FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Peterson, RE Maes, HH Holmans, P Sanders, AR Levinson, DF Shi, JX Kendler, KS Gejman, PV Webb, BT AF Peterson, Roseann E. Maes, Hermine H. Holmans, Peter Sanders, Alan R. Levinson, Douglas F. Shi, Jianxin Kendler, Kenneth S. Gejman, Pablo V. Webb, Bradley T. TI Genetic risk sum score comprised of common polygenic variation is associated with body mass index SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MELANOCORTIN-4 RECEPTOR; FTO GENE; CHILDHOOD OBESITY; COMPLEX DISEASES; ADULT OBESITY; WEIGHT CHANGE; HUMAN HEIGHT; LIFE-STYLE; VARIANTS AB Genome-wide association studies (GWAS) of body mass index (BMI) using large samples have yielded approximately a dozen robustly associated variants and implicated additional loci. Individually these variants have small effects and in aggregate explain a small proportion of the variance. As a result, replication attempts have limited power to achieve genome-wide significance, even with several thousand subjects. Since there is strong prior evidence for genetic influence on BMI for specific variants, alternative approaches to replication can be applied. Instead of testing individual loci sequentially, a genetic risk sum score (GRSS) summarizing the total number of risk alleles can be tested. In the current study, GRSS comprising 56 top variants catalogued from two large meta-analyses was tested for association with BMI in the Molecular Genetics of Schizophrenia controls (2,653 European-Americans, 973 African-Americans). After accounting for covariates known to influence BMI (ancestry, sex, age), GRSS was highly associated with BMI (p value = 3.19E-06) although explained a limited amount of the variance (0.66%). However, area under receiver operator criteria curve (AUC) estimates indicated that the GRSS and covariates significantly predicted overweight and obesity classification with maximum discriminative ability for predicting class III obesity (AUC = 0.697). The relative contributions of the individual loci to GRSS were examined post hoc and the results were not due to a few highly significant variants, but rather the result of numerous variants of small effect. This study provides evidence of the utility of a GRSS as an alternative approach to replication of common polygenic variation in complex traits. C1 [Peterson, Roseann E.; Maes, Hermine H.; Kendler, Kenneth S.; Webb, Bradley T.] Virginia Commonwealth Univ, Sch Med, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA. [Maes, Hermine H.] Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA USA. [Maes, Hermine H.; Kendler, Kenneth S.; Webb, Bradley T.] Virginia Commonwealth Univ, Sch Med, Dept Psychiat, Richmond, VA USA. [Peterson, Roseann E.; Maes, Hermine H.; Kendler, Kenneth S.] Virginia Commonwealth Univ, Sch Med, Dept Human & Mol Genet, Richmond, VA USA. [Sanders, Alan R.; Gejman, Pablo V.] NorthShore Univ HealthSyst, Ctr Psychiat Genet, Dept Psychiat & Behav Sci, Evanston, IL USA. [Holmans, Peter] Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, MRC,Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Peterson, RE (reprint author), Virginia Commonwealth Univ, Sch Med, Virginia Inst Psychiat & Behav Genet, Biotech 1,800 E Leigh St, Richmond, VA 23298 USA. EM repeterson@vcu.edu; btwebb@vcu.edu RI Webb, Bradley/B-1459-2009; Holmans, Peter/F-4518-2015 OI Webb, Bradley/0000-0002-0576-5366; Holmans, Peter/0000-0003-0870-9412 FU National Institute of Health [DA26119, DA018673, DA025109]; Genetic Association Information Network (GAIN) [U01MH79469, U01MH79470, R01MH81800 U01MH79469] FX This work was supported by National Institute of Health [DA26119 to R. E. P. and H. H. M., DA018673, DA025109 to H. H. M.]. Data and biomaterials from the National Institute of Mental Health Genetics Initiative MGS-C sample were collected by NorthShore University HealthSystem, Evanston, IL, R01 MH59571, Pablo V. Gejman, MD (Collaboration Coordinator; PI) as part of a collaborative R01 application comprising ten sites. From 2003 to 2006, the principal investigators and co-investigators were: NorthShore University HealthSystem, Evanston, IL, R01 MH59571, Pablo V. Gejman, MD (Collaboration Coordinator; PI); Alan R. Sanders, MD, Emory University School of Medicine, Atlanta, GA, R01 MH59587; Farooq Amin, MD (PI), University of California, San Francisco, CA, R01 MH60870; William F. Byerley, MD (PI), University of Iowa, Iowa, IA, R01 MH59566; Donald W. Black, MD (PI); Raymond R. Crowe, MD, Washington University, St. Louis, MO, R01 MH60879; C. Robert Cloninger, MD (PI), University of Colorado, Denver, CO, R01 MH59565, Robert Freedman, MD (PI); Ann Olincy, MD, Stanford University, Palo Alto, CA, R01 MH61675; Douglas F. Levinson, MD (PI), Louisiana State University, New Orleans, LA, R01 MH67257; Nancy G. Buccola, APRN, BC, MSN (PI), University of Queensland, Brisbane, Queensland, Australia, R01 MH59588; Bryan J. Mowry, MD (PI), Mt. Sinai School of Medicine, New York, NY, R01 MH59586; Jeremy M. Silverman, PhD (PI). Our schizophrenia GWAS (genotyping and analyses) was supported by the Genetic Association Information Network (GAIN) and grants U01MH79469 (Pablo V. Gejman, MD), U01MH79470 (Douglas F. Levinson, MD), and R01MH81800 U01MH79469 (Pablo V. Gejman, MD). We thank the individuals who volunteered for the control sample for their participation. Special thanks to Charles O. Gardner for statistical consultation, Brien P. Riley for insightful comments on the manuscript and T. Bernard Bigdeli for recommendations on Fig. 2. NR 59 TC 35 Z9 35 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD FEB PY 2011 VL 129 IS 2 BP 221 EP 230 DI 10.1007/s00439-010-0917-1 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 706CJ UT WOS:000286194000010 PM 21104096 ER PT J AU Mumford, SL Schisterman, EF Siega-Riz, AM Gaskins, AJ Steiner, AZ Daniels, JL Olshan, AF Hediger, ML Hovey, K Wactawski-Wende, J Trevisan, M Bloom, MS AF Mumford, Sunni L. Schisterman, Enrique F. Siega-Riz, Anna Maria Gaskins, Audrey J. Steiner, Anne Z. Daniels, Julie L. Olshan, Andrew F. Hediger, Mary L. Hovey, Kathleen Wactawski-Wende, Jean Trevisan, Maurizio Bloom, Michael S. TI Cholesterol, endocrine and metabolic disturbances in sporadic anovulatory women with regular menstruation SO HUMAN REPRODUCTION LA English DT Article DE anovulation; lipoproteins; menstrual cycle; endocrine disturbances ID POLYCYSTIC-OVARY-SYNDROME; MARGINAL STRUCTURAL MODELS; LIPOPROTEIN PROFILE; INSULIN-RESISTANCE; OXIDATIVE STRESS; PLASMA; CYCLE; PROGESTERONE; SIMVASTATIN; INFERTILITY AB BACKGROUND: Sporadic anovulation among regularly menstruating women is not well understood. It is hypothesized that cholesterol abnormalities may lead to hormone imbalances and incident anovulation. The objective was to evaluate the association between lipoprotein cholesterol levels and endocrine and metabolic disturbances and incident anovulation among ovulatory and anovulatory women reporting regular menstruation. METHODS: The BioCycle Study was a prospective cohort study conducted at the University at Buffalo from September 2005 to 2007, which followed 259 self-reported regularly menstruating women aged 18-44 years, for one or two complete menstrual cycles. Sporadic anovulation was assessed across two menstrual cycles. RESULTS: Mean total and low-density lipoprotein cholesterol and triglycerides levels across the menstrual cycles were higher during anovulatory cycles (mean difference: 4.6 (P = 0.01), 3.0 (P = 0.06) and 6.4 (P = 0.0002) mg/dl, respectively, adjusted for age and BMI). When multiple total cholesterol (TC) measures prior to expected ovulation were considered, we observed a slight increased risk of anovulation associated with increased levels of TC (odds ratio per 5 mg/dl increase, 1.07; 95% confidence interval, 0.99, 1.16). Sporadic anovulation was associated with an increased LH:FSH ratio (P = 0.002), current acne (P = 0.02) and decreased sex hormone-binding globulin levels (P = 0.005). CONCLUSIONS: These results do not support a strong association between lipoprotein cholesterol levels and sporadic anovulation. However, sporadic anovulation among regularly menstruating women is associated with endocrine disturbances which are typically observed in women with polycystic ovary syndrome. C1 [Mumford, Sunni L.; Schisterman, Enrique F.; Hediger, Mary L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, Rockville, MD 20852 USA. [Mumford, Sunni L.; Siega-Riz, Anna Maria; Daniels, Julie L.; Olshan, Andrew F.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Siega-Riz, Anna Maria] Univ N Carolina, Dept Nutr, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Steiner, Anne Z.] Univ N Carolina, Dept Obstet & Gynecol, Sch Med, Chapel Hill, NC 27599 USA. [Hovey, Kathleen; Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. [Trevisan, Maurizio] Univ Nevada Hlth Sci Syst, Las Vegas, NV 89101 USA. [Bloom, Michael S.] SUNY Albany, Dept Environm Hlth Sci, Rensselaer, NY 12144 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, 6100 Execut Blvd 7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI 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 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. NR 39 TC 8 Z9 8 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD FEB PY 2011 VL 26 IS 2 BP 423 EP 430 DI 10.1093/humrep/deq322 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 709VW UT WOS:000286470500020 PM 21115506 ER PT J AU Cupul-Uicab, LA Baird, DD Skjaerven, R Saha-Chaudhuri, P Haug, K Longnecker, MP AF Cupul-Uicab, L. A. Baird, D. D. Skjaerven, R. Saha-Chaudhuri, P. Haug, K. Longnecker, M. P. TI In utero exposure to maternal smoking and women's risk of fetal loss in the Norwegian Mother and Child Cohort (MoBa) SO HUMAN REPRODUCTION LA English DT Article DE tobacco smoking; in utero exposure; miscarriage; pregnancy; stillbirth ID EARLY-PREGNANCY; BIRTH-WEIGHT; HABITS; CESSATION AB BACKGROUND: Whether in utero exposure to tobacco smoke increases a woman's risk of fetal loss later in life is unknown, though data on childhood exposure suggest an association may exist. This study evaluated the association between in utero exposure to tobacco smoke and fetal loss in the Norwegian Mother and Child Cohort Study (MoBa), which enrolled similar to 40% of the pregnant women in Norway from 1999 to 2008. METHODS: Information on exposure to tobacco smoke in utero, the woman's own smoking behavior during pregnancy and other factors was obtained by a questionnaire completed at similar to 17 weeks of gestation. Subsequent late miscarriage (fetal death < 20 weeks) and stillbirth (fetal death >= 20 weeks) were ascertained from the Norwegian Medical Birth Registry. This analysis included 76 357 pregnancies (MoBa data set version 4.301) delivered by the end of 2008; 59 late miscarriages and 270 stillbirths occurred. Cox proportional hazards models were fit for each outcome and for all fetal deaths combined. RESULTS: The adjusted hazard ratio (HR) of late miscarriage was 1.23 [95% confidence interval (CI), 0.72-2.12] in women with exposure to maternal tobacco smoke in utero when compared with non-exposed women. The corresponding adjusted HR for stillbirths was 1.11 (95% CI, 0.85-1.44) and for all fetal deaths combined, it was 1.12 (95% CI, 0.89-1.43). CONCLUSIONS: The relatively wide CI around the HR for miscarriage reflected the limited power to detect an association, due to enrollment around 17 weeks of gestation. However, for in utero exposure to tobacco smoke and risk of stillbirth later in life, where the study power was adequate, our data provided little support for an association. C1 [Cupul-Uicab, L. A.; Baird, D. D.; Longnecker, M. P.] NIEHS, Epidemiol Branch, NIH, DHHS,USA, Res Triangle Pk, NC 27709 USA. [Skjaerven, R.] Univ Bergen, Sect Med Stat, Bergen, Norway. [Skjaerven, R.] Univ Bergen, Med Birth Registry Norway, Bergen, Norway. [Saha-Chaudhuri, P.] NIEHS, Biostat Branch, NIH, DHHS,USA, Res Triangle Pk, NC 27709 USA. [Haug, K.] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway. RP Cupul-Uicab, LA (reprint author), NIEHS, Epidemiol Branch, NIH, DHHS,USA, MD A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cupuluicabl@niehs.nih.gov RI Saha Chaudhuri, Paramita/F-3835-2010; Baird, Donna/D-5214-2017; CUPUL UICAB, LEA/C-8699-2014; OI Baird, Donna/0000-0002-5544-2653; CUPUL UICAB, LEA/0000-0001-6190-4474; Longnecker, Matthew/0000-0001-6073-5322; Saha Chaudhuri, Paramita/0000-0003-1987-320X FU Intramural Research Program; National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH); Norwegian Ministry of Health [ES044008]; National Institute of Environmental Health Sciences, NIH/NIEHS [N01-ES-85433]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10] FX This study was supported, in part, by the Intramural Research Program, the National Institute of Environmental Health Sciences (NIEHS) and the National Institutes of Health (NIH). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health, contract ES044008 with the National Institute of Environmental Health Sciences, NIH/NIEHS (grant no N01-ES-85433), NIH/NINDS (grant no. 1 UO1 NS 047537-01) and the Norwegian Research Council/FUGE (grant no. 151918/S10). NR 40 TC 6 Z9 6 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD FEB PY 2011 VL 26 IS 2 BP 458 EP 465 DI 10.1093/humrep/deq334 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 709VW UT WOS:000286470500025 PM 21147823 ER PT J AU Abbasi, S Shin, DM Beaty, N Masiuk, M Chen, S Gonzalez-Garcia, I Zhao, M Goding, J Morse, HC Wang, HS AF Abbasi, Sadia Shin, Dong-Mi Beaty, Natalie Masiuk, Marek Chen, Sophia Gonzalez-Garcia, Ines Zhao, Ming Goding, James Morse, Herbert C., III Wang, Hongsheng TI Characterization of Monoclonal Antibodies to the Plasma Cell Alloantigen ENPP1 SO HYBRIDOMA LA English DT Article ID INFANTILE ARTERIAL CALCIFICATION; MEMBRANE GLYCOPROTEIN PC-1; ANTIGEN PC-1; INSULIN-RESISTANCE; MOUSE; MICE; PHOSPHODIESTERASE/PYROPHOSPHATASE; INHIBITION; MUTATION; FAMILY AB The ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) has documented roles in mineralization, nucleotide recycling, and insulin resistance. While ENPP1 was first identified as an alloantigen on mouse plasma cells (PCs), later studies revealed expression in many tissues. Previously described monoclonal antibodies against ENPP1 expressed at the cell surface recognized cells only from mice bearing the a allotype, ENPP1(a), precluding studies of mice bearing the alternative allele, ENPP1(b). Here, we characterize a novel anti-ENPP1 monoclonal antibody that recognizes both alleles and can be used for flow cytometry. C1 [Abbasi, Sadia; Shin, Dong-Mi; Beaty, Natalie; Masiuk, Marek; Chen, Sophia; Gonzalez-Garcia, Ines; Morse, Herbert C., III; Wang, Hongsheng] NIAID, Immunopathol Lab, NIH, Rockville, MD 20850 USA. [Zhao, Ming] NIAID, Res Technol Branch, NIH, Rockville, MD 20850 USA. [Goding, James] Monash Univ, Dept Physiol, Clayton, Vic 3168, Australia. RP Wang, HS (reprint author), NIAID, Immunopathol Lab, NIH, Twinbrook 1,5640 Fishers Lane,Rm 1421, Rockville, MD 20850 USA. EM wanghongs@niaid.nih.gov RI Masiuk, Marek/M-8485-2014; OI Morse, Herbert/0000-0002-9331-3705 FU 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 26 TC 5 Z9 5 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1554-0014 J9 HYBRIDOMA JI Hybridoma PD FEB PY 2011 VL 30 IS 1 BP 11 EP 17 DI 10.1089/hyb.2010.0089 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Immunology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology GA 726NF UT WOS:000287728900002 PM 21466281 ER PT J AU Buhtoiarov, IN Sondel, PM Wigginton, JM Buhtoiarova, TN Yanke, EM Mahvi, DA Rakhmilevich, AL AF Buhtoiarov, Ilia N. Sondel, Paul M. Wigginton, Jon M. Buhtoiarova, Tatiana N. Yanke, Eric M. Mahvi, David A. Rakhmilevich, Alexander L. TI Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages SO IMMUNOLOGY LA English DT Article DE anti-CD40; chemotherapy; CpG-ODN; immunotherapy; monocytes; macrophages; tumour recognition ID COLONY-STIMULATING FACTOR; CD8 T-CELLS; SUPPRESSOR-CELLS; BONE-MARROW; IN-VITRO; ACTIVATED MACROPHAGES; SELECTIVE EXPRESSION; MOUSE MACROPHAGES; INTERFERON-GAMMA; IMMUNE-SYSTEM AB P>We studied the effectiveness of monoclonal anti-CD40 + cytosine-phosphate-guanosine-containing oligodeoxynucleotide 1826 (CpG-ODN) immunotherapy (IT) in mice treated with multidrug chemotherapy (CT) consisting of vincristine, cyclophosphamide and doxorubicin. Combining CT with IT led to synergistic anti-tumour effects in C57BL/6 mice with established B16 melanoma or 9464D neuroblastoma. CT suppressed the functions of T cells and natural killer (NK) cells, but primed naive peritoneal macrophages (M phi) to in vitro stimulation with lipopolysaccharide (LPS), resulting in augmented nitric oxide (NO) production. IT, given after CT, did not restore the responsiveness of T cells and NK cells, but further activated M phi to secrete NO, interferon-gamma (IFN-gamma) and interleukin (IL)-12p40 and to suppress the proliferation of tumour cells in vitro. These functional changes were accompanied by immunophenotype alterations on M phi, including the up-regulation of Gr-1. CD11b(+) F4/80(+) M phi comprised the major population of B16 tumour-infiltrating leucocytes. CT + IT treatment up-regulated molecules associated with the M1 effector M phi phenotype [CD40, CD80, CD86, major histocompatibility complex (MHC) class II, IFN-gamma, tumour necrosis factor-alpha (TNF-alpha) and IL-12] and down-regulated molecules associated with the M2 inhibitory M phi phenotype (IL-4R alpha, B7-H1, IL-4 and IL-10) on the tumour-associated M phi compared with untreated controls. Together, the results show that CT and anti-CD40 + CpG-ODN IT synergize in the induction of anti-tumour effects which are associated with the phenotypic repolarization of tumour-associated M phi. C1 [Buhtoiarov, Ilia N.; Sondel, Paul M.; Buhtoiarova, Tatiana N.; Yanke, Eric M.; Mahvi, David A.; Rakhmilevich, Alexander L.] Univ Wisconsin, Dept Human Oncol, Madison, WI 53705 USA. [Buhtoiarov, Ilia N.; Sondel, Paul M.; Rakhmilevich, Alexander L.] Univ Wisconsin, UW Paul P Carbone Comprehens Canc Ctr, Madison, WI 53705 USA. [Sondel, Paul M.] Univ Wisconsin, Dept Pediat, Madison, WI 53705 USA. [Wigginton, Jon M.] NCI, Pediat Oncol Branch, Ctr Canc Res, Frederick, MD 21701 USA. RP Rakhmilevich, AL (reprint author), Univ Wisconsin, Dept Human Oncol, 4136 WIMR,1111 Highland Ave, Madison, WI 53705 USA. EM rakhmil@humonc.wisc.edu OI Tatiana, Buhtoiarova/0000-0003-2051-5135 FU National Institutes of Health [CA87025, CA032685]; Midwest Athletes Against Childhood Cancer Fund; UW Cure Kids Cancer Coalition FX This work was supported by The National Institutes of Health Grants CA87025 and CA032685 (to PMS), grants from the Midwest Athletes Against Childhood Cancer Fund (to PMS, ALR and INB), and the grant from the UW Cure Kids Cancer Coalition (INB and PMS). The authors thank Drs Jacquelyn A. Hank and Jacek Gan of The University of Wisconsin for helpful discussions. INB is a UICC fellow. NR 52 TC 41 Z9 42 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD FEB PY 2011 VL 132 IS 2 BP 226 EP 239 DI 10.1111/j.1365-2567.2010.03357.x PG 14 WC Immunology SC Immunology GA 703RS UT WOS:000285999600008 PM 21039467 ER PT J AU Bornstein, MH Arterberry, ME Mash, C Manian, N AF Bornstein, Marc H. Arterberry, Martha E. Mash, Clay Manian, Nanmathi TI Discrimination of facial expression by 5-month-old infants of nondepressed and clinically depressed mothers SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article DE Face; Discrimination; Infancy; Maternal depression ID MATERNAL DEPRESSION; FACE RECOGNITION; COGNITIVE-DEVELOPMENT; 3-MONTH-OLD INFANTS; PERCEPTION; NEWBORNS; SPECIALIZATION; RESPONSES; CHILDREN; BEHAVIOR AB Five-month-old infants of nondepressed and clinically depressed mothers were habituated to either a face with a neutral expression or the same face with a smile. Infants of nondepressed mothers subsequently discriminated between neutral and smiling facial expressions, whereas infants of clinically depressed mothers failed to make the same discrimination. Published by Elsevier Inc. C1 [Bornstein, Marc H.; Mash, Clay; Manian, Nanmathi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Publ Hlth Serv, Bethesda, MD 20892 USA. [Arterberry, Martha E.] Colby Coll, Waterville, ME 04901 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Publ Hlth Serv, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov FU Intramural NIH HHS [Z01 HD001119-20] NR 65 TC 13 Z9 13 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD FEB PY 2011 VL 34 IS 1 BP 100 EP 106 DI 10.1016/j.infbeh.2010.10.002 PG 7 WC Psychology, Developmental SC Psychology GA 728RI UT WOS:000287891800010 PM 21112092 ER PT J AU de Falco, S Venuti, P Esposito, G Bornstein, MH AF de Falco, Simona Venuti, Paola Esposito, Gianluca Bornstein, Marc H. TI Maternal and paternal pragmatic speech directed to young children with Down syndrome and typical development SO INFANT BEHAVIOR & DEVELOPMENT LA English DT Article DE Language; Parenting; Down syndrome ID MOTHERS SPEECH; EMOTIONAL AVAILABILITY; LANGUAGE-DEVELOPMENT; UNITED-STATES; PRELINGUAL INFANTS; FATHERS; PARENTS; GENDER; PLAY; ATTENTION AB The aim of this study was to compare functional features of maternal and paternal speech directed to children with Down syndrome and developmental age-matched typically developing children. Altogether 88 parents (44 mothers and 44 fathers) and their 44 young children (22 children with Down syndrome and 22 typically developing children) participated. Parents' speech directed to children was obtained through observation of naturalistic parent-child dyadic interactions. Verbatim transcripts of maternal and paternal language were categorized in terms of the primary function of each speech unit. Parents (both mothers and fathers) of children with Down syndrome used more affect-salient speech compared to parents of typically developing children. Although parents used the same amounts of information-salient speech, parents of children with Down syndrome used more direct statements and asked fewer questions than did parents of typically developing children. Concerning parent gender, in both groups mothers used more language than fathers and specifically more descriptions. These findings held controlling for child age and MLU and family SES. This study highlights strengths and weaknesses of parental communication to children with Down syndrome and helps to identify areas of potential improvement through intervention. (C) 2010 Elsevier Inc. All rights reserved. C1 [de Falco, Simona; Venuti, Paola; Esposito, Gianluca] Univ Trent, Dept Cognit Sci, Trento, Italy. [Esposito, Gianluca] RIKEN, Brain Sci Inst, Kuroda Res Unit, Saitama, Japan. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP de Falco, S (reprint author), Univ Trent, Dept Cognit Sci, Trento, Italy. EM simona.defalco@unitn.it RI Esposito, Gianluca/B-1374-2012 OI Esposito, Gianluca/0000-0002-9442-0254 FU Intramural NIH HHS [Z01 HD001119-20] NR 78 TC 6 Z9 7 U1 3 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-6383 J9 INFANT BEHAV DEV JI Infant Behav. Dev. PD FEB PY 2011 VL 34 IS 1 BP 161 EP 169 DI 10.1016/j.infbeh.2010.12.002 PG 9 WC Psychology, Developmental SC Psychology GA 728RI UT WOS:000287891800016 PM 21215458 ER PT J AU Kampitak, T Suwanpimolkul, G Browne, S Suankratay, C AF Kampitak, T. Suwanpimolkul, G. Browne, S. Suankratay, C. TI Anti-interferon-gamma autoantibody and opportunistic infections: case series and review of the literature SO INFECTION LA English DT Review DE Anti-interferon-gamma autoantibody; Interferon-gamma; Opportunistic infections; Mycobacteriosis; Salmonellosis ID NONTUBERCULOUS MYCOBACTERIAL INFECTIONS; IFN-GAMMA; AVIUM COMPLEX; SUSCEPTIBILITY; PATIENT; GENETICS; DISEASES AB Immune defects in interleukin-12-dependent interferon-gamma (IFN-gamma) pathways are associated with disseminated infections caused by non-tuberculous mycobacteria (NTM) and Salmonella. Recently, there have been an increasing number of reports of acquired autoantibodies to IFN-gamma in adults, especially in Asian patients. We describe here three human immunodeficiency virus-negative Thai adults who had persistent or recurrent disseminated infections caused by NTM, Salmonella, and other opportunistic pathogens, possibly due to anti-IFN-gamma autoantibodies. The antibodies were shown to exhibit very high inhibitory activity to IFN-gamma. Two patients also developed Sweet's syndrome during the course of infections. In addition, we also review all previous reports of patients with anti-IFN-gamma antibodies who were susceptible to NTM and Salmonella infections. C1 [Suwanpimolkul, G.; Suankratay, C.] Chulalongkorn Univ Hosp, Fac Med, Dept Med, Div Infect Dis, Bangkok 10330, Thailand. [Kampitak, T.] Chulalongkorn Univ, Fac Med, Div Allergy & Clin Immunol, Bangkok 10330, Thailand. [Browne, S.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Suankratay, C (reprint author), Chulalongkorn Univ Hosp, Fac Med, Dept Med, Div Infect Dis, Bangkok 10330, Thailand. EM chusana.s@chula.ac.th NR 21 TC 35 Z9 37 U1 0 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0300-8126 J9 INFECTION JI Infection PD FEB PY 2011 VL 39 IS 1 BP 65 EP 71 DI 10.1007/s15010-010-0067-3 PG 7 WC Infectious Diseases SC Infectious Diseases GA 726HF UT WOS:000287710100011 PM 21128092 ER PT J AU Henriet, SSV Hermans, PWM Verweij, PE Simonetti, E Holland, SM Sugui, JA Kwon-Chung, KJ Warris, A AF Henriet, Stefanie S. V. Hermans, Peter W. M. Verweij, Paul E. Simonetti, Elles Holland, Steven M. Sugui, Janyce A. Kwon-Chung, Kyung J. Warris, Adilia TI Human Leukocytes Kill Aspergillus nidulans by Reactive Oxygen Species-Independent Mechanisms SO INFECTION AND IMMUNITY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; ALVEOLAR MACROPHAGES; HUMAN POLYMORPHONUCLEAR; MONONUCLEAR PHAGOCYTES; TRYPTOPHAN CATABOLISM; P47(PHOX-/-) MICE; HOST-DEFENSE; FUMIGATUS; VIRULENCE; CELLS AB Invasive aspergillosis is a major threat for patients suffering from chronic granulomatous disease (CGD). Although Aspergillus fumigatus is the most commonly encountered Aspergillus species, the presence of A. nidulans appears to be disproportionately high in CGD patients. The purpose of this study was to investigate the involvement of the NADPH oxidase and the resulting reactive oxygen species (ROS) in host defense against fungi and to clarify their relationship toward A. nidulans. Murine CGD alveolar macrophages (AM) and polymorphonuclear leukocytes (PMN) and peripheral blood mononuclear cells (PBMC) from healthy controls and CGD patients were challenged with either A. fumigatus or A. nidulans. Analysis of the antifungal effects of ROS revealed that A. nidulans, in contrast to A. fumigatus, is not susceptible to ROS. In addition, infection with live A. nidulans did not result in any measurable ROS release. Remarkably, human CGD PMN and PBMC and murine CGD AM were at least equipotent at arresting conidial germination compared to healthy controls. Blocking of the NADPH oxidase resulted in significantly reduced damage of A. fumigatus but did not affect A. nidulans hyphae. Furthermore, the microbicidal activity of CGD PMN was maintained toward A. nidulans but not A. fumigatus. In summary, antifungal resistance to A. nidulans is not directly ROS related. The etiology of A. nidulans infections in CGD cannot be explained by the simple absence of the direct microbicidal effect of ROS. In vivo, the NADPH oxidase is a critical regulator of innate immunity whose unraveling will improve our understanding of fungal pathogenesis in CGD. C1 [Warris, Adilia] Radboud Univ Nijmegen, Med Ctr, Dept Pediat Infect Dis & Immunol, Nijmegen Inst Infect Inflammat & Immun, NL-6500 HB Nijmegen, Netherlands. [Henriet, Stefanie S. V.; Hermans, Peter W. M.; Simonetti, Elles; Warris, Adilia] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, NL-6500 HB Nijmegen, Netherlands. [Verweij, Paul E.] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6500 HB Nijmegen, Netherlands. [Holland, Steven M.; Sugui, Janyce A.; Kwon-Chung, Kyung J.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Warris, A (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Pediat Infect Dis & Immunol, Nijmegen Inst Infect Inflammat & Immun, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM a.warris@cukz.umcn.nl RI Warris, Adilia/F-4882-2010; Hermans, Peter/H-8042-2014; Verweij, P.E./H-8108-2014; Warris, A./L-4745-2015; Simonetti, Elles/N-2966-2016 FU European Society of Pediatric Infectious Disease/Wyeth; Division of Intramural Research, NIAID, NIH FX This work was supported by a European Society of Pediatric Infectious Disease/Wyeth fellowship grant (2008 to 2010) and by the Division of Intramural Research, NIAID, NIH. NR 32 TC 16 Z9 16 U1 0 U2 3 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 FEB PY 2011 VL 79 IS 2 BP 767 EP 773 DI 10.1128/IAI.00921-10 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 709SP UT WOS:000286462000022 PM 21078850 ER PT J AU Dixit, R Patole, MS Shouche, YS AF Dixit, Rajnikant Patole, Millind S. Shouche, Yogesh S. TI Identification of putative innate immune related genes from a cell line of the mosquito Aedes albopictus following bacterial challenge SO INNATE IMMUNITY LA English DT Article DE Aedes albopictus; innate immunity; subtractive hybridization; mosquito; ESTs ID FIBRINOGEN-RELATED PROTEINS; COMPLEMENT-LIKE PROTEIN; ANOPHELES-GAMBIAE; PSEUDOMONAS-AERUGINOSA; RECOGNITION PROTEIN; MALARIA PARASITES; DROSOPHILA; RESPONSES; ACTIVATION; DEFENSIN AB We report identification of putative innate immune related genes from a cell line of the mosquito Aedes albopictus challenged with heat-killed bacteria. Using a subtractive hybridization and sequencing approach, we analyzed a total 309 expressed sequence tags (ESTs) which clustered in 40 contigs. Thirty-five percent of genes yielded homology to known immune genes corresponding to antimicrobial peptides (AMPs), pathogen-associated molecular patterns, protease and immune signaling cascades. Interestingly, most of the genes have not been previously described from this mosquito and thus represent a class of novel immune genes. Further, 25% sequences did not match to any known species in the non-redundant databases, appear to be specific to the mosquito A. albopictus and merit further study. C1 [Dixit, Rajnikant; Patole, Millind S.; Shouche, Yogesh S.] Natl Ctr Cell Sci, Mol Biol Unit, Pune, Maharashtra, India. RP Dixit, R (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM dixit2k@yahoo.com RI DIXIT, RAJNIKANT/D-2566-2009 OI DIXIT, RAJNIKANT/0000-0002-3536-8329 FU Department of Biotechnology, New Delhi, Government of India FX This work was financially supported by the Department of Biotechnology, New Delhi, Government of India. The authors are also thankful to Sarang Satoor for technical support during sequencing of ESTs. NR 37 TC 2 Z9 2 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-4259 J9 INNATE IMMUN-LONDON JI Innate Immun. PD FEB PY 2011 VL 17 IS 1 BP 106 EP 117 DI 10.1177/1753425909350484 PG 12 WC Biochemistry & Molecular Biology; Immunology; Medicine, Research & Experimental; Microbiology SC Biochemistry & Molecular Biology; Immunology; Research & Experimental Medicine; Microbiology GA 717DV UT WOS:000287024400010 PM 20123933 ER PT J AU Rodriguez, AC Garcia-Pineres, AJ Hildesheim, A Herrero, R Trivett, M Williams, M Atmella, I Ramirez, M Villegas, M Schiffman, M Burk, R Freer, E Bonilla, J Bratti, C Pinto, LA AF Cecilia Rodriguez, Ana Garcia-Pineres, Alfonso J. Hildesheim, Allan Herrero, Rolando Trivett, Matthew Williams, Marcus Atmella, Ivannia Ramirez, Margarita Villegas, Maricela Schiffman, Mark Burk, Robert Freer, Enrique Bonilla, Jose Bratti, Concepcion Pinto, Ligia A. TI Alterations of T-cell surface markers in older women with persistent human papillomavirus infection SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HPV persistent infection; T-cell distribution; T-cell activation and differentiation; older women ID CERVICAL INTRAEPITHELIAL NEOPLASIA; NATURAL-HISTORY; COSTA-RICA; IMMUNE-RESPONSES; LANGERHANS CELLS; UTERINE CERVIX; HPV INFECTION; YOUNG-WOMEN; LESIONS; CANCER AB We previously reported decreased lymphocyte proliferative responses among older women with persistent human papillomavirus (HPV) infection. To characterize the phenotype of peripheral lymphocytes associated with persistent HPV infection, we evaluated the expression of different cell surface markers in peripheral blood mononuclear cells (PBMCs) from a case-control study within a 10,049 woman population-based cohort study in Guanacaste, Costa Rica. Women in the cohort aged 46-74 and with HPV results at their 5th year anniversary visit were considered, and all women (n = 87) with persistent HPV infections, all women (n = 196) with transient HPV infections and a random sample of HPV DNA-negative women (n = 261) frequency-matched to cases on age were selected for this study. A median of 3 years after the case-control matching visit, cervical cells were collected for liquid-based cytology and repeat HPV DNA genotyping. Blood was obtained from which PBMCs were extracted and cryopreserved for immunological phenotyping via flow cytometry. Significant increases in risk of HPV persistence were observed for 3 marker subsets indicative of immune cell activation/differentiation. Relative risk estimates were 5.4 (95% CI = 2.2-13.3) for CD69(+)CD4(+), 2.6 (95% CI = 1.2-5.9) for HLADR(+)CD3(+)CD4(+) and 2.3 (95% CI = 1.1-4.7) for CD45RO(+)CD27(-)CD8(+). A significant decrease in HPV persistence was observed for a subset marker indicative of an immature, undifferentiated memory state CD45RO(+)CD27(+)CD4(+) (OR = 0.36; 95% CI = 0.17-0.76). Adjustment for these markers only partially explained the previously reported association between decreased lymphoproliferative responses and persistent HPV infection. Whether phenotypic alterations observed predispose to HPV persistence or result from it should be the focus of future studies. C1 [Herrero, Rolando; Villegas, Maricela; Bratti, Concepcion] INCIENSA Fdn, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Cecilia Rodriguez, Ana; Hildesheim, Allan; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Garcia-Pineres, Alfonso J.; Trivett, Matthew; Williams, Marcus; Pinto, Ligia A.] SAIC Frederick Inc, HPV Immunol Lab, NCI Frederick, Frederick, MD USA. [Atmella, Ivannia; Ramirez, Margarita; Freer, Enrique; Bonilla, Jose] Univ Costa Rica, Escuela Quim, Ctr Invest Estruct Microscop, San Jose, Costa Rica. [Atmella, Ivannia; Ramirez, Margarita; Freer, Enrique; Bonilla, Jose] Univ Costa Rica, Ctr Invest Biol Celular & Mol, San Jose, Costa Rica. [Burk, Robert] Yeshiva Univ, Albert Einstein Coll Med, Dept Pediat, Dept Microbiol & Immunol,Dept Epidemiol & Populat, Bronx, NY USA. [Burk, Robert] Yeshiva Univ, Albert Einstein Coll Med, Dept Obstet Gynecol & Womens Hlth, Bronx, NY USA. RP Rodriguez, AC (reprint author), INCIENSA Fdn, Proyecto Epidemiol Guanacaste, Torre La Sabana,7Mo Piso,Sabana Norte, San Jose, Costa Rica. EM acrodriguez@racsa.co.cr RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU National Cancer Institute, National Institutes of Health [N01-CP21081, N01-CP33061, N01-CP40542, N01-CP50535, N01-CP81023, N02-CP-31003, U01-CA78527, CA78527, N01-CO-12400]; The National Institutes of Health Office for Research on Women's Health (ORWH), Oak Ridge Institute for Science and Education FX Grant sponsor: National Cancer Institute, National Institutes of Health; Grant numbers: N01-CP21081, N01-CP33061, N01-CP40542, N01-CP50535, N01-CP81023, N02-CP-31003, U01-CA78527, CA78527, N01-CO-12400; Grant sponsor: The National Institutes of Health Office for Research on Women's Health (ORWH), Oak Ridge Institute for Science and Education (Interagency Agreement Between the U.S. Department of Energy, the National Institutes of Health) NR 42 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2011 VL 128 IS 3 BP 597 EP 607 DI 10.1002/ijc.25371 PG 11 WC Oncology SC Oncology GA 693ZN UT WOS:000285264000010 PM 20473864 ER PT J AU Atchison, EA Gridley, G Carreon, JD Leitzmann, MF McGlynn, KA AF Atchison, Elizabeth A. Gridley, Gloria Carreon, J. Daniel Leitzmann, Michael F. McGlynn, Katherine A. TI Risk of cancer in a large cohort of U.S. veterans with diabetes SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE diabetes; cancer; risk; hyperinsulinemia; hormones; body mass index ID POPULATION-BASED COHORT; BODY-MASS INDEX; GROWTH-FACTOR-I; PROSTATE-CANCER; COLORECTAL-CANCER; PANCREATIC-CANCER; HEPATOCELLULAR-CARCINOMA; GLUCOSE-CONCENTRATION; PHYSICAL-ACTIVITY; PLASMA-GLUCOSE AB Prior studies of cancer risk among diabetic men have reported inconsistent findings. The aim of this study was to assess the risk of cancer among a large cohort (n = 4,501,578) of black and white U. S. veterans admitted to Veterans Affairs hospitals. The cancer risk among men with diabetes (n = 594,815) was compared to the risk among men without diabetes (n = 3,906,763). Poisson regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). Overall, men with diabetes had a significantly lower risk of cancer (RR = 0.93, 95% CI = 0.93-0.94). Men with diabetes, however, had increased risks of cancers of the liver (RR = 1.95, 95% CI = 1.82-2.09), pancreas (RR = 1.50, 95% CI = 1.42-1.59), biliary tract (RR = 1.41, 95% CI = 1.22-1.62), colon (RR = 1.20, 95% CI = 1.16-1.25), rectum (RR = 1.12, 95% CI = 1.07-1.18), and kidney (RR = 1.09, 95% CI = 1.03-1.16), as well as leukemia (RR = 1.14, 95% CI = 1.08-1.21) and melanoma (RR = 1.13, 95% CI = 1.03-1.24). In contrast, men with diabetes had decreased risks of cancers of the prostate (RR = 0.89, 95% CI 5 0.87-0.91), brain (RR = 0.91, 95% CI = 0.82-0.99), buccal cavity (RR = 0.85, 95% CI = 0.82-0.89), lung (RR = 0.79, 95% CI = 5 0.77-0.80), esophagus (RR = 0.77, 95% CI = 0.72-0.82), and larynx (RR = 0.76, 95% CI = 0.71-0.80). These findings indicate that black and white men with diabetes are at significantly lower risk of total cancer and of two of the most common cancers among U. S. males; lung and prostate cancers. These decreased risks were offset, however, by increased risks of cancer at several sites. Hyperinsulinemia may explain the increased risks of the digestive cancers, while lower testosterone levels, in the case of prostate cancer, and higher BMI, in the case of lung cancer, may explain the decreased risks of those tumors. C1 [McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Leitzmann, Michael F.] Regensburg Univ Med Ctr, Dept Epidemiol & Prevent Med, Regensburg, Germany. RP McGlynn, KA (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, EPS Suite 550,6120 Execut Blvd, Bethesda, MD 20892 USA. EM mcglynnk@mail.nih.gov FU National Cancer Institute, NIH, DHHS FX This research was supported by the Intramural Research Program of the National Cancer Institute, NIH, DHHS. We thank the Medical Administration Service of the U.S. Veterans Health Services and Research Administration for providing the data on which this study is based, Mr. David Check of the Biostatistics Branch, DCEG, NCI for analytic support and Mr. Dave Campbell and Mr. Eric Boyd of Information Management Services, Inc for computer programming support. NR 68 TC 112 Z9 117 U1 1 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2011 VL 128 IS 3 BP 635 EP 643 DI 10.1002/ijc.25362 PG 9 WC Oncology SC Oncology GA 693ZN UT WOS:000285264000014 PM 20473855 ER PT J AU Biran, A Brownstein, M Haklai, R Kloog, Y AF Biran, Anat Brownstein, Michael Haklai, Ronit Kloog, Yoel TI Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer; FTS; HDAC inhibitors; Aurora kinase; Ras; VPA ID CHRONIC MYELOID-LEUKEMIA; PANCREATIC TUMOR-GROWTH; VALPROIC ACID; CELL-CYCLE; FARNESYLTHIOSALICYLIC ACID; CHROMOSOMAL PASSENGERS; MULTIPLE-MYELOMA; NUDE-MICE; APOPTOSIS; ARREST AB Histone deacetylase (HDAC) inhibitors, such as valproic acid (VPA), constitute a novel class of anticancer agents that cause an increase in acetylated histones and thus restore the expression of dormant tumor-suppressor and other genes related to cell differentiation, cell-cycle arrest or apoptosis of tumor cells. The Ras inhibitor farnesylthiosalicylic acid (FTS, salirasib) attenuates cancer cell proliferation in vitro and in vivo and, under certain circumstances, induces cell death. FTS by itself does not induce differentiation or complete growth arrest. The abovementioned activity of VPA as a differentiation agent suggested that it might be worth investigating its possible therapeutic potential in synergistic combination with FTS. Here, we examined whether the combined application of VPA and FTS could synergistically inhibit the proliferation of cancer cells that express oncogenic K-Ras (A549 nonsmall-cell lung carcinoma cells), DLD1 (colon carcinoma cells) or chronically active wild-type K-Ras and constitutively active B-Raf (ARO, thyroid carcinoma cells). The results showed that combined treatment with VPA and FTS synergistically reduces proliferation in all of these cancer cell lines by downregulating Ras and blocking the expression of Survivin and Aurora A. These alterations, which were most pronounced following the combined treatment, led to a mitotic crisis, as reflected by mislocalization of the chromosomal passenger complex. Our findings thus demonstrate that combination therapy with VPA and FTS might offer a promising therapeutic approach to the treatment of epithelial tumors. C1 [Biran, Anat; Haklai, Ronit; Kloog, Yoel] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. [Brownstein, Michael] NIH, Bethesda, MD 20892 USA. RP Kloog, Y (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiochem, IL-69978 Tel Aviv, Israel. EM kloog@post.tau.ac.il FU Israel Science Foundation [912/06]; Prajs-Drimmer Institute for The Development of Anti-degenerative Drugs FX Grant sponsors: The Israel Science Foundation 912/06, The Prajs-Drimmer Institute for The Development of Anti-degenerative Drugs NR 55 TC 25 Z9 28 U1 0 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2011 VL 128 IS 3 BP 691 EP 701 DI 10.1002/ijc.25367 PG 11 WC Oncology SC Oncology GA 693ZN UT WOS:000285264000021 PM 20473860 ER PT J AU Fitzgerald, PJ AF Fitzgerald, Paul J. TI Author's reply to: norepinephrine antagonists and cancer risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter DE norepinephrine; adrenoceptor; hypertension; epidemiology; clonidine; propranolol; prazosin; atenolol C1 [Fitzgerald, Paul J.] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Zanvyl Krieger Mind Brain Inst, Baltimore, MD 21218 USA. RP Fitzgerald, PJ (reprint author), NIAAA, 5625 Fishers Lane,Room 2N09, Bethesda, MD 20852 USA. EM pfitz@mbi.mb.jhu.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2011 VL 128 IS 3 BP 738 EP 739 DI 10.1002/ijc.25352 PG 2 WC Oncology SC Oncology GA 693ZN UT WOS:000285264000029 ER PT J AU Beydoun, MA Wang, YF AF Beydoun, Mayay A. Wang, Youfaufa TI Socio-demographic disparities in distribution shifts over time in various adiposity measures among American children and adolescents: What changes in prevalence rates could not reveal SO INTERNATIONAL JOURNAL OF PEDIATRIC OBESITY LA English DT Article ID BODY-MASS INDEX; WAIST CIRCUMFERENCE; UNITED-STATES; ENVIRONMENTAL CONTRIBUTIONS; OBESITY EPIDEMIC; NEIGHBORHOOD CHARACTERISTICS; CHILDHOOD OBESITY; PHYSICAL-ACTIVITY; HEIGHT RATIO; FOOD-PRICES AB Background. While obesity prevalence in the US has been increasing, adiposity shifts may vary across socio-demographic groups, and various adiposity measures may reveal different patterns. Methods. To study changes over time in adiposity measures, distributional shifts in body mass index (BMI, kg/m= 95= 24. Generalized estimating equations were used to examine associations between 6= 55%]; plus up to 10% each of epigallocatechin, epicatechin, and epigallocatechin gallate) appeared to be the causative agents for the observed toxicities because they are the active ingredients of green tea extract studied. Conduct of the study in nonfasted dogs under the same testing conditions and dose levels showed unremarkable results. Assuming both studies were valid, at the identified no observed adverse effect levels (NOAEL) of each study, systemic exposures (based on area under the curve [AUC]) were actually lower in fasted than nonfasted dogs, suggesting that fasting may have rendered the target organ systems potentially more vulnerable to the effects of green tea extract. The toxicity mechanisms that produced lethality are not known, but the results are scientifically intriguing. Because tea drinking has become more popular in the United States and abroad, the mode of action and site of action of green tea extract-induced lethal toxicities during fasting and the role of other phytochemical components of Folia Camellia sinensis (including nonpolyphenol fractions, which are often consumed when whole-leaf products are presented) warrant further investigation. C1 [Wu, Kuei-Meng] US FDA, Div Antiviral Prod, CDER, Silver Spring, MD 20993 USA. [Yao, Jiaqin] US FDA, Div Dermatol & Dent Prod, CDER, Silver Spring, MD 20993 USA. [Boring, Daniel] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Wu, KM (reprint author), US FDA, Div Antiviral Prod, CDER, Silver Spring, MD 20993 USA. EM kueimeng.wu@fda.hhs.gov NR 9 TC 8 Z9 8 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 J9 INT J TOXICOL JI Int. J. Toxicol. PD FEB PY 2011 VL 30 IS 1 BP 19 EP 20 DI 10.1177/1091581810387445 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 733RJ UT WOS:000288280200002 PM 21098339 ER PT J AU Tanofsky-Kraff, M Shomaker, LB Olsen, C Roza, CA Wolkoff, LE Columbo, KM Raciti, G Zocca, JM Wilfley, DE Yanovski, SZ Yanovski, JA AF Tanofsky-Kraff, Marian Shomaker, Lauren B. Olsen, Cara Roza, Caroline A. Wolkoff, Laura E. Columbo, Kelli M. Raciti, Gina Zocca, Jaclyn M. Wilfley, Denise E. Yanovski, Susan Z. Yanovski, Jack A. TI A Prospective Study of Pediatric Loss of Control Eating and Psychological Outcomes SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE binge eating disorder; loss of control eating; depression; childhood; adolescence ID CHILDRENS DEPRESSION INVENTORY; DISORDER EXAMINATION; ADOLESCENT GIRLS; BULIMIA-NERVOSA; PSYCHOMETRIC PROPERTIES; FEMALE ADOLESCENTS; COMMUNITY SAMPLE; PUBERTAL CHANGES; NATURAL COURSE; ADULT OBESITY AB Loss of control (LOC) eating in youth is associated cross-sectionally with eating-related and psychosocial distress and is predictive of excessive weight gain. However, few longitudinal studies have examined the psychological impact and persistence of pediatric LOC eating. We administered the Eating Disorder Examination and self-reported measures of depressive and anxiety symptoms to 195 boys and girls (mean age = 10.4 years, SD = 1.5) at baseline and again 4.7 years (SD = 1.2) later to 118 of these youth. Missing data were imputed. Baseline report of LOC was associated with the development of partial- or full-syndrome binge eating disorder (p = .03), even after accounting for the contribution of sex, race, baseline characteristics (age, disordered eating attitudes, and mood symptoms), body mass index growth between baseline and follow-up, and years in study. Half (52.2%; 95% CI [1.15, 6.22]) of children who endorsed experiencing LOC at baseline reported persistence of LOC at follow-up (p = .02). Compared with children who never reported LOC eating or reported LOC only at baseline, those with persistent LOC experienced significantly greater increases in disordered eating attitudes (ps < .001) and depressive symptoms (p = .027) over time. These data suggest that LOC eating in children is a problematic behavior that frequently persists into adolescence and that persistent LOC eating is associated with worsening of emotional distress. C1 [Tanofsky-Kraff, Marian; Shomaker, Lauren B.; Wolkoff, Laura E.; Columbo, Kelli M.; Raciti, Gina] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Tanofsky-Kraff, Marian; Shomaker, Lauren B.; Wolkoff, Laura E.; Columbo, Kelli M.; Raciti, Gina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,US Dept HHS, Bethesda, MD USA. [Olsen, Cara] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Wilfley, Denise E.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mtanofsky@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [ZIA HD000641-14, Z99 HD999999]; NICHD NIH HHS [Z01 HD000641]; NIDDK NIH HHS [1R01DK080906-01A1, R01 DK080906, R01 DK080906-04]; NIMH NIH HHS [K24 MH070446, K24MH070446] NR 66 TC 80 Z9 80 U1 4 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD FEB PY 2011 VL 120 IS 1 BP 108 EP 118 DI 10.1037/a0021406 PG 11 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA 717VB UT WOS:000287074400010 PM 21114355 ER PT J AU Rao, U Sidhartha, T Harker, KR Bidesi, AS Chen, LA Ernst, M AF Rao, Uma Sidhartha, Tanuj Harker, Karen R. Bidesi, Anup S. Chen, Li-Ann Ernst, Monique TI Relationship Between Adolescent Risk Preferences on a Laboratory Task and Behavioral Measures of Risk-Taking SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescent; Decision-making; Risky behavior; Reward; Punishment ID FAMILY HISTORY METHOD; PUBERTAL CHANGES; DECISION-MAKING; SUBSTANCE USE; REWARD; BRAIN; DISORDERS; VALIDITY; ADULTS; RELIABILITY AB Purpose: The goal of the study was to assess individual differences among adolescents regarding risk-taking behavior in the laboratory. The second aim was to evaluate whether the laboratory-based risk-taking behavior is associated with other behavioral and psychological measures associated with risk-taking behavior. Methods: A total of 82 adolescents with no personal history of psychiatric disorder completed a computerized decision-making task, the Wheel of Fortune. On the basis of the choices made between clearly defined probabilities and real monetary outcomes, this task assesses risk preferences when participants are confronted with potential rewards and losses. The participants also completed a variety of behavioral and psychological measures associated with risk-taking behavior. Results: Performance on the task varied on the basis of probability and anticipated outcomes. In the winning sub-task, participants selected low-probability-high-magnitude reward (high-risk choice) less frequently than high-probability-low-magnitude reward (low-risk choice). In the losing sub-task, participants selected low-probability-high-magnitude loss more often than high-probability-low-magnitude loss. On average, the selection of probabilistic rewards was optimal and similar to performance in adults. There were, however, individual differences in performance, and one-third of the adolescents made high-risk choice more frequently than low-risk choice while selecting a reward. After controlling for sociodemographic and psychological variables, high-risk choice on the winning task predicted "real-world" risk-taking behavior and substance-related problems. Conclusions: These findings highlight individual differences in risk-taking behavior. Regarding validity of the Wheel of Fortune task, the preliminary data suggest that it might be a valuable laboratory tool for studying behavioral and neurobiological processes associated with risk-taking behavior in adolescents. (C) 2011 Society for Adolescent Health and Medicine. All rights reserved. C1 [Rao, Uma; Harker, Karen R.; Bidesi, Anup S.; Chen, Li-Ann] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Sidhartha, Tanuj] Community Psychiat Associates, Vallejo, CA USA. [Ernst, Monique] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Rao, U (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5223 Harry Hiles Blvd, Dallas, TX 75390 USA. EM uma.rao@utsouthwestern.edu FU National Institutes of Health [DA14037, DA15131, DA17804, DA17805, MH62464, MH68391, RR00633]; Sarah M. and Charles E. Seay Endowed Chair in Child Psychiatry at UT South-western Medical Center FX This work was supported in part by grants from the National Institutes of Health (DA14037, DA15131, DA17804, DA17805, MH62464, MH68391, and RR00633), and the Sarah M. and Charles E. Seay Endowed Chair in Child Psychiatry at UT South-western Medical Center. The authors are grateful to Dallas and Fort Worth Independent School Districts for their support in recruiting research participants and for providing office space for assessments at the Youth and Family Resource Centers. NR 39 TC 7 Z9 7 U1 4 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD FEB PY 2011 VL 48 IS 2 BP 151 EP 158 DI 10.1016/j.jadohealth.2010.06.008 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 709PW UT WOS:000286454000007 PM 21257113 ER PT J AU Datta, S Milner, JD AF Datta, Shrimati Milner, Joshua D. TI Altered T-cell receptor signaling in the pathogenesis of allergic disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE T-cell receptor; T(H)2; atopy ID IMMUNOLOGICAL SYNAPSE; AUTOIMMUNE ARTHRITIS; DOCK8 MUTATIONS; OMENN-SYNDROME; CUTTING EDGE; ACTIVATION; MICE; RESPONSES; KINASE; IMMUNODEFICIENCY AB Mounting evidence from animal models has demonstrated that alterations in T-cell receptor (TCR) signaling alone can lead to dramatically skewed differentiation of naive T cells into T(H)2 cells, to T(H)2 effector functions, and to T(H)2-related diseases. There is significant potential relevance of these observations to human disease. Specifically, a number of immunodeficiencies associated with atopic disease might have atopy as a manifestation because of aberrant TCR signaling. It is therefore important to attempt to identify a role for defects in TCR signaling in the pathogenesis of common atopic diseases. (J Allergy Clin Immunol 2011;127:351-4.) C1 [Datta, Shrimati; Milner, Joshua D.] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Milner, JD (reprint author), 9000 Rockville Pike,NIH Bldg 10 12S236A, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU National Institutes of Health/National Institute of Allergy and Infectious Diseases FX Supported by the Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases. NR 33 TC 10 Z9 11 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 BP 351 EP 354 DI 10.1016/j.jaci.2010.11.033 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA 714KH UT WOS:000286808000006 PM 21281865 ER PT J AU Gergen, PJ AF Gergen, Peter J. TI Surveillance of the cost of asthma in the 21st century SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material ID UNITED-STATES; COMORBIDITY; THERAPY; BURDEN C1 NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. RP Gergen, PJ (reprint author), NIAID, Div Allergy Immunol & Transplantat, 6610 Rockledge Dr,Rm 3067, Bethesda, MD 20892 USA. EM pgergen@niaid.nih.gov NR 15 TC 4 Z9 4 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 BP 370 EP 371 DI 10.1016/j.jaci.2010.11.023 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 714KH UT WOS:000286808000009 PM 21194741 ER PT J AU Santiago, HC Bennuru, S Boyd, A Eberhard, M Nutman, TB AF Santiago, Helton C. Bennuru, Sasisekhar Boyd, Alexis Eberhard, Mark Nutman, Thomas B. TI Structural and immunologic cross-reactivity among filarial and mite tropomyosin: Implications for the hygiene hypothesis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergy; antibody cross-reactivity; Dermatophagoides pteronyssinus; filariasis; hygiene hypothesis; tropomyosin ID IMMUNOGLOBULIN-E ANTIBODY; FC-GAMMA-RIIB; HELMINTH INFECTIONS; ASCARIS-LUMBRICOIDES; BLOCKING ANTIBODIES; PARASITE INFECTION; IGE BINDING; SERUM-IGE; T-CELLS; B-CELLS AB Background: The hygiene hypothesis suggests that parasitic infection modulates host immune responses and decreases atopy. Other data suggest parasitic infections may induce allergic responsiveness. Objective: To assess the structural and immunologic relationships between the known Dermatophagoides pteronyssinus (Der p 10) tropomyosin allergen and filarial tropomyosin of Onchocerca volvulus (OvTrop). Methods: The molecular, structural, and immunologic relationships between OvTrop and Der p 10 were compared. Levels of OvTrop-specific and Der p 10-specific IgE, IgG, and IgG(4) in sera of filaria-infected and filarial-uninfected D pteronyssinus-atopic individuals were compared, as were the responses in nonhuman primates infected with the filarial parasite Loa loa. Cross-reactivity was compared by antigen-mediated depletion assays and functionality by passive basophil sensitization. Results: Filarial and mite tropomyosins were very similar, with 72% identity at the amino acid level, and overlapping predicted 3-dimensional structures. The prevalence of IgE and IgG to Der p 10 was increased in filaria-infected individuals compared with uninfected subjects. There was a strong correlation between serum levels of Ov- and Der p 10-tropomyosin-specific IgE, IgG, and IgG4 (P < .0001; r > 0.79). Preincubation of sera from anti-Der p 10-positive subjects with OvTrop completely depleted IgE, IgG, and IgG4 anti-Der p 10. Basophils sensitized with sera from individuals allergic to Der p 10 released histamine similarly when triggered with OvTrop or Der p 10. Primates experimentally infected with L loa developed IgE that cross-reacted with Der p 10. Conclusion: Filarial infection induces strong cross-reactive antitropomyosin antibody responses that may affect sensitization and regulation of allergic reactivity. (J Allergy Clin Immunol 2011;127:479-86.) C1 [Santiago, Helton C.; Bennuru, Sasisekhar; Boyd, Alexis; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Boyd, Alexis] George Washington Univ, Washington, DC USA. [Eberhard, Mark] Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA USA. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Bldg 4,Room B105, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov RI Santiago, Helton/F-8704-2012; Vacinas, Inct/J-9431-2013 OI Santiago, Helton/0000-0002-5695-8256; FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Supported by the Intramural Research Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 50 TC 30 Z9 30 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 BP 479 EP 486 DI 10.1016/j.jaci.2010.11.007 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 714KH UT WOS:000286808000023 PM 21185070 ER PT J AU Esteitie, R Jones, NS Toskala, E Cruz, AA Powe, DG Naclerio, R Shusterman, DJ Lieberman, P Baraniuk, JN Mullol, J Baroody, FM Wagenmann, M White, M Scadding, G Settipane, R Fokkens, W Pawankar, R Togias, A AF Esteitie, R. Jones, N. S. Toskala, E. Cruz, A. A. Powe, D. G. Naclerio, R. Shusterman, D. J. Lieberman, P. Baraniuk, J. N. Mullol, J. Baroody, F. M. Wagenmann, M. White, M. Scadding, G. Settipane, R. Fokkens, W. Pawankar, R. Togias, A. TI Nonallergic Rhinitis-Identifying Gaps in Research SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Esteitie, R.; Baraniuk, J. N.] Georgetown Univ, Washington, DC USA. [Jones, N. S.; Powe, D. G.] Nottingham Univ Hosp NHS Trust, Queens Med Ctr, Nottingham, England. [Toskala, E.] Finnish Inst Occupat Hlth, Helsinki, Finland. [Cruz, A. A.] Univ Fed Bahia, Salvador, BA, Brazil. [Naclerio, R.; Baroody, F. M.] Univ Chicago, Chicago, IL 60637 USA. [Shusterman, D. J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lieberman, P.] Univ Tennesse, Coll Med, Mmephis, TN USA. [Mullol, J.] Hosp Clinic IDIBAPS, Barcelona, Catalonia, Spain. [Wagenmann, M.] Univ Klinkum Duesseldorf, HNO Klin, Dusseldorf, Germany. [White, M.] Inst Asthma & Allergy, Wheaton, MD USA. [Scadding, G.] Royal Natl TNE Hosp, London, England. [Settipane, R.] Brown Univ, Providence, RI 02912 USA. [Fokkens, W.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Pawankar, R.] Nipon Med Sch, Tokyo, Japan. [Togias, A.] NIAID, Bethesda, MD 20892 USA. RI Wagenmann, Martin/B-2524-2012 OI Wagenmann, Martin/0000-0002-9734-0241 NR 0 TC 0 Z9 0 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB254 EP AB254 DI 10.1016/j.jaci.2010.12.1013 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846401127 ER PT J AU Khoury, P Klion, A AF Khoury, P. Klion, A. TI Diagnostic Utility Of Serum Biomarkers In Distinguishing Between Churg-strauss Syndrome And Hypereosinophilic Syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Khoury, P.; Klion, A.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB207 EP AB207 DI 10.1016/j.jaci.2010.12.824 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400805 ER PT J AU Kirshenbaum, AS Fischer, ER O'Brien, K Gahl, WA Metcalfe, DD AF Kirshenbaum, A. S. Fischer, E. R. O'Brien, K. Gahl, W. A. Metcalfe, D. D. TI Ultrastructural Differences in Cutaneous Mast Cells from Patients with Hermansky-Pudlak Syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Kirshenbaum, A. S.; Fischer, E. R.; Metcalfe, D. D.] NIAID, NIH, Bethesda, MD 20892 USA. [O'Brien, K.; Gahl, W. A.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB132 EP AB132 DI 10.1016/j.jaci.2010.12.527 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400509 ER PT J AU Komarow, HD Yang, B Nelson, C Young, M O'Brien, M Medic, N Chew, S Milner, J Gadina, M Metcalfe, DD AF Komarow, H. D. Yang, B. Nelson, C. Young, M. O'Brien, M. Medic, N. Chew, S. Milner, J. Gadina, M. Metcalfe, D. D. TI Lack of Evidence for Activation of the Inflammasome in Typical Physical Urticarias SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Komarow, H. D.; Nelson, C.; Young, M.; O'Brien, M.; Medic, N.; Chew, S.; Milner, J.; Metcalfe, D. D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Yang, B.; Gadina, M.] NIAMS, Off Sci & Technol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB102 EP AB102 DI 10.1016/j.jaci.2010.12.409 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846400392 ER PT J AU Myles, IA Fowler, C Valdez, P Datta, S AF Myles, I. A. Fowler, C. Valdez, P. Datta, S. TI The Adaptive Immune Response in Cutaneous Methicillin-Resistant Staphylococcus Aureus Infections SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Myles, I. A.; Fowler, C.; Valdez, P.; Datta, S.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB230 EP AB230 DI 10.1016/j.jaci.2010.12.916 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846401031 ER PT J AU Upadhyaya, B Yin, Y Prussin, C AF Upadhyaya, B. Yin, Y. Prussin, C. TI Heterogeneous IL-5 Expression Defines Two Phenotypically Distinct Human Th2 Subpopulations SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT American-Academy-of-Allergy-Asthma-and-Immunology Annual Meeting CY MAR 18-22, 2011 CL San Francisco, CA SP Amer Acad Allergy Asthma & Immunol C1 [Upadhyaya, B.; Yin, Y.; Prussin, C.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2011 VL 127 IS 2 SU S BP AB264 EP AB264 DI 10.1016/j.jaci.2010.12.1050 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 832YI UT WOS:000295846401164 ER PT J AU Shiozuka, C Taguchi, A Matsuda, J Noguchi, Y Kunieda, T Uchio-Yamada, K Yoshioka, H Hamanaka, R Yano, S Yokoyama, S Mannen, K Kulkarni, AB Furukawa, K Ishii, S AF Shiozuka, Chikara Taguchi, Atsumi Matsuda, Junichiro Noguchi, Yoko Kunieda, Takanori Uchio-Yamada, Kozue Yoshioka, Hidekatsu Hamanaka, Ryoji Yano, Shinji Yokoyama, Shigeo Mannen, Kazuaki Kulkarni, Ashok B. Furukawa, Koichi Ishii, Satoshi TI Increased globotriaosylceramide levels in a transgenic mouse expressing human alpha 1,4-galactosyltransferase and a mouse model for treating Fabry disease SO JOURNAL OF BIOCHEMISTRY LA English DT Article DE active-site-specific chaperone therapy; Fabry disease; globotriaosylceramide; mouse model ID MUTANT ALPHA-GALACTOSIDASE; SITE-SPECIFIC CHAPERONE; DEFICIENT MICE; GENE-TRANSFER; IN-VITRO; 1-DEOXYGALACTONOJIRIMYCIN; CELLS; THERAPY; BINDING; GLYCOSPHINGOLIPIDS AB Fabry disease is a lysosomal storage disorder caused by an alpha-galactosidase A (alpha-Gal A) deficiency and resulting in the accumulation of glycosphingolipids, predominantly globotriaosylceramide (Gb3). A transgenic mouse expressing the human alpha-Gal A R301Q mutant in an alpha-Gal A-knockout background (TgM/KO) should be useful for studying active-site-specific chaperone (ASSC) therapy for Fabry disease. However, the Gb3 content in the heart tissue of this mouse was too low to detect an ASSC-induced effect. To increase the Gb3 levels in mouse organs, we created transgenic mice (TgG3S) expressing human alpha 1,4-galactosyltransferase (Gb3 synthase). High levels of Gb3 were observed in all major organs of the TgG3S mouse. A TgG3S (+/-)M(+/-)/KO mouse was prepared by cross-breeding the TgG3S and TgM/KO mice and the Gb3 content in the heart of the TgG3S(+/-)M(+/-)/KO mouse was 1.4 mu g/mg protein, higher than in the TgM(+/-)/KO (< 0.1 mu g/mg protein). Treatment with an ASSC, 1-deoxygalactonojirimycin, caused a marked induction of alpha-Gal A activity and a concomitant reduction of the Gb3 content in the TgG3S(+/-) M(+/-)/KO mouse organs. These data indicated that the TgG3S(+/-) M(+/-)/KO mouse was suitable for studying ASSC therapy for Fabry disease, and that the TgG3S mouse would be useful for studying the effect of high Gb3 levels in mouse organs. C1 [Taguchi, Atsumi; Yoshioka, Hidekatsu; Ishii, Satoshi] Oita Univ, Dept Matrix Med, Fac Med, Yufu, Oita 8795593, Japan. [Shiozuka, Chikara; Taguchi, Atsumi; Ishii, Satoshi] Obihiro Univ Agr & Vet Med, Dept Agr & Life Sci, Obihiro, Hokkaido 0808555, Japan. [Matsuda, Junichiro; Noguchi, Yoko; Kunieda, Takanori; Uchio-Yamada, Kozue] Natl Inst Biomed Innovat, Lab Anim Models Human Dis, Osaka 5670085, Japan. [Hamanaka, Ryoji] Oita Univ, Dept Cell Biol, Fac Med, Oita 8795593, Japan. [Yano, Shinji; Yokoyama, Shigeo] Oita Univ, Dept Diagnost Pathol, Fac Med, Oita 8795593, Japan. [Mannen, Kazuaki] Oita Univ, Div Lab Anim Sci, Oita 8795593, Japan. [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Furukawa, Koichi] Nagoya Univ, Sch Med, Dept Biochem 2, Nagoya, Aichi 4660065, Japan. [Ishii, Satoshi] GlycoPharma Corp, Biochem Lab, Oita 8700822, Japan. RP Ishii, S (reprint author), Oita Univ, Dept Matrix Med, Fac Med, Hasama Cho Idaigaoka 1-1, Yufu, Oita 8795593, Japan. EM ishiis01@oita-u.ac.jp FU Japan Society for the Promotion of Science [KAKENHI (20590300)] FX Grant-in-Aid for Scientific Research (C) [KAKENHI (20590300)] from Japan Society for the Promotion of Science. NR 30 TC 7 Z9 7 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0021-924X J9 J BIOCHEM JI J. Biochem. PD FEB PY 2011 VL 149 IS 2 BP 161 EP 170 DI 10.1093/jb/mvq125 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 709XH UT WOS:000286474200006 PM 20961863 ER PT J AU Kumari, D Biacsi, RE Usdin, K AF Kumari, Daman Biacsi, Rea Erika Usdin, Karen TI Repeat Expansion Affects Both Transcription Initiation and Elongation in Friedreich Ataxia Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-POLYMERASE-II; EPIGENETIC CHANGES; METHYLTRANSFERASE COMPLEX; CHROMATIN-STRUCTURE; HISTONE H3; GENE; DNA; METHYLATION; SEQUENCES; IDENTIFICATION AB Expansion of a GAA.TTC repeat in the first intron of the frataxin (FXN) gene causes an mRNA deficit that results in Friedreich ataxia (FRDA). The region flanking the repeat on FRDA alleles is associated with more extensive DNA methylation than is seen on normal alleles and histone modifications typical of repressed genes. However, whether these changes are responsible for the mRNA deficit is controversial. Using chromatin immunoprecipitation and cell lines from affected and unaffected individuals, we show that certain marks of active chromatin are also reduced in the promoter region of the FXN gene in patient cells. Thus, the promoter chromatin may be less permissive for transcription initiation than it is on normal alleles. Furthermore, we show that the initiating form of RNA polymerase II and histone H3 trimethylated on lysine 4, a chromatin mark tightly linked to transcription initiation, are both present at lower levels on FRDA alleles. In addition, a mark of transcription elongation, trimethylated H3K36, shows a reduced rate of accumulation downstream of the repeat. Our data thus suggest that repeat expansion reduces both transcription initiation and elongation in FRDA cells. Our findings may have implications for understanding the mechanism responsible for FRDA as well as for therapeutic approaches to reverse the transcription deficit. C1 [Kumari, Daman; Biacsi, Rea Erika; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Sect Gene Struct & Dis, Lab Mol & Cellular Biol, NIH, Bldg 8,Rm 2A19,8 Ctr Dr, Bethesda, MD 20892 USA. EM ku@helix.nih.gov FU NIDDK, National Institutes of Health [DK057810] FX This work was supported, in whole or in part, by National Institutes of Health Grant DK057810 from the Intramural Program of the NIDDK (to K. U.). NR 39 TC 42 Z9 42 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB PY 2011 VL 286 IS 6 BP 4209 EP 4215 DI 10.1074/jbc.M110.194035 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716MW UT WOS:000286975700019 PM 21127046 ER PT J AU Ma, DD Zhang, R Sun, Y Rios, HF Haruyama, N Han, XL Kulkarni, AB Qin, CL Feng, JQ AF Ma, Dedong Zhang, Rong Sun, Yao Rios, Hector F. Haruyama, Naoto Han, Xianglong Kulkarni, Ashok B. Qin, Chunlin Feng, Jian Q. TI A Novel Role of Periostin in Postnatal Tooth Formation and Mineralization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DENTIN MATRIX PROTEIN-1; TRANSFORMING GROWTH-FACTOR-BETA-1; SIBLING PROTEINS; PERIODONTAL-LIGAMENT; ENAMEL DEFECTS; NULL MUTATION; MOUSE TEETH; BONE; MICE; SIALOPHOSPHOPROTEIN AB Periostin plays multiple functions during development. Our previous work showed a critical role of this disulfide-linked cell adhesion protein in maintenance of periodontium integrity in response to occlusal load. In this study, we attempted to address whether this mechanical response molecule played a direct role in postnatal tooth development. Our key findings are 1) periostin is expressed in preodontoblasts, and odontoblasts; and the periostin-null incisor displayed a massive increase in dentin formation after mastication; 2) periostin is also expressed in the ameloblast cells, and an enamel defect is identified in both the adult-null incisor and molar; 3) deletion of periostin leads to changes in expression profiles of many non-collagenous protein such as DSPP, DMP1, BSP, and OPN in incisor dentin; 4) the removal of a biting force leads to reduction of mineralization, which is partially prevented in periostin-null mice; and 6) both in vitro and in vivo data revealed a direct regulation of periostin by TGF-beta 1 in dentin formation. In conclusion, periostin plays a novel direct role in controlling postnatal tooth formation, which is required for the integrity of both enamel and dentin. C1 [Ma, Dedong] Shandong Univ, Dept Resp Med, Qilu Hosp, Jinan 250012, Peoples R China. [Ma, Dedong; Zhang, Rong; Sun, Yao; Han, Xianglong; Qin, Chunlin; Feng, Jian Q.] Baylor Coll Dent, Texas A&M Hlth Sci Ctr, Dallas, TX 75246 USA. [Zhang, Rong] Fourth Mil Med Univ, Dept Operat Dent & Endodont, Sch Stomatol, Xian 710032, Peoples R China. [Rios, Hector F.] