Examining the Role of the HIV-1 Reverse Transcriptase p51 Subunit in Positioning and Hydrolysis of RNA/DNA Hybrids SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RIBONUCLEASE H ACTIVITY; CONNECTION DOMAIN; CRYSTAL-STRUCTURE; ANGSTROM RESOLUTION; TEMPLATE-PRIMER; RESISTANCE; INHIBITOR; COMPLEX; N348I; MUTAGENESIS AB Recent crystallographic analysis of p66/p51 human immuno-deficiency virus (HIV) type 1 reverse transcriptase (RT) complexed with a non-polypurine tract RNA/DNA hybrid has illuminated novel and important contacts between structural elements at the C terminus of the noncatalytic p51 subunit and the nucleic acid duplex in the vicinity of the ribonuclease H (RNase H) active site. In particular, a short peptide spanning residues Phe-416-Pro-421 was shown to interact with theDNA strand, cross the minor groove of the helix, and then form Van der Waals contacts with the RNA strand adjacent to the scissile phosphate. At the base of the adjoining alpha-helix M', Tyr-427 forms a hydrogen bond with Asn-348, the latter of which, when mutated to Ile, is implicated in resistance to both nucleoside and non-nucleoside RT inhibitors. Based on our structural data, we analyzed the role of the p51 C terminus by evaluating selectively mutated p66/p51 heterodimers carrying (i) p51 truncations that encroach on alpha-M', (ii) alterations that interrupt the Asn-348-Tyr- 427 interaction, and (iii) alanine substitutions throughout the region Phe-416-Pro-421. Collectively, our data support the notion that the p51 C terminus makes an important contribution toward hybrid binding and orienting the RNA strand for catalysis at the RNase H active site. C1 [Chung, Suhman; Miller, Jennifer T.; Le Grice, Stuart F. J.] NCI, Natl Inst Hlth, Ctr Canc Res, RT Biochem Sect,HIV Drug Resistance Program, Frederick, MD 21702 USA. [Lapkouski, Mikalai; Tian, Lan; Yang, Wei] NIDDK, Natl Inst Hlth, Mol Biol Lab, Bethesda, MD 20892 USA. RP Le Grice, SFJ (reprint author), NCI, Natl Inst Hlth, Ctr Canc Res, RT Biochem Sect,HIV Drug Resistance Program, Frederick, MD 21702 USA. EM legrices@mail.nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU NIDDK, National Institutes of Health; NCI, National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Programs of the NIDDK and NCI, respectively, of the National Institutes of Health (to W.Y. and S.F.J.L.G.) NR 32 TC 8 Z9 8 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 MAY 31 PY 2013 VL 288 IS 22 BP 16177 EP 16184 DI 10.1074/jbc.M113.465641 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 156LA UT WOS:000319822300068 PM 23595992 ER PT J AU McGuire, AL Joffe, S Koenig, BA Biesecker, BB McCullough, LB Blumenthal-Barby, JS Caulfield, T Terry, SF Green, RC AF McGuire, Amy L. Joffe, Steven Koenig, Barbara A. Biesecker, Barbara B. McCullough, Laurence B. Blumenthal-Barby, Jennifer S. Caulfield, Timothy Terry, Sharon F. Green, Robert C. TI Ethics and Genomic Incidental Findings SO SCIENCE LA English DT Editorial Material C1 [McGuire, Amy L.; McCullough, Laurence B.; Blumenthal-Barby, Jennifer S.] Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. [Joffe, Steven] Harvard Univ, Dana Farber Canc Inst, Boston Childrens Hosp, Sch Med,Dept Pediat Oncol,Dept Med, Boston, MA 02215 USA. [Koenig, Barbara A.] Univ Calif San Francisco, Inst Hlth & Aging, Dept Anthropol Hist & Social Med, Dept Social & Behav Sci, San Francisco, CA 94143 USA. [Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Caulfield, Timothy] Univ Alberta, Hlth Law Inst, Edmonton, AB T6G 2H5, Canada. [Terry, Sharon F.] Genet Alliance, Washington, DC 20008 USA. [Green, Robert C.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Green, Robert C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP McGuire, AL (reprint author), Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. EM amcguire@bcm.edu; steven_joffe@dfci.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 FU Intramural NIH HHS; NCI NIH HHS [CA154517, R01 CA154517, R01-CA154517]; NHGRI NIH HHS [HG006500, HG003178, HG005092, HG006485, HG006492, HG006612-02, HG006615, HG02213, P20 HG007243, R01 HG002213, R01 HG003178, R01 HG005092, R01 HG006615, R21 HG006612, U01 HG006485, U01 HG006492, U01 HG006500] NR 11 TC 86 Z9 87 U1 2 U2 19 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 MAY 31 PY 2013 VL 340 IS 6136 BP 1047 EP 1048 DI 10.1126/science.1240156 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 154HJ UT WOS:000319664500024 PM 23686340 ER PT J AU Kato, H Jiang, JS Zhou, BR Rozendaal, M Feng, HQ Ghirlando, R Xiao, TS Straight, AF Bai, YW AF Kato, Hidenori Jiang, Jiansheng Zhou, Bing-Rui Rozendaal, Marieke Feng, Hanqiao Ghirlando, Rodolfo Xiao, T. Sam Straight, Aaron F. Bai, Yawen TI A Conserved Mechanism for Centromeric Nucleosome Recognition by Centromere Protein CENP-C SO SCIENCE LA English DT Article ID A NUCLEOSOMES; FUNCTIONAL DISSECTION; KINETOCHORE PROTEIN; CHROMATIN; COMPLEX; DNA; DOMAIN; NMR AB Chromosome segregation during mitosis requires assembly of the kinetochore complex at the centromere. Kinetochore assembly depends on specific recognition of the histone variant CENP-A in the centromeric nucteosome by centromere protein C (CENP-C). We have defined the determinants of this recognition mechanism and discovered that CENP-C binds a hydrophobic region in the CENP-A tail and docks onto the acidic patch of histone H2A and H2B. We further found that the more broadly conserved CENP-C motif uses the same mechanism for CENP-A nucteosome recognition. Our findings reveal a conserved mechanism for protein recruitment to centromeres and a histone recognition mode whereby a disordered peptide binds the histone tail through hydrophobic interactions facilitated by nucleosome docking. C1 [Kato, Hidenori; Zhou, Bing-Rui; Feng, Hanqiao; Bai, Yawen] NCI, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. [Jiang, Jiansheng; Xiao, T. Sam] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Rozendaal, Marieke; Straight, Aaron F.] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov RI Xiao, Tsan/I-7616-2013; Xiao, Tsan/A-8590-2010; OI Xiao, Tsan/0000-0001-9688-475X; Straight, Aaron/0000-0001-5885-7881 FU National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; NIH [R01 GM074728]; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; U.S. Department of Energy [DE-AC02-06CH11357] FX We thank the staff at the Advanced Photon Source (APS) (23-ID beamline) for technical support; C. Carroll for initial participation of the project; J. Barrowman for manuscript editing; A. Kelly, C. Wu, and C. Klee for comments; H. Kurumizaka and K. Morikawa for human histone plasmids and advice for CENP-A nucleosome reconstitution; and S. Tan for the 601 DNA prasmid. Supported by the intramural programs of the National Cancer Institute (H.K., H.F., B.-R.Z, and Y.B.); the National Institute of Allergy and Infectious Diseases (J.J. and T.S.X.); the National Institute of Diabetes and Digestive and Kidney Diseases (R.G.); NIH grant R01 GM074728 (M.R. and A.F.S.); and National Cancer Institute grant Y1-CO-1020, National Institute of General Medical Sciences grant Y1-GM-1104, and U.S. Department of Energy grant DE-AC02-06CH11357 (APS). The structure PDB ID is 4INM. NR 28 TC 89 Z9 89 U1 2 U2 23 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 MAY 31 PY 2013 VL 340 IS 6136 BP 1110 EP 1113 DI 10.1126/science.1235532 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 154HJ UT WOS:000319664500048 PM 23723239 ER PT J AU McLellan, JS Chen, M Leung, S Graepel, KW Du, XL Yang, YP Zhou, TQ Baxa, U Yasuda, E Beaumont, T Kumar, A Modjarrad, K Zheng, ZZ Zhao, M Xia, NS Kwong, PD Graham, BS AF McLellan, Jason S. Chen, Man Leung, Sherman Graepel, Kevin W. Du, Xiulian Yang, Yongping Zhou, Tongqing Baxa, Ulrich Yasuda, Etsuko Beaumont, Tim Kumar, Azad Modjarrad, Kayvon Zheng, Zizheng Zhao, Min Xia, Ningshao Kwong, Peter D. Graham, Barney S. TI Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody SO SCIENCE LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; MONOCLONAL-ANTIBODY; F-GLYCOPROTEIN; PROTEIN; INFECTION; EPITOPES; CONFORMATION; MOTAVIZUMAB; CHILDREN; SEQUENCE AB The prefusion state of respiratory syncytiat virus (RSV) fusion (F) glycoprotein is the target of most RSV-neutralizing activity in human sera, but its metastability has hindered characterization. To overcome this obstacle, we identified prefusion-specific antibodies that were substantially more potent than the prophylactic antibody palivizumab. The cocrystal structure for one of these antibodies, D25, in complex with the F glycoprotein revealed D25 to lock F in its prefusion state by binding to a quaternary epitope at the trimer apex. Electron microscopy showed that two other antibodies, AM22 and 5C4, also bound to the newly identified site of vulnerability, which we named antigenic site empty set. These studies should enable design of improved vaccine antigens and define new targets for passive prevention of RSV-induced disease, C1 [McLellan, Jason S.; Chen, Man; Leung, Sherman; Graepel, Kevin W.; Du, Xiulian; Yang, Yongping; Zhou, Tongqing; Kumar, Azad; Modjarrad, Kayvon; Kwong, Peter D.; Graham, Barney S.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Baxa, Ulrich] SAIC Frederick Inc, Electron Microscopy Lab, Adv Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Yasuda, Etsuko; Beaumont, Tim] Univ Amsterdam, Acad Med Ctr, AIMM Therapeut, NL-1105 AZ Amsterdam, Netherlands. [Zheng, Zizheng; Zhao, Min; Xia, Ningshao] Xiamen Univ, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen 361005, Peoples R China. RP McLellan, JS (reprint author), NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mclellanja@niaid.nih.gov; pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program (National Institute of Allergy and Infectious Diseases); National Natural Science Foundation of China [81161120419]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank members of the Structural Biology Section, Structural Bioinformatics Core Section, and Viral Pathogenesis Laboratory at the Vaccine Research Center for helpful comments, and J. Chrzas, J. Gonczy, U. Chinte, and staff at SER-CAT (Southeast Regional Collaborative Access Team) for help with x-ray diffraction data collection. The data presented in this manuscript are tabulated in the main paper and supplementary materials. Atomic coordinates and structure factors of the reported crystal structures have been deposited in the Protein Data Bank under accession codes 4JHA and 4JHW. Support for this work was provided by the Intramural Research Program (National Institute of Allergy and Infectious Diseases) and the National Natural Science Foundation of China (81161120419). Use of insertion device 22 (SER-CAT) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. T.B. is an inventor on an international patent application describing the technology used to isolate D25 and AM22 (Means and methods for influencing the stability of antibody producing cells, WO2007067046A1). E.Y. and T.B. are inventors on international patent applications for antibody D25 (RSV-specific binding molecules and means for producing them, WO2008147196A2) and antibody AM22 (RSV-specific binding molecule, WO2011043643A1). J.S.M., P.D.K, and B.S.G. are inventors on a U.S. patent application describing the use of prefusion-stabilized RSV F glycoproteins as vaccine antigens (Prelusion RSV F proteins and their use, 61(798,389). J.S.M, MC., Z.Z., M.Z., N.X., and B.S.G. are inventors on a Chinese patent application for antibody 5C4 and its epitope (Anti-RSV high neutralization antibody and the peptide can be used for prevention of RSV infection and related disease, 201310082338.1). NR 34 TC 172 Z9 180 U1 46 U2 84 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 MAY 31 PY 2013 VL 340 IS 6136 BP 1113 EP 1117 DI 10.1126/science.1234914 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 154HJ UT WOS:000319664500049 PM 23618766 ER PT J AU Dominguez, MH Chattopadhyay, PK Ma, S Lamoreaux, L McDavid, A Finak, G Gottardo, R Koup, RA Roederer, M AF Dominguez, Maria H. Chattopadhyay, Pratip K. Ma, Steven Lamoreaux, Laurie McDavid, Andrew Finak, Greg Gottardo, Raphael Koup, Richard A. Roederer, Mario TI Highly multiplexed quantitation of gene expression on single cells SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Single cell; Gene expression; T-cell activation; qPCR ID T-CELLS; HIV-INFECTION; VACCINE; QUALITY AB Highly multiplexed, single-cell technologies reveal important heterogeneity within cell populations. Recently, technologies to simultaneously measure expression of 96 (or more) genes from a single cell have been developed for immunologic monitoring. Here, we report a rigorous, optimized, quantitative methodology for using this technology. Specifically: we describe a unique primer/probe qualification method necessary for quantitative results; we show that primers do not compete in highly multiplexed amplifications; we define the limit of detection for this assay as a single mRNA transcript; and, we show that the technical reproducibility of the system is very high. We illustrate two disparate applications of the platform: a "bulk" approach that measures expression patterns from 100 cells at a time in high throughput to define gene signatures, and a single-cell approach to define the coordinate expression patterns of multiple genes and reveal unique subsets of cells. Published by Elsevier B.V. C1 [Dominguez, Maria H.; Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Ma, Steven; Lamoreaux, Laurie; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [McDavid, Andrew; Finak, Greg; Gottardo, Raphael] Univ Washington, Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Div Publ Hlth Sci, Seattle, WA 98195 USA. RP Chattopadhyay, PK (reprint author), 40 Convent Dr,Room 5612, Bethesda, MD 20892 USA. EM pchattop@mail.nih.gov OI Finak, Greg/0000-0003-4341-9090; McDavid, Andrew/0000-0002-6581-1213; Chattopadhyay, Pratip/0000-0002-5457-9666 FU NIAID, NIH; Collaboration for AIDS Vaccine Discovery (CAVD) from the Bill & Melinda Gates Foundation [OPP1032325] FX The authors would like to acknowledge the following individuals and contributions: Margaret Beddall, Stephen P. Perfetto, David Ambrozak, and Richard Nguyen (for cell processing, flow cytometry, and cell sorting); Ken Livak, Alain Mir, Andy May, Candida Brown, John Lynch, and Gajus Worthington (for discussion and advice on gene expression assays); the Nonhuman Primate Core of the Vaccine Research Center (for obtaining and preparing Rhesus macaque samples); Christopher Fletez-Brant for programming in R; and members of ImmunoTechnology Section and Laboratory of Immunology (for helpful discussion). This work was supported by the Intramural Research Program of the NIAID, NIH, and by the Collaboration for AIDS Vaccine Discovery (CAVD), Grant #OPP1032325, from the Bill & Melinda Gates Foundation. NR 25 TC 24 Z9 24 U1 1 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAY 31 PY 2013 VL 391 IS 1-2 BP 133 EP 145 DI 10.1016/j.jim.2013.03.002 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 137WA UT WOS:000318467700014 PM 23500781 ER PT J AU Prager, KC Greig, DJ Alt, DP Galloway, RL Hornsby, RL Palmer, LJ Soper, J Wu, QZ Zuerner, RL Gulland, FMD Lloyd-Smith, JO AF Prager, K. C. Greig, Denise J. Alt, David P. Galloway, Renee L. Hornsby, Richard L. Palmer, Lauren J. Soper, Jennifer Wu, Qingzhong Zuerner, Richard L. Gulland, Frances M. D. Lloyd-Smith, James O. TI Asymptomatic and chronic carriage of Leptospira interrogans serovar Pomona in California sea lions (Zalophus californianus) SO VETERINARY MICROBIOLOGY LA English DT Article DE Sea lion; Leptospira; Disease ecology; Persistence; Asymptomatic/subclinical carrier; Maintenance host ID IDENTIFICATION; INFECTION AB Since 1970, periodic outbreaks of leptospirosis, caused by pathogenic spirochetes in the genus Leptospira, have caused morbidity and mortality of California sea lions (Zalophus californianus) along the Pacific coast of North America. Yearly seasonal epizootics of varying magnitude occur between the months of July and December, with major epizootics occurring every 3-5 years. Genetic and serological data suggest that Leptospira interrogans serovar Pomona is the infecting serovar and is enzootic in the California sea lion population, although the mechanism of persistence is unknown. We report asymptomatic carriage of Leptospira in 39% (33/85) of wild, free-ranging sea lions sampled during the epizootic season, and asymptomatic seroconversion with chronic asymptomatic carriage in a rehabilitated sea lion. This is the first report of asymptomatic carriage in wild, free-ranging California sea lions and the first example of seroconversion and asymptomatic chronic carriage in a sea lion. Detection of asymptomatic chronic carriage of Leptospira in California sea lions, a species known to suffer significant disease and mortality from the same Leptospira strain, goes against widely-held notions regarding leptospirosis in accidental versus maintenance host species. Further, chronic carriage could provide a mechanism for persistent circulation of Leptospira in the California sea lion population, particularly if these animals shed infectious leptospires for months to years. (C) 2013 Elsevier B.V. All rights reserved. C1 [Prager, K. C.; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Prager, K. C.; Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Prager, K. C.; Greig, Denise J.; Soper, Jennifer; Gulland, Frances M. D.] Marine Mammal Ctr, Sausalito, CA 94965 USA. [Alt, David P.; Hornsby, Richard L.; Zuerner, Richard L.] Natl Anim Dis Ctr, Infect Bacterial Dis Res Unit, Ames, IA 50010 USA. [Galloway, Renee L.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Palmer, Lauren J.] Marine Mammal Care Ctr, San Pedro, CA 90731 USA. [Wu, Qingzhong] Natl Ocean Serv, Hollings Marine Lab, Charleston, SC 29412 USA. [Zuerner, Richard L.] Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, S-75007 Uppsala, Sweden. RP Prager, KC (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, 610 Charles E Young Dr South,Box 723905, Los Angeles, CA 90095 USA. EM kcprager@ucla.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU John H. Prescott Marine Mammal Rescue Assistance Grant Program; Hellman Family Foundation; De Logi Chair in Biological Sciences FX We would like to thank the volunteers and staff from TMMC and MMCC/FM who helped in sample collection from stranded and wild-caught sea lions. We would also like to thank the John H. Prescott Marine Mammal Rescue Assistance Grant Program, the Hellman Family Foundation and the De Logi Chair in Biological Sciences for their financial support. This work was performed in part at the University of California Natural Reserve System Ano Nuevo Island Reserve. We would like to thank Ano Nuevo State Park rangers for their logistical support. NR 26 TC 5 Z9 5 U1 1 U2 28 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1135 J9 VET MICROBIOL JI Vet. Microbiol. PD MAY 31 PY 2013 VL 164 IS 1-2 BP 177 EP 183 DI 10.1016/j.vetmic.2013.01.032 PG 7 WC Microbiology; Veterinary Sciences SC Microbiology; Veterinary Sciences GA 133IF UT WOS:000318131400023 PM 23419822 ER PT J AU Karim, ZA Zhang, JC Banerjee, M Chicka, MC Al Hawas, R Hamilton, TR Roche, PA Whiteheart, SW AF Karim, Zubair A. Zhang, Jinchao Banerjee, Meenakshi Chicka, Michael C. Al Hawas, Rania Hamilton, Tara R. Roche, Paul A. Whiteheart, Sidney W. TI I kappa B kinase phosphorylation of SNAP-23 controls platelet secretion SO BLOOD LA English DT Article ID MOLECULAR-MECHANISMS; GRANULE RELEASE; ACTIVATED PLATELETS; SYNTAXIN 2; EXOCYTOSIS; COMPLEX; PROTEINS; SNARE; MICE; INFLAMMATION AB Platelet secretion plays a key role in thrombosis, thus the platelet secretory machinery offers a unique target to modulate hemostasis. We report the regulation of platelet secretion via phosphorylation of SNAP-23 at Ser95. Phosphorylation of this t-soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) occurs upon activation of known elements of the platelet signaling cascades (ie, phospholipase C, [Ca2+](i), protein kinase C) and requires I kappa B kinase (IKK)-beta. Other elements of the nuclear factor kappa B/I kappa B cascade (ie, IKK-alpha,-beta,-gamma/NEMO and CARMA/MALT1/Bcl10 complex) are present in anucleate platelets and I kappa B is phosphorylated upon activation, suggesting that this pathway is active in platelets and implying a nongenomic role for IKK. Inhibition of IKK-beta, either pharmacologically (with BMS-345541, BAY11-7082, or TPCA-1) or by genetic manipulation (platelet factor 4 Cre: IKK-beta f(lox/flox)), blocked SNAP-23 phosphorylation, platelet secretion, and SNARE complex formation; but, had no effect on platelet morphology or other metrics of platelet activation. Consistently, SNAP-23 phosphorylation enhanced membrane fusion of SNARE-containing proteoliposomes. In vivo studies with IKK inhibitors or platelet-specific IKK-beta knockout mice showed that blocking IKK-beta activity significantly prolonged tail bleeding times, suggesting that currently available IKK inhibitors may affect hemostasis. C1 [Karim, Zubair A.; Zhang, Jinchao; Banerjee, Meenakshi; Chicka, Michael C.; Al Hawas, Rania; Hamilton, Tara R.; Whiteheart, Sidney W.] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. [Roche, Paul A.] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Whiteheart, SW (reprint author), Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Biomed & Biol Sci Res Bldg,741 S Limestone St, Lexington, KY 40536 USA. EM whitehe@uky.edu FU National Institutes of Health National Heart, Lung, and Blood Institute [HL56652, HL082193]; American Heart Association Great Rivers Affiliate Post-Doctoral Fellowship; National Institutes of Health Intramural Research Program FX This work was supported by grants from the National Institutes of Health National Heart, Lung, and Blood Institute (HL56652 and HL082193) (S. W. W.); the American Heart Association Great Rivers Affiliate Post-Doctoral Fellowship to M. C. C.; and a grant from the National Institutes of Health Intramural Research Program (P.A.R.). NR 49 TC 31 Z9 31 U1 0 U2 17 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 MAY 30 PY 2013 VL 121 IS 22 BP 4567 EP 4574 DI 10.1182/blood-2012-11-470468 PG 8 WC Hematology SC Hematology GA 184ML UT WOS:000321894100019 PM 23613522 ER PT J AU Li, LQ Freudenberg, J Cui, KR Dale, R Song, SH Dean, A Zhao, KJ Jothi, R Love, PE AF Li, LiQi Freudenberg, Johannes Cui, Kairong Dale, Ryan Song, Sang-Hyun Dean, Ann Zhao, Keji Jothi, Raja Love, Paul E. TI Ldb1-nucleated transcription complexes function as primary mediators of global erythroid gene activation SO BLOOD LA English DT Article ID GENOME-WIDE IDENTIFICATION; KRUPPEL-LIKE FACTOR; FACTOR GATA-1; CHIP-SEQ; CHROMATIN OCCUPANCY; MASTER REGULATOR; POSITIVE ROLE; DIFFERENTIATION; ERYTHROPOIESIS; BINDING AB Erythropoiesis is dependent on the lineage-specific transcription factors Gata1, Tal1, and Klf1. Several erythroid genes have been shown to require all 3 factors for their expression, suggesting that they function synergistically; however, there is little direct evidence for widespread cooperation. Gata1 and Tal1 can assemble within higher-order protein complexes (Ldb1 complexes) that include the adapter molecules Lmo2 and Ldb1. Ldb1 proteins are capable of coassociation, and long-range Ldb1-mediated oligomerization of enhancer- and promoter-bound Ldb1 complexes has been shown to be required for beta-globin gene expression. In this study, we generated a genomewide map of Ldb1 complex binding sites that revealed widespread binding at erythroid genes and at known erythroid enhancer elements. Ldb1 complex binding sites frequently colocalized with Klf1 binding sites and with consensus binding motifs for other erythroid transcription factors. Transcriptomic analysis demonstrated a strong correlation between Ldb1 complex binding and Ldb1 dependency for gene expression and identified a large cohort of genes coregulated by Ldb1 complexes and Klf1. Together, these results provide a foundation for defining the mechanism and scope of Ldb1 complex activity during erythropoiesis. C1 [Li, LiQi; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Freudenberg, Johannes; Jothi, Raja] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Dale, Ryan; Song, Sang-Hyun; Dean, Ann] Natl Inst Diabet & Digest & Kidney Dis, Lab Cellular & Dev Biol, NIH, Bethesda, MD USA. RP Love, PE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM jothi@mail.nih.gov; lovep@mail.nih.gov RI Jothi, Raja/G-3780-2015; OI Dale, Ryan/0000-0003-2664-3744 FU Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health and Human Development [1ZIAHD001803-19]; National Institute of Environmental Health Sciences [1ZIAES102625-04]; National Heart, Lung and Blood Institute [1ZHL006031-04]; National Institute of Diabetes and Digestive and Kidney Diseases [DK075033-04] FX This work was supported by the Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health and Human Development project 1ZIAHD001803-19 (P. E. L.), National Institute of Environmental Health Sciences project 1ZIAES102625-04 (R.J.), National Heart, Lung and Blood Institute project 1ZHL006031-04 (K.Z.), and National Institute of Diabetes and Digestive and Kidney Diseases project DK075033-04 (A.D.). NR 49 TC 34 Z9 34 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 MAY 30 PY 2013 VL 121 IS 22 BP 4575 EP 4585 DI 10.1182/blood-2013-01-479451 PG 11 WC Hematology SC Hematology GA 184ML UT WOS:000321894100020 PM 23610375 ER PT J AU Chandrasekharappa, SC Lach, FP Kimble, DC Kamat, A Teer, JK Donovan, FX Flynn, E Sen, SK Thongthip, S Sanborn, E Smogorzewska, A Auerbach, AD Ostrander, EA AF Chandrasekharappa, Settara C. Lach, Francis P. Kimble, Danielle C. Kamat, Aparna Teer, Jamie K. Donovan, Frank X. Flynn, Elizabeth Sen, Shurjo K. Thongthip, Supawat Sanborn, Erica Smogorzewska, Agata Auerbach, Arleen D. Ostrander, Elaine A. CA NISC Comparative Sequencing Progra TI Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia SO BLOOD LA English DT Article ID SELECTION; IDENTIFICATION; MUTATIONS; CAPTURE; GENE AB Current methods for detecting mutations in Fanconi anemia (FA)-suspected patients are inefficient and often miss mutations. We have applied recent advances in DNA sequencing and genomic capture to the diagnosis of FA. Specifically, we used custom molecular inversion probes or TruSeq-enrichment oligos to capture and sequence FA and related genes, including introns, from 27 samples from the International Fanconi Anemia Registry at The Rockefeller University. DNA sequencing was complemented with custom array comparative genomic hybridization (aCGH) and RNA sequencing (RNA-seq) analysis. aCGH identified deletions/duplications in 4 different FA genes. RNA-seq analysis revealed lack of allele specific expression associated with a deletion and splicing defects caused by missense, synonymous, and deep-in-intron variants. The combination of TruSeq-targeted capture, aCGH, and RNA-seq enabled us to identify the complementation group and biallelic germline mutations in all 27 families: FANCA (7), FANCB (3), FANCC (3), FANCD1 (1), FANCD2 (3), FANCF (2), FANCG (2), FANCI (1), FANCJ (2), and FANCL (3). FANCC mutations are often the cause of FA in patients of Ashkenazi Jewish (AJ) ancestry, and we identified 2 novel FANCC mutations in 2 patients of AJ ancestry. We describe here a strategy for efficient molecular diagnosis of FA. C1 [Chandrasekharappa, Settara C.; Kimble, Danielle C.; Kamat, Aparna; Donovan, Frank X.; Flynn, Elizabeth; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Lach, Francis P.; Thongthip, Supawat; Sanborn, Erica; Smogorzewska, Agata] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA. [Teer, Jamie K.; Sen, Shurjo K.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Auerbach, Arleen D.] Rockefeller Univ, Human Genet & Hematol Program, New York, NY 10065 USA. [NISC Comparative Sequencing Progra] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. RP Auerbach, AD (reprint author), Rockefeller Univ, Human Genet & Hematol Program, 1230 York Ave, New York, NY 10065 USA. EM chandra@mail.nih.gov; auerbac@mail.rockefeller.edu OI Auerbach, Arleen/0000-0002-6911-8379; Ostrander, Elaine/0000-0001-6075-9738 FU National Institutes of Health National Center for Research Resources [UL1RR024143]; Anderson Cancer Center at the Rockefeller University Burroughs Wellcome Fund Career Award for Medical Scientists; Fanconi Anemia Research Fund; Doris Duke Clinical Scientist Development Award FX This work was supported in part by a grant from the National Institutes of Health National Center for Research Resources (grant UL1RR024143) (A. D. A. and A. S.), by the Anderson Cancer Center at the Rockefeller University Burroughs Wellcome Fund Career Award for Medical Scientists (A. S.), and by a grant from the Fanconi Anemia Research Fund (S. C. C.). A. S. is a Rita Allen Foundation, Irma T. Hirschl, and Alexandrine and Alexander Sinsheimer Foundation scholar and is a recipient of a Doris Duke Clinical Scientist Development Award. E.A.O., S. C. C., J.K.T., D. C. K., A. K., F. X. D., E. F., and S. K. S. gratefully acknowledge the Intramural Program of the National Human Genome Research Institute, Bethesda, MD. NR 23 TC 23 Z9 24 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 MAY 30 PY 2013 VL 121 IS 22 BP E138 EP E148 DI 10.1182/blood-2012-12-474585 PG 11 WC Hematology SC Hematology GA 184ML UT WOS:000321894100001 PM 23613520 ER PT J AU Case, CM Sackett, DL Wangsa, D Karpova, T McNally, JG Ried, T Camps, J AF Case, Chanelle M. Sackett, Dan L. Wangsa, Danny Karpova, Tatiana McNally, James G. Ried, Thomas Camps, Jordi TI CKAP2 Ensures Chromosomal Stability by Maintaining the Integrity of Microtubule Nucleation Sites SO PLOS ONE LA English DT Article ID MEROTELIC KINETOCHORE ORIENTATION; MAMMALIAN TISSUE-CELLS; HUMAN MITOTIC SPINDLE; DIFFERENT MECHANISMS; CANCER-CELLS; AURORA-A; IN-SITU; PROTEIN; PHOSPHORYLATION; INSTABILITY AB Integrity of the microtubule spindle apparatus and intact cell division checkpoints are essential to ensure the fidelity of distributing chromosomes into daughter cells. Cytoskeleton-associated protein 2, CKAP2, is a microtubule-associated protein that localizes to spindle poles and aids in microtubule stabilization, but the exact function and mechanism of action are poorly understood. In the present study, we utilized RNA interference to determine the extent to which the expression of CKAP2 plays a role in chromosome segregation. CKAP2-depleted cells showed a significant increase of multipolar mitoses and other spindle pole defects. Notably, when interrogated for microtubule nucleation capacity, CKAP2-depleted cells showed a very unusual phenotype as early as two minutes after release from mitotic block, consisting of dispersal of newly polymerized microtubule filaments through the entire chromatin region, creating a cage-like structure. Nevertheless, spindle poles were formed after one hour of mitotic release suggesting that centrosome-mediated nucleation remained dominant. Finally, we showed that suppression of CKAP2 resulted in a higher incidence of merotelic attachments, anaphase lagging, and polyploidy. Based on these results, we conclude that CKAP2 is involved in the maintenance of microtubule nucleation sites, focusing microtubule minus ends to the spindle poles in early mitosis, and is implicated in maintaining genome stability. C1 [Case, Chanelle M.; Wangsa, Danny; Ried, Thomas; Camps, Jordi] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Case, Chanelle M.] George Washington Univ, Inst Biomed Sci, Washington, DC USA. [Sackett, Dan L.] NICHHD, Sect Cell Biophys, NIH, Bethesda, MD 20892 USA. [Karpova, Tatiana; McNally, James G.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ried, T (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov; campsj@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH); Intramural Research Program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development, NIH FX This project was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH), and partially supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 3 Z9 3 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 MAY 30 PY 2013 VL 8 IS 5 AR e64575 DI 10.1371/journal.pone.0064575 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 177SC UT WOS:000321394700051 PM 23737987 ER PT J AU Thomas, R Thomas, RS Auerbach, SS Portier, CJ AF Thomas, Reuben Thomas, Russell S. Auerbach, Scott S. Portier, Christopher J. TI Biological Networks for Predicting Chemical Hepatocarcinogenicity Using Gene Expression Data from Treated Mice and Relevance across Human and Rat Species SO PLOS ONE LA English DT Article ID RENAL TUBULAR TOXICITY; HEPATOCELLULAR-CARCINOMA; UNITED-STATES; N-ACETYLGLUCOSAMINYLTRANSFERASE; LIVER-CANCER; RISK-FACTORS; CARCINOGENICITY; PROFILES; KEGG; STEATOHEPATITIS AB Background: Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. Objectives: To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Methods: Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Results: Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Conclusions: Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. C1 [Thomas, Reuben] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Thomas, Russell S.] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Auerbach, Scott S.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Biomol Screening Branch, Res Triangle Pk, NC USA. [Portier, Christopher J.] US Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30329 USA. [Portier, Christopher J.] US Ctr Dis Control & Prevent, Agcy Tox Subst & Dis Registry, Atlanta, GA USA. RP Portier, CJ (reprint author), US Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30329 USA. EM cip7@cdc.gov RI Portier, Christopher/A-3160-2010; OI Portier, Christopher/0000-0002-0954-0279; Thomas, Russell/0000-0002-2340-0301 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; Hamner Institutes from the American Chemistry Council's Long-Range Research Initiative FX This research was supported [in part] by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The mouse studies and associated microarray analyses were supported by a grant to The Hamner Institutes from the American Chemistry Council's Long-Range Research Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 7 Z9 7 U1 2 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 MAY 30 PY 2013 VL 8 IS 5 AR e63308 DI 10.1371/journal.pone.0063308 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 177SC UT WOS:000321394700007 PM 23737943 ER PT J AU Anafi, RC Pellegrino, R Shockley, KR Romer, M Tufik, S Pack, AI AF Anafi, Ron C. Pellegrino, Renata Shockley, Keith R. Romer, Micah Tufik, Sergio Pack, Allan I. TI Sleep is not just for the brain: transcriptional responses to sleep in peripheral tissues SO BMC GENOMICS LA English DT Article DE Sleep; Circadian Rhythms; Sleep Deprivation; Unfolded Protein Response; Heart; Lung; Synchronization ID UNFOLDED PROTEIN RESPONSE; MAMMALIAN CIRCADIAN OSCILLATORS; LARGE GENE LISTS; OXIDATIVE STRESS; EXCISION-REPAIR; ENDOPLASMIC-RETICULUM; STATISTICAL TESTS; BODY-TEMPERATURE; CEREBRAL-CORTEX; DNA-DAMAGE AB Background: Many have assumed that the primary function of sleep is for the brain. We evaluated the molecular consequences of sleep and sleep deprivation outside the brain, in heart and lung. Using microarrays we compared gene expression in tissue from sleeping and sleep deprived mice euthanized at the same diurnal times. Results: In each tissue, nearly two thousand genes demonstrated statistically significant differential expression as a function of sleep/wake behavioral state. To mitigate the influence of an artificial deprivation protocol, we identified a subset of these transcripts as specifically sleep-enhanced or sleep-repressed by requiring that their expression also change over the course of unperturbed sleep. 3% and 6% of the assayed transcripts showed "sleep specific" changes in the lung and heart respectively. Sleep specific transcripts in these tissues demonstrated highly significant overlap and shared temporal dynamics. Markers of cellular stress and the unfolded protein response were reduced during sleep in both tissues. These results mirror previous findings in brain. Sleep-enhanced pathways reflected the unique metabolic functions of each tissue. Transcripts related to carbohydrate and sulfur metabolic processes were enhanced by sleep in the lung, and collectively favor buffering from oxidative stress. DNA repair and protein metabolism annotations were significantly enriched among the sleep-enhanced transcripts in the heart. Our results also suggest that sleep may provide a Zeitgeber, or synchronizing cue, in the lung as a large cluster of transcripts demonstrated systematic changes in inter-animal variability as a function of both sleep duration and circadian time. Conclusion: Our data support the notion that the molecular consequences of sleep/wake behavioral state extend beyond the brain to include peripheral tissues. Sleep state induces a highly overlapping response in both heart and lung. We conclude that sleep enhances organ specific molecular functions and that it has a ubiquitous role in reducing cellular metabolic stress in both brain and peripheral tissues. Finally, our data suggest a novel role for sleep in synchronizing transcription in peripheral tissues. C1 [Anafi, Ron C.; Pellegrino, Renata; Romer, Micah; Pack, Allan I.] Univ Penn, Perelman Sch Med, Div Sleep Med, Philadelphia, PA 19104 USA. [Anafi, Ron C.; Pellegrino, Renata; Romer, Micah; Pack, Allan I.] Univ Penn, Perelman Sch Med, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA. [Pellegrino, Renata] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Pellegrino, Renata; Tufik, Sergio] Univ Fed Sao Paulo UNIFESP, Sao Paulo, Brazil. [Shockley, Keith R.] NIEHS, US Dept HHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Anafi, RC (reprint author), Univ Penn, Perelman Sch Med, Div Sleep Med, Philadelphia, PA 19104 USA. EM ron.anafi@uphs.upenn.edu FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences; National Institutes of Health [AG-17628]; American Sleep Medicine Foundation; National Heart Lung Blood Institute [HL090021]; [K12] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. This work was also supported National Institutes of Health Program Project Grant AG-17628 to AP, a Physician Scientist Training Award from the American Sleep Medicine Foundation to RA, and support from a K12 sponsored by the National Heart Lung Blood Institute (HL090021). We thank P. Bushel and G. Kissling (Biostatistics Branch, NIEHS) for reviewing the manuscript and providing helpful suggestions. We also thank J. Hogenesch, D. Raizen, and T. Price for their thoughtful comments. NR 85 TC 18 Z9 19 U1 3 U2 22 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 MAY 30 PY 2013 VL 14 AR 362 DI 10.1186/1471-2164-14-362 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 177OZ UT WOS:000321386100002 PM 23721503 ER PT J AU Ward, Y Lake, R Martin, PL Killian, K Salerno, P Wang, T Meltzer, P Merino, M Cheng, SY Santoro, M Garcia-Rostan, G Kelly, K AF Ward, Y. Lake, R. Martin, P. L. Killian, K. Salerno, P. Wang, T. Meltzer, P. Merino, M. Cheng, S-Y Santoro, M. Garcia-Rostan, G. Kelly, K. TI CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model SO ONCOGENE LA English DT Article DE CD97; LPAR; thyroid cancer; metastasis; vascular invasion; anaplastic ID LYSOPHOSPHATIDIC ACID; PROSTATE-CANCER; MAMMARY TUMORIGENESIS; TUMOR PROGRESSION; HORMONE RECEPTOR; EXPRESSION; CARCINOMAS; AUTOTAXIN; INVASION; 7-TRANSMEMBRANE AB CD97, a member of the adhesion family of G-protein-coupled receptors (GPCRs), complexes with and potentiates lysophosphatidic acid (LPA) receptor signaling to the downstream effector RHOA. We show here that CD97 was expressed in a majority of thyroid cancers but not normal thyroid epithelium and that the level of CD97 expression was further elevated with progression to poorly differentiated and undifferentiated carcinoma. Intratumoral progression also showed that CD97 expression correlates with invasiveness and dedifferentiation. To determine the functional role of CD97, we produced a transgenic model of thyroglobulin promoter-driven CD97 expression. Transgenic CD97 in combination with Thrb(PV), an established mouse model of thyroid follicular cell carcinogenesis, significantly increased the occurrence of vascular invasion and lung metastasis. Expression of transgenic CD97 in thyroid epithelium led to elevated ERK phosphorylation and increased numbers of Ki67 + cells in developing tumors. In addition, tumor cell cultures derived from CD97 transgenic as compared with non-transgenic mice demonstrated enhanced, constitutive and LPA-stimulated ERK activation. In human thyroid cancer cell lines, CD97 depletion reduced RHO-GTP and decreased LPA-stimulated invasion but not EGF-stimulated invasion, further suggesting that CD97 influences an LPA-associated mechanism of progression. Consistent with the above, CD97 expression in human thyroid cancers correlated with LPA receptor and markers of aggressiveness including Ki67 and pAKT. This study shows an autonomous effect of CD97 on thyroid cancer progression and supports the investigation of this GPCR as a therapeutic target for these cancers. C1 [Ward, Y.; Lake, R.; Martin, P. L.; Kelly, K.] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Killian, K.; Meltzer, P.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Salerno, P.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wang, T.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Merino, M.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Cheng, S-Y] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Santoro, M.] Univ Naples Federico II, Dipartimento Biol & Patol Cellulare & Mol, Naples, Italy. [Garcia-Rostan, G.] Univ Valladolid, Spanish Res Council, Inst Biol & Mol Genet, Valladolid, Spain. RP Kelly, K (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bldg 37 Room 1068, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov FU Intramural Research Program; Center for Cancer Research; National Cancer Institute; Programa Ramon y Cajal-Ministerio de Ciencia e Innovacion; Social EU Funds; Universidad de Valladolid, Spain FX This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute and the Programa Ramon y Cajal-Ministerio de Ciencia e Innovacion, Social EU Funds, Universidad de Valladolid, Spain. We acknowledge Barbara J Taylor, Subhadra Banerjee, William G Telford, and Veena Kapoor of the CCR FACS Core Facilities and Christopher D Heger of the CCR Antibody and Protein Purification Unit for their excellent technical support. We thank Drs Cameselle-Teijeiro, X Matias-Guiu, A Herrero and M Fresno-Forcelledo for providing human PDC and UC samples. NR 33 TC 16 Z9 16 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 30 PY 2013 VL 32 IS 22 BP 2726 EP 2738 DI 10.1038/onc.2012.301 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 156FU UT WOS:000319808000004 PM 22797060 ER PT J AU Tang, Y Horikawa, I Ajiro, M Robles, AI Fujita, K Mondal, AM Stauffer, JK Zheng, ZM Harris, CC AF Tang, Y. Horikawa, I. Ajiro, M. Robles, A. I. Fujita, K. Mondal, A. M. Stauffer, J. K. Zheng, Z-M Harris, C. C. TI Downregulation of splicing factor SRSF3 induces p53 beta, an alternatively spliced isoform of p53 that promotes cellular senescence SO ONCOGENE LA English DT Article DE SRSF3; p53; isoform; cellular senescence; alternative splicing ID PRE-MESSENGER-RNA; SR PROTEIN-PHOSPHORYLATION; ONCOGENE-INDUCED SENESCENCE; DNA-DAMAGE; RS-DOMAIN; GENE-EXPRESSION; OVARIAN-CANCER; FACTOR SRP20; LUNG-CANCER; IN-VIVO AB Most human pre-mRNA transcripts are alternatively spliced, but the significance and fine-tuning of alternative splicing in different biological processes is only starting to be understood. SRSF3 (SRp20) is a member of a highly conserved family of splicing factors that have critical roles in key biological processes, including tumor progression. Here, we show that SRSF3 regulates cellular senescence, a p53-mediated process to suppress tumorigenesis, through TP53 alternative splicing. Downregulation of SRSF3 was observed in normal human fibroblasts undergoing replicative senescence, and was associated with the upregulation of p53 beta, an alternatively spliced isoform of p53 that promotes p53-mediated senescence. Knockdown of SRSF3 by short interfering RNA ( siRNA) in early-passage fibroblasts induced senescence, which was associated with elevated expression of p53 beta at mRNA and protein levels. Knockdown of p53 partially rescued SRSF3-knockdown-induced senescence, suggesting that SRSF3 acts on p53-mediated cellular senescence. RNA pulldown assays demonstrated that SRSF3 binds to an alternatively spliced exon uniquely included in p53b mRNA through the consensus SRSF3-binding sequences. RNA crosslinking and immunoprecipitation assays ( CLIP) also showed that SRSF3 in vivo binds to endogenous p53 pre-mRNA at the region containing the p53 beta-unique exon. Splicing assays using a transfected TP53 minigene in combination with siRNA knockdown of SRSF3 showed that SRSF3 functions to inhibit the inclusion of the p53 beta-unique exon in splicing of p53 pre-mRNA. These data suggest that downregulation of SRSF3 represents an endogenous mechanism for cellular senescence that directly regulates the TP53 alternative splicing to generate p53 beta. This study uncovers the role for general splicing machinery in tumorigenesis, and suggests that SRSF3 is a direct regulator of p53. C1 [Tang, Y.; Horikawa, I.; Robles, A. I.; Fujita, K.; Mondal, A. M.; Harris, C. C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ajiro, M.; Zheng, Z-M] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stauffer, J. K.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Room 3068,37 Convent Dr, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Tang, Yizhe/A-8682-2014 FU Intramural Research Program of the NIH; NCI FX This research was supported by the Intramural Research Program of the NIH, NCI. We thank the NIH Fellows Editorial Board for improving the readability of the manuscript. NR 75 TC 26 Z9 27 U1 6 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 MAY 30 PY 2013 VL 32 IS 22 BP 2792 EP 2798 DI 10.1038/onc.2012.288 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 156FU UT WOS:000319808000010 PM 22777358 ER PT J AU Dasso, M AF Dasso, Mary TI BIOCHEMISTRY Rear view of an enzyme SO NATURE LA English DT Editorial Material ID CHAIN FORMATION; SUMO; UBC9; SUMOYLATION; COMPLEX C1 NICHHD, Program Cellular Regulat & Metab, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHHD, Program Cellular Regulat & Metab, Bethesda, MD 20892 USA. EM dassom@mail.nih.gov OI Dasso, Mary/0000-0002-5410-1371 NR 11 TC 2 Z9 2 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 30 PY 2013 VL 497 IS 7451 BP 576 EP 577 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 152UF UT WOS:000319556100033 PM 23698365 ER PT J AU Dykhuizen, EC Hargreaves, DC Miller, EL Cui, KR Korshunov, A Kool, M Pfister, S Cho, YJ Zhao, KJ Crabtree, GR AF Dykhuizen, Emily C. Hargreaves, Diana C. Miller, Erik L. Cui, Kairong Korshunov, Andrey Kool, Marcel Pfister, Stefan Cho, Yoon-Jae Zhao, Keji Crabtree, Gerald R. TI BAF complexes facilitate decatenation of DNA by topoisomerase II alpha SO NATURE LA English DT Article ID CHROMATIN REMODELING COMPLEX; HUMAN GENOME; GENETIC LANDSCAPE; BURKITT-LYMPHOMA; MEDULLOBLASTOMA; PLURIPOTENCY; MUTATIONS; ESBAF; BETA; CHECKPOINT AB Recent exon-sequencing studies of human tumours have revealed that subunits of BAF (mammalian SWI/SNF) complexes are mutated in more than 20% of all human malignancies(1,2), but the mechanisms involved in tumour suppression are unclear. BAF chromatin-remodelling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure(3) and the placement of Polycomb repressive complex 2 (PRC2) across the genome(4,5). Several proteins dedicated to this multisubunit complex, including BRG1 (also known as SMARCA4) and BAF250a (also known as ARID1A), are mutated at frequencies similar to those of recognized tumour suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastomas(6-9) and more than 15% of Burkitt's lymphomas(10,11). Here we show a previously unknown function of BAF complexes in decatenating newly replicated sister chromatids, a requirement for proper chromosome segregation during mitosis. We find that deletion of Brg1 in mouse cells, as well as the expression of BRG1 point mutants identified in human tumours, leads to anaphase bridge formation (in which sister chromatids are linked by catenated strands of DNA) and a G2/M-phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes interact directly with endogenous topoisomerase II alpha (TOP2A) through BAF250a and are required for the binding of TOP2A to approximately 12,000 sites across the genome. Our results demonstrate that TOP2A chromatin binding is dependent on the ATPase activity of BRG1, which is compromised in oncogenic BRG1 mutants. These studies indicate that the ability of TOP2A to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumour suppressors. C1 [Dykhuizen, Emily C.; Hargreaves, Diana C.; Miller, Erik L.; Crabtree, Gerald R.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Dykhuizen, Emily C.; Hargreaves, Diana C.; Crabtree, Gerald R.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Miller, Erik L.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Cui, Kairong; Zhao, Keji] NIH, Bethesda, MD 20892 USA. [Korshunov, Andrey] German Canc Res Ctr, CCU Neuropathol, D-69120 Heidelberg, Germany. [Kool, Marcel; Pfister, Stefan] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany. [Pfister, Stefan] Univ Heidelberg Hosp, Dept Pediat Oncol, D-69120 Heidelberg, Germany. [Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurol & Neurosurg, Stanford, CA 94305 USA. RP Crabtree, GR (reprint author), Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. EM crabtree@stanford.edu RI Kool, Marcel/H-2541-2013; Pfister, Stefan/F-6860-2013 OI Pfister, Stefan/0000-0002-5447-5322 FU NIH; American Cancer Society; Helen Hay Whitney Foundation; NHLBI FX We would like to acknowledge the DNA Sequencing Core facility of the National Heart, Lung, and Blood Institute (NHLBI) for sequencing the ChIP-seq libraries. This work was supported by the NIH (G.R.C.), The American Cancer Society (E.C.D.), The Helen Hay Whitney Foundation (D.C.H.) and the Division of Intramural Research program of NHLBI (K.Z.). G.R.C. is an investigator at the Howard Hughes Medical Institute. NR 37 TC 67 Z9 67 U1 7 U2 54 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 30 PY 2013 VL 497 IS 7451 BP 624 EP + DI 10.1038/nature12146 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 152UF UT WOS:000319556100045 PM 23698369 ER PT J AU Ley, TJ Miller, C Ding, L Raphael, BJ Mungall, AJ Robertson, AG Hoadley, K Triche, TJ Laird, PW Baty, JD Fulton, LL Fulton, R Heath, SE Kalicki-Veizer, J Kandoth, C Klco, JM Koboldt, DC Kanchi, KL Kulkarni, S Lamprecht, TL Larson, DE Lin, L Lu, C McLellan, MD McMichael, JF Payton, J Schmidt, H Spencer, DH Tomasson, MH Wallis, JW Wartman, LD Watson, MA Welch, J Wendl, MC Ally, A Balasundaram, M Birol, I Butterfield, Y Chiu, R Chu, A Chuah, E Chun, HJ Corbett, R Dhalla, N Guin, R He, A Hirst, C Hirst, M Holt, RA Jones, S Karsan, A Lee, D Li, HI Marra, MA Mayo, M Moore, RA Mungall, K Parker, J Pleasance, E Plettner, P Schein, J Stoll, D Swanson, L Tam, A Thiessen, N Varhol, R Wye, N Zhao, YJ Gabriel, S Getz, G Sougnez, C Zou, LH Leiserson, MDM Vandin, F Wu, HT Applebaum, F Baylin, SB Akbani, R Broom, BM Chen, K Motter, TC Nguyen, K Weinstein, JN Zhang, NZ Ferguson, ML Adams, C Black, A Bowen, J Gastier-Foster, J Grossman, T Lichten-Berg, T Wise, L Davidsen, T Demchok, JA Shaw, KRM Sheth, M Sofia, HJ Yang, LM Downing, JR Eley, G Alonso, S Ayala, B Baboud, J Backus, M Barletta, SP Berton, DL Chu, AL Girshik, S Jensen, MA Kahn, A Kothiyal, P Nicholls, MC Pihl, TD Pot, DA Raman, R Sanbhadti, RN Snyder, EE Srinivasan, D Walton, JS Wan, YH Wang, ZN Issa, JPJ Le Beau, M Carroll, M Kantarjian, H Kornblau, S Bootwalla, MS Lai, PH Shen, H Van den Berg, DJ Weisenberger, DJ Link, DC Walter, MJ Ozenberger, BA Mardis, ER Westervelt, P Graubert, TA DiPersio, JF Wilson, RK AF Ley, Timothy J. Miller, Christopher Ding, Li Raphael, Benjamin J. Mungall, Andrew J. Robertson, A. Gordon Hoadley, Katherine Triche, Timothy J., Jr. Laird, Peter W. Baty, Jack D. Fulton, Lucinda L. Fulton, Robert Heath, Sharon E. Kalicki-Veizer, Joelle Kandoth, Cyriac Klco, Jeffery M. Koboldt, Daniel C. Kanchi, Krishna-Latha Kulkarni, Shashikant Lamprecht, Tamara L. Larson, David E. Lin, Ling Lu, Charles McLellan, Michael D. McMichael, Joshua F. Payton, Jacqueline Schmidt, Heather Spencer, David H. Tomasson, Michael H. Wallis, John W. Wartman, Lukas D. Watson, Mark A. Welch, John Wendl, Michael C. Ally, Adrian Balasundaram, Miruna Birol, Inanc Butterfield, Yaron Chiu, Readman Chu, Andy Chuah, Eric Chun, Hye-Jung Corbett, Richard Dhalla, Noreen Guin, Ranabir He, An Hirst, Carrie Hirst, Martin Holt, Robert A. Jones, Steven Karsan, Aly Lee, Darlene Li, Haiyan I. Marra, Marco A. Mayo, Michael Moore, Richard A. Mungall, Karen Parker, Jeremy Pleasance, Erin Plettner, Patrick Schein, Jacquie Stoll, Dominik Swanson, Lucas Tam, Angela Thiessen, Nina Varhol, Richard Wye, Natasja Zhao, Yongjun Gabriel, Stacey Getz, Gad Sougnez, Carrie Zou, Lihua Leiserson, Mark D. M. Vandin, Fabio Wu, Hsin-Ta Applebaum, Frederick Baylin, Stephen B. Akbani, Rehan Broom, Bradley M. Chen, Ken Motter, Thomas C. Nguyen, Khanh Weinstein, John N. Zhang, Nianziang Ferguson, Martin L. Adams, Christopher Black, Aaron Bowen, Jay Gastier-Foster, Julie Grossman, Thomas Lichten-Berg, Tara Wise, Lisa Davidsen, Tanja Demchok, John A. Shaw, Kenna R. Mills Sheth, Margi Sofia, Heidi J. Yang, Liming Downing, James R. Eley, Greg Alonso, Shelley Ayala, Brenda Baboud, Julien Backus, Mark Barletta, Sean P. Berton, Dominique L. Chu, Anna L. Girshik, Stanley Jensen, Mark A. Kahn, Ari Kothiyal, Prachi Nicholls, Matthew C. Pihl, Todd D. Pot, David A. Raman, Rohini Sanbhadti, Rashmi N. Snyder, Eric E. Srinivasan, Deepak Walton, Jes-Sica Wan, Yunhu Wang, Zhining Issa, Jean-Pierre J. Le Beau, Michelle Carroll, Martin Kantarjian, Hagop Kornblau, Steven Bootwalla, Moiz S. Lai, Phillip H. Shen, Hui Van den Berg, David J. Weisenberger, Daniel J. Link, Daniel C. Walter, Matthew J. Ozenberger, Bradley A. Mardis, Elaine R. Westervelt, Peter Graubert, Timothy A. DiPersio, John F. Wilson, Richard K. CA Canc Genome Atlas Res Network TI Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; COPY NUMBER ALTERATIONS; EUROPEAN LEUKEMIANET; EXPRESSION PROFILES; MONOSOMAL KARYOTYPE; MICRORNA EXPRESSION; COMPLEX KARYOTYPE; CANCER; MUTATIONS; GENE AB BACKGROUND Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. C1 [Ley, Timothy J.; Miller, Christopher; Ding, Li; Fulton, Lucinda L.; Fulton, Robert; Kalicki-Veizer, Joelle; Kandoth, Cyriac; Koboldt, Daniel C.; Kanchi, Krishna-Latha; Larson, David E.; Lin, Ling; Lu, Charles; McLellan, Michael D.; McMichael, Joshua F.; Schmidt, Heather; Wallis, John W.; Wendl, Michael C.; Mardis, Elaine R.; Wilson, Richard K.] Washington Univ, Genome Inst, St Louis, MO 63110 USA. [Ley, Timothy J.; Tomasson, Michael H.; Link, Daniel C.; Walter, Matthew J.; Westervelt, Peter; Graubert, Timothy A.; DiPersio, John F.] Siteman Canc Ctr, St Louis, MO USA. [Raphael, Benjamin J.; Leiserson, Mark D. M.; Vandin, Fabio; Wu, Hsin-Ta] Brown Univ, Providence, RI 02912 USA. [Raphael, Benjamin J.; Leiserson, Mark D. M.; Vandin, Fabio; Wu, Hsin-Ta] Ctr Computat Mol Biol, Providence, RI USA. [Mungall, Andrew J.; Robertson, A. Gordon; Ally, Adrian; Balasundaram, Miruna; Birol, Inanc; Butterfield, Yaron; Chiu, Readman; Chu, Andy; Chuah, Eric; Chun, Hye-Jung; Corbett, Richard; Dhalla, Noreen; Guin, Ranabir; Hirst, Carrie; Hirst, Martin; Holt, Robert A.; Jones, Steven; Karsan, Aly; Lee, Darlene; Li, Haiyan I.; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Karen; Parker, Jeremy; Pleasance, Erin; Plettner, Patrick; Schein, Jacquie; Stoll, Dominik; Swanson, Lucas; Tam, Angela; Thiessen, Nina; Varhol, Richard; Wye, Natasja; Zhao, Yongjun] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Hoadley, Katherine] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Triche, Timothy J., Jr.; Laird, Peter W.; Bootwalla, Moiz S.; Lai, Phillip H.; Shen, Hui; Van den Berg, David J.; Weisenberger, Daniel J.] Univ So Calif, Epigenome Ctr, Los Angeles, CA USA. [Baty, Jack D.; Heath, Sharon E.; Klco, Jeffery M.; Kulkarni, Shashikant; Lamprecht, Tamara L.; Payton, Jacqueline; Spencer, David H.; Tomasson, Michael H.; Wartman, Lukas D.; Watson, Mark A.; Welch, John; Link, Daniel C.; Walter, Matthew J.; Westervelt, Peter; Graubert, Timothy A.; DiPersio, John F.] Washington Univ, St Louis, MO 63110 USA. [Gabriel, Stacey; Getz, Gad; Sougnez, Carrie; Zou, Lihua] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Applebaum, Frederick] Fred Hutchinson Canc Res Ctr, Div Med Oncol, Seattle Canc Care Alliance, Seattle, WA 98104 USA. [Baylin, Stephen B.] Johns Hopkins Univ, Baltimore, MD USA. [Akbani, Rehan; Broom, Bradley M.; Chen, Ken; Motter, Thomas C.; Nguyen, Khanh; Weinstein, John N.; Zhang, Nianziang; Kantarjian, Hagop; Kornblau, Steven] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ferguson, Martin L.] MLF Consulting, Boston, MA USA. [Adams, Christopher; Black, Aaron; Bowen, Jay; Gastier-Foster, Julie; Grossman, Thomas; Lichten-Berg, Tara; Wise, Lisa] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Davidsen, Tanja; Demchok, John A.; Shaw, Kenna R. Mills; Sheth, Margi; Yang, Liming] NCI, Bethesda, MD 20892 USA. [Sofia, Heidi J.; Ozenberger, Bradley A.] NHGRI, Bethesda, MD 20892 USA. [Downing, James R.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Eley, Greg] Sciementis LLC, Statham, GA USA. [Alonso, Shelley; Ayala, Brenda; Baboud, Julien; Backus, Mark; Barletta, Sean P.; Berton, Dominique L.; Chu, Anna L.; Girshik, Stanley; Jensen, Mark A.; Kahn, Ari; Kothiyal, Prachi; Nicholls, Matthew C.; Pihl, Todd D.; Pot, David A.; Raman, Rohini; Sanbhadti, Rashmi N.; Snyder, Eric E.; Srinivasan, Deepak; Walton, Jes-Sica; Wan, Yunhu; Wang, Zhining] SRA Int, Fairfax, VA USA. [Issa, Jean-Pierre J.] Temple Univ, Philadelphia, PA 19122 USA. [Le Beau, Michelle] Univ Chicago, Chicago, IL 60637 USA. [Carroll, Martin] Univ Penn, Philadelphia, PA 19104 USA. RP Ley, TJ (reprint author), Washington Univ, Sch Med, Div Oncol, Stem Cell Biol Sect, Campus Box 8007,660 S Euclid Ave, St Louis, MO 63110 USA. EM timley@wustl.edu RI Tang, Macy/B-9798-2014; Waha, Andreas/J-2950-2014; Holt, Robert/C-3303-2009; Laird, Peter/G-8683-2012; Karsan, Aly/K-2067-2015; Hirst, Martin/B-7684-2016; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; OI Graubert, Timothy/0000-0002-7710-1171; Klco, Jeffery/0000-0003-2961-6960; Triche, Tim/0000-0001-5665-946X; Kandoth, Cyriac/0000-0002-1345-3573; Larson, David/0000-0001-7934-5906; Birol, Inanc/0000-0003-0950-7839; Pot, David/0000-0002-1480-9826 FU National Institutes of Health [U24CA143845, U24CA143858, U24CA144025, U24CA143882, U24CA143866, U24CA143867, U24CA143848, U24CA143840, U24CA143835, U24CA143799, U24CA143883, U24CA143843, U54HG003067, U54HG003079, U54HG003273, P01CA101937] FX Supported by grants from the National Institutes of Health (U24CA143845, U24CA143858, U24CA144025, U24CA143882, U24CA143866, U24CA143867, U24CA143848, U24CA143840, U24CA143835, U24CA143799, U24CA143883, U24CA143843, U54HG003067, U54HG003079, U54HG003273, and P01CA101937).; Funded by the National Institutes of Health. NR 49 TC 707 Z9 715 U1 25 U2 141 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 MAY 30 PY 2013 VL 368 IS 22 BP 2059 EP 2074 DI 10.1056/NEJMoa1301689 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 153AT UT WOS:000319574200004 ER PT J AU Hataye, JM Palmore, TN Powers, JH AF Hataye, Jason M. Palmore, Tara N. Powers, John H., III TI Duodenal Infusion of Feces for Recurrent Clostridium difficile SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hataye, Jason M.; Palmore, Tara N.] NIH, Bethesda, MD 20892 USA. [Powers, John H., III] SAIC Frederick, Frederick, MD USA. RP Hataye, JM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM jason.hataye@nih.gov NR 4 TC 1 Z9 1 U1 0 U2 3 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 MAY 30 PY 2013 VL 368 IS 22 BP 2143 EP 2144 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 153AT UT WOS:000319574200017 PM 23718170 ER PT J AU Adleman, NE Kayser, RR Olsavsky, AK Bones, BL Muhrer, EJ Fromm, SJ Pine, DS Zarate, C Leibenluft, E Brotman, MA AF Adleman, Nancy E. Kayser, Reilly R. Olsavsky, Aviva K. Bones, Brian L. Muhrer, Eli J. Fromm, Stephen J. Pine, Daniel S. Zarate, Carlos Leibenluft, Ellen Brotman, Melissa A. TI Abnormal fusiform activation during emotional-face encoding assessed with functional magnetic resonance imaging SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Functional magnetic resonance imaging (fMRI); Bipolar disorder; Encoding; Affective disorder; Fusiform gyrus ID PEDIATRIC BIPOLAR DISORDER; FACIAL AFFECT RECOGNITION; CHILDREN; DEFICITS; MEMORY; FMRI AB This functional magnetic resonance imaging study shows that children and adults with bipolar disorder (BD), compared with healthy subjects, exhibit impaired memory for emotional faces and abnormal fusiform activation during encoding. Fusiform activation abnormalities in BD were correlated with mania severity and may therefore represent a trait and state BD biomarker. Published by Elsevier Ireland Ltd. C1 [Adleman, Nancy E.; Kayser, Reilly R.; Olsavsky, Aviva K.; Bones, Brian L.; Muhrer, Eli J.; Fromm, Stephen J.; Pine, Daniel S.; Leibenluft, Ellen; Brotman, Melissa A.] NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kayser, Reilly R.; Bones, Brian L.] Georgetown Univ, Sch Med, Washington, DC USA. [Olsavsky, Aviva K.] UCLA Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Zarate, Carlos] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Adleman, NE (reprint author), 9000 Rockville Pike,Bldg 15K,Room 204, Bethesda, MD 20892 USA. EM adlemann@mail.nih.gov RI Brotman, Melissa/H-7409-2013 FU Intramural Research Program of the NIMH; NIH; Pfizer Inc. FX This research was supported (in part) by the Intramural Research Program of the NIMH. Dr. Olsavsky's research was made possible through the Clinical Research Training Program, a public private partnership supported jointly by the NIH and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine in major depression; he has assigned his rights in the patent to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors report no financial relationships with commercial interests. We would like to thank the staff of the Emotion and Development Branch at NIMH and the subjects and families for their participation. NR 16 TC 12 Z9 12 U1 2 U2 4 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 MAY 30 PY 2013 VL 212 IS 2 BP 161 EP 163 DI 10.1016/j.pscychresns.2013.01.006 PG 3 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 150BX UT WOS:000319366300011 PM 23541333 ER PT J AU Bumb, A Sarkar, SK Billington, N Brechbiel, MW Neuman, KC AF Bumb, Ambika Sarkar, Susanta K. Billington, Neil Brechbiel, Martin W. Neuman, Keir C. TI Silica Encapsulation of Fluorescent Nanodiamonds for Colloidal Stability and Facile Surface Functionalization SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MICROSCOPY; MOLECULES; DIAMOND AB Fluorescent nanodiamonds (FNDs) emit in the near-IR and do not photobleach or photoblink. These properties make FNDs better suited for numerous imaging applications compared with commonly used fluorescence agents such as organic dyes and quantum dots. However, nanodiamonds do not form stable suspensions in aqueous buffer, are prone to aggregation, and are difficult to functionalize. Here we present a method for encapsulating nanodiamonds with silica using an innovative liposome-based encapsulation process that renders the particle surface biocompatible, stable, and readily functionalized through routine linking chemistries. Furthermore, the method selects for a desired particle size and produces a monodisperse agent. We attached biotin to the silica coated FNDs and tracked the three-dimensional motion of a biotinylated FND tethered by a single DNA molecule with high spatial and temporal resolution. C1 [Bumb, Ambika; Sarkar, Susanta K.; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Billington, Neil] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Brechbiel, Martin W.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Neuman, KC (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 South Dr,Bldg 50,Room 3517, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011; OI Neuman, Keir/0000-0002-0863-5671; Billington, Neil/0000-0003-2306-0228 FU National Institutes of Health (NCI); National Institutes of Health (NHLBI) FX This research was supported by the National Institutes of Health (NCI and NHLBI). We thank Joe Barchi for help with FTIR, the NHLBI Biophysical Core Facility and Grzegorz Piszczek for help with scattering measurements, Jonathan Silver for help in preparing the DNA molecules, Richard Leapman and Maria Aronova at NIBIB for assistance, and Gopalakrishnan Balasubramanian for helpful discussions. NR 25 TC 34 Z9 34 U1 8 U2 109 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 29 PY 2013 VL 135 IS 21 BP 7815 EP 7818 DI 10.1021/ja4016815 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 156XH UT WOS:000319856700007 PM 23581827 ER PT J AU He, J Huang, XL Li, YC Liu, YJ Babu, T Aronova, MA Wang, SJ Lu, ZY Chen, XY Nie, ZH AF He, Jie Huang, Xinglu Li, Yan-Chun Liu, Yijing Babu, Taarika Aronova, Maria A. Wang, Shouju Lu, Zhongyuan Chen, Xiaoyuan Nie, Zhihong TI Self-Assembly of Amphiphilic Plasmonic Micelle-Like Nanoparticles in Selective Solvents SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ENCAPSULATING GOLD NANOPARTICLES; COPOLYMER MICROPHASE SEPARATION; DISSIPATIVE PARTICLE DYNAMICS; BLOCK-COPOLYMERS; INORGANIC NANOPARTICLES; POLYMERIC ASSEMBLIES; TRIBLOCK COPOLYMERS; DIBLOCK COPOLYMERS; QUANTUM DOTS; VESICLES AB Amphiphilic plasmonic micelle like nanoparticles (APMNs) composed of gold nanoparticles (AuNPs) and amphiphilic block copolymers (BCPs) structurally resemble polymer micelles with well-defined architectures and chemistry. The APMNs can be potentially considered as a prototype for modeling a higher level self assembly of micelles The understanding of such secondary self assembly is of particular importance for the bottom up design of new hierarchical nanostructures. This, article describes the self assembly, modeling, and applications of APMN assemblies in selective solvents. In a mixture of water/tetrahydrofuran, APMNs assembled into various superstructures, including unimolecular micelles, clusters with controlled number of APMNs, and vesicles, depending on the lengths of polymer tethers and the sizes of AuNP cores. The delicate interplay of entropy and enthalpy contributions to the overall free energy associated with the assembly process, which is strongly dependent on the spherical architecture of APMNs, yields an assembly diagram that is different from the assembly of linear BCPs. Our experimental and computational studies suggested that the morphologies of assemblies were largely determined by the deformability of the effective nanoparticles (that is, nanoparticles together with tethered chains as a whole). The assemblies of APMNs resulted in strong absorption in near-infrared range due to the remarkable plasmonic coupling of Au cores, thus facilitating their biomedical applications in bioimaging and photothermal therapy of cancer. C1 [He, Jie; Liu, Yijing; Babu, Taarika; Nie, Zhihong] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Huang, Xinglu; Wang, Shouju; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Aronova, Maria A.] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Li, Yan-Chun; Lu, Zhongyuan] Jilin Univ, Inst Theoret Chem, State Key Lab Theoret & Computat Chem, Changchun 130023, Peoples R China. RP Lu, ZY (reprint author), Jilin Univ, Inst Theoret Chem, State Key Lab Theoret & Computat Chem, Changchun 130023, Peoples R China. EM luzhy@jlu.edu.cn; shawn.chen@nih.gov; znie@umd.edu RI Li, Yan-Chun/G-4689-2013; Lu, Zhong-Yuan/G-8269-2011; Nie, Zhihong/D-7495-2011; Liu, Yijing/D-6666-2016; OI Li, Yan-Chun/0000-0002-7872-8208; Nie, Zhihong/0000-0001-9639-905X; He, Jie/0000-0003-0252-3094 FU University of Maryland; NIBIB, NIH; Arnold and Mabel Beckman Foundation; Maryland Nano Center; NispLab; FabLab; NSF FX Z.N. acknowledges financial support of startup funds from the University of Maryland. X.C. thanks the Intramural Research Program (IRP) of the NIBIB, NIH. T.B. thanks the support of the Arnold and Mabel Beckman Foundation. We also acknowledge the support of the Maryland Nano Center and its NispLab and FabLab. The NispLab is supported in part by the NSF as a MRSEC Shared Experimental Facilities. NR 72 TC 106 Z9 107 U1 34 U2 422 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 29 PY 2013 VL 135 IS 21 BP 7974 EP 7984 DI 10.1021/ja402015s PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 156XH UT WOS:000319856700030 PM 23642094 ER PT J AU Batra, VK Perera, L Lin, P Shock, DD Beard, WA Pedersen, LC Pedersen, LG Wilson, SH AF Batra, Vinod K. Perera, Lalith Lin, Ping Shock, David D. Beard, William A. Pedersen, Lars C. Pedersen, Lee G. Wilson, Samuel H. TI Amino Acid Substitution in the Active Site of DNA Polymerase beta Explains the Energy Barrier of the Nucleotidyl Transfer Reaction SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PARTICLE MESH EWALD; ESCHERICHIA-COLI; MECHANISM; FIDELITY; INSERTION; EFFICIENCY; SYSTEM AB DNA polymerase beta (pol beta) is a bifunctional enzyme widely studied for its roles in base excision DNA repair, where one key function is gap filling DNA synthesis. In spite of significant progress in recent years, the atomic level mechanism of the DNA synthesis reaction has remained poorly understood. Based on crystal structures of pol beta in complex with its substrates and theoretical considerations of amino acids and metals in the active site, we have proposed that a nearby carboxylate group of Asp256 enables the reaction by accepting a proton from the primer O3'group, thus activating O3'as the nucleophile in the reaction path. Here, we tested this proposal by altering the side chain of Asp256 to Glu and then exploring the impact of this conservative change on the reaction. The D256E enzyme is more than 1000 fold less active than the wild type enzyme, and the crystal structures are subtly different in the active sites of the D256E and wild type enzymes. Theoretical analysis of DNA synthesis by the D256E enzyme shows that the O3'proton still transfers to the nearby carboxylate of residue 256. However, the electrostatic stabilization and location of the O3' proton transfer during the reaction path are dramatically altered compared with wild type Surprisingly, this is due to repositioning of the Arg254 side chain in the Glu256 enzyme active site, such that Arg254 is not in position to stabilize the proton transfer from O3'. The theoretical results with the wild type enzyme indicate an early charge reorganization associated with the O3' proton transfer, and this does not occur in the D256E enzyme. The charge reorganization is mediated by the catalytic magnesium ion in the active site. C1 [Batra, Vinod K.; Perera, Lalith; Shock, David D.; Beard, William A.; Pedersen, Lars C.; Pedersen, Lee G.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Pedersen, Lee G.] Univ N Carolina, Dept Chem, CB3290, Chapel Hill, NC 27599 USA. [Lin, Ping] Penn State Univ, University Pk, PA 16802 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES050158, Z01-ES050161, Z01-ES043010, Z01-ES102645]; NIH [HL-006350] FX This research was supported by Research Project Numbers Z01-ES050158 and Z01-ES050161 (S.H.W.), Z01-ES043010 (L.G.P.) and Z01-ES102645 (L.C.P.) in the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. L.G.P. also acknowledges support from NIH HL-006350. NR 35 TC 19 Z9 19 U1 0 U2 28 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 29 PY 2013 VL 135 IS 21 BP 8078 EP 8088 DI 10.1021/ja403842j PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 156XH UT WOS:000319856700042 PM 23647366 ER PT J AU Cizza, G Piaggi, P Lucassen, EA de Jonge, L Walter, M Mattingly, MS Kalish, H Csako, G Rother, KI AF Cizza, Giovanni Piaggi, Paolo Lucassen, Eliane A. de Jonge, Lilian Walter, Mary Mattingly, Megan S. Kalish, Heather Csako, Gyorgy Rother, Kristina I. CA Sleep Extension Study Grp TI Obstructive Sleep Apnea Is a Predictor of Abnormal Glucose Metabolism in Chronically Sleep Deprived Obese Adults SO PLOS ONE LA English DT Article ID INSULIN-RESISTANCE; DAYTIME SLEEPINESS; MEN; SENSITIVITY; DURATION AB Context: Sleep abnormalities, including obstructive sleep apnea (OSA), have been associated with insulin resistance. Objective: To determine the relationship between sleep, including OSA, and glucose parameters in a prospectively assembled cohort of chronically sleep-deprived obese subjects. Design: Cross-sectional evaluation of a prospective cohort study. Setting: Tertiary Referral Research Clinical Center. Main Outcome Measure(s): Sleep duration and quality assessed by actigraphy, sleep diaries and questionnaires, OSA determined by a portable device; glucose metabolism assessed by oral glucose tolerance test (oGTT), and HbA(1)c concentrations in 96 obese individuals reporting sleeping less than 6.5 h on a regular basis. Results: Sixty % of subjects had an abnormal respiratory disturbance index (RDI >= 5) and 44% of these subjects had abnormal oGTT results. Severity of OSA as assessed by RDI score was associated with fasting glucose (R = 0.325, p = 0.001) and fasting insulin levels (rho = 0.217, p = 0.033). Subjects with moderate to severe OSA (RDI>15) had higher glucose concentrations at 120 min than those without OSA (RDI<5) (p = 0.017). Subjects with OSA also had significantly higher concentrations of plasma ACTH (p = 0.009). Several pro-inflammatory cytokines were higher in subjects with OSA (p<0.050). CRP levels were elevated in this sample, suggesting increased cardiovascular risk. Conclusions: OSA is associated with impaired glucose metabolism in obese, sleep deprived individuals. Since sleep apnea is common and frequently undiagnosed, health care providers should be aware of its occurrence and associated risks. C1 [Cizza, Giovanni; Lucassen, Eliane A.; de Jonge, Lilian; Walter, Mary; Mattingly, Megan S.] NIDDKD, Sect Neuroendocrinol Obes, Bethesda, MD 20892 USA. [Piaggi, Paolo] Univ Hosp Pisa, Endocrinol Unit, Obes Res Ctr, Pisa, Italy. [Lucassen, Eliane A.] Leiden Univ, Med Ctr, Neurophysiol Lab, Dept Mol Cell Biol, Leiden, Netherlands. [Kalish, Heather] Natl Inst Biomed & Bioengineering, Bethesda, MD USA. [Csako, Gyorgy] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Rother, Kristina I.] NIDDKD, Sect Pediat Diabet & Metab, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), NIDDKD, Sect Neuroendocrinol Obes, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov OI de Jonge, Lilian/0000-0001-5900-0695; Piaggi, Paolo/0000-0003-2774-9161 FU National Institutes of Health (NIH), Intramural Research Program: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This study was fully supported by the National Institutes of Health (NIH), Intramural Research Program: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 13 Z9 13 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 MAY 29 PY 2013 VL 8 IS 5 AR e65400 DI 10.1371/journal.pone.0065400 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 155DJ UT WOS:000319725500014 PM 23734252 ER PT J AU Bianco, P Barker, R Brustle, O Cattaneo, E Clevers, H Daley, GQ De Luca, M Goldstein, L Lindvall, O Mummery, C Robey, PG Brito, CSDE Smith, A AF Bianco, Paolo Barker, Roger Bruestle, Oliver Cattaneo, Elena Clevers, Hans Daley, George Q. De Luca, Michele Goldstein, Lawrence Lindvall, Olle Mummery, Christine Robey, Pamela G. de Sousa e Brito, Clara Sattler Smith, Austin TI Regulation of stem cell therapies under attack in Europe: for whom the bell tolls SO EMBO JOURNAL LA English DT Article ID MESENCHYMAL STROMAL CELLS; BONE; MEDICINE; TRANSPLANTATION; SCIENCE AB At the time of writing, the Italian Parliament is debating a new law that would make it legal to practice an unproven stem cell treatment in public hospitals. The treatment, offered by a private non-medical organization, may not be safe, lacks a rationale, and violates current national laws and European regulations. This case raises multiple concerns, most prominently the urgent need to protect patients who are severely ill, exposed to significant risks, and vulnerable to exploitation. The scientific community must consider the context-social, financial, medical, legal-in which stem cell science is currently situated and the need for stringent regulation. Additional concerns are emerging. These emanate from the novel climate, created within science itself, and stem cell science in particular, by the currently prevailing model of 'translational medicine'. Only rigorous science and rigorous regulation can ensure translation of science into effective therapies rather than into ineffective market products, and mark, at the same time, the sharp distinction between the striving for new therapies and the deceit of patients. C1 [Bianco, Paolo] Univ Roma La Sapienza, Dept Mol Med, Rome, Italy. [Barker, Roger] Univ Cambridge, Sch Clin Med, John van Geest Ctr Brain Repair, Cambridge, England. [Bruestle, Oliver] Univ Bonn, Inst Reconstruct Neurobiol, LIFE & BRAIN Ctr, Bonn, Germany. [Cattaneo, Elena] Univ Milan, Dept Biosci, Milan, Italy. [Cattaneo, Elena] Univ Milan, Ctr Stem Cell Res UniStem, Milan, Italy. [Clevers, Hans] Hubrecht Inst, Utrecht, Netherlands. [Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA USA. [De Luca, Michele] Univ Modena & Reggio Emilia, Ctr Regenerat Med Stefano Ferrari, Modena, Italy. [Goldstein, Lawrence] Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, San Diego, CA 92103 USA. [Goldstein, Lawrence] Univ Calif San Diego, Sch Med, Dept Neurosci, San Diego, CA 92103 USA. [Lindvall, Olle] Univ Lund Hosp, Lund Stem Cell Ctr, S-22185 Lund, Sweden. [Mummery, Christine] Leiden Univ, Med Ctr, Dept Anat & Embryol, Leiden, Netherlands. [Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [de Sousa e Brito, Clara Sattler] Univ Catolica, Fac Law, Lisbon, Portugal. [Smith, Austin] Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge, England. RP Bianco, P (reprint author), Univ Roma La Sapienza, Dipartimento Med Sperimentale, I-00185 Rome, Italy. EM paolo.bianco@uniroma1.it RI Robey, Pamela/H-1429-2011; De Luca, Michele/N-5883-2014; OI Robey, Pamela/0000-0002-5316-5576; De Luca, Michele/0000-0002-0850-8445; CATTANEO, ELENA/0000-0002-0755-4917 FU Medical Research Council [MC_PC_12009, G1100526]; Wellcome Trust [079249] NR 25 TC 35 Z9 35 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD MAY 29 PY 2013 VL 32 IS 11 BP 1489 EP 1495 DI 10.1038/emboj.2013.114 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 152WQ UT WOS:000319562800001 PM 23644381 ER PT J AU Anderson, CA Blackstone, C AF Anderson, Caroline A. Blackstone, Craig TI SUMO wrestling with Drp1 at mitochondria SO EMBO JOURNAL LA English DT Editorial Material ID FISSION AB Mitochondria undergo dynamic fission and fusion events, and disruptions in this balance can lead to cellular dysfunction or death. New work by Henley and colleagues identifies a key role for the SUMO protease SENP3 and its target Drp1, a key mediator of mitochondrial fission, in ischaemia. C1 [Anderson, Caroline A.; Blackstone, Craig] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Anderson, Caroline A.] UCL, Sch Pharm, Dept Pharmacol, London, England. RP Blackstone, C (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU Intramural NIH HHS NR 10 TC 7 Z9 7 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 29 PY 2013 VL 32 IS 11 BP 1496 EP 1498 DI 10.1038/emboj.2013.103 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 152WQ UT WOS:000319562800002 PM 23632859 ER PT J AU Grontved, L John, S Baek, S Liu, Y Buckley, JR Vinson, C Aguilera, G Hager, GL AF Grontved, Lars John, Sam Baek, Songjoon Liu, Ying Buckley, John R. Vinson, Charles Aguilera, Greti Hager, Gordon L. TI C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements SO EMBO JOURNAL LA English DT Article DE C/EBP; Chromatin; DNase-seq; GR; Liver tissue ID BINDING PROTEIN-BETA; REGULATORY ELEMENTS; IN-VIVO; PREADIPOCYTE DIFFERENTIATION; REMODELING COMPLEXES; HUMAN GENOME; MOUSE-LIVER; TRANSCRIPTION; ALPHA; SITES AB Mechanisms regulating transcription factor interaction with chromatin in intact mammalian tissues are poorly understood. Exploiting an adrenalectomized mouse model with depleted endogenous glucocorticoids, we monitor changes of the chromatin landscape in intact liver tissue following glucocorticoid injection. Upon activation of the glucocorticoid receptor (GR), proximal regions of activated and repressed genes are remodelled, and these remodelling events correlate with RNA polymerase II occupancy of regulated genes. GR is exclusively associated with accessible chromatin and 62% percent of GR-binding sites are occupied by C/EBP beta. At the majority of these sites, chromatin is preaccessible suggesting a priming function of C/EBP beta for GR recruitment. Disruption of C/EBP beta binding to chromatin results in attenuation of pre-programmed chromatin accessibility, GR recruitment and GR-induced chromatin remodelling specifically at sites co-occupied by GR and C/EBP beta. Collectively, we demonstrate a highly cooperative mechanism by which C/EBP beta regulates selective GR binding to the genome in liver tissue. We suggest that selective targeting of GR in other tissues is likely mediated by the combined action of cell-specific priming proteins and chromatin remodellers. C1 [Grontved, Lars; John, Sam; Baek, Songjoon; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Liu, Ying; Aguilera, Greti] Natl Inst Child Hlth & Dev, Sect Endocrine Physiol, NIH, Bethesda, MD USA. [Buckley, John R.; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,Room B602, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov OI Grontved, Lars/0000-0002-6735-8483 FU Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research (CCR); Lundbeck Foundation FX We thank Tina Miranda, Michael Guertin, Diego Presman and members Vinson lab for critical reading of the manuscript. LG was supported by a research grant from the Lundbeck Foundation. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research (CCR). NR 66 TC 52 Z9 53 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 29 PY 2013 VL 32 IS 11 BP 1568 EP 1583 DI 10.1038/emboj.2013.106 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 152WQ UT WOS:000319562800009 PM 23665916 ER PT J AU Sato, T Kaneda, A Tsuji, S Isagawa, T Yamamoto, S Fujita, T Yamanaka, R Tanaka, Y Nukiwa, T Marquez, VE Ishikawa, Y Ichinose, M Aburatani, H AF Sato, Teruyuki Kaneda, Atsushi Tsuji, Shingo Isagawa, Takayuki Yamamoto, Shogo Fujita, Takanori Yamanaka, Ryota Tanaka, Yukiko Nukiwa, Toshihiro Marquez, Victor E. Ishikawa, Yuichi Ichinose, Masakazu Aburatani, Hiroyuki TI PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer SO SCIENTIFIC REPORTS LA English DT Article ID LONG-TERM SURVIVAL; LIM PROTEIN AJUBA; PROSTATE-CANCER; HISTOLOGIC TYPE; STEM-CELLS; POLYCOMB; EZH2; EXPRESSION; COMPLEX; ADENOCARCINOMA AB Small cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. Expression array analysis of 23 SCLC cases and 42 normal tissues revealed that EZH2 and other PRC2 members were highly expressed in SCLC. ChIP-seq for H3K27me3 suggested that genes with H3K27me3(+) in SCLC were extended not only to PRC2-target genes in ES cells but also to other target genes such as cellular adhesion-related genes. These H3K27me3(+) genes in SCLC were repressed significantly, and introduction of the most repressed gene JUB into SCLC cell line lead to growth inhibition. Shorter overall survival of clinical SCLC cases correlated to repression of JUB alone, or a set of four genes including H3K27me3(+) genes. Treatment with EZH2 inhibitors, DZNep and GSK126, resulted in growth repression of SCLC cell lines. High PRC2 expression was suggested to contribute to gene repression in SCLC, and may play a role in genesis of SCLC. C1 [Sato, Teruyuki; Kaneda, Atsushi; Tsuji, Shingo; Isagawa, Takayuki; Yamamoto, Shogo; Fujita, Takanori; Yamanaka, Ryota; Tanaka, Yukiko; Aburatani, Hiroyuki] Univ Tokyo, Genome Sci Div, RCAST, Tokyo 1138654, Japan. [Sato, Teruyuki; Nukiwa, Toshihiro; Ichinose, Masakazu] Tohoku Univ, Grad Sch Med, Dept Resp Med, Sendai, Miyagi 980, Japan. [Kaneda, Atsushi] Chiba Univ, Dept Mol Oncol, Grad Sch Med, Chiba, Japan. [Kaneda, Atsushi] Japan Sci & Technol Agcy JST, CREST, Tokyo, Japan. [Marquez, Victor E.] NCI, Biol Chem Lab, Frederick Natl Lab Canc Res, Bethesda, MD 20892 USA. [Ishikawa, Yuichi] Canc Inst Hosp, Japanese Fdn Canc Res, Div Pathol, Tokyo, Japan. RP Kaneda, A (reprint author), Univ Tokyo, Genome Sci Div, RCAST, Tokyo 1138654, Japan. EM kaneda@genome.rcast.u-tokyo.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan; New Energy and Industrial Technology Development Organization (NEDO); JST Core Research for Evolutional Science and Technology (CREST) program; NIH, National Cancer Institute, Center for Cancer Research FX We thank Kaori Shiina, Hiroko Meguro and Kyoko Fujinaka for their technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the NFAT project from the New Energy and Industrial Technology Development Organization (NEDO), by JST Core Research for Evolutional Science and Technology (CREST) program, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 57 TC 30 Z9 34 U1 3 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 MAY 29 PY 2013 VL 3 AR 1911 DI 10.1038/srep01911 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 152TJ UT WOS:000319553700003 PM 23714854 ER PT J AU Wright, GEB Koornhof, PGJ Adeyemo, AA Tiffin, N AF Wright, Galen E. B. Koornhof, Pieter G. J. Adeyemo, Adebowale A. Tiffin, Nicki TI Ethical and legal implications of whole genome and whole exome sequencing in African populations SO BMC MEDICAL ETHICS LA English DT Article DE African populations; Ethical, legal, and societal issues; Next generation sequencing; Whole genome and whole exome sequencing ID INFORMED-CONSENT; INCIDENTAL FINDINGS; GENETIC RESEARCH; COMMUNITY ENGAGEMENT; RESEARCH PARTICIPANTS; DEVELOPING-COUNTRIES; HAPMAP PROJECT; MEDICINE; DISEASE; STIGMA AB Background: Rapid advances in high throughput genomic technologies and next generation sequencing are making medical genomic research more readily accessible and affordable, including the sequencing of patient and control whole genomes and exomes in order to elucidate genetic factors underlying disease. Over the next five years, the Human Heredity and Health in Africa (H3Africa) Initiative, funded by the Wellcome Trust (United Kingdom) and the National Institutes of Health (United States of America), will contribute greatly towards sequencing of numerous African samples for biomedical research. Discussion: Funding agencies and journals often require submission of genomic data from research participants to databases that allow open or controlled data access for all investigators. Access to such genotype-phenotype and pedigree data, however, needs careful control in order to prevent identification of individuals or families. This is particularly the case in Africa, where many researchers and their patients are inexperienced in the ethical issues accompanying whole genome and exome research; and where an historical unidirectional flow of samples and data out of Africa has created a sense of exploitation and distrust. In the current study, we analysed the implications of the anticipated surge of next generation sequencing data in Africa and the subsequent data sharing concepts on the protection of privacy of research subjects. We performed a retrospective analysis of the informed consent process for the continent and the rest-of-the-world and examined relevant legislation, both current and proposed. We investigated the following issues: (i) informed consent, including guidelines for performing culturally-sensitive next generation sequencing research in Africa and availability of suitable informed consent documents; (ii) data security and subject privacy whilst practicing data sharing; (iii) conveying the implications of such concepts to research participants in resource limited settings. Summary: We conclude that, in order to meet the unique requirements of performing next generation sequencing-related research in African populations, novel approaches to the informed consent process are required. This will help to avoid infringement of privacy of individual subjects as well as to ensure that informed consent adheres to acceptable data protection levels with regard to use and transfer of such information. C1 [Wright, Galen E. B.; Tiffin, Nicki] Univ Western Cape, South African Natl Bioinformat Inst, ZA-7535 Bellville, South Africa. [Koornhof, Pieter G. J.] Univ Western Cape, Dept Mercantile & Labour Law, ZA-7535 Bellville, South Africa. [Adeyemo, Adebowale A.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Wright, GEB (reprint author), Univ Western Cape, South African Natl Bioinformat Inst, ZA-7535 Bellville, South Africa. EM galen@sanbi.ac.za OI Wright, Galen/0000-0003-2415-7339; Adeyemo, Adebowale/0000-0002-3105-3231 FU South African National Research Foundation (NRF); Medical Research Council (MRC) of South Africa FX Support for GEBW by the South African National Research Foundation (NRF) is acknowledged. Support for NT by the Medical Research Council (MRC) of South Africa is acknowledged. Opinions expressed are those of the authors, and are not attributed to the NRF or the MRC. NR 82 TC 14 Z9 14 U1 2 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6939 J9 BMC MED ETHICS JI BMC Med. Ethics PD MAY 28 PY 2013 VL 14 AR 21 DI 10.1186/1472-6939-14-21 PG 15 WC Ethics; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Biomedical Social Sciences GA 179XI UT WOS:000321555300001 PM 23714101 ER PT J AU Nguyen, NM Kien, DTH Tuan, TV Quyen, NTH Tran, CNB Thi, LV Thi, DL Nguyen, HL Farrar, JJ Holmes, EC Rabaa, MA Bryant, JE Nguyen, TT Nguyen, HTC Nguyen, LTH Pham, MP Nguyen, HT Luong, TTH Wills, B Nguyen, CVV Wolbers, M Simmons, CP AF Nguyet Minh Nguyen Duong Thi Hue Kien Trung Vu Tuan Nguyen Than Ha Quyen Tran, Chau N. B. Long Vo Thi Dui Le Thi Hoa Lan Nguyen Farrar, Jeremy J. Holmes, Edward C. Rabaa, Maia A. Bryant, Juliet E. Truong Thanh Nguyen Huong Thi Cam Nguyen Lan Thi Hong Nguyen Mai Phuong Pham Hung The Nguyen Tai Thi Hue Luong Wills, Bridget Chau Van Vinh Nguyen Wolbers, Marcel Simmons, Cameron P. TI Host and viral features of human dengue cases shape the population of infected and infectious Aedes aegypti mosquitoes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE infectious disease; virology; entomology ID PLACEBO-CONTROLLED TRIAL; VIRUS TRANSMISSION; VACCINE; TEMPERATURE; VIREMIA; FEVER AB Dengue is the most prevalent arboviral disease of humans. The host and virus variables associated with dengue virus (DENV) transmission from symptomatic dengue cases (n = 208) to Aedes aegypti mosquitoes during 407 independent exposure events was defined. The 50% mosquito infectious dose for each ofDENV-1-4 ranged from 6.29 to 7.52 log10 RNA copies/mL of plasma. Increasing day of illness, declining viremia, and rising antibody titers were independently associated with reduced risk of DENV transmission. High early DENV plasma viremia levels in patients were a marker of the duration of human infectiousness, and blood meals containing high concentrations of DENV were positively associated with the prevalence of infectious mosquitoes 14 d after blood feeding. Ambulatory dengue cases had lower viremia levels compared with hospitalized dengue cases but nonetheless at levels predicted to be infectious to mosquitoes. These data define serotype-specific viremia levels that vaccines or drugs must inhibit to prevent DENV transmission. C1 [Nguyet Minh Nguyen; Duong Thi Hue Kien; Trung Vu Tuan; Nguyen Than Ha Quyen; Tran, Chau N. B.; Long Vo Thi; Dui Le Thi; Hoa Lan Nguyen; Farrar, Jeremy J.; Rabaa, Maia A.; Bryant, Juliet E.; Wills, Bridget; Wolbers, Marcel; Simmons, Cameron P.] Univ Oxford, Clin Res Unit, Ho Chi Minh City, Vietnam. [Farrar, Jeremy J.; Bryant, Juliet E.; Wills, Bridget; Wolbers, Marcel; Simmons, Cameron P.] Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford OX1 2JD, England. [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. [Truong Thanh Nguyen; Huong Thi Cam Nguyen; Lan Thi Hong Nguyen; Mai Phuong Pham; Hung The Nguyen; Tai Thi Hue Luong; Chau Van Vinh Nguyen] Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Simmons, Cameron P.] Univ Melbourne, Nossal Inst Global Hlth, Melbourne, Vic 3010, Australia. RP Simmons, CP (reprint author), Univ Oxford, Clin Res Unit, Dist 5, Ho Chi Minh City, Vietnam. EM csimmons@oucru.org OI Simmons, Cameron P./0000-0002-9039-7392; Rabaa, Maia/0000-0003-0529-2228; Farrar, Jeremy/0000-0002-2700-623X; Holmes, Edward/0000-0001-9596-3552 FU Wellcome Trust [084368/Z/07/Z] FX We thank the patients and their families for their participation in this study; the staff of the Hospital for Tropical Diseases; and Huynh Le Phuong Huy, Huynh Le Phuong Thuy, Nguyen Thi Giang, Vu Tuyet Nhu, and Vu Ty Hang for providing outstanding technical assistance. This work was supported by a Wellcome Trust Senior Fellowship award (Grant 084368/Z/07/Z to C.P.S.). NR 30 TC 60 Z9 63 U1 3 U2 31 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 MAY 28 PY 2013 VL 110 IS 22 BP 9072 EP 9077 DI 10.1073/pnas.1303395110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 165RC UT WOS:000320500000076 PM 23674683 ER PT J AU Stavrou, S Nitta, T Kotla, S Ha, D Nagashima, K Rein, AR Fan, H Ross, SR AF Stavrou, Spyridon Nitta, Takayuki Kotla, Swathi Ha, Dat Nagashima, Kunio Rein, Alan R. Fan, Hung Ross, Susan R. TI Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE intrinsic immunity; trex1; virus restriction factors ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRIM5-ALPHA RESTRICTION FACTOR; INFECTIOUS-ANEMIA VIRUS; APOBEC3 PROTEINS; IN-VIVO; CYTIDINE DEAMINATION; HIV-1; TYPE-1; REPLICATION; CELLS AB Pathogenic retroviruses have evolved multiple means for evading host restriction factors such as apolipoprotein B editing complex (APOBEC3) proteins. Here, we show that murine leukemia virus (MLV) has a unique means of counteracting APOBEC3 and other cytosolic sensors of viral nucleic acid. Using virus isolated from infected WT and APOBEC3 KO mice, we demonstrate that the MLV glycosylated Gag protein (glyco-Gag) enhances viral core stability. Moreover, in vitro endogenous reverse transcription reactions of the glyco-Gag mutant virus were substantially inhibited compared with WT virus, but only in the presence of APOBEC3. Thus, glyco-Gag rendered the reverse transcription complex in the viral core resistant to APOBEC3. Glyco-Gag in the virion also rendered MLV resistant to other cytosolic sensors of viral reverse transcription products in newly infected cells. Strikingly, glyco-Gag mutant virus reverted to glyco-Gag-containing virus only in WT and not APOBEC3 KO mice, indicating that counteracting APOBEC3 is the major function of glyco-Gag. Thus, in contrast to the HIV viral infectivity factor protein, which prevents APOBEC3 packaging in the virion, the MLV glyco-Gag protein uses a unique mechanism to counteract the antiviral action of APOBEC3 in vivo-namely, protecting the reverse transcription complex in viral cores from APOBEC3. These data suggest that capsid integrity may play a critical role in virus resistance to intrinsic cellular antiviral resistance factors that act at the early stages of infection. C1 [Stavrou, Spyridon; Kotla, Swathi; Ross, Susan R.] Univ Penn, Abramson Canc Ctr, Dept Microbiol, Philadelphia, PA 19103 USA. [Stavrou, Spyridon; Kotla, Swathi; Ross, Susan R.] Univ Penn, Inst Immunol, Perelman Sch Med, Philadelphia, PA 19103 USA. [Nitta, Takayuki; Ha, Dat; Fan, Hung] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. [Nitta, Takayuki; Ha, Dat; Fan, Hung] Univ Calif Irvine, Canc Res Inst, Irvine, CA 92697 USA. [Nagashima, Kunio] Frederick Natl Lab Canc Res, Sci Applicat Int Corp SAIC Frederick Inc, Adv Technol Program, Frederick, MD 21702 USA. [Rein, Alan R.] NCI, Ctr Canc Res, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Ross, SR (reprint author), Univ Penn, Abramson Canc Ctr, Dept Microbiol, Philadelphia, PA 19103 USA. EM rosss@mail.med.upenn.edu FU Public Health Service [R01-AI-085015, R01-CA-94188]; National Institutes of Health (NIH) [T32-CA115299, F32-AI100512, T32-AI07324]; Japan Society for the Promotion of Science Postdoctoral Fellow for Research Abroad; Barbara Burgess Memorial Fund; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN26120080001E] FX We thank Lorraine Albritton, David Derse (deceased), and Masaaki Miyazawa for reagents used in this study; Alice Telesnitzky for advice; and Kristin Blouch and Ferri Soheilian for expert technical assistance. This research was supported by Public Health Service Grants R01-AI-085015 (to S.R.R.) and R01-CA-94188 (to H. F.). S.S. was supported by National Institutes of Health (NIH) Grants T32-CA115299 and F32-AI100512. S.K. was supported by NIH Grant T32-AI07324, and T.N. was supported by a Japan Society for the Promotion of Science Postdoctoral Fellow for Research Abroad and the Barbara Burgess Memorial Fund. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part with federal funds from the National Cancer Institute, NIH, under Contract HHSN26120080001E. NR 53 TC 35 Z9 35 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 28 PY 2013 VL 110 IS 22 BP 9078 EP 9083 DI 10.1073/pnas.1217399110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 165RC UT WOS:000320500000077 PM 23671100 ER PT J AU Michaelides, M Miller, ML Subrize, M Kim, R Robison, L Hurd, YL Wang, GJ Volkow, ND Thanos, PK AF Michaelides, Michael Miller, Michael L. Subrize, Mike Kim, Ronald Robison, Lisa Hurd, Yasmin L. Wang, Gene-Jack Volkow, Nora D. Thanos, Panayotis K. TI Limbic activation to novel versus familiar food cues predicts food preference and alcohol intake SO BRAIN RESEARCH LA English DT Article DE Behavioral imaging; Positron emission tomography; Neuroimaging; Craving; Reward; Rat ID BRAIN GLUCOSE-METABOLISM; MATERNAL SEPARATION; INCENTIVE SALIENCE; ETHANOL INTAKE; WISTAR RATS; EXPECTATION; COCAINE; REGIONS; OBESITY AB Expectation of salient rewards and novelty seeking are processes implicated in substance use disorders but the neurobiological substrates underlying these associations are not well understood. To better understand the regional circuitry of novelty and reward preference, rats were conditioned to pair unique cues with bacon, an initially novel food, or chow, a familiar food. In the same animals, after training, cue-induced brain activity was measured, and the relationships between activity and preference for three rewards, the conditioned foods and ethanol (EtOH), were separately determined. Activity in response to the food paired cues was measured using brain glucose metabolism (BGluM). Rats favoring bacon-paired (BAP) cues had increased BGluM in mesocorticolimbic brain regions after exposure to these cues, while rats favoring chow-paired (CHP) cues showed relative deactivation in these regions. Rats exhibiting BAP cue-induced activation in prefrontal cortex (PFC) also consumed more EtOH while rats with cortical activation in response to CHP cues showed lower EtOH consumption. Additionally, long-term stable expression levels of PFC Grin2a, a subunit of the NMDA receptor, correlated with individual differences in EtOH preference insomuch that rats with high EtOH preference had enduringly low PFC Grin2a mRNA expression. No other glutamatergic, dopaminergic or endocannabinoid genes studied showed this relationship. Overall, these results suggest that natural variation in mesocorticolimbic sensitivity to reward-paired cues underlies behavioral preferences for and vulnerability to alcohol abuse, and support the notion of common neuronal circuits involved in food- and drug-seeking behavior. The findings also provide evidence that PFC NMDA-mediated glutamate signaling may modulate these associations. Published by Elsevier B.V. C1 [Michaelides, Michael; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Miller, Michael L.; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Hurd, Yasmin L.; Wang, Gene-Jack] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Michaelides, Michael; Subrize, Mike; Kim, Ronald; Robison, Lisa; Wang, Gene-Jack; Thanos, Panayotis K.] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol Lab, Upton, NY 11973 USA. [Volkow, Nora D.; Thanos, Panayotis K.] NIAAA, Lab Neuroimaging, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Thanos, PK (reprint author), Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol Lab, Bldg 490, Upton, NY 11973 USA. EM thanos@bnl.gov RI Michaelides, Michael/K-4736-2013; OI Michaelides, Michael/0000-0003-0398-4917; Miller, Michael/0000-0002-6350-5706 FU NIAAA [AA 11034, AA07574, AA07611]; T32 NIDA Training grant at Mount Sinai School of Medicine [5T32DA007135] FX This work was supported by the NIAAA (AA 11034, AA07574, and AA07611). MM was supported by the T32 NIDA Training grant (5T32DA007135) at Mount Sinai School of Medicine. NR 26 TC 3 Z9 3 U1 0 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 28 PY 2013 VL 1512 BP 37 EP 44 DI 10.1016/j.brainres.2013.03.006 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 160AG UT WOS:000320087800004 PM 23506787 ER PT J AU Yong, KJ Milenic, DE Baidoo, KE Brechbiel, MW AF Yong, K. J. Milenic, D. E. Baidoo, K. E. Brechbiel, M. W. TI Pb-212-radioimmunotherapy potentiates paclitaxel-induced cell killing efficacy by perturbing the mitotic spindle checkpoint SO BRITISH JOURNAL OF CANCER LA English DT Article DE Pb-212-TCMC-trastuzumab; paclitaxel; mitotic spindle checkpoint ID DISSEMINATED PERITONEAL DISEASE; DNA-DAMAGE REPAIR; RADIATION SENSITIZER; PANCREATIC-CANCER; TARGETING HER2; INDUCED APOPTOSIS; HUMANIZED 3S193; ALPHA-PARTICLE; OVARIAN-CANCER; TUMOR-CELLS AB Background: Paclitaxel has recently been reported by this laboratory to potentiate the high-LET radiation therapeutic Pb-212-TCMC-trastuzumab, which targets HER2. To elucidate mechanisms associated with this therapy, targeted a-particle radiation therapeutic Pb-212-TCMC-trastuzumab together with paclitaxel was investigated for the treatment of disseminated peritoneal cancers. Methods: Mice bearing human colon cancer LS-174T intraperitoneal xenografts were pre-treated with paclitaxel, followed by treatment with Pb-212-TCMC-trastuzumab and compared with groups treated with paclitaxel alone, Pb-212-TCMC-HuIgG, Pb-212-TCMC-trastuzumab and Pb-212-TCMC-HuIgG after paclitaxel pre-treatment. Results: Pb-212-TCMC-trastuzumab with paclitaxel given 24 h earlier induced increased mitotic catastrophe and apoptosis. The combined modality of paclitaxel and Pb-212-TCMC-trastuzumab markedly reduced DNA content in the S-phase of the cell cycle with a concomitant increase observed in the G2/M-phase. This treatment regimen also diminished phosphorylation of histone H3, accompanied by an increase in multi-micronuclei, or mitotic catastrophe in nuclear profiles and positively stained gamma H2AX foci. The data suggests, possible effects on the mitotic spindle checkpoint by the paclitaxel and Pb-212-TCMC-trastuzumab treatment. Consistent with this hypothesis, Pb-212-TCMC-trastuzumab treatment in response to paclitaxel reduced expression and phosphorylation of BubR1, which is likely attributable to disruption of a functional Aurora B, leading to impairment of the mitotic spindle checkpoint. In addition, the reduction of BubR1 expression may be mediated by the association of a repressive transcription factor, E2F4, on the promoter region of BubR1 gene. Conclusion: These findings suggest that the sensitisation to therapy of Pb-212-TCMC-trastuzumab by paclitaxel may be associated with perturbation of the mitotic spindle checkpoint, leading to increased mitotic catastrophe and cell death. C1 [Yong, K. J.; Milenic, D. E.; Baidoo, K. E.; Brechbiel, M. 