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. [Haruyama, Naoto; Kulkarni, Ashok B.] NIDCR, Funct Genom Sect, NIH, Bethesda, MD 20892 USA. RP Feng, JQ (reprint author), Dept Biomed Sci, 3302 Gaston Ave, Dallas, TX 75246 USA. EM jfeng@bcd.tamhsc.edu RI Haruyama, Naoto/D-1993-2011 OI Haruyama, Naoto/0000-0001-6225-5816 FU National Institutes of adhesive molecule [NIH/NIDCR DE015209, DE005092] FX This work was supported, in whole or in part, by the National Institutes of adhesive molecule highly expressed in the PDL, is essential for Health (NIH/NIDCR DE015209 (to J. Q. F.), and DE005092 (to C. Q.)). NR 38 TC 29 Z9 30 U1 3 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB PY 2011 VL 286 IS 6 BP 4302 EP 4309 DI 10.1074/jbc.M110.140202 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716MW UT WOS:000286975700029 PM 21131362 ER PT J AU Brams, M Gay, EA Saez, JC Guskov, A van Elk, R van der Schors, RC Peigneur, S Tytgat, J Strelkov, SV Smit, AB Yakel, JL Ulens, C AF Brams, Marijke Gay, Elaine A. Saez, Jose Colon Guskov, Albert van Elk, Rene van der Schors, Roel C. Peigneur, Steve Tytgat, Jan Strelkov, Sergei V. Smit, August B. Yakel, Jerrel L. Ulens, Chris TI Crystal Structures of a Cysteine-modified Mutant in Loop D of Acetylcholine-binding Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GATED ION-CHANNEL; X-RAY-STRUCTURE; AGONIST BINDING; AMINO-ACIDS; CONFORMATIONAL-CHANGES; EXTRACELLULAR DOMAIN; STRUCTURE VALIDATION; NICOTINIC RECEPTORS; GABA(A) RECEPTOR; VOLTAGE-SENSOR AB Covalent modification of alpha 7 W55C nicotinic acetylcholine receptors (nAChR) with the cysteine-modifying reagent [2-(trimethylammonium) ethyl] methanethiosulfonate (MTSET+) produces receptors that are unresponsive to acetylcholine, whereas methyl methanethiolsulfonate (MMTS) produces enhanced acetylcholine-gated currents. Here, we investigate structural changes that underlie the opposite effects of MTSET+ and MMTS using acetylcholine-binding protein (AChBP), a homolog of the extracellular domain of the nAChR. Crystal structures of Y53C AChBP show that MT-SET+-modification stabilizes loop C in an extended conformation that resembles the antagonist-bound state, which parallels our observation that MTSET+ produces unresponsive W55C nAChRs. The MMTS-modified mutant in complex with acetylcholine is characterized by a contracted C-loop, similar to other agonist-bound complexes. Surprisingly, we find two acetylcholine molecules bound in the ligand-binding site, which might explain the potentiating effect of MMTS modification in W55C nAChRs. Unexpectedly, we observed in the MMTS-Y53C structure that ten phosphate ions arranged in two rings at adjacent sites are bound in the vestibule of AChBP. We mutated homologous residues in the vestibule of alpha 1 GlyR and observed a reduction in the single channel conductance, suggesting a role of this site in ion permeation. Taken together, our results demonstrate that targeted modification of a conserved aromatic residue in loop D is sufficient for a conformational switch of AChBP and that a defined region in the vestibule of the extracellular domain contributes to ion conduction in an-ion-selective Cys-loop receptors. C1 [Ulens, Chris] KULeuven, Lab Struct Neurobiol, Dept Mol Cell Biol, B-3000 Louvain, Belgium. [Peigneur, Steve; Tytgat, Jan] KULeuven, Toxicol Lab, B-3000 Louvain, Belgium. [Strelkov, Sergei V.] KULeuven, Lab Biocrystallog, B-3000 Louvain, Belgium. [Gay, Elaine A.; Saez, Jose Colon; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [van Elk, Rene; van der Schors, Roel C.; Smit, August B.] Vrije Univ Amsterdam, Dept Mol & Cellular Neurobiol, Ctr Neurogenom & Cognit Res, NL-1081 HV Amsterdam, Netherlands. [Guskov, Albert] Nanyang Technol Univ, Div Struct & Computat Biol, Singapore 138673, Singapore. RP Ulens, C (reprint author), KULeuven, Lab Struct Neurobiol, Dept Mol Cell Biol, Herestr 49,PB 601, B-3000 Louvain, Belgium. EM chris.ulens@med.kuleuven.be RI Smit, August /E-8410-2011; Strelkov, Sergei/G-7425-2014; Guskov, Albert/G-1286-2016 OI Guskov, Albert/0000-0003-2340-2216 FU National Institutes of Health, NIEHS; FWO-Vlaanderen [G.0330.06, G.0257.08]; Belgian Federal Science Policy Office [P6/31]; EU [2020288]; KULeuven Onderzoekstoelage [OT/08/048] FX This research was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health, NIEHS (to E. A. G., J. C. S., and J. L. Y.), by Grants FWO-Vlaanderen (G.0330.06, G.0257.08), and the Belgian Federal Science Policy Office, Interuniversity Attraction Poles program (P6/31) (to J. T.), EU FP7 2020288 NeuroCypres (to C. U., A. B. S., and R. C. vd. S.), and KULeuven Onderzoekstoelage OT/08/048 (to S. V. S. and C. U.). NR 52 TC 31 Z9 31 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB PY 2011 VL 286 IS 6 BP 4420 EP 4428 DI 10.1074/jbc.M110.188730 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716MW UT WOS:000286975700042 PM 21115477 ER PT J AU Aoyagi, S Archer, TK AF Aoyagi, Sayura Archer, Trevor K. TI Differential Glucocorticoid Receptor-mediated Transcription Mechanisms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENE-EXPRESSION; RNA-POLYMERASE; IN-VIVO; NUCLEAR RECEPTORS; BINDING; ACTIVATION; PROMOTER; GENOME; CELLS; SUPERFAMILY AB Nuclear receptors such as the glucocorticoid receptor (GR) are ligand-dependent transcription factors that mediate transcription of target genes by recruiting factors that modulate chromatin structure. In this study, curcumin, a compound known to inhibit GR-mediated transcription, was used to examine the different mechanisms by which GR regulates transcription. The mechanisms of transcription regulation of metallothioneine-2A (MT2A) and solute carrier family 19 member 2 (SLC19A2), two GR target genes where the hormone-dependent gene activation is inhibited or unaffected by curcumin treatment, respectively, were analyzed by chromatin immunoprecipitation and RT-PCR experiments. The data suggest that the loss of hormone-dependent MT2A gene expression is due to the inhibition of continued transcription activity after initial assembly of the transcription machinery. In contrast, the hormone-dependent SLC19A2 gene expression is maintained because the continued transcription output after assembly of transcription machinery is unaffected by curcumin. These results suggest that the two GR target genes use alternate mechanisms to regulate expression levels at the level of continued transcription output after transcription machinery assembly. C1 [Aoyagi, Sayura; Archer, Trevor K.] NIEHS, Chromatin & Gene Express Sect, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Chromatin & Gene Express Sect, Mol Carcinogenesis Lab, NIH, 111 Alexander Dr,POB 12233,MD D4-01, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU National Institutes of Health of the NIEHS [Z01 ES071006-10] FX This work was supported, in whole or in part, by National Institutes of Health Project Z01 ES071006-10 through the Intramural Research Program of the NIEHS (to T. K. A.). NR 38 TC 6 Z9 6 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB PY 2011 VL 286 IS 6 BP 4610 EP 4619 DI 10.1074/jbc.M110.195040 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716MW UT WOS:000286975700061 PM 21127044 ER PT J AU Vasanth, S ZeRuth, G Kang, HS Jetten, AM AF Vasanth, Shivakumar ZeRuth, Gary Kang, Hong Soon Jetten, Anton M. TI Identification of Nuclear Localization, DNA Binding, and Transactivating Mechanisms of Kruppel-like Zinc Finger Protein Gli-Similar 2 (Glis2) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEONATAL DIABETES-MELLITUS; TRANSCRIPTION; REPRESSOR; ROLES; DIFFERENTIATION; EXPRESSION; APOPTOSIS; SEQUENCES; FIBROSIS; DISEASE AB Gli-similar 1-3 (Glis1-3) constitute a subfamily of Kruppel-like zinc finger (ZF) transcription factors that are closely related to the Gli protein family. Mutations in GLIS2 are linked to nephronophthisis, a chronic kidney disease characterized by renal fibrosis and atrophy in children and young adults. Currently, very little information exists about the mechanism of action of Glis2, its target genes, or the signaling pathways that regulate its activity. In this study, we show that a region within ZF3 is required for the nuclear localization of Glis2. Analysis of Glis2 DNA binding demonstrated that Glis2 binds effectively to the consensus Glis binding sequence (GlisBS) (G/C)TGGGGGGT(A/C). Although Glis2 was unable to induce transactivation of a GlisBS-dependent reporter, it effectively inhibited the GlisBS-mediated transactivation by Gli1. Mutations that disrupt the tetrahedral configuration of each ZF within Glis2 abolished Glis2 binding to GlisBS and also abrogated its inhibition of Gli1-mediated transactivation. In contrast, Glis2 was able to activate the murine insulin-2 (Ins2) promoter by binding directly to two GlisBS elements located at -263 and -99 within the Ins2 promoter. Phosphomimetic mutation of Ser(245) inhibited the binding of Glis2 to GlisBS and dramatically affected its transactivation of the Ins2 promoter and its ability to inhibit GlisBS-dependent transactivation by Gli1. In this study, we demonstrate that Glis2 can function as a transcriptional activator and that post-translational modification within its DNA-binding domain can regulate its transcriptional activity. This control may play a critical role in the Glis2-dependent regulation of target genes and renal function. C1 [Vasanth, Shivakumar; ZeRuth, Gary; Kang, Hong Soon; Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, Lab Resp Biol,NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), POB 12233,Mail Drop D2-01, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU National Institutes of Health of the NIEHS [Z01-ES-100485] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NIEHS (Z01-ES-100485). NR 29 TC 12 Z9 12 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB PY 2011 VL 286 IS 6 BP 4749 EP 4759 DI 10.1074/jbc.M110.165951 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716MW UT WOS:000286975700073 PM 21127075 ER PT J AU Billam, P Bonaparte, KL Liu, J Ruckwardt, TJ Chen, M Ryder, AB Wang, R Dash, P Thomas, PG Graham, BS AF Billam, Padma Bonaparte, Kathryn L. Liu, Jie Ruckwardt, Tracy J. Chen, Man Ryder, Alex B. Wang, Rui Dash, Pradyot Thomas, Paul G. Graham, Barney S. TI T Cell Receptor Clonotype Influences Epitope Hierarchy in the CD8+T Cell Response to Respiratory Syncytial Virus Infection SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTERNATIONAL IMMUNOGENETICS DATABASE; MURINE CYTOMEGALOVIRUS; REPERTOIRE DIVERSITY; STRUCTURAL BASIS; IMMUNE-RESPONSE; V-BETA; IMMUNODOMINANCE; MICE; VACCINE AB CD8+ T cell responses are important for recognizing and resolving viral infections. To better understand the selection and hierarchy of virus-specific T cell responses, we compared the T cell receptor (TCR) clonotype in parent and hybrid strains of respiratory syncytial virus-infected mice. K(d)M2(82-90) (SYIGSINNI) in BALB/c and (DM187-195)-M-b (NAITNAKII) in C57B1/6 are both dominant epitopes in parent strains but assume a distinct hierarchy, with K(d)M2(82-90) dominant to (DM187-195)-M-b in hybrid CB6F1/J mice. The dominant K(d)M2(82-90) response is relatively public and is restricted primarily to the highly prevalent V beta 13.2 in BALB/c and hybrid mice, whereas (DM187-195)-M-b responses in C57BL/6 mice are relatively private and involve multiple V beta subtypes, some of which are lost in hybrids. A significant frequency of TCR CDR3 sequences in the (DM187-195)-M-b response have a distinct "(D/E) WG" motif formed by a limited number of recombination strategies. Modeling of the dominant epitope suggested a flat, featureless structure, but (DM187-195)-M-b showed a distinctive structure formed by Lys(7). The data suggest that common recombination events in prevalent V beta genes may provide a numerical advantage in the T cell response and that distinct epitope structures may impose more limited options for successful TCR selection. Defining how epitope structure is interpreted to inform T cell function will improve the design of future gene-based vaccines. C1 [Billam, Padma; Bonaparte, Kathryn L.; Liu, Jie; Ruckwardt, Tracy J.; Chen, Man; Ryder, Alex B.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Wang, Rui] NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Dash, Pradyot; Thomas, Paul G.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Rm 2502,40 Convent Dr,MSC 3017, Bethesda, MD 20892 USA. EM bgraham@nih.gov OI Dash, Pradyot/0000-0001-5467-0657; Thomas, Paul G./0000-0001-7955-0256 FU National Institutes of Health NIAID FX This work was supported, in whole or in part, by the National Institutes of Health NIAID Intramural Program. NR 73 TC 12 Z9 12 U1 2 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB PY 2011 VL 286 IS 6 BP 4829 EP 4841 DI 10.1074/jbc.M110.191437 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716MW UT WOS:000286975700080 PM 21118816 ER PT J AU Diehl, AD Augustine, AD Blake, JA Cowell, LG Gold, ES Gondre-Lewis, TA Masci, AM Meehan, TF Morel, PA Nijnik, A Peters, B Pulendran, B Scheuermann, RH Yao, QA Zand, MS Mungall, CJ AF Diehl, Alexander D. Augustine, Alison Deckhut Blake, Judith A. Cowell, Lindsay G. Gold, Elizabeth S. Gondre-Lewis, Timothy A. Masci, Anna Maria Meehan, Terrence F. Morel, Penelope A. Nijnik, Anastasia Peters, Bjoern Pulendran, Bali Scheuermann, Richard H. Yao, Q. Alison Zand, Martin S. Mungall, Christopher J. TI Hematopoietic cell types: Prototype for a revised cell ontology SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Ontology; Hematopoietic cells; Immunology ID INTEGRATION AB The Cell Ontology (CL) aims for the representation of in vivo and in vitro cell types from all of biology. The CL is a candidate reference ontology of the OBO Foundry and requires extensive revision to bring it up to current standards for biomedical ontologies, both in its structure and its coverage of various subfields of biology. We have now addressed the specific content of one area of the CL, the section of the ontology dealing with hematopoietic cells. This section has been extensively revised to improve its content and eliminate multiple inheritance in the asserted hierarchy, and the groundwork has been laid for structuring the hematopoietic cell type terms as cross-products incorporating logical definitions built from relationships to external ontologies, such as the Protein Ontology and the Gene Ontology. The methods and improvements to the CL in this area represent a paradigm for improvement of the entire ontology over time. (C) 2010 Elsevier Inc. All rights reserved. C1 [Diehl, Alexander D.; Blake, Judith A.; Meehan, Terrence F.] Jackson Lab, Bar Harbor, ME 04609 USA. [Augustine, Alison Deckhut; Gondre-Lewis, Timothy A.; Yao, Q. Alison] NIAID, Bethesda, MD 20892 USA. [Cowell, Lindsay G.; Masci, Anna Maria] Duke Univ, Med Ctr, Durham, NC USA. [Gold, Elizabeth S.] Inst Syst Biol, Seattle, WA USA. [Morel, Penelope A.] Univ Pittsburgh, Pittsburgh, PA USA. [Nijnik, Anastasia] Univ British Columbia, Vancouver, BC, Canada. [Peters, Bjoern] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. [Pulendran, Bali] Emory Univ, Atlanta, GA 30322 USA. [Scheuermann, Richard H.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Zand, Martin S.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Mungall, Christopher J.] Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA. RP Diehl, AD (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM adiehl@informatics.jax.org RI Zand, Martin/A-8612-2015; Diehl, Alexander/G-9883-2016; OI Diehl, Alexander/0000-0001-9990-8331; Zand, Martin/0000-0002-7095-8682; Morel, Penelope/0000-0002-1743-3676; Masci, Anna Maria/0000-0003-1940-6740; Meehan, Terrence/0000-0003-1980-3228; Blake, Judith/0000-0001-8522-334X; Scheuermann, Richard/0000-0003-1355-892X FU NHGRI [HG002273]; NIAID [N01AI40076, N01AI50018, N01AI50020, R01AI077706, AI50019, N01AI50019] FX We thank NIAID for the support of the workshop and follow-up teleconferences. ADD, TFM, and JAB are supported by NHGRI grant HG002273, RHS by NIAID contract N01AI40076, PAM by NIAID contract N01AI50018, MZ by NIAID contract N01AI50020, LGC by NIAID contract R01AI077706 and AI50019, AMM by NIAID contract AI50019, and BP by NIAID contract N01AI50019. NR 10 TC 11 Z9 11 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2011 VL 44 IS 1 SI SI BP 75 EP 79 DI 10.1016/j.jbi.2010.01.006 PG 5 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 733UW UT WOS:000288289900008 PM 20123131 ER PT J AU Tenenbaum, JD Whetzel, PL Anderson, K Borromeo, CD Dinov, ID Gabriel, D Kirschner, B Mirel, B Morris, T Noy, N Nyulas, C Rubenson, D Saxman, PR Singh, H Whelan, N Wright, Z Athey, BD Becich, MJ Ginsburg, GS Musen, MA Smith, KA Tarantal, AF Rubin, DL Lyster, P AF Tenenbaum, Jessica D. Whetzel, Patricia L. Anderson, Kent Borromeo, Charles D. Dinov, Ivo D. Gabriel, Davera Kirschner, Beth Mirel, Barbara Morris, Tim Noy, Natasha Nyulas, Csongor Rubenson, David Saxman, Paul R. Singh, Harpreet Whelan, Nancy Wright, Zach Athey, Brian D. Becich, Michael J. Ginsburg, Geoffrey S. Musen, Mark A. Smith, Kevin A. Tarantal, Alice F. Rubin, Daniel L. Lyster, Peter TI The Biomedical Resource Ontology (BRO) to enable resource discovery in clinical and translational research SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Ontology; Biositemaps; Resources; Biomedical research; Resource annotation; Resource discovery; Search; Semantic web; Web 2.0; Clinical and Translational Science Awards AB The biomedical research community relies on a diverse set of resources, both within their own institutions and at other research centers. In addition, an increasing number of shared electronic resources have been developed. Without effective means to locate and query these resources, it is challenging, if not impossible, for investigators to be aware of the myriad resources available, or to effectively perform resource discovery when the need arises. In this paper, we describe the development and use of the Biomedical Resource Ontology (BRO) to enable semantic annotation and discovery of biomedical resources. We also describe the Resource Discovery System (RDS) which is a federated, inter-institutional pilot project that uses the BRO to facilitate resource discovery on the Internet. Through the RDS framework and its associated Biositemaps infrastructure, the BRO facilitates semantic search and discovery of biomedical resources, breaking down barriers and streamlining scientific research that will improve human health. (C) 2010 Elsevier Inc. All rights reserved. C1 [Tenenbaum, Jessica D.] Duke Univ, Sch Med, Duke Translat Med Inst, Durham, NC USA. [Anderson, Kent; Gabriel, Davera] Univ Calif Davis Hlth Syst, Clin & Translat Sci Ctr, Sacramento, CA USA. [Borromeo, Charles D.; Singh, Harpreet; Whelan, Nancy; Becich, Michael J.] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA USA. [Morris, Tim] Emory Univ, Res & Hlth Sci IT Div, Atlanta, GA 30322 USA. [Whetzel, Patricia L.; Noy, Natasha; Nyulas, Csongor; Musen, Mark A.] Stanford Univ, Stanford Ctr Biomed Informat Res, Stanford, CA 94305 USA. [Wright, Zach] Univ Michigan, Sch Med, Ctr Computat Med & Bioinformat, Ann Arbor, MI USA. [Tarantal, Alice F.] Univ Calif Davis, UC Davis Clin & Translat Sci Ctr, Sch Med, Dept Pediat, Davis, CA 95616 USA. [Tarantal, Alice F.] Univ Calif Davis, UC Davis Clin & Translat Sci Ctr, Sch Med, Dept Cell Biol & Human Anat, Davis, CA 95616 USA. [Kirschner, Beth; Mirel, Barbara; Athey, Brian D.] Univ Michigan, Natl Ctr Integrat Biomed Informat, Ann Arbor, MI 48109 USA. [Ginsburg, Geoffrey S.] Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. [Rubin, Daniel L.] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. [Dinov, Ivo D.] Univ Calif Los Angeles, Lab Neuro Imaging, Ctr Computat Biol, Los Angeles, CA USA. [Mirel, Barbara] Univ Michigan, Sch Educ, Ann Arbor, MI 48109 USA. [Lyster, Peter] Natl Inst Gen Med Sci, Ctr Bioinformat & Computat Biol, Bethesda, MD USA. [Saxman, Paul R.; Athey, Brian D.; Smith, Kevin A.] Univ Michigan, Michigan Inst Clin & Hlth Res, Ann Arbor, MI 48109 USA. [Rubenson, David] Stanford Univ, Ctr Canc, Stanford, CA 94305 USA. RP Tenenbaum, JD (reprint author), POB 17969, Durham, NC 27715 USA. EM jessie.tenenbaum@duke.edu OI Athey, Brian/0000-0002-9793-535X; Borromeo, Charles/0000-0003-4059-4547; Dinov, Ivo/0000-0003-3825-4375 FU [5UL1RR024128-03S1]; [1UL1RR024128-01]; [UL1RR024146]; [1UL1RR025008-01]; [1UL1RR024986-01]; [3U54DA0215190-4S1]; [1UL1RR024153-01]; [3UL1RR024153-03S1]; [3UL1 RR024153-03S1]; [U54 RR021813]; [U54DA021519]; [3U54HG004028-04S1]; [5U54HG004028-05] FX Numerous BRO classes and definitions have been shared with and borrowed from the Neuroscience Information Framework (NIFSTD) ontology in an ongoing partnership. Funding for this work was provided by grants 5UL1RR024128-03S1 and 1UL1RR024128-01 (.JDT, GSG), UL1RR024146 (KA, DG, AFT), 1UL1RR025008-01 (TM), 1UL1RR024986-01 and 3U54DA0215190-4S1 (BK, BA, KS), 1UL1RR024153-01 and 3UL1RR024153-03S1 (NW, MB, CB, HS), 3UL1 RR024153-03S1 (PW, CN, NN, DR, MM, NW, MB, CB, HS, BK, BA, KS), U54 RR021813 (IDD), U54DA021519 (BDA, BK), 3U54HG004028-04S1 and 5U54HG004028-05 (PW, CN, NN, DR, MM). NR 17 TC 29 Z9 30 U1 0 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2011 VL 44 IS 1 SI SI BP 137 EP 145 DI 10.1016/j.jbi.2010.10.003 PG 9 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 733UW UT WOS:000288289900015 PM 20955817 ER PT J AU Beerling, E Ritsma, L Vrisekoop, N Derksen, PWB van Rheenen, J AF Beerling, Evelyne Ritsma, Laila Vrisekoop, Nienke Derksen, Patrick W. B. van Rheenen, Jacco TI Intravital microscopy: new insights into metastasis of tumors SO JOURNAL OF CELL SCIENCE LA English DT Article DE Intravital imaging; Intravital microscopy; Cancer; Invasion; Metastasis ID GREEN FLUORESCENT PROTEIN; LIFETIME IMAGING MICROSCOPY; CONDITIONAL MOUSE MODEL; ENDOGENOUS STRUCTURAL PROTEINS; CELL PENETRATING PEPTIDES; BETA SIGNALING SWITCHES; IN-VIVO; BREAST-CANCER; REAL-TIME; BLOOD-VESSELS AB Metastasis, the process by which cells spread from the primary tumor to a distant site to form secondary tumors, is still not fully understood. Although histological techniques have provided important information, they give only a static image and thus compromise interpretation of this dynamic process. New advances in intravital microscopy (IVM), such as two-photon microscopy, imaging chambers, and multicolor and fluorescent resonance energy transfer imaging, have recently been used to visualize the behavior of single metastasizing cells at subcellular resolution over several days, yielding new and unexpected insights into this process. For example, IVM studies showed that tumor cells can switch between multiple invasion strategies in response to various densities of extracellular matrix. Moreover, other IVM studies showed that tumor cell migration and blood entry take place not only at the invasive front, but also within the tumor mass at tumor-associated vessels that lack an intact basement membrane. In this Commentary, we will give an overview of the recent advances in high-resolution IVM techniques and discuss some of the latest insights in the metastasis field obtained with IVM. C1 [Beerling, Evelyne; Ritsma, Laila; van Rheenen, Jacco] Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands. [Beerling, Evelyne; Ritsma, Laila; van Rheenen, Jacco] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands. [Vrisekoop, Nienke] NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Derksen, Patrick W. B.] Univ Med Ctr Utrecht, Dept Med Oncol, NL-3584 CX Utrecht, Netherlands. [Derksen, Patrick W. B.] Univ Med Ctr Utrecht, Ctr Canc, NL-3584 CX Utrecht, Netherlands. [Derksen, Patrick W. B.] Univ Med Ctr Utrecht, Dept Pathol, NL-3584 CX Utrecht, Netherlands. RP van Rheenen, J (reprint author), Hubrecht Inst KNAW, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. EM j.vanrheenen@hubrecht.eu RI van Rheenen, Jacco/G-3655-2014; Derksen, Patrick/C-6643-2008; OI Derksen, Patrick/0000-0003-0732-7762; Ritsma, Laila/0000-0002-0214-2008 FU Dutch Organization of Scientific Research (NWO) [91710330, 91796318, 175.010.2007.00]; Dutch Cancer Society [KWF: HUBR 2009-4621]; NIAID, NIH FX We thank Johan de Rooij, Onno Kranenburg and Stephan Huveneers for critically reading this manuscript, Tom Schonewille for technical assistance, and Anko de Graaff and the Hubrecht Imaging Center for imaging support. This work was supported by VIDI fellowships 91710330 (J.v.R. and E.B.) and 91796318 (P.W.B.D.) from the Dutch Organization of Scientific Research (NWO), a grant from the Dutch Cancer Society (KWF: HUBR 2009-4621) (L.R.) and an equipment grant (175.010.2007.00) from the Dutch Organization of Scientific Research (NWO). N.V. was supported by the intramural research program of NIAID, NIH. Deposited in PMC for release after 12 months. NR 138 TC 66 Z9 68 U1 1 U2 23 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB 1 PY 2011 VL 124 IS 3 BP 299 EP 310 DI 10.1242/jcs.072728 PG 12 WC Cell Biology SC Cell Biology GA 706MX UT WOS:000286223600002 PM 21242309 ER PT J AU Vergarajauregui, S Martina, JA Puertollano, R AF Vergarajauregui, Silvia Martina, Jose A. Puertollano, Rosa TI LAPTMs regulate lysosomal function and interact with mucolipin 1: new clues for understanding mucolipidosis type IV SO JOURNAL OF CELL SCIENCE LA English DT Article DE Mucolipin; LAPTM; TRPML; MLIV; Lysosomes ID MEMBRANE-PROTEIN; SACCHAROMYCES-CEREVISIAE; MULTIDRUG-RESISTANCE; GENE; CELLS; IDENTIFICATION; FIBROBLASTS; AUTOPHAGY; CHANNEL; YEAST AB Loss-of-function mutations in mucolipin 1 (MCOLN1) result in mucolipidosis type IV (MLIV), a lysosomal storage disorder characterized by severe mental and psychomotor retardation. MCOLN1 is a lysosomal ion channel that belongs to the transient receptor potential (TRP) superfamily. To better understand the cellular function of MCOLN1, a split-ubiquitin yeast two-hybrid screen was performed with the purpose of revealing new MCOLN1 interaction partners. The screen identified two members of the lysosome-associated protein transmembrane (LAPTM) family as novel interaction partners of MCOLN1. The binding between MCOLN1 and LAPTM members (LAPTMs) was confirmed by co-immunoprecipitation and yeast two-hybrid assays. In addition, MCOLN1 and LAPTMs extensively colocalize at late endosomes and lysosomes. Overexpression of LAPTM4b caused enlargement of lysosomes and defective lysosomal degradation, indicating that LAPTMs are important for proper lysosomal function. Interestingly, lysosomal swelling induced by LAPTM4b was rescued by expression of MCOLN1, suggesting a functional connection between the two proteins. Finally, depletion of endogenous LAPTMs by siRNA induced accumulation of concentric multi-lamellar structures and electron-dense inclusions that closely resemble the structures found in MLIV cells. Overall, our data provide new insight into the molecular mechanisms of MCOLN1 function and suggest a potential role for LAPTMs in MLIV pathogenesis. C1 [Vergarajauregui, Silvia; Martina, Jose A.; Puertollano, Rosa] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov FU NIH, National Heart, Lung and Blood Institute (NHLBI) FX We thank Mathew P. Daniels and Patricia S. Connelly from the NHLBI Electron Microscopy Core Facility for assistance. We also appreciate the editorial advice of the NIH Fellows Editorial Board. This project was supported by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute (NHLBI). The authors have no conflicts of interest to declare. Deposited in PMC for release after 12 months. NR 44 TC 21 Z9 21 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB 1 PY 2011 VL 124 IS 3 BP 459 EP 468 DI 10.1242/jcs.076240 PG 10 WC Cell Biology SC Cell Biology GA 706MX UT WOS:000286223600017 PM 21224396 ER PT J AU Duverger, O Chen, SX Lee, D Li, TW Chock, PB Morasso, MI AF Duverger, Olivier Chen, Susie X. Lee, Delia Li, Tianwei Chock, P. Boon Morasso, Maria I. TI SUMOylation of DLX3 by SUMO1 Promotes its Transcriptional Activity SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE DLX3; SUMOYLATION; SUMO1; NUCLEAR LOCALIZATION; DNA BINDING; TRANSCRIPTIONAL ACTIVITY ID NUCLEAR-LOCALIZATION; DNA-BINDING; CONJUGATION; ACTIVATION; PROTEINS; GENES; DIFFERENTIATION; EXPRESSION; MODIFIER; P53 AB Small ubiquitin-like modifiers (SUMO) are post-translational modifiers that regulate target protein activity in diverse ways. The most common group of SUMO substrates is transcription factors, whose transcriptional activity can be altered positively or negatively as a result of SUMOylation. DLX3 is a homeodomain transcription factor involved in placental development, in the differentiation of structures involving epithelial-mesenchymal interactions, such as hair, teeth and nails, and in bone mineralization. We identified two potential SUMOylation sites in the N-terminal domain of DLX3 at positions K83 and K112. Among the six members of the Distal-less family, DLX3 is the only member containing these sites, which are highly conserved among vertebrates. Co-expression experiments demonstrated that DLX3 can be SUMOylated by SUMO1. Site-directed mutagenesis of lysines 83 and 112 to arginines (K83R and K112R) demonstrated that only K112 is involved in SUMOylation. Immunocytochemical analysis determined that SUMOylation does not affect DLX3 translocation to the nucleus and favors perinuclear localization. Moreover, using electrophoresis mobility shift assay (EMSA), we found that DLX3 is still able to bind DNA when SUMOylated. Using luciferase reporter assays, we showed that DLX3(K112R) exhibits a significantly lower transcriptional activity compared to DLX3(WT), suggesting that SUMOylation has a positive effect on DLX3 activity. We identified a new level of regulation in the activity of DLX3 that may play a crucial role in the regulation of hair, teeth, and bone development. J. Cell. Biochem. 112: 445-452, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Duverger, Olivier; Chen, Susie X.; Lee, Delia; Morasso, Maria I.] NIAMS, Dev Skin Biol Sect, NIH, Bethesda, MD USA. [Li, Tianwei; Chock, P. Boon] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Morasso, MI (reprint author), 50 South Dr,Bldg 50,Room 1525, Bethesda, MD 20892 USA. EM morassom@mail.nih.gov FU NIAMS, National Institutes of Health FX The authors thank the Light Imaging Section of the Institute of Arthritis and Musculoskeletal and Skin (NIAMS). This work was supported by the Intramural Program of NIAMS, National Institutes of Health. NR 34 TC 10 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD FEB PY 2011 VL 112 IS 2 BP 445 EP 452 DI 10.1002/jcb.22891 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 717UC UT WOS:000287071900013 PM 21268066 ER PT J AU Lozito, TP Tuan, RS AF Lozito, Thomas P. Tuan, Rocky S. TI Mesenchymal Stem Cells Inhibit Both Endogenous and Exogenous MMPs via Secreted TIMPs SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID HUMAN BONE-MARROW; TISSUE-INHIBITOR; TNF-ALPHA; MATRIX METALLOPROTEINASE-2; INFLAMMATORY CYTOKINES; STROMAL CELLS; MIGRATION; DIFFERENTIATION; ANGIOGENESIS; ACTIVATION AB Mesenchymal stem cells (MSCs) have been shown to be perivascular, occupying a prime location for regulating vessel stability. Here, we focused on the MSC-contribution of key regulators of the perivascular niche, the matrix metalloproteinases (MMPs) and their inhibitors, the TIMPs. Despite secretion of active forms of MMPs by MSCs, MMP enzyme activity was not detected in MSC-conditioned medium (MSC-CM) due to TIMP-mediated inhibition. By means of bifunctional-crosslinking to probe endogenous MMP:TIMP interactions, we showed MMP-2-inhibition by TIMP-2. MSCs also inhibited high levels of exogenous MMP-2 and MMP-9 through TIMP-2 and TIMP-1, respectively. Furthermore, MSC-CM protected vascular matrix molecules and endothelial cell structures from MMP-induced disruption. MSCs remained matrix-protective when exposed to pro-inflammatory cytokines and hypoxia, countering these stresses with increased TIMP-1 expression and augmented MMP-inhibition. Thus, MSCs are revealed as robust sources of TIMP-mediated MMP-inhibition, capable of protecting the perivascular niche from high levels of MMPs even under pathological conditions. J. Cell. Physiol. 226: 385-396, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Lozito, Thomas P.; Tuan, Rocky S.] Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Sch Med, Pittsburgh, PA 15219 USA. [Lozito, Thomas P.; Tuan, Rocky S.] NIAMSD, Dept Hlth & Human Serv, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Sch Med, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU NIAMS IRP [Z01AR41131] FX Contract grant sponsor: NIAMS IRP;; Contract grant number: Z01AR41131. NR 32 TC 44 Z9 47 U1 3 U2 12 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD FEB PY 2011 VL 226 IS 2 BP 385 EP 396 DI 10.1002/jcp.22344 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 708HJ UT WOS:000286352600012 PM 20665704 ER PT J AU Bianciardi, M Fukunaga, M van Gelderen, P de Zwart, JA Duyn, JH AF Bianciardi, Marta Fukunaga, Masaki van Gelderen, Peter de Zwart, Jacco A. Duyn, Jeff H. TI Negative BOLD-fMRI signals in large cerebral veins SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE anticorrelated resting-state patterns; ependymal and pial vessels; high-resolution fMRI; large veins; negative BOLD; periventricular areas; 7T ID HUMAN VISUAL-CORTEX; HIGH-FIELD MRI; HUMAN BRAIN; NEURONAL-ACTIVITY; BLOOD; STATE; FLUCTUATIONS; ACTIVATION; NETWORKS; CONTRAST AB Reductions in blood oxygenation level dependent (BOLD)-functional magnetic resonance imaging (fMRI) signals below baseline levels have been observed under several conditions as negative activation in task-activation studies or anticorrelation in resting-state experiments. Converging evidence suggests that negative BOLD signals (NBSs) can generally be explained by local reductions in neural activity. Here, we report on NBSs that accompany hemodynamic changes in regions devoid of neural tissue. The NBSs were investigated with high-resolution studies of the visual cortex (VC) at 7 T. Task-activation studies were performed to localize a task-positive area in the VC. During rest, robust negative correlation with the task-positive region was observed in focal regions near the ventricles and dispersed throughout the VC. Both positive and NBSs were dependent on behavioral condition. Comparison with high-resolution structural images showed that negatively correlated regions overlapped with larger pial and ependymal veins near sulcal and ventricular cerebrospinal fluid (CSF). Results from multiecho fMRI showed that NBSs were consistent with increases in local blood volume. These findings confirm theoretical predictions that tie neural activity to blood volume increases, which tend to counteract positive fMRI signal changes associated with increased blood oxygenation. This effect may be more salient in high-resolution studies, in which positive and NBS may be more often spatially distinct. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 401-412; doi: 10.1038/jcbfm.2010.164; published online 22 September 2010 C1 [Bianciardi, Marta; Fukunaga, Masaki; van Gelderen, Peter; de Zwart, Jacco A.; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. RP Bianciardi, M (reprint author), NINDS, AMRI, LFMI, NIH, Bldg 10,Rm B1D-723A MSC 1065, Bethesda, MD 20892 USA. EM bianciardim@mail.nih.gov RI Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 33 TC 33 Z9 33 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2011 VL 31 IS 2 BP 401 EP 412 DI 10.1038/jcbfm.2010.164 PG 12 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 715XY UT WOS:000286930100003 PM 20859295 ER PT J AU Bright, MG Donahue, MJ Duyn, JH Jezzard, P Bulte, DP AF Bright, Molly G. Donahue, Manus J. Duyn, Jeff H. Jezzard, Peter Bulte, Daniel P. TI The effect of basal vasodilation on hypercapnic and hypocapnic reactivity measured using magnetic resonance imaging SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE BOLD; cerebrovascular reactivity; CO(2); hypercapnia; hypocapnia; respiration ID CEREBRAL BLOOD-VOLUME; POSITRON-EMISSION-TOMOGRAPHY; VASCULAR-SPACE-OCCUPANCY; CAROTID-ARTERY STENOSIS; CEREBROVASCULAR REACTIVITY; CARBON-DIOXIDE; BOLD SIGNAL; OXYGEN EXTRACTION; HEMODYNAMIC IMPAIRMENT; QUANTITATIVE BOLD AB Cerebrovascular reactivity to vasodilatory hypercapnic and vasoconstrictive hypocapnic challenges is known to be altered in several hemodynamic disorders, which is often attributable to changes in smooth muscle-mediated vascular compliance. Recently, attenuated reactivity to hypercapnia but enhanced reactivity to hypocapnia was observed in patients with chronic stroke. We hypothesize that the latter observation could be explained by a change in the basal vascular tone. In particular, reduced cerebral perfusion pressure, as is prevalent in these patients, may cause vasodilation through autoregulatory mechanisms, and this compensatory baseline condition may alter reactivity to vasoconstrictive hypocapnic challenges. To test this hypothesis, a predilated vascular condition was created in young, healthy subjects (n = 11; age = 23 to 36 years) using inhalation of 4% CO(2). Using blood oxygenation level-dependent functional magnetic resonance imaging at 3 T, breath holding and cued deep breathing respiratory challenges were administered to assess hypercapnia and hypocapnia reactivity, respectively. During the predilated condition, vasoconstrictive reactivity to hypocapnia was significantly (21.1%, P = 0.016) enhanced throughout the gray matter, whereas there was no significant change (6.4%, P = 0.459) in hypercapnic vasodilatory reactivity. This suggests that baseline vasodilation may explain the enhanced hypocapnia reactivity observed in some stroke patients, and that hypocapnia challenges may help identify the level of vascular compliance in patients with reduced cerebral perfusion pressure. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 426-438; doi: 10.1038/jcbfm.2010.187; published online 20 October 2010 C1 [Bright, Molly G.; Donahue, Manus J.; Jezzard, Peter; Bulte, Daniel P.] Univ Oxford, Oxford Ctr Funct MRI Brain, Dept Clin Neurol, Oxford OX3 9DU, England. [Bright, Molly G.; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Donahue, Manus J.] Johns Hopkins Univ, Sch Med, Div MR Res, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Donahue, Manus J.] Vanderbilt Univ, Dept Radiol & Radiol Sci, Nashville, TN USA. RP Bright, MG (reprint author), Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, FMRIB Ctr, Oxford OX3 9DU, England. EM mbright@fmrib.ox.ac.uk RI Bright, Molly/F-6394-2010; Bulte, Daniel/F-8679-2011; OI Bright, Molly/0000-0001-7257-9646; Jezzard, Peter/0000-0001-7912-2251 FU NIH, NINDS; EPSRC; UK MRC; Oxford NIHR Biomedical Research Centre; Dunhill Medical Trust FX This research was supported (in part) by the Intramural Research Program of the NIH, NINDS, as well as the EPSRC, UK MRC, Oxford NIHR Biomedical Research Centre, and Dunhill Medical Trust. NR 52 TC 15 Z9 16 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2011 VL 31 IS 2 BP 426 EP 438 DI 10.1038/jcbfm.2010.187 PG 13 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 715XY UT WOS:000286930100005 PM 20959855 ER PT J AU Basselin, M Ramadan, E Igarashi, M Chang, LS Chen, M Kraft, AD Harry, GJ Rapoport, SI AF Basselin, Mireille Ramadan, Epolia Igarashi, Miki Chang, Lisa Chen, Mei Kraft, Andrew D. Harry, G. Jean Rapoport, Stanley I. TI Imaging upregulated brain arachidonic acid metabolism in HIV-1 transgenic rats (Retracted article. See vol.35, pg. 1386, 2015) SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article; Retracted Publication DE arachidonic acid; brain imaging; eicosanoids; HIV-1; phospholipase A(2) ID CENTRAL-NERVOUS-SYSTEM; PHOSPHOLIPASE A(2); ADMINISTRATION INCREASES; FRONTAL-CORTEX; NEUROINFLAMMATION; DISEASE; CYCLOOXYGENASE-2; ACTIVATION; EXPRESSION; INHIBITOR AB Human immunodeficiency virus (HIV)-associated infection involves the entry of virus-bearing monocytes into the brain, followed by microglial activation, neuroinflammation, and upregulated arachidonic acid (AA) metabolism. The HIV-1 transgenic (Tg) rat, a noninfectious HIV-1 model, shows neurologic and behavioral abnormalities after 5 months of age. We hypothesized that brain AA metabolism would be elevated in older HIV-1 Tg rats in vivo. Arachidonic acid incorporation from the plasma into the brain of unanesthetized 7-to-9-month-old rats was imaged using quantitative autoradiography, after [1-C-14] AA infusion. Brain phospholipase (PLA(2)) activities and eicosanoid concentrations were measured, and enzymes were localized by immunostaining. AA incorporation coefficients k* and rates J(in), measures of AA metabolism, were significantly higher in 69 of 81 brain regions in HIV-1 Tg than in control rats, as were activities of cytosolic (c) PLA(2)-IV, secretory (s)PLA(2), and calcium independent (i) PLA(2)-VI, as well as prostaglandin E-2 and leukotriene B-4 concentrations. Immunostaining of somatosensory cortex showed elevated cPLA(2)-IV, sPLA(2)-IIA, and cyclooxygenase-2 in neurons. Brain AA incorporation and other markers of AA metabolism are upregulated in HIV-1 Tg rats, in which neurologic changes and neuroinflammation have been reported. Positron emission tomography with [1-C-11] AA could be used to test whether brain AA metabolism is upregulated in HIV-1-infected patients, in relation to cognitive and behavioral disturbances. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 486-493; doi: 10.1038/jcbfm.2010.111; published online 28 July 2010 C1 [Basselin, Mireille; Ramadan, Epolia; Igarashi, Miki; Chang, Lisa; Chen, Mei; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Kraft, Andrew D.; Harry, G. Jean] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC USA. RP Ramadan, E (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM ramadanir@mail.nih.gov FU National Institute on Aging; National Institute of Environmental Health Science, NIH FX The research was supported by the Intramural Research Programs of the National Institute on Aging and the National Institute of Environmental Health Science, NIH. NR 39 TC 26 Z9 27 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2011 VL 31 IS 2 BP 486 EP 493 DI 10.1038/jcbfm.2010.111 PG 8 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 715XY UT WOS:000286930100011 PM 20664612 ER PT J AU Liu, D Croteau, DL Souza-Pinto, N Pitta, M Tian, JY Wu, C Jiang, HY Mustafa, K Keijzers, G Bohr, VA Mattson, MP AF Liu, Dong Croteau, Deborah L. Souza-Pinto, Nadja Pitta, Michael Tian, Jingyan Wu, Christopher Jiang, Haiyang Mustafa, Khadija Keijzers, Guido Bohr, Vilhelm A. Mattson, Mark P. TI Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE BER; DNA repair; Drp1; focal ischemic stroke; mitochondria; 8-oxoG; OGG1; XRCC1 ID BASE-EXCISION-REPAIR; MILD COGNITIVE IMPAIRMENT; RAT-BRAIN; MITOCHONDRIAL-DNA; FREE-RADICALS; ALZHEIMERS-DISEASE; MICE DEFICIENT; LESIONS; AGE; MUTAGENESIS AB 7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1(-/-)) mice to examine the possible roles of OGG1 in the vulnerability of neurons to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and reduced membrane potential. Cortical neurons isolated from OGG1(-/-) mice were more vulnerable to oxidative insults than were OGG1(+/+) neurons, and OGG1(-/-) mice developed larger cortical infarcts and behavioral deficits after permanent middle cerebral artery occlusion compared with OGG1(+/+) mice. Accumulations of oxidative DNA base lesions (8-oxoG, FapyAde, and FapyGua) were elevated in response to ischemia in both the ipsilateral and contralateral hemispheres, and to a greater extent in the contralateral cortex of OGG1(-/-) mice compared with OGG1(+/+) mice. Ischemia-induced elevation of 8-oxoG incision activity involved increased levels of a nuclear isoform OGG1, suggesting an adaptive response to oxidative nuclear DNA damage. Thus, OGG1 has a pivotal role in repairing oxidative damage to nuclear DNA under ischemic conditions, thereby reducing brain damage and improving functional outcome. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 680-692; doi:10.1038/jcbfm.2010.147; published online 25 August 2010 C1 [Liu, Dong; Pitta, Michael; Wu, Christopher; Jiang, Haiyang; Mustafa, Khadija; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Croteau, Deborah L.; Souza-Pinto, Nadja; Tian, Jingyan; Keijzers, Guido; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. [Souza-Pinto, Nadja] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-01498 Sao Paulo, Brazil. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X; FU National Institute on Aging FX This study was supported by the Intramural Research Program of the National Institute on Aging. NR 36 TC 44 Z9 46 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2011 VL 31 IS 2 BP 680 EP 692 DI 10.1038/jcbfm.2010.147 PG 13 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 715XY UT WOS:000286930100029 PM 20736962 ER PT J AU Kannan, S Saadani-Makki, F Balakrishnan, B Dai, H Chakraborty, PK Janisse, J Muzik, O Romero, R Chugani, DC AF Kannan, Sujatha Saadani-Makki, Fadoua Balakrishnan, Bindu Dai, Hui Chakraborty, Pulak K. Janisse, James Muzik, Otto Romero, Roberto Chugani, Diane C. TI Decreased cortical serotonin in neonatal rabbits exposed to endotoxin in utero SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE autism; cerebral palsy; maternal inflammation; PET; serotonin; somatosensory ID PRIMARY SOMATOSENSORY CORTEX; CEREBRAL-PALSY; NEURODEVELOPMENTAL DISORDERS; INDOLEAMINE 2,3-DIOXYGENASE; THALAMOCORTICAL AXONS; KYNURENINE PATHWAY; MONOAMINE-OXIDASE; HUMAN PLACENTA; BRAIN; INFECTION AB Maternal intrauterine inflammation is implicated in neurodevelopmental disorders in the offspring. Serotonin is crucial for regulating maturation in the developing brain, and maternal inflammation may result in disruption of the serotonergic system in the perinatal period. Saline or endotoxin was injected intrauterine in pregnant rabbits term. Newborn rabbits underwent positron emission tomography (PET) imaging with alpha[(11)C]methyl-L-tryptophan (AMT) to evaluate tryptophan metabolism in vivo. Decrease in standard uptake value for AMT and decrease in serotonin concentration was noted in the frontal and parietal cortices of endotoxin kits when compared with controls. In addition, a significant decrease in serotonin-immunoreactive fibers and decreased expression of serotonin transporter (5HTT) was measured in the somatosensory cortex. There was a three-fold increase in the number of apoptotic cells in the ventrobasal (VB) thalamus without loss of raphe serotonergic cell bodies in endotoxin kits when compared with controls. Glutamateric VB neurons projecting to somatosensory cortex transiently express 5HTT and store serotonin, regulating development of the somatosensory cortex. Intrauterine inflammation results in alterations in cortical serotonin and disruption of serotonin-regulated thalamocortical development in the newborn brain. This may be a common link in neurodevelopmental disorders resulting in impairment of the somatosensory system, such as cerebral palsy and autism. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 738-749; doi:10.1038/jcbfm.2010.156; published online 8 September 2010 C1 [Kannan, Sujatha; Saadani-Makki, Fadoua; Balakrishnan, Bindu; Dai, Hui; Muzik, Otto; Chugani, Diane C.] Wayne State Univ, Sch Med, Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Chakraborty, Pulak K.; Muzik, Otto; Chugani, Diane C.] Wayne State Univ, Sch Med, Childrens Hosp Michigan, Dept Radiol, Detroit, MI 48201 USA. [Janisse, James] Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RP Kannan, S (reprint author), Wayne State Univ, Sch Med, Childrens Hosp Michigan, Dept Pediat, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM skannan@med.wayne.edu FU NICHD, NIH; Perinatology Research Branch, Eunice Kennedy Shriver NICHD, NIH, DHHS; [1K08HD050652] FX This study was supported in part by 1K08HD050652, NICHD, NIH, and the Perinatology Research Branch, Eunice Kennedy Shriver NICHD, NIH, DHHS. NR 40 TC 19 Z9 21 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2011 VL 31 IS 2 BP 738 EP 749 DI 10.1038/jcbfm.2010.156 PG 12 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 715XY UT WOS:000286930100034 PM 20827261 ER PT J AU Cheng, TJ Li, QL Wang, YL Bryant, SH AF Cheng, Tiejun Li, Qingliang Wang, Yanli Bryant, Stephen H. TI Binary Classification of Aqueous Solubility Using Support Vector Machines with Reduction and Recombination Feature Selection SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID THROUGHPUT SCREENING DATA; DRUG DISCOVERY; NEURAL-NETWORK; ORGANIC-COMPOUNDS; MDL KEYS; LOG P; PREDICTION; DESCRIPTORS; MODELS; COEFFICIENTS AB Aqueous solubility is recognized as a critical parameter in both the early- and late-stage drug discovery. Therefore, in silico modeling of solubility has attracted extensive interests in recent years. Most previous studies have been limited in using relatively small data sets with limited diversity, which in turn limits the predictability of derived models. In this work, we present a support vector machines model for the binary classification of solubility by taking advantage of the largest known public data set that contains over 46 000 compounds with experimental solubility. Our model was optimized in combination with a reduction and recombination feature selection strategy. The best model demonstrated robust performance in both cross-validation and prediction of two independent test sets, indicating it could be a practical tool to select soluble compounds for screening, purchasing, and synthesizing. Moreover, our work may be used for comparative evaluation of solubility classification studies ascribe to the use of completely public resources. C1 [Cheng, Tiejun; Li, Qingliang; Wang, Yanli; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Cheng, Tiejun/A-5344-2010; Li, Qingliang/N-5169-2015 OI Cheng, Tiejun/0000-0002-4486-3356; Li, Qingliang/0000-0002-6453-236X FU National Institutes of Health (NIH); National Institutes of Health (NIH), National Library of Medicine (NLM) FX We thank the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM) for funding support. We also thank the NIH Fellows Editorial Board (FEB) for manuscript revision. NR 59 TC 21 Z9 21 U1 2 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD FEB PY 2011 VL 51 IS 2 BP 229 EP 236 DI 10.1021/ci100364a PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 725ZP UT WOS:000287685700005 PM 21214224 ER PT J AU Ghysels, A Woodcock, HL Larkin, JD Miller, BT Shao, YH Kong, J Van Neck, D Van Speybroeck, V Waroquier, M Brooks, BR AF Ghysels, An Woodcock, H. Lee, III Larkin, Joseph D. Miller, Benjamin T. Shao, Yihan Kong, Jing Van Neck, Dimitri Van Speybroeck, Veronique Waroquier, Michel Brooks, Bernard R. TI Efficient Calculation of QM/MM Frequencies with the Mobile Block Hessian SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; MOLECULAR-DYNAMICS SIMULATIONS; PANCREATIC-CANCER CELLS; HARTREE-FOCK THEORY; CLUSTER CALCULATIONS; VIBRATIONAL ANALYSIS; HARMONIC-ANALYSIS; 2ND DERIVATIVES; LARGE SYSTEMS; METHOXY ADSORPTION AB The calculation of the analytical second derivative matrix (Hessian) is the bottleneck for vibrational analysis in QM/MM systems when an electrostatic embedding scheme is employed. Even with a small number of QM atoms in the system, the presence of MM atoms increases the computational cost dramatically: the long-range Coulomb interactions require that additional coupled perturbed self-consistent field (CPSCF) equations need to be solved for each MM atom displacement. This paper presents an extension to the Mobile Block Hessian (MBH) formalism for QM/MM calculations with blocks in the MM region and its implementation in a parallel version of the Q-Chem/CHARMM interface. MBH reduces both the CPU time and the memory requirements compared to the standard full Hessian QM/MM analysis, without the need to use a cutoff distance for the electrostatic interactions. Special attention is given to the treatment of link atoms which are usually present when the QM/MM border cuts through a covalent bond. Computational efficiency improvements are highlighted using a reduced chorismate mutase enzyme system, consisting of 24 QM atoms and 306 MM atoms, as a test example. In addition, the drug bortezomib, used for cancer treatment of myeloma, has been studied as a test case with multiple MBH block choices and both a QM and QM/MM description. The accuracy of the calculated Hessians is quantified by imposing Eckart constraints, which allows for the assessment of numerical errors in second derivative procedures. The results show that MBH within the QM/MM description not only is a computationally attractive method but also produces accurate results. C1 [Ghysels, An; Van Neck, Dimitri; Van Speybroeck, Veronique; Waroquier, Michel] Univ Ghent, Ctr Mol Modeling, B-9052 Zwijnaarde, Belgium. [Woodcock, H. Lee, III] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Larkin, Joseph D.; Miller, Benjamin T.; Shao, Yihan; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Shao, Yihan; Kong, Jing] Q Chem Inc, Pittsburgh, PA 15213 USA. RP Ghysels, A (reprint author), Univ Ghent, Ctr Mol Modeling, Technol Pk 903, B-9052 Zwijnaarde, Belgium. EM an.ghysels@ugent.be; hlw@mail.usf.edu RI Woodc, Henry/D-9275-2011; Ghysels, An/M-9095-2015; OI Miller, Benjamin/0000-0003-1647-0122; Woodcock, Henry/0000-0003-3539-273X FU Fund for Scientific Research Flanders (FWO); Research Board of Ghent University (BOF); BELSPO [IAP 6/27]; National Heart, Lung and Blood Institute, National Institutes of Health (NIH); European Research Council [240483]; NIH [1K22HL088341-01A1, GM073408]; University of South Florida FX This work is supported by the Fund for Scientific Research Flanders (FWO), the Research Board of Ghent University (BOF), and BELSPO in the frame of IAP 6/27. This work is also supported by the Intramural Research Program of the National Heart, Lung and Blood Institute, National Institutes of Health (NIH). Funding was also received from the European Research Council under FP7 with ERC grant agreement number 240483. H.L.W. would like to acknowledge NIH (1K22HL088341-01A1) and the University of South Florida (start-up) for funding. Y.S. and J.K. would like to thank NIH for a Small Business Innovative Research grant (GM073408). Computational resources and services used in this work were provided by the Lobos cluster of the National Institutes of Health. NR 77 TC 16 Z9 17 U1 2 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD FEB PY 2011 VL 7 IS 2 BP 496 EP 514 DI 10.1021/ct100473f PG 19 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 717MA UT WOS:000287049200023 PM 26596169 ER PT J AU Faucz, FR AF Faucz, Fabio Rueda TI Docetaxel Treatment in Castration-Resistant Prostate Cancer: the Triad Gene-Drug-Disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID EXPRESSION; ESTROGEN C1 [Faucz, Fabio Rueda] Pontificia Univ Catolica Parana, Mol Genet Lab, Grp Adv Mol Invest, Grad Program Hlth Sci, BR-80215901 Curitiba, Parana, Brazil. [Faucz, Fabio Rueda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, NIH, Bethesda, MD 20892 USA. RP Faucz, FR (reprint author), Pontificia Univ Catolica Parana, Mol Genet Lab, Grp Adv Mol Invest, Grad Program Hlth Sci, Rua Imaculada Conceicao,1155 Prado Velho, BR-80215901 Curitiba, Parana, Brazil. EM fabio.faucz@pucpr.br NR 14 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2011 VL 96 IS 2 BP 351 EP 353 DI 10.1210/jc.2010-2875 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716MG UT WOS:000286972500038 PM 21296995 ER PT J AU Eisenhofer, G Timmers, HJ Lenders, JWM Bornstein, SR Tiebel, O Mannelli, M King, KS Vocke, CD Linehan, WM Bratslavsky, G Pacak, K AF Eisenhofer, Graeme Timmers, Henri J. Lenders, Jacques W. M. Bornstein, Stefan R. Tiebel, Oliver Mannelli, Massimo King, Kathryn S. Vocke, Cathy D. Linehan, W. Marston Bratslavsky, Gennady Pacak, Karel TI Age at Diagnosis of Pheochromocytoma Differs According to Catecholamine Phenotype and Tumor Location SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HIPPEL-LINDAU-SYNDROME; GERMLINE MUTATIONS; PARAGANGLIOMA; PLASMA; METANEPHRINES; SUPPRESSOR; EXPRESSION AB Context: Pheochromocytomas and paragangliomas (PPGLs) are diagnosed earlier in patients with hereditary than sporadic disease. Whether other factors influence age at diagnosis is unclear. Objective: We examined ages at which PPGLs were diagnosed according to different catecholamine phenotypes and locations of tumors. Design & Setting: Retrospective multicenter study. Patients: Patients with PPGLs included 172 with and 183 without identified germline mutations or hereditary syndromes. Biochemical Measurements: Differences in plasma concentrations of metanephrine, a metabolite of epinephrine, were used to distinguish epinephrine-producing tumors from those lacking epinephrine production. Results: Patients with epinephrine-producing tumors were diagnosed 11 yr later (P < 0.001) than those with tumors lacking appreciable epinephrine production. Among patients without evidence of a hereditary condition, those with and without epinephrine-producing tumors had respective mean +/- SE ages of 50 +/- 2 and 42 +/- 2 yr (P < 0.001) at diagnosis. Patients with multiple endocrine neoplasia type 2 and neurofibromatosis type 1, all with epinephrine-producing tumors, were similarly diagnosed with disease at a later age than patients with tumors that lacked appreciable epinephrine production secondary to mutations of von Hippel-Lindau and succinate dehydrogenase genes (40 +/- 2 vs. 31 +/- 1 yr, P < 0.001). Among the latter patients, those with multifocal tumors were diagnosed earlier than those with solitary tumors (19 +/- 3 vs. 34 +/- 2 yr, P < 0.001). Conclusions: The variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of PPGLs from different chromaffin progenitor cells with variable susceptibility to disease causing mutations. Different optimal age cut-offs for mutation testing are indicated for patients with and without epinephrine-producing tumors (44-49 vs. 30-35 yr, respectively). (J Clin Endocrinol Metab 96: 375-384, 2011) C1 [Eisenhofer, Graeme] Univ Dresden, Div Clin Neurochem, Inst Clin Chem & Lab Med, D-01307 Dresden, Germany. [Eisenhofer, Graeme; Lenders, Jacques W. M.; Bornstein, Stefan R.] Univ Dresden, Dept Med 3, D-01307 Dresden, Germany. [Timmers, Henri J.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 GA Nijmegen, Netherlands. [Lenders, Jacques W. M.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands. [Mannelli, Massimo] Univ Florence, Dept Clin Pathophysiol, I-50139 Florence, Italy. [King, Kathryn S.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod & Adult Endocrinol Program, NIH, Bethesda, MD 20892 USA. [Vocke, Cathy D.; Linehan, W. Marston; Bratslavsky, Gennady] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Eisenhofer, G (reprint author), Univ Dresden, Div Clin Neurochem, Inst Clin Chem & Lab Med, Fetscherstr 74, D-01307 Dresden, Germany. EM Graeme.Eisenhofer@uniklinikum-dresden.de RI Lenders, J.W.M./L-4487-2015; OI Mannelli, Massimo/0000-0002-8001-9857 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Center for Cancer Research, National Cancer Institute, at the National Institutes of Health, Bethesda, Maryland; Deutsche Forschungsgesellschaft FX This work was supported by the intramural programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Center for Cancer Research, National Cancer Institute, at the National Institutes of Health, Bethesda, Maryland and the Deutsche Forschungsgesellschaft. NR 28 TC 29 Z9 32 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2011 VL 96 IS 2 BP 375 EP 384 DI 10.1210/jc.2010-1588 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716MG UT WOS:000286972500041 PM 21147885 ER PT J AU Neumann, S Eliseeva, E McCoy, JG Napolitano, G Giuliani, C Monaco, F Huang, WW Gershengorn, MC AF Neumann, Susanne Eliseeva, Elena McCoy, Joshua G. Napolitano, Giorgio Giuliani, Cesidio Monaco, Fabrizio Huang, Wenwei Gershengorn, Marvin C. TI A New Small-Molecule Antagonist Inhibits Graves' Disease Antibody Activation of the TSH Receptor SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID THYROID-STIMULATING HORMONE; THYROTROPIN RECEPTOR; TRANSMEMBRANE DOMAIN; HYPERTHYROIDISM; MODULATORS; BINDING; AGONIST AB Context: Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate the TSH receptor (TSHR). We previously reported the first small-molecule antagonist of human TSHR and showed that it inhibited receptor signaling stimulated by sera from four patients with GD. Objective: Our objective was to develop a better TSHR antagonist and use it to determine whether inhibition of TSAb activation of TSHR is a general phenomenon. Design: We aimed to chemically modify a previously reported small-molecule TSHR ligand to develop a better antagonist and determine whether it inhibits TSHR signaling by 30 GD sera. TSHR signaling was measured in two in vitro systems: model HEK-EM293 cells stably overexpressing human TSHRs and primary cultures of human thyrocytes. TSHR signaling was measured as cAMP production and by effects on thyroid peroxidase mRNA. Results: We tested analogs of a previously reported small-molecule TSHR inverse agonist and selected the best NCGC00229600 for further study. In the model system, NCGC00229600 inhibited basal and TSH-stimulated cAMP production. NCGC00229600 inhibition of TSH signaling was competitive even though it did not compete for TSH binding; that is, NCGC00229600 is an allosteric inverse agonist. NCGC00229600 inhibited cAMP production by 39 +/- 2.6% by all 30 GD sera tested. In primary cultures of human thyrocytes, NCGC00229600 inhibited TSHR-mediated basal and GD sera up-regulation of thyroperoxidase mRNA levels by 65 +/- 2.0%. Conclusion: NCGC00229600, a small-molecule allosteric inverse agonist of TSHR, is a general antagonist of TSH receptor activation by TSAbs in GD patient sera. (J Clin Endocrinol Metab 96: 548-554, 2011) C1 [Neumann, Susanne; Eliseeva, Elena; Gershengorn, Marvin C.] NHGRI, Clin Endocrinol Branch, NIDDK, NIH, Bethesda, MD 20892 USA. [Napolitano, Giorgio; Giuliani, Cesidio; Monaco, Fabrizio] Univ G DAnnunzio, Dept Med & Sci Aging, Unit Endocrinol, I-66100 Chieti, Italy. [McCoy, Joshua G.; Huang, Wenwei] NHGRI, Natl Inst Hlth Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Neumann, S (reprint author), NHGRI, Clin Endocrinol Branch, NIDDK, NIH, 50 S Dr, Bethesda, MD 20892 USA. EM SusanneN@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [Z01-DK047044, Z01-DK011006]; National Human Genome Research Institute; Molecular Libraries Initiative of the Roadmap for Medical Research, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases (Z01-DK047044 Z01-DK011006), the National Human Genome Research Institute, and the Molecular Libraries Initiative of the Roadmap for Medical Research, National Institutes of Health. NR 15 TC 29 Z9 34 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2011 VL 96 IS 2 BP 548 EP 554 DI 10.1210/jc.2010-1935 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716MG UT WOS:000286972500062 PM 21123444 ER PT J AU Beckmann, L Husing, A Setiawan, VW Amiano, P Clavel-Chapelon, F Chanock, SJ Cox, DG Diver, R Dossus, L Feigelson, HS Haiman, C Hallmans, G Hayes, RB Henderson, BE Hoover, RN Hunter, DJ Khaw, K Kolonel, LN Kraft, P Lund, E Le Marchand, L Peeters, PHM Riboli, E Stram, D Thomas, G Thun, MJ Tumino, R Trichopoulos, D Vogel, U Willett, WC Yeager, M Ziegler, R Hankinson, SE Kaaks, R AF Beckmann, L. Husing, A. Setiawan, V. W. Amiano, P. Clavel-Chapelon, F. Chanock, S. J. Cox, D. G. Diver, R. Dossus, L. Feigelson, H. S. Haiman, C. Hallmans, G. Hayes, R. B. Henderson, B. E. Hoover, R. N. Hunter, D. J. Khaw, K. Kolonel, L. N. Kraft, P. Lund, E. Le Marchand, L. Peeters, P. H. M. Riboli, E. Stram, D. Thomas, G. Thun, M. J. Tumino, R. Trichopoulos, D. Vogel, U. Willett, W. C. Yeager, M. Ziegler, R. Hankinson, S. E. Kaaks, R. CA BPC3 TI Comprehensive Analysis of Hormone and Genetic Variation in 36 Genes Related to Steroid Hormone Metabolism in Pre- and Postmenopausal Women from the Breast and Prostate Cancer Cohort Consortium (BPC3) SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MULTIETHNIC COHORT; PREMENOPAUSAL WOMEN; SEX-HORMONES; SHBG GENE; RISK; POLYMORPHISMS; ASSOCIATION; NUTRITION; ESTROGEN; ANDROGEN AB Context: Sex steroids play a central role in breast cancer development. Objective: This study aimed to relate polymorphic variants in 36 candidate genes in the sex steroid pathway to serum concentrations of sex steroid hormones and SHBG. Design: Data on 700 genetic polymorphisms were combined with existing hormone assays and data on breast cancer incidence, within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nurses' Health Study (NHS) cohorts; significant findings were reanalyzed in the Multiethnic Cohort (MEC). Setting and Participants: We analyzed data from a pooled sample of 3852 pre- and postmenopausal Caucasian women from EPIC and NHS and 454 postmenopausal women from MEC. Main Outcome Measures: Outcome measures were SHBG, testosterone, dehydroepiandrosterone (DHEAS), androstenedione, estrone (E1), and estradiol (E2) as well as breast cancer risk. Results: Globally significant associations were found among pre- and postmenopausal women combined between levels of SHBG and the SHBG gene and between DHEAS and the FSHR and AKR1C3 genes. Among postmenopausal women, serum E1 and E2 were significantly associated with the genes CYP19 and FSHR, and E1 was associated with ESR1. None of the variants related to serum hormone levels showed any significant association with breast cancer risk. Conclusions: We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS. (J Clin Endocrinol Metab 96: E360-E367, 2011) C1 [Beckmann, L.; Husing, A.; Dossus, L.; Kaaks, R.] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Setiawan, V. W.; Haiman, C.; Henderson, B. E.; Stram, D.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Amiano, P.] Basque Govt, Dept Hlth, Publ Hlth Div Gipuzkoa, Gipuzkoa 20003, Spain. [Amiano, P.] Ctr Invest Biomed Red Epidemiol & Salud Publ, Valencia 46010, Spain. [Clavel-Chapelon, F.] Univ Paris 11, Inst Federatif Rech 69, INSERM, ERI20, F-94805 Villejuif, France. [Chanock, S. J.; Hoover, R. N.; Thomas, G.; Ziegler, R.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cox, D. G.] Ctr Leon Berard, INSERM, UMR 590, F-69373 Lyon 8, France. [Diver, R.; Feigelson, H. S.; Thun, M. J.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30303 USA. [Hallmans, G.] Umea Univ, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. [Hayes, R. B.] NYU Med Ctr, Dept Environm Med, Div Epidemiol, New York, NY 10016 USA. [Hunter, D. J.; Kraft, P.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Khaw, K.] Univ Cambridge, Sch Clin Med, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge CB2 OSR, England. [Kolonel, L. N.; Le Marchand, L.] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Lund, E.] Univ Tromso, Inst Community Med, N-9037 Tromso, Norway. [Peeters, P. H. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3508 Utrecht, Netherlands. [Riboli, E.] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London SW7 2AZ, England. [Tumino, R.] Civile Maria Paterno Arezzo Hosp, Canc Registry, Ragusa, Italy. [Tumino, R.] Civile Maria Paterno Arezzo Hosp, Histopathol Unit, Ragusa, Italy. [Trichopoulos, D.] Hellenic Hlth Fdn, Athens, Greece. [Vogel, U.] Tech Univ Denmark, Natl Food Inst, DK-2860 Soborg, Denmark. [Vogel, U.] Natl Res Ctr Working Environm, DK-2100 Copenhagen, Denmark. [Willett, W. C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Willett, W. C.; Hankinson, S. E.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. [Yeager, M.] NCI, Core Genotyping Facil, Gaithersburg, MD 20892 USA. RP Kaaks, R (reprint author), German Canc Res Ctr, Div Canc Epidemiol, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. EM r.kaaks@dkfz.de RI Cox, David/A-2023-2009; Perez , Claudio Alejandro/F-8310-2010; Dossus, Laure/B-2875-2013; Clavel-Chapelon, Francoise/G-6733-2014; Vogel, Ulla/I-5048-2012; OI Cox, David/0000-0002-2152-9259; Perez , Claudio Alejandro/0000-0001-9688-184X; Dossus, Laure/0000-0003-2716-5748; Vogel, Ulla/0000-0001-6807-1524; Hayes, Richard/0000-0002-0918-661X FU German Research Foundation Deutsche Forschungsgemeinschaft [BE 3906/2-2]; U.S. National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]; National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics; [P01-CA87969]; [R01-CA49449] FX L.B. is supported by a grant from the German Research Foundation Deutsche Forschungsgemeinschaft (BE 3906/2-2). Grant support came from U.S. National Cancer Institute cooperative agreements U01-CA98233, U01-CA98710, U01-CA98216, and U01-CA98758; grants P01-CA87969 and R01-CA49449; and the Intramural Research Program of the National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 24 TC 18 Z9 18 U1 0 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2011 VL 96 IS 2 BP E360 EP E367 DI 10.1210/jc.2010-0912 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716MG UT WOS:000286972500017 PM 21177793 ER PT J AU Schmidt, PJ Luff, JA Haq, NA Vanderhoof, VH Koziol, DE Calis, KA Rubinow, DR Nelson, LM AF Schmidt, Peter J. Luff, Jamie A. Haq, Nazli A. Vanderhoof, Vien H. Koziol, Deloris E. Calis, Karim A. Rubinow, David R. Nelson, Lawrence M. TI Depression in Women with Spontaneous 46, XX Primary Ovarian Insufficiency SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID COMORBIDITY SURVEY REPLICATION; MENSTRUAL-CYCLE; TURNER-SYNDROME; EARLY MENOPAUSE; PERIMENOPAUSAL WOMEN; PSYCHIATRIC-ILLNESS; BIPOLAR DISORDER; MENTAL-DISORDERS; MOOD SYMPTOMS; FAILURE AB Context: A high prevalence of depressive symptoms is observed in women with primary ovarian insufficiency (POI) compared with women in whom the menopause is normally timed. Indeed, studies suggest that depression and/or its pharmacological treatment contribute to the onset of POI. Objectives: We characterize the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of POI and the onset of menstrual irregularity in women with POI. Design and Setting: We conducted a cross-sectional clinic-based study at the National Institutes of Health Clinical Research Center. Patients: A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study. Main Outcome Measures: The structured clinical interview for DSM-IV was performed. Results: Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P < 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events. Conclusions: POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship. (J Clin Endocrinol Metab 96: E278-E287, 2011) C1 [Schmidt, Peter J.; Luff, Jamie A.; Haq, Nazli A.; Rubinow, David R.] NIMH, Behav Endocrinol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Vanderhoof, Vien H.; Calis, Karim A.; Nelson, Lawrence M.] NICHHD, Integrat Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Koziol, Deloris E.] NIH, Biostat & Clin Epidemiol Serv, Off Deputy Director Clin Care, Ctr Clin,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Schmidt, PJ (reprint author), NIMH, Behav Endocrinol Branch, NIH, Dept Hlth & Human Serv, Bldg 10CRC,Room 25330,10 Ctr Dr MSC 1277, Bethesda, MD 20892 USA. EM peterschmidt@mail.nih.gov FU National Institute of Child Health and Human Development; NIMH FX P.J.S. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This work was written as part of the official duties of P.J.S. as a U.S. Government employee. The views expressed in this article do not necessarily represent the views of the National Institute of Mental Health (NIMH), National Institutes of Health, the Department of Health & Human Services, or the U.S. Government. No grants or fellowships supported the writing of this paper. This work was funded by the Intramural Research Programs of the National Institute of Child Health and Human Development and NIMH. NR 51 TC 10 Z9 10 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2011 VL 96 IS 2 BP E278 EP E287 DI 10.1210/jc.2010-0613 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716MG UT WOS:000286972500006 PM 21047929 ER PT J AU Sissung, TM Danesi, R Kirkland, CT Baum, CE Ockers, SB Stein, EV Venzon, D Price, DK Figg, WD AF Sissung, Tristan M. Danesi, Romano Kirkland, C. Tyler Baum, Caitlin E. Ockers, Sandra B. Stein, Erica V. Venzon, David Price, Douglas K. Figg, William D. TI Estrogen Receptor alpha and Aromatase Polymorphisms Affect Risk, Prognosis, and Therapeutic Outcome in Men with Castration-Resistant Prostate Cancer Treated with Docetaxel-Based Therapy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PHASE-II TRIAL; ANDROGEN; ASSOCIATION; THALIDOMIDE; GENES; METABOLISM; EXPRESSION; BREAST; 1B1 AB Context: Reactive estrogen species cause genotoxicity and interfere with docetaxel-mediated tubulin polymerization resulting in shortened survival in men with castrate-resistant prostate cancer (CRPC). Objective: We hypothesized that polymorphisms in estrogen synthesis and estrogen targets (i.e., CYP19 and ER alpha) would be linked to interindividual variation in CRPC risk, docetaxel response, and overall survival in men with CRPC. Materials and Methods: Patients with CRPC (n=115) treated with docetaxel, single-agent thalidomide (n=42), or healthy controls (n=289) were genotyped for the CYP19 R264C (rs700519) and the ER alpha PvuII T>C (rs2234693) and XbaI A>G (rs9340799) polymorphisms. Results: Patients carrying two copies of ER alpha polymorphisms had shorter progression-free survival on docetaxel than other patients (median survival difference >= 3.1 months; P <= 0.036). When the analysis was limited to nonobese patients, the relationship between the ER alpha Xbal A>G polymorphism and PFS improved (median survival difference = 3.5 months; P = 0.0078). The CYP19 R264C variant was related to the duration of survival after docetaxel in patients who were >70 years old (median survival difference = 10.6 months; P=0.041). Both ER alpha polymorphisms were also associated with increases in CRPC risk [P <= 0.032; double variants vs. wild-type odds ratio >= 2.6], and the association with the ER alpha PvuII T>C also improved in those men who were <70 years old (P = 0.0073; odds ratio = 3.0). Conclusions: This study demonstrates that estrogen-related genetic variation affects docetaxel clinical response and that this relationship is dependent on age and body-type in men with CRPC. Moreover, this study suggests ER alpha polymorphisms confer risk of developing prostate cancer, especially in men under 70 years of age. (J Clin Endocrinol Metab 96: E368-E372, 2011) C1 [Figg, William D.] NCI, Clin Pharmacol Program, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. [Kirkland, C. Tyler; Baum, Caitlin E.; Ockers, Sandra B.; Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Danesi, Romano] Univ Pisa, Dept Internal Med, I-56126 Pisa, Italy. [Stein, Erica V.] George Washington Univ, Inst Biomed Sci, Washington, DC 20052 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Med Oncol Clin Res Unit, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Stein, Erica/0000-0001-8778-8846 FU National Institutes of Health, National Cancer Institute, Bethesda, Maryland FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, Maryland. 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 organization imply endorsement by the U.S. Government. NR 20 TC 16 Z9 17 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2011 VL 96 IS 2 BP E368 EP E372 DI 10.1210/jc.2010-2070 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716MG UT WOS:000286972500018 PM 21106711 ER PT J AU O'Konek, JJ Illarionov, P Khursigara, DS Ambrosino, E Lzhak, L Castillo, BF Raju, R Khalili, M Kim, HY Howel, AR Besra, GS Porcelli, SA Berzofsky, JA Terabe, M AF O'Konek, Jessica J. Illarionov, Petr Khursigara, Deborah Stewart Ambrosino, Elena Lzhak, Liat Castillo, Bernard F., II Raju, Ravinder Khalili, Maryam Kim, Hee-Yong Howel, Amy R. Besra, Gurdyal S. Porcelli, Steven A. Berzofsky, Jay A. Terabe, Masaki TI Mouse and human iNKT cell agonist beta-mannosylceramide reveals a distinct mechanism of tumor immunity SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID KILLER T-CELLS; ALTERED PEPTIDE LIGANDS; V-ALPHA-14 NKT CELLS; ALPHA-GALACTOSYLCERAMIDE; IMMUNOREGULATORY AXIS; ANTITUMOR ACTIVITIES; INTERFERON-GAMMA; LIPID RAFTS; ACTIVATION; RECEPTOR AB Type 1 or invariant NKT (iNKT) cell agonists, epitomized by alpha-galactosylceramide, protect against cancer largely by IFN-gamma-dependent mechanisms. Here we describe what we believe to be a novel IFN-gamma-independent mechanism induced by beta-mannosylceramide, which also defines a potentially new class of iNKT cell agonist, with an unusual beta-linked sugar. Like alpha-galactosylceramide, beta-mannosylceramide directly activates iNKT cells from both mice and humans. In contrast to alpha-galactosylceramide, protection by beta-mannosylceramide was completely dependent on NOS and TNF-alpha, neither of which was required to achieve protection with alpha-galactosylceramide. Moreover, at doses too low for either alone to protect, beta-mannosylceramicie synergized with alpha-galactosylceramide to protect mice against tumors. These results suggest that treatment with beta-mannosylceramide provides a distinct mechanism of tumor protection that may allow efficacy where other agonists have failed. Furthermore, the ability of beta-mannosylceramide to synergize with alpha-galactosylceramide suggests treatment with this class of iNKT agonist may provide protection against tumors in humans. C1 [O'Konek, Jessica J.; Khursigara, Deborah Stewart; Ambrosino, Elena; Lzhak, Liat; Berzofsky, Jay A.; Terabe, Masaki] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Illarionov, Petr; Besra, Gurdyal S.] Univ Birmingham, Sch Biosci, Birmingham, W Midlands, England. [Castillo, Bernard F., II; Raju, Ravinder; Khalili, Maryam; Howel, Amy R.] Univ Connecticut, Dept Chem, Storrs, CT USA. [Kim, Hee-Yong] NIAAA, Lab Mol Signaling, NIH, Rockville, MD 20852 USA. [Porcelli, Steven A.] Albert Einstein Coll Med, Dept Microbiol & Immunol, New York, NY USA. [Porcelli, Steven A.] Albert Einstein Coll Med, Dept Med, New York, NY USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bldg 10,Room 6B04,10 Ctr Dr, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov; terabe@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; NIH [AI45889]; Medical Research Council (UK); Wellcome Trust [084923/B/08/7]; Royal Society; James Bardrick Research Chair FX The authors thank Satomi Takao, Karen Muindi, Susan Sharrow, and Tony Adams for their assistance in conducting these experiments; David Margulies and Howard Young for critical reading of the manuscript; Albert Bendelac for providing DN32.D3 iNKT cell hybridoma; Samuel Behar for providing iNKT cell hybridoma 24.9E; Nico Tjandra and Motoshi Suzuki for providing saposin C; and the NIH Tetramer Core Facility for supplying the PBS-57/CD 1d tetramers. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by NIH grant AI45889 (to S.A. Porcelli). G.S. Besra is a former Lister Institute-Jenner Research Fellow and received support from the Medical Research Council (UK), the Wellcome Trust (084923/B/08/7), a Royal Society Wolfson Research Merit Award, and the James Bardrick Research Chair. NR 65 TC 23 Z9 23 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2011 VL 121 IS 2 BP 683 EP 694 DI 10.1172/JCI42314 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 715UO UT WOS:000286913800031 PM 21245578 ER PT J AU Crawford, ED Grubb, R Black, A Andriole, GL Chen, MH Izmirlian, G Berg, CD D'Amico, AV AF Crawford, E. David Grubb, Robert, III Black, Amanda Andriole, Gerald L., Jr. Chen, Ming-Hui Izmirlian, Grant Berg, Christine D. D'Amico, Anthony V. TI Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADICAL PROSTATECTOMY; COMPETING RISK; RADIOTHERAPY; COMPLICATIONS; FAILURE; DEATH AB Purpose Estimates of prostate cancer-specific mortality (PCSM) were similar for men randomly assigned to intervention compared with usual care on the Prostate, Lung, Colorectal and Ovarian PC screening study. However, results analyzed by comorbidity strata remain unknown. Patients and Methods Between 1993 and 2001, of 76,693 men who were randomly assigned to usual care or intervention at 10 US centers, 73,378 (96%) completed a questionnaire that inquired about comorbidity and prostate-specific antigen (PSA) testing before random assignment. Fine and Gray's multivariable analysis was performed to assess whether the randomized screening arm was associated with the risk of PCSM in men with no or minimal versus at least one significant comorbidity, adjusting for age and prerandomization PSA testing. Results After 10 years of follow-up, 9,565 deaths occurred, 164 from PC. A significant decrease in the risk of PCSM ( 22 v 38 deaths; adjusted hazard ratio [AHR], 0.56; 95% CI, 0.33 to 0.95; P = .03) was observed in men with no or minimal comorbidity randomly assigned to intervention versus usual care, and the additional number needed to treat to prevent one PC death at 10 years was five. Among men with at least one significant comorbidity, those randomly assigned to intervention versus usual care did not have a decreased risk of PCSM ( 62 v 42 deaths; AHR, 1.43; 95% CI, 0.96 to 2.11; P = .08). Conclusion Selective use of PSA screening for men in good health appears to reduce the risk of PCSM with minimal overtreatment. J Clin Oncol 29: 355-361. (c) 2010 by American Society of Clinical Oncology C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Washington Univ, Sch Med, St Louis, MO USA. NCI, Rockville, MD USA. Univ Connecticut, Storrs, CT USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,,L-2 Level, Boston, MA 02115 USA. EM adamico@partners.org RI Berg , Christine/K-1047-2014 FU National Cancer Institute; University of Colorado [N01-CN-25514]; Georgetown University [N01-CN-25522]; Pacific Health Research Institute [N01-CN-25515]; Henry Ford Health System [N01-CN-25512]; University of Minnesota [N01-CN-25513]; Washington University [N01-CN-25516]; University of Pittsburgh Medical Center [N01-CN-25511]; University of Utah [N01-CN-25524]; Marshfield Clinic Research Foundation [N01-CN-25518]; University of Alabama at Birmingham [N01-CN-75022]; Westat [N01-CN-25476]; University of California at Los Angeles Immunogenetics Center [N01-CN-25404]; GlaxoSmithKline; Aeterna Zentaris; Antigenics; Ferring Pharmaceuticals FX Supported by the National Cancer Institute and Grants No. N01-CN-25514, University of Colorado; N01-CN-25522, Georgetown University; N01-CN-25515, Pacific Health Research Institute; N01-CN-25512, Henry Ford Health System; N01-CN-25513, University of Minnesota; N01-CN-25516, Washington University; N01-CN-25511, University of Pittsburgh Medical Center; N01-CN-25524, University of Utah; N01-CN-25518, Marshfield Clinic Research Foundation; N01-CN-75022, University of Alabama at Birmingham; N01-CN-25476, Westat; and N01-CN-25404, University of California at Los Angeles Immunogenetics Center.; Robert Grubb III, GlaxoSmithKline; Gerald L. Andriole Jr, Aeterna Zentaris, Antigenics, Ferring Pharmaceuticals, Veridex Expert Testimony: None Other Remuneration: None NR 25 TC 75 Z9 76 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 FEB 1 PY 2011 VL 29 IS 4 BP 355 EP 361 DI 10.1200/JCO.2010.30.5979 PG 7 WC Oncology SC Oncology GA 717XR UT WOS:000287081800020 PM 21041707 ER PT J AU Koshiol, J Lam, TK Gridley, G Check, D Brown, LM Landgren, O AF Koshiol, Jill Lam, Tram Kim Gridley, Gloria Check, David Brown, Linda Morris Landgren, Ola TI Racial Differences in Chronic Immune Stimulatory Conditions and Risk of Non-Hodgkin's Lymphoma in Veterans From the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MULTIPLE-SCLEROSIS; INTERLEUKIN-7 RECEPTOR; CIGARETTE-SMOKING; CANCER-RISK; POPULATION; RACE; ASSOCIATIONS; SYSTEM; ATOPY; MALIGNANCIES AB Purpose To examine underlying etiologic factors that may explain the racial disparity in non-Hodgkin's lymphoma (NHL) incidence patterns. Patients and Methods We assessed immune-related conditions and risk of developing NHL among more than 4 million hospitalized US veterans including 9,496 patients with NHL (7,999 white patients and 1,497 black patients) with up to 26 years of follow-up. We used time-dependent Poisson regression to estimate rate ratios (RRs) and 95% CIs for NHL risk among patients with a history of specific autoimmune diseases, infections, and allergies compared with patients without such history, adjusting for attained age, calendar year, race, number of hospital visits, and time between study entry and exit. Results Patients with infectious conditions had an increased risk of developing NHL (RR, 1.2; 95% CI, 1.1 to 1.2), particularly for gastrohepatic, genital, and systemic infectious conditions. Patients with autoimmune disease were generally more likely to develop NHL than patients without autoimmune disease, especially for conditions that typically present with detectable autoantibodies with systemic involvement (RR, 2.0; 95% CI, 1.8 to 2.2). Allergies were also associated with increased risk (RR, 1.4; 95% CI, 1.3 to 1.5). Although the risk of NHL was lower for blacks than whites (RR, 0.87; 95% CI, 0.82 to 0.92), blacks had a slightly higher risk of NHL associated with infections than whites (likelihood ratio test, P = .002) and a tendency toward higher risk associated with allergies (likelihood ratio test, P = .05). Risks associated with autoimmune conditions were similar by race (likelihood ratio test, P = .5). Conclusion The observed difference in NHL risk by race supports a role for race-related differences in genes regulating immune/inflammatory response. J Clin Oncol 29: 378-385. (c) 2010 by American Society of Clinical Oncology C1 [Koshiol, Jill] NCI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RTI Int, Rockville, MD USA. RP Koshiol, J (reprint author), NCI, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,MSC 7248, Bethesda, MD 20892 USA. EM koshiolj@mail.nih.gov RI Check, David/J-7184-2015 OI Check, David/0000-0003-3887-0493 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Office of Preventive Oncology, National Cancer Institute, Bethesda, MD FX Supported by general funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; and the Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute, Bethesda, MD. NR 50 TC 26 Z9 27 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2011 VL 29 IS 4 BP 378 EP 385 DI 10.1200/JCO.2010.30.1515 PG 8 WC Oncology SC Oncology GA 717XR UT WOS:000287081800023 PM 21172877 ER PT J AU Loeb, S Vonesh, EF Metter, EJ Carter, HB Gann, PH Catalona, WJ AF Loeb, Stacy Vonesh, Edward F. Metter, E. Jeffrey Carter, H. Ballentine Gann, Peter H. Catalona, William J. TI What Is the True Number Needed to Screen and Treat to Save a Life With Prostate-Specific Antigen Testing? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER MORTALITY; TRIAL AB Purpose The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20% mortality reduction with prostate-specific antigen (PSA) screening. However, they estimated a number needed to screen (NNS) of 1,410 and a number needed to treat (NNT) of 48 to prevent one prostate cancer death at 9 years. Although NNS and NNT are useful statistics to assess the benefits and harms of an intervention, in a survival study setting such as the ERSPC, NNS and NNT are time specific, and reporting values at one time point may lead to misinterpretation of results. Our objective was to re-examine the effect of varying follow-up times on NNS and NNT using data extrapolated from the ERSPC report. Materials and Methods On the basis of published ERSPC data, we modeled the cumulative hazard function using a piecewise exponential model, assuming a constant hazard of 0.0002 for the screening and control groups for years 1 to 7 of the trial and different constant rates of 0.00062 and 0.00102 for the screening and control groups, respectively, for years 8 to 12. Annualized cancer detection and drop-out rates were also approximated based on the observed number of individuals at risk in published ERSPC data. Results According to our model, the NNS and NNT at 9 years were 1,254 and 43, respectively. Subsequently, NNS decreased from 837 at year 10 to 503 at year 12, and NNT decreased from 29 to 18. Conclusion Despite the seemingly simplistic nature of estimating NNT, there is widespread misunderstanding of its pitfalls. With additional follow-up in the ERSPC, if the mortality difference continues to grow, the NNT to save a life with PSA screening will decrease. J Clin Oncol 29:464-467. (C) 2010 by American Society of Clinical Oncology C1 [Catalona, William J.] NW Feinberg Sch Med, Chicago, IL 60611 USA. NIA, Brady Urol Inst, Johns Hopkins Med Inst, Baltimore, MD 21224 USA. Univ Illinois, Chicago, IL USA. RP Catalona, WJ (reprint author), NW Feinberg Sch Med, 675 N St Clair,Ste 20-150, Chicago, IL 60611 USA. EM wcatalona@nmff.org OI Loeb, Stacy/0000-0003-3933-9207 FU Urological Research Foundation; Prostate Specialized Programs of Research Excellence Grant [P50 CA90386-05S2]; Robert H. Lurie Comprehensive Cancer Center [P30 CA60553]; National Institutes of Health, National Institute on Aging FX Supported by the Urological Research Foundation, Prostate Specialized Programs of Research Excellence Grant No. P50 CA90386-05S2, Robert H. Lurie Comprehensive Cancer Center Grant No. P30 CA60553 (W.J.C.) and the Intramural Research Program of the National Institutes of Health, National Institute on Aging (E.J.M.). NR 19 TC 51 Z9 52 U1 0 U2 12 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 FEB 1 PY 2011 VL 29 IS 4 BP 464 EP 467 DI 10.1200/JCO.2010.30.6373 PG 4 WC Oncology SC Oncology GA 717XR UT WOS:000287081800035 PM 21189374 ER PT J AU Dasari, A Rudek, MA Arcaroli, J Powell, RW Carducci, MA Laheru, D Wright, JJ Hidalgo, M Messersmith, WA Azad, NS AF Dasari, A. Rudek, M. A. Arcaroli, J. Powell, R. W. Carducci, M. A. Laheru, D. Wright, J. J. Hidalgo, M. Messersmith, W. A. Azad, N. S. TI Tolerance of full-dose sorafenib (S) combined with irinotecan (I; weekly, two on, one off) and cetuximab (C) in previously treated patients with advanced colorectal cancer (CRC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Colorado Denver, Aurora, CO USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Univ Colorado, Ctr Canc, Aurora, CO 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 522 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100519 PM 27985761 ER PT J AU Diaz, LA Azad, NS Laheru, D Le, DT Devoe, CE Cosgrove, D Zheng, L Arlen, PM Bristol, JA AF Diaz, L. A. Azad, N. S. Laheru, D. Le, D. T. Devoe, C. E. Cosgrove, D. Zheng, L. Arlen, P. M. Bristol, J. A. TI NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Hofstra Univ, Sch Med North Shore LIJ, Lake Success, NY USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. Neogenix Oncol Inc, 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 235 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100235 PM 27985427 ER PT J AU Duffy, AG Greten, T AF Duffy, A. G. Greten, T. TI Bleeding events and eligibility requirements in studies evaluating an antiangiogenic agent in hepatocellular carcinoma (HCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Duffy, A. G.; Greten, T.] NCI, Bethesda, MD 20892 USA. RI Greten, Tim/B-3127-2015 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 310 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100309 PM 27985842 ER PT J AU Salvatore, P Baldessarini, RJ Tohen, M Khalsa, HMK Sanchez-Toledo, JP Zarate, CA Vieta, E Maggini, C AF Salvatore, Paola Baldessarini, Ross J. Tohen, Mauricio Khalsa, Hari-Mandir K. Sanchez-Toledo, Jesus Perez Zarate, Carlos A., Jr. Vieta, Eduard Maggini, Carlo TI McLean-Harvard International First-Episode Project: Two-Year Stability of ICD-10 Diagnoses in 500 First-Episode Psychotic Disorder Patients SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID EARLY-ONSET PSYCHOSIS; FOLLOW-UP; BIPOLAR DISORDER; CLINICAL-PRACTICE; SCHIZOAFFECTIVE DISORDERS; TREATMENT INITIATION; SUBSTANCE USE; HIGH-RISK; SCHIZOPHRENIA; SYMPTOMS AB Objective: Because clinical and biologic research and optimal clinical practice require stability of diagnoses over time, we determined stability of ICD-10 psychotic disorder diagnoses and sought predictors of diagnostic instability. Method: Patients from the McLean-Harvard International First-Episode Project, conducted from 1989 to 2003, who were hospitalized for first psychotic illnesses (N=500) were diagnosed by ICD-10 criteria at baseline and 24 months, on the basis of extensive prospective assessments, to evaluate the longitudinal stability of specific categorical diagnoses and predictors of diagnostic change. Results: Diagnostic stability averaged 90.4%, ranking as follows: schizoaffective disorder (100.0%) > mania with psychosis (99.0%) > mixed affective episode (94.9%) > schizophrenia (94.6%) > delusional disorder (88.2%) > severe depressive episode with psychotic symptoms (85.2%)> acute psychosis with/without schizophrenia symptoms = unspecified psychosis (all 66.7%) > > acute schizophrenia-like psychosis (28.6%). Diagnoses changed by 24 months of follow-up to schizoaffective disorder (37.5%), bipolar disorder (25.0%), schizophrenia (16.7%), or unspecified non-organic psychosis (8.3%), mainly through emerging affective features. By logistic regression, diagnostic change was associated with Schneiderian first-rank psychotic symptoms at intake > lack of premorbid substance use. Conclusions: We found some psychotic disorder diagnoses to be more stable by ICD-10 than DSM-IV criteria in the same patients, with implications for revisions of both diagnostic systems. J Clin Psychiatry 2011;72(2): 183-193 (C) Copyright 2010 Physicians Postgraduate Press, Inc. C1 [Salvatore, Paola; Baldessarini, Ross J.; Tohen, Mauricio; Khalsa, Hari-Mandir K.; Sanchez-Toledo, Jesus Perez; Zarate, Carlos A., Jr.; Vieta, Eduard; Maggini, Carlo] McLean Hosp, Int Consortium Bipolar & Psychot Disorders Res, Mailman Res Ctr, Belmont, MA 02478 USA. [Salvatore, Paola; Baldessarini, Ross J.; Tohen, Mauricio; Khalsa, Hari-Mandir K.; Vieta, Eduard] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Salvatore, Paola; Baldessarini, Ross J.; Tohen, Mauricio; Khalsa, Hari-Mandir K.; Vieta, Eduard] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. [Salvatore, Paola; Maggini, Carlo] Univ Parma, Sect Psychiat, Dept Neurosci, I-43100 Parma, Italy. [Tohen, Mauricio] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Sanchez-Toledo, Jesus Perez] Univ Cambridge, Dept Psychiat, Cambridgeshire Early Intervent Serv CAMEO, Cambridge, England. [Zarate, Carlos A., Jr.] NIMH, Lab Mol Pathophysiol & Expt Therapeut, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Vieta, Eduard] Univ Barcelona, Inst Neurosci, Hosp Clin, August Pi & Sunyer Biomed Res Inst IDIBAPS,Ctr In, Barcelona, Spain. RP Salvatore, P (reprint author), McLean Hosp, Int Consortium Bipolar & Psychot Disorders Res, Mailman Res Ctr, Ctr Bldg G-7B,115 Mill St, Belmont, MA 02478 USA. EM psalvatore@mclean.harvard.edu RI Vieta, Eduard/I-6330-2013 OI Vieta, Eduard/0000-0002-0548-0053 FU National Alliance for Research on Schizophrenia and Depression (NARSAD); NIH [MH-04844, MH-10948]; Atlas Foundation; Bruce J. Anderson Foundation; McLean Private Donors Research Fund; Spanish Ministry of Education and Science and CIBERSAM; AstraZeneca; Bristol-Myers Squibb; Eli Lilly; Forrest; GlaxoSmithKline; Janssen-Cilag; Jazz; Merck; Novartis; Organon; Otsuka; Pfizer; Sanofi; Servier Corporations; [MH-47370]; [MH-73049] FX This work was supported by grants from National Alliance for Research on Schizophrenia and Depression (NARSAD) (Dr Salvatore); by NIH grants MH-04844 and MH-10948 and a grant from the Atlas Foundation (Dr Tohen); by grants MH-47370 and MH-73049 and from the Bruce J. Anderson Foundation and the McLean Private Donors Research Fund (Dr Baldessarini); and by the Spanish Ministry of Education and Science and CIBERSAM (Dr Vieta).; Dr Baldessarini has been a consultant for or investigator-initiated research collaborator with AstraZeneca, Auritec, Biotrofix, Eli Lilly, Istituto Finanziario Industriale (IFI), Janssen, JDS-Noven, Luitpold, NeuroHealing, Novartis, Pfizer, and SK-BioPharmaceutical Corporation; has taught or prepared educational materials for the New England Educational Institute (NEEI) and PriMed CME organizations; and holds or shares 6 unlicensed patents on novel compounds of potential pharmaceutical interest. Dr Tohen is a former employee and stockholder of Eli Lilly (2008); is a consultant for GlaxoSmithKline, Johnson & Johnson, AstraZeneca, and Eli Lilly; has received honoraria from GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, and Eli Lilly; and is a member of the speakers/advisory boards for AstraZeneca and Bristol-Myers Squibb. Dr Tohen's spouse is an employee and stockholder of Eli Lilly. Dr Vieta is a consultant for or receives grant/research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forrest, GlaxoSmithKline, Janssen-Cilag, Jazz, Merck, Novartis, Organon, Otsuka, Pfizer, Sanofi, and Servier Corporations. Drs Salvatore, Perez Sanchez-Toledo, Zarate, and Maggini and Ms Khalsa have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article. NR 82 TC 43 Z9 44 U1 4 U2 6 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2011 VL 72 IS 2 BP 183 EP 193 DI 10.4088/JCP.09m05311yel PG 11 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 729WR UT WOS:000287985400008 PM 20673546 ER PT J AU Kelly, DL Gorelick, DA Conley, RR Boggs, DL Linthicum, J Liu, F Feldman, S Ball, MP Wehring, HJ McMahon, RP Huestis, MA Heishman, SJ Warren, KR Buchanan, RW AF Kelly, Deanna L. Gorelick, David A. Conley, Robert R. Boggs, Douglas L. Linthicum, Jared Liu, Fang Feldman, Stephanie Ball, M. Patricia Wehring, Heidi J. McMahon, Robert P. Huestis, Marilyn A. Heishman, Stephen J. Warren, Kimberly R. Buchanan, Robert W. TI Effects of the Cannabinoid-1 Receptor Antagonist Rimonabant on Psychiatric Symptoms in Overweight People With Schizophrenia A Randomized, Double-Blind, Pilot Study SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE rimonabant; schizophrenia; obesity; metabolic syndrome; depression ID ENDOCANNABINOID SYSTEM; SCHIZOAFFECTIVE DISORDER; METABOLIC SYNDROME; OBESITY; PREVALENCE; DEPRESSION; AGENTS; DRUG; EFFICACY; ANXIETY AB Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizo-affective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m(2) or higher with hyperlipidemia or body mass index of 30 kg/m2 or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean T SE difference, -1.9 +/- 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (-1.4 +/- 0.35, P = 0.0004) and hostility (-0.7 +/- 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity. C1 [Kelly, Deanna L.; Boggs, Douglas L.; Linthicum, Jared; Liu, Fang; Feldman, Stephanie; Ball, M. Patricia; Wehring, Heidi J.; McMahon, Robert P.; Warren, Kimberly R.; Buchanan, Robert W.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. [Gorelick, David A.; Huestis, Marilyn A.; Heishman, Stephen J.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Bethesda, MD USA. [Conley, Robert R.] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Kelly, DL (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. EM dkelly@mprc.umaryland.edu RI McMahon, Robert/C-5462-2009 FU National Institutes of Mental Health (NIMH) [R34 MH 077839, P30 068580]; NIDA Residential Research Support Services [HSN271200599091CADB]; Sanofi-Aventis; National Institute on Drug Abuse (NIDA) FX This study was supported by the National Institutes of Mental Health (NIMH) grants R34 MH 077839 (PI Buchanan) and P30 068580 (PI Buchanan), the Intramural Research Program, National Institute on Drug Abuse (NIDA), and NIDA Residential Research Support Services Contract HSN271200599091CADB (PI Kelly).; Deanna L. Kelly, David Gorelick, Douglas L. Boggs, Robert P. McMahon, Jared Linthicum, Fang Liu, Stephanie Feldman, M. Patricia Ball, Heidi J. Wehring, Stephen J. Heishman, and Kimberly Warren have no competing interests or financial support to disclose. Robert R. Conley is a full-time employee and stockholder of Eli Lilly & Co. Marilyn A. Huestis has a cooperative research and development agreement with Sanofi-Aventis. Robert W. Buchanan is a member of the data and safety monitoring board of Cephalon, Otsuka, Pfizer, and Wyeth; a consultant for Abbott, GlaxoSmithKline, Merck, Organon, Sanofi-Aventis, Solvay, and Wyeth; and a member of the advisory board of AstraZeneca, Pfizer, and Roche. NR 46 TC 29 Z9 29 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2011 VL 31 IS 1 BP 86 EP 91 DI 10.1097/JCP.0b013e318204825b PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 700UY UT WOS:000285771000015 PM 21192149 ER PT J AU Sakolsky, DJ Perel, JM Emslie, GJ Clarke, GN Wagner, KD Vitiello, B Keller, MB Birmaher, B Asarnow, JR Ryan, ND McCracken, JT Strober, MJ Iyengar, S Porta, G Brent, DA AF Sakolsky, Dara J. Perel, James M. Emslie, Graham J. Clarke, Gregory N. Wagner, Karen Dineen Vitiello, Benedetto Keller, Martin B. Birmaher, Boris Asarnow, Joan Rosenbaum Ryan, Neal D. McCracken, James T. Strober, Michael J. Iyengar, Satish Porta, Giovanna Brent, David A. TI Antidepressant Exposure as a Predictor of Clinical Outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) Study SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE major depressive disorder; adolescents; plasma concentration; drug exposure; optimization ID MAJOR DEPRESSION; PLASMA-LEVELS; TIME-COURSE; VENLAFAXINE; PAROXETINE; METABOLITES; SERTRALINE; DISORDERS; RELEVANCE; TRIALS AB This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents. Adolescents (n = 334) with major depression who had not responded to a selective serotonin reuptake inhibitor (SSRI) were randomized to 1 of 4 treatments: switch to another SSRI (fluoxetine, citalopram, or paroxetine), switch to venlafaxine, switch to SSRI plus cognitive behavior therapy, or switch to venlafaxine plus cognitive behavior therapy. Adolescents who did not improve by 6 weeks had their dose increased. Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants. Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean (GM) showed a higher response rate compared to those with less than the GM, with parallel but nonsignificant findings for fluoxetine. A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12. Plasma levels of paroxetine, venlafaxine, or O-desmethylvenlafaxine were not related to clinical response. Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine. Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram. C1 [Brent, David A.] Univ Pittsburgh, Western Psychiat Inst & Clin, Sch Med, Pittsburgh, PA 15213 USA. [Emslie, Graham J.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Clarke, Gregory N.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Wagner, Karen Dineen] Univ Texas Med Branch, Dept Psychiat & Behav Hlth Sci, Galveston, TX USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Keller, Martin B.] Brown Univ, Dept Psychiat & Human Behav, Butler Hosp, Providence, RI 02912 USA. [Asarnow, Joan Rosenbaum; McCracken, James T.; Strober, Michael J.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Iyengar, Satish] Univ Pittsburgh, Dept Stat, Pittsburgh, PA USA. [Iyengar, Satish] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. RP Brent, DA (reprint author), Univ Pittsburgh, Western Psychiat Inst & Clin, Sch Med, Room 315,Bellefield Towers,3811 OHara St, Pittsburgh, PA 15213 USA. EM brentda@upmc.edu FU NIMH (Pittsburgh) [MH61835]; NIMH (Galveston) [MH61856]; NIMH (UCLA) [MH61864]; NIMH (Portland) [MH61869]; NIMH (Dallas) [MH61958]; NIMH (Brown) [MH62014]; Advanced Center for Early-Onset Mood and Anxiety Disorders [MH66371]; Clinical Research Training in Child Psychiatry [MH18951]; Solvay Pharmaceuticals, Inc; Abcomm, Inc; Solvay; Biobehavioral Diagnostics Inc; Forest Laboratories; Shire; Somerset; Philip Morris USA; AstraZeneca; Eli Lilly; Johnson Johnson; National Institute of Mental Health; Organon FX This study was funded by NIMH grants MH61835 (Pittsburgh); MH61856 (Galveston); MH61864 (UCLA); MH61869 (Portland); MH61958 (Dallas); and MH62014 (Brown), the Advanced Center for Early-Onset Mood and Anxiety Disorders (MH66371, PI: David Brent, MD) and Clinical Research Training in Child Psychiatry (MH18951, PI: David Brent, MD).; Dr Birmaher has participated in forums sponsored by Solvay Pharmaceuticals, Inc and Abcomm, Inc. He gave a presentation on bipolar disorders in children at a meeting sponsored by Solvay. Dr Birmaher also received royalties from Random House, Inc. Dr Emslie receives research support from Biobehavioral Diagnostics Inc, Forest Laboratories, Shire and Somerset, and is a consultant for Biobehavioral Diagnostics, Inc, Eli Lilly, Forest Laboratories, Inc, Pfizer, Inc, Shire, Validus Pharmaceuticals, and Wyeth Pharmaceuticals. Dr Keller has served on advisory boards for Abbott Laboratories, Bristol-Myers Squibb, CENEREX, Cyberonics, Cypress Bioscience, Forest Laboratories, Janssen, Novartis, Organon, and Pfizer. Dr Perel is a consultant and expert witness for a consortium of 10 pharmaceutical companies. No other financial disclosures were reported.; Dr Asarnow has consulted on cognitive-behavior therapy and quality improvement for depression and received unrestricted research funding from Philip Morris USA.; Dr Wagner reported (July 2005 to July 2010) that she has received research support from AstraZeneca, Eli Lilly, Johnson & Johnson, National Institute of Mental Health, and Organon, and was a consultant/advisory board member for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Novartis, Ortho-McNeil, Pfizer, Organon, Otsuka, Solvay, and Wyeth Ayerst. NR 26 TC 18 Z9 18 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2011 VL 31 IS 1 BP 92 EP 97 DI 10.1097/JCP.0b013e318204b117 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 700UY UT WOS:000285771000016 PM 21192150 ER PT J AU Derauf, C LaGasse, L Smith, L Newman, E Shah, R Arria, A Huestis, M Haning, W Strauss, A Della Grotta, S Dansereau, L Lin, H Lester, B AF Derauf, Chris LaGasse, Linda Smith, Lynne Newman, Elana Shah, Rizwan Arria, Amelia Huestis, Marilyn Haning, William Strauss, Arthur Della Grotta, Sheri Dansereau, Lynne Lin, Hai Lester, Barry TI Infant Temperament and High-Risk Environment Relate to Behavior Problems and Language in Toddlers SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article DE prenatal substance exposure; methamphetamine; temperament; child development; child behavior ID PRENATAL METHAMPHETAMINE EXPOSURE; MATERNAL LIFE-STYLE; EARLY INTERVENTION; CHILD-DEVELOPMENT; COCAINE EXPOSURE; PARENTING STRESS; BIRTH-WEIGHT; DIFFERENTIAL SUSCEPTIBILITY; INTRAUTERINE GROWTH; DRUG EXPOSURE AB Objective: This study examined the role that easy infant temperament and cumulative environmental risk play in predicting cognitive, language, and behavioral outcomes in 3-year-old children at high social risk. Methods: Subjects were 412 mother-infant dyads, recruited at birth, participating in a longitudinal study examining the effects of prenatal methamphetamine on child development. This analysis includes a subsample (n = 290) of the study with a completed 3-year visit. Temperament was assessed by the Infant Behavior Questionnaire at 12 months. Factor analysis from well-validated measures generated "easy" and "difficult" temperament profiles and a profile for high-risk environment. Caretaker receptive vocabulary served as a proxy for intelligence quotient. Outcomes at 3 years included motor and mental development, behavior problems, and language. Linear regression and hierarchical linear modeling examined the effects of temperament, high-risk environment, and caregiver receptive language on outcomes adjusting for maternal drug use and demographic and socioeconomic covariates. Results: Internalizing and externalizing behaviors were lower in children with easy temperament and higher with increased environmental risk. Easy temperament attenuated behavioral problems only in the setting of lower environmental risk. Caregiver receptive language was associated with lower internalizing scores. High-risk environment and temperament factors were not related to cognitive or motor outcomes. Prenatal methamphetamine exposure was not associated with 3-year-old outcomes, nor did it alter the protective effects of an easier temperament on child behavior. Conclusions: Children growing up in adverse social environments had increased behavioral problems and compromised language development. Conversely, an easy temperament acts as a protective factor for social-emotional development and could be related to resilience. C1 [Derauf, Chris] Univ Hawaii, John A Burns Sch Med, Dept Pediat, Honolulu, HI 96826 USA. [LaGasse, Linda; Della Grotta, Sheri; Dansereau, Lynne; Lin, Hai; Lester, Barry] Brown Univ, Div Pediat, Brown Ctr Study Children Risk, Warren Alpert Med Sch, Providence, RI 02912 USA. [LaGasse, Linda; Della Grotta, Sheri; Dansereau, Lynne; Lin, Hai; Lester, Barry] Brown Univ, Women & Infants Hosp, Providence, RI USA. [Smith, Lynne] Harbor UCLA Med Ctr, Los Angeles Biomed Inst, Torrance, CA 90509 USA. [Smith, Lynne] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Newman, Elana] Univ Tulsa, Tulsa, OK 74104 USA. [Shah, Rizwan] Blank Childrens Hosp, Des Moines, IA USA. [Arria, Amelia] Univ Maryland, Sch Publ Hlth, Ctr Young Adult Hlth & Dev, College Pk, MD 20742 USA. [Huestis, Marilyn] Natl Inst Drug Abuse, Chem & Drug Metab Sect, Baltimore, MD USA. [Strauss, Arthur] Long Beach Mem Med Ctr, Long Beach, CA USA. RP Derauf, C (reprint author), Univ Hawaii, John A Burns Sch Med, Dept Pediat, 1319 Punahou St, Honolulu, HI 96826 USA. EM dderauf@hawaii.edu OI Arria, Amelia/0000-0002-6360-9265 FU National Institutes on Drug Abuse, NIH [2R01DA014948, 1K23DA020801]; National Center for Research Resources [5P20RR011091, 3M01RR00425] FX This work was supported by NIH grants 2R01DA014948 and 1K23DA020801 from National Institutes on Drug Abuse and in part by the grants 5P20RR011091 and 3M01RR00425 from National Center for Research Resources. NR 75 TC 18 Z9 20 U1 4 U2 28 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD FEB-MAR PY 2011 VL 32 IS 2 BP 125 EP 135 DI 10.1097/DBP.0b013e31820839d7 PG 11 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 715WX UT WOS:000286925800009 PM 21200329 ER PT J AU Darney, S Fowler, B Grandjean, P Heindel, J Mattison, D Slikker, W AF Darney, Sally Fowler, Bruce Grandjean, Philippe Heindel, Jerrold Mattison, Donald Slikker, William, Jr. TI Prenatal Programming and Toxicity II (PPTOX II): Role of Environmental Stressors in the Developmental Origins of Disease SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Editorial Material C1 [Fowler, Bruce] Ctr Dis Control, Div Toxicol & Environm Med, ATSDR, Atlanta, GA 30333 USA. [Grandjean, Philippe] Univ So Denmark, Odense, Denmark. [Heindel, Jerrold] NIEHS, Organs & Syst Pathobiol Branch, Res Triangle Pk, NC USA. [Mattison, Donald] NICHD, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, HHS, Bethesda, MD USA. [Slikker, William, Jr.] US FDA, Natl Ctr Toxicol Res, Rockville, MD 20857 USA. OI Mattison, Donald/0000-0001-5623-0874 NR 2 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD FEB PY 2011 VL 2 IS 1 BP 2 EP 2 DI 10.1017/S2040174411000109 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 755LW UT WOS:000289933800001 ER PT J AU Louis, GMB Cooney, MA Peterson, CM AF Louis, G. M. Buck Cooney, M. A. Peterson, C. M. TI The ovarian dysgenesis syndrome SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Article DE early origins; exposome; ovarian dysgenesis ID PRENATAL DIETHYLSTILBESTROL EXPOSURE; ASSISTED REPRODUCTIVE TECHNOLOGY; NUTRITION EXAMINATION SURVEY; HIGH PLASMA-CONCENTRATIONS; ENDOMETRIAL CANCER-RISK; FOR-GESTATIONAL-AGE; BREAST-CANCER; FETAL-GROWTH; POLYCHLORINATED-BIPHENYLS; TESTICULAR CANCER AB New thinking has arisen about the origin of adult onset diseases stemming from a collective body of evidence commonly referred to as the developmental origins of health and disease. This conceptual paradigm posits that certain adult onset diseases arise during critical or sensitive windows of human development or even transgenerationally. The testicular dysgenesis hypothesis (TDS) postulates an in utero origin for adverse male reproductive outcomes, and is an excellent example of the early origins of the paradigm. Despite similarities in the development of the male and female reproductive tracks, noticeably absent is a collective body of evidence focusing on the plausibility of an early origin for gynecologic outcomes and later onset of adult diseases. Using the TDS paradigm, we synthesized the available literature relative to the ovarian dysgenesis syndrome (ODS), which we define as alterations in ovarian structure or function that may manifest as fecundity impairments, gynecologic disorders, gravid diseases or later onset adult diseases. We evaluated environmental exposures, particularly the role of endocrine disrupting chemicals, in relation to these outcomes, and found evidence (although fragmented) consistent with an in utero origin of gynecologic outcomes, which in turn is associated with later onset of adult diseases. The findings are interpreted within the ODS paradigm while delineating methodological challenges and future research opportunities designed to answer critical data gaps regarding the origin of fecundity, gravid health and chronic diseases affecting the female population. C1 [Louis, G. M. Buck; Cooney, M. A.] NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Peterson, C. M.] Univ Utah, Hlth Sci Ctr, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Salt Lake City, UT USA. RP Louis, GMB (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development FX This study is supported in part with intramural funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. NR 150 TC 24 Z9 24 U1 0 U2 9 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD FEB PY 2011 VL 2 IS 1 BP 25 EP 35 DI 10.1017/S2040174410000693 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 755LW UT WOS:000289933800005 ER PT J AU Collman, GW AF Collman, G. W. TI Developmental basis of disease: environmental impacts SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Article DE early life exposures; environmental chemicals; windows of susceptibility ID BISPHENOL-A; BIOMARKERS; EXPOSURES; WOMEN; BIRTH; PREGNANCY; HEALTH; CANCER; SERUM AB Exposure to environmental chemicals and other environmental stressors have health impacts on the fetus that may not be apparent until later in life. The concept of developmental origins of disease should be expanded to include these early life exposures in addition to the effects of nutrition and maternal factors. This paper will describe the toxicological, biological and epidemiological issues that are pertinent to conducting research on environmental exposures early in life and their health consequences over the life span. C1 NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Collman, GW (reprint author), NIEHS, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. EM collman@niehs.nih.gov NR 37 TC 2 Z9 2 U1 1 U2 3 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD FEB PY 2011 VL 2 IS 1 BP 49 EP 55 DI 10.1017/S2040174411000031 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 755LW UT WOS:000289933800007 ER PT J AU Wang, Y Beydoun, MA Li, J Liu, Y Moreno, LA AF Wang, Y. Beydoun, M. A. Li, J. Liu, Y. Moreno, L. A. TI Do children and their parents eat a similar diet? Resemblance in child and parental dietary intake: systematic review and meta-analysis SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Review ID FOOD FREQUENCY QUESTIONNAIRE; FAMILY RESEMBLANCE; PHYSICAL-ACTIVITY; NUTRIENT INTAKE; ENVIRONMENTAL-INFLUENCES; GENDER-DIFFERENCES; STANISLAS FAMILY; ENERGY-INTAKE; YOUNG-ADULTS; LOW-INCOME AB Objectives Parents are believed to have a strong influence on children's eating behaviours. However, previous findings on child-parent resemblance in dietary intakes are mixed. We systematically reviewed and meta-analysed the association (correlations) based on published studies. Methods We searched related studies published since 1980 and found 24 studies meeting inclusion criteria for review and 15 for meta-regression analysis. We compared the associations between parent-child pairs, nutrients, over time and by dietary assessment method. Results Most studies were based on small samples. Overall, they suggest a moderate or weak association, but findings varied remarkably. Our meta-analysis showed that average Fisher's transformed correlations were 0.20 (95% CI 0.13 to 0.28) for fat (% energy); for energy, 0.21 (0.18 to 0.24). The correlations varied by parent-child pairs, dietary assessment and countries. Food frequency questionnaires or mixed approaches yielded lower correlation than 24-h recalls or food records. Child self-reported intakes showed weaker correlation and better methodology quality showed stronger correlation in fat intake (% energy), which also became weaker over time. Conclusions Overall, the resemblance is weak, and it varied considerably across studies, nutrients, foods and parent-child pairs. C1 [Wang, Y.; Beydoun, M. A.; Li, J.; Liu, Y.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, Baltimore, MD 21205 USA. [Beydoun, M. A.] NIA, NIH, IRP, Baltimore, MD 21224 USA. [Moreno, L. A.] Univ Zaragoza, Univ Sch Hlth Sci, Dept Pediat, Zaragoza, Spain. RP Wang, Y (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. EM ywang@jhsph.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [1R03HD058077-01A1, R03HD058077-01A1S1]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK81335-01A1]; National Institute on Aging FX The study was supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, 1R03HD058077-01A1, R03HD058077-01A1S1), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01DK81335-01A1), and the National Institute on Aging Intramural Research Program. NR 44 TC 60 Z9 60 U1 3 U2 24 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD FEB PY 2011 VL 65 IS 2 BP 177 EP 189 DI 10.1136/jech.2009.095901 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 697UH UT WOS:000285543800016 PM 21051779 ER PT J AU Chang, CY Cook, MB Lee, YC Lin, JT Ando, T Bhatia, S Chow, WH El-Omar, EM Goto, H Li, YQ McColl, K Reddy, N Rhee, PL Sharma, P Sung, JJY Ghoshal, U Wong, JYY Wu, JCY Zhang, J Ho, KY AF Chang, Chi-Yang Cook, Michael B. Lee, Yi-Chia Lin, Jaw-Town Ando, Takafumi Bhatia, Shobna Chow, Wong-Ho El-Omar, Emad M. Goto, Hidemi Li, Yang-Qing McColl, Kenneth Reddy, Nageshwar Rhee, Poong-Lyul Sharma, Prateek Sung, Joseph J-Y Ghoshal, Uday Wong, Jennie Y-Y Wu, Justin C-Y Zhang, Jun Ho, Khek-Yu CA Asian Barrett's Consortium TI Current status of Barrett's esophagus research in Asia SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Review DE Barrett's esophagus; esophageal adenocarcinoma; gastroesophageal reflux disease; prevalence; risk factor ID GASTROESOPHAGEAL-REFLUX DISEASE; TERTIARY REFERRAL CENTER; SQUAMOUS-CELL CARCINOMA; BODY-MASS INDEX; RISK-FACTORS; EROSIVE ESOPHAGITIS; KOREAN POPULATION; ESOPHAGOGASTRIC JUNCTION; CLINICAL CHARACTERISTICS; ENDOSCOPIC ESOPHAGITIS AB In Western countries, the epidemiology of esophageal cancer has changed considerably over the past decades with a rise in the ratio of adenocarcinoma to squamous cell carcinoma. Although the prevalence of gastroesophageal reflux is increasing in Asia, the prevalences of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) have remained low in most Asian countries. The Asian Barrett's Consortium recently conducted a review of published studies on BE from Asia to assess the current status of BE research in Asia, and to recommend potential areas for future BE research in the region. Differences in study design, enrolled population, and endoscopic biopsy protocols used have led to substantial variability in the reported BE prevalence (0.06% to 19.9%) across Asia. In particular, some Japanese studies used diagnostic criteria that differed considerably from what was used in most Asian studies. As in Western countries, increased age, male sex, tobacco smoking, reflux symptoms, and erosive esophagitis have been found to be risk factors for BE in several case-control studies from Asia. The Prague C and M criteria, developed to provide better interobserver reliability in diagnosis and grading of BE, are currently under extensive evaluation in the Asian population. There is a need for standardized protocols for endoscopic and histopathologic diagnosis before initiating collaborative projects to identify etiologic determinants of BE and its ensuing malignant transformation. At present, data regarding the management and long-term outcome of BE are extremely limited in Asia. More studies of BE in this geographic area are warranted. C1 [Wong, Jennie Y-Y; Ho, Khek-Yu] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119228, Singapore. [Chang, Chi-Yang; Lin, Jaw-Town] E Da Hosp, Dept Internal Med, Kaohsiung, Taiwan. [Chang, Chi-Yang; Lin, Jaw-Town] I Shou Univ, Kaohsiung, Taiwan. [Lee, Yi-Chia; Lin, Jaw-Town] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan. [Cook, Michael B.; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, Kansas City, KS USA. [Sharma, Prateek] Vet Affairs Med Ctr, Div Gastroenterol & Hepatol, Kansas City, KS USA. [Sharma, Prateek] Univ Kansas, Sch Med, Kansas City, KS USA. [Zhang, Jun] Xi An Jiao Tong Univ, Div Gastroenterol, Affiliated Hosp 2, Xian, Peoples R China. [Ando, Takafumi; Goto, Hidemi] Nagoya Univ, Dept Gastroenterol, Grad Sch Med, Nagoya, Aichi 4648601, Japan. [Bhatia, Shobna] Seth GS Med Coll, Dept Gastroenterol, Mumbai, Maharashtra, India. [Bhatia, Shobna] KEM Hosp, Mumbai, Maharashtra, India. [Li, Yang-Qing] Univ Glasgow, Gardiner Inst, Glasgow, Lanark, Scotland. [El-Omar, Emad M.] Univ Aberdeen, Div Appl Med, Inst Med Sci, Aberdeen AB9 1FX, Scotland. [Li, Yang-Qing] Shandong Univ, Dept Gastroenterol, Qilu Hosp, Jinan, Peoples R China. [Reddy, Nageshwar] Asian Inst Gastroenterol, Hyderabad, Andhra Pradesh, India. [Rhee, Poong-Lyul] Sungkyunkwan Univ, Dept Med, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Ghoshal, Uday] SGPGI, Dept Gastroenterol, Lucknow, Uttar Pradesh, India. [Sung, Joseph J-Y; Wu, Justin C-Y] Chinese Univ Hong Kong, Dept Med & Therapeut, Prince Wales Hosp, Hong Kong, Hong Kong, Peoples R China. RP Ho, KY (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Level 10,NUHS Tower Block,1E Kent Ridge Rd, Singapore 119228, Singapore. EM khek_yu_ho@nuhs.edu.sg RI Cook, Michael/A-5641-2009; Rhee, Poong Lyul/C-9655-2011; Hossain, Sarah /C-7332-2009; Wu, Justin/N-6916-2015; OI Cook, Michael/0000-0002-0533-7302; Hossain, Sarah /0000-0003-1355-0979; LEE, YI-CHIA/0000-0002-8160-1216 FU Chief Scientist Office [CZB/4/709]; Intramural NIH HHS [ZIA CP010136-15] NR 77 TC 18 Z9 19 U1 1 U2 10 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0815-9319 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD FEB PY 2011 VL 26 IS 2 BP 240 EP 246 DI 10.1111/j.1440-1746.2010.06529.x PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 711OB UT WOS:000286600200007 PM 21155883 ER PT J AU Yabroff, KR Klabunde, CN Yuan, GG McNeel, TS Brown, ML Casciotti, D Buckman, DW Taplin, S AF Yabroff, K. Robin Klabunde, Carrie N. Yuan, Gigi McNeel, Timothy S. Brown, Martin L. Casciotti, Dana Buckman, Dennis W. Taplin, Stephen TI Are Physicians' Recommendations For Colorectal Cancer Screening Guideline-Consistent? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE guidelines mass screening; colorectal neoplasms/prevention & control; fecal occult blood test; flexible sigmoidoscopy; colonoscopy ID FECAL-OCCULT-BLOOD; PRIMARY-CARE PHYSICIANS; PREVENTIVE SERVICES; CLINICAL GUIDELINES; SOCIETY GUIDELINES; NATIONAL-SURVEY; SIGMOIDOSCOPY; SURVEILLANCE; INTERNISTS; RATIONALE AB BACKGROUND: Many older adults in the U. S. do not receive appropriate colorectal cancer (CRC) screening. Although primary care physicians' recommendations to their patients are central to the screening process, little information is available about their recommendations in relation to guidelines for the menu of CRC screening modalities, including fecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), colonoscopy, and double contrast barium enema (DCBE). The objective of this study was to explore potentially modifiable physician and practice factors associated with guideline- consistent recommendations for the menu of CRC screening modalities. METHODS: We examined data from a nationally representative sample of 1266 physicians in the U. S. surveyed in 2007. The survey included questions about physician and practice characteristics, perceptions about screening, and recommendations for age of initiation and screening interval for FOBT, FS, colonoscopy and DCBE in average risk adults. Physicians' screening recommendations were classified as guideline consistent for all, some, or none of the CRC screening modalities recommended. Analyses used descriptive statistics and polytomous logit regression models. RESULTS: Few (19.1%; 95% CI: 16.9%, 21.5%) physicians made guideline-consistent recommendations across all CRC screening modalities that they recommended. Inmultivariate analysis, younger physician age, board certification, north central geographic region, single specialty or multi-specialty practice type, fewer patients perweek, higher number of recommended modalities, use of electronic medical records, greater influence of patient preferences for screening, and published clinical evidence were associated with guideline-consistent screening recommendations (p<0.05). CONCLUSIONS: Physicians' CRC screening recommendations reflect both overuse and underuse, and fewmade guideline-consistent CRC screening recommendations across all modalities they recommended. Interventions that focus on potentially modifiable physician and practice factors that influence overuse and underuse and address the menu of recommended screening modalities will be important for improving screening practice. C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Yuan, Gigi; McNeel, Timothy S.; Buckman, Dennis W.] Informat Management Serv Inc, Rockville, MD USA. [Casciotti, Dana] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU National Cancer Institute [N02-PC-51308]; Agency for Healthcare Research and Quality [Y3-PC-5019-01, Y3-PC-5019-02]; Centers for Disease Control and Prevention [Y3-PC-6017-01] FX The survey was conducted under contract with Westat. Funding support was provided by the National Cancer Institute (contract numbers N02-PC-51308), the Agency for Healthcare Research and Quality (inter-agency agreement numbers Y3-PC-5019-01 and Y3-PC-5019-02) and the Centers for Disease Control and Prevention (inter-agency agreement number Y3-PC-6017-01). Presented in part at the American Public Health Association meeting November 10, 2009. NR 46 TC 30 Z9 31 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2011 VL 26 IS 2 BP 177 EP 184 DI 10.1007/s11606-010-1516-5 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 725TK UT WOS:000287668800017 PM 20949328 ER PT J AU Ohana, E Shcheynikov, N Yang, DK So, I Muallem, S AF Ohana, Ehud Shcheynikov, Nikolay Yang, Dongki So, Insuk Muallem, Shmuel TI Determinants of coupled transport and uncoupled current by the electrogenic SLC26 transporters SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID CLC CHLORIDE CHANNELS; ANION-EXCHANGE; MOLECULAR CHARACTERIZATION; PROKARYOTIC HOMOLOG; PROTEIN-STRUCTURE; PENDRED SYNDROME; STAS DOMAIN; MEMBRANE; CELLS; SELECTIVITY AB Members of the SLC26 family of anion transporters mediate the transport of diverse molecules ranging from halides to carboxylic acids and can function as coupled transporters or as channels. A unique feature of the two members of the family, Slc26a3 and Slc26a6, is that they can function as both obligate coupled and mediate an uncoupled current, in a channel-like mode, depending on the transported anion. To identify potential features that control the two modes of transport, we performed in silico modeling of Slc26a6, which suggested that the closest potential fold similarity of the Slc26a6 transmembrane domains is to the CLC transporters, despite their minimal sequence identity. Examining the predicted Slc26a6 fold identified a highly conserved glutamate (Glu(-); Slc26a6(E357)) with the predicted spatial orientation similar to that of the CLC-ec1 E148, which determines coupled or uncoupled transport by CLC-ec1. This raised the question of whether the conserved Glu(-) in Slc26a6(E357) and Slc26a3(E367) have a role in the unique transport modes by these transporters. Reversing the Glu(-) charge in Slc26a3 and Slc26a6 resulted in the inhibition of all modes of transport. However, most notably, neutralizing the charge in Slc26a6(E357A) eliminated all forms of coupled transport without affecting the uncoupled current. The Slc26a3(E367A) mutation markedly reduced the coupled transport and converted the stoichiometry of the residual exchange from 2Cl(-)/1HCO3(-) to 1Cl(-)/1HCO3(-), while completely sparing the current. These findings suggest the possibility that similar structural motif may determine multiple functional modes of these transporters. C1 [Ohana, Ehud; Shcheynikov, Nikolay; Yang, Dongki; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Ohana, Ehud; Shcheynikov, Nikolay; Yang, Dongki; Muallem, Shmuel] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA. [So, Insuk] Seoul Natl Univ, Coll Med, Dept Physiol & Biophys, Seoul 110799, South Korea. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov RI So, Insuk/J-2762-2012 FU National Institutes of Health [DE12309, DK076638]; Machiah Foundation [2008-0702]; Jewish Community Federation of San Francisco; Jewish Community Federation of Peninsula; Jewish Community Federation of Marin; Jewish Community Federation of Sonoma FX This work was supported by National Institutes of Health (grants DE12309 and DK076638). E. Ohana was supported in part by the Machiah Fellowship (grant 2008-0702) awarded through the Machiah Foundation, a supporting foundation of the Jewish Community Federation of San Francisco, the Peninsula, Marin, and Sonoma Counties. NR 45 TC 31 Z9 32 U1 0 U2 0 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 FEB PY 2011 VL 137 IS 2 BP 239 EP 251 DI 10.1085/jgp.201010531 PG 13 WC Physiology SC Physiology GA 721KG UT WOS:000287351400008 PM 21282402 ER PT J AU Kirklin, JK Naftel, DC Kormos, RL Stevenson, LW Pagani, FD Miller, MA Ulisney, KL Baldwin, JT Young, JB AF Kirklin, James K. Naftel, David C. Kormos, Robert L. Stevenson, Lynne W. Pagani, Francis D. Miller, Marissa A. Ulisney, Karen L. Baldwin, J. Timothy Young, James B. TI Third INTERMACS Annual Report: The evolution of destination therapy in the United States SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE mechanical circulatory support; destination therapy; INTERMACS; LVAD; advanced heart failure AB The third annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) provides documentation of the current landscape of durable mechanical circulatory support in the United States. With nearly 3,000 patients entered into the database, the transition to continuous-flow pump technology is evident and dramatic. This report focuses on the rapidly expanding experience with mechanical circulatory support as destination therapy. The current I-year survival of 75% with continuous-flow destination therapy provides a benchmark for the evolving application of this therapy. J Heart Lung Transplant 2011;30:115-23 (C) 2011 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Kirklin, James K.] Univ Alabama, Div Cardiovasc, Birmingham, AL 35294 USA. [Kormos, Robert L.] Univ Pittsburgh, Med Ctr, Presbyterian Univ Hosp, Pittsburgh, PA USA. [Stevenson, Lynne W.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Pagani, Francis D.] Univ Michigan, Ann Arbor, MI 48109 USA. [Ulisney, Karen L.] NHLBI, NIH, Div Cardiovasc Dis, Adv Technol & Surg Branch, Bethesda, MD 20892 USA. [Baldwin, J. Timothy] NHLBI, Rockledge Ctr 2, Bethesda, MD 20892 USA. [Young, James B.] Cleveland Clin Fdn, Lerner Coll Med, Cleveland, OH 44195 USA. RP Kirklin, JK (reprint author), Univ Alabama, Div Cardiovasc, 1900 Univ Blvd, Birmingham, AL 35294 USA. EM jkirklin@uab.edu FU National Institutes of Health [HHSN268200548198C] FX This work was supported by a National Institutes of Health Contract #HHSN268200548198C. NR 2 TC 178 Z9 184 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2011 VL 30 IS 2 BP 115 EP 123 DI 10.1016/j.healun.2010.12.001 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 710VN UT WOS:000286545200001 PM 21215378 ER PT J AU Calvisi, DF Ladu, S Conner, EA Seo, D Hsieh, JT Factor, VM Thorgeirsson, SS AF Calvisi, Diego F. Ladu, Sara Conner, Elizabeth A. Seo, Daekwan Hsieh, Jer-Tsong Factor, Valentina M. Thorgeirsson, Snorri S. TI Inactivation of Ras GTPase-activating proteins promotes unrestrained activity of wild-type Ras in human liver cancer SO JOURNAL OF HEPATOLOGY LA English DT Article DE Ras GAPs; HCC; Methylation ID HEPATOCELLULAR-CARCINOMA; PROGNOSTIC-SIGNIFICANCE; PROSTATE-CANCER; METHYLATION; ONCOGENES; GENE; SUPPRESSOR; EXPRESSION; INHIBITOR; MECHANISM AB Background & Aims: Aberrant activation of the RAS pathway is ubiquitous in human hepatocarcinogenesis, but the molecular mechanisms leading to RAS induction in the absence of RAS mutations remain under-investigated. We defined the role of Ras GTPase activating proteins (GAPs) in the constitutive activity of Ras signaling during human hepatocarcinogenesis. Methods: The mutation status of RAS genes and RAS effectors was assessed in a collection of human hepatocellular carcinomas (HCC). Levels of RAS GAPs (RASA1-4, RASAL1, nGAP, SYNGAP1, DAB2IP, and NF1) and the RASAL1 upstream inducer PITX1 were determined by real-time RT-PCR and immunoblotting. The promoter and genomic status of RASAL1, DAB2IP, NF1, and PITX1 were assessed by methylation assays and microsatellite analysis. Effects of RASAL1. DAB2IP, and PITX1 on HCC growth were evaluated by transfection and siRNA analyses of HCC cell lines. Results: In the absence of Ras mutations, downregulation of at least one RAS GAP (RASAL1, DAB2IP, or NF1) was found in all HCC samples. Low levels of DAB2IP and PITX1 were detected mostly in a HCC subclass from patients with poor survival, indicating that these proteins control tumor aggressiveness. In HCC cells, reactivation of RASAL1, DAB2IP, and PITX1 inhibited proliferation and induced apoptosis, whereas their silencing increased proliferation and resistance to apoptosis. Conclusions: Selective suppression of RASAL1, DAB2IP, or NF1 RAS GAPs results in unrestrained activation of Ras signaling in the presence of wild-type RAS in HCC. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Calvisi, Diego F.; Ladu, Sara; Conner, Elizabeth A.; Seo, Daekwan; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Calvisi, Diego F.] Univ Sassari, Dept Biomed Sci, Expt Pathol & Oncol Sect, I-07100 Sassari, Italy. [Hsieh, Jer-Tsong] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Hsieh, Jer-Tsong] China Med Univ, Grad Inst Canc Biol, Taichung 404, Taiwan. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Rm 4146A,37 Convent Dr, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov RI Xie, Huangming/B-2260-2012 FU National Cancer Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported by funds from the Intramural Research Program of National Cancer Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 24 TC 60 Z9 64 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD FEB PY 2011 VL 54 IS 2 BP 311 EP 319 DI 10.1016/j.jhep.2010.06.036 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 717TN UT WOS:000287070400019 PM 21067840 ER PT J AU Barber, DL Mayer-Barber, KD Feng, CG Sharpe, AH Sher, A AF Barber, Daniel L. Mayer-Barber, Katrin D. Feng, Carl G. Sharpe, Arlene H. Sher, Alan TI CD4 T Cells Promote Rather than Control Tuberculosis in the Absence of PD-1-Mediated Inhibition SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; MYCOBACTERIUM-TUBERCULOSIS; INTERFERON-GAMMA; PULMONARY TUBERCULOSIS; PD-1 EXPRESSION; INNATE IMMUNITY; IFN-GAMMA; B7 FAMILY; INFECTION; MICE AB Although CD4 T cells are required for host resistance to Mycobacterium tuberculosis, they may also contribute to pathology. In this study, we examine the role of the inhibitory receptor PD-1 and its ligand PD-L1 during M. tuberculosis infection. After aerosol exposure, PD-1 knockout (KO) mice develop high numbers of M. tuberculosis-specific CD4 T cells but display markedly increased susceptibility to infection. Importantly, we show that CD4 T cells themselves drive the increased bacterial loads and pathology seen in infected PD-1 KO mice, and PD-1 deficiency in CD4 T cells is sufficient to trigger early mortality. PD-L1 KO mice also display enhanced albeit less severe susceptibility, indicating that T cells are regulated by multiple PD ligands during M. tuberculosis infection. M. tuberculosis-specific CD8 T cell responses were normal in PD-1 KO mice, and CD8 T cells only had a minor contribution to the exacerbated disease in the M. tuberculosis-infected PD-1 KO and PD-L1 KO mice. Thus, in the absence of the PD-1 pathway, M. tuberculosis benefits from CD4 T cell responses, and host resistance requires inhibition by PD-1 to prevent T cell-driven exacerbation of the infection. The Journal of Immunology, 2011, 186: 1598-1607. C1 [Barber, Daniel L.; Mayer-Barber, Katrin D.; Feng, Carl G.; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sharpe, Arlene H.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Barber, DL (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 50 South Dr,Room 6146, Bethesda, MD 20892 USA. EM barberd@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This work was supported by the National Institute of Allergy and Infectious Diseases intramural research program. NR 50 TC 74 Z9 79 U1 1 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2011 VL 186 IS 3 BP 1598 EP 1607 DI 10.4049/jimmunol.1003304 PG 10 WC Immunology SC Immunology GA 708RE UT WOS:000286381200039 PM 21172867 ER PT J AU Morrow, AN Schmeisser, H Tsuno, T Zoon, KC AF Morrow, Angel N. Schmeisser, Hana Tsuno, Takaya Zoon, Kathryn C. TI A Novel Role for IFN-Stimulated Gene Factor 3(II) in IFN-gamma Signaling and Induction of Antiviral Activity in Human Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR ISGF3; INDUCED NUCLEAR FACTORS; BINDING PROTEIN GENE; INTERFERON-GAMMA; TYROSINE PHOSPHORYLATION; UNPHOSPHORYLATED STAT1; PROMOTER ELEMENT; MICE LACKING; IN-VIVO; ALPHA AB Type I (e.g., IFN-alpha, IFN-beta) and type II IFNs (IFN-gamma) have antiviral, antiproliferative, and immunomodulatory properties. Both types of IFN signal through the Jak/STAT pathway to elicit antiviral activity, yet IFN-gamma is thought to do so only through STAT1 homodimers, whereas type I IFNs activate both STAT1- and STAT2-containing complexes such as IFN-stimulated gene factor 3. In this study, we show that IFN-stimulated gene factor 3 containing unphosphorylated STAT2 (ISGF3(II)) also plays a role in IFN-gamma-mediated antiviral activity in humans. Using phosphorylated STAT1 as a marker for IFN signaling, Western blot analysis of IFN-alpha 2a-treated human A549 cells revealed that phospho-STAT1 (Y701) levels peaked at 1 h, decreased by 6 h, and remained at low levels for up to 48 h. Cells treated with IFN-gamma showed a biphasic phospho-STAT1 response with an early peak at 1-2 h and a second peak at 15-24 h. Gene expression microarray following IFN-gamma treatment for 24 h indicated an induction of antiviral genes that are induced by IFN-stimulated gene factor 3 and associated with a type I IFN response. Induction of these genes by autocrine type I and type III IFN signaling was ruled out using neutralizing Abs to these IFNs in biological assays and by quantitative RT-PCR. Despite the absence of autocrine IFNs, IFN-gamma treatment induced formation of ISGF3(II). This novel transcription factor complex binds to IFN-stimulated response element promoter sequences, as shown by chromatin immunoprecipitation analysis of the protein kinase R promoter. STAT2 and IFN regulatory factor 9 knockdown in A549 cells reversed IFN-gamma-mediated IFN-stimulated response element induction and antiviral activity, implicating ISGF3II formation as a significant component of the cellular response and biological activity of IFN-gamma. The Journal of Immunology, 2011, 186: 1685-1693. C1 [Morrow, Angel N.; Schmeisser, Hana; Tsuno, Takaya; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. [Morrow, Angel N.] Georgetown Univ, Dept Microbiol & Immunol, Washington, DC 20057 USA. RP Zoon, KC (reprint author), NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 48 TC 24 Z9 25 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2011 VL 186 IS 3 BP 1685 EP 1693 DI 10.4049/jimmunol.1001359 PG 9 WC Immunology SC Immunology GA 708RE UT WOS:000286381200048 PM 21178011 ER PT J AU Durbin, AP Schmidt, A Elwood, D Wanionek, KA Lovchik, J Thumar, B Murphy, BR Whitehead, SS AF Durbin, Anna P. Schmidt, Alexander Elwood, Dan Wanionek, Kimberli A. Lovchik, Janece Thumar, Bhavin Murphy, Brian R. Whitehead, Stephen S. TI Heterotypic Dengue Infection with Live Attenuated Monotypic Dengue Virus Vaccines: Implications for Vaccination of Populations in Areas Where Dengue Is Endemic SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HEMORRHAGIC-FEVER; NAIVE ADULTS; ANTIBODY; ENHANCEMENT; CANDIDATE; VIREMIA; VOLUNTEERS; SEVERITY; DISEASE; GREECE AB Background. Because infection with any of the 4 Dengue virus serotypes may elicit both protective neutralizing antibodies and nonneutralizing antibodies capable of enhancing subsequent heterotypic Dengue virus infections, the greatest risk for severe dengue occurs during a second, heterotypic Dengue virus infection. It remains unclear whether the replication of live attenuated vaccine viruses will be similarly enhanced when administered to Dengue-immune individuals. Methods. We recruited 36 healthy adults who had previously received a monovalent live Dengue virus vaccine 0.6-7.4 years earlier. Participants were assigned to 1 of 4 cohorts and were randomly chosen to receive placebo or a heterotypic vaccine. The level of replication, safety, and immunogenicity of the heterotypic vaccine virus was compared with that of Dengue virus immunologically naive vaccinees. Results. Vaccine virus replication and reactogenicity after monovalent Dengue virus vaccination in naive and heterotypically immune vaccinees was similar. In contrast to naive vaccinees, the antibody response in heterotypically immune vaccinees was broadly neutralizing and mimicked the response observed by natural secondary Dengue virus infection. Conclusions. Enhanced replication of these live attenuated Dengue virus vaccines was minimal in heterotypically immune vaccinees and suggests that the further evaluation of these candidate vaccines in populations with preexisting DENV immunity can proceed safely. C1 [Durbin, Anna P.; Elwood, Dan; Wanionek, Kimberli A.; Lovchik, Janece; Thumar, Bhavin; Whitehead, Stephen S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Schmidt, Alexander; Murphy, Brian R.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Durbin, AP (reprint author), 624 N Broadway,Rm 251, Baltimore, MD 21205 USA. EM adurbin@jhsph.edu RI Mavoa, Suzanne/B-5372-2010 FU National Institute of Allergy Infectious Diseases Division of Intramural Research, National Institutes of Health FX This work was supported by the National Institute of Allergy Infectious Diseases Division of Intramural Research, National Institutes of Health. NR 33 TC 23 Z9 23 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2011 VL 203 IS 3 BP 327 EP 334 DI 10.1093/infdis/jiq059 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 711SN UT WOS:000286611800008 PM 21208923 ER PT J AU Memoli, MJ Davis, AS Proudfoot, K Chertow, DS Hrabal, RJ Bristol, T Taubenberger, JK AF Memoli, Matthew J. Davis, A. Sally Proudfoot, Kathleen Chertow, Daniel S. Hrabal, Rachel J. Bristol, Tyler Taubenberger, Jeffery K. TI MultiDrug-Resistant 2009 Pandemic Influenza A(H1N1) Viruses Maintain Fitness and Transmissibility in Ferrets SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; H1N1 VIRUS; IN-VITRO; ADAMANTANE RESISTANCE; ISOLATED WORLDWIDE; RAPID SELECTION; A/H3N2 VIRUS; A VIRUSES; OSELTAMIVIR; NEURAMINIDASE AB Background. The 2009 influenza A(H1N1) pandemic called attention to the limited influenza treatment options available, especially in individuals at high risk of severe disease. Neuraminidase inhibitor-resistant seasonal H1N1 viruses have demonstrated the ability to transmit well despite early data indicating that resistance reduces viral fitness. 2009 H1N1 pandemic viruses have sporadically appeared containing resistance to neuraminidase inhibitors and the adamantanes, but the ability of these viruses to replicate, transmit, and cause disease in mammalian hosts has not been fully characterized. Methods. Two pretreatment wild-type viruses and 2 posttreatment multidrug-resistant viruses containing the neuraminidase H275Y mutation collected from immunocompromised patients infected with pandemic influenza H1N1 were tested for viral fitness, pathogenicity, and transmissibility in ferrets. Results. The pretreatment wild-type viruses and posttreatment resistant viruses containing the H275Y mutation all demonstrated significant pathogenicity and equivalent viral fitness and transmissibility. Conclusions. The admantane-resistant 2009 pandemic influenza A(H1N1) virus can develop the H275Y change in the neuraminidase gene conferring resistance to both oseltamivir and peramivir without any loss in fitness, transmissibility, or pathogenicity. This suggests that the dissemination of widespread multidrug resistance similar to neuraminidase inhibitor resistance in seasonal H1N1 is a significant threat. C1 [Memoli, Matthew J.; Davis, A. Sally; Proudfoot, Kathleen; Chertow, Daniel S.; Hrabal, Rachel J.; Bristol, Tyler; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Memoli, MJ (reprint author), NIAID, Resp Virus Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, MSC 3203,33 North Dr, Bethesda, MD 20892 USA. EM memolim@niaid.nih.gov OI Hagey, Rachel/0000-0002-4368-3169; Davis, Anne/0000-0001-5711-3936 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases FX This work was supported by the intramural funds of the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. NR 30 TC 40 Z9 41 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2011 VL 203 IS 3 BP 348 EP 357 DI 10.1093/infdis/jiq067 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 711SN UT WOS:000286611800012 PM 21208927 ER PT J AU Nurius, PS Macy, RJ Nwabuzor, I Holt, VL AF Nurius, Paula S. Macy, Rebecca J. Nwabuzor, Ijeoma Holt, Victoria L. TI Intimate Partner Survivors' Help-Seeking and Protection Efforts: A Person-Oriented Analysis SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE battered women; domestic violence; intervention/treatment; legal intervention ID DOMESTIC VIOLENCE; BATTERED WOMEN; SEXUAL ASSAULT; SOCIAL SUPPORT; MENTAL-HEALTH; VICTIMS; PROFILES; SERVICES; INTERVENTION; PERCEPTIONS AB Domestic violence advocates and researchers advocate for a survivor-centered approach for assisting women experiencing intimate partner violence (IPV), with individualized safety plans and services; yet little empirical work has been done to determine IPV survivors' specific combinations of vulnerabilities and assets that might inform such an approach. Using latent profile analysis of a cohort of 448 survivors, five distinct subgroups were previously identified in terms of biopsychosocial asset and vulnerability profiles. The purpose of the current study was to apply person-oriented methodology for survivor-centered investigation of differences in help-seeking and protective actions according to subgroup membership within this cohort. Though not differing demographically, the subgroups were found to differ significantly and meaningfully in their patterns of IPV help-seeking and protective actions. Thus, reliance on population-aggregate linear relationships between IPV exposure and safety efforts may risk overlooking important variation by vulnerability and asset profile, and knowledge of distinct clusters among functioning profiles may help with understanding of survivors' coping strategies. The authors outline service-need considerations across the subgroups and provide guidance for targeted outreach, locating IPV survivors and matching services to their needs. C1 [Nurius, Paula S.] Univ Washington, Sch Social Work, NIMH Funded Prevent Res Training Program, Seattle, WA 98105 USA. [Holt, Victoria L.] Univ Washington, Sch Publ Hlth, Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98195 USA. [Macy, Rebecca J.] Univ N Carolina, Sch Social Work, Chapel Hill, NC USA. RP Nurius, PS (reprint author), Univ Washington, Sch Social Work, NIMH Funded Prevent Res Training Program, 4101 15th Ave NE, Seattle, WA 98105 USA. EM nurius@u.washington.edu FU NICHD NIH HHS [R24 HD042828, R24 HD042828-10]; NIDA NIH HHS [1 R01 DA11151]; NIMH NIH HHS [5 T32 MH200010] NR 60 TC 18 Z9 19 U1 3 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD FEB PY 2011 VL 26 IS 3 BP 539 EP 566 DI 10.1177/0886260510363422 PG 28 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 717EJ UT WOS:000287025800008 PM 20448232 ER PT J AU Lang, JM Shennan, M Njauw, JCN Luo, S Bishop, JN Harland, M Hayward, NK Tucker, MA Goldstein, AM Landi, MT Puig, S Gruis, NA Bergman, W Bianchi-Scarra, G Ghiorzo, P Hogg, D Tsao, H AF Lang, Julie M. Shennan, Michael Njauw, Jenny C. -N. Luo, Su Bishop, Julia N. Harland, Mark Hayward, Nicholas K. Tucker, Margaret A. Goldstein, Alisa M. Landi, Maria T. Puig, Susana Gruis, Nelleke A. Bergman, Wilma Bianchi-Scarra, Giovanna Ghiorzo, Paola Hogg, David Tsao, Hensin TI A Flexible Multiplex Bead-Based Assay for Detecting Germline CDKN2A and CDK4 Variants in Melanoma-Prone Kindreds SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID NEURAL SYSTEM TUMORS; MALIGNANT-MELANOMA; UVEAL MELANOMA; MUTATIONS; FAMILIES; VALIDATION; GENOMEL; GENES AB The presence of recurrent high-risk mutations in cyclin-dependent kinase inhibitor 2A/cyclin-dependent kinase 4 (CDKN2A/CDK4) among melanoma-prone families suggests that a high-throughput, multiplex assay could serve as an effective initial screening tool. To this end, we have developed a multiplex bead-based assay for high-throughput CDKN2A/CDK4 genotyping in the context of familial melanoma. Genomic DNA from 1,603 subjects (1,005 in training set and 598 in validation set) were amplified by multiplex PCR using five CDKN2A/CDK4 primer sets followed by multiplex allele-specific primer extension for 39 distinct germline variants. The products were then sorted and analyzed using the Luminex xMAP system. Genotypes were compared with previously determined sequence data. In the Toronto training cohort, all 145 samples with known variants were detected by the bead assay (100% concordance). Analysis of the 598 samples from the GenoMEL validation set led to identification of 150/155 expected variants (96.77%). Overall, the bead assay correctly genotyped 1,540/1,603 (96.07%) of all individuals in the study and 1,540/1,545 (99.68%) of individuals whose variants were represented in the probe set. Out of a total of 62,517 allelic calls, 62,512 (99.99%) were correctly assigned. The multiplex bead-based assay is an accurate method for genotyping CDKN2A/CDK4 variants and is potentially useful in genotyping low-to-moderate melanoma risk single-nucleotide polymorphisms. C1 [Njauw, Jenny C. -N.; Luo, Su; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Njauw, Jenny C. -N.; Luo, Su; Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. [Lang, Julie M.; Shennan, Michael; Hogg, David] Univ Toronto, Dept Med, Toronto, ON, Canada. [Lang, Julie M.; Shennan, Michael; Hogg, David] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Bishop, Julia N.; Harland, Mark] Univ Leeds, St James Hosp, Epidemiol & Biostat Sect, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. [Hayward, Nicholas K.] Queensland Inst Med Res, Oncogenom Lab, Brisbane, Qld 4006, Australia. [Tucker, Margaret A.; Goldstein, Alisa M.; Landi, Maria T.] NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Puig, Susana] Hosp Clin Barcelona, Melanoma Unit, Dept Dermatol, IDIBAPS, Barcelona, Spain. [Puig, Susana] CIBER Enfermedades Raras, Barcelona, Spain. [Gruis, Nelleke A.; Bergman, Wilma] Leiden Univ, Dept Dermatol, Med Ctr, Leiden, Netherlands. [Bianchi-Scarra, Giovanna; Ghiorzo, Paola] Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. [Bianchi-Scarra, Giovanna] San Martino Hosp, Lab Genet Rare Hereditary Canc, Genoa, Italy. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, 55 Fruit St, Boston, MA 02114 USA. EM htsao@partners.org RI Bianchi Scarra, Giovanna/G-8933-2014; Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; OI Bianchi Scarra, Giovanna/0000-0002-6127-1192; hayward, nicholas/0000-0003-4760-1033; Puig, Susana/0000-0003-1337-9745; Gruis, Nelleke/0000-0002-5210-9150 FU American Cancer Society [RSG-07-085-01-MGO]; National Cancer Institute [P50 CA93683, K24 CA149202]; National Health and Medical Research Council of Australia; National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health (NIH); NIH [RO1 CA83115]; EU [LSHC-CT-2006-018702]; Fondo de Investigaciones Sanitarias, Spain; MGH Millennium Melanoma Fund; [PRIN-2008-W8JTPA] FX This work was supported by the American Cancer Society (RSG-07-085-01-MGO) and the National Cancer Institute (P50 CA93683 and K24 CA149202; all to HT), the National Health and Medical Research Council of Australia (to NKH), PRIN-2008-W8JTPA (to GBS), the National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health (NIH) (AMG, MTL, MAT), the NIH (RO1 CA83115), the EU FP6 contract LSHC-CT-2006-018702 (to GenoMEL), the Fondo de Investigaciones Sanitarias, Spain (to SP), and the generous donors of the MGH Millennium Melanoma Fund. NR 19 TC 11 Z9 12 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2011 VL 131 IS 2 BP 480 EP 486 DI 10.1038/jid.2010.331 PG 7 WC Dermatology SC Dermatology GA 705YU UT WOS:000286177500029 PM 21085193 ER PT J AU Faughnan, ME Palda, VA Garcia-Tsao, G Geisthoff, UW McDonald, J Proctor, DD Spears, J Brown, DH Buscarini, E Chesnutt, MS Cottin, V Ganguly, A Gossage, JR Guttmacher, AE Hyland, RH Kennedy, SJ Korzenik, J Mager, JJ Ozanne, AP Piccirillo, JF Picus, D Plauchu, H Porteous, MEM Pyeritz, RE Ross, DA Sabba, C Swanson, K Terry, P Wallace, MC Westermann, CJJ White, RI Young, LH Zarrabeitia, R AF Faughnan, M. E. Palda, V. A. Garcia-Tsao, G. Geisthoff, U. W. McDonald, J. Proctor, D. D. Spears, J. Brown, D. H. Buscarini, E. Chesnutt, M. S. Cottin, V. Ganguly, A. Gossage, J. R. Guttmacher, A. E. Hyland, R. H. Kennedy, S. J. Korzenik, J. Mager, J. J. Ozanne, A. P. Piccirillo, J. F. Picus, D. Plauchu, H. Porteous, M. E. M. Pyeritz, R. E. Ross, D. A. Sabba, C. Swanson, K. Terry, P. Wallace, M. C. Westermann, C. J. J. White, R. I. Young, L. H. Zarrabeitia, R. TI International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PULMONARY ARTERIOVENOUS-MALFORMATIONS; HEPATIC VASCULAR MALFORMATIONS; ND-YAG LASER; ARGON PLASMA COAGULATION; OSLER-WEBER-SYNDROME; QUALITY-OF-LIFE; ROW HELICAL CT; TO-LEFT SHUNT; CONTRAST ECHOCARDIOGRAPHY; GASTROINTESTINAL-TRACT AB Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations. C1 [Faughnan, M. E.; Hyland, R. H.] Univ Toronto, St Michaels Hosp, Div Respirol, Dept Med, Toronto, ON M5B 1W8, Canada. [Faughnan, M. E.] Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Palda, V. A.] Univ Toronto, Dept Hlth Policy, Toronto, ON M5B 1W8, Canada. [Palda, V. A.] Univ Toronto, Dept Management & Evaluat, Toronto, ON M5B 1W8, Canada. [Garcia-Tsao, G.] Yale Univ, Sch Med, Dept Internal Med, Sect Digest Dis, New Haven, CT 06510 USA. [Geisthoff, U. W.] Univ Saarland, Fac Med, D-6650 Homburg, Germany. [Geisthoff, U. W.] City Hosp, Dept Otorhinolaryngol, Holweide Hosp, Cologne, Germany. [McDonald, J.] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. [Spears, J.] Univ Toronto, St Michaels Hosp, Dept Surg, Toronto, ON M5B 1W8, Canada. [Brown, D. H.] Univ Toronto, Dept Otolaryngol Head & Neck Surg, Toronto, ON M5B 1W8, Canada. [Buscarini, E.] Osped Maggiore Crema, UO Gastroenterol & Endoscopia Digest, Crema, Italy. [Chesnutt, M. S.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, HHT Ctr Excellence, Dotter Intervent Inst, Portland, OR 97201 USA. [Cottin, V.] Univ Lyon, Hosp Civils Lyon, Natl Reference Ctr Rare Pulm Dis, Lyon, France. [Ganguly, A.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Gossage, J. R.] Med Coll Georgia, Augusta, GA 30912 USA. [Guttmacher, A. E.] NHGRI, NIH, Bethesda, MD 20892 USA. [Kennedy, S. J.] Childrens Hosp Eastern Ontario, Ontario Newborn Screening Program, Ottawa, ON K1H 8L1, Canada. [Kennedy, S. J.] Childrens Hosp Eastern Ontario, Reg Genet Program, Ottawa, ON K1H 8L1, Canada. [Korzenik, J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Mager, J. J.; Westermann, C. J. J.] St Antonius Hosp, Nieuwegein, Netherlands. [Ozanne, A. P.] Hop Bicetre, Paris, France. [Piccirillo, J. F.] Washington Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, St Louis, MO 63110 USA. [Picus, D.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Plauchu, H.] Hosp Civils Lyon, Natl Reference Ctr HHT Dis, Hotel Dieu Hosp, Lyon, France. [Porteous, M. E. M.] Western Gen Hosp, SE Scotland Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. [Ross, D. A.] St Vincents Med Ctr, Dept Surg, Bridgeport, CT USA. [Sabba, C.] Univ Bari, Dept Internal Med & Publ Hlth, Bari, Italy. [Swanson, K.] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA. [Terry, P.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Wallace, M. C.] Univ Hlth Network, Div Neurosurg, Krembil Neurosci Ctr, Toronto, ON, Canada. [White, R. I.] Yale Univ, Sch Med, Yale Vasc Malformat Ctr, New Haven, CT USA. [Young, L. H.] Yale Univ, Sch Med, Sect Cardiovasc Med, New Haven, CT USA. [Zarrabeitia, R.] Hosp Sierrallana, Med Interna Serv, Unidad HHT, Serv Cantabro Salud, Torrelavega, Cantabria, Spain. RP Faughnan, ME (reprint author), Univ Toronto, St Michaels Hosp, Div Respirol, Dept Med, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM faughnanm@smh.ca OI Sabba', Carlo/0000-0002-9874-8740 FU Argosy Foundation; HHT Foundation International Inc; Canadian Institutes of Health Research; St Michael's Hospital Department of Medicine; Nelson Arthur Hyland Foundation; Li Ka Shing Knowledge Institute of St Michael's Hospital; Ethek F Donahue Foundation FX John Abele on behalf of the Argosy Foundation, HHT Foundation International Inc, Canadian Institutes of Health Research, St Michael's Hospital Department of Medicine. Financial support for MEF: Nelson Arthur Hyland Foundation, Li Ka Shing Knowledge Institute of St Michael's Hospital.; VP received an honorarium for attending the HHT Guidelines Conference. DP received a grant (completed) from the Ethek F Donahue Foundation to study hormonal therapy in HHT. NR 131 TC 248 Z9 268 U1 3 U2 31 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD FEB PY 2011 VL 48 IS 2 BP 73 EP 87 DI 10.1136/jmg.2009.069013 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 711WM UT WOS:000286622100001 PM 19553198 ER PT J AU Vilar, S Ferino, G Phatak, SS Berk, B Cavasotto, CN Costanzi, S AF Vilar, Santiago Ferino, Giulio Phatak, Sharangdhar S. Berk, Barkin Cavasotto, Claudio N. Costanzi, Stefano TI Docking-based virtual screening for ligands of G protein-coupled receptors: Not only crystal structures but also in silico models SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE G protein-coupled receptors; Beta-adrenergic receptors; Virtual screening; Docking; Homology modeling ID STRUCTURE-BASED DISCOVERY; BETA(2)-ADRENERGIC RECEPTOR; DRUG DISCOVERY; BETA-2-ADRENERGIC RECEPTOR; AGONIST RECOGNITION; FLEXIBILITY; ACTIVATION; ANTAGONISTS; PREDICTION; BINDING AB G protein-coupled receptors (GPCRs) regulate a wide range of physiological functions and hold great pharmaceutical interest. Using the beta(2)-adrenergic receptor as a case study, this article explores the applicability of docking-based virtual screening to the discovery of GPCR ligands and defines methods intended to improve the screening performance. Our controlled computational experiments were performed on a compound dataset containing known agonists and blockers of the receptor as well as a large number of decoys. The screening based on the structure of the receptor crystallized in complex with its inverse agonist carazolol yielded excellent results, with a clearly delineated prioritization of ligands over decoys. Blockers generally were preferred over agonists; however, agonists were also well distinguished from decoys. A method was devised to increase the screening yields by generating an ensemble of alternative conformations of the receptor that accounts for its flexibility. Moreover, a method was devised to improve the retrieval of agonists, based on the optimization of the receptor around a known agonist. Finally, the applicability of docking-based virtual screening also to homology models endowed with different levels of accuracy was proved. This last point is of uttermost importance, since crystal structures are available only for a limited number of GPCRs, and extends our conclusions to the entire superfamily. The outcome of this analysis definitely supports the application of computer-aided techniques to the discovery of novel GPCR ligands, especially in light of the fact that, in the near future, experimental structures are expected to be solved and become available for an ever increasing number of GPCRs. Published by Elsevier Inc. C1 [Vilar, Santiago; Ferino, Giulio; Berk, Barkin; Costanzi, Stefano] NIDDK, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. [Phatak, Sharangdhar S.; Cavasotto, Claudio N.] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Houston, TX 77030 USA. RP Costanzi, S (reprint author), NIDDK, Lab Biol Modeling, NIH, DHHS, 9000 Rockville Plke,Bldg 12,Room 4003, Bethesda, MD 20892 USA. EM stefanoc@mail.nih.gov RI Costanzi, Stefano/G-8990-2013; berk, barkin/P-2088-2014; OI Costanzi, Stefano/0000-0003-3183-7332; Vilar Varela, Santiago/0000-0003-2663-4370 FU NIH, NIDDK FX This research was supported, in part, by the Intramural Research Program of the NIH, NIDDK. NR 49 TC 42 Z9 43 U1 0 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD FEB PY 2011 VL 29 IS 5 BP 614 EP 623 DI 10.1016/j.jmgm.2010.11.005 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 733BW UT WOS:000288236400004 PM 21146435 ER PT J AU Kim, T Barchi, JJ Marquez, VE Shapiro, BA AF Kim, Taejin Barchi, Joseph J., Jr. Marquez, Victor E. Shapiro, Bruce A. TI Understanding the effects of carbocyclic sugars constrained to north and south conformations on RNA nanodesign SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE RNA; North constrained sugar; South constrained sugar; Molecular dynamics simulations; RNA structure deformations; RNA nanodesign ID MOLECULAR-DYNAMICS; BIOLOGICAL-ACTIVITY; CRYSTAL-STRUCTURE; NUCLEIC-ACIDS; NEPLANOCIN-C; RESP MODEL; DNA; NMR; OLIGONUCLEOTIDES; NUCLEOSIDES AB Relatively new types of the modified nucleotides, namely carbocyclic sugars that are constrained to north or south (C2' or C3' exo) conformations, can be used for RNA nanoparticle design to control their structures and stability by rigidifying nucleotides and altering the helical properties of RNA duplexes. Two RNA structures, an RNA dodecamer and an HIV kissing loop complex where several nucleotides were replaced with north or south constrained sugars, were studied by molecular dynamics (MD) simulations. The substituted south constrained nucleotides in the dodecamer widened the major groove and narrowed and deepened the minor groove thus inducing local conformational changes that resemble a B-form DNA helix. In the HIV kissing loop complex, north and south constrained nucleotides were substituted into flanking bases and stems. The modified HIV kissing loop complex showed a lower RMSD value than the normal kissing loop complex. The overall twist angle was also changed and its standard deviation was reduced. In addition, the modified RNA dodecamer and HIV kissing loop complex were characterized by principal component analysis (PCA) and steered molecular dynamics (SMD). PCA results showed that the constrained sugars stabilized the overall motions. The results of the SMD simulations indicated that as the backbone delta angles were increased by elongation, more force was applied to the modified RNA due to the constrained sugar analogues. Published by Elsevier Inc. C1 [Kim, Taejin; Shapiro, Bruce A.] NCI, CCRNP, Frederick, MD 21701 USA. [Barchi, Joseph J., Jr.; Marquez, Victor E.] NCI, Med Chem Lab, Frederick, MD 21701 USA. RP Shapiro, BA (reprint author), NCI, CCRNP, Frederick, MD 21701 USA. EM shapirbr@mail.nih.gov RI Barchi Jr., Joseph/N-3784-2014 FU National Institutes of Health (NIH), National Cancer Institute (NCI) FX We would like to thank Igor Topol for the valuable discussions regarding the ab initio calculations. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research Nanobiology Program (CCRNP). The computational support was provided by the National Cancer Institute's Advanced Biomedical Computing Center (ABCC). NR 39 TC 1 Z9 1 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD FEB PY 2011 VL 29 IS 5 BP 624 EP 634 DI 10.1016/j.jmgm.2010.11.007 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 733BW UT WOS:000288236400005 PM 21159533 ER PT J AU Yun, SJ Yun, SJ Guy, HR AF Yun, Sijung Yun, Sajung Guy, H. Robert TI Analysis of the stabilities of hexameric amyloid-beta(1-42) models using discrete molecular dynamics simulations SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE A beta; Hexamer; Discrete molecular dynamics; Protein modeling; Stability; Amyloid ID AMYLOID-BETA-PROTEIN; ALZHEIMERS-DISEASE; OLIGOMERIZATION; RESIDUES; PEPTIDE; MEMORY; BRAIN AB Amyloid-beta (A beta) oligomers appear to play a pivotal role in Alzheimer's disease. A 42 residue long alloform, A beta 42, is closely related to etiology of the disease. In vitro results show evidences of hexamers; however structures of these hexamers have not been resolved experimentally. Here, we use discrete molecular dynamics (DMD) to analyze long duration stabilities of A beta 42 hexamer models developed previously in our lab. The hydrophobic core of these models is a six-stranded beta-barrel with 3-fold radial symmetry formed by residues 30-40. This core is shielded from water by residues 1-28. The nine models we analyzed differ by the relative positions of the core beta-strands, and whether the other segments surrounding the core contain a helices or beta-strands. A model of an annular protofibril composed of 36 A beta peptides was also simulated. Results of these model simulations were compared with results of aggregation simulations that started from six well separated random coils of A beta 42 and with simulations of two known beta-barrel structures. These results can be categorized into three groups: stable models with properties similar or superior to those of experimentally determined beta-barrel proteins, aggregation-prone models, and an amorphous aggregate from random coils. Conformations at the end of the simulation for aggregation-prone models have exposed hydrophobic core with dangling beta-strands on the surface. Hydrogen bond patterns within the beta-barrel were a critical factor for stability of the beta-barrel models. Aggregation-prone conformations imply that the association of these hexamers may be possible, which could lead to the formation of larger assemblies. (C) 2010 Elsevier Inc. All rights reserved. C1 [Yun, Sijung; Guy, H. Robert] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Yun, Sajung] Univ Hawaii Manoa, John A Burns Sch Med, Honolulu, HI 96813 USA. RP Guy, HR (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM sijungyun@yahoo.com; sijungyun@yahoo.com; hrguy46@yahoo.com FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Drs. Adina Milac, Yinon Shafrir, Stewart Durell, Daniel Flatow (LCB, NCI) for helpful discussions. We are grateful to Drs. Brigita Urbanc (Drexel U.), H. Eugene Stanley (Boston U.), and F. Ding (UNC) for providing the DMD with Kyte-Doolittle implicit solvent model. This study utilized the Biowulf Linux cluster at the National Institutes of Health (NIH), Bethesda, MD and was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 21 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD FEB PY 2011 VL 29 IS 5 BP 657 EP 662 DI 10.1016/j.jmgm.2010.11.008 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 733BW UT WOS:000288236400009 PM 21186130 ER PT J AU Yun, SJ Guy, HR AF Yun, Sijung Guy, H. Robert TI Stability tests on known and misfolded structures with discrete and all atom molecular dynamics simulations SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE Discrete molecular dynamics (DMD); Stability; Protein modelling; NAMD ID PROTEIN; AGGREGATION; MODEL; PEPTIDES; OLIGOMERIZATION; TRANSITION; MECHANISM; RESIDUES; ALPHA AB The brevity of molecular dynamics simulations often limits their utility in developing and evaluating structural models of proteins. The duration of simulations can be increased greatly using discrete molecular dynamics (DMD). However, the trade off is that coarse graining, implicit solvent, and other time-saving procedures reduce the accuracy of DMD simulations. Here we address some of these issues by comparing results of DMD and conventional all atom MD simulations on proteins of known structure and misfolded proteins. DMD simulations were performed at a range of temperatures to identify a 'physiological' temperature for DMD that mimicked molecular motions of conventional MD simulations at 310 K. We also compared results obtained with a new implicit solvent model developed here based on Miyazawa-Jernigan interaction pair potential to those obtained with a previously used model based on Kyte-Doolittle hydropathy scale. We compared DMD and all atom molecular dynamics with explicit water by simulating both correctly and incorrectly folded structures, and monomeric and dimeric a beta-barrel structures to analyze the ability of these procedures to distinguish between good and bad models. Deviations from the correct structures were substantially greater with DMD, as would be expected from coarse-graining and longer simulation time. Deviations were smallest for beta-strands and greatest for coiled loops. Structures of the incorrectly folded models were very poorly preserved during the DMD simulations; but both methods were able to distinguish between the correct and the incorrect structures based on differences in the magnitudes of the root mean squared deviation (RMSD) from the starting conformation. Published by Elsevier Inc. C1 [Yun, Sijung; Guy, H. Robert] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Guy, HR (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM sijungyun@yahoo.com; hrguy46@yahoo.com FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Drs. Adina Milac, Yinon Shafrir, Stewart Durell, Daniel Flatow (LCB, NCI) and Sajung Yun (U. of Hawaii) for helpful discussions. We are grateful to Drs. Brigita Urbanc (Drexel U.), H. Eugene Stanley (Boston U.), and F. Ding (UNC) for DMD with Kyte-Doolittle implicit solvent model. This study utilized the Biowulf Linux cluster at the National Institutes of Health (NIH), Bethesda, MD and was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 5 Z9 5 U1 1 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD FEB PY 2011 VL 29 IS 5 BP 663 EP 675 DI 10.1016/j.jmgm.2010.12.002 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 733BW UT WOS:000288236400010 PM 21215670 ER PT J AU Lu, ZY Van Wagoner, RM Harper, MK Baker, HL Hooper, JNA Bewley, CA Ireland, CM AF Lu, Zhenyu Van Wagoner, Ryan M. Harper, Mary Kay Baker, Heather L. Hooper, John N. A. Bewley, Carole A. Ireland, Chris M. TI Mirabamides E-H, HIV-Inhibitory Depsipeptides from the Sponge Stelletta clavosa SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID CONSTITUENT AMINO-ACIDS; PAPUA-NEW-GUINEA; MYRIASTRA-CLAVOSA; ABSOLUTE-CONFIGURATION; MARFEYS METHOD; NEAMPHAMIDE-A; MIRABILIS; PEPTIDES; LC/MS AB Four new depsipeptides, mirabamides E-H (1-4), and the known depsipeptide mirabamide C (5) have been isolated from the sponge Stelletta clavosa, collected from the Torres Strait. The planar structures were determined on the basis of extensive 1D and 2D NMR and HRESIMS. The absolute configurations were established by the advanced Marfey's method, NMR, and GC-MS. The four new compounds all showed strong inhibition of HIV-1 in a neutralization assay with IC(50) values of 121, 62, 68, and 41 nM, respectively. C1 [Lu, Zhenyu; Van Wagoner, Ryan M.; Harper, Mary Kay; Ireland, Chris M.] Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA. [Baker, Heather L.; Bewley, Carole A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Hooper, John N. A.] Queensland Museum, Biodivers Program, Brisbane, Qld 4101, Australia. RP Ireland, CM (reprint author), Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA. EM cireland@-pharm.utah.edu OI Hooper, John/0000-0003-1722-5954 FU NIH [RR06262, CA36622] FX The authors wish to acknowledge Prof. Y. Hamada, Chiba University, for providing standard 2S,3S,4R-dimethylglutamine and 2S,3S,4S-dimethylglutamine and Dr. P. Krishna and Dr. C. Nelson, University of Utah Mass Spectrometry and Proteomics Core Facility, for performing some of the HRESIMS experiments. The AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH, is acknowledged for reagents and cell lines used in the HIV-1 neutralization assays. Funding for the Varian INOVA 500 MHz NMR spectrometer was provided through NIH grant RR06262. This work was supported by NIH grant CA36622 (C.M.I.) and the NIH Intramural AIDS Targeted Antiviral Program (C.A.B.). NR 20 TC 26 Z9 27 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2011 VL 74 IS 2 BP 185 EP 193 DI 10.1021/np100613p PG 9 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 725IB UT WOS:000287637300012 PM 21280591 ER PT J AU Spiga, F Liu, Y Aguilera, G Lightman, SL AF Spiga, F. Liu, Y. Aguilera, G. Lightman, S. L. TI Temporal Effect of Adrenocorticotrophic Hormone on Adrenal Glucocorticoid Steroidogenesis: Involvement of the Transducer of Regulated Cyclic AMP-Response Element-Binding Protein Activity SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE adrenal glands; steroidogenesis; ACTH; transducer of regulated CREB activity 2 (TORC2); salt-inducible kinase 1 (SIK1) ID SALT-INDUCIBLE KINASE; RECEPTOR ANTAGONIST ORG-34850; MEDIATED GENE-EXPRESSION; CREB COACTIVATOR TORC2; CORTICOSTERONE RELEASE; TUMOR-CELLS; IN-VIVO; RAT; TRANSCRIPTION; STAR AB The availability of active steroidogenic acute regulatory protein (StAR) and side-chain cleavage cytochrome P450 (P450scc) are rate-limiting steps for steroidogenesis. Transcription of StAR and P450scc genes depends on cyclic AMP-response element-binding protein (CREB) phosphorylation and CREB co-activator, transducer of regulated CREB activity (TORC), which is regulated by salt-inducible kinase 1 (SIK1). In the present study, we investigated the relationship between TORC activation and adrenocorticotrophic hormone (ACTH)-induced steroidogenesis in vivo, by examining the time-course of the effect of ACTH injection (4 ng, i.v.) on the transcriptional activity of StAR and P450scc genes and the nuclear accumulation of transducer of regulated CREB activity 2 (TORC2) in rat adrenal cortex. ACTH produced rapid and transient increases in plasma corticosterone, with maximal responses between 5 and 15 min, and a decrease to almost basal values at 30 min. StAR and P450scc hnRNA levels increased 15 min following ACTH and decreased toward basal values at 30 min. Concomitant with an increase in nuclear phospho-CREB, ACTH injection induced nuclear accumulation of TORC2, with maximal levels at 5 min and a return to basal values by 30 min. The decline of nuclear TORC2 was paralleled by increases in SIK1 hnRNA and mRNA 15 and 30 min after injection, respectively. The early rises in plasma corticosterone preceding StAR and P450scc gene transcription suggest that post-transcriptional and post-translational changes in StAR protein mediate the early steroidogenic responses. Furthermore, the direct temporal relationship between nuclear accumulation of TORC2 and the increase in transcription of steroidogenic proteins, implicates TORC2 in the physiological regulation of steroidogenesis in the adrenal cortex. The delayed induction of SIK1 suggests a role for SIK1 in the declining phase of steroidogenesis. C1 [Spiga, F.] Univ Bristol, Sch Clin Sci, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol, Avon, England. [Liu, Y.; Aguilera, G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Spiga, F (reprint author), Univ Bristol, Sch Clin Sci, Henry Wellcome Labs Integrat Neurosci & Endocrino, Dorothy Hodgkin Bldg,Whitson St, Bristol, Avon, England. EM f.spiga@bristol.ac.uk FU Wellcome Trust [089647/Z/09/Z]; National Institutes of Health/National Institute of Child Health and Human Development; British Society for Neuroendocrinology FX This work was supported by a Wellcome Trust Programme Grant (089647/Z/09/Z) to S. L. L. and by the Intramural Research program of the National Institutes of Health/National Institute of Child Health and Human Development. The collaborative visit of Dr F. Spiga to NIH was supported by the British Society for Neuroendocrinology. NR 28 TC 24 Z9 24 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD FEB PY 2011 VL 23 IS 2 BP 136 EP 142 DI 10.1111/j.1365-2826.2010.02096.x PG 7 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 705ED UT WOS:000286110800004 PM 21083631 ER PT J AU Scott, BH Malone, BJ Semple, MN AF Scott, Brian H. Malone, Brian J. Semple, Malcolm N. TI Transformation of Temporal Processing Across Auditory Cortex of Awake Macaques SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID BINDING PROTEIN IMMUNOREACTIVITY; AMPLITUDE-MODULATED SOUNDS; RHESUS-MONKEY; RESPONSE PROPERTIES; FUNCTIONAL-ORGANIZATION; TONOTOPIC ORGANIZATION; NEURAL REPRESENTATIONS; FREQUENCY MODULATIONS; INFERIOR COLLICULUS; ACOUSTIC FEATURES AB Scott BH, Malone BJ, Semple MN. Transformation of temporal processing across auditory cortex of awake macaques. J Neurophysiol 105: 712-730, 2011. First published November 24, 2010; doi:10.1152/jn.01120.2009. The anatomy and connectivity of the primate auditory cortex has been modeled as a core region receiving direct thalamic input surrounded by a belt of secondary fields. The core contains multiple tonotopic fields (including the primary auditory cortex, AI, and the rostral field, R), but available data only partially address the degree to which those fields are functionally distinct. This report, based on single-unit recordings across four hemispheres in awake macaques, argues that the functional organization of auditory cortex is best understood in terms of temporal processing. Frequency tuning, response threshold, and strength of activation are similar between AI and R, validating their inclusion as a unified core, but the temporal properties of the fields clearly differ. Onset latencies to pure tones are longer in R (median, 33 ms) than in AI (20 ms); moreover, synchronization of spike discharges to dynamic modulations of stimulus amplitude and frequency, similar to those present in macaque and human vocalizations, suggest distinctly different windows of temporal integration in AI (20-30 ms) and R (100 ms). Incorporating data from the adjacent auditory belt reveals that the divergence of temporal properties within the core is in some cases greater than the temporal differences between core and belt. C1 [Scott, Brian H.; Malone, Brian J.; Semple, Malcolm N.] NYU, Ctr Neural Sci, New York, NY 10003 USA. RP Scott, BH (reprint author), NIMH, Neurochem Lab, NIH, 49 Convent Dr,Room 1B80, Bethesda, MD 20892 USA. EM brianscott@mail.nih.gov RI Scott, Brian/G-7932-2012; OI Scott, Brian/0000-0003-3949-9737 FU W. M. Keck Foundation; National Institutes of Health [DC-05287-01, MH-12293]; New York University FX This work was supported by a W. M. Keck Foundation grant to M. N. Semple, National Institutes of Health Grants DC-05287-01 to B. H. Scott and MH-12293 to B. J. Malone, and a James Arthur Fellowship from New York University to B. H. Scott. NR 72 TC 30 Z9 30 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2011 VL 105 IS 2 BP 712 EP 730 DI 10.1152/jn.01120.2009 PG 19 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 718OG UT WOS:000287133200019 PM 21106896 ER PT J AU Driscoll, DM Dal Monte, O Grafman, J AF Driscoll, David M. Dal Monte, Olga Grafman, Jordan TI A Need for Improved Training Interventions for the Remediation of Impairments in Social Functioning following Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Review DE brain injury; neuroplasticity; rehabilitation; social cognition; social skills ID EMOTION PERCEPTION DEFICITS; FACIAL AFFECT RECOGNITION; SCHIZOPHRENIA SPECTRUM DISORDERS; SEVERE HEAD-INJURY; COGNITIVE REHABILITATION; VIRTUAL-REALITY; MIND; SKILLS; AUTISM; ADULTS AB Social functioning deficits are a prominent feature of many neurological and psychiatric conditions, and may include disruption in the acquisition or application of basic or complex social skills. Such disturbances are often resistant to treatment, and individuals with such conditions are often faced with lifelong difficulties in maintaining personal relationships, employment, and independent living. In recent years, a number of psychosocial treatments have been developed to address this growing problem. In this article, we review studies investigating the use of psychosocial training interventions in individuals with acquired brain injuries, which frequently require intervention for impairments in cognitive and social functioning. We then discuss limitations of these studies and highlight specific areas in which such treatments might be improved in the future. C1 [Driscoll, David M.; Dal Monte, Olga; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 7D43,10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457; dal monte, olga/0000-0002-7823-4769 FU U.S. National Institute of Neurological Disorders and Stroke; Center for Neuroscience and Regenerative Medicine FX This work was supported by funding from the U.S. National Institute of Neurological Disorders and Stroke intramural research program, and the Center for Neuroscience and Regenerative Medicine. NR 77 TC 9 Z9 9 U1 5 U2 37 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD FEB PY 2011 VL 28 IS 2 BP 319 EP 326 DI 10.1089/neu.2010.1523 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 719UE UT WOS:000287234700015 PM 21121768 ER PT J AU Avdoshina, V Becker, J Campbell, LA Parsadanian, M Mhyre, T Tessarollo, L Mocchetti, I AF Avdoshina, Valeriya Becker, Jody Campbell, Lee A. Parsadanian, Maia Mhyre, Timothy Tessarollo, Lino Mocchetti, Italo TI Neurotrophins modulate the expression of chemokine receptors in the brain SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE NGF; NT-3; BDNF; CXCR4; CCR5 ID NEURONAL CELL-DEATH; IN-VIVO; HIPPOCAMPAL NEUROGENESIS; GROWTH-FACTOR; ADULT-RAT; CXCR4; GP120; HIV-1; CCR5; DEMENTIA AB In the central nervous system, chemokines are primarily mediators of inflammatory processes. Their receptors, in particular, CXCR4 and CCR5, serve as co-factors along with CD4 that permit Human immunodeficiency virus-1 (HIV) infection. Moreover, experimental evidence has shown that CXCR4 and CCR5 mediate the neurotoxic effects of the HIV envelope protein gp120, suggesting that these receptors could also promote the neuropathogenesis observed in HIV-positive individuals. Therefore, a better understanding of the molecular mechanisms governing the expression of chemokine receptors in the brain may lead to improved therapies that reduce HIV neurotoxicity. This study presents evidence that the expression of chemokine receptors in the brain is modulated by two neurotrophins in an area-specific manner. This new evidence suggests that the neurotrophins may be an adjunct therapy to reduce HIV-mediated neuronal injury evoked by chemokine receptor activation. C1 [Avdoshina, Valeriya; Campbell, Lee A.; Parsadanian, Maia; Mhyre, Timothy; Mocchetti, Italo] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. [Becker, Jody; Tessarollo, Lino] Natl Canc Inst, Ctr Canc Res, Mouse Canc Genet Program, Neural Dev Grp, Frederick, MD USA. RP Mocchetti, I (reprint author), Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. EM moccheti@georgetown.edu FU Public Health Service [DA026174, NS040670, T32 DA007291]; NIH, National Cancer Institute FX This work was supported by the Public Health Service grants DA026174, NS040670 (IM), and T32 DA007291 (LAC) and by the Intramural Research Program of the NIH, National Cancer Institute (JB and LT). NR 32 TC 6 Z9 6 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD FEB PY 2011 VL 17 IS 1 BP 58 EP 62 DI 10.1007/s13365-010-0004-3 PG 5 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 750XA UT WOS:000289580200007 PM 21165786 ER PT J AU Bailey, RL Gahche, JJ Lentino, CV Dwyer, JT Engel, JS Thomas, PR Betz, JM Sempos, CT Picciano, MF AF Bailey, Regan L. Gahche, Jaime J. Lentino, Cindy V. Dwyer, Johanna T. Engel, Jody S. Thomas, Paul R. Betz, Joseph M. Sempos, Christopher T. Picciano, Mary Frances TI Dietary Supplement Use in the United States, 2003-2006 SO JOURNAL OF NUTRITION LA English DT Article ID MULTIVITAMIN-MULTIMINERAL SUPPLEMENTS; INTERNATIONAL INTERFACE STANDARD; NUTRITION EXAMINATION SURVEY; NATIONAL-HEALTH; IRON-DEFICIENCY; FOOD DATABASES; CHILDREN; ADULTS AB Dietary supplement use has steadily increased over time since the 1970s; however, no current data exist for the U.S. population. Therefore, the purpose of this analysis was to estimate dietary supplement use using the NHANES 2003-2006, a nationally representative, cross-sectional survey. Dietary supplement use was analyzed for the U.S. population (>= 1y of age) by the DRI age groupings. Supplement use was measured through a questionnaire and was reported by 49% of the U.S. population (44% of males, 53% of females). Multivitamin-multimineral use was the most frequently reported dietary supplement (33%). The majority of people reported taking only 1 dietary supplement and did so on a daily basis. Dietary supplement use was lowest in obese adults and highest among non-Hispanic whites, older adults, and those with more than a high-school education. Between 28 and 30% reported using dietary supplements containing vitamins B-6, B-12, C, A, and E; 18-19% reported using iron, selenium, and chromium; and 26-27% reported using zinc- and magnesium-containing supplements. Botanical supplement use was more common in older than in younger age groups and was lowest in those aged 1-13 y but was reported by similar to 20% of adults. About one-half of the U.S. population and 70% of adults >= 71 y use dietary supplements; one-third use multivitamin-multimineral dietary supplements. Given the widespread use of supplements, data should be included with nutrient intakes from foods to correctly determine total nutrient exposure. J. Nutr. 141: 261-266,2011. C1 [Bailey, Regan L.; Lentino, Cindy V.; Dwyer, Johanna T.; Engel, Jody S.; Thomas, Paul R.; Betz, Joseph M.; Sempos, Christopher T.; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Gahche, Jaime J.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Bailey, RL (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 NR 24 TC 257 Z9 262 U1 9 U2 53 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2011 VL 141 IS 2 BP 261 EP 266 DI 10.3945/jn.110.133025 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 712XU UT WOS:000286700400015 PM 21178089 ER PT J AU Nicklett, EJ Szanton, S Sun, K Ferrucci, L Fried, LP Guralnik, JM Semba, RD AF Nicklett, Emily J. Szanton, Sarah Sun, Kai Ferrucci, Luigi Fried, Linda P. Guralnik, Jack M. Semba, Richard D. TI Neighborhood Socioeconomic Status Is Associated with Serum Carotenoid Concentrations in Older, Community-Dwelling Women SO JOURNAL OF NUTRITION LA English DT Article ID VEGETABLE INTAKE; URBAN NEIGHBORHOODS; PLASMA CAROTENOIDS; HEALTHY FOODS; FRUIT; AVAILABILITY; STORES; MORTALITY; DISPARITIES; ENVIRONMENT AB A high dietary intake of fruit and vegetables has been shown to be protective for health. Neighborhood socioeconomic differences may influence the consumption of carotenoid-rich foods, as indicated by serum carotenoid concentrations. To test this hypothesis, we examined the relationship between neighborhood socioeconomic status (SES) and serum carotenoid concentrations in a population-based sample of community-dwelling women, aged 70-79 y, who participated in the Women's Health and Aging Study II in Baltimore, Maryland. Neighborhood socioeconomic Z-scores were derived from characteristics of the census block of the participants. Serum carotenoid concentrations were measured at baseline and at 18, 36, 72, 98, and 108 mo follow-up visits. Neighborhood Z-scores were positively associated with serum alpha-carotene (P = 0.0006), beta-carotene (P=0.07), beta-cryptoxanthin (P=0.03), and lutein+zeaxanthin (P=0.004) after adjusting for age, race, BMI, smoking, inflammation, and season. There was no significant association between neighborhood Z-score and serum lycopene. Older, community-dwelling women from neighborhoods with lower SES have lower serum carotenoid concentrations, which reflect a lower consumption of carotenoid-rich fresh fruits and vegetables. J. Nutr. 141: 284-289, 2011. C1 [Nicklett, Emily J.; Sun, Kai; Semba, Richard D.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Szanton, Sarah] Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21205 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21225 USA. [Fried, Linda P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu RI Nicklett, Emily/A-4281-2012 FU National Institute on Aging [R01 AG027012, R01 AG029148]; National Institute on Aging, NIH FX Supported by National Institute on Aging grants R01 AG027012 and R01 AG029148 and the Intramural Research Program, National Institute on Aging, NIH. NR 43 TC 10 Z9 10 U1 2 U2 4 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2011 VL 141 IS 2 BP 284 EP 289 DI 10.3945/jn.110.129684 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 712XU UT WOS:000286700400018 PM 21178091 ER PT J AU Beydoun, MA Powell, LM Chen, XL Wang, YF AF Beydoun, May A. Powell, Lisa M. Chen, Xiaoli Wang, Youfa TI Food Prices Are Associated with Dietary Quality, Fast Food Consumption, and Body Mass Index among US Children and Adolescents SO JOURNAL OF NUTRITION LA English DT Article ID OBESITY EPIDEMIC; DRINK CONSUMPTION; WEIGHT-GAIN; HEALTH; FRUIT; STRATEGIES; PURCHASES; HEIGHT; TAXES; AGE AB Food prices are expected to affect dietary intakes, however, previous findings are mixed and few are based on nationally representative data. We examined the associations of price indices of fast foods (FF-PI) and fruits and vegetables (FV-PI) with dietary intakes and BMI among U.S. children and adolescents using data from the Continuing Survey of Food Intakes by Individuals (CSFII; 1994-1998) for 6759 children (2-9 y) and 1679 adolescents (10-18 y). FE-PI and FV-PI were linked to individuals, CSFII dietary data through city-level geocodes. Main outcomes included intakes of selected nutrients and food groups, a fast food consumption index (FF-CI), diet quality using the 2005 Healthy Eating Index (HE)), and BMI. Among children (2-9 y), a higher FF-PI (by $1) was associated with intakes of lower FF-CI (beta +/- SE: -0.9 +/- 0.3 count/d), higher HEI (6.6 +/- 2.5), higher intakes of fiber (2.7 +/- 0.7 g/d), calcium (225.7 +/- 52.3 mg/d), dairy (172.5 +/- 36.2 g/d), and fruits and vegetables (113.3 +/- 23.4 cup equivalents/d). FV-PI was inversely related to fiber intake (beta +/- SE: -3.3 +/- 1.5 g/d) and positively associated with BMI (4.3 +/- 1.2 kg/m(2)). Less consistent findings were ascribed to FV-PI and among adolescents (10-18 y). Significant associations were almost equally balanced between low and high family income groups, with some significant interactions between food prices and family income observed, particularly among children (2-9 y). Our findings suggest that among U.S. children aged 2-9 y, higher FE-PI is associated with better dietary quality, whereas higher FV-PI is linked to higher BMI and lower fiber intake. Associations varied by family income in children for many dietary intake variables. J. Nutr. 141: 304-311, 2011. C1 [Beydoun, May A.; Chen, Xiaoli; Wang, Youfa] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, Baltimore, MD 21205 USA. [Beydoun, May A.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Powell, Lisa M.] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL 60608 USA. RP Wang, YF (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Human Nutr, Dept Int Hlth, Baltimore, MD 21205 USA. EM ywang@jhsph.edu FU NIH/NIDDK [R01DK81335-01A1]; National Research Initiative of the USDA [2005-35215-15372]; National Institute on Aging FX Supported in part by research grants from the NIH/NIDDK (R01DK81335-01A1), the National Research Initiative of the USDA (grant no. 2005-35215-15372), and by the Intramural Research Program of the National Institute on Aging. NR 30 TC 23 Z9 24 U1 3 U2 11 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2011 VL 141 IS 2 BP 304 EP 311 DI 10.3945/jn.110.132613 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 712XU UT WOS:000286700400021 PM 21178080 ER PT J AU Caulfield, LE Zavaleta, N Chen, P Lazarte, F Albornoz, C Putnick, DL Bornstein, MH DiPietro, JA AF Caulfield, Laura E. Zavaleta, Nelly Chen, Ping Lazarte, Fabiola Albornoz, Carla Putnick, Diane L. Bornstein, Marc H. DiPietro, Janet A. TI Maternal Zinc Supplementation during Pregnancy Affects Autonomic Function of Peruvian Children Assessed at 54 Months of Age SO JOURNAL OF NUTRITION LA English DT Article ID HEART-RATE-VARIABILITY; FETAL NEUROBEHAVIORAL DEVELOPMENT; RESPIRATORY SINUS ARRHYTHMIA; RANDOMIZED CONTROLLED-TRIAL; CARDIAC VAGAL REGULATION; NERVOUS-SYSTEM; POLYVAGAL THEORY; PRENATAL IRON; ADDING ZINC; BEHAVIOR AB Maternal prenatal zinc supplementation improved fetal autonomic regulation in a nutrient-deficient population in Peru. To evaluate whether differences in autonomic regulation existed in early childhood, we studied 165 children from a zinc supplementation trial (80% of original sample) as part of a comprehensive evaluation at age 54 mo. Electrocardiogram (ECG) data were collected from the children at rest and while they underwent a cognitive testing battery following a standardized protocol. Of these, 79 were born to mothers receiving 25 mg/d zinc in addition to 60 mg/d iron and 250 mu g/d folic acid during pregnancy, and 86 were born to mothers receiving iron and folic acid only. Derived cardiac measures included heart period (HP), range, HP variability (HPV), mean square of successive differences (MSSD), and a measure of vagal tone (V). Children in the zinc supplementation group had greater HP (i.e. slower heart rate), greater range, higher time-independent (HPV) and time-dependent (MSSD) variability in HP, and higher V(P < 0.05) during baseline. Analyses conducted across the cognitive testing period revealed similar effects of prenatal zinc supplementation on cardiac patterns. Concurrent child zinc plasma concentration was also associated with longer HP, greater variability, and marginally higher range and V (P < 0.10). Differences in cardiac patterns due to prenatal zinc supplementation were detectable in children at 54 mo of age during conditions of both rest and challenge, indicating that supplementing zinc-deficient pregnant women has beneficial long-term consequences for neural development associated with autonomic regulation. J. Nutr. 141: 327-332, 2011. C1 [Caulfield, Laura E.; Chen, Ping] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. [DiPietro, Janet A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Heath, Baltimore, MD 21205 USA. [Putnick, Diane L.; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Zavaleta, Nelly; Lazarte, Fabiola; Albornoz, Carla] Inst Invest Nutr, Lima 12, Peru. RP Caulfield, LE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. EM lcaulfie@jhsph.edu OI Putnick, Diane/0000-0002-6323-749X FU NICHD [HD 042675]; NIH, National Institute of Child Health and Human Development; Nestle Research Foundation; USDA CSREES/NRI FX Supported by NICHD HD 042675. M.H.B. and D.L.P. are employed by NIH and their collaboration was supported by the Intramural Research Program of the NIH, National Institute of Child Health and Human Development. The original prenatal supplementation trial was funded by The Nestle Research Foundation and the USDA CSREES/NRI. Presented in part at Experimental Biology 10 in Anaheim, CA, April 24-28, 2010. NR 36 TC 8 Z9 8 U1 1 U2 2 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2011 VL 141 IS 2 BP 327 EP 332 DI 10.3945/jn.110.128843 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 712XU UT WOS:000286700400025 PM 21178078 ER PT J AU Davis, MF Kamel, F Hoppin, JA Alavanja, MCR Freeman, LB Gray, GC Nelson, K Silbergeld, E AF Davis, Meghan F. Kamel, Freya Hoppin, Jane A. Alavanja, Michael C. R. Freeman, Laura Beane Gray, Gregory C. Nelson, Kenrad Silbergeld, Ellen TI Neurologic Symptoms Associated With Raising Poultry and Swine Among Participants in the Agricultural Health Study SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID GUILLAIN-BARRE-SYNDROME; CAMPYLOBACTER-JEJUNI; PESTICIDE APPLICATORS; FEEDING OPERATION; PREVALENCE; INFECTION; ANTIBODIES; SPP.; PIGS; GASTROENTERITIS AB Objective: Guillain-Barre Syndrome (GBS) is the leading cause of acute peripheral neuropathy worldwide, often associated with recent foodborne infection with Campylobacter jejuni. In this cross-sectional analysis of data from the Agricultural Health Study, we tested whether swine and poultry exposure were associated with increased prevalence of GBS-like neurologic symptoms. Methods: Using multivariate analysis, we tested the symptoms such as numbness and weakness, relevant to inflammatory peripheral neuropathies, among farmers with self-reported occupational poultry or swine exposure compared with farmers who reported no occupational animal exposure. Results: Among swine farmers/workers, prevalence of weakness and numbness were increased (P < 0.05). Among poultry farmers/workers, prevalence of weakness and numbness were increased, but increased prevalence of weakness was not statistically significant. Conclusions: Occupational contact with live poultry or swine, potentially related to C. jejuni exposure, was associated with increased reporting of GBS-like symptoms. C1 [Davis, Meghan F.; Silbergeld, Ellen] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Nelson, Kenrad] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Kamel, Freya; Hoppin, Jane A.