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 Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; AREVA Med FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and also by AREVA Med. NR 44 TC 5 Z9 6 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 28 PY 2013 VL 108 IS 10 BP 2013 EP 2020 DI 10.1038/bjc.2013.189 PG 8 WC Oncology SC Oncology GA 152WE UT WOS:000319561300014 PM 23632482 ER PT J AU Petersen, SE Matthews, PM Bamberg, F Bluemke, DA Francis, JM Friedrich, MG Leeson, P Nagel, E Plein, S Rademakers, FE Young, AA Garratt, S Peakman, T Sellors, J Collins, R Neubauer, S AF Petersen, Steffen E. Matthews, Paul M. Bamberg, Fabian Bluemke, David A. Francis, Jane M. Friedrich, Matthias G. Leeson, Paul Nagel, Eike Plein, Sven Rademakers, Frank E. Young, Alistair A. Garratt, Steve Peakman, Tim Sellors, Jonathan Collins, Rory Neubauer, Stefan TI Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Review DE Cardiovascular magnetic resonance; Prospective cohort study; Population-based study; Nested-case control study; Biobank ID LEFT-VENTRICULAR FUNCTION; ATHEROSCLEROSIS MESA; ASYMPTOMATIC INDIVIDUALS; RISK-FACTORS; SUBCLINICAL ATHEROSCLEROSIS; DIASTOLIC DYSFUNCTION; ALZHEIMERS-DISEASE; MRI; HYPERTROPHY; CARDIOMYOPATHY AB UK Biobank is a prospective cohort study with 500,000 participants aged 40 to 69. Recently an enhanced imaging study received funding. Cardiovascular magnetic resonance (CMR) will be part of a multi-organ, multi-modality imaging visit in 3-4 dedicated UK Biobank imaging centres that will acquire and store imaging data from 100,000 participants (subject to successful piloting). In each of UK Biobank's dedicated bespoke imaging centres, it is proposed that 15-20 participants will undergo a 2 to 3 hour visit per day, seven days a week over a period of 5-6 years. The imaging modalities will include brain MRI at 3 Tesla, CMR and abdominal MRI at 1.5 Tesla, carotid ultrasound and DEXA scans using carefully selected protocols. We reviewed the rationale, challenges and proposed approaches for concise phenotyping using CMR on such a large scale. Here, we discuss the benefits of this imaging study and review existing and planned population based cardiovascular imaging in prospective cohort studies. We will evaluate the CMR protocol, feasibility, process optimisation and costs. Procedures for incidental findings, quality control and data processing and analysis are also presented. As is the case for all other data in the UK Biobank resource, this database of images and related information will be made available through UK Biobank's Access Procedures to researchers (irrespective of their country of origin and whether they are academic or commercial) for health-related research that is in the public interest. C1 [Petersen, Steffen E.] London Chest Hosp, NIHR Cardiovasc Biomed Res Unit Barts, William Harvey Res Inst, Ctr Lead Adv Cardiovasc Imaging, London E2 9JX, England. [Matthews, Paul M.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Brain Sci, London, England. [Matthews, Paul M.] GlaxoSmithKline Res & Dev Ltd, Munich, Germany. [Bamberg, Fabian] Univ Munich, Dept Radiol, Munich, Germany. [Bluemke, David A.] NIH Clin Ctr, Oxford, England. [Francis, Jane M.; Leeson, Paul; Neubauer, Stefan] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England. [Friedrich, Matthias G.] Univ Montreal, Montreal Heart Inst, Calgary, AB, Canada. [Friedrich, Matthias G.] Univ Calgary, Calgary, AB, Canada. [Nagel, Eike] Kings Coll London, British Heart Fdn Ctr Excellence,Med Engn Ctr,Div, Natl Inst Hlth Res NIHR,Wellcome Trust & Engn & P, Biomed Res Ctr,Guys & St Thomas NHS Fdn Trust,Ray, London WC2R 2LS, England. [Plein, Sven] Univ Leeds, Multidisciplinary Cardiovasc Res Ctr, Leeds LS2 9JT, W Yorkshire, England. [Plein, Sven] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. [Rademakers, Frank E.] Katholieke Univ Leuven Hosp, Louvain, Belgium. [Young, Alistair A.] Univ Auckland, Dept Anat Radiol, Auckland, New Zealand. [Garratt, Steve; Peakman, Tim; Sellors, Jonathan; Collins, Rory] UK Biobank, Stockport SK3 0SA, Cheshire, England. RP Petersen, SE (reprint author), London Chest Hosp, NIHR Cardiovasc Biomed Res Unit Barts, William Harvey Res Inst, Ctr Lead Adv Cardiovasc Imaging, Bonner Rd, London E2 9JX, England. EM s.e.petersen@qmul.ac.uk RI Nagel, Eike/C-6903-2008; Petersen, Steffen/A-8389-2011; OI Nagel, Eike/0000-0002-6044-950X; Petersen, Steffen/0000-0003-4622-5160; Matthews, Paul M/0000-0002-1619-8328; Bluemke, David/0000-0002-8323-8086 FU Philips Healthcare; National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts; Oxford NIHR Biomedical Research Centre; Oxford British Heart Foundation Centre of Research Excellence; BHF Senior Clinical Research fellowship; BHF Research Chair; Oxford BHF Centre for Research Excellence; MRC; Wellcome Trust; GlaxoSmithKline; Medical Research Council FX SP receives grant support from Philips Healthcare. PMM is a part-time employee of GlaxoSmithKline Research and Development, Ltd.; SEP was directly funded by the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts. SN acknowledges support from the Oxford NIHR Biomedical Research Centre and from the Oxford British Heart Foundation Centre of Research Excellence. SP and PL are funded by a BHF Senior Clinical Research fellowship. RC is supported by a BHF Research Chair and acknowledges the support of the Oxford BHF Centre for Research Excellence and the MRC and Wellcome Trust. PMM gratefully acknowledges training fellowships supporting his laboratory from the Wellcome Trust, GlaxoSmithKline and the Medical Research Council. We would like to thank the Clinical Trials Committee of the Society for Cardiovascular Magnetic Resonance (SCMR), the British Society of Cardiovascular Magnetic Resonance Research Group, the ESC Working Group on Cardiovascular Magnetic Resonance, members of the UK Biobank Imaging Working Group and members of the UK Biobank coordinating centre and many others for their invaluable contributions to this topic in numerous discussions. NR 42 TC 35 Z9 35 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD MAY 28 PY 2013 VL 15 AR 46 DI 10.1186/1532-429X-15-46 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 155IF UT WOS:000319740500001 PM 23714095 ER PT J AU Tang, M Nesbitt, AE Sperling, LJ Berthold, DA Schwieters, CD Gennis, RB Rienstra, CM AF Tang, Ming Nesbitt, Anna E. Sperling, Lindsay J. Berthold, Deborah A. Schwieters, Charles D. Gennis, Robert B. Rienstra, Chad M. TI Structure of the Disulfide Bond Generating Membrane Protein DsbB in the Lipid Bilayer SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE disulfide bond generation; DsbB; membrane protein; solid-state NMR; molecular dynamics simulation ID SOLID-STATE NMR; ANGLE-SPINNING NMR; NUCLEAR-MAGNETIC-RESONANCE; MOLECULAR-DYNAMICS; TRANSMEMBRANE HELICES; STRUCTURE REFINEMENT; CRYSTAL-STRUCTURE; ENZYME DSBB; SPECTROSCOPY; SHIFT AB The integral membrane protein DsbB in Escherichia coli is responsible for oxidizing the periplasmic protein DsbA, which forms disulfide bonds in substrate proteins. We have developed a high-resolution structural model by combining experimental X-ray and solid-state NMR with molecular dynamics (MD) simulations. We embedded the high-resolution DsbB structure, derived from the joint calculation with X-ray reflections and solid-state NMR restraints, into the lipid bilayer and performed MD simulations to provide a mechanistic view of DsbB function in the membrane. Further, we revealed the membrane topology of DsbB by selective proton spin diffusion experiments, which directly probe the correlations of DsbB with water and lipid acyl chains. NMR data also support the model of a flexible periplasmic loop and an interhelical hydrogen bond between Glu26 and Tyr153. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Tang, Ming; Nesbitt, Anna E.; Sperling, Lindsay J.; Berthold, Deborah A.; Gennis, Robert B.; Rienstra, Chad M.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Rienstra, CM (reprint author), Univ Illinois, A129 CLSL,600 South Mathews Ave,Box 50-6, Urbana, IL 61801 USA. EM rienstra@illinois.edu RI Tang, Ming/A-5348-2010 OI Tang, Ming/0000-0001-7479-6206 FU National Institutes of Health [R01GM075937, S10RR025037, R01HL103999, R01GM073770 ARRA, NRSA F32GM095344]; Molecular Biophysics Training Grant [PHS 5 T32 GM008276]; Ullyot Fellowship; National Institutes of Health Intramural Research Program of CIT FX This research was supported by the National Institutes of Health (R01GM075937, S10RR025037, R01HL103999, and R01GM073770 ARRA supplement to C.M.R., and NRSA F32GM095344 to A.E.N), a Molecular Biophysics Training Grant (PHS 5 T32 GM008276) and Ullyot Fellowship to L.J.S., and the National Institutes of Health Intramural Research Program of CIT to C.D.S. The authors thank the School of Chemical Sciences NMR Facility at the University of Illinois at Urbana-Champaign for assistance with data acquisition, Mike Hallock for helpful assistance with structure calculations, and Dr. Taras Pogorelov for helpful discussion with MD simulations. NR 62 TC 20 Z9 20 U1 2 U2 30 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 27 PY 2013 VL 425 IS 10 BP 1670 EP 1682 DI 10.1016/j.jmb.2013.02.009 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151WC UT WOS:000319490100007 PM 23416557 ER PT J AU Liu, G Gao, JH Ai, H Chen, XY AF Liu, Gang Gao, Jinhao Ai, Hua Chen, Xiaoyuan TI Applications and Potential Toxicity of Magnetic Iron Oxide Nanoparticles SO SMALL LA English DT Review DE iron oxide nanoparticles; magnetic resonance imaging; drug delivery; gene delivery; nanotoxicity ID TARGETED DRUG-DELIVERY; RESONANCE-IMAGING CONTRAST; TIME-RESOLVED MRI; IN-VIVO; GENE DELIVERY; CANCER-THERAPY; BIOMEDICAL APPLICATIONS; SIRNA DELIVERY; MOLECULAR-INTERACTIONS; FE3O4 NANOPARTICLES AB Owing to their unique physical and chemical properties, magnetic iron oxide nanoparticles have become a powerful platform in many diverse aspects of biomedicine, including magnetic resonance imaging, drug and gene delivery, biological sensing, and hyperthermia. However, the biomedical applications of magnetic iron oxide nanoparticles arouse serious concerns about their pharmacokinetics, metabolism, and toxicity. In this review, the updated research on the biomedical applications and potential toxicity of magnetic iron oxide nanoparticles is summarized. Much more effort is required to develop magnetic iron oxide nanoparticles with improved biocompatible surface engineering to achieve minimal toxicity, for various applications in biomedicine. C1 [Liu, Gang; Gao, Jinhao] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361005, Peoples R China. [Gao, Jinhao] Xiamen Univ, Coll Chem & Chem Engn, State Key Lab Phys Chem Solid Surfaces, Xiamen 361005, Peoples R China. [Ai, Hua] Sichuan Univ, Natl Engn Res Ctr Biomat, Chengdu 610064, Peoples R China. [Chen, Xiaoyuan] NIH, LOMIN, NIBIB, Bethesda, MD 20892 USA. [Liu, Gang] North Sichuan Med Coll, Sichuan Key Lab Med Imaging, Nanchong 637007, Peoples R China. RP Liu, G (reprint author), Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361005, Peoples R China. EM gangliu.cmitm@xmu.edu.cn; chenx5@mail.nih.gov RI Gao, Jinhao/F-5092-2010 OI Gao, Jinhao/0000-0003-3215-7013 FU Major State Basic Research Development Program of China (973 Program) [2013CB733802]; National Science Foundation of China (NSFC) [81101101, 51273165, 51173117, 50830107]; Chinese Academy of Sciences [2011T2J06]; Chinese Ministry of Education [212149]; Key Project of Sichuan Province [09ZA036, 2010SZ0294, 2011JQ0032]; Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported by the Major State Basic Research Development Program of China (973 Program) (No. 2013CB733802), National Science Foundation of China (NSFC) (81101101, 51273165, 51173117, 50830107), Chinese Academy of Sciences professorship for Senior International Scientists (2011T2J06), Key Project of Chinese Ministry of Education (212149), Key Project of Sichuan Province (09ZA036, 2010SZ0294, 2011JQ0032), and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 165 TC 112 Z9 119 U1 27 U2 353 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1613-6810 J9 SMALL JI Small PD MAY 27 PY 2013 VL 9 IS 9-10 SI SI BP 1533 EP 1545 DI 10.1002/smll.201201531 PG 13 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 146FT UT WOS:000319076000010 PM 23019129 ER PT J AU Teng, C Goodwin, B Shockley, K Xia, MH Huang, RL Norris, J Merrick, BA Jetten, AM Austin, CP Tice, RR AF Teng, Christina Goodwin, Bonnie Shockley, Keith Xia, Menghang Huang, Ruili Norris, John Merrick, B. Alex Jetten, Anton M. Austin, Christopher P. Tice, Raymond R. TI Bisphenol A affects androgen receptor function via multiple mechanisms SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Bisphenol A and related compounds; Androgen receptor; qHTS; Transfection; Imaging analysis ID ENDOCRINE-DISRUPTING CHEMICALS; TESTICULAR DYSGENESIS SYNDROME; MALE REPRODUCTIVE HEALTH; IN-VITRO; PROSTATE-CANCER; ENVIRONMENTAL CHEMICALS; MOLECULAR-MECHANISMS; NUCLEAR RECEPTORS; STRUCTURAL BASIS; ANTI-ANDROGENS AB Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the beta-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ER alpha) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ER alpha and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ER alpha agonists (half maximal effective concentration EC50 of 10-100 nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2 mu M). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2 mu M), did not compete with R1881 for AR binding, when tested at 30 mu M. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17 beta-estradiol (E2) which was used as control, BPA was able to enhance ER alpha nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. Published by Elsevier Ireland Ltd. C1 [Teng, Christina; Merrick, B. Alex; Tice, Raymond R.] NIEHS, DNTP Biomol Screening Branch, NIH, Res Triangle Pk, NC 27709 USA. [Jetten, Anton M.] NIEHS, DIR Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Shockley, Keith] NIEHS, DIR Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Goodwin, Bonnie; Xia, Menghang; Huang, Ruili; Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Norris, John] Duke Univ, Dept Pharmacol, Durham, NC USA. RP Teng, C (reprint author), NIEHS, BSB, DNTP, NIH,Biomol Screening Branch, 111 Alexander Dr,POB 12233,MD K2-17, Res Triangle Pk, NC 27709 USA. EM teng1@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU National Institute of Environmental Health Sciences, National Institutes of Health (NIH) FX We thank Brad Collins as coordinator of NTP for obtaining the compounds from MRIGlobal. We appreciate the valuable comments of John Bucher. This work was supported by the Intramural Research Programs of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health (NIH). NR 65 TC 43 Z9 43 U1 8 U2 52 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD MAY 25 PY 2013 VL 203 IS 3 BP 556 EP 564 DI 10.1016/j.cbi.2013.03.013 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 161RR UT WOS:000320211500003 PM 23562765 ER PT J AU Kim, NK Jayatillake, RV Spouge, JL AF Kim, Nak-Kyeong Jayatillake, Rasika V. Spouge, John L. TI NEXT-peak: a normal-exponential two-peak model for peak-calling in ChIP-seq data SO BMC GENOMICS LA English DT Article DE ChIP-seq; Normal-exponential distribution; Continuous mixture; Poisson regression; Goodness-of-fit ID FACTOR-BINDING SITES; GENOME; IDENTIFICATION; SEQUENCES; TOOL AB Background: Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) can locate transcription factor binding sites on genomic scale. Although many models and programs are available to call peaks, none has dominated its competition in comparison studies. Results: We propose a rigorous statistical model, the normal-exponential two-peak (NEXT-peak) model, which parallels the physical processes generating the empirical data, and which can naturally incorporate mappability information. The model therefore estimates total strength of binding (even if some binding locations do not map uniquely into a reference genome, effectively censoring them); it also assigns an error to an estimated binding location. The comparison study with existing programs on real ChIP-seq datasets (STAT1, NRSF, and ZNF143) demonstrates that the NEXT-peak model performs well both in calling peaks and locating them. The model also provides a goodness-of-fit test, to screen out spurious peaks and to infer multiple binding events in a region. Conclusions: The NEXT-peak program calls peaks on any test dataset about as accurately as any other, but provides unusual accuracy in the estimated location of the peaks it calls. NEXT-peak is based on rigorous statistics, so its model also provides a principled foundation for a more elaborate statistical analysis of ChIP-seq data. C1 [Kim, Nak-Kyeong; Jayatillake, Rasika V.] Old Dominion Univ, Dept Math & Stat, Norfolk, VA 23529 USA. [Spouge, John L.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Kim, NK (reprint author), Old Dominion Univ, Dept Math & Stat, Norfolk, VA 23529 USA. EM nxkim@odu.edu FU Old Dominion University Research Foundation; National Library of Medicine at the National Institutes of Health FX This work was supported by the Summer Research Fellowship Program of Old Dominion University Research Foundation and the Intramural Research Program of the National Library of Medicine at the National Institutes of Health. NR 20 TC 1 Z9 1 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 MAY 25 PY 2013 VL 14 AR UNSP 349 DI 10.1186/1471-2164-14-349 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 157RP UT WOS:000319917100001 PM 23706083 ER PT J AU Cuzick, J Sestak, I Bonanni, B Costantino, JP Cummings, S DeCensi, A Dowsett, M Forbes, JF Ford, L LaCroix, AZ Mershon, J Mitlak, BH Powles, T Veronesi, U Vogel, V Wickerham, DL AF Cuzick, Jack Sestak, Ivana Bonanni, Bernardo Costantino, Joseph P. Cummings, Steve DeCensi, Andrea Dowsett, Mitch Forbes, John F. Ford, Leslie LaCroix, Andrea Z. Mershon, John Mitlak, Bruce H. Powles, Trevor Veronesi, Umberto Vogel, Victor Wickerham, D. Lawrence CA SERM Chemoprevention Breast Canc O TI Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data SO LANCET LA English DT Article ID SURGICAL ADJUVANT BREAST; POSTMENOPAUSAL OSTEOPOROTIC WOMEN; BOWEL PROJECT P-1; RANDOMIZED-TRIAL; FOLLOW-UP; TAMOXIFEN; RALOXIFENE; RISK; OUTCOMES; CHEMOPREVENTION AB Background Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence. Methods We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. Results We analysed data for 83 399 women with 306 617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0.62, 95% CI 0.56-0.69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0.58, 0.51-0.66; p<0.0001 vs 25%, 0.75, 0.61-0.93; p=0.007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1.73, 95% CI 1.47-2.05; p<0.0001). We recorded a significant reduction of 34% in vertebral fractures (0.66, 0.59-0.73), but only a small effect for non-vertebral fractures (0.93, 0.87-0.99). Interpretation For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. C1 [Cuzick, Jack; Sestak, Ivana] Queen Mary Univ London, Ctr Canc Prevent, Wolfson Inst Prevent Med, London EC1M 6BQ, England. [Bonanni, Bernardo] European Inst Oncol, Milan, Italy. [Costantino, Joseph P.] Ctr Biostat, Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA USA. [Cummings, Steve] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [DeCensi, Andrea] EO Osped Galliera, Div Med Oncol, Genoa, Italy. [Dowsett, Mitch] Royal Marsden Hosp, Dept Acad Biochem, London SW3 6JJ, England. [Forbes, John F.] Univ Newcastle, Newcastle Mater Hosp, Dept Surg Oncol, Newcastle, NSW 2300, Australia. [Ford, Leslie] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [LaCroix, Andrea Z.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Mershon, John] Abbott Labs, Abbott Pk, IL 60064 USA. [Mitlak, Bruce H.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Powles, Trevor] Inst Canc Res, London SW3 6JB, England. [Veronesi, Umberto] European Inst Oncol, Milan, Italy. [Vogel, Victor] Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA USA. [Wickerham, D. Lawrence] Univ Pittsburgh, Dept Human Oncol, Pittsburgh, PA USA. RP Cuzick, J (reprint author), Queen Mary Univ London, Ctr Canc Prevent, Wolfson Inst Prevent Med, London EC1M 6BQ, England. EM j.cuzick@qmul.ac.uk OI Sestak, Ivana/0000-0001-6999-2851 FU Cancer Research UK; AstraZeneca FX Cancer Research UK.; JC has received a grant from AstraZeneca for chemoprevention trials. BHM is, and JM was, an employee and shareholder of Eli Lilly. IS, BB, JPC, VV, MD, TP, DLW, LF, SC, JFF, ADC, AZLC, UV declare that they have no conflicts of interest. NR 27 TC 121 Z9 123 U1 2 U2 43 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAY 25 PY 2013 VL 381 IS 9880 BP 1827 EP 1834 DI 10.1016/S0140-6736(13)60140-3 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 151EO UT WOS:000319443700028 PM 23639488 ER PT J AU Lohith, TG Osterweil, EK Fujita, M Jenko, KJ Bear, MF Innis, RB AF Lohith, Talakad G. Osterweil, Emily K. Fujita, Masahiro Jenko, Kimberly J. Bear, Mark F. Innis, Robert B. TI Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome? SO MOLECULAR AUTISM LA English DT Article DE Fragile X mental retardation protein; Fragile X syndrome; Glutamate receptor; mGluR5; Receptor density; Receptor expression ID MENTAL-RETARDATION; MOUSE MODEL; MESSENGER-RNA; PROTEINS; FXTAS AB Background: Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by loss of function of the fragile X mental retardation protein. Recent animal studies suggest that upregulated downstream signaling by metabotropic glutamate receptor 5 (mGluR5) might be an important mechanism for cognitive and behavioral abnormalities associated with FXS. However, mGluR5 density in human FXS remains unknown. Methods: Receptor binding and protein expression were measured in the postmortem prefrontal cortex of 14 FXS patients or carriers and 17 age-and sex-matched control subjects without neurological disorders. In-vitro binding assays were performed using [H-3]-labeled 3-methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity negative allosteric modulator of mGluR5, to measure receptor density and the radioligand's dissociation constant, which is inversely proportional to affinity. Immunoblotting was also performed, to measure mGluR5 protein expression. Results: The mGluR5 density increased with marginal significance (+16%; P = 0.058) in the prefrontal cortex of FXS patients or carriers compared with matched healthy controls. No significant change in dissociation constant (-4%; P = 0.293) was observed. Immunoblotting found a significant elevation (+32%; P = 0.048) in mGluR5 protein expression. Conclusions: Both mGluR5 binding density and protein expression were increased in the brains of FXS patients or carriers, but only expression was significantly different, which could be because of the small sample size and moderate variability. Another important caveat is that the effects of psychotropic medications on mGluR5 expression are largely unknown. Future in-vivo measurement of mGluR5 with positron emission tomography might characterize the role of this receptor in the pathophysiology of FXS and facilitate trials of mGluR5-oriented treatments for this disorder. C1 [Lohith, Talakad G.; Fujita, Masahiro; Jenko, Kimberly J.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Osterweil, Emily K.; Bear, Mark F.] MIT, Howard Hughes Med Inst, Picower Inst Learning & Memory, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Lohith, TG (reprint author), NIMH, Mol Imaging Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lohithtg@mail.nih.gov; innisr@mail.nih.gov OI Osterweil, Emily/0000-0003-0582-2284 FU National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This study was partly supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). We thank Dr. Paul J. Hagerman, Professor of the Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, USA for kindly providing the human tissue samples. Human tissue was also obtained from the National Institute of Child Health & Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. Ioline Henter (NIMH) provided valuable editorial assistance. NR 25 TC 16 Z9 16 U1 0 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD MAY 24 PY 2013 VL 4 AR 15 DI 10.1186/2040-2392-4-15 PG 8 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 254VE UT WOS:000327195700001 PM 23706040 ER PT J AU Hanifi, A McGoverin, C Ou, YT Safadi, F Spencer, RG Pleshko, N AF Hanifi, Arash McGoverin, Cushla Ou, Ya-Ting Safadi, Fayez Spencer, Richard G. Pleshko, Nancy TI Differences in infrared spectroscopic data of connective tissues in transflectance and transmittance modes SO ANALYTICA CHIMICA ACTA LA English DT Article DE Fourier transform infrared imaging spectroscopy; BaF2 window; Low-e slide; Transflectance; Transmittance ID COLLAGEN ORIENTATION; CARTILAGE; BONE; PROTEOGLYCAN; CONSEQUENCES; SCATTERING; VARIANCE AB Fourier transform infrared imaging spectroscopy (FT-IRIS) has been used extensively to characterize the composition and orientation of macromolecules in thin tissue sections. Earlier and current studies of normal and polarized FT-IRIS data have primarily used tissues sectioned onto infrared transmissive substrates, such as salt windows. Recently, the use of low-emissivity ("low-e") substrates has become of great interest because of their low cost and favorable infrared optical properties. However, data are collected in transflectance mode when using low-e slides and in transmittance mode using salt windows. In the current study we investigated the comparability of these two modes for assessment of the composition of connective tissues. FT-IRIS data were obtained in transflectance and transmittance modes from serial sections of cartilage, bone and tendon, and from a standard polymer, polymethylmethacrylate. Both non-polarized and polarized FTIR data differed in absorbance, and in some cases peak position, between transflectance and transmittance modes. However, the FT-IRIS analysis of the collagen fibril orientation in cartilage resulted in the expected zonal arrangement of fibrils in both transmittance and transflectance. We conclude that numerical comparison of FT-IRIS-derived parameters of tissue composition should account for substrate type and data collection mode, while analysis of overall tissue architecture may be more invariant between modes. (c) 2013 Elsevier B.V. All rights reserved. C1 [Hanifi, Arash; McGoverin, Cushla; Ou, Ya-Ting; Pleshko, Nancy] Temple Univ, Dept Bioengn, Tissue Imaging & Spect Lab, Philadelphia, PA 19122 USA. [Safadi, Fayez] Northeast Ohio Med Univ, Dept Anat & Neurobiol, Rootstown, OH USA. [Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. RP Pleshko, N (reprint author), Temple Univ, Dept Bioengn, 1947 N 12th St, Philadelphia, PA 19122 USA. EM npleshko@temple.edu FU NIH [EB000744, AR056145]; National Institute on Aging, NIH FX This study was supported by NIH EB000744 (NP) and AR056145 (NP) and the National Institute on Aging, NIH, intramural program (RGS). The study sponsors had no involvement in the study design, in the collection, analysis and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication. We acknowledge Ms. Roshanak Razmpour for sectioning hard tissue samples. NR 42 TC 5 Z9 5 U1 4 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0003-2670 J9 ANAL CHIM ACTA JI Anal. Chim. Acta PD MAY 24 PY 2013 VL 779 BP 41 EP 49 DI 10.1016/j.aca.2013.03.053 PG 9 WC Chemistry, Analytical SC Chemistry GA 152RO UT WOS:000319549000006 PM 23663670 ER PT J AU Tobe, R Naranjo-Suarez, S Everley, RA Carlson, BA Turanov, AA Tsuji, PA Yoo, MH Gygi, SP Gladyshev, VN Hatfield, DL AF Tobe, Ryuta Naranjo-Suarez, Salvador Everley, Robert A. Carlson, Bradley A. Turanov, Anton A. Tsuji, Petra A. Yoo, Min-Hyuk Gygi, Steven P. Gladyshev, Vadim N. Hatfield, Dolph L. TI High Error Rates in Selenocysteine Insertion in Mammalian Cells Treated with the Antibiotic Doxycycline, Chloramphenicol, or Geneticin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THIOREDOXIN REDUCTASE; GLUTATHIONE-PEROXIDASE; TRANSFER-RNA; PROTEIN-SYNTHESIS; CANCER-CELLS; SELENOPROTEINS; SELENIUM; AMINOGLYCOSIDES; TRANSLATION; SENSITIVITY AB Antibiotics target bacteria by interfering with essential processes such as translation, but their effects on translation in mammalian cells are less well characterized. We found that doxycycline, chloramphenicol, and Geneticin (G418) interfered with insertion of selenocysteine (Sec), which is encoded by the stop codon, UGA, into selenoproteins in murine EMT6 cells. Treatment of EMT6 cells with these antibiotics reduced enzymatic activities and Sec insertion into thioredoxin reductase 1 (TR1) and glutathione peroxidase 1 (GPx1). However, these proteins were differentially affected due to varying errors in Sec insertion at UGA. In the presence of doxycycline, chloramphenicol, or G418, the Sec-containing form of TR1 decreased, whereas the arginine-containing and truncated forms of this protein increased. We also detected antibiotic-specific misinsertion of cysteine and tryptophan. Furthermore, misinsertion of arginine in place of Sec was commonly observed in GPx1 and glutathione peroxidase 4. TR1 was the most affected and GPx1 was the least affected by these translation errors. These observations were consistent with the differential use of two Sec tRNA isoforms and their distinct roles in supporting accuracy of Sec insertion into selenoproteins. The data reveal widespread errors in inserting Sec into proteins and in dysregulation of selenoprotein expression and function upon antibiotic treatment. C1 [Tobe, Ryuta; Naranjo-Suarez, Salvador; Carlson, Bradley A.; Yoo, Min-Hyuk; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Everley, Robert A.; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Turanov, Anton A.; Gladyshev, Vadim N.] Harvard Univ, Brigham & Womens Hosp, Div Genet, Sch Med,Dept Med, Boston, MA 02115 USA. [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD 21252 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research; National Institutes of Health [GM065204, CA080946] FX This work was supported by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research (to D. L. H.) and by National Institutes of Health Grants GM065204 and CA080946 (to V. N. G.). NR 34 TC 6 Z9 6 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 24 PY 2013 VL 288 IS 21 BP 14709 EP 14715 DI 10.1074/jbc.M112.446666 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151HU UT WOS:000319452100005 PM 23589299 ER PT J AU Yu, WL Jiang, YL Pikis, A Cheng, W Bai, XH Ren, YM Thompson, J Zhou, CZ Chen, YX AF Yu, Wei-Li Jiang, Yong-Liang Pikis, Andreas Cheng, Wang Bai, Xiao-Hui Ren, Yan-Min Thompson, John Zhou, Cong-Zhao Chen, Yuxing TI Structural Insights into the Substrate Specificity of a 6-Phospho-beta-glucosidase BglA-2 from Streptococcus pneumoniae TIGR4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; BINDING CASSETTE TRANSPORTERS; GLYCOSYL HYDROLASES; BETA-GLUCOSIDASE; PHOSPHOTRANSFERASE SYSTEM; LACTOCOCCUS-LACTIS; CRYSTAL-STRUCTURE; MECHANISM; PROTEINS; BACTERIA AB The 6-phospho-beta-glucosidase BglA-2 (EC 3.2.1.86) from glycoside hydrolase family 1 (GH-1) catalyzes the hydrolysis of beta-1,4-linked cellobiose 6-phosphate (cellobiose-6'P) to yield glucose and glucose 6-phosphate. Both reaction products are further metabolized by the energy-generating glycolytic pathway. Here, we present the first crystal structures of the apo and complex forms of BglA-2 with thiocellobiose-6'P (a non-metabolizable analog of cellobiose-6'P) at 2.0 and 2.4 angstrom resolution, respectively. Similar to other GH-1 enzymes, the overall structure of BglA-2 from Streptococcus pneumoniae adopts a typical (beta/alpha)(8) TIM-barrel, with the active site located at the center of the convex surface of the beta-barrel. Structural analyses, in combination with enzymatic data obtained from site-directed mutant proteins, suggest that three aromatic residues, Tyr(126), Tyr(303), and Trp(338), at subsite +1 of BglA-2 determine substrate specificity with respect to 1,4-linked 6-phospho-beta-glucosides. Moreover, three additional residues, Ser(424), Lys(430), and Tyr(432) of BglA-2, were found to play important roles in the hydrolytic selectivity toward phosphorylated rather than non-phosphorylated compounds. Comparative structural analysis suggests that a tryptophan versus a methionine/alanine residue at subsite -1 may contribute to the catalytic and substrate selectivity with respect to structurally similar 6-phospho-beta-galactosidases and 6-phospho-beta-glucosidases assigned to the GH-1 family. C1 [Yu, Wei-Li; Jiang, Yong-Liang; Cheng, Wang; Bai, Xiao-Hui; Ren, Yan-Min; Zhou, Cong-Zhao; Chen, Yuxing] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230027, Anhui, Peoples R China. [Yu, Wei-Li; Jiang, Yong-Liang; Cheng, Wang; Bai, Xiao-Hui; Ren, Yan-Min; Zhou, Cong-Zhao; Chen, Yuxing] Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Anhui, Peoples R China. [Pikis, Andreas; Thompson, John] 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. RP Zhou, CZ (reprint author), Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230027, Anhui, Peoples R China. EM zcz@ustc.edu.cn; cyxing@ustc.edu.cn RI Zhou, Cong-Zhao/E-9174-2011; Chen, Yuxing/P-4156-2014 OI Zhou, Cong-Zhao/0000-0002-6881-7151; Chen, Yuxing/0000-0002-7560-1922 FU National Institutes of Health, NIDCR, Intramural Research Program; Ministry of Science and Technology of China [2009CB918800]; National Natural Science Foundation of China [31270781]; Research Fund for the Doctoral Program of Higher Education of China [20123402110004] FX This work was supported, in whole or in part, by the National Institutes of Health, NIDCR, Intramural Research Program. This work was also supported by Ministry of Science and Technology of China Grant 2009CB918800, National Natural Science Foundation of China Grant 31270781, and Research Fund for the Doctoral Program of Higher Education of China Grant 20123402110004. NR 43 TC 5 Z9 5 U1 1 U2 10 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 MAY 24 PY 2013 VL 288 IS 21 BP 14949 EP 14958 DI 10.1074/jbc.M113.454751 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151HU UT WOS:000319452100025 PM 23580646 ER PT J AU Lee, GS He, YZ Dougherty, EJ Jimenez-Movilla, M Avella, M Grullon, S Sharlin, DS Guo, CH Blackford, JA Awasthi, S Zhang, ZH Armstrong, SP London, EC Chen, WP Dean, J Simons, SS AF Lee, Geun-Shik He, Yuanzheng Dougherty, Edward J. Jimenez-Movilla, Maria Avella, Matteo Grullon, Sean Sharlin, David S. Guo, Chunhua Blackford, John A., Jr. Awasthi, Smita Zhang, Zhenhuan Armstrong, Stephen P. London, Edra C. Chen, Weiping Dean, Jurrien Simons, S. Stoney, Jr. TI Disruption of Ttll5/Stamp Gene (Tubulin Tyrosine Ligase-like Protein 5/SRC-1 and TIF2-associated Modulatory Protein Gene) in Male Mice Causes Sperm Malformation and Infertility SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BARDET-BIEDL-SYNDROME; GLUCOCORTICOID-RECEPTOR; CAENORHABDITIS-ELEGANS; ABNORMAL-DEVELOPMENT; CANCER CELLS; POLYGLUTAMYLATION; FLAGELLA; GROWTH; STAMP; TRANSCRIPTION AB TTLL5/STAMP (tubulin tyrosine ligase-like family member 5) has multiple activities in cells. TTLL5 is one of 13 TTLLs, has polyglutamylation activity, augments the activity of p160 coactivators (SRC-1 and TIF2) in glucocorticoid receptor-regulated gene induction and repression, and displays steroid-independent growth activity with several cell types. To examine TTLL5/STAMP functions in whole animals, mice were prepared with an internal deletion that eliminated several activities of the Stamp gene. This mutation causes both reduced levels of STAMP mRNA and C-terminal truncation of STAMP protein. Homozygous targeted mutant (Stamp(tm/tm)) mice appear normal except for marked decreases in male fertility associated with defects in progressive sperm motility. Abnormal axonemal structures with loss of tubulin doublets occur in most Stamp(tm/tm) sperm tails in conjunction with substantial reduction in alpha-tubulin polyglutamylation, which closely correlates with the reduction in mutant STAMP mRNA. The axonemes in other structures appear unaffected. There is no obvious change in the organs for sperm development of WT versus Stamp(tm/tm) males despite the levels of WT STAMP mRNA in testes being 20-fold higher than in any other organ examined. This defect in male fertility is unrelated to other Ttll genes or 24 genes previously identified as important for sperm function. Thus, STAMP appears to participate in a unique, tissue-selective TTLL-mediated pathway for alpha-tubulin polyglutamylation that is required for sperm maturation and motility and may be relevant for male fertility. C1 [Lee, Geun-Shik; He, Yuanzheng; Dougherty, Edward J.; Guo, Chunhua; Blackford, John A., Jr.; Awasthi, Smita; Zhang, Zhenhuan; Armstrong, Stephen P.; London, Edra C.; Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, Lab Endocrinol & Receptor Biol, Bethesda, MD 20892 USA. [Jimenez-Movilla, Maria; Avella, Matteo; Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, Bethesda, MD 20892 USA. [Grullon, Sean] NIDDK, Adipocyte Biol & Gene Regulat Sect, Lab Endocrinol & Receptor Biol, Bethesda, MD 20892 USA. [Sharlin, David S.] NIDDK, Nucl Receptor Biol Sect, Lab Endocrinol & Receptor Biol, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDK, Genom Core, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, LERB, NIH, Bldg 10,Rm 8N-307B, Bethesda, MD 20892 USA. EM stoneys@helix.nih.gov RI Guo, Chunhua/N-2586-2014; Jimenez-Movilla, Maria/I-1004-2015 OI Jimenez-Movilla, Maria/0000-0002-1572-8219 FU NIDDK, National Institutes of Health Intramural Research Program FX This work was supported, in whole or in part, by the NIDDK, National Institutes of Health Intramural Research Program. NR 51 TC 12 Z9 13 U1 1 U2 11 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 MAY 24 PY 2013 VL 288 IS 21 BP 15167 EP 15180 DI 10.1074/jbc.M113.453936 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151HU UT WOS:000319452100046 PM 23558686 ER PT J AU Kelly, L Bryan, K Kim, SY Janeway, KA Killian, JK Schildhaus, HU Miettinen, M Helman, L Meltzer, PS van de Rijn, M Debiec-Rychter, M O'Sullivan, M AF Kelly, Lorna Bryan, Kenneth Kim, Su Young Janeway, Katherine A. Killian, J. Keith Schildhaus, Hans-Ulrich Miettinen, Markku Helman, Lee Meltzer, Paul S. van de Rijn, Matt Debiec-Rychter, Maria O'Sullivan, Maureen CA NIH Pediat Wild-type GIST Clin TI Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST] SO PLOS ONE LA English DT Article ID HEPATOCELLULAR-CARCINOMA CELLS; MICRORNA EXPRESSION PROFILE; GENE-EXPRESSION; CARNEY TRIAD; UNIPARENTAL DISOMY; DOWN-REGULATION; KIT ACTIVATION; ANATOMIC SITE; WILD-TYPE; MUTATIONS AB In contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits [SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate post-transcriptional regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30 gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region. Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wildtype gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type, SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do express SDHB. All cases with Carney triad within our cohort cluster together tightly. C1 [Kelly, Lorna; O'Sullivan, Maureen] Trinity Coll Dublin, Sch Med, Dept Histopathol, Dublin, Ireland. [Kelly, Lorna; O'Sullivan, Maureen] Our Ladys Childrens Hosp, Natl Childrens Res Ctr, Dublin, Ireland. [Bryan, Kenneth] TEAGASC, Anim & Grassland Res & Innovat Ctr, Dunsany, Meath, Ireland. [Kim, Su Young; Killian, J. Keith; Miettinen, Markku; Helman, Lee; Meltzer, Paul S.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Janeway, Katherine A.] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Janeway, Katherine A.] Childrens Hosp, Boston, MA 02115 USA. [Schildhaus, Hans-Ulrich] Univ Cologne, Inst Pathol, Med Ctr, Cologne, Germany. [van de Rijn, Matt] Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA. [Debiec-Rychter, Maria] Catholic Univ Louvain, Dept Human Genet, B-3000 Louvain, Belgium. [Debiec-Rychter, Maria] Univ Hosp, Louvain, Belgium. RP O'Sullivan, M (reprint author), Trinity Coll Dublin, Sch Med, Dept Histopathol, Dublin, Ireland. EM maureen.osullivan@tcd.ie OI Bryan, Kenneth/0000-0002-9550-8354 FU Medical Research Charities Group; Health Research Board of Ireland; Children's Medical and Research Foundation; GIST Cancer Awareness Foundation [GCAF]; Life Raft Group; Fonds voor Wetenschappelijk Onderzoek Vlaanderen [G.0286.05 MD-R] FX Funding was obtained from the Medical Research Charities Group (http://www.mrcg.ie/) and Health Research Board of Ireland (http://www.hrb.ie) (MO'S), The Children's Medical and Research Foundation (http://www.cmrf.org) (MO'S), the GIST Cancer Awareness Foundation [GCAF] (http://www.gistawareness.org/)(MO'S), and research grants from the Life Raft Group (http://www.liferaftgroup.org/)(MD-R) and from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (http://www.fwo.be/)(grant # G.0286.05 MD-R). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 14 Z9 15 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 MAY 24 PY 2013 VL 8 IS 5 AR e64102 DI 10.1371/journal.pone.0064102 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150JB UT WOS:000319385300026 PM 23717541 ER PT J AU Mishra, SK Hoon, MA AF Mishra, Santosh K. Hoon, Mark A. TI The Cells and Circuitry for Itch Responses in Mice SO SCIENCE LA English DT Article ID GASTRIN-RELEASING-PEPTIDE; BEHAVIORAL-RESPONSES; SPINAL-CORD; RECEPTOR; SENSATION; NEURONS; PAIN; MECHANISMS; AFFERENTS AB Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb(-/-) mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb(-/-) mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor-expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next two stages of this dedicated neuronal pathway. C1 [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 NIH, NIDCR FX We are grateful to N. Ryba for encouragement and helpful advice and fur valuable suggestions. The Nppb-/- mice used for this research project were generated from embryonic stem cells obtained from the National Center for Research Resources (NCRR)-NIH-supported KOMP repository (www.komp.org) and engineered by the Wellcome Trust Sanger Institute and the Mouse Biology Program (www.mousebiology.org). We thank NIDCR Gene Targeting Facility for help generating Nppb mutant mice. The mouse strain STOCK Tg(GRP-EGFP) was obtained (rein the Mutant Mouse Regional Resource Center (MMRRC), a NCRR-NIH-funded strain repository, and was donated to the MMRRC by the National Institute of Neurological Disorders and Stroke-funded GENSAT RAC transgenic project. This research was supported by the intramural research program of the NIH, NIDCR. NR 21 TC 100 Z9 101 U1 1 U2 33 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 MAY 24 PY 2013 VL 340 IS 6135 BP 968 EP 971 DI 10.1126/science.1233765 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 149TK UT WOS:000319344100044 PM 23704570 ER PT J AU Molina-Cruz, A Garver, LS Alabaster, A Bangiolo, L Haile, A Winikor, J Ortega, C van Schaijk, BL Sauerwein, RW Taylor-Salmon, E Barillas-Mury, C AF Molina-Cruz, Alvaro Garver, Lindsey S. Alabaster, Amy Bangiolo, Lois Haile, Ashley Winikor, Jared Ortega, Corrie van Schaijk, Ben C. L. Sauerwein, Robert W. Taylor-Salmon, Emma Barillas-Mury, Carolina TI The Human Malaria Parasite Pfs47 Gene Mediates Evasion of the Mosquito Immune System SO SCIENCE LA English DT Article ID VECTOR ANOPHELES-GAMBIAE; PLASMODIUM-FALCIPARUM; SURFACE PROTEIN; SELECTION; FERTILITY; NITRATION; INVASION; PFS48/45 AB Plasmodium falciparum transmission by Anopheles gambiae mosquitoes is remarkably efficient, resulting in a very high prevalence of human malaria infection in sub-Saharan Africa. A combination of genetic mapping, linkage group selection, and functional genomics was used to identify Pfs47 as a P. falciparum gene that allows the parasite to infect A. gambiae without activating the mosquito immune system. Disruption of Pfs47 greatly reduced parasite survival in the mosquito, and this phenotype could be reverted by genetic complementation of the parasite or by disruption of the mosquito complement-like system. Pfs47 suppresses midgut nitration responses that are critical to activate the complement-like system. We provide direct experimental evidence that immune evasion mediated by Pfs47 is critical for efficient human malaria transmission by A. gambiae. C1 [Molina-Cruz, Alvaro; Garver, Lindsey S.; Alabaster, Amy; Bangiolo, Lois; Haile, Ashley; Winikor, Jared; Ortega, Corrie; Taylor-Salmon, Emma; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. [van Schaijk, Ben C. L.; Sauerwein, Robert W.] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6500 HB Nijmegen, Netherlands. RP Barillas-Mury, C (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. EM cbarillas@niaid.nih.gov RI Sauerwein, Robert/C-8519-2013 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. We thank K. Hayton and T. Wellems for advice with the genetic cross, A. Laughinghouse and K. Lee for technical support, and B. Marshall for editorial assistance. This work is subject to U.S. Patent no 61/684,333, filed 17 August 2012, "Transmission-blocking malaria vaccine." There are material transfer agreements or patents restricting use of Pfs48/45 and Pfs47 KO parasites. NR 15 TC 61 Z9 63 U1 1 U2 32 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 MAY 24 PY 2013 VL 340 IS 6135 BP 984 EP 987 DI 10.1126/science.1235264 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 149TK UT WOS:000319344100049 PM 23661646 ER PT J AU Vacchio, MS Bosselut, R AF Vacchio, Melanie S. Bosselut, Remy TI T Cell Metabolism: MicroRNAs Cap PTEN to Feed the Expanding Crowd SO IMMUNITY LA English DT Editorial Material ID SELECTION AB Cell proliferation during T cell development and effector responses require the resetting of metabolic activity to fit energy and anabolic needs. Henao-Mejia et al., (2013) show a critical role for a specific microRNA family in this process. C1 [Vacchio, Melanie S.; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM bosselur@helix.nih.gov NR 10 TC 1 Z9 1 U1 0 U2 0 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 MAY 23 PY 2013 VL 38 IS 5 BP 847 EP 848 DI 10.1016/j.immuni.2013.05.006 PG 2 WC Immunology SC Immunology GA AA2RT UT WOS:000330942500002 PM 23706663 ER PT J AU Rieder, SA Shevach, EM AF Rieder, Sadiye Amcaoglu Shevach, Ethan M. TI Eos, Goddess of Treg Cell Reprogramming SO IMMUNITY LA English DT Editorial Material ID REGULATORY T-CELLS AB Under certain conditions, Sharma et al. (2013) show in this issue of Immunity that a subpopulation of Foxp3(+) regulatory T cells loses expression of the transcription factor Eos and develops into Foxp3(+) T helper cells that facilitate priming of naive CD8(+) T cells. C1 [Rieder, Sadiye Amcaoglu; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 1 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 MAY 23 PY 2013 VL 38 IS 5 BP 849 EP 850 DI 10.1016/j.immuni.2013.05.001 PG 2 WC Immunology SC Immunology GA AA2RT UT WOS:000330942500003 PM 23706664 ER PT J AU Cruse, G Beaven, MA Ashmole, I Bradding, P Gilfillan, AM Metcalfe, DD AF Cruse, Glenn Beaven, Michael A. Ashmole, Ian Bradding, Peter Gilfillan, Alasdair M. Metcalfe, Dean D. TI A Truncated Splice-Variant of the Fc epsilon RI beta Receptor Subunit Is Critical for Microtubule Formation and Degranulation in Mast Cells SO IMMUNITY LA English DT Article ID IMMUNOGLOBULIN-E RECEPTOR; HIGH-AFFINITY RECEPTOR; SIGNALING PATHWAYS; MEDIATOR RELEASE; ACTIVATION; IGE; KINASE; ASSOCIATION; ATOPY; CHAIN AB Human linkage analyses have implicated the MS4A2-containing gene locus (encoding Fc epsilon RI beta) as a candidate for allergy susceptibility. We have identified a truncation of Fc epsilon RI beta (t-Fc epsilon RI beta) in humans that contains a putative calmodulin-binding domain and thus, we sought to identify the role of this variant in mast cell function. We determined that t-Fc epsilon RI beta is critical for microtubule formation and degranulation and that it may perform this function by trafficking adaptor molecules and kinases to the pericentrosomal and Golgi region in response to Ca2+ signals. Mutagenesis studies suggest that calmodulin binding to t-Fc epsilon RI beta in the presence of Ca2+ could be critical for t-Fc epsilon RI beta function. In addition, gene targeting of t-Fc epsilon RI beta attenuated microtubule formation, degranulation, and IL-8 production downstream of Ca2+ signals. Therefore, t-Fc epsilon RI beta mediates Ca2+-dependent microtubule formation, which promotes degranulation and cytokine release. Because t-Fc epsilon RI beta has this critical function, it represents a therapeutic target for the downregulation of allergic inflammation. C1 [Cruse, Glenn; Gilfillan, Alasdair M.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Ashmole, Ian; Bradding, Peter] Univ Leicester, Inst Lung Hlth, Dept Infect Immun & Inflammat, Glenfield Hosp, Leicester LE3 9QP, Leics, England. RP Cruse, G (reprint author), NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. EM glenncruse@hotmail.com FU Division of Intramural Research of NIAID; NHLBI within the National Institutes of Health; Novartis Pharmaceuticals; ERDF [05567] FX We thank the Biological Imaging Section, Research Technologies Branch, NIAID, NIH for expert advice in the acquisition and analysis of the confocal imaging. We also thank J. Rivera (NIAMS, NIH) for the generous gifts of Fc epsilon RI beta JRK Ab and Ms4a2-/- mice. Financial support was provided by the Division of Intramural Research of NIAID and NHLBI within the National Institutes of Health and in part from an unrestricted predoctoral fellowship from Novartis Pharmaceuticals (GC). Work in Leicester was conducted in laboratories partly funded by ERDF #05567. NR 41 TC 17 Z9 21 U1 0 U2 3 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 MAY 23 PY 2013 VL 38 IS 5 BP 906 EP 917 DI 10.1016/j.immuni.2013.04.007 PG 12 WC Immunology SC Immunology GA AA2RT UT WOS:000330942500010 PM 23643722 ER PT J AU Church, TR Black, WC Aberle, DR Berg, CD Clingan, KL Duan, FH Fagerstrom, RM Gareen, IF Gierada, DS Jones, GC Mahon, I Marcus, PM Sicks, JD Jain, A Baum, S AF Church, Timothy R. Black, William C. Aberle, Denise R. Berg, Christine D. Clingan, Kathy L. Duan, Fenghai Fagerstrom, Richard M. Gareen, Ilana F. Gierada, David S. Jones, Gordon C. Mahon, Irene Marcus, Pamela M. Sicks, JoRean D. Jain, Amanda Baum, Sarah CA Natl Lung Screening Trial Res Team TI Results of Initial Low-Dose Computed Tomographic Screening for Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SPIRAL CT; UNITED-STATES; TRIAL; MORTALITY; PROJECT; STATISTICS; PROSTATE; SMOKING AB BACKGROUND Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. We describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST to inform and improve lung-cancer-screening programs. METHODS At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptomatic participants, 55 to 74 years of age, with a history of at least 30 pack-years of smoking. The participants were randomly assigned to undergo annual screening, with the use of either low-dose CT or chest radiography, for 3 years. Nodules or other suspicious findings were classified as positive results. This article reports findings from the initial screening examination. RESULTS A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants (98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 participants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography group had a positive screening result; in the respective groups, 6369 participants (90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, including imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121 (5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively. CONCLUSIONS The NLST initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancer is achievable at U. S. screening centers that have staff experienced in chest CT. C1 [Church, Timothy R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55455 USA. [Black, William C.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Aberle, Denise R.] Univ Calif Los Angeles, Los Angeles, CA USA. [Berg, Christine D.; Fagerstrom, Richard M.; Marcus, Pamela M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Clingan, Kathy L.] WESTAT Corp, Rockville, MD 20850 USA. [Duan, Fenghai; Gareen, Ilana F.; Sicks, JoRean D.; Jain, Amanda; Baum, Sarah] Brown Univ, ACRIN, Biostat Ctr, Providence, RI 02912 USA. [Gierada, David S.] Washington Univ, Sch Med, St Louis, MO USA. [Jones, Gordon C.] Informat Management Syst, Rockville, MD USA. [Mahon, Irene] ACRIN, Headquarters & Data Management Ctr, Philadelphia, PA USA. RP Church, TR (reprint author), Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, 200 Oak St SE,Suite 350, Minneapolis, MN 55455 USA. EM trc@cccs.umn.edu RI Gareen, Ilana/I-2816-2014; Duan, Fenghai/J-3709-2014; Berg , Christine/K-1047-2014; OI Gareen, Ilana/0000-0002-0457-5595; Duan, Fenghai/0000-0002-5084-0070; Church, Timothy R./0000-0003-3292-5035; Aberle, Denise/0000-0002-8858-3401 FU National Cancer Institute FX Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385. NR 31 TC 216 Z9 222 U1 7 U2 32 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 MAY 23 PY 2013 VL 368 IS 21 BP 1980 EP 1991 DI 10.1056/NEJMoa1209120 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 194KD UT WOS:000322630700008 ER PT J AU Vandergeeten, C Fromentin, R DaFonseca, S Lawani, MB Sereti, I Lederman, MM Ramgopal, M Routy, JP Sekaly, RP Chomont, N AF Vandergeeten, Claire Fromentin, Remi DaFonseca, Sandrina Lawani, Mariam B. Sereti, Irini Lederman, Michael M. Ramgopal, Moti Routy, Jean-Pierre Sekaly, Rafick-Pierre Chomont, Nicolas TI Interleukin-7 promotes HIV persistence during antiretroviral therapy SO BLOOD LA English DT Article ID T-CELL HOMEOSTASIS; INFECTED INDIVIDUALS; IL-7; RESERVOIR; ACTIVATION; EXPRESSION; RECOVERY; BURDEN; HAART; NAIVE AB HIV persists in latently infected memory CD4(+) T cells during antiretroviral therapy (ART). When administered to HIV-infected subjects receiving suppressive ART, interleukin-7 (IL-7) increases the number of CD4(+) T cells by promoting their survival and proliferation. However, little is known about the impact of IL-7 on HIV persistence during ART. By isolating large numbers of CD4(+) T cells from HIV-infected subjects, we demonstrate that IL-7 enhances viral production in productively infected cells but does not disrupt viral latency in latently infected cells. When administered to virally suppressed subjects, IL-7 led to the rapid proliferation of memory CD4(+) T cells, which resulted in a 70% increase in the absolute number of circulating CD4(+) T cells harboring integrated HIV DNA 4 weeks after therapy. The genetic diversity of the viral reservoir increased transiently in the majority of the subjects studied before returning to baseline values. Altogether, our results indicate that IL-7 promotes the mechanisms of HIV persistence during ART by enhancing residual levels of viral production and inducing proliferation of latently infected cells, and suggest that IL-7 does not represent a suitable candidate therapeutic strategy for HIV eradication. This trial was registered at www.clinicaltrials.gov as #NCT00099671 (AIDS Clinical Trials Group protocol 5214). C1 [Vandergeeten, Claire; Fromentin, Remi; DaFonseca, Sandrina; Lawani, Mariam B.; Sekaly, Rafick-Pierre; Chomont, Nicolas] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34987 USA. [Sereti, Irini] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Lederman, Michael M.] Case Western Reserve Univ, Univ Hosp, Case Med Ctr, Cleveland, OH 44106 USA. [Ramgopal, Moti] Midway Immunol & Res Ctr, Ft Pierce, FL USA. [Routy, Jean-Pierre] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Div Hematol, Montreal, PQ H3A 1A1, Canada. [Routy, Jean-Pierre] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Chron Viral Illness Serv, Montreal, PQ H3A 1A1, Canada. RP Chomont, N (reprint author), Vaccine & Gene Therapy Inst Florida, 9801 SW Discovery Way, Port St Lucie, FL 34987 USA. EM nchomont@vgtifl.org FU American Foundation for AIDS Research (amfAR) [108264]; National Institute of Allergy and Infectious Diseases; amfAR [107175-44-RGRL]; Fonds de la recherche en Sante du Quebec (Reseau Syndrome d'immunodeficience acquise et maladies infectieuses); Canadian Institutes of Health Research [HOP 103230]; National Institutes of Health [1U19AI096109] FX R.F. is supported by the American Foundation for AIDS Research (amfAR, fellowship number 108264). The work of I. S. is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. This work was supported in part by the amfAR (107175-44-RGRL), the Fonds de la recherche en Sante du Quebec (Reseau Syndrome d'immunodeficience acquise et maladies infectieuses), the Canadian Institutes of Health Research (HOP 103230), and the National Institutes of Health (1U19AI096109 to the Delaney AIDS Research Enterprise to find a cure). J.-P.R. holds the Louis Lowenstein Chair in Hematology & Oncology. NR 26 TC 60 Z9 60 U1 1 U2 6 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 MAY 23 PY 2013 VL 121 IS 21 BP 4321 EP 4329 DI 10.1182/blood-2012-11-465625 PG 9 WC Hematology SC Hematology GA 184FS UT WOS:000321873900015 PM 23589672 ER PT J AU Ramanathan, HN Zhang, GF Ye, YH AF Ramanathan, Harish N. Zhang, Guofeng Ye, Yihong TI Monoubiquitination of EEA1 regulates endosome fusion and trafficking SO CELL AND BIOSCIENCE LA English DT Article DE EEA1; Endosome recycling; Ubiquitin; Endosome fusion; Rab5; E3-independent ubiquitination ID POLYUBIQUITIN CHAINS; AAA-ATPASE; PHOSPHATIDYLINOSITOL 3-PHOSPHATE; MEMBRANE-FUSION; FYVE FINGER; UBIQUITIN; ENDOCYTOSIS; PROTEINS; RECOGNITION; MECHANISMS AB Background: Early endosomal autoantigen 1 (EEA1) is a membrane tethering factor required for the fusion and maturation of early endosomes in endocytosis. How the activity of EEA1 is regulated in cells is unclear. Results: Here we show that endogenous EEA1 is prone to monoubiquitination at multiple sites, owing to an intrinsic affinity to ubiquitin conjugating enzymes (E2). The E2 interactions enable a ubiquitin ligase (E3) independent mechanism that decorate EEA1 with multiple mono-ubiquitin moieties. Expression of an ubiquitin-EEA1 chimera that mimics native mono-ubiquitinated EEA1 generates giant endosomes abutting the nucleus. Several lines of evidence suggest that this phenotype is due to increased endosome fusion and a simultaneous blockade on an endosome recycling pathway. The latter is likely caused by diminished endosome fission in cells expressing ubiquitin-EEA1. Conclusion: Our results demonstrate that ubiquitination may dramatically affect the activity of an endosome fusion factor to alter endosome morphology and trafficking pattern, and thereby implicating an unexpected role of ubiquitin signaling in endocytosis. C1 [Ramanathan, Harish N.; Ye, Yihong] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Zhang, Guofeng] NIBIB, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDKD, Mol Biol Lab, NIH, 5 Ctr Dr, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU Intramural Research Program of the NIDDK at the National Institutes of Health FX We thank J. Zimmerberg for helpful discussions, J. Donaldson for Rab5-expressing plasmids. The research is supported by the Intramural Research Program of the NIDDK at the National Institutes of Health. NR 36 TC 6 Z9 6 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD MAY 23 PY 2013 VL 3 AR 24 DI 10.1186/2045-3701-3-24 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 159DA UT WOS:000320023100001 PM 23701900 ER PT J AU Jacobson, KA AF Jacobson, Kenneth A. TI Structure-Based Approaches to Ligands for G-Protein-Coupled Adenosine and P2Y Receptors, from Small Molecules to Nanoconjugates SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MOUSE INTRAOCULAR-PRESSURE; A(2A) RECEPTOR; CRYSTAL-STRUCTURE; A(3) RECEPTOR; NUCLEOTIDE RECEPTORS; SELECTIVE AGONISTS; CRYSTALLOGRAPHIC STRUCTURE; INTERNATIONAL UNION; INSULIN-SECRETION; FLOW-CYTOMETRY AB Adenosine receptor (ARs) and P2Y receptors (P2YRs) that respond to extracellular nucleosides/nucleotides are associated with new directions for therapeutics. The X-ray structures of the A(2A)AR complexes with agonists and antagonists are examined in relationship to the G-protein-coupled receptor (GPCR) superfamily and applied to drug discovery. Much of the data on AR ligand structure from early SAR studies now are explainable from the A(2A)AR X-ray crystallography. The ligand-receptor interactions in related GPCR complexes can be identified by means of modeling approaches, e.g., molecular docking. Thus, molecular recognition in binding and activation processes has been studied effectively using homology modeling and applied to ligand design. Virtual screening has yielded new nonnucleoside AR antagonists, and existing ligands have been improved with knowledge of the receptor interactions. New agonists are being explored for central nervous system and peripheral therapeutics based on in vivo activity, such as chronic neuropathic pain. Ligands for receptors more distantly related to the X-ray template, i.e., P2YRs, have been introduced and are mainly used as pharmacological tools for elucidating the physiological role of extracellular nucleotides. Other ligand tools for drug discovery include fluorescent probes, radioactive probes, multivalent probes, and functionalized nanoparticles. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIDDK Intramural Research Program FX Support from the NIDDK Intramural Research Program is acknowledged. Stefano Costanzi (Department of Chemistry, American University, Washington, DC) is thanked for graphic images, and Silvia Paoletta, Evgeny Kiselev, and Francesca Deflorian (NIDDK, NIH) are thanked for helpful discussions. NR 127 TC 16 Z9 16 U1 0 U2 43 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 MAY 23 PY 2013 VL 56 IS 10 BP 3749 EP 3767 DI 10.1021/jm400422s PG 19 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 154CW UT WOS:000319650100001 PM 23597047 ER PT J AU Agniswamy, J Shen, CH Wang, YF Ghosh, AK Rao, KV Xu, CX Sayer, JM Louis, JM Weber, IT AF Agniswamy, Johnson Shen, Chen-Hsiang Wang, Yuan-Fang Ghosh, Arun K. Rao, Kalapala Venkateswara Xu, Chun-Xiao Sayer, Jane M. Louis, John M. Weber, Irene T. TI Extreme Multidrug Resistant HIV-1 Protease with 20 Mutations Is Resistant to Novel Protease Inhibitors with P1 '-Pyrrolidinone or P2-Tris-tetrahydrofuran SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTIRETROVIRAL DRUG-RESISTANCE; CLINICAL INHIBITORS; ANTIVIRAL ACTIVITY; CRYSTAL-STRUCTURES; MUTANTS; BINDING; UPDATE; POTENT; INDIVIDUALS; REFINEMENT AB Extreme drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with the clinical inhibitor amprenavir (1) and two potent antiviral investigational inhibitors GRL-02031 (2) and GRL-0519 (3). Clinical inhibitors are >1000-fold less active on PR20 than on wild-type enzyme, which is consistent with dissociation constants (K-L) from isothermal titration calorimetry of 40 nM for 3, 178 nM for amprenavir, and 960 nM for 2. High resolution crystal structures of PR20-inhibitor complexes revealed altered interactions compared with the corresponding wild-type PR complexes in agreement with relative inhibition. Amprenavir lacks interactions due to PR20 mutations in the S2/S2' subsites relative to PR. Inhibitors 2 and 3 lose interactions with Arg8' in PR20 relative to the wild-type enzyme because Arg8' shifts to interact with mutated L10F side chain. Overall, inhibitor 3 compares favorably with darunavir in affinity for PR20 and shows promise for further development. C1 [Agniswamy, Johnson; Shen, Chen-Hsiang; Wang, Yuan-Fang; Weber, Irene T.] Georgia State Univ, Dept Biol, Mol Basis Dis Program, Atlanta, GA 30303 USA. [Ghosh, Arun K.; Rao, Kalapala Venkateswara; Xu, Chun-Xiao] Purdue Univ, Dept Chem & Med Chem, W Lafayette, IN 47907 USA. [Sayer, Jane M.; Louis, John M.] NIDDKD, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Weber, IT (reprint author), Georgia State Univ, Dept Biol, Mol Basis Dis Program, POB 4010, Atlanta, GA 30303 USA. EM iweber@gsu.edu RI shen, chen-hsiang/D-7309-2016 FU National Institutes of Health [GM062920, GM053386]; Georgia State University Molecular Basis of Disease Fellowship; Georgia State University Research Program Enhancement Award in Bioinformatics; Intramural Research Program of the NIDDK; Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH FX The research was supported in part by the National Institutes of Health grants GM062920 (I.T.W.) and GM053386 (A.K.G.), by the Georgia State University Molecular Basis of Disease Fellowship and the Georgia State University Research Program Enhancement Award in Bioinformatics (H.-C.S.), and by the Intramural Research Program of the NIDDK and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. This research was authored, in whole or in part, by National Institutes of Health staff. Data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22ID at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at www.ser-cat.org/members.html. Amprenavir and darunavir were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. NR 47 TC 13 Z9 13 U1 1 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 23 PY 2013 VL 56 IS 10 BP 4017 EP 4027 DI 10.1021/jm400231v PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 154CW UT WOS:000319650100019 PM 23590295 ER PT J AU Metzger, MB Liang, YH Das, R Mariano, J Li, SJ Li, J Kostova, Z Byrd, RA Ji, XH Weissman, AM AF Metzger, Meredith B. Liang, Yu-He Das, Ranabir Mariano, Jennifer Li, Shengjian Li, Jess Kostova, Zlatka Byrd, R. Andrew Ji, Xinhua Weissman, Allan M. TI A Structurally Unique E2-Binding Domain Activates Ubiquitination by the ERAD E2, Ubc7p, through Multiple Mechanisms SO MOLECULAR CELL LA English DT Article ID ENDOPLASMIC-RETICULUM; CONJUGATING ENZYME; E3 LIGASE; IN-VIVO; SACCHAROMYCES-CEREVISIAE; ALLOSTERIC ACTIVATION; MAT-ALPHA-2 REPRESSOR; QUALITY-CONTROL; CHAIN FORMATION; DEGRADATION AB Cue1p is an integral component of yeast endoplasmic reticulum (ER)-associated degradation (ERAD) ubiquitin ligase (E3) complexes. It tethers the ERAD ubiquitin-conjugating enzyme (E2), Ubc7p, to the ER and prevents its degradation, and also activates Ubc7p via unknown mechanisms. We have now determined the crystal structure of the Ubc7p-binding region (U7BR) of Cue1p with Ubc7p. The U7BR is a unique E2-binding domain that includes three a-helices that interact extensively with the "backside" of Ubc7p. Residues essential for E2 binding are also required for activation of Ubc7p and for ERAD. We establish that the U7BR stimulates both RING-independent and RING-dependent ubiquitin transfer from Ubc7p. Moreover, the U7BR enhances ubiquitin-activating enzyme (E1)-mediated charging of Ubc7p with ubiquitin. This demonstrates that an essential component of E3 complexes can simultaneously bind to E2 and enhance its loading with ubiquitin. These findings provide mechanistic insights into how ubiquitination can be stimulated. C1 [Metzger, Meredith B.; Mariano, Jennifer; Li, Shengjian; Li, Jess; Kostova, Zlatka; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. [Liang, Yu-He; Ji, Xinhua] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Das, Ranabir; Li, Jess; Byrd, R. Andrew] NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Weissman, AM (reprint author), NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. EM weissmaa@mail.nih.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Stanley Lipkowitz and Yien Che Tsai for helpful discussion and comments regarding this manuscript. X-ray diffraction data were collected at the 22-BM synchrotron beamline of the Southeast Regional Collaborative Access Team (SER-CAT) at the Advanced Photon Source, Argonne National Laboratory. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 44 TC 30 Z9 30 U1 1 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 MAY 23 PY 2013 VL 50 IS 4 BP 516 EP 527 DI 10.1016/j.molcel.2013.04.004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 157JY UT WOS:000319893600007 PM 23665230 ER PT J AU Yutin, N Raoult, D Koonin, EV AF Yutin, Natalya Raoult, Didier Koonin, Eugene V. TI Virophages, polintons, and transpovirons: a complex evolutionary network of diverse selfish genetic elements with different reproduction strategies SO VIROLOGY JOURNAL LA English DT Article ID DNA VIRUSES; MAXIMUM-LIKELIHOOD; GIANT VIRUS; PSI-BLAST; MIMIVIRUS; EUKARYOTES; DATABASE; GENOME; TRANSPOSONS; SUPERFAMILY AB Background: Recent advances of genomics and metagenomics reveal remarkable diversity of viruses and other selfish genetic elements. In particular, giant viruses have been shown to possess their own mobilomes that include virophages, small viruses that parasitize on giant viruses of the Mimiviridae family, and transpovirons, distinct linear plasmids. One of the virophages known as the Mavirus, a parasite of the giant Cafeteria roenbergensis virus, shares several genes with large eukaryotic self-replicating transposon of the Polinton (Maverick) family, and it has been proposed that the polintons evolved from a Mavirus-like ancestor. Results: We performed a comprehensive phylogenomic analysis of the available genomes of virophages and traced the evolutionary connections between the virophages and other selfish genetic elements. The comparison of the gene composition and genome organization of the virophages reveals 6 conserved, core genes that are organized in partially conserved arrays. Phylogenetic analysis of those core virophage genes, for which a sufficient diversity of homologs outside the virophages was detected, including the maturation protease and the packaging ATPase, supports the monophyly of the virophages. The results of this analysis appear incompatible with the origin of polintons from a Mavirus-like agent but rather suggest that Mavirus evolved through recombination between a polinton and an unknownvirus. Altogether, virophages, polintons, a distinct Tetrahymena transposable element Tlr1, transpovirons, adenoviruses, and some bacteriophages form a network of evolutionary relationships that is held together by overlapping sets of shared genes and appears to represent a distinct module in the vast total network of viruses and mobile elements. Conclusions: The results of the phylogenomic analysis of the virophages and related genetic elements are compatible with the concept of network-like evolution of the virus world and emphasize multiple evolutionary connections between bona fide viruses and other classes of capsid-less mobile elements. C1 [Yutin, Natalya; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Raoult, Didier] Univ Aix Marseille 2, CNRS, UMR IRD 6236, URMITE,Fac Med, F-13385 Marseille 5, France. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 44 TC 40 Z9 41 U1 0 U2 17 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 MAY 23 PY 2013 VL 10 AR UNSP 158 DI 10.1186/1743-422X-10-158 PG 15 WC Virology SC Virology GA 158LV UT WOS:000319973700001 PM 23701946 ER PT J AU Shi, YB AF Shi, Yun-Bo TI The 2012 Ming K Jeang award for excellence in cell & bioscience SO CELL AND BIOSCIENCE LA English DT Editorial Material AB Three research groups led by Dr. Lixin Feng of Shanghai JiaoTong University School of Medicine, Shanghai, China, Dr. Walter Wahli of University of Lausanne, Lausanne, Switzerland, and Dr. Gutian Xiao of University of Pittsburgh Cancer Institute, Pittsburgh, USA, won the 2012 Ming K Jeang Award for Excellence in Cell & Bioscience. C1 NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD MAY 23 PY 2013 VL 3 AR 23 DI 10.1186/2045-3701-3-23 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 155FC UT WOS:000319731400001 PM 23701868 ER PT J AU Kouzine, F Wojtowicz, D Yamane, A Resch, W Kieffer-Kwon, KR Bandle, R Nelson, S Nakahashi, H Awasthi, P Feigenbaum, L Menoni, H Hoeijmakers, J Vermeulen, W Ge, H Przytycka, TM Levens, D Casellas, R AF Kouzine, Fedor Wojtowicz, Damian Yamane, Arito Resch, Wolfgang Kieffer-Kwon, Kyong-Rim Bandle, Russell Nelson, Steevenson Nakahashi, Hirotaka Awasthi, Parirokh Feigenbaum, Lionel Menoni, Herve Hoeijmakers, Jan Vermeulen, Wim Ge, Hui Przytycka, Teresa M. Levens, David Casellas, Rafael TI Global Regulation of Promoter Melting in Naive Lymphocytes SO CELL LA English DT Article ID RNA-POLYMERASE-II; EMBRYONIC STEM-CELLS; TRANSCRIPTION FACTORS IIE; IN-VIVO; C-MYC; BASAL TRANSCRIPTION; HUMAN GENOME; QUADRUPLEX STRUCTURES; HISTONE ACETYLATION; ACTIVE PROMOTERS AB Lymphocyte activation is initiated by a global increase in messenger RNA synthesis. However, the mechanisms driving transcriptome amplification during the immune response are unknown. By monitoring single-stranded DNA genome wide, we show that the genome of naive cells is poised for rapid activation. In G(0), similar to 90% of promoters from genes to be expressed in cycling lymphocytes are polymerase loaded but unmelted and support only basal transcription. Furthermore, the transition from abortive to productive elongation is kinetically limiting, causing polymerases to accumulate nearer to transcription start sites. Resting lymphocytes also limit the expression of the transcription factor IIH complex, including XPB and XPD helicases involved in promoter melting and open complex extension. To date, two rate-limiting steps have been shown to control global gene expression in eukaryotes: preinitiation complex assembly and polymerase pausing. Our studies identify promoter melting as a third key regulatory step and propose that this mechanism ensures a prompt lymphocyte response to invading pathogens. C1 [Kouzine, Fedor; Bandle, Russell; Levens, David] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wojtowicz, Damian; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Yamane, Arito; Resch, Wolfgang; Kieffer-Kwon, Kyong-Rim; Nelson, Steevenson; Nakahashi, Hirotaka; Casellas, Rafael] NIAMS, NIH, Bethesda, MD 20892 USA. [Casellas, Rafael] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Awasthi, Parirokh; Feigenbaum, Lionel] NCI, Sci Applicat Int Corp, NIH, Bethesda, MD 20892 USA. [Wojtowicz, Damian] Univ Warsaw, Inst Informat, PL-02098 Warsaw, Poland. [Menoni, Herve; Hoeijmakers, Jan; Vermeulen, Wim] Erasmus MC, Dept Genet, NL-3015 GE Rotterdam, Netherlands. [Ge, Hui] Ascentgene Inc, Rockville, MD 20850 USA. RP Levens, D (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM levens@helix.nih.gov; casellar@mail.nih.gov RI Yamane, Arito/A-2959-2013; Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NAIMS); National Cancer Institute (Center for Cancer Research); National Library of Medicine of the NIH FX We thank G. Gutierrez for technical assistance with the genome analyzer; J. Simone and J. Lay for bone marrow sorts; J. Qian and K. Zaal for the B cell confocal micrographs; and C. Benham for SIDD mapping. We thank the Casellas and Levens lab members for critically reading the manuscript. We also thank A. Hoofring from the National Institutes of Health (NIH) Medical Arts for designing the pictures shown in Figure 6D. This work was supported in part by the Intramural Research Program of National Institute of Arthritis and Musculoskeletal and Skin Diseases (NAIMS), the National Cancer Institute (Center for Cancer Research), and the National Library of Medicine of the NIH. This study utilized the high-performance computational capabilities of the Helix Systems at the NIH (http://helix.nih.gov). All animal experiments were performed according to the NIH guidelines for laboratory animals and were approved by the Scientific Committee of the NIAMS Animal Facilities. For questions regarding computational analysis, please contact T.M.P. (przytyck@ncbi.nlm.nih.gov). NR 76 TC 52 Z9 52 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 23 PY 2013 VL 153 IS 5 BP 988 EP 999 DI 10.1016/j.cell.2013.04.033 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 151JN UT WOS:000319456800008 PM 23706737 ER PT J AU Seol, Y Neuman, KC AF Seol, Yeonee Neuman, Keir C. TI SnapShot: Force Spectroscopy and Single-Molecule Manipulation SO CELL LA English DT Editorial Material ID OPTICAL TWEEZERS; MAGNETIC TWEEZERS; MICROSCOPY C1 [Seol, Yeonee; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Seol, Y (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Intramural NIH HHS NR 9 TC 1 Z9 1 U1 1 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 23 PY 2013 VL 153 IS 5 BP 1168 EP + PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 151JN UT WOS:000319456800024 PM 23706746 ER PT J AU Costa, JA Nguyen, DA Leal-Pinto, E Gordon, RE Hanss, B AF Costa, Justin A. Nguyen, Dac A. Leal-Pinto, Edgar Gordon, Ronald E. Hanss, Basil TI Wicking: A Rapid Method for Manually Inserting Ion Channels into Planar Lipid Bilayers SO PLOS ONE LA English DT Article ID ALPHA-HEMOLYSIN; MEMBRANE INTERACTION; MICROFLUIDIC DEVICE; DNA-MOLECULES; PROTEIN; CLIC1; RECONSTITUTION; MANIPULATION; NCC27; FORM AB The planar lipid bilayer technique has a distinguished history in electrophysiology but is arguably the most technically difficult and time-consuming method in the field. Behind this is a lack of experimental consistency between laboratories, the challenges associated with painting unilamellar bilayers, and the reconstitution of ion channels into them. While there has be a trend towards automation of this technique, there remain many instances where manual bilayer formation and subsequent membrane protein insertion is both required and advantageous. We have developed a comprehensive method, which we have termed "wicking", that greatly simplifies many experimental aspects of the lipid bilayer system. Wicking allows one to manually insert ion channels into planar lipid bilayers in a matter of seconds, without the use of a magnetic stir bar or the addition of other chemicals to monitor or promote the fusion of proteoliposomes. We used the wicking method in conjunction with a standard membrane capacitance test and a simple method of proteoliposome preparation that generates a heterogeneous mixture of vesicle sizes. To determine the robustness of this technique, we selected two ion channels that have been well characterized in the literature: CLIC1 and alpha-hemolysin. When reconstituted using the wicking technique, CLIC1 showed biophysical characteristics congruent with published reports from other groups; and alpha-hemolysin demonstrated Type A and B events when threading single stranded DNA through the pore. We conclude that the wicking method gives the investigator a high degree of control over many aspects of the lipid bilayer system, while greatly reducing the time required for channel reconstitution. C1 [Costa, Justin A.; Nguyen, Dac A.; Hanss, Basil] Icahn Sch Med Mt Sinai, Div Nephrol, Dept Med, New York, NY USA. [Costa, Justin A.; Nguyen, Dac A.; Hanss, Basil] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY USA. [Leal-Pinto, Edgar] Virginia Commonwealth Univ, Dept Physiol & Biophys, Richmond, VA USA. [Gordon, Ronald E.] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY USA. [Nguyen, Dac A.] Mt Sinai Sch Med, NIH Med Scientist Training Program, New York, NY USA. [Nguyen, Dac A.] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, Dept Syst Biol Dis & Therapeut, New York, NY USA. RP Hanss, B (reprint author), Icahn Sch Med Mt Sinai, Div Nephrol, Dept Med, New York, NY USA. EM basil.hanss@mssm.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/National Institutes of Health (NIH) [DK065838]; National Institute of General Medical Sciences [T32GM062754]; NIH FX These studies were supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/National Institutes of Health (NIH) to BH (DK065838). JC is a trainee in the Integrated Pharmacological Sciences Training Program supported by grant T32GM062754 from the National Institute of General Medical Sciences. DN is supported by the NIH Medical Scientist Training Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 3 Z9 3 U1 2 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 MAY 23 PY 2013 VL 8 IS 5 AR e60836 DI 10.1371/journal.pone.0060836 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 151BM UT WOS:000319435600001 PM 23717384 ER PT J AU Chen, Y Dodd, SJ Tangrea, MA Emmert-Buck, MR Koretsky, AP AF Chen, Yun Dodd, Stephen J. Tangrea, Michael A. Emmert-Buck, Michael R. Koretsky, Alan P. TI Measuring collective cell movement and extracellular matrix interactions using magnetic resonance imaging SO SCIENTIFIC REPORTS LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; APPARENT DIFFUSION-COEFFICIENT; PLANE ILLUMINATION MICROSCOPY; RECEPTOR TYROSINE KINASE; MAMMARY EPITHELIAL ACINI; GEL CONTRACTION ASSAY; IRON-OXIDE PARTICLES; IN-VIVO; MDCK CELLS; MECHANICAL-PROPERTIES AB Collective cell behaviors in migration and force generation were studied at the mesoscopic-level using cells grown in a 3D extracellular matrix (ECM) simulating tissues. Magnetic resonance imaging (MRI) was applied to investigate dynamic cell mechanics at this level. MDCK, NBT2, and MEF cells were embedded in 3D ECM, forming clusters that then migrated and generated forces affecting the ECM. The cells demonstrated MRI contrast due to iron accumulation in the clusters. Timelapse-MRI enabled the measurement of dynamic stress fields generated by the cells, as well as simultaneous monitoring of the cell distribution and ECM deformation/remodeling. We found cell clusters embedded in the 3D ECM can exert translational forces to pull and push, as well as torque, their surroundings. We also observed that the sum of forces generated by multiple cell clusters may result in macroscopic deformation. In summary, MRI can be used to image cell-ECM interactions mesoscopically. C1 [Chen, Yun; Dodd, Stephen J.; Koretsky, Alan P.] NINDS, NIH, Bethesda, MD 20892 USA. [Tangrea, Michael A.; Emmert-Buck, Michael R.] NCI, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM KoretskyA@ninds.nih.gov RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Chen, Yun/0000-0001-6917-7814 FU Intramural Research Program of the NIH, NINDS; Center for Cancer Research, NCI FX This research was supported (in part) by the Intramural Research Program of the NIH, NINDS, and also the Center for Cancer Research, NCI. NR 66 TC 5 Z9 5 U1 3 U2 26 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 MAY 23 PY 2013 VL 3 AR 1879 DI 10.1038/srep01879 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 149IW UT WOS:000319313300005 PM 23698816 ER PT J AU Enoch, MA Baghal, B Yuan, QP Goldman, D AF Enoch, Mary-Anne Baghal, Basel Yuan, Qiaoping Goldman, David TI A Factor Analysis of Global GABAergic Gene Expression in Human Brain Identifies Specificity in Response to Chronic Alcohol and Cocaine Exposure SO PLOS ONE LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; SUBUNIT MESSENGER-RNAS; GABA(A) RECEPTORS; RAT-BRAIN; SUBTYPES; EVOLUTION; DEFINES; CLUSTER; PROFILE; TRANSCRIPTION AB Although expression patterns of GABAergic genes in rodent brain have largely been elucidated, no comprehensive studies have been performed in human brain. The purpose of this study was to identify global patterns of GABAergic gene expression in healthy adults, including trans and cis effects in the GABA(A) gene clusters, before determining the effects of chronic alcohol and cocaine exposure on gene expression in the hippocampus. RNA-Seq data from 'BrainSpan' was obtained across 16 brain regions from postmortem samples from nine adults. A factor analysis was performed on global expression of 21 GABAergic pathway genes. Factor specificity for response to chronic alcohol/cocaine exposure was subsequently determined from the analysis of RNA-Seq data from postmortem hippocampus of eight alcoholics, eight cocaine addicts and eight controls. Six gene expression factors were identified. Most genes loaded (>= 0.5) onto one factor; six genes loaded onto two. The largest factor (0.30 variance) included the chromosome 5 gene cluster that encodes the most common GABA(A) receptor, alpha(1)beta(2)gamma(2), and genes encoding the alpha(3)beta(3)gamma(2) receptor. Genes within this factor were largely unresponsive to chronic alcohol/cocaine exposure. In contrast, the chromosome 4 gene cluster factor (0.14 variance) encoding the alpha(2)beta(1)gamma(1) receptor was influenced by chronic alcohol/cocaine exposure. Two other factors (0.17 and 0.06 variance) showed expression changes in alcoholics/cocaine addicts; these factors included genes involved in GABA synthesis and synaptic transport. Finally there were two factors that included genes with exceptionally low (0.10 variance) and high (0.09 variance) expression in the cerebellum; the former factor was unaffected by alcohol/cocaine exposure. This study has shown that there appears to be specificity of GABAergic gene groups, defined by covariation in expression, for response to chronic alcohol/cocaine exposure. These findings might have implications for combating stress-related craving and relapse. C1 [Enoch, Mary-Anne; Baghal, Basel; Yuan, Qiaoping; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. RP Enoch, MA (reprint author), NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health [AA000305-09 LNG] FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, program number AA000305-09 LNG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 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 MAY 22 PY 2013 VL 8 IS 5 AR UNSP e64014 DI 10.1371/journal.pone.0064014 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163UP UT WOS:000320362700090 PM 23717525 ER PT J AU Li, XL Qi, YC Ma, XR Huang, FJ Guo, H Jiang, XH Hong, J Lin, DP Cui, B Ning, G Xu, LY Wang, S AF Li, Xiaoli Qi, Yicheng Ma, Xinran Huang, Fengjiao Guo, Hua Jiang, Xiaohua Hong, Jie Lin, Dongping Cui, Bin Ning, Guang Xu, Lingyan Wang, Shu TI Chemokine (C-C Motif) Ligand 20, a Potential Biomarker for Graves' Disease, Is Regulated by Osteopontin SO PLOS ONE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CCR6-EXPRESSING TH17 CELLS; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; INTERFERON-GAMMA; T-CELLS; MULTIPLE-SCLEROSIS; DENDRITIC CELLS; SERUM-LEVELS; EXPRESSION AB Context: Graves' disease (GD) is a common autoimmune disease involving the thyroid gland. The altered balance of pro- and anti-inflammatory cytokines plays an important role in the pathogenesis of GD. Chemokine (C-C motif) ligand 20 (CCL20) is important for interleukin-17 (IL-17) signal activation and a potent chemoattractant for Th17 cells. Meanwhile, Osteopontin (OPN), a broadly expressed pleiotropic cytokine, has been implicated in GD through inducing Th1-involved response to enhance the production of proinflammatory cytokines and chemokines, but little is known about the role of OPN in regulating CCL20 and IL-17 signaling. Objective: This study sought to explore the possibility of CCL20 level as a biomarker for GD, as well as investigate the role of OPN in regulating CCL20 production. Methods: Fifty untreated GD patients, fifteen euthyroid GD patients, twelve TRAb-negative GD patients and thirty-five healthy control donors were recruited. OPN, CCL20 and other clinical GD diagnosis parameters were measured. CD4+T cells were isolated from peripheral blood mononuclear cells (PBMCs) using antibody-coated magnetic beads. Enzyme-linked immune-sorbent assay and quantitative polymerase chain reaction were used to determine CCL20 expression level. Results: We found that the plasma CCL20 level was enhanced in GD patients and decreased in euthyroid and TRAb-negative GD patients. In addition, CCL20 level correlated with GD clinical diagnostic parameters and plasma OPN level. Moreover, we demonstrated that recombinant OPN and plasma from untreated GD patients increased the expression of CCL20 in CD4+T cells, which could be blocked by OPN antibody. Furthermore, we found that the effect of OPN on CCL20 expression was mediated by beta 3 integrin receptor, IL-17, NF-kappa B and MAPK pathways. Conclusions: These results demonstrated that CCL20 might serve as a biomarker for GD and suggested the possible role of OPN in induction of CCL20 expression. C1 [Li, Xiaoli; Qi, Yicheng; Huang, Fengjiao; Guo, Hua; Jiang, Xiaohua; Hong, Jie; Cui, Bin; Ning, Guang; Wang, Shu] Shanghai Jiao Tong Univ, Sch Med, Dept Endocrinol & Metab, Ruijin Hosp,Shanghai Clin Ctr Endocrine & Metab D, Shanghai, Peoples R China. [Li, Xiaoli; Qi, Yicheng; Ma, Xinran; Cui, Bin; Ning, Guang; Xu, Lingyan; Wang, Shu] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Lab Endocrinol & Metab, Shanghai, Peoples R China. [Li, Xiaoli; Qi, Yicheng; Ma, Xinran; Cui, Bin; Ning, Guang; Xu, Lingyan; Wang, Shu] Shanghai Jiao Tong Univ, Sch Med SJTUSM, Shanghai 200030, Peoples R China. [Ma, Xinran; Xu, Lingyan] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Lin, Dongping] Shanghai Jiao Tong Univ, Dept Endocrinol & Metab, Peoples Hosp 9, Shanghai 200030, Peoples R China. RP Ning, G (reprint author), Shanghai Jiao Tong Univ, Sch Med, Dept Endocrinol & Metab, Ruijin Hosp,Shanghai Clin Ctr Endocrine & Metab D, Shanghai, Peoples R China. EM guangning@medmail.com.cn; xul7@mail.nih.gov; shuw@sibs.ac.cn FU National Natural Science Foundation of China [81270872]; Shanghai Municipal Natural Science Foundation [11495803400]; Sector Funds of Ministry of Health [201002002, 201202008]; The National Key New Drug Creation and Manufacturing Program of Ministry of Science and Technology [2012ZX09303006-001] FX This study was supported by the grants from the National Natural Science Foundation of China (No.81270872), Shanghai Municipal Natural Science Foundation (No. 11495803400), the Sector Funds of Ministry of Health (No. 201002002, No. 201202008) and The National Key New Drug Creation and Manufacturing Program of Ministry of Science and Technology (No. 2012ZX09303006-001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 4 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 MAY 22 PY 2013 VL 8 IS 5 AR e64277 DI 10.1371/journal.pone.0064277 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163UP UT WOS:000320362700128 PM 23717583 ER PT J AU Volkow, ND Tomasi, D Wang, GJ Telang, F Fowler, JS Goldstein, RZ Klein, N Wong, C Swanson, JM Shumay, E AF Volkow, Nora D. Tomasi, Dardo Wang, Gene-Jack Telang, Frank Fowler, Joanna S. Goldstein, Rita Z. Klein, Nelly Wong, Christopher Swanson, James M. Shumay, Elena TI Association between Dopamine D4 Receptor Polymorphism and Age Related Changes in Brain Glucose Metabolism SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; E TYPE-4 ALLELE; COGNITIVE DECLINE; D4 GENE; DEFICIT/HYPERACTIVITY DISORDER; DIFFERENTIAL SUSCEPTIBILITY; ALZHEIMERS-DISEASE; HEALTHY-SUBJECTS; NOVELTY SEEKING; DRD4 GENE AB Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3), which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive) including the beneficial effects of physical activity on longevity, influence the effects of aging on the human brain. We used positron emission tomography (PET) and [F-18]fluoro-D-glucose ((18)FDG) to measure brain glucose metabolism (marker of brain function) under baseline conditions (no stimulation) in 82 healthy individuals (age range 22-55 years). We determined their DRD4 genotype and found an interaction with age: individuals who did not carry the 7-repeat allele (7R-, n = 53) had a significant (p<0.0001) negative association between age and relative glucose metabolism (normalized to whole brain glucose metabolism) in frontal (r = -0.52), temporal (r = -0.51) and striatal regions (r = -0.47, p<0.001); such that older individuals had lower metabolism than younger ones. In contrast, for carriers of the 7R allele (7R+ n = 29), these correlations with age were not significant and they only showed a positive association with cerebellar glucose metabolism (r = +0.55; p = 0.002). Regression slopes of regional brain glucose metabolism with age differed significantly between the 7R+ and 7R- groups in cerebellum, inferior temporal cortex and striatum. These results provide evidence that the DRD4 genotype might modulate the associations between regional brain glucose metabolism and age and that the carriers of the 7R allele appear to be less sensitive to the effects of age on brain glucose metabolism. C1 [Volkow, Nora D.; Tomasi, Dardo] NIDA, NIH, Bethesda, MD 20892 USA. [Volkow, Nora D.; Telang, Frank; Wong, Christopher] NIAAA, NIH, Bethesda, MD USA. [Wang, Gene-Jack; Fowler, Joanna S.; Goldstein, Rita Z.; Klein, Nelly; Shumay, Elena] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Swanson, James M.] Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. RP Volkow, ND (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI Tomasi, Dardo/J-2127-2015 FU National Institutes of Health (Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse) FX This research was supported by the National Institutes of Health (Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse). The funding agency had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 3 Z9 5 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 22 PY 2013 VL 8 IS 5 AR UNSP e63492 DI 10.1371/journal.pone.0063492 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163UP UT WOS:000320362700027 PM 23717434 ER PT J AU Wang, GS Hu, N Yang, HH Wang, LM Su, H Wang, CY Clifford, R Dawsey, EM Li, JM Ding, T Han, XY Giffen, C Goldstein, AM Taylor, PR Lee, MP AF Wang, Gangshi Hu, Nan Yang, Howard H. Wang, Lemin Su, Hua Wang, Chaoyu Clifford, Robert Dawsey, Erica M. Li, Jian-Min Ding, Ti Han, Xiao-You Giffen, Carol Goldstein, Alisa M. Taylor, Philip R. Lee, Maxwell P. TI Comparison of Global Gene Expression of Gastric Cardia and Noncardia Cancers from a High-Risk Population in China SO PLOS ONE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; NUTRITION INTERVENTION TRIALS; DISEASE-SPECIFIC MORTALITY; CLINICAL-SIGNIFICANCE; DISTINCTIVE PATTERNS; SOMATIC MUTATIONS; FAMILY-HISTORY; ESOPHAGEAL; LINXIAN; SUPPLEMENTATION AB Objective: To profile RNA expression in gastric cancer by anatomic subsites as an initial step in identifying molecular subtypes and providing targets for early detection and therapy. Methods: We performed transcriptome analysis using the Affymetrix GeneChip U133A in gastric cardia adenocarcinomas (n = 62) and gastric noncardia adenocarcinomas (n = 72) and their matched normal tissues from patients in Shanxi Province, and validated selected dysregulated genes with additional RNA studies. Expression of dysregulated genes was also related to survival of cases. Results: Principal Component Analysis showed that samples clustered by tumor vs. normal, anatomic location, and histopathologic features. Paired t-tests of tumor/normal tissues identified 511 genes whose expression was dysregulated (P<4.7E-07 and at least two-fold difference in magnitude) in cardia or noncardia gastric cancers, including nearly one-half (n = 239, 47%) dysregulated in both cardia and noncardia, one-fourth dysregulated in cardia only (n = 128, 25%), and about one-fourth in noncardia only (n = 144, 28%). Additional RNA studies confirmed profiling results. Expression was associated with case survival for 20 genes in cardia and 36 genes in noncardia gastric cancers. Conclusions: The dysregulated genes identified here represent a comprehensive starting point for future efforts to understand etiologic heterogeneity, develop diagnostic biomarkers for early detection, and test molecularly-targeted therapies for gastric cancer. C1 [Wang, Gangshi; Hu, Nan; Wang, Lemin; Su, Hua; Wang, Chaoyu; Dawsey, Erica M.; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Yang, Howard H.; Lee, Maxwell P.] NCI, Off Director, Ctr Canc Res, Bethesda, MD 20892 USA. [Clifford, Robert] Walter Reed Army Inst Res, Multidrug Resistant Organism Repository & Surveil, Silver Spring, MD USA. [Li, Jian-Min; Ding, Ti; Han, Xiao-You] Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. [Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD USA. RP Taylor, PR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov; leemax@mail.nih.gov FU National Institutes of Health; Center for Cancer Research; National Cancer Institute, the Division of Cancer Epidemiology and Genetics FX This research is funded by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, the Division of Cancer Epidemiology and Genetics, and the 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 49 TC 17 Z9 18 U1 1 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 MAY 22 PY 2013 VL 8 IS 5 AR UNSP e63826 DI 10.1371/journal.pone.0063826 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163UP UT WOS:000320362700068 PM 23717493 ER PT J AU Daye, PM Optican, LM Roze, E Gaymard, B Pouget, P AF Daye, Pierre M. Optican, Lance M. Roze, Emmanuel Gaymard, Bertrand Pouget, Pierre TI Neuromimetic model of saccades for localizing deficits in an atypical eye-movement pathology SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID INFANTILE NYSTAGMUS SYNDROME; MOTOR SYSTEM MODEL; SUPERIOR COLLICULUS; BURST NEURONS; HORSERADISH-PEROXIDASE; OMNIPAUSE NEURONS; PATIENT DATA; MONKEY; CEREBELLUM; BRAIN AB Background: When patients with ocular motor deficits come to the clinic, in numerous situations it is hard to relate their behavior to one or several deficient neural structures. We sought to demonstrate that neuromimetic models of the ocular motor brainstem could be used to test assumptions of the neural deficits linked to a patient's behavior. Methods: Eye movements of a patient with unexplained neurological pathology were recorded. We analyzed the patient's behavior in terms of a neuromimetic saccadic model of the ocular motor brainstem to formulate a pathophysiological hypothesis. Results: Our patient exhibited unusual ocular motor disorders including increased saccadic peak velocities ( up to approximate to 1000 deg/s), dynamic saccadic overshoot, left-right asymmetrical post-saccadic drift and saccadic oscillations. We show that our model accurately reproduced the observed disorders allowing us to hypothesize that those disorders originated from a deficit in the cerebellum. Conclusion: Our study suggests that neuromimetic models could be a good complement to traditional clinical tools. Our behavioral analyses combined with the model simulations localized four different features of abnormal eye movements to cerebellar dysfunction. Importantly, this assumption is consistent with clinical symptoms. C1 [Daye, Pierre M.; Optican, Lance M.] NIH, Sensorimotor Res Lab, Bethesda, MD 20892 USA. [Roze, Emmanuel; Gaymard, Bertrand; Pouget, Pierre] Univ Paris 06, INSERM, CNRS 7225, UMRS 975, Paris, France. [Roze, Emmanuel; Gaymard, Bertrand] Hop La Pitie Salpetriere, AP HP, Dept Neurol, Paris, France. RP Daye, PM (reprint author), NIH, Sensorimotor Res Lab, Bldg 10, Bethesda, MD 20892 USA. EM pierre.daye@gmail.com NR 50 TC 4 Z9 4 U1 1 U2 7 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 MAY 22 PY 2013 VL 11 AR 125 DI 10.1186/1479-5876-11-125 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 157LP UT WOS:000319897900001 PM 23694702 ER PT J AU Lee, HS Lee, NCO Grimes, BR Samoshkin, A Kononenko, AV Bansal, R Masumoto, H Earnshaw, WC Kouprina, N Larionov, V AF Lee, Hee-Sheung Lee, Nicholas C. O. Grimes, Brenda R. Samoshkin, Alexander Kononenko, Artem V. Bansal, Ruchi Masumoto, Hiroshi Earnshaw, William C. Kouprina, Natalay Larionov, Vladimir TI A new assay for measuring chromosome instability (CIN) and identification of drugs that elevate CIN in cancer cells SO BMC CANCER LA English DT Article DE Human artificial chromosome; HAC; Chromosome instability; CIN; Drug treatment ID HUMAN ARTIFICIAL CHROMOSOME; VITRO MICRONUCLEUS TEST; CONDITIONAL CENTROMERE; KINETOCHORE; APOPTOSIS; ERRORS; NONDISJUNCTION; MISSEGREGATION; CONSTRUCTION; SEGREGATION AB Background: Aneuploidy is a feature of most cancer cells that is often accompanied by an elevated rate of chromosome mis-segregation termed chromosome instability (CIN). While CIN can act as a driver of cancer genome evolution and tumor progression, recent findings point to the existence of a threshold level beyond which CIN becomes a barrier to tumor growth and therefore can be exploited therapeutically. Drugs known to increase CIN beyond the therapeutic threshold are currently few in number, and the clinical promise of targeting the CIN phenotype warrants new screening efforts. However, none of the existing methods, including the in vitro micronuclei (MNi) assay, developed to quantify CIN, is entirely satisfactory. Methods: We have developed a new assay for measuring CIN. This quantitative assay for chromosome mis-segregation is based on the use of a non-essential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene. Thus, cells that inherit the HAC display green fluorescence, while cells lacking the HAC do not. This allows the measurement of HAC loss rate by routine flow cytometry. Results: Using the HAC-based chromosome loss assay, we have analyzed several well-known anti-mitotic, spindle-targeting compounds, all of which have been reported to induce micronuclei formation and chromosome loss. For each drug, the rate of HAC loss was accurately measured by flow cytometry as a proportion of non-fluorescent cells in the cell population which was verified by FISH analysis. Based on our estimates, despite their similar cytotoxicity, the analyzed drugs affect the rates of HAC mis-segregation during mitotic divisions differently. The highest rate of HAC mis-segregation was observed for the microtubule-stabilizing drugs, taxol and peloruside A. Conclusion: Thus, this new and simple assay allows for a quick and efficient screen of hundreds of drugs to identify those affecting chromosome mis-segregation. It also allows ranking of compounds with the same or similar mechanism of action based on their effect on the rate of chromosome loss. The identification of new compounds that increase chromosome mis-segregation rates should expedite the development of new therapeutic strategies to target the CIN phenotype in cancer cells. C1 [Lee, Hee-Sheung; Lee, Nicholas C. O.; Samoshkin, Alexander; Kononenko, Artem V.; Kouprina, Natalay; Larionov, Vladimir] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Grimes, Brenda R.; Bansal, Ruchi] Indiana Univ Sch Med, Dept Med & Mol Genet, Indiana Univ Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Human Genome Res, Lab Cell Engn, Kisarazu, Chiba 2920818, Japan. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. RP Larionov, V (reprint author), NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. EM larionov@mail.nih.gov RI Lee, Nicholas/F-3668-2015; OI lee, nicholas/0000-0003-2628-6599 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA; Wellcome Trust Principal Research Fellowship [073915]; Ministry of Education, Culture, Sports, Science and Technology of Japan; Kazusa DNA Research Institute Foundation; Indiana Genomics Initiative (INGEN); Lilly Endowment FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA (V.L.), a Wellcome Trust Principal Research Fellowship [grant number 073915] (W.C.E.), the Grand-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology of Japan (H.M.) and the Kazusa DNA Research Institute Foundation (H.M.) and the Indiana Genomics Initiative (INGEN) (B.R.G.). INGEN is supported in part by the Lilly Endowment. Reversine and ZM-447439 were kindly provided by Dr. Alexey Arnautov (National Institute of Child Health and Human Development/NICHHD, NIH). Ixabepilone and docetaxel were obtained from Dr. Marianne Poruchynsky (National Cancer Institute/NCI, NIH). Peloruside A was kindly provided by Dr. Dan Sackett (National Institute of Child Health and Human Development/NICHHD, NIH). The authors also would like to thank the CRC, LRBGE Fluorescence Imaging Facility (NIH) and personally Drs. Karpova and Dr. McNally for instructions, consultations and help with the usage of a DeltaVision microscopy imaging system. We also would like to thank Dr. Elisabetta Leo for help in some experiments. NR 35 TC 9 Z9 9 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 22 PY 2013 VL 13 AR 252 DI 10.1186/1471-2407-13-252 PG 12 WC Oncology SC Oncology GA 157HA UT WOS:000319885600001 PM 23694679 ER PT J AU Suto, N Elmer, GI Wang, B You, ZB Wise, RA AF Suto, Nobuyoshi Elmer, Greg I. Wang, Bin You, Zhi-Bing Wise, Roy A. TI Bidirectional Modulation of Cocaine Expectancy by Phasic Glutamate Fluctuations in the Nucleus Accumbens SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL GLUTAMATE; EXPERIENCE ESTABLISHES CONTROL; DRUG-SEEKING BEHAVIOR; INDUCED REINSTATEMENT; ENVIRONMENTAL STIMULI; LOCOMOTOR-ACTIVITY; CORE; SHELL; RECEPTORS; RELAPSE AB While glutamate in the nucleus accumbens (NAS) contributes to the promotion of drug-seeking by drug-predictive cues, it also appears to play a role in the inhibition of drug-seeking following extinction procedures. Thus we measured extracellular fluctuations of NAS glutamate in response to discriminative stimuli that signaled either cocaine availability or cocaine omission. We trained rats to self-administer intravenous cocaine and then to recognize discriminative odor cues that predicted either sessions where cocaine was available or alternating sessions where it was not (saline substituted for cocaine). Whereas responding in cocaine availability sessions remained stable, responding in cocaine omission sessions progressively declined to chance levels. We then determined the effects of each odor cue on extracellular glutamate in the core and shell subregions of NAS preceding and accompanying lever pressing under an extinction condition. Glutamate levels were elevated in both core and shell by the availability odor and depressed in the core but not the shell by the omission odor. Infusion of kynurenic acid (an antagonist for ionotropic glutamate receptors) into core but not shell suppressed responding associated with the availability odor, but had no effect on the suppression associated with the omission odor. Thus cocaine-predictive cues appear to promote cocaine seeking in part by elevating glutamatergic neurotransmission in the core of NAS, whereas cocaine-omission cues appear to suppress cocaine seeking in part by depressing glutamatergic receptor activation in the same region. C1 [Suto, Nobuyoshi; Wang, Bin; You, Zhi-Bing; Wise, Roy A.] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Suto, Nobuyoshi; Elmer, Greg I.] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Suto, Nobuyoshi] Scripps Res Inst, Dept Mol & Cellular Neurosci, La Jolla, CA 92037 USA. RP Suto, N (reprint author), Scripps Res Inst, Dept Mol & Cellular Neurosci, 10550 North Torrey Pines Rd,SP30-2120, La Jolla, CA 92037 USA. EM nsuto@scripps.edu FU National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services [N01DA59909, DA033533]; [AA007456] FX This work is supported by funding from National Institute on Drug Abuse/Intramural Research Program/National Institutes of Health/Department of Health and Human Services, N01DA59909 and DA033533. N.S. was partially supported by AA007456. We thank Stephanie Myal for her technical assistance. NR 46 TC 6 Z9 6 U1 1 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 22 PY 2013 VL 33 IS 21 BP 9050 EP 9055 DI 10.1523/JNEUROSCI.0503-13.2013 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 150LF UT WOS:000319391200014 PM 23699516 ER PT J AU Zhang, Z Wang, DS Sun, T Xu, JH Chiang, HC Shin, W Wu, LG AF Zhang, Zhen Wang, Dongsheng Sun, Tao Xu, Jianhua Chiang, Hsueh-Cheng Shin, Wonchul Wu, Ling-Gang TI The SNARE Proteins SNAP25 and Synaptobrevin Are Involved in Endocytosis at Hippocampal Synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SYNAPTIC-VESICLE ENDOCYTOSIS; KISS-AND-RUN; ADRENAL CHROMAFFIN CELLS; SINGLE NANOPARTICLES; DYNAMIC CONTROL; ACTIVE ZONE; RETRIEVAL; FUSION; EXOCYTOSIS; TERMINALS AB SNAP25, an essential component of the soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor (SNARE) complex that mediates exocytosis, is not considered to play a role in endocytosis, which couples to exocytosis by retrieving a similar amount of exocytosed vesicles. By knocking down SNAP25 and imaging slow endocytosis at a conventional synapse, the rat cultured hippocampal synapse, we found that SNAP25 is involved in slow, clathrin-dependent endocytosis. With similar techniques, we found that not only SNAP25, but also synaptobrevin is involved in slow endocytosis. These results provide the first evidence showing the dual role of SNAP25 and synaptobrevin in both exocytosis and slow endocytosis at conventional synapses. Such a dual role may contribute to mediate the coupling between exocytosis and clathrin-dependent endocytosis at conventional synapses, a mechanism critical for the maintenance of synaptic transmission and the normal structure of nerve terminals. C1 [Zhang, Zhen; Wang, Dongsheng; Sun, Tao; Chiang, Hsueh-Cheng; Shin, Wonchul; Wu, Ling-Gang] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. [Xu, Jianhua] Georgia Hlth Sci Univ, Inst Mol Med & Genet, Augusta, GA 30912 USA. [Xu, Jianhua] Georgia Hlth Sci Univ, Dept Neurol, Augusta, GA 30912 USA. RP Wu, LG (reprint author), Natl Inst Neurol Disorders & Stroke, 35 Convent Dr,Bldg 35,Room 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov OI Xu, Jianhua/0000-0003-0084-8856 FU NINDS Intramural Research Program FX This work was supported by the NINDS Intramural Research Program. We thank Edaeni Hamid for comments on this manuscript, and Dr. Yongling Zhu (Northwestern University, Chicago) for providing synaptophysin-pHluorin2X plasmid. NR 31 TC 22 Z9 23 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 MAY 22 PY 2013 VL 33 IS 21 BP 9169 EP 9175 DI 10.1523/JNEUROSCI.0301-13.2013 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 150LF UT WOS:000319391200025 PM 23699527 ER PT J AU Liu, Y Smith, LI Huang, V Poon, V Coello, A Olah, M Spiga, F Lightman, SL Aguilera, G AF Liu, Ying Smith, Lorna I. Huang, Victoria Poon, Victoria Coello, Ana Olah, Mark Spiga, Francesca Lightman, Stafford L. Aguilera, Greti TI Transcriptional regulation of episodic glucocorticoid secretion SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 15th Conference on the Adrenal Cortex (Adrenal) CY JUN 19-22, 2012 CL League City, TX DE Steroidogenic acute regulatory protein (StAR); Melanocortin type 2 receptor (MC2R); Melanocortin receptor associated protein (MRAP); Stress; ACTH; Transcription ID SALT-INDUCIBLE KINASE; MESSENGER-RIBONUCLEIC-ACID; BINDING PROTEIN-ACTIVITY; HORMONE TRANSCRIPTION; GENE-TRANSCRIPTION; ADRENOCORTICOTROPIC HORMONE; STEROIDOGENIC ENZYMES; CORTISOL SECRETION; BETA-ENDORPHIN; ADRENAL-CORTEX AB Circadian and ultradian variations of basal glucocorticoid secretion and transient elevations during stress are essential for homeostasis. Using intronic qRT-PCR to measure changes in primary transcript (hnRNA) we have shown that secretory events induced by stress or ACTH injection are followed by episodic increases in transcription of rate limiting steroidogenic proteins, such as steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage and melanocortin receptor associated protein. These transcriptional episodes imply rapid turnover of steroidogenic proteins and the need of de nova synthesis following each secretory event. In addition to episodic ACTH secretion, it is likely that intracellular feedback mechanisms at the adrenal fasciculata level contribute to the generation of episodes of transcription. The time relationship between activation and translocation of the CREB co-activator, transducer of regulated CREB activity (TORC) to the nucleus preceding transcriptional episodes suggest the involvement of TORC in the transcriptional activation of StAR and other steroidogenic proteins. Published by Elsevier Ireland Ltd. C1 [Liu, Ying; Smith, Lorna I.; Huang, Victoria; Poon, Victoria; Coello, Ana; Olah, Mark; Aguilera, Greti] NICHHD, Sect Endocrine Physiol, NIH, Bethesda, MD 20892 USA. [Smith, Lorna I.; Spiga, Francesca; Lightman, Stafford L.] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol, Avon, England. RP Aguilera, G (reprint author), Eunice Kennedy Shriver Inst Child Hlth & Human De, Sect Endocrine Physiol, NIH, Bldg 10 CRC,Rm 1E-3330, Bethesda, MD 20892 USA. EM Greti_Aguilera@nih.gov FU Intramural Research Program of the National Institutes of Health/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/Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 59 TC 12 Z9 12 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 MAY 22 PY 2013 VL 371 IS 1-2 SI SI BP 62 EP 70 DI 10.1016/j.mce.2012.10.011 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 146NA UT WOS:000319096600009 PM 23138111 ER PT J AU Ziegler, CG Ullrich, M Schally, AV Bergmann, R Pietzsch, J Gebauer, L Gondek, K Qin, N Pacak, K Ehrhart-Bornstein, M Eisenhofer, G Bornstein, SR AF Ziegler, C. G. Ullrich, M. Schally, A. V. Bergmann, R. Pietzsch, J. Gebauer, L. Gondek, K. Qin, N. Pacak, K. Ehrhart-Bornstein, M. Eisenhofer, G. Bornstein, S. R. TI Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 15th Conference on the Adrenal Cortex (Adrenal) CY JUN 19-22, 2012 CL League City, TX DE Pheochromocytoma; Peptide analogs; Targeted tumor therapy ID MALIGNANT PHEOCHROMOCYTOMA; CYTOTOXIC ANALOGS; CUSHINGS-SYNDROME; OVARIAN CANCERS; THERAPY; DIAGNOSIS; GROWTH; TUMORS; ANTAGONISTS; LHRH AB Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPCs) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MU cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Ziegler, C. G.; Ullrich, M.; Gebauer, L.; Gondek, K.; Qin, N.; Ehrhart-Bornstein, M.; Eisenhofer, G.; Bornstein, S. R.] Univ Hosp Carl Gustav Carus, Dept Med 3, Dresden, Germany. [Schally, A. V.] Univ Miami, Miller Sch Med, VA Med Ctr, Miami, FL 33136 USA. [Schally, A. V.] Univ Miami, Miller Sch Med, Dept Pathol, Dept Med,Div Endocrinol & Hematol Oncol, Miami, FL 33136 USA. [Bergmann, R.; Pietzsch, J.] Helmholtz Zentrum, Dept Radiopharmaceut & Chem Biol, Inst Radiopharmaceut Canc Res, Berlin, Germany. [Pietzsch, J.] Tech Univ Dresden, Dept Chem & Food Chem, D-01307 Dresden, Germany. [Pacak, K.] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Ziegler, CG (reprint author), Tech Univ Dresden, Univ Clinicum Carl Gustav Carus, Med Theoret Ctr MTZ, Fetscherstr 74, D-01307 Dresden, Germany. EM Christian.Ziegler@uniklinikum-dresden.de OI Pietzsch, Jens/0000-0002-1610-1493; Schally, Andrew/0000-0003-1273-6747 FU Deutsche Forschungsgemeinschaft [ZI-1362/2-1, BE-2607/1-1] FX This work was supported by The Deutsche Forschungsgemeinschaft (Grants ZI-1362/2-1 (C.G.Z. & G.E.), and BE-2607/1-1 (R.B. & J.P)). We are very thankful to Prof. Arthur Tischler and Dr. James Powers for providing us both the MPC as well as the MTT cell lines. NR 35 TC 3 Z9 3 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAY 22 PY 2013 VL 371 IS 1-2 SI SI BP 189 EP 194 DI 10.1016/j.mce.2012.12.011 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 146NA UT WOS:000319096600025 PM 23267837 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI cAMP/PKA signaling defects in tumors: Genetics and tissue-specific pluripotential cell-derived lesions in human and mouse SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 15th Conference on the Adrenal Cortex (Adrenal) CY JUN 19-22, 2012 CL League City, TX DE Adrenal glands; cAMP signaling pathway; Adrenocortical hyperplasia; PRKAR1A gene; Tumor ID PROTEIN-KINASE-A; NODULAR ADRENOCORTICAL-DISEASE; MACRONODULAR ADRENAL-HYPERPLASIA; GASTROINTESTINAL STROMAL TUMORS; HYPERALDOSTERONISM TYPE-II; PHOSPHODIESTERASE 11A PDE11A; CARNEY-STRATAKIS-SYNDROME; MCCUNE-ALBRIGHT SYNDROME; CANCER STEM-CELLS; SUBUNIT TYPE 1A AB In the last few years, bench and clinical studies led to significant new insight into how cyclic adenosine monophosphate (cAMP) signaling, the molecular pathway that had been identified in the early 2000s as the one involved in most benign cortisol-producing adrenal hyperplasias, affects adrenocortical growth and development, as well as tumor formation. A major discovery was the identification of tissue-specific pluripotential cells (TSPCs) as the culprit behind tumor formation not only in the adrenal, but also in bone. Discoveries in animal studies complemented a number of clinical observations in patients. Gene identification continued in parallel with mouse and other studies on the cAMP signaling and other pathways. C1 [Stratakis, Constantine A.] NICHD, Sect Genet & Endocrinol SEGEN, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] NIH, Interinst Pediat Endocrinol Training Program, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, East Labs, SEGEN PDEGEN, NIH, CRC Rm 1-3330,Bldg 10 CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS [ZIA HD008920-01] NR 188 TC 21 Z9 21 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAY 22 PY 2013 VL 371 IS 1-2 SI SI BP 208 EP 220 DI 10.1016/j.mce.2013.01.015 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 146NA UT WOS:000319096600028 PM 23485729 ER PT J AU Swartz, KJ AF Swartz, Kenton J. TI The scorpion toxin and the potassium channel SO ELIFE LA English DT Article ID K+ CHANNEL; PEPTIDE INHIBITOR; CHARYBDOTOXIN; PORE; SHAKER C1 NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov NR 12 TC 1 Z9 2 U1 0 U2 6 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 21 PY 2013 VL 2 AR e00873 DI 10.7554/eLife.00873 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 274OJ UT WOS:000328615500005 PM 23705072 ER PT J AU Gruschus, JM Yap, TL Pistolesi, S Maltsev, AS Lee, JC AF Gruschus, James M. Thai Leong Yap Pistolesi, Sara Maltsev, Alexander S. Lee, Jennifer C. TI NMR Structure of Calmodulin Complexed to an N-Terminally Acetylated alpha-Synuclein Peptide SO BIOCHEMISTRY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; A-BETA COMPONENT; PARKINSONS-DISEASE; SYNTHETIC MEMBRANES; PRECURSOR PROTEIN; CHROMAFFIN CELLS; CHEMICAL-SHIFTS; VESICLE FUSION; KNOCKOUT MICE; BINDING AB Calmodulin (CaM) is a calcium binding protein that plays numerous roles in Ca-dependent cellular processes, including uptake and release of neurotransmitters in neurons. alpha-Synuclein (alpha-syn), one of the most abundant proteins in central nervous system neurons, helps maintain presynaptic vesicles containing neurotransmitters and moderates their Ca-dependent release into the synapse. Ca-Bound CaM interacts with alpha-syn most strongly at its N-terminus. The N-terrninal region of alpha-syn is important for membrane binding; thus, CaM could modulate membrane association of alpha-syn in a Ca-dependent manner. In contrast, Ca-free CaM has negligible interaction. The interaction with CaM leads to significant signal broadening in both CaM and alpha-syn NMR Spectra, most likely due to conformational exchange. The broadening is much reduced when binding a peptide consisting of the first 19 residues of alpha-syn. In neurons, most alpha-syn is acetylated at the N-terminus, and acetylation leads to a 10-fold increase in binding strength for the alpha-syn peptide (K-D = 35 +/- 10 mu M). The N-terminally acetylated peptide adopts a helical structure at the N-terminus with the acetyl group contacting the N-terminal domain of CaM and with less ordered helical :structure toward the C-terminus of the peptide contacting the CaM C-terminal domain. Comparison with known structures shows that the CaM/alpha-syn complex most closely resembles Ca-bound CaM in a complex with an IQ motif peptide. However, a search comparing the alpha-Syn peptide. sequence with known CaM targets, including IQ motifs, found no homologies; thus, the N-terminal alpha-syn CaM binding site appears to be a novel CaM target sequence. C1 [Gruschus, James M.; Thai Leong Yap; Pistolesi, Sara; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Maltsev, Alexander S.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gruschus, JM (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM gruschuj@helix.nih.gov; leej4@nhlbi.nih.gov RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU Intramural Research Program at the National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This work is supported by the Intramural Research Program at the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 57 TC 10 Z9 10 U1 0 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 21 PY 2013 VL 52 IS 20 BP 3436 EP 3445 DI 10.1021/bi400199p PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 154WZ UT WOS:000319708700005 PM 23607618 ER PT J AU Mahler, B Chen, YW Ford, J Thiel, C Wistow, G Wu, ZR AF Mahler, Bryon Chen, Yingwei Ford, Jason Thiel, Caleb Wistow, Graeme Wu, Zhengrong TI Structure and Dynamics of the Fish Eye Lens Protein, gamma M7-Crystallin SO BIOCHEMISTRY LA English DT Article ID GAMMA-D-CRYSTALLIN; TOOTHFISH DISSOSTICHUS-MAWSONI; X-RAY-ANALYSIS; TRYPTOPHAN FLUORESCENCE; S-CRYSTALLIN; MOLECULAR-STRUCTURE; STABILITY; DOMAIN; NMR; BETA AB The vertebrate eye lens contains high concentrations of. crystallins. The dense lenses of fish are particularly abundant in a class called gamma M-crystallin whose members are characterized by an unusually high methionine content and partial loss of the four tryptophan residues conserved in all gamma-crystallins from mammals which are proposed to contribute to protection from UV-damage. Here, we present the structure and dynamics of gamma M7-crystallin from zebrafish (Danio rerio). The solution structure shares the typical two-domain, four-Greek-key motif arrangement of other gamma-crystallins, with the major difference noted in the final loop of the N-terminal domain, spanning residues 65-72. This is likely due to the absence of the conserved tryptophans. Many of the methionine residues are exposed on the surface but are mostly well and frequently have contacts with aromatic side chains. This may contribute to the specialized surface properties of these proteins that exist under high molecular crowding in the fish lens. NMR relaxation data show increased backbone conformational motions in the loop regions of gamma M7 compared to those of mouse gamma S-crystallin and show that fast internal motion of the interdomain linker in gamma-crystallins correlates with linker length. Unfolding studies monitored by tryptophan fluorescence confirm results from mutant mouse gamma S-crystallin and show that unfolding of a beta gamma-crystallin domain likely starts from unfolding of the variable loop containing the more fluorescently quenched tryptophan residue, resulting in a native like unfolding intermediate C1 [Mahler, Bryon; Ford, Jason; Thiel, Caleb; Wu, Zhengrong] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. [Chen, Yingwei; Wistow, Graeme] NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. RP Wu, ZR (reprint author), Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. EM wu.473@osu.edu FU NIH [R21EY018423, R0IAG031903]; NEI intramural program FX Z.W. is funded by NIH grant R21EY018423 and partially by grant R0IAG031903. Y.C. and G.W. are funded by the NEI intramural program. NR 53 TC 6 Z9 6 U1 2 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 21 PY 2013 VL 52 IS 20 BP 3579 EP 3587 DI 10.1021/bi400151c PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 154WZ UT WOS:000319708700018 PM 23597261 ER PT J AU Bowman-Colin, C Xia, B Bunting, S Klijn, C Drost, R Bouwman, P Fineman, L Chen, XX Culhane, AC Cai, H Rodig, SJ Bronson, RT Jonkers, J Nussenzweig, A Kanellopoulou, C Livingston, DM AF Bowman-Colin, Christian Xia, Bing Bunting, Samuel Klijn, Christiaan Drost, Rinske Bouwman, Peter Fineman, Laura Chen, Xixi Culhane, Aedin C. Cai, Hong Rodig, Scott J. Bronson, Roderick T. Jonkers, Jos Nussenzweig, Andre Kanellopoulou, Chryssa Livingston, David M. TI Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mouse model; familial breast cancer ID EARLY EMBRYONIC LETHALITY; HOMOLOGOUS RECOMBINATION; SUSCEPTIBILITY GENE; BRCA1 DEFICIENCY; FANCONI-ANEMIA; CELLULAR PROLIFERATION; GENOMIC INSTABILITY; CRE RECOMBINASE; MOUSE MODELS; SOLID TUMORS AB Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2-mediated DNA repair and tumor suppression functions, we targeted Palb2 in the mouse. Palb2-deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germline deletion of Palb2 led to early embryonic lethality. Somatic deletion of Palb2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both Palb2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in Palb2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and Palb2 mammary tumor development. However, unlike the case of Brca1-mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of Palb2- or Brca2-mutant primary lymphocytes. Therefore, Palb2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying Palb2 mammary tumor suppression functions can now be explored genetically in vivo. C1 [Bowman-Colin, Christian; Fineman, Laura; Chen, Xixi; Kanellopoulou, Chryssa; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Culhane, Aedin C.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Xia, Bing; Cai, Hong] Canc Inst New Jersey, New Brunswick, NJ 08901 USA. [Bunting, Samuel] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Klijn, Christiaan; Drost, Rinske; Bouwman, Peter; Jonkers, Jos] Netherlands Canc Inst, Div Mol Pathol, NL-1066 CX Amsterdam, Netherlands. [Culhane, Aedin C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Rodent Histol Core, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. RP Kanellopoulou, C (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM chrysi.kanellopoulou@nih.gov; david_livingston@dfci.harvard.edu OI Klijn, Christiaan/0000-0003-0878-4121 FU National Cancer Institute [P01CA80111]; Specialized Program of Research Excellence grant in breast cancer research [2P50CA089393]; Susan G. Komen Foundation for the Cure [SAC110022]; Breast Cancer Research Foundation FX We thank Drs. Ron DePinho and William Kaelin for Trp53fl/fl mice and Dr. Bing Xia for openly exchanging information on PALB2 KO mice with our laboratory. We also thank Drs. Kristine McKinney, Nana Naetar-Kerenyi, Patricia Dahia, and Stefan Muljo for critical reading of this manuscript; Dvora Ghitza and Dr. Klaus Rajewsky for help with the tetraploid complementation assays; Dr. Rene Maehr for V6.5 ES cells; Dr. Ronny Drapkin for the antibody developed against mouse BRCA1; and James Horner for ES cell micro-injections. We also thank all members of the D. M. L. laboratory for cooperation, expertise, and reagent sharing, as well as fruitful discussions. Finally, we thank the staff from the Dana-Farber Cancer Institute Animal Resources Facility for excellent technical support and Anuradha Kohli and Nancy Gerard for outstanding administrative support. This work was supported by National Cancer Institute Grant P01CA80111, by a Specialized Program of Research Excellence grant in breast cancer research (2P50CA089393 to the Dana-Farber/Harvard Cancer Center), by the Susan G. Komen Foundation for the Cure (SAC110022), and grants from the Breast Cancer Research Foundation. NR 53 TC 13 Z9 13 U1 1 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 MAY 21 PY 2013 VL 110 IS 21 BP 8632 EP 8637 DI 10.1073/pnas.1305362110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163IE UT WOS:000320328700071 PM 23657012 ER PT J AU Alazawi, W Heath, H Waters, JA Woodfin, A O'Brien, AJ Scarzello, AJ Ma, B Lopez-Otalora, Y Jacobs, M Petts, G Goldin, RD Nourshargh, S Gamero, AM Foster, GR AF Alazawi, William Heath, Helen Waters, Jennifer A. Woodfin, Abigail O'Brien, Alastair J. Scarzello, Anthony J. Ma, Bin Lopez-Otalora, Yolanda Jacobs, Michael Petts, Gemma Goldin, Robert D. Nourshargh, Sussan Gamero, Ana M. Foster, Graham R. TI Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NF-KAPPA-B; NECROSIS FACTOR-ALPHA; DEPENDENT TRANSCRIPTION; MONOCLONAL-ANTIBODIES; INTERFERON-ALPHA; I INTERFERONS; MICE; LIPOPOLYSACCHARIDE; ACTIVATION; EXPRESSION AB Deregulated Toll-like receptor (TLR)-triggered inflammatory responses that depend on NF-kappa B are detrimental to the host via excessive production of proinflammatory cytokines, including TNF-alpha. Stat2 is a critical component of type I IFN signaling, but it is not thought to participate in TLR signaling. Our study shows that LPS-induced lethality in Stat2(-/-) mice is accelerated as a result of increased cellular transmigration. Blocking intercellular adhesion molecule-1 prevents cellular egress and confers survival of Stat2(-/-) mice. The main determinant of cellular egress in Stat2(-/-) mice is the genotype of the host and not the circulating leukocyte. Surprisingly, lethality and cellular egress observed on Stat2(-/-) mice are not associated with excessive increases in classical sepsis cytokines or chemokines. Indeed, in the absence of Stat2, cytokine production in response to multiple TLR agonists is reduced. We find that Stat2 loss leads to reduced expression of NF-kappa B target genes by affecting nuclear translocation of NF-kappa B. Thus, our data reveal the existence of a different mechanism of LPS-induced lethality that is independent of NF-kappa B triggered cytokine storm but dependent on cellular egress. C1 [Alazawi, William; Heath, Helen; Waters, Jennifer A.; Foster, Graham R.] Univ London, Blizard Inst, Barts & London Sch Med, London E1 2AT, England. [Woodfin, Abigail; Ma, Bin; Nourshargh, Sussan] Univ London, William Harvey Res Inst, Barts & London Sch Med, London EC1M 6BQ, England. [O'Brien, Alastair J.] UCL, Dept Med, London WC1E 6BT, England. [Scarzello, Anthony J.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Lopez-Otalora, Yolanda; Gamero, Ana M.] Temple Univ, Dept Biochem, Philadelphia, PA 19140 USA. [Jacobs, Michael] UCL, Dept Infect, London WC1E 6BT, England. [Petts, Gemma; Goldin, Robert D.] Univ London Imperial Coll Sci Technol & Med, Dept Pathol, London SW7 2AZ, England. RP Gamero, AM (reprint author), Temple Univ, Dept Biochem, Philadelphia, PA 19140 USA. EM gameroa@temple.edu; g.r.foster@qmul.ac.uk FU Academy of Medical Sciences; Pennsylvania Department of Health FX We thank Dr. Christian Schindler for sharing Stat2-/- mice, Ms. Della Reynolds for assistance in establishing immortalized bone marrow-derived macrophage cell lines, Dr. Darren Baker (Biogen Idec, Cambridge, MA) for assistance and reagents, Mr. Tony Price for assistance with mouse experiments, and Dr. Richard Waite for assistance with bacterial cultures. This work was supported by a Starter Grant for Clinical Lecturers from the Academy of Medical Sciences (to W. A.) and a grant from the Pennsylvania Department of Health (to A.M.G.). NR 42 TC 13 Z9 13 U1 0 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 21 PY 2013 VL 110 IS 21 BP 8656 EP 8661 DI 10.1073/pnas.1221652110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 163IE UT WOS:000320328700075 PM 23653476 ER PT J AU Kim, Y Suktitipat, B Yanek, LR Faraday, N Wilson, AF Becker, DM Becker, LC Mathias, RA AF Kim, Yoonhee Suktitipat, Bhoom Yanek, Lisa R. Faraday, Nauder Wilson, Alexander F. Becker, Diane M. Becker, Lewis C. Mathias, Rasika A. TI Targeted Deep Resequencing Identifies Coding Variants in the PEAR1 Gene That Play a Role in Platelet Aggregation SO PLOS ONE LA English DT Article ID CARDIOVASCULAR-DISEASE; RARE VARIANTS; HUMAN GENOME; HERITABILITY; ASPIRIN; AGGREGABILITY; ASSOCIATION; ACTIVATION; TESTS AB Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1) gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52 +/- 13) selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate). Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5%) were noted in African Americans compared to European Americans (108 vs. 45). The common intronic GWAS-identified variant (rs12041331) demonstrated the most significant association signal in African Americans (p = 4.020 x 10(-4)); no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331). Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965) supports the results noted in the sequenced discovery sample: p = 3.56 x 10(-4), 2.27 x 10(-7), 5.20 x 10(-5) for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans, and show that exonic variants play an additional role in platelet aggregation in European Americans. C1 [Kim, Yoonhee; Suktitipat, Bhoom; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Kim, Yoonhee; Suktitipat, Bhoom; Yanek, Lisa R.; Becker, Diane M.; Becker, Lewis C.; Mathias, Rasika A.] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. RP Mathias, RA (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA. EM rmathias@jhmi.edu OI Suktitipat, Bhoom/0000-0001-8034-7757 FU National Heart, Lung, and Blood Institute [HL72518, HL087698]; National Center for Research Resources [M01-RR000052]; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; MOSAIC award from The Johns Hopkins University Provosts Office FX This work was supported in part by grants from the National Heart, Lung, and Blood Institute, (HL72518 and HL087698), and the National Center for Research Resources (M01-RR000052) and by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. R.A. Mathias was supported in part by the MOSAIC award from The Johns Hopkins University Provosts Office. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 13 Z9 13 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 MAY 21 PY 2013 VL 8 IS 5 AR e64179 DI 10.1371/journal.pone.0064179 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 149OK UT WOS:000319330200120 PM 23704978 ER PT J AU Takebe, Y Saucedo, CJ Lund, G Uenishi, R Hase, S Tsuchiura, T Kneteman, N Ramessar, K Tyrrell, DLJ Shirakura, M Wakita, T McMahon, JB O'Keefe, BR AF Takebe, Yutaka Saucedo, Carrie J. Lund, Garry Uenishi, Rie Hase, Saiki Tsuchiura, Takayo Kneteman, Norman Ramessar, Koreen Tyrrell, D. Lorne J. Shirakura, Masayuki Wakita, Takaji McMahon, James B. O'Keefe, Barry R. TI Antiviral Lectins from Red and Blue-Green Algae Show Potent In Vitro and In Vivo Activity against Hepatitis C Virus SO PLOS ONE LA English DT Article ID ANTI-HIV PROTEIN; CYANOBACTERIUM SCYTONEMA-VARIUM; CULTURED CYANOBACTERIUM; ENVELOPE PROTEIN; RECOMBINANT PRODUCTION; INACTIVATING PROTEIN; GLYCOSYLATION SITES; HCV INFECTION; CYANOVIRIN-N; GRIFFITHSIN AB Hepatitis C virus (HCV) infection is a significant public health problem with over 170,000,000 chronic carriers and infection rates increasing worldwide. Chronic HCV infection is one of the leading causes of hepatocellular carcinoma which was estimated to result in,10,000 deaths in the United States in the year 2011. Current treatment options for HCV infection are limited to PEG-ylated interferon alpha (IFN-alpha), the nucleoside ribavirin and the recently approved HCV protease inhibitors telaprevir and boceprevir. Although showing significantly improved efficacy over the previous therapies, treatment with protease inhibitors has been shown to result in the rapid emergence of drug-resistant virus. Here we report the activity of two proteins, originally isolated from natural product extracts, which demonstrate low or sub-nanomolar in vitro activity against both genotype I and genotype II HCV. These proteins inhibit viral infectivity, binding to the HCV envelope glycoproteins E1 and E2 and block viral entry into human hepatocytes. In addition, we demonstrate that the most potent of these agents, the protein griffithsin, is readily bioavailable after subcutaneous injection and shows significant in vivo efficacy in reducing HCV viral titers in a mouse model system with engrafted human hepatocytes. These results indicate that HCV viral entry inhibitors can be an effective component of anti-HCV therapy and that these proteins should be studied further for their therapeutic potential. C1 [Takebe, Yutaka; Uenishi, Rie; Hase, Saiki; Tsuchiura, Takayo] Natl Inst Infect Dis, AIDS Res Ctr, Tokyo, Japan. [Saucedo, Carrie J.] SAIC Frederick, Mol Targets Lab, Frederick, MD USA. [Lund, Garry; Kneteman, Norman; Tyrrell, D. Lorne J.] KMT Hepatech, Edmonton, AB, Canada. [Ramessar, Koreen; McMahon, James B.; O'Keefe, Barry R.] NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21701 USA. [Shirakura, Masayuki; Wakita, Takaji] Natl Inst Infect Dis, Tokyo, Japan. RP O'Keefe, BR (reprint author), NCI, Ctr Canc Res, Mol Targets Lab, Frederick, MD 21701 USA. EM okeefeba@mail.nih.gov FU Ministry of Health, Labor and Welfare (JAPAN); Human Sciences Foundation; Intramural research Program of the NIH; National Cancer Institute; Center for Cancer Research; National Cancer Institute, National Institutes of Health [N01-CO-12400, HHSN261200800001E]; NIAID FX Y.T. is supported by grants of the hepatitis study group from the Ministry of Health, Labor and Welfare (JAPAN) and the Human Sciences Foundation. This research was supported by the Intramural research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 and HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The patents for both Griffithsin and Scytovirin are wholly owned by the U.S. Government. Drs. O'Keefe and McMahon are named inventors on patents for both proteins. Norman Kneteman, Garry Lund and Lorne Tyrrell are affiliated to KMT Hepatech which is a contract research organization funded by NIAID for hepatitis C studies with no competing interests. KMT Hepatech has no rights or interests in further developing the antiviral proteins griffithsin and scytovirin for commercial use. Their involvement in this manuscript does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 43 TC 20 Z9 22 U1 1 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 MAY 21 PY 2013 VL 8 IS 5 AR e64449 DI 10.1371/journal.pone.0064449 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 149OK UT WOS:000319330200137 PM 23700478 ER PT J AU Gudheti, MV Curthoys, NM Gould, TJ Kim, D Gunewardene, MS Gabor, KA Gosse, JA Kim, CH Zimmerberg, J Hess, ST AF Gudheti, Manasa V. Curthoys, Nikki M. Gould, Travis J. Kim, Dahan Gunewardene, Mudalige S. Gabor, Kristin A. Gosse, Julie A. Kim, Carol H. Zimmerberg, Joshua Hess, Samuel T. TI Actin Mediates the Nanoscale Membrane Organization of the Clustered Membrane Protein Influenza Hemagglutinin SO BIOPHYSICAL JOURNAL LA English DT Article ID SINGLE-MOLECULE TRACKING; VIRUS HEMAGGLUTININ; PLASMA-MEMBRANE; LIM-KINASE; CELL BIOLOGY; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; DEPOLYMERIZING FACTOR; FILAMENT DYNAMICS; LIPID RAFTS; F-ACTIN AB The influenza viral membrane protein hemagglutinin (HA) is required at high concentrations on virion and host-cell membranes for infectivity. Because the role of actin in membrane organization is not completely understood, we quantified the relationship between HA and host-cell actin at the nanoscale. Results obtained using superresolution fluorescence photoactivation localization microscopy (FPALM) in nonpolarized cells show that HA clusters colocalize with actin-rich membrane regions (ARMRs). Individual molecular trajectories in live cells indicate restricted HA mobility in ARMRs, and actin disruption caused specific changes to HA clustering. Surprisingly, the actin-binding protein cofilin was excluded from some regions within several hundred nanometers of HA clusters, suggesting that HA clusters or adjacent proteins within the same clusters influence local actin structure. Thus, with the use of imaging, we demonstrate a dynamic relationship between glycoprotein membrane organization and the actin cytoskeleton at the nanoscale. C1 [Gudheti, Manasa V.; Curthoys, Nikki M.; Gould, Travis J.; Kim, Dahan; Gunewardene, Mudalige S.; Gabor, Kristin A.; Hess, Samuel T.] Univ Maine, Dept Phys & Astron, Orono, ME 04469 USA. [Gabor, Kristin A.; Gosse, Julie A.; Kim, Carol H.] Univ Maine, Dept Mol & Biomed Sci, Orono, ME USA. [Gabor, Kristin A.; Gosse, Julie A.; Kim, Carol H.; Hess, Samuel T.] Univ Maine, Grad Sch Biomed Sci & Engn, Orono, ME USA. [Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Hess, ST (reprint author), Univ Maine, Dept Phys & Astron, Orono, ME 04469 USA. EM sam.hess@umit.maine.edu FU National Institutes of Health (NIH) [K25-AI65459, NIH R15-GM094713, NSF MRI CHE-0722759, IGERT-0221625]; Maine Technology Institute [MTAF 1106, 2061]; UMaine V.P. for Research; Maine Economic Improvement Fund (MEIF); Intramural Research Program of the National Institute of Child Health and Human Development; MEIF FX This work was funded by the National Institutes of Health (NIH Career Award K25-AI65459, NIH R15-GM094713, NSF MRI CHE-0722759, and IGERT-0221625), the Maine Technology Institute (MTAF 1106 and 2061), UMaine V.P. for Research, the Maine Economic Improvement Fund (MEIF), and the Intramural Research Program of the National Institute of Child Health and Human Development. T.J.G. benefited from an MEIF doctoral dissertation fellowship. S.T.H. and T.J.G. hold patents in superresolution microscopy. S.T.H. serves on the scientific advisory board of Vutara, Inc. NR 80 TC 38 Z9 38 U1 3 U2 38 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 MAY 21 PY 2013 VL 104 IS 10 BP 2182 EP 2192 DI 10.1016/j.bpj.2013.03.054 PG 11 WC Biophysics SC Biophysics GA 149KN UT WOS:000319318400012 PM 23708358 ER PT J AU Sodt, AJ Pastor, RW AF Sodt, Alexander J. Pastor, Richard W. TI Bending Free Energy from Simulation: Correspondence of Planar and Inverse Hexagonal Lipid Phases SO BIOPHYSICAL JOURNAL LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; LATERAL PRESSURE PROFILES; MEMBRANE CURVATURE; PHOSPHOLIPID-MEMBRANES; ELASTIC PROPERTIES; SURFACE-TENSION; FORCE-FIELD; BILAYERS; MODEL; PROTEIN AB Simulations of two distinct systems, one a planar bilayer, the other the inverse hexagonal phase, indicate consistent mechanical properties and curvature preferences, with single DOPE leaflets having a spontaneous curvature, R-0 = -26 angstrom (experimentally similar to-29.2 angstrom) and DOPC leaflets preferring to be approximately flat (R-0 = -65 angstrom, experimentally similar to-87.3 angstrom). Additionally, a well-defined pivotal plane, where a DOPE leaflet bends at constant area, has been determined to be near the glycerol region of the lipid, consistent with the experimentally predicted plane. By examining the curvature frustration of both high and low curvature, the transferability of experimentally determined bending constants is supported. The techniques herein can be applied to predict the effect of biologically active molecules on the mechanical properties of lipid bilayers under well-controlled conditions. C1 [Sodt, Alexander J.; Pastor, Richard W.] NHLBI, NIH, Rockville, MD USA. RP Pastor, RW (reprint author), NHLBI, NIH, Rockville, MD USA. EM pastorr@nhlbi.nih.gov FU Intramural Research Program of the National Institutes of Health, National Heart, Lung and Blood Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung and Blood Institute. NR 55 TC 22 Z9 22 U1 2 U2 43 PU CELL PRESS PI CAMBRIDGE PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD MAY 21 PY 2013 VL 104 IS 10 BP 2202 EP 2211 DI 10.1016/j.bpj.2013.03.048 PG 10 WC Biophysics SC Biophysics GA 149KN UT WOS:000319318400014 PM 23708360 ER PT J AU Nishibe, R Watanabe, W Ueda, T Yamasaki, N Koller, R Wolff, L Honda, Z Ohtsubo, M Honda, H AF Nishibe, Rio Watanabe, Wataru Ueda, Takeshi Yamasaki, Norimasa Koller, Richard Wolff, Linda Honda, Zen-ichiro Ohtsubo, Motoaki Honda, Hiroaki TI CIZ1, a p21(Cip1/Waf1)-interacting protein, functions as a tumor suppressor in vivo SO FEBS LETTERS LA English DT Article DE CIZ1 (Cip1 interacting zinc finger protein 1); p21(Cip1/Waf1); Cell proliferation; Tumorigenesis ID REPLICATION FACTOR CIZ1; MAMMALIAN DNA-REPLICATION; SUBNUCLEAR DISTRIBUTION; CANCER; EXPRESSION; LEUKEMIA; CELLS; NETWORKS; PATHWAYS; DAMAGE AB CIZ1 is a nuclear protein involved in DNA replication and is also implicated in human diseases including cancers. To gain an insight into its function in vivo, we generated mice lacking Ciz1. Ciz1-deficient (Ciz1(-/-)) mice grew without any obvious abnormalities, and Ciz1(-/-) mouse embryonic fibroblasts (MEFs) did not show any defects in cell cycle status, cell growth, and DNA damage response. However, Ciz1(-/-) MEFs were sensitive to hydroxyurea-mediated replication stress and susceptible to oncogene-induced cellular transformation. In addition, Ciz1(-/-) mice developed various types of leukemias by retroviral insertional mutagenesis. These results indicate that CIZ1 functions as a tumor suppressor in vivo. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved. C1 [Nishibe, Rio; Watanabe, Wataru; Ueda, Takeshi; Yamasaki, Norimasa; Honda, Hiroaki] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Minami Ku, Hiroshima 7348553, Japan. [Honda, Zen-ichiro] Ochanomizu Univ, Hlth Care Ctr, Bunkyo Ku, Tokyo 1128611, Japan. [Honda, Zen-ichiro] Ochanomizu Univ, Grad Sch Humanities & Sci, Inst Environm Sci Human Life, Bunkyo Ku, Tokyo 1128611, Japan. [Koller, Richard; Wolff, Linda] NCI, Leukemogenesis Sect, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Ohtsubo, Motoaki] Beppu Univ, Fac Food Sci & Nutr, Dept Food & Fermentat, Beppu, Oita 8748501, Japan. RP Honda, H (reprint author), Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. EM hhonda@hiroshima-u.ac.jp FU Naito Foundation FX We thank Yuki Sakai for animal care, Yu Iwai and Rika Tai for mouse genotyping and molecular experiments, and Yoshihiro Takihara for feedback and discussion. We also thank RIKEN BioResource Center for providing us with B6.Cg-Tg(CAG-Cre)CZ-MO2Osb mice (RBRC01828). This work was supported in part by the Naito Foundation. NR 24 TC 6 Z9 6 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 21 PY 2013 VL 587 IS 10 BP 1529 EP 1535 DI 10.1016/j.febslet.2013.03.034 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 143WF UT WOS:000318898600011 PM 23583447 ER PT J AU Farrell, MS Roth, BL AF Farrell, Manillas S. Roth, Bryan L. TI Pharmacosynthetics: Reimagining the pharmacogenetic approach SO BRAIN RESEARCH LA English DT Review DE Pharmacosynthetics; Pharmacogenetics; DREADD; RASSL; Synthetic biology ID PROTEIN-COUPLED RECEPTORS; NEURONAL-ACTIVITY; TRANSGENIC MICE; REMOTE-CONTROL; CELL-FUNCTION; DOPAMINE; SENSITIZATION; LIGAND; DRUGS; ACTIVATION AB Pharmacology, in its broadest interpretation, is defined as the study of the interaction between physiological entities and drugs. In modern neuropsychopharmacology, this interaction is viewed as the drug itself on one side and signal transducer (receptor), the signal transduction cascade (effector proteins, second messengers), the cellular response (transcriptional regulation, activity modulation), the organ response (brain circuitry modulation), and, finally, the whole organism response (behavior) on the other. In other words, pharmacology has structured itself around the idea that the exogenous molecule (the drug) encodes a "signal" leading to everything on the other side including, in extreme renditions, a physiological response. The inference is that engaging a particular signal transduction pathway in a defined cell type leads inexorably to a prototypic physiological response. Thus, for instance, serotonergic activation of 5-HT2A receptors in rat aortic smooth muscle cells leads to an increase in intracellular Ca+ (via IP3 release) and smooth muscle contraction (Roth et al., 1986). Here, we suggest that the invention of synthetic ligand-GPCR pairs (aka DREADDs, RASSLS, 'pharmacogenetics') permits the study of pharmacology using a shifted equation: more of the signal transduction elements moved to the left and, subsequently, under experimental control. For the purposes of disambiguation and to clarify this new interpretation as a creation of pharmacological manipulation, we present the term pharmacosynthetics to describe what has heretofore been called pharmacogenetics or chemicogenetics. This review discusses this new interpretation and reviews recent applications of the technology and considerations of the approach. This article is part of a Special Issue entitled Optogenetics (7th BRES) (C) 2012 Elsevier B.V. All rights reserved. C1 [Farrell, Manillas S.; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 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, Carolina Inst Dev Disabil, 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 Farrell, MS (reprint author), Univ N Carolina, Chapel Hill Med Sch, Dept Pharmacol, Genet Med Bldg Room 4009, Chapel Hill, NC 27599 USA. EM martilias_farrell@med.unc.edu RI Roth, Bryan/F-3928-2010 FU NIH [1F31MH091921, RO1MH61887, U19MH82441]; NIMH Psychoactive Drug Screening Program; Michael Hooker Chair in Pharmacology 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. NR 60 TC 30 Z9 30 U1 1 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 20 PY 2013 VL 1511 SI SI BP 6 EP 20 DI 10.1016/j.brainres.2012.09.043 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 159ZY UT WOS:000320087000002 PM 23063887 ER PT J AU Thuring, A Brannstrom, KJ Ewerlof, M Hernandez-Andrade, E Ley, D Lingman, G Liuba, K Marsal, K Jansson, T AF Thuring, Ann Brannstrom, K. Jonas Ewerlof, Maria Hernandez-Andrade, Edgar Ley, David Lingman, Goran Liuba, Karina Marsal, Karel Jansson, Tomas TI Operator Auditory Perception and Spectral Quantification of Umbilical Artery Doppler Ultrasound Signals SO PLOS ONE LA English DT Article ID FLOW VELOCITY WAVEFORMS; BLOOD-FLOW; FETAL ANEMIA; RESISTANCE; MODEL AB Objective: An experienced sonographer can by listening to the Doppler audio signals perceive various timbres that distinguish different types of umbilical artery flow despite an unchanged pulsatility index (PI). Our aim was to develop an objective measure of the Doppler audio signals recorded from fetoplacental circulation in a sheep model. Methods: Various degrees of pathological flow velocity waveforms in the umbilical artery, similar to those in human complicated pregnancies, were induced by microsphere embolization of the placental bed (embolization model, 7 lamb fetuses, 370 Doppler recordings) or by fetal hemodilution (anemia model, 4 lamb fetuses, 184 recordings). A subjective 11-step operator auditory scale (OAS) was related to conventional Doppler parameters, PI and time average mean velocity (TAM), and to sound frequency analysis of Doppler signals (sound frequency with the maximum energy content [MAX(peak)] and frequency band at maximum level minus 15 dB [MAX(peak-15dB)] over several heart cycles). Results: We found a negative correlation between the OAS and PI: median Rho -0.73 (range -0.35- -0.94) and -0.68 (range -0.57- -0.78) in the two lamb models, respectively. There was a positive correlation between OAS and TAM in both models: median Rho 0.80 (range 0.58-0.95) and 0.90 (range 0.78-0.95), respectively. A strong correlation was found between TAM and the results of sound spectrum analysis; in the embolization model the median r was 0.91 (range 0.88-0.97) for MAX(peak) and 0.91 (range 0.82-0.98) for MAX(peak-15 dB). In the anemia model, the corresponding values were 0.92 (range 0.78-0.96) and 0.96 (range 0.89-0.98), respectively. Conclusion: Audio-spectrum analysis reflects the subjective perception of Doppler sound signals in the umbilical artery and has a strong correlation to TAM-velocity. This information might be of importance for clinical management of complicated pregnancies as an addition to conventional Doppler parameters. C1 [Thuring, Ann; Lingman, Goran; Liuba, Karina; Marsal, Karel] Lund Univ, Dept Obstet & Gynecol, Clin Sci Lund, Lund, Sweden. [Brannstrom, K. Jonas] Lund Univ, Dept Logoped Phoniatr & Audiol, Lund, Sweden. [Ewerlof, Maria; Jansson, Tomas] Lund Univ, Dept Biomed Engn, Clin Sci Lund, Lund, Sweden. [Hernandez-Andrade, Edgar] Wayne State Univ, Perinatol Res Branch, NICHHD, NIH, Detroit, MI USA. [Ley, David] Lund Univ, Dept Pediat, Clin Sci Lund, Lund, Sweden. RP Thuring, A (reprint author), Lund Univ, Dept Obstet & Gynecol, Clin Sci Lund, Lund, Sweden. EM ann.thuring@med.lu.se FU Swedish government; Swedish Research Council [14940] FX Ann Thuring, K. Jonas Brannstrom and David Ley were supported by the grants to researchers in the Public Health Service from the Swedish government. The study was supported by the Swedish Research Council (grant No. 14940). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 1 Z9 1 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 MAY 20 PY 2013 VL 8 IS 6 AR e64033 DI 10.1371/journal.pone.0064033 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 158JQ UT WOS:000319966400044 PM 23700452 ER PT J AU Porter, JB Wood, J Olivieri, N Vichinsky, EP Taher, A Neufeld, E Giardina, P Thompson, A Moore, B Evans, P Kim, HY Macklin, EA Trachtenberg, F AF Porter, John B. Wood, John Olivieri, Nancy Vichinsky, Elliott P. Taher, Ali Neufeld, Ellis Giardina, Patricia Thompson, Alexis Moore, Blaine Evans, Patricia Kim, Hae-Young Macklin, Eric A. Trachtenberg, Felicia TI Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Thalassemia; Heart failure; Deferoxamine; Deferiprone; Combination ID BETA-THALASSEMIA; CHELATION-THERAPY; MYOCARDIAL IRON; MAGNETIC-RESONANCE; RENAL-FUNCTION; DEFERASIROX; SIDEROSIS; TRIAL AB Background: Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear. Methods: A 1 year prospective study comparing deferoxamine (DFO) monotherapy or when combined with deferiprone (DFP) for patients with left ventricular ejection fraction (LVEF) <56% was conducted by the Thalassemia Clinical Research Network (TCRN). All patients received DFO at 50-60 mg/kg 12-24 hr/day sc or iv 7 times weekly, combined with either DFP 75 at mg/kg/day (combination arm) or placebo (DFO monotherapy arm). The primary endpoint was the change in LVEF by CMR. Results: Improvement in LVEF was significant in both study arms at 6 and 12 months (p = 0.04), normalizing ventricular function in 9/16 evaluable patients. With combination therapy, the LVEF increased from 49.9% to 55.2% (+5.3% p = 0.04; n = 10) at 6 months and to 58.3% at 12 months (+8.4% p = 0.04; n = 7). With DFO monotherapy, the LVEF increased from 52.8% to 55.7% (+2.9% p = 0.04; n = 6) at 6 months and to 56.9% at 12 months (+4.1% p = 0.04; n = 4). The LVEF trend did not reach statistical difference between study arms (p = 0.89). In 2 patients on DFO monotherapy during the study and in 1 patient on combined therapy during follow up, heart failure deteriorated fatally. The study was originally powered for 86 participants to determine a 5% difference in LVEF improvement between treatments. The study was prematurely terminated due to slow recruitment and with the achieved sample size of 20 patients there was 80% power to detect an 8.6% difference in EF, which was not demonstrated. Myocardial T2* improved in both arms (combination +1.9 +/- 1.6 ms p = 0.04; and DFO monotherapy +1.9 +/- 1.4 ms p = 0.04), but with no significant difference between treatments (p = 0.65). Liver iron (p = 0.03) and ferritin (p < 0.001) both decreased significantly in only the combination group. Conclusions: Both treatments significantly improved LVEF and myocardial T2*. Although this is the largest and only randomized study in patients with LV decompensation, further prospective evaluation is needed to identify optimal chelation management in these high-risk patients. C1 [Porter, John B.; Evans, Patricia] UCL, London, England. [Wood, John] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Olivieri, Nancy] Univ Hlth Network, Toronto Gen Hosp, Toronto, ON, Canada. [Vichinsky, Elliott P.] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Taher, Ali] Amer Univ Beirut, Beirut, Lebanon. [Neufeld, Ellis] Childrens Hosp, Boston, MA 02115 USA. [Giardina, Patricia] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Thompson, Alexis] Childrens Mem Hosp, Chicago, IL 60614 USA. [Moore, Blaine] NHLBI, Bethesda, MD 20892 USA. [Kim, Hae-Young; Trachtenberg, Felicia] New England Res Inst, Watertown, MA 02172 USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Porter, John B.] UCL, UCL Canc Inst, Dept Haematol, London WC1E 6BT, England. RP Porter, JB (reprint author), UCL, London, England. EM j.porter@ucl.ac.uk OI Porter, John/0000-0003-3000-9359; Macklin, Eric/0000-0003-1618-3502 FU NIH-NHLBI [U01 HL065238, U01-HL65232, NIH/NCRR UL1-RR-024134, U01-HL72291]; Harvard Catalyst CTSC [UL1-RR-025758, U01-HL65233, U01-HL65239, U01-HL65244, CTSC UL1-RR024996, U01-HL65238] FX This work was supported by the following NIH-NHLBI cooperative agreements: U01 HL065238; U01-HL65232 and NIH/NCRR UL1-RR-024134 to the Children's Hospital of Philadelphia; U01-HL72291 and by Harvard Catalyst CTSC UL1-RR-025758 to Children's Hospital, Boston; U01-HL65233 to University Health Network Toronto General Hospital; U01-HL65239 to Children's Hospital & Research Center Oakland; U01-HL65244 and CTSC UL1-RR024996 to Weill Medical College of Cornell University; and U01-HL65238 to New England Research Institutes. NR 21 TC 16 Z9 16 U1 4 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD MAY 20 PY 2013 VL 15 AR 38 DI 10.1186/1532-429X-15-38 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 155IB UT WOS:000319740100001 PM 23688265 ER PT J AU Kofinger, J Hummer, G AF Koefinger, Juergen Hummer, Gerhard TI Atomic-resolution structural information from scattering experiments on macromolecules in solution SO PHYSICAL REVIEW E LA English DT Article ID X-RAY-SCATTERING; NEUTRON-SCATTERING; PROTEINS; WATER; SIMULATIONS; DYNAMICS; HYDRATION; LYSOZYME; COLLAPSE; PHASE AB The pair-distance distribution function (PDDF) contains all structural information probed in an elastic scattering experiment of macromolecular solutions. However, in small-angle x-ray scattering (SAXS) or small-angle neutron scattering (SANS) experiments only their Fourier transform is measured over a restricted range of scattering angles. We therefore developed a mathematically simple and computationally efficient method to calculate the PDDFs as well as accurate scattering intensities from molecular dynamics simulations. The calculated solution scattering intensities are in excellent agreement with SAXS and wide-angle x-ray scattering (WAXS) experiments for a series of proteins. The corresponding PDDFs are remarkably rich in features reporting on the detailed protein structure. Using an inverse Fourier transform method, most of these features can be recovered if scattering intensities are measured up to a momentum transfer of q approximate to 2-3 angstrom(-1). Our results establish that high-precision solution scattering experiments utilizing x-ray free-electron lasers and third generation synchrotron sources can resolve subnanometer structural detail, well beyond size, shape, and fold. C1 [Koefinger, Juergen; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Kofinger, J (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM juergen.koefinger@nih.gov; gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank Dr. Alexander Grishaev and Dr. Ad Bax for providing the experimental data shown in Fig. 1 of this article. We also thank Dr. Alexander Grishaev and Dr. Philip Anfinrud for many helpful discussions. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and utilized the biowulf and helix systems at the National Institutes of Health. NR 36 TC 19 Z9 19 U1 3 U2 38 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD MAY 20 PY 2013 VL 87 IS 5 AR 052712 DI 10.1103/PhysRevE.87.052712 PG 7 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 148ON UT WOS:000319254900006 PM 23767571 ER PT J AU Landsman, V Pfeiffer, RM AF Landsman, V. Pfeiffer, R. M. TI On estimating average effects for multiple treatment groups SO STATISTICS IN MEDICINE LA English DT Article DE biased sampling; causal inference; generalized propensity scores; missing data ID PROPENSITY SCORE; MODELS; BIAS AB We propose to estimate average exposure (or treatment) effects from observational data for multiple exposure groups by fitting an approximation of the marginal sample distribution of the response variable in each exposure group to the data. The marginal sample distribution is a function of the true distribution of the response variable in the population and the assignment rule governing the allocation of the subjects to different exposure groups. The assignment rule can depend on the response variable in addition to measured covariates, and hence the method is appropriate even when the assumption of ignorable treatment assignment is not justified. We estimate the exposure effects are estimated based on the population expectation (PE) of the outcome variable. We compare the PE approach with an instrumental variable method and with several other methods including propensity score based approaches that assume ignorable assignment mechanisms. We evaluate the robustness of the PE method under model misspecifications and illustrate it using data from a study of the impact of soy consumption on urinary concentrations of estrogen and estrogen metabolites in Asian American women. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 [Landsman, V.] St Michaels Hosp, Ctr Global Hlth Res, Toronto, ON M5B 1W8, Canada. [Pfeiffer, R. M.] NCI, Bethesda, MD 20852 USA. RP Landsman, V (reprint author), St Michaels Hosp, Ctr Global Hlth Res, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM landsmanv@smh.ca NR 17 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 MAY 20 PY 2013 VL 32 IS 11 BP 1829 EP 1841 DI 10.1002/sim.5690 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 136GQ UT WOS:000318350800003 PM 23208873 ER PT J AU Abdel-Fatah, TMA Russell, R Maloney, DJ Mohan, V Dorjsuren, D Rueda, O Gorguc, I Mukherjee, A Jadhav, A Simeonov, A Wison, DM Agarwal, DR Ball, G Chan, S Caldas, C Ellis, IO Madhusudan, S AF Abdel-Fatah, Tarek M. A. Russell, Roslin Maloney, David J. Mohan, Vivek Dorjsuren, Dorjbal Rueda, Oscar Gorguc, Ipek Mukherjee, Abhik Jadhav, Ajit Simeonov, Anton Wison, David M., III Agarwal, Devika Ravindra Ball, Graham Chan, Stephen Caldas, Carlos Ellis, Ian O. Madhusudan, Srinivasan TI Evaluation of flap endonuclease-1 (FEN1) as a prognostic, predictive, and therapeutic target in breast (BC) and ovarian cancer (OVC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Nottingham Univ City Hosp NHS Trust, Nottingham, England. Canc Res UK, Cambridge Res Inst, Cambridge, England. Natl Ctr Adv Translat Sci, NIH Chem Genom Ctr, Rockville, MD USA. Univ Nottingham, Acad Unit Oncl, Lab Mol Oncl, Nottingham NG7 2RD, England. Univ Nottingham, Div Pathol, Sch Mol Med Sci, Nottingham NG7 2RD, England. NIH, Lab Mol Gerontol, Biomed Res Ctr, Baltimore, MD USA. Nottingham Trent Univ, Sch Sci & Technol, Nottingham, England. Nottingham Trent Univ, Sch Sci & Technol, Van Geest Canc Res Ctr, Nottingham, England. City Hosp Nottingham, Nottingham, England. Univ Nottingham Hosp, Sch Mol Med Sci, Nottingham NG7 2UH, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1016 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600239 ER PT J AU Akshintala, S Marcus, L Warren, KE Murphy, RF Goodspeed, WJ Goodwin, A Brewer, CC Zalewski, C King, KA Kim, A Widemann, BC AF Akshintala, Srivandana Marcus, Leigh Warren, Katherine E. Murphy, Robert F. Goodspeed, Wendy J. Goodwin, Anne Brewer, Carmen C. Zalewski, Christopher King, Kelly A. Kim, AeRang Widemann, Brigitte C. TI Phase I trial and pharmacokinetic (PK) study of satraplatin in children and young adults with refractory solid tumors including brain tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2554 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601072 ER PT J AU Allison, KH Abraham, LA Weaver, DL Tosteson, ANA Onega, T Geller, BM Kerlikowske, K Carney, PA Ichikawa, LE Buist, DSM Elmore, JG AF Allison, Kimberly H. Abraham, Linn A. Weaver, Donald L. Tosteson, Anna N. A. Onega, Tracy Geller, Berta M. Kerlikowske, Karla Carney, Patricia A. Ichikawa, Laura E. Buist, Diana S. M. Elmore, Joann G. TI Tissue sampling frequency and breast pathology diagnoses following mammography: Time trends and age group analysis from the Breast Cancer Surveillance Consortium (BCSC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Stanford Univ, Sch Med, Stanford, CA 94305 USA. Grp Hlth Res Inst, Seattle, WA USA. Natl Surg Adjuvant Breast & Bowel Project, Burlington, VT USA. Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Dartmouth Med Sch, Lebanon, NH USA. Dartmouth Med Sch, Norris Cotton Canc Ctr, Lebanon, NH USA. Univ Vermont, Burlington, VT USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 559 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600064 ER PT J AU Andreopoulou, E Vigoda, IS Valero, V Hershman, DL Raptis, G Vahdat, LT Han, HS Wright, JJ Pellegrino, CM Alvarez, RH Fehn, K Fineberg, S Sparano, JA AF Andreopoulou, Eleni Vigoda, Ivette Sara Valero, Vicente Hershman, Dawn L. Raptis, George Vahdat, Linda T. Han, Hyo S. Wright, John Joseph Pellegrino, Christine M. Alvarez, Ricardo H. Fehn, Karen Fineberg, Susan Sparano, Joseph A. TI A phase I-II study of tipifarnib plus weekly paclitaxel (P) followed by dose-dense doxorubicin/cyclophosphamide (AC) in stage IIb-IIIc breast cancer (BC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Mt Sinai Sch Med, Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY USA. Weill Cornell Med Coll, New York, NY USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. NCI, Rockville, MD USA. Montefiore Med Ctr, New York, NY USA. Montefiore Med Ctr, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1118 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600545 ER PT J AU Apolo, AB Parnes, HL Madan, RA Gulley, JL Wright, JJ Khadar, K Trepel, JB Schlom, J Arlen, PM Merino, M Steinberg, SM Choyke, PL Lindenberg, ML Kurdziel, KA Folio, L Figg, WD Agarwal, PK Bottaro, DP Dahut, WL AF Apolo, Andrea Borghese Parnes, Howard L. Madan, Ravi Amrit Gulley, James L. Wright, John Joseph Khadar, Kattie Trepel, Jane B. Schlom, Jeffrey Arlen, Philip M. Merino, Maria Steinberg, Seth M. Choyke, Peter L. Lindenberg, Maria Liza Kurdziel, Karen A. Folio, Les Figg, William Douglas Agarwal, Piyush K. Bottaro, Donald P. Dahut, William L. TI A phase II study of cabozantinib (XL184) in patients with advanced/metastatic urothelial carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, CCR, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branchd, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS4589 PG 2 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605449 ER PT J AU Apolo, AB Lee, YH Cecchi, F Agarwal, PK Parnes, HL Khadar, K Summerell, A Gulley, JL Compton, K Figg, WD Dahut, WL Bottaro, DP AF Apolo, Andrea Borghese Lee, Young H. Cecchi, Fabiola Agarwal, Piyush K. Parnes, Howard L. Khadar, Kattie Summerell, Amelia Gulley, James L. Compton, Kathryn Figg, William Douglas Dahut, William L. Bottaro, Donald P. TI Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 4543 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601557 ER PT J AU Arnaldez, FI Chakka, S Smith, CJ Yeung, CL Caplen, N Helman, LJ AF Arnaldez, Fernanda Irene Chakka, Sirisha Smith, Carly J. Yeung, Choh L. Caplen, Natasha Helman, Lee J. TI Integrated analysis of RNAi screens in pediatric rhabdomyosarcoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, NIH, Genet Branch, Gene Silencing Sect, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Gene Silencing Sect, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 10040 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600197 ER PT J AU Baio, G Valdora, F Pace, D Salvi, S Villosio, N Truini, M Calabrese, M Neumaier, CE AF Baio, Gabriella Valdora, Francesca Pace, Daniele Salvi, Sandra Villosio, Nicolo Truini, Mauro Calabrese, Massimo Neumaier, Carlo Emanuele TI The key role of correlation between MR spectroscopy choline peak and calcium sensing receptor for breast cancer: Diagnosis by a 3T MR scanner. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Irccs Azienda Osped Univ SAN Martino, Natl Canc Inst, Diagnost Imaging & Senol Unit, IST, Genoa, Italy. Natl Inst Canc Res, Dept Pathol, Genoa, Italy. AUO San Martino IST, Genoa, Italy. RI Baio, Gabriella/M-7621-2015 OI Baio, Gabriella/0000-0002-8397-5318 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e22132 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605256 ER PT J AU Baird, K Reinke, DK Pressey, JG Mascarenhas, L Federman, N Marina, N Chawla, SP Lagmay, JP Goldberg, JM Milhem, MM Loeb, DM Butrynski, JE Janeway, KA Turpin, B Staddon, AP Spunt, SL Rodler, ET Schuetze, S Okuno, SH Heiman, LJ AF Baird, Kristin Reinke, Denise K. Pressey, Joseph Gerald Mascarenhas, Leo Federman, Noah Marina, Neyssa Chawla, Sant P. Lagmay, Joanne Pigues Goldberg, John M. Milhem, Mohammed M. Loeb, David Mark Butrynski, James E. Janeway, Katherine A. Turpin, Brian Staddon, Arthur P. Spunt, Sheri L. Rodler, Eve T. Schuetze, Scott Okuno, Scott H. Heiman, Lee J. TI A randomized, double-blinded, placebo-controlled, multi-institutional, cross-over, phase II. 5 study of saracatinib (AZD0530), a selective Src kinase inhibitor, in patients with recurrent osteosarcoma localized to the lung. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. Sarcoma Alliance Res Collaborat, Ann Arbor, MI USA. Univ Alabama Birmingham, Birmingham, AL USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Sarcoma Oncol Ctr, Santa Monica, CA USA. Nationwide Childrens Hosp, Gainesville, FL USA. Univ Miami, Miller Sch Med, Miami, FL 33136 USA. Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. Johns Hopkins Univ, Baltimore, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. Univ Penn, Philadelphia, PA 19104 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Seattle Canc Care Alliance, Seattle, WA USA. Univ Michigan, Ann Arbor, MI 48109 USA. Mayo Clin, Rochester, MN USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS10591 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605357 ER PT J AU Balasubramaniam, S Bryla, C Redon, CE Lee, MJ Peer, C Trepel, JB Rajan, A Bonner, W Figg, WD Fojo, AT Piekarz, R Giaccone, G Bates, SE AF Balasubramaniam, Sanjeeve Bryla, Christina Redon, Christophe E. Lee, Min-Jung Peer, Cody Trepel, Jane B. Rajan, Arun Bonner, William Figg, William Douglas Fojo, Antonio Tito Piekarz, Richard Giaccone, Giuseppe Bates, Susan Elaine TI Phase I trial of belinostat in combination with cisplatin (Cis) and etoposide (Etop). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, CCR, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2527 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601045 ER PT J AU Barta, SK Samuel, M Xue, XN Lee, JY Mounier, N Kaplan, LD Ribera, JM Spina, M Tirelli, U Weiss, R Galicier, L Boue, F Wilson, WH Wyen, C Dunleavy, K Little, RF Remick, SC Goldfinger, M Noy, A Sparano, JA AF Barta, Stefan K. Samuel, Michael Xue, Xiaonan Lee, Jeanette Y. Mounier, Nicolas Kaplan, Lawrence D. Ribera, Josep-Maria Spina, Michele Tirelli, Umberto Weiss, Rudolf Galicier, Lionel Boue, Francois Wilson, Wyndham Hopkins Wyen, Christoph Dunleavy, Kieron Little, Richard F. Remick, Scot C. Goldfinger, Mendel Noy, Ariela Sparano, Joseph A. TI A pooled analysis of 1,546 patients with AIDS-related lymphoma (ARL): An assessment of prognostic factors by treatment era SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Univ Arkansas Med Sci, Dept Biostat, Little Rock, AR 72205 USA. Ctr Hosp Univ Archet, Nice, France. Univ Calif San Francisco, San Francisco, CA 94143 USA. Hosp Badalona Germans Trias & Pujol, Barcelona, Spain. Natl Canc Inst, Aviano, Italy. Hop St Louis, Assistance Publ Hop Paris, Paris, France. Hop Antoine Beclere, Clamart, France. NCI, Bethesda, MD 20892 USA. Univ Hosp Cologne, Cologne, Germany. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. W Virginia Univ, Sch Med, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 8524 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602620 ER PT J AU Bennett, CL Carson, KR Newsome, SD Kim, EJ Norris, LB Jalan, P Raisch, DW Major, G AF Bennett, Charles L. Carson, Kenneth Robert Newsome, Scott D. Kim, Ellen J. Norris, LeAnn B. Jalan, Pankaj Raisch, Dennis W. Major, Gene TI Progressive multifocal leucoencephalopathy (PML): A novel complication of brentuximab vedotin from the Southern Network on Adverse Reactions (SONAR) project. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ S Carolina, Coll Pharm, Columbia, SC 29208 USA. Med Univ S Carolina, Columbia, SC USA. Washington Univ, St Louis, MO USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Hosp Univ Penn, Philadelphia, PA 19104 USA. South Carolina Coll Pharm, Columbia, SC USA. South Carolina Coll Pharm, Springfield, IL USA. Univ New Mexico, VA Ctr Cooperat Pharmaceut Studies, Albuquerque, NM 87131 USA. Univ Illinois, Sch rvIedicine, NINDS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e22181 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605300 ER PT J AU Blagoev, KB Pichun, MEB Wilkerson, J Blanco-Codesido, M Dominguez, EE Garcia-Altonso, P Fojo, AT AF Blagoev, Krastan B. Pichun, Mauricio Emmanuel Burotto Wilkerson, Julia Blanco-Codesido, Montserrat Dominguez, Edward Espinal Garcia-Altonso, Pilar Fojo, Antonio Tito TI Relationship of the emergence of KRAS mutations and resistance to panitumumab in second-line treatment of colorectal cancer (CRC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Natl Sci Fdn, Arlington, VA 22230 USA. NCI, NIH, Bethesda, MD 20892 USA. Hosp Gen Univ Gregorio Maranon, Madrid, Spain. Gregorio Maranon Univ Hosp, Madrid, Spain. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e14592 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419603549 ER PT J AU Bradley, C Yabroff, KR Warren, JL Chawley, N Zerutoc, C Lamont, EB AF Bradley, Cathy Yabroff, K. Robin Warren, Joan L. Chawley, Neetu Zerutoc, Chris Lamont, Elizabeth B. TI Trends in chemotherapy-related treatment of late-stage colon and rectal cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Virginia Commonwealth Univ, Richmond, VA USA. NCI, Bethesda, MD 20892 USA. Informat Management Serv Inc, Bethesda, MD USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6604 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602320 ER PT J AU Bria, E Pilotto, S Bonomi, M Milella, M Massari, F Fojo, AT Sperduti, I Giannarelli, D Tortora, G AF Bria, Emilio Pilotto, Sara Bonomi, Maria Milella, Michele Massari, Francesco Fojo, Antonio Tito Sperduti, Isabella Giannarelli, Diana Tortora, Giampaolo TI Targeted agents (TA) for advanced solid tumors (AST): What is the likelihood of being helped or harmed (LHH)? Assessing the clinical impact of therapies with FDA/EMEA approval SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Verona, Azienda Osped Univ Integrata, I-37100 Verona, Italy. Regina Elena Inst Canc Res, Rome, Italy. NCI, NIH, Bethesda, MD 20892 USA. Ist Nazl Tumori Regina Elena, Rome, Italy. RI Sperduti, Isabella /K-8902-2016 OI Sperduti, Isabella /0000-0001-5115-3099 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e17555 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604425 ER PT J AU Burris, HA Giaccone, G Im, SA Bauer, TM Trepel, JB Nordstrom, JL Li, H Carlin, DA Baughman, JE Stewart, S Bang, YJ AF Burris, Howard A. Giaccone, Giuseppe Im, Seock-Ah Bauer, Todd Michael Trepel, Jane B. Nordstrom, Jeffrey L. Li, Hua Carlin, David A. Baughman, Jan E. Stewart, Stanford Bang, Yung-Jue TI Phase I study of margetuximab (MGAH22), an FC-modified chimeric monoclonal antibody (MAb), in patients (pts) with advanced solid tumors expressing the HER2 oncoprotein. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Tennessee Oncol, Sarah Cannon Res Inst, Nashville, TN USA. NCI, Bethesda, MD 20892 USA. Seoul Natl Univ Hosp, Seoul 110744, South Korea. MacroGenics Inc, Rockville, MD USA. MacroGenics Inc, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 3004 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601137 ER PT J AU Carter, CA Rajan, A Szabo, E Khozin, S Thomas, A Brzezniak, CE Guha, U Doyle, LA Keen, C Steinberg, SM Xi, LQ Raffeld, M Reckamp, KL Koehler, S Gitlitz, BJ Salgia, R Gandara, DR Vokes, EE Giaccone, G AF Carter, Corey Allan Rajan, Arun Szabo, Eva Khozin, Sean Thomas, Anish Brzezniak, Christina E. Guha, Udayan Doyle, L. Austin Keen, Corrine Steinberg, Seth M. Xi, Liqiang Raffeld, Mark Reckamp, Karen L. Koehler, Stephen Gitlitz, Barbara Jennifer Salgia, Ravi Gandara, David R. Vokes, Everett E. Giaccone, Giuseppe TI Two parallel randomized phase II studies of selumetinib (S) and erlotinib (E) in advanced non-small cell lung cancer selected by KRAS mutations. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NCI, Bethesda, MD 20892 USA. Natl Canc Inst CTEP, Rockville, MD USA. NCI, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. NCI, Mol Diagnost Core Lab, CCR, NIH, Bethesda, MD 20892 USA. City Hope Comprehens Canc Ctr, Duarte, CA USA. City Hope Natl Med Ctr, Duarte, CA USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. Univ Chicago, Chicago, IL 60637 USA. Univ Calif Davis, Ctr Comprehens Canc, Sacramento, CA 95817 USA. Univ Chicago Med & Biol Sci, Chicago, IL USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 8026 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602507 ER PT J AU Chandwani, KD Zhao, FM Morrow, GR De Shields, T Minasian, LM Manola, J Fisch, M AF Chandwani, Kavita Dayal Zhao, Fengmin Morrow, Gary R. De Shields, Teresa Minasian, Lori M. Manola, Judith Fisch, Michael TI Lack of patient-clinician concordance (LOC) across disease and treatment status in cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Rochester, Med Ctr, Rochester, NY 14642 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Washington Univ, Sch Med St Louis, St Louis, MO USA. NCI, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e20520 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604791 ER PT J AU Chavez-Mac Gregor, M Barlow, WE Gonzalez-Angulo, AM Rastogi, P Mamounas, EP Ganz, PA Schott, A Paik, S Lew, D Bandos, H Hortobagyi, GN AF Chavez-Mac Gregor, Mariana Barlow, William E. Gonzalez-Angulo, Ana M. Rastogi, Priya Mamounas, Eleftherios P. Ganz, Patricia A. Schott, Anne Paik, Soonmyung Lew, Danika Bandos, Hanna Hortobagyi, Gabriel N. TI Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy with or without one year of everolimus in patients with high-tisk, hormone receptor- (HR) positive and HER2-neu-negative breast cancer: SWOG/NSABP S1207. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Breast Med Oncol Dept, Houston, TX 77030 USA. Canc Res & Biostat, Seattle, WA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Natl Surg Breast & Bowel Project, Orlando, FL USA. MD Anderson Canc Ctr Orlando, Orlando, FL USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Southwest Oncol Grp Stat Ctr, Seattle, WA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, NSABP Biostat Ctr, Pittsburgh, PA 15261 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS657 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605487 ER PT J AU Chawla, N Yabroff, KR Mariotto, A McNeel, TS Schrag, D Warren, JL AF Chawla, Neetu Yabroff, K. Robin Mariotto, Angela McNeel, Timothy S. Schrag, Deborah Warren, Joan L. TI Accuracy and completeness of diagnosis codes for cancer metastasis on Medicare claims SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. IMS, Rockville, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6521 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602240 ER PT J AU Ciprotti, M Tebbutt, NC Lee, FT Lee, ST McKee, DC O'Keefe, GJ Gong, SJ Chong, G Gan, HK Hopkins, W Chappell, B Scott, FE Brechbiel, MW Tse, AN Jansen, M Matsumura, M Watanabe, R Beckman, RA Greenberg, J Scott, AM AF Ciprotti, Marika Tebbutt, Niall C. Lee, Fook Thean Lee, Sze Ting McKee, Dave C. O'Keefe, Graeme J. Gong, Sylvia J. Chong, Geoffrey Gan, Hui Kong Hopkins, Wendie Chappell, Bridget Scott, Fiona Elizabeth Brechbiel, Martin W. Tse, Archie N. Jansen, Mendel Matsumura, Manabu Watanabe, Rira Beckman, Robert A. Greenberg, Jonathan Scott, Andrew Mark TI A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Ludwig Inst Canc Res, Melbourne, Vic 3050, Australia. Austin Hlth, Heidelberg, Vic, Australia. NCI, Bethesda, MD 20892 USA. Daiichi Sankyo Co Ltd, Edison, NJ USA. Daiichi Sankyo Co Ltd, Gerrards Cross, England. Daiichi Sankyo Co Ltd, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2583 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601100 ER PT J AU Cobleigh, MA Anderson, SJ Julian, TB Siziopikou, KP Arthur, DW Rabinovitch, R Zheng, P Mamounas, EP Wolmark, N AF Cobleigh, Melody A. Anderson, Stewart J. Julian, Thomas B. Siziopikou, Kalliopi P. Arthur, Douglas W. Rabinovitch, Rachel Zheng, Ping Mamounas, Eleftherios P. Wolmark, Norman TI NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+DCIS resected by lumpectomy (Lx). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Rush Univ, Med Ctr, Chicago, IL 60612 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Natl Surg Adjuvant Breast & Bowel Project Biostat, Pittsburgh, PA 15261 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Northwestern Univ, Feinberg Sch Med, Natl Surg Breast & Bowel Program, Chicago, IL 60611 USA. Virginia Commonwealth Univ, Richmond, VA USA. Univ Colorado, Natl Surg Breast & Bowel Project, Aurora, CO USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. MD Anderson Canc Ctr Orlando, Orlando, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS666 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605499 ER PT J AU Duffy, AG Rahma, OE Ulahannan, SV Fioravanti, S Venkatesan, A Turkbey, IB Choyke, PL Trepel, JB Figg, WD Greten, TF AF Duffy, Austin G. Rahma, Osama E. Ulahannan, Susanna Varkey Fioravanti, Suzanne Venkatesan, Aradhana Turkbey, Ismail B. Choyke, Peter L. Trepel, Jane B. Figg, William Douglas Greten, Tim F. TI A phase II study of TR105 in patients with hepatocellular carcinoma (HCC) who have progressed on sorafenib. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 [Duffy, Austin G.; Rahma, Osama E.; Ulahannan, Susanna Varkey; Fioravanti, Suzanne; Venkatesan, Aradhana; Turkbey, Ismail B.; Choyke, Peter L.; Trepel, Jane B.; Figg, William Douglas; Greten, Tim F.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI Greten, Tim/B-3127-2015; Figg Sr, William/M-2411-2016 OI Greten, Tim/0000-0002-0806-2535; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e15177 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604055 ER PT J AU Falcone, A Cremolini, C Masi, G Lonardi, S Zagonel, V Salvatore, L Trenta, P Tomasello, G Ronzoni, M Ciuffreda, L Zaniboni, A Tonini, G Buonadonna, A Valsuani, C Chiara, S Carlomagno, C Boni, C Marcucci, L Boni, L Loupakis, F AF Falcone, Alfredo Cremolini, Chiara Masi, Gianluca Lonardi, Sara Zagonel, Vittorina Salvatore, Lisa Trenta, Patrizia Tomasello, Gianluca Ronzoni, Monica Ciuffreda, Libero Zaniboni, Alberto Tonini, Giuseppe Buonadonna, Angela Valsuani, Chiara Chiara, Silvana Carlomagno, Chiara Boni, Corrado Marcucci, Lorenzo Boni, Luca Loupakis, Fotios TI FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Azienda Ospedaliero Univ Pisana, UO Oncol Med 2, Ist Toscano Tumori, Pisa, Italy. Ist Oncol Veneto IRCCS, Padua, Italy. DH Oncol, Policlin Umberto I, Rome, Italy. Ist Ospitalieri Cremona, Cremona, Italy. Ist Sci San Raffaele, Dipartimento Oncol Med, Milan, Italy. Molinette Mauriziano Hosp, Med Oncol Unit, Turin, Italy. Casa Cura Poliambulanza, Brescia, Italy. Univ Campus Biomed, Dept Med Oncol, Rome, Italy. Ist Nazl Tumori, Dipartimento Oncol Med, Aviano, Italy. Osped Versilia, UO Oncol Med, Viareggio, Italy. Natl Canc Inst, Med Oncol Unit, Genoa, Italy. Univ Naples Federico II, Dept Mol & Clin Endocrinol & Oncol, Naples, Italy. Arcispedale S Maria Nuova, Div Oncol, Reggio Emilia, Italy. USL 5 Pontedera, Div Med Oncol, Pontedera, Italy. Ist Toscano Tumori, Florence, Italy. RI zagonel, vittorina/F-4226-2014; Lonardi, Sara/F-4228-2014 OI zagonel, vittorina/0000-0002-0829-2525; Lonardi, Sara/0000-0002-7593-8138 NR 0 TC 16 Z9 17 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 3505 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601242 ER PT J AU Fawzy, MR Abernethy, AP Schoen, MW Rogak, LJ Mendoza, TR St Germain, DC Paul, DB Baumgartner, P Gangoli, V Chilukuri, R Mitchell, SA Reeve, BB Castro, KM Shalley, E Basch, EM AF Fawzy, Maria R. Abernethy, Amy Pickar Schoen, Martin W. Rogak, Lauren J. Mendoza, Tito R. St Germain, Diane C. Paul, Diane B. Baumgartner, Paul Gangoli, Vinay Chilukuri, Ram Mitchell, Sandra A. Reeve, Bryce B. Castro, Kathleen M. Shalley, Eve Basch, Ethan M. TI Usability testing of the PRO-CTCAE measurement system in patients with cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Duke Univ, Durham, NC USA. Duke Univ, Med Ctr, Durham, NC USA. George Warren Brown Sch Social Work, St Louis, MT USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. Patient Advocate & Canc Survivor, Brooklyn, NY USA. SemanticBits LLC, Herndon, VA USA. NCI, Rockville, MD USA. Univ N Carolina, Chapel Hill, NC USA. Essex Mnagement LLC, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e17560 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604429 ER PT J AU Fehrenbacher, L Jeong, JH Rastogi, P Geyer, CE Paik, S Ganz, PA Land, SR Costantino, JP Swain, SM Mamounas, EP Wolmark, N AF Fehrenbacher, Louis Jeong, Jong-Hyeon Rastogi, Priya Geyer, Charles E. Paik, Soonmyung Ganz, Patricia A. Land, Stephanie R. Costantino, Joseph P. Swain, Sandra M. Mamounas, Eleftherios P. Wolmark, Norman TI NSABP B-47: A randomized phase III trial of adjuvant therapy comparing chemotherapy alone to chemotherapy plus trastuzumab in women with node-positive or high-risk node-negative HER2-low invasive breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Natl Surg Adjuvant Breast & Bowel Project, Vallejo, CA USA. Kaiser Permanente Calif, Vallejo, CA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. NSABP, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Natl Surg Adjuvant Breast & Bowel Project,Biostat, Pittsburgh, PA 15261 USA. NSABP, Washington, DC USA. MedStar Washington Hosp Ctr, Washington Canc Inst, Washington, DC USA. MD Anderson Canc Ctr Orlando, Orlando, FL USA. Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS1139 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605372 ER PT J AU Forsythe, LP Parry, C Alfano, CM Kent, EE Leach, C Haggstrom, D Ganz, PA Aziz, N Rowland, JH AF Forsythe, Laura Pence Parry, Carla Alfano, Catherine M. Kent, Erin E. Leach, Corinne Haggstrom, David Ganz, Patricia A. Aziz, Noreen Rowland, Julia Howe TI Gaps in survivorship care plan delivery and potential benefits to survivorship care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Patient Centered Outcomes Res Inst, Washington, DC USA. NCI, Rockville, MD USA. NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. Amer Canc Soc, Atlanta, GA 30329 USA. Indiana Univ Sch Med, Indianapolis, IN 46202 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. NINR, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 9594 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419603077 ER PT J AU Friedman, DN Chou, JF Oeffinger, KC Ford, J Sklar, CA Li, YL McCabe, MS Robison, LL Kleinerman, R Marr, B Abramson, DH Dunkel, IJ AF Friedman, Danielle Novetsky Chou, Joanne F. Oeffinger, Kevin C. Ford, Jennifer Sklar, Charles A. Li, Yuelin McCabe, Mary S. Robison, Leslie L. Kleinerman, Ruth Marr, Brian Abramson, David H. Dunkel, Ira J. TI Chronic medical conditions in adult survivors of retinoblastoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. NCI, Rockville, MD USA. RI Friedman, Danielle Novetsky/B-7551-2016 OI Friedman, Danielle Novetsky/0000-0003-4668-9176 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 10019 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600173 ER PT J AU Gandini, S Heckman-Stoddard, BM Puntoni, M Dunn, BK Ford, L Bonanni, B Szabo, E De Censi, A AF Gandini, Sara Heckman-Stoddard, Brandy M. Puntoni, Matteo Dunn, Barbara K. Ford, Leslie Bonanni, Bernardo Szabo, Eva De Censi, Andrea TI Chemopreventation of cancer with metformin: A meta-analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 European Inst Oncol, Milan, Italy. Natl Canc Inst, Canc Prevent Div, Rockville, MD USA. EO Osped Galliera, Genoa, Italy. Natl Canc Inst, Canc Prevent Div, Bethesda, MD USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1516 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600575 ER PT J AU Gangadhar, TC Beumer, JH Espinoza-Delgado, I Anyang, BN Karovic, S Sharma, M Wen, YJ Janisch, LA Kindler, HL Nanda, R Karrison, T Ratain, MJ Maitland, ML AF Gangadhar, Tara C. Beumer, Jan Hendrik Espinoza-Delgado, Igor Anyang, Bean N. Karovic, Sanja Sharma, Manish Wen, Yujia Janisch, Linda A. Kindler, Hedy Lee Nanda, Rita Karrison, Theodore Ratain, Mark J. Maitland, Michael L. TI Dose-ranging randomized pharmacokinetic (PK) and pharmacodynamic (PD) study of vorinostat in patients with advanced solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NCI, CTEP, Bethesda, MD 20892 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Univ Chicago, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2571 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601089 ER PT J AU Gilbert, MR Dignam, J Won, M Blumenthal, DT Vogelbaum, MA Aldape, KD Colman, H Chakravarti, A Jeraj, R Armstrong, TS Wefel, JS Brown, PD Jaeckle, KA Schiff, D Atkins, JN Brachman, D Werner-Wasik, M Komaki, R Sulman, EP Mehta, MP AF Gilbert, Mark R. Dignam, James Won, Minhee Blumenthal, Deborah T. Vogelbaum, Michael A. Aldape, Kenneth D. Colman, Howard Chakravarti, Arnab Jeraj, Robert Armstrong, Terri S. Wefel, Jeffrey Scott Brown, Paul D. Jaeckle, Kurt A. Schiff, David Atkins, James Norman Brachman, David Werner-Wasik, Maria Komaki, Ritsuko Sulman, Erik P. Mehta, Minesh P. TI RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Utah, Huntsman Can Inst, Salt Lake City, UT USA. Ohio State Univ, Arthur G James Canc Ctr, Columbus, OH 43210 USA. Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. Univ Texas Hlth Sci Ctr Houston, Sch Nursing, Houston, TX 77030 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Arizona Oncol Serv Fdn, Phoenix, AZ USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Univ Maryland, Baltimore, MD 21201 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600002 ER PT J AU Glover, JM Gorlick, RG Khanna, C Barkauskas, DA AF Glover, Jason Michael Gorlick, Richard Greg Khanna, Chand Barkauskas, Donald A. TI The Children's Oncology Group and QuadW Foundation osteosarcoma banking experience SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Randall Childrens Hosp, Portland, OR USA. Childrens Hosp, Bronx, NY USA. NCI, Bethesda, MD 20892 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 10053 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600211 ER PT J AU Goncalves, PH Kummar, S Siu, LL Hansen, AR Savvides, P Sukari, A Chao, J Heilbrun, LK Pilat, MJ Smith, DW Casetta, L Boerner, SA LoRusso, P AF Goncalves, Priscila Hermont Kummar, Shivaani Siu, Lillian L. Hansen, Aaron Richard Savvides, Panayiotis Sukari, Ammar Chao, Joseph Heilbrun, Lance K. Pilat, Mary Jo Smith, Daryn W. Casetta, Lindsay Boerner, Scott Anthony LoRusso, Patricia TI A phase II study of suberoylanilide hydroxamic acid (SAHA) in subjects with locally advanced, recurrent, or metastatic adenoid cystic carcinoma (ACC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. NCI, Dev Therapeut Clin, Bethesda, MD 20892 USA. Princess Margaret Canc Ctr, Toronto, ON, Canada. Univ Toronto, Univ Hlth Network, Div Med Oncol & Hematol, Princess Margaret Canc Ctr,Dept Med, Toronto, ON, Canada. Univ Hosp Cleveland Med Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6045 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602168 ER PT J AU Goodwin, PJ Parulekar, W Gelmon, KA Shepherd, LE Ligibel, JA Hershman, DL Rastogi, P Mayer, IA Hobday, TJ Lemieux, J Thompson, AM Pritchard, KI Whelan, TJ Mukherjee, SD Chalchal, HI Oja, CD Tonkin, KS Bernstein, V Chen, BSE Stambolic, V AF Goodwin, Pamela Jean Parulekar, Wendy Gelmon, Karen A. Shepherd, Lois E. Ligibel, Jennifer A. Hershman, Dawn L. Rastogi, Priya Mayer, Ingrid A. Hobday, Timothy J. Lemieux, Julie Thompson, Alastair Mark Pritchard, Kathleen I. Whelan, Timothy Joseph Mukherjee, Som Dave Chalchal, Haji I. Oja, Conrad D. Tonkin, Katia Sonia Bernstein, Vanessa Chen, Bingshu E. Stambolic, Vuk TI Effect of metformin versus placebo on weight and metabolic factors in initial patients enrolled onto NCIC CTG MA.32, a multicenter adjuvant randomized controlled trial in early-stage breast cancer (BC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Queens Univ, NCIC Clin Trials Grp, Canc Res Inst, Kingston, ON, Canada. Univ British Columbia, British Columbia Canc Agcy, NCIC Clin Trials Grp, Vancouver, BC, Canada. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Columbia Univ, Med Ctr, New York, NY USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. Mayo Clin, Coll Med, Rochester, MN USA. Hop St Sacrement, CHU Quebec, Ctr Rech, Unite Rech Sante Populat, Quebec City, PQ, Canada. Natl Inst Canc Res, Breast Clin Studies Grp, London, England. Univ Toronto, Sunnybrook Hlth Sci Ctr, Odette Canc Ctr, Toronto, ON, Canada. McMaster Univ, Hamilton Hlth Sci, Juravinski Canc Ctr, Hamilton, ON, Canada. Allan Blair Canc Ctr, Regina, SK, Canada. British Columbia Canc Agcy, Fraser Valley Ctr, Surrey, BC, Canada. Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada. Univ British Columbia, British Columbia Canc Agcy, Vancouver Isl Ctr, Vancouver, BC V5Z 1M9, Canada. Univ Toronto, Ontario Canc Inst, Univ Hlth Network, Princess Margaret Hosp, Toronto, ON M5S 1A1, Canada. RI Whelan, Timothy/D-3185-2017 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1033 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600256 ER PT J AU Gorin, SS Haggstrom, D Fairfield, K Han, P Krebs, P Clauser, SB AF Gorin, Sherri Sheinfeld Haggstrom, David Fairfield, Kathleen Han, Paul Krebs, Paul Clauser, Steven B. CA QCCC CCI Working Grp TI Cancer care coordination systematic review and meta-analysis: Twenty-two years of empirical studies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, SAIC, Rockville, MD USA. Indiana Univ, Indianapolis, IN 46204 USA. VAMC, Indianapolis, IN USA. Maine Med Ctr, Portland, ME 04102 USA. NYU, Med Ctr, New York, NY 10016 USA. NCI, Outcomes Res Branch, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6536 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602254 ER PT J AU Gramza, AW Balasubramaniam, S Fojo, AT Ward, J Wells, SA AF Gramza, Ann Wild Balasubramaniam, Sanjeeve Fojo, Antonio Tito Ward, Jean Wells, Samuel A. TI Phase I/II trial of crolibulin and cisplatin in solid tumors with a focus on anaplastic thyroid cancer: Phase I results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 [Gramza, Ann Wild; Balasubramaniam, Sanjeeve; Fojo, Antonio Tito; Ward, Jean; Wells, Samuel A.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6074 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602197 ER PT J AU Hobday, TJ Qin, R Moore, MJ Reidy, DL Strosberg, JR Kindler, HL Shah, MH Lenz, HJ Kaubisch, A Chen, HX Erlichman, C AF Hobday, Timothy J. Qin, Rui Moore, Malcolm J. Reidy, Diane Lauren Strosberg, Jonathan R. Kindler, Hedy Lee Shah, Manisha H. Lenz, Heinz-Josef Kaubisch, Andreas Chen, Helen X. Erlichman, Charles TI Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mayo Clin, Rochester, MN USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Ohio State Univ, Ctr Comprehens Canc, Arthur G James Canc Hosp, Columbus, OH 43210 USA. Richard J Solove Res Inst, Columbus, OH USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. NCI, CTEP, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 4032 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601406 ER PT J AU Hourigan, CS Goswami, M Alkharouf, N Bhagwat, M Sardon, HM Williams, AL Mccoy, JP Ito, S Strickland, SA Savanl, BN Fraser, JW Sadrzadeh, H Fathi, AT Qin, L Hess, A Smith, BD Karp, JE Barrett, AJ AF Hourigan, Christopher Simon Goswami, Meghali Alkharouf, Nawal Bhagwat, Medha Sardon, Heidi May Williams, Ann L. Mccoy, J. Phillip Ito, Sawa Strickland, Stephen Anthony Savanl, Bipin N. Fraser, James W. Sadrzadeh, Hossein Fathi, Amir Tahmasb Qin, Lu Hess, Allan Smith, B. Douglas Karp, Judith E. Barrett, A. John TI Systematic analysis of potential targets for immunotherapy in acute myeloid leukemia. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NHLBI, Hematol Branch, Myeloid Malignancies Sect, Bethesda, MD 20892 USA. Natl Inst Hlth Lib, Bioinformat Program, Bethesda, MD USA. NHLBI, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, Stem Cell Allogene Transplantat Sect, Bethesda, MD 20892 USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Ctr Leukemia & Bone Marrow Transplant Unit, Div Hematology Oncol,Massachusetts Gen Hosp, Boston, MA USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 3104 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601236 ER PT J AU Huang, CH Ganti, AK Neupane, P Sittampalam, GS Schmitt, S Nirmalanandhan, S Williamson, SK Wick, J Smart, J Spencer, SE Godwin, AK Van Veldhuizen, PJ AF Huang, Chao H. Ganti, Apar Kishor Neupane, Prakash Sittampalam, G. Sitta Schmitt, Sarah Nirmalanandhan, Sanjit Williamson, Stephen K. Wick, Jo Smart, Janie Spencer, Sarah Ellen Godwin, Andrew K. Van Veldhuizen, Peter J. TI Circulating tumor cells (CTC) as a biomarker of response in patients with extensive-stage small cell lung cancer (EX-SCLC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Kansas City VA Med Ctr, Kansas City, MO USA. Nebraska Western Iowa Hlth Care Syst, Omaha, NE USA. Univ Kansas, Westwood, KS USA. NIH, Rockville, MD USA. Univ Kansas, Inst Adv Med Innovat, Kansas City, KS USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Univ Kansas, Ctr Canc, Westwood, KS USA. Univ Kansas, Dept Biostat, Kansas City, KS USA. Univ Kansas, Canc Ctr Mol Oncol, Kansas City, KS USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e22048 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605186 ER PT J AU Jackson, E Dees, EC Kauh, JS Harvey, RD Neuger, A Lush, R Antonia, SJ Minton, SE Ismail-Khan, R Han, HS Vahanian, NN Ramsey, WJ Link, CJ Streicher, H Sullivan, D Soliman, HH AF Jackson, Erica Dees, Elizabeth Claire Kauh, John S. Harvey, R. Donald Neuger, Anthony Lush, Richard Antonia, Scott J. Minton, Susan E. Ismail-Khan, Roohi Han, Hyo S. Vahanian, Nicholas N. Ramsey, William Jay Link, Charles J. Streicher, Howard Sullivan, Daniel Soliman, Hatem Hussein TI A phase I study of indoximod in combination with docetaxel in metastatic solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ S Florida, Morsani Coll Med, Tampa, FL USA. UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. Emory Univ, Sch Med, Dept Hematol & Med Oncol, Winship Canc Inst, Atlanta, GA USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. NewLink Genet, Ames, IA USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 3026 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601158 ER PT J AU Janelsins, MC Mustian, KM Yao, S Heckler, CE Palesh, O Ontko, M Dakhil, SR Smiskol, P Melnik, M Gross, HM Ahles, T Ambrosone, CB Morrow, GR AF Janelsins, Michelle Christine Mustian, Karen Michelle Yao, Song Heckler, Charles E. Palesh, Oxana Ontko, Mary Dakhil, Shaker R. Smiskol, Paul Melnik, Marianne Gross, Howard M. Ahles, Tim Ambrosone, Christine B. Morrow, Gary R. TI Cognitive function in breast cancer and lymphoma patients receiving chemotherapy: An ongoing nationwide University of Rochester Cancer Center (URCC) Community Clinical Oncology Program (CCOP) observational study with 1,200 patients and controls. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Rochester, Med Ctr, Rochester, NY 14642 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Dayton CCOP, Dayton, OH USA. Canc Ctr Kansas, Wichita, KS USA. Metro Minnesota CCOP, Minneapolis, MN USA. Grand Rapids CCOP, Michigan Canc Res Consortium, Ann Arbor, MI USA. Dayton CCOP, NSABP, Dayton, OH USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS9647 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605530 ER PT J AU Janosky, MD Demaria, S Novik, Y Oratz, R Tiersten, A Goldberg, JD Wang, E Marincola, F Formenti, S Adams, S AF Janosky, Maxwell Dale Demaria, Sandra Novik, Yelena Oratz, Ruth Tiersten, Amy Goldberg, Judith D. Wang, Ena Marincola, Francesco Formenti, Silvia Adams, Sylvia TI Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NYU, New York, NY USA. NYU, Sch Med, New York, NY USA. NYU, Langone Med Ctr, Inst Canc, New York, NY USA. NIH, Bethesda, MD 20892 USA. NYU, Langone Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS3122 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605416 ER PT J AU Johann, DJ Mukherjee, S Prieto, D Blonder, J AF Johann, Donald Joseph Mukherjee, Sumana Prieto, DaRue Blonder, Josip TI Approaching individualized care with a clinical tissue proteomics methodology. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e22180 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605299 ER PT J AU Johnson, BE Kris, MG Berry, LD Kwiatkowski, DJ Iafrate, AJ Varella-Garcia, M Wistuba, II Franklin, WA Ladanyi, M Su, PF Sequist, LV Khuri, FR Garon, EB Pao, W Rudin, CM Schiller, JH Haura, EB Giaccone, G Minna, JD Bunn, PA AF Johnson, Bruce E. Kris, Mark G. Berry, Lynne D. Kwiatkowski, David J. Iafrate, Anthony John Varella-Garcia, Marileila Wistuba, Ignacio Ivan Franklin, Wilbur A. Ladanyi, Marc Su, Pei-Fang Sequist, Lecia V. Khuri, Fadlo Raja Garon, Edward B. Pao, William Rudin, Charles M. Schiller, Joan H. Haura, Eric B. Giaccone, Giuseppe Minna, John D. Bunn, Paul A. TI A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Vanderbilt Univ, Nashville, TN 37235 USA. Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. Univ Colorado, Sch Med, Aurora, CO USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Colorado, Denver, CO 80202 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. Univ Calif Los Angeles, Santa Monica, CA USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. NCI, Bethesda, MD 20892 USA. Univ Colorado, Ctr Canc, Aurora, CO USA. NR 0 TC 15 Z9 16 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 8019 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602500 ER PT J AU Jonasch, E Corn, PG Pagliaro, LC Lara, P Wang, XM Do, KA Garza, R Bird, S Drabick, JJ Marcott, V Quinn, D Doyle, A Tannir, NM AF Jonasch, Eric Corn, Paul Gettys Pagliaro, Lance C. Lara, Primo Wang, Xuemei Do, Kim-Anh Garza, Racheal Bird, Shelly Drabick, Joseph J. Marcott, Valerie Quinn, David Doyle, Austin Tannir, Nizar M. TI Randomized phase II CTEP study of MK2206 versus everolimus in VEGF inhibitor refractory renal cell carcinoma patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. UC Davis Comprehens Canc Ctr, Div Hematol & Oncol, Sacramento, CA USA. Penn State Hershey Canc Inst, Hershey, PA USA. Univ So Calif, Los Angeles, CA USA. NCI, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 4517 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601531 ER PT J AU Julian, TB Anderson, SJ Krag, DN Harlow, SP Costantino, JP Ashikaga, T Weaver, DL Mamounas, EP Wolmark, N AF Julian, Thomas B. Anderson, Stewart J. Krag, David N. Harlow, Seth P. Costantino, Joseph P. Ashikaga, Takamaru Weaver, Donald L. Mamounas, Eleftherios P. Wolmark, Norman TI 10-yr follow-up results of NSABP B-32, a randomized phase HI clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Allegheny Gen Hosp, Allegheny Canc Ctr, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Natl Surg Adjuvant Breast & Bowel Project Biostat, Pittsburgh, PA 15261 USA. Univ Vermont, Natl Surg Adjuvant Breast & Bowel Project, Burlington, VT USA. Univ Vermont, Coll Med, Dept Med Biostat, Burlington, VT USA. Univ Vermont, Coll Med, Dept Pathol, Natl Surg Adjuvant Breast & Bowel Project, Burlington, VT 05405 USA. MD Anderson Canc Ctr Orlando, Orlando, FL USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1000 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600153 ER PT J AU Karzai, FH Madan, RA Apolo, AB Parnes, HL Wright, JJ Trepel, JB Beatson, MA Harold, N Couvillon, A Steinberg, SM Price, DK Gulley, JL Figg, WD Dahut, WL AF Karzai, Fatima H. Madan, Ravi Amrit Apolo, Andrea Borghese Parnes, Howard L. Wright, John Joseph Trepel, Jane B. Beatson, Melony A. Harold, Nancy Couvillon, Anna Steinberg, Seth M. Price, Douglas K. Gulley, James L. Figg, William Douglas Dahut, William L. TI A phase I study of cabozantinib (Cabo) plus docetaxel (D) and prednisone (P) in metastatic castrate resistant prostate cancer (mCRPC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS5095 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605458 ER PT J AU Karzai, FH Madan, RA Apolo, AB Ning, YMM Parnes, HL Arlen, PM Beatson, MA Harold, N Couvillon, A Wright, JJ Chen, C Dawson, NA Gulley, JL Figg, WD Dahut, WL AF Karzai, Fatima H. Madan, Ravi Amrit Apolo, Andrea Borghese Ning, Yangmin M. Parnes, Howard L. Arlen, Philip M. Beatson, Melony A. Harold, Nancy Couvillon, Anna Wright, John Joseph Chen, Clara Dawson, Nancy Ann Gulley, James L. Figg, William Douglas Dahut, William L. TI Use of supportive measures to improve outcome and decrease toxicity in docetaxel-based antiangiogenesis combinations in metastatic castrate resistant prostate cancer (mCRPC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, US FDA, Silver Spring, MD USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Neogenix Oncol, Rockville, MD USA. NCI, Rockville, MD USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e16017 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604209 ER PT J AU Katki, HA Kovalchik, SA Tammemagi, M Berg, CD Caporaso, N Riley, T Korch, M Silvestri, GA Chaturvedi, A AF Katki, Hormuzd A. Kovalchik, Stephanie A. Tammemagi, Martin Berg, Christine D. Caporaso, Neil Riley, Tom Korch, Mary Silvestri, Gerard A. Chaturvedi, Anil TI Variation in the efficacy of low-dose computed tomographic lung screening based on risk of lung cancer mortality in the National Lung Screening Trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. Brock Univ, Hamilton, ON, Canada. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Informat Management Serv Inc, Rockville, MD USA. Med Univ S Carolina, Charleston, SC 29425 USA. NCI, Rockville, MD USA. RI Berg , Christine/K-1047-2014; Katki, Hormuzd/B-4003-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1523 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600582 ER PT J AU Kim, JW Marte, JL Singh, NK Heery, CR Madan, RA Pazdur, M McMahon, S Rauckhorst, M Schlom, J Kantoff, PW Gulley, JL AF Kim, Joseph W. Marte, Jennifer L. Singh, Nishith K. Heery, Christopher Ryan Madan, Ravi Amrit Pazdur, Mary McMahon, Sheri Rauckhorst, Myrna Schlom, Jeffrey Kantoff, Philip W. Gulley, James L. TI Safety profile of recombinant poxviral TRICOM vaccines. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e16036 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604226 ER PT J AU Koczywas, M Lenz, HJ Mortimer, JE El-Khoueiry, AB Frankel, PH Gandara, DR Cristea, MC Chung, VM Lim, D Reckamp, KL Lau, DHM Ye, W Doyle, LA Carroll, MI Newman, EM AF Koczywas, Marianna Lenz, Heinz-Josef Mortimer, Joanne E. El-Khoueiry, Anthony B. Frankel, Paul Henry Gandara, David R. Cristea, Mihaela C. Chung, Vincent M. Lim, Dean Reckamp, Karen L. Lau, Derick H. M. Ye, Wei Doyle, L. Austin Carroll, Mary I. Newman, Edward M. TI PHI-55: (NCI#7427): A phase I study of halichondrin B analog (E7389) in combination with cisplatin (CDDP) in advanced solid tumors: A CCC, NCI/CTEP-sponsored trial (grant U01 CA 062505). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 City Hope Natl Med Ctr, Duarte, CA USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. Univ Calif Davis, Ctr Comprehens Canc, Sacramento, CA 95817 USA. Univ Calif Davis, Sacramento, CA 95817 USA. NCI, CTEP, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2564 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601082 ER PT J AU Komiya, T Blumenthal, GM Ballas, MS Dechowdhury, R Manu, M Fioravanti, S Hornyak, TJ Wank, S Weinstein, D Morris, J Hewitt, SM Memmott, R Dennis, PA Morrow, B AF Komiya, Takefumi Blumenthal, Gideon Michael Ballas, Marc S. Dechowdhury, Roopa Manu, Michell Fioravanti, Suzanne Hornyak, Thomas J. Wank, Stephen Weinstein, Douglas Morris, Jennifer Hewitt, Stephen M. Memmott, Regan Dennis, Phillip A. Morrow, Betsy TI A pilot study of sirolimus (S) in subjects with Cowden syndrome (CS) with germ-line mutations in PTEN. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. US FDA, Silver Spring, MD USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. Maryland Oncol Hematol, Silver Spring, MD USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NIDDK, Bethesda, MD 20892 USA. NCI, Laboraory Pathol, Gaithersburg, MD USA. NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2532 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601050 ER PT J AU Ladanyi, M Cagle, PT Beasley, MB Chitale, D Dacic, S Giaccone, G Jenkins, RB Kwiatkowski, DJ Saldivar, JS Squire, J Thunnissen, E Lindeman, NI AF Ladanyi, Marc Cagle, Phil T. Beasley, Mary Beth Chitale, Dhananjay Dacic, Sanja Giaccone, Giuseppe Jenkins, Robert B. Kwiatkowski, David J. Saldivar, Juan-Sebastian Squire, Jeremy Thunnissen, Erik Lindeman, Neal Ian TI The CAP-IASLC-AMP molecular testing guideline for the selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Methodist Hosp, Houston, TX 77030 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. Henry Ford Hlth Syst, Dept Pathol, Detroit, MI USA. Univ Pittsburgh, Pittsburgh, PA USA. NCI, Bethesda, MD 20892 USA. Mayo Clin, Rochester, MN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. Queens Univ, Dept Pathol & Mol Med, Kingston, ON, Canada. Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 11085 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600502 ER PT J AU Le, DT Wang-Gillam, A Picozzi, VJ Greten, TF Crocenzi, TS Springett, GM Morse, M Zeh, H Cohen, DJ Fine, RL Onners, B Uram, JN Murphy, A Skoble, J Lemmens, E Grous, JJ Dubensky, T Brockstedt, DG Jaffee, EM AF Le, Dung T. Wang-Gillam, Andrea Picozzi, Vincent J. Greten, Tim F. Crocenzi, Todd S. Springett, Gregory M. Morse, Michael Zeh, Herbert Cohen, Deirdre Jill Fine, Robert Lance Onners, Beth Uram, Jennifer N. Murphy, Aimee Skoble, Justin Lemmens, Ed Grous, John J. Dubensky, Thomas Brockstedt, Dirk G. Jaffee, Elizabeth M. TI Interim safety and efficacy analysis of a phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Washington Univ, Sch Med St Louis, St Louis, MO USA. Virginia Mason Med Ctr, Seattle, WA 98101 USA. NCI, Bethesda, MD 20892 USA. Providence Canc Ctr, Portland, OR USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. NYU, Inst Canc, New York, NY USA. Columbia Univ, New York, NY USA. Aduro BioTech Inc, Berkeley, CA USA. RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 4040 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601414 ER PT J AU Lee, DW Shah, N Steller-Stevenson, M Sabatino, M Richards, K Delbrook, C Kochenderter, J Rosenberg, SA Stroncek, D Mackall, C Wayne, AS AF Lee, Daniel Warnell Shah, Nirali Steller-Stevenson, Maryalice Sabatino, Marianna Richards, Kelly Delbrook, Cindy Kochenderter, James Rosenberg, Steven A. Stroncek, Dave Mackall, Crystal Wayne, Alan S. TI Autologous-collected anti-CD19 chimeric antigen receptor T cells (19CARTs) for pediatric acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL): Clinical activity and cytokine release without graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 10006 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600162 ER PT J AU Lee, JM Annunziata, CM Hays, JL Noonan, AM Minasian, LM Zujewski, J Yu, MS Ji, JJ Sissung, T Houston, ND Kohn, EC AF Lee, Jung-Min Annunziata, Christina M. Hays, John L. Noonan, Anne M. Minasian, Lori M. Zujewski, JoAnne Yu, Minshu Ji, Jiuping Jay Sissung, Tristan Houston, Nicole D. Kohn, Elise C. TI Phase I/Ib study of the PARP inhibitor olaparib (O) with carboplatin (C) in BRCA1/2 mutation carriers with breast or ovarian cancer (Br/OvCa) (NCT00647062). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Mol Signaling Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. SAIC Frederick Inc, Frederick Natl Labs, Bethesda, MD USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2514 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601032 ER PT J AU Lopez-Chavez, A Thomas, A Rajan, A Steinberg, SM Dilts, DM Doyle, A Giaccone, G AF Lopez-Chavez, Ariel Thomas, Anish Rajan, Arun Steinberg, Seth M. Dilts, David M. Doyle, Austin Giaccone, Giuseppe TI CUSTOM (Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies trial): A radical redesign of clinical trial structure-Use of mass customization and product postponement SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. NCI, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6524 PG 2 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602243 ER PT J AU Luu, TH Frankel, PH Lim, D Cristea, MC Beumer, JH Appleman, LJ Lenz, HJ Gandara, DR Piekarz, R Newman, EM AF Luu, Thehang H. Frankel, Paul Henry Lim, Dean Cristea, Mihaela C. Beumer, Jan Hendrik Appleman, Leonard Joseph Lenz, Heinz-Josef Gandara, David R. Piekarz, Richard Newman, Edward M. TI Phi-53: (NCI#7251): Phase I trial of belinostat (PXD101) in combination with 13-cis-retinoic acid (13c-RA) in advanced solid tumor malignancies-A California Cancer Consortium NCI/CTEP sponsored trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 City Hope Natl Med Ctr, Duarte, CA USA. City Hope Beckman Res Inst, Duarte, CA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Univ Calif Davis, Ctr Comprehens Canc, Sacramento, CA 95817 USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2526 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601044 ER PT J AU Lynch, JA Fiore, L Kelley, MJ Borzecki, A Lathan, CS Hassett, M Rugo, HS Khoury, MJ Freedman, AN AF Lynch, Julie Ann Fiore, Louis Kelley, Michael J. Borzecki, Ann Lathan, Christopher S. Hassett, Michael Rugo, Hope S. Khoury, Muin J. Freedman, Andrew N. TI Current status of the implementation of gene expression testing in breast cancer management in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Vet Hlth Adm, Bedford, MA USA. Vet Hlth Adm, Boston, MA USA. Vet Hlth Adm, Durham, NC USA. Dana Farber Canc Inst, Boston, MA 02115 USA. UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. NCI, Epidemiol & Genom Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6562 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602278 ER PT J AU Mackall, C Baird, K Bernstein, DB Wood, BJ Steinberg, SM Beq, S Croughs, T Sabatino, M Stroncek, D Merchant, MS AF Mackall, Crystal Baird, Kristin Bernstein, Donna B. Wood, Bradford J. Steinberg, Seth M. Beq, Stephanie Croughs, Therese Sabatino, Marianna Stroncek, Dave Merchant, Melinda S. TI Survival in metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS) following consolidation immunotherapy with autologous lymphocyte infusion, dendritic cell vaccines +/- CYT107 (rhIL-7) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. NCI, Dept Radiol & Imaging Sci, NIH, Bethesda, MD 20892 USA. Cytheris SA, Issy Les Moulineaux, France. NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 10013 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600167 ER PT J AU Madan, RA Singh, NK Gramza, AW Fojo, AT Heery, CR Kim, JW McMahon, S Rauckhorst, M King, TH Apelian, D Schlom, J Gulley, JL AF Madan, Ravi Amrit Singh, Nishith K. Gramza, Ann Wild Fojo, Antonio Tito Heery, Christopher Ryan Kim, Joseph W. McMahon, Sheri Rauckhorst, Myrna King, Thomas H. Apelian, David Schlom, Jeffrey Gulley, James L. TI A phase II study of a yeast-based therapeutic cancer vaccine, GI-6207, targeting CEA in patients with minimally symptomatic, metastatic medullary thyroid cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Tumor Immunol & Biol Lab, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. GlobeImmune Inc, Louisville, CO USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS3127 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605421 ER PT J AU Mahar, AL Halabi, S McShane, LM Groome, PA Compton, CC AF Mahar, Alyson L. Halabi, Susan McShane, Lisa M. Groome, Patricia A. Compton, Carolyn C. CA Amer Joint Comm Canc TI A survey of clinical prediction took in colorectal and lung cancers and melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Queens Univ, Canc Res Inst, Div Canc Care & Epidemiol, Kingston, ON, Canada. Queens Univ, Dept Community Hlth & Epidemiol, Kingston, ON, Canada. Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. Alliance Stat & Data Ctr, Durham, NC USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Crit Path Inst, Tucson, AZ USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1592 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600651 ER PT J AU Mai, SK Reuschenbach, M Ottstadt, M Welzel, G Trunk, M Wentzensen, N Lohr, F Doeberitz, MV Wenz, FK AF Mai, Sabine Kathrin Reuschenbach, Miriam Ottstadt, Martine Welzel, Grit Trunk, Marcus Wentzensen, Nicolas Lohr, Frank Doeberitz, Magnus von Knebel Wenz, Frederik K. TI HPV status to predict outcome for anal cancer treated with radiochemotherapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Heidelberg Univ, Dept Radiat Oncol, Mannheim Med Ctr, Mannheim, Germany. Univ Clin Heidelberg, Inst Pathol, Abt Angew Tumorbiol, Heidelberg, Germany. Heidelberg Univ, Inst Pathol, Mannheim Med Ctr, Mannheim, Germany. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 4065 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601438 ER PT J AU Manasanch, EE Korde, N Yuan, C Kwok, M Tageja, N Bhutani, M Flanders, AW Zingone, A Costello, R Tembhare, P Mulquin, M Zuchlinski, D Maric, I Calvo, KR Steinberg, SM Roschewski, MJ Landgren, O Braylan, R Stetler-Stevenson, M AF Manasanch, Elisabet E. Korde, Neha Yuan, Constance Kwok, Mary Tageja, Nishant Bhutani, Manisha Flanders, Aaron W. Zingone, Adriana Costello, Rene Tembhare, Prashant Mulquin, Marcia Zuchlinski, Diamond Maric, Irina Calvo, Katherine R. Steinberg, Seth M. Roschewski, Mark J. Landgren, Ola Braylan, Raul Stetler-Stevenson, Maryalice TI Biologic variations of plasma cells in the bone marrow of smoldering multiple myeloma (SMM) and multiple myeloma (MM) patients: Multiple biopsies in the same patient. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Hematol Sect, Dept Lab Med, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Ctr Canc Res, Bethesda, MD 20892 USA. NIH, Hematol Serv, DLM, CCR, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e19506 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604695 ER PT J AU Masi, G Loupakis, F Salvatore, L Cremolini, C Fornaro, L Schirripa, M Granetto, C Miraglio, E Di Costanzo, F Antonuzzo, L Marcucci, L Barbara, C Boni, C Banzi, M Chiara, S Garbarino, D Valsuani, C Bonetti, A Boni, L Falcone, A AF Masi, Gianluca Loupakis, Fotios Salvatore, Lisa Cremolini, Chiara Fornaro, Lorenzo Schirripa, Marta Granetto, Cristina Miraglio, Emanuela Di Costanzo, Francesco Antonuzzo, Lorenzo Marcucci, Lorenzo Barbara, Cecilia Boni, Corrado Banzi, Maria Chiara, Silvana Garbarino, Daniela Valsuani, Chiara Bonetti, Andrea Boni, Luca Falcone, Alfredo TI Second-line chemotherapy (CT) with or without bevacizumab (BV) in metastatic colorectal cancer (mCRC) patients (pts) who progressed to a first-line treatment containing BV: Updated results of the phase III "BEBYP" trial by the Gruppo Oncologico Nord Ovest (GONO) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Azienda Osped Univ Pisana, Ist Toscano Tumori, UO Oncol Med 2, Pisa, Italy. Dipartimento Oncol AUSL 2, Lucca, Italy. Azienda Sanitaria Osped S Croce & Carle, UO Oncol Med, Cuneo, Italy. Azienda Osped Univ Careggi, UO Oncol Med, Florence, Italy. Div Oncol Med USL 5, Pontedera, Italy. Osped Civile Livorno, Dept Med Oncol, Livorno, Italy. Santa Maria Nuova Hosp, Reggio Emilia, Italy. Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. Natl Canc Inst, Med Oncol Unit, Genoa, Italy. Osped Versilia, UO Oncol Med, Viareggio, Italy. Mater Salutis Hosp, AULSS Reg Veneto 21, Dept Oncol, Legnago, Italy. Ist Toscano Tumori, Florence, Italy. NR 0 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 3615 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601350 ER PT J AU Massett, H Jaeckle, KA Dilts, DM Denicoff, A Souhan, E Hopkins, JR Mann, BS AF Massett, Holly Jaeckle, Kurt A. Dilts, David M. Denicoff, Andrea Souhan, Erin Hopkins, Jenny R. Mann, Bhupinder Singh TI Rapid online feedback to improve clinical trial accrual: CODEL anaplastic glioma (AG) (NCCTG/Alliance N0577) as a model SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Rockville, MD USA. Mayo Clin, Jacksonville, FL 32224 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. EMMES Corp, Rockville, MD USA. Westat Corp, Rockville, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1596 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600654 ER PT J AU Mekhail, T Waterhouse, DM Hadley, TJ Webb, CD Burris, HA Hainsworth, JD Greco, FA Spigel, DR AF Mekhail, Tarek Waterhouse, David Michael Hadley, Terence J. Webb, Charles D. Burris, Howard A. Hainsworth, John D. Greco, F. Anthony Spigel, David R. TI First-line carboplatin, pemetrexed, and panitumumab in patients with advanced nonsquamous KRAS wild type (WT) non-small cell lung cancer (NSCLC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Florida Hosp Canc Inst, Orlando, FL USA. Oncol Hematol Care SCRI, Cincinnati, OH USA. Baptist Hosp East, Louisville, KY USA. NCI, Louisville, KY USA. Tennessee Oncol, Sarah Cannon Res Inst, Nashville, TN USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 8062 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602542 ER PT J AU Melnyk, N Xie, XQ Koh, DJY Rajpal, M Moss, RA Gibbon, D Cleary, JM Tran, MT Scott, P Stein, MN Tan, AR Adams, S Lindquist, DC Harris, PJ Takebe, N Lin, HX Aisner, J White, E DiPaola, RS Mehnert, JM AF Melnyk, Nataliya Xie, Xiaoqi Koh, Danny Ju Yong Rajpal, Megha Moss, Rebecca Anne Gibbon, Darlene Cleary, James M. Minh-Thu Tran Scott, Pamela Stein, Mark N. Tan, Antoinette R. Adams, Shari Lindquist, Diana C. Harris, Pamela Jo Takebe, Naoko Lin, Hongxia Aisner, Joseph White, Eileen DiPaola, Robert S. Mehnert, Janice M. TI CTEP #8342 autophagy modulation with antiangiogenic therapy: A phase I trial of sunitinib (Su) and hydroxychloroquine (HCQ) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Med & Dent New Jersey, New Brunswick, NJ USA. Univ Med & Dent New Jersey, Piscataway, NJ 08854 USA. Robert Wood Johnson Med Sch, Piscataway, NJ USA. UMDNJ Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. Canc Inst New Jersey, New Brunswick, NJ USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Canc Therapy Evaluat Program, Invest Drug Branch, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2553 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601071 ER PT J AU Moon, Y Park, KS Kim, J Sarfaraz, S Voeller, D Trung, P Wang, YS Giaccone, G AF Moon, Yongwha Park, Kang-seo Kim, John Sarfaraz, Sami Voeller, Donna Trung, Pham Wang, Yisong Giaccone, Giuseppe TI LAMC2 as a prognostic marker that promotes metastasis of lung adenocarcinoma through epithelial-mensenchymal transition (EMT) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 11034 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600446 ER PT J AU Moreno-Aspitia, A Liu, HS Hillman, DW Rowland, KM Geiger, X Stella, PJ Kourlas, P Gross, HM Karlin, NJ Bury, MJ Soori, GS Nassar, A Perez, EA AF Moreno-Aspitia, Alvaro Liu, Heshan Hillman, David W. Rowland, Kendrith M. Geiger, Xochiquelzal Stella, Philip J. Kourlas, Peter Gross, Howard M. Karlin, Nina J. Bury, Martin J. Soori, Gamini S. Nassar, Aziza Perez, Edith A. CA Alliance Clinical Trials Oncology TI N0937(Alliance): Final clinical results and correlative data front the phase II trial of cisplatin (C) and the novel agent brostallicin (B) in patients with metastatic triple-negative breast cancer (mTNBC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mayo Clin, Jacksonville, FL 32224 USA. Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA. Carle Clin Associates, Urbana, IL USA. St Joseph Mercy Hlth Syst, Ann Arbor, MI USA. Columbus Onc Assoc Inc, Columbus, OH USA. Dayton CCOP, NSABP, Dayton, OH USA. Mayo Clin, Scottsdale, AZ USA. Grand Rapids Clin Oncol Program, Grand Rapids, IA USA. Missouri Valley Canc Consortium, Omaha, NE USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1059 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600368 ER PT J AU Morgan, R Oza, AM Qin, R Fruth, B Hirte, H Mackay, H Tsoref, D Strevel, EL Welch, S Sullivan, D Wenham, RM Fleming, GF Brewer, M Chen, HX Doyle, LA Gandara, DR Sparano, JA Einstein, MH Erlichman, C AF Morgan, Robert Oza, Amit M. Qin, Rui Fruth, Briant Hirte, Hal Mackay, Helen Tsoref, Daliah Strevel, Elizabeth Laureen Welch, Stephen Sullivan, Daniel Wenham, Robert M. Fleming, Gini F. Brewer, Molly Chen, Helen X. Doyle, L. Austin Gandara, David R. Sparano, Joseph A. Einstein, Mark H. Erlichman, Charles TI A multicenter phase II study of bevacizumab (B) and temsirolimus (T) in women with recurrent epithelial ovarian cancer (OC): A study of the Mayo, Chicago, California, New York, Southeast, and Princess Margaret Phase II Consortia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 City Hope Natl Med Ctr, Duarte, CA USA. Univ Hlth Network, Margaret Canc Ctr, Toronto, ON, Canada. Mayo Clin, Rochester, MN USA. Mayo Clin, Ctr Canc, Rochester, MN USA. Juravinski Canc Ctr, Hamilton, ON, Canada. Univ Toronto, Dept Med, Princess Margaret Canc Ctr, Univ Hlth Network,Div Med Oncol & Hematol, Toronto, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Peel Reg Canc Ctr, Mississauga, ON, Canada. London Reg Canc Program, London, ON, Canada. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Alliance Clin Trials Oncol, Chicago, IL USA. Univ Connecticut, Farmington, CT USA. CTEP Natl Canc Inst, Bethesda, MD USA. Natl Canc Inst CTEP, Rockville, MD USA. Univ Calif Davis, Ctr Comprehens Canc, Sacramento, CA 95817 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 5517 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602031 ER PT J AU Morikawa, A Peereboom, DM Smith, QR Thorsheim, H Lockman, PR Simmons, AJ Weil, RJ Tabar, V Steeg, PS Seidman, AD AF Morikawa, Aki Peereboom, David M. Smith, Quentin R. Thorsheim, Helen Lockman, Paul R. Simmons, Ahkeem James Weil, Robert J. Tabar, Viviane Steeg, Patricia Schriver Seidman, Andrew David TI Clinical evidence for drug penetration of capecitabine and lapatinib uptake in resected brain metastases from women with metastatic breast cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Cleveland Clin, Cleveland, OH 44106 USA. Texas Tech Univ Hlth Sci Ctr, Amarillo, TX USA. NCI, Womens Canc Sect, Mol Pharmacol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 514 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600019 ER PT J AU Morris, JC Rossi, GR Harold, N Tennant, L Ramsey, WJ Vahanian, NN Link, CJ AF Morris, John Charles Rossi, Gabriela R. Harold, Nancy Tennant, Lucinda Ramsey, William Jay Vahanian, Nicholas N. Link, Charles J. TI Potential chemo-sensitization effect of tergenpumatucel-L immunotherapy in treated patients with advanced non-small cell lung cancer (NSCLC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Cincinnati, Cincinnati, OH USA. NewLink Genet, Ames, IA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 8094 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602573 ER PT J AU Morton, LM Fossa, SD Stovall, M Van Leeuwen, FE Johannesen, TB Rajaraman, P Aleman, BM Dores, G Gilbert, ES Hall, P Holowaty, EJ Joensuu, H Kaijser, M Lynch, C Pukkala, E Storm, HH Smith, SA Fraumeni, JF Travis, LB Hauptmann, M AF Morton, Lindsay M. Fossa, Sophie D. Stovall, Marilyn Van Leeuwen, Flora E. Johannesen, Tom B. Rajaraman, Preetha Aleman, Berthe M. Dores, Graca Gilbert, Ethel S. Hall, Per Holowaty, Eric J. Joensuu, Heikki Kaijser, Magnus Lynch, Charles Pukkala, Eero Storm, Hans H. Smith, Susan A. Fraumeni, Joseph F. Travis, Lois B. Hauptmann, Michael TI Stomach cancer risk following radiotherapy for testicular cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. Oslo Univ Hosp, Dept Oncol, Oslo, Norway. Univ Oslo, Oslo, Norway. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Netherlands Canc Inst, Amsterdam, Netherlands. Canc Registry Norway, Oslo, Norway. Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. Dept Vet Affairs Med Ctr, Oklahoma City, OK USA. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden. Univ Iowa, Iowa City, IA USA. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Danish Canc Soc, Copenhagen, Denmark. Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Univ Rochester, Sch Med & Dent, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 4536 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601550 ER PT J AU Mrozek, E Wesolowski, R Lustberg, MB Layman, RM Ling, YH Schaaf, LJ Phelps, MA Ivy, SP Grever, MR Shapiro, CL AF Mrozek, Ewa Wesolowski, Robert Lustberg, Maryam B. Layman, Rachel M. Ling, Yonghua Schaaf, Larry J. Phelps, Mitch A. Ivy, S. Percy Grever, Michael R. Shapiro, Charles L. TI A phase I study of neoadjuvant chemotherapy (NCT) with the gamma secretase (GS) inhibitor RO4929097 in combination with paclitaxel (P) and carboplatin (C) in women with triple-negative breast cancer (TNBC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Ohio State Univ, Ctr Comprehens Canc, Arthur G James Canc Hosp, Columbus, OH 43210 USA. Richard J Solove Res Inst, Columbus, OH USA. Ohio State Univ, Columbus, OH 43210 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Ohio State Univ, Med Ctr, Div Med Oncol, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Breast Program, Columbus, OH 43210 USA. RI Layman, Rachel/E-3475-2011; Mrozek, Ewa/E-3708-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1043 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600266 ER PT J AU Myers, AP Broaddus, R Makker, V Konstantinopoulos, PA Drapkin, R Horowitz, NS Liu, J Van Hummelen, P Meric-Bernstam, F Birrer, MJ Doyle, LA Coleman, RL Aghajanian, C Mills, GB Cantley, L Matulonis, UA Westin, SN AF Myers, Andrea P. Broaddus, Russell Makker, Vicky Konstantinopoulos, Panagiotis A. Drapkin, Ronny Horowitz, Neil S. Liu, Joyce Van Hummelen, Paul Meric-Bernstam, Funda Birrer, Michael J. Doyle, L. Austin Coleman, Robert L. Aghajanian, Carol Mills, Gordon B. Cantley, Lewis Matulonis, Ursula A. Westin, Shannon Neville CA SU2C Dream Team PI3K Womens Canc TI Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dana Farber Harvard Canc Ctr, Boston, MA 02114 USA. Natl Canc Inst CTEP, Rockville, MD USA. Harvard Univ, Cambridge, MA 02138 USA. RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 0 TC 2 Z9 2 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 5524 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602038 ER PT J AU O'Reilly, EM Lowery, MA Yu, KH Capanu, M Stadler, ZK Epstein, AS Golan, T Segal, A Segal, M Salo-Mullen, EE Tang, LH Hollywood, E Moynahan, ME Do, KG Moore, MJ Kindler, HL Mayer, RJ Chen, AP Kelsen, DP AF O'Reilly, Eileen Mary Lowery, Maeve Aine Yu, Kenneth H. Capanu, Marinela Stadler, Zsofia Kinga Epstein, Andrew S. Golan, Talia Segal, Amiel Segal, Michal Salo-Mullen, Erin E. Tang, Laura H. Hollywood, Ellen Moynahan, Mary Ellen Do, Kinh G. Moore, Malcolm J. Kindler, Hedy Lee Mayer, Robert J. Chen, Alice P. Kelsen, David Paul TI Randomized phase II study of gemcitabine (G), cisplatin (C) with or without veliparib (V) (arms A, B) and a phase II single-arm study of single-agent veliparib (arm C) in patients with BRCA or PALB2-mutated pancreas adenocarcinoma (PC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. Shaare Zedek Med Ctr, Jerusalem, Israel. Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. Univ Toronto, Dept Med, Princess Margaret Canc Ctr, Univ Hlth Network,Div Med Oncol & Hematol, Toronto, ON, Canada. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS4144 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605428 ER PT J AU Parchment, RE Kinders, RJ Ji, JJ Srivastava, AK Ferry-Galow, KV Tomaszewski, JE Doroshow, JH AF Parchment, Ralph E. Kinders, Robert J. Ji, Jiuping Jay Srivastava, Apurva K. Ferry-Galow, Katherine V. Tomaszewski, Joseph E. Doroshow, James H. TI Creating clinical target validation groups via quality assured transfer of robust clinical pharmacodynamic (PD) assays from the NCI: Clinical implementation of a PAR immunoassay in tumor biopsies. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. SAIC Frederick Inc, Frederick Natl Labs, Frederick, MD USA. Div Canc Treatment & Diag, Bethesda, MD USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e22080 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605215 ER PT J AU Pichun, MEB Wilkerson, J Stein, WD Motzer, RJ Bates, SE Fojo, T AF Pichun, Mauricio Emmanuel Burotto Wilkerson, Julia Stein, Wilfred Donald Motzer, Robert John Bates, Susan Elaine Fojo, Tito TI Continuation of sunitinib following RECIST progression on first-line sunitinib SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Jerusalem, Israel. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 4585 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601599 ER PT J AU Pinto, C Di Fabio, F Rosati, G Lolli, I Ruggeri, E Ciuffreda, L Ferrari, D Tumolo, S Rosti, G Tralongo, P Ferrara, R Alabiso, O Chiara, S Ianniello, GP Di Costanzo, F Frassoldati, A Iacono, C Adamo, V Mattioli, R Valeri, M AF Pinto, Carmine Di Fabio, Francesca Rosati, Gerardo Lolli, Ivan Ruggeri, Enzo Ciuffreda, Libero Ferrari, Daris Tumolo, Salvatore Rosti, Giovanni Tralongo, Paolo Ferrara, Raimondo Alabiso, Oscar Chiara, Silvana Ianniello, Giovanni Paolo Di Costanzo, Francesco Frassoldati, Antonio Iacono, Carmelo Adamo, Vincenzo Mattioli, Rodolfo Valeri, Michele TI Management of skin toxicity and cetuximab-based regimen compliance in first-line chemotherapy of metastatic colorectal cancer (mCRC) patients (pts): Results of observer study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 St Orsola Marcello Malpighi Hosp, Med Oncol Unit, Bologna, Italy. San Carlo Hosp, Med Oncol Unit, Potenza, Italy. IRCCS Saverio de Bellis, Med Oncol Unit, Castellana Grotte, Italy. Belcolle Hosp, Med Oncol Unit, Viterbo, Italy. Molinette Mauriziano Hosp, Med Oncol Unit, Turin, Italy. San Paolo Hosp, Med Oncol Unit, Milan, Italy. S Maria Angeli Hosp, Dept Med Oncol, Pordenone, Italy. St Maria Ca Foncello Hosp, Med Oncol Unit, Treviso, Italy. G Di Maria Hosp, Med Oncol Unit, Avola, Italy. Dimiccoli Hosp, Med Oncol Unit, Barletta, Italy. Maggiore della Carita Hosp, Med Oncol Unit, Novara, Italy. Natl Canc Inst, Med Oncol Unit, Genoa, Italy. Med Oncol Unit, Caserta, Italy. Careggi Hosp, Med Oncol Unit, Florence, Italy. St Anna Hosp, Med Oncol Unit, Ferrara, Italy. M Paterno Hosp, Med Oncol Unit, Ragusa, Italy. AO Papardo, Med Oncol Unit, Messina, Italy. Univ Messina, Dept Human Pathol, Messina, Italy. Santa Croce Hosp, Med Oncol Unit, Fano, PU, Italy. Gen Hosp, Med Oncol Unit, Macerata, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e14557 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419603523 ER PT J AU Polizzotto, MN Uldrick, TS Wyvill, K Aleman, K Sereti, L Tosato, G Whitby, D Bevans, M Maldarelli, F Figg, WD Steinberg, SM Yarchoan, R AF Polizzotto, Mark Niccolo Uldrick, Thomas S. Wyvill, Kathleen Aleman, Karen Sereti, Lrini Tosato, Giovanna Whitby, Denise Bevans, Margaret Maldarelli, Frank Figg, William Douglas Steinberg, Seth M. Yarchoan, Robert TI Phase I/II study of the safety, pharmacokinetics, and efficacy of pomalidomide in the treatment of Kaposi sarcoma in individuals with or without HIV. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, HIVAIDS Malignancy Branch, CCR, Bethesda, MD 20892 USA. NIAID, HIV Pathogenesis Unit, LIR, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, CCR, Bethesda, MD 20892 USA. Frederick Natl Lab Canc Res, Viral Oncol Sect, Frederick, MD USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NCI, Host Virus Interact Branch, HIV Drug Resistance Program, CCR, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS10595 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605361 ER PT J AU Portnow, J Badie, B Synold, TW Annala, A Chen, BH Frank, J Moats, RA Wood, J D'Apuzzo, M Bedell, V Frankel, PH Aboody, KS AF Portnow, Jana Badie, Behnam Synold, Timothy W. Annala, Alexander Chen, Bihong Frank, Joseph Moats, Rex A. Wood, John D'Apuzzo, Massimo Bedell, Victoria Frankel, Paul Henry Aboody, Karen S. TI A first-in-human study of neural stem cells (NSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC) in patients with recurrent high-grade glioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 City Hope Natl Med Ctr, Duarte, CA USA. NIH, Bethesda, MD 20892 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. City Hope Beckman Res Inst, Duarte, CA USA. RI Moats, Rex/F-5995-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2018 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600679 ER PT J AU Pothuri, B Muggia, F Sparano, JA Blank, SV Curtin, JP Chuang, E Hershman, DL Chen, A Liebes, L AF Pothuri, Bhavana Muggia, Franco Sparano, Joseph A. Blank, Stephanie V. Curtin, John Patrick Chuang, Ellen Hershman, Dawn L. Chen, Alice Liebes, Leonard TI Dose-dependent pharmacokinetic (PK) interaction of pegylated liposomal doxorubicin (PLD) with escalating doses of veliparib in a phase I study. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NYU, Sch Med, New York, NY USA. NYU, New York, NY USA. Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. Weill Cornell Med Coll, New York, NY USA. Columbia Univ, Med Ctr, New York, NY USA. NCI, Rockville, MD USA. NYU, Med Ctr, New York, NY 10016 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2591 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601108 ER PT J AU Proia, DA Nagai, M Jimenez, JP Zhang, CH Sang, J Guo, W Beebe, K Lee, MJ Sequeira, M Smith, D Acquaviva, J He, SQ Trepel, JB Neckers, L Bahcall, SR Vukovic, VM AF Proia, David A. Nagai, Masazumi Jimenez, John-Paul Zhang, Chaohua Sang, Jim Guo, Wei Beebe, Kristin Lee, Min-Jung Sequeira, Manuel Smith, Donald Acquaviva, Jaime He, Suqin Trepel, Jane B. Neckers, Len Bahcall, Safi R. Vukovic, Vojislav M. TI Antimetastatic activity of ganetespib: Preclinical studies and assessment of progressions due to new lesions in the GALAXY-1 NSCLC trial. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Synta Pharmaceut Inc, Lexington, MA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e19097 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604627 ER PT J AU Roila, F Ballatori, E Fabi, A Fatigoni, S Chiara, S Ionta, MT Aieta, M Clerico, M Palladino, MA Indelli, M Garrone, O Bustreo, S Ruggeri, B AF Roila, Fausto Ballatori, Enzo Fabi, Alessandra Fatigoni, Sonia Chiara, Silvana Ionta, Maria Teresa Aieta, Michele Clerico, Mario Palladino, Maria Angela Indelli, Monica Garrone, Ornella Bustreo, Sara Ruggeri, Benedetta CA Italian Grp Antiemetic Res TI Aprepitant (AP) versus dexamethasone (D) for preventing delayed emesis induced by anthracyclines plus cyclophosphamide (A plus C) chemotherapy (CT) in breast cancer patients (pts): A double-blind, multicenter, randomized study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Med Oncol, Terni, Italy. Univ Aquila, I-67100 Laquila, Italy. Regina Elena Inst Canc Res, Rome, Italy. Natl Canc Inst, Med Oncol Unit, Genoa, Italy. Med Oncol II, Cagliari, Italy. Rionero Vulture, Oncol, Potenza, Italy. Osped Inferm Biella, Biella, Italy. Hosp Piacenza, Piacenza, Italy. Arcispedale St Anna, Ferrara, Italy. Santa Croce Gen Hosp, Cuneo, Italy. Molinette Mauriziano Hosp, Med Oncol, Turin, Italy. Clin Govt ASUR Marche, Ascoli Piceno, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 9614 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419603097 ER PT J AU Schwandt, A Harris, PJ Hunsberger, S Deleporte, A Smith, GL Vulih, D Anderson, BD Ivy, SP AF Schwandt, Anita Harris, Pamela Jo Hunsberger, Sally Deleporte, Amelie Smith, Gary L. Vulih, Diana Anderson, Barry Douglas Ivy, S. Percy TI The role of age on dose-limiting toxicities (DLTs) in phase I dose-escalation trials. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Case Western Reserve Univ, Sch Med, Cleveland, OH USA. NCI, Bethesda, MD 20892 USA. Inst Jules Bordet, B-1000 Brussels, Belgium. NCI, Canc Therapeut Evaluat Program, Bethesda, MD 20892 USA. Theradex Syst Inc, Princeton, NJ USA. Theradex, Princeton, NJ USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 9517 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602820 ER PT J AU Shah, AA Karzai, F Madan, RA Figg, WD Chau, CH Gulley, JL Chun, G Wright, JJ Apolo, AB Parnes, HL Dahut, WL AF Shah, Avani Atul Karzai, Fatima Madan, Ravi Amrit Figg, William Douglas Chau, Cindy H. Gulley, James L. Chun, Guinevere Wright, John Joseph Apolo, Andrea Borghese Parnes, Howard L. Dahut, William L. TI A phase II study of trebananib (AMG 386) and abiraterone in metastatic castration resistant prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. NCI, Lab Tumor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Rockville, MD USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS5102 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605465 ER PT J AU Singh, NK Kim, JW Heery, CR Dahut, WL Couvilion, A Rauckhorst, M McMahon, S Schlom, J Fojo, T Arlen, PM Gulley, JL Madan, RA AF Singh, Nishith K. Kim, Joseph W. Heery, Christopher Ryan Dahut, William L. Couvilion, Anna Rauckhorst, Myrna McMahon, Sheri Schlom, Jeffrey Fojo, Tito Arlen, Philip M. Gulley, James L. Madan, Ravi Amrit TI A randomized phase II clinical trial of enzalutamide in combination with the therapeutic cancer vaccine, PSA tricom, in metastatic, castration resistant prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Lab Turnor Immunol & Biol, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA TPS5104 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605467 ER PT J AU Sohl, SJ Weaver, KE Birdee, G Kent, EE Danhauer, S Hamilton, AS AF Sohl, Stephanie Jean Weaver, Kathryn E. Birdee, Gurjeet Kent, Erin E. Danhauer, Suzanne Hamilton, Ann S. TI Characteristcs associated with complementary and alternative medicine use among racially and ethnically diverse long-term cancer survivors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. Wake Forest Univ Hlth Sci, Winston Salem, NC USA. NCI, Rockville, MD USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ So Calif, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e20532 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419604803 ER PT J AU Soliman, HH Minton, SE Han, HS Ismail-Khan, R Mahipal, A Janssen, W Streicher, H Vahanian, NN Link, CJ Ramsey, WJ Antonia, SJ Sullivan, D AF Soliman, Hatem Hussein Minton, Susan E. Han, Hyo S. Ismail-Khan, Roohi Mahipal, Amit Janssen, William Streicher, Howard Vahanian, Nicholas N. Link, Charles J. Ramsey, William Jay Antonia, Scott J. Sullivan, Daniel TI A phase I study of ad.p53 DC vaccine in combination with indoximod in metastatic solid tumors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NewLink Genet, Ames, IA USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 3069 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601201 ER PT J AU Somio, G Frankel, PH Luu, TH Ma, C Arun, B Garcia, A Cigler, T Fleming, GF Harvey, HA Sparano, JA Nanda, R Chew, HK Moynihan, TJ Vahdat, LT Goetz, MP Hurria, A Mortimer, JE Gandara, DR Chen, AP Weitzel, JN AF Somio, George Frankel, Paul Henry Luu, Thehang H. Ma, Cynthia Arun, Banu Garcia, Agustin Cigler, Tessa Fleming, Gini F. Harvey, Harold A. Sparano, Joseph A. Nanda, Rita Chew, Helen K. Moynihan, Timothy Jerome Vahdat, Linda T. Goetz, Matthew P. Hurria, Arti Mortimer, Joanne E. Gandara, David R. Chen, Alice P. Weitzel, Jeffrey N. TI Efficacy of the combination of ABT-888 (veliparib) and carboplatin in patients with BRCA-associated breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 City Hope Natl Med Ctr, Ctr Canc, Duarte, CA USA. City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. City Hope Natl Med Ctr, Duarte, CA USA. Washington Univ, Sch Med St Louis, St Louis, MO USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ So Calif, Los Angeles, CA USA. Weill Cornell Med Coll, New York, NY USA. Alliance Clin Trials Oncol, Chicago, IL USA. Milton S Hershey Med Ctr, Hershey, PA USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. Mayo Clin, Rochester, MN USA. Univ Calif Davis, Ctr Comprehens Canc, Sacramento, CA 95817 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 1024 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600247 ER PT J AU Soriano, G Landrum, MB Weeks, JC Arora, NK Malin, J Ganz, PA van Ryn, M Keating, NL AF Soriano, Gabriela Landrum, Mary Beth Weeks, Jane C. Arora, Neeraj K. Malin, Jennifer Ganz, Patricia A. van Ryn, Michelle Keating, Nancy Lynn TI The role of families in decisions about cancer treatments SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Mem Sloan Kettering Canc Ctr, Brookline, MA USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NSABP, Los Angeles, CA USA. Univ Calif Los Angeles, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90095 USA. Univ Minnesota, Minneapolis, MN USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6528 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602247 ER PT J AU Spreafico, A Chi, KN Sridhar, SS Smith, DC Carducci, MA Kavsak, P Wong, TS Wang, L Ivy, SP Mukherjee, SD Kollmannsberger, CK Hotte, SJ AF Spreafico, Anna Chi, Kim N. Sridhar, Srikala S. Smith, David C. Carducci, Michael Anthony Kavsak, Peter Wong, Tracy S. Wang, Lisa Ivy, S. Percy Mukherjee, Som Dave Kollmannsberger, Christian K. Hotte, Sebastien J. TI A randomized phase II study of cediranib (CED) alone versus CED plus dasatinib (DAS) in patients (pts) with castration-resistant prostate cancer (CRPC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Princess Margaret Canc Ctr, Toronto, ON, Canada. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Univ Michigan, Ann Arbor, MI 48109 USA. Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Juravinski Canc Ctr, Hamilton, ON, Canada. Princess Margaret Canc Ctr, Dept Biostat, Toronto, ON, Canada. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. BC Canc Agcy, Vancouver, BC, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 5039 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601637 ER PT J AU Srivastava, AK Hollingshead, MG Weiner, J Covey, JM Liston, D Peggins, JO Bottaro, DP Wright, JJ Kinders, RJ Tomaszewski, JE Parchment, RE Doroshow, JH AF Srivastava, Apurva K. Hollingshead, Melinda G. Weiner, Jennifer Covey, Joseph M. Liston, Dane Peggins, James O. Bottaro, Donald P. Wright, John Joseph Kinders, Robert J. Tomaszewski, Joseph E. Parchment, Ralph E. Doroshow, James H. TI Application of MET pharmacodynamic assays to compare effectiveness of five MET inhibitors to engage target in tumor tissue. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. NCI, Frederick, MD 21701 USA. NCI, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. Div Canc Treatment & Diag, Bethesda, MD USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 11103 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600521 ER PT J AU Stamatakis, L Shuch, B Singer, EA Nix, J Truong, H Friend, JC Fowler, S Bratslavsky, G Metwalli, AR Shih, JH Linehan, WM Srinivasan, R AF Stamatakis, Lambros Shuch, Brian Singer, Eric A. Nix, Jeffrey Truong, Hong Friend, Julia C. Fowler, Sarah Bratslavsky, Gennady Metwalli, Adam R. Shih, Joanna H. Linehan, W. Marston Srinivasan, Ramaprasad TI Phase II trial of vandetanib in Von Hippel-Lindau-associated renal cell carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 4584 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601598 ER PT J AU Steel, JL Kim, KH Gamblin, TC Fraser, D Biala, M Savkova, A Butterfield, L Geller, DA Marsh, JW Tsung, A AF Steel, Jennifer Lynne Kim, Kevin H. Gamblin, T. Clark Fraser, Danyelle Biala, Michelle Savkova, Alexandra Butterfield, Lisa Geller, David A. Marsh, J. Wallis Tsung, Allan TI The course of depression, inflammation in the serum and tumor microenvironment, and survival in the context of advanced cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NSABP, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Liver Canc Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Comprehens Liver Canc Ctr, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 9507 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602811 ER PT J AU Su, JM Thompson, PA Adesina, A Li, XN Kilburn, LB Onar-Thomas, A Kocak, M Chyla, B McKeegan, EM Warren, KE Goldman, S Pollack, I Fouladi, M Chen, A Smith, MA Giranda, VL Boyett, JM Blaney, S Kun, LE AF Su, Jack M. Thompson, Patrick Andrew Adesina, Adekunle Li, Xiao-Nan Kilburn, Lindsay Baker Onar-Thomas, Arzu Kocak, Mehmet Chyla, Brenda McKeegan, Evelyn Mary Warren, Katherine E. Goldman, Stewart Pollack, Ian Fouladi, Maryam Chen, Alice Smith, Malcolm A. Giranda, Vincent L. Boyett, James M. Blaney, Susan Kun, Larry E. CA Pediat Brain Tumor Consortium TI A phase I clinical trial of veliparib and temozolomide in children with recurrent central nervous system tumors: A Pediatric Brain Tumor Consortium report SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. Texas Childrens Canc Ctr, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Abbott Labs, Abbott Pk, IL 60064 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. NCI, Rockville, MD USA. Canc Thrpy Evaluat Program, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2036 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600697 ER PT J AU Sulman, EP Won, M Blumenthal, DT Vogelbaum, MA Colman, H Jenkins, RB Chakravarti, A Jeraj, R Brown, PD Jaeckle, KA Schiff, D Dignam, J Atkins, JN Brachman, D Werner-Wasik, M Komaki, R Gilbert, MR Mehta, MP Aldape, KD AF Sulman, Erik P. Won, Minhee Blumenthal, Deborah T. Vogelbaum, Michael A. Colman, Howard Jenkins, Robert B. Chakravarti, Arnab Jeraj, Robert Brown, Paul D. Jaeckle, Kurt A. Schiff, David Dignam, James Atkins, James Norman Brachman, David Werner-Wasik, Maria Komaki, Ritsuko Gilbert, Mark R. Mehta, Minesh P. Aldape, Kenneth D. TI Molecular predictors of outcome and response to bevacizumab (BEV) based on analysis of RTOG 0825, a phase III trial comparing chemoradiation (CRT) with and without BEV in patients with newly diagnosed glioblastoma (GBM). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Mayo Clin, Rochester, MN USA. Ohio State Univ, Arthur G James Canc Ctr, Columbus, OH 43210 USA. Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. Mayo Clin, Jacksonville, FL 32224 USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. Natl Surg Adjuvant Breast & Bowel Project, Goldboro, NC USA. SCCC CCOP, Goldboro, NC USA. Arizona Oncol Serv Fdn, Phoenix, AZ USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Univ Maryland, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA LBA2010 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605335 ER PT J AU Tageja, N Wang, WX Plyler, R Corrigan-Cummins, M Korde, N Manasanch, EE Bhutani, M Kwok, M Flanders, AW Zuchlinski, D Mulquin, M Costello, R Roschewski, MJ Landgren, O Calvo, KR Zingone, A AF Tageja, Nishant Wang, Weixin Plyler, Ryan Corrigan-Cummins, Meghan Korde, Neha Manasanch, Elisabet E. Bhutani, Manisha Kwok, Mary Flanders, Aaron W. Zuchlinski, Diamond Mulquin, Marcia Costello, Rene Roschewski, Mark J. Landgren, Ola Calvo, Katherine R. Zingone, Adriana TI Altered cytokine profiles in multiple myeloma (MM) and precursor disease: Predictors of progression and potential targets for treatment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Hematol Serv, DLM, CCR,NIH, Bethesda, MD 20892 USA. NIH, Hematol Serv, DLM, CCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 8597 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602692 ER PT J AU Tan, AR Toppmeyer, D Wong, STL Lin, HX Gounder, M Moss, RA Stein, MN Mehnert, JM Kim, S Chen, AP DiPaola, RS AF Tan, Antoinette R. Toppmeyer, Deborah Wong, Serena Tsan-Lai Lin, Hongxia Gounder, Murugesan Moss, Rebecca Anne Stein, Mark N. Mehnert, Janice M. Kim, Sinae Chen, Alice P. DiPaola, Robert S. TI Assessment of gamma H2AX levels in circulating tumor cells in patients treated with veliparib in combination with doxorubicin and cyclophosphamide in metastatic breast cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Canc Inst New Jersey, New Brunswick, NJ USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2582 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601099 ER PT J AU Tan, DSP Kollmannsberger, CK Hotte, SJ Cescon, DW Diaz-Padilla, I Hedley, DW Renouf, DJ Razak, ARA Gelmon, KA Hirte, HW Wang, LS Wizemann, M Moscow, J Chen, HX Siu, LL Bedard, PL AF Tan, David Shao Peng Kollmannsberger, Christian K. Hotte, Sebastien J. Cescon, David W. Diaz-Padilla, Ivan Hedley, David W. Renouf, Daniel John Razak, Albiruni R. A. Gelmon, Karen A. Hirte, Hal W. Wang, Lisa Wizemann, Monika Moscow, Jeffrey Chen, Helen X. Siu, Lillian L. Bedard, Philippe L. CA Princess Margaret Hosp Phase I TI Phase I trial of trebananib (AMG 386) plus temsirolimus (Tr plus T) in patients (pts) with advanced solid tumors (PJC-008/NCI#9041) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Princess Margaret Canc Ctr, Toronto, ON, Canada. BC Canc Agcy, Vancouver, BC, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. Univ Toronto, Princess Margaret Hosp, Univ Hlth Network, Toronto, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Ontario Canc Inst, Toronto, ON M4X 1K9, Canada. Princess Margaret Canc Ctr, Dept Biostat, Toronto, ON, Canada. J457 KY Clin, Lexington, KY USA. CTEP Natl Canc Inst, Bethesda, MD USA. Univ Toronto, Princess Margaret Canc Ctr, Univ Hlth Network, Div Med Oncol & Hematol,Dept Med, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2534 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601052 ER PT J AU Uldrick, TS Wyvill, K Peer, C Polizzotto, MN O'Mahony, D Bernstein, W Aleman, K Steinberg, SM Venzon, DJ Pittaluga, S Little, RF Figg, WD Yarchoan, R AF Uldrick, Thomas S. Wyvill, Kathleen Peer, Cody Polizzotto, Mark Niccolo O'Mahony, Deirdre Bernstein, Wendy Aleman, Karen Steinberg, Seth M. Venzon, David J. Pittaluga, Stefania Little, Richard F. Figg, William Douglas Yarchoan, Robert TI Phase I and pharmacokinetic study of sorafenib in Kaposi sarcoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, HIV AIDS Malignancy Branch, CCR, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, CCR, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. NCI, Pathol Lab, CCR, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 10588 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600366 ER PT J AU Wan, XL Yeung, CL Heske, C Mendoza, A Helman, LJ AF Wan, Xiaolin Yeung, Choh L. Heske, Christine Mendoza, Arnulfo Helman, Lee J. TI Role of IGF-1R inhibition on an Src-family kinase bypass resistance pathway: A rational basis for cotargeting IGF-1R and Src kinase in pediatric sarcomas? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, CCR, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, CRC, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 10025 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600180 ER PT J AU Warren, JL Mariotto, A Melbert, D Schrag, D Doria-Rose, P Penson, DF Yabroff, KR AF Warren, Joan L. Mariotto, Angela Melbert, Danielle Schrag, Deborah Doria-Rose, Paul Penson, David F. Yabroff, K. Robin TI Sensitivity of Medicare claims to identify recurrence SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Bethesda, MD 20892 USA. Informat Management Serv Inc, Beltsville, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 6522 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602241 ER PT J AU Warren, KE Jacoby, E Fangusaro, JR AF Warren, Katherine E. Jacoby, Elad Fangusaro, Jason R. TI Diffuse intrinsic pontine gliomas (DIPG) in adolescents can have differing presentations but similar outcomes compared to those of middle childhood. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 2101 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419601017 ER PT J AU Weiss, M Gertz, MA Little, RF Rajkumar, V Jacobus, SJ Abonour, R Anderson, KC Barlogie, B Callander, NS Gorak, EJ Matous, J Mills, GM Kane, RC Katz, MS Jensen, L Omel, J Orlowski, RZ Richardson, PGG Munshi, NC AF Weiss, Matthias Gertz, Morie A. Little, Richard F. Rajkumar, Vincent Jacobus, Susanna J. Abonour, Rafat Anderson, Kenneth Carl Barlogie, Bart Callander, Natalie Scott Gorak, Edward J. Matous, Jeffrey Mills, Glenn Morris Kane, Robert C. Katz, Michael S. Jensen, LeeAnn Omel, James Orlowski, Robert Z. Richardson, Paul Gerard Guy Munshi, Nikhil C. TI Strategies to overcome barriers to accrual (BtA) to NCI-sponsored clinical trials: A project of the NCI-Myeloma Steering Committee Accrual Working Group (NCI-MYSC AWG) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. Mayo Clin, Rochester, MN USA. NCI, Rockville, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. Myeloma Inst Res & Therapy, Little Rock, AR USA. Univ Wisconsin, Madison, WI USA. Geisinger Med Ctr, Danville, PA 17822 USA. Rocky Mt Canc Centers, Denver, CO USA. LSU Hlth Sci Ctr, Shreveport, LA USA. US FDA, Silver Spring, MD USA. Int Myeloma Fdn, North Hollywood, CA USA. Patient Advocate, Rockville, MD USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. VA Boston Healthcare Syst, Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 8592 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419602687 ER PT J AU Widemann, BC Reinke, DK Helman, LJ Ludwig, JA Schuetze, S Staddon, AP Milhem, MM Rushing, DA Moertel, CL Goldman, S Livingston, MB Wagner, LM Rodler, ET Dombi, E Perry, A Annunziata, CM Long, L Viskochil, D Steinberg, SM Baker, LH AF Widemann, Brigitte C. Reinke, Denise K. Helman, Lee J. Ludwig, Joseph A. Schuetze, Scott Staddon, Arthur P. Milhem, Mohammed M. Rushing, Daniel A. Moertel, Christopher L. Goldman, Stewart Livingston, Michael B. Wagner, Lars M. Rodler, Eve T. Dombi, Eva Perry, Arie Annunziata, Christina M. Long, Lauren Viskochil, David Steinberg, Seth M. Baker, Laurence H. TI SARC006: Phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 (NF1)-associated high-grade malignant peripheral nerve sheath tumors (MPNSTs). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Sarcoma Alliance Res Collaborat, Ann Arbor, MI USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. Indiana Univ, Indianapolis, IN 46204 USA. Univ Minnesota, Minneapolis, MN USA. Childrens Mem Chicago, Chicago, IL USA. Carolinas Healthcare Syst, Levine Canc Inst, Charlotte, NC USA. Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. Seattle Canc Care Alliance, Seattle, WA USA. NCI, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Utah, Salt Lake City, UT USA. NCI, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 10522 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600295 ER PT J AU Wilkerson, J Bates, SE Stein, WD Fojo, T AF Wilkerson, Julia Bates, Susan Elaine Stein, Wilfred Donald Fojo, Tito TI Using a program that computes tumor decay (d) and regrowth (g) rates and the fraction (Phi) of tumor killed to assist in clinical trials and improve patient survival. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA e22213 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419605329 ER PT J AU Wright, CE Jagoda, E Cecchi, F Bhadrasetty, V Histed, S Williams, M Kramer-Marek, G Mena, E Rosenblum, L Lang, LX Szajek, L Paik, C Choyke, PL Marik, J Tinianow, J Merchant, M Bottaro, DP AF Wright, Cara Elizabeth Jagoda, Elaine Cecchi, Fabiola Bhadrasetty, Veerendra Histed, Stephanie Williams, Mark Kramer-Marek, Gabriela Mena, Esther Rosenblum, Lauren Lang, Lixin Szajek, Lawrence Paik, Chang Choyke, Peter L. Marik, Jan Tinianow, Jeffrey Merchant, Mark Bottaro, Donald P. TI Developing a molecular imaging agent for Met using onartuzumab (MetMAb). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 31-JUN 04, 2013 CL Chicago, IL SP Amer Soc Clin Oncol C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, CCR, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. NCI, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, CCR, NIH, Bethesda, MD 20892 USA. Genentech Inc, San Francisco, CA 94080 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2013 VL 31 IS 15 SU S MA 11083 PG 1 WC Oncology SC Oncology GA AG4VY UT WOS:000335419600500 ER PT J AU Posakony, JJ Ferre-D'Amare, AR AF Posakony, Jeffrey J. Ferre-D'Amare, Adrian R. TI Glucosamine and Glucosamine-6-phosphate Derivatives: Catalytic Cofactor Analogues for the glmS Ribozyme SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID INHIBITORS; RIBOSWITCH; EFFICIENT; ALCOHOLS; CLEAVAGE; NITROGEN; AZIDES AB Two analogues of glucosamine-6-phosphate (GlcN6P, 1) and five of glucosamine (GlcN, 2) were prepared for evaluation as catalytic cofactors of the glmS ribozyme, a bacterial gene-regulatory RNA that controls cell wall biosynthesis. Glucosamine and allosamine with 3-azido substitutions were prepared by S(N)2 reactions of the respective 1,2,4,6-protected sugars; final acidic hydrolysis afforded the fully deprotected compounds as their TFA salts. A 6-phospho-2-aminoglucolactam (31) was prepared from glucosamine in a 13-step synthesis, which included a late-stage POCl3-phosphorylation. A simple and widely applicable 2-step procedure with the triethylsilyl (TES) protecting group was developed to selectively expose the 6-OH group in N-protected glucosamine analogues, which provided another route to chemical phosphorylation. Mitsunobu chemistry afforded 6-cyano (35) and 6-azido (36) analogues of GlcN-(Cbz), and the selectivity for the 6-position was confirmed by NMR (COSY, HMBC, HMQC) experiments. Compound 36 was converted to the fully deprotected 6-azido-GlcN (37) and 2,6-diaminoglucose (38) analogues. A 2-hydroxylamino glucose (42) analogue was prepared via an oxaziridine (41). Enzymatic phosphorylation of 42 and chemical phosphorylation of its 6-OH precursor (43) were possible, but 42 and the 6-phospho product (44) were unstable under neutral or basic conditions. Chemical phosphorylation of the previously described 2-guanidinyl-glucose (46) afforded its 6-phospho analogue (49) after final deprotection. C1 [Posakony, Jeffrey J.; Ferre-D'Amare, Adrian R.] NHLBI, Bethesda, MD 20892 USA. RP Posakony, JJ (reprint author), NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM jeff.posakony@nih.gov; adrian.ferre@nih.gov FU Howard Hughes Medical Institute; Bill and Melinda Gates foundation; Intramural Research Program of the NIH, National Heart, Lung and Blood Institute FX We would like to thank N. Tjandra and his group (National Heart, Lung and Blood Institute, NHLBI) for assistance with NMR experiments. D.-Y. Lee of the NHLBI Biochemistry Core Facility, R. Levine (NHLBI), P. Gafken (Proteomics Core at Fred Hutchinson Cancer Research Center, FHCRC) and D. Shen's group (University of Washington) assisted with MS and LC-MS experiments. We also thank M. Roth and J. Simon (both FHCRC) for the generous loan of equipment and reagents. This research was supported in part by the Howard Hughes Medical Institute, the Bill and Melinda Gates foundation and the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute. NR 34 TC 10 Z9 10 U1 1 U2 46 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD MAY 17 PY 2013 VL 78 IS 10 BP 4730 EP 4743 DI 10.1021/jo400192e PG 14 WC Chemistry, Organic SC Chemistry GA 155BU UT WOS:000319721200010 PM 23578404 ER PT J AU Singh, A Winterbottom, EF Ji, YJ Hwang, YS Daar, IO AF Singh, Arvinder Winterbottom, Emily F. Ji, Yon Ju Hwang, Yoo-Seok Daar, Ira O. TI Abelson Interactor 1 (Abi1) and Its Interaction with Wiskott-Aldrich Syndrome Protein (Wasp) Are Critical for Proper Eye Formation in Xenopus Embryos SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ABL TRANSFORMING ACTIVITY; TYROSINE KINASE; FORMATION REQUIRE; BINDING-PROTEIN; CELL-ADHESION; RETINAL FATE; N-WASP; ACTIN; EPS8; PHOSPHORYLATION AB Ab1 interactor 1 (Abi1) is a scaffold protein that plays a central role in the regulation of actin cytoskeleton dynamics as a constituent of several key protein complexes, and homozygous loss of this protein leads to embryonic lethality in mice. Because this scaffold protein has been shown in cultured cells to be a critical component of pathways controlling cell migration and actin regulation at cell-cell contacts, we were interested to investigate the in vivo role of Abi1 in morphogenesis during the development of Xenopus embryos. Using morpholino-mediated translation inhibition, we demonstrate that knockdown of Abi1 in the whole embryo, or specifically in eye field progenitor cells, leads to disruption of eye morphogenesis. Moreover, signaling through the Src homology 3 domain of Abi1 is critical for proper movement of retinal progenitor cells into the eye field and their appropriate differentiation, and this process is dependent upon an interaction with the nucleation-promoting factor Wasp (Wiskott-Aldrich syndrome protein). Collectively, our data demonstrate that the Abi1 scaffold protein is an essential regulator of cell movement processes required for normal eye development in Xenopus embryos and specifically requires an Src homology 3 domain-dependent interaction with Wasp to regulate this complex morphogenetic process. C1 [Singh, Arvinder; Winterbottom, Emily F.; Ji, Yon Ju; Hwang, Yoo-Seok; Daar, Ira O.] NCI, Lab Cell & Dev Signaling, NIH, Frederick, MD 21702 USA. RP Daar, IO (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM daar@ncifcrf.gov OI Daar, Ira/0000-0003-2657-526X FU National Institutes of Health Intramural Research Program of the NCI FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program of the NCI. NR 42 TC 3 Z9 3 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 17 PY 2013 VL 288 IS 20 BP 14135 EP 14146 DI 10.1074/jbc.M112.445643 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148OB UT WOS:000319253500018 PM 23558677 ER PT J AU Kasiviswanathan, R Minko, IG Lloyd, RS Copeland, WC AF Kasiviswanathan, Rajesh Minko, Irina G. Lloyd, R. Stephen Copeland, William C. TI Translesion Synthesis Past Acrolein-derived DNA Adducts by Human Mitochondrial DNA Polymerase gamma SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PEPTIDE CROSS-LINKS; NUCLEOTIDE INCORPORATION; 1,N(2)-PROPANODEOXYGUANOSINE ADDUCTS; 1,N-2-PROPANODEOXYGUANOSINE ADDUCTS; 1,N-2-DEOXYGUANOSINE ADDUCTS; DEOXYGUANOSINE ADDUCT; REPLICATION BYPASS; SEQUENTIAL ACTION; ESCHERICHIA-COLI; OXIDATIVE STRESS AB Acrolein, a mutagenic aldehyde, is produced endogenously by lipid peroxidation and exogenously by combustion of organic materials, including tobacco products. Acrolein reacts with DNA bases forming exocyclic DNA adducts, such as gamma-hydroxy-1,N-2-propano-2'-deoxyguanosine (gamma-HOPdG) and gamma-hydroxy-1,N-6-propano-2'-deoxyadenosine (gamma-HOPdA). The bulky gamma-HOPdG adduct blocks DNA synthesis by replicative polymerases but can be bypassed by translesion synthesis polymerases in the nucleus. Although acrolein-induced adducts are likely to be formed and persist in mitochondrial DNA, animal cell mitochondria lack specialized translesion DNA synthesis polymerases to tolerate these lesions. Thus, it is important to understand how pol gamma, the sole mitochondrial DNA polymerase in human cells, acts on acrolein-adducted DNA. To address this question, we investigated the ability of pol gamma to bypass the minor groove gamma-HOPdG and major groove gamma-HOPdA adducts using single nucleotide incorporation and primer extension analyses. The efficiency of pol gamma-catalyzed bypass of gamma-HOPdG was low, and surprisingly, pol gamma preferred to incorporate purine nucleotides opposite the adduct. Pol gamma also exhibited similar to 2-fold lower rates of excision of the misincorporated purine nucleotides opposite gamma-HOPdG compared with the corresponding nucleotides opposite dG. Extension of primers from the termini opposite gamma-HOPdG was accomplished only following error-prone purine nucleotide incorporation. However, pol gamma preferentially incorporated dT opposite the gamma-HOPdA adduct and efficiently extended primers from the correctly paired terminus, indicating that gamma-HOPdA is probably non-mutagenic. In summary, our data suggest that acrolein-induced exocyclic DNA lesions can be bypassed by mitochondrial DNA polymerase but, in the case of the minor groove gamma-HOPdG adduct, at the cost of unprecedented high mutation rates. C1 [Kasiviswanathan, Rajesh; Copeland, William C.] NIEHS, Mitochondrial DNA Replicat Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Minko, Irina G.; Lloyd, R. Stephen] Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97239 USA. [Lloyd, R. Stephen] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU National Institutes of Health Intramural Research Program; NIEHS [ES065078, ES065080, ES05355]; NCI [CA106858]; National Institute of Mental Health [R03 MH 094179] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program, Grants ES065078 and ES065080 from NIEHS (to W. C. C.), Grant ES05355 from NIEHS (to R. S. L.), NCI Grant CA106858 (to R. S. L.), and National Institute of Mental Health Grant R03 MH 094179 (to R. S. L.). NR 59 TC 10 Z9 10 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 17 PY 2013 VL 288 IS 20 BP 14247 EP 14255 DI 10.1074/jbc.M113.458802 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148OB UT WOS:000319253500029 PM 23543747 ER PT J AU Pan, TC Zhang, RZ Markova, D Arita, M Zhang, YJ Bogdanovich, S Khurana, TS Bonnemann, CG Birk, DE Chu, ML AF Pan, Te-Cheng Zhang, Rui-Zhu Markova, Dessislava Arita, Machiko Zhang, Yejia Bogdanovich, Sasha Khurana, Tejvir S. Boennemann, Carsten G. Birk, David E. Chu, Mon-Li TI COL6A3 Protein Deficiency in Mice Leads to Muscle and Tendon Defects Similar to Human Collagen VI Congenital Muscular Dystrophy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETHLEM MYOPATHY; TENASCIN-X; ALPHA-3 CHAIN; C5 DOMAIN; RECOMBINANT EXPRESSION; MICROFIBRIL FORMATION; VONWILLEBRAND-FACTOR; MYOSTATIN BLOCKADE; SEQUENCE-ANALYSIS; GLOBULAR DOMAINS AB Collagen VI is a ubiquitously expressed extracellular microfibrillar protein. Its most common molecular form is composed of the alpha 1(VI), alpha 2(VI), and alpha 3(VI) collagen alpha chains encoded by the COL6A1, COL6A2, and COL6A3 genes, respectively. Mutations in any of the three collagen VI genes cause congenital muscular dystrophy types Bethlem and Ullrich as well as intermediate phenotypes characterized by muscle weakness and connective tissue abnormalities. The alpha 3(VI) collagen alpha chain has much larger N- and C-globular domains than the other two chains. Its most C-terminal domain can be cleaved off after assembly into microfibrils, and the cleavage product has been implicated in tumor angiogenesis and progression. Here we characterize a Col6a3 mutant mouse that expresses a very low level of a nonfunctional alpha 3(VI) collagen chain. The mutant mice are deficient in extracellular collagen VI microfibrils and exhibit myopathic features, including decreased muscle mass and contractile force. Ultrastructurally abnormal collagen fibrils were observed in tendon, but not cornea, of the mutant mice, indicating a distinct tissue-specific effect of collagen VI on collagen I fibrillogenesis. Overall, the mice lacking normal alpha 3(VI) collagen chains displayed mild musculoskeletal phenotypes similar to mice deficient in the alpha 1(VI) collagen alpha chain, suggesting that the cleavage product of the alpha 3(VI) collagen does not elicit essential functions in normal growth and development. The Col6a3 mouse mutant lacking functional alpha 3(VI) collagen chains thus serves as an animal model for COL6A3-related muscular dystrophy. C1 [Pan, Te-Cheng; Zhang, Rui-Zhu; Markova, Dessislava; Arita, Machiko; Chu, Mon-Li] Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. [Zhang, Yejia] Rush Univ, Med Ctr, Dept Orthoped Surg, Chicago, IL 60612 USA. [Zhang, Yejia] Rush Univ, Med Ctr, Dept Phys Med & Rehabil, Chicago, IL 60612 USA. [Bogdanovich, Sasha; Khurana, Tejvir S.] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Bogdanovich, Sasha; Khurana, Tejvir S.] Univ Penn, Sch Med, Penn Muscle Inst, Philadelphia, PA 19104 USA. [Boennemann, Carsten G.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20824 USA. [Birk, David E.] Univ S Florida, Morsani Coll Med, Dept Mol Pharmacol & Physiol, Tampa, FL 33612 USA. RP Chu, ML (reprint author), Thomas Jefferson Univ, Dept Dermatol & Cutaneous Biol, 233 S 10th St, Philadelphia, PA 19107 USA. EM mon-li.chu@jefferson.edu RI Birk, David/I-4072-2012 OI Birk, David/0000-0002-4865-9088 FU National Institutes of Health [AR053251, AR44745] FX This work was supported, in whole or in part, by National Institutes of Health Grants AR053251 (to M. L. C.) and AR44745 (to D. E. B.). NR 48 TC 20 Z9 20 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 17 PY 2013 VL 288 IS 20 BP 14320 EP 14331 DI 10.1074/jbc.M112.433078 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148OB UT WOS:000319253500036 PM 23564457 ER PT J AU Assumpcao, TCF Ma, DY Schwarz, A Reiter, K Santana, JM Andersen, JF Ribeiro, JMC Nardone, G Yu, LL Francischetti, IMB AF Assumpcao, Teresa C. F. Ma, Dongying Schwarz, Alexandra Reiter, Karine Santana, Jaime M. Andersen, John F. Ribeiro, Jose M. C. Nardone, Glenn Yu, Lee L. Francischetti, Ivo M. B. TI Salivary Antigen-5/CAP Family Members Are Cu2+-dependent Antioxidant Enzymes That Scavenge O-2(radical anion) and Inhibit Collagen-induced Platelet Aggregation and Neutrophil Oxidative Burst SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXTRACELLULAR-SUPEROXIDE DISMUTASE; SECONDARY STRUCTURE ANALYSES; HYDROGEN-PEROXIDE; PULSE-RADIOLYSIS; BINDING-SPECIFICITY; ARACHIDONIC-ACID; COPPER-BINDING; NADPH OXIDASE; ACTIVATION; OXYGEN AB The function of the antigen-5/CAP family of proteins found in the salivary gland of bloodsucking animals has remained elusive for decades. Antigen-5 members from the hematophagous insects Dipetalogaster maxima (DMAV) and Triatoma infestans (TIAV) were expressed and discovered to attenuate platelet aggregation, ATP secretion, and thromboxane A(2) generation by low doses of collagen (< 1 mu g/ml) but no other agonists. DMAV did not interact with collagen, glycoprotein VI, or integrin alpha 2 beta 1. This inhibitory profile resembles the effects of antioxidants Cu,Zn-superoxide dismutase (Cu,Zn-SOD) in platelet function. Accordingly, DMAV was found to inhibit cytochrome c reduction by O-2(radical anion) generated by the xanthine/xanthine oxidase, implying that it exhibits antioxidant activity. Moreover, our results demonstrate that DMAV blunts the luminescence signal of O-2(radical anion) generated by phorbol 12-myristate 13-acetate-stimulated neutrophils. Mechanistically, inductively coupled plasma mass spectrometry and fluorescence spectroscopy revealed that DMAV, like Cu,Zn-SOD, interacts with Cu2+, which provides redox potential for catalytic removal of O-2(radical anion). Notably, surface plasmon resonance experiments (BIAcore) determined that DMAV binds sulfated glycosaminoglycans (e.g. heparin, K-D similar to 100 nmol/liter), as reported for extracellular SOD. Finally, fractions of the salivary gland of D. maxima with native DMAV contain Cu2+ and display metal-dependent antioxidant properties. Antigen-5/CAP emerges as novel family of Cu2+-dependent antioxidant enzymes that inhibit neutrophil oxidative burst and negatively modulate platelet aggregation by a unique salivary mechanism. C1 [Assumpcao, Teresa C. F.; Ma, Dongying; Andersen, John F.; Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD USA. [Schwarz, Alexandra] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, CR-37005 Ceske Budejovice, Czech Republic. [Reiter, Karine] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Bethesda, MD 20852 USA. [Santana, Jaime M.] Univ Brasilia, Dept Cell Biol, Pathogen Host Interface Lab, BR-70910900 Brasilia, DF, Brazil. [Nardone, Glenn] NIAID, Res Technol Branch, NIH, Bethesda, MD 20852 USA. [Yu, Lee L.] NIST, Div Chem Sci, Gaithersburg, MD 20899 USA. RP Francischetti, IMB (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Rm 2E-32C, Bethesda, MD 20852 USA. EM ifrancischetti@niaid.nih.gov RI ma, dongying/D-8623-2012; Santana, Jaime/H-5319-2013; Ribeiro, Jose/J-7011-2015; Yu, Lee/N-7263-2015 OI Yu, Lee/0000-0002-8043-6853 FU National Institutes of Health Grant [ZIA Al000810-16]; Intramural Research Program of the Division of Intramural Research, NIAID, National Institutes of Health; Fundacao de Amparo a Pesquisa do Distrito Federal, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; Financiadora de Estudos e Projetos; Grant Agency of the Czech Republic Grant [P302/11/P798]; Ministry of Education, Youth, and Sports of the Czech Republic KONTAKT II Grant [LH12002] FX This work was supported, in whole or in part, by National Institutes of Health Grant ZIA Al000810-16 and by the Intramural Research Program of the Division of Intramural Research, NIAID, National Institutes of Health. This work was also supported by and Brazilian grants from Fundacao de Amparo a Pesquisa do Distrito Federal, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, and Financiadora de Estudos e Projetos.; Supported by Grant Agency of the Czech Republic Grant P302/11/P798 and Ministry of Education, Youth, and Sports of the Czech Republic KONTAKT II Grant LH12002. NR 90 TC 22 Z9 22 U1 1 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 MAY 17 PY 2013 VL 288 IS 20 BP 14341 EP 14361 DI 10.1074/jbc.M113.466995 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148OB UT WOS:000319253500038 PM 23564450 ER PT J AU Mital, J Miller, NJ Dorward, DW Dooley, CA Hackstadt, T AF Mital, Jeffrey Miller, Natalie J. Dorward, David W. Dooley, Cheryl A. Hackstadt, Ted TI Role for Chlamydial Inclusion Membrane Proteins in Inclusion Membrane Structure and Biogenesis SO PLOS ONE LA English DT Article ID ENDOGENOUSLY SYNTHESIZED SPHINGOMYELIN; INFECTED-CELLS; TRACHOMATIS INCLUSION; PLASMA-MEMBRANE; GOLGI-APPARATUS; TISSUE TROPISM; RAB GTPASES; HOST-CELL; INCA; IDENTIFICATION AB The chlamydial inclusion membrane is extensively modified by the insertion of type III secreted effector proteins. These inclusion membrane proteins (Incs) are exposed to the cytosol and share a common structural feature of a long, bi-lobed hydrophobic domain but little or no primary amino acid sequence similarity. Based upon secondary structural predictions, over 50 putative inclusion membrane proteins have been identified in Chlamydia trachomatis. Only a limited number of biological functions have been defined and these are not shared between chlamydial species. Here we have ectopically expressed several C. trachomatis Incs in HeLa cells and find that they induce the formation of morphologically distinct membranous vesicular compartments. Formation of these vesicles requires the bi-lobed hydrophobic domain as a minimum. No markers for various cellular organelles were observed in association with these vesicles. Lipid probes were incorporated by the Inc-induced vesicles although the lipids incorporated were dependent upon the specific Inc expressed. Co-expression of Inc pairs indicated that some colocalized in the same vesicle, others partially overlapped, and others did not associate at all. Overall, it appears that Incs may have an intrinsic ability to induce membrane formation and that individual Incs can induce membranous structures with unique properties. C1 [Mital, Jeffrey; Miller, Natalie J.; Dooley, Cheryl A.; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. [Mital, Jeffrey] Quinnipiac Univ, Dept Biomed Sci, Hamden, CT USA. [Dorward, David W.] NIAID, Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. EM Ted_Hackstadt@NIH.Gov FU Intramural Research Program of the NIAID/NIH FX This work was supported by the Intramural Research Program of the NIAID/NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 17 Z9 17 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 MAY 17 PY 2013 VL 8 IS 5 AR UNSP e63426 DI 10.1371/journal.pone.0063426 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146RJ UT WOS:000319107900044 PM 23696825 ER PT J AU Narendran, G Andrade, BB Porter, BO Chandrasekhar, C Venkatesan, P Menon, PA Subramanian, S Anbalagan, S Bhavani, KP Sekar, S Padmapriyadarshini, C Kumar, S Ravichandran, N Raja, K Bhanu, K Mahilmaran, A Sekar, L Sher, A Sereti, I Swaminathan, S AF Narendran, Gopalan Andrade, Bruno B. Porter, Brian O. Chandrasekhar, Chockalingam Venkatesan, Perumal Menon, Pradeep A. Subramanian, Sudha Anbalagan, Selvaraj Bhavani, Kannabiran P. Sekar, Sathiyavelu Padmapriyadarshini, Chandrasekaran Kumar, Satagopan Ravichandran, Narayanan Raja, Krishnaraj Bhanu, Kesavamurthy Mahilmaran, Ayyamperumal Sekar, Lakshmanan Sher, Alan Sereti, Irini Swaminathan, Soumya TI Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) in HIV Patients with Culture Confirmed Pulmonary Tuberculosis in India and the Potential Role of IL-6 in Prediction SO PLOS ONE LA English DT Article ID ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; INTRACRANIAL TUBERCULOMAS; RESTORATION DISEASE; RISK-FACTORS; INITIATION; COINFECTION; AIDS AB Background: The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively. Methods: HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS. Results: Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14-47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7-16) after ART initiation. Corticosteroids were required for treatment of most IRIS events that resolved within a median of 13 days (IQR: 9-23). Two patients died due to CNS TB-IRIS. Lower CD4(+) T-cell counts, higher plasma HIV RNA levels, lower CD4/CD8 ratio, lower hemoglobin, shorter ATT to ART interval, extra-pulmonary or miliary TB and higher plasma IL-6 and CRP levels at baseline were associated with paradoxical TB-IRIS in the univariate analysis. Shorter ATT to ART interval, lower hemoglobin and higher IL-6 and CRP levels remained significant in the multivariate analysis. Conclusion: Paradoxical TB-IRIS frequently complicates HIV-TB therapy in India. IL-6 and CRP may assist in predicting IRIS events and serve as potential targets for immune interventions. C1 [Narendran, Gopalan; Venkatesan, Perumal; Menon, Pradeep A.; Subramanian, Sudha; Anbalagan, Selvaraj; Bhavani, Kannabiran P.; Padmapriyadarshini, Chandrasekaran; Sekar, Lakshmanan; Swaminathan, Soumya] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Andrade, Bruno B.; Porter, Brian O.; Sher, Alan; Sereti, Irini] NIAID, NIH, Bethesda, MD 20892 USA. [Chandrasekhar, Chockalingam; Kumar, Satagopan; Ravichandran, Narayanan; Raja, Krishnaraj; Mahilmaran, Ayyamperumal] Govt Hosp Thorac Med, Chennai, Tamil Nadu, India. [Sekar, Sathiyavelu; Bhanu, Kesavamurthy] Govt Rajiv Gandhi Hosp, Chennai, Tamil Nadu, India. RP Swaminathan, S (reprint author), Natl Inst Res TB, Chennai, Tamil Nadu, India. EM soumyas@trcchennai.in RI Andrade, Bruno/J-9111-2012 OI Andrade, Bruno/0000-0001-6833-3811 FU NIH Intramural-to-India Program; Indian Council of Medical Research (ICMR) ad hoc grant; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the NIH Intramural-to-India Program 2008 and an Indian Council of Medical Research (ICMR) ad hoc grant. The work of BBA, BOP, AS, and IS was supported by the Intramural Research Program from the National Institute of Allergy and Infectious Diseases, 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 US Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 34 Z9 36 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 MAY 17 PY 2013 VL 8 IS 5 AR e63541 DI 10.1371/journal.pone.0063541 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146RJ UT WOS:000319107900048 PM 23691062 ER PT J AU Robinson, OJ Vytal, K Cornwell, BR Grillon, C AF Robinson, Oliver J. Vytal, Katherine Cornwell, Brian R. Grillon, Christian TI The impact of anxiety upon cognition: perspectives from human threat of shock studies SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Review DE anxiety; cognition; threat of shock; anxiety disorders; perception; attention; learning and memory; executive function ID POSTTRAUMATIC-STRESS-DISORDER; OBSESSIVE-COMPULSIVE DISORDER; ANTERIOR CINGULATE CORTEX; DIGIT SPAN PERFORMANCE; SHORT-TERM-MEMORY; EMOTIONAL STROOP INTERFERENCE; GENERALIZED SOCIAL PHOBIA; WORKING-MEMORY; PREPULSE INHIBITION; DECISION-MAKING AB Anxiety disorders constitute a sizeable worldwide health burden with profound social and economic consequences. The symptoms are wide-ranging; from hyperarousal to difficulties with concentrating. This latter effect falls under the broad category of altered cognitive performance which is the focus of this review. Specifically, we examine the interaction between anxiety and cognition focusing on the translational threat of unpredictable shock paradigm; a method previously used to characterize emotional responses and defensive mechanisms that is now emerging as valuable tool for examining the interaction between anxiety and cognition. In particular, we compare the impact of threat of shock on cognition in humans to that of pathological anxiety disorders. We highlight that both threat of shock and anxiety disorders promote mechanisms associated with harm avoidance across multiple levels of cognition(from perception to attention to learning and executive function)-a "hot" cognitive function which can be both adaptive and maladaptive depending upon the circumstances. This mechanism comes at a cost to other functions such as working memory, but leaves some functions, such as planning, unperturbed. We also highlight a number of cognitive effects that differ across anxiety disorders and threat of shock. These discrepant effects are largely seen in "cold" cognitive functions involving control mechanisms and may reveal boundaries between adaptive(e. g., response to threat) and maladaptive (e.g., pathological) anxiety. We conclude by raising a number of unresolved questions regarding the role of anxiety in cognition that may provide fruitful avenues for future research. C1 [Robinson, Oliver J.; Vytal, Katherine; Cornwell, Brian R.; 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 FU Intramural Research Program of the National Institutes of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health. NR 238 TC 38 Z9 38 U1 22 U2 86 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 MAY 17 PY 2013 VL 7 AR 203 DI 10.3389/fnhum.2013.00203 PG 21 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 145UE UT WOS:000319042800001 PM 23730279 ER PT J AU Perou, R Bitsko, RH Blumberg, SJ Pastor, P Ghandour, RM Gfroerer, JC Hedden, SL Crosby, AE Visser, SN Schieve, LA Parks, SE Hall, JE Brody, D Simile, CM Thompson, WW Baio, J Avenevoli, S Kogan, MD Huang, LN AF Perou, Ruth Bitsko, Rebecca H. Blumberg, Stephen J. Pastor, Patricia Ghandour, Reem M. Gfroerer, Joseph C. Hedden, Sarra L. Crosby, Alex E. Visser, Susanna N. Schieve, Laura A. Parks, Sharyn E. Hall, Jeffrey E. Brody, Debra Simile, Catherine M. Thompson, William W. Baio, Jon Avenevoli, Shelli Kogan, Michael D. Huang, Larke N. TI Mental Health Surveillance Among Children - United States, 2005-2011 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article AB Mental disorders among children are described as "serious deviations from expected cognitive, social, and emotional development" (US Department of Health and Human Services Health Resources and Services Administration, Maternal and Child Health Bureau. Mental health: A report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Mental Health Services, and National Institutes of Health, National Institute of Mental Health; 1999). These disorders are an important public health issue in the United States because of their prevalence, early onset, and impact on the child, family, and community, with an estimated total annual cost of $247 billion. A total of 13%-20% of children living in the United States experience a mental disorder in a given year, and surveillance during 1994-2011 has shown the prevalence of these conditions to be increasing. Suicide, which can result from the interaction of mental disorders and other factors, was the second leading cause of death among children aged 12-17 years in 2010. Surveillance efforts are critical for documenting the impact of mental disorders and for informing policy, prevention, and resource allocation. This report summarizes information about ongoing federal surveillance systems that can provide estimates of the prevalence of mental disorders and indicators of mental health among children living in the United States, presents estimates of childhood mental disorders and indicators from these systems during 2005-2011, explains limitations, and identifies gaps in information while presenting strategies to bridge those gaps. Attention-deficit/hyperactivity disorder (6.8%) was the most prevalent parent-reported current diagnosis among children aged 3-17 years, followed by behavioral or conduct problems (3.5%), anxiety (3.0%), depression (2.1%), autism spectrum disorders (1.1%), and Tourette syndrome (0.2% among children aged 6-17 years). An estimated 4.7% of adolescents aged 12-17 years reported an illicit drug use disorder in the past year, 4.2% had an alcohol abuse disorder in the past year, and 2.8% had cigarette dependence in the past month. The overall suicide rate for persons aged 10-19 years was 4.5 suicides per 100,000 persons in 2010. Approximately 8% of adolescents aged 12-17 years reported >= 14 mentally unhealthy days in the past month. Future surveillance of mental disorders among children should include standard case definitions of mental disorders to ensure comparability and reliability of estimates across surveillance systems, better document the prevalence of mental disorders among preschool-age children, and include additional conditions such as specific anxiety disorders and bipolar disorder. Standard surveillance case definitions are needed to reliably categorize and count mental disorders among surveillance systems, which will provide a more complete picture of the prevalence of mental disorders among children. More comprehensive surveillance is needed to develop a public health approach that will both help prevent mental disorders and promote mental health among children. C1 [Perou, Ruth; Bitsko, Rebecca H.; Visser, Susanna N.] CDC, Div Human Dev & Disabil, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Blumberg, Stephen J.; Simile, Catherine M.] CDC, Div Hlth Interview Stat, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Pastor, Patricia] CDC, Off Anal & Epidemiol, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Ghandour, Reem M.; Kogan, Michael D.] US Hlth Resources & Serv Adm, Off Epidemiol & Res, Maternal & Child Hlth Bur, Rockville, MD 20857 USA. [Gfroerer, Joseph C.; Hedden, Sarra L.] Subst Abuse & Mental Hlth Serv Adm, Ctr Behav Hlth Stat & Qual, Rockville, MD USA. [Crosby, Alex E.; Parks, Sharyn E.; Hall, Jeffrey E.] CDC, Div Violence Prevent, Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. [Schieve, Laura A.; Baio, Jon] CDC, Div Birth Defects & Dev Disabil, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Brody, Debra] CDC, Div Hlth Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Thompson, William W.] CDC, Div Populat Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Avenevoli, Shelli] NIMH, Bethesda, MD 20892 USA. [Huang, Larke N.] Subst Abuse & Mental Hlth Serv Adm, Off Policy Planning & Innovat, Rockville, MD USA. EM rperou@cdc.gov NR 0 TC 108 Z9 111 U1 7 U2 19 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD MAY 17 PY 2013 VL 62 IS 2 SU S BP 1 EP 35 PG 35 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V40JZ UT WOS:000209476200001 PM 23677130 ER PT J AU Chakraborty, AR Robey, RW Luchenko, VL Zhan, ZR Piekarz, RL Gillet, JP Kossenkov, AV Wilkerson, J Showe, LC Gottesman, MM Collie, NL Bates, SE AF Chakraborty, Arup R. Robey, Robert W. Luchenko, Victoria L. Zhan, Zhirong Piekarz, Richard L. Gillet, Jean-Pierre Kossenkov, Andrew V. Wilkerson, Julia Showe, Louise C. Gottesman, Michael M. Collie, Nathan L. Bates, Susan E. TI MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor SO BLOOD LA English DT Article ID T-CELL LYMPHOMA; THERAPEUTIC ACTIVITIES; DEPSIPEPTIDE FR901228; UP-REGULATION; CANCER; EXPRESSION; APOPTOSIS; FK228; MODEL; PHOSPHORYLATION AB To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four-to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials. C1 [Chakraborty, Arup R.; Collie, Nathan L.] Texas Tech Univ, Dept Biol Sci, Lubbock, TX 79409 USA. [Chakraborty, Arup R.; Robey, Robert W.; Luchenko, Victoria L.; Zhan, Zhirong; Wilkerson, Julia; Bates, Susan E.] NCI, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Piekarz, Richard L.; Gottesman, Michael M.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Gillet, Jean-Pierre] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kossenkov, Andrew V.; Showe, Louise C.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Bates, SE (reprint author), NCI, NIH, 9000 Rockville Pike,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM batess@helix.nih.gov OI Wilkerson, Julia/0000-0002-6965-0867 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Celgene Corporation; NCI [RO1 CA132098]; National Institutes of Health, Cancer Center Support Grant [P30 CA010815] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and by a Cooperative Research and Development Agreement with Celgene Corporation, as well as by NCI grant RO1 CA132098 (to L. C. S.). The Wistar Institute Genomics and Bioinformatics facilities are supported by National Institutes of Health, Cancer Center Support Grant P30 CA010815. NR 39 TC 22 Z9 23 U1 2 U2 9 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 MAY 16 PY 2013 VL 121 IS 20 BP 4115 EP 4125 DI 10.1182/blood-2012-08-449140 PG 11 WC Hematology SC Hematology GA 184EY UT WOS:000321871900017 PM 23532732 ER PT J AU Brautigam, CA Padrick, SB Schuck, P AF Brautigam, Chad A. Padrick, Shae B. Schuck, Peter TI Multi-Signal Sedimentation Velocity Analysis with Mass Conservation for Determining the Stoichiometry of Protein Complexes SO PLOS ONE LA English DT Article ID ANALYTICAL ULTRACENTRIFUGATION; EQUILIBRIUM-ANALYSIS; AFFINITY; BINDING; MACROMOLECULES; DISTRIBUTIONS; CONSTRAINTS; COEFFICIENT; LIPOPROTEIN; BOUNDARY AB Multi-signal sedimentation velocity analytical ultracentrifugation (MSSV) is a powerful tool for the determination of the number, stoichiometry, and hydrodynamic shape of reversible protein complexes in two- and three-component systems. In this method, the evolution of sedimentation profiles of macromolecular mixtures is recorded simultaneously using multiple absorbance and refractive index signals and globally transformed into both spectrally and diffusion-deconvoluted component sedimentation coefficient distributions. For reactions with complex lifetimes comparable to the time-scale of sedimentation, MSSV reveals the number and stoichiometry of co-existing complexes. For systems with short complex lifetimes, MSSV reveals the composition of the reaction boundary of the coupled reaction/migration process, which we show here may be used to directly determine an association constant. A prerequisite for MSSV is that the interacting components are spectrally distinguishable, which may be a result, for example, of extrinsic chromophores or of different abundances of aromatic amino acids contributing to the UV absorbance. For interacting components that are spectrally poorly resolved, here we introduce a method for additional regularization of the spectral deconvolution by exploiting approximate knowledge of the total loading concentrations. While this novel mass conservation principle does not discriminate contributions to different species, it can be effectively combined with constraints in the sedimentation coefficient range of uncomplexed species. We show in theory, computer simulations, and experiment, how mass conservation MSSV as implemented in SEDPHAT can enhance or even substitute for the spectral discrimination of components. This should broaden the applicability of MSSV to the analysis of the composition of reversible macromolecular complexes. C1 [Brautigam, Chad A.; Padrick, Shae B.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. EM peter.schuck@nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, DHHS FX This work was supported by the intramural research program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 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 MAY 16 PY 2013 VL 8 IS 5 AR e62694 DI 10.1371/journal.pone.0062694 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146HW UT WOS:000319081900004 PM 23696787 ER PT J AU Wood, AR Perry, JRB Tanaka, T Hernandez, DG Zheng, HF Melzer, D Gibbs, JR Nalls, MA Weedon, MN Spector, TD Richards, JB Bandinelli, S Ferrucci, L Singleton, AB Frayling, TM AF Wood, Andrew R. Perry, John R. B. Tanaka, Toshiko Hernandez, Dena G. Zheng, Hou-Feng Melzer, David Gibbs, J. Raphael Nalls, Michael A. Weedon, Michael N. Spector, Tim D. Richards, J. Brent Bandinelli, Stefania Ferrucci, Luigi Singleton, Andrew B. Frayling, Timothy M. TI Imputation of Variants from the 1000 Genomes Project Modestly Improves Known Associations and Can Identify Low-frequency Variant - Phenotype Associations Undetected by HapMap Based Imputation SO PLOS ONE LA English DT Article ID WIDE ASSOCIATION; HAPLOTYPE MAP; COMMON; POPULATION; RISK AB Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% <= MAF <5%) and rare variants (<1%)) can enhance previously identified associations and identify novel loci, we selected 93 quantitative circulating factors where data was available from the InCHIANTI population study. These phenotypes included cytokines, binding proteins, hormones, vitamins and ions. We selected these phenotypes because many have known strong genetic associations and are potentially important to help understand disease processes. We performed a genome-wide scan for these 93 phenotypes in InCHIANTI. We identified 21 signals and 33 signals that reached P<5x10(-8) based on HapMap and 1000 Genomes imputation, respectively, and 9 and 11 that reached a stricter, likely conservative, threshold of P<5x10(-11) respectively. Imputation of 1000 Genomes genotype data modestly improved the strength of known associations. Of 20 associations detected at P<5x10(-8) in both analyses (17 of which represent well replicated signals in the NHGRI catalogue), six were captured by the same index SNP, five were nominally more strongly associated in 1000 Genomes imputed data and one was nominally more strongly associated in HapMap imputed data. We also detected an association between a low frequency variant and phenotype that was previously missed by HapMap based imputation approaches. An association between rs112635299 and alpha-1 globulin near the SERPINA gene represented the known association between rs28929474 (MAF = 0.007) and alpha1-antitrypsin that predisposes to emphysema (P = 2.5x10(-12)). Our data provide important proof of principle that 1000 Genomes imputation will detect novel, low frequency-large effect associations. C1 [Wood, Andrew R.; Perry, John R. B.; Melzer, David; Weedon, Michael N.; Frayling, Timothy M.] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter, Devon, England. [Perry, John R. B.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Perry, John R. B.; Spector, Tim D.; Richards, J. Brent] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Hernandez, Dena G.; Gibbs, J. Raphael; Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, Baltimore, MD 21224 USA. [Hernandez, Dena G.; Gibbs, J. Raphael] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Hernandez, Dena G.; Gibbs, J. Raphael] UCL, Inst Neurol, Reta Lila Labs, London, England. [Zheng, Hou-Feng; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ H3T 1E2, Canada. [Zheng, Hou-Feng; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Dept Human Genet, Montreal, PQ H3T 1E2, Canada. [Zheng, Hou-Feng; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Dept Epidemiol, Montreal, PQ H3T 1E2, Canada. [Zheng, Hou-Feng; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Dept Biostat, Montreal, PQ H3T 1E2, Canada. [Bandinelli, Stefania] Tuscany Reg Hlth Agcy, Florence, Italy. [Bandinelli, Stefania] Univ Florence, IOT, Florence, Italy. [Bandinelli, Stefania] Univ Florence, Dept Med & Surg Crit Care, Florence, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. RP Frayling, TM (reprint author), Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter, Devon, England. EM tim.frayling@pms.ac.uk RI Singleton, Andrew/C-3010-2009; OI Melzer, David/0000-0002-0170-3838 FU Wellcome Trust [083270/Z/07/Z] FX This work was supported by the Wellcome Trust 083270/Z/07/Z. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 16 Z9 16 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 16 PY 2013 VL 8 IS 5 AR e64343 DI 10.1371/journal.pone.0064343 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146HW UT WOS:000319081900084 PM 23696881 ER PT J AU Xiao, S White, JF Betenbaugh, MJ Grisshammer, R Shiloach, J AF Xiao, Su White, Jim F. Betenbaugh, Michael J. Grisshammer, Reinhard Shiloach, Joseph TI Transient and Stable Expression of the Neurotensin Receptor NTS1: A Comparison of the Baculovirus-Insect Cell and the T-REx-293 Expression Systems SO PLOS ONE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; HIGH-LEVEL EXPRESSION; INTEGRAL MEMBRANE-PROTEINS; PURIFICATION; PEPTIDE; OVEREXPRESSION; RHODOPSIN; MUTANTS; LINES AB Nowadays, baculovirus-infected insect cells and tetracycline-inducible mammalian cell lines (T-REx-293) are intensively used for G protein-coupled receptor (GPCR) production for crystallography purposes. Here we constructed a suspension T-REx-293 cell line to stably express an engineered neurotensin receptor 1 (NTS1) mutant and we quantitatively compared this cell line with the transient baculovirus-insect cell system throughout a milligram-scale NTS1 expression and purification process. The two systems were comparable with respect to functional NTS1 expression levels and receptor binding affinity for the agonist [H-3] neurotensin. However, NTS1 surface display on T-REx-293 cells determined by radio-ligand binding assays was 2.8 fold higher than that on insect cells. This work demonstrates two approaches for preparing milligram quantities of purified NTS1 suitable for structural studies and provides useful input to users in choosing and optimizing an appropriate expression host for other GPCRs. C1 [Xiao, Su; Shiloach, Joseph] NIDDKD, Biotechnol Core Lab, Bethesda, MD 20892 USA. [White, Jim F.; Grisshammer, Reinhard] NINDS, Membrane Prot Struct & Funct Unit, NIH, Rockville, MD USA. [Xiao, Su; Betenbaugh, Michael J.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD USA. RP Grisshammer, R (reprint author), NINDS, Membrane Prot Struct & Funct Unit, NIH, Rockville, MD USA. EM rkgriss@helix.nih.gov; josephs@intra.niddk.nih.gov RI Betenbaugh, Michael J./A-3252-2010; Grisshammer, Reinhard/C-3089-2015 OI Betenbaugh, Michael J./0000-0002-6336-4659; FU Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases); 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 (SX, JS: National Institute of Diabetes and Digestive and Kidney Diseases; JFW, RG: 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 35 TC 8 Z9 10 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 MAY 16 PY 2013 VL 8 IS 5 AR e63679 DI 10.1371/journal.pone.0063679 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146HW UT WOS:000319081900051 PM 23696845 ER PT J AU Wang, C Wu, HX Katritch, V Han, GW Huang, XP Liu, W Siu, FY Roth, BL Cherezov, V Stevens, RC AF Wang, Chong Wu, Huixian Katritch, Vsevolod Han, Gye Won Huang, Xi-Ping Liu, Wei Siu, Fai Yiu Roth, Bryan L. Cherezov, Vadim Stevens, Raymond C. TI Structure of the human smoothened receptor bound to an antitumour agent SO NATURE LA English DT Article ID RESOLUTION CRYSTAL-STRUCTURE; PROTEIN-COUPLED RECEPTOR; OPIOID RECEPTOR; INTERNATIONAL UNION; LIPIDIC MESOPHASES; FRIZZLED RECEPTORS; MEMBRANE-PROTEINS; HEDGEHOG; ACTIVATION; PATHWAY AB The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 angstrom resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops. C1 [Wang, Chong; Wu, Huixian; Katritch, Vsevolod; Han, Gye Won; Liu, Wei; Siu, Fai Yiu; Cherezov, Vadim; Stevens, Raymond C.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina Chapel Hill, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Dept Pharmacol, Sch Med, Chapel Hill, NC 27514 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina Chapel Hill, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27514 USA. RP Stevens, RC (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM stevens@scripps.edu RI Cherezov, Vadim/L-9812-2013; Wu, Huixian/N-6353-2014; Roth, Bryan/F-3928-2010; Katritch, Vsevolod/Q-8357-2016; Stevens, Raymond/K-7272-2015; OI Cherezov, Vadim/0000-0002-5265-3914; Wu, Huixian/0000-0003-1357-9747; Stevens, Raymond/0000-0002-4522-8725; Katritch, Vsevolod/0000-0003-3883-4505 FU National Institutes of Health [P50 GM073197, U54 GM094618]; NIMH Psychoactive Drug Screening Program; Michael Hooker Chair of Pharmacology; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; [F32 DK088392]; [R01 MH61887]; [U19 MH82441]; [R01 DA27170] FX This work was supported by the National Institutes of Health Common Fund grant P50 GM073197 for technology development (V. C. and R. C. S.), PSI:Biology grant U54 GM094618 for biological studies and structure production (target GPCR-131) (V. K., V. C. and R. C. S.); F32 DK088392 (F.Y.S.); R01 MH61887, U19 MH82441, R01 DA27170 and the NIMH Psychoactive Drug Screening Program (X.-P. H. and B. L. R.) and the Michael Hooker Chair of Pharmacology (B. L. R.). We thank J. Velasquez for help with molecular biology, T. Trinh and M. Chu for help with baculovirus expression, K. Kadyshevskaya for assistance with figure preparation, A. Walker for assistance with manuscript preparation, D. Wacker for assistance with SAD data collection and processing and J. Smith, R. Fischetti and N. Sanishvili for assistance in development and use of the minibeam and beamtime at beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104. NR 49 TC 191 Z9 195 U1 6 U2 77 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 16 PY 2013 VL 497 IS 7449 BP 338 EP + DI 10.1038/nature12167 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 144PN UT WOS:000318952000031 PM 23636324 ER PT J AU Liang, TJ Ghany, MG AF Liang, T. Jake Ghany, Marc G. TI Current and Future Therapies for Hepatitis C Virus Infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID SUSTAINED VIROLOGICAL RESPONSE; GENOTYPE 1 INFECTION; PROTEASE INHIBITOR; HCV INFECTION; ANTIVIRAL THERAPY; TREATMENT-NAIVE; PLUS RIBAVIRIN; VIRAL LOAD; TELAPREVIR; BOCEPREVIR C1 [Liang, T. Jake; Ghany, Marc G.] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDKD, Liver Dis Branch, NIH, Bldg 10-9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM jakel@bldg10.niddk.nih.gov FU Intramural NIH HHS [Z99 DK999999, ZIA DK054504-16, ZIA DK054504-17, ZIA DK054505-16, ZIA DK054505-17, ZIA DK054511-06, ZIA DK054511-07] NR 72 TC 215 Z9 217 U1 2 U2 66 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 MAY 16 PY 2013 VL 368 IS 20 BP 1907 EP 1917 DI 10.1056/NEJMra1213651 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 143VK UT WOS:000318896200010 PM 23675659 ER PT J AU Beeharry, N Rattner, JB Caviston, JP Yen, T AF Beeharry, Neil Rattner, Jerome B. Caviston, Juliane P. Yen, Tim TI Centromere fragmentation is a common mitotic defect of S and G(2) checkpoint override SO CELL CYCLE LA English DT Article DE cell cycle checkpoints; MUGs; DNA damage; centromere; mitotic catastrophe ID PANCREATIC-CANCER CELLS; DNA-REPLICATION; IN-VIVO; HUMAN CHK1; KINETOCHORES; INHIBITION; MITOSIS; GEMCITABINE; ABROGATION; DAMAGE AB DNA damaging agents, including those used in the clinic, activate cell cycle checkpoints, which blocks entry into mitosis. Given that checkpoint override results in cell death via mitotic catastrophe, inhibitors of the DNA damage checkpoint are actively being pursued as chemosensitization agents. Here we explored the effects of gemcitabine in combination with Chk1 inhibitors in a panel of pancreatic cancer cell lines and found variable abilities to override the S phase checkpoint. In cells that were able to enter mitosis, the chromatin was extensively fragmented, as assessed by metaphase spreads and Comet assay. Notably, electron microscopy and high-resolution light microscopy showed that the kinetochores and centromeres appeared to be detached from the chromatin mass, in a manner reminiscent of mitosis with unreplicated genomes (MUGs). Cell lines that were unable to override the S phase checkpoint were able to override a G(2) arrest induced by the alkylator MMS or the topoisomerase II inhibitors doxorubicin or etoposide. Interestingly, checkpoint override from the topoisomerase II inhibitors generated fragmented kinetochores (MUGs) due to unreplicated centromeres. Our studies show that kinetochore and centromere fragmentation is a defining feature of checkpoint override and suggests that loss of cell viability is due in part to acentric genomes. Furthermore, given the greater efficacy of forcing cells into premature mitosis from topoisomerase II-mediated arrest as compared with gemcitabine-mediated arrest, topoisomerase II inhibitors maybe more suitable when used in combination with checkpoint inhibitors. C1 [Beeharry, Neil; Caviston, Juliane P.; Yen, Tim] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA. [Rattner, Jerome B.] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB, Canada. RP Beeharry, N (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Neil.Beeharry@fccc.edu; Timothy.Yen@fccc.edu OI Yen, Tim/0000-0003-2159-0997 FU NIH [GM086877, CA06927, DoD OC100172]; Common Wealth of PA; PA CURE; Greenburg Foundation; Plain and Fancy Fellowship, FCCC FX We wish to thank the NCI/Kyowa Hakko Kirin Co., Ltd for the use of UCN-01 for these studies. Hela GFP-CENP A cells, GFP and CENP-A antibodies were kindly provided by Dr Ben Black, University of Pennsylvania. We also thank the following facilities at Fox Chase Cancer Center for providing assistance with equipment and technical advice: Imaging Facility, Flow Cytometry Facility and Tissue Culture Facility. This work was supported in part by NIH GM086877, core grant CA06927, DoD OC100172 and Appropriation from Common Wealth of PA, the PA CURE and the Greenburg Foundation (T.J.Y.), and the Plain and Fancy Fellowship, FCCC (N.B.). NR 31 TC 13 Z9 13 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 15 PY 2013 VL 12 IS 10 BP 1588 EP 1597 DI 10.4161/cc.24740 PG 10 WC Cell Biology SC Cell Biology GA 203RQ UT WOS:000323311200019 PM 23624842 ER PT J AU Huang, ZJ Wu, X Garcia, AJ Fik, TJ Tatem, AJ AF Huang, Zhuojie Wu, Xiao Garcia, Andres J. Fik, Timothy J. Tatem, Andrew J. TI An Open-Access Modeled Passenger Flow Matrix for the Global Air Network in 2010 SO PLOS ONE LA English DT Article ID ORIGIN-DESTINATION MATRIX; HUB FACILITIES; TRANSPORTATION; TRAVEL; SPREAD; CENTRALITY; MOBILITY; GROWTH; RISK AB The expanding global air network provides rapid and wide-reaching connections accelerating both domestic and international travel. To understand human movement patterns on the network and their socioeconomic, environmental and epidemiological implications, information on passenger flow is required. However, comprehensive data on global passenger flow remain difficult and expensive to obtain, prompting researchers to rely on scheduled flight seat capacity data or simple models of flow. This study describes the construction of an open-access modeled passenger flow matrix for all airports with a host city-population of more than 100,000 and within two transfers of air travel from various publicly available air travel datasets. Data on network characteristics, city population, and local area GDP amongst others are utilized as covariates in a spatial interaction framework to predict the air transportation flows between airports. Training datasets based on information from various transportation organizations in the United States, Canada and the European Union were assembled. A log-linear model controlling the random effects on origin, destination and the airport hierarchy was then built to predict passenger flows on the network, and compared to the results produced using previously published models. Validation analyses showed that the model presented here produced improved predictive power and accuracy compared to previously published models, yielding the highest successful prediction rate at the global scale. Based on this model, passenger flows between 1,491 airports on 644,406 unique routes were estimated in the prediction dataset. The airport node characteristics and estimated passenger flows are freely available as part of the Vector-Borne Disease Airline Importation Risk (VBD-Air) project at: www.vbd-air.com/data. C1 [Huang, Zhuojie; Garcia, Andres J.; Fik, Timothy J.; Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Huang, Zhuojie; Garcia, Andres J.; Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32611 USA. [Wu, Xiao] Univ Florida, Dept Stat, Gainesville, FL 32611 USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. RP Huang, ZJ (reprint author), Univ Florida, Dept Geog, Gainesville, FL 32611 USA. EM seenhzj@gmail.com FU Transportation Research Board of the National Academy of Sciences [ACRP02-20]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation [49446, 1032350]; National Science Foundation in the Quantitative Spatial Ecology, Evolution, and Environment Program at the University of Florida [0801544] FX AJT and ZH acknowledge support from the Transportation Research Board of the National Academy of Sciences, through contract #ACRP02-20. AJT also acknowledges funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from the Bill and Melinda Gates Foundation (#49446 and# 1032350). AJG was partially supported by the National Science Foundation under Grant No. 0801544 in the Quantitative Spatial Ecology, Evolution, and Environment Program at the University of Florida. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 5 Z9 5 U1 7 U2 26 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 MAY 15 PY 2013 VL 8 IS 5 AR e64317 DI 10.1371/journal.pone.0064317 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 145XK UT WOS:000319052700088 PM 23691194 ER PT J AU Jansma, JM de Zwart, JA van Gelderen, P Duyn, JH Drevets, WC Furey, ML AF Jansma, J. Martijn de Zwart, Jacco A. van Gelderen, Peter Duyn, Jeff H. Drevets, Wayne C. Furey, Maura L. TI In vivo evaluation of the effect of stimulus distribution on FIR statistical efficiency in event-related fMRI SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Event-related fMRI; Multicollinearity; Finite impulse response analysis; m-Sequence ID MULTIPLE TRIAL TYPES; FUNCTIONAL MRI; EXPERIMENTAL-DESIGNS; TEMPORAL DYNAMICS; IMPULSE-RESPONSE; BOLD RESPONSE; BRAIN; POWER; OPTIMIZATION; ACTIVATION AB Technical developments in MRI have improved signal to noise, allowing use of analysis methods such as Finite impulse response (FIR) of rapid event related functional MRI (er-fMRI). FIR is one of the most informative analysis methods as it determines onset and full shape of the hemodynamic response function (HRF) without any a priori assumptions. FIR is however vulnerable to multicollinearity, which is directly related to the distribution of stimuli over time. Efficiency can be optimized by simplifying a design, and restricting stimuli distribution to specific sequences, while more design flexibility necessarily reduces efficiency. However, the actual effect of efficiency on fMRI results has never been tested in vivo. Thus, it is currently difficult to make an informed choice between protocol flexibility and statistical efficiency. The main goal of this study was to assign concrete fMRI signal to noise values to the abstract scale of FIR statistical efficiency. Ten subjects repeated a perception task with five random and m-sequence based protocol, with varying but, according to literature, acceptable levels of multicollinearity. Results indicated substantial differences in signal standard deviation, while the level was a function of multicollinearity. Experiment protocols varied up to 55.4% in standard deviation. Results confirm that quality of fMRI in an FIR analysis can significantly and substantially vary with statistical efficiency. Our in vivo measurements can be used to aid in making an informed decision between freedom in protocol design and statistical efficiency. Published by Elsevier B.V. C1 [Jansma, J. Martijn; Drevets, Wayne C.; Furey, Maura L.] NIMH, Mood & Anxiety Disorders Program, Mol Imaging Branch, Sect Neuroimaging Mood & Anxiety Disorders,NIH, Bethesda, MD USA. [de Zwart, Jacco A.; van Gelderen, Peter; Duyn, Jeff H.] NINDS, Adv MRI Lab Funct Mol Imaging, NIH, Bethesda, MD USA. RP Jansma, JM (reprint author), Univ Med Ctr Utrecht, Dept Neurol & Neurosurg, Rudolf Magnus Inst Neurosci, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. EM jjansma2@umcutrecht.nl RI Furey, Maura/H-5273-2013 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 34 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD MAY 15 PY 2013 VL 215 IS 2 BP 190 EP 195 DI 10.1016/j.jneumeth.2013.02.017 PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 158GP UT WOS:000319957800004 PM 23473798 ER PT J AU Sahores, A Luque, GM Wargon, V May, M Molinolo, A Becu-Villalobos, D Lanari, C Lamb, CA AF Sahores, Ana Luque, Guillermina M. Wargon, Victoria May, Maria Molinolo, Alfredo Becu-Villalobos, Damasia Lanari, Claudia Lamb, Caroline A. TI Novel, Low Cost, Highly Effective, Handmade Steroid Pellets for Experimental Studies SO PLOS ONE LA English DT Article ID MOUSE MAMMARY-GLAND; BREAST-CANCER; OVARIECTOMIZED RATS; PROGESTERONE-RECEPTORS; SILASTIC IMPLANTS; ESTROGEN-RECEPTOR; SILICONE-RUBBER; MICE; GROWTH; 17-BETA-ESTRADIOL AB The basic component of Silastic (R) glue (Dow Corning) used to prepare Silastic (R) pellets is polydimethylsiloxane. This compound is also present in other commercial adhesives such as FASTIX (R) (Akapol SA) that are available in any store for that category. In the present study we developed low cost, easy to prepare handmade steroid pellets (HMSP) by mixing 17 beta-estradiol, progesterone or other synthetic steroids with FASTIX (R) adhesive. We assessed serum levels of 17 beta-estradiol, progesterone, prolactin and luteinizing hormone in ovariectomized mice treated for 24 and 48 h or 7, 14 and 28 days with 20 mu g or 5 mg of 17 beta-estradiol or 5 mg progesterone HMSP. We found a time dependent and significant increase in the levels of both natural hormones, and a downregulation of serum luteinizing hormone levels, while both 17 beta-estradiol doses increased serum prolactin. Uterine weights at sacrifice and histological examination of the uteri and the mammary glands correlated with estrogen or progestin action. Finally, we evaluated the biological effects of HMSP compared to commercial pellets or daily injections in the stimulation or inhibition of hormone dependent mammary tumor growth, and found that HMSP were as effective as the other methods of hormone administration. These data show that HMSP represent a useful, low cost, easily accessible method for administering steroids to mice. C1 [Sahores, Ana; Luque, Guillermina M.; Wargon, Victoria; May, Maria; Becu-Villalobos, Damasia; Lanari, Claudia; Lamb, Caroline A.] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt IBYME, Buenos Aires, DF, Argentina. [Molinolo, Alfredo] Natl Inst Dent & Craniofacial Res, NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. RP Lamb, CA (reprint author), Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt IBYME, Buenos Aires, DF, Argentina. EM carolinealamb@gmail.com FU Fundacion Sales; Secretaia de Ciencia y Tecnologia [989, 459]; PIP [692]; intramural Research Program, National Institute of Dental and Craniofacial Research-National Institutes of Health FX This work was supported by Fundacion Sales (Specific Grant 2010-2012), Secretaia de Ciencia y Tecnologia (PICT 2008 No989; PICT 2010 No459), PIP 2010-2012 No692. AM is supported by the intramural Research Program, National Institute of Dental and Craniofacial Research-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 32 TC 6 Z9 6 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 15 PY 2013 VL 8 IS 5 AR e64049 DI 10.1371/journal.pone.0064049 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 145XK UT WOS:000319052700074 PM 23691144 ER PT J AU Wang, GJ Volkow, ND Wigal, T Kollins, SH Newcorn, JH Telang, F Logan, J Jayne, M Wong, CT Han, H Fowler, JS Zhu, W Swanson, JM AF Wang, Gene-Jack Volkow, Nora D. Wigal, Timothy Kollins, Scott H. Newcorn, Jeffrey H. Telang, Frank Logan, Jean Jayne, Millard Wong, Christopher T. Han, Hao Fowler, Joanna S. Zhu, Wei Swanson, James M. TI Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in Patients with Attention Deficit Hyperactive Disorder SO PLOS ONE LA English DT Article ID DEFICIT/HYPERACTIVITY DISORDER; METHYLPHENIDATE TREATMENT; BEHAVIORAL SENSITIZATION; ORAL METHYLPHENIDATE; COCAINE; RATS; ADULTS; ADHD; STRIATUM; EXPOSURE AB Objective: Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated. Method: We used positron emission tomography and [C-11] cocaine (dopamine transporter radioligand) to measure dopamine transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands. Results: Twelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p<0.01); whereas there were no changes in control subjects retested at 12-month interval. Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment (caudate: p<0.007; putamen: p<0.005). Conclusion: Upregulation of dopamine transporter availability during long- term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding dopamine transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories. C1 [Wang, Gene-Jack] SUNY Stony Brook, Dept Radiol, Stony Brook, NY 11794 USA. [Wang, Gene-Jack; Logan, Jean; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Wang, Gene-Jack; Newcorn, Jeffrey H.; Fowler, Joanna S.] Mt Sinai Sch Med, Dept Psychol, New York, NY USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD USA. [Volkow, Nora D.; Telang, Frank; Jayne, Millard; Wong, Christopher T.] NIAAA, Intramural Res Program, Neuroimaging Lab, Upton, NY USA. [Wigal, Timothy; Swanson, James M.] Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. [Kollins, Scott H.] Duke Univ, Dept Psychiat, Durham, NC 27706 USA. [Han, Hao; Zhu, Wei] SUNY Stony Brook, Dept Math & Appl Sci, Stony Brook, NY 11794 USA. RP Wang, GJ (reprint author), SUNY Stony Brook, Dept Radiol, Stony Brook, NY 11794 USA. EM gjwang@bnl.gov RI Han, Hao/D-5618-2015; OI Han, Hao/0000-0002-9387-7279; Newcorn, Jeffrey /0000-0001-8993-9337; Logan, Jean/0000-0002-6993-9994 FU National Institutes of Health [R01MH66961]; Orexigen Therapeutics Inc. FX The work was supported by the National Institutes of Health: R01MH66961 to Dr. GJW. The PET study was carried out at Brookhaven National Laboratory with infrastructure support from the U.S. Department of Energy Office of Biological and Environmental Research (DE-ACO2-76CH00016), M01RR10710 (the General Clinical Research Center of Stony Brook University). An Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism (Z01AA000550) supported Drs. NDV and FT and Mr. MJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Dr. GJW received research funding from the Orexigen Therapeutics Inc.; Dr. NDV reports no competing interests; Dr. TW reports no competing interests; Dr. SHK reports no competing interests; Dr. JHN reports no competing interests; Dr. FT reports no competing interests; Dr. JL reports no competing interests; Mr. MJ reports no competing interests; Mr. CTW reports no competing interests; Mr. HH reports no competing interests; Dr. JSF reports no competing interests; Dr. WZ reports no competing interests; Dr. JMS reports no competing interests. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 29 TC 18 Z9 18 U1 2 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 MAY 15 PY 2013 VL 8 IS 5 AR e63023 DI 10.1371/journal.pone.0063023 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 145XK UT WOS:000319052700016 PM 23696790 ER PT J AU Rogers, IS Massaro, JM Truong, QA Mahabadi, AA Kriegel, MF Fox, CS Thanassoulis, G Isselbacher, EM Hoffmann, U O'Donnell, CJ AF Rogers, Ian S. Massaro, Joseph M. Truong, Quynh A. Mahabadi, Amir A. Kriegel, Matthias F. Fox, Caroline S. Thanassoulis, George Isselbacher, Eric M. Hoffmann, Udo O'Donnell, Christopher J. TI Distribution, Determinants, and Normal Reference Values of Thoracic and Abdominal Aortic Diameters by Computed Tomography (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DIMENSIONS; DISEASE; CHILDREN; ADULTS; WOMEN; AREA; MEN; AGE AB Current screening and detection of asymptomatic aortic aneurysms is based largely on uniform cut-point diameters. The aims of this study were to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease. Measurements of the diameters of the ascending thoracic aorta (AA), descending thoracic aorta (DTA), infrarenal abdominal aorta (IRA), and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study (FHS) participants. Mean diameters were stratified by gender, age, and body surface area. Univariate associations with risk factor levels were examined, and multivariate linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameters were 34.1 mm for the AA, 25.8 mm for the DTA, 19.3 mm for the IRA, and 18.7 mm for the LAA. For women, the average diameters were 31.9 mm for the AA, 23.1 mm for the DTA, 16.7 mm for the IRA, and 16.0 mm for the LAA. The mean aortic diameters were strongly correlated (p<0.0001) with age and body surface area in age-adjusted analyses, and these relations remained significant in multivariate regression analyses. Positive associations of diastolic blood pressure with AA and DTA diameters in both genders and pack-years of cigarette smoking with DTA diameter in women and IRA diameter in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by computed tomography are larger in men compared with women, vary significantly with age and body surface area, and are associated with modifiable cardiovascular disease risk factors, including diastolic blood pressure and cigarette smoking. Published by Elsevier Inc. (Am J Cardiol 2013;111:1510-1516) C1 [Rogers, Ian S.; Truong, Quynh A.; Mahabadi, Amir A.; Kriegel, Matthias F.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Rogers, Ian S.; Truong, Quynh A.; Isselbacher, Eric M.; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Rogers, Ian S.] Stanford Univ, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA. [Massaro, Joseph M.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Massaro, Joseph M.; Fox, Caroline S.; Thanassoulis, George; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Mahabadi, Amir A.] Univ Duisburg Essen, Dept Cardiol, West German Heart Ctr, Essen, Germany. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Thanassoulis, George] McGill Univ, Div Cardiol, Ctr Hlth, Montreal, PQ, Canada. [Thanassoulis, George] McGill Univ, Div Clin Epidemiol, Ctr Hlth, Montreal, PQ, Canada. RP O'Donnell, CJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM odonnellc@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute's FHS [N01-HC-25195]; National Institutes of Health [1T32 HL076136, K23 HL098370, L30 HL093806]; American Heart Association [12CRP12060237] FX From the Framingham Heart Study (FHS) of the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland, and Boston University School of Medicine, Boston, Massachusetts. This work was supported by the National Heart, Lung, and Blood Institute's FHS (Contract N01-HC-25195). Drs. Rogers and Truong received salary support from Grant 1T32 HL076136 from the National Institutes of Health. Dr. Rogers also received salary support from Grant 12CRP12060237 from the American Heart Association. Dr. Truong also received salary support from Grants K23 HL098370 and L30 HL093806 from the National Institutes of Health. NR 19 TC 32 Z9 33 U1 0 U2 6 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2013 VL 111 IS 10 BP 1510 EP 1516 DI 10.1016/j.amjcard.2013.01.306 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 150EB UT WOS:000319371900023 PM 23497775 ER PT J AU Penninx, BWJH Milaneschi, Y Lamers, F Vogelzangs, N AF Penninx, Brenda W. J. H. Milaneschi, Yuri Lamers, Femke Vogelzangs, Nicole TI Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile SO BMC MEDICINE LA English DT Review DE Depression; Metabolic syndrome; Inflammation; Cortisol; Autonomic Tone; Cardiovascular; Obesity; Symptom profile; Treatment ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; PRO-INFLAMMATORY CYTOKINES; CARDIAC VAGAL CONTROL; METABOLIC SYNDROME; MAJOR DEPRESSION; RATE-VARIABILITY; TREATMENT RESPONSE; NERVOUS-SYSTEM; GENERAL-POPULATION AB Depression is the most common psychiatric disorder worldwide. The burden of disease for depression goes beyond functioning and quality of life and extends to somatic health. Depression has been shown to subsequently increase the risk of, for example, cardiovascular, stroke, diabetes and obesity morbidity. These somatic consequences could partly be due to metabolic, immuno-inflammatory, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations which have been suggested to be more often present among depressed patients. Evidence linking depression to metabolic syndrome abnormalities indicates that depression is especially associated with its obesity-related components (for example, abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Slightly less consistent observations are for autonomic dysregulation among depressed patients. The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. This review finishes with potential treatment implications for the downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with somatic health decline. C1 [Penninx, Brenda W. J. H.; Milaneschi, Yuri; Vogelzangs, Nicole] Vrije Univ Amsterdam, Med Ctr, EMGO Inst & Neurosci Campus Amsterdam, Dept Psychiat, Amsterdam, Netherlands. [Lamers, Femke] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, NL-1081 HL Amsterdam, Netherlands. [Penninx, Brenda W. J. H.] GGZinGeest, NL-1081 HL Amsterdam, Netherlands. RP Penninx, BWJH (reprint author), Vrije Univ Amsterdam, Med Ctr, EMGO Inst & Neurosci Campus Amsterdam, Dept Psychiat, Amsterdam, Netherlands. EM b.penninx@vumc.nl FU VICI grant (NWO) [91811602]; Intramural Research Training Award from the National Institute of Mental Health; VU University Medical Center EMGO Institute for Health and Care Research FX Penninx was supported through a VICI grant (NWO grant 91811602), Lamers was supported through an Intramural Research Training Award from the National Institute of Mental Health, and Vogelzangs was supported through a fellowship from the VU University Medical Center EMGO Institute for Health and Care Research. NR 157 TC 119 Z9 123 U1 16 U2 67 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD MAY 15 PY 2013 VL 11 AR UNSP 129 DI 10.1186/1741-7015-11-129 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 149CD UT WOS:000319294700001 PM 23672628 ER PT J AU Jorgensen, MG Thomason, MK Havelund, J Valentin-Hansen, P Storz, G AF Jorgensen, Mikkel Girke Thomason, Maureen K. Havelund, Johannes Valentin-Hansen, Poul Storz, Gisela TI Dual function of the McaS small RNA in controlling biofilm formation SO GENES & DEVELOPMENT LA English DT Article DE Hfq; CsrA; CsrB; PGA; c-di-GMP ID ESCHERICHIA-COLI K-12; MESSENGER-RNA; PROTEIN CSRA; POLYSACCHARIDE ADHESIN; GLYCOGEN BIOSYNTHESIS; STATIONARY-PHASE; EXPRESSION; BINDING; GENE; REGULATORS AB Many bacterial small RNAs (sRNAs) regulate gene expression through base-pairing with mRNAs, and it has been assumed that these sRNAs act solely by this one mechanism. Here we report that the multicellular adhesive (McaS) sRNA of Escherichia coli uniquely acts by two different mechanisms: base-pairing and protein titration. Previous work established that McaS base pairs with the mRNAs encoding master transcription regulators of curli and flagella synthesis, respectively, resulting in down-regulation and up-regulation of these important cell surface structures. In this study, we demonstrate that McaS activates synthesis of the exopolysaccharide beta-1,6 N-acetyl-D-glucosamine (PGA) by binding the global RNA-binding protein CsrA, a negative regulator of pgaA translation. The McaS RNA bears at least two CsrA-binding sequences, and inactivation of these sites compromises CsrA binding, PGA regulation, and biofilm formation. Moreover, ectopic McaS expression leads to induction of two additional CsrA-repressed genes encoding diguanylate cyclases. Collectively, our study shows that McaS is a dual-function sRNA with roles in the two major post-transcriptional regulons controlled by the RNA-binding proteins Hfq and CsrA. C1 [Jorgensen, Mikkel Girke; Havelund, Johannes; Valentin-Hansen, Poul] Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark. [Thomason, Maureen K.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Thomason, Maureen K.] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. RP Valentin-Hansen, P (reprint author), Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark. EM valentin@bmb.sdu.dk; storzg@mail.nih.gov OI Storz, Gisela/0000-0001-6698-1241 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Danish Council for Independent Research (FNU); Lundbeck Foundation; Villum Foundation FX We thank T. Romeo for the csrA::kan mutant strain, M. Otto for the anti-PIA antiserum, and S. Gottesman, N. De Lay, and members of the Storz laboratory for comments on the manuscript. Work in the G.S. laboratory was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Work in the P.V.-H. laboratory was supported by The Danish Council for Independent Research (FNU). M.G.J. was supported by the Lundbeck Foundation and Villum Foundation. NR 56 TC 49 Z9 50 U1 1 U2 20 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAY 15 PY 2013 VL 27 IS 10 BP 1132 EP 1145 DI 10.1101/gad.214734.113 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 150MC UT WOS:000319393800006 PM 23666921 ER PT J AU Bates, SE AF Bates, Susan E. TI PFS: The Endpoint We Love and Love to Hate SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 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 MAY 15 PY 2013 VL 19 IS 10 BP 2606 EP 2606 DI 10.1158/1078-0432.CCR-13-0869 PG 1 WC Oncology SC Oncology GA 144AO UT WOS:000318911600003 PM 23669419 ER PT J AU Sridhara, R Mandrekar, SJ Dodd, LE AF Sridhara, Rajeshwari Mandrekar, Sumithra J. Dodd, Lori E. TI Missing Data and Measurement Variability in Assessing Progression-Free Survival Endpoint in Randomized Clinical Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR PROGRESSION; ONCOLOGY; CANCER; METAANALYSIS AB Progression-free survival (PFS) is frequently used as the primary efficacy endpoint in the evaluation of cancer treatment that is considered for marketing approval. Missing or incomplete data problems become more acute with a PFS endpoint (compared with overall survival). In a given clinical trial, it is common to observe incomplete data due to premature treatment discontinuation, missed or flawed assessments, change of treatment, lack of follow-up, and unevaluable data. When incomplete data issues are substantial, interpretation of the data becomes tenuous. Plans to prevent, minimize, or properly analyze incomplete data are critical for generalizability of results from the clinical trial. Variability in progressive disease measurement between radiologists further contributes to data problems with a PFS endpoint. The repercussions of this on phase III clinical trials are complex and depend on several factors, including the magnitude of the variability and whether there is a systematic reader evaluation bias favoring one treatment arm particularly in open-label trials. (C) 2013 AACR. C1 [Sridhara, Rajeshwari] US FDA, CDER OTS OB DBV, Silver Spring, MD 20993 USA. [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Mandrekar, Sumithra J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. RP Sridhara, R (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rajeshwari.sridhara@fda.hhs.gov; doddl@mail.nih.gov NR 22 TC 10 Z9 10 U1 2 U2 4 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 MAY 15 PY 2013 VL 19 IS 10 BP 2613 EP 2620 DI 10.1158/1078-0432.CCR-12-2938 PG 8 WC Oncology SC Oncology GA 144AO UT WOS:000318911600005 PM 23669421 ER PT J AU Zhang, JJ Zhang, LJ Chen, HY Murgo, AJ Dodd, LE Pazdur, R Sridhara, R AF Zhang, Jenny J. Zhang, Lijun Chen, Huanyu Murgo, Anthony J. Dodd, Lori E. Pazdur, Richard Sridhara, Rajeshwari TI Assessment of Audit Methodologies for Bias Evaluation of Tumor Progression in Oncology Clinical Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID METAANALYSIS AB As progression-free survival (PFS) has become increasingly used as the primary endpoint in oncology phase III trials, the U.S. Food and Drug Administration (FDA) has generally required a complete-case blinded independent central review (BICR) of PFS to assess and reduce potential bias in the investigator or local site evaluation. However, recent publications and FDA analyses have shown a high correlation between local site evaluation and BICR assessments of the PFS treatment effect, which questions whether complete-case BICR is necessary. One potential alternative is to use BICR as an audit tool to detect evaluation bias in the local site evaluation. In this article, the performance characteristics of two audit methods proposed in the literature are evaluated on 26 prospective, randomized phase III registration trials in nonhematologic malignancies. The results support that a BICR audit to assess potential bias in the local site evaluation is a feasible approach. However, implementation and logistical challenges need further consideration and discussion. (C) 2013 AACR. C1 [Zhang, Jenny J.; Zhang, Lijun; Chen, Huanyu; Sridhara, Rajeshwari] US FDA, Div Biometr 5, Off Biostat, Off Translat Sci, Silver Spring, MD 20993 USA. [Murgo, Anthony J.; Pazdur, Richard] US FDA, Off Hematol & Oncol Prod, Off New Drugs, Ctr Drug Evaluat Res, Silver Spring, MD 20993 USA. [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Sridhara, R (reprint author), US FDA, WO21,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM rajeshwari.sridhara@fda.hhs.gov NR 8 TC 8 Z9 8 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 MAY 15 PY 2013 VL 19 IS 10 BP 2637 EP 2645 DI 10.1158/1078-0432.CCR-12-3364 PG 9 WC Oncology SC Oncology GA 144AO UT WOS:000318911600008 PM 23532893 ER PT J AU Lee, TH Han, SH Yang, JD Kim, D Ahmed, M AF Lee, Tae Hoon Han, Seung Hye Yang, Ju Dong Kim, Donghee Ahmed, Monjur TI Prediction of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: An Enhanced Model of BARD Score SO GUT AND LIVER LA English DT Article DE Non-alcoholic fatty liver disease; Liver cirrhosis; International normalized ratio ID HEPATIC STEATOSIS; UNITED-STATES; NAFLD; PREVALENCE; STEATOHEPATITIS; POPULATION; DIAGNOSIS; STIFFNESS; MARKERS; SYSTEM AB Background/Aims: The BARD score is a model to detect advanced liver fibrosis in nonalcoholic fatty liver disease (NAFLD) patients. The aims of this study were to identify additional factors and then to build an enhanced version of the BARD score. Methods: One hundred seven patients with biopsy-proven NAFLD were enrolled retrospectively. Logistic regressions were performed to identify independent risk factors for advanced liver fibrosis (stage 3 or 4). An enhanced model of the BARD score (BARDI score) was built and evaluated with a receiver operating characteristic (ROC) curve. Results: In multivariate analysis, age (odds ratio [OR], 0.89; p=0.04), aspartate aminotransferase/alanine aminotransferase ratio (OR, 1.73; p<0.01), and international normalized ratio (INR) (OR, 8.85; p<0.01) were independently significant factors. The BARDI score was created by adding the INR to the BARD. The area under the ROC curve of the BARDI score was significantly larger than that of the BARD score (0.881 vs 0.808, p<0.01). A BARDI score of 3 or more showed a positive predictive value (PPV) of 51.0% and a negative predictive value (NPV) of 96.0%. Conclusions: The BARDI score had an improved PPV over the BARD score and maintained an excellent NPV. Further study is warranted for its external validation and comparison with other models. C1 [Lee, Tae Hoon] Marshall Univ, Sch Med, Dept Internal Med, Huntington, WV USA. [Han, Seung Hye] NIH, Bethesda, MD 20892 USA. [Yang, Ju Dong; Kim, Donghee] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Kim, Donghee] Seoul Natl Univ Hosp Healthcare Syst, Inst Healthcare Res, Dept Internal Med, Seoul, South Korea. [Ahmed, Monjur] Thomas Jefferson Univ, Jefferson Med Coll, Div Gastroenterol & Hepatol, Philadelphia, PA 19107 USA. RP Ahmed, M (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Div Gastroenterol & Hepatol, 132 South 10th St,Main Bldg,Suite 480, Philadelphia, PA 19107 USA. EM monjur.ahmed@jefferson.edu OI Kim, Donghee/0000-0003-1919-6800 NR 19 TC 7 Z9 7 U1 0 U2 6 PU EDITORIAL OFFICE GUT & LIVER PI SEOUL PA 305 LOTTE GOLD ROSE II, 890-59, DAECHI 4-DONG, GANGNAM-GU, SEOUL, 135-839, SOUTH KOREA SN 1976-2283 J9 GUT LIVER JI Gut Liver PD MAY 15 PY 2013 VL 7 IS 3 BP 323 EP 328 DI 10.5009/gnl.2013.7.3.323 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 146OI UT WOS:000319100000010 PM 23710314 ER PT J AU Dhanoa, BS Cogliati, T Satish, AG Bruford, EA Friedman, JS AF Dhanoa, Bajinder S. Cogliati, Tiziana Satish, Akhila G. Bruford, Elspeth A. Friedman, James S. TI Update on the Kelch-like (KLHL) gene family SO HUMAN GENOMICS LA English DT Review DE KLHL; Kelch domain; BTB domain; Ubiquitination; Gene family; Evolution; Mendelian disease; Gene nomenclature; Cancer ID DOMINANT RETINITIS-PIGMENTOSA; TRANSCRIPTION FACTOR NRF2; PROTEIN INTERACTION MOTIF; GIANT AXONAL NEUROPATHY; UBIQUITIN LIGASE; SUBCELLULAR-LOCALIZATION; PROTEASOMAL DEGRADATION; BTB/POZ DOMAIN; LUNG-CANCER; KEAP1 AB The Kelch-like (KLHL) gene family encodes a group of proteins that generally possess a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. BTB domains facilitate protein binding and dimerization. The BACK domain has no known function yet is of functional importance since mutations in this domain are associated with disease. Kelch domains form a tertiary structure of beta-propellers that have a role in extracellular functions, morphology, and binding to other proteins. Presently, 42 KLHL genes have been classified by the HUGO Gene Nomenclature Committee (HGNC), and they are found across multiple human chromosomes. The KLHL family is conserved throughout evolution. Phylogenetic analysis of KLHL family members suggests that it can be subdivided into three subgroups with KLHL11 as the oldest member and KLHL9 as the youngest. Several KLHL proteins bind to the E3 ligase cullin 3 and are known to be involved in ubiquitination. KLHL genes are responsible for several Mendelian diseases and have been associated with cancer. Further investigation of this family of proteins will likely provide valuable insights into basic biology and human disease. C1 [Dhanoa, Bajinder S.; Friedman, James S.] Univ Colorado, Sch Med, Dept Ophthalmol, Aurora, CO 80045 USA. [Cogliati, Tiziana; Satish, Akhila G.] NEI, N NRL, NIH, Bethesda, MD 20892 USA. [Bruford, Elspeth A.] EMBL EBI, HUGO Gene Nomenclature Comm HGNC, Hinxton CB10 1SD, Cambs, England. RP Friedman, JS (reprint author), Univ Colorado, Sch Med, Dept Ophthalmol, Aurora, CO 80045 USA. EM james.friedman@ucdenver.edu OI Bruford, Elspeth/0000-0002-8380-5247 FU NHGRI NIH HHS [P41 HG003345] NR 48 TC 43 Z9 45 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 J9 HUM GENOMICS JI Hum. Genomics PD MAY 15 PY 2013 VL 7 AR 13 DI 10.1186/1479-7364-7-13 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 151FV UT WOS:000319447000001 PM 23676014 ER PT J AU Xue, L Sheng, JS Wu, XS Wu, W Luo, FJ Shin, WC Chiang, HC Wu, LG AF Xue, Lei Sheng, Jiansong Wu, Xin-Sheng Wu, Wei Luo, Fujun Shin, Wonchul Chiang, Hsueh-Cheng Wu, Ling-Gang TI Most Vesicles in a Central Nerve Terminal Participate in Recycling SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SYNAPTIC VESICLES; TRANSMITTER RELEASE; 2 MODES; ENDOCYTOSIS; SINGLE; DEPRESSION; POOLS; CALYX; SYNAPSES; CNS AB Studies over the last decade using FM dyes to label vesicles at many terminals, including the calyx-type nerve terminal, led to a well accepted "principle" that only a small fraction of vesicles (similar to 5-20%) participate in recycling under physiological conditions. This principle imposes a large challenge in maintaining synaptic transmission during repetitive firing, because the small recycling pool may limit the number of available vesicles for release and nerve terminals would have to distinguish the recycling pool from the reserve pool and keep reserve pool vesicles from being used. By recording the presynaptic capacitance changes and the postsynaptic EPSC at rat calyx of Held synapses in the absence or presence of transmitter glutamate in nerve terminals, we developed a new method to count functional recycling vesicles. We found that essentially all vesicles in calyces participated in recycling, challenging the small-recycling-pool principle established by FM dye labeling. Nerve terminals may use all available vesicles to maximize their ability in maintaining synaptic transmission during repetitive firing. C1 [Xue, Lei; Sheng, Jiansong; Wu, Xin-Sheng; Wu, Wei; Luo, Fujun; Shin, Wonchul; Chiang, Hsueh-Cheng; Wu, Ling-Gang] Natl Inst Neurol Disorders & Stroke, Synapt Transmiss Sect, Bethesda, MD 20892 USA. [Xue, Lei] Fudan Univ, Dept Physiol & Biophys, Shanghai 200433, Peoples R China. RP Wu, LG (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Transmiss Sect, 35 Convent Dr,Bldg 35,Room 2B-1012, Bethesda, MD 20892 USA. EM lxue@fudan.edu.cn; wul@ninds.nih.gov RI Luo, Fujun/I-1016-2013; SHENG, JIANSONG/K-1914-2013 FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. NR 34 TC 11 Z9 11 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 15 PY 2013 VL 33 IS 20 BP 8820 EP 8826 DI 10.1523/JNEUROSCI.4029-12.2013 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 146SZ UT WOS:000319112600022 PM 23678124 ER PT J AU McCormick, BJJ Sanchez-Vazquez, MJ Lewis, FI AF McCormick, B. J. J. Sanchez-Vazquez, M. J. Lewis, F. I. TI Using Bayesian networks to explore the role of weather as a potential determinant of disease in pigs SO PREVENTIVE VETERINARY MEDICINE LA English DT Article DE Bayesian networks; Climate; Weather; Pigs; Surveillance ID SCABIEI VAR CANIS; CLIMATE-CHANGE; ASCARIS-SUUM; SARCOPTIC MANGE; GREAT-BRITAIN; LIVESTOCK; HEALTH; SWINE; PATHOLOGIES; BUILDINGS AB Many pathogens are sensitive to climatic variables and this is reflected in their seasonality of occurrence and transmission. The identification of environmental conditions that influence disease occurrence can be subtle, particularly considering their complex interdependencies in addition to those relationships between climate and disease. Statistical treatment of environmental variables is often dependent on their correlations and thus descriptions of climate are often restricted to means rather than accounting for the more precise aspects (including mean, maximum, minimum, variability). Here we utilize a novel multivariate statistical modelling approach, additive Bayesian network (ABN) analyses, to identify the inter-linkages of different weather variables to better capture short-term environmental conditions that are important drivers of disease. We present a case study that explores weather as a driver of disease in livestock systems. We utilize quality assurance health scheme data on ten major diseases of pigs from 875 finishing pig herds distributed across the United Kingdom over 7 years (2005-2011). We examine the relationship between the occurrence of these pathologies and contemporary weather conditions measured by local meteorological stations. All ten pathologies were associated with at least 2 other pathologies (maximum 6). Three pathologies were associated directly with temperature variables: papular dermatitis, enzootic pneumonia and milk spots. Latitude was strongly associated with multiple pathologies, though associations with longitude were eliminated when clustering for repeated observations of farms was assessed. The identification of relationships between climatic factors and different (potentially related) diseases offers a more comprehensive insight into the complex role of seasonal drivers and herd health status than traditional analytical methods. (C) 2013 Elsevier B.V. All rights reserved. C1 [McCormick, B. J. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Sanchez-Vazquez, M. J.] OIE Org Mondiale Sante Anim, F-75017 Paris, France. [Lewis, F. I.] Univ Zurich, Epidemiol Sect, Zurich, Switzerland. RP Lewis, FI (reprint author), Univ Zurich, Epidemiol Sect, Zurich, Switzerland. EM fraseriain.lewis@uzh.ch RI Lewis, Fraser/A-3635-2011 OI Lewis, Fraser/0000-0003-1145-8271 FU Intramural NIH HHS [Z99 TW999999] NR 61 TC 4 Z9 4 U1 4 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5877 J9 PREV VET MED JI Prev. Vet. Med. PD MAY 15 PY 2013 VL 110 IS 1 SI SI BP 54 EP 63 DI 10.1016/j.prevetmed.2013.02.001 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA 143SH UT WOS:000318888000007 PM 23465608 ER PT J AU Polepally, PR White, K Vardy, E Roth, BL Ferreira, D Zjawiony, JK AF Polepally, Prabhakar R. White, Kate Vardy, Eyal Roth, Bryan L. Ferreira, Daneel Zjawiony, Jordan K. TI Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Salvia divinorum; Salvinorin A and B; Dicarboxylic ester-type ligands; Kappa-opioid receptor agonists ID A ANALOGS; IN-VITRO; PROBES; AGONIST; POTENT AB Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective kappa-opioid receptor agonist. To better understand the ligand-receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at kappa-, delta- and mu-opioid receptors. Most of the analogues show high affinity to the kappa-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (K-i = 2 nM), analogues 5, 7, and 14 exhibit significant affinity for the kappa-receptor (K-i = 21, 36 and 39 nM). (C) 2013 Elsevier Ltd. All rights reserved. C1 [Polepally, Prabhakar R.; Ferreira, Daneel; Zjawiony, Jordan K.] Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. [Polepally, Prabhakar R.; Ferreira, Daneel; Zjawiony, Jordan K.] Univ Mississippi, Sch Pharm, Pharmaceut Sci Res Inst, University, MS 38677 USA. [White, Kate; Vardy, Eyal; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [White, Kate; Vardy, Eyal; Roth, Bryan L.] Univ N Carolina, Sch Pharm, NIMH Psychoact Drug Screening Program, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. RP Zjawiony, JK (reprint author), Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. EM jordan@olemiss.edu RI Polepally, Prabhakar /G-9202-2014; Roth, Bryan/F-3928-2010 FU NIH [R01 DA017204]; NIMH Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill, NC FX This work was supported by the NIH Grant R01 DA017204 and the NIMH Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill, NC 27599. We thank Mr. Daniel J. Siebert from the Salvia divinorum Research and Information Center for supplying the plant material, and Dr. Bin Wang for the assistance with HRESIMS. NR 17 TC 10 Z9 10 U1 1 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 15 PY 2013 VL 23 IS 10 BP 2860 EP 2862 DI 10.1016/j.bmcl.2013.03.111 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 141TS UT WOS:000318750000004 PM 23587424 ER PT J AU Abzug, MJ Nachman, SA Muresan, P Handelsman, E Watts, DH Fenton, T Heckman, B Petzold, E Weinberg, A Levin, MJ AF Abzug, Mark J. Nachman, Sharon A. Muresan, Petronella Handelsman, Edward Watts, D. Heather Fenton, Terence Heckman, Barbara Petzold, Elizabeth Weinberg, Adriana Levin, Myron J. CA Int Maternal Pediat Adolescent TI Safety and Immunogenicity of 2009 pH1N1 Vaccination in HIV-Infected Pregnant Women SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE pH1N1; vaccine; HIV-infected; pregnancy; immunogenicity ID PANDEMIC H1N1 INFLUENZA; IMMUNE-RESPONSE; ANTIBODY-RESPONSE; A(H1N1) VACCINE; YOUNG-ADULTS; A VACCINE; TRIAL; IMMUNIZATION; CHILDREN; MOTHERS AB Background. Pregnant women infected with human immunodeficiency virus (HIV) may have particular vulnerability to 2009 pandemic H1N1 influenza (pH1N1) infection. The safety and immunogenicity of pH1N1 vaccination in HIV-infected pregnant women are unknown. Methods. HIV-infected women 18-39 years of age and 14-34 weeks' gestation on antiretroviral therapy received two 30-mu g doses of unadjuvanted, inactivated pH1N1 vaccine 21 days apart. Hemagglutination inhibition titers were measured at entry, 21 days after dose 1, and 10 and 21 days after dose 2, and, in mothers and infants, at delivery and 3 and 6 months postdelivery. Results. No severe vaccine-related adverse events were observed among 127 subjects. At entry, 21% had seroprotective (>= 1:40) titers. Seroprotection and seroresponse (>= 4-fold rise) occurred in 73% and 66% after dose 1 and 80% and 72% after dose 2, respectively. Of women lacking seroprotection at entry, 66% attained seroprotection after dose 1 and 75% after dose 2. Seroprotective titers were present in 67% of mothers and 65% of infants at delivery (median 66 days after dose 2), 60% of mothers and 26% of infants at 3 months postdelivery, and 59% of mothers and 12% of infants at 6 months postdelivery. Conclusions. Two 30-mu g doses were moderately immunogenic in HIV-infected pregnant women. No concerning vaccine-related safety signals were observed. Seroprotection persisted in most women postpartum. Efficient transplacental antibody transfer occurred, but seroprotection in infants waned rapidly. Vaccination to protect HIV-infected pregnant women and their newborns from new influenza strains is feasible, but more immunogenic platforms should be evaluated. C1 [Abzug, Mark J.; Weinberg, Adriana; Levin, Myron J.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Abzug, Mark J.; Weinberg, Adriana; Levin, Myron J.] Childrens Hosp Colorado, Aurora, CO 80045 USA. [Nachman, Sharon A.] SUNY Stony Brook, Hlth Sci Ctr, Dept Pediat, Stony Brook, NY 11794 USA. [Muresan, Petronella; Fenton, Terence] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Handelsman, Edward] NIAID, Div Aids, Bethesda, MD 20892 USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Heckman, Barbara] Frontier Sci & Technol Res Fdn Inc, Buffalo, NY USA. [Petzold, Elizabeth] Social & Sci Syst, Silver Spring, MD USA. RP Abzug, MJ (reprint author), Childrens Hosp Colorado, 13123 E 16th Ave,Box B055, Aurora, CO 80045 USA. EM mark.abzug@childrenscolorado.org FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group; IMPAACT Group [1 U01 AI068616]; NIAID; NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network; NICHD [N01-DK-9-001/HHSN2672008 00001C]; NIH/NCATS Colorado CTSI grant [UL1 TR000154]; NIH/NCRR UCSF-CTSI [UL1 RR024131]; General Clinical Research Centers/National Institutes of Health [RR00069] FX Overall support for the IMPAACT study group was provided by the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (AI068632). This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID cooperative agreement 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group and 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN2672008 00001C); NIH/NCATS Colorado CTSI grant number UL1 TR000154; NIH/NCRR UCSF-CTSI (grant number UL1 RR024131); and General Clinical Research Centers/National Institutes of Health (grant M01 number RR00069). Pharmaceutical support was provided by Novartis, through the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, US Department of Health and Human Services. NR 38 TC 15 Z9 15 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2013 VL 56 IS 10 BP 1488 EP 1497 DI 10.1093/cid/cit057 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 140EF UT WOS:000318636500023 PM 23378284 ER PT J AU Schultheis, PJ Fleming, SM Clippinger, AK Lewis, J Tsunemi, T Giasson, B Dickson, DW Mazzulli, JR Bardgett, ME Haik, KL Ekhator, O Chava, AK Howard, J Gannon, M Hoffman, E Chen, YH Prasad, V Linn, SC Tamargo, RJ Westbroek, W Sidransky, E Krainc, D Shull, GE AF Schultheis, Patrick J. Fleming, Sheila M. Clippinger, Amy K. Lewis, Jada Tsunemi, Taiji Giasson, Benoit Dickson, Dennis W. Mazzulli, Joseph R. Bardgett, Mark E. Haik, Kristi L. Ekhator, Osunde Chava, Anil Kumar Howard, John Gannon, Matt Hoffman, Elizabeth Chen, Yinhuai Prasad, Vikram Linn, Stephen C. Tamargo, Rafael J. Westbroek, Wendy Sidransky, Ellen Krainc, Dimitri Shull, Gary E. TI Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited -synuclein accumulation and age-dependent sensorimotor deficits SO HUMAN MOLECULAR GENETICS LA English DT Article ID P-TYPE ATPASE; KUFOR-RAKEB-SYNDROME; PALLIDO-PYRAMIDAL DEGENERATION; SUPRANUCLEAR UPGAZE PARESIS; ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; ATP13A2 MUTATIONS; TRANSGENIC MICE; DOPAMINERGIC-NEURONS; CEREBROSPINAL-FLUID AB Mutations in ATP13A2 (PARK9), encoding a lysosomal P-type ATPase, are associated with both KuforRakeb syndrome (KRS) and neuronal ceroid lipofuscinosis (NCL). KRS has recently been classified as a rare genetic form of Parkinsons disease (PD), whereas NCL is a lysosomal storage disorder. Although the transport activity of ATP13A2 has not been defined, in vitro studies show that its loss compromises lysosomal function, which in turn is thought to cause neuronal degeneration. To understand the role of ATP13A2 dysfunction in disease, we disrupted its gene in mice. Atp13a2(/) and Atp13a2(/) mice were tested behaviorally to assess sensorimotor and cognitive function at multiple ages. In the brain, lipofuscin accumulation, -synuclein aggregation and dopaminergic pathology were measured. Behaviorally, Atp13a2(/) mice displayed late-onset sensorimotor deficits. Accelerated deposition of autofluorescent storage material (lipofuscin) was observed in the cerebellum and in neurons of the hippocampus and the cortex of Atp13a2(/) mice. Immunoblot analysis showed increased insoluble -synuclein in the hippocampus, but not in the cortex or cerebellum. There was no change in the number of dopaminergic neurons in the substantia nigra or in striatal dopamine levels in aged Atp13a2(/) mice. These results show that the loss of Atp13a2 causes sensorimotor impairments, -synuclein accumulation as occurs in PD and related synucleinopathies, and accumulation of lipofuscin deposits characteristic of NCL, thus providing the first direct demonstration that null mutations in Atp13a2 can cause pathological features of both diseases in the same organism. C1 [Schultheis, Patrick J.; Clippinger, Amy K.; Haik, Kristi L.; Chava, Anil Kumar; Linn, Stephen C.] No Kentucky Univ, Dept Biol Sci, Highland Hts, KY 41099 USA. [Bardgett, Mark E.; Gannon, Matt; Hoffman, Elizabeth] No Kentucky Univ, Dept Psychol Sci, Highland Hts, KY 41099 USA. [Fleming, Sheila M.; Ekhator, Osunde] Univ Cincinnati, Dept Psychol & Neurol, Cincinnati, OH 45267 USA. [Chen, Yinhuai; Prasad, Vikram; Shull, Gary E.] Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA. [Lewis, Jada; Giasson, Benoit; Howard, John] Univ Florida, Dept Neurosci, Gainesville, FL 32610 USA. [Lewis, Jada; Giasson, Benoit; Howard, John] Univ Florida, Ctr Translat Res Neurodegenerat Dis, Gainesville, FL 32610 USA. [Dickson, Dennis W.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Tsunemi, Taiji; Mazzulli, Joseph R.; Krainc, Dimitri] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Sch Med, Boston, MA 02114 USA. [Tsunemi, Taiji; Mazzulli, Joseph R.; Krainc, Dimitri] Mass Gen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Tamargo, Rafael J.; Westbroek, Wendy; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Schultheis, PJ (reprint author), No Kentucky Univ, Dept Biol Sci, Highland Hts, KY 41099 USA. EM schultheisp@nku.edu FU National Institutes of Health [NS070268, GM103436, DK050594, HL061974, NS077022, MH094955, NS076054]; UF CTRND; Department of Neuroscience; UC Gardner Family Center for Parkinson's Disease and Movement Disorders; Intramural Research program of the National Human Genome Research Institute at the National Institutes of Health, Bethesda, MD, USA FX This work was supported by the National Institutes of Health (NS070268 to P.J.S., GM103436 to P.J.S. and M. E. B., DK050594 and HL061974 to G. E. S., NS077022 to S. M. F., MH094955 to M. E. B., NS076054 to D. K.); the UF CTRND and Department of Neuroscience; the UC Gardner Family Center for Parkinson's Disease and Movement Disorders and the Intramural Research program of the National Human Genome Research Institute at the National Institutes of Health, Bethesda, MD, USA. NR 84 TC 36 Z9 38 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2013 VL 22 IS 10 BP 2067 EP 2082 DI 10.1093/hmg/ddt057 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 139CL UT WOS:000318559000013 PM 23393156 ER PT J AU Crosslin, DR McDavid, A Weston, N Zheng, XW Hart, E Andrade, M Kullo, IJ McCarty, CA Doheny, KF Pugh, E Kho, A Hayes, MG Ritchie, MD Saip, A Crawford, DC Crane, PK Newton, K Carrell, DS Gallego, CJ Nalls, MA Li, R Mirel, DB Crenshaw, A Couper, DJ Tanaka, T van Rooij, FJA Chen, MH Smith, AV Zakai, NA Yango, Q Garcia, M Liu, YM Lumley, T Folsom, AR Reiner, AP Felix, JF Dehghan, A Wilson, JG Bis, JC Fox, CS Glazer, NL Cupples, A Coresh, J Eiriksdottir, G Gudnason, V Bandinelli, S Frayling, TM Chakravarti, A van Duijn, CM Melzer, D Levy, D Boerwinkle, E Singleton, AB Hernandez, DG Longo, DL Witteman, JCM Psaty, BM Ferrucci, L Harris, TB O'Donnell, CJ Ganesh, SK Larson, EB Carlson, CS Jarvik, GP AF Crosslin, David R. McDavid, Andrew Weston, Noah Zheng, Xiuwen Hart, Eugene de Andrade, Mariza Kullo, Iftikhar J. McCarty, Catherine A. Doheny, Kimberly F. Pugh, Elizabeth Kho, Abel Hayes, M. Geoffrey Ritchie, Marylyn D. Saip, Alexander Crawford, Dana C. Crane, Paul K. Newton, Katherine Carrell, David S. Gallego, Carlos J. Nalls, Michael A. Li, Rongling Mirel, Daniel B. Crenshaw, Andrew Couper, David J. Tanaka, Toshiko van Rooij, Frank J. A. Chen, Ming-Huei Smith, Albert V. Zakai, Neil A. Yango, Qiong Garcia, Melissa Liu, Yongmei Lumley, Thomas Folsom, Aaron R. Reiner, Alex P. Felix, Janine F. Dehghan, Abbas Wilson, James G. Bis, Joshua C. Fox, Caroline S. Glazer, Nicole L. Cupples, Adrienne Coresh, Josef Eiriksdottir, Gudny Gudnason, Vilmundur Bandinelli, Stefania Frayling, Timothy M. Chakravarti, Aravinda van Duijn, Cornelia M. Melzer, David Levy, Daniel Boerwinkle, Eric Singleton, Andrew B. Hernandez, Dena G. Longo, Dan L. Witteman, Jacqueline C. M. Psaty, Bruce M. Ferrucci, Luigi Harris, Tamara B. O'Donnell, Christopher J. Ganesh, Santhi K. Larson, Eric B. Carlson, Chris S. Jarvik, Gail P. CA CHARGE Hematology Working Grp Elect Med Records Genomics eMERGE TI Genetic variation associated with circulating monocyte count in the eMERGE Network SO HUMAN MOLECULAR GENETICS LA English DT Article ID BLOOD-CELL COUNT AB With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value 2.7810(16), 0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value 1.8810(7), 0.30) and a region of replication found in ribophorin I (RPN1) (P-value 2.6310(16), 0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value 2.2910(7), 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value 5.6810(17), 0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count. C1 [Crosslin, David R.; Gallego, Carlos J.; Jarvik, Gail P.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Crosslin, David R.; Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Zheng, Xiuwen; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Crane, Paul K.] Univ Washington, Div Gen Internal Med, Seattle, WA 98195 USA. [Reiner, Alex P.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Bis, Joshua C.; Glazer, Nicole L.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.; Glazer, Nicole L.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [McDavid, Andrew; Carlson, Chris S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Weston, Noah; Hart, Eugene; Newton, Katherine; Carrell, David S.; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA. [de Andrade, Mariza] Div Biomed Stat & Informat, Rochester, MN USA. [Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [McCarty, Catherine A.] Marshfield Clin Fdn Med Res & Educ, Ctr Human Genet, Marshfield, WI 54449 USA. [Doheny, Kimberly F.; Pugh, Elizabeth] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD USA. [Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Chakravarti, Aravinda] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Kho, Abel] Northwestern Univ, Div Gen Internal Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Kho, Abel] Northwestern Univ, Div Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Hayes, M. Geoffrey] Northwestern Univ, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, Ctr Syst Genom, University Pk, PA 16802 USA. [Saip, Alexander] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN USA. [Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Garcia, Melissa; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Li, Rongling] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Mirel, Daniel B.; Crenshaw, Andrew; Singleton, Andrew B.; Hernandez, Dena G.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Couper, David J.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [van Rooij, Frank J. A.; Felix, Janine F.; Dehghan, Abbas; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Rooij, Frank J. A.; Felix, Janine F.; Dehghan, Abbas; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Netherlands Consortium Healthy Aging NGI NCHA, Netherlands Genom Initiat, Leiden, Netherlands. [Chen, Ming-Huei; Yango, Qiong; Fox, Caroline S.; Cupples, Adrienne; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Yango, Qiong; Cupples, Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Liu, Yongmei] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Bandinelli, Stefania] Geriatr Unit ASF, Florence, Italy. [Frayling, Timothy M.; Melzer, David] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Melzer, David] PCMD, European Ctr Environm & Human Hlth, Truro, England. [Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Hernandez, Dena G.] UCL, Dept Mol Neurosci, London, England. [Hernandez, Dena G.] UCL, Inst Neurol, Reta Lila Labs, London, England. [Longo, Dan L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Dept Grp Hlth, Seattle, WA USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. RP Crosslin, DR (reprint author), Univ Washington, Dept Genome Sci, S213,Campus Mail Box 355065, Seattle, WA 98195 USA. EM davidcr@u.washington.edu RI Crane, Paul/C-8623-2014; Singleton, Andrew/C-3010-2009; Jarvik, Gail/N-6476-2014; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; OI Cupples, L. Adrienne/0000-0003-0273-7965; Felix, Janine/0000-0002-9801-5774; Crane, Paul/0000-0003-4278-7465; McDavid, Andrew/0000-0002-6581-1213; Zheng, Xiuwen/0000-0002-1390-0708; Jarvik, Gail/0000-0002-6710-8708; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Melzer, David/0000-0002-0170-3838; Dehghan, Abbas/0000-0001-6403-016X FU National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA [HG004610, AG06781, HG04599, HG004608, HG004609, HG004438, HG004424, HG004603]; State of Washington Life Sciences Discovery Fund award; NIA/NIH [AG000932-02]; NIH [N01-AG-12100, HHSN268200625226C, UL1RR025005, HHSN268200782096C]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, R01 HL-071862]; National Human Genome Research Institute [U01HG004402]; Intramural Research Program of the NIH, National Institute on Aging; MedStar Research Institute; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix for genotyping services [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; Intramural Research Program of the NIH, National Institute on Aging, NIA [N01AG62101, N01AG62103, N01AG62106]; NIA [1R01AG032098-01A1]; Italian Ministry of Health [ICS 110.1RS97.71]; U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336]; Intramural Research Program, National Institute on Aging, National Institutes of Health, USA; Netherlands Organization of Scientific Research NWO [175.010.2005.011, 911.03.012]; Research Institute for Diseases in the Elderly (RIDE); Netherlands Genomics Initiative (NGI)/NWO [050 060 810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Netherlands Heart Foundation; Ministry of Education, Culture, and Science; Ministry of Health, Welfare, and Sports; European Commission (DG XII); Municipality of Rotterdam; Netherlands Organization for Scientific Research (NWO, VICI) [918-76-619]; Netherlands Organization for Scientific Research (NWO) FX eMERGE: This study was supported by the following U01 grants from the National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), Bethesda, MD, USA: (i) HG004610, AG06781 (Group Health Cooperative), (ii) HG04599 (Mayo Clinic), (iii) HG004608 (Marshfield Clinic), (iv) HG004609 (Northwestern University), (v) HG004438 (CIDR), (vi) HG004424 (BROAD) and (vii) HG004603 (Vanderbilt University). Additional support was provided by a State of Washington Life Sciences Discovery Fund award to the Northwest Institute of Genetic Medicine (GPJ). CHARGE: This research was made possible by NIA/NIH contract AG000932-02 (2009) Characterization of Normal Genomic Variability. This study utilized the high-performance computational capabilities of the BiowulfLinux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). The Age, Gene/Environment Susceptibility Reykjavik Study was funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. The National Heart, Lung, and Blood Institute's Framingham Heart Study is a joint project of the National Institutes of Health and Boston University School of Medicine and was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195) and its contract with Affymetrix for genotyping services (contract No. N02-HL-6-4278). Analyses reflect the efforts and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The Health ABC Study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, NIA contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The InChianti Study was supported as a 'targeted project' (ICS 110.1RS97.71) by the Italian Ministry of Health, by the U.S. National Institute on Aging (Contracts N01-AG-916413, N01-AG-821336, 263 MD 9164 13 and 263 MD 821336), and in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health, USA.; The GWAS database of the Rotterdam Study was funded through the Netherlands Organization of Scientific Research NWO (nr. 175.010.2005.011, 911.03.012) and the Research Institute for Diseases in the Elderly (RIDE). This study was supported by the Netherlands Genomics Initiative (NGI)/NWO project number 050 060 810 (Netherlands Consortium for Healthy Ageing). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands organization for scientific research (NWO), the Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Netherlands Heart Foundation, the Ministry of Education, Culture, and Science, the Ministry of Health, Welfare, and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. J.F.F. and A. D. were supported by the Netherlands Organization for Scientific Research (NWO, VICI no. 918-76-619). The participation of A. P. R. was supported by National Heart, Lung, and Blood Institute grant R01 HL-071862. NR 17 TC 27 Z9 28 U1 0 U2 8 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 MAY 15 PY 2013 VL 22 IS 10 BP 2119 EP 2127 DI 10.1093/hmg/ddt010 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 139CL UT WOS:000318559000017 PM 23314186 ER PT J AU Peer, CJ Rao, M Spencer, SD Shahbazi, S Steeg, PS Schrump, DS Figg, WD AF Peer, Cody J. Rao, Mahadev Spencer, Shawn D. Shahbazi, Shandiz Steeg, Patricia S. Schrump, David S. Figg, William D. TI A rapid ultra HPLC-MS/MS method for the quantitation and pharmacokinetic analysis of 3-deazaneplanocin A in mice SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE 3-Deazaneplanocin; Ultra HPLC-MS/MS; Pharmacokinetics ID HISTONE METHYLTRANSFERASE EZH2; RENAL-CELL CARCINOMA; ZESTE HOMOLOG 2; PROSTATE-CANCER; DNA METHYLATION; PROLIFERATION; EXPRESSION; ENHANCER; PROGRESSION; INHIBITOR AB 3-Deazaneplanocin A (DZNep) has been shown to have anti-cancer activity in numerous cancer types and its continued preclinical, and eventual clinical, drug development will require rapid and sensitive bioanalytical methods in order to quantitate this drug for pharmacokinetic analyses. The ultra HPLC with positive thermospray tandem mass spectrometric (LC-MS/MS) detection affords the most sensitive (limit of quantitation 5 ng/mL) and rapid (3 min run time) bioanalytical method to date for DZNep. Due to the polar nature of this drug and the internal standard (tubercidin), a hydrophilic-interaction column (HILIC) was used. The method was accurate, with less than 10% deviation from nominal values, as well as precise, where both within-day and between-day precisions were less than 15%. A liquid-liquid extraction procedure was able to recover similar to 90% of drug from a small volume (50 mu L) of mouse plasma. This method was successfully applied to a pharmacokinetic study in mice intravenously injected with DZNep. Published by Elsevier B.V. C1 [Peer, Cody J.; Shahbazi, Shandiz; Figg, William D.] NCI, Clin Pharmacol Program, Off Clin Director, Bethesda, MD 20892 USA. [Rao, Mahadev; Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Spencer, Shawn D.] Fairleigh Dickinson Univ, Sch Pharm, Div Pharmaceut Sci, Florham Pk, NJ USA. [Steeg, Patricia S.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), Clin Pharmacol Program, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wf13e@nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural NIH HHS [ZIC SC006536-19] NR 26 TC 4 Z9 4 U1 1 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD MAY 15 PY 2013 VL 927 SI SI BP 142 EP 146 DI 10.1016/j.jchromb.2013.01.003 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 140PS UT WOS:000318668000013 PM 23352636 ER PT J AU Striebel, JF Race, B Pathmajeyan, M Rangel, A Chesebro, B AF Striebel, J. F. Race, B. Pathmajeyan, M. Rangel, A. Chesebro, B. TI LACK OF INFLUENCE OF PRION PROTEIN GENE EXPRESSION ON KAINATE-INDUCED SEIZURES IN MICE: STUDIES USING CONGENIC, COISOGENIC AND TRANSGENIC STRAINS SO NEUROSCIENCE LA English DT Article DE prion; kainic acid; seizures; Prnp; flanking genes; knockout mice ID CELL-DEATH; PRP; KNOCKOUT; NEURODEGENERATION; SUSCEPTIBILITY; RECEPTORS; EPILEPSY; SCRAPIE; MODELS; ACID AB Prion protein (PrP) is a glycosylphosphatidylinositol (GPI) anchored cell surface protein expressed by many cells, including those of the mammalian nervous system. At present the physiologic functions of PrP remain unclear. Deletion of Prnp, the gene encoding PrP in mice, has been shown to alter normal synaptic and electrophysiologic activities, indicating a potential role in seizure susceptibility. However, published efforts to link PIP with seizures, using both in vivo and in vitro models, are conflicting and difficult to interpret due to use of various mouse backgrounds and seizure induction techniques. Here we investigated the role of PrP in kainic acid (KA)-induced seizure sensitivity, using three types of mice. In contrast to previous published results, Prnp-/- mice on the C57BL/10SnJ background had a significant decrease in KA-induced seizure susceptibility. In genetic complementation experiments using a PrP-expressing transgene, genes derived from strain 129/OIa, which flanked the Prnp-/- locus in C57BL/10SnJ mice, rather than Prnp itself, appeared to account for this effect. Furthermore, using coisogenic 129/OIa mice differing only at Prnp, this difference was not reproduced when comparing PrP-negative and PrP-positive mice. In contrast, substrains of PrP-expressing C57BL mice, showed large variations in KA-induced seizure sensitivity. The magnitude of these differences in susceptibility was larger than that associated with the presence of the Prnp gene, suggesting extensive influence of genes other than Prnp on seizure sensitivity in this system. Published by Elsevier Ltd. on behalf of IBRO. C1 [Striebel, J. F.; Race, B.; Pathmajeyan, M.; Rangel, A.; Chesebro, B.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT USA. EM bchesebro@nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases FX The authors thank Jeff Severson, Donna Norton and Nicolette Arndt for animal husbandry, Katie Phillips, Jay Carroll and Kimberly Meade-White for technical assistance with seizure experiments, and Suzette Priola, Kim Hasenkrug and Leonard Evans for critique of the manuscript. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 24 TC 10 Z9 11 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAY 15 PY 2013 VL 238 BP 11 EP 18 DI 10.1016/j.neuroscience.2013.02.004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 141SH UT WOS:000318746300002 PM 23415788 ER PT J AU Woods, AS Jackson, SN AF Woods, A. S. Jackson, S. N. TI HOW ADENYLATE CYCLASE CHOREOGRAPHS THE PAS DE DEUX OF THE RECEPTORS HETEROMERIZATION DANCE SO NEUROSCIENCE LA English DT Article DE dopamine receptors; adenosine receptor; receptor heteromers; noncovalent interactions; disordered proteins; phosphorylation ID ELECTROSTATIC INTERACTION; PROTEIN-PHOSPHORYLATION; LINEAR MOTIFS; PHOSPHATE; BINDING; DISORDER; ARGININE; A(2A) AB Our work suggests that heteromer formation, mainly involves linear motifs (LMs) found in disordered regions of proteins. Local disorder imparts plasticity to LMs. Most molecular recognition of proteins occurs between short linear segments, known as LMs. Interaction of short continuous epitopes is not constrained by sequence and has the advantage of resulting in interactions with micromolar affinities which suit transient, reversible complexes such as receptor heteromers. Electrostatic interactions between epitopes of the G-protein coupled receptors (GPCR) involved, are the key step in driving heteromer formation forward. The first step in heteromerization, involves phosphorylating Ser/Thr in an epitope containing a casein kinase 112-consensus site. Our data suggest that dopaminergic neurotransmission, through cAMP-dependent protein kinase A (PKA) slows down heteromerization. The negative charge, acquired by the phosphorylation of a Ser/Thr in a PKA consensus site in the Arg-rich epitope, affects the activity of the receptors involved in heteromerization by causing allosteric conformational changes, due to the repulsive effect generated by the negatively charged phosphate. In addition to modulating heteromerization, it affects the stability of the heteromers' interactions and their binding affinity. So here we have an instance where phosphorylation is not just an on/off switch, instead by weakening the noncovalent bond, heteromerization acts like a rheostat that controls the stability of the heteromer through activation or inhibition of adenylate cyclase by the neurotransmitter Dopamine depending on which Dopamine receptor it docks at. Published by Elsevier Ltd. on behalf of IBRO. C1 [Woods, A. S.; Jackson, S. N.] NIDA IRP, Struct Biol Unit, Integrat Neurosci Branch, NIH, Baltimore, MD 21224 USA. RP Woods, AS (reprint author), NIDA IRP, NIH, 333 Cassell Dr,Room 1120, Baltimore, MD 21224 USA. EM awoods@mail.nih.gov FU National Institute on Drug Abuse; Office of National Drug Control Policy (ONDCP) FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse. The authors thank Drs. Marisela Morales and Aurelie Roux for their intellectual input, the Office of National Drug Control Policy (ONDCP) for instrumentation funding, without which this and other projects could not have been accomplished. NR 27 TC 10 Z9 10 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAY 15 PY 2013 VL 238 BP 335 EP 344 DI 10.1016/j.neuroscience.2013.02.006 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 141SH UT WOS:000318746300031 PM 23434492 ER PT J AU Jiang, ZH Rompala, GR Zhang, SQ Cowell, RM Nakazawa, K AF Jiang, Zhihong Rompala, Gregory R. Zhang, Shuqin Cowell, Rita M. Nakazawa, Kazu TI Social Isolation Exacerbates Schizophrenia-Like Phenotypes via Oxidative Stress in Cortical Interneurons SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Interneuron; NMDA receptor hypofunction; oxidative stress; parvalbumin; PGC-1 alpha; schizophrenia; social isolation; transgenic mice ID RECENT-ONSET SCHIZOPHRENIA; NADPH-OXIDASE; ANTIOXIDANT DEFENSE; GAMMA-OSCILLATIONS; TRANSGENIC MICE; ANIMAL-MODELS; NEURONS; ACTIVATION; MICROGLIA; HIPPOCAMPUS AB Background: Our previous studies indicated that N-methyl-D-aspartate receptor (NMDAR) deletion from a subset of corticolimbic interneurons in the mouse brain during early postnatal development is sufficient to trigger several behavioral and pathophysiological features resembling the symptoms of human schizophrenia. Interestingly, many of these behavioral phenotypes are exacerbated by social isolation stress. However, the mechanisms underlying the exacerbating effects of social isolation are unclear. Methods: With gamma-aminobutyric acid-ergic interneuron-specific NMDAR hypofunction mouse model (Ppp1r2-Cre/fGluN1 knockout [KO] mice), we investigated whether oxidative stress is implicated in the social isolation-induced exacerbation of schizophrenia-like phenotypes and further explored the underlying mechanism of elevated oxidative stress in KO mice. Results: The reactive oxygen species (ROS) level in the cortex of group-housed KO mice was normal at 8 weeks although increased at 16 weeks old. Postweaning social isolation (PWSI) augmented the ROS levels in KO mice at both ages, which was accompanied by the onset of behavioral phenotype. Chronic treatment with apocynin, an ROS scavenger, abolished markers of oxidative stress and partially alleviated schizophrenia-like behavioral phenotypes in KO mice. Markers of oxidative stress after PWSI were especially prominent in cortical parvalbumin (PV)-positive interneurons. The vulnerability of PV interneurons to oxidative stress was associated with downregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), a master regulator of mitochondrial energy metabolism and antioxidation. Conclusions: These results suggest that a PWSI-mediated impairment in antioxidant defense mechanisms, presumably mediated by PGC-1 alpha, downregulation in the NMDAR-deleted PV-positive interneurons, results in oxidative stress, which, in turn, might contribute to exacerbation of schizophrenia-like behavioral phenotypes. C1 [Jiang, Zhihong; Rompala, Gregory R.; Zhang, Shuqin; Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cowell, Rita M.] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. RP Nakazawa, K (reprint author), NIMH, 35 Convent Dr,Bldg 35,Room 1C915, Bethesda, MD 20892 USA. EM nakazawk@mail.nih.gov RI Cowell, Rita/J-5083-2013; Nakazawa, Kazutoshi/J-6195-2015 OI Cowell, Rita/0000-0001-5814-9412; Nakazawa, Kazutoshi/0000-0001-5699-9093 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; [MH077955-05] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and MH077955-05 (RMC). NR 56 TC 33 Z9 35 U1 2 U2 15 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 MAY 15 PY 2013 VL 73 IS 10 BP 1024 EP 1034 DI 10.1016/j.biopsych.2012.12.004 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 137SV UT WOS:000318458600013 PM 23348010 ER PT J AU Leeman-Neill, RJ Brenner, AV Little, MP Bogdanova, TI Hatch, M Zurnadzy, LY Mabuchi, K Tronko, MD Nikiforov, YE AF Leeman-Neill, Rebecca J. Brenner, Alina V. Little, Mark P. Bogdanova, Tetiana I. Hatch, Maureen Zurnadzy, Liudmyla Y. Mabuchi, Kiyohiko Tronko, Mykola D. Nikiforov, Yuri E. TI RET/PTC and PAX8/PPAR chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics SO CANCER LA English DT Article DE Chernobyl; papillary thyroid carcinoma; iodine-131; RET; PTC; PAX8; PPAR ID ATOMIC-BOMB SURVIVORS; PAPILLARY CARCINOMAS; EXTERNAL RADIATION; HIGH PREVALENCE; ACCIDENT; DISEASES; COHORT; EXPOSURE; CHILDREN; RET AB BACKGROUND: Childhood exposure to iodine-131 from the 1986 nuclear accident in Chernobyl, Ukraine, led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited. METHODS: Mutational analysis was performed on 62 PTCs diagnosed in a Ukrainian cohort of patients who were < 18 years old in 1986 and received 0.008 to 8.6 Gy of 131I to the thyroid. Associations between mutation types and 131I dose and other characteristics were explored. RESULTS: RET/PTC (ret proto-oncogene/papillary thyroid carcinoma) rearrangements were most common (35%), followed by BRAF (15%) and RAS (8%) point mutations. Two tumors carrying PAX8/PPAR (paired box 8/peroxisome proliferator-activated receptor gamma) rearrangement were identified. A significant negative association with 131I dose for BRAF and RAS point mutations and a significant concave association with 131I dose, with an inflection point at 1.6 Gy and odds ratio of 2.1, based on a linear-quadratic model for RET/PTC and PAX8/PPAR rearrangements were found. The trends with dose were significantly different between tumors with point mutations and rearrangements. Compared with point mutations, rearrangements were associated with residence in the relatively iodine-deficient Zhytomyr region, younger age at exposure or surgery, and male sex. CONCLUSIONS: These results provide the first demonstration of PAX8/PPAR rearrangements in post-Chernobyl tumors and show different associations for point mutations and chromosomal rearrangements with 131I dose and other factors. These data support the relationship between chromosomal rearrangements, but not point mutations, and 131I exposure and point to a possible role of iodine deficiency in generation of RET/PTC rearrangements in these patients. Cancer 2013. (c) 2013 American Cancer Society. C1 [Leeman-Neill, Rebecca J.; Nikiforov, Yuri E.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. [Brenner, Alina V.; Little, Mark P.; Hatch, Maureen; Mabuchi, Kiyohiko] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bogdanova, Tetiana I.; Zurnadzy, Liudmyla Y.; Tronko, Mykola D.] Natl Acad Med Sci Ukraine, State Inst VP Komisarenko Inst Endocrinol & Metab, Kiev, Ukraine. RP Nikiforov, YE (reprint author), Univ Pittsburgh, Dept Pathol, Presbyterian Univ Hosp, 200 Lothrop St,Room C-606, Pittsburgh, PA 15213 USA. EM nikiforovye@upmc.edu FU National Institutes of Health (NIH) [R01 CA88041]; Intramural Research Program of the NIH, National Cancer Institute FX Supported by National Institutes of Health (NIH) grant R01 CA88041 and in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 36 TC 34 Z9 41 U1 1 U2 16 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 MAY 15 PY 2013 VL 119 IS 10 BP 1792 EP 1799 DI 10.1002/cncr.27893 PG 8 WC Oncology SC Oncology GA 138JT UT WOS:000318505500007 PM 23436219 ER PT J AU George, PJ Anuradha, R Kumaran, PP Chandrasekaran, V Nutman, TB Babu, S AF George, Parakkal Jovvian Anuradha, Rajamanickam Kumaran, Paramasivam Paul Chandrasekaran, Vedachalam Nutman, Thomas B. Babu, Subash TI Modulation of Mycobacterial-Specific Th1 and Th17 Cells in Latent Tuberculosis by Coincident Hookworm Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; CHRONIC HELMINTH INFECTIONS; VACCINE CVD 103-HGR; LYMPHATIC FILARIASIS; ACTIVE TUBERCULOSIS; SCHISTOSOMA-MANSONI; TETANUS VACCINATION; INTESTINAL HELMINTH; RESPONSES; PARASITES AB Hookworm infections and tuberculosis (TB) are coendemic in many parts of the world. It has been suggested that infection with helminth parasites could suppress the predominant Th1 (IFN-g-mediated) response needed to control Mycobacterium tuberculosis infection and enhance susceptibility to infection and/or disease. To determine the role of coincident hookworm infection on responses at steady-state and on M. tuberculosis-specific immune responses in latent TB (LTB), we examined the cellular responses in individuals with LTB with or without concomitant hookworm infection. By analyzing the expression of Th1, Th2, and Th17 subsets of CD4(+) T cells, we were able to demonstrate that the presence of coincident hookworm infection significantly diminished both spontaneously expressed and M. tuberculosis-specific mono-and dual-functional Th1 and Th17 cells. Hookworm infection, in contrast, was associated with expanded frequencies of mono-and dual-functional Th2 cells at both steady-state and upon Ag stimulation. This differential induction of CD4(+) T cell subsets was abrogated upon mitogen stimulation. Additionally, coincident hookworm infection was associated with increased adaptive T regulatory cells but not natural regulatory T cells in LTB. Finally, the CD4(+) T cell cytokine expression pattern was also associated with alterations in the systemic levels of Th1 and Th2 cytokines. Thus, coincident hookworm infection exerts a profound inhibitory effect on protective Th1 and Th17 responses in LTB and may predispose toward the development of active tuberculosis in humans. The Journal of Immunology, 2013, 190: 5161-5168. C1 [George, Parakkal Jovvian; Anuradha, Rajamanickam; Babu, Subash] Natl Inst Hlth, Int Ctr Excellence Res, Madras 600031, Tamil Nadu, India. [Kumaran, Paramasivam Paul; Chandrasekaran, Vedachalam] Natl Inst Res TB, Madras 600031, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Natl Inst Res TB, Natl Inst Hlth, Int Ctr Excellence Res, Madras 600031, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 44 TC 14 Z9 17 U1 0 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2013 VL 190 IS 10 BP 5161 EP 5168 DI 10.4049/jimmunol.1203311 PG 8 WC Immunology SC Immunology GA 138YB UT WOS:000318546700027 PM 23576678 ER PT J AU Conlon, J Burdette, DL Sharma, S Bhat, N Thompson, M Jiang, ZZ Rathinam, VAK Monks, B Jin, TC Xiao, TS Vogel, SN Vance, RE Fitzgerald, KA AF Conlon, Joseph Burdette, Dara L. Sharma, Shruti Bhat, Numana Thompson, Mikayla Jiang, Zhaozhao Rathinam, Vijay A. K. Monks, Brian Jin, Tengchuan Xiao, T. Sam Vogel, Stefanie N. Vance, Russell E. Fitzgerald, Katherine A. TI Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYCLIC DI-GMP; NF-KAPPA-B; FIBROBLAST-GROWTH-FACTOR; INNATE IMMUNE SENSOR; FLAVONE ACETIC-ACID; TOLL-LIKE RECEPTORS; INTRACELLULAR DNA; DENDRITIC CELLS; I INTERFERON; HEMORRHAGIC NECROSIS AB Vascular disrupting agents such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) represent a novel approach for cancer treatment. DMXAA has potent antitumor activity in mice and, despite significant preclinical promise, failed human clinical trials. The antitumor activity of DMXAA has been linked to its ability to induce type I IFNs in macrophages, although the molecular mechanisms involved are poorly understood. In this study, we identify stimulator of IFN gene (STING) as a direct receptor for DMXAA leading to TANK-binding kinase 1 and IFN regulatory factor 3 signaling. Remarkably, the ability to sense DMXAA was restricted to murine STING. Human STING failed to bind to or signal in response to DMXAA. Human STING also failed to signal in response to cyclic dinucleotides, conserved bacterial second messengers known to bind and activate murine STING signaling. Collectively, these findings detail an unexpected species-specific role for STING as a receptor for an anticancer drug and uncover important insights that may explain the failure of DMXAA in clinical trials for human cancer. C1 [Conlon, Joseph; Sharma, Shruti; Bhat, Numana; Thompson, Mikayla; Jiang, Zhaozhao; Rathinam, Vijay A. K.; Monks, Brian; Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Dept Med, Worcester, MA 01605 USA. [Burdette, Dara L.; Vance, Russell E.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Jin, Tengchuan; Xiao, T. Sam] NIH, Immunol Lab, Struct Immunobiol Unit, Bethesda, MD 20892 USA. [Vogel, Stefanie N.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Fitzgerald, KA (reprint author), Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Dept Med, Worcester, MA 01605 USA. EM kate.fitzgerald@umassmed.edu RI Xiao, Tsan/A-8590-2010; Xiao, Tsan/I-7616-2013; Jin, Tengchuan/B-5883-2014; Monks, Brian/B-8362-2015 OI Xiao, Tsan/0000-0001-9688-475X; Jin, Tengchuan/0000-0002-1395-188X; Monks, Brian/0000-0003-4008-3093 FU National Institutes of Health [AI067497, AI063302, AI080749]; Dainippon Sumitomo Pharma (Japan); Burroughs Wellcome Fund; [AI091100] FX This work was supported by National Institutes of Health Grants AI067497 (to K. A. F.) and AI063302 and AI080749 (to R. E. V.), by postdoctoral fellowship AI091100 (to D. L. B.), and by Dainippon Sumitomo Pharma (Japan). R. E. V. is supported by an investigator award from the Burroughs Wellcome Fund. NR 58 TC 62 Z9 64 U1 1 U2 17 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2013 VL 190 IS 10 BP 5216 EP 5225 DI 10.4049/jimmunol.1300097 PG 10 WC Immunology SC Immunology GA 138YB UT WOS:000318546700033 PM 23585680 ER PT J AU Mihlrad, L AF Mihlrad, Leigh TI Other People's Money: Inside the Housing Crisis and the Demise of the Greatest Real Estate Deal Ever Made SO LIBRARY JOURNAL LA English DT Book Review C1 [Mihlrad, Leigh] NIH, Bethesda, MD 20892 USA. RP Mihlrad, L (reprint author), NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU REED BUSINESS INFORMATION PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD MAY 15 PY 2013 VL 138 IS 9 BP 85 EP 85 PG 1 WC Information Science & Library Science SC Information Science & Library Science GA 143TJ UT WOS:000318890800126 ER PT J AU Chew, EY Clemons, TE SanGiovanni, JP Danis, R Ferris, FL Elman, M Antoszyk, A Ruby, A Orth, D Bressler, S Fish, G Hubbard, B Klein, M Chandra, S Blodi, B Domalpally, A Friberg, T Wong, W Rosenfeld, P Agron, E Toth, C Bernstein, P Sperduto, R AF Chew, Emily Y. Clemons, Traci E. SanGiovanni, John Paul Danis, Ronald Ferris, Frederick L., III Elman, Michael Antoszyk, Andrew Ruby, Alan Orth, David Bressler, Susan Fish, Gary Hubbard, Baker Klein, Michael Chandra, Suresh Blodi, Barbara Domalpally, Amitha Friberg, Thomas Wong, Wai Rosenfeld, Philip Agron, Elvira Toth, Cynthia Bernstein, Paul Sperduto, Robert CA Age-Related Eye Dis Study 2 AREDS2 TI Lutein plus Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BETA-CAROTENE; VITAMIN-C; DOCOSAHEXAENOIC ACID; DIETARY CAROTENOIDS; VISUAL FUNCTION; UNITED-STATES; SUPPLEMENTATION; PLACEBO; PREVENTION; CANCER AB Importance Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C and E, beta carotene, and zinc) has been shown to reduce the risk of progression to advanced age-related macular degeneration (AMD). Observational data suggest that increased dietary intake of lutein + zeaxanthin (carotenoids), omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]), or both might further reduce this risk. Objectives To determine whether adding lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation. Design, Setting, and Participants The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double-masked, placebo-controlled phase 3 study with a 2 x 2 factorial design, conducted in 2006-2012 and enrolling 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye. Interventions Participants were randomized to receive lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), lutein + zeaxanthin and DHA + EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both. Main Outcomes and Measures Development of advanced AMD. The unit of analyses used was by eye. Results Median follow-up was 5 years, with 1940 study eyes (1608 participants) progressing to advanced AMD. Kaplan-Meier probabilities of progression to advanced AMD by 5 years were 31% (493 eyes [406 participants]) for placebo, 29% (468 eyes [399 participants]) for lutein + zeaxanthin, 31% (507 eyes [416 participants]) for DHA + EPA, and 30% (472 eyes [387 participants]) for lutein + zeaxanthin and DHA + EPA. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD (hazard ratio [HR], 0.90 [98.7% CI, 0.76-1.07]; P=.12 for lutein + zeaxanthin; 0.97 [98.7% CI, 0.82-1.16]; P=.70 for DHA + EPA; 0.89 [98.7% CI, 0.75-1.06]; P=.10 for lutein + zeaxanthin and DHA + EPA). There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs no beta carotene group (23 [2.0%] vs 11 [0.9%], nominal P=.04), mostly in former smokers. Conclusions and Relevance Addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation. Trial Registration clinicaltrials.gov Identifier: NCT00345176 C1 [Chew, Emily Y.; SanGiovanni, John Paul; Ferris, Frederick L., III; Wong, Wai; Agron, Elvira] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.; Sperduto, Robert] EMMES Corp, Rockville, MD USA. [Danis, Ronald; Chandra, Suresh; Blodi, Barbara; Domalpally, Amitha] Univ Wisconsin, Fundus Reading Ctr, Madison, WI 53706 USA. [Elman, Michael] Elman Retina Grp, Baltimore, MD USA. [Antoszyk, Andrew] Charlotte Eye Ear Nose & Throat, Charlotte, NC USA. [Ruby, Alan] Vis Res Fdn, Royal Oak, MI USA. [Orth, David] Ingalls Mem Hosp, Harvey, IL USA. [Bressler, Susan] Johns Hopkins Univ, Wilmer Eye Inst, Retina Div, Baltimore, MD 21218 USA. [Fish, Gary] Texas Retina Associates, Dallas, TX USA. [Hubbard, Baker] Emory Univ, Ctr Eye, Atlanta, GA 30322 USA. [Klein, Michael] Devers Eye Inst, Portland, OR USA. [Friberg, Thomas] Univ Pittsburgh, Med Ctr, Ctr Eye, Pittsburgh, PA USA. [Rosenfeld, Philip] Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Toth, Cynthia] Duke Univ, Durham, NC USA. [Bernstein, Paul] Univ Utah, Moran Eye Ctr, Salt Lake City, UT 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 RI Domalpally, Amitha/B-2367-2015 FU National Eye Institute (NEI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland [HHS-N-260-2005-00007-C, N01-EY-5-0007]; NIH, Office of Dietary Supplements; NIH, National Center for Complementary and Alternative Medicine; NIH, National Institute on Aging; NIH, National Heart, Lung, and Blood Institute; NIH, National Institute of Neurological Disorders and Stroke; Southwest Clinical Research Associates LLC.; Genentech; Allergan; Bayer Healthcare; Lumenis Inc; Notal Vision Ltd; Novartis; Regeneron; Thrombogenics; sanofi-aventis; Bausch Lomb; Office of Research Administration; Texas Retina Associates; Carl Zeiss Meditec; Alexion; Potentia; GlaxoSmithKline; Topcon FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ferris reported holding a patent for the Age-Related Eye Disease Study (AREDS) formulation with Bausch & Lomb. Dr Antoszyk reported receiving grant and travel support from Southwest Clinical Research Associates LLC. Dr Ruby reported receiving payment for lectures from Genentech. Dr Bressler reported receiving grant and travel support from the Emmes Corporation; serving as a consultant for GlaxoSmithKline; receiving grants or grants pending from Allergan, Bayer Healthcare, Genentech, Lumenis Inc, Notal Vision Ltd, Novartis, Regeneron, Thrombogenics, and sanofi-aventis; receiving payment for lectures from providers of continuing medical education materials; and serving as an investigator on a grant to The Johns Hopkins University sponsored by Bausch & Lomb; this grant is negotiated and administered by the School of Medicine, which receives the grant through the Office of Research Administration (individual investigators who participate in such sponsored projects are not directly compensated by the sponsor but may receive salary or other support from the institution to support their effort on the projects). Dr Fish reported receiving grant and travel support from Texas Retina Associates. Dr Rosenfeld reported serving as a consultant for Oraya, Novartis, Chengdu Kanghong Biotech, Acucela, Thrombogenics, and Canon; receiving grants or grants pending from Carl Zeiss Meditec, Alexion, Potentia, and GlaxoSmithKline; and receiving payment for lectures from Carl Zeiss Meditec, Allergan, and Topcon. Dr Toth reported receiving grant and travel support from the Emmes Corporation and serving as a consultant to ALCON. Dr Bernstein reported serving as a consultant for Kemin Health, Kalsec, DSM, and Science Based Health. No other authors reported disclosures.; This study was supported by the intramural program funds and contracts from the National Eye Institute (NEI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland (contract HHS-N-260-2005-00007-C; ADB contract N01-EY-5-0007). Funds were generously contributed to these contracts by the following NIH institutes: Office of Dietary Supplements; National Center for Complementary and Alternative Medicine; National Institute on Aging; National Heart, Lung, and Blood Institute; and National Institute of Neurological Disorders and Stroke. The study medications and raw materials were provided by Alcon, Bausch & Lomb, DSM, and Pfizer. NR 35 TC 225 Z9 229 U1 21 U2 106 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 MAY 15 PY 2013 VL 309 IS 19 BP 2005 EP 2015 DI 10.1001/jama.2013.4997 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 143GQ UT WOS:000318855500023 ER PT J AU Nygaard, I Brubaker, L Zyczynski, HM Cundiff, G Richter, H Gantz, M Fine, P Menefee, S Ridgeway, B Visco, A Warren, LK Zhang, M Meikle, S AF Nygaard, Ingrid Brubaker, Linda Zyczynski, Halina M. Cundiff, Geoffrey Richter, Holly Gantz, Marie Fine, Paul Menefee, Shawn Ridgeway, Beri Visco, Anthony Warren, Lauren Klein Zhang, Min Meikle, Susan TI Long-term Outcomes Following Abdominal Sacrocolpopexy for Pelvic Organ Prolapse SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID UNITED-STATES; SIMULTANEOUS SPLENECTOMY; LIVER-TRANSPLANTATION; URINARY-INCONTINENCE; RANDOMIZED-TRIAL; SURGERY; INDEX; BURCH; WOMEN; RISK AB Importance More than 225 000 surgeries are performed annually in the United States for pelvic organ prolapse (POP). Abdominal sacrocolpopexy is considered the most durable POP surgery, but little is known about safety and long-term effectiveness. Objectives To describe anatomic and symptomatic outcomes up to 7 years after abdominal sacrocolpopexy, and to determine whether these are affected by concomitant anti-incontinence surgery (Burch urethropexy). Design, Setting, and Participants Long-term follow-up of the randomized, masked 2-year Colpopexy and Urinary Reduction Efforts (CARE) trial of women with stress continence who underwent abdominal sacrocolpopexy between 2002 and 2005 for symptomatic POP and also received either concomitant Burch urethropexy or no urethropexy. Ninety-two percent (215/233) of eligible 2-year CARE trial completers were enrolled in the extended CARE study; and 181 (84%) and 126 (59%) completed 5 and 7 years of follow-up, respectively. The median follow-up was 7 years. Main Outcomes and Measures Symptomatic POP failure requiring retreatment or self-reported bulge; or anatomic POP failure requiring retreatment or Pelvic Organ Prolapse Quantification evaluation demonstrating descent of the vaginal apex below the upper third of the vagina, or anterior or posterior vaginal wall prolapse beyond the hymen. Stress urinary incontinence (SUI) with more than 1 symptom or interval treatment; or overall UI score of 3 or greater on the Incontinence Severity Index. Results Of 215 women enrolled in the extended CARE study, 104 had undergone abdominal sacrocolpopexy plus Burch urethropexy and 111 had undergone abdominal sacrocolpopexy alone. Pelvic organ prolapse and urinary incontinence failure rates gradually increased during 7 years of follow-up. [GRAPHICS] Probability of mesh erosion at 7 years (estimated by the Kaplan-Meier method) was 10.5% (95% CI, 6.8% to 16.1%). Conclusions and Relevance During 7 years of follow-up, abdominal sacrocolpopexy failure rates increased in both groups. Urethropexy prevented SUI longer than no urethropexy. Abdominal sacrocolpopexy effectiveness should be balanced with long-term risks of mesh or suture erosion. Trial Registration clinicaltrials.gov Identifier: NCT00099372 C1 [Nygaard, Ingrid] Univ Utah, Sch Med, Salt Lake City, UT 84132 USA. [Brubaker, Linda] Loyola Univ, Chicago, IL 60611 USA. [Zyczynski, Halina M.] Univ Pittsburgh, Pittsburgh, PA USA. [Cundiff, Geoffrey] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Richter, Holly] Univ Alabama Birmingham, Birmingham, AL USA. [Gantz, Marie; Warren, Lauren Klein] RTI Int, Res Triangle Pk, NC USA. [Fine, Paul] Baylor Coll Med, Houston, TX 77030 USA. [Menefee, Shawn] Kaiser Permanente, San Diego, CA USA. [Ridgeway, Beri] Cleveland Clin, Cleveland, OH 44106 USA. [Visco, Anthony] Duke Univ, Durham, NC USA. [Zhang, Min] Univ Michigan, Ann Arbor, MI 48109 USA. [Meikle, Susan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Nygaard, I (reprint author), Univ Utah, Sch Med, 30 N 1900 E, Salt Lake City, UT 84132 USA. EM ingrid.nygaard@hsc.utah.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD41249, U10 HD41250, U10 HD41261, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215, U10 HD54241, U10 HD054136, U10 HD054215, U10 HD041261, U10 HD041267, U10 HD069006, U10 HD054214, U10 HD041250, U01 HD069031]; Office of Research on Women's Health at the National Institutes of Health; Pelvalon; Astellas; University of Califonia/Pfizer; Pfizer; Warner Chilcott FX The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Zyczynski reported serving as a consultant to Johnson & Johnson and Key Tech. Dr Richter reported receiving research grants from Pelvalon, Astellas, University of Califonia/Pfizer, Pfizer, and Warner Chilcott; and serving as a consultant to Astellas (advisory board), GlaxoSmithKline, Uromedica, IDEO, Pfizer, and Xanodyne. Dr Visco reported serving as a consultant to Intuitive Surgical. No other disclosures were reported.; This research was supported by grants U01 HD41249, U10 HD41250, U10 HD41261, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215, U10 HD54241, U10 HD054136, U10 HD054215, U10 HD041261, U10 HD041267, U10 HD069006, U10 HD054214, U10 HD041250, and U01 HD069031 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Office of Research on Women's Health at the National Institutes of Health. NR 29 TC 102 Z9 105 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 MAY 15 PY 2013 VL 309 IS 19 BP 2016 EP 2024 DI 10.1001/jama.2013.4919 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 143GQ UT WOS:000318855500024 PM 23677313 ER PT J AU Haginaka, J Kitabatake, T Hirose, I Matsunaga, H Moaddel, R AF Haginaka, Jun Kitabatake, Tomoko Hirose, Iyo Matsunaga, Hisami Moaddel, Ruin TI Interaction of cepharanthine with immobilized heat shock protein 90 alpha (Hsp90 alpha) and screening of Hsp90 alpha inhibitors (vol 434, pg 202, 2013) SO ANALYTICAL BIOCHEMISTRY LA English DT Correction C1 [Haginaka, Jun; Kitabatake, Tomoko; Hirose, Iyo; Matsunaga, Hisami] Mukogawa Womens Univ, Sch Pharm & Pharmaceut Sci, Nishinomiya, Hyogo 6638179, Japan. [Moaddel, Ruin] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Haginaka, J (reprint author), Mukogawa Womens Univ, Sch Pharm & Pharmaceut Sci, 11-68 Koshien Kyuban Cho, Nishinomiya, Hyogo 6638179, Japan. EM haginaka@mukogawa-u.ac.jp NR 1 TC 0 Z9 0 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 2013 VL 436 IS 2 BP 65 EP 65 DI 10.1016/j.ab.2013.01.028 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 128US UT WOS:000317795800001 ER PT J AU Singh, N Ravichandran, S Norton, DD Fugmann, SD Moaddel, R AF Singh, Nagendra Ravichandran, Sarangan Norton, Darrell D. Fugmann, Sebastian D. Moaddel, Ruin TI Synthesis and characterization of a SIRT6 open tubular column: Predicting deacetylation activity using frontal chromatography SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Frontal displacement chromatography; Pharmacophore model; Luteolin; Histone deacetylation assay ID DISEASE; CHROMATIN; SIRTUINS AB SIRT6 is a histone deacetylase that has been proposed as a potential therapeutic target for metabolic disorders and the prevention of age-associated diseases. Thus the identification of compounds that modulate SIRT6 activity could be of great therapeutic importance. We have previously reported on the identification of quercetin and vitexin as SIRT6 inhibitors, using SIRT6-coated magnetic beads. In this study, we have immobilized SIRT6 onto the surface of an open tubular capillary and characterized the quercetin binding site using frontal displacement chromatography. Structurally related flavonoids were tested for their activity on SIRT6, including apigenin, naringenin, luteolin, and kaempferol. In addition to obtaining their binding activity using frontal affinity chromatographic techniques, we also ranked the compounds based on their ability to displace quercetin. The data suggest that a single displacement curve is representative of the enzymatic activity of the tested ligand. In addition, using the inhibition data obtained in this study, we developed a preliminary pharmacophore model that confirmed the experimental data. Published by Elsevier Inc. C1 [Singh, Nagendra; Norton, Darrell D.; Fugmann, Sebastian D.; Moaddel, Ruin] NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Ravichandran, Sarangan] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Simulat Anal & Math Modeling Grp, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Moaddel, R (reprint author), NIA, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. EM moaddelru@grc.nia.nih.gov RI Singh, Nagendra/K-8966-2015 FU NIA Intramural Research Program; National Cancer Institute/National Institutes of Health [HHSN261200800001E] FX This work was supported in part by funds from the NIA Intramural Research Program (R.M.) and from National Cancer Institute/National Institutes of Health Contract HHSN261200800001E. S.R. thanks Katalin Nadassy, Tina Yeh, and Jodi Shaulsky from Accelrys, Inc., for many discussions during the analysis of the pharmacophore modeling results. NR 18 TC 15 Z9 15 U1 0 U2 32 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 2013 VL 436 IS 2 BP 78 EP 83 DI 10.1016/j.ab.2013.01.018 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 128US UT WOS:000317795800005 PM 23376017 ER PT J AU Raran-Kurussi, S Tozser, J Cherry, S Tropea, JE Waugh, DS AF Raran-Kurussi, Sreejith Toezser, Jozsef Cherry, Scott Tropea, Joseph E. Waugh, David S. TI Differential temperature dependence of tobacco etch virus and rhinovirus 3C proteases SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE 3C protease; Affinity tag removal; Fusion protein protease; Protease; Prescission protease; Tobacco etch virus (TEV) protease AB Because of their stringent sequence specificity, the 3C-like proteases from tobacco etch virus (TEV) and human rhinovirus are often used for the removal of affinity tags. The latter enzyme is rumored to have greater catalytic activity at 4 degrees C, the temperature at which fusion protein substrates are usually digested. Here we report that experiments with fusion protein and peptide substrates confirm this conjecture. Whereas the catalytic efficiency of rhinovirus 3C protease is approximately the same at its optimum temperature (30 degrees C) and at 4 degrees C, TEV protease is 10-fold less active at the latter temperature due primarily to a reduction in k(cat). Published by Elsevier Inc. C1 [Raran-Kurussi, Sreejith; Cherry, Scott; Tropea, Joseph E.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Toezser, Jozsef] Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, H-4032 Debrecen, Hungary. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM waughd@mail.nih.gov RI Tozser, Jozsef/A-7840-2008 OI Tozser, Jozsef/0000-0003-0274-0056 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; Hungarian Science and Research Fund [OTKA K101591] FX We thank An Geerlof for the rhinovirus 3C protease expression vector. This research was funded by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and in part by the by the Hungarian Science and Research Fund (OTKA K101591 to J.E.T.). NR 12 TC 8 Z9 8 U1 5 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 2013 VL 436 IS 2 BP 142 EP 144 DI 10.1016/j.ab.2013.01.031 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 128US UT WOS:000317795800014 PM 23395976 ER PT J AU Petralia, RS Schwartz, CM Wang, YX Kawamoto, EM Mattson, MP Yao, PJ AF Petralia, Ronald S. Schwartz, Catherine M. Wang, Ya-Xian Kawamoto, Elisa M. Mattson, Mark P. Yao, Pamela J. TI Sonic hedgehog promotes autophagy in hippocampal neurons SO BIOLOGY OPEN LA English DT Article DE Sonic hedgehog; Autophagy; Hippocampal neurons; Synapses AB The Sonic hedgehog (Shh) signaling pathway is well known in patterning of the neural tube during embryonic development, but its emerging role in differentiated neurons is less understood. Here we report that Shh enhances autophagy in cultured hippocampal neurons. Microarray analysis reveals the upregulation of multiple autophagy-related genes in neurons in response to Shh application. Through analysis of the autophagy-marker LC3 by immunoblot analysis and immunocytochemistry, we confirm activation of the autophagy pathway in Shh-exposed neurons. Using electron microscopy, we find autophagosomes and associated structures with a wide range of morphologies in synaptic terminals of Shh-exposed neurons. Moreover, we show that Shh-triggered autophagy depends on class III Phosphatidylinositol 3-kinase complexes (PtdIns3K). These results identify a link between Shh and autophagy pathways and, importantly, provide a lead for further understanding the physiology of Shh signaling activity in neurons. (C) 2013. Published by The Company of Biologists Ltd. C1 [Petralia, Ronald S.; Wang, Ya-Xian] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Schwartz, Catherine M.; Kawamoto, Elisa M.; Mattson, Mark P.; Yao, Pamela J.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. RP Yao, PJ (reprint author), NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov FU Intramural Research Program of the NIA/NIH; Intramural Research Program of the [NIDCD/NIH] FX We thank Dr Carolyn Marie Ott and Dr Jennifer Lippincott-Schwartz for discussions and reagents; Dr Simonetta Camandola for advice on PtdIns3K related experiments; Dr James K. Chen for Shh-N expressing HEK 293 cells; Dr Jay Debnath for LC3 antibody; Dr Steven Finkbeiner for information on 10-NCP; Dr JunyingYuan for FYVE-DsRed; Dr Fred Indig for confocal microscopy. This work was supported by the Intramural Research Programs of the NIA/NIH and NIDCD/NIH. NR 61 TC 14 Z9 16 U1 2 U2 7 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD MAY 15 PY 2013 VL 2 IS 5 BP 499 EP 504 DI 10.1242/bio.20134275 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA V36IO UT WOS:000209206200009 PM 23789099 ER PT J AU Chang, C Liu, ZM Chen, MC Liu, X Duyn, JH AF Chang, Catie Liu, Zhongming Chen, Michael C. Liu, Xiao Duyn, Jeff H. TI EEG correlates of time-varying BOLD functional connectivity SO NEUROIMAGE LA English DT Article ID DEFAULT-MODE NETWORK; ALPHA OSCILLATIONS; BRAIN NETWORKS; FMRI SIGNALS; HEART-RATE; FLUCTUATIONS; SLEEP; CORTEX; ARCHITECTURE; WAKEFULNESS AB Recent resting-state fMRI studies have shown that the apparent functional connectivity (FC) between brain regions may undergo changes on time-scales of seconds to minutes, the basis and importance of which are largely unknown. Here, we examine the electrophysiological correlates of within-scan FC variations during a condition of eyes-closed rest. A sliding window analysis of simultaneous EEG-fMRI data was performed to examine whether temporal variations in coupling between three major networks (default mode; DMN, dorsal attention; DAN, and salience network; SN) are associated with temporal variations in mental state, as assessed from the amplitude of alpha and theta oscillations in the EEG. In our dataset, alpha power showed a significant inverse relationship with the strength of connectivity between DMN and DAN. In addition, alpha power covaried with the spatial extent of anticorrelation between DMN and DAN, with higher alpha power associated with larger anticorrelation extent. Results suggest an electrical signature of the time-varying FC between the DAN and DMN, potentially reflecting neural and state-dependent variations. Published by Elsevier Inc. C1 [Chang, Catie; Liu, Zhongming; Liu, Xiao; Duyn, Jeff H.] NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. [Chen, Michael C.] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. RP Chang, C (reprint author), NINDS, Adv MRI Sect, LFMI, NIH, 10 Ctr Dr,Rm B1D723, Bethesda, MD 20892 USA. EM catie.chang@nih.gov RI Liu, Xiaobing/C-6216-2013; Liu, Xiao/C-5943-2016 OI Liu, Xiaobing/0000-0002-5347-5566; FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. We thank Gary Glover and Qingei Luo for assistance with the Stanford data acquisition, and are grateful to Gang Chen and Ziad Saad for helpful discussion and advice regarding statistics. NR 74 TC 72 Z9 72 U1 7 U2 53 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 MAY 15 PY 2013 VL 72 BP 227 EP 236 DI 10.1016/j.neuroimage.2013.01.049 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 120JO UT WOS:000317166800022 PM 23376790 ER PT J AU Chandramohan, V Bao, XH Kaneko, MK Kato, Y Keir, ST Szafranski, SE Kuan, CT Pastan, IH Bigner, DD AF Chandramohan, Vidyalakshmi Bao, Xuhui Kaneko, Mika Kato Kato, Yukinari Keir, Stephen T. Szafranski, Scott E. Kuan, Chien-Tsun Pastan, Ira H. Bigner, Darell D. TI Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE podoplanin; glioblastoma multiforme; medulloblastoma; recombinant immunotoxin; single-chain disulfide Fv ID EPITHELIAL-MESENCHYMAL TRANSITION; CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR RECEPTOR; MONOCLONAL-ANTIBODIES; CANCER; GLIOBLASTOMA; PROGRESSION; METASTASIS; XENOGRAFTS; PROTEINS AB Our study demonstrates the glioma tumor antigen podoplanin to be present at very high levels (>90%) in both glioblastoma (D2159MG, D08-0308MG and D08-0493MG) and medulloblastoma (D283MED, D425MED and DAOY) xenografts and cell line. We constructed a novel recombinant single-chain antibody variable region fragment (scFv), NZ-1, specific for podoplanin from the NZ-1 hybridoma. NZ-1-scFv was then fused to Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide (NZ-1-PE38KDEL). The immunotoxin (IT) was further stabilized by a disulfide (ds) bond between the heavy-chain and light-chain variable regions as the construct NZ-1-(scdsFv)-PE38KDEL. NZ-1-(scdsFv)-PE38KDEL exhibited significant reactivity to glioblastoma and medulloblastoma cells. The affinity of NZ-1-(scdsFv), NZ-1-(scdsFv)-PE38KDEL and NZ-1 antibody for podoplanin peptide was 2.1 x 108 M, 8.0 x 108 M and 3.9 x 1010 M, respectively. In a protein stability assay, NZ-1-(scdsFv)-PE38KDEL retained 3398% of its activity, whereas that of NZ-1-PE38KDEL declined to 13% of its initial levels after incubation at 37 degrees C for 3 days. In vitro cytotoxicity of the NZ-1-(scdsFv)-PE38KDEL was measured in cells isolated from glioblastoma xenografts, D2159MG, D08-0308MG and D08-0493MG, and in the medulloblastoma D283MED, D425MED and DOAY xenografts and cell line. The NZ-1-(scdsFv)-PE38KDEL IT was highly cytotoxic, with an 50% inhibitory concentration in the range of 1.629 ng/ml. Significantly, NZ-1-(scdsFv)-PE38KDEL demonstrated tumor growth delay, averaging 24 days (p < 0.001) and 21 days (p < 0.001) in D2159MG and D283MED in vivo tumor models, respectively. Crucially, in the D425MED intracranial tumor model, NZ-1-(scdsFv)-PE38KDEL caused a 41% increase in survival (p 0.001). In preclinical studies, NZ-1-(scdsFv)-PE38KDEL exhibited significant potential as a targeting agent for malignant brain tumors. C1 [Chandramohan, Vidyalakshmi; Bao, Xuhui; Keir, Stephen T.; Szafranski, Scott E.; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27710 USA. [Chandramohan, Vidyalakshmi; Bao, Xuhui; Keir, Stephen T.; Szafranski, Scott E.; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Bao, Xuhui] Fudan Univ, Huashan Hosp, Dept Neurosurg, Shanghai 200433, Peoples R China. [Kaneko, Mika Kato; Kato, Yukinari] Yamagata Univ, Fac Med, Adv Mol Epidemiol Res Inst, Mol Tumor Marker Res Team,Oncol Res Ctr, Yamagata 990, Japan. [Pastan, Ira H.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bigner, DD (reprint author), Duke Univ, Med Ctr, Dept Pathol, Box 3156,177 MSRB1,Res Dr, Durham, NC 27710 USA. EM bigne001@mc.duke.edu FU National Cancer Institute [NINDS 5P50 NS20023-29, 5R37 CA011898-42]; Southeastern Brain Tumor Foundation; Silvian Foundation; Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsor: The National Cancer Institute; Grant numbers: NINDS 5P50 NS20023-29, NCI Merit Award 5R37 CA011898-42; Grant sponsors: Southeastern Brain Tumor Foundation, Silvian Foundation, Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; This work was supported by The National Cancer Institute [Grant numbers: NINDS 5P50 NS20023-29, and NCI Merit Award 5R37 CA011898-42 (D.D. Bigner)] and also by Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (I.H. Pastan). NR 31 TC 20 Z9 30 U1 4 U2 37 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 MAY 15 PY 2013 VL 132 IS 10 BP 2339 EP 2348 DI 10.1002/ijc.27919 PG 10 WC Oncology SC Oncology GA 097ZO UT WOS:000315512300011 PM 23115013 ER PT J AU Melin, B Dahlin, AM Andersson, U Wang, ZM Henriksson, R Hallmans, G Bondy, ML Johansen, C Feychting, M Ahlbom, A Kitahara, CM Wang, SS Ruder, AM Carreon, T Butler, MA Inskip, PD Purdue, M Hsing, AW Mechanic, L Gillanders, E Yeager, M Linet, M Chanock, SJ Hartge, P Rajaraman, P AF Melin, Beatrice Dahlin, Anna M. Andersson, Ulrika Wang, Zhaoming Henriksson, Roger Hallmans, Goran Bondy, Melissa L. Johansen, Christoffer Feychting, Maria Ahlbom, Anders Kitahara, Cari M. Wang, Sophia S. Ruder, Avima M. Carreon, Tania Butler, Mary Ann Inskip, Peter D. Purdue, Mark Hsing, Ann W. Mechanic, Leah Gillanders, Elizabeth Yeager, Meredith Linet, Martha Chanock, Stephen J. Hartge, Patricia Rajaraman, Preetha TI Known glioma risk loci are associated with glioma with a family history of brain tumours - A case-control gene association study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Glioma; brain tumours; genome-wide association study; single nucleotide polymorphism ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CONSORTIUM; EPIDEMIOLOGY; GLIOGENE; DESIGN; RTEL1 AB Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four casecontrol studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in casecontrol designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.250.61; Bonferroni adjusted ptrend, 1.7 x 104). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours. C1 [Melin, Beatrice; Dahlin, Anna M.; Andersson, Ulrika; Henriksson, Roger] Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden. [Wang, Zhaoming; Yeager, Meredith; Chanock, Stephen J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Core Genotyping Facil, Gaithersburg, MD USA. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Bondy, Melissa L.] Baylor Coll Med, Dept Pediat, Hematol Oncol Sect, Houston, TX 77030 USA. [Johansen, Christoffer] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Feychting, Maria; Ahlbom, Anders] Karolinska Inst, Inst Environm Med, Div Epidemiol, S-10401 Stockholm, Sweden. [Kitahara, Cari M.; Inskip, Peter D.; Purdue, Mark; Hsing, Ann W.; Linet, Martha; Hartge, Patricia; Rajaraman, Preetha] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 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. [Ruder, Avima M.; Carreon, Tania] NIOSH, Div Surveillance Hazard Evaluat & Field Studies, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Butler, Mary Ann] NIOSH, Div Appl Res & Technol, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Mechanic, Leah; Gillanders, Elizabeth] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. RP Melin, B (reprint author), Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden. EM beatrice.melin@onkologi.umu.se RI Kitahara, Cari/R-8267-2016 FU National Institutes of Health, National Cancer Institute (Intramural Research Program); Royal Swedish Academy of Science (Acta Oncologica); Swedish Cancer Foundation; Northern Sweden Cancer Society; Swedish Research Council; Umea University Hospital (Cutting Edge); Umea University (Young Investigator Award); NIH [NIH 5R01 CA119215]; NIOSH Initiative for Cancer Control Projects for Farmers; CDC/NIOSH operating funds; Acta Oncologica through the Royal Swedish Academy of Science FX Grant sponsor: National Institutes of Health, National Cancer Institute (Intramural Research Program); Grant sponsors: Royal Swedish Academy of Science (Acta Oncologica), the Swedish Cancer Foundation, Northern Sweden Cancer Society, Swedish Research Council, Umea University Hospital (Cutting Edge), Umea University (Young Investigator Award); Grant sponsors: NIH; Grant number: NIH 5R01 CA119215; Grant sponsors: NIOSH Initiative for Cancer Control Projects for Farmers and CDC/NIOSH operating funds; Peter Hui from Integrated Management Systems is acknowledged for statistical support. The study was supported by Acta Oncologica through the Royal Swedish Academy of Science (B.M. salary). NR 21 TC 15 Z9 15 U1 0 U2 22 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 MAY 15 PY 2013 VL 132 IS 10 BP 2464 EP 2468 DI 10.1002/ijc.27922 PG 5 WC Oncology SC Oncology GA 097ZO UT WOS:000315512300024 PM 23115063 ER PT J AU Nezich, CL Youle, RJ AF Nezich, Catherine L. Youle, Richard J. TI Make or break for mitochondria SO ELIFE LA English DT Editorial Material ID PROTEIN; COMPLEX; GTPASE; MMM1P; DNA C1 [Nezich, Catherine L.] MRC, Mitochondrial Biol Unit, Cambridge, England. [Nezich, Catherine L.; Youle, Richard J.] NINDS, NIH, Bethesda, MD 20892 USA. RP Nezich, CL (reprint author), MRC, Mitochondrial Biol Unit, Cambridge, England. EM neziche@ninds.gov; youler@ninds.nih.gov NR 10 TC 2 Z9 2 U1 1 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 14 PY 2013 VL 2 AR e00804 DI 10.7554/eLife.00804 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 274OC UT WOS:000328614800006 PM 23682317 ER PT J AU Liu, YM Lam, KH Shung, KK Li, JY Zhou, QF AF Liu, Yuanming Lam, Kwok Ho Shung, K. Kirk Li, Jiangyu Zhou, Qifa TI Enhanced piezoelectric performance of composite sol-gel thick films evaluated using piezoresponse force microscopy SO JOURNAL OF APPLIED PHYSICS LA English DT Article; Proceedings Paper CT 21st IEEE International Symposium on Applications of Ferroelectrics held jointly with 11th European Conference on the Applications of Polar Dielectrics and 4th Conference on Piezoresponse Force Microscopy and Nanoscale Phenomena in Polar Materials CY JUL 09-13, 2012 CL Univ Aveiro, Aveiro, PORTUGAL SP IEEE, IEEE, Ultrason, Ferroelect & Frequency Control (UFFC) Soc HO Univ Aveiro ID ELECTROMECHANICAL PROPERTIES; ELECTRICAL-PROPERTIES; CERAMICS; MEMS AB Conventional composite sol-gel method has been modified to enhance the piezoelectric performance of ceramic thick films. Lead zirconate titanate (PZT) and lead magnesium niobate-lead titanate (PMN-PT) thick films were fabricated using the modified sol-gel method for ultrasonic transducer applications. In this work, piezoresponse force microscopy was employed to evaluate the piezoelectric characteristics of PZT and PMN-PT composite sol-gel thick films. The images of the piezoelectric response and the strain-electric field hysteresis loop behavior were measured. The effective piezoelectric coefficient (d(33,eff)) of the films was determined from the measured loop data. It was found that the effective local piezoelectric coefficient of both PZT and PMN-PT composite films is comparable to that of their bulk ceramics. The promising results suggest that the modified composite sol-gel method is a promising way to prepare the high-quality, crack-free ceramic thick films. (C) 2013 AIP Publishing LLC C1 [Liu, Yuanming; Li, Jiangyu] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. [Lam, Kwok Ho; Shung, K. Kirk; Zhou, Qifa] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Lam, Kwok Ho; Shung, K. Kirk; Zhou, Qifa] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Zhou, QF (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu RI Liu, Yuanming/D-5031-2012; Li, Jiangyu/B-3191-2008; Lam, K.H./B-7765-2014 OI Li, Jiangyu/0000-0003-0533-1397; Lam, K.H./0000-0003-1456-9049 FU NIBIB NIH HHS [P41 EB002182] NR 28 TC 4 Z9 4 U1 0 U2 28 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-8979 J9 J APPL PHYS JI J. Appl. Phys. PD MAY 14 PY 2013 VL 113 IS 18 AR 187205 DI 10.1063/1.4801975 PG 5 WC Physics, Applied SC Physics GA 149BX UT WOS:000319294100111 PM 23798771 ER PT J AU Kirino, Y Zhou, Q Ishigatsubo, Y Mizuki, N Tugal-Tutkun, I Seyahi, E Ozyazgan, Y Ugurlu, S Erer, B Abaci, N Ustek, D Meguro, A Ueda, A Takeno, M Inoko, H Ombrello, MJ Satorius, CL Maskeri, B Mullikin, JC Sun, HW Gutierrez-Cruz, G Kim, Y Wilson, AF Kastner, DL Gul, A Remmers, EF AF Kirino, Yohei Zhou, Qing Ishigatsubo, Yoshiaki Mizuki, Nobuhisa Tugal-Tutkun, Ilknur Seyahi, Emire Ozyazgan, Yilmaz Ugurlu, Serdal Erer, Burak Abaci, Neslihan Ustek, Duran Meguro, Akira Ueda, Atsuhisa Takeno, Mitsuhiro Inoko, Hidetoshi Ombrello, Michael J. Satorius, Colleen L. Maskeri, Baishali Mullikin, James C. Sun, Hong-Wei Gutierrez-Cruz, Gustavo Kim, Yoonhee Wilson, Alexander F. Kastner, Daniel L. Gul, Ahmet Remmers, Elaine F. TI Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behcet disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE complex genetics; genetic association ID GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; RARE VARIANTS; SUSCEPTIBILITY LOCI; CROHNS-DISEASE; LOW-FREQUENCY; MUTATIONS; COMMON; POLYMORPHISMS; IL23R-IL12RB2 AB Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behcet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (IL10, IL23R, CCR1, STAT4, KLRK1, KLRC1, KLRC2, KLRC3, KLRC4, and ERAP1) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R (P = 6.9 x 10(-5)), and one gene involved in innate immunity, TLR4 (P = 8.0 x 10(-4)), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied (P = 0.0063-0.045). Furthermore, carriage of the familial Mediterranean fever gene (MEFV) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 x 10(-12)). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis. C1 [Kirino, Yohei; Zhou, Qing; Ombrello, Michael J.; Satorius, Colleen L.; Kastner, Daniel L.; Remmers, Elaine F.] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Kirino, Yohei; Ishigatsubo, Yoshiaki; Ueda, Atsuhisa; Takeno, Mitsuhiro] Yokohama City Univ, Grad Sch Med, Dept Internal Med & Clin Immunol, Yokohama, Kanagawa 2360004, Japan. [Mizuki, Nobuhisa; Meguro, Akira] Yokohama City Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Yokohama, Kanagawa 2360004, Japan. [Tugal-Tutkun, Ilknur] Istanbul Univ, Istanbul Fac Med, Dept Ophthalmol, TR-34093 Istanbul, Turkey. [Abaci, Neslihan; Ustek, Duran] Istanbul Univ, Inst Expt Med, Dept Genet, TR-34093 Istanbul, Turkey. [Seyahi, Emire; Ugurlu, Serdal] Istanbul Univ, Cerrahpasa Fac Med, Dept Internal Med, Div Rheumatol, TR-34098 Istanbul, Turkey. [Ozyazgan, Yilmaz] Istanbul Univ, Cerrahpasa Fac Med, Dept Ophthalmol, TR-34098 Istanbul, Turkey. [Erer, Burak; Gul, Ahmet] Istanbul Univ, Istanbul Fac Med, Dept Internal Med, Div Rheumatol, TR-34093 Istanbul, Turkey. [Inoko, Hidetoshi] Tokai Univ, Sch Med, Dept Mol Life Sci, Div Mol Med Sci & Mol Med, Isehara, Kanagawa 2591193, Japan. [Maskeri, Baishali; Mullikin, James C.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Rockville, MD 20852 USA. [Sun, Hong-Wei] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Gutierrez-Cruz, Gustavo] NIAMSD, Genome Anal Core Facil, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Kim, Yoonhee; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. RP Kastner, DL (reprint author), NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM kastnerd@mail.nih.gov; remmerse@mail.nih.gov RI Ustek, Duran/C-3484-2009; 桐野, 洋平/B-3701-2009; Yu, Xiaomin/I-6407-2016 OI Ustek, Duran/0000-0002-0060-2859; 桐野, 洋平/0000-0002-9488-661X; FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Human Genome Research Institute; Center for Human Immunology, Autoimmunity, and Inflammation of the NIH; Istanbul University Research Fund; Japanese Ministry of Health, Labor, and Welfare; Japan Rheumatism Foundation FX We thank Dr. Benjamin Neale (Broad Institute of MIT and Harvard) for providing the C-alpha test script and Dr. Ivona Aksentijevich (National Human Genome Research Institute, National Institutes of Health) for comments on the manuscript. This research was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Human Genome Research Institute and by the Center for Human Immunology, Autoimmunity, and Inflammation of the NIH; by the Istanbul University Research Fund; and by Research on Specific Disease of the Health Science Research Grants from the Japanese Ministry of Health, Labor, and Welfare and the Japan Rheumatism Foundation. NR 31 TC 46 Z9 46 U1 2 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 MAY 14 PY 2013 VL 110 IS 20 BP 8134 EP 8139 DI 10.1073/pnas.1306352110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 156EH UT WOS:000319803500040 PM 23633568 ER PT J AU Zhao, Y Gregory, MT Biertumpfel, C Hua, YJ Hanaoka, F Yang, W AF Zhao, Ye Gregory, Mark T. Biertuempfel, Christian Hua, Yue-Jin Hanaoka, Fumio Yang, Wei TI Mechanism of somatic hypermutation at the WA motif by human DNA polymerase eta SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pi-cation stacking; A-to-G transition; immunoglobulin ID IMMUNOGLOBULIN GENE HYPERMUTATION; XERODERMA-PIGMENTOSUM VARIANT; STRUCTURAL BASIS; TRANSLESION SYNTHESIS; MUTATIONS; MOUSE; BASE; CISPLATIN; FIDELITY; STRAND AB Somatic hypermutation is programmed base substitutions in the variable regions of Ig genes for high-affinity antibody generation. Two motifs, RGYW and WA (R, purine; Y, pyrimidine; W, A or T), have been found to be somatic hypermutation hotspots. Overwhelming evidence suggests that DNA polymerase eta (Pol eta) is responsible for converting the WA motif to WG by misincorporating dGTP opposite the templating T. To elucidate the molecular mechanism, crystal structures and kinetics of human Pol eta substituting dGTP for dATP in four sequence contexts, TA, AA, GA, and CA, have been determined and compared. The T: dGTP wobble base pair is stabilized by Gln-38 and Arg-61, two uniquely conserved residues among Pol eta. Weak base paring of the W (T:A or A:T) at the primer end and their distinct interactions with Pol eta lead to misincorporation of G in the WA motif. Between two WA motifs, our kinetic and structural data indicate that A-to-G mutation occurs more readily in the TA context than AA. Finally, Pol eta can extend the T:G mispair efficiently to complete the mutagenesis. C1 [Zhao, Ye; Hua, Yue-Jin] Zhejiang Univ, Inst Nucl Agr Sci, Hangzhou 310029, Zhejiang, Peoples R China. [Zhao, Ye; Gregory, Mark T.; Biertuempfel, Christian; Yang, Wei] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Hanaoka, Fumio] Gakushuin Univ, Fac Sci, Tokyo 1718588, Japan. RP Hua, YJ (reprint author), Zhejiang Univ, Inst Nucl Agr Sci, Hangzhou 310029, Zhejiang, Peoples R China. EM yjhua@zju.edu.cn; 20070117@gakushuin.ac.jp; wei.yang@nih.gov RI Yang, Wei/D-4926-2011; Zhao, Ye/I-2936-2014 OI Yang, Wei/0000-0002-3591-2195; Zhao, Ye/0000-0002-5455-2586 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Chinese Ministry of Education; National Natural Science Foundation of China [31210103904]; Ministry of Education (KAKENHI) FX We thank Drs. R. Craigie and D. Leahy for critical reading of the manuscript. This work was supported by the Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Y.Z., M. T. G., C. B., and W.Y.); a Chinese Ministry of Education scholarship (Y.Z.); National Natural Science Foundation of China Grant 31210103904 (to Y.-J.H.); and Grants-in-Aid for Scientific Research from the Ministry of Education (KAKENHI) (to F.H.). NR 41 TC 18 Z9 18 U1 0 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 MAY 14 PY 2013 VL 110 IS 20 BP 8146 EP 8151 DI 10.1073/pnas.1303126110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 156EH UT WOS:000319803500042 PM 23630267 ER PT J AU Barber, JS Yokomizo, LK Sheikh, V Freeman, AF Garabedian, E van Dijk, E Sokolic, R Candotti, F Weng, NP Sereti, I Milner, JD AF Barber, John S. Yokomizo, Lauren K. Sheikh, Virginia Freeman, Alexandra F. Garabedian, Elizabeth van Dijk, Evert Sokolic, Robert Candotti, Fabio Weng, Nan-ping Sereti, Irini Milner, Joshua D. TI Peptide library-based evaluation of T-cell receptor breadth detects defects in global and regulatory activation in human immunologic diseases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE atopy; immune deficiency ID REPERTOIRE DIVERSITY; TCR REPERTOIRES; MEMORY; RESPONSES; IMMUNITY; IDENTIFICATION; LYMPHOCYTES; EFFECTOR; LIGANDS; VIRUS AB The ability of T-cells to respond to foreign antigens and to appropriately regulate this response is crucial for maintaining immune homeostasis. Using combinatorial peptide libraries, we functionally measured broad T-cell reactivity and observed impaired reactivity in established models of T-cell receptor repertoire restriction and in previously unrecognized disease contexts. By concurrently analyzing T-regulatory and T-effector cells, we show strong functional correlation between these subsets in healthy individuals and, strikingly, that alterations of this balance are associated with T helper type 2 (Th2)-mediated disease in a lymphopenic setting. Finally, we demonstrate that peptide-based priming of polyclonal naive cells with relatively low concentrations skews toward Th2 differentiation. These findings provide unique insight into the pathophysiology and functional consequences of abnormal T-cell repertoires and into differentiation of human naive T-cells. C1 [Barber, John S.; Yokomizo, Lauren K.; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Sheikh, Virginia; Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Garabedian, Elizabeth; Sokolic, Robert; Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [van Dijk, Evert] Pepscan Presto BV, NL-8243 RC Lelystad, Netherlands. [Weng, Nan-ping] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Milner, JD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU NIAID FX We thank the members of the J.D.M. laboratory for their helpful discussions; the National Institute of Allergy and Infectious Diseases (NIAID) Flow Cytometry Core for assistance with cell sorting; all of the patients and clinical staff for invaluable contributions, C. Prussin for advice; and D. Douek, S. Boyd, and R. Germain for critical reading of the manuscript. The intramural research program of the NIAID supported this work. NR 44 TC 1 Z9 2 U1 2 U2 5 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 MAY 14 PY 2013 VL 110 IS 20 BP 8164 EP 8169 DI 10.1073/pnas.1302103110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 156EH UT WOS:000319803500045 PM 23637345 ER PT J AU Guo, LY Martens, C Bruno, D Porcella, SF Yamane, H Caucheteux, SM Zhu, JF Paul, WE AF Guo, Liying Martens, Craig Bruno, Daniel Porcella, Stephen F. Yamane, Hidehiro Caucheteux, Stephane M. Zhu, Jinfang Paul, William E. TI Lipid phosphatases identified by screening a mouse phosphatase shRNA library regulate T-cell differentiation and Protein kinase B AKT signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NF-KAPPA-B; PHOSPHOINOSITIDE 3-KINASE; PHOSPHATIDYLINOSITOL 3-PHOSPHATE; TUMOR SUPPRESSION; MYOTUBULARIN PHOSPHATASES; TRANSCRIPTION FACTORS; P110-DELTA ISOFORM; ACTIVATION; PTEN; PATHWAY AB Screening a complete mouse phosphatase lentiviral shRNA library using high-throughput sequencing revealed several phosphatases that regulate CD4 T-cell differentiation. We concentrated on two lipid phosphatases, the myotubularin-related protein (MTMR)9 and -7. Silencing MTMR9 by shRNA or siRNA resulted in enhanced T-helper (Th)1 differentiation and increased Th1 protein kinase B (PKB)/AKT phosphorylation while silencing MTMR7 caused increased Th2 and Th17 differentiation and increased AKT phosphorylation in these cells. Irradiated mice reconstituted with MTMR9 shRNA-transduced bone marrow cells had an elevated proportion of T-box transcription factor T-bet expressors among their CD4 T cells. After adoptive transfer of naive cells from such reconstituted mice, immunization resulted in a greater proportion of T-box transcription factor T-bet-expressing cells. Thus, myotubularin-related proteins have a role in controlling in vitro and in vivo Th-cell differentiation, possibly through regulation of phosphatidylinositol [3,4,5]-trisphosphate activity. C1 [Guo, Liying; Yamane, Hidehiro; Caucheteux, Stephane M.; Paul, William E.] NIAID, Cytokine Biol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Zhu, Jinfang] NIAID, Mol & Cellular Immunoregulat Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Martens, Craig; Bruno, Daniel; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Paul, WE (reprint author), NIAID, Cytokine Biol Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wpaul@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012 FU Intramural Research Program of the National Institutes of Health, NIAID FX We thank Julie Edwards [Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID)] for cell sorting, Kevin Holmes (Research Technologies Branch, NIAID) for analyzing data with FCS Express, Joanna H. Shih (Biometric Research Branch, National Cancer Institute) for statistical analysis, and Shirley Starnes for editorial assistance. This research was supported by the Intramural Research Program of the National Institutes of Health, NIAID. NR 51 TC 11 Z9 11 U1 0 U2 5 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 MAY 14 PY 2013 VL 110 IS 20 BP E1849 EP E1856 DI 10.1073/pnas.1305070110 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 156EH UT WOS:000319803500004 PM 23630283 ER PT J AU Ding, D Adams, MA Sallis, JF Norman, GJ Hovell, MF Chambers, CD Hofstetter, CR Bowles, HR Hagstromer, M Craig, CL Gomez, LF De Bourdeaudhuij, I Macfarlane, DJ Ainsworth, BE Bergman, P Bull, FC Carr, H Klasson-Heggebo, L Inoue, S Murase, N Matsudo, S Matsudo, V McLean, G Sjostrom, M Tomten, H Lefevre, J Volbekiene, V Bauman, AE AF Ding, Ding Adams, Marc A. Sallis, James F. Norman, Gregory J. Hovell, Melbourn F. Chambers, Christina D. Hofstetter, C. Richard Bowles, Heather R. Hagstromer, Maria Craig, Cora L. Fernando Gomez, Luis De Bourdeaudhuij, Ilse Macfarlane, Duncan J. Ainsworth, Barbara E. Bergman, Patrick Bull, Fiona C. Carr, Harriette Klasson-Heggebo, Lena Inoue, Shigeru Murase, Norio Matsudo, Sandra Matsudo, Victor McLean, Grant Sjostrom, Michael Tomten, Heidi Lefevre, Johan Volbekiene, Vida Bauman, Adrian E. TI Perceived neighborhood environment and physical activity in 11 countries: Do associations differ by country? SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Physical activity; Built environment; Neighborhood environment; International; Generalizability; Moderator ID BUILT ENVIRONMENT; ACTIVITY QUESTIONNAIRE; WALKING BEHAVIOR; SHORT-FORM; ADULTS; OBESITY; WALKABILITY; VALIDITY; RELIABILITY; INACTIVITY AB Background: Increasing empirical evidence supports associations between neighborhood environments and physical activity. However, since most studies were conducted in a single country, particularly western countries, the generalizability of associations in an international setting is not well understood. The current study examined whether associations between perceived attributes of neighborhood environments and physical activity differed by country. Methods: Population representative samples from 11 countries on five continents were surveyed using comparable methodologies and measurement instruments. Neighborhood environment x country interactions were tested in logistic regression models with meeting physical activity recommendations as the outcome, adjusted for demographic characteristics. Country-specific associations were reported. Results: Significant neighborhood environment attribute x country interactions implied some differences across countries in the association of each neighborhood attribute with meeting physical activity recommendations. Across the 11 countries, land-use mix and sidewalks had the most consistent associations with physical activity. Access to public transit, bicycle facilities, and low-cost recreation facilities had some associations with physical activity, but with less consistency across countries. There was little evidence supporting the associations of residential density and crime-related safety with physical activity in most countries. Conclusion: There is evidence of generalizability for the associations of land use mix, and presence of sidewalks with physical activity. Associations of other neighborhood characteristics with physical activity tended to differ by country. Future studies should include objective measures of neighborhood environments, compare psychometric properties of reports across countries, and use better specified models to further understand the similarities and differences in associations across countries. C1 [Ding, Ding; Adams, Marc A.; Sallis, James F.; Norman, Gregory J.; Chambers, Christina D.] Univ Calif San Diego, Dept Family Prevent Med, La Jolla, CA 92093 USA. [Ding, Ding; Hovell, Melbourn F.; Hofstetter, C. Richard] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Ding, Ding; Bauman, Adrian E.] Univ Sydney, Sydney Sch Publ Hlth, Fac Med, Camperdown, NSW, Australia. [Adams, Marc A.; Ainsworth, Barbara E.] Arizona State Univ, Sch Nutr & Hlth Promot, Phoenix, AZ USA. [Bowles, Heather R.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Bethesda, MD 20892 USA. [Hagstromer, Maria] Karolinska Inst, Div Physiotherapy, Stockholm, Sweden. [Hagstromer, Maria] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. [Craig, Cora L.] Canadian Fitness & Lifestyle Res Inst, Ottawa, ON, Canada. [Fernando Gomez, Luis] Pontificia Univ Javeriana, Bogota, Colombia. [De Bourdeaudhuij, Ilse] Univ Ghent, Dept Movement & Sport Sci, B-9000 Ghent, Belgium. [Macfarlane, Duncan J.] Univ Hong Kong Macfarlane, Inst Human Performance, Hong Kong, Hong Kong, Peoples R China. [Bergman, Patrick] Linneaus Univ, Sch Educ Psychol & Sports Sci, Kalmar, Sweden. [Bull, Fiona C.] Univ Western Australia, Sch Populat Hlth, Crawley, WA, Australia. [Carr, Harriette] New Zealand Minist Hlth, Wellington, New Zealand. [Klasson-Heggebo, Lena] Valnesfjord Rehabil Ctr, Osterkloft, Norway. [Inoue, Shigeru] Tokyo Med Univ, Dept Prevent Med & Publ Hlth, Tokyo 1608402, Japan. [Murase, Norio] Tokyo Med Univ, Dept Sports Med Hlth Promot, Tokyo 1608402, Japan. [Matsudo, Sandra; Matsudo, Victor] CELAFISCS, Phys Fitness Res Ctr Sao Caetano Sul, Ctr Studies, Sao Paulo, Brazil. [McLean, Grant] Sport New Zealand McLean, Wellington, New Zealand. [Sjostrom, Michael] Karolinska Inst, Novum, Unit Prevent Nutr, Dept Biosci & Nutr, Stockholm, Sweden. [Tomten, Heidi] Oppegard Municipal, Oppegard, Norway. [Lefevre, Johan] Katholieke Univ Leuven, Dept Kinesiol & Rehabil Sci, Louvain, Belgium. [Volbekiene, Vida] Lithuanian Acad Phys Educ, Dept Sport Sci, Kaunas, Lithuania. RP Ding, D (reprint author), Univ Calif San Diego, Dept Family Prevent Med, La Jolla, CA 92093 USA. EM melody.ding@sydney.edu.au RI Bull, Fiona/G-4148-2012; Bergman, Patrick/B-5906-2012; Adams, Marc/C-3513-2013; OI Bergman, Patrick/0000-0003-4934-8684; Adams, Marc/0000-0001-6310-1472; Hagstromer, Maria/0000-0002-4607-8677 NR 44 TC 26 Z9 26 U1 3 U2 55 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 MAY 14 PY 2013 VL 10 AR UNSP 57 DI 10.1186/1479-5868-10-57 PG 11 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 150LE UT WOS:000319391100002 PM 23672435 ER PT J AU Thornton, LE Cameron, AJ McNaughton, SA Waterlander, WE Sodergren, M Svastisalee, C Blanchard, L Liese, AD Battersby, S Carter, MA Sheeshka, J Kirkpatrick, SI Sherman, S Cowburn, G Foster, C Crawford, DA AF Thornton, Lukar E. Cameron, Adrian J. McNaughton, Sarah A. Waterlander, Wilma E. Sodergren, Marita Svastisalee, Chalida Blanchard, Laurence Liese, Angela D. Battersby, Sarah Carter, Mary-Ann Sheeshka, Judy Kirkpatrick, Sharon I. Sherman, Sandy Cowburn, Gill Foster, Charlie Crawford, David A. TI Does the availability of snack foods in supermarkets vary internationally? SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Snack foods; Food environment; Supermarket; International comparison ID SOFT DRINKS; PHYSICAL-ACTIVITY; VENDING MACHINES; EXTRA FOODS; OBESITY; CONSUMPTION; HEALTHY; PATTERNS; ENERGY; CHILDREN AB Background: Cross-country differences in dietary behaviours and obesity rates have been previously reported. Consumption of energy-dense snack foods and soft drinks are implicated as contributing to weight gain, however little is known about how the availability of these items within supermarkets varies internationally. This study assessed variations in the display of snack foods and soft drinks within a sample of supermarkets across eight countries. Methods: Within-store audits were used to evaluate and compare the availability of potato chips (crisps), chocolate, confectionery and soft drinks. Displays measured included shelf length and the proportion of checkouts and end-of-aisle displays containing these products. Audits were conducted in a convenience sample of 170 supermarkets across eight developed nations (Australia, Canada, Denmark, Netherlands, New Zealand, Sweden, United Kingdom (UK), and United States of America (US)). Results: The mean total aisle length of snack foods (adjusted for store size) was greatest in supermarkets from the UK (56.4 m) and lowest in New Zealand (21.7 m). When assessed by individual item, the greatest aisle length devoted to chips, chocolate and confectionery was found in UK supermarkets while the greatest aisle length dedicated to soft drinks was in Australian supermarkets. Only stores from the Netherlands (41%) had less than 70% of checkouts featuring displays of snack foods or soft drinks. Conclusion: Whilst between-country variations were observed, overall results indicate high levels of snack food and soft drinks displays within supermarkets across the eight countries. Exposure to snack foods is largely unavoidable within supermarkets, increasing the likelihood of purchases and particularly those made impulsively. C1 [Thornton, Lukar E.; Cameron, Adrian J.; McNaughton, Sarah A.; Crawford, David A.] Deakin Univ, Ctr Phys Act & Nutr Res, Sch Exercise & Nutr Sci, Melbourne, Vic 3125, Australia. [Waterlander, Wilma E.] Vrije Univ Amsterdam, Fac Earth & Life Sci, Dept Hlth Sci, Amsterdam, Netherlands. [Waterlander, Wilma E.] Vrije Univ Amsterdam, Fac Earth & Life Sci, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Waterlander, Wilma E.] Univ Auckland, Sch Populat Hlth, Natl Inst Hlth Innovat, Auckland 1, New Zealand. [Sodergren, Marita] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Family Med, Huddinge, Sweden. [Svastisalee, Chalida] Metropolitan Univ Coll, Copenhagen, Denmark. [Blanchard, Laurence] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Liese, Angela D.] Univ S Carolina, Dept Epidemiol & Biostat, Ctr Res Nutr & Hlth Dispar, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Battersby, Sarah] Univ S Carolina, Dept Geog, Columbia, SC 29208 USA. [Carter, Mary-Ann] Univ Otago, Dept Publ Hlth, Wellington, New Zealand. [Sheeshka, Judy] Victoria Univ Technol, Sch Biomed & Hlth Sci, Melbourne, Vic 3000, Australia. [Kirkpatrick, Sharon I.] US Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. [Sherman, Sandy] Food Trust, Philadelphia, PA USA. [Cowburn, Gill; Foster, Charlie] Univ Oxford, British Heart Fdn Hlth Promot Res Grp, Dept Publ Hlth, Oxford, England. RP Thornton, LE (reprint author), Deakin Univ, Ctr Phys Act & Nutr Res, Sch Exercise & Nutr Sci, Melbourne Burwood Campus,221 Burwood Highway, Melbourne, Vic 3125, Australia. EM lukar.thornton@deakin.edu.au RI McNaughton, Sarah/B-2075-2012; Crawford, David /K-6301-2015; OI McNaughton, Sarah/0000-0001-5936-9820; Crawford, David /0000-0002-2467-7556; Waterlander, Wilma/0000-0003-0956-178X; Kirkpatrick, Sharon/0000-0001-9896-5975; Thornton, Lukar/0000-0001-8759-8671 FU Deakin University; National Health and Medical Research Council [1013313]; Australian Research Council [FT100100581]; British Heart Foundation; Nordea Foundation FX The collection of data within Melbourne was supported by funding through Deakin University. LET is supported by a Deakin University Alfred Deakin Postdoctoral Research Fellowship. AJC is supported by a National Health and Medical Research Council Fellowship (#1013313). SAM is supported by an Australian Research Council Future Fellowship (FT100100581). CF is funded by the British Heart Foundation. CS is supported by The Nordea Foundation. NR 66 TC 16 Z9 16 U1 7 U2 23 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 MAY 14 PY 2013 VL 10 AR 56 DI 10.1186/1479-5868-10-56 PG 9 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 150LE UT WOS:000319391100001 PM 23672409 ER PT J AU Chen, J Qian, HH Horai, R Chan, CC Caspi, RR AF Chen, Jun Qian, Haohua Horai, Reiko Chan, Chi-Chao Caspi, Rachel R. TI Use of Optical Coherence Tomography and Electroretinography to Evaluate Retinal Pathology in a Mouse Model of Autoimmune Uveitis SO PLOS ONE LA English DT Article ID MACULAR EDEMA; UVEORETINITIS; DISEASE; SYSTEM; MICE AB Experimental autoimmune uveoretinitis (EAU) in mice is a model for human autoimmune uveitis. Longitudinal follow-up is only possible by non-invasive techniques, but the information obtained by visual fundus examination can be limited. We therefore evaluated the efficacy of optical coherence tomography (OCT) and electroretinography (ERG) to monitor pathological and functional changes of the retina in vivo. OCT imaging and ERG recording as a measure of visual function were compared with visual fundoscopic imaging and histology findings in the same mouse. Our results showed that OCT imaging of the retina was well correlated with clinical and histological observations in mice during EAU. However, OCT imaging was more sensitive than fundoscopic imaging in detecting the cell infiltrates at the early phase of disease onset. Furthermore, by allowing multi-layer cross-and horizontal-sectional visualizations of retinal lesions longitudinally in a noninvasive fashion, OCT added information that could not be obtained by fundoscopic and histological examinations. Lastly, retinal thickness obtained by OCT imaging provided a key indicator reflecting disease activity, which showed a close association with visual dysfunction as measured by ERG recordings in EAU mice. Thus, our findings demonstrate that OCT is a highly sensitive and reliable technique, and a valuable method for the semi-quantitative evaluation of retinal inflammation in vivo in the mouse. C1 [Chen, Jun; Horai, Reiko; Chan, Chi-Chao; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Qian, Haohua] NEI, Vis Funct Core, NIH, Bethesda, MD 20892 USA. RP Chen, J (reprint author), Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. EM chenju@mail.nih.gov; caspir@mail.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU NIH-National Eye Institute Intramural funding [EY000184] FX This work was supported by NIH-National Eye Institute Intramural funding, grant # EY000184. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 11 Z9 11 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 MAY 14 PY 2013 VL 8 IS 5 AR e63904 DI 10.1371/journal.pone.0063904 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146RE UT WOS:000319107400085 PM 23691112 ER PT J AU Cuthbert, BN Insel, TR AF Cuthbert, Bruce N. Insel, Thomas R. TI Toward the future of psychiatric diagnosis: the seven pillars of RDoC SO BMC MEDICINE LA English DT Article DE Diagnosis; DSM; ICD; Psychiatric diagnosis; Psychopathology; RDoC; Research domain criteria ID RESEARCH DOMAIN CRITERIA; MENTAL-DISORDERS; PSYCHOPATHOLOGY; NEUROSCIENCE; DSM-5; CLASSIFICATION; CHALLENGES; DEPRESSION; CONSTRUCTS; UTILITY AB Background: Current diagnostic systems for mental disorders rely upon presenting signs and symptoms, with the result that current definitions do not adequately reflect relevant neurobiological and behavioral systems-impeding not only research on etiology and pathophysiology but also the development of new treatments. Discussion: The National Institute of Mental Health began the Research Domain Criteria (RDoC) project in 2009 to develop a research classification system for mental disorders based upon dimensions of neurobiology and observable behavior. RDoC supports research to explicate fundamental biobehavioral dimensions that cut across current heterogeneous disorder categories. We summarize the rationale, status and long-term goals of RDoC, outline challenges in developing a research classification system (such as construct validity and a suitable process for updating the framework) and discuss seven distinct differences in conception and emphasis from current psychiatric nosologies. Summary: Future diagnostic systems cannot reflect ongoing advances in genetics, neuroscience and cognitive science until a literature organized around these disciplines is available to inform the revision efforts. The goal of the RDoC project is to provide a framework for research to transform the approach to the nosology of mental disorders. C1 [Cuthbert, Bruce N.; Insel, Thomas R.] NIMH, NIH, Bethesda, MD 20892 USA. [Cuthbert, Bruce N.; Insel, Thomas R.] Express Parcel Delivery, Rockville, MD 20852 USA. RP Cuthbert, BN (reprint author), NIMH, NIH, 6001 Execut Blvd,MSC 9632,Room 7121, Bethesda, MD 20892 USA. EM bcuthber@mail.nih.gov NR 34 TC 406 Z9 413 U1 12 U2 91 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD MAY 14 PY 2013 VL 11 AR 126 DI 10.1186/1741-7015-11-126 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 146DM UT WOS:000319069500001 PM 23672542 ER PT J AU Beydoun, MA Beydoun, HA Boueiz, A Shroff, MR Zonderman, AB AF Beydoun, May A. Beydoun, Hind A. Boueiz, Adel Shroff, Monal R. Zonderman, Alan B. TI Antioxidant status and its association with elevated depressive symptoms among US adults: National Health and Nutrition Examination Surveys 2005-6 SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Depressive symptoms; Antioxidants; Carotenoids; Adults ID OXIDATIVE STRESS; VITAMIN-E; LIPID-PEROXIDATION; METABOLIC SYNDROME; IMMOBILIZATION STRESS; PSYCHOLOGICAL STRESS; ALCOHOL DEPENDENCE; MAJOR DEPRESSION; SAMPLE SELECTION; BETA-CAROTENE AB We examined the relationship of elevated depressive symptoms with antioxidant status. Cross-sectional data from the National Health and Nutrition Examination Surveys 2005-6 on US adults aged 20-85 years were analysed. Depressive symptoms were measured using the Patient Health Questionnaire with a score cut-off point of 10 to define 'elevated depressive symptoms'. Serum antioxidant status was measured by serum levels of carotenoids, retinol (free and retinyl esters), vitamin C and vitamin E. The main analyses consisted of multiple logistic and zero-inflated Poisson regression models, taking into account sampling design complexity. The final sample consisted of 1798 US adults with complete data. A higher total serum carotenoid level was associated with a lower likelihood of elevated depressive symptoms with a reduction in the odds by 37% overall with each SD increase in exposure, and by 34% among women (P<0.05). A dose-response relationship was observed when total serum carotenoids were expressed as quartiles (Q(4 (1.62-10.1 mu mol/l)) v. Q(1 (0.06-0.86 mu mol/l)): OR 0.41; 95% CI 0.23, 0.76, P<0.001; P for trend=0.035), though no significant associations were found with the other antioxidant levels. Among carotenoids, beta-carotene (men and women combined) and lutein + zeaxanthins (women only, after control for dietary lutein + zeaxanthin intake and supplement use) had an independent inverse association with elevated depressive symptoms among US adults. None of the other serum antioxidants had a significant association with depressive symptoms, independently of total carotenoids and other covariates. In conclusion, total carotenoids (mainly beta-carotene and lutein + zeaxanthins) in serum were associated with reduced levels of depressive symptoms among community-dwelling US adults. C1 [Beydoun, May A.; Zonderman, Alan B.] NIA, NIH, Biomed Res Ctr, IRP, Baltimore, MD 21224 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Boueiz, Adel] Johns Hopkins Univ, Dept Internal Med, Baltimore, MD USA. [Shroff, Monal R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institute on Aging, NIA/NIH/IRP FX This study was fully supported by the Intramural Research Program of the National Institute on Aging, NIA/NIH/IRP. The contributions of each author are as follows: M. A. B. contributed to the conceptualisation of the study, the literature review, the plan of the analysis, the data management and statistical analysis, and the writing and revision of the manuscript; H. A. B. contributed to the literature search and review, the plan of the analysis, the writing of part of the paper and the revision of the manuscript; A. B. carried out the literature search and review, wrote part of the paper and revised the manuscript; M. R. S. carried out the literature search, drafted the plan of the analysis, wrote part of the paper and revised the manuscript; A. B. Z. drafted the plan of the analysis, wrote part of the paper and revised the manuscript. The authors declare that there is no conflict of interest. NR 80 TC 10 Z9 10 U1 0 U2 12 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD MAY 14 PY 2013 VL 109 IS 9 BP 1714 EP 1729 DI 10.1017/S0007114512003467 PG 16 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 136LT UT WOS:000318364100020 PM 22935166 ER PT J AU Ross, JS Mocanu, M Lampropulos, JF Tse, T Krumholz, HM AF Ross, Joseph S. Mocanu, Marian Lampropulos, Julianna F. Tse, Tony Krumholz, Harlan M. TI Time to Publication Among Completed Clinical Trials SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Ross, Joseph S.] Yale Univ, Sch Med, Dept Med, Gen Internal Med Sect, New Haven, CT 06520 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Sect Cardiovasc Med, New Haven, CT 06520 USA. [Ross, Joseph S.; Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Robert Wood Johnson Fdn Clin Scholars Program, New Haven, CT 06520 USA. [Ross, Joseph S.; Lampropulos, Julianna F.; Krumholz, Harlan M.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. [Mocanu, Marian] Mayo Clin, Dept Med, Sect Cardiovasc Med, Rochester, MN USA. [Tse, Tony] Natl Lib Med, Natl Inst Hlth, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Krumholz, Harlan M.] Yale Univ, Sch Epidemiol & Publ Hlth, Sect Hlth Policy & Adm, New Haven, CT USA. RP Ross, JS (reprint author), Yale Univ, Sch Med, Gen Internal Med Sect, POB 208093, New Haven, CT 06520 USA. EM joseph.ross@yale.edu FU Intramural NIH HHS; NHLBI NIH HHS [1U01HL105270-02, U01 HL105270]; NIA NIH HHS [K08 AG032886]; PHS HHS [HHSN276201000788P] NR 7 TC 17 Z9 17 U1 0 U2 6 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 MAY 13 PY 2013 VL 173 IS 9 BP 825 EP 828 DI 10.1001/jamainternmed.2013.136 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 159JN UT WOS:000320041800028 PM 23460252 ER PT J AU Prasad, V Cheung, M Cifu, A AF Prasad, Vinay Cheung, Michael Cifu, Adam TI Routine Noninvasive Testing and Highly Sensitive Troponin Immunoassays reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Cheung, Michael] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Cifu, Adam] Univ Chicago, Chicago, IL 60637 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 1 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 MAY 13 PY 2013 VL 173 IS 9 BP 833 EP 834 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 159JN UT WOS:000320041800035 PM 23700018 ER PT J AU Utreras, E Prochazkova, M Terse, A Gross, J Keller, J Iadarola, MJ Kulkarni, AB AF Utreras, Elias Prochazkova, Michaela Terse, Anita Gross, Jacklyn Keller, Jason Iadarola, Michael J. Kulkarni, Ashok B. TI TGF-beta 1 sensitizes TRPV1 through Cdk5 signaling in odontoblast-like cells SO MOLECULAR PAIN LA English DT Article DE TGF-beta 1; Cdk5; p35; TRPV1; MDPC-23 cells ID CYCLIN-DEPENDENT KINASE-5; HUMAN DENTAL-PULP; TRANSFORMING GROWTH-FACTOR-BETA-1; EXPRESSION; CHANNELS; TEETH; LINE; PAIN; PHOSPHORYLATION; MDPC-23 AB Background: Odontoblasts are specialized cells that form dentin and they are believed to be sensors for tooth pain. Transforming growth factor-beta 1 (TGF-beta 1), a pro-inflammatory cytokine expressed early in odontoblasts, plays an important role in the immune response during tooth inflammation and infection. TGF-beta 1 is also known to participate in pain signaling by regulating cyclin-dependent kinase 5 (Cdk5) in nociceptive neurons of the trigeminal and dorsal root ganglia. However, the precise role of TGF-beta 1 in tooth pain signaling is not well characterized. The aim of our present study was to determine whether or not in odontoblasts Cdk5 is functionally active, if it is regulated by TGF-beta 1, and if it affects the downstream pain receptor, transient receptor potential vanilloid-1 (TRPV1). Results: We first determined that Cdk5 and p35 are indeed expressed in an odontoblast-enriched primary preparation from murine teeth. For the subsequent analysis, we used an odontoblast-like cell line (MDPC-23) and found that Cdk5 is functionally active in these cells and its kinase activity is upregulated during cell differentiation. We found that TGF-beta 1 treatment potentiated Cdk5 kinase activity in undifferentiated MDPC-23 cells. SB431542, a specific inhibitor of TGF-beta 1 receptor 1 (Tgfbr1), when co-administered with TGF-beta 1, blocked the induction of Cdk5 activity. TGF-beta 1 treatment also activated the ERK1/2 signaling pathway, causing an increase in early growth response-1 (Egr-1), a transcription factor that induces p35 expression. In MDPC-23 cells transfected with TRPV1, Cdk5-mediated phosphorylation of TRPV1 at threonine-407 was significantly increased after TGF-beta 1 treatment. In contrast, SB431542 co-treatment blocked TRPV1 phosphorylation. Moreover, TGF-beta 1 treatment enhanced both proton-and capsaicin-induced Ca2+ influx in TRPV1-expressing MDPC-23 cells, while co-treatment with either SB431542 or roscovitine blocked this effect. Conclusions: Cdk5 and p35 are expressed in a murine odontoblast-enriched primary preparation of cells from teeth. Cdk5 is also functionally active in odontoblast-like MDPC-23 cells. TGF-beta 1 sensitizes TRPV1 through Cdk5 signaling in MDPC-23 cells, suggesting the direct involvement of odontoblasts and Cdk5 in dental nociceptive pain transduction. C1 [Utreras, Elias; Prochazkova, Michaela; Terse, Anita; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Utreras, Elias] Univ Chile, Fac Sci, Lab Cellular & Neuronal Dynam, Santiago, Chile. [Gross, Jacklyn; Keller, Jason; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, NIH, Bethesda, MD 20892 USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, 30 Convent Dr,Bldg 30,Room 130, Bethesda, MD 20892 USA. EM ak40m@nih.gov RI utreras, elias/I-1038-2013 OI utreras, elias/0000-0002-1004-0466 FU Division of Intramural Research, National Institute of Dental and Craniofacial Research, NIH, Bethesda MD, USA; PAI [79100009]; FONDECYT [11110136] FX We thank Shelagh Johnson for expert editorial assistance and Bradford Hall for his helpful discussion. The work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, NIH, Bethesda MD, USA and PAI 79100009 and FONDECYT 11110136 (to E.U.). NR 56 TC 7 Z9 8 U1 1 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD MAY 13 PY 2013 VL 9 AR 24 DI 10.1186/1744-8069-9-24 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 161FT UT WOS:000320178500001 PM 23668392 ER PT J AU Cooks, T Pateras, IS Tarcic, O Solomon, H Schetter, AJ Wilder, S Lozano, G Pikarsky, E Forshew, T Rozenfeld, N Harpaz, N Itzkowitz, S Harris, CC Rotter, V Gorgoulis, VG Oren, M AF Cooks, Tomer Pateras, Ioannis S. Tarcic, Ohad Solomon, Hilla Schetter, Aaron J. Wilder, Sylvia Lozano, Guillermina Pikarsky, Eli Forshew, Tim Rozenfeld, Nitzan Harpaz, Noam Itzkowitz, Steven Harris, Curtis C. Rotter, Varda Gorgoulis, Vassilis G. Oren, Moshe TI Mutant p53 Prolongs NF-kappa B Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer SO CANCER CELL LA English DT Article ID COLITIS-ASSOCIATED NEOPLASIA; DEXTRAN SULFATE SODIUM; LI-FRAUMENI-SYNDROME; ULCERATIVE-COLITIS; MOUSE MODEL; TUMOR-SUPPRESSOR; GENE-EXPRESSION; CELLS; MUTATIONS; COLON AB The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-alpha-induced NF-kappa B activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-kappa B activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC. C1 [Cooks, Tomer; Tarcic, Ohad; Solomon, Hilla; Wilder, Sylvia; Rotter, Varda; Oren, Moshe] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Pateras, Ioannis S.; Gorgoulis, Vassilis G.] Univ Athens, Sch Med, Mol Carcinogenesis Grp, Dept Histol Embryol, Athens 15771, Greece. [Schetter, Aaron J.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Lozano, Guillermina] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Pikarsky, Eli] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Immunol & Canc Res, IL-91120 Jerusalem, Israel. [Pikarsky, Eli] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pathol, IL-91120 Jerusalem, Israel. [Forshew, Tim; Rozenfeld, Nitzan] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England. [Harpaz, Noam] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA. [Itzkowitz, Steven] Mt Sinai Sch Med, Dept Med, Div Gastroenterol, New York, NY 10029 USA. [Gorgoulis, Vassilis G.] Acad Athens, Biomed Res Fdn, Athens 11527, Greece. RP Oren, M (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. EM moshe.oren@weizmann.ac.il FU European Commission [223151, 284460]; National Cancer Institute [R37 CA40099]; Center of Excellence grant from the Israel Science Foundation [1779/11]; Dr. Miriam and Sheldon Adelson Medical Research Foundation; Center of Excellence grant from the Flight Attendant Medical Research Institute; Scientific Advisory Board of Exact Sciences Corporation FX We thank Ori Brenner and Gilgi Friedlander for help with histopathological analysis and expression microarray analysis, respectively. We also thank Ronnie Apte, Elena Voronov, Derek Mann, Neil Perkins, and Yinon Ben-Neriah for helpful advice and suggestions. This work was supported in part by European Commission FP7 funding (INFLACARE agreement number 223151; INSPiRE agreement number 284460), Grant number R37 CA40099 from the National Cancer Institute, a Center of Excellence grant (1779/11) from the Israel Science Foundation, the Dr. Miriam and Sheldon Adelson Medical Research Foundation, and a Center of Excellence grant from the Flight Attendant Medical Research Institute. M.O. is the incumbent of the Andre Lwoff Chair in Molecular Biology. The European Commission is not liable for any use that may be made of the information contained herein. S.I. receives research support and is on the Scientific Advisory Board of Exact Sciences Corporation. NR 59 TC 107 Z9 111 U1 1 U2 35 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAY 13 PY 2013 VL 23 IS 5 BP 634 EP 646 DI 10.1016/j.ccr.2013.03.022 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 146PQ UT WOS:000319103400012 PM 23680148 ER PT J AU Malley, JD Dasgupta, A Moore, JH AF Malley, James D. Dasgupta, Abhijit Moore, Jason H. TI The limits of p-values for biological data mining SO BIODATA MINING LA English DT Editorial Material C1 [Malley, James D.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Dasgupta, Abhijit] NIAMSD, NIH, Bethesda, MD 20892 USA. [Moore, Jason H.] Inst Quantitat Biomed Sci, Dept Genet, Lebanon, NH USA. [Moore, Jason H.] Inst Quantitat Biomed Sci, Dept Community & Family Med, Lebanon, NH USA. [Moore, Jason H.] Dartmouth Coll, Geisel Sch Med, Lebanon, NH 03756 USA. RP Moore, JH (reprint author), Inst Quantitat Biomed Sci, Dept Genet, Lebanon, NH USA. EM jason.h.moore@dartmouth.edu FU NEI NIH HHS [R01 EY022300]; NIAID NIH HHS [R01 AI059694]; NLM NIH HHS [R01 LM010098, R01 LM009012] NR 3 TC 6 Z9 6 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-0381 J9 BIODATA MIN JI BioData Min. PD MAY 11 PY 2013 VL 6 AR UNSP 10 DI 10.1186/1756-0381-6-10 PG 2 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 209WU UT WOS:000323792100001 PM 23663551 ER PT J AU Birn, AE Fee, E AF Birn, Anne-Emanuelle Fee, Elizabeth TI The art of medicine The Rockefeller Foundation and the international health agenda SO LANCET LA English DT Editorial Material C1 [Birn, Anne-Emanuelle] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Birn, AE (reprint author), Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. EM ae.birn@utoronto.ca NR 6 TC 5 Z9 5 U1 1 U2 5 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 MAY 11 PY 2013 VL 381 IS 9878 BP 1618 EP 1619 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 146SX UT WOS:000319112400013 PM 23671918 ER PT J AU Gagnon, D Senechal, H D'Abramo, CM Alvarez, J McBride, AA Archambault, J AF Gagnon, David Senechal, Helene D'Abramo, Claudia M. Alvarez, Jennifer McBride, Alison A. Archambault, Jacques TI Genetic analysis of the E2 transactivation domain dimerization interface from bovine papillomavirus type 1 SO VIROLOGY LA English DT Article DE BPV1; E2; Transactivation; DNA replication; Transactivation domain; Dimer; Dimerization; Redox; High-throughput assay; Protein interface ID TRANSCRIPTIONAL ACTIVATION FUNCTION; DNA-REPLICATION; MITOTIC CHROMOSOMES; CRYSTAL-STRUCTURE; VIRAL-DNA; PROTEIN; BRD4; GENOME; COMPLEX; BINDING AB The bovine papillomavirus type 1 (BPV1) E2 protein binds as a dimer to the viral genome to promote its transcription, replication and maintenance in keratinocytes. Although BPV1 E2 dimerizes primarily through its DNA-binding domain, it was shown previously that its transactivation domain (TAD) can also dimerize in vitro through formation of a disulfide bond between cysteine 57 (C57) of adjacent monomers and of an ion pair between arginine 172 (R172) and aspartic acid 175 (D175). The function of this TAD dimerization interface in vivo remains unknown. Here, we report the effects of substituting C57, R172 and D175 by alanine on the transactivation activity of BPV E2 as well as on its ability to support viral DNA replication using a novel luciferase-based assay. Results for this mutational analysis suggest that the TAD dimerization interface is not essential for either process but may contribute to the DNA replication activity of BPV1 E2. (C) 2013 Elsevier Inc. All rights reserved. C1 [Gagnon, David; Senechal, Helene; D'Abramo, Claudia M.; Alvarez, Jennifer; Archambault, Jacques] Inst Rech Clin Montreal, Mol Virol Lab, Montreal, PQ H2W 1R7, Canada. [Gagnon, David; Senechal, Helene; D'Abramo, Claudia M.; Alvarez, Jennifer; Archambault, Jacques] Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. [McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Archambault, J (reprint author), Inst Rech Clin Montreal, Mol Virol Lab, 110 Pine Ave W, Montreal, PQ H2W 1R7, Canada. EM jacques.archambault@ircm.qc.ca OI Archambault, Jacques/0000-0001-8107-3428; McBride, Alison/0000-0001-5607-5157 FU Intramural Research Program of the NIAID, NIH; Cancer Research Society (CRS); Canadian Institutes of Health Research (CIHR) FX We thank Gretchen Meinke for help in generating Fig. 1. This work was supported by grants from the Intramural Research Program of the NIAID, NIH, to AAM from the Cancer Research Society (CRS) and the Canadian Institutes of Health Research (CIHR) to JA. HS holds a studentship from the CIHR. NR 44 TC 6 Z9 6 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 0042-6822 J9 VIROLOGY JI Virology PD MAY 10 PY 2013 VL 439 IS 2 BP 132 EP 139 DI 10.1016/j.virol.2013.02.012 PG 8 WC Virology SC Virology GA 168EC UT WOS:000320687500009 PM 23490049 ER PT J AU Donekal, S Ambale-Venkatesh, B Berkowitz, S Wu, CO Choi, EY Fernandes, V Yan, R Harouni, AA Bluemke, DA Lima, JAC AF Donekal, Sirisha Ambale-Venkatesh, Bharath Berkowitz, Seth Wu, Colin O. Choi, Eui Young Fernandes, Veronica Yan, Raymond Harouni, Ahmed A. Bluemke, David A. Lima, Joao A. C. TI Inter-study reproducibility of cardiovascular magnetic resonance tagging SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE CMR tagging; HARP; Test-retest reproducibility; SPAMM; Circumferential strain; Radial strain; Principal strains; Torsion ID SPECKLE-TRACKING ECHOCARDIOGRAPHY; LEFT-VENTRICULAR FUNCTION; REGIONAL MYOCARDIAL-FUNCTION; ASYMPTOMATIC INDIVIDUALS; STRAIN; ATHEROSCLEROSIS; MRI; RELIABILITY; DYSFUNCTION; TORSION AB Background: The aim of this study is to determine the test-retest reliability of the measurement of regional myocardial function by cardiovascular magnetic resonance (CMR) tagging using spatial modulation of magnetization. Methods: Twenty-five participants underwent CMR tagging twice over 12 +/- 7 days. To assess the role of slice orientation on strain measurement, two healthy volunteers had a first exam, followed by image acquisition repeated with slices rotated +/- 15 degrees out of true short axis, followed by a second exam in the true short axis plane. To assess the role of slice location, two healthy volunteers had whole heart tagging. The harmonic phase (HARP) method was used to analyze the tagged images. Peak midwall circumferential strain (Ecc), radial strain (Err), Lambda 1, Lambda 2, and Angle a were determined in basal, mid and apical slices. LV torsion, systolic and early diastolic circumferential strain and torsion rates were also determined. Results: LV Ecc and torsion had excellent intra-, interobserver, and inter-study intra- class correlation coefficients (ICC range, 0.7 to 0.9). Err, Lambda 1, Lambda 2 and angle had excellent intra- and interobserver ICC than inter-study ICC. Angle had least inter-study reproducibility. Torsion rates had superior intra-, interobserver, and inter-study reproducibility to strain rates. The measurements of LV Ecc were comparable in all three slices with different short axis orientations (standard deviation of mean Ecc was 0.09, 0.18 and 0.16 at basal, mid and apical slices, respectively). The mean difference in LV Ecc between slices was more pronounced in most of the basal slices compared to the rest of the heart. Conclusions: Intraobserver and interobserver reproducibility of all strain and torsion parameters was excellent. Inter-study reproducibility of CMR tagging by SPAMM varied between different parameters as described in the results above and was superior for Ecc and LV torsion. The variation in LV Ecc measurement due to altered slice orientation is negligible compared to the variation due to slice location. C1 [Donekal, Sirisha; Ambale-Venkatesh, Bharath; Berkowitz, Seth; Choi, Eui Young; Fernandes, Veronica; Yan, Raymond; Bluemke, David A.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD 21287 USA. [Wu, Colin O.] NIH, Dept Stat, Rockledge Ctr 2, Bethesda, MD 20892 USA. [Harouni, Ahmed A.; Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Dept Cardiol, 600 N Wolfe St, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Ambale Venkatesh, Bharath/F-4941-2016; OI Ambale Venkatesh, Bharath/0000-0002-2330-2373; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC -95169]; NCRR [UL1-RR-024156, UL1-RR-025005] FX This research was supported by contracts N01-HC-95159 through N01-HC -95169 from the National Heart, Lung, and Blood Institute and by grants UL1-RR-024156 and UL1-RR-025005 from NCRR. The authors thank the other investigators, staff, and participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 33 TC 19 Z9 19 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD MAY 10 PY 2013 VL 15 AR 37 DI 10.1186/1532-429X-15-37 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 152ZG UT WOS:000319570300001 PM 23663535 ER PT J AU Waisberg, M Lin, CK Huang, CY Pena, M Orandle, M Bolland, S Pierce, SK AF Waisberg, Michael Lin, Christina K. Huang, Chiung-Yu Pena, Mirna Orandle, Marlene Bolland, Silvia Pierce, Susan K. TI The Impact of Genetic Susceptibility to Systemic Lupus Erythematosus on Placental Malaria in Mice SO PLOS ONE LA English DT Article ID FALCIPARUM-MALARIA; CEREBRAL MALARIA; PROGNOSTIC-SIGNIFICANCE; CLINICAL-IMPLICATIONS; AUTOIMMUNE DISEASE; THROMBOCYTOPENIA; INFECTION; POPULATIONS; PROTECTION; COMPLEMENT AB Severe malaria, including cerebral malaria (CM) and placental malaria (PM), have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE), conferred resistance to CM. Protection appeared to be mediated by immune mechanisms that allowed SLE-prone mice, prior to the onset of overt SLE symptoms, to better control their inflammatory response to Plasmodium infection. Here we extend these findings to ask does SLE susceptibility have 1) a cost to reproductive fitness and/or 2) an effect on PM in mice? The rates of conception for WT and SLE susceptible (SLEs) mice were similar as were the number and viability of fetuses in pregnant WT and SLEs mice indicating that SLE susceptibility does not have a reproductive cost. We found that Plasmodium chabaudi AS (Pc) infection disrupted early stages of pregnancy before the placenta was completely formed resulting in massive decidual necrosis 8 days after conception. Pc-infected pregnant SLEs mice had significantly more fetuses (similar to 1.8 fold) but SLE did not significantly affect fetal viability in infected animals. This was despite the fact that Pc-infected pregnant SLEs mice had more severe symptoms of malaria as compared to Pc-infected pregnant WT mice. Thus, although SLE susceptibility was not protective in PM in mice it also did not have a negative impact on reproductive fitness. C1 [Waisberg, Michael; Lin, Christina K.; Pena, Mirna; Bolland, Silvia; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Huang, Chiung-Yu] NIAID, Biostat Res Branch, NIH, Rockville, MD USA. [Orandle, Marlene] NIAID, Comparat Med Branch, NIH, Rockville, MD USA. RP Waisberg, M (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM waisberg@gmail.com 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 28 TC 2 Z9 2 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 MAY 10 PY 2013 VL 8 IS 5 AR e62820 DI 10.1371/journal.pone.0062820 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143FO UT WOS:000318852400012 PM 23675429 ER PT J AU Jin, TC Perry, A Smith, P Jiang, JS Xiao, TS AF Jin, Tengchuan Perry, Andrew Smith, Patrick Jiang, Jiansheng Xiao, T. Sam TI Structure of the Absent in Melanoma 2 (AIM2) Pyrin Domain Provides Insights into the Mechanisms of AIM2 Autoinhibition and Inflammasome Assembly SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEASE-ACTIVATING FACTOR-1; X-RAY-DIFFRACTION; CRYSTAL-STRUCTURE; 3-DIMENSIONAL STRUCTURE; CASPASE ACTIVATION; FOLD SUPERFAMILY; CYTOPLASMIC DNA; EFFECTOR-DOMAIN; INNATE-IMMUNITY; NMR STRUCTURE AB Absent in melanoma 2 (AIM2) is a cytosolic double-stranded (dsDNA) sensor essential for innate immune responses against DNA viruses and bacteria such as Francisella and Listeria. Upon dsDNA engagement, the AIM2 amino-terminal pyrin domain (PYD) is responsible for downstream signaling to the adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) through homotypic PYD-PYD interactions and the assembly of an inflammasome. Toward a better understanding of the AIM2 signaling mechanism, we determined the crystal structure of the human AIM2 PYD. The structure reveals a death domain fold with a short alpha 3 helix that is buttressed by a highly conserved lysine residue at the alpha 2 helix, which may stabilize the alpha 3 helix for potential interaction with partner domains. The surface of the AIM2 PYD exhibits distinct charge distribution with highly acidic alpha 1-alpha 2 helices and highly basic alpha 5-alpha 6 helices. A prominent solvent-exposed hydrophobic patch formed by residues Phe-27 and Phe-28 at the alpha 2 helix resembles a similar surface involved in the death effector domain homotypic interactions. Docking studies suggest that the AIM2 PYD may bind the AIM2 hematopoietic interferon-inducible nuclear (HIN) domain or ASC PYD using overlapping surface near the alpha 2 helix. This may ensure that AIM2 interacts with the downstream adapter ASC only upon release of the autoinhibition by the dsDNA ligand. Our work thus unveils novel structural features of the AIM2 PYD and provides insights into the potential mechanisms of the PYD-HIN and PYD-PYD interactions important for AIM2 autoinhibition and inflammasome assembly. C1 [Jin, Tengchuan; Perry, Andrew; Smith, Patrick; Jiang, Jiansheng; Xiao, T. Sam] NIAID, NIH, Immunol Lab, Struct Immunobiol Unit, Bethesda, MD 20892 USA. RP Xiao, TS (reprint author), NIAID, NIH, Immunol Lab, Struct Immunobiol Unit, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM xiaot@niaid.nih.gov RI Xiao, Tsan/A-8590-2010; Xiao, Tsan/I-7616-2013; Jin, Tengchuan/B-5883-2014 OI Xiao, Tsan/0000-0001-9688-475X; Jin, Tengchuan/0000-0002-1395-188X FU National Institutes of Health grant from the Division of Intramural Research, NIAID; NCI [Y1-CO-1020]; NIGMS, National Institutes of Health [Y1-GM-1104] FX This work was supported, in whole or in part, by a National Institutes of Health grant from the Division of Intramural Research, NIAID (to T. S. X.).; We thank Dr. Lars C. Pedersen at the NIEHS, National Institutes of Health for the MBP fusion plasmids, Dr. David S. Waugh at the NCI, National Institutes of Health for the tobacco etch virus protease expression construct, and Dr. Gerhard Wagner at Harvard Medical School for the GB1 encoding plasmid. We thank Dr. Tinghe Wu for help with the ASC PYD expression construct and Dr. D. Eric Anderson at the Mass Spectrometry facility of the NIDDK, National Institutes of Health for technical support. We are grateful to the beam line scientists at the GM/CA-CAT, Advanced Photon Source for support, which is funded in whole or in part with federal funds from the NCI (Grant Y1-CO-1020) and NIGMS (Grant Y1-GM-1104), National Institutes of Health. NR 60 TC 45 Z9 46 U1 1 U2 10 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 MAY 10 PY 2013 VL 288 IS 19 BP 13225 EP 13235 DI 10.1074/jbc.M113.468033 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 143EV UT WOS:000318850300009 PM 23530044 ER PT J AU Bosch, B Heipertz, EL Drake, JR Roche, PA AF Bosch, Berta Heipertz, Erica L. Drake, James R. Roche, Paul A. TI Major Histocompatibility Complex (MHC) Class II-Peptide Complexes Arrive at the Plasma Membrane in Cholesterol-rich Microclusters SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID T-CELL-ACTIVATION; DENDRITIC CELLS; LIPID RAFTS; RECEPTOR MICROCLUSTERS; IMMUNOLOGICAL SYNAPSE; MONOCLONAL-ANTIBODIES; ANTIGEN; TRANSPORT; MICRODOMAINS; MOLECULES AB Dendritic cells (DCs) function by stimulating naive antigen-specific CD4 T cells to proliferate and secrete a variety of immunomodulatory factors. The ability to activate naive T cells comes from the capacity of DCs to internalize, degrade, and express peptide fragments of antigenic proteins on their surface bound to MHC class II molecules (MHC-II). Although DCs express tens of thousands of distinct MHC-II, very small amounts of specific peptide-MHC-II complexes are required to interact with and activate T cells. We now show that stimulatory MHC-II I-Ak-HEL(46-61) complexes that move from intracellular antigen-processing compartments to the plasma membrane are not randomly distributed on the DC surface. Confocal immunofluorescence microscopy and quantitative immunoelectron microscopy reveal that the majority of newly generated MHC-II I-Ak-HEL(46-61) complexes are expressed in sub-100-nm microclusters on the DC membrane. These microclusters are stabilized in cholesterol-containing microdomains, and cholesterol depletion inhibits the stability of these clusters as well as the ability of the DCs to function as antigen-presenting cells. These results demonstrate that specific cohorts of peptide-MHC-II complexes expressed on the DC surface are present in cholesterol-dependent microclusters and that cluster integrity is important for antigen-specific naive CD4 T cell activation by DCs. C1 [Bosch, Berta; Heipertz, Erica L.; Roche, Paul A.] NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. [Drake, James R.] Albany Med Coll, Ctr Immunol & Microbial Dis, Albany, NY 12208 USA. RP Roche, PA (reprint author), NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov FU National Institutes of Health [AI-065773]; Intramural Research Program of the National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grant AI-065773 (to J. R. D.) as well as the Intramural Research Program of the National Institutes of Health (to P. A. R.). NR 29 TC 19 Z9 19 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 10 PY 2013 VL 288 IS 19 BP 13236 EP 13242 DI 10.1074/jbc.M112.442640 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 143EV UT WOS:000318850300010 PM 23532855 ER PT J AU Toepfer, C Caorsi, V Kampourakis, T Sikkel, MB West, TG Leung, MC Al-Saud, SA MacLeod, KT Lyon, AR Marston, SB Sellers, JR Ferenczi, MA AF Toepfer, Christopher Caorsi, Valentina Kampourakis, Thomas Sikkel, Markus B. West, Timothy G. Leung, Man-Ching Al-Saud, Sara A. MacLeod, Kenneth T. Lyon, Alexander R. Marston, Steven B. Sellers, James R. Ferenczi, Michael A. TI Myosin Regulatory Light Chain (RLC) Phosphorylation Change as a Modulator of Cardiac Muscle Contraction in Disease SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VERTEBRATE STRIATED-MUSCLE; HUMAN HEART-FAILURE; SKELETAL-MUSCLE; SARCOMERE-LENGTH; FAILING HUMAN; MOLECULAR MOTORS; ISOMETRIC FORCE; SMOOTH-MUSCLE; RAT-HEART; FIBERS AB Understanding how cardiac myosin regulatory light chain (RLC) phosphorylation alters cardiac muscle mechanics is important because it is often altered in cardiac disease. The effect this protein phosphorylation has on muscle mechanics during a physiological range of shortening velocities, during which the heart generates power and performs work, has not been addressed. We have expressed and phosphorylated recombinant Rattus norvegicus left ventricular RLC. In vitro we have phosphorylated these recombinant species with cardiac myosin light chain kinase and zipper-interacting protein kinase. We compare rat permeabilized cardiac trabeculae, which have undergone exchange with differently phosphorylated RLC species. We were able to enrich trabecular RLC phosphorylation by 40% compared with controls and, in a separate series, lower RLC phosphorylation to 60% of control values. Compared with the trabeculae with a low level of RLC phosphorylation, RLC phosphorylation enrichment increased isometric force by more than 3-fold and peak power output by more than 7-fold and approximately doubled both maximum shortening speed and the shortening velocity that generated peak power. We augmented these measurements by observing increased RLC phosphorylation of human and rat HF samples from endocardial left ventricular homogenate. These results demonstrate the importance of increased RLC phosphorylation in the up-regulation of myocardial performance and suggest that reduced RLC phosphorylation is a key aspect of impaired contractile function in the diseased myocardium. C1 [Toepfer, Christopher; Caorsi, Valentina; Al-Saud, Sara A.; Ferenczi, Michael A.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Mol Med Sect, London SW7 2AZ, England. [Kampourakis, Thomas] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England. [Sikkel, Markus B.; Leung, Man-Ching; MacLeod, Kenneth T.; Lyon, Alexander R.; Marston, Steven B.] Natl Heart & Lung Inst, Imperial Ctr Translat & Expt Med, London W12 0NN, England. [West, Timothy G.] Royal Vet Coll London, Struct & Motion Lab, N Mymms AL9 7TA, England. [Lyon, Alexander R.] Royal Brompton Hosp, Cardiovasc Biomed Res Unit, London SW3 6MP, England. [Toepfer, Christopher; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Ferenczi, Michael A.] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 637553, Singapore. RP Ferenczi, MA (reprint author), Nanyang Technol Univ, Lee Kong Chian Sch Med, RTP Level 4,50 Nanyang Dr, Singapore 637553, Singapore. EM m.ferenczi@ntu.edu.sg RI Ferenczi, Michael/F-9510-2015; OI Ferenczi, Michael/0000-0002-0349-331X; Sikkel, Markus/0000-0001-9801-8978; Toepfer, Christopher/0000-0003-4671-2030 FU National Institutes of Health; NHLBI [HL004232]; Wellcome Trust [091460/Z/10/Z, 092852/Z/10/Z]; Biotechnology and Biological Sciences Research Council [BB/I019448/1]; British Heart Foundation FX This work was supported, in whole or in part, by National Institutes of Health, NHLBI Grant HL004232 12. This work presented herein was also supported by Wellcome Trust Grants 091460/Z/10/Z, 092852/Z/10/Z, 092852/Z/10/Z, Biotechnology and Biological Sciences Research Council Grant BB/I019448/1, and The British Heart Foundation (to M.-C. L., S. B. M., and M.A.F.). NR 56 TC 24 Z9 24 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 MAY 10 PY 2013 VL 288 IS 19 BP 13446 EP 13454 DI 10.1074/jbc.M113.455444 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 143EV UT WOS:000318850300029 PM 23530050 ER PT J AU Yumoto, K Thomas, PS Lane, J Matsuzaki, K Inagaki, M Ninomiya-Tsuji, J Scott, GJ Ray, MK Ishii, M Maxson, R Mishina, Y Kaartinen, V AF Yumoto, Kenji Thomas, Penny S. Lane, Jamie Matsuzaki, Kouichi Inagaki, Maiko Ninomiya-Tsuji, Jun Scott, Gregory J. Ray, Manas K. Ishii, Mamoru Maxson, Robert Mishina, Yuji Kaartinen, Vesa TI TGF-beta-activated Kinase 1 (Tak1) Mediates Agonist-induced Smad Activation and Linker Region Phosphorylation in Embryonic Craniofacial Neural Crest-derived Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-BETA; CAUSES CLEFT-PALATE; SIGNAL-TRANSDUCTION; RECEPTOR KINASE; MICE; BMP; MOUSE; PATHWAYS; FUSION; FAMILY AB Although the importance of TGF-beta superfamily signaling in craniofacial growth and patterning is well established, the precise details of its signaling mechanisms are still poorly understood. This is in part because of the concentration of studies on the role of the Smad-dependent (so-called "canonical") signaling pathways relative to the Smad-independent ones in many biological processes. Here, we have addressed the role of TGF-beta beta-activated kinase 1 (Tak1, Map3k7), one of the key mediators of Smad-independent (noncanonical) TGF-beta superfamily signaling in craniofacial development, by deleting Tak1 specifically in the neural crest lineage. Tak1-deficient mutants display a round skull, hypoplastic maxilla and mandible, and cleft palate resulting from a failure of palatal shelves to appropriately elevate and fuse. Our studies show that in neural crest-derived craniofacial ecto-mesenchymal cells, Tak1 is not only required for TGF-beta -and bone morphogenetic protein-induced p38 Mapk activation but also plays a role in agonist-induced C-terminal and linker region phosphorylation of the receptor-mediated R-Smads. Specifically, we demonstrate that the agonist-induced linker region phosphorylation of Smad2 at Thr-220, which has been shown to be critical for full transcriptional activity of Smad2, is dependent on Tak1 activity and that in palatal mesenchymal cells TGF beta RI and Tak1 kinases mediate both overlapping and distinct TGF-beta 2-induced transcriptional responses. To summarize, our results suggest that in neural crest-derived ecto-mesenchymal cells, Tak1 provides a critical point of intersection in a complex dialogue between the canonical and noncanonical arms of TGF-beta superfamily signaling required for normal craniofacial development. C1 [Yumoto, Kenji; Thomas, Penny S.; Lane, Jamie; Mishina, Yuji; Kaartinen, Vesa] Univ Michigan, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Matsuzaki, Kouichi] Kansai Med Univ, Dept Gastroenterol & Hepatol, Moriguchi, Osaka 5708506, Japan. [Inagaki, Maiko; Ninomiya-Tsuji, Jun] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. [Scott, Gregory J.; Ray, Manas K.] NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Ishii, Mamoru; Maxson, Robert] Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA. RP Kaartinen, V (reprint author), Univ Michigan, Dept Biol & Mat Sci, 1011 N Univ Ave, Ann Arbor, MI 48109 USA. EM vesak@umich.edu OI Kaartinen, Vesa/0000-0002-9432-510X FU National Institutes of Health [R01DE020843, ES071003-11, RO1 DE013085, HL074862, S10RR026475-01] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01DE020843 and ES071003-11 (to Y. M.), RO1 DE013085 and HL074862 (to V. K.), and S10RR026475-01 (to the University of Michigan mu CT Core Facility). NR 47 TC 15 Z9 18 U1 0 U2 13 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 MAY 10 PY 2013 VL 288 IS 19 BP 13467 EP 13480 DI 10.1074/jbc.M112.431775 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 143EV UT WOS:000318850300031 PM 23546880 ER PT J AU Seol, Y Gentry, AC Osheroff, N Neuman, KC AF Seol, Yeonee Gentry, Amanda C. Osheroff, Neil Neuman, Keir C. TI Chiral Discrimination and Writhe-dependent Relaxation Mechanism of Human Topoisomerase II alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C-TERMINAL DOMAIN; SINGLE-MOLECULE MEASUREMENTS; POSITIVELY SUPERCOILED DNA; MAGNETIC TWEEZERS; IN-VITRO; ATP; TOPOLOGY; ENZYME; IV; DECATENATION AB Type IIA topoisomerases (Topo IIA) are essential enzymes that relax DNA supercoils and remove links joining replicated chromosomes. Human topoisomerase II alpha (htopo II alpha), one of two human isoforms, preferentially relaxes positive supercoils, a feature shared with Escherichia coli topoisomerase IV (Topo IV). The mechanistic basis of this chiral discrimination remains unresolved. To address this important issue, we measured the relaxation of individual supercoiled and "braided" DNA molecules by htopo II alpha using a magnetic tweezers-based single-molecule assay. Our study confirmed the chiral discrimination activity of htopo II alpha and revealed that the strand passage rate depends on DNA twist, tension on the DNA, and the C-terminal domain (CTD). Similar to Topo IV, chiral discrimination by htopo II alpha results from chiral interactions of the CTDs with DNA writhe. In contrast to Topo IV, however, these interactions lead to chiral differences in relaxation rate rather than processivity. Increasing tension or twist disrupts the CTD-DNA interactions with a subsequent loss of chiral discrimination. Together, these results suggest that transfer segment (T-segment) capture is the rate-limiting step in the strand passage cycle. We propose a model for T-segment capture that provides a mechanistic basis for chiral discrimination and provides a coherent explanation for the effects of DNA twist and tension on eukaryotic type IIA topoisomerases. C1 [Seol, Yeonee; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Gentry, Amanda C.; Osheroff, Neil] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Gentry, Amanda C.; Osheroff, Neil] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. RP Neuman, KC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU National Heart, Lung, and Blood Institute, National Institutes of Health; National Institutes of Health [GM033944, 5 T32 CA09582] FX This research was supported, in whole or in part, by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (to K. C. N.) and by extramural National Institutes of Health Grant GM033944 (to N. O.); Recipient of National Institutes of Health Trainee Grant 5 T32 CA09582. NR 50 TC 6 Z9 6 U1 3 U2 16 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 MAY 10 PY 2013 VL 288 IS 19 BP 13695 EP 13703 DI 10.1074/jbc.M112.444745 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 143EV UT WOS:000318850300052 PM 23508957 ER PT J AU Van Itallie, CM Aponte, A Tietgens, AJ Gucek, M Fredriksson, K Anderson, JM AF Van Itallie, Christina M. Aponte, Angel Tietgens, Amber Jean Gucek, Marjan Fredriksson, Karin Anderson, James Melvin TI The N and C Termini of ZO-1 Are Surrounded by Distinct Proteins and Functional Protein Networks SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TIGHT JUNCTION PROTEIN; CELL-CELL ADHESION; TUMOR-SUPPRESSOR PROTEIN; EPITHELIAL-CELLS; PDZ DOMAIN; ACTIN CYTOSKELETON; ADHERENS JUNCTION; E-CADHERIN; SEQUENCE SIMILARITY; MEMBRANE-PROTEINS AB The proteins and functional protein networks of the tight junction remain incompletely defined. Among the currently known proteins are barrier-forming proteins like occludin and the claudin family; scaffolding proteins like ZO-1; and some cytoskeletal, signaling, and cell polarity proteins. To define a more complete list of proteins and infer their functional implications, we identified the proteins that are within molecular dimensions of ZO-1 by fusing biotin ligase to either its N or C terminus, expressing these fusion proteins in Madin-Darby canine kidney epithelial cells, and purifying and identifying the resulting biotinylated proteins by mass spectrometry. Of a predicted proteome of similar to 9000, we identified more than 400 proteins tagged by biotin ligase fused to ZO-1, with both identical and distinct proteins near the N- and C-terminal ends. Those proximal to the N terminus were enriched in transmembrane tight junction proteins, and those proximal to the C terminus were enriched in cytoskeletal proteins. We also identified many unexpected but easily rationalized proteins and verified partial colocalization of three of these proteins with ZO-1 as examples. In addition, functional networks of interacting proteins were tagged, such as the basolateral but not apical polarity network. These results provide a rich inventory of proteins and potential novel insights into functions and protein networks that should catalyze further understanding of tight junction biology. Unexpectedly, the technique demonstrates high spatial resolution, which could be generally applied to defining other subcellular protein compartmentalization. C1 [Van Itallie, Christina M.; Tietgens, Amber Jean; Fredriksson, Karin; Anderson, James Melvin] NHLBI, Lab Tight Junct Struct & Funct, NIH, Bethesda, MD 20892 USA. [Aponte, Angel; Gucek, Marjan] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. RP Van Itallie, CM (reprint author), NHLBI, NIH, Bldg 50,Rm 45425,50 South Dr, Bethesda, MD 20892 USA. EM Christina.vanitallie@nih.gov FU National Institutes of Health Division of Intramural Research FX This work was supported, in whole or in part, by the National Institutes of Health Division of Intramural Research. NR 96 TC 20 Z9 20 U1 1 U2 16 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 MAY 10 PY 2013 VL 288 IS 19 BP 13775 EP 13788 DI 10.1074/jbc.M113.466193 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 143EV UT WOS:000318850300059 PM 23553632 ER PT J AU Kantarjian, H Wilson, W Ravandi, F Estey, E AF Kantarjian, Hagop Wilson, Wyndham Ravandi, Farhad Estey, Elihu TI Decitabine in Older Adults With Acute Myeloid Leukemia: Why Was the Dream Broken? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Kantarjian, Hagop; Ravandi, Farhad] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Wilson, Wyndham] NIH, Bethesda, MD 20892 USA. [Estey, Elihu] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Kantarjian, H (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. FU NCI NIH HHS [P30 CA016672] NR 4 TC 9 Z9 9 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 10 PY 2013 VL 31 IS 14 BP 1795 EP 1796 DI 10.1200/JCO.2012.48.1465 PG 2 WC Oncology SC Oncology GA 141ZW UT WOS:000318766300020 PM 23547076 ER PT J AU Insel, TR Landis, SC Collins, FS AF Insel, Thomas R. Landis, Story C. Collins, Francis S. TI The NIH BRAIN Initiative SO SCIENCE LA English DT Editorial Material ID ACTIVITY MAP C1 [Insel, Thomas R.; Landis, Story C.; Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM insel@mail.nih.gov; slandis@codon.nih.gov; collinsf@od.nih.gov NR 12 TC 85 Z9 89 U1 2 U2 43 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 10 PY 2013 VL 340 IS 6133 BP 687 EP 688 DI 10.1126/science.1239276 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139XR UT WOS:000318619000020 PM 23661744 ER PT J AU Georgiev, IS Doria-Rose, NA Zhou, TQ Do Kwon, Y Staupe, RP Moquin, S Chuang, GY Louder, MK Schmidt, SD Altae-Tran, HR Bailer, RT McKee, K Nason, M O'Dell, S Ofek, G Pancera, M Srivatsan, S Shapiro, L Connors, M Migueles, SA Morris, L Nishimura, Y Martin, MA Mascola, JR Kwong, PD AF Georgiev, Ivelin S. Doria-Rose, Nicole A. Zhou, Tongqing Do Kwon, Young Staupe, Ryan P. Moquin, Stephanie Chuang, Gwo-Yu Louder, Mark K. Schmidt, Stephen D. Altae-Tran, Han R. Bailer, Robert T. McKee, Krisha Nason, Martha O'Dell, Sijy Ofek, Gilad Pancera, Marie Srivatsan, Sanjay Shapiro, Lawrence Connors, Mark Migueles, Stephen A. Morris, Lynn Nishimura, Yoshiaki Martin, Malcolm A. Mascola, John R. Kwong, Peter D. TI Delineating Antibody Recognition in Polyclonal Sera from Patterns of HIV-1 Isolate Neutralization SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; HEPATITIS-C VIRUS; MEMORY B-CELLS; POTENT NEUTRALIZATION; INFLUENZA-VIRUS; STRUCTURAL DEFINITION; BROAD NEUTRALIZATION; CD4-BINDING SITE; RATIONAL DESIGN AB Serum characterization and antibody isolation are transforming our understanding of the humoral immune response to viral infection. Here, we show that epitope specificities of HIV-1-neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates. We determined "neutralization fingerprints" for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains and showed that similarity in neutralization fingerprint correlated with similarity in epitope. We used these fingerprints to delineate specificities of polyclonal sera from 24 HIV-1-infected donors and a chimeric siman-human immunodeficiency virus-infected macaque. Delineated specificities matched published specificities and were further confirmed by antibody isolation for two sera. Patterns of virus-isolate neutralization can thus afford a detailed epitope-specific understanding of neutralizing-antibody responses to viral infection. C1 [Georgiev, Ivelin S.; Doria-Rose, Nicole A.; Zhou, Tongqing; Do Kwon, Young; Staupe, Ryan P.; Moquin, Stephanie; Chuang, Gwo-Yu; Louder, Mark K.; Schmidt, Stephen D.; Altae-Tran, Han R.; Bailer, Robert T.; McKee, Krisha; Nason, Martha; O'Dell, Sijy; Ofek, Gilad; Pancera, Marie; Srivatsan, Sanjay; Shapiro, Lawrence; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Connors, Mark; Migueles, Stephen A.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Morris, Lynn] Natl Inst Communicable Dis, ZA-2131 Johannesburg, South Africa. [Morris, Lynn] Univ Witwatersrand, ZA-2001 Johannesburg, South Africa. [Morris, Lynn] Ctr AIDS Programme Res South Africa CAPRISA, ZA-4013 Durban, South Africa. [Nishimura, Yoshiaki; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@nih.gov; pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010; Zhou, Tongqing/A-6880-2010; Schmidt, Stephen/B-5398-2012 OI Zhou, Tongqing/0000-0002-3935-4637; FU Intramural Research Program of the Vaccine Research Center, NIAID, NIH; International AIDS Vaccine Initiative; NIAID, NIH [U19 AI51794]; South African Department of Science and Technology; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH, and by the International AIDS Vaccine Initiative. The CAPRISA cohort was established through grants from NIAID, NIH (U19 AI51794) and the South African Department of Science and Technology. The authors are grateful to J. Stuckey for assistance with graphics and thank B. Korber, D. Montefiori, and M. Roederer and members of the Structural Biology Section, Structural Bioinformatics Core, Humoral Immunology Section, and Humoral Immunology Core at the NIH Vaccine Research Center for helpful discussions or comments on the manuscript. We thank J. Baalwa, D. Ellenberger, D. Gabuzda, F. Gao, B. Hahn, K. Hong, J. Kim, F. McCutchan, D. Montefiori, L. Morris, J. Overbaugh, E. Sanders-Buell, G. Shaw, R. Swanstrom, M. Thomson, S. Tovanabutra, C. Williamson, and L. Zhang for contributing the HIV-1 Envelope plasmids used in our neutralization panels. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. The NIH has filed a patent relating to neutralizing antibodies in this manuscript: WIPO no. WO 2011/038290 A2, titled "Neutralizing antibodies to HIV-1 and their use," with inventors J. R. M., P. D. K., M. C., L. S., and G.O. Structure factors and coordinates for the VRC06 and VRC23 antibody cocrystal structures with HIV-1 gp120 have been deposited with the Protein Data Bank under accession codes 4JB9 and 4J6R, respectively. Scripts for the neutralization-based antibody clustering and serologic analysis are included in the online supplementary material and methods (appendix S2) and are available from I. S. G. or P. D. K. upon request. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38. NR 50 TC 77 Z9 77 U1 4 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAY 10 PY 2013 VL 340 IS 6133 BP 751 EP 756 DI 10.1126/science.1233989 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139XR UT WOS:000318619000041 PM 23661761 ER PT J AU Gutin, LS Merz, AE Bakalov, VK Gharib, AM Bondy, CA AF Gutin, Liat S. Merz, Alexa E. Bakalov, Vladimir K. Gharib, Ahmed M. Bondy, Carolyn A. TI Parity and aortic dimensions in healthy women SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Pregnancy; Parity; Aorta; Magnetic resonance; Aging ID PREGNANCY; DISSECTION C1 [Gutin, Liat S.; Merz, Alexa E.; Bakalov, Vladimir K.; Bondy, Carolyn A.] NICHHD, Sect Epigenet & Dev, Bethesda, MD USA. [Gharib, Ahmed M.] NIDDKD, Integrat Cardiovasc Imaging Sect, Bethesda, MD USA. RP Bondy, CA (reprint author), NIH, CRC 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X FU Intramural NIH HHS [ZIA HD000628-22] NR 8 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAY 10 PY 2013 VL 165 IS 2 BP 383 EP 384 DI 10.1016/j.ijcard.2012.08.022 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 128CX UT WOS:000317747600045 PM 22999343 ER PT J AU Hsu, AP Johnson, KD Falcone, EL Sanalkumar, R Sanchez, L Hickstein, DD Cuellar-Rodriguez, J Lemieux, JE Zerbe, CS Bresnick, EH Holland, SM AF Hsu, Amy P. Johnson, Kirby D. Falcone, E. Liana Sanalkumar, Rajendran Sanchez, Lauren Hickstein, Dennis D. Cuellar-Rodriguez, Jennifer Lemieux, Jacob E. Zerbe, Christa S. Bresnick, Emery H. Holland, Steven M. TI GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome SO BLOOD LA English DT Article ID GENOME-WIDE ANALYSIS; ACUTE MYELOID-LEUKEMIA; SPORADIC MONOCYTOPENIA; AUTOSOMAL-DOMINANT; TRANSCRIPTIONAL CONTROL; CHROMATIN OCCUPANCY; REGULATORS; CELLS; MYELODYSPLASIA; HEMATOPOIESIS AB Previous reports of GATA2 mutations have focused on the coding region of the gene or full gene deletions. We recently identified 2 patients with novel insertion/deletion mutations predicted to result in mRNA nonsense-mediated decay, suggesting haploinsufficiency as the mechanism of GATA2 deficient disease. We therefore screened patients without identified exonic lesions for mutations within conserved noncoding and intronic regions. We discovered 1 patient with an intronic deletion mutation, 4 patients with point mutations within a conserved intronic element, and 3 patients with reduced or absent transcription from 1 allele. All mutations affected GATA2 transcription. Full-length cDNA analysis provided evidence for decreased expression of the mutant alleles. The intronic deletion and point mutations considerably reduced the enhancer activity of the intron 5 enhancer. Analysis of 512 immune system genes revealed similar expression profiles in all clinically affected patients and reduced GATA2 transcript levels. These mutations strongly support the haploinsufficient nature of GATA2 deficiency and identify transcriptional mechanisms and targets that lead to MonoMAC syndrome. C1 [Hsu, Amy P.; Falcone, E. Liana; Cuellar-Rodriguez, Jennifer; Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Johnson, Kirby D.; Sanalkumar, Rajendran; Bresnick, Emery H.] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison Blood Res Program,Carbone Canc Ctr, Wisconsin Inst Med Res,Sch Med & Publ Hlth, Madison, WI USA. [Sanchez, Lauren] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Lemieux, Jacob E.] Harvard Univ, Sch Med, Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Boston, MA USA. RP Holland, SM (reprint author), CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [DK68634] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by a grant from National Institutes of Health (DK68634) to E.H.B. NR 37 TC 50 Z9 51 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 MAY 9 PY 2013 VL 121 IS 19 BP 3830 EP 3837 DI 10.1182/blood-2012-08-452763 PG 8 WC Hematology SC Hematology GA 184EO UT WOS:000321870900013 PM 23502222 ER PT J AU Lanikova, L Lorenzo, F Yang, CZ Vankayalapati, H Drachtman, R Divoky, V Prchal, JT AF Lanikova, Lucie Lorenzo, Felipe Yang, Chunzhang Vankayalapati, Hari Drachtman, Richard Divoky, Vladimir Prchal, Josef T. TI Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer SO BLOOD LA English DT Article ID TUMOR-SUPPRESSOR GENE; CHUVASH POLYCYTHEMIA; LINDAU DISEASE; OVEREXPRESSION; ERYTHROCYTOSIS; IDENTIFICATION; NF-E2 AB Germline von Hippel-Lindau (VHL) gene mutations underlie dominantly inherited familial VHL tumor syndrome comprising a predisposition for renal cell carcinoma, pheochromocytoma/paraganglioma, cerebral hemangioblastoma, and endolymphatic sac tumors. However, recessively inherited congenital polycythemia, exemplified by Chuvash polycythemia, has been associated with 2 separate 39 VHL gene mutations in exon 3. It was proposed that different positions of loss-of-function VHL mutations are associated with VHL syndrome cancer predisposition and only C-terminal domain-encoding VHL mutations would cause polycythemia. However, now we describe a new homozygous VHL exon 2 mutation of the VHL gene:(c.413C>T):P138L, which is associated in the affected homozygote with congenital polycythemia but not in her, or her-heterozygous relatives, with cancer or other VHL syndrome tumors. We show that VHL P-138L has perturbed interaction with hypoxia-inducible transcription factor (HIF)alpha a. Further, VHL P-138L protein has decreased stability in vitro. Similarly to what was reported in Chuvash polycythemia and some other instances of HIFs upregulation, VHL P138L erythroid progenitors are hypersensitive to erythropoietin. Interestingly, the level of RUNX1/AML1 and NF-E2 transcripts that are specifically upregulated in acquired polycythemia vera were also upregulated in VHL P-138L granulocytes. C1 [Lanikova, Lucie; Lorenzo, Felipe; Prchal, Josef T.] Univ Utah, Div Hematol, Salt Lake City, UT 84132 USA. [Lanikova, Lucie; Lorenzo, Felipe; Prchal, Josef T.] VA Hlth Care, Salt Lake City, UT USA. [Lanikova, Lucie; Divoky, Vladimir] Palacky Univ, Fac Med & Dent, Dept Biol, CR-77147 Olomouc, Czech Republic. [Yang, Chunzhang] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Vankayalapati, Hari] Huntsman Canc Inst, Salt Lake City, UT USA. [Drachtman, Richard] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. RP Prchal, JT (reprint author), Univ Utah, Div Hematol, 30N 1900E,5C402 SOM, Salt Lake City, UT 84132 USA. EM josef.prchal@hsc.utah.edu RI Lanikova, Lucie/F-7720-2013 FU Czech Science Foundation [P301/12/1503]; European Structural Funds [CZ.1.07/2.3.00/20.0164]; [LF_2012_016] FX This work was supported by the Czech Science Foundation (project P301/12/1503), the European Structural Funds (project CZ.1.07/2.3.00/20.0164) and by grant LF_2012_016 (L.L. and V.D.). NR 30 TC 11 Z9 11 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 MAY 9 PY 2013 VL 121 IS 19 BP 3918 EP 3924 DI 10.1182/blood-2012-11-469296 PG 7 WC Hematology SC Hematology GA 184EO UT WOS:000321870900022 PM 23538339 ER PT J AU Kaipparettu, BA Ma, YW Park, JH Lee, TL Zhang, YQ Yotnda, P Creighton, CJ Chan, WY Wong, LJC AF Kaipparettu, Benny Abraham Ma, Yewei Park, Jun Hyoung Lee, Tin-Lap Zhang, Yiqun Yotnda, Patricia Creighton, Chad J. Chan, Wai-Yee Wong, Lee-Jun C. TI Crosstalk from Non-Cancerous Mitochondria Can Inhibit Tumor Properties of Metastatic Cells by Suppressing Oncogenic Pathways SO PLOS ONE LA English DT Article ID VITAMIN-E ANALOGS; DNA MUTATIONS; BREAST-CANCER; TRANSMITOCHONDRIAL CYBRIDS; PATHOGENIC MUTATIONS; ANTICANCER AGENTS; APOPTOSIS; MTDNA; TUMORIGENESIS; DEPLETION AB Mitochondrial-nucleus cross talks and mitochondrial retrograde regulation can play a significant role in cellular properties. Transmitochondrial cybrid systems (cybrids) are an excellent tool to study specific effects of altered mitochondria under a defined nuclear background. The majority of the studies using the cybrid model focused on the significance of specific mitochondrial DNA variations in mitochondrial function or tumor properties. However, most of these variants are benign polymorphisms without known functional significance. From an objective of rectifying mitochondrial defects in cancer cells and to establish mitochondria as a potential anticancer drug target, understanding the role of functional mitochondria in reversing oncogenic properties under a cancer nuclear background is very important. Here we analyzed the potential reversal of oncogenic properties of a highly metastatic cell line with the introduction of non-cancerous mitochondria. Cybrids were established by fusing the mitochondria DNA depleted 143B TK- rho 0 cells from an aggressive osteosarcoma cell line with mitochondria from benign breast epithelial cell line MCF10A, moderately metastatic breast cancer cell line MDA-MB-468 and 143B cells. In spite of the uniform cancerous nuclear background, as observed with the mitochondria donor cells, cybrids with benign mitochondria showed high mitochondrial functional properties including increased ATP synthesis, oxygen consumption and respiratory chain activities compared to cybrids with cancerous mitochondria. Interestingly, benign mitochondria could reverse different oncogenic characteristics of 143B TK- cell including cell proliferation, viability under hypoxic condition, anti-apoptotic properties, resistance to anti-cancer drug, invasion, and colony formation in soft agar, and in vivo tumor growth in nude mice. Microarray analysis suggested that several oncogenic pathways observed in cybrids with cancer mitochondria are inhibited in cybrids with non-cancerous mitochondria. These results suggest the critical oncogenic regulation by mitochondrial-nuclear cross talk and highlights rectifying mitochondrial functional properties as a promising target in cancer therapy. C1 [Kaipparettu, Benny Abraham; Ma, Yewei; Park, Jun Hyoung; Wong, Lee-Jun C.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Kaipparettu, Benny Abraham; Zhang, Yiqun; Creighton, Chad J.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Lee, Tin-Lap; Chan, Wai-Yee] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Gen, NIH, Bethesda, MD USA. [Lee, Tin-Lap; Chan, Wai-Yee] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. [Yotnda, Patricia] Baylor Coll Med, Ctr Gene Therapy, Houston, TX 77030 USA. RP Kaipparettu, BA (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM kaippare@bcm.edu; ljwong@bcm.edu RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU DOD [W81XWH-11-1-0292]; National Institutes of Health/National Cancer Institute (NIH/NCI) [U54-CA149196]; DLD Cancer Center Pilot Project; NIH/NCI grant [R01 CA-100023] FX This work was partially supported by DOD (W81XWH-11-1-0292), National Institutes of Health/National Cancer Institute (NIH/NCI) (U54-CA149196 Pilot Project) and DLD Cancer Center Pilot Project to B. Kaipparettu and NIH/NCI (R01 CA-100023) grant to L. Wong. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 20 Z9 20 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 MAY 9 PY 2013 VL 8 IS 5 AR e61747 DI 10.1371/journal.pone.0061747 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 155HD UT WOS:000319737700005 PM 23671572 ER PT J AU Fromm, G Gilchrist, DA Adelman, K AF Fromm, George Gilchrist, Daniel A. Adelman, Karen TI SnapShot! Transcription Regulation: Pausing SO CELL LA English DT Editorial Material ID ELONGATION; COMPLEX C1 [Fromm, George; Gilchrist, Daniel A.; Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Fromm, G (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. OI Gilchrist, Daniel/0000-0003-1668-2790 FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES101987] NR 11 TC 3 Z9 3 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 9 PY 2013 VL 153 IS 4 BP 930 EP + DI 10.1016/j.cell.2013.04.011 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 143CN UT WOS:000318844000020 PM 23663787 ER PT J AU Daniel, JA Nussenzweig, A AF Daniel, Jeremy A. Nussenzweig, Andre TI The AID-Induced DNA Damage Response in Chromatin SO MOLECULAR CELL LA English DT Review ID CLASS-SWITCH RECOMBINATION; INDUCED CYTIDINE DEAMINASE; RECURRENT CHROMOSOMAL TRANSLOCATIONS; FRAGILE SITE INSTABILITY; DOUBLE-STRAND BREAKS; RNA-POLYMERASE-II; SOMATIC HYPERMUTATION; V(D)J RECOMBINATION; HOMOLOGOUS RECOMBINATION; GENOMIC INSTABILITY AB Chemical modifications to the DNA and histone protein components of chromatin can modulate gene expression and genome stability. Understanding the physiological impact of changes in chromatin structure remains an important question in biology. As one example, in order to generate antibody diversity with somatic hypermutation and class switch recombination, chromatin must be made accessible for activation-induced cytidine deaminase (AID)-mediated deamination of cytosines in DNA. These lesions are recognized and removed by various DNA repair pathways but, if not handled properly, can lead to formation of oncogenic chromosomal translocations. In this review, we focus the discussion on how chromatin-modifying activities and -binding proteins contribute to the native chromatin environment in which AID-induced DNA damage is targeted and repaired. Outstanding questions remain regarding the direct roles of histone posttranslational modifications and the significance of AID function outside of antibody diversity. C1 [Daniel, Jeremy A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, DK-2200 Copenhagen N, Denmark. [Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. RP Daniel, JA (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. EM jeremy.daniel@cpr.ku.dk; andre_nussenzweig@nih.gov RI Daniel, Jeremy/S-4729-2016 OI Daniel, Jeremy/0000-0002-1981-5571 FU Novo Nordisk Foundation; Danish Council for Independent Research in Medical Sciences; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We thank Rafael Casellas and Joan Yuan for critical reading of the manuscript and apologize for not being able to cite more primary literature because of space limitations. Work in the laboratory of J.A.D. is supported by the Novo Nordisk Foundation and the Danish Council for Independent Research in Medical Sciences. Work in the laboratory of A.N. is supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. NR 127 TC 29 Z9 30 U1 0 U2 13 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 MAY 9 PY 2013 VL 50 IS 3 BP 309 EP 321 DI 10.1016/j.molce1.2013.04.017 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 147RA UT WOS:000319183500003 PM 23664375 ER PT J AU Lujan, SA Williams, JS Clausen, AR Clark, AB Kunkel, TA AF Lujan, Scott A. Williams, Jessica S. Clausen, Anders R. Clark, Alan B. Kunkel, Thomas A. TI Ribonucleotides Are Signals for Mismatch Repair of Leading-Strand Replication Errors SO MOLECULAR CELL LA English DT Article ID DNA-POLYMERASE-EPSILON; SACCHAROMYCES-CEREVISIAE; MUTL-ALPHA; SUBSTRATE-SPECIFICITY; EXCISION-REPAIR; YEAST; DELTA; PCNA; EXTRACTS; FORK AB To maintain genome stability, mismatch repair of nuclear DNA replication errors must be directed to the nascent strand, likely by DNA ends and PCNA. Here we show that the efficiency of mismatch repair in Saccharomyces cerevisiae is reduced by inactivating RNase H2, which nicks DNA containing ribonucleotides incorporated during replication. In strains encoding mutator polymerases, this reduction is preferential for repair of mismatches made by leading-strand DNA polymerase epsilon as compared to lagging-strand DNA polymerase delta. The results suggest that RNase-H2-dependent processing of ribonucleotides transiently present in DNA after replication may direct mismatch repair to the continuously replicated nascent leading strand. C1 [Lujan, Scott A.; Williams, Jessica S.; Clausen, Anders R.; Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Lujan, Scott A.; Williams, Jessica S.; Clausen, Anders R.; Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov RI Clausen, Anders R./I-7229-2012; OI Clausen, Anders Ranegaard/0000-0002-5069-0930 FU Division of Intramural Research of the National Institutes of Health [Z01 ES065070]; National Institute of Environmental Health Sciences FX We thank Jeffrey Stumpf and Kin Chan for helpful comments on the manuscript. We acknowledge the Molecular Genetics Core Facility at the National Institute of Environmental Health Sciences for sequence analysis of 5-FOA-resistant mutants. 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. NR 38 TC 69 Z9 69 U1 1 U2 12 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 MAY 9 PY 2013 VL 50 IS 3 BP 437 EP 443 DI 10.1016/j.molcel.2013.03.017 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 147RA UT WOS:000319183500014 PM 23603118 ER PT J AU Xie, Y Tobin, LA Camps, J Wangsa, D Yang, J Rao, M Witasp, E Awad, KS Yoo, N Ried, T Kwong, KF AF Xie, Y. Tobin, L. A. Camps, J. Wangsa, D. Yang, J. Rao, M. Witasp, E. Awad, K. S. Yoo, N. Ried, T. Kwong, K. F. TI MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells SO ONCOGENE LA English DT Article DE microRNA; cancer; XIAP ID MODULATES MULTIDRUG-RESISTANCE; X-LINKED INHIBITOR; TARGETING BCL2; SUPPRESSES TUMORIGENICITY; STRUCTURAL BASIS; DOWN-REGULATION; UP-REGULATION; LUNG-CANCER; MIR-24; GENE AB MicroRNAs have been implicated as important mediators of cancer cell homeostasis, and accumulating data suggest compelling roles for them in the apoptosis pathway. X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death, but the mechanisms that determine the diverse range of XIAP expression seen in cancer remains unclear. In this study, we present evidence that miR-24 directly targets the 3'UTR of the XIAP messenger RNA (mRNA) to exert translational repression. Using a heuristic algorithm of bioinformatics analysis and in vitro screening, we identified miR-24 as a candidate regulator of XIAP expression. Array comparative genomic hybridization and spectral karyotype analysis reveal that genomic copy number loss at the miR-24 locus is concordant with the loss of endogenous miR-24 in cancer cells. Using a luciferase construct of the XIAP 3'UTR, we showed that miR-24 specifically coordinates to the XIAP mRNA. Interference with miR-24's binding of the critical seed region, resulting from site-directed mutagenesis of the 3'UTR, significantly abrogated miR-24's effects on XIAP expression. Moreover, miR-24 overexpression can overcome apoptosis resistance in cancer cells via downregulation of XIAP expression, and the resulting cancer cell death induced by tumor necrosis factor-related apoptosis-inducing ligand is executed by the canonical caspase-mediated apoptosis pathway. In summary, our data suggest a novel mechanism by which miR-24 directly modulates XIAP expression level and consequently the apoptosis threshold in cancer cells. C1 [Xie, Y.; Tobin, L. A.; Yang, J.; Rao, M.; Witasp, E.; Yoo, N.; Kwong, K. F.] NCI, Sect Thorac Oncol, Surg Branch, NIH, Bethesda, MD 20892 USA. [Camps, J.; Wangsa, D.; Ried, T.] NCI, Clin Genet Branch, NIH, Bethesda, MD 20892 USA. [Witasp, E.] Swedish Chem Agcy, Sundbyberg, Sweden. [Awad, K. S.] NCI, Dept Crit Care Med, NIH Clin Ctr, NIH, Bethesda, MD 20892 USA. [Kwong, K. F.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kwong, KF (reprint author), NCI, Sect Thorac Oncol, Surg Branch, NIH, 10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kwongk2@mail.nih.gov FU National Institutes of Health; NIH FX We thank Steven A Rosenberg for reviewing the manuscript. This work was supported by the National Institutes of Health, Intramural Research Program (TR and KFK) and NIH Postdoctoral Cancer Research Training Awards (YX, JC, EW and KSA). NR 59 TC 40 Z9 43 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 9 PY 2013 VL 32 IS 19 BP 2442 EP 2451 DI 10.1038/onc.2012.258 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 140ZL UT WOS:000318694900008 PM 22733138 ER PT J AU Ng, SSM Li, A Pavlakis, GN Ozato, K Kino, T AF Ng, Sinnie Sin Man Li, Andrew Pavlakis, George N. Ozato, Keiko Kino, Tomoshige TI Viral Infection Increases Glucocorticoid-Induced Interleukin-10 Production through ERK-Mediated Phosphorylation of the Glucocorticoid Receptor in Dendritic Cells: Potential Clinical Implications SO PLOS ONE LA English DT Article ID ACTIVATED PROTEIN-KINASE; DOUBLE-STRANDED-RNA; STRESS HORMONES; GENE-EXPRESSION; INNATE IMMUNITY; IL-10 GENE; IN-VIVO; INDUCTION; RESPONSES; INFLAMMATION AB The hypothalamic-pituitary-adrenal axis plays a central role in the adaptive response to stress including infection of pathogens through glucocorticoids. Physical and/or mental stress alter susceptibility to viral infection possibly by affecting this regulatory system, thus we explored potential cellular targets and mechanisms that underlie this phenomenon in key immune components dendritic cells (DCs). Dexamethasone (DEX) treatment and subsequent Newcastle disease virus (NDV) infection most significantly and cooperatively stimulated mRNA expression of the interleukin (IL)-10 in murine bone marrow-derived DCs among 89 genes involved in the Toll-like receptor signaling pathways. NDV increased DEX-induced IL-10 mRNA and protein expression by 7- and 3-fold, respectively, which was observed from 3 hours after infection. Conventional DCs (cDCs), but not plasmacytoid DCs (pDCs) were major sources of IL-10 in bone marrow-derived DCs treated with DEX and/or infected with NDV. Murine cytomegalovirus and DEX increased serum IL-10 cooperatively in female mice. Pre-treatment of DCs with the extracellular signal-regulated kinase (ERK) inhibitor U0126 abolished cooperative induction of IL-10 by DEX and NDV. Further, ERK overexpression increased IL-10 promoter activity stimulated by wild-type human GR but not by its mutant defective in serine 203, whereas ERK knockdown abolished NDV/DEX cooperation on IL-10 mRNA and phosphorylation of the mouse GR at serine 213. NDV also increased DEX-induced mRNA expression of three known glucocorticoid-responsive genes unrelated to the Toll-like receptor signaling pathways in DCs. These results indicate that virus and glucocorticoids cooperatively increase production of anti-inflammatory cytokine IL-10 by potentiating the transcriptional activity of GR in DCs, through which virus appears to facilitate its own propagation in infected hosts. The results may further underlie in part known exacerbation of IL-10/T helper-2-related allergic disorders by stress and viral infection. C1 [Ng, Sinnie Sin Man; Li, Andrew; Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Ng, Sinnie Sin Man] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Ng, Sinnie Sin Man; Pavlakis, George N.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Ozato, Keiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mol Growth & Regulat, NIH, Bethesda, MD USA. RP Kino, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. EM kinot@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health, Bethesda, MD; National Cancer Institute, Frederick, MD; National Institutes of Health FX This study was funded by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health, Bethesda, MD, and the National Cancer Institute, Frederick, MD, the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 11 Z9 11 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 MAY 8 PY 2013 VL 8 IS 5 AR e63587 DI 10.1371/journal.pone.0063587 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 145YI UT WOS:000319055600065 PM 23667643 ER PT J AU Qiang, W Kelley, K Tycko, R AF Qiang, Wei Kelley, Kevin Tycko, Robert TI Polymorph-Specific Kinetics and Thermodynamics of beta-Amyloid Fibril Growth SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ATOMIC-FORCE MICROSCOPY; SOLID-STATE NMR; DOCK-LOCK MECHANISM; MASS-PER-LENGTH; ALZHEIMERS-DISEASE; A-BETA(1-40); PEPTIDE; PROTEIN; ELONGATION; DYNAMICS AB Amyloid fibrils formed by the 40-residue beta-amyloid peptide (A beta(1-40)) are highly polymorphic, with molecular structures that depend on the details of growth conditions. Underlying differences in physical properties are not well understood. Here, we investigate differences in growth kinetics and thermodynamic stabilities of two A beta(1-40) fibril polymorphs for which detailed structural models are available from solid-state nuclear magnetic resonance (NMR) studies. Rates of seeded fibril elongation in the presence of excess soluble A beta(1-40) and shrinkage in the absence of soluble A beta(1-40) are determined with atomic force microscopy (AFM). From these rates, we derive polymorph-specific values for the soluble A beta(1-40) concentration at quasi-equilibrium, from which relative stabilities can be derived. The AFM results are supported by direct measurements by ultraviolet absorbance, using a novel dialysis system to establish quasi-equilibrium. At 24 degrees C, the two polymorphs have significantly different elongation and shrinkage kinetics but similar thermodynamic stabilities. At 37 degrees C, differences in kinetics are reduced, and thermodynamic stabilities are increased significantly. Fibril length distributions in AFM images provide support for an intermittent growth model, in which fibrils switch randomly between an "on" state (capable of elongation) and an "off" state (incapable of elongation). We also monitor interconversion between polymorphs at 24 degrees C by solid-state NMR, showing that the two-fold symmetric "agitated" (A) polymorph is more stable than the three-fold symmetric "quiescent" (Q) polymorph. Finally, we show that the two polymorphs have significantly different rates of fragmentation in the presence of shear forces, a difference that helps explain the observed predominance of the A structure when fibrils are grown in agitated solutions. C1 [Qiang, Wei; Kelley, Kevin; Tycko, Robert] NIDDKD, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. We thank Dr. Wai-Ming Yau for synthesizing and purifying A beta1-40. NR 55 TC 56 Z9 57 U1 3 U2 82 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 EI 1520-5126 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 8 PY 2013 VL 135 IS 18 BP 6860 EP 6871 DI 10.1021/ja311963f PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 143AS UT WOS:000318839300029 PM 23627695 ER PT J AU Balijepalli, A Robertson, JWF Reiner, JE Kasianowicz, JJ Pastor, RW AF Balijepalli, Arvind Robertson, Joseph W. F. Reiner, Joseph E. Kasianowicz, John J. Pastor, Richard W. TI Theory of Polymer-Nanopore Interactions Refined Using Molecular Dynamics Simulations SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ALPHA-HEMOLYSIN CHANNEL; SOLID-STATE NANOPORE; ION-CHANNEL; GAS-PHASE; FREE-ENERGY; POLYETHYLENE-GLYCOL; BROWNIAN DYNAMICS; MASS-SPECTROMETRY; RNA MOLECULES; PROTEIN PORE AB Molecular dynamics simulations were used to refine a theoretical model that describes the interaction of single polyethylene glycol (PEG) molecules with alpha-hemolysin (alpha HL) nanopores. The simulations support the underlying assumptions of the model, that PEG decreases the pore conductance by binding cations (which reduces the number of mobile ions in the pore) and by volume exclusion, and provide bounds for fits to new experimental data. Estimation of cation binding indicates that four monomers coordinate a single K+ in a crown-ether-like structure, with, on average, 1.5 cations bound to a PEG 29-mer at a bulk electrolyte concentration of 4 M KCl. Additionally, PEG is more cylindrical and has a larger cross-section area in the pore than in solution, although its volume is similar. Two key experimental quantities of PEG are described by the model: the ratio of single channel current in the presence of PEG to that in the polymer's absence (blockade depth) and the mean residence time of PEG in the pore. The refined theoretical model is simultaneously fit to the experimentally determined current blockade depth and the mean residence times for PEGs with 15 to 45 monomers, at applied transmembrane potentials of -40 to -80 mV and for three electrolyte concentrations. The model estimates the free energy of the PEG-cation complexes to be -5.3 k(B)T. Finally the entropic penalty of confining PEG to the pore is found to be inversely proportional to the electrolyte concentration. C1 [Balijepalli, Arvind; Pastor, Richard W.] Natl Inst Hlth, Natl Heart Lung & Blood Inst, Bethesda, MD 20892 USA. [Balijepalli, Arvind; Robertson, Joseph W. F.; Kasianowicz, John J.] Natl Inst Stand & Technol, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Reiner, Joseph E.] Virginia Commonwealth Univ, Dept Phys, Richmond, VA 23220 USA. RP Pastor, RW (reprint author), Natl Inst Hlth, Natl Heart Lung & Blood Inst, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov OI Reiner, Joseph/0000-0002-1056-8703 FU NRC/NIST-NIH Research Fellowship; NIH, National Heart, Lung. and Blood Institute FX We thank Wonpil Im and Kyu Il Lee for helpful discussions regarding simulations of ion channels. This work was supported in part by a NRC/NIST-NIH Research Fellowship (A.B.). This research was also supported in part by the Intramural Research Program of the NIH, National Heart, Lung. and Blood Institute, and utilized the high-performance computational capabilities at the National Institutes of Health, Bethesda, MD (NHLBI LoBoS cluster). A.B. thanks the Theoretical and Computational Biophysics Group at the University of Illinois at Urbana-Champaign for training in NAMD. NAMD was developed by the Theoretical and Computational Biophysics Group in the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign. NR 75 TC 27 Z9 27 U1 3 U2 98 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 8 PY 2013 VL 135 IS 18 BP 7064 EP 7072 DI 10.1021/ja4026193 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 143AS UT WOS:000318839300051 PM 23590258 ER PT J AU Lu, W Bushong, EA Shih, TP Ellisman, MH Nicoll, RA AF Lu, Wei Bushong, Eric A. Shih, Tiffany P. Ellisman, Mark H. Nicoll, Roger A. TI The Cell-Autonomous Role of Excitatory Synaptic Transmission in the Regulation of Neuronal Structure and Function SO NEURON LA English DT Article ID OCULAR DOMINANCE COLUMNS; DENDRITIC SPINE DENSITY; SPONTANEOUS RETINAL ACTIVITY; VISUAL MAP DEVELOPMENT; CA1 PYRAMIDAL CELLS; ENVIRONMENTAL ENRICHMENT; HIPPOCAMPAL-NEURONS; RECEPTIVE-FIELDS; NERVOUS-SYSTEM; INTRINSIC EXCITABILITY AB The cell-autonomous role of synaptic transmission in the regulation of neuronal structural and electrical properties is unclear. We have now employed a genetic approach to eliminate glutamatergic synaptic transmission onto individual CA1 pyramidal neurons in a mosaic fashion in vivo. Surprisingly, while electrical properties are profoundly affected in these neurons, as well as inhibitory synaptic transmission, we found little perturbation of neuronal morphology, demonstrating a functional segregation of excitatory synaptic transmission from neuronal morphological development. C1 [Lu, Wei; Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Lu, Wei] NINDS, Synapse & Neural Circuit Res Unit, NIH, Bethesda, MD 20892 USA. [Bushong, Eric A.; Shih, Tiffany P.; Ellisman, Mark H.] Univ Calif San Diego, Natl Ctr Microscopy & Imaging Res, La Jolla, CA 92093 USA. [Bushong, Eric A.; Shih, Tiffany P.; Ellisman, Mark H.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. EM roger.nicoll@ucsf.edu FU NIH Pathway to Independence Award from NIMH; NINDS Intramural Research Program; NIMH; NIH NCRR [P41 GM103412]; National Institute of General Medical Sciences from the National Institutes of Health [8 P41 GM103412-24]; NIH NIGMS [R01 GM082949]; Maryann Martone FX We thank K. Bjorgan and M. Cerpas for technical assistance and all members from the Nicoll laboratory and Ellisman laboratory for helpful discussions. We are also grateful to the generosity of Professors Peter Seeburg and Rolf Sprengel at Max Planck Institute for Medical Research, Heidelberg, Germany, for sharing individual gene-targeted conditional mice for GluA1, GluA2, or GluA3, from which we were able to make the triple-floxed Gria1-3fl/fl mice. W.L. was funded by an NIH Pathway to Independence Award from NIMH and is supported by the NINDS Intramural Research Program. R.A.N. is funded by grants from NIMH. The microscopy studies were carried out at the National Center for Microscopy and Imaging Research at UCSD supported by an award from NIH NCRR (P41 GM103412) and the National Institute of General Medical Sciences (8 P41 GM103412-24) from the National Institutes of Health to M.H.E. The image data obtained for this project are available in the Cell Image Library/Cell Centered Database supported by grants from the NIH NIGMS (R01 GM082949) to M.H.E. and Maryann Martone. NR 78 TC 18 Z9 19 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY 8 PY 2013 VL 78 IS 3 BP 433 EP 439 DI 10.1016/j.neuron.2013.02.030 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 144SW UT WOS:000318961700006 PM 23664612 ER PT J AU Yamaguchi, T Danjo, T Pastan, I Hikida, T Nakanishi, S AF Yamaguchi, Takashi Danjo, Teruko Pastan, Ira Hikida, Takatoshi Nakanishi, Shigetada TI Distinct Roles of Segregated Transmission of the Septo-Habenular Pathway in Anxiety and Fear SO NEURON LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PROBE-BURYING TESTS; LATERAL HABENULA; PLUS-MAZE; RAT; ZEBRAFISH; RECEPTOR; LESIONS; CONNECTIONS; COMPLEX AB The posterior septum consisting of the triangular septum (TS) and the bed nucleus of the anterior commissure (BAG) is predominantly linked with the medial habenula (MHb) and has been implicated in the control of anxiety and fear responses. However, its anatomical and functional linkage has largely remained elusive. We established a transgenic mouse model in which the TS and BAG projection neurons were visualized by GFP fluorescence and selectively eliminated by immunotoxin-mediated cell targeting. The linkage between the TS/BAC and the MHb constitutes two parallel pathways composed of the TS-ventral MHb, the core part of the interpeduncular nucleus (IPN), and the BAG-dorsal MHb, the peripheral part of the IPN. Ablation of the TS and BAG projection neurons selectively impaired anxiety and enhanced fear responses and learning, respectively. Inputs from the TS and BAC to the MHb are thus segregated by two parallel pathways and play specialized roles in controlling emotional behaviors. C1 [Yamaguchi, Takashi; Danjo, Teruko; Hikida, Takatoshi; Nakanishi, Shigetada] Osaka Biosci Inst, Dept Syst Biol, Suita, Osaka 5650874, Japan. [Yamaguchi, Takashi] Osaka Univ, Grad Sch Med, Dept Aging Sci, Suita, Osaka 5650871, Japan. [Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Nakanishi, S (reprint author), Osaka Biosci Inst, Dept Syst Biol, Suita, Osaka 5650874, Japan. EM snakanis@obi.or.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [22220005, 23120011, 23680034]; JST PRESTO Program; Takeda Science Foundation; Naito Foundation FX We thank S. Chaki and T. Shimazaki for technical advice on the behavioral analysis. This work was supported by Research Grants-in-Aid 22220005 (S.N.), 23120011 (T.H. and S.N.), and 23680034 (T.H.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by grants from the JST PRESTO Program (T.H.), the Takeda Science Foundation (S.N.), and the Naito Foundation (T.H.). NR 41 TC 49 Z9 50 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY 8 PY 2013 VL 78 IS 3 BP 537 EP 544 DI 10.1016/j.neuron.2013.02.035 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 144SW UT WOS:000318961700014 PM 23602500 ER PT J AU Otto, M AF Otto, Michael TI Blocking the Spread of Resistance SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID STAPHYLOCOCCUS-AUREUS; VANCOMYCIN; VIRULENCE; GENES C1 NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 NR 10 TC 0 Z9 0 U1 1 U2 13 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 MAY 8 PY 2013 VL 5 IS 184 AR 184fs17 DI 10.1126/scitranslmed.3006128 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 142AD UT WOS:000318767000002 PM 23658243 ER PT J AU Mash, C Bornstein, MH Arterberry, ME AF Mash, Clay Bornstein, Marc H. Arterberry, Martha E. TI Brain dynamics in young infants' recognition of faces: EEG oscillatory activity in response to mother and stranger SO NEUROREPORT LA English DT Article DE early infancy; electroencephalography; face recognition ID 6-MONTH-OLD INFANTS; MEMORY; SYNCHRONIZATION; HUMANS; WORDS AB The brain electrical responses of 3-month-old infants were compared between images of familiar and unfamiliar faces. Infants were shown images of their mothers and of appearance-matched female strangers for 500ms per trial while their electroencephalography was recorded. Electroencephalographic signals were segmented from stimulus onset through 1200 ms, and segments were analyzed in the time-frequency domain with a continuous wavelet transform. Differentiated responses were apparent in three time windows: 370-480, 610-690, and 830-960 ms. Across response windows, event-related synchronization or desynchronization was observed in beta or gamma frequency bands at the left frontal, midline central, bilateral temporal, and right parietal sites. In conclusion, these findings provide the first evidence of organized brain activity underlying familiar face recognition in very young infants and are discussed in relation to comparable patterns that have been observed in adults. NeuroReport 24:359-363 (C) 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. NeuroReport 2013, 24:359-363 C1 [Mash, Clay; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Child & Family Res, Bethesda, MD 20892 USA. [Arterberry, Martha E.] Colby Coll, Dept Psychol, Waterville, ME 04901 USA. RP Mash, C (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Child & Family Res, 6705 Rockledge Dr,Ste 8030, Bethesda, MD 20892 USA. EM mashc@mail.nih.gov FU Division of Intramural Research, NICHD/NIH FX The authors thank A. Bradley, N. Cummins, M. Cusick, B. Harrington, P. Horn, S. Jones, L. May, E. Moran, C. Padilla, and M. Stevenson for assistance. This work was supported by the Division of Intramural Research, NICHD/NIH. NR 25 TC 2 Z9 2 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD MAY 8 PY 2013 VL 24 IS 7 BP 359 EP 363 DI 10.1097/WNR.0b013e32835f6828 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 126AI UT WOS:000317583100003 PM 23470433 ER PT J AU Ziats, MN Rennert, OM AF Ziats, Mark N. Rennert, Owen M. TI Sex-biased gene expression in the developing brain: implications for autism spectrum disorders SO MOLECULAR AUTISM LA English DT Letter DE Autistic disorder; Gene expression; Sex differences ID DE-NOVO MUTATIONS; TRANSCRIPTOME AB Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex-biased genes relate to specific mechanistic processes. We discovered that male-biased genes are enriched for the processes of extracellular matrix formation/glycoproteins, immune response, chromatin, and cell cytoskeleton. We highlight that these pathways have been repeatedly implicated in autism and demonstrate that autism candidate genes are also enriched for these pathways. We propose that the overlap of these male-specific brain transcriptional modules with the same pathways in autism spectrum disorders may partially explain the increased incidence of autism in males. C1 [Ziats, Mark N.; Rennert, Owen M.] NICHHD, NIH, Bethesda, MD 20814 USA. [Ziats, Mark N.] Robinson Coll, NIH Univ Cambridge Biomed Scholars Program, Cambridge CB3 9AN, England. [Ziats, Mark N.] Baylor Coll Med MSTP, Houston, TX 77030 USA. RP Ziats, MN (reprint author), NICHHD, NIH, 49 Convent Dr,Bldg 49,Room 2C08, Bethesda, MD 20814 USA. EM ziatsm@mail.nih.gov NR 14 TC 8 Z9 8 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD MAY 7 PY 2013 VL 4 AR 10 DI 10.1186/2040-2392-4-10 PG 3 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 254VA UT WOS:000327195300001 PM 23651621 ER PT J AU Hoppe, T AF Hoppe, Travis TI A simplified representation of anisotropic charge distributions within proteins SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID 2ND VIRIAL-COEFFICIENT; LIQUID PHASE-TRANSITION; FAST MULTIPOLE METHOD; SERUM-ALBUMIN; PK(A) VALUES; ELECTROSTATICS; LYSOZYME; CRYSTALLIZATION; RATIONALIZATION; MACROMOLECULES AB Effective coarse-grained representations of protein-protein interaction potentials are vital in the modeling of large scale systems. We develop a method to fit an arbitrary number of effective charges to approximate the electrostatic potential of a protein at a given pH in an ionic solution. We find that the effective charges can reproduce an input potential calculated from a high resolution Poisson-Boltzmann calculation. Since the effective charges used in this model are not constrained to the locations of the original charged groups, the extra degrees of freedom allows us to reproduce the field anisotropy with fewer charges. The fitting procedure uses a number of approximations in the charge magnitudes, initial conditions, and multipoles to speed convergence. The most significant gains are found by fitting the multipole moments of the effective charge potential to the moments of the original field. We show that the Yukawa potential is not only sufficient as a pair-wise summation in reproducing the potential, but comes naturally from the linearized expansion of the Poisson-Boltzmann equation. We compute interaction energies and find excellent agreement to the original potential. From the effective charge model we compute the electrostatic contribution to the second virial coefficient. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Hoppe, T (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. EM hoppeta@mail.nih.gov OI Hoppe, Travis/0000-0002-4694-3050 FU NIDDK at the NIH FX We would like to thank Allen Minton for his help and support in the production and editing of this paper. The work was supported in part by the intramural program of NIDDK at the NIH. This study utilized the high-performance computational capabilities of the Helix/Biowulf Systems at the National Institutes of Health, Bethesda, MD (http://helix.nih.gov). NR 45 TC 4 Z9 4 U1 0 U2 11 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 MAY 7 PY 2013 VL 138 IS 17 AR 174110 DI 10.1063/1.4803099 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 149AE UT WOS:000319289600012 PM 23656117 ER PT J AU Farthing, DE Buxbaum, NP Bare, CV Treadwell, SM Kapoor, V Williams, KM Gress, RE AF Farthing, Don E. Buxbaum, Nataliya P. Bare, Catherine V. Treadwell, Shirin M. Kapoor, Veena Williams, Kirsten M. Gress, Ronald E. TI Sensitive GC-MS/MS Method to Measure Deuterium Labeled Deoxyadenosine in DNA from Limited Mouse Cell Populations SO ANALYTICAL CHEMISTRY LA English DT Article ID VERSUS-HOST-DISEASE; MASS-SPECTROMETRY; IN-VIVO; PROLIFERATION; GLUCOSE; RATES AB A rapid and sensitive gas chromatography-tandem mass spectrometry (GC-MS/MS) method was developed to quantitatively measure low levels of DNA base deoxyadenosine (dA) and its isotopologues (e.g., dA M+1) from limited mouse cell populations. Mice undergoing allogeneic hematopoietic transplantation (AHSCT) received deuterated water at biologically relevant time intervals post AHSCT, allowing labeling of DNA upon cell division, which was detected as the dA M+1 isotopologue. Targeted mouse cell populations were isolated from lymphoid organs and purified by multiparameter fluorescence activated cell sorting. Cell lysis, DNA extraction, and hydrolysis were accomplished using available commercial procedures. The novel analytical method utilized a hydrophilic-lipophilic balanced sample preparation, rapid online hot GC inlet gas phase sample derivatization, fast GC low thermal mass technology, and a recently marketed GC-MS/MS system. Calibration standards containing dA and fortified with relevant levels of dA M+1 (0.25-20%) and dA M+5 (internal standard) were used for sample quantitation. The method employed a quadratic fit for calibration of dA M+1 (0.25-20%) and dA, demonstrated excellent accuracy and precision, and had limits of detection of 100 fg on-column for the dA isotopologues. The method was validated and required only 20 000 cells to characterize population dynamics of cells involved in the biology of chronic graft-versus-host disease, the main cause of late morbidity and nonrelapse-mortality following AHSCT. The high sensitivity and specificity of the method makes it useful for investigating in vivo kinetics on limited and important cell populations (e.g., T regulatory cells) from disease conditions or in disease models that are immune-mediated, such as diabetes, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), arthritis, inflammatory bowel disease, and multiple sclerosis. C1 [Farthing, Don E.; Buxbaum, Nataliya P.; Bare, Catherine V.; Treadwell, Shirin M.; Kapoor, Veena; Williams, Kirsten M.; Gress, Ronald E.] NCI, NIH, Expt Transplantat & Immunol ETIB, Bethesda, MD 20892 USA. [Williams, Kirsten M.] George Washington Univ, Med Ctr, Div Blood & Marrow Transplantat, Ctr Canc & Blood Disorders,Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Farthing, DE (reprint author), NCI, NIH, Expt Transplantat & Immunol ETIB, Bethesda, MD 20892 USA. EM farthingde@mail.nih.gov OI Buxbaum, Nataliya/0000-0002-5199-1997 FU National Cancer Institute (NCI), National Institutes of Health (NIH) FX We sincerely thank Mr. Steven Fox (SAIC-Frederick, Inc., Frederick, MD) for sharing historical and technical knowledge on the use of GC/MS for analysis of deoxyadenosine and its isotopologues; Dr. Wayne Chu (currently at Genentech, San Francisco, CA) for sharing his preliminary work using stable isotopes in mouse models; Dr. William Telford (NCI, Bethesda, MD) for his technical assistance with flow cytometry; Dr. Phil Lucas (NCI, Bethesda, MD) for sharing his knowledge on the capabilities of the Promega Maxwell 16 system and on best practices for handling DNA samples; Dr. Shoba Amarnath (NCI, Bethesda, MD) for sharing her T regulatory cell fixation and staining protocol. Mr. Graham Robinett (Agilent Technologies, Inc.) and Dr. Anthony Macherone (Agilent Technologies, Inc.) are thanked for their technical support on the Agilent GC-MS/MS system and Mass Hunter workstation software. This study was supported by intramural funds provided by the National Cancer Institute (NCI), National Institutes of Health (NIH). NR 21 TC 2 Z9 2 U1 0 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD MAY 7 PY 2013 VL 85 IS 9 BP 4613 EP 4620 DI 10.1021/ac400309d PG 8 WC Chemistry, Analytical SC Chemistry GA 141WB UT WOS:000318756100058 PM 23541182 ER PT J AU Fozzatti, L Kim, DW Park, JW Willingham, MC Hollenberg, AN Cheng, SY AF Fozzatti, Laura Kim, Dong Wook Park, Jeong Won Willingham, Mark C. Hollenberg, Anthony N. Cheng, Sheue-Yann TI Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor alpha SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE growth retardation; lipid metabolism; fertility defect ID GENE; MICE; RESISTANCE; ADIPOGENESIS; ADIPOCYTES; PROMOTER; GROWTH AB Genetic evidence from patients with mutations of the thyroid hormone receptor alpha gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TR alpha 1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TR alpha 1 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1(PV) mice, expressing a dominant negative TR alpha 1 mutant (TR alpha 1PV), with mice expressing a mutant Ncor1 allele (Ncor1(Delta ID) mice) that cannot recruit the TR or PV mutant. TR alpha 1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1 Delta ID ameliorated abnormalities in the thyroid-pituitary axis of Thra1(PV/+) mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1(PV/+) mice expressing NCOR1 Delta ID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor gamma and CCAAT/enhancerbinding protein a gene, due to the inability of TR alpha 1PV to recruit NCOR1 Delta ID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TR alpha 1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TR alpha 1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TR alpha 1 mutant-mediated hypothyroidismin patients. C1 [Fozzatti, Laura; Kim, Dong Wook; Park, Jeong Won; Cheng, Sheue-Yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Willingham, Mark C.] Wake Forest Univ, Dept Pathol, Winston Salem, NC 27157 USA. [Hollenberg, Anthony N.] Harvard Univ, Sch Med, Beth Israel Med Ctr, Div Endocrinol Metab & Diabet, Boston, MA 02215 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health Extramural Grant [DK056123] FX We thank Dr. O. Gavrilova (National Institute of Diabetes and Digestive and Kidney Diseases) for valuable advice and assistance during the course of the present work and for critical reading of the manuscript. The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health and by National Institutes of Health Extramural Grant DK056123 (to A.N.H.). NR 28 TC 10 Z9 10 U1 2 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 MAY 7 PY 2013 VL 110 IS 19 BP 7850 EP 7855 DI 10.1073/pnas.1222334110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 149NP UT WOS:000319327700073 PM 23610395 ER PT J AU Lundstrom, W Highfill, S Walsh, STR Beq, S Morse, E Kockum, I Alfredsson, L Olsson, T Hillert, J Mackall, CL AF Lundstrom, Wangko Highfill, Steven Walsh, Scott T. R. Beq, Stephanie Morse, Elizabeth Kockum, Ingrid Alfredsson, Lars Olsson, Tomas Hillert, Jan Mackall, Crystal L. TI Soluble IL7R alpha potentiates IL-7 bioactivity and promotes autoimmunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunology; soluble receptors; tolerance ID T-CELL HOMEOSTASIS; GENOME-WIDE ASSOCIATION; MULTIPLE-SCLEROSIS; INTERLEUKIN-7 RECEPTOR; HIV-INFECTION; DENDRITIC CELLS; TRANSGENIC MICE; IN-VIVO; DISEASE; SURVIVAL AB Human soluble interleukin-7 receptor (sIL7R)alpha circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7R alpha has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7R alpha competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7R alpha also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7R alpha and also demonstrate a potentiating effect of sIL7R alpha on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7R alpha levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7R alpha potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7R alpha. C1 [Lundstrom, Wangko; Highfill, Steven; Morse, Elizabeth; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lundstrom, Wangko; Kockum, Ingrid; Olsson, Tomas; Hillert, Jan] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Walsh, Scott T. R.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Walsh, Scott T. R.] Univ Maryland, Dept Cell Biol & Mol Genet, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA. [Beq, Stephanie] Cytheris SA, F-92130 Issy Le Moulineaux, France. [Alfredsson, Lars] Karolinska Inst, Inst Environm Med, S-17176 Stockholm, Sweden. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov OI Alfredsson, Lars/0000-0003-1688-6697 FU National Institutes of Health (NIH); NIH [AI72142] FX We thank Drs. Al Singer, Scott Durum, and Hyun Park for careful review of this manuscript and helpful discussions. This work was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH). S. T. R. W. was supported by NIH Grant AI72142. NR 58 TC 35 Z9 36 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 7 PY 2013 VL 110 IS 19 BP E1761 EP E1770 DI 10.1073/pnas.1222303110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 149NP UT WOS:000319327700009 PM 23610432 ER PT J AU Cho, HJ Kang, JH Park, KK Choe, JY Park, YY Moon, YS Chung, IK Chang, HW Kim, CH Choi, YH Kim, WJ Moon, SK Chang, YC AF Cho, Hyun-Ji Kang, Jeong-Han Park, Kwan-Kyu Choe, Jung-Yoon Park, Yoon-Yub Moon, Yong-Suk Chung, Il-Kyung Chang, Hyeun-Wook Kim, Cheorl-Ho Choi, Yung Hyun Kim, Wun-Jae Moon, Sung-Kwon Chang, Young-Chae TI Comparative proteome analysis of Tumor necrosis factor alpha-stimulated human Vascular Smooth Muscle Cells in response to melittin SO PROTEOME SCIENCE LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; BEE VENOM; INDUCED MIGRATION; IN-VITRO; PROHIBITIN; PROTEINS; PEPTIDE; CALRETICULIN; NEUTROPHILS; EXPRESSION AB Background: Bee venom has been used to relieve pain and to treat inflammatory diseases, including rheumatoid arthritis, in humans. To better understand the mechanisms of the anti-inflammatory and anti-atherosclerosis effect of bee venom, gel electrophoresis and mass spectrometry were used to identify proteins whose expression was altered in human Vascular Smooth Muscle Cells (hVSMCs) stimulated by tumor necrosis factor alpha after 12 h in the presence of melittin. Results: To obtain valuable insights into the anti-inflammatory and anti-atherosclerosis mechanisms of melittin, two-dimensional (2-D) gel electrophoresis and MALDI-TOF/TOF were used. The proteome study, we showed 33 significant proteins that were differentially expressed in the cells treated with tumor necrosis factor alpha and melittin. Thirteen proteins were significantly increased in the cells treated with tumor necrosis factor alpha, and those proteins were reduced in the cells treated with melittin. Five of the proteins that showed increased expression in the cells treated with tumor necrosis factor alpha are involved in cell migration, including calreticulin, an essential factor of development that plays a role in transcription regulation. The proteins involved in cell migration were reduced in the melittin treated cells. The observed changes in the expression of GRP75, prohibitin, and a select group of other proteins were validated with reverse transcribed-PCR. It was confirmed that the observed change in the protein levels reflected a change in the genes level. In addition, the phosphorylation of EGFR and ERK was validated by analyzing the protein pathway. Conclusion: Taken together, these data established that the expression of some proteins was significantly changed by melittin treatment in tumor necrosis factor alpha stimulated the cells and provided insights into the mechanism of the melittin function for its potential use as an anti-inflammatory agent. C1 [Cho, Hyun-Ji; Park, Kwan-Kyu; Choe, Jung-Yoon; Park, Yoon-Yub; Moon, Yong-Suk; Chang, Young-Chae] Catholic Univ Daegu, Sch Med, Res Inst Biomed Engn, Taegu 705718, South Korea. [Cho, Hyun-Ji; Park, Kwan-Kyu; Choe, Jung-Yoon; Park, Yoon-Yub; Moon, Yong-Suk; Chang, Young-Chae] Catholic Univ Daegu, Sch Med, Dept Med, Taegu 705718, South Korea. [Kang, Jeong-Han] NCI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Chung, Il-Kyung] Catholic Univ Daegu, Dept Biotechnol, Gyongsan 712702, South Korea. [Chang, Hyeun-Wook] Yeungnam Univ, Coll Pharm, Gyongsan 712749, South Korea. [Kim, Cheorl-Ho] Sungkyunkwan Univ, Dept Biol Sci, Sungkyunkwan 440746, Kyunggi Do, South Korea. [Choi, Yung Hyun] Dong Eui Univ, Coll Oriental Med, Dept Biochem, Pusan 614052, South Korea. [Kim, Wun-Jae] Chungbuk Natl Univ, Personalized Tumor Engn Res Ctr, Dept Urol, Cheongju 361763, Chungbuk, South Korea. [Moon, Sung-Kwon] Chung Ang Univ, Dept Food Sci & Technol, Ansung 456756, South Korea. RP Chang, YC (reprint author), Catholic Univ Daegu, Sch Med, Res Inst Biomed Engn, Taegu 705718, South Korea. EM ycchang@cu.ac.kr FU Biogreen 21 Program, Rural Development Administration, Republic of Korea [PJ00953402]; National Research Foundation of Korea (NRF, Personalized Tumor Engineering Research Center) grant; Korea government (MEST) [2012-0000481] FX This work was supported by a grant (PJ00953402) from Biogreen 21 Program, Rural Development Administration, Republic of Korea and also by the National Research Foundation of Korea (NRF, Personalized Tumor Engineering Research Center) grant funded by the Korea government (MEST) (NO. 2012-0000481). NR 33 TC 3 Z9 3 U1 0 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-5956 J9 PROTEOME SCI JI Proteome Sci. PD MAY 7 PY 2013 VL 11 AR 20 DI 10.1186/1477-5956-11-20 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 144UH UT WOS:000318965600001 PM 23651618 ER PT J AU Perrin, BS Ichiye, T AF Perrin, B. Scott, Jr. Ichiye, Toshiko TI Identifying Residues That Cause pH-Dependent Reduction Potentials SO BIOCHEMISTRY LA English DT Article ID PROTEINS AB The pH dependence of the reduction potential E degrees for a metalloprotein indicates that the protonation state of at least one residue near the redox site changes and may be important for its activity. The responsible residue is usually identified by site-specific mutagenesis, which may be time-consuming. Here, the titration of E degrees for Chromatium vinosum high-potential iron-sulfur protein is predicted to be in good agreement with experiment using density functional theory and Poisson-Boltzmann calculations if only the sole histidine undergoes changes in protonation. The implementation of this approach into CHARMMing, a user-friendly web-based portal, allows users to identify residues in other proteins causing similar pH dependence. C1 [Perrin, B. Scott, Jr.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Ichiye, Toshiko] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. RP Ichiye, T (reprint author), Georgetown Univ, Dept Chem, Box 571227, Washington, DC 20057 USA. EM ti9@georgetown.edu FU National Institutes of Health [R01-GM045303]; William G. McGowan Foundation FX Supported by National Institutes of Health Grant R01-GM045303 and the William G. McGowan Foundation. NR 16 TC 3 Z9 3 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 7 PY 2013 VL 52 IS 18 BP 3022 EP 3024 DI 10.1021/bi4002858 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 141WD UT WOS:000318756300002 PM 23607577 ER PT J AU Gurnev, PA Yang, ST Melikov, KC Chernomordik, LV Bezrukov, SM AF Gurnev, Philip A. Yang, Sung-Tae Melikov, Kamran C. Chernomordik, Leonid V. Bezrukov, Sergey M. TI Cationic Cell-Penetrating Peptide Binds to Planar Lipid Bilayers Containing Negatively Charged Lipids but does not Induce Conductive Pores SO BIOPHYSICAL JOURNAL LA English DT Article ID ARGININE-RICH PEPTIDES; ION CHANNELS; TAT PEPTIDE; MEMBRANES; TRANSLOCATION; MECHANISM; STATES AB Using a cation-selective gramicidin A channel as a sensor of the membrane surface charge, we studied interactions of oligoarginine peptide R9C, a prototype cationic cell-penetrating peptide (CPP), with planar lipid membranes. We have found that R9C sorption to the membrane depends strongly on its lipid composition from virtually nonexistent for membranes made of uncharged lipids to very pronounced for membranes containing negatively charged lipids, with charge overcompensation at R9C concentrations exceeding 1 mu M. The sorption was reversible as it was removed by addition of polyanionic dextran sulfate to the membrane bathing solution. No membrane poration activity of R9C (as would be manifested by increased bilayer conductance) was detected in the charged or neutral membranes, including those with asymmetric negative/neutral and negative/positive lipid leaflets. We conclude that interaction of R9C with planar lipid bilayers does not involve pore formation in all studied lipid combinations up to 20 mu M peptide concentration. However, R9C induces leakage of negatively charged but not neutral liposomes in a process that involves lipid mixing between liposomes. Our findings suggest that direct traversing of CPPs through the uncharged outer leaflet of the plasma membrane bilayer is unlikely and that permeabilization necessarily involves both anionic lipids and CPP-dependent fusion between opposing membranes. C1 [Gurnev, Philip A.] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. [Gurnev, Philip A.; Yang, Sung-Tae; Melikov, Kamran C.; Chernomordik, Leonid V.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Gurnev, PA (reprint author), Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. EM gurnev@physics.umass.edu FU National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 23 TC 6 Z9 6 U1 0 U2 29 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 MAY 7 PY 2013 VL 104 IS 9 BP 1933 EP 1939 DI 10.1016/j.bpj.2013.02.053 PG 7 WC Biophysics SC Biophysics GA 141VJ UT WOS:000318754300014 PM 23663836 ER PT J AU Kornyshev, AA Leikin, S AF Kornyshev, Alexei A. Leikin, Sergey TI Helical Structure Determines Different Susceptibilities of dsDNA, dsRNA, and tsDNA to Counterion-Induced Condensation SO BIOPHYSICAL JOURNAL LA English DT Article ID DNA DOUBLE HELICES; INTERMOLECULAR FORCES; B-DNA; ATTRACTION; CATIONS; MODEL; ELECTROSTATICS; NUCLEOSOME; POLYAMINES; DEPENDENCE AB Recent studies of counterion-induced condensation of nucleic acid helices into aggregates produced several puzzling observations. For instance, trivalent cobalt hexamine ions condensed double-stranded (ds) DNA oligomers but not their more highly charged dsRNA counterparts. Divalent alkaline earth metal ions condensed triple-stranded (ts) DNA oligomers but not dsDNA. Here we show that these counterintuitive experimental results can be rationalized within the electrostatic zipper model of interactions between molecules with helical charge motifs. We report statistical mechanical calculations that reveal dramatic and nontrivial interplay between the effects of helical structure and thermal fluctuations on electrostatic interaction between oligomeric nucleic acids. Combining predictions for oligomeric and much longer helices, we also interpret recent experimental studies of the role of counterion charge, structure, and chemistry. We argue that an electrostatic zipper attraction might be a major or even dominant force in nucleic acid condensation. C1 [Kornyshev, Alexei A.] Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AY, England. [Leikin, Sergey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, NIH, Bethesda, MD USA. RP Leikin, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, NIH, Bethesda, MD USA. EM leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU Engineering and Physical Sciences Research Council, UK [EP/H004319/1]; Human Frontiers Science Foundation [RGP0049/2010-C102]; Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by funding from the Engineering and Physical Sciences Research Council, UK (grant No. EP/H004319/1) and Human Frontiers Science Foundation (grant No. RGP0049/2010-C102) to A.A.K. as well as funding from the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health, to S.L. NR 60 TC 7 Z9 7 U1 0 U2 23 PU CELL PRESS PI CAMBRIDGE PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD MAY 7 PY 2013 VL 104 IS 9 BP 2031 EP 2041 DI 10.1016/j.bpj.2013.03.033 PG 11 WC Biophysics SC Biophysics GA 141VJ UT WOS:000318754300024 PM 23663846 ER PT J AU Mutoh, S Sobhany, M Moore, R Perera, L Pedersen, L Sueyoshi, T Negishi, M AF Mutoh, Shingo Sobhany, Mack Moore, Rick Perera, Lalith Pedersen, Lee Sueyoshi, Tatsuya Negishi, Masahiko TI Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling SO SCIENCE SIGNALING LA English DT Article ID ACTIVE/ANDROSTANE RECEPTOR; NUCLEAR RECEPTOR; CYP2B GENE; LIVER; PROTEIN; RACK1; HEPATOCYTES; INDUCTION; KINASE; SRC AB Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr(52), which then promoted the dephosphorylation of CAR at Thr(38) by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR. C1 [Mutoh, Shingo; Sobhany, Mack; Moore, Rick; Sueyoshi, Tatsuya; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Perera, Lalith; Pedersen, Lee] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Pedersen, Lee] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Intramural Research Program of the NIH [HL-06350]; National Institute of Environmental Health Sciences [Z01ES1005-01] FX This research was supported by the Intramural Research Program of the NIH (HL-06350) and the National Institute of Environmental Health Sciences (Z01ES1005-01). NR 35 TC 55 Z9 56 U1 1 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 J9 SCI SIGNAL JI Sci. Signal. PD MAY 7 PY 2013 VL 6 IS 274 AR ra31 DI 10.1126/scisignal.2003705 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 140YE UT WOS:000318691600001 PM 23652203 ER PT J AU Andrade, BB Kumar, NP Mayer-Barber, KD Barber, DL Sridhar, R Rekha, VVB Jawahar, MS Nutman, TB Sher, A Babu, S AF Andrade, Bruno B. Kumar, Nathella Pavan Mayer-Barber, Katrin D. Barber, Daniel L. Sridhar, Rathinam Rekha, Vaithilingam V. Banu Jawahar, Mohideen S. Nutman, Thomas B. Sher, Alan Babu, Subash TI Plasma Heme Oxygenase-1 Levels Distinguish Latent or Successfully Treated Human Tuberculosis from Active Disease SO PLOS ONE LA English DT Article ID PULMONARY TUBERCULOSIS; CARBON-MONOXIDE; INFECTION; DIAGNOSIS; NEOPTERIN; PROMOTES AB Background: Tuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO-1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB. Methods: Cross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro-inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India. Results: Systemic levels of HO-1 were dramatically increased in individuals with active pulmonary and extra-pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL)-10, interferon (IFN)-gamma and IL-17 and diminished levels of tumor necrosis factor (TNF)-alpha. Conclusion: These findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins. C1 [Andrade, Bruno B.; Mayer-Barber, Katrin D.; Barber, Daniel L.; Nutman, Thomas B.; Sher, Alan; Babu, Subash] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Kumar, Nathella Pavan; Babu, Subash] Int Ctr Excellence Res, Natl Inst Hlth, Madras, Tamil Nadu, India. [Sridhar, Rathinam] Govt Stanley Med Hosp, Madras, Tamil Nadu, India. [Rekha, Vaithilingam V. Banu; Jawahar, Mohideen S.] Natl Inst Res TB, Madras, Tamil Nadu, India. [Babu, Subash] NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Andrade, BB (reprint author), NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. EM bruno.andrade@nih.gov RI Andrade, Bruno/J-9111-2012 OI Andrade, Bruno/0000-0001-6833-3811 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, 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 US Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 18 Z9 18 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 MAY 6 PY 2013 VL 8 IS 5 AR e62618 DI 10.1371/journal.pone.0062618 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 177QL UT WOS:000321390200031 PM 23671613 ER PT J AU Zou, J Le, K Xu, SW Chen, JW Liu, ZP Chao, XJ Geng, B Luo, JN Zeng, SY Ye, JT Liu, PQ AF Zou, Jian Le, Kang Xu, Suowen Chen, Jianwen Liu, Zhiping Chao, Xiaojuan Geng, Biao Luo, Jiani Zeng, Siyu Ye, Jiantao Liu, Peiqing TI Fenofibrate ameliorates cardiac hypertrophy by activation of peroxisome proliferator-activated receptor-alpha partly via preventing p65-NF kappa B binding to NFATc4 SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Fenofibrate; Cardiac hypertrophy; NFATc4; p65-NF kappa B; PPAR-alpha ID NF-KAPPA-B; ANGIOTENSIN-II; HEART-FAILURE; CARDIOMYOCYTE HYPERTROPHY; TRANSCRIPTION FACTOR; CALCINEURIN; PATHWAY; INVOLVEMENT; BLOCKADE; CALCIUM AB Fenofibrate, a specific peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonist, was reported to inhibit cardiac hypertrophy. However, the detailed molecular mechanisms and particularly the transcriptional components that are decisive in this process remain to be elucidated. Here we found that fenofibrate ameliorated cardiac hypertrophy in vitro and in vivo. Fenofibrate prevented nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4) and p65 subunit of nuclear factor-kappa B (p65-NF kappa B) induced by pressure overload or angiotensinII (AngII). Moreover, fenofibrate increased the association of PPAR-alpha with NFATc4 in nucleus, which inhibited the interaction of NFATc4 with p65-NF kappa B. Our results suggested that the anti-hypertrophic effect of fenofibrate may be partially attributed to activation of PPAR-alpha, which decreases the binding of p65-NF kappa B to NFATc4 and thereby inhibits transactivation of NFATc4. (c) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Zou, Jian; Chen, Jianwen; Liu, Zhiping; Chao, Xiaojuan; Geng, Biao; Luo, Jiani; Zeng, Siyu; Ye, Jiantao; Liu, Peiqing] Sun Yat Sen Univ, Sch Pharmaceut Sci, Dept Pharmacol & Toxicol, Guangzhou 510006, Guangdong, Peoples R China. [Le, Kang; Xu, Suowen] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Ye, JT (reprint author), Sun Yat Sen Univ, Sch Pharmaceut Sci, Dept Pharmacol & Toxicol, Guangzhou 510006, Guangdong, Peoples R China. RI Le, Kang/D-1630-2016 FU National Natural Science Foundation of China [81072641, 81273499, 81200096]; National Science and Technology Major Project of China "Key New Drug Creation and Manufacturing Program" [2011ZX09401-307]; Natural Science Foundation of Guangdong Province [S2011030003190]; Guangdong Province [2008A030201013, 2012A080201007]; Guangzhou City [2008Z1-E571]; Department of Education of Guangdong Province [CXZD1006] FX This work was supported by grants from the National Natural Science Foundation of China (Nos. 81072641, 81273499, and 81200096); the National Science and Technology Major Project of China "Key New Drug Creation and Manufacturing Program" (No. 2011ZX09401-307), Team item of Natural Science Foundation of Guangdong Province (No. S2011030003190), Major Project of Guangdong Province (Nos. 2008A030201013 and 2012A080201007) and Major Project of Guangzhou City (No. 2008Z1-E571). Major Project of Department of Education of Guangdong Province (No. CXZD1006). NR 35 TC 18 Z9 21 U1 1 U2 22 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 MAY 6 PY 2013 VL 370 IS 1-2 BP 103 EP 112 DI 10.1016/j.mce.2013.03.006 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 152RG UT WOS:000319548200011 PM 23518069 ER PT J AU Madenspacher, JH Azzam, KM Gowdy, KM Malcolm, KC Nick, JA Dixon, D Aloor, JJ Draper, DW Guardiola, JJ Shatz, M Menendez, D Lowe, J Lu, J Bushel, P Li, LP Merrick, BA Resnick, MA Fessler, MB AF Madenspacher, Jennifer H. Azzam, Kathleen M. Gowdy, Kymberly M. Malcolm, Kenneth C. Nick, Jerry A. Dixon, Darlene Aloor, Jim J. Draper, David W. Guardiola, John J. Shatz, Maria Menendez, Daniel Lowe, Julie Lu, Jun Bushel, Pierre Li, Leping Merrick, B. Alex Resnick, Michael A. Fessler, Michael B. TI p53 integrates host defense and cell fate during bacterial pneumonia SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ALVEOLAR MACROPHAGE APOPTOSIS; FACTOR-BINDING SITES; KAPPA-B ACTIVATION; TUMOR-SUPPRESSOR; NITRIC-OXIDE; PNEUMOCOCCAL PNEUMONIA; KNOCKOUT MICE; INFLAMMATION; LUNG; NEUTROPHILS AB Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53(-/-) mice display genome-wide induction of NF-kappa B response element-enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor-treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53(-/-) neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53(-/-) mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult. C1 [Madenspacher, Jennifer H.; Azzam, Kathleen M.; Gowdy, Kymberly M.; Aloor, Jim J.; Draper, David W.; Guardiola, John J.; Fessler, Michael B.] NIEHS, NIH, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Dixon, Darlene] NIEHS, NIH, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Dixon, Darlene; Merrick, B. Alex] NIEHS, NIH, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Shatz, Maria; Menendez, Daniel; Lowe, Julie; Resnick, Michael A.] NIEHS, NIH, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Lu, Jun; Bushel, Pierre; Li, Leping] NIEHS, NIH, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Malcolm, Kenneth C.; Nick, Jerry A.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. RP Fessler, MB (reprint author), NIEHS, NIH, Lab Resp Biol, POB 12233, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health NIEHS [Z01 ES102005]; [1R01HL090991] FX This research was supported by the Intramural Research Program of the National Institutes of Health NIEHS (Z01 ES102005) and by 1R01HL090991. NR 56 TC 19 Z9 19 U1 0 U2 7 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 MAY 6 PY 2013 VL 210 IS 5 BP 891 EP 904 DI 10.1084/jem.20121674 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 139UG UT WOS:000318609700003 PM 23630228 ER PT J AU Kiviranta, R Yamana, K Saito, H Ho, DK Laine, J Tarkkonen, K Nieminen-Pihala, V Hesse, E Correa, D Maatta, J Tessarollo, L Rosen, ED Horne, WC Jenkins, NA Copeland, NG Warming, S Baron, R AF Kiviranta, Riku Yamana, Kei Saito, Hiroaki Ho, Daniel K. Laine, Julius Tarkkonen, Kati Nieminen-Pihala, Vappu Hesse, Eric Correa, Diego Maatta, Jorma Tessarollo, Lino Rosen, Evan D. Horne, William C. Jenkins, Nancy A. Copeland, Neal G. Warming, Soren Baron, Roland TI Coordinated transcriptional regulation of bone homeostasis by Ebf1 and Zfp521 in both mesenchymal and hematopoietic lineages SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ZINC-FINGER PROTEIN; KAPPA-B LIGAND; OSTEOBLAST DIFFERENTIATION; OSTEOCLAST DIFFERENTIATION; RECEPTOR ACTIVATOR; CELL-FACTOR; GENE-EXPRESSION; BETA-CATENIN; IN-VITRO; PROGENITORS AB Bone homeostasis is maintained by the coupled actions of hematopoietic bone-resorbing osteoclasts (OCs) and mesenchymal bone-forming osteoblasts (OBs). Here we identify early B cell factor 1 (Ebf1) and the transcriptional coregulator Zfp521 as components of the machinery that regulates bone homeostasis through coordinated effects in both lineages. Deletion of Zfp521 in OBs led to impaired bone formation and increased OB-dependent osteoclastogenesis (OC-genesis), and deletion in hematopoietic cells revealed a strong cell-autonomous role for Zfp521 in OC progenitors. In adult mice, the effects of Zfp521 were largely caused by repression of Ebf1, and the bone phenotype of Zfp521(+/-) mice was rescued in Zfp521(+/-):Ebf1(+/-) mice. Zfp521 interacted with Ebf1 and repressed its transcriptional activity. Accordingly, deletion of Zfp521 led to increased Ebf1 activity in OBs and OCs. In vivo, Ebf1 overexpression in OBs resulted in suppressed bone formation, similar to the phenotype seen after OB-targeted deletion of Zfp521. Conversely, Ebf1 deletion led to cell-autonomous defects in both OB-dependent and cell-intrinsic OC-genesis, a phenotype opposite to that of the Zfp521 knockout. Thus, we have identified the interplay between Zfp521 and Ebf1 as a novel rheostat for bone homeostasis. C1 [Kiviranta, Riku; Yamana, Kei; Saito, Hiroaki; Ho, Daniel K.; Hesse, Eric; Correa, Diego; Horne, William C.; Baron, Roland] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. [Kiviranta, Riku; Yamana, Kei; Saito, Hiroaki; Ho, Daniel K.; Hesse, Eric; Correa, Diego; Horne, William C.; Baron, Roland] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02115 USA. [Rosen, Evan D.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Kiviranta, Riku; Yamana, Kei; Saito, Hiroaki; Ho, Daniel K.; Hesse, Eric; Correa, Diego; Horne, William C.; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Kiviranta, Riku; Laine, Julius; Tarkkonen, Kati; Nieminen-Pihala, Vappu] Univ Turku, Turku Univ Hosp, Dept Med Biochem & Genet, FI-20520 Turku, Finland. [Kiviranta, Riku; Laine, Julius; Tarkkonen, Kati; Nieminen-Pihala, Vappu] Univ Turku, Turku Univ Hosp, Dept Med, FI-20520 Turku, Finland. [Maatta, Jorma] Univ Turku, Turku Univ Hosp, Turku Ctr Dis Modeling, FI-20520 Turku, Finland. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Jenkins, Nancy A.; Copeland, Neal G.] Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Warming, Soren] Genentech Inc, San Francisco, CA 94080 USA. RP Baron, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. EM roland_baron@hsdm.harvard.edu OI Maatta, Jorma/0000-0001-8752-6862 FU National Institutes of Health-National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR048218, AR57769]; Academy of Finland [10945, 120116]; Gideon and Sevgi Rodan Fellowship from the International Bone and Mineral Society; Finnish Cultural Foundation; Emil Aaltonen Foundation; Sigrid Juselius Foundation FX This work was supported in part by National Institutes of Health-National Institute of Arthritis and Musculoskeletal and Skin Diseases grants to R. Baron (AR048218 and AR57769). Additional support was provided by the Academy of Finland (Projects 10945 and 120116 to R. Kiviranta), the Gideon and Sevgi Rodan Fellowship from the International Bone and Mineral Society (to R. Kiviranta and E. Hesse), the Finnish Cultural Foundation (to R. Kiviranta), the Emil Aaltonen Foundation (to R. Kiviranta), and the Sigrid Juselius Foundation (R. Kiviranta). NR 48 TC 16 Z9 16 U1 1 U2 6 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 MAY 6 PY 2013 VL 210 IS 5 BP 969 EP 985 DI 10.1084/jem.20121187 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 139UG UT WOS:000318609700008 PM 23569325 ER PT J AU Singh, SK Williams, CA Klarmann, K Burkett, SS Keller, JR Oberdoerffer, P AF Singh, Satyendra K. Williams, Carrie A. Klarmann, Kimberly Burkett, Sandra S. Keller, Jonathan R. Oberdoerffer, Philipp TI Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID BONE-MARROW-CELLS; SELF-RENEWAL; DNA-DAMAGE; SACCHAROMYCES-CEREVISIAE; GENOTOXIC STRESS; GENE-EXPRESSION; ADULT MICE; DIFFERENTIATION; MOUSE; P53 AB The (histone) deacetylase Sirt1 is a mediator of genomic and epigenetic maintenance, both of which are critical aspects of stem cell homeostasis and tightly linked to their functional decline in aging and disease. We show that Sirt1 ablation in adult hematopoietic stem and progenitor cells (HSPCs) promotes aberrant HSPC expansion specifically under conditions of hematopoietic stress, which is associated with genomic instability as well as the accumulation of DNA damage and eventually results in a loss of long-term progenitors. We further demonstrate that progenitor cell expansion is mechanistically linked to the selective up-regulation of the HSPC maintenance factor and polycomb target gene Hoxa9. We show that Sirt1 binds to the Hoxa9 gene, counteracts acetylation of its histone target H4 lysine 16, and in turn promotes polycomb-specific repressive histone modification. Together, these findings demonstrate a dual role for Sirt1 in HSPC homeostasis, both via epigenetic regulation of a key developmental gene and by promoting genome stability in adult stem cells. C1 [Singh, Satyendra K.; Williams, Carrie A.; Burkett, Sandra S.; Oberdoerffer, Philipp] NCI, Mouse Canc Genet Program, SAIC Frederick Inc, Frederick Natl Lab, Ft Detrick, MD 21702 USA. [Klarmann, Kimberly; Keller, Jonathan R.] NCI, Lab Canc Prevent, SAIC Frederick Inc, Frederick Natl Lab, Ft Detrick, MD 21702 USA. RP Oberdoerffer, P (reprint author), NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. EM oberdoerfferp@mail.nih.gov FU National Cancer Institute, The National Institutes of Health, The National Institutes of Health intramural research program [HHSN26120080001E] FX This work was supported by federal funds from the National Cancer Institute, The National Institutes of Health, The National Institutes of Health intramural research program, and under contract HHSN26120080001E. NR 61 TC 32 Z9 35 U1 1 U2 5 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 MAY 6 PY 2013 VL 210 IS 5 BP 987 EP 1001 DI 10.1084/jem.20121608 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 139UG UT WOS:000318609700009 PM 23630229 ER PT J AU Li, CY Xiong, KM Wu, YX Liu, YW Chen, L Stewart, RR Peoples, RW Yi, CL AF Li, Chao-Ying Xiong, Ke-Ming Wu, Yu-Xiang Liu, Yu-Wei Chen, Lin Stewart, Randall R. Peoples, Robert W. Yi, Chu-Li TI Conserved extracellular cysteines differentially regulate the potentiation produced by Zn2+ in rat P2X4 receptors SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE P2X; P2X4 receptor; Cysteine; Disulfide bond; Mutation; Zinc; Efficacy ID ECTODOMAIN CYSTEINES; P2X(4) RECEPTORS; CHANNEL; TRAFFICKING; ETHANOL; COPPER; ROLES; ZINC AB One feature of the amino acid sequence of P2X receptors identified from mammalian species, Xenopus laevis and zebrafish is the conservation of ten cysteines in the extracellular loop. Little information is available about the role of these conserved ectodomain cysteines in the function of P2X receptors. Here, we investigated the possibility that ten conserved cysteine residues in the extracellular loop of the rat P2X4 receptor may regulate zinc potentiation of the receptor using a series of individual cysteine to alanine point mutations and functional characterization of recombinant receptors expressed in Xenopus oocytes. For the C116A, C132A, C159A, C165A, C217A and C227A mutants, 10 mu M zinc did not significantly affect the current activated by an EC40 concentration of ATP. By contrast, 5 mu M zinc shifted the ATP concentration-response curve to the right in a parallel manner for both the C261A and C270A mutants and the magnitudes of those shifts were similar to that of the wildtype receptor. Interestingly, for the C126A and C149A mutants, 5 mu M zinc potentiated ATP-activated current, but increased the maximal response to ATP by 90% and 81% respectively, without significantly changing the EC50 value of ATP. Thus, these results suggest that cysteines and disulfide bonds between cysteines are differentially involved in the potentiation of the rat P2X4 receptor by zinc. (C) 2013 Published by Elsevier B.V. C1 [Li, Chao-Ying; Wu, Yu-Xiang; Liu, Yu-Wei; Chen, Lin; Yi, Chu-Li] Jianghan Univ, Wuhan Inst Biomed Sci, Wuhan 430056, Peoples R China. [Xiong, Ke-Ming; Stewart, Randall R.] NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Peoples, Robert W.] Marquette Univ, Dept Biomed Sci, Milwaukee, WI 53201 USA. RP Li, CY (reprint author), Jianghan Univ, Wuhan Inst Biomed Sci, Wuhan 430056, Peoples R China. EM licy.whibs@yahoo.cn; yicl.whibs@yahoo.cn RI Liu, Yuwei/H-6985-2013 FU Wuhan Science and Technology Foundation [200970634270, 201150699189-23]; National Natural Science Foundaton of China [30970927] FX We thank Dr. Gary Buell for providing the cDNA for the P2X4 subunit. This work was supported by the Wuhan Science and Technology Foundation (200970634270 and 201150699189-23) and National Natural Science Foundaton of China (30970927). NR 14 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 5 PY 2013 VL 707 IS 1-3 BP 11 EP 16 DI 10.1016/j.ejphar.2013.03.011 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 143XN UT WOS:000318902600002 PM 23524095 ER PT J AU Mbulaiteye, SM Buonaguro, FM AF Mbulaiteye, Sam M. Buonaguro, Franco M. TI Infections and cancer: debate about using vaccines as a cancer control tool SO INFECTIOUS AGENTS AND CANCER LA English DT Editorial Material AB In 2012, Infectious Agents and Cancer commissioned a thematic series collection of articles on Prevention of HPV related cancer. The articles have attracted wide interest and stimulated debate, including about the utility of vaccines in cancer control. The application of vaccines to cancer control fulfills a promise envisioned at the turn of the 20th century when remarkable experiments showed that some cancers were caused by infections. This suggested the possibility of applying infection-control strategies to cancer control. Vaccines represent the most practical cost-effective technology to prevent wide human suffering and death from many acute infectious diseases, such as small pox or polio. Hitherto applied to control of acute fatal infections, vaccines, if developed, might provide a potent way to control cancer. The articles in the HPV thematic series show success in developing and applying a vaccine against human papilloma virus (HPV). A vaccine is also available against hepatitis B virus (HBV), which causes liver cancer. These vaccines augment the tools available to control the associated cancers. Scientific endeavor continues for six other cancer-associated infections, mostly viruses. Not surprisingly, debate about the safety of vaccines targeting cancer has been triggered in the scientific community. Questions about safety have been raised for those populations where other means to control these cancers may be available. Although it is difficult to quantify risk from vaccines in individuals where other cancer control services exist, it is likely to be low. Vaccines are much safer today than before. Technological advancement in vaccine development and manufacture and improved regulatory review and efficient distribution have minimized substantially the risk for harm from vaccines. Formal and informal debate about the pros and cons of applying vaccines as a cancer control tools is ongoing in scientific journals and on the web. Infectious Agents and Cancer encourages evidence-based discussion to clarify understanding of the role of vaccines in cancer control. In a similar vein, the journal will not consider anecdotal reports and rhetorical arguments because they are unlikely to inform policy, regulation, or the public. C1 [Mbulaiteye, Sam M.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Buonaguro, Franco M.] Ist Nazl Tumori Fond Pascale, Dpt Expt Oncol, Mol Biol & Viral Oncol Unit, Naples, Italy. RP Buonaguro, FM (reprint author), Ist Nazl Tumori Fond Pascale, Dpt Expt Oncol, Mol Biol & Viral Oncol Unit, Naples, Italy. EM fmbuonaguro@tin.it NR 15 TC 1 Z9 1 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD MAY 4 PY 2013 VL 8 AR UNSP 16 DI 10.1186/1750-9378-8-16 PG 4 WC Oncology; Immunology SC Oncology; Immunology GA 241JT UT WOS:000326163700002 PM 23642130 ER PT J AU Resnik, DB Elliott, KC AF Resnik, David B. Elliott, Kevin C. TI Taking Financial Relationships into Account When Assessing Research SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Article DE bias; conflict of interest; disclosure policies; financial relationships; objectivity; scientific research ID CONFLICT-OF-INTEREST; INTEREST POLICIES; MEDICAL JOURNALS; BIOMEDICAL-RESEARCH; INTEREST DISCLOSURE; RANDOMIZED-TRIAL; PUBLICATION BIAS; CHEMICAL SAFETY; INDUSTRY; SCIENCE AB Many scientific journals, government agencies, and universities require disclosure of sources of funding and financial interests related to research, such as stock ownership, consulting arrangements with companies, and patents. Although disclosure has become one of the central approaches for responding to financial conflicts of interest (COIs) in research, critics contend that information about financial COIs does not serve as a reliable indicator of research credibility, and therefore, studies should be evaluated solely based on their scientific merits. We argue that, while it is indeed important to evaluate studies on their scientific merits, it is often difficult to detect significant influences of financial relationships that affect research credibility. Moreover, at least five factors can be examined to determine whether financial relationships are likely to enhance, undermine, or have no impact on the credibility of research. These include as follows: whether sponsors, institutions, or researchers have a significant financial stake in the outcome of a study; whether the financial interests of the sponsors, institutions, or researchers coincide with the goal of conducting research that is objective and reliable; whether the sponsor, institution, or researchers have a history of biasing research in order to promote their financial goals; how easy it is to manipulate the research in order to achieve financial goals; and whether oversight mechanisms are in place which are designed to minimize bias. Since these factors vary from case to case, evaluating the impact of financial relationships depends on the circumstances. In some situations, one may decide that the financial relationships significantly undermine the study's credibility; in others, one may decide that they have no impact on credibility or even enhance it. C1 [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Elliott, Kevin C.] Univ S Carolina, Dept Philosophy, Columbia, SC 29208 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-05] NR 74 TC 16 Z9 17 U1 2 U2 19 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0898-9621 J9 ACCOUNT RES JI Account. Res. PD MAY 4 PY 2013 VL 20 IS 3 BP 184 EP 205 DI 10.1080/08989621.2013.788383 PG 22 WC Medical Ethics SC Medical Ethics GA 159WD UT WOS:000320077100003 PM 23672544 ER PT J AU Ma, HY Lu, YN Malone, KE Marchbanks, PA Deapen, DM Spirtas, R Burkman, RT Strom, BL McDonald, JA Folger, SG Simon, MS Sullivan-Halley, J Press, MF Bernstein, L AF Ma, Huiyan Lu, Yani Malone, Kathleen E. Marchbanks, Polly A. Deapen, Dennis M. Spirtas, Robert Burkman, Ronald T. Strom, Brian L. McDonald, Jill A. Folger, Suzanne G. Simon, Michael S. Sullivan-Halley, Jane Press, Michael F. Bernstein, Leslie TI Mortality risk of black women and white women with invasive breast cancer by hormone receptors, HER2, and p53 status SO BMC CANCER LA English DT Article DE Breast cancer; Mortality; Racial disparity; Triple negative; Luminal A; ER; PR; HER2; p53 ID REPRODUCTIVE EXPERIENCES; PROGESTERONE-RECEPTOR; ESTROGEN-RECEPTOR; TUMOR SUBTYPES; SURVIVAL; RACE; MUTATIONS; EXPRESSION; GENE; OVEREXPRESSION AB Background: Black women are more likely than white women to have an aggressive subtype of breast cancer that is associated with higher mortality and this may contribute to the observed black-white difference in mortality. However, few studies have investigated the black-white disparity in mortality risk stratified by breast cancer subtype, defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Furthermore, it is not known whether additional consideration of p53 protein status influences black-white differences in mortality risk observed when considering subtypes defined by ER, PR and HER2 status. Methods: Four biomarkers were assessed by immunohistochemistry in paraffin-embedded breast tumor tissue from 1,204 (523 black, 681 white) women with invasive breast cancer, aged 35-64 years at diagnosis, who accrued a median of 10 years' follow-up. Multivariable Cox proportional hazards regression models were fit to assess subtype-specific black-white differences in mortality risk. Results: No black-white differences in mortality risk were observed for women with triple negative (ER-negative [ER-], PR-, and HER2-) subtype. However, older (50-64 years) black women had greater overall mortality risk than older white women if they had been diagnosed with luminal A (ER-positive [ER+] or PR+ plus HER2-) breast cancer (all-cause hazard ratio, HR, 1.88; 95% confidence interval, CI, 1.18 to 2.99; breast cancer-specific HR, 1.51; 95% CI, 0.83 to 2.74). This black-white difference among older women was further confined to those with luminal A/p53-tumors (all-cause HR, 2.22; 95% CI, 1.30 to 3.79; breast cancer-specific HR, 1.89; 95% CI, 0.93 to 3.86). Tests for homogeneity of race-specific HRs comparing luminal A to triple negative subtype and luminal A/p53- to luminal A/p53+ subtype did not achieve statistical significance, although statistical power was limited. Conclusions: Our findings suggest that the subtype-specific black-white difference in mortality risk occurs mainly among older women diagnosed with luminal A/p53-breast cancer, which is most likely treatable. These results further suggest that factors other than subtype may be relatively more important in explaining the increased mortality risk seen in older black women. C1 [Ma, Huiyan; Lu, Yani; Sullivan-Halley, Jane; Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. [Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Marchbanks, Polly A.; McDonald, Jill A.; Folger, Suzanne G.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30333 USA. [Deapen, Dennis M.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90033 USA. [Press, Michael F.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Spirtas, Robert] Natl Inst Child Hlth & Dev, Formerly Contracept & Reprod Hlth Branch, Populat Res Ctr, Bethesda, MD 20892 USA. [Burkman, Ronald T.] Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA 01199 USA. [Strom, Brian L.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Simon, Michael S.] Wayne State Univ, Dept Oncol, Karmanos Canc Inst, Detroit, MI 48201 USA. RP Ma, HY (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. EM hma@coh.org FU National Institute for Child Health and Human Development [NO1-HD-3-3175]; National Cancer Institute [K05-CA136967]; National Cancer Institute, NIH; Emory University [N01-HD-3-3168]; Fred Hutchinson Cancer Research Center [N01-HD-2-3166]; Karmanos Cancer Institute at Wayne State University [N01-HD-3-3174]; University of Pennsylvania [NO1-HD-3-3276]; University of Southern California [N01-HD-3-3175]; Interagency Agreement with Centers for Disease Control and Prevention [Y01-HD-7022]; California Department of Health Services; Breast Cancer Research Foundation; [N01-CN-65064]; [N01-PC-67010] FX This work was supported by National Institute for Child Health and Human Development grant NO1-HD-3-3175 and National Cancer Institute grant K05-CA136967. Data collection for the Women's CARE Study was supported by the National Institute of Child Health and Human Development and National Cancer Institute, NIH, through contracts with Emory University (N01-HD-3-3168), Fred Hutchinson Cancer Research Center (N01-HD-2-3166), Karmanos Cancer Institute at Wayne State University (N01-HD-3-3174), University of Pennsylvania (NO1-HD-3-3276), and University of Southern California (N01-HD-3-3175) and Interagency Agreement with Centers for Disease Control and Prevention (Y01-HD-7022). Collection of cancer incidence data in LA County by University of Southern California was supported by California Department of Health Services as part of statewide cancer reporting program mandated by California Health and Safety Code, Section 103885. Support for use of SEER cancer registries through contracts N01-CN-65064 (Detroit) and N01-PC-67010 (LA). Biomarker determination and analyses were supported by a contract from the National Institute of Child Health and Human Development (NO1-HD-3-3175) and a grant from the Breast Cancer Research Foundation (MFPress). NR 59 TC 12 Z9 12 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 4 PY 2013 VL 13 AR 225 DI 10.1186/1471-2407-13-225 PG 11 WC Oncology SC Oncology GA 140TQ UT WOS:000318678600001 PM 23642215 ER PT J AU Dallas, S Block, ML Thompson, DM Bonini, MG Ronaldson, PT Bendayan, R Miller, DS AF Dallas, Shannon Block, Michelle L. Thompson, Deborah M. Bonini, Marcelo G. Ronaldson, Patrick T. Bendayan, Reina Miller, David S. TI Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Drug transporters; HIV; Inflammation; MEK1/2; Microglia; Multidrug resistance proteins; NF-kappa beta; P-glycoprotein; Saquinavir; Solute carrier uptake transporters; Toll-like receptor ID BLOOD-BRAIN-BARRIER; MULTIDRUG-RESISTANCE PROTEIN-1; CENTRAL-NERVOUS-SYSTEM; NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; P-GLYCOPROTEIN; FUNCTIONAL EXPRESSION; RAT-BRAIN; MONOCLONAL-ANTIBODIES; INFLAMMATORY RESPONSE AB Background: Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide. Methods: To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent microglia exposed to the prototypical inflammatory mediator lipopolysaccharide (LPS). Results: [H-3]-Saquinavir accumulation by microglia was rapid, and was increased up to two-fold in the presence of the specific P-glycoprotein inhibitor, PSC833. After six or 24 hours of exposure to 10 ng/ml LPS, saquinavir accumulation was decreased by up to 45%. LPS did not directly inhibit saquinavir transport, and did not affect P-glycoprotein protein expression. LPS exposure did not alter RNA and/or protein expression of other transporters including multidrug resistance-associated protein 1 and several solute carrier uptake transporters. Conclusions: The decrease in saquinavir accumulation in microglia following treatment with LPS is likely multi-factorial, since drug accumulation was attenuated by inhibitors of NF-kappa beta and the MEK1/2 pathway in the microglia cell line HAPI, and in primary microglia cultures from toll-like receptor 4 deficient mice. These data provide new pharmacological insights into why microglia act as a difficult-to-treat viral sanctuary site. C1 [Dallas, Shannon; Thompson, Deborah M.; Bonini, Marcelo G.; Miller, David S.] NIH, Nat Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Dallas, Shannon] Janssen R&D, Drug Safety Sci, Drug Metab & Pharmacokinet, Spring House, PA USA. [Block, Michelle L.] Virginia Commonwealth Univ Med Campus, Dept Anat & Neurobiol, Richmond, VA USA. [Thompson, Deborah M.] North Carolina Biotechnol Ctr, Res Triangle Pk, NC USA. [Bonini, Marcelo G.] Univ Illinois, Cardiol Sect, Chicago, IL USA. [Bonini, Marcelo G.] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL USA. [Ronaldson, Patrick T.; Bendayan, Reina] Univ Toronto, Fac Pharm, Dept Pharmaceut Sci, Toronto, ON, Canada. [Ronaldson, Patrick T.] Univ Arizona, Coll Med, Dept Med Pharmacol, Tucson, AZ USA. RP Dallas, S (reprint author), NIH, Nat Inst Environm Hlth Sci, Res Triangle Pk, NC USA. EM sdallas@its.jnj.com FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health FX Funded by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. The authors wish to thank Shannon Levesque and Destiny Sykes for their excellent technical support. NR 46 TC 1 Z9 1 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAY 4 PY 2013 VL 10 AR 58 DI 10.1186/1742-2094-10-58 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 143FV UT WOS:000318853100001 PM 23642074 ER PT J AU Ikeda, H Delargy, AH Yokogawa, T Urban, JM Burgess, HA Ono, F AF Ikeda, Hiromi Delargy, Alison H. Yokogawa, Tohei Urban, Jason M. Burgess, Harold A. Ono, Fumihito TI Intrinsic Properties of Larval Zebrafish Neurons in Ethanol SO PLOS ONE LA English DT Article ID DANIO-RERIO; LOCOMOTOR-ACTIVITY; MODEL SYSTEM; ALCOHOL; HINDBRAIN; BEHAVIOR; APOPTOSIS; EXPOSURE; MAUTHNER; EMBRYOS AB The behavioral effects of ethanol have been studied in multiple animal models including zebrafish. Locomotion of zebrafish larvae is resistant to high concentrations of ethanol in bath solution. This resistance has been attributed to a lower systemic concentration of ethanol in zebrafish when compared with bath solution, although the mechanism to maintain such a steep gradient is unclear. Here we examined whether the intrinsic properties of neurons play roles in this resistance. In order to minimize the contribution of metabolism and diffusional barriers, larvae were hemisected and the anterior half immersed in a range of ethanol concentrations thereby ensuring the free access of bath ethanol to the brain. The response to vibrational stimuli of three types of reticulospinal neurons: Mauthner neurons, vestibulospinal neurons, and MiD3 neurons were examined using an intracellular calcium indicator. The intracellular [Ca2+] response in MiD3 neurons decreased in 100 mM ethanol, while Mauthner neurons and vestibulospinal neurons required >300 mM ethanol to elicit similar effects. The ethanol effect in Mauthner neurons was reversible following removal of ethanol. Interestingly, activities of MiD3 neurons displayed spontaneous recovery in 300 mM ethanol, suggestive of acute tolerance. Finally, we examined with mechanical vibration the startle response of free-swimming larvae in 300 mM ethanol. Ethanol treatment abolished long latency startle responses, suggesting a functional change in neural processing. These data support the hypothesis that individual neurons in larval zebrafish brains have distinct patterns of response to ethanol dictated by specific molecular targets. C1 [Ikeda, Hiromi; Delargy, Alison H.; Urban, Jason M.; Ono, Fumihito] NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, NIH, Rockville, MD 20852 USA. [Yokogawa, Tohei; Burgess, Harold A.] NICHD, Unit Behav Neurogenet, NIH, Bethesda, MD USA. RP Ono, F (reprint author), NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, NIH, Rockville, MD 20852 USA. EM onof@mail.nih.gov RI Burgess, Harold/B-8474-2015 OI Burgess, Harold/0000-0003-1966-7801 FU intramural program at the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the intramural program at the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 8 Z9 8 U1 1 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 MAY 3 PY 2013 VL 8 IS 5 AR e63318 DI 10.1371/journal.pone.0063318 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 175AS UT WOS:000321202100062 PM 23658822 ER PT J AU Knockel, J Molina-Cruz, A Fischer, E Muratova, O Haile, A Barillas-Mury, C Miller, LH AF Knoeckel, Julia Molina-Cruz, Alvaro Fischer, Elizabeth Muratova, Olga Haile, Ashley Barillas-Mury, Carolina Miller, Louis H. TI An Impossible Journey? The Development of Plasmodium falciparum NF54 in Culex quinquefasciatus SO PLOS ONE LA English DT Article ID COMPLEMENT-LIKE PROTEIN; HUMAN MALARIA PARASITES; VECTOR ANOPHELES-GAMBIAE; VALLEY FEVER VIRUS; OOKINETE INVASION; ENTOMOLOGIC INVESTIGATIONS; REFRACTORY STRAIN; MIDGUT EPITHELIUM; MOSQUITOS DIPTERA; FEEDING PATTERNS AB Although Anopheles mosquitoes are the vectors for human Plasmodium spp., there are also other mosquito species-among them culicines (Culex spp., Aedes spp.)-present in malaria-endemic areas. Culicine mosquitoes transmit arboviruses and filarial worms to humans and are vectors for avian Plasmodium spp., but have never been observed to transmit human Plasmodium spp. When ingested by a culicine mosquito, parasites could either face an environment that does not allow development due to biologic incompatibility or be actively killed by the mosquito's immune system. In the latter case, the molecular mechanism of killing must be sufficiently powerful that Plasmodium is not able to overcome it. To investigate how human malaria parasites develop in culicine mosquitoes, we infected Culex quinquefasciatus with Plasmodium falciparum NF54 and monitored development of parasites in the blood bolus and midgut epithelium at different time points. Our results reveal that ookinetes develop in the midgut lumen of C. quinquefasciatus in slightly lower numbers than in Anopheles gambiae G3. After 30 hours, parasites have invaded the midgut and can be observed on the basal side of the midgut epithelium by confocal and transmission electron microscopy. Very few of the parasites in C. quinquefasciatus are alive, most of them are lysed. Eight days after the mosquito's blood meal, no oocysts can be found in C. quinquefasciatus. Our results suggest that the mosquito immune system could be involved in parasite killing early in development after ookinetes have crossed the midgut epithelium and come in contact with the mosquito hemolymph. C1 [Knoeckel, Julia; Molina-Cruz, Alvaro; Haile, Ashley; Barillas-Mury, Carolina; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Fischer, Elizabeth] NIAID, Rocky Mt Labs, Elect Microscopy Unit, Res Technol Branch,NIH, Hamilton, MT 59840 USA. [Muratova, Olga] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. RP Knockel, J (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM julia.knoeckel@gmail.com; lmiller@niaid.nih.gov OI Knoeckel, Julia/0000-0001-6688-7714 FU National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 4 Z9 4 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 MAY 3 PY 2013 VL 8 IS 5 AR e63387 DI 10.1371/journal.pone.0063387 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 175AS UT WOS:000321202100065 PM 23658824 ER PT J AU Kuroiwa, Y Takakusagi, Y Kusayanagi, T Kuramochi, K Imai, T Hirayama, T Ito, I Yoshida, M Sakaguchi, K Sugawara, F AF Kuroiwa, Yuki Takakusagi, Yoichi Kusayanagi, Tomoe Kuramochi, Kouji Imai, Takahiko Hirayama, Tomoko Ito, Ichiaki Yoshida, Michiteru Sakaguchi, Kengo Sugawara, Fumio TI Identification and Characterization of the Direct Interaction between Methotrexate (MTX) and High-Mobility Group Box 1 (HMGB1) Protein SO PLOS ONE LA English DT Article ID RHEUMATOID-ARTHRITIS; AFFINITY PURIFICATION; BIOTIN DERIVATIVES; CYTOKINE ACTIVITY; BINDING PEPTIDE; RECEPTOR; DNA; ACTIVATION; AMPHOTERIN; DISEASE AB Background: Methotrexate (MTX) is an agent used in chemotherapy of tumors and autoimmune disease including rheumatoid arthritis (RA). In addition, MTX has some anti-inflammatory activity. Although dihydrofolate reductase (DHFR) is a well-known target for the anti-tumor effect of MTX, the mode of action for the anti-inflammatory activity of MTX is not fully understood. Methodology/Result: Here, we performed a screening of MTX-binding proteins using T7 phage display with a synthetic biotinylated MTX derivative. We then characterized the interactions using surface plasmon resonance (SPR) analysis and electrophoretic mobility shift assay (EMSA). Using a T7 phage display screen, we identified T7 phages that displayed part of high-mobility group box 1 (HMGB1) protein (K86-V175). Binding affinities as well as likely binding sites were characterized using genetically engineered truncated versions of HMGB1 protein (Al G1-K87, Bj: F88-K181), indicating that MTX binds to HMGB1 via two independent sites with a dissociation constants (K-D) of 0.50 +/- 0.03 mu M for Al and 0.24 +/- 0.01 mu M for Bj. Although MTX did not inhibit the binding of HMGB1 to DNA via these domains, HMGB1/RAGE association was impeded in the presence of MTX. These data suggested that binding of MTX to part of the RAGE-binding region (K149-V175) in HMGB1 might be significant for the anti-inflammatory effect of MTX. Indeed, in murine macrophage-like cells (RAW 264.7), TNF-alpha release and mitogenic activity elicited by specific RAGE stimulation with a truncated monomeric HMGB1 were inhibited in the presence of MTX. Conclusions/Significance: These data demonstrate that HMGB1 is a direct binding protein of MTX. Moreover, binding of MTX to RAGE-binding region in HMGB1 inhibited the HMGB1/RAGE interaction at the molecular and cellular levels. These data might explain the molecular basis underlying the mechanism of action for the anti-inflammatory effect of MTX. C1 [Kuroiwa, Yuki; Takakusagi, Yoichi; Kusayanagi, Tomoe; Kuramochi, Kouji; Imai, Takahiko; Hirayama, Tomoko; Sakaguchi, Kengo; Sugawara, Fumio] Tokyo Univ Sci, Fac Sci & Technol, Dept Appl Biol Sci, Noda, Chiba 278, Japan. [Ito, Ichiaki; Yoshida, Michiteru] Tokyo Univ Sci, Fac Ind Sci & Technol, Dept Biol Sci & Technol, Noda, Chiba 278, Japan. [Takakusagi, Yoichi] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD USA. RP Sugawara, F (reprint author), Tokyo Univ Sci, Fac Sci & Technol, Dept Appl Biol Sci, Noda, Chiba 278, Japan. EM sugawara@rs.noda.tus.ac.jp FU The Ministry of Education, Culture, Sports, Science and Technology of Japan, Japan Society for the Promotion of Science; Tokyo University of Science FX This work was supported by a Grant-in-Aid for Scientific Research (The Ministry of Education, Culture, Sports, Science and Technology of Japan, Japan Society for the Promotion of Science), and research grant from Tokyo University of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 14 Z9 16 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 3 PY 2013 VL 8 IS 5 AR e63073 DI 10.1371/journal.pone.0063073 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 175AS UT WOS:000321202100051 PM 23658798 ER PT J AU Valdes, JJ Schwarz, A de Vaca, IC Calvo, E Pedra, JHF Guallar, V Kotsyfakis, M AF Valdes, James J. Schwarz, Alexandra Cabeza de Vaca, Israel Calvo, Eric Pedra, Joao H. F. Guallar, Victor Kotsyfakis, Michalis TI Tryptogalinin Is a Tick Kunitz Serine Protease Inhibitor with a Unique Intrinsic Disorder SO PLOS ONE LA English DT Article ID MAST-CELL TRYPTASE; HORSEFLY SALIVARY-GLANDS; ATOM FORCE-FIELD; IXODES-SCAPULARIS; SOFT TICK; STRUCTURE PREDICTION; ORNITHODOROS-SAVIGNYI; PLATELET-AGGREGATION; SIALOSTATIN-L; FACTOR-XA AB Background: A salivary proteome-transcriptome project on the hard tick Ixodes scapularis revealed that Kunitz peptides are the most abundant salivary proteins. Ticks use Kunitz peptides (among other salivary proteins) to combat host defense mechanisms and to obtain a blood meal. Most of these Kunitz peptides, however, remain functionally uncharacterized, thus limiting our knowledge about their biochemical interactions. Results: We discovered an unusual cysteine motif in a Kunitz peptide. This peptide inhibits several serine proteases with high affinity and was named tryptogalinin due to its high affinity for beta-tryptase. Compared with other functionally described peptides from the Acari subclass, we showed that tryptogalinin is phylogenetically related to a Kunitz peptide from Rhipicephalus appendiculatus, also reported to have a high affinity for b-tryptase. Using homology-based modeling (and other protein prediction programs) we were able to model and explain the multifaceted function of tryptogalinin. The N-terminus of the modeled tryptogalinin is detached from the rest of the peptide and exhibits intrinsic disorder allowing an increased flexibility for its high affinity with its inhibiting partners (i.e., serine proteases). Conclusions: By incorporating experimental and computational methods our data not only describes the function of a Kunitz peptide from Ixodes scapularis, but also allows us to hypothesize about the molecular basis of this function at the atomic level. C1 [Valdes, James J.; Schwarz, Alexandra; Kotsyfakis, Michalis] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, CR-37005 Ceske Budejovice, Czech Republic. [Cabeza de Vaca, Israel; Guallar, Victor] Barcelona Supercomp Ctr, Res Program Computat Biol, Inst Res Biomed BSC IRB, Joint Barcelona Supercomp Ctr, Barcelona, Spain. [Cabeza de Vaca, Israel; Guallar, Victor] ICREA, Barcelona, Spain. [Calvo, Eric] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Pedra, Joao H. F.] Univ Calif Riverside, Ctr Dis Vector Res, Riverside, CA 92521 USA. [Pedra, Joao H. F.] Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA. RP Valdes, JJ (reprint author), Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, Branisovska 31, CR-37005 Ceske Budejovice, Czech Republic. EM valdjj@gmail.com RI Kotsyfakis, Michail/G-9525-2014; Valdes, James/G-9812-2014; Guallar, Victor/B-1579-2013; OI Kotsyfakis, Michail/0000-0002-7526-1876; Valdes, James/0000-0002-0237-8061; Guallar, Victor/0000-0002-4580-1114; Pedra, Joao/0000-0001-8740-2667; Calvo, Eric/0000-0001-7880-2730 FU European Social Fund; state budget of the Czech Republic; Grant Agency of the Czech Republic [P302/11/P798]; Ministry of Education, Youth and Sports of the Czech Republic [LH12002]; Academy of Sciences of the Czech Republic; European Project [ERC-2009-Adg 25027-PELE]; Academy of Sciences of the Czech Republic [Z60220518, P502/12/2409]; European Union [PIRG07-GA-2010-268177]; National Institutes of Health, USA; [CZ.1.07/2.3.00/30.0032] FX JJV was sponsored by project CZ.1.07/2.3.00/30.0032, co-financed by the European Social Fund and the state budget of the Czech Republic. AS was funded by the Grant Agency of the Czech Republic (Grant No. P302/11/P798) and the Ministry of Education, Youth and Sports of the Czech Republic (KONTAKT II grant no. LH12002), and MK received support from the Academy of Sciences of the Czech Republic (Jan Evangelista Purkyne Fellowship). Computational resources were provided by the Barcelona Supercomputing Center and the work was supported by the ERC-2009-Adg 25027-PELE European Project. The authors also want to acknowledge the financial support of the Academy of Sciences of the Czech Republic (grant no. Z60220518 and P502/12/2409), the 7th Framework Program of the European Union (Marie Curie Reintegration grant, grant no. PIRG07-GA-2010-268177). Because Extramural Funds from the National Institutes of Health, USA, supported this work and because EC is a government employee, this is also considered a government work (in the USA public domain). Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMed Central for display and use by the public. PubMed Central may tag or modify the work consistent with its customary practices. Rights can be established outside of the USA subject to a government use license. NR 79 TC 13 Z9 14 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 MAY 3 PY 2013 VL 8 IS 5 AR e62562 DI 10.1371/journal.pone.0062562 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 175AS UT WOS:000321202100017 PM 23658744 ER PT J AU Swaminathan, S Hu, XJ Zheng, X Kriga, Y Shetty, J Zhao, YM Stephens, R Tran, B Baseler, MW Yang, J Lempicki, RA Huang, DW Lane, HC Imamichi, T AF Swaminathan, Sanjay Hu, Xiaojun Zheng, Xin Kriga, Yuliya Shetty, Jyoti Zhao, Yongmei Stephens, Robert Bao Tran Baseler, Michael W. Yang, Jun Lempicki, Richard A. Huang, Dawei Lane, H. Clifford Imamichi, Tomozumi TI Interleukin-27 treated human macrophages induce the expression of novel microRNAs which may mediate anti-viral properties SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Interleukin-27; Macrophages; microRNAs; HIV; HSV-1; HSV-2; HHV-8 ID CELLULAR MICRORNAS; HIV-1 INFECTION; SEQUENCING DATA; TARGETS; IL-27; INTERFERON; GENES; CELLS; CYTOSKELETON; FAMILY AB Interleukin-27 (IL-27) is a pleiotropic cytokine which plays important and diverse roles in the immune system. We have previously demonstrated that IL-27 induces potent anti-viral effects against HIV-1, HIV-2, SIV, HSV-2, KSHV and influenza viruses in macrophages. This induction occurred in an interferon (IFN) independent manner and involved down regulation of SPTBN1. MicroRNAs (miRNAs) are critical regulators of mRNA translation and turnover. There have been reports that some miRNAs inhibit viral replication. In this study, we hypothesized that IL-27 could induce the expression of novel miRNAs in macrophages which may have functional relevance in terms of anti-viral activity and primary monocytes were differentiated into macrophages using either M-CSF (M-Mac) or a combination of M-CSF and IL-27 (I-Mac) for seven days. Following this, total RNA was extracted from these cells and deep sequencing was performed, in parallel with gene expression microarrays. Using the novel miRNA discovery software, miRDeep, seven novel miRNAs were discovered in these macrophages. Four of which were preferentially expressed in I-Mac (miR-SX1, -SX2, -SX3 and -SX6) whilst three were detected in both M-Mac and I-Mac (miR-SX4, -SX5 and -SX7). The expression of six of the seven novel miRNAs was highly correlated with qRT-PCR using specific primer/probes designed for the novel miRNAs. Gene expression microarray further demonstrated that a number of genes were potentially targeted by these differentially expressed novel miRNAs. Finally, several of these novel miRNAs (miR-SX1, -SX4, -SX5, -SX6 and -SX7) were shown to target the open reading frames of a number of viruses (including HSV-1, HSV-2 and HHV-8) which may partially explain the anti-viral properties observed. (c) 2013 Elsevier Inc. All rights reserved. C1 [Swaminathan, Sanjay; Hu, Xiaojun; Zheng, Xin; Baseler, Michael W.; Yang, Jun; Lempicki, Richard A.; Huang, Dawei; Imamichi, Tomozumi] Sci Applicat Int Corp SAIC Frederick Inc, Frederick Natl Lab Canc Res, Appl & Dev Res Directorate, Frederick, MD 21702 USA. [Kriga, Yuliya; Shetty, Jyoti; Bao Tran] SAIC Frederick Inc, FNLCR, Adv Technol Program Directorate, Frederick, MD 21702 USA. [Zhao, Yongmei; Stephens, Robert] SAIC Frederick Inc, FNLCR, Informat Syst Program Directorate, Frederick, MD 21702 USA. [Lane, H. Clifford] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Imamichi, T (reprint author), SAIC Frederick Inc, Lab Human Retrovirol, Frederick Natl Lab Canc Res, Bldg 550,Room 126,1050 Boyles St, Frederick, MD 21702 USA. EM timamichi@mail.nih.gov RI 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 We thank Alicia Gussio for assistance for supplying materials. 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. NR 25 TC 13 Z9 19 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 3 PY 2013 VL 434 IS 2 BP 228 EP 234 DI 10.1016/j.bbrc.2013.03.046 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 146NW UT WOS:000319098800008 PM 23535375 ER PT J AU McNeill, DR Paramasivam, M Baldwin, J Huang, J Vyjayanti, VN Seidman, MM Wilson, DM AF McNeill, Daniel R. Paramasivam, Manikandan Baldwin, Jakita Huang, Jing Vyjayanti, Vaddadi N. Seidman, Michael M. Wilson, David M., III TI NEIL1 Responds and Binds to Psoralen-induced DNA Interstrand Crosslinks SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; DAMAGE RESPONSE; HUMAN-CELLS; GLYCOSYLASE; DISEASE; BIOLOGY; CANCER AB Recent evidence suggests a role for base excision repair (BER) proteins in the response to DNA interstrand crosslinks, which block replication and transcription, and lead to cell death and genetic instability. Employing fluorescently tagged fusion proteins and laser microirradiation coupled with confocal microscopy, we observed that the endonuclease VIII-like DNA glycosylase, NEIL1, accumulates at sites of oxidative DNA damage, as well as trioxsalen (psoralen)-induced DNA interstrand crosslinks, but not to angelicin monoadducts. While recruitment to the oxidative DNA lesions was abrogated by the anti-oxidant N-acetylcysteine, this treatment did not alter the accumulation of NEIL1 at sites of interstrand crosslinks, suggesting distinct recognition mechanisms. Consistent with this conclusion, recruitment of the NEIL1 population variants, G83D, C136R, and E181K, to oxidative DNA damage and psoralen-induced interstrand crosslinks was differentially affected by the mutation. NEIL1 recruitment to psoralen crosslinks was independent of the nucleotide excision repair recognition factor, XPC. Knockdown of NEIL1 in LN428 glioblastoma cells resulted in enhanced recruitment of XPC, a more rapid removal of digoxigenin-tagged psoralen adducts, and decreased cellular sensitivity to trioxsalen plus UVA, implying that NEIL1 and BER may interfere with normal cellular processing of interstrand crosslinks. While exhibiting no enzymatic activity, purified NEIL1 protein bound stably to psoralen interstrand crosslink-containing synthetic oligonucleotide substrates in vitro. Our results indicate that NEIL1 recognizes specifically and distinctly interstrand crosslinks in DNA, and can obstruct the efficient removal of lethal crosslink adducts. C1 [McNeill, Daniel R.; Paramasivam, Manikandan; Huang, Jing; Vyjayanti, Vaddadi N.; Seidman, Michael M.; Wilson, David M., III] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Baldwin, Jakita] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov FU National Institutes of Health, National Institute on Aging FX This research was supported in whole by the Intramural Research Program at the National Institutes of Health, National Institute on Aging. NR 24 TC 7 Z9 7 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 3 PY 2013 VL 288 IS 18 BP 12426 EP 12436 DI 10.1074/jbc.M113.456087 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139AZ UT WOS:000318555100002 PM 23508956 ER PT J AU Tonkin, ML Arredondo, SA Loveless, BC Serpa, JJ Makepeace, KAT Sundar, N Petrotchenko, EV Miller, LH Grigg, ME Boulanger, MJ AF Tonkin, Michelle L. Arredondo, Silvia A. Loveless, Bianca C. Serpa, Jason J. Makepeace, Karl A. T. Sundar, Natarajan Petrotchenko, Evgeniy V. Miller, Louis H. Grigg, Michael E. Boulanger, Martin J. TI Structural and Biochemical Characterization of Plasmodium falciparum 12 (Pf12) Reveals a Unique Interdomain Organization and the Potential for an Antiparallel Arrangement with Pf41 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GAMETE-SURFACE PROTEIN; TRANSMISSION-BLOCKING IMMUNITY; MULTIPLE SEQUENCE ALIGNMENT; TOXOPLASMA-GONDII; BALANCING SELECTION; MAXIMUM-LIKELIHOOD; MALARIA PARASITES; SRS SUPERFAMILY; TARGET ANTIGEN; PFS230 AB Plasmodium falciparum is the most devastating agent of human malaria. A major contributor to its virulence is a complex lifecycle with multiple parasite forms, each presenting a different repertoire of surface antigens. Importantly, members of the 6-Cys s48/45 family of proteins are found on the surface of P. falciparum in every stage, and several of these antigens have been investigated as vaccine targets. Pf12 is the archetypal member of the 6-Cys protein family, containing just two s48/45 domains, whereas other members have up to 14 of these domains. Pf12 is strongly recognized by immune sera from naturally infected patients. Here we show that Pf12 is highly conserved and under purifying selection. Immunofluorescence data reveals a punctate staining pattern with an apical organization in late schizonts. Together, these data are consistent with an important functional role for Pf12 in parasite-host cell attachment or invasion. To infer the structural and functional diversity between Pf12 and the other 11 6-Cys domain proteins, we solved the 1.90A resolution crystal structure of the Pf12 ectodomain. Structural analysis reveals a unique organization between the membrane proximal and membrane distal domains and clear homology with the SRS-domain containing proteins of Toxoplasma gondii. Cross-linking and mass spectrometry confirm the previously identified Pf12-Pf41 heterodimeric complex, and analysis of individual cross-links supports an unexpected antiparallel organization. Collectively, the localization and structure of Pf12 and details of its interaction with Pf41 reveal important insight into the structural and functional properties of this archetypal member of the 6-Cys protein family. C1 [Tonkin, Michelle L.; Loveless, Bianca C.; Boulanger, Martin J.] Univ Victoria, Victoria, BC V8W 3P6, Canada. [Arredondo, Silvia A.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Serpa, Jason J.; Makepeace, Karl A. T.; Petrotchenko, Evgeniy V.] Univ Victoria, Genome British Columbia Prote Ctr, Victoria, BC V8Z 7X8, Canada. [Sundar, Natarajan; Grigg, Michael E.] NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Boulanger, MJ (reprint author), Univ Victoria, POB 3055 STN CSC, Victoria, BC V8W 3P6, Canada. EM mboulang@uvic.ca FU Canadian Institutes of Health Research [MOP82915]; NIAID, National Institutes of Health; Natural Sciences and Engineering Research Council of Canada [CGS-D3]; Genome Canada/Genome British Columbia Technology Development Grant FX This work was supported, in whole or in part, by Canadian Institutes of Health Research Grant MOP82915 (to M.J.B.). This work was also supported by the intramural funds of the NIAID, National Institutes of Health (to L.H.M.); Supported by a Natural Sciences and Engineering Research Council of Canada Alexander Graham Bell Canada Graduate Scholarship (CGS-D3).; Supported by a Genome Canada/Genome British Columbia Technology Development Grant. NR 68 TC 23 Z9 25 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 MAY 3 PY 2013 VL 288 IS 18 BP 12805 EP 12817 DI 10.1074/jbc.M113.455667 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139AZ UT WOS:000318555100036 PM 23511632 ER PT J AU Chiu, JC Kaub, K Zou, S Liedo, P Altamirano-Robles, L Ingram, D Carey, JR AF Chiu, Joanna C. Kaub, Kevin Zou, Sige Liedo, Pablo Altamirano-Robles, Leopoldo Ingram, Donald Carey, James R. TI Deleterious effect of suboptimal diet on rest-activity cycle in Anastrepha ludens manifests itself with age SO SCIENTIFIC REPORTS LA English DT Article ID DROSOPHILA-MELANOGASTER; BEHAVIORAL RHYTHMS; LOCOMOTOR BEHAVIOR; VIDEO-TRACKING; REDUCED SLEEP; FRUIT-FLY; LIFE-SPAN; MUTANTS; LONGEVITY; GRADIENTS AB Activity patterns and sleep-wake cycles are among the physiological processes that change most prominently as animals age, and are often good indicators of healthspan. In this study, we used the video-based high-resolution Behavioral Monitoring System (BMS) to monitor the daily activity cycle of tephritid fruit flies Anastrepha ludens over their lifetime. Surprisingly, there was no dramatic change in activity profile with respect to age if flies were consistently fed with a nutritionally balanced diet. However, if flies were fed with sugar-only diet, their activity profile decreased in amplitude at old age, suggesting that suboptimal diet affected activity patterns, and its detrimental effect may not manifest itself until the animal ages. Moreover, by simulating different modes of behavior monitoring with a range of resolution and comparing the resulting conclusions, we confirmed the superior performance of video-based monitoring using high-resolution BMS in accurately representing activity patterns in an insect model. C1 [Chiu, Joanna C.; Kaub, Kevin; Carey, James R.] Univ Calif Davis, Coll Agr & Environm Sci, Dept Entomol, Davis, CA 95616 USA. [Zou, Sige] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Liedo, Pablo] El Colegio Frontera Sur ECOSUR, Dept Entomol, Tapachula, Chiapas, Mexico. [Altamirano-Robles, Leopoldo] INAOE, Comp Vis Lab, Puebla, Mexico. [Ingram, Donald] Louisiana State Univ, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. RP Carey, JR (reprint author), Univ Calif Davis, Coll Agr & Environm Sci, Dept Entomol, Davis, CA 95616 USA. EM jrcarey@ucdavis.edu RI Liedo, Pablo/E-9313-2010 OI Liedo, Pablo/0000-0002-0004-1721 FU NIH [P01 AG022500-01, P01 AG08761-10, NS069542]; Intramural Research Program of NIA, NIH FX We thank A. Oropeza, R. Bustamente, E. de Leon, S. Rodriguez, R. Rincon and G. Rodas for excellent technical support and G. Olivera-Romero, S. Soriano-Monje and D. Tenorio-Perez for assistance in the development of the BMS at INAOE. The Moscamed-Moscafrut facility (DGSV, SENASICA) in Metapa, Chiapas, Mexico, for providing mexflies and lab space. This work was supported by NIH P01 AG022500-01 and P01 AG08761-10 to J.R.C.; the Intramural Research Program of NIA, NIH to S.Z.; and NIH NS069542 to J.C.C. NR 39 TC 1 Z9 1 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 MAY 3 PY 2013 VL 3 AR 1773 DI 10.1038/srep01773 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BL UT WOS:000318334300002 PM 23639915 ER PT J AU Wang, C Jiang, Y Ma, JM Wu, HX Wacker, D Katritch, V Han, GW Liu, W Huang, XP Vardy, E McCorvy, JD Gao, X Zhou, XE Melcher, K Zhang, CH Bai, F Yang, HY Yang, LL Jiang, HL Roth, BL Cherezov, V Stevens, RC Xu, HE AF Wang, Chong Jiang, Yi Ma, Jinming Wu, Huixian Wacker, Daniel Katritch, Vsevolod Han, Gye Won Liu, Wei Huang, Xi-Ping Vardy, Eyal McCorvy, John D. Gao, Xiang Zhou, X. Edward Melcher, Karsten Zhang, Chenghai Bai, Fang Yang, Huaiyu Yang, Linlin Jiang, Hualiang Roth, Bryan L. Cherezov, Vadim Stevens, Raymond C. Xu, H. Eric TI Structural Basis for Molecular Recognition at Serotonin Receptors SO SCIENCE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; VALVULAR HEART-DISEASE; CARDIAC VALVULOPATHY; AGONIST; SCHIZOPHRENIA; FENFLURAMINE; PHARMACOLOGY; DISORDERS; MUTATION; LIGANDS AB Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT2B receptor, the 5-HT1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs. C1 [Wang, Chong; Jiang, Yi; Ma, Jinming; Wu, Huixian; Wacker, Daniel; Katritch, Vsevolod; Han, Gye Won; Liu, Wei; Cherezov, Vadim; Stevens, Raymond C.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Jiang, Yi; Zhang, Chenghai; Xu, H. Eric] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Mat Med Ctr, Van Andel Res Inst,CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China. [Ma, Jinming; Gao, Xiang; Zhou, X. Edward; Melcher, Karsten; Zhang, Chenghai; Xu, H. Eric] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA. [Huang, Xi-Ping; Vardy, Eyal; McCorvy, John D.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, NIMH,Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Huang, Xi-Ping; Vardy, Eyal; McCorvy, John D.; Roth, Bryan L.] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Bai, Fang] Dalian Univ Technol, Fac Chem Environm & Biol Sci & Technol, State Key Lab Technol, Dept Engn Mech, Dalian 116023, Peoples R China. [Yang, Huaiyu; Yang, Linlin; Jiang, Hualiang] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China. RP Stevens, RC (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM stevens@scripps.edu; eric.xu@vai.org RI Ma, Jinming/N-3704-2014; Wu, Huixian/N-6353-2014; Ma, Jinming/D-5613-2015; Roth, Bryan/F-3928-2010; Katritch, Vsevolod/Q-8357-2016; Cherezov, Vadim/L-9812-2013; Stevens, Raymond/K-7272-2015; OI Ma, Jinming/0000-0002-7171-1059; Wu, Huixian/0000-0003-1357-9747; Ma, Jinming/0000-0002-0019-8219; Cherezov, Vadim/0000-0002-5265-3914; Stevens, Raymond/0000-0002-4522-8725; Bai, Fang/0000-0003-1468-5568; Katritch, Vsevolod/0000-0003-3883-4505 FU National Institute of General Medical Sciences (NIGMS) PSI: Biology grant [U54 GM094618, GPCR-118]; NIH Common Fund in Structural Biology grant [P50 GM073197]; Jay and Betty Van Andel Foundation [R01 DK071662]; Ministry of Science and Technology (China) [2012ZX09301001-005, 2012CB910403]; Amway (China) [R01 MH61887, U19 MH82441, R01 DA27170]; National Institute of Mental Health Psychoactive Drug Screening Program; Michael Hooker Chair of Pharmacology; Boehringer Ingelheim Fonds Ph.D. Fellowship; National Cancer Institute [Y1-CO-1020]; NIGMS [Y1-GM-1104]; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor Grant [085P1000817]; Office of Science of the U.S. Department of Energy FX This work was supported by National Institute of General Medical Sciences (NIGMS) PSI: Biology grant U54 GM094618 for biological studies and structure production (target GPCR-118) (V. K., V. C., and R. C. S.); NIH Common Fund in Structural Biology grant P50 GM073197 for technology development (V. C. and R. C. S.); the Jay and Betty Van Andel Foundation, R01 DK071662, Ministry of Science and Technology (China) grants 2012ZX09301001-005 and 2012CB910403, and Amway (China) (H. E. X.); R01 MH61887, U19 MH82441, R01 DA27170, and the National Institute of Mental Health Psychoactive Drug Screening Program (X.-P. H., E. V., J.D.M., and B. L. R.); and the Michael Hooker Chair of Pharmacology (B. L. R.). D. W. is supported by a Boehringer Ingelheim Fonds Ph.D. Fellowship. We thank J. Velasquez for help on molecular biology; T. Trinh, K. Allin, and M. Chu for help on baculovirus expression; I. Wilson for careful review and scientific feedback on the manuscript; K. Kadyshevskaya for assistance with figure preparation; A. Walker for assistance with manuscript preparation; J. Smith, R. Fischetti, and N. Sanishvili for assistance in development and use of the minibeam and beamtime at GM/CA-CAT beamline 23-ID at the Advanced Photon Source (APS), which is supported by National Cancer Institute grant Y1-CO-1020 and NIGMS grant Y1-GM-1104; and Z. Wawrzak and J. S. Brunzelle for assistance in data collection at the beamlines of sector 21 (Life Sciences Collaborative Access Team), which is funded in part by the Michigan Economic Development Corporation and Michigan Technology Tri-Corridor Grant 085P1000817. Use of the APS was supported by the Office of Science of the U.S. Department of Energy. The coordinates and the structure factors have been deposited in the Protein Data Bank (PDB) under accession codes 4IAR (5-HT1B/ERG) and 4IAQ (5-HT1B/DHE). R.C.S. is a founder and paid consultant for Receptos, a GPCR structure-based drug discovery company. NR 27 TC 161 Z9 167 U1 4 U2 126 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 MAY 3 PY 2013 VL 340 IS 6132 BP 610 EP 614 DI 10.1126/science.1232807 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 135EA UT WOS:000318268900048 PM 23519210 ER PT J AU Wacker, D Wang, C Katritch, V Han, GW Huang, XP Vardy, E McCorvy, JD Jiang, Y Chu, MH Siu, FY Liu, W Xu, HE Cherezov, V Roth, BL Stevens, RC AF Wacker, Daniel Wang, Chong Katritch, Vsevolod Han, Gye Won Huang, Xi-Ping Vardy, Eyal McCorvy, John D. Jiang, Yi Chu, Meihua Siu, Fai Yiu Liu, Wei Xu, H. Eric Cherezov, Vadim Roth, Bryan L. Stevens, Raymond C. TI Structural Features for Functional Selectivity at Serotonin Receptors SO SCIENCE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; CRYSTAL-STRUCTURE; PATHWAYS; AGONISTS AB Drugs active at G protein-coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for beta-arrestin signaling at the 5-HT2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT2B receptor bound to ERG and compared it with the 5-HT1B/ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities. C1 [Wacker, Daniel; Wang, Chong; Katritch, Vsevolod; Han, Gye Won; Jiang, Yi; Chu, Meihua; Siu, Fai Yiu; Liu, Wei; Cherezov, Vadim; Stevens, Raymond C.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Huang, Xi-Ping; Vardy, Eyal; McCorvy, John D.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, NIMH,Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Huang, Xi-Ping; Vardy, Eyal; McCorvy, John D.; Roth, Bryan L.] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Jiang, Yi; Xu, H. Eric] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Mat Med Ctr, Van Andel Res Inst,CAS Key Lab Receptor Res, Shanghai 200031, Peoples R China. [Xu, H. Eric] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, NIMH,Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu; stevens@scripps.edu RI Stevens, Raymond/K-7272-2015; Cherezov, Vadim/L-9812-2013; Roth, Bryan/F-3928-2010; Katritch, Vsevolod/Q-8357-2016 OI Stevens, Raymond/0000-0002-4522-8725; Katritch, Vsevolod/0000-0003-3883-4505; Cherezov, Vadim/0000-0002-5265-3914; FU National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative [U54 GM094618]; NIH [P50 GM073197]; Jay and Betty Van Andel Foundation, Amway (China) [R01 DK071662]; Ministry of Science and Technology (China) [2012ZX09301001-005, 2012CB910403, U19 MH82441, R01 MH61887]; National Institute of Mental Health Psychoactive Drug Screening Program; Michael Hooker Chair of Pharmacology; Boehringer Ingelheim Fonds Ph.D. Fellowship; Receptos; GPCR structure-based drug discovery company; National Cancer Institute [Y1-CO-1020]; NIGMS [Y1-GM-1104]; Office of Science of the U.S. Department of Energy FX This work was supported by the National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative: Biology grant U54 GM094618 for biological studies and structure production (target GPCR-4) (V. K., V. C., and R. C. S.); NIH Common Fund in Structural Biology grant P50 GM073197 for technology development (V. C. and R. C. S.); the Jay and Betty Van Andel Foundation, Amway (China), grant R01 DK071662; Ministry of Science and Technology (China) grants 2012ZX09301001-005 and 2012CB910403 (H. E. X.); grants U19 MH82441, R01 MH61887, and the National Institute of Mental Health Psychoactive Drug Screening Program (X.-P. H., E. V., and B. L. R.); and the Michael Hooker Chair of Pharmacology (B. L. R.). D. W. is supported by a Boehringer Ingelheim Fonds Ph.D. Fellowship. R. C. S. is a founder and paid consultant for Receptos, a GPCR structure-based drug discovery company. We thank J. Velasquez for help on molecular biology; T. Trinh, K. Allin, and M. Chu for help on baculovirus expression; L. N. Collins for help on initial construct selection; K. Kadyshevskaya for assistance with figure preparation; A. Walker for assistance with manuscript preparation; I. Wilson for careful review and scientific feedback on the manuscript; T. Kenakin (University of North Carolina) for helpful discussions regarding the quantification of ligand bias; J. Smith, R. Fischetti, and N. Sanishvili for assistance in development and use of the minibeam and beamtime at GM/CA-CAT beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and NIGMS grant Y1-GM-1104. Use of the Advanced Photon Source was supported by the Office of Science of the U.S. Department of Energy. Coordinates and the structure factors of the 5-HT2B/ERG complex have been deposited in the Protein Data Bank under the accession code 4IB4. NR 27 TC 206 Z9 216 U1 11 U2 111 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 MAY 3 PY 2013 VL 340 IS 6132 BP 615 EP 619 DI 10.1126/science.1232808 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 135EA UT WOS:000318268900049 PM 23519215 ER PT J AU Flood, VH Friedman, KD Gill, JC Haberichter, SL Christopherson, PA Branchford, BR Hoffmann, RG Abshire, TC Dunn, AL Di Paola, JA Hoots, WK Brown, DL Leissinger, C Lusher, JM Ragni, MV Shapiro, AD Montgomery, RR AF Flood, Veronica H. Friedman, Kenneth D. Gill, Joan Cox Haberichter, Sandra L. Christopherson, Pamela A. Branchford, Brian R. Hoffmann, Raymond G. Abshire, Thomas C. Dunn, Amy L. Di Paola, Jorge A. Hoots, W. Keith Brown, Deborah L. Leissinger, Cindy Lusher, Jeanne M. Ragni, Margaret V. Shapiro, Amy D. Montgomery, Robert R. TI No increase in bleeding identified in type 1 VWD subjects with D1472H sequence variation SO BLOOD LA English DT Article ID VON-WILLEBRAND-DISEASE; DIAGNOSIS; MANAGEMENT; RISTOCETIN; PHENOTYPE AB The diagnosis of von Willebrand disease (VWD) is complicated by issues with current laboratory testing, particularly the ristocetin cofactor activity assay (VWF:RCo). We have recently reported a sequence variation in the von Willebrand factor (VWF) A1 domain, p.D1472H (D1472H), associated with a decrease in the VWF:RCo/VWF antigen (VWF:Ag) ratio but not associated with bleeding in healthy control subjects. This report expands the previous study to include subjects with symptoms leading to the diagnosis of type 1 VWD. Type 1 VWD subjects with D1472H had a significant decrease in the VWF:RCo/VWF:Ag ratio compared with those without D1472H, similar to the findings in the healthy control population. No increase in bleeding score was observed, however, for VWD subjects with D1472H compared with those without D1472H. These results suggest that the presence of the D1472H sequence variation is not associated with a significant increase in bleeding symptoms, even in type 1 VWD subjects. C1 [Flood, Veronica H.; Gill, Joan Cox; Haberichter, Sandra L.; Branchford, Brian R.; Abshire, Thomas C.; Montgomery, Robert R.] Med Coll Wisconsin, Dept Pediat, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Flood, Veronica H.; Gill, Joan Cox; Haberichter, Sandra L.; Abshire, Thomas C.; Montgomery, Robert R.] Childrens Hosp Wisconsin, Childrens Res Inst, Milwaukee, WI 53201 USA. [Friedman, Kenneth D.; Gill, Joan Cox; Haberichter, Sandra L.; Christopherson, Pamela A.; Abshire, Thomas C.; Montgomery, Robert R.] BloodCtr Wisconsin, Blood Res Inst, Milwaukee, WI USA. [Gill, Joan Cox] Med Coll Wisconsin, Zimmerman Program Clin Ctr, Milwaukee, WI 53226 USA. [Branchford, Brian R.; Di Paola, Jorge A.] Univ Colorado, Sch Med, Aurora, CO USA. [Hoffmann, Raymond G.] Med Coll Wisconsin, Dept Pediat, Div Quantitat Hlth Sci, Milwaukee, WI 53226 USA. [Abshire, Thomas C.; Dunn, Amy L.] Emory Univ, Sch Med, Aflac Canc Ctr, Atlanta, GA USA. [Abshire, Thomas C.; Dunn, Amy L.] Emory Univ, Sch Med, Blood Disorders Serv, Atlanta, GA USA. [Di Paola, Jorge A.] Univ Iowa, Iowa City, IA USA. [Hoots, W. Keith; Brown, Deborah L.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Hoots, W. Keith] NHLBI, NIH, Bethesda, MD 20892 USA. [Leissinger, Cindy] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Lusher, Jeanne M.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Ragni, Margaret V.] Univ Pittsburgh, Pittsburgh, PA USA. [Shapiro, Amy D.] Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USA. RP Flood, VH (reprint author), Comprehens Ctr Bleeding Disorders, 8739 Watertown Plank Rd,POB 2178, Milwaukee, WI 53201 USA. EM vflood@mcw.edu OI Branchford, Brian/0000-0002-4076-270X FU National Institutes of Health [HL081588, HL102260]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000055] FX This work was supported by National Institutes of Health program project grant HL081588 (R.R.M.) and K08 grant HL102260 (V.H.F.). This work was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health through grant number 8UL1TR000055. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 15 TC 13 Z9 13 U1 0 U2 3 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 MAY 2 PY 2013 VL 121 IS 18 BP 3742 EP 3744 DI 10.1182/blood-2012-12-471672 PG 3 WC Hematology SC Hematology GA 184EG UT WOS:000321870000029 PM 23520336 ER PT J AU Lockwood, WW Chandel, SK Stewart, GL Erdjument-Bromage, H Beverly, LJ AF Lockwood, William W. Chandel, Sahiba K. Stewart, Greg L. Erdjument-Bromage, Hediye Beverly, Levi J. TI The Novel Ubiquitin Ligase Complex, SCFFbxw4, Interacts with the COP9 Signalosome in an F-Box Dependent Manner, Is Mutated, Lost and Under-Expressed in Human Cancers SO PLOS ONE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HAND FOOT MALFORMATION; BETA-CATENIN; PROTEIN; GENE; SHFM3; PROTEOLYSIS; 10Q24; NOTCH; FBW7 AB Identification of novel proteins that can potentially contribute to carcinogenesis is a requisite venture. Herein, we report the first biochemical characterization of the novel F-box and WD40 containing protein, FBXW4. We have identified interacting protein partners and demonstrated that FBXW4 is part of a ubiquitin ligase complex. Furthermore, the Fbxw4 locus is a common site of proviral insertion in a variety of retroviral insertional mutagenesis murine cancer models and Fbxw4 mRNA is highly expressed in the involuting murine mammary gland. To begin to characterize the biochemical function of Fbxw4, we used proteomic analysis to demonstrate that Fbxw4 interacts with Skp1 (SKP1), Cullin1 (CUL1), Ring-box1 (RBX1) and all components of the COP9 signalosome. All of these interactions are dependent on an intact F-box domain of Fbxw4. Furthermore, Fbxw4 is capable of interacting with ubiquitinated proteins within cells in an F-box dependent manner. Finally, we demonstrate that FBXW4 is mutated, lost and under-expressed in a variety of human cancer cell lines and clinical patient samples. Importantly, expression of FBXW4 correlates with survival of patients with non-small cell lung cancer. Taken together, we suggest that FBXW4 may be a novel tumor suppressor that regulates important cellular processes. C1 [Chandel, Sahiba K.; Beverly, Levi J.] Univ Louisville, James Graham Brown Canc Ctr, Div Hematol & Oncol, Dept Med, Louisville, KY 40292 USA. [Lockwood, William W.] NHGRI, Canc Biol & Genet Sect, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Stewart, Greg L.] Columbia Canc Res Ctr, Vancouver, BC, Canada. [Erdjument-Bromage, Hediye] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA. RP Beverly, LJ (reprint author), Univ Louisville, James Graham Brown Canc Ctr, Div Hematol & Oncol, Dept Med, Louisville, KY 40292 USA. EM Levi.Beverly@Louisville.edu FU National Institutes of Health (NIH), Molecular Targets COBRE [8P20GM103482-10]; Wendy Will Case Cancer Fund [GB220413]; Kosair Pediatric Cancer Research Program award; NCI [P30 CA08748]; NIH [P01 CA94060, PO1 CA129243-01]; NIH intramural NCI; NHGRI FX This work was supported by the National Institutes of Health (NIH), Molecular Targets COBRE, 8P20GM103482-10 (to LJB), Wendy Will Case Cancer Fund, GB220413 (to LJB), Kosair Pediatric Cancer Research Program award (to LJB). This work was also supported by NCI Cancer Center support grant P30 CA08748 to Microchemistry and Proteomics Core Laboratory (to HEB), Memorial Sloan-Kettering Cancer Center. This work was also supported, in part, by NIH Grant P01 CA94060 and PO1 CA129243-01 (to Harold Varmus) and by NIH intramural NCI and NHGRI funds (to Harold Varmus). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 8 Z9 8 U1 0 U2 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 MAY 2 PY 2013 VL 8 IS 5 AR e63610 DI 10.1371/journal.pone.0063610 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 175AF UT WOS:000321200500078 PM 23658844 ER PT J AU Getz, G Gabriel, SB Cibulskis, K Lander, E Sivachenko, A Sougnez, C Lawrence, M Kandoth, C Dooling, D Fulton, R Fulton, L Kalicki-Veizer, J McLellan, MD O'Laughlin, M Schmidt, H Wilson, RK Ye, K Ding, L Mardis, ER Ally, A Balasundaram, M Birol, I Butterfield, YSN Carlsen, R Carter, C Chu, A Chuah, E Chun, HJE Dhalla, N Guin, R Hirst, C Holt, RA Jones, SJM Lee, D Li, HI Marra, MA Mayo, M Moore, RA Mungall, AJ Plettner, P Schein, JE Sipahimalani, P Tam, A Varhol, RJ Robertson, AG Pashtan, I Saksena, G Onofrio, RC Schumacher, SE Tabak, B Carter, SL Hernandez, B Gentry, J Salvesen, HB Ardlie, K Getz, G Winckler, W Beroukhim, R Gabriel, SB Meyerson, M Hadjipanayis, A Lee, S Mahadeshwar, HS Park, P Protopopov, A Ren, XJ Seth, S Song, XZ Tang, JB Xi, RB Yang, LX Zeng, D Kucherlapati, R Chin, L Zhang, JH Auman, JT Balu, S Bodenheimer, T Buda, E Hayes, DN Hoyle, AP Jefferys, SR Jones, CD Meng, SW Mieczkowski, PA Mose, LE Parker, JS Perou, CM Roach, J Shi, Y Simons, JV Soloway, MG Tan, DH Topal, MD Waring, S Wu, JY Hoadley, KA Baylin, SB Bootwalla, MS Lai, PH Triche, TJ Van Den Berg, D Weisenberger, DJ Laird, PW Shen, H Chin, L Zhang, JH Getz, G Cho, J DiCara, D Frazer, S Heiman, D Jing, R Lin, P Mallard, W Stojanov, P Voet, D Zhang, HL Zou, LH Noble, M Lawrence, M Reynolds, SM Shmulevich, I Aksoy, BA Antipin, Y Ciriello, G Dresdner, G Gao, JJ Gross, B Jacobsen, A Ladanyi, M Reva, B Sander, C Sinha, R Sumer, SO Taylor, BS Cerami, E Weinhold, N Schultz, N Shen, RL Benz, S Goldstein, T Haussler, D Ng, S Szeto, C Stuart, J Benz, CC Yau, C Zhang, W Annala, M Broom, BM Casasent, TD Ju, ZL Liang, H Liu, GY Lu, YL Unruh, AK Wakefield, C Weinstein, JN Zhang, NX Liu, YX Broaddus, R Akbani, R Mills, GB Adams, C Barr, T Black, AD Bowen, J Deardurff, J Frick, J Gastier-Foster, JM Grossman, T Harper, HA Hart-Kothari, M Helsel, C Hobensack, A Kuck, H Kneile, K Leraas, K Lichtenberg, TM McAllister, C Pyatt, RE Ramirez, NC Tabler, TR Vanhoose, N White, P Wise, L Zmuda, E Barnabas, N Berry-Green, C Blanc, V Boice, L Button, M Farkas, A Green, A MacKenzie, J Nicholson, D Kalloger, SE Gilks, CB Karlan, BY Lester, J Orsulic, S Borowsky, M Cadungog, M Czerwinski, C Huelsenbeck-Dill, L Iacocca, M Petrelli, N Petrelli, N Witkin, G Nemirovich-Danchenko, E Potapova, O Rotin, D Berchuck, A Birrer, M DiSaia, P Monovich, L Curley, E Gardner, J Mallery, D Penny, R Dowdy, SC Winterhoff, B Dao, L Gostout, B Meuter, A Teoman, A Dao, F Olvera, N Bogomolniy, F Garg, K Soslow, RA Levine, DA Abramov, M Bartlett, JMS Kodeeswaran, S Parfitt, J Moiseenko, F Clarke, BA Goodman, MT Carney, ME Matsuno, RK Fisher, J Huang, M Rathmell, WK Thorne, L Van Le, L Dhir, R Edwards, R Elishaev, E Zorn, K Broaddus, R Goodfellow, PJ Mutch, D Schultz, N Liu, YX Akbani, R Cherniack, AD Cerami, E Weinhold, N Shen, H Hoadley, KA Kahn, AB Bell, DW Pollock, PM Wang, C Wheeler, DA Shinbrot, E Karlan, BY Berchuck, A Dowdy, SC Winterhoff, B Goodman, MT Robertson, AG Beroukhim, R Pashtan, I Salvesen, HB Laird, PW Noble, M Stuart, J Ding, L Kandoth, C Gilks, CB Soslow, RA Goodfellow, PJ Mutch, D Broaddus, R Zhang, W Mills, GB Kucherlapati, R Mardis, ER Levine, DA Ayala, B Chu, AL Jensen, MA Kothiyal, P Pihl, TD Pontius, J Pot, DA Snyder, EE Srinivasan, D Kahn, AB Shaw, KRM Sheth, M Davidsen, T Eley, G Ferguson, ML Demchok, JA Yang, LM Guyer, MS Ozenberger, BA Sofia, HJ Kandoth, C Schultz, N Cherniack, AD Akbani, R Liu, YX Shen, H Robertson, AG Pashtan, I Shen, R Benz, CC Yau, C Laird, PW Ding, L Zhang, W Mills, GB Kucherlapati, R Mardis, ER Levine, DA AF Getz, Gad Gabriel, Stacey B. Cibulskis, Kristian Lander, Eric Sivachenko, Andrey Sougnez, Carrie Lawrence, Mike Kandoth, Cyriac Dooling, David Fulton, Robert Fulton, Lucinda Kalicki-Veizer, Joelle McLellan, Michael D. O'Laughlin, Michelle Schmidt, Heather Wilson, Richard K. Ye, Kai Ding, Li Mardis, Elaine R. Ally, Adrian Balasundaram, Miruna Birol, Inanc Butterfield, Yaron S. N. Carlsen, Rebecca Carter, Candace Chu, Andy Chuah, Eric Chun, Hye-Jung E. Dhalla, Noreen Guin, Ranabir Hirst, Carrie Holt, Robert A. Jones, Steven J. M. Lee, Darlene Li, Haiyan I. Marra, Marco A. Mayo, Michael Moore, Richard A. Mungall, Andrew J. Plettner, Patrick Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Varhol, Richard J. Robertson, A. Gordon Pashtan, Itai Saksena, Gordon Onofrio, Robert C. Schumacher, Steven E. Tabak, Barbara Carter, Scott L. Hernandez, Bryan Gentry, Jeff Salvesen, Helga B. Ardlie, Kristin Getz, Gad Winckler, Wendy Beroukhim, Rameen Gabriel, Stacey B. Meyerson, Matthew Hadjipanayis, Angela Lee, Semin Mahadeshwar, Harshad S. Park, Peter Protopopov, Alexei Ren, Xiaojia Seth, Sahil Song, Xingzhi Tang, Jiabin Xi, Ruibin Yang, Lixing Zeng, Dong Kucherlapati, Raju Chin, Lynda Zhang, Jianhua Auman, J. Todd Balu, Saianand Bodenheimer, Tom Buda, Elizabeth Hayes, D. Neil Hoyle, Alan P. Jefferys, Stuart R. Jones, Corbin D. Meng, Shaowu Mieczkowski, Piotr A. Mose, Lisle E. Parker, Joel S. Perou, Charles M. Roach, Jeff Shi, Yan Simons, Janae V. Soloway, Mathew G. Tan, Donghui Topal, Michael D. Waring, Scot Wu, Junyuan Hoadley, Katherine A. Baylin, Stephen B. Bootwalla, Moiz S. Lai, Phillip H. Triche, Timothy J., Jr. Van Den Berg, DavidJ. Weisenberger, Daniel J. Laird, Peter W. Shen, Hui Chin, Lynda Zhang, Jianhua Getz, Gad Cho, Juok DiCara, Daniel Frazer, Scott Heiman, David Jing, Rui Lin, Pei Mallard, Will Stojanov, Petar Voet, Doug Zhang, Hailei Zou, Lihua Noble, Michael Lawrence, Mike Reynolds, Sheila M. Shmulevich, Ilya Aksoy, B. Arman Antipin, Yevgeniy Ciriello, Giovanni Dresdner, Gideon Gao, Jianjiong Gross, Benjamin Jacobsen, Anders Ladanyi, Marc Reva, Boris Sander, Chris Sinha, Rileen Sumer, S. Onur Taylor, Barry S. Cerami, Ethan Weinhold, Nils Schultz, Nikolaus Shen, Ronglai Benz, Stephen Goldstein, Ted Haussler, David Sam Ng Szeto, Christopher Stuart, Joshua Benz, Christopher C. Yau, Christina Zhang, Wei Annala, Matti Broom, Bradley M. Casasent, Tod D. Ju, Zhenlin Liang, Han Liu, Guoyan Lu, Yiling Unruh, Anna K. Wakefield, Chris Weinstein, John N. Zhang, Nianxiang Liu, Yuexin Broaddus, Russell Akbani, Rehan Mills, Gordon B. Adams, Christopher Barr, Thomas Black, Aaron D. Bowen, Jay Deardurff, John Frick, Jessica Gastier-Foster, Julie M. Grossman, Thomas Harper, Hollie A. Hart-Kothari, Melissa Helsel, Carmen Hobensack, Aaron Kuck, Harkness Kneile, Kelley Leraas, KristenM. Lichtenberg, Tara M. McAllister, Cynthia Pyatt, Robert E. Ramirez, Nilsa C. Tabler, Teresa R. Vanhoose, Nathan White, Peter Wise, Lisa Zmuda, Erik Barnabas, Nandita Berry-Green, Charlenia Blanc, Victoria Boice, Lori Button, Michael Farkas, Adam Green, Alex MacKenzie, Jean Nicholson, Dana Kalloger, Steve E. Gilks, C. Blake Karlan, Beth Y. Lester, Jenny Orsulic, Sandra Borowsky, Mark Cadungog, Mark Czerwinski, Christine Huelsenbeck-Dill, Lori Iacocca, Mary Petrelli, Nicholas Petrelli, Nicholas Witkin, Gary Nemirovich-Danchenko, Elena Potapova, Olga Rotin, Daniil Berchuck, Andrew Birrer, Michael DiSaia, Phillip Monovich, Laura Curley, Erin Gardner, Johanna Mallery, David Penny, Robert Dowdy, Sean C. Winterhoff, Boris Dao, Linda Gostout, Bobbie Meuter, Alexandra Teoman, Attila Dao, Fanny Olvera, Narciso Bogomolniy, Faina Garg, Karuna Soslow, Robert A. Levine, Douglas A. Abramov, Mikhail Bartlett, John M. S. Kodeeswaran, Sugy Parfitt, Jeremy Moiseenko, Fedor Clarke, Blaise A. Goodman, Marc T. Carney, Michael E. Matsuno, Rayna K. Fisher, Jennifer Huang, Mei Rathmell, W. Kimryn Thorne, Leigh Van Le, Linda Dhir, Rajiv Edwards, Robert Elishaev, Esther Zorn, Kristin Broaddus, Russell Goodfellow, Paul J. Mutch, David Schultz, Nikolaus Liu, Yuexin Akbani, Rehan Cherniack, Andrew D. Cerami, Ethan Weinhold, Nils Shen, Hui Hoadley, Katherine A. Kahn, Ari B. Bell, Daphne W. Pollock, Pamela M. Wang, Chen Wheeler, David A. Shinbrot, Eve Karlan, Beth Y. Berchuck, Andrew Dowdy, Sean C. Winterhoff, Boris Goodman, Marc T. Robertson, A. Gordon Beroukhim, Rameen Pashtan, Itai Salvesen, Helga B. Laird, Peter W. Noble, Michael Stuart, Joshua Ding, Li Kandoth, Cyriac Gilks, C. Blake Soslow, Robert A. Goodfellow, Paul J. Mutch, David Broaddus, Russell Zhang, Wei Mills, Gordon B. Kucherlapati, Raju Mardis, Elaine R. Levine, Douglas A. Ayala, Brenda Chu, Anna L. Jensen, Mark A. Kothiyal, Prachi Pihl, Todd D. Pontius, Joan Pot, David A. Snyder, Eric E. Srinivasan, Deepak Kahn, Ari B. Shaw, Kenna R. Mills Sheth, Margi Davidsen, Tanja Eley, Greg Ferguson, Martin L. Demchok, John A. Yang, Liming Guyer, Mark S. Ozenberger, Bradley A. Sofia, Heidi J. Kandoth, Cyriac Schultz, Nikolaus Cherniack, Andrew D. Akbani, Rehan Liu, Yuexin Shen, Hui Robertson, A. Gordon Pashtan, Itai Shen, Ronglai Benz, Christopher C. Yau, Christina Laird, Peter W. Ding, Li Zhang, Wei Mills, Gordon B. Kucherlapati, Raju Mardis, Elaine R. Levine, Douglas A. CA Canc Genome Atlas Res Network TI Integrated genomic characterization of endometrial carcinoma SO NATURE LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; MICROSATELLITE INSTABILITY; MATRIX FACTORIZATION; SOMATIC MUTATIONS; HIGH-FREQUENCY; LUNG-CANCER; TUMORS; COLON; DOXORUBICIN; PROTEIN AB We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine seroustumours and similar to 25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours. C1 [Getz, Gad; Gabriel, Stacey B.; Cibulskis, Kristian; Lander, Eric; Sivachenko, Andrey; Sougnez, Carrie; Lawrence, Mike; Pashtan, Itai; Saksena, Gordon; Onofrio, Robert C.; Schumacher, Steven E.; Tabak, Barbara; Carter, Scott L.; Hernandez, Bryan; Gentry, Jeff; Salvesen, Helga B.; Ardlie, Kristin; Winckler, Wendy; Beroukhim, Rameen; Meyerson, Matthew; Chin, Lynda; Cho, Juok; DiCara, Daniel; Frazer, Scott; Heiman, David; Jing, Rui; Lin, Pei; Mallard, Will; Stojanov, Petar; Voet, Doug; Zhang, Hailei; Zou, Lihua; Noble, Michael; Cherniack, Andrew D.] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02139 USA. [Kandoth, Cyriac; Dooling, David; Fulton, Robert; Fulton, Lucinda; Kalicki-Veizer, Joelle; McLellan, Michael D.; O'Laughlin, Michelle; Schmidt, Heather; Wilson, Richard K.; Ye, Kai; Ding, Li; Mardis, Elaine R.] Washington Univ, Genome Inst, St Louis, MO 63108 USA. [Mardis, Elaine R.; Ally, Adrian; Balasundaram, Miruna; Birol, Inanc; Butterfield, Yaron S. N.; Carlsen, Rebecca; Carter, Candace; Chu, Andy; Chuah, Eric; Chun, Hye-Jung E.; Dhalla, Noreen; Guin, Ranabir; Hirst, Carrie; Holt, Robert A.; Jones, Steven J. M.; Lee, Darlene; Li, Haiyan I.; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Plettner, Patrick; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Varhol, Richard J.; Robertson, A. Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02215 USA. Haukeland Hosp, Dept Obstet & Gynecol, N-5021 Bergen, Norway. Univ Bergen, Dept Clin Med, N-5020 Bergen, Norway. [Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Hadjipanayis, Angela; Ren, Xiaojia; Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Lee, Semin; Park, Peter; Xi, Ruibin; Yang, Lixing] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Mahadeshwar, Harshad S.; Protopopov, Alexei; Seth, Sahil; Song, Xingzhi; Tang, Jiabin; Zeng, Dong; Zhang, Jianhua] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Inst Appl Canc Sci, Houston, TX 77054 USA. [Park, Peter] Boston Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Auman, J. Todd] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Auman, J. Todd] Univ N Carolina, Inst Pharmacogenet & Individualized Therapy, Chapel Hill, NC 27599 USA. [Balu, Saianand; Bodenheimer, Tom; Buda, Elizabeth; Hayes, D. Neil; Hoyle, Alan P.; Jefferys, Stuart R.; Meng, Shaowu; Mose, Lisle E.; Parker, Joel S.; Perou, Charles M.; Shi, Yan; Simons, Janae V.; Soloway, Mathew G.; Tan, Donghui; Topal, Michael D.; Waring, Scot; Wu, Junyuan; Rathmell, W. Kimryn] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Hayes, D. Neil] Univ N Carolina, Div Med Oncol, Dept Internal Med, Chapel Hill, NC 27599 USA. [Jones, Corbin D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Mieczkowski, Piotr A.; Perou, Charles M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Perou, Charles M.; Topal, Michael D.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Roach, Jeff] Univ N Carolina, Res Comp Ctr, Chapel Hill, NC 27599 USA. [Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Canc Biol Div, Baltimore, MD 21231 USA. [Bootwalla, Moiz S.; Lai, Phillip H.; Triche, Timothy J., Jr.; Van Den Berg, DavidJ.; Weisenberger, Daniel J.; Laird, Peter W.; Shen, Hui] Univ So Calif, Epigenome Ctr, Los Angeles, CA 90089 USA. [Reynolds, Sheila M.; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Aksoy, B. Arman; Antipin, Yevgeniy; Ciriello, Giovanni; Dresdner, Gideon; Gao, Jianjiong; Gross, Benjamin; Jacobsen, Anders; Reva, Boris; Sander, Chris; Sinha, Rileen; Sumer, S. Onur; Cerami, Ethan; Weinhold, Nils; Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Taylor, Barry S.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Benz, Stephen; Goldstein, Ted; Haussler, David; Sam Ng; Szeto, Christopher; Stuart, Joshua] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Benz, Stephen; Goldstein, Ted; Sam Ng; Szeto, Christopher; Stuart, Joshua] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Benz, Christopher C.; Yau, Christina] Buck Inst Age Res, Novato, CA 94945 USA. [Zhang, Wei; Annala, Matti; Liu, Guoyan; Liu, Yuexin] Univ Texas MD Anderson Canc Ctr, Canc Genom Core Lab, Houston, TX 77054 USA. [Liu, Guoyan; Liu, Yuexin; Broaddus, Russell] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Tampere Univ Technol, FI-33720 Tampere, Finland. [Bootwalla, Moiz S.; Van Den Berg, DavidJ.; Weisenberger, Daniel J.; Broom, Bradley M.; Ju, Zhenlin; Liang, Han; Unruh, Anna K.; Wakefield, Chris; Akbani, Rehan] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Lu, Yiling; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Adams, Christopher; Barr, Thomas; Black, Aaron D.; Bowen, Jay; Deardurff, John; Frick, Jessica; Gastier-Foster, Julie M.; Grossman, Thomas; Harper, Hollie A.; Hart-Kothari, Melissa; Helsel, Carmen; Hobensack, Aaron; Kuck, Harkness; Kneile, Kelley; Leraas, KristenM.; Lichtenberg, Tara M.; McAllister, Cynthia; Pyatt, Robert E.; Ramirez, Nilsa C.; Tabler, Teresa R.; Vanhoose, Nathan; White, Peter; Wise, Lisa; Zmuda, Erik] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Gastier-Foster, Julie M.; Ramirez, Nilsa C.; Goodfellow, Paul J.] Ohio State Univ, Columbus, OH 43210 USA. [Barnabas, Nandita; Berry-Green, Charlenia; Blanc, Victoria; Button, Michael; Farkas, Adam; Green, Alex; MacKenzie, Jean; Nicholson, Dana] Asterand, Detroit, MI 48202 USA. [Boice, Lori; Fisher, Jennifer; Huang, Mei; Thorne, Leigh; Van Le, Linda] Univ N Carolina, Chapel Hill, NC 27599 USA. [Kalloger, Steve E.; Gilks, C. Blake] British Columbia Canc Agcy, OvCaRe British Columbia, Vancouver, BC V5Z 4E6, Canada. [Kalloger, Steve E.; Gilks, C. Blake] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Borowsky, Mark; Cadungog, Mark; Czerwinski, Christine; Huelsenbeck-Dill, Lori; Iacocca, Mary; Petrelli, Nicholas; Witkin, Gary] Helen F Graham Canc Ctr Christiana Care, Newark, DC 19713 USA. [Nemirovich-Danchenko, Elena; Potapova, Olga; Rotin, Daniil] Cureline Inc, San Francisco, CA 94080 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC 27710 USA. [Birrer, Michael] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [DiSaia, Phillip] Univ Calif Irvine, Med Ctr, Orange, CA 92868 USA. [Monovich, Laura] Nationwide Childrens Hosp, Res Inst, GOG Tissue Bank, Columbus, OH 43205 USA. [Curley, Erin; Gardner, Johanna; Mallery, David; Penny, Robert] Int Genom Consortium, Phoenix, AZ 85004 USA. [Dowdy, Sean C.; Winterhoff, Boris; Gostout, Bobbie; Meuter, Alexandra; Teoman, Attila] Mayo Clin, Div Gynecol Oncol, Dept OB Gyn, Rochester, MN 55905 USA. [Dao, Linda] Mayo Clin, Dept Pathol, Rochester, MN 55905 USA. [Dao, Fanny; Olvera, Narciso; Bogomolniy, Faina; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10065 USA. [Garg, Karuna; Soslow, Robert A.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Abramov, Mikhail] NN Blokhin Russian Canc Res Ctr RAMS, Moscow 115478, Russia. [Bartlett, John M. S.; Kodeeswaran, Sugy] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [Parfitt, Jeremy] London Hlth Sci Ctr, Ontario Tumour Bank, London, ON N6A 5A5, Canada. [Moiseenko, Fedor] St Petersburg Acad Univ, St Petersburg 199034, Russia. [Clarke, Blaise A.; Demchok, John A.; Yang, Liming] Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2C4, Canada. [Goodman, Marc T.; Carney, Michael E.; Matsuno, Rayna K.; Eley, Greg] Univ Hawaii, Honolulu, HI 96813 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Los Angeles, CA 90024 USA. [Dhir, Rajiv; Edwards, Robert; Elishaev, Esther; Zorn, Kristin] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Goodfellow, Paul J.; Mutch, David] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Kahn, Ari B.; Ayala, Brenda; Chu, Anna L.; Jensen, Mark A.; Kothiyal, Prachi; Pihl, Todd D.; Pontius, Joan; Pot, David A.; Snyder, Eric E.; Srinivasan, Deepak] SRA Int, Fairfax, VA 22033 USA. [Bell, Daphne W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Pollock, Pamela M.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia. [Wang, Chen] Mayo Clin, Dept Biomed Stat & Informat, Rochester, MN 55905 USA. [Wheeler, David A.; Shinbrot, Eve] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Shaw, Kenna R. Mills; Sheth, Margi; Davidsen, Tanja] NCI, Canc Genome Atlas Program Off, NIH, Bethesda, MD 20892 USA. Scimentis LLC, Atlanta, GA 30666 USA. [Ferguson, Martin L.] MLF Consulting, Arlington, MD 02474 USA. [Guyer, Mark S.; Ozenberger, Bradley A.; Sofia, Heidi J.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Getz, G (reprint author), MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02139 USA. RI Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; salvesen, Helga/C-1187-2017; Jones, Steven/C-3621-2009; Jacobsen, Anders/K-1081-2013; Schumacher, Steven/E-9821-2013; Reva, Boris/B-6436-2014; Tang, Macy/B-9798-2014; White, Peter/E-4301-2011; Moiseenko, Fedor/E-1775-2014; Holt, Robert/C-3303-2009; Ye, Kai/B-3640-2012; Laird, Peter/G-8683-2012; Schein, Jacquie/G-3674-2015; Gao, Jianjiong/B-5673-2016; Wang, Chen/B-3244-2011 OI Seth, Sahil/0000-0003-4579-3959; Pot, David/0000-0002-1480-9826; Sinha, Rileen/0000-0001-5497-5055; Casasent, Anna/0000-0002-7857-179X; Perou, Charles/0000-0001-9827-2247; Lee, Semin/0000-0002-9015-6046; Birol, Inanc/0000-0003-0950-7839; salvesen, Helga/0000-0002-4438-8831; Liang, Han/0000-0001-7633-286X; Schultz, Nikolaus/0000-0002-0131-4904; Benz, Stephen/0000-0002-4067-0602; Kandoth, Cyriac/0000-0002-1345-3573; Triche, Tim/0000-0001-5665-946X; Soslow, Robert/0000-0002-7269-5898; Jacobsen, Anders/0000-0001-6847-4980; Schumacher, Steven/0000-0002-6819-5647; Reva, Boris/0000-0002-8805-389X; White, Peter/0000-0002-5218-5903; Moiseenko, Fedor/0000-0003-2544-9042; Gao, Jianjiong/0000-0002-5739-1781; Wang, Chen/0000-0003-2638-3081 FU US National Institutes of Health [5U24CA143799-04, 5U24CA143835-04, 5U24CA143840-04, 5U24CA143843-04, 5U24CA143845-04, 5U24CA143848-04, 5U24CA143858-04, 5U24CA143866-04, 5U24CA143867-04, 5U24CA143882-04, 5U24CA143883-04, 5U24CA144025-04, U54HG003067-11, U54HG003079-10, U54HG003273-10] FX We wish to thank all patients and families who contributed to this study. We thank M. Sheth and L. Lund for administrative coordination of TCGA activities, G. Monemvasitis for editing the manuscript, and C. Gunter for critical reading of the manuscript. This work was supported by the following grants from the US National Institutes of Health: 5U24CA143799-04, 5U24CA143835-04, 5U24CA143840-04, 5U24CA143843-04, 5U24CA143845-04, 5U24CA143848-04, 5U24CA143858-04, 5U24CA143866-04, 5U24CA143867-04, 5U24CA143882-04, 5U24CA143883-04, 5U24CA144025-04, U54HG003067-11, U54HG003079-10 and U54HG003273-10. NR 40 TC 642 Z9 646 U1 15 U2 160 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 2 PY 2013 VL 497 IS 7447 BP 67 EP 73 DI 10.1038/nature12113 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 134OK UT WOS:000318221500035 ER PT J AU Ko, M An, J Bandukwala, HS Chavez, L Aijo, T Pastor, WA Segal, MF Li, HM Koh, KP Lahdesmaki, H Hogan, PG Aravind, L Rao, A AF Ko, Myunggon An, Jungeun Bandukwala, Hozefa S. Chavez, Lukas Aijo, Tarmo Pastor, William A. Segal, Matthew F. Li, Huiming Koh, Kian Peng Lahdesmaki, Harri Hogan, Patrick G. Aravind, L. Rao, Anjana TI Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX SO NATURE LA English DT Article ID WNT SIGNALING PATHWAY; EMBRYONIC STEM-CELLS; CPG ISLANDS; 5-HYDROXYMETHYLCYTOSINE CONTENT; DNA METHYLATION; BINDING PROTEIN; MAMMALIAN DNA; DIFFERENTIATION; COMPLEX; 5-CARBOXYLCYTOSINE AB TET (ten-eleven-translocation) proteins are Fe(II)- and alpha-ketogluta-rate-dependent dioxygenases(1-3) that modify the methylation status of DNA by successively oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine(1,3-5), potential intermediates in the active erasure of DNA-methylation marks(5,6). Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling(7) that has been implicated in malignant renal cell carcinoma(8) and colonic villous adenoma(9), regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2. Unexpectedly, IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation. IDAX depletion prevents TET2 downregulation in differentiating mouse embryonic stem cells, and short hairpin RNA against IDAX increases TET2 protein expression in the human monocytic cell line U937. Notably, we find that the expression and activity of TET3 is also regulated through its CXXC domain. Taken together, these results establish the separate and linked CXXC domains of TET2 and TET3, respectively, as previously unknown regulators of caspase activation and TET enzymatic activity. C1 [Ko, Myunggon; An, Jungeun; Bandukwala, Hozefa S.; Chavez, Lukas; Aijo, Tarmo; Pastor, William A.; Segal, Matthew F.; Hogan, Patrick G.; Rao, Anjana] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA. [Aijo, Tarmo; Lahdesmaki, Harri] Aalto Univ, Sch Sci, Dept Informat & Comp Sci, FI-00076 Aalto, Finland. [Li, Huiming; Koh, Kian Peng; Rao, Anjana] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Li, Huiming; Koh, Kian Peng; Rao, Anjana] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Rao, Anjana] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA. RP Rao, A (reprint author), La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA. EM arao@liai.org OI Chavez, Lukas/0000-0002-8718-8848 FU National Institutes of Health (NIH) [HD065812, CA151535]; California Institute of Regenerative Medicine and Translational Research [RM-01729]; Leukemia and Lymphoma Society [TRP 6187-12]; NIH [AI40127]; Leukemia and Lymphoma Society; Lady Tata Memorial Trust; GlaxoSmithKline-Immune Disease Institute Alliance; National Science Foundation FX We thank G. Seumois, M. Ku and J. Day for help with library preparation, B. Ren for use of his Illumina Hi-Seq 2000, J. A. Zepeda-Martinez for the recombinant Flag-TET2CD, and members of the Rao laboratory for discussions. This work was supported by National Institutes of Health (NIH) R01 grants HD065812 and CA151535, grant RM-01729 from the California Institute of Regenerative Medicine and Translational Research, grant TRP 6187-12 from the Leukemia and Lymphoma Society (to A. R.) and NIH R01 grant AI40127 (to P. G. H. and A. R). We also gratefully acknowledge a Special Fellow Award from the Leukemia and Lymphoma Society (to M. K.), postdoctoral fellowships from the Lady Tata Memorial Trust and from the GlaxoSmithKline-Immune Disease Institute Alliance (to H. S. B.) and a predoctoral graduate research fellowship from the National Science Foundation (to W.A.P.). NR 40 TC 86 Z9 90 U1 4 U2 55 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 2 PY 2013 VL 497 IS 7447 BP 122 EP + DI 10.1038/nature12052 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 134OK UT WOS:000318221500046 PM 23563267 ER PT J AU Sharifi, R Morra, R Appel, CD Tallis, M Chioza, B Jankevicius, G Simpson, MA Matic, I Ozkan, E Golia, B Schellenberg, MJ Weston, R Williams, JG Rossi, MN Galehdari, H Krahn, J Wan, A Trembath, RC Crosby, AH Ahel, D Hay, R Ladurner, AG Timinszky, G Williams, RS Ahel, I AF Sharifi, Reza Morra, Rosa Appel, C. Denise Tallis, Michael Chioza, Barry Jankevicius, Gytis Simpson, Michael A. Matic, Ivan Ozkan, Ege Golia, Barbara Schellenberg, Matthew J. Weston, Ria Williams, Jason G. Rossi, Marianna N. Galehdari, Hamid Krahn, Juno Wan, Alexander Trembath, Richard C. Crosby, Andrew H. Ahel, Dragana Hay, Ron Ladurner, Andreas G. Timinszky, Gyula Williams, R. Scott Ahel, Ivan TI Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease SO EMBO JOURNAL LA English DT Article DE ADP-ribose; DNA damage; macrodomain; neurodegeneration; PARP ID POLY(ADP-RIBOSE) PAR POLYMER; MAMMALIAN-CELLS; RIBOSYLATION; MECHANISM; BINDING; DNA; IDENTIFICATION; CHROMATIN; FEATURES; REPAIR AB Adenosine diphosphate (ADP)-ribosylation is a post-translational protein modification implicated in the regulation of a range of cellular processes. A family of proteins that catalyse ADP-ribosylation reactions are the poly(ADP-ribose) (PAR) polymerases (PARPs). PARPs covalently attach an ADP-ribose nucleotide to target proteins and some PARP family members can subsequently add additional ADP-ribose units to generate a PAR chain. The hydrolysis of PAR chains is catalysed by PAR glycohydrolase (PARG). PARG is unable to cleave the mono(ADP-ribose) unit directly linked to the protein and although the enzymatic activity that catalyses this reaction has been detected in mammalian cell extracts, the protein(s) responsible remain unknown. Here, we report the homozygous mutation of the c6orf130 gene in patients with severe neurodegeneration, and identify C6orf130 as a PARP-interacting protein that removes mono(ADP-ribosyl) ation on glutamate amino acid residues in PARP-modified proteins. X-ray structures and biochemical analysis of C6orf130 suggest a mechanism of catalytic reversal involving a transient C6orf130 lysyl-(ADP-ribose) intermediate. Furthermore, depletion of C6orf130 protein in cells leads to proliferation and DNA repair defects. Collectively, our data suggest that C6orf130 enzymatic activity has a role in the turnover and recycling of protein ADP-ribosylation, and we have implicated the importance of this protein in supporting normal cellular function in humans. C1 [Sharifi, Reza; Chioza, Barry; Ozkan, Ege; Wan, Alexander; Crosby, Andrew H.] St Georges Univ London, Human Genet Res Ctr, Div Biomed Sci, London SW17 0RE, England. [Morra, Rosa; Tallis, Michael; Weston, Ria; Rossi, Marianna N.; Ahel, Dragana; Ahel, Ivan] Univ Manchester, Paterson Inst Canc Res, Canc Res UK, Manchester M20 4BX, Lancs, England. [Appel, C. Denise; Schellenberg, Matthew J.; Williams, Jason G.; Krahn, Juno; Williams, R. Scott] NIEHS, Struct Biol Lab, US Dept HHS, NIH, Res Triangle Pk, NC 27709 USA. [Jankevicius, Gytis; Golia, Barbara; Ladurner, Andreas G.; Timinszky, Gyula] Univ Munich, Inst Physiol Chem, Fac Med, Butenandt Inst Physiol Chem, D-81377 Munich, Germany. [Simpson, Michael A.; Trembath, Richard C.] Kings Coll London, Guys Hosp, London WC2R 2LS, England. [Matic, Ivan; Hay, Ron] Univ Dundee, Coll Life Sci, Wellcome Trust Ctr Gene Regulat & Express, Dundee DD1 4HN, Scotland. [Galehdari, Hamid] Ahvaz Shahid Chamran Univ, Fac Sci, Dept Genet, Ahwaz, Iran. [Ladurner, Andreas G.] CIPSM, Munich, Germany. [Ladurner, Andreas G.] Munich Cluster Syst Neurol SyNergy, Munich, Germany. RP Sharifi, R (reprint author), St Georges Univ London, Human Genet Res Ctr, Div Biomed Sci, London SW17 0RE, England. EM rsharifi@sgul.ac.uk; andreas.ladurner@med.lmu.de; gyula.timinszky@med.Imu.de; williamsrs@niehs.nih.gov; iahel@picr.man.ac.uk RI Simpson, Michael/F-4737-2011; Matic, Ivan/F-7284-2010; Williams, Robert/A-6059-2015; Jankevicius, Gytis/C-7126-2015; Crosby, Andrew/E-2218-2015; OI Simpson, Michael/0000-0002-8539-8753; Matic, Ivan/0000-0003-0170-7991; Jankevicius, Gytis/0000-0002-0212-3923; Chioza, Barry/0000-0002-3546-1726; Trembath, Richard/0000-0003-0550-3400; Weston, Ria/0000-0001-8316-0728 FU US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765]; Cancer Research UK; European Research Council; CIPSM; SyNergy; HFSP; LMU; EU ITN network 'Nucleosome4D'; MRC, UK; SGUL; UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre FX RSW is supported by the intramural research program of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) grant 1Z01ES102765. We thank L Pedersen of the NIEHS collaborative crystallography group, and the Advanced Photon Source (APS) Southeast Regional Collaborative Access Team (SER-CAT) staff for assistance with crystallographic data collection. IA is supported by Cancer Research UK and the European Research Council. IM is a Sir Henry Wellcome Postdoctoral Fellow. AGL is supported by CIPSM, SyNergy, HFSP, the LMU and the EU ITN network 'Nucleosome4D', which partly funded the PhD research of GJ. GJ is a member of the International Max Planck Research School for Molecular and Cellular Life Sciences (IMPRS). GT is supported by the LMU. RS is supported by the grants awarded from MRC, UK, and SGUL. Research at KCL was supported by the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. We thank the patients and families participated in this study. We also thank the Blood Transfusion Organisation-IRAN-Khouzestan. NR 42 TC 77 Z9 78 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 2 PY 2013 VL 32 IS 9 BP 1225 EP 1237 DI 10.1038/emboj.2013.51 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 146VL UT WOS:000319122600005 PM 23481255 ER PT J AU Hwang, LC Vecchiarelli, AG Han, YW Mizuuchi, M Harada, Y Funnell, BE Mizuuchi, K AF Hwang, Ling Chin Vecchiarelli, Anthony G. Han, Yong-Woon Mizuuchi, Michiyo Harada, Yoshie Funnell, Barbara E. Mizuuchi, Kiyoshi TI ParA-mediated plasmid partition driven by protein pattern self-organization SO EMBO JOURNAL LA English DT Article DE bacterial chromosome segregation; diffusion ratchet; nucleoid; protein gradient; spatial organization ID BACTERIAL-DNA SEGREGATION; F-PLASMID; P1 PARA; INTRACELLULAR-LOCALIZATION; NONSPECIFIC DNA; ATP; SOPA; BINDING; SITE; DEPENDS AB DNA segregation ensures the stable inheritance of genetic material prior to cell division. Many bacterial chromosomes and low-copy plasmids, such as the plasmids P1 and F, employ a three-component system to partition replicated genomes: a partition site on the DNA target, typically called parS, a partition site binding protein, typically called ParB, and a Walker-type ATPase, typically called ParA, which also binds non-specific DNA. In vivo, the ParA family of ATPases forms dynamic patterns over the nucleoid, but how ATP-driven patterning is involved in partition is unknown. We reconstituted and visualized ParA-mediated plasmid partition inside a DNA-carpeted flowcell, which acts as an artificial nucleoid. ParA and ParB transiently bridged plasmid to the DNA carpet. ParB-stimulated ATP hydrolysis by ParA resulted in ParA disassembly from the bridging complex and from the surrounding DNA carpet, which led to plasmid detachment. Our results support a diffusion-ratchet model, where ParB on the plasmid chases and redistributes the ParA gradient on the nucleoid, which in turn mobilizes the plasmid. C1 [Hwang, Ling Chin; Vecchiarelli, Anthony G.; Mizuuchi, Michiyo; Mizuuchi, Kiyoshi] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Han, Yong-Woon; Harada, Yoshie] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Kyoto, Japan. [Funnell, Barbara E.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. RP Mizuuchi, K (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5 Room 237,5 Mem Dr, Bethesda, MD 20892 USA. EM kmizu@helix.nih.gov RI Hwang, Ling Chin/G-4078-2014 FU Canadian Institutes of Health Research [37997]; Program for Next Generation World-Leading Researchers [LS072]; World Premier International Research Center Initiative (WPI) MEXT, Japan; MEXT, Japan [23770204]; Nancy Nossal Fellowship FX We are grateful to Vassili Ivanov for help with the microscope. This work was supported by the intramural research fund for NIDDK, NIH, HHS, US Government, grant 37997 from the Canadian Institutes of Health Research to BEF, Program for Next Generation World-Leading Researchers, LS072 to YH, World Premier International Research Center Initiative (WPI) MEXT, Japan to YWH and YH, Grant for Young Scientists (B) from the MEXT, Japan, 23770204 to YWH, and the Nancy Nossal Fellowship to LCH and AGV. NR 30 TC 41 Z9 41 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 2 PY 2013 VL 32 IS 9 BP 1238 EP 1249 DI 10.1038/emboj.2013.34 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 146VL UT WOS:000319122600006 PM 23443047 ER PT J AU Wise, AL Gyi, L Manolio, TA AF Wise, Anastasia L. Gyi, Lin Manolio, Teri A. TI eXclusion: Toward Integrating the X Chromosome in Genome-wide Association Analyses SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PROSTATE-CANCER SUSCEPTIBILITY; LOCI; VARIANTS; RISK AB The X chromosome lags behind autosomal chromosomes in genome-wide association study (GWAS) findings. Indeed, the X chromosome is commonly excluded from GWAS analyses despite being assayed on all current GWAS microarray platforms. This raises the question: why are so few hits reported on the X chromosome? This commentary aims to examine this question through review of the current X chromosome results in the National Human Genome Research Institute Catalog of Published Genome-Wide Association Studies (NHGRI GWAS Catalog). It will also investigate commonly cited reasons for exclusion of the X chromosome from GWAS and review the tools currently available for X chromosome analysis. It will conclude with recommendations for incorporating X chromosome analyses in future studies. C1 [Wise, Anastasia L.; Gyi, Lin; Manolio, Teri A.] NHGRI, Bethesda, MD 20892 USA. RP Wise, AL (reprint author), NHGRI, Bethesda, MD 20892 USA. EM anastasia.wise@nih.gov NR 24 TC 34 Z9 34 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 2 PY 2013 VL 92 IS 5 BP 643 EP 647 DI 10.1016/j.ajhg.2013.03.017 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 139KY UT WOS:000318582800001 PM 23643377 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI Incidental Variants Are Critical for Genomics SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID INFORMED-CONSENT; CHAIR PERSPECTIVES; GENETIC RESEARCH; RETURN; DISCLOSURE; RESEARCHER; MEDICINE; BIOBANKS AB The topic of incidental variants detected through exome and genome sequencing is controversial, both in clinical practice and in research. The arguments for and against the deliberate analysis and return of incidental variants focus on issues of clinical validity, clinical utility, autonomy, clinical and research infrastructure and costs, and, in the research arena, therapeutic misconception. These topics are briefly reviewed and an argument is made that these variants are the future of genomic medicine. As a field, we should take full advantage of all opportunities to study these variants by searching them out, returning them to patients and research participants, and studying their utility for predictive medicine. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov FU National Human Genome Research Institute of the National Institutes of Health FX The author is grateful to Barbara Biesecker for reviewing a presubmission draft of this manuscript and to the anonymous reviewers for their helpful suggestions. The author is supported by the intramural research program of the National Human Genome Research Institute of the National Institutes of Health. The opinions expressed here are those of the author and do not necessarily reflect the views of the institutions to which he is affiliated. The author is an uncompensated consultant to the Illumina Corporation and receives honoraria from Wiley-Blackwell for editing. NR 37 TC 21 Z9 21 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 2 PY 2013 VL 92 IS 5 BP 648 EP 651 DI 10.1016/j.ajhg.2013.04.001 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 139KY UT WOS:000318582800002 PM 23643378 ER PT J AU Stranecky, V Hoischen, A Hartmannova, H Zaki, MS Chaudhary, A Zudaire, E Noskova, L Baresova, V Pristoupilova, A Hodanova, K Sovova, J Hulkova, H Piherova, L Hehir-Kwa, JY de Silva, D Senanayake, MP Farrag, S Zeman, J Martasek, P Baxova, A Afifi, HH St Croix, B Brunner, HG Temtamy, S Kmoch, S AF Stranecky, Viktor Hoischen, Alexander Hartmannova, Hana Zaki, Maha S. Chaudhary, Amit Zudaire, Enrique Noskova, Lenka Baresova, Veronika Pristoupilova, Anna Hodanova, Katerina Sovova, Jana Hulkova, Helena Piherova, Lenka Hehir-Kwa, Jayne Y. de Silva, Deepthi Senanayake, Manouri P. Farrag, Sameh Zeman, Jiri Martasek, Pavel Baxova, Alice Afifi, Hanan H. St Croix, Brad Brunner, Han G. Temtamy, Samia Kmoch, Stanislav TI Mutations in ANTXR1 Cause GAPO Syndrome SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CAPILLARY MORPHOGENESIS PROTEIN-2; EXONIC SPLICING ENHANCERS; OF-THE-LITERATURE; ANTHRAX TOXIN; ACTIN CYTOSKELETON; TUMOR ENDOTHELIUM; RECEPTOR; TEM8; EXPRESSION; MARKER-8 AB The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. We studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262C>T [p.Arg88*] and c.505C>T [p.Arg169*]) or splicing mutations (c.1435-12A>G [p.Gly479Phefs*119]) in ANTXR1, which encodes anthrax toxin receptor 1. The nonsense mutations predictably trigger nonsense-mediated mRNA decay, resulting in the loss of ANTXR1. The transcript with the splicing mutation theoretically encodes a truncated ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C terminus. GAPO syndrome's major phenotypic features, which include dental abnormalities and the accumulation of extracellular matrix, recapitulate those found in Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix regulation. Thus, we propose that mutations affecting ANTXR1 function are responsible for this disease's characteristic generalized defect in extracellular-matrix homeostasis. C1 [Stranecky, Viktor; Hartmannova, Hana; Noskova, Lenka; Baresova, Veronika; Pristoupilova, Anna; Hodanova, Katerina; Sovova, Jana; Hulkova, Helena; Piherova, Lenka; Kmoch, Stanislav] Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Prague 12000 2, Czech Republic. [Hoischen, Alexander; Hehir-Kwa, Jayne Y.; Brunner, Han G.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen Ctr Mol Life Sci,Inst Genet & Metab Dis, NL-6500 HC Nijmegen, Netherlands. [Zaki, Maha S.; Afifi, Hanan H.; Temtamy, Samia] Natl Res Ctr, Dept Clin Genet, Cairo 12311, Egypt. [Chaudhary, Amit; Zudaire, Enrique; St Croix, Brad] Frederick Natl Lab Canc Res, Tumor Angiogenesis Sect, Frederick, MD 21702 USA. [de Silva, Deepthi] Univ Kelaniya, Fac Med, Ragama 11010, Sri Lanka. [Senanayake, Manouri P.] Univ Colombo, Fac Med, Dept Paediat, Colombo 08, Sri Lanka. [Farrag, Sameh; Zeman, Jiri; Martasek, Pavel] Charles Univ Prague, Fac Med 1, Dept Pediat, Prague 12000 2, Czech Republic. [Baxova, Alice] Charles Univ Prague, Fac Med 1, Dept Med Genet, Prague 12000 2, Czech Republic. RP Kmoch, S (reprint author), Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Prague 12000 2, Czech Republic. EM skmoch@lfl.cuni.cz RI Brunner, Han/C-9928-2013; Hoischen, Alexander/D-1282-2013; Hehir, g. J.Y./L-4358-2015; Pristoupilova, Anna/F-4990-2017; OI Hoischen, Alexander/0000-0002-8072-4476; Pristoupilova, Anna/0000-0003-0047-9405; Afifi, Hanan Hosny/0000-0002-2502-4776; temtamy, samia/0000-0002-6452-823X; Zaki, Maha/0000-0001-7840-0002 FU Charles University [PRVOUK-P24/LF1/3, UNCE 204011, SVV2012/2645, CZ.1.05/1.1.00/02.0109]; Biotechnology and Biomedicine Centre of the Academy of Sciences; European Regional Development Fund; Ministry of Education [NT13116-4/2012]; Ministry of Health of the Czech Republic; National Cancer Institute, National Institutes of Health, US Department of Health and Social Services; Netherlands Organization for Health Research and Development [ZonMW 916-12-095] FX This work was supported by Charles University institutional programs PRVOUK-P24/LF1/3, UNCE 204011, and SVV2012/2645; by the Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (CZ.1.05/1.1.00/02.0109); by the European Regional Development Fund; by grant NT13116-4/2012 from the Ministry of Education and Ministry of Health of the Czech Republic; and by the intramural research program of the National Cancer Institute, National Institutes of Health, US Department of Health and Social Services. A.H. was supported by the Netherlands Organization for Health Research and Development (ZonMW 916-12-095). We thank clinical colleagues and families who contributed samples used in this study, as well as members of the Genomic Disorders Group Nijmegen for their technical support. A.C. and B.S.C. are coinventors of filed patents related to the development of ANTXR1 antibodies for cancer therapy. NR 38 TC 25 Z9 26 U1 0 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY 2 PY 2013 VL 92 IS 5 BP 792 EP 799 DI 10.1016/j.ajhg.2013.03.023 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 139KY UT WOS:000318582800014 PM 23602711 ER PT J AU Thun, MJ Lopez, AD Hartge, P AF Thun, Michael J. Lopez, Alan D. Hartge, Patricia TI Smoking-Related Mortality in the United States Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Thun, Michael J.] Amer Canc Soc, Atlanta, GA 30329 USA. [Lopez, Alan D.] Univ Queensland, Brisbane, Qld, Australia. [Hartge, Patricia] NCI, Bethesda, MD 20892 USA. RP Thun, MJ (reprint author), Amer Canc Soc, Atlanta, GA 30329 USA. NR 1 TC 8 Z9 8 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 2 PY 2013 VL 368 IS 18 BP 1753 EP 1753 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 134MN UT WOS:000318214400027 PM 23635064 ER PT J AU Matsuo, M Coon, SL Klein, DC AF Matsuo, Masahiro Coon, Steven L. Klein, David C. TI RGS2 is a feedback inhibitor of melatonin production in the pineal gland SO FEBS LETTERS LA English DT Article DE Melatonin; Pineal gland; Regulator of G-protein signaling; RGS2; Norepinephrine ID ARYLALKYLAMINE-N-ACETYLTRANSFERASE; ADRENERGIC REGULATION; RAT PINEALOCYTES; ACTIVATION; IDENTIFICATION; EXPRESSION; PROTEINS; RHYTHM AB The 24-h rhythmic production of melatonin by the pineal gland is essential for coordinating circadian physiology. Melatonin production increases at night in response to the release of norepinephrine from sympathetic nerve processes which innervate the pineal gland. This signal is transduced through G-protein-coupled adrenergic receptors. Here, we found that the abundance of regulator of G-protein signaling 2 (RGS2) increases at night, that expression is increased by norepinephrine and that this protein has a negative feedback effect on melatonin production. These data are consistent with the conclusion that RGS2 functions on a daily basis to negatively modulate melatonin production. Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Matsuo, Masahiro; Coon, Steven L.; Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NIH, Bldg 49,Rm 6A82, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov FU NICHD FX This work was supported by the Intramural Research Program of the NICHD. We express appreciation to Peter Chidiac for providing the RGS2 adenovirus and valuable scientific input. NR 24 TC 6 Z9 7 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 2 PY 2013 VL 587 IS 9 BP 1392 EP 1398 DI 10.1016/j.febslet.2013.03.016 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 128DU UT WOS:000317750100021 PM 23523917 ER PT J AU Banerjee, D Biggs, ML Mercer, L Mukamal, K Kaplan, R Barzilay, J Kuller, L Kizer, JR Djousse, L Tracy, R Zieman, S Lloyd-Jones, D Siscovick, D Carnethon, M AF Banerjee, Dipanjan Biggs, Mary L. Mercer, Laina Mukamal, Kenneth Kaplan, Robert Barzilay, Joshua Kuller, Lewis Kizer, Jorge R. Djousse, Luc Tracy, Russell Zieman, Susan Lloyd-Jones, Donald Siscovick, David Carnethon, Mercedes TI Insulin Resistance and Risk of Incident Heart Failure Cardiovascular Health Study SO CIRCULATION-HEART FAILURE LA English DT Article DE epidemiology; heart failure; insulin ID IDIOPATHIC DILATED CARDIOMYOPATHY; DIABETIC CARDIOMYOPATHY; METABOLIC SYNDROME; GENE-EXPRESSION; DISEASE; SENSITIVITY; PROGRESSION; MORTALITY; GEOMETRY; MASS AB Background-Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance as compared with matched controls. Insulin resistance leads to structural abnormalities in the heart, such as increased left atrial size, left ventricular mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether insulin resistance precedes the development of HF or whether the relationship between insulin resistance and HF is present among adults with HF caused by nonischemic heart disease. Methods and Results-We examined 4425 participants (60% women) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes mellitus at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry. There were 1216 cases of incident HF (1103 without antecedent myocardial infarction) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (hazard ratio, 1.10; 95% confidence interval, 1.05-1.15, per SD change) when adjusted for age, sex, race, field center, physical activity, smoking, alcohol intake, high-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent myocardial infarction (hazard ratio, 1.10; 95% confidence interval, 1.05-1.15). Measures of left atrial size, left ventricular mass, and peak A velocity at baseline were associated both with fasting insulin levels and with HF; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (hazard ratio, 1.08; 95% confidence interval, 1.03-1.14 per 1-SD increase in fasting insulin). Conclusions-Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in Cardiovascular Health Study participants, including those without an antecedent myocardial infarction. C1 [Banerjee, Dipanjan] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Biggs, Mary L.; Mercer, Laina; Siscovick, David] Univ Washington, Seattle, WA 98195 USA. [Mukamal, Kenneth] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kaplan, Robert] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Barzilay, Joshua] Kaiser Permanente Georgia, Tucker, GA USA. [Kuller, Lewis] Univ Pittsburgh, Pittsburgh, PA USA. [Kizer, Jorge R.] Weill Cornell Med Coll, New York, NY USA. [Djousse, Luc] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Tracy, Russell] Univ Vermont, Burlington, VT USA. [Zieman, Susan] NIA, Bethesda, MD 20892 USA. [Carnethon, Mercedes] Northwestern Univ, Evanston, IL USA. RP Banerjee, D (reprint author), Stanford Univ, Sch Med, Falk CVRB 275,300 Pasteur Dr, Stanford, CA 94305 USA. EM dipanjan@stanford.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute [HHSN268201200036C, N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295, R01HL094555]; National Institute on Aging [1R01AG031890]; National Institute of Neurological Disorders and Stroke; [AG-023629]; [AG-15928]; [AG-20098]; [AG-027058] FX This work was supported by contract numbers HHSN268201200036C, N01-HC-85239, and N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grants HL080295 and R01HL094555 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, AG-027058, and grant 1R01AG031890 from the National Institute on Aging. NR 33 TC 13 Z9 14 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAY PY 2013 VL 6 IS 3 BP 364 EP 370 DI 10.1161/CIRCHEARTFAILURE.112.000022 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA8ZM UT WOS:000331383500009 PM 23575256 ER PT J AU Ebong, IA Goff, DC Rodriguez, CJ Chen, HY Sibley, CT Bertoni, AG AF Ebong, Imo A. Goff, David C., Jr. Rodriguez, Carlos J. Chen, Haiying Sibley, Christopher T. Bertoni, Alain G. TI Association of Lipids With Incident Heart Failure Among Adults With and Without Diabetes Mellitus Multiethnic Study of Atherosclerosis SO CIRCULATION-HEART FAILURE LA English DT Article DE diabetes mellitus; heart failure; lipids ID DENSITY-LIPOPROTEIN CHOLESTEROL; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; RISK-FACTORS; MYOCARDIAL STEATOSIS; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; FOLLOW-UP; OBESITY; TRIGLYCERIDES AB Background-Dyslipidemia is a known risk factor for coronary disease, but its role in heart failure (HF) development is less well-defined. Methods and Results-We included 5688 participants, aged 45 to 84 years, without clinical cardiovascular disease, and not receiving lipid-lowering medications at baseline, from the Multiethnic Study of Atherosclerosis. Cox-proportional hazards models were used to evaluate associations of triglyceride, total cholesterol/high-density lipoprotein-cholesterol (HDL-C) ratio, HDL-C, and non HDL-C with incident HF. We investigated for effect-modification by diabetes mellitus status and sex. During a median follow-up of 8.5 years, there were 152 incident HF cases. There were no interactions by sex. We observed significant interactions between triglyceride and diabetes mellitus (P-interaction < 0.05). We stratified our analyses by diabetes mellitus status. In participants with diabetes, the hazard ratios were 2.03 (0.97-4.27) and 1.68 (1.18-2.38) for high triglyceride and log of triglyceride, respectively, after adjusting for confounders, comorbidities, and diabetes mellitus severity/treatment. The association of high triglyceride with incident HF was attenuated by interim myocardial infarction. The hazard ratios were greatest in participants with diabetes who also had high triglyceride, low HDL-C, or high total cholesterol/HDL-C ratio (3.59 [2.03-6.33], 3.62 [2.06-6.36], and 3.54 [1.87-6.70], respectively). Lipid measures were not associated with incident HF in individuals without diabetes. Conclusions-The risk of incident HF is greater in individuals with diabetes mellitus who also have high triglyceride, low HDL-C, or high total cholesterol/HDL-C ratio. The association of high triglyceride with incident HF is partly mediated by myocardial infarction. C1 [Ebong, Imo A.] Univ So Calif, Dept Med, Los Angeles, CA 90089 USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Aurora, CO USA. [Rodriguez, Carlos J.; Bertoni, Alain G.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Rodriguez, Carlos J.; Bertoni, Alain G.] Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Winston Salem, NC 27103 USA. [Chen, Haiying] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Sibley, Christopher T.] NIH, Bethesda, MD 20892 USA. RP Ebong, IA (reprint author), Univ So Calif, Dept Med, 2020 Zonal Ave, Los Angeles, CA 90089 USA. EM ebong@usc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NHLBI [5 T32 HL087730-03] FX Multiethnic Study of Atherosclerosis was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute (NHLBI). T32 training grant was supported by grant 5 T32 HL087730-03 from NHLBI. NR 39 TC 13 Z9 14 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAY PY 2013 VL 6 IS 3 BP 371 EP + DI 10.1161/CIRCHEARTFAILURE.112.000093 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA8ZM UT WOS:000331383500010 PM 23529112 ER PT J AU Doenst, T Cleland, JGF Rouleau, JL She, LL Wos, S Ohman, EM Krzeminska-Pakula, M Airan, B Jones, RH Siepe, M Sopko, G Velazquez, EJ Racine, N Gullestad, L Filgueira, JL Lee, KL AF Doenst, Torsten Cleland, John G. F. Rouleau, Jean L. She, Lilin Wos, Stanislaw Ohman, E. Magnus Krzeminska-Pakula, Maria Airan, Balram Jones, Robert H. Siepe, Matthias Sopko, George Velazquez, Eric J. Racine, Normand Gullestad, Lars Luis Filgueira, Jose Lee, Kerry L. CA STICH Investigators TI Influence of Crossover on Mortality in a Randomized Study of Revascularization in Patients With Systolic Heart Failure and Coronary Artery Disease SO CIRCULATION-HEART FAILURE LA English DT Article DE coronary bypass surgery; heart failure; medical therapy ID SURGICAL-TREATMENT; BYPASS SURGERY; TRIAL; THERAPY AB Background-To assess the influence of therapy crossovers on treatment comparisons and mortality at 5 years in patients with ischemic heart disease and heart failure randomly assigned to medical therapy alone (MED) or to MED and coronary artery bypass graft (CABG) surgery in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Methods and Results-The influence of early crossover (within the first year after randomization) on 5-year mortality was assessed using time-dependent multivariable Cox models. CABG was performed in 65/602 patients (10.8%) assigned to MED, and 55/610 patients (9.0%) assigned to CABG received MED only. Common reasons for crossover from MED to CABG were progressive symptoms or acute decompensation. MED-assigned patients who underwent CABG had lower 5-year mortality than those who received MED only (25% vs 42%; hazard ratio, 0.50; 95% confidence interval, 0.30-0.85; P=0.008). The main reason for crossover from CABG to MED was patient/family decision. Five patients did not undergo their assigned CABG within a year but died before receiving surgery without status change. They were deemed crossover to MED. The CABG-to-MED crossover population had higher 5-year mortality compared with those treated with CABG per-protocol (59% vs 33%; hazard ratio, 2.01; 95% confidence interval, 1.36-2.96; P<0.001). CABG was associated with lower mortality compared with MED in per-protocol and several time-dependent analyses (all P<0.05). Conclusions-CABG reduced mortality in both the per-protocol and crossover STICH patient populations. Crossover from assigned therapy, therefore, diminished the impact of CABG on survival in STICH when analyzed by intention to treat. C1 [Doenst, Torsten] Univ Jena, Dept Cardiothorac Surg, D-07747 Jena, Germany. [Cleland, John G. F.] Univ Hull, Castle Hill Hosp, Dept Cardiol, Cottingham, England. [Rouleau, Jean L.; Racine, Normand] Univ Montreal, Dept Med, Montreal Heart Inst, Montreal, PQ H3C 3J7, Canada. [Ohman, E. Magnus; Velazquez, Eric J.] Duke Univ, Sch Med, Dept Med Cardiol, Durham, NC USA. [Jones, Robert H.] Duke Univ, Sch Med, Dept Surg Cardiothorac, Durham, NC USA. [Lee, Kerry L.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [She, Lilin; Ohman, E. Magnus; Jones, Robert H.; Velazquez, Eric J.; Lee, Kerry L.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Wos, Stanislaw] Med Univ Silesia, Dept Cardiac Surg 2, Katowice, Poland. [Krzeminska-Pakula, Maria] Inst Kardiol AM, Dept Cardiol, Lodz, Poland. [Airan, Balram] All India Inst Med Sci, Dept Cardiovasc & Thorac Surg, New Delhi, India. [Siepe, Matthias] Univ Freiburg, Dept Cardiovasc Surg, D-79106 Freiburg, Germany. [Sopko, George] NHLBI, Heart Failure & Arrhythmias Branch, NIH, Bethesda, MD 20892 USA. [Gullestad, Lars] Oslo Univ Hosp, Rikshosp, Dept Cardiol, Oslo, Norway. [Luis Filgueira, Jose] Casa Galicia, Montevideo, Uruguay. RP Doenst, T (reprint author), Univ Jena, Dept Cardiothorac Surg, Erlanger Allee 101, D-07747 Jena, Germany. EM doenst@med.uni-jena.de OI Cleland, John/0000-0002-1471-7016 FU [U01HL69015]; [U01HL69013] FX The Surgical Treatment for Ischemic Heart Failure trial was supported by grants U01HL69015 and U01HL69013. NR 12 TC 16 Z9 16 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAY PY 2013 VL 6 IS 3 BP 443 EP + DI 10.1161/CIRCHEARTFAILURE.112.000130 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA8ZM UT WOS:000331383500019 PM 23515275 ER PT J AU Heidenreich, PA Albert, NM Allen, LA Bluemke, DA Butler, J Fonarow, GC Ikonomidis, JS Khavjou, O Konstam, MA Maddox, TM Nichol, G Pham, M Pina, IL Trogdon, JG AF Heidenreich, Paul A. Albert, Nancy M. Allen, Larry A. Bluemke, David A. Butler, Javed Fonarow, Gregg C. Ikonomidis, John S. Khavjou, Olga Konstam, Marvin A. Maddox, Thomas M. Nichol, Graham Pham, Michael Pina, Ileana L. Trogdon, Justin G. CA American Heart Assoc Advocacy Council Cardiovasc Radiol Council Clin Cardiol Council Epidemiol Prevent Stroke TI Forecasting the Impact of Heart Failure in the United States A Policy Statement From the American Heart Association SO CIRCULATION-HEART FAILURE LA English DT Article DE AHA Scientific Statements; heart failure ID COLLEGE-OF-CARDIOLOGY; HIGH BLOOD-PRESSURE; CARE TRANSITIONS INTERVENTION; 2011 PERFORMANCE-MEASURES; TASK-FORCE; CARDIOVASCULAR-DISEASE; MEDICARE BENEFICIARIES; PHYSICIAN CONSORTIUM; SCIENTIFIC STATEMENT; PRACTICE GUIDELINES AB Background-Heart failure (HF) is an important contributor to both the burden and cost of national healthcare expenditures, with more older Americans hospitalized for HF than for any other medical condition. With the aging of the population, the impact of HF is expected to increase substantially. Methods and Results-We estimated future costs of HF by adapting a methodology developed by the American Heart Association to project the epidemiology and future costs of HF from 2012 to 2030 without double counting the costs attributed to comorbid conditions. The model assumes that HF prevalence will remain constant by age, sex, and race/ethnicity and that rising costs and technological innovation will continue at the same rate. By 2030, >8 million people in the United States (1 in every 33) will have HF. Between 2012 and 2030, real (2010$) total direct medical costs of HF are projected to increase from $21 billion to $53 billion. Total costs, including indirect costs for HF, are estimated to increase from $31 billion in 2012 to $70 billion in 2030. If one assumes all costs of cardiac care for HF patients are attributable to HF (no cost attribution to comorbid conditions), the 2030 projected cost estimates of treating patients with HF will be 3-fold higher ($160 billion in direct costs). Conclusions-The estimated prevalence and cost of care for HF will increase markedly because of aging of the population. Strategies to prevent HF and improve the efficiency of care are needed. C1 [Heidenreich, Paul A.] Stanford Univ, Stanford, CA 94305 USA. [Albert, Nancy M.] Cleveland Clin Fdn, Cleveland, OH USA. [Allen, Larry A.] Univ Colorado, Boulder, CO 80309 USA. [Bluemke, David A.] NIH, Bethesda, MD USA. [Butler, Javed] Emory Univ, Atlanta, GA 30322 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Ikonomidis, John S.] Med Univ S Carolina, Charleston, SC USA. [Khavjou, Olga; Trogdon, Justin G.] RTI, Res Triangle Pk, NC USA. [Konstam, Marvin A.] Tufts Med Ctr, Boston, MA USA. [Nichol, Graham] Univ Washington, Harborview Med Ctr, Seattle, WA 98195 USA. [Pina, Ileana L.] Montefiore Einstein Med Ctr, Bronx, NY USA. RP Heidenreich, PA (reprint author), Stanford Univ, Stanford, CA 94305 USA. OI Heidenreich, Paul/0000-0001-7730-8490; Bluemke, David/0000-0002-8323-8086 FU NHLBI NIH HHS [K23 HL105896] NR 85 TC 363 Z9 370 U1 7 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAY PY 2013 VL 6 IS 3 BP 606 EP 619 DI 10.1161/HHF.0b013e318291329a PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA8ZM UT WOS:000331383500036 PM 23616602 ER PT J AU Szabo, E Mao, JT Lam, S Reid, ME Keith, RL AF Szabo, Eva Mao, Jenny T. Lam, Stephen Reid, Mary E. Keith, Robert L. TI Chemoprevention of Lung Cancer Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines SO CHEST LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; RANDOMIZED CONTROLLED-TRIAL; GROWTH-FACTOR RECEPTOR; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; BRONCHIAL SQUAMOUS METAPLASIA; LONG-TERM SUPPLEMENTATION; INTERMEDIATE END-POINTS; RISK PREDICTION MODEL; GROUND-GLASS OPACITY; CARCINOMA IN-SITU AB Background: Lung cancer is the most common cause of cancer death in men and women in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk of developing lung cancer compared with lifetime never smokers. Chemoprevention refers to the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention. Methods: Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations. Results: None of the phase 3 trials with the agents beta-carotene, retinol, 13-cis-retinoic acid, alpha-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium has demonstrated beneficial and reproducible results. To facilitate the evaluation of promising agents and to lessen the need for a large sample size, extensive time commitment, and expense, surrogate end point biomarker trials are being conducted to assist in identifying the most promising agents for later-stage chemoprevention trials. With the understanding of important cellular signaling pathways and the expansion of potentially important targets, agents (many of which target inflammation and the arachidonic acid pathway) are being developed and tested which may prevent or reverse lung carcinogenesis. Conclusions: By integrating biologic knowledge, additional early-phase trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points. C1 [Szabo, Eva] NCI, Lung & Upper Aerodigest Canc Res Grp, NIH, Bethesda, MD 20892 USA. [Mao, Jenny T.] Univ New Mexico, New Mexico VA Hlth Care Syst, Div Pulm Crit Care & Sleep Med, Albuquerque, NM 87131 USA. [Lam, Stephen] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Reid, Mary E.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Keith, Robert L.] Univ Colorado, Sch Med, VA Eastern Colorado Hlth Care Syst, Denver, CO 80220 USA. RP Keith, RL (reprint author), Univ Colorado, VA Eastern Colorado Hlth Care Syst, Div Pulm Sci & Crit Care Med, 1055 Clermont St,Box 151, Denver, CO 80220 USA. EM Robert.keith@ucdenver.edu FU Lung Cancer Research Foundation; Boehringer Ingelheim Pharmaceuticals, Inc. FX The overall process for the development of these guidelines, including matters pertaining to funding and conflicts of interest, are described in the methodology article. The development of this guideline was supported primarily by the American College of Chest Physicians. The lung cancer guidelines conference was supported in part by a grant from the Lung Cancer Research Foundation. The publication and dissemination of the guidelines was supported in part by a 2009 independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc. COI Grids reflecting the conflicts of interest that were current as of the date of the conference and voting are posted in the online supplementary materials. NR 169 TC 9 Z9 9 U1 0 U2 2 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD MAY PY 2013 VL 143 IS 5 SU S BP E40 EP E60 DI 10.1378/chest.12-2348 PG 21 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AB1HL UT WOS:000331542000003 ER PT J AU Iglesias-Rios, L Parascandola, M AF Iglesias-Rios, Lisbeth Parascandola, Mark TI A Historical Review of R. J. Reynolds' Strategies for Marketing Tobacco to Hispanics in the United States SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID CIGARETTE-SMOKING; INDUSTRY DOCUMENTS; PUBLIC-HEALTH; RACIAL/ETHNIC DISPARITIES; ETHNIC IDENTIFICATION; ADOLESCENT SMOKING; CULTURAL-VALUES; ASIAN-AMERICAN; SUBSTANCE USE; QUIT SMOKING AB Hispanics are the fastest growing racial/ethnic group in the United States, and smoking is the leading preventable cause of morbidity and mortality among this population. We analyzed tobacco industry documents on R. J. Reynolds' marketing strategies toward the Hispanic population using tobacco industry document archives from the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu) between February-July 2011 and April-August 2012. Our analysis revealed that by 1980 the company had developed a sophisticated surveillance system to track the market behavior of Hispanic smokers and understand their psychographics, cultural values, and attitudes. This information was translated into targeted marketing campaigns for the Winston and Camel brands. Marketing targeted toward Hispanics appealed to values and sponsored activities that could be perceived as legitimating. Greater understanding of tobacco industry marketing strategies has substantial relevance for addressing tobacco-related health disparities. C1 [Iglesias-Rios, Lisbeth; Parascandola, Mark] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. RP Iglesias-Rios, L (reprint author), NCI, Tobacco Control Res Branch, 6130 Execut Blvd,EPN 4039A, Bethesda, MD 20892 USA. EM lisgle@umich.edu NR 191 TC 8 Z9 8 U1 5 U2 10 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2013 VL 103 IS 5 BP E15 EP E27 DI 10.2105/AJPH.2013.301256 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA2UJ UT WOS:000330949300011 PM 23488493 ER PT J AU Baxter, LL Pavan, WJ AF Baxter, Laura L. Pavan, William J. TI The etiology and molecular genetics of human pigmentation disorders SO WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY LA English DT Article AB Pigmentation, defined as the placement of pigment in skin, hair, and eyes for coloration, is distinctive because the location, amount, and type of pigmentation provides a visual manifestation of genetic heterogeneity in pathways regulating the pigment-producing cells, melanocytes. The scope of this genetic heterogeneity in humans ranges from normal to pathological pigmentation phenotypes. Clinically, normal human pigmentation encompasses a variety of skin and hair color as well as punctate pigmentation such as melanocytic nevi (moles) or ephelides (freckles), while abnormal human pigmentation exhibits markedly reduced or increased pigment levels, known as hypopigmentation and hyperpigmentation, respectively. Elucidation of the molecular genetics underlying pigmentation has revealed genes important for melanocyte development and function. Furthermore, many pigmentation disorders show additional defects in cells other than melanocytes, and identification of the genetic insults in these disorders has revealed pleiotropic genes, where a single gene is required for various functions in different cell types. Thus, unravelling the genetics of easily visualized pigmentation disorders has identified molecular similarities between melanocytes and less visible cell types/tissues, arising from a common developmental origin and/or shared genetic regulatory pathways. Herein we discuss notable human pigmentation disorders and their associated genetic alterations, focusing on the fact that the developmental genetics of pigmentation abnormalities are instructive for understanding normal pathways governing development and function of melanocytes. (C) 2012 Wiley Periodicals, Inc. C1 [Baxter, Laura L.; Pavan, William J.] NHGRI, Mouse Embryol Sect, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, Mouse Embryol Sect, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM bpavan@nhgri.nih.gov FU Intramural NIH HHS [Z01 HG000070-12] NR 0 TC 9 Z9 10 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1759-7684 EI 1759-7692 J9 WIRES DEV BIOL JI Wiley Interdiscip. Rev.-Dev. Biol. PD MAY-JUN PY 2013 VL 2 IS 3 BP 379 EP 392 DI 10.1002/wdev.72 PG 14 WC Developmental Biology SC Developmental Biology GA 175XB UT WOS:000321265800005 PM 23799582 ER PT J AU Ismayil, A Hyun-Jin Tia, T Michael, B Anthony, C Edward, GL Mark, IT AF Ismayil, Ahmet Hyun-Jin Tia, Turner Michael, Brines Anthony, Cerami Edward, Lakatta G. Mark, Talan, I TI A Novel Small Non-Erytropoietic Helix B Peptide Effectively Controls Elevated Blood Pressure in Three Different Experimental Models of Hypertension SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Meeting Abstract DE Non-Erythropoietic Derivative of Erythropoietin; Animal Models of Hypertension; Small Peptide C1 [Ismayil, Ahmet; Hyun-Jin; Tia, Turner; Edward, Lakatta G.; Mark, Talan, I] NIA, Baltimore, MD 21224 USA. [Michael, Brines; Anthony, Cerami] Araim Pharmaceut, Ossining, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD MAY PY 2013 VL 15 SU 1 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AA0EX UT WOS:000330769400003 ER PT J AU Olga, VF Victoria, YS Edward, GL Alexei, YB AF Olga, Fedorova, V Victoria, Shilova Y. Edward, Lakatta G. Alexei, Bagrov Y. TI Featured Posters - Hypertension and Aging SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Meeting Abstract DE Aging and vascular fibrosis; Marinobufagenin and Na/K-ATPase signaling; ANP and PKG/cGMP-dependent signaling; Gene silencing C1 [Olga, Fedorova, V; Victoria, Shilova Y.; Edward, Lakatta G.; Alexei, Bagrov Y.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD MAY PY 2013 VL 15 SU 1 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AA0EX UT WOS:000330769400108 ER PT J AU Xue, H Greiser, A Zuehlsdorff, S Jolly, MP Guehring, J Arai, AE Kellman, P AF Xue, Hui Greiser, Andreas Zuehlsdorff, Sven Jolly, Marie-Pierre Guehring, Jens Arai, Andrew E. Kellman, Peter TI Phase-Sensitive Inversion Recovery for Myocardial T-1 Mapping with Motion Correction and Parametric Fitting SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE T-1 mapping; phase-sensitive inversion recovery; motion correction; MOLLI; cardiac MRI ID RESOLUTION; INFARCTION; MRI AB The assessment of myocardial fibrosis and extracellular volume requires accurate estimation of myocardial T(1)s. While image acquisition using the modified Look-Locker inversion recovery technique is clinically feasible for myocardial T-1 mapping, respiratory motion can limit its applicability. Moreover, the conventional T-1 fitting approach using the magnitude inversion recovery images can lead to less stable T-1 estimates and increased computational cost. In this article, we propose a novel T-1 mapping scheme that is based on phase-sensitive image reconstruction and the restoration of polarity of the MR signal after inversion. The motion correction is achieved by registering the reconstructed images after background phase removal. The restored signal polarity of the inversion recovery signal helps the T-1 fitting resulting in improved quality of the T-1 map and reducing the computational cost. Quantitative validation on a data cohort of 45 patients proves the robustness of the proposed method against varying image contrast. Compared to the magnitude T-1 fitting, the proposed phase-sensitive method leads to less fluctuation in T-1 estimates. (C) 2012 Wiley Periodicals, Inc. C1 [Xue, Hui; Jolly, Marie-Pierre] Siemens Corp, Corp Res, Princeton, NJ 08540 USA. [Greiser, Andreas; Guehring, Jens] Siemens AG, Healthcare Sect, Imaging & Therapy Div, Erlangen, Germany. [Zuehlsdorff, Sven] Siemens Healthcare USA Inc, CMR R&D, Chicago, IL USA. [Arai, Andrew E.; Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Xue, H (reprint author), Siemens Corp, Corp Res, 755 Coll Rd East, Princeton, NJ 08540 USA. EM huiue@siemens.com FU Intramural NIH HHS [Z99 HL999999, ZIA HL004607-14] NR 18 TC 23 Z9 23 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAY PY 2013 VL 69 IS 5 BP 1408 EP 1420 DI 10.1002/mrm.24385 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AA5DY UT WOS:000331117400003 PM 22736380 ER PT J AU Matsumoto, S Saito, K Yasui, H Morris, HD Munasinghe, JP Lizak, M Merkle, H Ardenkjaer-Larsen, JH Choudhuri, R Devasahayam, N Subramanian, S Koretsky, AP Mitchell, JB Krishna, MC AF Matsumoto, Shingo Saito, Keita Yasui, Hironobu Morris, H. Douglas Munasinghe, Jeeva P. Lizak, Martin Merkle, Hellmut Ardenkjaer-Larsen, Jan Henrik Choudhuri, Rajani Devasahayam, Nallathamby Subramanian, Sankaran Koretsky, Alan P. Mitchell, James B. Krishna, Murali C. TI EPR Oxygen Imaging and Hyperpolarized C-13 MRI of Pyruvate Metabolism as Noninvasive Biomarkers of Tumor Treatment Response to a Glycolysis Inhibitor 3-Bromopyruvate SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE 3-bromopyruvate; EPR imaging; HIF-1; hyperpolarized C-13 MRI; MCT1, tumor hypoxia ID ELECTRON-PARAMAGNETIC-RESONANCE; CANCER-CELLS; SOLID TUMORS; DRUG-RESISTANCE; CYCLING HYPOXIA; HSP90 INHIBITOR; THERAPY; EXPRESSION; PATHWAYS; MICE AB The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation and promote glycolysis for energy production. Thereby, inhibition of glycolysis has the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate blocks glycolysis pathway by inhibiting hypoxia inducible enzymes and enhanced cytotoxicity of 3-bromopyruvate under hypoxic conditions has been reported in vitro. However, the efficacy of 3-bromopyruvate was substantially attenuated in hypoxic tumor regions (pO(2) < 10 mmHg) in vivo using squamous cell carcinoma (SCCVII)-bearing mouse model. Metabolic MRI studies using hyperpolarized C-13-labeled pyruvate showed that monocarboxylate transporter-1 is the major transporter for pyruvate and the analog 3-bromopyruvate in SCCVII tumor. The discrepant results between in vitro and in vivo data were attributed to biphasic oxygen dependent expression of monocarboxylate transporter-1 in vivo. Expression of monocarboxylate transporter-1 was enhanced in moderately hypoxic (8-15 mmHg) tumor regions but down regulated in severely hypoxic (<5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia-activated drugs. (C) 2012 Wiley Periodicals, Inc. C1 [Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yasui, Hironobu] Hokkaido Univ, Grad Sch Vet Med, Dept Environm Vet Sci, Radiat Biol Lab, Sapporo, Hokkaido, Japan. [Morris, H. Douglas; Munasinghe, Jeeva P.; Lizak, Martin; Merkle, Hellmut; Koretsky, Alan P.] NINDS, Mouse Imaging Facil, Bethesda, MD 20892 USA. [Ardenkjaer-Larsen, Jan Henrik] GE Healthcare, Brondby, Denmark. [Ardenkjaer-Larsen, Jan Henrik] Tech Univ Denmark, DK-2800 Lyngby, Denmark. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM murali@helix.nih.gov RI Koretsky, Alan/C-7940-2015; Ardenkjar-Larsen, Jan Henrik/B-5765-2017; OI Koretsky, Alan/0000-0002-8085-4756; Ardenkjar-Larsen, Jan Henrik/0000-0001-6167-6926; Morris, H. Douglas/0000-0002-7942-3748 FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH FX Grant sponsors: Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. NR 45 TC 20 Z9 20 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAY PY 2013 VL 69 IS 5 BP 1443 EP 1450 DI 10.1002/mrm.24355 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AA5DY UT WOS:000331117400007 PM 22692861 ER PT J AU Drozdovitch, V Minenko, V Khrouch, V Leshcheva, S Gavrilin, Y Khrutchinsky, A Kukhta, T Kutsen, S Luckyanov, N Shinkarev, S Tretyakevich, S Trofimik, S Voilleque, P Bouville, A AF Drozdovitch, Vladimir Minenko, Victor Khrouch, Valeri Leshcheva, Svetlana Gavrilin, Yury Khrutchinsky, Arkady Kukhta, Tatiana Kutsen, Semion Luckyanov, Nickolas Shinkarev, Sergey Tretyakevich, Sergey Trofimik, Sergey Voilleque, Paul Bouville, Andre TI Thyroid Dose Estimates for a Cohort of Belarusian Children Exposed to Radiation from the Chernobyl Accident SO RADIATION RESEARCH LA English DT Article ID RADIOACTIVE CONTAMINATION; BYELARUS; CANCER; RECONSTRUCTION; UKRAINE; RADIONUCLIDES; I-131; UNCERTAINTIES; POPULATION; FALLOUT AB The U. S. National Cancer Institute, in collaboration with the Belarusian Ministry of Health, is conducting a study of thyroid cancer and other thyroid diseases in a cohort of about 12,000 persons who were exposed to fallout from the Chernobyl accident in April 1986. The study subjects were 18 years old or younger at the time of exposure and resided in Belarus in the most contaminated areas of the Gomel and Mogilev Oblasts, as well as in the city of Minsk. All cohort members had at least one direct thyroid measurement made in April-June 1986. Individual data on residential history, consumption of milk, milk products and leafy vegetables as well as administration of stable iodine were collected for all cohort members by means of personal interviews conducted between 1996 and 2007. Based on the estimated I-131 activities in the thyroids, which were derived from the direct thyroid measurements, and on the responses to the questionnaires, individual thyroid doses from intakes of I-131 were reconstructed for all cohort members. In addition, radiation doses to the thyroid were estimated for the following minor exposure pathways: (a) intake of short-lived I-132, I-133 and Te-132 by inhalation and ingestion; (b) external irradiation from radionuclides deposited on the ground; and (c) ingestion intake of Cs-134 and Cs-137. Intake of I-131 was the major pathway for thyroid exposure; its mean contribution to the thyroid dose was 92%. The thyroid doses from I-131 intakes varied from 0.5 mGy to almost 33 Gy; the mean was estimated to be 0.58 Gy, while the median was 0.23 Gy. The reconstructed doses are being used to evaluate the risk of thyroid cancer and other thyroid diseases in the cohort. (C) 2013 by Radiation Research Society C1 [Drozdovitch, Vladimir] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Minenko, Victor; Khrutchinsky, Arkady; Kutsen, Semion; Trofimik, Sergey] Res Inst Nucl Problems, Minsk, Byelarus. [Khrouch, Valeri; Gavrilin, Yury; Shinkarev, Sergey] Burnasyan Fed Med Biophys Ctr, Moscow, Russia. [Leshcheva, Svetlana] Republican Res Ctr Radiat Med & Human Ecol, Gomel, Byelarus. [Kukhta, Tatiana] United Inst Informat Problems, Minsk, Byelarus. [Luckyanov, Nickolas; Bouville, Andre] US Natl Canc Inst Retired, Minsk, Byelarus. [Tretyakevich, Sergey] Minist Emergencies, Dept Nucl & Radiat Safety, Minsk, Byelarus. [Voilleque, Paul] MJP Risk Assessment Inc, Denver, CO USA. RP Drozdovitch, V (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS 7100, Bethesda, MD 20892 USA. EM drozdovv@mail.nih.gov RI Kuten, Semen/F-6699-2016; Shinkarev, Sergey /B-3254-2017 OI Kuten, Semen/0000-0003-0827-8421; FU National Institutes of Health, National Cancer Institute (U.S.); ISTC Project [B-488p]; National Institute of Allergy and Infectious Diseases (USA); National Cancer Institute, NIAID [Y2-Al-5077]; NCI [Y3-CO-5117] FX This work has been funded by the National Institutes of Health, National Cancer Institute (U.S.) within the framework of the Belarus-U.S. Study of Thyroid Cancer and Other Diseases Following the Chernobyl Accident; the ISTC Project no. B-488p; and the Intra-Agency Agreement between the National Institute of Allergy and Infectious Diseases (USA) and the National Cancer Institute, NIAID agreement no. Y2-Al-5077 and NCI agreement no. Y3-CO-5117. We would like to thank our colleagues who contributed to the development of the dose reconstruction methods at different stages of the study: Drs L. Anspaugh (U. S.), A. Ulanovsky (Germany), Yu. Konstantinov (Russia), V. Averin (Belarus) and A. Mirkhaidarov (Belarus). The authors are grateful to all of the subjects who participated in the study. Special thanks are to the staff that conducted personal interviews and processed and verified the information collected during personal interviews into databases: Mss. T. Avramenko, N. Garbuzova, T. Lazuko, L. Sentebova, E. Shemiakina, and Mr. S. Stelmashok (Belarusian Medical Academy of Post-Graduate Education, Minsk, Belarus); Mss. N. Aprishko, E. Drozd, G. Evtushkova, T. Shitikova, A. Silina, and Mr. V. Tolstoy (Republican Research Center for Radiation Medicine and Human Ecology, Gomel, Belarus). The authors would like to thank the NIH Library Writing Center for manuscript editing assistance. NR 37 TC 11 Z9 12 U1 1 U2 6 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD MAY PY 2013 VL 179 IS 5 BP 597 EP 609 DI 10.1667/RR3153.1 PG 13 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AA3IK UT WOS:000330985900011 PM 23560632 ER PT J AU Mitchell, JA Bottai, M Park, Y Marshall, SJ Moore, S Matthews, CE AF Mitchell, Jonathan A. Bottai, Matteo Park, Yikung Marshall, Simon J. Moore, Steve Matthews, Charles E. TI Excessive Sedentary Behavior is Positively Associated with Changes in the BMI Frequency Distribution SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract CT 60th Annual Meeting of the American-College-of-Sports-Medicine CY MAY 28-JUN 01, 2013 CL Indianapolis, IN SP Amer Coll Sports Med C1 [Mitchell, Jonathan A.] Univ Penn, Philadelphia, PA 19104 USA. [Bottai, Matteo] Karolinska Inst, Stockholm, Sweden. [Park, Yikung; Moore, Steve; Matthews, Charles E.] NCI, Bethesda, MD 20892 USA. [Marshall, Simon J.] Univ Calif San Diego, San Diego, CA 92103 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 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2013 VL 45 IS 5 SU 1 MA 236 BP 45 EP 45 PG 1 WC Sport Sciences SC Sport Sciences GA 300ND UT WOS:000330469700138 ER PT J AU Viskochil, R Kozey-Keadle, S Malin, SK Chipkin, SR Freedson, PS Braun, B AF Viskochil, Richard Kozey-Keadle, Sarah Malin, Steven K. Chipkin, Stuart R. Freedson, Patty S. Braun, Barry TI Exercise Training Combined With Metformin Lowers Proinsulin Concentrations In Adults With Prediabetes SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract CT 60th Annual Meeting of the American-College-of-Sports-Medicine CY MAY 28-JUN 01, 2013 CL Indianapolis, IN SP Amer Coll Sports Med C1 [Viskochil, Richard; Chipkin, Stuart R.; Freedson, Patty S.; Braun, Barry] Univ Massachusetts, Amherst, MA 01003 USA. [Kozey-Keadle, Sarah] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Malin, Steven K.] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 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 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2013 VL 45 IS 5 SU 1 MA 859 BP 193 EP 193 PG 1 WC Sport Sciences SC Sport Sciences GA 300ND UT WOS:000330469701292 ER PT J AU Steeves, JA Fitzhugh, EC Peskoe, S Fairchild, V Bradwin, G McGlynn, KA Platz, EA Joshu, CE AF Steeves, Jeremy A. Fitzhugh, Eugene C. Peskoe, Sarah Fairchild, Victoria Bradwin, Gary McGlynn, Katherine A. Platz, Elizabeth A. Joshu, Corinne E. TI Relationship Between Physical Activity And Serum Testosterone Levels In Us Men: Results From Nhanes 1999-2004 SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract CT 60th Annual Meeting of the American-College-of-Sports-Medicine CY MAY 28-JUN 01, 2013 CL Indianapolis, IN SP Amer Coll Sports Med C1 [Steeves, Jeremy A.; McGlynn, Katherine A.] NCI, Rockville, MD USA. [Fitzhugh, Eugene C.] Univ Tennessee, Knoxville, TN USA. [Peskoe, Sarah; Fairchild, Victoria; Platz, Elizabeth A.; Joshu, Corinne E.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bradwin, Gary] Harvard Univ, Sch Med, Boston, MA USA. [Bradwin, Gary] Childrens Hosp, Boston, MA 02115 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 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2013 VL 45 IS 5 SU 1 MA 1150 BP 258 EP 258 PG 1 WC Sport Sciences SC Sport Sciences GA 300ND UT WOS:000330469702100 ER PT J AU Gennuso, KP Matthews, CE Schoeller, DA Colbert, LH AF Gennuso, Keith P. Matthews, Charles E. Schoeller, Dale A. Colbert, Lisa H. TI Validity and Reliability of Two Self-report Measures to Assess Sedentary Behavior in Older Adults SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract CT 60th Annual Meeting of the American-College-of-Sports-Medicine CY MAY 28-JUN 01, 2013 CL Indianapolis, IN SP Amer Coll Sports Med C1 [Gennuso, Keith P.; Schoeller, Dale A.; Colbert, Lisa H.] Univ Wisconsin, Madison, WI USA. [Matthews, Charles E.] NCI, NIH, Bethesda, MD 20892 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 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2013 VL 45 IS 5 SU 1 MA 1422 BP 324 EP 324 PG 1 WC Sport Sciences SC Sport Sciences GA 300ND UT WOS:000330469702316 ER PT J AU Chin, LMK Keyser, RE Woolstenhulme, JG Drinkard, B Connors, G Nathan, SD Chan, L AF Chin, Lisa M. K. Keyser, Randall E. Woolstenhulme, Joshua G. Drinkard, Bart Connors, Gerilynn Nathan, Steven D. Chan, Leighton TI Characterization of the Ventilatory Drive in Patients with Pulmonary Hypertension and Interstitial Lung Disease SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract CT 60th Annual Meeting of the American-College-of-Sports-Medicine CY MAY 28-JUN 01, 2013 CL Indianapolis, IN SP Amer Coll Sports Med C1 [Chin, Lisa M. K.; Woolstenhulme, Joshua G.; Drinkard, Bart; Chan, Leighton] NIH, Bethesda, MD 20892 USA. [Keyser, Randall E.] George Mason Univ, Fairfax, VA 22030 USA. [Connors, Gerilynn; Nathan, Steven D.] Inova Fairfax Hosp, Falls Church, VA 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 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2013 VL 45 IS 5 SU 1 MA 1441 BP 330 EP 330 PG 1 WC Sport Sciences SC Sport Sciences GA 300ND UT WOS:000330469702335 ER EF