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Alavanja, Michael C. R.; Freeman, Laura Beane] NCI, Rockville, MD USA. [Gray, Gregory C.] Univ Florida, Dept Environm & Global Hlth, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA. RP Davis, MF (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, 615 N Wolfe St, Baltimore, MD 21205 USA. EM mdavis@jhsph.edu RI Davis, Meghan/C-1494-2013; Beane Freeman, Laura/C-4468-2015; OI Davis, Meghan/0000-0002-3475-4578; Beane Freeman, Laura/0000-0003-1294-4124; Kamel, Freya/0000-0001-5052-6615 FU National Institutes of Health; National Institute of Environmental Health Sciences [Z01-ES049030-11]; National Cancer Institute [Z01-CP010119]; Johns Hopkins Bloomberg School of Public Health FX The authors thank Dr Guy McKhann for his invaluable assistance. This work was supported in part by the intramural research program of the National Institutes of Health, the National Institute of Environmental Health Sciences (Z01-ES049030-11), and the National Cancer Institute (Z01-CP010119). Meghan Davis is supported by a Johns Hopkins Bloomberg School of Public Health Sommer scholarship. Each author declares that he or she has no actual or potential competing financial interest. NR 41 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD FEB PY 2011 VL 53 IS 2 BP 190 EP 195 DI 10.1097/JOM.0b013e31820805d5 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 718OF UT WOS:000287133100014 PM 21270654 ER PT J AU Karami, S Boffetta, P Brennan, P Stewart, PA Zaridze, D Matveev, V Janout, V Kollarova, H Bencko, V Navratilova, M Szeszenia-Dabrowska, N Mates, D Gromiec, JP Sobotka, R Chow, WH Rothman, N Moore, LE AF Karami, Sara Boffetta, Paolo Brennan, Paul Stewart, Patricia A. Zaridze, David Matveev, Vsevolod Janout, Vladimir Kollarova, Helena Bencko, Vladimir Navratilova, Marie Szeszenia-Dabrowska, Neonila Mates, Dana Gromiec, Jan P. Sobotka, Roman Chow, Wong-Ho Rothman, Nathaniel Moore, Lee E. TI Renal Cancer Risk and Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Plastics SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID SYNTHETIC RUBBER INDUSTRY; CELL CARCINOMA; KIDNEY CANCER; MORTALITY; WORKERS; STYRENE; EUROPE; ACRYLONITRILE; POLYMORPHISMS; MONTREAL AB Objective: To investigate whether occupational exposure to polycyclic aromatic hydrocarbons and certain plastic monomers increased renal cell carcinoma (RCC) risk. Methods: Unconditional logistic regression was used to calculate RCC risk in relation to exposure. Results: No association between RCC risk and having ever been occupationally exposed to any polycyclic aromatic hydrocarbons or plastics was observed. Duration of exposure and average exposure also showed no association with risk. Suggestive positive associations between RCC risk and cumulative exposure to styrene (P-trend = 0.02) and acrylonitrile (P-trend = 0.06) were found. Cumulative exposure to petroleum/gasoline engine emissions was inversely associated with risk (P-trend = 0.02). Conclusions: Results indicate a possible association between occupational styrene and acrylonitrile exposure and RCC risk. Additional studies are needed to replicate findings, as this is the first time these associations have been reported and they may be due to chance. C1 [Boffetta, Paolo; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Karami, Sara; Stewart, Patricia A.; Chow, Wong-Ho; Rothman, Nathaniel; Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Matveev, Vsevolod] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Janout, Vladimir; Kollarova, Helena] Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Navratilova, Marie] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Mates, Dana] Natl Inst Publ Hlth, Bucharest, Romania. [Gromiec, Jan P.] Nofer Inst Occupat Med, Dept Chem Hazards, Lodz, Poland. [Sobotka, Roman] Charles Univ Prague, Dept Urol, Prague, Czech Republic. [Sobotka, Roman] Gen Teaching Hosp, Prague, Czech Republic. RP Karami, S (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,DHHS, 6120 Execut Blvd,EPS 8121, Rockville, MD 20852 USA. EM karamis@mail.nih.gov RI Szeszenia-Dabrowska, Neonila/F-7190-2010; Zaridze, David/K-5605-2013; Sobotka, Roman/J-3077-2014; Janout, Vladimir/M-5133-2014; OI mates, dana/0000-0002-6219-9807 FU National Institutes of Health FX This study was funded by National Institutes of Health. NR 36 TC 14 Z9 15 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD FEB PY 2011 VL 53 IS 2 BP 218 EP 223 DI 10.1097/JOM.0b013e31820a40a3 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 718OF UT WOS:000287133100018 PM 21270648 ER PT J AU Johnson, TV Gupta, PK Vudathala, DK Blair, IA Tanna, AP AF Johnson, Thomas V. Gupta, Preeya K. Vudathala, Daljit K. Blair, Ian A. Tanna, Angelo P. TI Thermal Stability of Bimatoprost, Latanoprost, and Travoprost Under Simulated Daily Use SO JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID OPEN-ANGLE GLAUCOMA; INTRAOCULAR-PRESSURE REDUCTION; NORMAL-TENSION GLAUCOMA; AQUEOUS-HUMOR DYNAMICS; OCULAR HYPERTENSION; OPHTHALMIC SOLUTION; PATIENT ADHERENCE; HUMAN EYES; MECHANISM; 0.005-PERCENT AB Purpose: To determine the stability of bimatoprost, latanoprost, and travoprost under conditions of simulated daily use and varying degrees of thermal stress. Methods: Commercially available bimatoprost, latanoprost, and travoprost were obtained in their original bottles as distributed by the manufacturers. Bottles were stored in calibrated, nonhumidified, light-free incubators maintained at 27 degrees C, 37 degrees C, or 50 degrees C for 3, 9, 15, or 30 days. Capped bottles were inverted and left uncapped for 1 min daily to simulate patient use; no drops were expelled. Bimatoprost concentration was analyzed using liquid chromatography with ultraviolet detection at 210 nm. Latanoprost and travoprost concentrations were analyzed by liquid chromatography/tandem mass spectrometry (MS/MS) using selected reaction monitoring. Results: Off-the-shelf control bottles of bimatoprost contained 102% of the labeled concentration. In all combinations of stress temperature and duration, mean bimatoprost concentration ranged from 100% to 116% of the labeled concentration with no measurable degradation. Off-the-shelf control bottles of latanoprost contained 115% of the labeled concentration. Mean latanoprost concentration ranged from 97% to 120% of the labeled concentration. Latanoprost was stable at 27 degrees C. When stressed at 37 degrees C or 50 degrees C, latanoprost degraded at a rate of 0.15 or 0.29 mu g/mL/day, respectively. Off-the-shelf control bottles of travoprost contained 120% of the labeled concentration. Mean travoprost concentration ranged from 83% to 142% of the labeled concentration. Travoprost was stable at 27 degrees C and 37 degrees C, although concentration measurements at 37 degrees C exhibited high variability. When stressed at 50 degrees C, travoprost degraded at a rate of 0.46 mu g/mL/day. Conclusions: Higher than expected concentrations for stressed drug samples are likely a result of evaporation. Under the conditions of thermal stress tested in this study, bimatoprost remained stable for all conditions tested. Latanoprost degradation was measurable only in samples stressed at 37 degrees C and 50 degrees C, whereas travoprost degradation was statistically significant only in samples stressed at 50 degrees C. C1 [Tanna, Angelo P.] Northwestern Univ, Feinberg Sch Med, Dept Ophthalmol, Chicago, IL 60611 USA. [Johnson, Thomas V.] Univ Cambridge, Ctr Brain Repair, Cambridge, England. [Johnson, Thomas V.] Univ Cambridge, Dept Ophthalmol, Cambridge, England. [Johnson, Thomas V.] NEI, Mol Mech Glaucoma Sect, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Gupta, Preeya K.] Duke Univ, Ctr Eye, Dept Ophthalmol, Durham, NC 27710 USA. [Vudathala, Daljit K.; Blair, Ian A.] Univ Penn, Dept Pharmacol, Ctr Excellence Environm Toxicol, Philadelphia, PA 19104 USA. [Vudathala, Daljit K.; Blair, Ian A.] Univ Penn, Dept Pharmacol, Ctr Canc Pharmacol, Philadelphia, PA 19104 USA. [Vudathala, Daljit K.] Univ Penn, Sch Vet Med, Dept Pathobiol, Kennett Sq, PA 19348 USA. RP Tanna, AP (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Ophthalmol, 645 N Michigan Ave,Suite 440, Chicago, IL 60611 USA. EM atanna@northwestern.edu RI Johnson, Thomas/C-9351-2011 OI Johnson, Thomas/0000-0002-5372-5457 FU National Institutes of Health [R01CA091016, P30ES013508]; Gates-Cambridge Trust; Pennsylvania Animal Diagnostic Laboratory System; Northwestern University Feinberg School of Medicine Department of Ophthalmology; Alcon; Allergan; Pfizer FX T.V.J. was supported by a National Institutes of Health OxCam Scholarship, the Gates-Cambridge Trust. I. A. B. was supported by NIH Grants R01CA091016 and P30ES013508. D. K. V. was supported by Pennsylvania Animal Diagnostic Laboratory System. A. P. T. was supported by an unrestricted grant from Research to Prevent Blindness to the Northwestern University Feinberg School of Medicine Department of Ophthalmology. The authors are grateful to S. R. Grossman for helpful advice with the statistical analyses.; Angelo P. Tanna: Alcon, Allergan, and Apotex (consultant); Alcon, Allergan, and Pfizer (educational grant support). The other authors report no conflicts of interest with any material presented in this article. NR 37 TC 5 Z9 5 U1 1 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1080-7683 J9 J OCUL PHARMACOL TH JI J. Ocular Pharmacol. Ther. PD FEB PY 2011 VL 27 IS 1 BP 51 EP 59 DI 10.1089/jop.2010.0115 PG 9 WC Ophthalmology; Pharmacology & Pharmacy SC Ophthalmology; Pharmacology & Pharmacy GA 723BU UT WOS:000287482000008 PM 21117945 ER PT J AU Meert, KL Shear, K Newth, CJL Harrison, R Berger, J Zimmerman, J Anand, KJS Carcillo, J Donaldson, AE Dean, JM Willson, DF Nicholson, C AF Meert, Kathleen L. Shear, Katherine Newth, Christopher J. L. Harrison, Rick Berger, John Zimmerman, Jerry Anand, K. J. S. Carcillo, Joseph Donaldson, Amy E. Dean, J. Michael Willson, Douglas F. Nicholson, Carol CA Eunice Kennedy Shriver Natl Inst C TI Follow-Up Study of Complicated Grief among Parents Eighteen Months after a Child's Death in the Pediatric Intensive Care Unit SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID BEREAVEMENT; DISORDER; ATTACHMENT; DISTRESS; RISK AB Objective: We previously demonstrated that parents whose children die in a pediatric intensive care unit (PICU) have a high level of complicated grief symptoms 6 months after the death. In this study, we investigate the change in the extent of complicated grief symptoms among these parents between 6 and 18 months postdeath and identify factors predicting improvement. Methods: One hundred thirty-eight parents of 106 children completed surveys at 6 and 18 months. Surveys included the Inventory of Complicated Grief (ICG), measures of grief avoidance, attachment, caregiving and social support, and demographics. Multivariable analysis was performed using generalized estimating equations to identify characteristics independently associated with improvement in ICG score. Results: ICG scores were 33.4 +/- 13.6 at 6 months and 28.0 +/- 13.5 at 18 months, representing an improvement in ICG score of 5.4 + 8.0 (95% confidence interval [CI] 4.1-6.8, p < 0.001). Variables independently associated with greater improvement in ICG score included traumatic death and greater grief avoidance. Variables independently associated with less improvement included being the biological parent and having more responsive caregiving. Parents with one or two surviving children had more improvement in ICG score than those with no surviving children whereas parents with three or more surviving children had less improvement. Conclusion: Complicated grief symptoms decrease among parents between 6 and 18 months after their child's death in the PICU; however, high symptom levels persists for some. Better understanding of the trajectory of complicated grief will allow parents at risk for persistent distress to receive professional support. C1 [Meert, Kathleen L.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Shear, Katherine] Columbia Univ, New York, NY USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Harrison, Rick] Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA USA. [Berger, John] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Zimmerman, Jerry] Seattle Childrens Hosp, Seattle, WA USA. [Anand, K. J. S.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Donaldson, Amy E.; Dean, J. Michael] Univ Utah, Salt Lake City, UT USA. [Willson, Douglas F.] Univ Virginia, Childrens Hosp, Charlottesville, VA USA. [Nicholson, Carol] NICHHD, Bethesda, MD 20892 USA. RP Meert, KL (reprint author), Childrens Hosp Michigan, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM kmeert@med.wayne.edu OI Anand, Kanwaljeet/0000-0001-6498-1483 FU National Institute of Child Health and Human Development; Department of Health and Human Services [U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, U01HD049934] FX The study was funded by cooperative agreements from the National Institute of Child Health and Human Development and the Department of Health and Human Services (U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012 and U01HD049934). The authors have no other financial relationships to disclose in relation to this manuscript. NR 32 TC 28 Z9 29 U1 0 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD FEB PY 2011 VL 14 IS 2 BP 207 EP 214 DI 10.1089/jpm.2010.0291 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 719UM UT WOS:000287236200017 PM 21281122 ER PT J AU Thoma, ME Gray, RH Kiwanuka, N Aluma, S Wang, MC Sewankambo, N Wawer, MJ AF Thoma, Marie E. Gray, Ronald H. Kiwanuka, Noah Aluma, Simon Wang, Mei-Cheng Sewankambo, Nelson Wawer, Maria J. TI Longitudinal Changes in Vaginal Microbiota Composition Assessed by Gram Stain Among Never Sexually Active Pre- and Postmenarcheal Adolescents in Rakai, Uganda SO JOURNAL OF PEDIATRIC AND ADOLESCENT GYNECOLOGY LA English DT Article DE Vaginal microbiota; pH; Menarche; Lactobacilli; Bacterial vaginosis; Gram stain; Nugent score ID GENITOURINARY MEDICINE CLINICS; BACTERIAL VAGINOSIS; HUMAN-PAPILLOMAVIRUS; WOMEN; LACTOBACILLI; ACQUISITION; FLORA; RISK; ASSOCIATION; INFECTIONS AB Study Objective: To describe changes in vaginal microbiota and pH over time among never sexually active adolescents at different menarcheal stages. Design: A cohort of 49 sexually inexperienced Ugandan adolescents provided weekly self-collected vaginal swabs and behavioral/health information for up to two years. Menarcheal stage was classified as: not experiencing menarche during follow-up (premenarcheal, n = 9), achieving menarche during follow-up (perimenarcheal, n = 20), and being postmenarcheal (n = 20) at enrollment. Vaginal microbiota were characterized as morphotypes of large gram-positive rods, small gram-negative or variable rods, and curved gram-negative rods based on Nugent Gram-stain criteria. Baseline measures were compared using nonparametric tests. Mean changes ( [3) in morphotypes and pH over time were estimated using longitudinal mixed-effects models. Results: The baseline median (IQR: interquartile range) Nugent score was 8 (7-8) in premenarcheal, 4.5 (1-8) in perimenarcheal, and 1 (0-3) in postmenarcheal girls (P = 0.001). For each respective menarcheal stage, the median (IQR) counts of gram-positive rods were 0 (0-0), 10 (0-30), and 30 (18-30) (P = 0.002) and gram-negative or variable rods were 30 (30-30), 16 (0.5-30), and 0.5 (0-2.5) (P = 0.002) at enrollment. Counts of gram-positive rods increased (beta = 0.259, 95% CI: 0.156, 0.362) and gram-negative or variable rods decreased (beta = -0.201, 95% CI:-0.298,-0.103) significantly over time in premenarcheal girls, but not in other groups. Vaginal pH declined significantly in peri- and postmenarcheal girls only. Conclusion: Vaginal microbiota composition varied by menarcheal stage at enrollment. Over time, significant changes in vaginal morphotypes occurred in premenarcheal girls, suggesting this may be an important period of transition. C1 [Thoma, Marie E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Gray, Ronald H.; Wang, Mei-Cheng; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kiwanuka, Noah] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Kiwanuka, Noah] Makerere Univ, Rakai Hlth Sci Program, Kampala, Uganda. [Aluma, Simon] Rakai Hlth Sci Program, Kalisizo, Uganda. [Sewankambo, Nelson] Makerere Univ, Coll Hlth Sci, Kampala, Uganda. RP Thoma, ME (reprint author), NICHD, DESPR, NIH, 6100 Execut Blvd,Room 7813E, Bethesda, MD 20892 USA. EM thomame@mail.nih.gov OI Sewankambo, Nelson/0000-0001-9362-053X FU National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [R01AI47608]; NIH, National Institute for Allergy and Infectious Diseases (NIAID) [T32AI050056]; Eunice Kennedy Shriver NICHD; Center for Disease Control and Prevention (CDC) [R36PS001104] FX This work was supported in part by the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH grant R01AI47608 (to M.J.W.); the NIH, National Institute for Allergy and Infectious Diseases (NIAID), NIH grant T32AI050056 (to J.M.Z.), the Intramural Program of the Eunice Kennedy Shriver NICHD (to M.E.T.), and the Cooperative Agreement number R36PS001104 (to M.E.T.) from the Center for Disease Control and Prevention (CDC). Its contents are solely the responsibility of the authors and do not represent the official views of the CDC. NR 23 TC 12 Z9 12 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-3188 J9 J PEDIATR ADOL GYNEC JI J. Pediatr Adolesc. Gynecol. PD FEB PY 2011 VL 24 IS 1 BP 42 EP 47 DI 10.1016/j.jpag.2010.07.002 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 716HZ UT WOS:000286961000010 PM 20709584 ER PT J AU Maciag, AE Chakrapani, H Saavedra, JE Morris, NL Holland, RJ Kosak, KM Shami, PJ Anderson, LM Keefer, LK AF Maciag, Anna E. Chakrapani, Harinath Saavedra, Joseph E. Morris, Nicole L. Holland, Ryan J. Kosak, Ken M. Shami, Paul J. Anderson, Lucy M. Keefer, Larry K. TI The Nitric Oxide Prodrug JS-K Is Effective against Non-Small-Cell Lung Cancer Cells In Vitro and In Vivo: Involvement of Reactive Oxygen Species SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MANGANESE-SUPEROXIDE-DISMUTASE; DNA-DAMAGE; APOPTOSIS; PEROXYNITRITE; INHIBITION; ADENOCARCINOMA; INACTIVATION; MITOCHONDRIA; SENSITIVITY; NITRATION AB Non-small-cell lung cancer is among the most common and deadly forms of human malignancies. Early detection is unusual, and there are no curative therapies in most cases. Diazeniumdiolate- based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Here, we show that O-2-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin- 1-yl]diazen-1-ium-1,2-diolate (JS-K) is a potent cytotoxic agent against a subset of human non-small-cell lung cancer cell lines both in vitro and as xenografts in mice. JS-K treatment led to 75% reduction in the growth of H1703 lung adenocarcinoma cells in vivo. Differences in sensitivity to JS-K in different lung cancer cell lines seem to be related to their endogenous levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS). Other related factors, levels of peroxiredoxin 1 (PRX1) and 8-oxo-deoxyguanosine glycosylase (OGG1), also correlated with drug sensitivity. Treatment of the lung adenocarcinoma cells with JS-K resulted in oxidative/nitrosative stress in cells with high basal levels of ROS/RNS, which, combined with the arylating properties of the compound, was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization, and cytochrome c release. Inactivation of manganese superoxide dismutase by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. Taken together, the data suggest that diazeniumdiolate-based NO-releasing prodrugs may have application as a personalized therapy for lung cancers characterized by high levels of ROS/RNS. PRX1 and OGG1 proteins, which can be easily measured, could function as biomarkers for identifying tumors sensitive to the therapy. C1 [Maciag, Anna E.; Saavedra, Joseph E.] NCI, SAIC Frederick Inc, Basic Sci Program, Frederick, MD 21702 USA. [Morris, Nicole L.] NCI, SAIC Frederick Inc, Lab Anim Sci Program, Frederick, MD 21702 USA. [Chakrapani, Harinath; Holland, Ryan J.; Anderson, Lucy M.; Keefer, Larry K.] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Kosak, Ken M.; Shami, Paul J.] Univ Utah, Div Med Oncol, Huntsman Canc Inst, Salt Lake City, UT USA. RP Maciag, AE (reprint author), NCI, SAIC Frederick Inc, Basic Sci Program, Bldg 538,Rm 206, Frederick, MD 21702 USA. EM maciaga@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institutes of Health National Cancer Institute [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the National Institutes of Health National Cancer Institute [Contract HHSN261200800001E]. NR 40 TC 38 Z9 40 U1 1 U2 9 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2011 VL 336 IS 2 BP 313 EP 320 DI 10.1124/jpet.110.174904 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 707TA UT WOS:000286309800003 PM 20962031 ER PT J AU Chen, C Wei, X Rao, XQ Wu, J Yang, SL Chen, FQ Ma, D Zhou, JF Dackor, RT Zeldin, DC Wang, DW AF Chen, Chen Wei, Xin Rao, Xiaoquan Wu, Jun Yang, Shenglan Chen, Fuqiong Ma, Ding Zhou, Jianfeng Dackor, Ryan T. Zeldin, Darryl C. Wang, Dao Wen TI Cytochrome P450 2J2 Is Highly Expressed in Hematologic Malignant Diseases and Promotes Tumor Cell Growth SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; EPOXYGENASE-DERIVED EICOSANOIDS; ARACHIDONIC-ACID METABOLISM; SIGNALING PATHWAYS; EPOXYEICOSATRIENOIC ACIDS; FUNCTIONAL-SIGNIFICANCE; MOLECULAR-CLONING; EMERGING ROLE; IN-VIVO; KINASE AB Cytochrome P450 2J2 (CYP2J2) epoxygenase converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs) that exert multiple biological effects in the cardiovascular system and in various human solid cancers. However, it is unknown whether this enzyme is expressed or plays any role in malignant hematological diseases. In this study, we found strong and highly selective CYP2J2 expression in five human-derived malignant hematological cell lines and in leukemia cells from peripheral blood and bone marrow in 36 of 42 patients (86%) with malignant hematologic diseases. Furthermore, increased levels of EETs were detected in urine and blood samples from these patients. Addition of exogenous EET or CYP2J2 overexpression in cultured human-derived malignant hematologic cell lines markedly accelerated proliferation and attenuated apoptosis. Addition of the selective CYP2J2 inhibitor compound 26 (C26; 1-[4-(vinyl) phenyl]-4-[4-(diphenyl-hydroxymethyl)-piperidinyl]-butanone hydrochloride) inhibited cell proliferation and increased apoptosis, an effect that was significantly reversed by EET. CYP2J2 overexpression and exogenous EET activated AMP-activated protein kinase, c-Jun NH(2)-terminal kinase, and phosphatidylinositol 3-kinase/Akt signaling pathways, and increased epidermal growth factor receptor phosphorylation levels. CYP2J2 overexpression also enhanced malignant xenograft growth, which was efficiently inhibited by oral administration of C26 in Tie2-CYP2J2 transgenic mice and in severe combined immunodeficiency (SCID) xenograft mice. Together, these results suggest that CYP2J2 plays a key role in the pathogenesis of human hematologic malignant diseases. Selective inhibition of CYP2J2 may be a promising therapeutic strategy for these conditions. C1 [Chen, Chen; Wei, Xin; Rao, Xiaoquan; Wu, Jun; Yang, Shenglan; Chen, Fuqiong; Ma, Ding; Zhou, Jianfeng; Wang, Dao Wen] Huazhong Univ Sci & Technol, Dept Internal Med, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Peoples R China. [Chen, Chen; Wei, Xin; Rao, Xiaoquan; Wu, Jun; Yang, Shenglan; Chen, Fuqiong; Ma, Ding; Zhou, Jianfeng; Wang, Dao Wen] Huazhong Univ Sci & Technol, Gene Therapy Ctr, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Peoples R China. [Dackor, Ryan T.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Dept Internal Med, Tongji Hosp, Tongji Med Coll, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn FU China Natural Science Foundation Committee [30540087, 30430320]; 973 Program [2007CB512004, 2002CB513107]; International Project; National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES025034] FX This work was supported by the China Natural Science Foundation Committee [Grants 30540087, 30430320]; the 973 Program [Grants 2007CB512004, 2002CB513107]; and the International Project. This work was also supported, in part, by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Grant Z01-ES025034]. NR 39 TC 32 Z9 33 U1 2 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2011 VL 336 IS 2 BP 344 EP 355 DI 10.1124/jpet.110.174805 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 707TA UT WOS:000286309800007 PM 21030485 ER PT J AU Toll, L Jimenez, L Waleh, N Jozwiak, K Woo, AYH Xiao, RP Bernier, M Wainer, IW AF Toll, L. Jimenez, L. Waleh, N. Jozwiak, K. Woo, A. Y-H. Xiao, R-P. Bernier, M. Wainer, I. W. TI beta(2)-Adrenergic Receptor Agonists Inhibit the Proliferation of 1321N1 Astrocytoma Cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID BETA-ADRENERGIC-RECEPTORS; ACTIVATED PROTEIN-KINASE; MOLECULAR-FIELD ANALYSIS; HIGH-AFFINITY BINDING; CYCLIC-AMP; FENOTEROL DERIVATIVES; INTACT-CELLS; CANCER CELLS; TUMOR-GROWTH; CAMP AB Astrocytomas and glioblastomas have been particularly difficult to treat and refractory to chemotherapy. However, significant evidence has been presented that demonstrates a decrease in astrocytoma cell proliferation subsequent to an increase in cAMP levels. The 1321N1 astrocytoma cell line, as well as other astrocytomas and glioblastomas, expresses beta(2)-adrenergic receptors (beta(2)-ARs) that are coupled to G(s) activation and consequent cAMP production. Experiments were conducted to determine whether the beta(2)-AR agonist (R, R')-fenoterol and other beta(2)-AR agonists could attenuate mitogenesis and, if so, by what mechanism. Receptor binding studies were conducted to characterize beta(2)-AR found in 1321N1 and U118 cell membranes. In addition, cells were incubated with (R, R')-fenoterol and analogs to determine their ability to stimulate intracellular cAMP accumulation and inhibit [H-3] thymidine incorporation into the cells. 1321N1 cells contain significant levels of beta(2)-AR as determined by receptor binding. (R, R')-fenoterol and other beta(2)-AR agonists, as well as forskolin, stimulated cAMP accumulation in a dose-dependent manner. Accumulation of cAMP induced a decrease in [H-3] thymidine incorporation. There was a correlation between concentration required to stimulate cAMP accumulation and inhibit [H-3] thymidine incorporation. U118 cells have a reduced number of beta(2)-ARs and a concomitant reduction in the ability of beta(2)-AR agonists to inhibit cell proliferation. These studies demonstrate the efficacy of beta(2)-AR agonists for inhibition of growth of the astrocytoma cell lines. Because a significant portion of brain tumors contain beta(2)-ARs to a greater extent than whole brain, (R, R')-fenoterol, or some analog, may be useful in the treatment of brain tumors after biopsy to determine beta(2)-AR expression. C1 [Wainer, I. W.] NIA, Clin Invest Lab, Biomed Res Ctr, NIH,Intramural Res Program, Baltimore, MD 21224 USA. [Woo, A. Y-H.; Xiao, R-P.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Toll, L.; Jimenez, L.; Waleh, N.] SRI Int, Menlo Pk, CA 94025 USA. [Jozwiak, K.] Med Univ Lublin, Dept Chem, Lublin, Poland. RP Wainer, IW (reprint author), NIA, Clin Invest Lab, Biomed Res Ctr, NIH,Intramural Res Program, 8B133,251 Bayview Blvd, Baltimore, MD 21224 USA. EM wainerir@grc.nia.nih.gov RI Woo, Anthony/D-4305-2014; OI Woo, Anthony/0000-0003-0662-698X; Bernier, Michel/0000-0002-5948-368X FU National Institutes on Aging [N01AG-3-1009]; Foundation for Polish Science FOCUS [4/2006]; National Institute on Aging FX This work was supported in part by funds from the National Institute on Aging Intramural Research Program, the National Institutes on Aging [Contract N01AG-3-1009], and the Foundation for Polish Science FOCUS 4/2006 Programme. NR 39 TC 18 Z9 18 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2011 VL 336 IS 2 BP 524 EP 532 DI 10.1124/jpet.110.173971 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 707TA UT WOS:000286309800026 PM 21071556 ER PT J AU Li, SM Kopajtic, TA O'Callaghan, MJ Agoston, GE Cao, JJ Newman, AH Katz, JL AF Li, Su-Min Kopajtic, Theresa A. O'Callaghan, Matthew J. Agoston, Gregory E. Cao, Jianjing Newman, Amy Hauck Katz, Jonathan L. TI N-Substituted Benztropine Analogs: Selective Dopamine Transporter Ligands with a Fast Onset of Action and Minimal Cocaine-Like Behavioral Effects SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MOLECULAR-FIELD ANALYSIS; UPTAKE INHIBITORS; 3-ALPHA-DIPHENYLMETHOXYTROPANE ANALOGS; POPULATION PHARMACOKINETICS; LOCOMOTOR-ACTIVITY; BRAIN DISTRIBUTION; IN-VITRO; RATS; RECEPTOR; BINDING AB Previous studies suggested that differences between the behavioral effects of cocaine and analogs of benztropine were related to the relatively slow onset of action of the latter compounds. Several N-substituted benztropine analogs with a relatively fast onset of effects were studied to assess whether a fast onset of effects would render the effects more similar to those of cocaine. Only one of the compounds increased locomotor activity, and the increases were modest compared with those of 10 to 20 mg/kg cocaine. In rats trained to discriminate 10 mg/kg cocaine from saline none of the compounds produced more than 40% cocaine-like responds up to 2 h after injection. None of the compounds produced place-conditioning when examined up to 90 min after injection, indicating minimal abuse liability. The compounds had 5.6 to 30 nM affinities at the dopamine transporter (DAT), with uniformly lower affinities at norepinephrine and serotonin transporters (from 490-4600 and 1420-7350 nM, respectively). Affinities at muscarinic M(1) receptors were from 100-to 300-fold lower than DAT affinities, suggesting minimal contribution of those sites to the behavioral effects of the compounds. Affinities at histaminic H(1) sites were from 11- to 43-fold lower than those for the DAT. The compounds also had affinity for sigma, 5-hydroxytryptamine(1) (5-HT(1)), and 5-HT(2) receptors that may have contributed to their behavioral effects. Together, the results indicate that a slow onset of action is not a necessary condition for reduced cocaine-like effects of atypical DAT ligands and suggest several mechanisms that may contribute to the reduced cocaine-like efficacy of these compounds. C1 [Li, Su-Min; Kopajtic, Theresa A.; O'Callaghan, Matthew J.; Katz, Jonathan L.] Natl Inst Drug Abuse, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Agoston, Gregory E.; Cao, Jianjing; Newman, Amy Hauck] Natl Inst Drug Abuse, Med Chem Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), Natl Inst Drug Abuse, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH, 250 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 FU National Institutes of Health, National Institute on Drug Abuse FX This work was supported by the National Institutes of Health, National Institute on Drug Abuse Intramural Research Program. NR 38 TC 18 Z9 19 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2011 VL 336 IS 2 BP 575 EP 585 DI 10.1124/jpet.110.173260 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 707TA UT WOS:000286309800031 PM 21088247 ER PT J AU Litt, DM Iannotti, RJ Wang, J AF Litt, Dana M. Iannotti, Ronald J. Wang, Jing TI Motivations for Adolescent Physical Activity SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE measurement; exercise; children ID EXTRINSIC MOTIVATION; SPORT PARTICIPATION; SEDENTARY BEHAVIOR; COLLEGE-STUDENTS; FIT INDEXES; EXERCISE; TRACKING; MODELS; READINESS; CHILDHOOD AB Background: Motivating adolescents to maintain levels of physical activity (PA) is important because regular PA in adolescence contributes to physical, psychological, and social well-being and PA during adolescence has been associated with activity levels in adulthood. Purpose: The overall aim of this study is to validate a measure of external reward, health values, and personal interest motivations for adolescent PA developed by Wold and Kannas and to examine the relationship between these motivations and level of PA. Methods: A nationally representative sample of 9011 adolescents completed the Health Behavior in School-aged Children survey instrument. Ten items were used to measure PA motivations. Multiple group confirmatory factor analysis and structural equation modeling were applied to test the 3-factor structure of the motivation scale and to examine the relationship between the 3 motivations and PA. Results: The Wold and Kannas's motivation measure assessed external, social, and health motivations which predicted PA in adolescents. Conclusions: The Wold and Kannas's motivation measure is suitable for assessing motivations for PA in US adolescents and may contribute to both theoretical and intervention studies that address this public health need. C1 [Litt, Dana M.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Iannotti, Ronald J.; Wang, Jing] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Rockville, MD USA. RP Litt, DM (reprint author), George Washington Univ, Dept Psychol, Washington, DC 20052 USA. FU Intramural NIH HHS NR 38 TC 4 Z9 5 U1 3 U2 33 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD FEB PY 2011 VL 8 IS 2 BP 220 EP 226 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 719SI UT WOS:000287228900010 PM 21415449 ER PT J AU Cea-del Rio, CA Lawrence, JJ Erdelyi, F Szabo, G McBain, CJ AF Cea-del Rio, Christian A. Lawrence, J. Josh Erdelyi, Ferenc Szabo, Gabor McBain, Chris J. TI Cholinergic modulation amplifies the intrinsic oscillatory properties of CA1 hippocampal cholecystokinin-positive interneurons SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID MEMBRANE-POTENTIAL OSCILLATIONS; STRATUM LACUNOSUM-MOLECULARE; NEURONS IN-VITRO; GABA RELEASE; PYRAMIDAL CELLS; RAT HIPPOCAMPUS; POTASSIUM CONDUCTANCES; CORTICAL INTERNEURONS; RECEPTOR ACTIVATION; GABAERGIC NEURONS AB Non-technical summary In the mammalian hippocampus, the neurotransmitter acetylcholine (ACh) promotes learning and memory storage. During sensory processing and learning, large ACh-dependent electrical oscillatory events are observed, which involve the synchronization of both inhibitory and excitatory neural circuits. While the actions of ACh are known on excitatory hippocampal circuits, its actions on specific inhibitory circuits are poorly understood. We show that two types of cholecystokinin-positive local circuit inhibitory interneuron, the so-called 'basket cells' and 'Schaffer collateral-associated' cells, which innervate separately the cell body and dendritic regions of principal cells, are modulated similarly by cholinergic receptor activation. In both cell types activation of their muscarinic receptors triggers a general increase of excitability and intrinsic oscillatory activity, and a more efficient engagement to slow network oscillations. Knowledge of how cholinergic neuromodulation acts on neurochemically identical but morphologically distinct inhibitory interneurons will allow us to understand the role played by this important neuromodulator during hippocampal-dependent tasks in vivo.Cholecystokinin (CCK)-containing interneuron subpopulations provide GABAergic inhibition to multiple surface domains of CA1 hippocampal pyramidal cells. CCK-basket cells (BCs) control AP initiation through perisomatic inhibition, whereas dendritically projecting Schaffer collateral-associated (SCAs) cells probably shape dendritic excitability and synaptic integration. We have shown previously that muscarinic receptor (mAChR) activation regulates firing properties and excitability of CCK-BCs; however, little is known about mAChR modulation of the related but anatomically distinct CCK-SCA population. Here, using whole-cell recordings and single-cell RT-PCR, we show that muscarine elicited a biphasic hyperpolarizing-depolarizing voltage response in CCK-SCAs, which was mediated by opposing actions of M1 and M3 mAChRs, respectively. In addition, like CCK-BCs, CCK-SCAs exhibited an M3-mediated increase in AP firing frequency and an afterdepolarization mediated synergistically by both M1 and M3 mAChRs. Spontaneous M3-mediated membrane potential oscillations (1-2 Hz) were observed in both CCK-SCAs and CCK-BCs. Using sinusoidal current injection we examined how mAChR activation of CCK interneurons alters intrinsic oscillatory properties and AP frequency preference. In CCK-BCs and CCK-SCAs, APs occurred preferentially at delta/theta frequencies (1-7 Hz) under control conditions. mAChR activation extended the AP phase-locking bandwidth into the theta and beta frequency range for CCK-SCAs and CCK-BCs respectively. This was accompanied by changes in both AP phase and precision. In conclusion, anatomically distinct CCK+ cells show similar changes in excitability, firing pattern activity and oscillatory preferences during cholinergic modulation suggesting that CCK+ interneurons probably act cooperatively to collectively synchronize the hippocampal network along the somatodendritic axis of the CA1 pyramidal cells during muscarinic receptor activation. C1 [Cea-del Rio, Christian A.; Lawrence, J. Josh; McBain, Chris J.] NICHHD, Program Dev Neurobiol, Bethesda, MD 20892 USA. [Lawrence, J. Josh] Univ Montana, Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, Missoula, MT 59801 USA. [Erdelyi, Ferenc; Szabo, Gabor] Hungarian Acad Sci, Inst Expt Med, Lab Mol Biol & Genet, Budapest, Hungary. RP McBain, CJ (reprint author), Porter Neurosci Ctr, Bldg 35,Rm 3C903,35 Lincoln Dr, Bethesda, MD 20892 USA. EM mcbainc@mail.nih.gov RI Szabo, Gabor/A-5087-2008 OI Szabo, Gabor/0000-0001-5438-5151 FU NICHD FX NICHD intramural funding (C.J.McB.) supported this work. We are grateful to Drs Bruno Cauli for primers, Jurgen Wess for all muscarinic acetylcholine receptor knockout mice, Ludovic Tricoire for the training in the scRT-PCR technique, Jordan Pauli and David Bonislawski for the processing and imaging acquisition of the GAD65-GFP/Neurotrace and GAD65-GFP/vAChT slice picture in Supplemental Fig S3, and Vincent Schram and the NICHD Microscopy and Imaging Core for assisting in the acquisition of tiled 3D confocal images of biocytin-labelled cells. C.A.C.-dR. was a doctoral student from the graduate program partnership between NIH and the CNIV of the University of Valparaiso, Chile. We finally thank Brian Jeffries for immunocytochemistry, biocytin labelling and morphological drawings, and members of the McBain and Lawrence laboratories for helpful comments on the manuscript. NR 47 TC 21 Z9 21 U1 0 U2 10 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB 1 PY 2011 VL 589 IS 3 BP 609 EP 627 DI 10.1113/jphysiol.2010.199422 PG 19 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 713NG UT WOS:000286744100017 PM 21115639 ER PT J AU Chen, QR Yu, LR Tsang, P Wei, JS Song, YK Cheuk, A Chung, JY Hewitt, SM Veenstra, TD Khan, J AF Chen, Qing-Rong Yu, Li-Rong Tsang, Patricia Wei, Jun S. Song, Young K. Cheuk, Adam Chung, Joon-Yong Hewitt, Stephen M. Veenstra, Timothy D. Khan, Javed TI Systematic Proteome Analysis Identifies Transcription Factor YY1 as a Direct Target of miR-34a SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE miR-34a; YY1; ICAT; proteomics; neuroblastoma ID P53 TUMOR-SUPPRESSOR; MICRORNAS; APOPTOSIS; GENES; NEUROBLASTOMA; ACTIVATION; EXPRESSION; NETWORK; CANCER; YIN-YANG-1 AB MicroRNA 34a (miR-34a) is a potential tumor suppressor gene and has been identified as a miRNA component of the p53 network. To better understand the biological pathways involved in miR-34a action, a parallel global protein and mRNA expression profiling on miR-34a treated neuroblastoma cells (IMR32) was performed using isotope-coded affinity tags (ICAT) and Affymetrix U133plus2 microarray, respectively. Global profiling showed that miR-34a causes much smaller mRNA expression changes compared to changes at the protein level. A total of 1495 proteins represented by two or more peptides were identified from the quantitative ICAT analysis, of which 143 and 192 proteins are significantly up-or down-regulated by miR-34a, respectively. Pathway analysis of these differentially expressed proteins showed the enrichment of apoptosis and cell death processes in up-regulated proteins but DNA replication and cell cycle processes in the down-regulated proteins. Ribosomal proteins are the most significant set down-regulated by miR-34a. Additionally, biological network analysis to identify direct interactions among the differentially expressed proteins demonstrated that the expression of the ubiquitous transcription factor YY1, as well as its downstream proteins, is significantly reduced by miR-34a. We further demonstrated that miR-34a directly targets YY1 through a miR-34a-binding site within the 3' UTR of YY1 using a luciferase reporter system. YY1 is a negative regulator of p53, and it plays an essential role in cancer biology. Therefore, YY1 is another important direct target of miR-34a which closely regulates TP53 activities. C1 [Chen, Qing-Rong; Tsang, Patricia; Wei, Jun S.; Song, Young K.; Cheuk, Adam; Khan, Javed] NCI, Oncogenom Sect, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD 20877 USA. [Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Adv Technol Ctr, Gaithersburg, MD 20877 USA. [Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Appl Mol Pathol Lab, Adv Technol Ctr, Gaithersburg, MD 20877 USA. [Yu, Li-Rong; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Khan, J (reprint author), NCI, Oncogenom Sect, Pediat Oncol Branch, Adv Technol Ctr, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 33 TC 40 Z9 45 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2011 VL 10 IS 2 BP 479 EP 487 DI 10.1021/pr1006697 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 715GI UT WOS:000286868500010 PM 21182263 ER PT J AU Assumpcao, TCF Charneau, S Santiago, PBM Francischetti, IMB Meng, ZJ Araujo, CN Pham, V Queiroz, RML de Castro, CN Ricart, CA Santana, JM Ribeiro, JMC AF Assumpcao, Teresa C. F. Charneau, Sebastien Santiago, Paula B. M. Francischetti, Ivo M. B. Meng, Zhaojing Araujo, Carla N. Pham, Van M. Queiroz, Rayner M. L. de Castro, Cleudson Nery Ricart, Carlos Andre Santana, Jaime M. Ribeiro, Jose M. C. TI Insight into the Salivary Transcriptome and Proteome of Dipetalogaster maxima SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE saliva; hematophagy; transcriptome; proteome; triatomine; D. maxima ID ESCHERICHIA-COLI HEMOLYSIN; ADULT FEMALE MOSQUITO; MULTIPLE SEQUENCE ALIGNMENT; HISTIDINE-RICH GLYCOPROTEIN; TRIATOMA-INFESTANS; CHAGAS-DISEASE; RHODNIUS-PROLIXUS; DROSOPHILA-MELANOGASTER; 5'-NUCLEOTIDASE FAMILY; PLATELET-AGGREGATION AB Dipetalogaster maxima is a blood-sucking Hemiptera that inhabits sylvatic areas in Mexico. It usually takes its blood meal from lizards, but following human population growth, it invaded suburban areas, feeding also on humans and domestic animals. Hematophagous insect salivary glands produce potent pharmacologic compounds that counteract host hemostasis, including anticlotting, antiplatelet, and vasodilatory molecules. To obtain further insight into the salivary biochemical and pharmacologic complexity of this insect, a cDNA library from its salivary glands was randomly sequenced. Salivary proteins were also submitted to one- and two-dimensional gel electrophoresis (1DE and 2DE) followed by mass spectrometry analysis. We present the analysis of a set of 2728 cDNA sequences, 1375 of which coded for proteins of a putative secretory nature. The saliva 2DE proteome displayed approximately 150 spots. The mass spectrometry analysis revealed mainly lipocalins, pallidipins, antigen 5-like proteins, and apyrases. The redundancy of sequence identification of saliva-secreted proteins suggests that proteins are present in multiple isoforms or derive from gene duplications. C1 [Charneau, Sebastien; Santiago, Paula B. M.; Araujo, Carla N.; Queiroz, Rayner M. L.; de Castro, Cleudson Nery; Ricart, Carlos Andre; Santana, Jaime M.] Univ Brasilia, Dept Cell Biol, Dept Trop, Brasilia, DF, Brazil. [Charneau, Sebastien; Santiago, Paula B. M.; Araujo, Carla N.; Queiroz, Rayner M. L.; de Castro, Cleudson Nery; Ricart, Carlos Andre; Santana, Jaime M.] Univ Brasilia, Fac Ceilandia, Brasilia, DF, Brazil. [Assumpcao, Teresa C. F.; Francischetti, Ivo M. B.; Pham, Van M.; Ribeiro, Jose M. C.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Meng, Zhaojing] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, NIH, Frederick, MD 21701 USA. RP Santana, JM (reprint author), Univ Brasilia, Dept Cell Biol, Dept Trop, Brasilia, DF, Brazil. EM jsantana@unb.br; jribeiro@niaid.nih.gov RI Ricart, Carlos/A-7128-2013; Santana, Jaime/H-5319-2013; OI Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; CNPq; FINEP; FAP-DF; CAPES; PRONEX 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. 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 organization imply endorsement by the government of the United States of America. This work was supported by Brazilian Grants from CNPq, FINEP, FAP-DF, CAPES, and PRONEX. NR 89 TC 21 Z9 23 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2011 VL 10 IS 2 BP 669 EP 679 DI 10.1021/pr100866h PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 715GI UT WOS:000286868500026 PM 21058630 ER PT J AU Alves, G Ogurtsov, AY Yu, YK AF Alves, Gelio Ogurtsov, Aleksey Y. Yu, Yi-Kuo TI Assigning statistical significance to proteotypic peptides via database searches SO JOURNAL OF PROTEOMICS LA English DT Article DE Peptide identification; Statistical significance; E-value; Proteotypic peptides; Knowledge integration ID PROTEIN IDENTIFICATIONS; SPECTRUM LIBRARIES; MASS-SPECTROMETRY; MS/MS SPECTRA; PROTEOMICS; CONFIDENCE; PREDICTION; STRATEGY; MODEL AB Querying MS/MS spectra against a database containing only proteotypic peptides reduces data analysis time due to reduction of database size. Despite the speed advantage, this search strategy is challenged by issues of statistical significance and coverage. The former requires separating systematically significant identifications from less confident identifications, while the latter arises when the underlying peptide is not present, due to single amino acid polymorphisms (SAPs) or post-translational modifications (PTMs), in the proteotypic peptide libraries searched. To address both issues simultaneously, we have extended RAId's knowledge database to include proteotypic information, utilized RAId's statistical strategy to assign statistical significance to proteotypic peptides, and modified RAId's programs to allow for consideration of proteotypic information during database searches. The extended database alleviates the coverage problem since all annotated modifications, even those that occurred within proteotypic peptides, may be considered. Taking into account the likelihoods of observation, the statistical strategy of RAId provides accurate E-value assignments regardless whether a candidate peptide is proteotypic or not. The advantage of including proteotypic information is evidenced by its superior retrieval performance when compared to regular database searches. Published by Elsevier B.V. C1 [Alves, Gelio; Ogurtsov, Aleksey Y.; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov FU National Library of Medicine of the National Institutes of Health/DHHS; NIH FX We thank the administrative group of the NIH Biowulf clusters, where all the computational tasks were carried out. This work was supported by the Intramural Research Program of the National Library of Medicine of the National Institutes of Health/DHHS. Funding to pay the Open Access publication charges for this article was provided by the NIH. NR 25 TC 5 Z9 6 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD FEB 1 PY 2011 VL 74 IS 2 BP 199 EP 211 DI 10.1016/j.jprot.2010.10.005 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 716FD UT WOS:000286953600005 PM 21055489 ER PT J AU Higley, AE Spiller, K Grundt, P Newman, AH Kiefer, SW Xi, ZX Gardner, EL AF Higley, Amanda E. Spiller, Krista Grundt, Peter Newman, Amy Hauck Kiefer, Stephen W. Xi, Zheng-Xiong Gardner, Eliot L. TI PG01037, a novel dopamine D-3 receptor antagonist, inhibits the effects of methamphetamine in rats SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE brain reward; brain-stimulation reward; cue-induced reinstatement; D-3 receptor; methamphetamine; PG01037; self-administration ID BRAIN-STIMULATION REWARD; COCAINE-SEEKING BEHAVIOR; ABUSE THERAPEUTIC AGENTS; PROGRESSIVE-RATIO; D3 RECEPTOR; INDUCED REINSTATEMENT; REINFORCING EFFICACY; PLACE PREFERENCE; SELF-STIMULATION; ANIMAL-MODELS AB Our previous studies have shown that the selective dopamine D-3 receptor antagonists SB-277011A or NGB 2904 significantly attenuate cocaine self-administration under a progressive-ratio reinforcement schedule and cocaine-, methamphetamine-or nicotine-enhanced brain stimulation reward. However, the poor bioavailability of SB-277011A has limited its potential use in humans. In the present study, we investigated the effects of the novel D-3 receptor antagonist PG01037 on methamphetamine self-administration, methamphetamine-associated cue-induced reinstatement of drug seeking and methamphetamine-enhanced brain stimulation reward. Rats were allowed to intravenously self-administer methamphetamine under fixed-ratio 2 and progressive-ratio reinforcement conditions, and then the effects of PG01037 on methamphetamine self-administration and cue-induced reinstatement were assessed. Additional groups of rats were trained for intracranial electrical brain stimulation reward and the effects of PG01037 and methamphetamine on brain stimulation reward were assessed. Acute intraperitoneal administration of PG01037 (3, 10, 30mg/kg) failed to alter methamphetamine or sucrose self-administration under fixed-ratio 2 reinforcement, but significantly lowered the break-point levels for methamphetamine or sucrose self-administration under progressive-ratio reinforcement. In addition, PG01037 significantly inhibited methamphetamine-associated cue-triggered reinstatement of drug-seeking behavior and methamphetamine-enhanced brain stimulation reward. These data suggest that the novel D-3 antagonist PG01037 significantly attenuates the rewarding effects as assessed by progressive-ratio self-administration and brain stimulation reward, and inhibits methamphetamine-associated cue-induced reinstatement of drug-seeking behavior These findings support the potential use of PG01037 or other selective D-3 antagonists in the treatment of methamphetamine addiction. C1 [Higley, Amanda E.; Spiller, Krista; Xi, Zheng-Xiong; Gardner, Eliot L.] NIDA, Neuropsychopharmacol Sect, Intramural Res Program, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Higley, Amanda E.; Kiefer, Stephen W.] Kansas State Univ, Dept Psychol, Manhattan, KS 66506 USA. [Grundt, Peter; Newman, Amy Hauck] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Higley, AE (reprint author), NIDA, Neuropsychopharmacol Sect, Intramural Res Program, NIH,Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM ahigley@scripps.edu FU National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 76 TC 43 Z9 43 U1 0 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD FEB PY 2011 VL 25 IS 2 BP 263 EP 273 DI 10.1177/0269881109358201 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 715IV UT WOS:000286878400010 PM 20142301 ER PT J AU Fiedorowicz, JG He, JP Merikangas, KR AF Fiedorowicz, Jess G. He, Jianping Merikangas, Kathleen R. TI The association between mood and anxiety disorders with vascular diseases and risk factors in a nationally representative sample SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE Anxiety disorders; Diabetes mellitus; Hypertension; Obesity; Mood disorders; Vascular diseases ID MAJOR DEPRESSIVE DISORDER; CORONARY-HEART-DISEASE; MENTAL-HEALTH SURVEYS; REPLICATION NCS-R; NUTRITION EXAMINATION SURVEY; GENERAL MEDICAL CONDITIONS; BIPOLAR-DISORDER; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; EXCESS MORTALITY AB Objective: To investigate the association between mood and anxiety disorders and vascular diseases after controlling for vascular disease risk factors. Methods: Using a nationally representative sample of adults (N=5692) from the National Comorbidity Survey-Replication (NCS-R), participants with mood disorders were hierarchically classified as having any lifetime history of mania, hypomania, or major depression. Anxiety disorders were also assessed. The reference group consisted of those without mental disorders. Vascular disease was determined by self-reported history of heart disease, heart attack, or stroke on the NCS-R survey. Vascular risk factors included diabetes, high blood pressure, and obesity. Results: In multivariate logistic regression models that controlled for obesity, high blood pressure, smoking and diabetes, vascular disease was associated with bipolar disorder in women [odds ratio (OR) 2.80, 95% confidence interval (CI) 1.63-4.80], and major depressive disorder in men (OR 1.85, 95% CI 1.17-2.92). Controlling for anxiety disorders reduced the associations in both men and women, and in fact, anxiety disorders were more strongly associated with vascular diseases in men, whereas bipolar disorder continued to be an important correlate of vascular disease in women. Conclusion: These findings demonstrate the importance of evaluation of sex differences, mood disorder subtype and co-occurring anxiety disorders in assessing the association between mood disorders and vascular diseases. Future research should investigate potential biologic mechanisms for these associations in order to define potential targets for intervention. (C) 2011 Elsevier Inc. All rights reserved. C1 [Fiedorowicz, Jess G.] Univ Iowa, Dept Psychiat, Roy J & Lucille A Carver Coll Med, Hosp & Clin, Iowa City, IA 52242 USA. [Fiedorowicz, Jess G.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [He, Jianping; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Fiedorowicz, JG (reprint author), 200 Hawkins Dr,W278GH, Iowa City, IA 52242 USA. EM jess-fiedorowicz@uiowa.edu OI Fiedorowicz, Jess/0000-0003-2057-4071 FU Department of Psychiatry at the University of Iowa; National Institute of Mental Health; National Institutes of Health [1K23MH083695-01A210]; NARSAD; Nellie Ball Trust Research Fund; Institute for Clinical and Translational Science at the University of Iowa [3 UL1 RR024979-03S4]; CHDI foundation FX This work was supported by the Department of Psychiatry at the University of Iowa and the Intramural Research Program of the National Institute of Mental Health. Dr. Fiedorowicz is supported by the National Institutes of Health (1K23MH083695-01A210), NARSAD, the Nellie Ball Trust Research Fund, Institute for Clinical and Translational Science at the University of Iowa (3 UL1 RR024979-03S4), and CHDI foundation. Dr. Fiedorowicz currently serves as a site physician for colleagues' studies with Neurosearch, Vitalin/Enzymatic Therapy, and the National Center for Complementary and Alternative Medicine/the US Food and Drug Administration Orphan Products division. NR 70 TC 44 Z9 47 U1 5 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD FEB PY 2011 VL 70 IS 2 BP 145 EP 154 DI 10.1016/j.jpsychores.2010.07.010 PG 10 WC Psychiatry SC Psychiatry GA 716ET UT WOS:000286952600006 PM 21262417 ER PT J AU Musicki, B Champion, HC Hsu, LL Bivalacqua, TJ Burnett, AL AF Musicki, Biljana Champion, Hunter C. Hsu, Lewis L. Bivalacqua, Trinity J. Burnett, Arthur L. TI Post-Translational Inactivation of Endothelial Nitric Oxide Synthase in the Transgenic Sickle Cell Mouse Penis SO JOURNAL OF SEXUAL MEDICINE LA English DT Article DE Priapism; eNOS Phosphorylation; HSP90; Caveolin-1 ID AKT-DEPENDENT PHOSPHORYLATION; INDEPENDENT ENOS ACTIVATION; RECURRENT PRIAPISM; SUPEROXIDE ANION; HSP90; CAVEOLIN; BALANCE; DISEASE; KINASE; DOMAIN AB Introduction. Sickle cell disease (SCD)-associated priapism is characterized by endothelial nitric oxide synthase (eNOS) dysfunction in the penis. However, the mechanism of decreased eNOS function/activation in the penis in association with SCD is not known. Aims. Our hypothesis in the present study was that eNOS is functionally inactivated in the SCD penis in association with impairments in eNOS post-translational phosphorylation and the enzyme's interactions with its regulatory proteins. Methods. Sickle cell transgenic (sickle) mice were used as an animal model of SCD. Wild-type (WT) mice served as controls. Penes were excised at baseline for molecular studies. eNOS phosphorylation on Ser-1177 (positive regulatory site) and Thr-495 (negative regulatory site), total eNOS, and phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177) expressions, and eNOS interactions with heat-shock protein 90 (HSP90) and caveolin-1 were measured by Western blot. Constitutive NOS catalytic activity was measured by conversion of L-[14C]arginine-to-L-[14C]citrulline in the presence of calcium. Main Outcome Measures. Molecular mechanisms of eNOS dysfunction in the sickle mouse penis. Results. eNOS phosphorylated on Ser-1177, an active portion of eNOS, was decreased in the sickle mouse penis compared with WT penis. eNOS interaction with its positive protein regulator HSP90, but not with its negative protein regulator caveolin-1, and phosphorylated AKT expression, as well as constitutive NOS activity, were also decreased in the sickle mouse penis compared with WT penis. eNOS phosphorylated on Thr-495, total eNOS, HSP90, and caveolin-1 protein expressions in the penis were not affected by SCD. Conclusions. These findings provide a molecular basis for chronically reduced eNOS function in the penis by SCD, which involves decreased eNOS phosphorylation on Ser-1177 and decreased eNOS-HSP90 interaction. Musicki B, Champion HC, Hsu LL, Bivalacqua TJ, and Burnett AL. Post-translational inactivation of endothelial nitric oxide synthase in the transgenic sickle cell mouse penis. J Sex Med 2011;8:419-426. C1 [Musicki, Biljana; Bivalacqua, Trinity J.; Burnett, Arthur L.] Johns Hopkins Univ, Dept Urol, Baltimore, MD 21287 USA. [Champion, Hunter C.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Hsu, Lewis L.] Natl Heart Lung Blood Inst, Vasc Med Branch, NIH, Bethesda, MD USA. [Hsu, Lewis L.] Childrens Natl Med Ctr, Div Hematol, Washington, DC 20010 USA. RP Musicki, B (reprint author), Johns Hopkins Univ, Dept Urol, Baltimore, MD 21287 USA. EM bmusicki@jhmi.edu FU NIH/NIDDK [RO1DK067223] FX This work was supported by NIH/NIDDK grant RO1DK067223 to A.L.B. NR 45 TC 12 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1743-6095 J9 J SEX MED JI J. Sex. Med. PD FEB PY 2011 VL 8 IS 2 BP 419 EP 426 DI 10.1111/j.1743-6109.2010.02123.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 714WE UT WOS:000286838900011 PM 21143412 ER PT J AU Yothers, G Sampson, AR AF Yothers, Greg Sampson, Allan R. TI Simultaneous confidence band for the difference of segmented linear models SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Segmented linear model; Asymptotic simultaneous confidence band; Treatment comparison; Subset selection ID REGRESSION AB Consider comparing between two treatments a response variable, whose expectation depends on the value of a continuous covariate in some nonlinear fashion. We fit separate segmented linear models to each treatment to approximate the nonlinear relationship. For this setting, we provide a simultaneous confidence band for the difference between treatments of the expected value functions. The treatments are said to differ significantly on intervals of the covariate where the simultaneous confidence band does not contain zero. We consider segmented linear models where the locations of the changepoints are both known and unknown. The band is obtained from asymptotic results. (C) 2010 Elsevier B.V. All rights reserved. C1 [Yothers, Greg] Univ Pittsburgh, Dept Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15260 USA. [Sampson, Allan R.] Univ Pittsburgh, Dept Stat, Pittsburgh, PA 15260 USA. RP Yothers, G (reprint author), Univ Pittsburgh, Dept Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15260 USA. EM yothers@nsabp.pitt.edu OI Yothers, Greg/0000-0002-7965-7333 FU NIH/NCI [U10CA69651]; NSF [DMS00 72207]; NIH [1 P50 MH084053] FX The work of the first author was supported in part by a grant from the NIH/NCI (U10CA69651). The work of the second author was supported in part by grants from the NSF (DMS00 72207) and NIH (1 P50 MH084053). The authors want to thank the referee for extremely thoughtful comments that have improved the presentation of our paper. NR 14 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD FEB PY 2011 VL 141 IS 2 BP 1059 EP 1068 DI 10.1016/j.jspi.2010.09.011 PG 10 WC Statistics & Probability SC Mathematics GA 682FJ UT WOS:000284386500043 PM 26166937 ER PT J AU Rutledge, RM Esser, L Ma, JC Xia, D AF Rutledge, Robert M. Esser, Lothar Ma, Jichun Xia, Di TI Toward understanding the mechanism of action of the yeast multidrug resistance transporter Pdr5p: A molecular modeling study SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE ABC transporter; Homology modeling; Membrane protein; Nucleotide-binding domain; Transmembrane domain; Substrate specificity ID SECONDARY STRUCTURE PREDICTION; MULTIPLE SEQUENCE ALIGNMENTS; NUCLEOTIDE-BINDING DOMAINS; ABC TRANSPORTERS; MEMBRANE-PROTEINS; DRUG-RESISTANCE; SACCHAROMYCES-CEREVISIAE; CANDIDA-ALBICANS; ATP; SOFTWARE AB Pleotropic drug resistant protein 5 (Pdr5p) is a plasma membrane ATP-binding cassette (ABC) transporter and the major drug efflux pump in Saccharomyces cerevisiae. The Pdr5p family of fungal transporters possesses a number of structural features significantly different from other modeled or crystallized ABC transporters, which include a reverse topology, an atypical ATP-binding site, a very low sequence similarity in the transmembrane section and long linkers between domains. These features present a considerable hurdle in molecular modeling studies of these important transporters. Here, we report the creation of an atomic model of Pdr5p based on a combination of homology modeling and ab initio methods, incorporating information from consensus transmembrane segment prediction, residue lipophilicity, and sequence entropy. Reported mutations in the transmembrane substrate-binding pocket that altered drug-resistance were used to validate the model, and one mutation that changed the communication pattern between transmembrane and nucleotide-binding domains was used in model improvement. The predictive power of the model was demonstrated experimentally by the increased sensitivity of yeast mutants to clotrimazole having alanine substitutions for Thr1213 and Gln1253, which are predicted to be in the substrate-binding pocket, without reducing the amount of Pdr5p in the plasma membrane. The quality and reliability of our model are discussed in the context of various approaches used for modeling different parts of the structure. Published by Elsevier Inc. C1 [Rutledge, Robert M.; Esser, Lothar; Ma, Jichun; Xia, Di] NCI, NIH, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Xia, D (reprint author), NCI, NIH, Cell Biol Lab, Ctr Canc Res, 37 Convent Dr Bldg 37,Room 2122C, Bethesda, MD 20892 USA. EM dixia@helix.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; NIH [GM07721] FX This research was supported by the intramural research program of NIH, National Cancer Institute, Center for Cancer Research and by an NIH Grant GM07721 to John Golin. We thank Prof. Dr. John Golin for confirming the results initially obtained by Jakub Janecka and for reading several drafts of this paper. NR 61 TC 27 Z9 27 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD FEB PY 2011 VL 173 IS 2 BP 333 EP 344 DI 10.1016/j.jsb.2010.10.012 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 714YD UT WOS:000286846700015 PM 21034832 ER PT J AU Guyer, AE Choate, VR Grimm, KJ Pine, DS Keenan, K AF Guyer, Amanda E. Choate, Victoria R. Grimm, Kevin J. Pine, Daniel S. Keenan, Kate TI Emerging Depression Is Associated With Face Memory Deficits in Adolescent Girls SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE depression; memory; face emotion; adolescence ID OVERGENERAL AUTOBIOGRAPHICAL MEMORY; COGNITIVE VULNERABILITY; GENDER-DIFFERENCES; PREADOLESCENT GIRLS; EMOTIONAL MEMORY; MAJOR DEPRESSION; PUBERTAL STATUS; MOOD DISORDERS; CHILDREN; PSYCHOPATHOLOGY AB Objective: To examine the association between memory for previously encoded emotional faces and depression symptoms assessed over 4 years in adolescent girls. Investigating the interface between memory deficits and depression in adolescent girls may provide clues about depression pathophysiology. Method: Participants were 213 girls recruited from a longitudinal, community-based study; the majority were African American. Scores on depressive screening measures at age 8 were used to increase the base rate of depression. Depression symptoms and diagnoses were assessed annually for 4 years. In year 4, when the girls were 12 to 13 years old, a face emotion encoding task was administered during which ratings were generated in response to sad, fearful, angry, and happy faces. A surprise memory task followed whereby participants identified which of two faces, displaying neutral expressions, they had seen previously. Results: Girls with higher depression symptom levels from ages 9 to 12 years evidenced lower accuracy in identifying previously encoded emotional faces. Controlling for IQ, higher depression symptom level was associated with a memory deficit specific to previously encoded sad and happy faces. These effects were not moderated by race. Conclusions: Individual differences in face memory deficits relate to individual differences in emerging, early adolescent depression, and may be vulnerability markers for depression. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(2):180-190. C1 [Guyer, Amanda E.] Univ Calif Davis, Dept Human & Community Dev, Ctr Mind & Brain, Davis, CA 95618 USA. [Keenan, Kate] Univ Chicago, Chicago, IL 60637 USA. [Choate, Victoria R.; Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. RP Guyer, AE (reprint author), Univ Calif Davis, Dept Human & Community Dev, Ctr Mind & Brain, 267 Cousteau Pl, Davis, CA 95618 USA. EM aeguyer@ucdavis.edu FU National Institute of Mental Health (NIMH) [R01 MH66167, K99/R00 MH080076] FX This study was supported by National Institute of Mental Health (NIMH) grant R01 MH66167 (K.K.), the NIMH Intramural Research Program, and NIMH grant K99/R00 MH080076 (A.E.G.). NR 61 TC 10 Z9 10 U1 3 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2011 VL 50 IS 2 BP 180 EP 190 DI 10.1016/j.jaac.2010.11.008 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 712ZL UT WOS:000286704700010 PM 21241955 ER PT J AU Ma, DQ Darling, T Moss, J Lee, CCR AF Ma, Deqin Darling, Thomas Moss, Joel Lee, Chyi-Chia Richard TI Histologic variants of periungual fibromas in tuberous sclerosis complex SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Ma, Deqin; Lee, Chyi-Chia Richard] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Darling, Thomas] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. RP Lee, CCR (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2B50,10 Ctr Dr, Bethesda, MD 20892 USA. EM leechy@mail.nih.gov RI Lee, Chyi-Chia/I-1938-2013; OI Lee, Chyi-Chia/0000-0002-5306-7781; Darling, Thomas/0000-0002-5161-1974 FU Intramural NIH HHS [Z99 CA999999] NR 6 TC 5 Z9 5 U1 0 U2 1 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 FEB PY 2011 VL 64 IS 2 BP 442 EP 444 DI 10.1016/j.jaad.2010.03.002 PG 3 WC Dermatology SC Dermatology GA 714AX UT WOS:000286780400028 PM 21238836 ER PT J AU Yang, XR Chang-Claude, J Goode, EL Couch, FJ Nevanlinna, H Milne, RL Gaudet, M Schmidt, MK Broeks, A Cox, A Fasching, PA Hein, R Spurdle, AB Blows, F Driver, K Flesch-Janys, D Heinz, J Sinn, P Vrieling, A Heikkinen, T Aittomaki, K Heikkila, P Blomqvist, C Lissowska, J Peplonska, B Chanock, S Figueroa, J Brinton, L Hall, P Czene, K Humphreys, K Darabi, H Liu, JJ Van 't Veer, LJ Van Leeuwen, FE Andrulis, IL Glendon, G Knight, JA Mulligan, AM O'Malley, FP Weerasooriya, N John, EM Beckmann, MW Hartmann, A Weihbrecht, SB Wachter, DL Jud, SM Loehberg, CR Baglietto, L English, DR Giles, GG McLean, CA Severi, G Lambrechts, D Vandorpe, T Weltens, C Paridaens, R Smeets, A Neven, P Wildiers, H Wang, XS Olson, JE Cafourek, V Fredericksen, Z Kosel, M Vachon, C Cramp, HE Connley, D Cross, SS Balasubramanian, SP Reed, MWR Dork, T Bremer, M Meyer, A Karstens, JH Ay, A Park-Simon, TW Hillemanns, P Perez, JIA Rodriguez, PM Zamora, P Bentez, J Ko, YD Fischer, HP Hamann, U Pesch, B Bruning, T Justenhoven, C Brauch, H Eccles, DM Tapper, WJ Gerty, SM Sawyer, EJ Tomlinson, IP Jones, A Kerin, M Miller, N McInerney, N Anton-Culver, H Ziogas, A Shen, CY Hsiung, CN Wu, PE Yang, SL Yu, JC Chen, ST Hsu, GC Haiman, CA Henderson, BE Le Marchand, L Kolonel, LN Lindblom, A Margolin, S Jakubowska, A Lubinski, J Huzarski, T Byrski, T Gorski, B Gronwald, J Hooning, MJ Hollestelle, A van den Ouweland, AMW Jager, A Kriege, M Tilanus-Linthorst, MMA Collee, M Wang-Gohrke, S Pylkas, K Jukkola-Vuorinen, A Mononen, K Grip, M Hirvikoski, P Winqvist, R Mannermaa, A Kosma, VM Kauppinen, J Kataja, V Auvinen, P Soini, Y Sironen, R Bojesen, SE Orsted, DD Kaur-Knudsen, D Flyger, H Nordestgaard, BG Holland, H Chenevix-Trench, G Manoukian, S Barile, M Radice, P Hankinson, SE Hunter, DJ Tamimi, R Sangrajrang, S Brennan, P Mckay, J Odefrey, F Gaborieau, V Devilee, P Huijts, PEA Tollenaar, RAEM Seynaeve, C Dite, GS Apicella, C Hopper, JL Hammet, F Tsimiklis, H Smith, LD Southey, MC Humphreys, MK Easton, D Pharoah, P Sherman, ME Garcia-Closas, M AF Yang, Xiaohong R. Chang-Claude, Jenny Goode, Ellen L. Couch, Fergus J. Nevanlinna, Heli Milne, Roger L. Gaudet, Mia Schmidt, Marjanka K. Broeks, Annegien Cox, Angela Fasching, Peter A. Hein, Rebecca Spurdle, Amanda B. Blows, Fiona Driver, Kristy Flesch-Janys, Dieter Heinz, Judith Sinn, Peter Vrieling, Alina Heikkinen, Tuomas Aittomaeki, Kristiina Heikkilae, Paeivi Blomqvist, Carl Lissowska, Jolanta Peplonska, Beata Chanock, Stephen Figueroa, Jonine Brinton, Louise Hall, Per Czene, Kamila Humphreys, Keith Darabi, Hatef Liu, Jianjun Van 't Veer, Laura J. Van Leeuwen, Flora E. Andrulis, Irene L. Glendon, Gord Knight, Julia A. Mulligan, Anna Marie O'Malley, Frances P. Weerasooriya, Nayana John, Esther M. Beckmann, Matthias W. Hartmann, Arndt Weihbrecht, Sebastian B. Wachter, David L. Jud, Sebastian M. S. Loehberg, Christian R. Baglietto, Laura English, Dallas R. Giles, Graham G. McLean, Catriona A. Severi, Gianluca Lambrechts, Diether Vandorpe, Thijs Weltens, Caroline Paridaens, Robert Smeets, Ann Neven, Patrick Wildiers, Hans Wang, Xianshu Olson, Janet E. Cafourek, Victoria Fredericksen, Zachary Kosel, Matthew Vachon, Celine Cramp, Helen E. Connley, Daniel Cross, Simon S. Balasubramanian, Sabapathy P. Reed, Malcolm W. R. Doerk, Thilo Bremer, Michael Meyer, Andreas Karstens, Johann H. Ay, Aysun Park-Simon, Tjoung-Won Hillemanns, Peter Arias Perez, Jose Ignacio Menendez Rodriguez, Primitiva Zamora, Pilar Bentez, Javier Ko, Yon-Dschun Fischer, Hans-Peter Hamann, Ute Pesch, Beate Bruening, Thomas Justenhoven, Christina Brauch, Hiltrud Eccles, Diana M. Tapper, William J. Gerty, Sue M. Sawyer, Elinor J. Tomlinson, Ian P. Jones, Angela Kerin, Michael Miller, Nicola McInerney, Niall Anton-Culver, Hoda Ziogas, Argyrios Shen, Chen-Yang Hsiung, Chia-Ni Wu, Pei-Ei Yang, Show-Lin Yu, Jyh-Cherng Chen, Shou-Tung Hsu, Giu-Cheng Haiman, Christopher A. Henderson, Brian E. Le Marchand, Loic Kolonel, Laurence N. Lindblom, Annika Margolin, Sara Jakubowska, Anna Lubinski, Jan Huzarski, Tomasz Byrski, Tomasz Gorski, Bohdan Gronwald, Jacek Hooning, Maartje J. Hollestelle, Antoinette van den Ouweland, Ans M. W. Jager, Agnes Kriege, Mieke Tilanus-Linthorst, Madeleine M. A. Collee, Margriet Wang-Gohrke, Shan Pylkaes, Katri Jukkola-Vuorinen, Arja Mononen, Kari Grip, Mervi Hirvikoski, Pasi Winqvist, Robert Mannermaa, Arto Kosma, Veli-Matti Kauppinen, Jaana Kataja, Vesa Auvinen, Paeivi Soini, Ylermi Sironen, Reijo Bojesen, Stig E. Orsted, David Dynnes Kaur-Knudsen, Diljit Flyger, Henrik Nordestgaard, Borge G. Holland, Helene Chenevix-Trench, Georgia Manoukian, Siranoush Barile, Monica Radice, Paolo Hankinson, Susan E. Hunter, David J. Tamimi, Rulla Sangrajrang, Suleeporn Brennan, Paul Mckay, James Odefrey, Fabrice Gaborieau, Valerie Devilee, Peter Huijts, P. E. A. Tollenaar, R. A. E. M. Seynaeve, C. Dite, Gillian S. Apicella, Carmel Hopper, John L. Hammet, Fleur Tsimiklis, Helen Smith, Letitia D. Southey, Melissa C. Humphreys, Manjeet K. Easton, Douglas Pharoah, Paul Sherman, Mark E. Garcia-Closas, Montserrat TI Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; DIFFERENT HISTOPATHOLOGIC TYPES; PROGESTERONE-RECEPTOR STATUS; EPITHELIAL OVARIAN-CANCER; BASAL-LIKE SUBTYPE; POSTMENOPAUSAL WOMEN; SUSCEPTIBILITY LOCI; HORMONE-RECEPTOR; REPAIR GENES; ESTROGEN AB Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case-case analyses, of the epidemiological risk factors examined, early age at menarche (<= 12 years) was less frequent in case patients with PR- than PR+ tumors (P = .001). Nulliparity (P = 3 x 10(-6)) and increasing age at first birth (P = 2 x 10(-9)) were less frequent in ER- than in ER+ tumors. Obesity (body mass index [BMI] >= 30 kg/m(2)) in younger women (<= 50 years) was more frequent in ER /PR than in ER+/PR+ tumors (P = 1 x 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR- than in PR+ tumors (P = 6 x 10(-4)). The triple-negative (ER-/PR-/HER2-) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/ or epidermal growth factor receptor [EGFR] 1) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. Conclusions This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology. 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[Milne, Roger L.] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Bentez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Grp, Madrid, Spain. [Gaudet, Mia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Schmidt, Marjanka K.; Broeks, Annegien; Van 't Veer, Laura J.; Van Leeuwen, Flora E.] Netherlands Canc Inst, Amsterdam Breast Canc Study, Amsterdam, Netherlands. [Cox, Angela; Cramp, Helen E.; Connley, Daniel] Univ Sheffield, Sch Med, Dept Oncol, Inst Canc Studies, Sheffield, S Yorkshire, England. [Chanock, Stephen] Univ Sheffield, Sch Med, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Balasubramanian, Sabapathy P.; Reed, Malcolm W. R.] Univ Sheffield, Sch Med, Acad Unit Surg Oncol, Dept Oncol, Sheffield, S Yorkshire, England. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Beckmann, Matthias W.; Weihbrecht, Sebastian B.; Jud, Sebastian M. S.; Loehberg, Christian R.] Univ Hosp Erlangen, Univ Breast Ctr, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Erlangen, Germany. [Hartmann, Arndt; Wachter, David L.] Univ Hosp Erlangen, Univ Breast Ctr, Univ Breast Ctr Franconia, Inst Pathol, Erlangen, Germany. [Spurdle, Amanda B.; Holland, Helene; Chenevix-Trench, Georgia] Univ Queensland, Royal Brisbane Hosp, Queensland Inst Med Res Post Off, Herston, Qld, Australia. [Blows, Fiona; Driver, Kristy; Humphreys, Manjeet K.; Easton, Douglas; Pharoah, Paul; Garcia-Closas, Montserrat] Univ Cambridge, Dept Oncol, Cambridge, England. [Flesch-Janys, Dieter; Heinz, Judith] Univ Med Ctr Hamburg Eppendorf, Dept Med Biometr & Epidemiol, Hamburg, Germany. [Sinn, Peter] Univ Hosp, Dept Pathol, Heidelberg, Germany. [Liu, Jianjun] Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Liu, Jianjun] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Peplonska, Beata] Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. [Hall, Per; Czene, Kamila; Humphreys, Keith; Darabi, Hatef] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Liu, Jianjun] Genome Inst Singapore, Singapore, Singapore. [Andrulis, Irene L.; Glendon, Gord; Weerasooriya, Nayana] Canc Care Ontario, Ontario Canc Genet Network OCGN, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Knight, Julia A.] Univ Toronto, Mt Sinai Hosp, Dalla Lana Sch Publ Hlth, Prosserman Ctr Hlth Res,Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Mulligan, Anna Marie] Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [O'Malley, Frances P.] Univ Toronto, Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5G 1X5, Canada. [John, Esther M.] Canada No Calif Canc Ctr, Fremont, CA USA. 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[Eccles, Diana M.; Tapper, William J.; Gerty, Sue M.] Univ Southampton, Sch Med, Southampton Univ Hosp NHS Trust, Southampton, Hants, England. [Sawyer, Elinor J.] Guys Hosp, Guys Kings St Thomas Canc Ctr, London SE1 9RT, England. [Sawyer, Elinor J.; Tomlinson, Ian P.; Jones, Angela; McInerney, Niall] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Kerin, Michael; Miller, Nicola; McInerney, Niall] Univ Coll Hosp Galway, Inst Clin Sci, Galway, Ireland. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Yang, Show-Lin] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang] China Med Univ, Grad Inst Environm Sci, Taichung, Taiwan. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Hsu, Giu-Cheng] Triserv Gen Hosp, Dept Radiol, Taipei, Taiwan. [Chen, Shou-Tung] Changhua Christian Hosp, Dept Surg, Changhua, Taiwan. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden. [Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Byrski, Tomasz; Gorski, Bohdan; Gronwald, Jacek] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; Jager, Agnes; Kriege, Mieke; Tilanus-Linthorst, Madeleine M. A.; Collee, Margriet] Erasmus Univ, Dept Med Oncol, Med Ctr, Rotterdam Family Canc Clin, Rotterdam, Netherlands. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Pylkaes, Katri; Jukkola-Vuorinen, Arja; Mononen, Kari; Grip, Mervi; Hirvikoski, Pasi; Winqvist, Robert] Univ Oulu, Oulu Univ Hosp, Oulu, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana; Soini, Ylermi; Sironen, Reijo] Univ Eastern Finland, Inst Clin Med, Dept Pathol, Kuopio, Finland. [Auvinen, Paeivi] Kuopio Univ Hosp, Dept Oncol, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Kauppinen, Jaana; Soini, Ylermi; Sironen, Reijo] Bioctr Kuopio, Kuopio, Finland. [Kataja, Vesa] Vaasa Cent Hosp, Dept Oncol, Vaasa, Finland. Peter MacCallum Canc Ctr, Melbourne, Australia. [Bojesen, Stig E.; Orsted, David Dynnes; Kaur-Knudsen, Diljit; Flyger, Henrik; Nordestgaard, Borge G.] Univ Copenhagen, Herlev Univ Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Bojesen, Stig E.; Orsted, David Dynnes; Kaur-Knudsen, Diljit; Flyger, Henrik; Nordestgaard, Borge G.] Univ Copenhagen, Herlev Univ Hosp, Dept Breast Surg, Copenhagen, Denmark. [Margolin, Sara] Fdn IRCCS Ist Nazl Tumori, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy. [Radice, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Dept Expt Oncol & Mol Med, Milan, Italy. [Barile, Monica] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Hankinson, Susan E.; Hunter, David J.; Tamimi, Rulla] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hankinson, Susan E.; Hunter, David J.; Tamimi, Rulla] Harvard Univ, Sch Med, Boston, MA USA. [Hankinson, Susan E.; Hunter, David J.; Tamimi, Rulla] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Sangrajrang, Suleeporn] Natl Canc Inst, Mol Epidemiol Unit, Bangkok, Thailand. [Brennan, Paul; Mckay, James; Odefrey, Fabrice; Gaborieau, Valerie] Int Agcy Res Canc, F-69372 Lyon, France. [Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Huijts, P. E. A.] Leiden Univ, Dept Clin Genet, Med Ctr, Leiden, Netherlands. [Tollenaar, R. A. E. M.] Leiden Univ, Dept Surg Oncol, Med Ctr, Leiden, Netherlands. [Seynaeve, C.] Erasmus MC Daniel den Hoed Canc Ctr, Rotterdam Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Hammet, Fleur; Tsimiklis, Helen; Smith, Letitia D.; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3010, Australia. RP Yang, XR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Sci, 6120 Execut Blvd, Rockville, MD 20852 USA. EM royang@mail.nih.gov RI Dork, Thilo/J-8620-2012; Bruning, Thomas/G-8120-2015; Gronwald, Jacek/A-4576-2017; manoukian, siranoush/E-7132-2017; Spurdle, Amanda/A-4978-2011; BYRSKI, Tomasz/I-2844-2014; Jakubowska, Anna/O-8050-2014; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Hartikainen, Jaana/E-6256-2015; Vrieling, Alina/A-2725-2016; Peplonska, Beata/F-6004-2010; Knight, Julia/A-6843-2012; Shen, CY/F-6271-2010; Verdrengh, Evelien/H-4571-2012; Kerin, Michael/D-6748-2013; Andrulis, Irene/E-7267-2013; Radice, Paolo/O-3119-2013; Smith, Letitia /J-9035-2014 OI Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188; Bruning, Thomas/0000-0001-9560-5464; Gronwald, Jacek/0000-0002-3643-2871; manoukian, siranoush/0000-0002-6034-7562; Hollestelle, Antoinette/0000-0003-1166-1966; Dite, Gillian/0000-0002-2448-2548; Czene, Kamila/0000-0002-3233-5695; Spurdle, Amanda/0000-0003-1337-7897; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; FU European Community [223175, HEALTH-F2-2009-223175]; Australian Breast Cancer Family Study (ABCFS); National Cancer Institute (NCI), National Institutes of Health (NIH) [RFA CA-06-503]; Breast Cancer Family Registry (BCFR); Cancer Care Ontario [U01 CA69467]; Northern California Cancer Center [U01 CA69417]; University of Melbourne [U01 CA69638]; National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Copenhagen University Hospital, Herlev Hospital; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra Cancer; Fondo de Investigacion Sanitario [PI081120, PI081583]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Robert Bosch Foundation of Medical Research, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Deutsche Krebshilfe [70492, 70-2892-BR I]; state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm [P. 685]; Helsinki University Central Hospital; Academy of Finland [110663]; Finnish Cancer Society; Sigrid Juselius Foundation; European Union Framework Programme 6 [LSHC-CT-2003-503297]; Stichting tegen Kanker [232-2008]; Swedish Cancer Society; Gustav V Jubilee Foundation; Cancer Society in Stockholm; Bert von Kantzow Foundation; Kuopio University Central EVO; Academy of Finland; University of Kuopio; EVO of Vaasa Hospital District; Kathleen Cuningham Foundation Consortium; NHMRC [145684, 288704, 454508, 209057, 251533, 396414, 504711]; National Breast Cancer Foundation; Queensland Cancer Fund; Cancer Councils of Victoria; Cancer Councils of Tasmania; Cancer Councils of South Australia; Cancer Councils of New South Wales; Cancer Foundation of Western Australia; Hamburg Cancer Society; German Cancer Research Center; NIH [CA122340, ARRA CA122340Z, R01-CA63464, R37-CA54281, CA87969]; NCI [CA116201]; Cancer Council Victoria, VicHealth FX This study was supported in part by the European Community's Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175). The individual Breast Cancer Association Consortium (BCAC) studies were funded by the following sources: Australian Breast Cancer Family Study (ABCFS) and Ontario Familial Breast Cancer Registry (OBCFR): National Cancer Institute (NCI), National Institutes of Health (NIH) under RFA CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Northern California Cancer Center (U01 CA69417), and University of Melbourne (U01 CA69638).; Breast Cancer in Galway Genetic Study (BIGGS): E.J.S. is funded by the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London.; Copenhagen General Population Study (CGPS): The Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Copenhagen University Hospital, Herlev Hospital.; Spanish National Cancer Centre Breast Cancer Study (CNIO-BCS): The Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra Cancer and the Fondo de Investigacion Sanitario PI081120 to J.B. and PI081583 to R.L.M.).; Gene Environment Interaction and Breast Cancer in Germany (GENICA): Federal Ministry of Education and Research (BMBF) Germany (01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114), the Robert Bosch Foundation of Medical Research, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.; Genetic Epidemiology Study of Breast Cancer by Age 50 (GESBC): Deutsche Krebshilfe (70492) and the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm (P. 685).; Helsinki Breast Cancer Study (HEBCS): The Helsinki University Central Hospital Research Fund, Academy of Finland (110663), the Finnish Cancer Society, and the Sigrid Juselius Foundation.; Leuven Multidisciplinary Breast Centre (LMBC): European Union Framework Programme 6 Project LSHC-CT-2003-503297 (the Cancerdegradome) and by the 'Stichting tegen Kanker' (232-2008).; Karolinska Breast Cancer Study (KARBAC): The Swedish Cancer Society, the Gustav V Jubilee Foundation, the Cancer Society in Stockholm, and the Bert von Kantzow Foundation.; Kuopio Breast Cancer Project (KBCP): The Kuopio University Central EVO Research Fund, Academy of Finland, the Finnish Cancer Society, the University of Kuopio and EVO research funding of Vaasa Hospital District.; Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer (kConFab): NHMRC (145684, 288704 and 454508), the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. A. B. S. is supported by an NHMRC Senior Research Fellowship, and G. C.-T. by an NHMRC Senior Principal Research Fellowship.; Mammary Carcinoma Risk Factor Investigation (MARIE): Deutsche Krebshilfe e. V. (70-2892-BR I), the Hamburg Cancer Society, and the German Cancer Research Center.; Mayo Clinic Breast Cancer Study (MCBCS): NIH (CA122340), NIH recovery act (ARRA CA122340Z), and an NCI-sponsored Specialized Program Of Research Excellence (SPORE) Breast Cancer to the Mayo Clinic CA116201).; Melbourne Collaborative Cohort Study (MCCS): The Cancer Council Victoria, VicHealth, and NHMRC (209057, 251533, 396414, 504711).; Multiethnic Cohort (MEC): NIH (R01-CA63464 and R37-CA54281).; Nurses Health Study (NHS): NIH (CA87969).; Oulu Breast Cancer Study (OBCS): Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Finland, and Oulu University Hospital.; Leiden University Medical Centre Breast Cancer Study (ORIGO): The Dutch Cancer Society.; Polish Breast Cancer Study (PBCS): Intramural Research Program of US NIH, NCI, Division of Cancer Epidemiology and Genetics (DCEG). NR 69 TC 266 Z9 272 U1 5 U2 48 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB PY 2011 VL 103 IS 3 BP 250 EP 263 DI 10.1093/jnci/djq526 PG 14 WC Oncology SC Oncology GA 717EU UT WOS:000287027000010 PM 21191117 ER PT J AU Iwamoto, T Bianchini, G Booser, D Qi, YA Coutant, C Shiang, CYH Santarpia, L Matsuoka, J Hortobagyi, GN Symmans, WF Holmes, FA O'Shaughnessy, J Hellerstedt, B Pippen, J Andre, F Simon, R Pusztai, L AF Iwamoto, Takayuki Bianchini, Giampaolo Booser, Daniel Qi, Yuan Coutant, Charles Shiang, Christine Ya-Hui Santarpia, Libero Matsuoka, Junji Hortobagyi, Gabriel N. Symmans, William Fraser Holmes, Frankie A. O'Shaughnessy, Joyce Hellerstedt, Beth Pippen, John Andre, Fabrice Simon, Richard Pusztai, Lajos TI Gene Pathways Associated With Prognosis and Chemotherapy Sensitivity in Molecular Subtypes of Breast Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SET ENRICHMENT; EXPRESSION; RECEPTOR; ORIGINS; METASTASIS; VALIDATION; SIGNATURES; PATTERNS; WOMEN; PLUS AB Background We hypothesized that distinct biological processes might be associated with prognosis and chemotherapy sensitivity in the different types of breast cancers. Methods We performed gene set analyses with BRB-ArrayTools statistical software including 2331 functionally annotated gene sets (ie, lists of genes that correspond to a particular biological pathway or biochemical function) assembled from Ingenuity Pathway Analysis and Gene Ontology databases corresponding to almost all known biological processes. Gene set analysis was performed on gene expression data from three cohorts of 234, 170, and 175 patients with HER2-normal lymph node-negative breast cancer who received no systemic adjuvant therapy to identify gene sets associated prognosis and three additional cohorts of 198, 85, and 62 patients with HER2-normal stage I-III breast cancer who received preoperative chemotherapy to identify gene sets associated with pathological complete response to therapy. These analyses were performed separately for estrogen receptor (ER)-positive and ER-negative breast cancers. Interaction between gene sets and survival and treatment response by breast cancer subtype was assessed in individual datasets and also in pooled datasets. Statistical significance was estimated with permutation test. All statistical tests were two-sided. Results For ER-positive cancers, from 370 to 434 gene sets were associated with prognosis (P <= .05) and from 209 to 267 gene sets were associated with chemotherapy response in analysis by individual dataset. For ER-positive cancers, 131 gene sets were associated with prognosis and 69 were associated with pathological complete response (P <= .001) in pooled analysis. Increased expression of cell cycle-related gene sets was associated with poor prognosis, and B-cell immunity-related gene sets were associated with good prognosis. For ER-negative cancers, from 175 to 288 gene sets were associated with prognosis and from 212 to 285 gene sets were associated with chemotherapy response. In pooled analyses of ER-negative cancers, 14 gene sets were associated with prognosis and 23 were associated with response. Gene sets involved in sphingolipid and glycolipid metabolism were associated with better prognosis and those involved in base excision repair, cell aging, and spindle microtubule regulation were associated with chemotherapy response. Conclusion Different biological processes were associated with prognosis and chemotherapy response in ER-positive and ER-negative breast cancers. C1 [Iwamoto, Takayuki; Bianchini, Giampaolo; Booser, Daniel; Coutant, Charles; Shiang, Christine Ya-Hui; Santarpia, Libero; Hortobagyi, Gabriel N.; Pusztai, Lajos] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77230 USA. [Qi, Yuan] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77230 USA. [Symmans, William Fraser] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77230 USA. [Iwamoto, Takayuki; Matsuoka, Junji] Okayama Univ, Dept Gastroenterol Surg & Surg Oncol, Okayama, Japan. [Santarpia, Libero] Hosp Prato, Dept Oncol, Translat Res Unit, Prato, Italy. [Santarpia, Libero] Ist Toscano Tumori, Prato, Italy. [Holmes, Frankie A.] Texas Oncol, US Oncol, Houston, TX USA. [O'Shaughnessy, Joyce; Pippen, John] Texas Oncol, US Oncol, Baylor Sammons Canc Ctr, Dallas, TX USA. [Andre, Fabrice] Inst Gustave Roussy, Dept Med Oncol, Villejuif, France. [Hellerstedt, Beth] Texas Oncol, US Oncol, Austin, TX USA. [Simon, Richard] NCI, Biometr Branch, Rockville, MD USA. RP Pusztai, L (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Unit 1354,POB 301439, Houston, TX 77230 USA. EM lpusztai@mdanderson.org OI Santarpia, Libero/0000-0001-6777-1449 FU Ministere Francais des Affaires Etrangeres et Europeennes; Fondation de France; Federation Nationale des Centres de Lutte Contre le Cancer; Breast Cancer Research Foundation; MD Anderson Cancer Center; Commonwealth Cancer Foundation; College National des Gynecologues et Obstetriciens Francais; Association pour la Recherche sur le Cancer FX The Breast Cancer Research Foundation (L.P. and W.F.S.), The MD Anderson Cancer Center Faculty Incentive Funds (W.F.S.), and the Commonwealth Cancer Foundation (L.P. and W.F.S.). C.C. received support from l'Association pour la Recherche sur le Cancer, Lavoisier program le Ministere Francais des Affaires Etrangeres et Europeennes, le College National des Gynecologues et Obstetriciens Francais, and la Fondation de France and the la Federation Nationale des Centres de Lutte Contre le Cancer. NR 32 TC 84 Z9 87 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB PY 2011 VL 103 IS 3 BP 264 EP 272 DI 10.1093/jnci/djq524 PG 9 WC Oncology SC Oncology GA 717EU UT WOS:000287027000011 PM 21191116 ER PT J AU Buckner, CA Venkatesan, A Locklin, JK Wood, BJ AF Buckner, Carey A. Venkatesan, Aradhana Locklin, Julia K. Wood, Bradford J. TI Real-time Sonography With Electromagnetic Tracking Navigation for Biopsy of a Hepatic Neoplasm Seen Only on Arterial Phase Computed Tomography SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE electromagnetic tracking; fusion imaging; multimodality intervention ID LIVER-LESIONS; ABLATION AB This case illustrates the ability of electromagnetic tracking navigation to localize difficult targets in real time during biopsy or ablation of lesions that are only transiently apparent on arterial phase computed tomography and may be unapparent on sonography. Readily available technology enabling multimodality registration to sonography allows for the use of positron emission tomographic, magnetic resonance imaging, and computed tomographic information during sonographically guided procedures and examinations. C1 [Buckner, Carey A.] NIH, Ctr Intervent Oncol, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Buckner, CA (reprint author), NIH, Ctr Intervent Oncol, Ctr Clin, 9000 Rockville Pike,Bldg 10,Room 1C504, Bethesda, MD 20892 USA. EM bucknerca@cc.nih.gov FU National Institutes of Health (NIH) FX We thank Deborah Kim, MRT(N) (Traxtal/Phdips Healthcare, Toronto, Ontario, Canada), for technical assistance during the biopsy procedure. This study was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) and was related to a Cooperative Research and Development Agreement between the NIH and Philips Healthcare. The mention of commercial devices or products, their source, or their use in connection with the material reported herein is not to be construed as either an actual or implied endorsement of such products by the NIH, the US Department of Health and Human Services, or the US Public Health Service. Dr Wood and the NIH may have intellectual property in the field. NR 7 TC 8 Z9 8 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD FEB PY 2011 VL 30 IS 2 BP 253 EP 256 PG 4 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 770ZI UT WOS:000291126600012 PM 21266564 ER PT J AU Safronetz, D Rockx, B Feldmann, F Belisle, SE Palermo, RE Brining, D Gardner, D Proll, SC Marzi, A Tsuda, Y LaCasse, RA Kercher, L York, A Korth, MJ Long, D Rosenke, R Shupert, WL Aranda, CA Mattoon, JS Kobasa, D Kobinger, G Li, Y Taubenberger, JK Richt, JA Parnell, M Ebihara, H Kawaoka, Y Katze, MG Feldmann, H AF Safronetz, David Rockx, Barry Feldmann, Friederike Belisle, Sarah E. Palermo, Robert E. Brining, Douglas Gardner, Don Proll, Sean C. Marzi, Andrea Tsuda, Yoshimi LaCasse, Rachel A. Kercher, Lisa York, Anthony Korth, Marcus J. Long, Dan Rosenke, Rebecca Shupert, W. Lesley Aranda, Celia Alpuche Mattoon, John S. Kobasa, Darwyn Kobinger, Gary Li, Yan Taubenberger, Jeffery K. Richt, Juergen A. Parnell, Michael Ebihara, Hideki Kawaoka, Yoshihiro Katze, Michael G. Feldmann, Heinz TI Pandemic Swine-Origin H1N1 Influenza A Virus Isolates Show Heterogeneous Virulence in Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOKINE RESPONSES; IMMUNE-RESPONSE; INFECTION; DISEASE; MICE; PATHOGENESIS; FERRETS; HUMANS; HEMAGGLUTININ; TRANSMISSION AB The first influenza pandemic of the new millennium was caused by a newly emerged swine-origin influenza virus (SOIV) (H1N1). This new virus is characterized by a previously unknown constellation of gene segments derived from North American and Eurasian swine lineages and the absence of common markers predictive of human adaptation. Overall, human infections appeared to be mild, but an alarming number of young individuals presented with symptoms atypical for seasonal influenza. The new SOIV also showed a sustained human-to-human transmissibility and higher reproduction ratio than common seasonal viruses, altogether indicating a higher pathogenic potential for this newly emerged virus. To study the virulence of the SOIV, we used a recently established cynomolgus macaque model and compared parameters of clinical disease, virology, host responses, and pathology/histopathology with a current seasonal H1N1 virus. We here show that infection of macaques with two genetically similar but clinically distinct SOIV isolates from the early stage of the pandemic (A/Mexico/4108/2009 and A/Mexico/InDRE4487/2009) resulted in upper and lower respiratory tract infections and clinical disease ranging from mild to severe pneumonia that was clearly advanced over the mild infection caused by A/Kawasaki/UTK-4/2009, a current seasonal strain. Unexpectedly, we observed heterogeneity among the two SOIV isolates in virus replication, host transcriptional and cytokine responses, and disease progression, demonstrating a higher pathogenic potential for A/Mexico/InDRE4487/2009. Differences in virulence may explain more severe disease, as was seen with certain individuals infected with the emerged pandemic influenza virus. Thus, the nonhuman primate model closely mimics influenza in humans. C1 [Safronetz, David; Rockx, Barry; Feldmann, Friederike; Marzi, Andrea; Tsuda, Yoshimi; York, Anthony; Shupert, W. Lesley; Ebihara, Hideki; Feldmann, Heinz] Virol Lab, Hamilton, MT USA. [Brining, Douglas; Gardner, Don; LaCasse, Rachel A.; Kercher, Lisa; Long, Dan; Rosenke, Rebecca; Parnell, Michael] Rocky Mt Vet Branch, Hamilton, MT USA. NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Belisle, Sarah E.; Palermo, Robert E.; Proll, Sean C.; Korth, Marcus J.; Katze, Michael G.] Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA. [Belisle, Sarah E.; Palermo, Robert E.; Proll, Sean C.; Korth, Marcus J.; Katze, Michael G.] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Aranda, Celia Alpuche] Inst Diagnost & Referencia Epidemiol, Mexico City 11340, DF, Mexico. [Mattoon, John S.] Washington State Univ, Dept Vet Clin Sci, Pullman, WA 99164 USA. [Kobasa, Darwyn; Kobinger, Gary; Li, Yan] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. [Richt, Juergen A.] Kansas State Univ, Coll Vet Med, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA. [Kawaoka, Yoshihiro] Univ Tokyo, Inst Med Sci, Dept Microbiol & Immunol, Div Virol, Tokyo 1088639, Japan. [Kawaoka, Yoshihiro] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Influenza Res Inst, Madison, WI 53706 USA. [Kawaoka, Yoshihiro] ERATO Infect Induced Host Responses Project, Kawaguchi, Saitama 3320012, Japan. [Kawaoka, Yoshihiro] Hokkaido Univ, Creat Res Initiat, Sapporo, Hokkaido 0600818, Japan. RP Feldmann, H (reprint author), Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM honey@u.washington.edu; feldmannh@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Public Health Service [P51RR000166, R24RR016354]; NIAID [HHSN272200800060C, HHSN266200700010C]; Public Health Agency of Canada [310641]; ERATO (Japan Science and Technology Agency); Ministry of Education, Culture, Sports, Science, and Technology of Japan; National Institute of Allergy and Infectious Diseases Public Health Service FX The study was financially supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Public Health Service grants P51RR000166 and R24RR016354 and NIAID contract HHSN272200800060C awarded to M. G. K.; The Public Health Agency of Canada and the Team Grant 310641 awarded to D. K., H. F., and G. K.; and by Grants-in-Aid for Specially Promoted Research and for Scientific Research, by a Contract Research Fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases, by ERATO (Japan Science and Technology Agency), by the Special Co-ordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by National Institute of Allergy and Infectious Diseases Public Health Service research grants, and by an NIAID-funded Center for Research on Influenza Pathogenesis (CRIP, HHSN266200700010C), all awarded to Y.K. NR 38 TC 55 Z9 57 U1 0 U2 0 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 FEB PY 2011 VL 85 IS 3 BP 1214 EP 1223 DI 10.1128/JVI.01848-10 PG 10 WC Virology SC Virology GA 705PC UT WOS:000286147400006 PM 21084481 ER PT J AU Keller, PW Adamson, CS Heymann, JB Freed, EO Steven, AC AF Keller, Paul W. Adamson, Catherine S. Heymann, J. Bernard Freed, Eric O. Steven, Alasdair C. TI HIV-1 Maturation Inhibitor Bevirimat Stabilizes the Immature Gag Lattice SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; AMINO-TERMINAL DOMAIN; CAPSID PROTEIN; BETULINIC ACID; ELECTRON CRYOTOMOGRAPHY; CRYOELECTRON TOMOGRAPHY; PARTICLE MATURATION; IN-VITRO; RESISTANCE; PA-457 AB Maturation of nascent virions, a key step in retroviral replication, involves cleavage of the Gag polyprotein by the viral protease into its matrix (MA), capsid (CA), and nucleocapsid (NC) components and their subsequent reorganization. Bevirimat (BVM) defines a new class of antiviral drugs termed maturation inhibitors. BVM acts by blocking the final cleavage event in Gag processing, the separation of CA from its C-terminal spacer peptide 1 (SP1). Prior evidence suggests that BVM binds to Gag assembled in immature virions, preventing the protease from accessing the CA-SP1 cleavage site. To investigate this hypothesis, we used cryo-electron tomography to examine the structures of (noninfectious) HIV-1 viral particles isolated from BVM-treated cells. We find that these particles contain an incomplete shell of density underlying the viral envelope, with a hexagonal honeycomb structure similar to the Gag lattice of immature HIV but lacking the innermost, NC-related, layer. We conclude that the shell represents a remnant of the immature Gag lattice that has been processed, except at the CA-SP1 sites, but has remained largely intact. We also compared BVM-treated particles with virions formed by the mutant CA5, in which cleavage between CA and SP1 is also blocked. Here, we find a thinner CA-related shell with no visible evidence of honeycomb organization, indicative of an altered conformation and further suggesting that binding of BVM stabilizes the immature lattice. In both cases, the observed failure to assemble mature capsids correlates with the loss of infectivity. C1 [Keller, Paul W.; Heymann, J. Bernard; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Adamson, Catherine S.] Univ St Andrews, Sch Med, St Andrews KY16 9TF, Fife, Scotland. [Adamson, Catherine S.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bldg 50,Room 1517,50 South Dr,MSC 8025, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Heymann, Bernard/F-6825-2011; OI Heymann, Bernard/0000-0002-8872-5326 FU NIAMS; NCI; NIH FX This work was supported by the Intramural Research Programs of NIAMS and NCI and by the NIH Intramural AIDS Targeted Antiviral Program. NR 56 TC 45 Z9 45 U1 3 U2 14 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 FEB PY 2011 VL 85 IS 4 BP 1420 EP 1428 DI 10.1128/JVI.01926-10 PG 9 WC Virology SC Virology GA 709EP UT WOS:000286420900001 PM 21106735 ER PT J AU Klingeborn, M Race, B Meade-White, KD Rosenke, R Striebel, JF Chesebro, B AF Klingeborn, Mikael Race, Brent Meade-White, Kimberly D. Rosenke, Rebecca Striebel, James F. Chesebro, Bruce TI Crucial Role for Prion Protein Membrane Anchoring in the Neuroinvasion and Neural Spread of Prion Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB DISEASE; FOLLICULAR DENDRITIC CELLS; HUMAN GROWTH-HORMONE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; CEREBRAL BETA-AMYLOIDOSIS; TRANSGENIC MICE; PERIPHERAL-NERVES; SCRAPIE AGENT; MOUSE SCRAPIE; INTRAPERITONEAL INFECTION AB In nature prion diseases are usually transmitted by extracerebral prion infection, but clinical disease results only after invasion of the central nervous system (CNS). Prion protein (PrP), a host-encoded glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein, is necessary for prion infection and disease. Here, we investigated the role of the anchoring of PrP on prion neuroinvasion by studying various inoculation routes in mice expressing either anchored or anchorless PrP. In control mice with anchored PrP, intracerebral or sciatic nerve inoculation resulted in rapid CNS neuroinvasion and clinical disease (154 to 156 days), and after tongue, ocular, intravenous, or intraperitoneal inoculation, CNS neuroinvasion was only slightly slower (193 to 231 days). In contrast, in anchorless PrP mice, these routes resulted in slow and infrequent CNS neuroinvasion. Only intracerebral inoculation caused brain PrPres, a protease-resistant isoform of PrP, and disease in both types of mice. Thus, anchored PrP was an essential component for the rapid neural spread and CNS neuroinvasion of prion infection. C1 [Klingeborn, Mikael; Race, Brent; Meade-White, Kimberly D.; Striebel, James F.; Chesebro, Bruce] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [Rosenke, Rebecca] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. EM bchesebro@nih.gov 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. NR 60 TC 28 Z9 28 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 FEB PY 2011 VL 85 IS 4 BP 1484 EP 1494 DI 10.1128/JVI.02167-10 PG 11 WC Virology SC Virology GA 709EP UT WOS:000286420900007 PM 21123371 ER PT J AU Boonyaratanakornkit, J Bartlett, E Schomacker, H Surman, S Akira, S Bae, YS Collins, P Murphy, B Schmidt, A AF Boonyaratanakornkit, Jim Bartlett, Emmalene Schomacker, Henrick Surman, Sonja Akira, Shizuo Bae, Yong-Soo Collins, Peter Murphy, Brian Schmidt, Alexander TI The C Proteins of Human Parainfluenza Virus Type 1 Limit Double-Stranded RNA Accumulation That Would Otherwise Trigger Activation of MDA5 and Protein Kinase R SO JOURNAL OF VIROLOGY LA English DT Article ID NF-KAPPA-B; ANTIVIRAL SIGNALING PROTEIN; SENDAI-VIRUS; RIG-I; VACCINE CANDIDATES; INNATE IMMUNITY; INTERFERON-BETA; GENE-PRODUCTS; P/C GENE; ATTENUATING MUTATIONS AB Human parainfluenza virus type 1 (HPIV1) is an important respiratory pathogen in young children, the immunocompromised, and the elderly. We found that infection with wild-type (WT) HPIV1 suppressed the innate immune response in human airway epithelial cells by preventing not only phosphorylation of interferon regulatory factor 3 (IRF3) but also degradation of I kappa B beta, thereby inhibiting IRF3 and NF-kappa B activation, respectively. Both of these effects were ablated by a F170S substitution in the HPIV1 C proteins (F170S) or by silencing the C open reading frame [P(C-)], resulting in a potent beta interferon (IFN-beta) response. Using murine knockout cells, we found that IFN-beta induction following infection with either mutant relied mainly on melanoma-associated differentiation gene 5 (MDA5) rather than retinoic acid-inducible gene I (RIG-I). Infection with either mutant, but not WT HPIV1, induced a significant accumulation of intracellular double-stranded RNA (dsRNA). These mutant viruses directed a marked increase in the accumulation of viral genome, antigenome, and mRNA that was coincident with the accumulation of dsRNA. In addition, the amount of viral proteins was reduced compared to that of WT HPIV1. Thus, the accumulation of dsRNA might be a result of an imbalance in the N protein/genomic RNA ratio leading to incomplete encapsidation. Protein kinase R (PKR) activation and IFN-beta induction followed the kinetics of dsRNA accumulation. Interestingly, the C proteins did not appear to directly inhibit intracellular signaling involved in IFN-beta induction; instead, their role in preventing IFN-beta induction appeared to be in suppressing the formation of dsRNA. PKR activation contributed to IFN-beta induction and also was associated with the reduction in the amount of viral proteins. Thus, the HPIV1 C proteins normally limit the accumulation of dsRNA and thereby limit activation of IRF3, NF-kappa B, and PKR. If C protein function is compromised, as in the case of F170S HPIV1, the resulting PKR activation and reduction in viral protein levels enable the host to further reduce C protein levels and to mount a potent antiviral type I IFN response. C1 [Boonyaratanakornkit, Jim; Bartlett, Emmalene; Schomacker, Henrick; Surman, Sonja; Collins, Peter; Murphy, Brian; Schmidt, Alexander] NIAID, LID, RNA Viruses Sect, NIH, Bethesda, MD 20892 USA. [Akira, Shizuo] Osaka Univ, Host Def Lab, WPI Immunol Frontier Res Ctr, Suita, Osaka 5650871, Japan. [Bae, Yong-Soo] Sungkyunkwan Univ, Dept Biol Sci, Suwon 440746, Gyeonggi Do, South Korea. RP Schmidt, A (reprint author), NIAID, LID, RNA Viruses Sect, NIH, Bldg 50,Room 6511,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM schmidta@niaid.nih.gov RI Akira, Shizuo/C-3134-2009 FU NIH, National Institute of Allergy and Infectious Diseases; NIH; MedImmune, LLC FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. This research was also supported in part by a cooperative research and development agreement (CRADA) between NIH and MedImmune, LLC, for the development of PIV and RSV vaccines. NR 77 TC 26 Z9 27 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2011 VL 85 IS 4 BP 1495 EP 1506 DI 10.1128/JVI.01297-10 PG 12 WC Virology SC Virology GA 709EP UT WOS:000286420900008 PM 21123378 ER PT J AU Majerciak, V Uranishi, H Kruhlak, M Pilkington, GR Massimelli, MJ Bear, J Pavlakis, GN Felber, BK Zheng, ZM AF Majerciak, Vladimir Uranishi, Hiroaki Kruhlak, Michael Pilkington, Guy R. Massimelli, Maria Julia Bear, Jenifer Pavlakis, George N. Felber, Barbara K. Zheng, Zhi-Ming TI Kaposi's Sarcoma-Associated Herpesvirus ORF57 Interacts with Cellular RNA Export Cofactors RBM15 and OTT3 To Promote Expression of Viral ORF59 SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSPORT ELEMENT RTE; MESSENGER-RNA; SIGNALING PATHWAY; NUCLEAR-LOCALIZATION; FUNCTIONAL-ANALYSIS; GENE-EXPRESSION; SPLIT-ENDS; PROTEIN; UAP56; DROSOPHILA AB Kaposi's sarcoma-associated herpesvirus (KSHV) encodes ORF57, which promotes the accumulation of specific KSHV mRNA targets, including ORF59 mRNA. We report that the cellular export NXF1 cofactors RBM15 and OTT3 participate in ORF57-enhanced expression of KSHV ORF59. We also found that ectopic expression of RBM15 or OTT3 augments ORF59 production in the absence of ORF57. While RBM15 promotes the accumulation of ORF59 RNA predominantly in the nucleus compared to the levels in the cytoplasm, we found that ORF57 shifted the nucleocytoplasmic balance by increasing ORF59 RNA accumulation in the cytoplasm more than in the nucleus. By promoting the accumulation of cytoplasmic ORF59 RNA, ORF57 offsets the nuclear RNA accumulation mediated by RBM15 by preventing nuclear ORF59 RNA from hyperpolyadenylation. ORF57 interacts directly with the RBM15 C-terminal portion containing the SPOC domain to reduce RBM15 binding to ORF59 RNA. Although ORF57 homologs Epstein-Barr virus (EBV) EB2, herpes simplex virus (HSV) ICP27, varicella-zoster virus (VZV) IE4/ORF4, and cytomegalovirus (CMV) UL69 also interact with RBM15 and OTT3, EBV EB2, which also promotes ORF59 expression, does not function like KSHV ORF57 to efficiently prevent RBM15-mediated nuclear accumulation of ORF59 RNA and RBM15's association with polyadenylated RNAs. Collectively, our data provide novel insight elucidating a molecular mechanism by which ORF57 promotes the expression of viral intronless genes. C1 [Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Uranishi, Hiroaki; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pilkington, Guy R.; Bear, Jenifer; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kruhlak, Michael] NCI, Expt Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Room 6N106, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This study was supported by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. NR 53 TC 23 Z9 24 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2011 VL 85 IS 4 BP 1528 EP 1540 DI 10.1128/JVI.01709-10 PG 13 WC Virology SC Virology GA 709EP UT WOS:000286420900011 PM 21106733 ER PT J AU Almqvist, S Kleinman, HK Werthen, M Thomsen, P Agren, MS AF Almqvist, S. Kleinman, H. K. Werthen, M. Thomsen, P. Agren, M. S. TI Effects of amelogenins on angiogenesis-associated processes of endothelial cells SO JOURNAL OF WOUND CARE LA English DT Article DE amelogenins; wound healing; cell adhesion; migration; proliferation; organ culture ID PERIODONTAL-LIGAMENT CELLS; ENAMEL MATRIX PROTEINS; IN-VITRO; GINGIVAL FIBROBLASTS; BASEMENT-MEMBRANE; INTEGRIN; GROWTH; VIVO; ATTACHMENT; EXPRESSION AB Objective: To study the effects of an amelogenin mixture on integrin-dependent adhesion, DNA synthesis and apoptosis of cultured human dermal microvascular endothelial cells and angiogenesis in an organotypic assay. Method: Immobilised antibodies against specific integrins (alpha 1, alpha 2, alpha 3, alpha 4, alpha 5, alpha v, beta 1, beta 2, beta 3, beta 4, beta 6, alpha v beta 3, alpha v beta 5 and alpha 5 beta 1) were used to capture treated human dermal microvascular endothelial cells, which were detected colourimetrically. DNA synthesis of the cells was monitored by 5-bromo-2'-deoxyuridine incorporation and apoptosis by a TdT-mediated dUTP nick-end labelling technique.Tubule formation from aortic arches of 13-d-old chick embryos were followed over 48h. Results: The amelogenin mixture increased microvessel outgrowth by 76% (p<0.01, n=12) from the aortic explants. Also, amelogenins increased the adhesion (p<0.01, n=5) by multiple angiogenesis-associated integrin subunits and alpha v beta 3, alpha v beta 5 and alpha 5 beta 1 heterodimers on human dermal microvascular endothelial cells at a non-mitogenic concentration (100 mu g/ml). Conversely, amelogenins at 1,000 mu g/ml decreased microvessel formation possibly due to attenuation of corresponding integrins despite increasing (p<0.001, n=8) DNA synthesis. No significant apoptosis was detected in human dermal microvascular endothelial cells cultured on Matrigel with and without amelogenins. Conclusion: Increased surface expression of integrins on endothelial cells may contribute to the pro-angiogenic property of amelogenins. C1 [Almqvist, S.; Thomsen, P.] Univ Gothenburg, Sahlgrenska Acad, Dept Biomat, Gothenburg, Sweden. [Almqvist, S.; Werthen, M.; Thomsen, P.] Inst Biomat & Cell Therapy, Gothenburg, Sweden. [Almqvist, S.; Werthen, M.] Molnlycke Hlth Care AB, Gothenburg, Sweden. [Kleinman, H. K.] NIDCR, NIH, Bethesda, MD USA. [Thomsen, P.] BIOMATCELL VINN Excellence Ctr Biomat & Cell Ther, Gothenburg, Sweden. [Agren, M. S.] Bispebjerg Hosp, Dept Surg K, DK-2400 Copenhagen, Denmark. [Agren, M. S.] Bispebjerg Hosp, Copenhagen Wound Healing Ctr, DK-2400 Copenhagen, Denmark. RP Almqvist, S (reprint author), Univ Gothenburg, Sahlgrenska Acad, Dept Biomat, Gothenburg, Sweden. EM sofia.almqvist@biomaterials.gu.se FU Swedish Research Council [K2009-52X-09495-22-3]; Hjalmar Svensson Foundation; Molnlycke Health Care AB; VINNOVA VinnVaxt Program Biomedical Development in Western Sweden, Region Vastra Gotaland; Danish Medical Research Council [22-02-0287] FX Drs. Almqvist and Werthen are employees of Molnlycke Health Care AB. The studies were supported by the Swedish Research Council (grant K2009-52X-09495-22-3), Hjalmar Svensson Foundation, Molnlycke Health Care AB, the VINNOVA VinnVaxt Program Biomedical Development in Western Sweden, Region Vastra Gotaland and the Danish Medical Research Council (22-02-0287). NR 52 TC 2 Z9 2 U1 0 U2 2 PU MA HEALTHCARE LTD PI LONDON PA ST JUDES CHURCH, DULWICH ROAD, LONDON SE24 0PB, ENGLAND SN 0969-0700 J9 J WOUND CARE JI J. Wound Care PD FEB PY 2011 VL 20 IS 2 BP 68 EP + PG 7 WC Dermatology SC Dermatology GA 929YV UT WOS:000303102700005 PM 21378680 ER PT J AU Miller, RA Harrison, DE Astle, CM Baur, JA Boyd, AR de Cabo, R Fernandez, E Flurkey, K Javors, MA Nelson, JF Orihuela, CJ Pletcher, S Sharp, ZD Sinclair, D Starnes, JW Wilkinson, JE Nadon, NL Strong, R AF Miller, Richard A. Harrison, David E. Astle, C. M. Baur, Joseph A. Boyd, Angela Rodriguez de Cabo, Rafael Fernandez, Elizabeth Flurkey, Kevin Javors, Martin A. Nelson, James F. Orihuela, Carlos J. Pletcher, Scott Sharp, Zelton Dave Sinclair, David Starnes, Joseph W. Wilkinson, J. Erby Nadon, Nancy L. Strong, Randy TI Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE TOR; Rapamycin; Life span; Resveratrol ID CANCER-THERAPY; C-ELEGANS; DROSOPHILA-MELANOGASTER; CAENORHABDITIS-ELEGANS; REDUCTASE INHIBITOR; DIETARY RESTRICTION; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; DWARF MICE; MTOR AB Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging. C1 [Miller, Richard A.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Miller, Richard A.; Pletcher, Scott] Univ Michigan, Geriatr Ctr, Ann Arbor, MI 48109 USA. [Miller, Richard A.] Ann Arbor VA Med Ctr, Grad Res Educ & Clin Ctr, Ann Arbor, MI USA. [Harrison, David E.; Astle, C. M.; Flurkey, Kevin] Jackson Lab, Bar Harbor, ME 04609 USA. [Baur, Joseph A.] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Baur, Joseph A.] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Boyd, Angela Rodriguez; Orihuela, Carlos J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [de Cabo, Rafael] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Fernandez, Elizabeth; Javors, Martin A.; Nelson, James F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Fernandez, Elizabeth; Javors, Martin A.; Nelson, James F.; Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Pletcher, Scott] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Sharp, Zelton Dave] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, San Antonio, TX 78229 USA. [Sharp, Zelton Dave] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Sinclair, David] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Starnes, Joseph W.] Univ N Carolina, Dept Kinesiol, Greensboro, NC 27412 USA. [Wilkinson, J. Erby] Univ Michigan, Sch Med, Unit Lab Anim Med, Ann Arbor, MI USA. [Nadon, Nancy L.] NIA, Biol Aging Program, Bethesda, MD 20892 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX 78229 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. RP Miller, RA (reprint author), Univ Michigan, Dept Pathol, BSRB Room 3001,Box 2200,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM millerr@umich.edu RI Baur, Joseph/D-8163-2011; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Baur, Joseph/0000-0001-8262-6549; Sinclair, David/0000-0002-9936-436X; , rafael/0000-0003-2830-5693 FU National Institute on Aging at the National Institutes of Health [U01-AG022303, U01-AG025707, U01-AG022308, R21-AG029313, U01-AG022307, R01-AG13319]; Department of Veterans Affairs; National Institute on Aging FX This work was supported by the National Institute on Aging at the National Institutes of Health (U01-AG022303 to R.A.M., U01-AG025707 and U01-AG022308 to D.E.H., R21-AG029313 to C.J.O., and U01-AG022307 and R01-AG13319 to R.S.); and the Department of Veterans Affairs (R.A.M. and R.S.). R.d.C. is supported by the Intramural Research Program of the National Institute on Aging. NR 51 TC 350 Z9 355 U1 2 U2 40 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2011 VL 66 IS 2 BP 191 EP 201 DI 10.1093/gerona/glq178 PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 710TZ UT WOS:000286541200005 PM 20974732 ER PT J AU Doublier, S Lupia, E Catanuto, P Periera-Simon, S Xia, XM Korach, K Berho, M Elliot, SJ Karl, M AF Doublier, Sophie Lupia, Enrico Catanuto, Paola Periera-Simon, Simone Xia, Xiaomei Korach, Ken Berho, Mariana Elliot, Sharon J. Karl, Michael TI Testosterone and 17 beta-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice SO KIDNEY INTERNATIONAL LA English DT Article DE apoptosis; disease and progression; glomerulosclerosis; podocyte; pathophysiology of renal ID GLOMERULAR EPITHELIAL-CELLS; GROWTH-FACTOR-BETA; RENAL-DISEASE; MESANGIAL CELLS; TGF-BETA; FACTOR-I; EXPRESSION; INJURY; PROGRESSION; NEPHROPATHY AB Podocyte damage and apoptosis are thought to be important if not essential in the development of glomerulosclerosis. Female estrogen receptor knockout mice develop glomerulosclerosis at 9 months of age due to excessive ovarian testosterone production and secretion. Here, we studied the pathogenesis of glomerulosclerosis in this mouse model to determine whether testosterone and/or 17 beta-estradiol directly affect the function and survival of podocytes. Glomerulosclerosis in these mice was associated with the expression of desmin and the loss of nephrin, markers of podocyte damage and apoptosis. Ovariectomy preserved the function and survival of podocytes by eliminating the source of endogenous testosterone production. In contrast, testosterone supplementation induced podocyte apoptosis in ovariectomized wild-type mice. Importantly, podocytes express functional androgen and estrogen receptors, which, upon stimulation by their respective ligands, have opposing effects. Testosterone induced podocyte apoptosis in vitro by androgen receptor activation, but independent of the TGF-beta 1 signaling pathway. Pretreatment with 17 beta-estradiol prevented testosterone-induced podocyte apoptosis, an estrogen receptor-dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-beta 1- or TNF-alpha-induced apoptosis. Thus, podocytes are target cells for testosterone and 17 beta-estradiol. These hormones modulate podocyte damage and apoptosis. Kidney International (2011) 79, 404-413; doi:10.1038/ki.2010.398; published online 20 October 2010 C1 [Karl, Michael] Florida Int Coll Med, Div Endocrinol, Dept Med, Miami, FL 33199 USA. [Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Periera-Simon, Simone; Xia, Xiaomei; Berho, Mariana; Elliot, Sharon J.] Univ Miami, Leonard M Miller Sch Med, Dept Surg, Study Grp, Miami, FL USA. [Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Periera-Simon, Simone; Xia, Xiaomei; Berho, Mariana; Elliot, Sharon J.] Univ Miami, Leonard M Miller Sch Med, Dept Surg, Lab Sex & Gender Differences Hlth & Dis, Miami, FL USA. [Doublier, Sophie] Univ Turin, Dept Genet, Turin, Italy. [Lupia, Enrico] Univ Turin, Dept Clin Pathophysiol, Turin, Italy. [Korach, Ken] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Karl, M (reprint author), Florida Int Coll Med, Div Endocrinol, Dept Med, Miami, FL 33199 USA. EM Michael.Karl@jhsmiami.org FU NIH [RO1AG17170-06]; Progetto di Ricerca Sanitaria Finalizzata-Regione Piemonte FX This work was supported by NIH Grant RO1AG17170-06 (to SJE and MK), and Progetto di Ricerca Sanitaria Finalizzata-Regione Piemonte (to EL). NR 47 TC 32 Z9 34 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2011 VL 79 IS 4 BP 404 EP 413 DI 10.1038/ki.2010.398 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 713HL UT WOS:000286726500006 PM 20962747 ER PT J AU Clifton, GL Valadka, A Zygun, D Coffey, CS Drever, P Fourwinds, S Janis, LS Wilde, E Taylor, P Harshman, K Conley, A Puccio, A Levin, HS McCauley, SR Bucholz, RD Smith, KR Schmidt, JH Scott, JN Yonas, H Okonkwo, DO AF Clifton, Guy L. Valadka, Alex Zygun, David Coffey, Christopher S. Drever, Pamala Fourwinds, Sierra Janis, L. Scott Wilde, Elizabeth Taylor, Pauline Harshman, Kathy Conley, Adam Puccio, Ava Levin, Harvey S. McCauley, Stephen R. Bucholz, Richard D. Smith, Kenneth R. Schmidt, John H. Scott, James N. Yonas, Howard Okonkwo, David O. TI Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial SO LANCET NEUROLOGY LA English DT Article ID TERM MILD HYPOTHERMIA; SEVERE HEAD-INJURY; MODERATE HYPOTHERMIA; INTRACRANIAL HYPERTENSION; ADMISSION; PRESSURE; EFFICACY; THERAPY AB Background The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. Methods The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2.5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35 degrees C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33 degrees C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. Findings Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1.6 h (SD 0.5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35 C for the 52 patients in the hypothermia group was 2.6 h (SD 1.2) and to 33 degrees C was 4.4 h (1.5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1.08, 95% CI 0.76-1.53; p=0.67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1.30, 95% CI 0.58-2.52; p=0.52). Interpretation This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury. C1 [Clifton, Guy L.; Valadka, Alex; Drever, Pamala; Conley, Adam] Univ Texas Houston, Vivian L Smith Ctr Neurol Res, Dept Neurosurg, Med Sch Houston, Houston, TX USA. [Valadka, Alex] Seton Brain & Spine Inst, Austin, TX USA. [Zygun, David; Taylor, Pauline] Univ Calgary, Dept Crit Care Med, Calgary, AB, Canada. [Scott, James N.] Univ Calgary, Dept Radiol, Calgary, AB, Canada. [Coffey, Christopher S.] Univ Iowa, Dept Biostat, Iowa City, IA USA. [Coffey, Christopher S.] Univ Alabama, Dept Biostat, Sch Publ Hlth, Birmingham, AL 35294 USA. [Fourwinds, Sierra] Silverwind Res, La Veta, CO USA. [Janis, L. Scott] NINDS, Rockville, MD USA. [Wilde, Elizabeth; Levin, Harvey S.; McCauley, Stephen R.] Baylor Coll Med, Houston, TX 77030 USA. [Bucholz, Richard D.; Smith, Kenneth R.] St Louis Univ, Div Neurosurg, St Louis, MO 63103 USA. [Schmidt, John H.] Neurol Associates, Charleston, WV USA. [Yonas, Howard] Univ New Mexico, Dept Neurosurg, Albuquerque, NM 87131 USA. [Harshman, Kathy; Puccio, Ava; Okonkwo, David O.] Univ Pittsburgh, Dept Neurosurg, Pittsburgh, PA USA. RP Clifton, GL (reprint author), 6431 Fannin St,Suite 7-130, Houston, TX 77030 USA. EM guy.l.clifton@uth.tmc.edu FU National Institute of Neurological Disorders and Stroke [5U01 NS043353-06] FX This study was supported by a grant (5U01 NS043353-06) from the National Institute of Neurological Disorders and Stroke. NR 23 TC 159 Z9 170 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD FEB PY 2011 VL 10 IS 2 BP 131 EP 139 DI 10.1016/S1474-4422(10)70300-8 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 721IT UT WOS:000287347500008 PM 21169065 ER PT J AU Fernandez-Rhodes, LE Kokkinis, AD White, MJ Watts, CA Auh, S Jeffries, NO Shrader, JA Lehky, TJ Li, L Ryder, JE Levy, EW Solomon, BI Harris-Love, MO La Peon, A Schindler, AB Chen, C Di Prospero, NA Fischbeck, KH AF Fernandez-Rhodes, Lindsay E. Kokkinis, Angela D. White, Michelle J. Watts, Charlotte A. Auh, Sungyoung Jeffries, Neal O. Shrader, Joseph A. Lehky, Tanya J. Li, Li Ryder, Jennifer E. Levy, Ellen W. Solomon, Beth I. Harris-Love, Michael O. La Peon, Alison Schindler, Alice B. Chen, Cheunju Di Prospero, Nicholas A. Fischbeck, Kenneth H. TI Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial SO LANCET NEUROLOGY LA English DT Article ID TRANSGENIC MOUSE MODEL; ANDROGEN RECEPTOR; STATISTICAL MUNE; EXPRESSION; DISEASE; FEATURES AB Background Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a neuromuscular deficit that is mitigated by androgen-reducing treatment. We aimed to assess the efficacy and safety of the 5 alpha-reductase inhibitor dutasteride in patients with SBMA, and to identify outcome measures for use in future studies of the disease. Methods We undertook a randomised, double-blind, placebo-controlled, single-site clinical trial in ambulatory, symptomatic men with genetically confirmed SBMA. Participants were assigned by random number table to receive dutasteride (0.5 mg per day) or placebo orally for 24 months. Patients and investigators were masked to treatment allocation. The primary outcome measure was quantitative muscle assessment (QMA). The final efficacy analysis included all patients who were compliant with study treatment at 24 months. This trial was registered with ClinicalTrials.gov, NCT00303446. Findings 50 men were randomly assigned to treatment groups (25 dutasteride, 25 placebo), and 44 were included in the efficacy analysis (21 dutasteride, 23 placebo). At 24 months, the placebo group showed a decrease of 4.5% (-0.30 kg/kg) from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1.3% (0.14 kg/kg); the difference between groups (5.8%, 95% CI-5.9 to 17.6; p=0.28) was not significant. Prespecified secondary outcome measures of creatine kinase, muscle strength and function, motor nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. Quality of life, as measured by the physical component summary of the Medical Outcomes Study 36-item Short Form version 2, favoured dutasteride (change in score from baseline: placebo, -3.6%, vs dutasteride, 2.1%; p=0.01), whereas the mental component summary favoured placebo (3.3% vs -3.2%, p=0.03). The dutasteride group had fewer patients reporting falls than did the placebo group (9 vs 16; p=0.048); there were no other significant differences in reported adverse events. Interpretation Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of both positive and negative effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials. C1 [Fernandez-Rhodes, Lindsay E.; Kokkinis, Angela D.; White, Michelle J.; Watts, Charlotte A.; La Peon, Alison; Schindler, Alice B.; Chen, Cheunju; Di Prospero, Nicholas A.; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. [Auh, Sungyoung] NINDS, Clin Neurosci Program, Bethesda, MD 20892 USA. [Lehky, Tanya J.] NINDS, Electromyog Branch, Bethesda, MD 20892 USA. [Jeffries, Neal O.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Shrader, Joseph A.; Li, Li; Ryder, Jennifer E.; Levy, Ellen W.; Solomon, Beth I.; Harris-Love, Michael O.] NIH, Ctr Clin, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Fischbeck, KH (reprint author), 35-2A1000,35 Convent Dr, Bethesda, MD 20892 USA. EM kf@ninds.nih.gov RI Harris-Love, Michael/J-1359-2014 OI Harris-Love, Michael/0000-0002-1842-3269 FU US National Institutes of Health; NIH; Pfizer FX Funding US National Institutes of Health.; ADK owns stock in GlaxoSmithKline. MJW's stipend was paid by a fellowship from the NIH Clinical Research Training Program, which is supported in part by funds paid to the NIH Foundation by Pfizer. NADP is employed by and receives stock options from Johnson and Johnson. KHF serves as an unpaid member of advisory boards for Biogen Idec and Prosensa. All other authors declare that they have no conflicts of interest. NR 30 TC 57 Z9 60 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD FEB PY 2011 VL 10 IS 2 BP 140 EP 147 DI 10.1016/S1474-4422(10)70321-5 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 721IT UT WOS:000287347500009 PM 21216197 ER PT J AU Kapogiannis, D Mattson, MP AF Kapogiannis, Dimitrios Mattson, Mark P. TI Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease SO LANCET NEUROLOGY LA English DT Article ID AMYLOID-BETA-PEPTIDE; TRANSGENIC MOUSE MODEL; NGF GENE DELIVERY; A-BETA; NEUROTROPHIC FACTOR; CALORIE RESTRICTION; CORTICAL-NEURONS; HUMAN BRAIN; SYNAPTIC PLASTICITY; DIETARY RESTRICTION AB Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimer's disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans. C1 [Mattson, Mark P.] NIA, Neurosci Lab, Biomed Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. [Kapogiannis, Dimitrios] NIA, Clin Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Biomed Res Ctr, Intramural Res Program, Room 05C214,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. We thank Peter Rapp and Lennart Mucke for their valuable comments on the manuscript. NR 138 TC 149 Z9 152 U1 4 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD FEB PY 2011 VL 10 IS 2 BP 187 EP 198 DI 10.1016/S1474-4422(10)70277-5 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 721IT UT WOS:000287347500013 PM 21147038 ER PT J AU Kobilo, T Yuan, CY van Praag, H AF Kobilo, Tali Yuan, Chunyan van Praag, Henriette TI Endurance factors improve hippocampal neurogenesis and spatial memory in mice SO LEARNING & MEMORY LA English DT Article ID ACTIVATED PROTEIN-KINASE; SKELETAL-MUSCLE; MITOCHONDRIAL BIOGENESIS; AMP KINASE; EXERCISE; BRAIN; RECEPTOR; COGNITION; NEURONS; PROLIFERATION AB Physical activity improves learning and hippocampal neurogenesis. It is unknown whether compounds that increase endurance in muscle also enhance cognition. We investigated the effects of endurance factors, peroxisome proliferator-activated receptor delta agonist GW501516 and AICAR, activator of AMP-activated protein kinase on memory and neurogenesis. Mice were injected with GW for 7 d or AICAR for 7 or 14 d. Two weeks thereafter mice were tested in the Morris water maze. AICAR (7 d) and GW improved spatial memory. Moreover, AICAR significantly, and GW modestly, elevated dentate gyrus neurogenesis. Thus, pharmacological activation of skeletal muscle may mediate cognitive effects. C1 [Kobilo, Tali; Yuan, Chunyan; van Praag, Henriette] NIA, Neuroplast & Behav Unit, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, Neuroplast & Behav Unit, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU NIH, National Institute on Aging (NIA) FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging (NIA). We thank Donna Tignor, James Hopkins, Mike Still, and Derrick Haire for animal care and technical assistance. We thank Dr. Jaroslaw Aronowski for insightful comments on the manuscript. NR 44 TC 36 Z9 37 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 J9 LEARN MEMORY JI Learn. Mem. PD FEB PY 2011 VL 18 IS 2 BP 103 EP 107 DI 10.1101/lm.2001611 PG 5 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 721YB UT WOS:000287392600003 PM 21245211 ER PT J AU Novikov, A AF Novikov, Alexander TI Advanced theory of driven birdcage resonator with losses for biomedical magnetic resonance imaging and spectroscopy SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Birdcage; Losses; Damping; Kirchhoff; Green's functions; Laplace transform; Perturbation; Loss tangent ID DIELECTRIC-PROPERTIES; CAGE RESONATOR; SAMPLES; COIL; TISSUES; DESIGN; PROBE; PASS AB A complete time-dependent physics theory of symmetric unperturbed driven hybrid birdcage resonator was developed for general application. In particular, the theory can be applied for radiofrequency (RF) coil engineering, computer simulations of coil-sample interaction, etc. Explicit time dependence is evaluated for different forms of driving voltage. The major steps of the solution development are shown and appropriate explanations are given. Green's functions and spectral density formula were developed for any form of periodic driving voltage. The concept of distributed power losses based on transmission line theory is developed for evaluation of local losses of a coil. Three major types of power losses are estimated as equivalent series resistances in the circuit of the birdcage resonator. Values of generated resistances in legs and end-rings are estimated. An application of the theory is shown for many practical cases. Experimental curve of B-1 field polarization dependence is measured for eight-sections birdcage coil. It was shown that the steady-state driven resonance frequencies do not depend on damping factor unlike the free oscillation (transient) frequencies. An equivalent active resistance is generated due to interaction of RF electromagnetic field with a sample. Resistance of the conductor (enhanced by skin effect), Eddy currents and dielectric losses are the major types of losses which contribute to the values of generated resistances. A biomedical sample for magnetic resonance imaging and spectroscopy is the source of the both Eddy current and dielectric losses of a coil. As demonstrated by the theory, Eddy current loss is the major effect of coil shielding. Published by Elsevier Inc. C1 [Novikov, Alexander] NIMH, NIH, Bethesda, MD 20892 USA. [Novikov, Alexander] NICHHD, NIH, Bethesda, MD 20892 USA. RP Novikov, A (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM anovikov41@yahoo.com FU National Institutes of Health (NTH), National Institute of Mental Health FX This project was supported by the Intramural Research Program of the National Institutes of Health (NTH), National Institute of Mental Health. NR 38 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD FEB PY 2011 VL 29 IS 2 BP 260 EP 271 DI 10.1016/j.mri.2010.08.001 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 721XG UT WOS:000287390500014 PM 20869184 ER PT J AU Reiter, DA Roque, RA Lin, PC Irrechukwu, O Doty, S Longo, DL Pleshko, N Spencer, RG AF Reiter, David A. Roque, Remigio A. Lin, Ping-Chang Irrechukwu, Onyi Doty, Stephen Longo, Dan L. Pleshko, Nancy Spencer, Richard G. TI Mapping Proteoglycan-Bound Water in Cartilage: Improved Specificity of Matrix Assessment Using Multiexponential Transverse Relaxation Analysis SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE transverse relaxation; proteoglycan mapping; multiexponential relaxation; cartilage ID FIXED CHARGE-DENSITY; ARTICULAR-CARTILAGE; MAGNETIC-RESONANCE; MULTIPLE-SCLEROSIS; MRI; NMR; T-2; COLLAGEN; TISSUE; GLYCOSAMINOGLYCANS AB Association of MR parameters with cartilage matrix components remains an area of ongoing investigation. Multiexponential analysis of nonlocalized transverse relaxation data has previously been used to quantify water compartments associated with matrix macromolecules in cartilage. We extend this to mapping the proteoglycan (PG)-bound water fraction in cartilage, using mature and young bovine nasal cartilage model systems, toward the goal of matrix component-specific imaging. PG-bound water fraction from mature and young bovine nasal cartilage was 0.31 +/- 0.04 and 0.22 +/- 0.06, respectively, in agreement with biochemically derived PG content and PG-to-water weight ratios. Fourier transform infrared imaging spectroscopic-derived PG maps normalized by water content (IR-PG(ww)) showed spatial correspondence with PG-bound water fraction maps. Extensive simulation analysis demonstrated that the accuracy and precision of our determination of PG-bound water fraction was within 2%, which is well-within the observed tissue differences. Our results demonstrate the feasibility of performing imaging-based multiexponential analysis of transverse relaxation data to map PG in cartilage. Magn Reson Med 65:377-384, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Reiter, David A.; Roque, Remigio A.; Lin, Ping-Chang; Irrechukwu, Onyi; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. [Doty, Stephen] Hosp Special Surg, Microscopy Core Facil, Div Res, New York, NY 10021 USA. [Longo, Dan L.] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. [Pleshko, Nancy] Temple Univ, Dept Mech Engn, Philadelphia, PA 19122 USA. RP Reiter, DA (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, NIH, GRC 4D-06, Baltimore, MD 21224 USA. EM reiterda@mail.nih.gov OI Lin, Ping-Chang/0000-0003-0918-4072 FU NIH [R01 EB000744, AR046121]; NIH, National Institute on Aging FX Grant sponsor: NIH; Grant numbers: R01 EB000744, AR046121; Grant sponsor: Intramural Research Program of the NIH, National Institute on Aging. NR 36 TC 25 Z9 26 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2011 VL 65 IS 2 BP 377 EP 384 DI 10.1002/mrm.22673 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 712CT UT WOS:000286643000010 PM 21264931 ER PT J AU Day, SE Kettunen, MI Cherukuri, MK Mitchell, JB Lizak, MJ Morris, HD Matsumoto, S Koretsky, AP Brindle, KM AF Day, Sam E. Kettunen, Mikko I. Cherukuri, Murali Krishna Mitchell, James B. Lizak, Martin J. Morris, H. Douglas Matsumoto, Shingo Koretsky, Alan P. Brindle, Kevin M. TI Detecting Response of Rat C6 Glioma Tumors to Radiotherapy Using Hyperpolarized [1-C-13]Pyruvate and C-13 Magnetic Resonance Spectroscopic Imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE glioma; radiotherapy; pyruvate ID IN-VIVO; BRAIN-TUMORS; FLUORODEOXYGLUCOSE; PYRUVATE AB We show here that hyperpolarized [1-C-13]pyruvate can be used to detect treatment response in a glioma tumor model; a tumor type where detection of response with (18)fluoro-2-deoxyglucose, using positron emission tomography, is limited by the high background signals from normal brain tissue. C-13 chemical shift images acquired following intravenous injection of hyperpolarized [1-C-13]pyruvate into rats with implanted C6 gliomas showed significant labeling of lactate within the tumors but comparatively low levels in surrounding brain.Labeled pyruvate was observed at high levels in blood vessels above the brain and from other major vessels elsewhere but was detected at only low levels in tumor and brain.The ratio of hyperpolarized C-13 label in tumor lactate compared to the maximum pyruvate signal in the blood vessels was decreased from 0.38 +/- 0.16 to 0.23 +/- 0.13, (a reduction of 34%) by 72 h following whole brain irradiation with 15 Gy. Magn Reson Med 65:557-563,2011. (C) 2010 Wiley-Liss, Inc. C1 [Day, Sam E.; Kettunen, Mikko I.; Brindle, Kevin M.] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England. [Day, Sam E.; Lizak, Martin J.; Morris, H. Douglas; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Kettunen, Mikko I.; Brindle, Kevin M.] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England. RP Brindle, KM (reprint author), Univ Cambridge, Dept Biochem, 80 Tennis Court Rd, Cambridge CB2 1GA, England. EM kmb1001@cam.ac.uk RI Kettunen, Mikko/K-2299-2012; Koretsky, Alan/C-7940-2015 OI Kettunen, Mikko/0000-0002-2004-660X; Koretsky, Alan/0000-0002-8085-4756 FU Cancer Research UK [C197/A3514]; NINDS; NIH; NCI FX Grant sponsor: Cancer Research UK Programme grant; Grant number: C197/A3514; Grant sponsors: NINDS, NIH, NCI (Intramural Research Program). NR 23 TC 55 Z9 57 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2011 VL 65 IS 2 BP 557 EP 563 DI 10.1002/mrm.22698 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 712CT UT WOS:000286643000031 PM 21264939 ER PT J AU Han, PKJ Klabunde, CN Breen, N Yuan, GG Grauman, A Davis, WW Taplin, SH AF Han, Paul K. J. Klabunde, Carrie N. Breen, Nancy Yuan, Gigi Grauman, Alyssa Davis, William W. Taplin, Stephen H. TI Multiple Clinical Practice Guidelines for Breast and Cervical Cancer Screening Perceptions of US Primary Care Physicians SO MEDICAL CARE LA English DT Article DE clinical practice guidelines; perceptions; cancer screening; primary care physicians ID TASK-FORCE RECOMMENDATIONS; PREVENTIVE CARE; ATTITUDES; QUALITY; PREFERENCES; VALIDATION; AMBIGUITY; VIGNETTES; UNCERTAINTY; MAMMOGRAPHY AB Background: Multiple clinical practice guidelines exist for breast and cervical cancer screening, and differ in aggressiveness with respect to the recommended frequency and target populations for screening. Objectives: To determine (1) US primary care physicians' (PCPs) perceptions of the influence of different clinical practice guidelines; (2) the relationship between the number, aggressiveness, and agreement of influential guidelines and the aggressiveness of physicians' screening recommendations; and (3) factors associated with guideline perceptions. Research Design and Methods: A nationally representative sample of 1212 PCPs was surveyed in 2006-2007. Cross-sectional analyses examined physicians' perceptions of the influence of different breast and cervical cancer screening guidelines, the relationship of guideline perceptions to screening recommendations in response to hypothetical vignettes, and the predictors of guideline perceptions. Results: American Cancer Society and American College of Obstetricians and Gynecologists guidelines were perceived as more influential than other guidelines. Most physicians (62%) valued multiple guidelines, and conflicting and aggressive rather than conservative guideline combinations. The number, aggressiveness, and agreement of influential guidelines were associated with the aggressiveness of screening recommendations (P < 0.01)-which was highest for physicians valuing multiple-aggressive, lowest for physicians valuing multiple-conservative, and intermediate for physicians valuing multiple-conflicting, single, and no guidelines. Obstetrician/gynecologists specialty predicted valuation of aggressive guidelines (P < 0.001). Conclusions: PCPs' perceptions of cancer screening guidelines vary, relate to screening recommendations in logically-consistent ways, and are predicted by specialty and other factors. The number, aggressiveness, and agreement of valued guidelines are associated with screening recommendations, suggesting that guideline multiplicity is an important problem in clinical decision-making. C1 [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04101 USA. [Klabunde, Carrie N.; Breen, Nancy; Grauman, Alyssa; Davis, William W.; Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Yuan, Gigi] Informat Management Serv Inc, Silver Spring, MD USA. RP Han, PKJ (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, 39 Forest Ave, Portland, ME 04101 USA. EM hanp@mmc.org OI Han, Paul/0000-0003-0165-1940 FU Agency for Healthcare Research and Quality [Y3-PC-5019-01, Y3-PC-5019-02]; Centers for Disease Control and Prevention [Y3-PC-6017-01]; National Cancer Institute at the National Institutes of Health [N02-PC-51308] FX Supported by the Agency for Healthcare Research and Quality (inter-agency agreement numbers Y3-PC-5019-01 and Y3-PC-5019-02); the Centers for Disease Control and Prevention (inter-agency agreement number Y3-PC-6017-01); and by intramural research funds from the National Cancer Institute at the National Institutes of Health (contract number N02-PC-51308). NR 57 TC 20 Z9 20 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD FEB PY 2011 VL 49 IS 2 BP 139 EP 148 DI 10.1097/MLR.0b013e318202858e PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 706BR UT WOS:000286191000005 PM 21206294 ER PT J AU Freed, M de Zwart, JA Loud, JT El Khouli, RH Myers, KJ Greene, MH Duyn, JH Badano, A AF Freed, Melanie de Zwart, Jacco A. Loud, Jennifer T. El Khouli, Riham H. Myers, Kyle J. Greene, Mark H. Duyn, Jeff H. Badano, Aldo TI An anthropomorphic phantom for quantitative evaluation of breast MRI SO MEDICAL PHYSICS LA English DT Article DE breast imaging; phantom; standardization; MRI ID CONTRAST-ENHANCED MRI; PREOPERATIVE ASSESSMENT; PARAMETER-ESTIMATION; SURGICAL-MANAGEMENT; DIAGNOSTIC-ACCURACY; RELAXATION-TIMES; CANCER; TISSUE; IMPACT; OPTIMIZATION AB Purpose: In this study, the authors aim to develop a physical, tissue-mimicking phantom for quantitative evaluation of breast MRI protocols. The objective of this phantom is to address the need for improved standardization in breast MRI and provide a platform for evaluating the influence of image protocol parameters on lesion detection and discrimination. Quantitative comparisons between patient and phantom image properties are presented. Methods: The phantom is constructed using a mixture of lard and egg whites, resulting in a random structure with separate adipose- and glandular-mimicking components. T(1) and T(2) relaxation times of the lard and egg components of the phantom were estimated at 1.5 T from inversion recovery and spin-echo scans, respectively, using maximum-likelihood methods. The image structure was examined quantitatively by calculating and comparing spatial covariance matrices of phantom and patient images. A static, enhancing lesion was introduced by creating a hollow mold with stereolithography and filling it with a gadolinium-doped water solution. Results: Measured phantom relaxation values fall within 2 standard errors of human values from the literature and are reasonably stable over 9 months of testing. Comparison of the covariance matrices of phantom and patient data demonstrates that the phantom and patient data have similar image structure. Their covariance matrices are the same to within error bars in the anterior-posterior direction and to within about two error bars in the right-left direction. The signal from the phantom's adipose-mimicking material can be suppressed using active fat-suppression protocols. A static, enhancing lesion can also be included with the ability to change morphology and contrast agent concentration. Conclusions: The authors have constructed a phantom and demonstrated its ability to mimic human breast images in terms of key physical properties that are relevant to breast MRI. This phantom provides a platform for the optimization and standardization of breast MRI imaging protocols for lesion detection and characterization. [DOI: 10.1118/1.3533899] C1 [Freed, Melanie; Myers, Kyle J.; Badano, Aldo] US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Freed, Melanie] Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. [de Zwart, Jacco A.; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Loud, Jennifer T.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [El Khouli, Riham H.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [El Khouli, Riham H.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [El Khouli, Riham H.] Suez Canal Univ, Sch Med, Dept Diagnost Radiol, Ismailia, Egypt. RP Freed, M (reprint author), US FDA, Div Imaging & Appl Math, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM melanie.freed@fda.hhs.gov OI badano, aldo/0000-0003-3712-6670 FU Office of Women's Health at the Food and Drug Administration; Center for Devices and Radiological Health; U.S. Department of Energy; U.S. Food and Drug Administration; NINDS/NIH; NCI FX The authors thank Rachel Brem (GWU Hospital), Brian Garra (FDA/CDRH), and Eileen Thompson (GWU Hospital) for acquisition of GE clinical images of the phantom; Eugene O'Bryan, Randy Bidinger, and Bruce Fleharty (FDA/CDRH) for advice on design and construction of custom phantom jars; Brandon D. Gallas (FDA/CDRH) for discussions on covariance matrices and maximum-likelihood estimation; Christian Graff for discussions on bounded maximization; and Han Wen (NHLBI/NIH) for providing MRI scan time. The authors also acknowledge the use of facilities in Radiology and Imaging Sciences at the NIH Clinical Center. This study was supported, in part, by a research grant from the Office of Women's Health at the Food and Drug Administration. This project was supported, in part, by an appointment to the Research Participation Program at the Center for Devices and Radiological Health administered by Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. This research was sponsored, in part, by the Intramural Research Program of NINDS/NIH. J. T. Loud and M. H. Greene were supported by funding from the NCI Intramural Research Program. NR 60 TC 13 Z9 13 U1 0 U2 10 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 FEB PY 2011 VL 38 IS 2 BP 743 EP 753 DI 10.1118/1.3533899 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 716DI UT WOS:000286945000022 PM 21452712 ER PT J AU Armato, SG McLennan, G Bidaut, L McNitt-Gray, MF Meyer, CR Reeves, AP Zhao, BS Aberle, DR Henschke, CI Hoffman, EA Kazerooni, EA MacMahon, H van Beek, EJR Yankelevitz, D Biancardi, AM Bland, PH Brown, MS Engelmann, RM Laderach, GE Max, D Pais, RC Qing, DPY Roberts, RY Smith, AR Starkey, A Batra, P Caligiuri, P Farooqi, A Gladish, GW Jude, CM Munden, RF Petkovska, I Quint, LE Schwartz, LH Sundaram, B Dodd, LE Fenimore, C Gur, D Petrick, N Freymann, J Kirby, J Hughes, B Casteele, AV Gupte, S Sallam, M Heath, MD Kuhn, MH Dharaiya, E Burns, R Fryd, DS Salganicoff, M Anand, V Shreter, U Vastagh, S Croft, BY Clarke, LP AF Armato, Samuel G., III McLennan, Geoffrey Bidaut, Luc McNitt-Gray, Michael F. Meyer, Charles R. Reeves, Anthony P. Zhao, Binsheng Aberle, Denise R. Henschke, Claudia I. Hoffman, Eric A. Kazerooni, Ella A. MacMahon, Heber van Beek, Edwin J. R. Yankelevitz, David Biancardi, Alberto M. Bland, Peyton H. Brown, Matthew S. Engelmann, Roger M. Laderach, Gary E. Max, Daniel Pais, Richard C. Qing, David P-Y Roberts, Rachael Y. Smith, Amanda R. Starkey, Adam Batra, Poonam Caligiuri, Philip Farooqi, Ali Gladish, Gregory W. Jude, C. Matilda Munden, Reginald F. Petkovska, Iva Quint, Leslie E. Schwartz, Lawrence H. Sundaram, Baskaran Dodd, Lori E. Fenimore, Charles Gur, David Petrick, Nicholas Freymann, John Kirby, Justin Hughes, Brian Casteele, Alessi Vande Gupte, Sangeeta Sallam, Maha Heath, Michael D. Kuhn, Michael H. Dharaiya, Ekta Burns, Richard Fryd, David S. Salganicoff, Marcos Anand, Vikram Shreter, Uri Vastagh, Stephen Croft, Barbara Y. Clarke, Laurence P. TI The Lung Image Database Consortium, (LIDC) and Image Database Resource Initiative (IDRI): A Completed Reference Database of Lung Nodules on CT Scans SO MEDICAL PHYSICS LA English DT Article DE lung nodule; computed tomography (CT); thoracic imaging; interobserver variability; computer-aided diagnosis (CAD) ID COMPUTED-TOMOGRAPHY SCANS; PULMONARY NODULES; SCREENING TRIAL; AIDED DETECTION; CANCER; TRUTH; PERFORMANCE; SELECTION; NELSON; CAD AB Purpose: The development of computer-aided diagnostic (CAD) methods for lung nodule detection, classification, and quantitative assessment can be facilitated through a well-characterized repository of computed tomography (CT) scans. The Lung Image Database Consortium (LIDC) and Image Database Resource Initiative (IDRI) completed such a database, establishing a publicly available reference for the medical imaging research community. Initiated by the National Cancer Institute (NCI), further advanced by the Foundation for the National Institutes of Health (FNIH), and accompanied by the Food and Drug Administration (FDA) through active participation, this public-private partnership demonstrates the success of a consortium founded on a consensus-based process. Methods: Seven academic centers and eight medical imaging companies collaborated to identify, address, and resolve challenging organizational, technical, and clinical issues to provide a solid foundation for a robust database. The LIDC/IDRI Database contains 1018 cases, each of which includes images from a clinical thoracic CT scan and an associated XML file that records the results of a two-phase image annotation process performed by four experienced thoracic radiologists. In the initial blinded-read phase, each radiologist independently reviewed each CT scan and marked lesions belonging to one of three categories ("nodule >= 3 mm," "nodule < 3 mm," and "non-nodule >= 3 mm"). In the subsequent unblinded-read phase, each radiologist independently reviewed their own marks along with the anonymized marks of the three other radiologists to render a final opinion. The goal of this process was to identify as completely as possible all lung nodules in each CT scan without requiring forced consensus. Results: The Database contains 7371 lesions marked "nodule" by at least one radiologist. 2669 of these lesions were marked "nodule >= 3 mm" by at least one radiologist, of which 928 (34.7%) received such marks from all four radiologists. These 2669 lesions include nodule outlines and subjective nodule characteristic ratings. Conclusions: The LIDC/IDRI Database is expected to provide an essential medical imaging research resource to spur CAD development, validation, and dissemination in clinical practice. [DOI: 10.1118/1.3528204] C1 [Armato, Samuel G., III; MacMahon, Heber; Engelmann, Roger M.; Roberts, Rachael Y.; Caligiuri, Philip] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [McLennan, Geoffrey] Univ Iowa, Carver Coll Med, Dept Internal Med, Div Pulm, Iowa City, IA 52242 USA. [McNitt-Gray, Michael F.; Aberle, Denise R.; Brown, Matthew S.; Pais, Richard C.; Qing, David P-Y; Batra, Poonam; Jude, C. Matilda; Petkovska, Iva] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90024 USA. [Meyer, Charles R.] Univ Michigan, Dept Radiol, Sch Med, Ann Arbor, MI 48109 USA. [Reeves, Anthony P.; Biancardi, Alberto M.] Cornell Univ, Sch Elect & Comp Engn, Ithaca, NY 14853 USA. [Zhao, Binsheng] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10065 USA. [Henschke, Claudia I.; Yankelevitz, David; Max, Daniel; Farooqi, Ali] Mt Sinai Sch Med, Dept Radiol, New York, NY 10029 USA. [Hoffman, Eric A.; van Beek, Edwin J. R.; Smith, Amanda R.] Univ Iowa, Carver Coll Med, Dept Radiol, Iowa City, IA 52242 USA. [Kazerooni, Ella A.] Univ Michigan Hlth Syst, Dept Radiol, Cardiovasc Ctr 5482, Ann Arbor, MI 48109 USA. [Bland, Peyton H.; Laderach, Gary E.] Univ Michigan, Dept Radiol, BSRB A502, Ann Arbor, MI 48109 USA. [Gladish, Gregory W.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Unit 1478, Houston, TX 77030 USA. [Munden, Reginald F.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Imaging, Unit 1478, Houston, TX 77030 USA. [Schwartz, Lawrence H.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA. [Sundaram, Baskaran] Univ Michigan Hlth Syst, Dept Radiol, CVC 5481, Ann Arbor, MI 48109 USA. [Fenimore, Charles] NIST, Informat Access Div, Gaithersburg, MD 20899 USA. [Gur, David] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15213 USA. [Petrick, Nicholas] US FDA, Silver Spring, MD 20993 USA. [Freymann, John; Kirby, Justin] SAIC Frederick Inc, Bethesda, MD 20892 USA. [Hughes, Brian] TerpSys, Rockville, MD 20852 USA. [Casteele, Alessi Vande] Agfa HealthCare NV, B-2640 Mortsel, Belgium. [Gupte, Sangeeta] FUJIFILM Med Syst USA Inc, Stamford, CT 06902 USA. [Sallam, Maha] iCAD Inc, Nashua, NH 03062 USA. [Heath, Michael D.] Carestream Hlth Inc, Rochester, NY 14615 USA. [Kuhn, Michael H.] Philips Med Syst DMC GmbH, D-22315 Hamburg, Germany. [Dharaiya, Ekta] Philips Healthcare, Highland Hts, OH 44143 USA. [Burns, Richard; Fryd, David S.] Riverain Med, Miamisburg, OH 45342 USA. [Salganicoff, Marcos; Anand, Vikram] Siemens Med Solut USA Inc, Malvern, PA 19355 USA. [Shreter, Uri] GE Healthcare, Waukesha, WI 53188 USA. [Vastagh, Stephen] Med Imaging & Technol Alliance, Arlington, VA 22209 USA. [Croft, Barbara Y.; Clarke, Laurence P.] NCI, Canc Imaging Program, Bethesda, MD 20892 USA. [Henschke, Claudia I.] Weill Cornell Med Coll, Dept Radiol, New York, NY USA. RP Armato, SG (reprint author), Univ Chicago, Dept Radiol, 5841 S Maryland Ave,MC 2026, Chicago, IL 60637 USA. EM s-armato@uchicago.edu RI Croft, Barbara/D-1248-2013; OI Croft, Barbara/0000-0003-2544-150X; Bidaut, Luc/0000-0001-8253-2606; Munden, Reginald/0000-0003-3836-5067; Aberle, Denise/0000-0002-8858-3401 FU USPHS [U01CA091085, U01CA091090, U01CA091099, U01CA091100, U01CA091103]; NCI [HHSN261200800001E]; Foundation for the National Institutes of Health; University of Chicago; American Legacy Foundation; Flight Attendants' Medical Research Institute; AstraZeneca, Inc.; GlaxoSmithKline and Carestream Health Inc. FX This paper is dedicated to the memory of Geoffrey McLennan, M. D., Ph.D., who served as the Chair of the LIDC/IDRI Steering Committee since the inception of the project. Dr. McLennan provided the constant source of motivation, perspective, and determination that moved this database from an idea to reality. His extraordinary scientific and clinical vision, combined with his unfettered perseverance and uncompromising optimism, will be greatly missed by all his co-authors, colleagues, and friends. The authors would like express their sincere appreciation to the late Robert F. Wagner, Ph.D., whose enlightened perspective on medical image analysis performance studies provided the foundation for the statistical considerations on which the LIDC/IDRI Database was founded. Supported in part by USPHS Grant Nos. U01CA091085, U01CA091090, U01CA091099, U01CA091100, and U01CA091103 and by NCI Contract No. HHSN261200800001E. Funding was obtained through the Foundation for the National Institutes of Health from contributions provided by the medical imaging companies that participated in the IDRI. Disclosure statement: S. G. A. and H. M. receive royalties and licensing fees through the University of Chicago related to computer-aided diagnosis. H. M. is a consultant to Riverain, a company that produces software for lung nodule detection. A. P. R. is a paid consultant of and holds stock in VisionGate, Inc. A. P. R. is a coinventor on a patent and other pending patents owned by Cornell Research Foundation which are non-exclusively licensed to General Electric and are related to technology involving computer-aided diagnostic methods, including measurement of nodules. A. P. R. receives research support in the form of grants and contracts from: NCI, American Legacy Foundation, Flight Attendants' Medical Research Institute, AstraZeneca, Inc., GlaxoSmithKline and Carestream Health Inc. D.Y. is a named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest including measurement of nodules. Some of these, which are owned by Cornell Research Foundation (CRF) are nonexclusively licensed to General Electric. As an inventor of these patents, D.Y. is entitled to a share of any compensation which CRF may receive from its commercialization of these patents. NR 45 TC 139 Z9 144 U1 3 U2 38 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 FEB PY 2011 VL 38 IS 2 BP 915 EP 931 DI 10.1118/1.3528204 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 716DI UT WOS:000286945000038 PM 21452728 ER PT J AU Choi, L Liu, ZW Matthews, CE Buchowski, MS AF Choi, Leena Liu, Zhouwen Matthews, Charles E. Buchowski, Maciej S. TI Validation of Accelerometer Wear and Nonwear Time Classification Algorithm SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE NONWEAR CATEGORIZATION; PHYSICAL ACTIVITY ASSESSMENT; ACCELEROMETRY; SEDENTARY BEHAVIOR ID PREDICTING ENERGY-EXPENDITURE; PHYSICAL-ACTIVITY; SEDENTARY BEHAVIORS; WEIGHT-LOSS; CHILDREN; RISK; ADULTS; ADOLESCENTS; MORTALITY; OBESITY AB CHOI, L., Z. LIU, C. E. MATTHEWS, and M. S. BUCHOWSKI. Validation of Accelerometer Wear and Nonwear Time Classification Algorithm. Med. Sci. Sports Exerc., Vol. 43, No. 2, pp. 357-364, 2011. Introduction: The use of movement monitors (accelerometers) for measuring physical activity (PA) in intervention and population-based studies is becoming a standard methodology for the objective measurement of sedentary and active behaviors and for the validation of subjective PA self-reports. A vital step in PA measurement is the classification of daily time into accelerometer wear and nonwear intervals using its recordings (counts) and an accelerometer-specific algorithm. Purpose: The purpose of this study was to validate and improve a commonly used algorithm for classifying accelerometer wear and nonwear time intervals using objective movement data obtained in the whole-room indirect calorimeter. Methods: We conducted a validation study of a wear or nonwear automatic algorithm using data obtained from 49 adults and 76 youth wearing accelerometers during a strictly monitored 24-h stay in a room calorimeter. The accelerometer wear and nonwear time classified by the algorithm was compared with actual wearing time. Potential improvements to the algorithm were examined using the minimum classification error as an optimization target. Results: The recommended elements in the new algorithm are as follows: 1) zero-count threshold during a nonwear time interval, 2) 90-min time window for consecutive zero or nonzero counts, and 3) allowance of 2-min interval of nonzero counts with the upstream or downstream 30-min consecutive zero-count window for detection of artifactual movements. Compared with the true wearing status, improvements to the algorithm decreased nonwear time misclassification during the waking and the 24-h periods (all P values < 0.001). Conclusions: The accelerometer wear or nonwear time algorithm improvements may lead to more accurate estimation of time spent in sedentary and active behaviors. C1 [Choi, Leena; Liu, Zhouwen; Buchowski, Maciej S.] Vanderbilt Univ, Energy Balance Lab, Div Gastroenterol Hepatol & Nutr, Nashville, TN 37232 USA. [Choi, Leena] Vanderbilt Univ, Med Ctr, Med Ctr N, Dept Biostat,Sch Med, Nashville, TN 37232 USA. [Matthews, Charles E.] NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Buchowski, Maciej S.] Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN 37232 USA. RP Choi, L (reprint author), Vanderbilt Univ, Med Ctr, Med Ctr N, Dept Biostat,Sch Med, Room D2213,1161 21st Ave S, Nashville, TN 37232 USA. EM leena.choi@vanderbilt.edu RI Buchowski, Maciej/A-2683-2008; matthews, Charles/E-8073-2015 OI Buchowski, Maciej/0000-0002-0566-1743; matthews, Charles/0000-0001-8037-3103 FU NCRR/NIH [1UL1 RR024975]; Vanderbilt Diabetes Research and Training Center [DK20593]; National Institutes of Health (NIH); [R01 HL082988]; [R01 DK69465] FX This study was supported in part by R01 HL082988, R01 DK69465, the Vanderbilt Institute for Clinical and Translational Research (VICTR) grant No. 1UL1 RR024975 from NCRR/NIH, and the Vanderbilt Diabetes Research and Training Center grant No. DK20593.; Disclosure of funding: National Institutes of Health (NIH). NR 35 TC 175 Z9 175 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD FEB PY 2011 VL 43 IS 2 BP 357 EP 364 DI 10.1249/MSS.0b013e3181ed61a3 PG 8 WC Sport Sciences SC Sport Sciences GA 707TN UT WOS:000286311100022 PM 20581716 ER PT J AU Marakalala, MJ Guler, R Matika, L Murray, G Jacobs, M Brombacher, F Rothfuchs, AG Sher, A Brown, GD AF Marakalala, Mohlopheni J. Guler, Reto Matika, Lungile Murray, Graeme Jacobs, Muazzam Brombacher, Frank Rothfuchs, Antonio Gigliotti Sher, Alan Brown, Gordon D. TI The Syk/CARD9-coupled receptor Dectin-1 is not required for host resistance to Mycobacterium tuberculosis in mice SO MICROBES AND INFECTION LA English DT Article DE C-type lectin receptors; Syk; CARD9; Dectin-1; Pulmonary disease; Inflammation ID PATTERN-RECOGNITION RECEPTOR; FUNGAL-INFECTION; INDUCTION; IMMUNITY; TLR2 AB There is interest in identifying the pattern recognition receptors involved in initiating protective or non-protective host responses to Mycobacterium tuberculosis (Mtb). Here we explored the role of the Syk/CARD9-coupled receptor, Dectin-1, using an aerosol model of Mtb infection in wild-type and Dectin-1 deficient mice. We observed a reduction in pulmonary bacilli burdens in the Dectin-1 deficient animals, but this did not correlate with significant changes in pulmonary pathology, cytokine levels or ability of these animals to survive the infection. Thus Dectin-1 makes a minor contribution to susceptibility to Mtb infections in mice. (C) 2010 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. C1 [Brown, Gordon D.] Univ Aberdeen, Sect Immunol & Infect, Div Appl Med, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Marakalala, Mohlopheni J.; Guler, Reto; Matika, Lungile; Jacobs, Muazzam; Brombacher, Frank; Brown, Gordon D.] Univ Cape Town, Inst Infect Dis & Mol Med, Div Immunol, ZA-7700 Rondebosch, South Africa. [Guler, Reto; Brombacher, Frank] Int Ctr Genet Engn & Biotechnol, Cape Town, South Africa. [Murray, Graeme] Univ Aberdeen, Div Appl Med, Sect Translat Med, Aberdeen AB9 1FX, Scotland. [Rothfuchs, Antonio Gigliotti] NIAID, Lab Parasit Dis, Bethesda, MD USA. [Rothfuchs, Antonio Gigliotti; Sher, Alan] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-10401 Stockholm, Sweden. RP Brown, GD (reprint author), Univ Aberdeen, Sect Immunol & Infect, Div Appl Med, Inst Med Sci, Foresterhill, Aberdeen AB25 2ZD, Scotland. EM gordon.brown@abdn.ac.uk RI Guler, Reto/A-4013-2011; brown, gordon/B-4249-2012; Rothfuchs, Antonio/F-5981-2013; OI Rothfuchs, Antonio/0000-0001-6001-7240; MARAKALALA, MOHLOPHENI /0000-0001-7476-1652 FU National Research Foundation; Medical Research Council of South Africa; Claude Leon Foundation; University of Cape Town; Wellcome Trust FX We acknowledge the excellent technical assistance from Lizette Fick, Nasiema Allie, Mark Barkhuizen, and Faried Abbass. This work was supported in part by the National Research Foundation, Medical Research Council of South Africa, Claude Leon Foundation, the University of Cape Town, and the Wellcome Trust for funding. MJM is an NRF Innovation postdoctoral Fellow. NR 17 TC 21 Z9 21 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD FEB PY 2011 VL 13 IS 2 BP 198 EP 201 DI 10.1016/j.micinf.2010.10.013 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 721IO UT WOS:000287347000010 PM 21034845 ER PT J AU Varatharajalu, R Parandaman, V Ndao, M Andersen, JF Neva, FA AF Varatharajalu, Ravi Parandaman, Vijayalakshmi Ndao, Momar Andersen, John F. Neva, Franklin A. TI Strongyloides stercoralis excretory/secretory protein strongylastacin specifically recognized by IgE antibodies in infected human sera SO MICROBIOLOGY AND IMMUNOLOGY LA English DT Article DE diagnosis; IgE; strongylastacin; strongyloidiasis ID PROCOLLAGEN C-PROTEINASE; TRICHINELLA-SPIRALIS; EXTRACELLULAR-MATRIX; LARVAL MIGRATION; HOOKWORM LARVAE; IMMUNE EVASION; PARASITE; METALLOPROTEASES; IDENTIFICATION; MTP-1 AB The infective, microscopic Strongyloides stercoralis larvae in contaminated soil can penetrate human skin with the help of excretory/secretory proteases. These proteases play a critical role in infection and transmigration of the parasite to the intestines. Strongylastacin is similar to astacin (from the digestive gland of the crayfish Astacus astacus), a multi-domain protein with a signal peptide, a pro-enzyme, a catalytic domain containing the zinc binding consensus astacin family signature sequence HEXXHXXGFXHEXXRXDR, and a second conserved zinc binding motif SIMHY at N- terminal region. An EGF-1 like domain and a CUB domain are located at the COOH- terminal. In this study, the excretory/secretory Strongylastacin gene from S. stercoralis infective larval stage was cloned and expressed as a 45 kDa in Escherichia coli. Immunoblot analysis showed the presence of natural IgG antibodies against strongylastacin in six infected and six non-endemic normal sera. These findings were confirmed in an ELISA of 32 S. stercoralis infected and 32 presumed normal human sera; all contained natural anti-strongylastacin IgG antibodies. By contrast, IgE antibodies specific to strongylastacin were present in sera from individuals infected with S. stercoralis but not in uninfected control sera. Moreover, recombinant strongylastacin did not cross-react with IgE antibodies either from patients infected with filaria or patients with tropical pulmonary eosinophilic (TPE) who had increased IgE antibodies. The present authors conclude that strongylastacin, an excretory/secretory antigen, elicits specific IgE antibodies in S. stercoralis infected humans. Non-specific IgG antibodies to strongylastacin are present in both infected and normal humans. Further investigation is needed to understand the role of the host protective response against strongylastacin. C1 [Varatharajalu, Ravi; Andersen, John F.; Neva, Franklin A.] NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Parandaman, Vijayalakshmi] Johns Hopkins Univ, Dept Bioinformat, Gaithersburg, MD 20878 USA. [Ndao, Momar] McGill Univ, Natl Reference Lab Parasitol, Montreal, PQ, Canada. RP Varatharajalu, R (reprint author), George Washington Univ, Lipid Sect, Dept Biochem & Mol Biol, Vet Affairs Med Ctr, Res Bldg,50 Irving St, Washington, DC 20422 USA. EM rvaratha@gwu.edu NR 35 TC 9 Z9 9 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0385-5600 J9 MICROBIOL IMMUNOL JI Microbiol. Immunol. PD FEB PY 2011 VL 55 IS 2 BP 115 EP 122 DI 10.1111/j.1348-0421.2010.00289.x PG 8 WC Immunology; Microbiology SC Immunology; Microbiology GA 711UU UT WOS:000286617700007 PM 21204942 ER PT J AU Arnold, MA Shandilya, S Galli, S Killian, JK Raffeld, M Tsokos, M Meltzer, PS Warren, KE Quezado, MM AF Arnold, M. A. Shandilya, S. Galli, S. Killian, J. K. Raffeld, M. Tsokos, M. Meltzer, P. S. Warren, K. E. Quezado, M. M. TI Morphological and Molecular Profiling of Pediatric Brain Stem Gliomas SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Arnold, M. A.; Shandilya, S.; Galli, S.; Killian, J. K.; Raffeld, M.; Tsokos, M.; Meltzer, P. S.; Warren, K. E.; Quezado, M. M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1 BP 4A EP 4A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282300002 ER PT J AU Aung, PP Pathak, A Xi, L Filie, AC Raffeld, M AF Aung, P. P. Pathak, A. Xi, L. Filie, A. C. Raffeld, M. TI Identification of a DNA Methylation Marker That Differentiates Malignant Mesothelioma from Reactive Mesothelial Cells on Effusion Samples SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Aung, P. P.; Pathak, A.; Xi, L.; Filie, A. C.; Raffeld, M.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 339 BP 83A EP 83A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282300341 ER PT J AU Chowdhuri, SR Fetsch, P Hughes, MS Filie, AC AF Chowdhuri, S. Roy Fetsch, P. Hughes, M. S. Filie, A. C. TI KBA.62 and KIT Expression Patterns in Fine-Needle Aspirates of Malignant Melanoma Metastatic to the Liver SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Chowdhuri, S. Roy; Fetsch, P.; Hughes, M. S.; Filie, A. C.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 427 BP 103A EP 104A PG 2 WC Pathology SC Pathology GA 720LN UT WOS:000287282300429 ER PT J AU Chowdhuri, SR Xi, L Pham, T Hanson, J Giaccone, G Emmerert-Buck, M Raffeld, M Filie, AC AF Chowdhuri, S. Roy Xi, L. Pham, T. Hanson, J. Giaccone, G. Emmerert-Buck, M. Raffeld, M. Filie, A. C. TI High Sensitivity EGFR Mutation Detection in Cytologic Preparations Enabled by Laser Capture Microdissection (LCM) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Chowdhuri, S. Roy; Xi, L.; Pham, T.; Hanson, J.; Giaccone, G.; Emmerert-Buck, M.; Raffeld, M.; Filie, A. C.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 428 BP 104A EP 104A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282300430 ER PT J AU Liu, YC Rosenberg, SA Lee, CCR AF Liu, Y-C Rosenberg, S. A. Lee, C-C R. TI Target Marker for Immunotherapy in Metastatic Melanomas of Rare Morphology Subtypes. SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Liu, Y-C; Rosenberg, S. A.; Lee, C-C R.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 499 BP 120A EP 120A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282300501 ER PT J AU Aung, PP Russell, L Weinstein, D Heller, T Kleiner, D Kammula, U Rudloff, U Avital, I Quezado, M AF Aung, P. P. Russell, L. Weinstein, D. Heller, T. Kleiner, D. Kammula, U. Rudloff, U. Avital, I. Quezado, M. TI Morphologic Findings in a Novel Familial Polyposis Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 597 BP 143A EP 143A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282300599 ER PT J AU Aly, FZ Hanson, JC Yang, W Kreitman, MS Merino, MJ Linehan, MW Pinto, PA Adams, LG Stevenson, HS Edelman, DC Emmert-Buck, MR Rodriguez-Canales, J AF Aly, F. Z. Hanson, J. C. Yang, W. Kreitman, M. S. Merino, M. J. Linehan, M. W. Pinto, P. A. Adams, L. G. Stevenson, H. S. Edelman, D. C. Emmert-Buck, M. R. Rodriguez-Canales, J. TI Regional Variation in Epigenetic Patterns in Prostate Cancer. SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Aly, F. Z.; Hanson, J. C.; Yang, W.; Kreitman, M. S.; Merino, M. J.; Linehan, M. W.; Pinto, P. A.; Adams, L. G.; Stevenson, H. S.; Edelman, D. C.; Emmert-Buck, M. R.; Rodriguez-Canales, J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 739 BP 176A EP 176A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282300741 ER PT J AU Cannata-Ortiz, P Rodriguez, BW Bratslavsky, G Linehan, WM Merino, MJ AF Cannata-Ortiz, P. Rodriguez, B. Walter Bratslavsky, G. Linehan, W. M. Merino, M. J. TI Hybrid Tumors: All You Need To Know and More SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Cannata-Ortiz, P.; Rodriguez, B. Walter; Bratslavsky, G.; Linehan, W. M.; Merino, M. J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 766 BP 182A EP 183A PG 2 WC Pathology SC Pathology GA 720LN UT WOS:000287282300768 ER PT J AU Romero, VAV Rodriguez, BAW Sobel, M Linehan, WM Merino, MJ AF Romero, V. A. Valera Rodriguez, B. A. Walter Sobel, M. Linehan, W. M. Merino, M. J. TI miR-210 (Hypoxia-Responsive) a Marker of Poor Prognosis in Clear Cell Renal Cell Carcinoma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Romero, V. A. Valera; Rodriguez, B. A. Walter; Sobel, M.; Linehan, W. M.; Merino, M. J.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 965 BP 228A EP 229A PG 2 WC Pathology SC Pathology GA 720LN UT WOS:000287282301120 ER PT J AU Rodriguez, BAW Vargas, AP Romero, VAV Sobel, M Pinto, P Merino, MJ AF Rodriguez, B. A. Walter Vargas, A. P. Romero, V. A. Valera Sobel, M. Pinto, P. Merino, M. J. TI microRNA Expression Profiling in Prostate Cancer: Possible Role as a Biomarkers and/or Molecular Therapy SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Rodriguez, B. A. Walter; Vargas, A. P.; Romero, V. A. Valera; Sobel, M.; Pinto, P.; Merino, M. J.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 968 BP 229A EP 229A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301123 ER PT J AU Parrilla-Castellar, ER Merino, MJ AF Parrilla-Castellar, E. R. Merino, M. J. TI Cross-Sectional Study of Cervical Cancer among Hispanic Versus Non-Hispanic White Women Living in the United States SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Parrilla-Castellar, E. R.; Merino, M. J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1113 BP 262A EP 262A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301268 ER PT J AU Huppmann, AR Leung, AA Jaffe, ES Raffeld, M Pittaluga, S AF Huppmann, A. R. Leung, A. A. Jaffe, E. S. Raffeld, M. Pittaluga, S. TI SOX11 Is a Marker of Follicular Dendritic Cell Neoplasms SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Huppmann, A. R.; Leung, A. A.; Jaffe, E. S.; Raffeld, M.; Pittaluga, S.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1284 BP 302A EP 302A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301439 ER PT J AU Liu, Q Jegalian, A Raffeld, M Pittaluga, S Jaffe, ES AF Liu, Q. Jegalian, A. Raffeld, M. Pittaluga, S. Jaffe, E. S. TI Pediatric Follicular Lymphoma: A Comparison with Follicular Lymphoma in Young Adults SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Liu, Q.; Jegalian, A.; Raffeld, M.; Pittaluga, S.; Jaffe, E. S.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1308 BP 307A EP 307A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301463 ER PT J AU Maric, I Simakova, O Olivares, N Chew, S Metcalfe, DD Wilson, TM AF Maric, I. Simakova, O. Olivares, N. Chew, S. Metcalfe, D. D. Wilson, T. M. TI Monocytosis in Systemic Mastocytosis: Clinico-Pathological and Prognostic Correlates. SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 NIH, CC, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1310 BP 308A EP 308A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301465 ER PT J AU Song, JY Dunleavy, K Grant, N Davies-Hill, T Raffeld, M Wilson, WH Jaffe, ES Pittaluga, S AF Song, J. Y. Dunleavy, K. Grant, N. Davies-Hill, T. Raffeld, M. Wilson, W. H. Jaffe, E. S. Pittaluga, S. TI Clinicopathologic Features of Lymphomatoid Granulomatosis, a Single Institute Experience SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Song, J. Y.; Dunleavy, K.; Grant, N.; Davies-Hill, T.; Raffeld, M.; Wilson, W. H.; Jaffe, E. S.; Pittaluga, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1369 BP 322A EP 323A PG 2 WC Pathology SC Pathology GA 720LN UT WOS:000287282301524 ER PT J AU Summers, TA Eberle, FC Pittaluga, S Wilson, WH Dunleavy, K Raffeld, M Hewitt, SM Jaffe, ES AF Summers, T. A. Eberle, F. C. Pittaluga, S. Wilson, W. H. Dunleavy, K. Raffeld, M. Hewitt, S. M. Jaffe, E. S. TI Gray Zone Lymphomas: Becoming More Black and White? SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Summers, T. A.; Eberle, F. C.; Pittaluga, S.; Wilson, W. H.; Dunleavy, K.; Raffeld, M.; Hewitt, S. M.; Jaffe, E. S.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1375 BP 324A EP 324A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301530 ER PT J AU Tembhare, PR Yuan, CM Xi, L Janik, J Morris, J Raffeld, M Stetler-Stevenson, M AF Tembhare, P. R. Yuan, C. M. Xi, L. Janik, J. Morris, J. Raffeld, M. Stetler-Stevenson, M. TI Detection of T Cell Clonality at Diagnosis, in Small Samples and Monitoring of Minimal Residual Disaease (MAD) Using TCR-V Beta Repertoire Analysis SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 NCI, Ctr Canc Res, Mark O Hatfield Clin Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1381 BP 326A EP 326A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301536 ER PT J AU Wang, W Plyler, R Janik, JE Jaffe, ES Calvo, KR AF Wang, W. Plyler, R. Janik, J. E. Jaffe, E. S. Calvo, K. R. TI microRNA Profiling of Follicular Lymphoma and Tumor Infiltrating T-Cells SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NCI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1391 BP 328A EP 328A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301546 ER PT J AU Parrilla-Castellar, E Zhou, W Liu, J Tessarallo, L Levens, D AF Parrilla-Castellar, E. Zhou, W. Liu, J. Tessarallo, L. Levens, D. TI FBP Knock-Out Leads to a Hematopoietic Maturation Defect. SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 NIH, Bethesda, MD 20892 USA. NIH, Frederick, MD USA. RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1686 BP 396A EP 396A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282302132 ER PT J AU Liu, C Galli, S Tsokos, M AF Liu, C. Galli, S. Tsokos, M. TI miR-17-5b Inhibition Decreases Rhabdomyosarcoma Cell Growth In Vitro SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Liu, C.; Galli, S.; Tsokos, M.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1712 BP 402A EP 402A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282302158 ER PT J AU Vargas, MP Carter, D Merino, MJ AF Vargas, M. P. Carter, D. Merino, M. J. TI Pulmonary Lesions Associated with BHD Syndrome. SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Vargas, M. P.; Carter, D.; Merino, M. J.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1813 BP 426A EP 427A PG 2 WC Pathology SC Pathology GA 720LN UT WOS:000287282302259 ER PT J AU Killian, K Wang, L Walker, B Glatfelter, A Smith, WI Meltzer, PS AF Killian, K. Wang, L. Walker, B. Glatfelter, A. Smith, W. I. Meltzer, P. S. TI Rapid and Reliable Method To Isolate Nuclei from FFPE Specimens for Genomic-Scale Molecular Profiling. SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Suburban Hosp, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1887 BP 443A EP 444A PG 2 WC Pathology SC Pathology GA 720LN UT WOS:000287282302332 ER PT J AU Rana, R Surapureddi, S Kam, W Ferguson, S Goldstein, JA AF Rana, Ritu Surapureddi, Sailesh Kam, WayneKid Ferguson, Stephen Goldstein, Joyce A. TI Med25 Is Required for RNA Polymerase II Recruitment to Specific Promoters, Thus Regulating Xenobiotic and Lipid Metabolism in Human Liver SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEAR FACTOR 4-ALPHA; CONSTITUTIVE ANDROSTANE RECEPTOR; PEROXISOMAL BETA-OXIDATION; GENE-EXPRESSION; HUMAN HEPATOCYTES; TRANSCRIPTIONAL REGULATION; SYNERGISTIC ACTIVATION; MEDIATOR COMPLEX; CYP2C GENES; PROTEIN AB Hepatocyte nuclear factor 4 alpha (HNF4 alpha) controls the expression of many critical metabolic pathways, and the Mediator complex occupies a central role in recruiting RNA polymerase II (Pol II) to these gene promoters. An impaired transcriptional HNF4 alpha network in human liver is responsible for many pathological conditions, such as altered drug metabolism, fatty liver, and diabetes. Here, we report that Med25, an associated member of the Mediator complex, is required for the association of HNF4 alpha with Mediator, its several cofactors, and RNA Pol II. Further, increases and decreases in endogenous Med25 levels are reflected in the composition of the transcriptional complex, Pol II recruitment, and the expression of HNF4 alpha-bound target genes. A novel feature of Med25 is that it imparts "selectivity." Med25 affects only a significant subset of HNF4 alpha target genes that selectively regulate drug and lipid metabolism. These results define a role for Med25 and the Mediator complex in the regulation of xenobiotic metabolism and lipid homeostasis. C1 [Rana, Ritu; Surapureddi, Sailesh; Kam, WayneKid; Goldstein, Joyce A.] NIEHS, Human Metab Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Ferguson, Stephen] Invitrogen Corp CellzDirect, Durham, NC 27703 USA. RP Goldstein, JA (reprint author), NIEHS, Human Metab Sect, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM goldste1@niehs.nih.gov RI Rana, Ritu/F-2591-2011; Goldstein, Joyce/A-6681-2012 FU NIH, National Institute of Environmental Health Sciences, under NIH [Z01ES02124] FX This study was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, under NIH intramural project number Z01ES02124. NR 65 TC 34 Z9 36 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2011 VL 31 IS 3 BP 466 EP 481 DI 10.1128/MCB.00847-10 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 706AV UT WOS:000286185900009 PM 21135126 ER PT J AU Eriksson, PR Ganguli, D Clark, DJ AF Eriksson, Peter R. Ganguli, Dwaipayan Clark, David J. TI Spt10 and Swi4 Control the Timing of Histone H2A/H2B Gene Activation in Budding Yeast SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CELL-CYCLE REGULATION; TRANSCRIPTION FACTORS MBP1; SACCHAROMYCES-CEREVISIAE; CHROMATIN-STRUCTURE; DNA-BINDING; G1-SPECIFIC TRANSCRIPTION; PERIODIC TRANSCRIPTION; ALTER TRANSCRIPTION; FLUORESCENT PROTEIN; GENOME STABILITY AB The expression of the histone genes is regulated during the cell cycle to provide histones for nucleosome assembly during DNA replication. In budding yeast, histones H2A and H2B are expressed from divergent promoters at the HTA1-HTB1 and HTA2-HTB2 loci. Here, we show that the major activator of HTA1-HTB1 is Spt10, a sequence-specific DNA binding protein with a putative histone acetyltransferase (HAT) domain. Spt10 binds to two pairs of upstream activation sequence (UAS) elements in the HTA1-HTB1 promoter: UAS1 and UAS2 drive HTA1 expression, and UAS3 and UAS4 drive HTB1 expression. UAS3 and UAS4 also contain binding sites for the cell cycle regulator SBF (an Swi4-Swi6 heterodimer), which overlap the Spt10 binding sites. The binding of Spt10 and binding of SBF to UAS3 and UAS4 are mutually exclusive in vitro. Both SBF and Spt10 are bound in cells arrested with alpha-factor, apparently awaiting a signal to activate transcription. Soon after the removal of alpha-factor, SBF initiates a small, early peak of HTA1 and HTB1 transcription, which is followed by a much larger peak due to Spt10. Both activators dissociate from the HTA1-HTB1 promoter after expression has been activated. Thus, SBF and Spt10 cooperate to control the timing of HTA1-HTB1 expression. C1 [Eriksson, Peter R.; Ganguli, Dwaipayan; Clark, David J.] NICHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Clark, DJ (reprint author), NICHD, Program Genom Differentiat, NIH, Bldg 6A,Room 2A14,6 Ctr Dr, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov FU NIH (NICHD) FX This work was supported by the Intramural Research Program of the NIH (NICHD). NR 69 TC 15 Z9 15 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2011 VL 31 IS 3 BP 557 EP 572 DI 10.1128/MCB.00909-10 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 706AV UT WOS:000286185900016 PM 21115727 ER PT J AU Lee, EK Lee, MJ Abdelmohsen, K Kim, W Kim, MM Srikantan, S Martindale, JL Hutchison, ER Kim, HH Marasa, BS Selimyan, R Egan, JM Smith, SR Fried, SK Gorospe, M AF Lee, Eun Kyung Lee, Mi Jeong Abdelmohsen, Kotb Kim, Wook Kim, Mihee M. Srikantan, Subramanya Martindale, Jennifer L. Hutchison, Emmette R. Kim, Hyeon Ho Marasa, Bernard S. Selimyan, Roza Egan, Josephine M. Smith, Steven R. Fried, Susan K. Gorospe, Myriam TI miR-130 Suppresses Adipogenesis by Inhibiting Peroxisome Proliferator-Activated Receptor gamma Expression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; ADIPOCYTE DIFFERENTIATION; GENE-EXPRESSION; PPAR-GAMMA; C/EBP-BETA; TRANSCRIPTIONAL REGULATION; REGULATORY FUNCTIONS; NEGATIVE REGULATOR; ANIMAL DEVELOPMENT; BINDING PROTEIN-1 AB Adipose tissue development is tightly regulated by altering gene expression. MicroRNAs are strong post-transcriptional regulators of mammalian differentiation. We hypothesized that microRNAs might influence human adipogenesis by targeting specific adipogenic factors. We identified microRNAs that showed varying abundance during the differentiation of human preadipocytes into adipocytes. Among them, miR-130 strongly affected adipocyte differentiation, as overexpressing miR-130 impaired adipogenesis and reducing miR-130 enhanced adipogenesis. A key effector of miR-130 actions was the protein peroxisome proliferator-activated receptor gamma (PPAR gamma), a major regulator of adipogenesis. Interestingly, miR-130 potently repressed PPAR gamma expression by targeting both the PPAR gamma mRNA coding and 3' untranslated regions. Adipose tissue from obese women contained significantly lower miR-130 and higher PPAR gamma mRNA levels than that from nonobese women. Our findings reveal that miR-130 reduces adipogenesis by repressing PPAR gamma biosynthesis and suggest that perturbations in this regulation is linked to human obesity. C1 [Lee, Eun Kyung; Abdelmohsen, Kotb; Kim, Mihee M.; Srikantan, Subramanya; Martindale, Jennifer L.; Kim, Hyeon Ho; Marasa, Bernard S.; Selimyan, Roza; Gorospe, Myriam] NIA IRP, LMBI, NIH, Baltimore, MD 21224 USA. [Lee, Mi Jeong; Fried, Susan K.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Kim, Wook; Egan, Josephine M.] NIA IRP, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Hutchison, Emmette R.] NIA IRP, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Smith, Steven R.] Florida Hosp Burnham Inst, Translat Res Inst, Winter Pk, FL 32789 USA. RP Gorospe, M (reprint author), NIA IRP, LMBI, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI Lee, Mi-Jeong/0000-0002-8171-7913; Fried, Susan/0000-0003-1101-9332; srikantan, subramanya/0000-0003-1810-6519 FU National Institute on Aging, National Institutes of Health [DK46200, DK072488, DK080448, DK052398]; [DK072476] FX This research was funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, by grants DK46200, DK072488, DK080448, and DK052398 (to S.K.F. and M.J.L.) and by grant DK072476 (to S.R.S.). NR 40 TC 127 Z9 153 U1 1 U2 19 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 FEB PY 2011 VL 31 IS 4 BP 626 EP 638 DI 10.1128/MCB.00894-10 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 711MV UT WOS:000286596600003 PM 21135128 ER PT J AU Cuddapah, S Schones, DE Cui, KR Roh, TY Barski, A Wei, G Rochman, M Bustin, M Zhao, KJ AF Cuddapah, Suresh Schones, Dustin E. Cui, Kairong Roh, Tae-Young Barski, Artem Wei, Gang Rochman, Mark Bustin, Michael Zhao, Keji TI Genomic Profiling of HMGN1 Reveals an Association with Chromatin at Regulatory Regions SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CHROMOSOMAL-PROTEIN HMG-17; MOBILITY GROUP PROTEIN-14; TRANSCRIPTION FACTOR YY1; HISTONE H1; HYPERSENSITIVE SITES; LINKER HISTONE; BINDING; NUCLEOSOMES; DOMAIN; GENES AB The interaction of architectural proteins such as the linker histone H1 and high-mobility-group (HMG) proteins with nucleosomes leads to changes in chromatin structure and histone modifications and alters the cellular transcription profile. The interaction of HMG proteins with chromatin is dynamic. However, it is not clear whether the proteins are constantly and randomly redistributed among all the nucleosomes or whether they preferentially associate with, and turn over at, specific regions in chromatin. To address this question, we examined the genome-wide distribution of the nucleosome binding protein HMGN1 and compared it to that of regulatory chromatin marks. We find that HMGN1 is not randomly distributed throughout the genome. Instead, the protein preferentially localizes to DNase I hypersensitive (HS) sites, promoters, functional enhancers, and transcription factor binding sites. Our results suggest that HMGN1 is part of the cellular machinery that modulates transcriptional fidelity by generating, maintaining, or preferentially interacting with specific sites in chromatin. C1 [Rochman, Mark; Bustin, Michael] NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. [Cuddapah, Suresh; Schones, Dustin E.; Cui, Kairong; Roh, Tae-Young; Barski, Artem; Wei, Gang; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov; zhaok@nhlbi.nih.gov RI Wei, Gang/A-3291-2011; Bustin, Michael/G-6155-2015; OI Barski, Artem/0000-0002-1861-5316 FU National Heart, Lung and Blood Institute; Center for Cancer Research, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute and of the Center for Cancer Research, National Institutes of Health. NR 58 TC 25 Z9 25 U1 0 U2 1 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 FEB PY 2011 VL 31 IS 4 BP 700 EP 709 DI 10.1128/MCB.00740-10 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 711MV UT WOS:000286596600009 PM 21173166 ER PT J AU Nakamura, K Tan, F Li, ZJ Thiele, CJ AF Nakamura, Katsuya Tan, Fei Li, Zhijie Thiele, Carol J. TI NGF activation of TrkA induces vascular endothelial growth factor expression via induction of hypoxia-inducible factor-1 alpha SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE NGF/TrkA; BDNF/TrkB; VEGF; HIF-1 alpha; Dorsal root ganglion neurons; Cerebellar granule neurons; Neuroblastoma ID NEUROTROPHIC FACTOR ACTIVATION; SH-SY5Y NEUROBLASTOMA-CELLS; AXONAL REGENERATION; PC12 CELLS; IN-VITRO; ANGIOGENESIS; DIFFERENTIATION; DEATH; GENE; RECRUITMENT AB Communication between the vasculature and nervous system is important during embryogenesis but the molecular mechanisms mediating this are ill-defined. We evaluated the molecular mechanisms by which Nerve Growth Factor (NGF) and Brain-derived neurotrophic factor (BDNF) regulate VEGF production. NGF activation of TrkA causes a marked increase in VEGF secretion by neuronal cells. The NGF induced increase in VEGF is accompanied by an increase in HIF-1 alpha. Pharmacologic inhibitors of the Trk tyrosine kinase, PI-3 kinase and mTOR paths prevent NGF stimulated increases in HIF-1 alpha and VEGF. NGF induced increase in VEGF transcription is dependent on a hypoxia response element (HRE) in the VEGF promoter. Mutation of the HRE or siRNA mediated silencing of HIF-1 alpha expression blocks NGF induced increases in VEGF transcription. In primary cultures of TrkA expressing neurons from dorsal root ganglion. NGF induces VEGF expression that is accompanied by increases in HIF-1 alpha but not HIF-2 alpha expression. In CGN neurons, BDNF induces VEGF that is dependent on induction of HIF-1 alpha. Our study indicates that neurotrophin activation of Trk stimulates an increase in VEGF transcription that is mediated by induction of HIF-1 alpha. Published by Elsevier Inc. C1 [Thiele, Carol J.] NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH,CRC, Bethesda, MD 20892 USA. RP Thiele, CJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH,CRC, 1-3940 MSC-1105, Bethesda, MD 20892 USA. EM knakamura@kokura2.hosp.go.jp; tanfei66@hotmail.com; ct47a@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX The authors are grateful to Dr. Giovanni Melillo and Dr. Annamaria Rapisarda for insightful discussions. We'd like to thank the members of the Cell and Molecular Biology Section for their encouragement. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 28 Z9 33 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD FEB PY 2011 VL 46 IS 2 BP 498 EP 506 DI 10.1016/j.mcn.2010.12.002 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 716EL UT WOS:000286951800013 PM 21145972 ER PT J AU Freeman, A Franciscovich, A Bowers, M Sandstrom, DJ Sanyal, S AF Freeman, Amanda Franciscovich, Amy Bowers, Mallory Sandstrom, David J. Sanyal, Subhabrata TI NFAT regulates pre-synaptic development and activity-dependent plasticity in Drosophila SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article DE Drosophila; NFAT; Plasticity; Synapse; Neuron; Transcription ID LONG-TERM FACILITATION; SYNAPTIC PLASTICITY; FASCICLIN-II; FUNCTIONAL COMPONENTS; GENETIC DISSECTION; NEUROMUSCULAR-JUNCTION; TRANSCRIPTION FACTOR; HIPPOCAMPAL-NEURONS; NEURAL DEVELOPMENT; NERVOUS-SYSTEM AB The calcium-regulated transcription factor NFAT is emerging as a key regulator of neuronal development and plasticity but precise cellular consequences of NFAT function remain poorly understood. Here, we report that the single Drosophila NFAT homolog is widely expressed in the nervous system including motor neurons and unexpectedly controls neural excitability. Likely due to this effect on excitability, NFAT regulates overall larval locomotion and both chronic and acute forms of activity-dependent plasticity at the larval glutamatergic neuro-muscular synapse. Specifically, NFAT-dependent synaptic phenotypes include changes in the number of pre-synaptic boutons, stable modifications in synaptic microtubule architecture and pre-synaptic transmitter release, while no evidence is found for synaptic retraction or alterations in the level of the synaptic cell adhesion molecule FasII. We propose that NFAT regulates pre-synaptic development and constrains long-term plasticity by dampening neuronal excitability. (C) 2010 Elsevier Inc. All rights reserved. C1 [Freeman, Amanda; Franciscovich, Amy; Bowers, Mallory; Sanyal, Subhabrata] Emory Univ, Dept Cell Biol, Atlanta, GA 30322 USA. [Sandstrom, David J.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sanyal, S (reprint author), Emory Univ, Dept Cell Biol, Room 444,615 Michael St NE,Whitehead Bldg, Atlanta, GA 30322 USA. EM ssanya2@emory.edu OI Sanyal, Subhabrata/0000-0003-2590-2732 FU URC; Emory University; NARSAD; NIDA [DA027979-01]; FIRST fellowship FX We acknowledge members of the Sanyal lab., Howard Nash, Veronica Rodrigues and Mani Ramaswami for useful discussions and insights. DJS thanks Howard Nash for space, material and intellectual support. We also thank the confocal microscopy facilities at the Cell Biology department at Emory University. We are grateful to Dan Hultmark for the NFATDelta AB flies, and the Vienna Drosophila RNAi Center for NFAT-RNAi flies. The anti-Syt (Kaushiki Menon and Kai Zinn) and anti-Elav (Gerald Rubin) antibodies were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA 52242. This work was supported by grants from the URC, Emory University, a NARSAD Young Investigator Fellowship and grant DA027979-01 from NIDA to SS and the FIRST fellowship to AF. NR 60 TC 14 Z9 14 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD FEB PY 2011 VL 46 IS 2 BP 535 EP 547 DI 10.1016/j.mcn.2010.12.010 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 716EL UT WOS:000286951800017 PM 21185939 ER PT J AU Nikolenko, GN Kotelkin, AT Oreshkova, SF Ilyichev, AA AF Nikolenko, G. N. Kotelkin, A. T. Oreshkova, S. F. Ilyichev, A. A. TI Mechanisms of HIV-1 drug resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors SO MOLECULAR BIOLOGY LA English DT Article DE HIV-1; drug resistance; resistance mechanism; nucleoside and nonnucleoside inhibitors; reverse transcriptase; RNase H; connection; discrimination; excision; affinity ID HUMAN-IMMUNODEFICIENCY-VIRUS; RNASE-H ACTIVITY; PLUS-STRAND DNA; EXPERIENCED HIV-1-INFECTED PATIENTS; PLACEBO-CONTROLLED TRIAL; HIGH-LEVEL RESISTANCE; IN-VITRO SELECTION; RIBONUCLEASE-H; CRYSTAL-STRUCTURE; CONNECTION SUBDOMAIN AB A global AIDS epidemics caused by human immunodeficiency virus type 1 (HIV-1), involving more than 2 million newly infected people annually, has existed for more than 25 years. The major obstacle in combating the global epidemic is rapid evolution of the virus by the selection of drug resistance mutations. Selection of drug-resistant HIV variants is so rapid that drug resistance is known for all of the approved anti-AIDS drugs. The review summarizes the scientific achievements in the field of reverse transcriptase drug resistance to licensed antiviral drugs, such as nucleoside (NRTI) and nonnucleoside (NNRTI) inhibitors. Principal mechanisms of their antiviral action, major drug resistance mutations, and molecular aspects of the classic mechanisms of HIV resistance to NRTIs and NNRTIs are described. The role of RNase H activity, which was recently implicated in drug resistance to reverse transcriptase inhibitors, is a focus of detailed discussion. A new NRTI and NNRTI dual resistance mechanism associated with reverse transcriptase mutations in the C-terminal region, which includes RNase H and connection domains, is analyzed. Comprehensive analysis of the factors affecting HIV drug resistance is important for understanding the molecular mechanisms of resistance and improving drug design and anti-HIV therapy. C1 [Nikolenko, G. N.; Oreshkova, S. F.; Ilyichev, A. A.] Vector State Res Ctr Virol & Biotechnol, Dept Immunotherapeut Cpds, Koltsov 630559, Novosibirsk Reg, Russia. [Nikolenko, G. N.] NCI, NIH, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Kotelkin, A. T.] Howard Univ Hosp, Ctr Sickle Cell Dis, Washington, DC 20001 USA. [Ilyichev, A. A.] Novosibirsk State Univ, Novosibirsk 630090, Russia. RP Nikolenko, GN (reprint author), Vector State Res Ctr Virol & Biotechnol, Dept Immunotherapeut Cpds, Koltsov 630559, Novosibirsk Reg, Russia. EM gnikolenko@comcast.net; sv_oresh@mail.ru RI Ilyichev, Alexander/B-1327-2012 OI Ilyichev, Alexander/0000-0001-5356-0843 FU NIH (National Cancer Institute, Center for Cancer Research) FX This work was supported by an NIH internal research program (National Cancer Institute, Center for Cancer Research). NR 111 TC 5 Z9 5 U1 6 U2 18 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0026-8933 J9 MOL BIOL+ JI Mol. Biol. PD FEB PY 2011 VL 45 IS 1 BP 93 EP 109 DI 10.1134/S0026893311010092 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 724SD UT WOS:000287595600011 ER PT J AU Shapiro, B Ho, SYW Drummond, AJ Suchard, MA Pybus, OG Rambaut, A AF Shapiro, Beth Ho, Simon Y. W. Drummond, Alexei J. Suchard, Marc A. Pybus, Oliver G. Rambaut, Andrew TI A Bayesian Phylogenetic Method to Estimate Unknown Sequence Ages SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE heterochronous sequences; ancient DNA; molecular clock; viral evolution; measurably evolving populations ID ANCIENT DNA; POPULATION-DYNAMICS; MOLECULAR EVOLUTION; INFLUENZA-VIRUS; CLIMATIC-CHANGE; BROWN BEARS; PLEISTOCENE; HIV-1; RATES; EXTINCTION AB Heterochronous data sets comprise molecular sequences sampled at different points in time. If the temporal range of the sampled sequences is large relative to the rate of mutation, the sampling times can directly calibrate evolutionary rates to calendar time. Here, we extend this calibration process to provide a full probabilistic method that utilizes temporal information in heterochronous data sets to estimate sampling times (leaf-ages) for sequenced for which this information unavailable. Our method is similar to relaxing the constraints of the molecular clock on specific lineages within a phylogenetic tree. Using a combination of synthetic and empirical data sets, we demonstrate that the method estimates leaf-ages reliably and accurately. Potential applications of our approach include incorporating samples of uncertain or radiocarbon-infinite age into ancient DNA analyses, evaluating the temporal signal in a particular sequence or data set, and exploring the reliability of sequence ages that are somehow contentious. C1 [Shapiro, Beth] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Ho, Simon Y. W.] Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia. [Drummond, Alexei J.] Univ Auckland, Dept Comp Sci, Auckland 1, New Zealand. [Drummond, Alexei J.] Univ Auckland, Bioinformat Inst, Auckland 1, New Zealand. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Shapiro, B (reprint author), Penn State Univ, Dept Biol, University Pk, PA 16802 USA. EM beth.shapiro@psu.edu RI Ho, Simon/A-8417-2008; pybus, oliver/B-2640-2012; Drummond, Alexei/A-3209-2010; OI Ho, Simon/0000-0002-0361-2307; Drummond, Alexei/0000-0003-4454-2576; Pybus, Oliver/0000-0002-8797-2667; Rambaut, Andrew/0000-0003-4337-3707; Shapiro, Beth/0000-0002-2733-7776 FU National Institute of Health [R01 GM083603, R01 GM083983, R01 GM086887]; National Science Foundation [ARC 0909456]; National Evolutionary Synthesis Center (NESCent), NSF [EF-0423641] FX This work was partially supported by the National Institute of Health (R01 GM083603, R01 GM083983, and R01 GM086887), National Science Foundation (ARC 0909456), and the National Evolutionary Synthesis Center (NESCent), NSF #EF-0423641. NR 52 TC 51 Z9 51 U1 1 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD FEB PY 2011 VL 28 IS 2 BP 879 EP 887 DI 10.1093/molbev/msq262 PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 718HS UT WOS:000287112300002 PM 20889726 ER PT J AU Fan, HY Liu, ZL Johnson, PF Richards, JS AF Fan, Heng-Yu Liu, Zhilin Johnson, Peter F. Richards, JoAnne S. TI CCAAT/Enhancer-Binding Proteins (C/EBP)-alpha and -beta Are Essential for Ovulation, Luteinization, and the Expression of Key Target Genes SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID OVARIAN GRANULOSA-CELLS; PROSTAGLANDIN ENDOPEROXIDE SYNTHASE-2; FOLLICLE-STIMULATING-HORMONE; GROWTH-FACTOR RECEPTOR; C/EBP-BETA; OOCYTE COMPLEXES; CUMULUS CELLS; PROGESTERONE-RECEPTOR; P-GLYCOPROTEIN; FACTOR NETWORK AB LH activation of the epidermal growth factor receptor/RAS/ERK1/2 pathway is essential for ovulation and luteinization because granulosa cell (GC) depletion of Erk1/2 (Erk1/2(gc-/-) mice) renders mice infertile. As mediators of ERK1/2-dependent GC differentiation, the CCAAT/enhancer-binding proteins, (C/EBP)alpha and C/EBP beta, were also disrupted. Female Cebpb(gc-/-) mutant mice, but not Cebpa(gc-/-) mice, were subfertile whereas Cebpa/b(gc-/-) double-mutant females were sterile. Follicles failed to ovulate, ovaries were devoid of corpora lutea, luteal cell marker genes (Lhcgr, Prlr, Ptgfr, Cyp11a1, and Star) were absent, and serum progesterone levels were low. Microarray analyses identified numerous C/EBP alpha/beta target genes in equine chorionic gonadotropin (eCG)-human (h)CG-treated mice. At 4 h post-hCG, a subset (19%) of genes altered in the Cebpalb-depleted cells was also altered in Erk1/2-depleted cells; hence they are common effectors of ERK1/2. Additional genes down-regulated in the Cebpalb-depleted cells at 8 and 24 h post-hCG include known (Akr1b7, Runx2, Star, Saa3) and novel (Abcb1b, Apln, Igfbp4, Prlr, Ptgfr Timp4) C/EBP targets and effectors of luteal and vascular cell development. Bhmt, a gene controlling methionine metabolism and thought to be expressed exclusively in liver and kidney, was high in wild-type luteal cells but totally absent in Cebpalb mutant cells. Because numerous genes potentially associated with vascular development were suppressed in the mutant cells, C/EBP alpha/beta appear to dictate the luteinization process by also controlling genes that regulate the formation of the extensive vascular network required to sustain luteal cells. Thus, C/EBP alpha/beta mediate the terminal differentiation of GCs during the complex process of luteinization. (Molecular Endocrinology 25: 253-268, 2011) C1 [Fan, Heng-Yu; Liu, Zhilin; Richards, JoAnne S.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Johnson, Peter F.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. RP Richards, JS (reprint author), Baylor Coll Med BCM MS130, Dept Mol & Cellular Biol, Houston, TX 77030 USA. EM joanner@bcm.tmc.edu RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 FU National Institutes of Health (NIH) [NIH-HD16229, NIH-HD07495]; NIH, National Cancer Institute, Center for Cancer Research; National Research Service [NIH-HD058429-01A1] FX This work was supported by: National Institutes of Health (NIH) Grants NIH-HD16229, NIH-HD07495 (SCCPIR), Project II (to J.S.R.), the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to P.F.J.), and National Research Service Award NIH-HD058429-01A1 (to H.Y.F.). NR 76 TC 44 Z9 49 U1 0 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD FEB PY 2011 VL 25 IS 2 BP 253 EP 268 DI 10.1210/me.2010-0318 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 711MQ UT WOS:000286596100005 PM 21177758 ER PT J AU Cable, C Finkel, RS Lehky, TJ Biassou, NM Wiggs, EA Bunin, N Pierson, TM AF Cable, Casey Finkel, Richard S. Lehky, Tanya J. Biassou, Nadia M. Wiggs, Edythe A. Bunin, Nancy Pierson, Tyler Mark TI Unrelated umbilical cord blood transplant for juvenile metachromatic leukodystrophy: A 5-year follow-up in three affected siblings SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Umbilical cord blood transplant; Metachromatic leukodystrophy; Neurological disease; Neuroimaging ID BONE-MARROW-TRANSPLANTATION; NERVE-CONDUCTION; STABILIZATION; GENETICS; DISEASES; OUTCOMES; CHILDREN; THERAPY AB Unrelated umbilical cord blood transplantation (UCBT) was used to treat three siblings with juvenile metachromatic leukodystrophy (jMLD). The efficacy of this therapy was measured over a 5-year period with serial neurological examinations, neuroimaging, nerve conduction studies (NCS), and neuropsychological evaluations (NPE). Outcomes were a function of disease stage at time of UCBT with alteration of disease course occurring in the first 2 years after UCBT and then subsequent halting of progression and stabilization of symptoms and disease. Published by Elsevier Inc. C1 [Cable, Casey; Pierson, Tyler Mark] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Finkel, Richard S.] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Lehky, Tanya J.] NINDS, EMG Sect, NIH, Bethesda, MD 20892 USA. [Biassou, Nadia M.] NIH, Div Neuroradiol, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Wiggs, Edythe A.] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. [Bunin, Nancy] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. RP Pierson, TM (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 35,Room 2A1012,35 Convent Dr,MSC 3705, Bethesda, MD 20892 USA. EM piersonty@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002974-09, Z99 NS999999] NR 21 TC 16 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2011 VL 102 IS 2 BP 207 EP 209 DI 10.1016/j.ymgme.2010.10.002 PG 3 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 715CW UT WOS:000286859000017 PM 21035368 ER PT J AU Maegawa, G Obie, C Ribbens, J Whiteley, G Thomas, G Ferrer, M Zheng, W Maegawa, G AF Maegawa, Gustavo Obie, Cassandra Ribbens, Jameson Whiteley, Grace Thomas, George Ferrer, Marc Zheng, Wei Maegawa, Gustavo TI Developing of cell-based high-throughput screening assay for the identification of potential therapeutic small molecules for metachromatic leukodystrophy SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 7th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 16-18, 2011 CL Las Vegas, NV SP Lysosomal Dish Network C1 [Obie, Cassandra; Ribbens, Jameson; Whiteley, Grace; Maegawa, Gustavo] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Obie, Cassandra; Ribbens, Jameson; Whiteley, Grace; Maegawa, Gustavo] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ferrer, Marc; Zheng, Wei] NIH, Chem Genom Ctr, Rockville, MD USA. [Thomas, George] Johns Hopkins Med Inst, Kennedy Krieger Inst, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2011 VL 102 IS 2 BP S27 EP S27 DI 10.1016/j.ymgme.2010.11.091 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 715CW UT WOS:000286859000109 ER PT J AU Patterson, M Brown, T Zaccariello, M Vaurio, R Porter, F AF Patterson, Marc Brown, Tanya Zaccariello, Michael Vaurio, Rebecca Porter, Forbes TI Longitudinal study of cognition in Niemann-Pick Disease, Type C SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 7th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 16-18, 2011 CL Las Vegas, NV SP Lysosomal Dish Network C1 [Patterson, Marc; Brown, Tanya; Zaccariello, Michael] Mayo Clin, Rochester, MN USA. [Vaurio, Rebecca] Kennedy Krieger Inst, Baltimore, MD USA. [Porter, Forbes] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2011 VL 102 IS 2 BP S34 EP S34 DI 10.1016/j.ymgme.2010.11.116 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 715CW UT WOS:000286859000133 ER PT J AU Wang, JD Xie, J Zhou, XJ Cheng, Z Gu, N Teng, GJ Hu, QJ Zhu, FP Chang, SH Zhang, F Lu, GM Chen, XY AF Wang, Jiandong Xie, Jin Zhou, Xiaojun Cheng, Zhen Gu, Ning Teng, Gaojun Hu, Qiujue Zhu, Feipeng Chang, Shuanghui Zhang, Fan Lu, Guangming Chen, Xiaoyuan TI Ferritin Enhances SPIO Tracking of C6 Rat Glioma Cells by MRI SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Ferritin reporter; Superparamagnetic iron oxide (SPIO) particle; Cell tracking; MRI ID STEM-CELL; IN-VIVO; GENE-EXPRESSION; TRANSGENIC MICE; THERAPY; NANOPARTICLES; REPORTER; MODEL; VITRO AB To investigate the effect of ferritin protein overexpression on superparamagnetic iron oxide (SPIO) particle labeling of C6 rat glioma cells, and track the labeled cells in vivo using magnetic resonance imaging (MRI). A plasmid of H-chain of murine ferritin gene was constructed and transfected into C6 cells. The parental and the transfected C6 cells labeled with SPIO were bilaterally inoculated subcutaneously into nude mice. The mice were imaged by multiple T2-weighted MR scans after C6 cell inoculation. The mice were killed 2 weeks later, and the concentration of iron in the tumor tissue was measured by inductively coupled plasma. The iron concentration in xenografts derived from SPIO-labeled C6 cells that were transfected with ferritin plasmid was significantly higher than that in xenografts from parental C6 cells that were labeled with SPIO but not transfected (p = 0.034, N = 5). Ferritin-transfected C6 cells showed an improved T-2 contrast in vivo compared with parental cells labeled with SPIO but not transfected. Coordinating ferritin with SPIO can lead to a longer MRI cellular tracking period. C1 [Xie, Jin; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Wang, Jiandong; Hu, Qiujue; Zhu, Feipeng; Chang, Shuanghui; Zhang, Fan; Lu, Guangming] Nanjing Univ, Sch Med, Dept Radiol, Nanjing Jinling Hosp, Nanjing 210002, Peoples R China. [Wang, Jiandong; Zhou, Xiaojun] Nanjing Univ, Sch Med, Dept Pathol, Nanjing Jinling Hosp, Nanjing 210002, Peoples R China. [Cheng, Zhen] Lucas Ctr, Mol Imaging Program, Dept Radiol, Stanford, CA 94305 USA. [Gu, Ning] Southeast Univ, Dept Radiol, Nanjing 210009, Peoples R China. [Teng, Gaojun] Southeast Univ, Dept Chem, Nanjing 210009, Peoples R China. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, 31 Ctr Dr,Suite 1C14,MSC 2281, Bethesda, MD 20892 USA. EM cjr.luguangming@vip.163.com; shawn.chen@nih.gov RI Xie, Jin/E-8193-2010; Cheng, Zhen/K-2843-2012 FU Ministry of Science and Technology of China [CB705707]; China Nanjing Medical Science and Technology Research Project [06Z37]; National Natural Science Foundation of China [30970813, 30930028]; NIH; National Institute of Biomedical Imaging and Bioengineering; Siemens Ltd. FX The authors would like to thank Dr. Laura Jean Pisani at the Stanford School of Medicine for MRI technical support, and Dr. Hui Mao at the Emory University School of Medicine for helpful discussion of experimental details. This work was supported, in part, by the National Basic Research Priorities Program 973 Project (CB705707) from the Ministry of Science and Technology of China, China Nanjing Medical Science and Technology Research Project (No. 06Z37), the National Natural Science Foundation of China (30970813, 30930028), and the Intramural Research Program of the NIH, including the National Institute of Biomedical Imaging and Bioengineering. Dr. Jiandong Wang acknowledges financial support from Siemens Ltd. China Medical Solution for study at Stanford. NR 19 TC 9 Z9 10 U1 2 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD FEB PY 2011 VL 13 IS 1 BP 87 EP 93 DI 10.1007/s11307-010-0338-5 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 708WS UT WOS:000286395600012 PM 20440566 ER PT J AU Bu, LH Li, RF Jin, ZN Wen, XF Liu, SA Yang, BF Shen, BZ Chen, XY AF Bu, Lihong Li, Renfei Jin, Zhongnan Wen, Xiaofei Liu, Shuang Yang, Baofeng Shen, Baozhong Chen, Xiaoyuan TI Evaluation of (99) (TcN)-Tc-m-MPO as a New Myocardial Perfusion Imaging Agent in Normal Dogs and in an Acute Myocardial Infarction Canine Model: Comparison with (99) Tc-m-Sestamibi SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE (TcN)-Tc-99m-MPO; Myocardial perfusion imaging; Biodistribution; Liver clearance; Myocardial infarction; SPECT ID CATIONIC TC-99M-NITRIDO COMPLEXES; NUCLEAR CARDIOLOGY; LIVER CLEARANCE; TC-99M; RADIOPHARMACEUTICALS; BIODISTRIBUTION; ETHER; TC-99M-SESTAMIBI; RADIOTRACERS; STIMULATION AB (99) (TcN)-Tc-m-MPO ([(99) (TcN)-Tc-m(mpo)(PNP5)](+): mpo = 2-mercaptopyridine oxide and PNP5 = N-ethoxyethyl-N,N-bis[2-(bis(3-methoxypropyl)phosphino)ethyl]amine) is a cationic (99) Tc-m-nitrido complex, which has favorable biodistribution and myocardial uptake with rapid liver clearance in Sprague Dawley rats. The objective of this study was to compare the biodistribution and pharmacokinetics of (99) (TcN)-Tc-m-MPO and (99) Tc-m-Sestamibi in normal dogs, and to evaluate the potential of (99) (TcN)-Tc-m-MPO as a myocardial perfusion agent in canines with acute myocardial infarction. Five normal mongrel dogs were injected intravenously with (99) (TcN)-Tc-m-MPO. Venous blood samples were collected via a femoral vein catheter at 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40, 60, and 90 min post-injection (p.i.). Anterior-posterior planar images were acquired by gamma-camera at 10, 20, 30, 60, 90, and 120 min p.i. Regions of interest (ROIs) were drawn around the heart, liver, and lungs. The heart/liver and heart/lung ratios were calculated by dividing the mean counts in heart ROI by the mean counts in the liver and lung ROI, respectively. For comparison, (99) Tc-m-sestamibi was also evaluated in the same five dogs. The interval period between the two examinations was 1 week to eliminate possible interference between these two radiotracers. In addition, single positron emission computed tomography (SPECT) images in the canine infarct model were collected 24 h after myocardial infarction at 30 and 60 min after the administration of (99) (TcN)-Tc-m-MPO (n = 4) or (99) Tc-m-Sestamibi (n = 4). It was found that (99) (TcN)-Tc-m-MPO and (99) Tc-m-Sestamibi displayed very similar blood clearance characteristics during the first 90 min p.i. Both (99) (TcN)-Tc-m-MPO and (99) Tc-m-Sestamibi had a rapid blood clearance with less than 50% of initial radioactivity remaining at 1 min and less than 5% at 30 min p.i. (99) (TcN)-Tc-m-MPO and (99) Tc-m-Sestamibi both showed good heart/lung contrast. The heart/liver ratio of (99) (TcN)-Tc-m-MPO increased with time (0.53 +/- 0.06 at 10 min, 0.90 +/- 0.062 at 30 min, and 1.22 +/- 0.06 at 60 min p.i.), whereas the heart/liver ratio of (99) Tc-m-Sestamibi remained low at all time points (0.50 +/- 0.03 at 10 min, 0.64 +/- 0.03 at 30 min, and 0.60 +/- 0.02 at 60 min p.i.). SPECT imaging studies in canines with acute myocardial infarction indicated that good visualization of the left ventricular wall and perfusion defects could be achieved at 30 min after administration of (99) (TcN)-Tc-m-MPO but not after (99) Tc-m-Sestamibi. The combination of reasonable heart uptake with rapid hepatobiliary excretion makes (99) (TcN)-Tc-m-MPO a promising new radiotracer for myocardial perfusion imaging. C1 [Bu, Lihong; Chen, Xiaoyuan] Stanford Univ, Dept Radiol, MIPS, Stanford, CA 94305 USA. [Bu, Lihong; Yang, Baofeng; Shen, Baozhong] Harbin Med Coll, Dept Pharmacol, Harbin 150001, Heilongjiang, Peoples R China. [Bu, Lihong; Li, Renfei; Jin, Zhongnan; Wen, Xiaofei; Shen, Baozhong] Harbin Med Coll, Dept Med Imaging, Hosp 4, Harbin 150001, Heilongjiang, Peoples R China. [Liu, Shuang] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Stanford Univ, Dept Radiol, MIPS, Stanford, CA 94305 USA. EM shenbzh@vip.sina.com; shawn.chen@nih.gov FU Chinese Ministry of Science and Technology [2009DFB30040]; National Science Foundation for Postdoctoral Scientists of China [20070420165]; Science and Technology Tackle Key Problem Plan Foundation of Harbin [2007AA3CS085] FX This work was supported, in part, by the following research grants: 2009DFB30040 from the international cooperation projects of the Chinese Ministry of Science and Technology, 20070420165 from the National Science Foundation for Postdoctoral Scientists of China, 2007AA3CS085 from the Science and Technology Tackle Key Problem Plan Foundation of Harbin. The authors wish to thank Drs. Fan Wang and Bing Jia from Peking University for technical support. NR 31 TC 8 Z9 8 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD FEB PY 2011 VL 13 IS 1 BP 121 EP 127 DI 10.1007/s11307-010-0304-2 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 708WS UT WOS:000286395600016 PM 20458635 ER PT J AU Li, MS Khursigara, CM Subramaniam, S Hazelbauer, GL AF Li, Mingshan Khursigara, Cezar M. Subramaniam, Sriram Hazelbauer, Gerald L. TI Chemotaxis kinase CheA is activated by three neighbouring chemoreceptor dimers as effectively as by receptor clusters SO MOLECULAR MICROBIOLOGY LA English DT Article ID BACTERIAL CHEMOTAXIS; ESCHERICHIA-COLI; ASPARTATE RECEPTOR; SIGNAL-TRANSDUCTION; LIGAND-BINDING; COMPLEX; NANODISCS; ARRAYS; PROTEINS; LOCATION AB P>Chemoreceptors are central to bacterial chemotaxis. These transmembrane homodimers form trimers of dimers. Trimers form clusters of a few to thousands of receptors. A crucial receptor function is 100-fold activation, in signalling complexes, of sensory histidine kinase CheA. Significant activation has been shown to require more than one receptor dimer but the number required for full activation was unknown. We investigated this issue using Nanodiscs, soluble, nanoscale (similar to 10 nm diameter) plugs of lipid bilayer, to limit the number of neighbouring receptors contributing to activation. Utilizing size-exclusion chromatography, we separated primary preparations of receptor-containing Nanodiscs, otherwise heterogeneous for number and orientation of inserted receptors, into fractions enriched for specific numbers of dimers per disc. Fractionated, clarified Nanodiscs carrying approximately five dimers per disc were as effective in activating kinase as native membrane vesicles containing many neighbouring dimers. At five independently inserted dimers per disc, every disc would have at least three dimers oriented in parallel and thus able act together as they would in native membrane. We conclude full kinase activation involves interaction of CheA with groups of three receptor dimers, presumably as a trimer of dimers, and that more extensive interactions among receptors are not necessary for full kinase activation. C1 [Li, Mingshan; Hazelbauer, Gerald L.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Khursigara, Cezar M.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hazelbauer, GL (reprint author), Univ Missouri, Dept Biochem, 117 Schweitzer Hall, Columbia, MO 65211 USA. EM hazelbauerg@missouri.edu FU National Institute of General Medical Sciences [GM29963]; Center for Cancer Research, National Cancer Institute, NIH FX We thank Wing-Cheung Lai for optimization of the kinase assay for Tar in native membrane and in Nanodiscs. This work was supported in part by Grant GM29963 to G.L.H. from the National Institute of General Medical Sciences and by funds to S.S. from the Center for Cancer Research, National Cancer Institute, NIH. NR 39 TC 22 Z9 22 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2011 VL 79 IS 3 BP 677 EP 685 DI 10.1111/j.1365-2958.2010.07478.x PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 710OU UT WOS:000286521900011 PM 21255111 ER PT J AU Sehba, FA Pluta, RM Zhang, JH AF Sehba, Fatima A. Pluta, Ryszard M. Zhang, John H. TI Metamorphosis of Subarachnoid Hemorrhage Research: from Delayed Vasospasm to Early Brain Injury SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Subarachnoid hemorrhage; Delayed vasospasm; Cerebral ischemia; Early brain injury; Therapeutic interventions ID CEREBRAL-BLOOD-FLOW; NITRIC-OXIDE SYNTHASE; RUPTURED INTRACRANIAL ANEURYSM; HIGH-DOSE METHYLPREDNISOLONE; MICROVASCULAR BASAL LAMINA; ADHESION MOLECULE-1 LEVELS; ETA-RECEPTOR ANTAGONIST; CANINE BASILAR ARTERY; CEREBROSPINAL-FLUID; DOUBLE-BLIND AB Delayed vasospasm that develops 3-7 days after aneurysmal subarachnoid hemorrhage (SAH) has traditionally been considered the most important determinant of delayed ischemic injury and poor outcome. Consequently, most therapies against delayed ischemic injury are directed towards reducing the incidence of vasospasm. The clinical trials based on this strategy, however, have so far claimed limited success; the incidence of vasospasm is reduced without reduction in delayed ischemic injury or improvement in the long-term outcome. This fact has shifted research interest to the early brain injury (first 72 h) evoked by SAH. In recent years, several pathological mechanisms that activate within minutes after the initial bleed and lead to early brain injury are identified. In addition, it is found that many of these mechanisms evolve with time and participate in the pathogenesis of delayed ischemic injury and poor outcome. Therefore, a therapy or therapies focused on these early mechanisms may not only prevent the early brain injury but may also help reduce the intensity of later developing neurological complications. This manuscript reviews the pathological mechanisms of early brain injury after SAH and summarizes the status of current therapies. C1 [Sehba, Fatima A.] Mt Sinai Sch Med, Dept Neurosurg, New York, NY 10029 USA. [Sehba, Fatima A.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Pluta, Ryszard M.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD USA. [Pluta, Ryszard M.] JAMA, Chicago, IL USA. [Zhang, John H.] Loma Linda Univ, Dept Neurosurg, Med Ctr, Loma Linda, CA USA. RP Sehba, FA (reprint author), Mt Sinai Sch Med, Dept Neurosurg, Box 1136, New York, NY 10029 USA. EM fatima.sehba@mssm.edu OI Zhang, John H./0000-0002-4319-4285 FU American Heart Association [GRNT4570012]; National Institutes of Health [RO1 NS050576, NS053407]; Intramural Research Program; National Institutes of Stroke and Neurological Disorders, NIH FX This work was supported by the American Heart Association grant number GRNT4570012 (FAS), and the National Institutes of Health, grant numbers RO1 NS050576 (FAS) and NS053407 (JHZ), and by the Intramural Research Program (RMP) of the National Institutes of Stroke and Neurological Disorders, NIH. NR 170 TC 93 Z9 104 U1 3 U2 15 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD FEB PY 2011 VL 43 IS 1 BP 27 EP 40 DI 10.1007/s12035-010-8155-z PG 14 WC Neurosciences SC Neurosciences & Neurology GA 709KV UT WOS:000286437800003 PM 21161614 ER PT J AU Rosemond, E Rossi, M McMillin, SM Scarselli, M Donaldson, JG Wess, J AF Rosemond, Erica Rossi, Mario McMillin, Sara M. Scarselli, Marco Donaldson, Julie G. Wess, Juergen TI Regulation of M-3 Muscarinic Receptor Expression and Function by Transmembrane Protein 147 SO MOLECULAR PHARMACOLOGY LA English DT Article ID COLON-CANCER CELLS; ACETYLCHOLINE-RECEPTORS; INDUCED PROLIFERATION; INTERACTING PROTEINS; YEAST; ACTIVATION; GROWTH; TRANSACTIVATION; PHARMACOLOGY; PHYSIOLOGY AB The M-3 muscarinic acetylcholine receptor (M3R) regulates many fundamental physiological functions. To identify novel M3R-interacting proteins, we used a recently developed yeast two-hybrid screen (split ubiquitin method) to detect interactions among membrane proteins. This screen led to the identification of many novel M3R-associated proteins, including the putative membrane protein transmembrane protein 147 (Tmem147). The amino acid sequence of Tmem147 is highly conserved among mammals, but its physiological roles are unknown at present. We initially demonstrated that Tmem147 could be coimmunoprecipitated with M3Rs in cotransfected mammalian cells (COS-7 cells). Confocal imaging studies showed that Tmem147 was localized to endoplasmic reticulum (ER) membranes and that the Tmem147/M3R interaction occurred in the ER of cotransfected COS-7 cells, resulting in impaired trafficking of the M3R to the cell surface. To study the role of Tmem147 in modulating M3R function in a more physiologically relevant setting, we carried out studies with H508 human colon cancer cells that endogenously express M3Rs and Tmem147. Treatment of H508 cells with carbachol, a hydrolytically stable acetylcholine analog, promoted H508 cell proliferation and activation of the mitogenic kinase, p90RSK. Small interfering RNA-mediated knockdown of Tmem147 expression significantly augmented the stimulatory effects of carbachol on H508 cell proliferation and p90RSK activation. These effects were associated with an increase in the density of cell surface M3Rs. Our data clearly indicate that Tmem147 represents a potent negative regulator of M3R function, most likely by interacting with M3Rs in an intracellular compartment (ER). These findings may lead to new strategies aimed at modulating M3R activity for therapeutic purposes. C1 [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Scarselli, Marco; Donaldson, Julie G.] NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov OI Scarselli, Marco/0000-0001-5087-3182 FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. NR 39 TC 11 Z9 12 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2011 VL 79 IS 2 BP 251 EP 261 DI 10.1124/mol.110.067363 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 707TT UT WOS:000286311800005 PM 21056967 ER PT J AU Barrett, AJ Melenhorst, JJ AF Barrett, A. John Melenhorst, J. Joseph TI Is Human Cell Therapy Research Caught in a Mousetrap? SO MOLECULAR THERAPY LA English DT Editorial Material ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; T-LYMPHOCYTES; HUMAN IMMUNOLOGY; GENE-THERAPY; GRAFT; INTERLEUKIN-2; MICE; MICROFLORA; MEN C1 [Barrett, A. John] NHLBI, Allogene Stem Cell Transplant Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Allogene Stem Cell Transplant Sect, Hematol Branch, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM barrettjj@mail.nih.gov NR 41 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD FEB PY 2011 VL 19 IS 2 BP 224 EP 227 DI 10.1038/mt.2010.304 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 715WM UT WOS:000286923000002 ER PT J AU Lasaro, MO Haut, LH Zhou, XY Xiang, ZQ Zhou, DM Li, Y Giles-Davis, W Li, H Engram, JC DiMenna, LJ Bian, A Sazanovich, M Parzych, EM Kurupati, R Small, JC Wu, TL Leskowitz, RM Klatt, NR Brenchley, JM Garber, DA Lewis, M Ratcliffe, SJ Betts, MR Silvestri, G Ertl, HC AF Lasaro, Marcio O. Haut, Larissa H. Zhou, Xiangyang Xiang, Zhiquan Zhou, Dongming Li, Yan Giles-Davis, Wynetta Li, Hua Engram, Jessica C. DiMenna, Lauren J. Bian, Ang Sazanovich, Marina Parzych, Elizabeth M. Kurupati, Raj Small, Juliana C. Wu, Te-Lang Leskowitz, Rachel M. Klatt, Nicole R. Brenchley, Jason M. Garber, David A. Lewis, Mark Ratcliffe, Sarah J. Betts, Michael R. Silvestri, Guido Ertl, Hildegund C. TI Vaccine-induced T cells Provide Partial Protection Against High-dose Rectal SIVmac239 Challenge of Rhesus Macaques SO MOLECULAR THERAPY LA English DT Article ID IMMUNODEFICIENCY VIRUS CHALLENGE; SIMIAN-IMMUNODEFICIENCY; DISEASE PROGRESSION; HIV-INFECTION; REPLICATION; RESPONSES; IMMUNITY; VECTORS; MONKEYS; GAG AB Despite enormous efforts by the scientific community, an effective HIV vaccine remains elusive. To further address to what degree T cells in absence of antibodies may protect against simian immunodeficiency virus (SIV) disease progression, rhesus macaques were vaccinated intramuscularly with a chimpanzee-derived Ad vector (AdC) serotype 6 and then boosted intramuscularly with a serologically distinct AdC vector of serotype 7 both expressing Gag of SIVmac239. Animals were subsequently boosted intramuscularly with a modified vaccinia Ankara (MVA) virus expressing Gag and Tat of the homologous SIV before mucosal challenge with a high dose of SIVmac239 given rectally. Whereas vaccinated animals showed only a modest reduction of viral loads, their overall survival was improved, in association with a substantial protection from the loss of CD4(+) T cells. In addition, the two vaccinated Mamu-A*01(+) macaques controlled viral loads to levels below detection within weeks after challenge. These data strongly suggest that T cells, while unable to affect SIV acquisition upon high-dose rectal infection, can reduce disease progression. Induction of potent T-cell responses should thus remain a component of our efforts to develop an efficacious vaccine to HIV-1. C1 [Lasaro, Marcio O.; Haut, Larissa H.; Zhou, Xiangyang; Xiang, Zhiquan; Zhou, Dongming; Li, Yan; Giles-Davis, Wynetta; Li, Hua; DiMenna, Lauren J.; Bian, Ang; Sazanovich, Marina; Parzych, Elizabeth M.; Kurupati, Raj; Small, Juliana C.; Wu, Te-Lang; Leskowitz, Rachel M.; Silvestri, Guido] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Haut, Larissa H.] Univ Fed Santa Catarina, Dept Microbiol Imunol & Parasitol, Florianopolis, SC, Brazil. [Engram, Jessica C.; Silvestri, Guido] Univ Penn, Sch Med, Dept Pathol, Philadelphia, PA 19104 USA. [Klatt, Nicole R.; Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Garber, David A.; Silvestri, Guido] Emory Univ, Sch Med, Atlanta, GA USA. [Lewis, Mark] Bioqual Inc, Rockville, MD USA. [Ratcliffe, Sarah J.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Betts, Michael R.] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. RP Ertl, HC (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM ertl@wistar.upenn.edu OI DiMenna, Lauren/0000-0002-2477-1294; Ratcliffe, Sarah/0000-0002-6644-8284 FU NIH/DAIDS; US National Cancer Institute [CA10815]; Pennsylvania Department of Health FX This work was funded by grants from NIH/DAIDS and institutional grants to the Wistar Institute including a US National Cancer Institute Cancer Core Grant (CA10815) and the Commonwealth Universal Research Enhancement Program from the Pennsylvania Department of Health. We thank Christina Cole for help in preparation of the manuscript. The authors declared no conflict of interest. NR 32 TC 5 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD FEB PY 2011 VL 19 IS 2 BP 417 EP 426 DI 10.1038/mt.2010.238 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 715WM UT WOS:000286923000028 PM 21081905 ER PT J AU Lin, X Xie, J Niu, G Zhang, F Gao, HK Yang, M Quan, QM Aronova, MA Zhang, GF Lee, S Leaprnan, R Chen, XY AF Lin, Xin Xie, Jin Niu, Gang Zhang, Fan Gao, Haokao Yang, Min Quan, Qimeng Aronova, Maria A. Zhang, Guofeng Lee, Seulki Leaprnan, Richard Chen, Xiaoyuan TI Chimeric Ferritin Nanocages for Multiple Function Loading and Multimodal Imaging SO NANO LETTERS LA English DT Article DE Ferritin nanocage; multimodality molecular imaging; positron emission tomography; near-infrared fluorescence imaging; integrin; RGD peptide ID SMALL-ANIMAL PET; TUMOR ANGIOGENESIS; DRUG-DELIVERY; RGD PEPTIDES; NANOPARTICLES; CANCER; CELLS; OXIDE; IRON; HETERODIMER AB Nanomaterials provide large surface areas, relative to their volumes, on which to load functions. One challenge, however, has been to achieve precise control in loading multiple functionalities. Traditional bioconjugation techniques, which randomly target the surface functional groups of nanomaterials, have been found increasingly inadequate for such control, which is a drawback that may substantially slow down or prohibit the translational efforts. In the current study, we evaluated ferritin nanocages as candidate nanoplatforms for multifunctional loading. Ferritin nanocages can be either genetically or chemically modified to impart functionalities to their surfaces, and metal cations can be encapsulated in their interiors by association with metal binding sites. Moreover, different types of ferritin nanocages can be disassembled under acidic condition and reassembled at pH of 7.4, providing a facile way to achieve function hybridization. We were able to use combinations of these unique properties to produce a number of multifunctional ferritin nanostructures with precise control of their composition. We then studied these nanoparticles, both in vitro and in vivo, to evaluate their potential suitability as multimodality imaging probes. A good tumor targeting profile was observed, which was attributable to both the enhanced permeability and retention (EPR) effect and biovector mediated targeting. This, in combination with the generalizability of the function loading techniques, promises ferritin particles as a powerful nanoplatfom in the era of nanomedicine. C1 [Lin, Xin; Xie, Jin; Niu, Gang; Zhang, Fan; Gao, Haokao; Yang, Min; Quan, Qimeng; Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Aronova, Maria A.; Zhang, Guofeng; Leaprnan, Richard] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM Shawn.Chen@nih.gov RI Xie, Jin/E-8193-2010 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH; National Science Foundation of China (NSFC) [81028009]; NTH Pathway to Independence Grant [K99/R00]; National Institute of Standards and Technology (NIST) FX This work was supported in part by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH and the International Cooperative Program of National Science Foundation of China (NSFC) (81028009). J.X. is partially supported by an NTH Pathway to Independence Grant (K99/R00). S.L. acknowledges a National Research Council Research Associateship Award funded by the National Institute of Standards and Technology (NIST) and the IRP of NIBIB, NTH. We thank Dr. Henry S. Eden for proof-reading the manuscript. NR 32 TC 104 Z9 108 U1 9 U2 102 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 J9 NANO LETT JI Nano Lett. PD FEB PY 2011 VL 11 IS 2 BP 814 EP 819 DI 10.1021/nl104141g PG 6 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 717LZ UT WOS:000287049100085 PM 21210706 ER PT J AU Grabow, WW Zakrevsky, P Afonin, KA Chworos, A Shapiro, BA Jaeger, L AF Grabow, Wade W. Zakrevsky, Paul Afonin, Kirill A. Chworos, Arkadiusz Shapiro, Bruce A. Jaeger, Luc TI Self-Assembling RNA Nanorings Based on RNAI/II Inverse Kissing Complexes SO NANO LETTERS LA English DT Article DE RNA architectonics; bionanotechnology; silencing RNA; supramolecular assembly; RNA interaction; RNA motif ID DIMERIZATION INITIATION SITE; APTAMER-SIRNA CHIMERAS; COLE1 ROM PROTEIN; CHEMICAL-MODIFICATION; TERTIARY INTERACTIONS; COMBINATORIAL RNAI; DNA NANOSTRUCTURES; LOOP COMPLEX; STEM-LOOPS; DESIGN AB RNA is an attractive biopolymer for nanodesign of self-assembling particles for nanobiotechnology and synthetic biology. Here, we experimentally characterize by biochemical and biophysical methods the formation of thermostable and ribonuclease resistant RNA nanorings previously proposed by computational design. High yields of fully programmable nanorings were produced based on several RNAI/II kissing complex variants selected for their ability to promote polygon self-assembly. This self-assembly strategy relying on the particular geometry of bended kissing complexes has potential for developing short interfering RNA delivery agents. C1 [Grabow, Wade W.; Zakrevsky, Paul; Afonin, Kirill A.; Chworos, Arkadiusz; Jaeger, Luc] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. [Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, NIH, Frederick, MD 21702 USA. [Jaeger, Luc] Univ Calif Santa Barbara, Biomol Sci & Engn Program, Santa Barbara, CA 93106 USA. [Chworos, Arkadiusz] Polish Acad Sci, Ctr Mol & Macromol Studies, PL-90363 Lodz, Poland. RP Jaeger, L (reprint author), Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. EM jaeger@chem.ucsb.edu FU NIH [R01GM-079604]; NIH, National Cancer Institute, Center for Cancer Research FX The authors thank Dr. Isil Severcan for her early involvement in the project and Jannine Tuttle for her assistance acquiring AFM images. This research was supported by NIH R01GM-079604 (to L.J.). This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to B.A.S.). U. wishes to dedicate this paper to St. Giuseppe Moscati and St. Gianna Beretta Mona. NR 59 TC 87 Z9 88 U1 4 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD FEB PY 2011 VL 11 IS 2 BP 878 EP 887 DI 10.1021/nl104271s PG 10 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 717LZ UT WOS:000287049100096 PM 21229999 ER PT J AU Rouxel, T Grandaubert, J Hane, JK Hoede, C van de Wouw, AP Couloux, A Dominguez, V Anthouard, V Bally, P Bourras, S Cozijnsen, AJ Ciuffetti, LM Degrave, A Dilmaghani, A Duret, L Fudal, I Goodwin, SB Gout, L Glaser, N Linglin, J Kema, GHJ Lapalu, N Lawrence, CB May, K Meyer, M Ollivier, B Poulain, J Schoch, CL Simon, A Spatafora, JW Stachowiak, A Turgeon, BG Tyler, BM Vincent, D Weissenbach, J Amselem, J Quesneville, H Oliver, RP Wincker, P Balesdent, MH Howlett, BJ AF Rouxel, Thierry Grandaubert, Jonathan Hane, James K. Hoede, Claire van de Wouw, Angela P. Couloux, Arnaud Dominguez, Victoria Anthouard, Veronique Bally, Pascal Bourras, Salim Cozijnsen, Anton J. Ciuffetti, Lynda M. Degrave, Alexandre Dilmaghani, Azita Duret, Laurent Fudal, Isabelle Goodwin, Stephen B. Gout, Lilian Glaser, Nicolas Linglin, Juliette Kema, Gert H. J. Lapalu, Nicolas Lawrence, Christopher B. May, Kim Meyer, Michel Ollivier, Benedicte Poulain, Julie Schoch, Conrad L. Simon, Adeline Spatafora, Joseph W. Stachowiak, Anna Turgeon, B. Gillian Tyler, Brett M. Vincent, Delphine Weissenbach, Jean Amselem, Joelle Quesneville, Hadi Oliver, Richard P. Wincker, Patrick Balesdent, Marie-Helene Howlett, Barbara J. TI Effector diversification within compartments of the Leptosphaeria maculans genome affected by Repeat-Induced Point mutations SO NATURE COMMUNICATIONS LA English DT Article ID TRANSPOSABLE ELEMENTS; MOLECULAR EVOLUTION; PATHOGEN EFFECTORS; BRASSICA-NAPUS; GENE-TRANSFER; OILSEED RAPE; STEM CANKER; AVIRULENCE; PLANT; FUNGAL AB Fungi are of primary ecological, biotechnological and economic importance. Many fundamental biological processes that are shared by animals and fungi are studied in fungi due to their experimental tractability. Many fungi are pathogens or mutualists and are model systems to analyse effector genes and their mechanisms of diversification. In this study, we report the genome sequence of the phytopathogenic ascomycete Leptosphaeria maculans and characterize its repertoire of protein effectors. The L. maculans genome has an unusual bipartite structure with alternating distinct guanine and cytosine-equilibrated and adenine and thymine (AT)-rich blocks of homogenous nucleotide composition. The AT-rich blocks comprise one-third of the genome and contain effector genes and families of transposable elements, both of which are affected by repeat-induced point mutation, a fungal-specific genome defence mechanism. This genomic environment for effectors promotes rapid sequence diversification and underpins the evolutionary potential of the fungus to adapt rapidly to novel host-derived constraints. C1 [Rouxel, Thierry; Grandaubert, Jonathan; Bally, Pascal; Bourras, Salim; Degrave, Alexandre; Dilmaghani, Azita; Fudal, Isabelle; Gout, Lilian; Glaser, Nicolas; Linglin, Juliette; Meyer, Michel; Ollivier, Benedicte; Simon, Adeline; Balesdent, Marie-Helene] INRA Bioger, UR1290, F-78850 Thiverval Grignon, France. [Hane, James K.] Murdoch Univ, Murdoch, WA 6150, Australia. [Hoede, Claire; Dominguez, Victoria; Lapalu, Nicolas; Amselem, Joelle; Quesneville, Hadi] INRA URGI, F-78026 Versailles, France. [van de Wouw, Angela P.; Cozijnsen, Anton J.; May, Kim; Howlett, Barbara J.] Univ Melbourne, Sch Bot, Melbourne, Vic 3010, Australia. [Couloux, Arnaud; Anthouard, Veronique; Poulain, Julie; Weissenbach, Jean] Inst Genom CEA DSV, GENOSCOPE, Ctr Natl Sequencage, F-91057 Evry, France. [Ciuffetti, Lynda M.; Spatafora, Joseph W.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Duret, Laurent] Univ Lyon 1, Lab Biometrie & Biol Evolut, CNRS, UMR 5558, F-69622 Villeurbanne, France. [Goodwin, Stephen B.] Purdue Univ, USDA ARS, Crop Prod & Pest Control Res Unit, W Lafayette, IN 47907 USA. [Kema, Gert H. J.] Wageningen UR, Dept Biointeract & Plant Hlth, NL-6700 AB Wageningen, Netherlands. [Lawrence, Christopher B.; Tyler, Brett M.] Virginia Polytech Inst & State Univ, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. [Schoch, Conrad L.] NIH NLM NCBI, Bethesda, MD 20892 USA. [Stachowiak, Anna] Polish Acad Sci, Inst Plant Genet, PL-60479 Poznan, Poland. [Turgeon, B. Gillian] Cornell Univ, Ithaca, NY 14853 USA. [Vincent, Delphine] INRA, BIOGECO UMR1202, F-33612 Cestas, France. [Oliver, Richard P.] Curtin Univ, Australian Ctr Necrotroph Fungal Pathogens, Perth, WA 6845, Australia. RP Rouxel, T (reprint author), INRA Bioger, UR1290, Ave Lucien Bretignieres,BP 01, F-78850 Thiverval Grignon, France. EM rouxel@versailles.inra.fr RI Vincent, Delphine/C-6664-2011; Schoch, Conrad/J-4825-2012; Hane, James/A-7062-2011; Dilmaghani, Azita/G-3889-2015 OI Goodwin, Stephen/0000-0001-5708-9729; Hane, James/0000-0002-7651-0977; Duret, Laurent/0000-0003-2836-3463; Dilmaghani, Azita/0000-0001-6556-8332 FU Marc-Henri Lebrun (INRA-Bioger); Francis Martin (INRA, Interactions arbres/micro-organismes, Champenoux, France); Genoscope, Institut de Genomique, CEA, France; Agence Nationale de la Recherche [ANR-07-GPLA-051G]; ANR [ANR-06-BLAN-0399, ANR-07-GPLA-015]; Australian Grains Research and Development Corporation; NIH, National Library of Medicine; U.S. National Science Foundation [DEB-0717476, IOS-0924861]; 'Dothideomycete' community; INRA-SPE department; 'Leptosphaeria maculans' scientific and applied community FX We acknowledge Marc-Henri Lebrun (INRA-Bioger) and Francis Martin (INRA, Interactions arbres/micro-organismes, Champenoux, France) for support and advice. The genome sequencing of L. maculans was funded by the Genoscope, Institut de Genomique, CEA, France. The establishment of databases and interfaces was funded by Agence Nationale de la Recherche (GnpAnnot project; ANR-07-GPLA-051G). Wholegenome effector analysis was funded by ANR (FungEffector project; ANR-06-BLAN-0399). Recombination analysis and P.B. were funded by ANR (AvirLep project; ANR-07-GPLA-015). B.J.H and R.P.O. thank the Australian Grains Research and Development Corporation for funding. C.L.S was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. J.W.S acknowledges support from the U.S. National Science Foundation, grant number DEB-0717476. B.M.T. was supported in part by the U.S. National Science Foundation, grant number IOS-0924861. Thanks are due to INRA-SPE department, the 'Leptosphaeria maculans' scientific and applied community, and the 'Dothideomycete' community for support of the L. maculans genome initiative. NR 59 TC 144 Z9 164 U1 6 U2 59 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2011 VL 2 DI 10.1038/ncomms1189 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 732YP UT WOS:000288225900031 PM 21326234 ER PT J AU Kobayashi, SD Deleo, FR AF Kobayashi, Scott D. Deleo, Frank R. TI A MRSA-terious enemy among us SO NATURE MEDICINE LA English DT Editorial Material ID STAPHYLOCOCCUS-AUREUS INFECTIONS; VACCINE; MICE; INSIGHTS AB Infection with methicillin-resistant Staphylococcus aureus (MRSA) can cause symptoms ranging from mild skin infections to more severe disease in various organs, even among healthy individuals. The ability of this pathogen to escape our immune arsenal and overcome antibiotic therapy poses a challenge to preventing their spread and treating the related symptoms. In 'Bench to Bedside', Scott Kobayashi and Frank DeLeo explore new approaches for vaccine development that focus on antigens required for establishment of disease. Studies with infected mice immunized against S. aureus coagulases-important for abscess formation and bloodstream infection-suggest such an approach may be used to reduce bacterial load and protect against severe disease in humans. In 'Bedside to Bench', Michael Otto examines a large human study where the presence of genes encoding Panton-Valentine leukocidin toxin (PVL) in community-associated MRSA did not correlate with complicated skin structure infections-a result opposing the widespread notion that PVL is the primary CA-MRSA virulence factor. C1 [Kobayashi, Scott D.; Deleo, Frank R.] US Natl Inst Allergy & Infect Dis, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Kobayashi, SD (reprint author), US Natl Inst Allergy & Infect Dis, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov NR 16 TC 9 Z9 9 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2011 VL 17 IS 2 BP 168 EP 169 DI 10.1038/nm0211-168 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 716LK UT WOS:000286969900022 PM 21297611 ER PT J AU Otto, M AF Otto, Michael TI End of the PVL controversy? SO NATURE MEDICINE LA English DT Editorial Material ID PANTON-VALENTINE LEUKOCIDIN; STAPHYLOCOCCUS-AUREUS DISEASE; VIRULENCE DETERMINANT; INFECTIONS; SKIN; RESISTANCE C1 US Natl Inst Allergy & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), US Natl Inst Allergy & Infect Dis, NIH, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 NR 15 TC 29 Z9 29 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2011 VL 17 IS 2 BP 169 EP 170 DI 10.1038/nm0211-172 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 716LK UT WOS:000286969900023 PM 21297612 ER PT J AU Takebe, N Harris, PJ Warren, RQ Ivy, SP AF Takebe, Naoko Harris, Pamela J. Warren, Ronald Q. Ivy, S. Percy TI Targeting cancer stem cells by inhibiting Wnt, notch, and Hedgehog pathways SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID ACUTE MYELOID-LEUKEMIA; TUMOR-INITIATING CELLS; EPITHELIAL-MESENCHYMAL TRANSITIONS; GAMMA-SECRETASE INHIBITORS; GROWTH-FACTOR RECEPTOR; NF-KAPPA-B; BETA-CATENIN; PANCREATIC-CANCER; BREAST-CANCER; SMALL-MOLECULE AB Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy. CSCs use many of the same signaling pathways that are found in normal stem cells, such as Wnt, Notch, and Hedgehog (Hh). The origin of CSCs is not fully understood, but data suggest that they originate from normal stem or progenitor cells, or possibly other cancer cells. Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth. Development of agents that target critical steps in the Wnt, Notch, and Hh pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are described in this Review. C1 [Takebe, Naoko; Harris, Pamela J.; Ivy, S. Percy] NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Invest Drug Branch, Bethesda, MD 20852 USA. [Warren, Ronald Q.] PSI Int Inc, Bethesda, MD 20817 USA. RP Ivy, SP (reprint author), NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Invest Drug Branch, EPN7131,6130 Execut Blvd, Bethesda, MD 20852 USA. EM ivyp@ctep.nci.nih.gov NR 137 TC 373 Z9 399 U1 20 U2 189 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD FEB PY 2011 VL 8 IS 2 BP 97 EP 106 DI 10.1038/nrclinonc.2010.196 PG 10 WC Oncology SC Oncology GA 713GF UT WOS:000286722400008 PM 21151206 ER PT J AU Dimyan, MA Cohen, LG AF Dimyan, Michael A. Cohen, Leonardo G. TI Neuroplasticity in the context of motor rehabilitation after stroke SO NATURE REVIEWS NEUROLOGY LA English DT Review ID TRANSCRANIAL MAGNETIC STIMULATION; CONSTRAINT-INDUCED MOVEMENT; PAIRED ASSOCIATIVE STIMULATION; USE-DEPENDENT PLASTICITY; ACUTE ISCHEMIC-STROKE; NEUROMUSCULAR ELECTRICAL-STIMULATION; NONINVASIVE CORTICAL STIMULATION; BRAIN-COMPUTER INTERFACES; RANDOMIZED CLINICAL-TRIAL; THETA-BURST STIMULATION AB Approximately one-third of patients with stroke exhibit persistent disability after the initial cerebrovascular episode, with motor impairments accounting for most poststroke disability. Exercise and training have long been used to restore motor function after stroke. Better training strategies and therapies to enhance the effects of these rehabilitative protocols are currently being developed for poststroke disability. The advancement of our understanding of the neuroplastic changes associated with poststroke motor impairment and the innate mechanisms of repair is crucial to this endeavor. Pharmaceutical, biological and electrophysiological treatments that augment neuroplasticity are being explored to further extend the boundaries of poststroke rehabilitation. Potential motor rehabilitation therapies, such as stem cell therapy, exogenous tissue engineering and brain-computer interface technologies, could be integral in helping patients with stroke regain motor control. As the methods for providing motor rehabilitation change, the primary goals of poststroke rehabilitation will be driven by the activity and quality of life needs of individual patients. This Review aims to provide a focused overview of neuroplasticity associated with poststroke motor impairment, and the latest experimental interventions being developed to manipulate neuroplasticity to enhance motor rehabilitation. C1 [Dimyan, Michael A.; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, 10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Dimyan, Michael/B-1715-2012; Winstein, Carolee/A-8375-2008; OI Dimyan, Michael/0000-0002-9715-9741 FU National Institute of Neurological Disorders and Stroke, NIH FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. The original illustrations used for Figure 1 were by G. Qushair of SciLingua. NR 183 TC 122 Z9 132 U1 10 U2 88 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD FEB PY 2011 VL 7 IS 2 BP 76 EP 85 DI 10.1038/nrneurol.2010.200 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 717DT UT WOS:000287024200007 PM 21243015 ER PT J AU Ombrello, MJ Kastner, DL AF Ombrello, Michael J. Kastner, Daniel L. TI Expanding clinical spectrum and broadening therapeutic horizons SO NATURE REVIEWS RHEUMATOLOGY LA English DT Editorial Material ID AUTOINFLAMMATORY DISEASE; INTERLEUKIN-1; AMYLOIDOSIS; ANAKINRA C1 [Ombrello, Michael J.; Kastner, Daniel L.] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ombrello, MJ (reprint author), NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, 10 Ctr Dr,10C101, Bethesda, MD 20892 USA. EM ombrellomj@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999, ZIA HG200370-01, ZIA HG200372-01, ZIA HG200374-01, ZIA HG200371-01, ZIA HG200373-01] NR 10 TC 7 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 EI 1759-4804 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD FEB PY 2011 VL 7 IS 2 BP 82 EP 84 DI 10.1038/nrrheum.2010.229 PG 3 WC Rheumatology SC Rheumatology GA 715XD UT WOS:000286927000006 PM 21289614 ER PT J AU Li, M DiMaio, F Zhou, DW Gustchina, A Lubkowski, J Dauter, Z Baker, D Wlodawer, A AF Li, Mi DiMaio, Frank Zhou, Dongwen Gustchina, Alla Lubkowski, Jacek Dauter, Zbigniew Baker, David Wlodawer, Alexander TI Crystal structure of XMRV protease differs from the structures of other retropepsins SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID CHRONIC-FATIGUE-SYNDROME; HIV-1 PROTEASE; VIRUS PROTEASE; DRUG DESIGN; INHIBITORS; GENE AB Using energy and density guided Rosetta refinement to improve molecular replacement, we determined the crystal structure of the protease encoded by xenotropic murine leukemia virus-related virus (XMRV). Despite overall similarity of XMRV protease to other retropepsins, the topology of its dimer interface more closely resembles those of the monomeric, pepsin-like enzymes. Thus, XMRV protease may represent a distinct branch of the aspartic protease family. C1 [Li, Mi; Zhou, Dongwen; Gustchina, Alla; Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD USA. [DiMaio, Frank; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Lubkowski, Jacek] NCI, Macromol Assembly Struct & Cell Signaling Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne Natl Lab, Argonne, IL USA. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. EM wlodawer@nih.gov RI Baker, David/K-8941-2012 OI Baker, David/0000-0001-7896-6217 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; US National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT), located at the Advanced Photon Source (APS), Argonne National Laboratory. Use of the APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. This work was supported in part by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research and with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 18 TC 20 Z9 21 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD FEB PY 2011 VL 18 IS 2 BP 227 EP 229 DI 10.1038/nsmb.1964 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 716LD UT WOS:000286969200017 PM 21258323 ER PT J AU Stein, U Arlt, F Smith, J Sack, U Herrmann, P Walther, W Lemm, M Fichtner, I Shoemaker, RH Schlag, PM AF Stein, Ulrike Arlt, Franziska Smith, Janice Sack, Ulrike Herrmann, Pia Walther, Wolfgang Lemm, Margit Fichtner, Iduna Shoemaker, Robert H. Schlag, Peter M. TI Intervening in beta-Catenin Signaling by Sulindac Inhibits S100A4-Dependent Colon Cancer Metastasis SO NEOPLASIA LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; BINDING PROTEIN S100A4; COLORECTAL-CANCER; MOLECULAR TARGET; CARCINOMA-CELLS; REGULATES EXPRESSION; PLUS SULINDAC; WNT; GENE; CHEMOPREVENTION AB Colon cancer metastasis is often associated with activation of the Wnt/beta-catenin signaling pathway and high expression of the metastasis mediator S100A4. We previously demonstrated the transcriptional regulation of S100A4 by beta-catenin and the importance of the interconnection of these cellular programs for metastasis. Here we probe the hypothesis that the nonsteroidal anti-inflammatory drug sulindac sulfide can inhibit colon cancer metastasis by intervening in beta-catenin signaling and thereby interdicting S100A4. We treated colon cancer cell lines heterozygous for gain-of-function and wild-type beta-catenin with sulindac. We analyzed sulindac's effects on beta-catenin expression and subcellular localization, beta-catenin binding to the T-cell factor (TCF)/S100A4 promoter complex, S100A4 promoter activity, S100A4 expression, cell motility, and proliferation. Mice intrasplenically transplanted with S100A4-overexpressing colon cancer cells were treated with sulindac. Tumor growth and metastasis, and their beta-catenin and S100A4 expressions, were determined. We report the expression knockdown of beta-catenin by sulindac, leading to its reduced nuclear accumulation. The binding of beta-catenin to TCF was clearly lowered, resulting in reduced S100A4 promoter activity and expression. This correlated well with the inhibition of cell migration and invasion, which could be rescued by ectopic S100A4 expression. In mice, sulindac treatment resulted in reduced tumor growth in the spleen (P =.014) and decreased liver metastasis in a human colon cancer xenograft model (P =.025). Splenic tumors and liver metastases of sulindac-treated mice showed lowered beta-catenin and S100A4 levels. These results suggest that modulators of beta-catenin signaling such as sulindac offer potential as antimetastatic agents by interdicting S100A4 expression. C1 [Stein, Ulrike; Arlt, Franziska; Herrmann, Pia; Walther, Wolfgang] Charite, Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, D-13125 Berlin, Germany. [Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. [Schlag, Peter M.] Charite, Charite Comprehens Canc Ctr, D-13353 Berlin, Germany. RP Stein, U (reprint author), Charite, Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, Robert Rossle Str 10, D-13125 Berlin, Germany. EM ustein@mdc-berlin.de FU Deutsche Forschungsgemeinschaft [STE 671/8-1] FX This work was supported by the Deutsche Forschungsgemeinschaft (STE 671/8-1, to U.St. and P.M.S.). NR 54 TC 37 Z9 42 U1 1 U2 8 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD FEB PY 2011 VL 13 IS 2 BP 131 EP 144 DI 10.1593/neo.101172 PG 14 WC Oncology SC Oncology GA 716DC UT WOS:000286944300005 PM 21403839 ER PT J AU Grohar, PJ Griffin, LB Yeung, C Chen, QR Pommier, Y Khanna, C Khan, J Helman, LJ AF Grohar, Patrick J. Griffin, Laurie B. Yeung, Choh Chen, Qing-Rong Pommier, Yves Khanna, Chand Khan, Javed Helman, Lee J. TI Ecteinascidin 743 Interferes with the Activity of EWS-FLI1 in Ewing Sarcoma Cells SO NEOPLASIA LA English DT Article ID NUCLEOTIDE-EXCISION-REPAIR; SOFT-TISSUE SARCOMAS; DNA-BINDING; PHASE-II; TRABECTEDIN ECTEINASCIDIN-743; TRANSCRIPTIONAL ACTIVATION; MINOR-GROOVE; GENE; EXPRESSION; SIGNATURE AB ET-743 (trabectedin; Yondelis) is approved in Europe for the treatment of soft tissue sarcomas. Emerging phase 1 and 2 clinical data have shown high response rates in myxoid liposarcoma in part owing to the inhibition of the FUS-CHOP transcription factor. In this report, we show that modulation of specific oncogenic transcription factors by ET-743 may extend to other tumor types. We demonstrate that, among a panel of pediatric sarcomas, Ewing sarcoma family of tumors (ESFTs) cell lines bearing the EWS-FLI1 transcription factor are the most sensitive to treatment with ET-743 compared with osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. We show that ET-743 reverses a gene signature of induced downstream targets of EWS-FLI1 in two different ESFT cell lines (P =.001). In addition, ET-743 directly suppresses the promoter activity of a known EWS-FLI1 downstream target NR0B1 luciferase reporter construct without changing the activity of a constitutively active control in ESFT cells. Furthermore, the effect is specific to EWS-FLI1, as forced expression of EWS-FLI1 in a cell type that normally lacks this fusion protein, HT1080 cells, induces the same NR0B1 promoter, but this activation is completely blocked by ET-743 treatment. Finally, we used gene set enrichment analysis to confirm that other mechanisms of ET-743 are active in ESFT cells. These results suggest a particular role for ET-743 in the treatment of translocation-positive tumors. In addition, the modulation of EWS-FLI1 makes it a novel targeting agent for ESFT and suggests that further development of this compound for the treatment of ESFT is warranted. C1 [Grohar, Patrick J.; Griffin, Laurie B.; Yeung, Choh; Helman, Lee J.] NCI, Pediat Oncol Branch, NIH, Mol Oncol Sect, Bethesda, MD 20892 USA. [Chen, Qing-Rong; Khan, Javed] NCI, Oncogenom Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Khanna, Chand] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Grohar, PJ (reprint author), NCI, Pediat Oncol Branch, NIH, Mol Oncol Sect, Bldg 10,Rm CRC-1W-3750, Bethesda, MD 20892 USA. EM groharp@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU National Cancer Institute, National Institutes of Health; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Sarcoma Alliance FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. P.J.G. receives grant support from the Sarcoma Alliance for Research through Collaboration's Career Development Award. NR 42 TC 54 Z9 57 U1 1 U2 3 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD FEB PY 2011 VL 13 IS 2 BP 145 EP 153 DI 10.1593/neo.101202 PG 9 WC Oncology SC Oncology GA 716DC UT WOS:000286944300006 PM 21403840 ER PT J AU Weyerbrock, A Walbridge, S Saavedra, JE Keefer, LK Oldfield, EH AF Weyerbrock, Astrid Walbridge, Stuart Saavedra, Joseph E. Keefer, Larry K. Oldfield, Edward H. TI Differential effects of nitric oxide on blood-brain barrier integrity and cerebral blood flow in intracerebral C6 gliomas SO NEURO-ONCOLOGY LA English DT Article DE blood-brain barrier permeability; cerebral blood flow; glioma; nitric oxide; quantitative autoradiography (QAR) ID RG-2 RAT GLIOMAS; TO-TISSUE TRANSPORT; TUMOR BARRIER; MICROVASCULAR PERMEABILITY; VASCULAR-PERMEABILITY; REGIONAL MEASUREMENTS; MALIGNANT GLIOMA; BEARING RATS; CYCLIC-GMP; DEXAMETHASONE AB Nitric oxide (NO) signaling in tumors and endothelial cells regulates vascular permeability and blood flow and therefore influences tumor uptake and response to therapeutic compounds. As delivery and efficacy of chemotherapy is impaired in CNS neoplasms due to a partially intact blood-brain barrier (BBB), we studied the effects of NO released by the short-acting NO donor disodium 1[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate methanolate (PROLI/NO) on BBB integrity and blood flow in C6 gliomas using [(14)C]-aminoisobutyric acid (ALB) and [(14)C]-iodoantipyrine quantitative autoradiography. PROLI/NO selectively increased intratumoral uptake of [(14)C]AIB and [(14)C]sucrose when given as a 3-minute intracarotid infusion or a 15-minute i.v. infusion (AIB: tumor, K(1) = 68.7 +/- 3.2 vs 24.9 +/- 0.9 mu L g(-1) min(-1), P<.0001; sucrose, K(1) = 16.9 +/- 0.9 vs 11.5 +/- 0.9 mu g(-1) min(-1), P = .0007). This effect was achieved without significant changes in cerebral and tumor blood flow or arterial blood pressure, which indicates that the effect on vascular permeability is independent of changes in vascular tone induced by NO. This effect was mediated by activation of the NO/3',5'-cyclic guanosine monophosphate (cGMP) pathway, as it was blocked by guanylate cyclase inhibition by LY83583 and reproduced by the delivery of 8-bromoguanosine 5'-monophosphate or inhibition of cGMP degradation by the phosphodiesterase inhibitor zaprinast. Inhibition of inducible NO synthase by aminoguanidine or cyclooxygenase inhibition by indometacin or dexamethasone did not reduce the blood-tumor barrier (BTB) response to PROLI/NO. PROLI/NO, and perhaps other NO-donating compounds, can be used to selectively increase BTB permeability in gliomas through the NO/cGMP pathway at doses that do not cause unwanted vasodilatory changes in blood flow and that do not affect the systemic circulation. C1 [Weyerbrock, Astrid] Univ Med Ctr Freiburg, Dept Neurosurg, D-79106 Freiburg, Germany. [Weyerbrock, Astrid; Walbridge, Stuart; Oldfield, Edward H.] Natl Inst Neurol Disorders & Stroke, NIH, Surg Neurol Branch, Bethesda, MD USA. [Keefer, Larry K.] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. [Saavedra, Joseph E.] SAIC Frederick, Intramural Res Support Program, Frederick, MD USA. [Oldfield, Edward H.] Univ Virginia, Dept Neurosurg, Charlottesville, VA USA. RP Weyerbrock, A (reprint author), Univ Med Ctr Freiburg, Dept Neurosurg, Breisacher Str 64, D-79106 Freiburg, Germany. EM astrid.weyerbrock@uniklinik-freiburg.de RI Weyerbrock, Astrid/E-8493-2014; Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 49 TC 16 Z9 16 U1 3 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD FEB PY 2011 VL 13 IS 2 BP 203 EP 211 DI 10.1093/neuonc/noq161 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 716VX UT WOS:000287002700006 PM 21041233 ER PT J AU McCarthy, BJ Rankin, KM Aldape, K Bondy, ML Brannstrom, T Broholm, H Feychting, M Il'yasova, D Inskip, PD Johansen, C Mellin, BS Ruder, AM Butler, MA Scheurer, ME Schuz, J Schwartzbaum, JA Wrensch, MR Davis, FG AF McCarthy, Bridget J. Rankin, Kristin M. Aldape, Ken Bondy, Melissa L. Brannstrom, Thomas Broholm, Helle Feychting, Maria Il'yasova, Dora Inskip, Peter D. Johansen, Christoffer Mellin, Beatrice S. Ruder, Avima M. Butler, Mary Ann Scheurer, Michael E. Schuz, Joachim Schwartzbaum, Judith A. Wrensch, Margaret R. Davis, Faith G. TI Risk factors for oligodendroglial tumors: A pooled international study SO NEURO-ONCOLOGY LA English DT Article DE anaplastic oligodendroglioma; epidemiology; mixed glioma; oligodendroglioma; risk factors ID NERVOUS-SYSTEM; BRAIN-TUMORS; REPRODUCTIVE FACTORS; ADULT GLIOMA; ARMS 1P; 19Q; SURVIVAL; ASSOCIATION; HISTORY; SUSCEPTIBILITY AB Oligodendroglial tumors are rare subtypes of brain tumors and are often combined with other glial tumors in epidemiological analyses. However, different demographic associations and clinical characteristics suggest potentially different risk factors. The purpose of this study was to investigate possible risk factors for oligodendroglial tumors (including oligodendroglioma, anaplastic oligodendroglioma, and mixed glioma). Data from 7 case control studies (5 US and 2 Scandinavian) were pooled. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age group, gender, and study site. Data on 617 cases and 1260 controls were available for analyses. Using data from all 7 studies, history of allergies and/or asthma was associated with a decreased risk of anaplastic oligodendroglioma (OR = 0.6; 95% CI: 0.4-0.9), and history of asthma only was associated with a decreased risk of oligodendroglioma (OR = 0.5; 95% CI: 0.3-0.9) and anaplastic oligodendroglioma (OR = 0.3; 95% CI: 0.1-0.9). A family history of brain tumors was associated with an increased risk of anaplastic oligodendroglioma (OR = 2.2; 95% CI: 1.1-4.5). Having had chicken pox was associated with a decreased risk of oligodendroglioma (OR = 0.6; 95% CI: 0.4-0.9) and anaplastic oligodendroglioma (OR = 0.5; 95% CI: 0.3-0.9) in the US studies. Although there is some overlap in risk factors between oligodendroglial tumors and gliomas as a group, it is likely that additional factors specific to oligodendroglial tumors have yet to be identified. Large, multi-institution international studies will be necessary to better characterize these etiological risk factors. C1 [McCarthy, Bridget J.] Univ Illinois, Sch Publ Hlth, Dept Epidemiol Biostat, Div Epidemiol, Chicago, IL 60612 USA. [Aldape, Ken] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Bondy, Melissa L.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Brannstrom, Thomas] Umea Univ, Dept Med Biosci, Umea, Sweden. [Mellin, Beatrice S.] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Broholm, Helle] Copenhagen Univ Hosp, Dept Pathol, Ctr Diagnost Invest, Rigshosp, Copenhagen, Denmark. [Feychting, Maria] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Il'yasova, Dora] Duke Univ, Preston Robert Tisch Brain Tumor Ctr Duke, Med Ctr, Durham, NC USA. [Il'yasova, Dora] Duke Univ, Dept Community & Family Med, Med Ctr, Div Prevent Res, Durham, NC USA. [Inskip, Peter D.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Johansen, Christoffer; Schuz, Joachim] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Ruder, Avima M.; Butler, Mary Ann] Ctr Dis Control & Prevent, Dept Hlth & Human Serv, NIOSH, Cincinnati, OH USA. [Scheurer, Michael E.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Scheurer, Michael E.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Schwartzbaum, Judith A.] Ohio State Univ, Div Epidemiol, Sch Publ Hlth, Columbus, OH 43210 USA. [Wrensch, Margaret R.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. RP McCarthy, BJ (reprint author), Univ Illinois, Sch Publ Hlth, Dept Epidemiol Biostat, Div Epidemiol, 1603 W Taylor St,M-C 923, Chicago, IL 60612 USA. EM bjm3@uic.edu RI Ruder, Avima/I-4155-2012; OI Ruder, Avima/0000-0003-0419-6664; Scheurer, Michael/0000-0002-8379-6088 FU National Brain Tumor Foundation (NBTF); National Cancer Institute [R01CA070917, R01 CA52689, N01-CO-12400, R01CA122163]; National Institutes of Health [P20CA96890, P50CA108786, P50CA097257]; National Cancer Institute, National Institutes of Health, Department of Health and Human Services; National Institute for Occupational Safety and Health Initiative for Cancer Control; Centers for Disease Control/National Institute for Occupational Safety and Health; College of Medicine, Ohio State University; Swedish Research Council; Swedish Cancer Society; Northern Sweden Cancer Society; European Union [QLK4-CT-1999-01563]; International Union against Cancer (UICC); Mobile Manufacturers' Forum and GSM Association; Acta Oncologica through the Swedish Royal Academy of Science; Danish Cancer Society FX An epidemiology grant from the National Brain Tumor Foundation (NBTF) to B.J.M. has funded this research. Research for the US studies was supported by extramural [National Cancer Institute (R01CA070917 to M.L.B., K.A., M.E.S.; R01 CA52689 to M.R.W.; N01-CO-12400 to P.I.D.); National Institutes of Health Specialized Program of Research Excellence (P20CA96890 and P50CA108786 to F.G.D., K.R.M., D.I., B.J.M.; P50CA097257 to M.R.W.) and intramural funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services to P.D.I., and the National Institute for Occupational Safety and Health Initiative for Cancer Control Projects for Farmers, and Centers for Disease Control/National Institute for Occupational Safety and Health operating funds to A.M.R. and M.A.B. Funding support for J.A.S. was provided by The Neurosciences Signature Program, College of Medicine, Ohio State University and the National Cancer Institute, R01CA122163. Funding support for the Swedish Interphone Study to B.S.M., M.F., J.S., and T.B. included the Swedish Research Council, the Swedish Cancer Society, the Northern Sweden Cancer Society, European Union Fifth Framework Program (contract number QLK4-CT-1999-01563), and the International Union against Cancer (UICC); the UICC received funds for this purpose from the Mobile Manufacturers' Forum and GSM Association. Provision of funds to the INTERPHONE study investigators via the UICC was governed by agreements that guaranteed INTERPHONE's complete scientific independence. The terms of these agreements are publicly available at http://www.iarc.fr/en/research-groups/RAD/RCAd.html; Acta Oncologica sponsored the Research Fellowship of B.S.M. through the Swedish Royal Academy of Science. Funding for the Danish Interphone Study to C.J., H.B., and J.S. included European Union Fifth Framework Program (contract number QLK4-CT-1999-01563), the International Union against Cancer (UICC), under the same conditions as stated above, and the Danish Cancer Society. NR 44 TC 9 Z9 9 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD FEB PY 2011 VL 13 IS 2 BP 242 EP 250 DI 10.1093/neuonc/noq173 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 716VX UT WOS:000287002700010 PM 21149253 ER PT J AU Zanotti-Fregonara, P Zoghbi, SS Liow, JS Luong, E Boellaard, R Gladding, RL Pike, VW Innis, RB Fujita, M AF Zanotti-Fregonara, Paolo Zoghbi, Sami S. Liow, Jeih-San Luong, Elise Boellaard, Ronald Gladding, Robert L. Pike, Victor W. Innis, Robert B. Fujita, Masahiro TI Kinetic analysis in human brain of [C-11](R)-rolipram, a positron emission tomographic radioligand to image phosphodiesterase 4: A retest study and use of an image-derived input function SO NEUROIMAGE LA English DT Article DE Phosphodiesterase 4; Compartment model; Logan plot; Image-derived input function; Metabolite-corrected arterial input function; Test retest reproducibility ID INDEPENDENT COMPONENT ANALYSIS; PET; QUANTIFICATION; BINDING; MODEL; RAT AB [C-11](R)-rolipram provides a measure of the density of phosphodiesterase 4 (PDE4) in brain, an enzyme that metabolizes cAMP. The aims of this study were to perform kinetic modeling of [C-11](R)-rolipram in healthy humans using an arterial input function and to replace this arterial input in humans with an image-derived input function. Methods: Twelve humans had two injections of [C-11](R)-rolipram. An image-derived input function was obtained from the carotid arteries and four blood samples. The samples were used for partial volume correction and for estimating the parent concentration using HPLC analysis. Results: An unconstrained two-compartment model and Logan analysis measured distribution volume V-T, with good identifiability but with moderately high retest variability (15%). Similar results were obtained using the image input (ratio image/arterial V-T = 1.00 +/- 0.06). Conclusions: Binding of [C-11](R)-rolipram to PDE4 can be quantified in human brain using kinetic modeling and an arterial input function. Image input function from carotid arteries provides an equally accurate and reproducible method to quantify PDE4. Published by Elsevier Inc. C1 [Zanotti-Fregonara, Paolo; Zoghbi, Sami S.; Liow, Jeih-San; Luong, Elise; Gladding, Robert L.; Pike, Victor W.; Innis, Robert B.; Fujita, Masahiro] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Boellaard, Ronald] Vrije Univ Amsterdam, Med Ctr, Dept Nucl Med & PET Res, NL-1081 HV Amsterdam, Netherlands. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, Bldg 10,Room B1D43,31 Ctr Dr,MSC 1026, Bethesda, MD 20892 USA. EM FujitaM@intra.nimh.nih.gov OI Boellaard, Ronald/0000-0002-0313-5686 FU Intramural NIH HHS [Z01 MH002852-04] NR 27 TC 20 Z9 20 U1 2 U2 5 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 FEB 1 PY 2011 VL 54 IS 3 BP 1903 EP 1909 DI 10.1016/j.neuroimage.2010.10.064 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 707QV UT WOS:000286302000016 PM 21034834 ER PT J AU Furl, N Kumar, S Alter, K Durrant, S Shawe-Taylor, J Griffiths, TD AF Furl, Nicholas Kumar, Sukhbinder Alter, Kai Durrant, Simon Shawe-Taylor, John Griffiths, Timothy D. TI Neural prediction of higher-order auditory sequence statistics SO NEUROIMAGE LA English DT Article DE Magnetoencephalography (MEG); Predictive coding; Temporoparietal junction (TPJ); Statistical learning ID NATURAL SOUNDS; TEMPORAL INTEGRATION; CORTICAL RESPONSES; SPEECH-PERCEPTION; CORTEX; MUSIC; BRAIN; WINDOWS; TIME; ASYMMETRY AB During auditory perception, we are required to abstract information from complex temporal sequences such as those in music and speech. Here, we investigated how higher-order statistics modulate the neural responses to sound sequences, hypothesizing that these modulations are associated with higher levels of the peri-Sylvian auditory hierarchy. We devised second-order Markov sequences of pure tones with uniform first-order transition probabilities. Participants learned to discriminate these sequences from random ones. Magnetoencephalography was used to identify evoked fields in which second-order transition probabilities were encoded. We show that improbable tones evoked heightened neural responses after 200 ms post-tone onset during exposure at the learning stage or around 150 ms during the subsequent test stage, originating near the right temporoparietal junction. These signal changes reflected higher-order statistical learning, which can contribute to the perception of natural sounds with hierarchical structures. We propose that our results reflect hierarchical predictive representations, which can contribute to the experiences of speech and music. Published by Elsevier Inc. C1 [Furl, Nicholas; Shawe-Taylor, John] UCL, Dept Comp Sci, London WC1E 6BT, England. [Kumar, Sukhbinder; Alter, Kai; Griffiths, Timothy D.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Durrant, Simon] Univ Manchester, Sch Psychol Sci, Manchester M13 9PL, Lancs, England. RP Furl, N (reprint author), NIH, Bldg 49,BIEE17,49 Convent Dr, Bethesda, MD 20892 USA. EM furlno@mail.nih.gov OI furl, nicholas/0000-0003-2488-1343; Griffiths, Timothy/0000-0001-8066-4381 FU United Kingdom Engineering and Physical Sciences Research Council [EP/D063612/1] FX We are grateful to our University College London colleagues from the Functional Imaging Laboratory: Dr. Gareth Barnes, Dr. Dominik Bach, Prof. Ray Dolan, Dr. Stefan Kiebel, Dr. Guillaume Flandin, Dr. Katharina von Kriegstein, and Dr. Tobias Overath; and from the Ear Institute: Dr. Alain de Cheveigne and Dr. Maria Chait. They, together with the MEG and SPM communities at the Functional Imaging Laboratory, have provided invaluable advice and support on all aspects of this project. Editorial assistance for the article was provided by the National Institutes of Health Fellows Editorial Board. This work was supported by a United Kingdom Engineering and Physical Sciences Research Council grant (Learning the Structure of Music, EP/D063612/1) to J.S.T. NR 62 TC 20 Z9 20 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2011 VL 54 IS 3 BP 2267 EP 2277 DI 10.1016/j.neuroimage.2010.10.038 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 707QV UT WOS:000286302000049 PM 20970510 ER PT J AU Liu, YX Lo, YC Qian, L Crews, FT Wilson, B Chen, HL Wu, HM Chen, SH Wei, K Lu, RB Ali, S Hong, JS AF Liu, Yuxin Lo, Yi-Ching Qian, Li Crews, Fulton Tim Wilson, Belinda Chen, Hui-Ling Wu, Hung-Ming Chen, Shih-Heng Wei, Ke Lu, Ru-Band Ali, Syed Hong, Jau-Shyong TI Verapamil protects dopaminergic neuron damage through a novel anti-inflammatory mechanism by inhibition of microglial activation SO NEUROPHARMACOLOGY LA English DT Article DE Calcium channel blocker; Oxidative stress and neuroinflammation ID CALCIUM-CHANNEL BLOCKERS; LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; NITRIC-OXIDE SYNTHASE; SUPEROXIDE GENERATION; RACEMIC VERAPAMIL; CEREBRAL-ISCHEMIA; HUMAN-NEUTROPHILS; NEUROPROTECTION; EXPRESSION; ANTAGONISTS AB Verapamil has been shown to be neuroprotective in several acute neurotoxicity models due to blockade of calcium entry into neurons. However, the potential use of veraparnil to treat chronic neurodegenerative diseases has not been reported. Using rat primary mesencephalic neuron/glia cultures, we report that verapamil significantly inhibited LPS-induced dopaminergic neurotoxicity in both pre- and post-treatment experiments. Reconstituted culture studies revealed that the presence of microglia was essential in verapamil-elicited neuroprotection. Mechanistic studies showed that decreased production of inflammatory mediators from LPS-stimulated microglia underlay neuroprotective property of verapamil. Further studies demonstrated that microglial NADPH oxidase (PHOX), the key superoxide-producing enzyme, but not calcium channel in neurons, is the site of action for the neuroprotective effect of verapamil. This conclusion was supported by the following two observations: 1) Verapamil failed to show protective effect on LPS-induced dopaminergic neurotoxicity in PHOX-deficient (deficient in the catalytic subunit of gp91(phox)) neuron/glia cultures: 2) Ligand binding studies showed that the binding of [H-3]Verapamil onto gp91(phox) transfected COS7 cell membranes was higher than the non-transfected control. The calcium channel-independent neuroprotective property of verapamil was further supported by the finding that R(+)-verapamil, a less active form in blocking calcium channel, showed the same potency in neuroprotection, inhibition of pro-inflammatory factors production and binding capacity to gp91(phox) membranes as R(-)-verapamil, the active isomer of calcium channel blocker. In conclusion, our results demonstrate a new indication of verapamil-mediated neuroprotection through a calcium channel-independent pathway and provide a valuable avenue for the development of therapy for inflammation-related neurodegenerative diseases. Published by Elsevier Ltd. C1 [Liu, Yuxin; Lo, Yi-Ching; Qian, Li; Wilson, Belinda; Chen, Hui-Ling; Wu, Hung-Ming; Chen, Shih-Heng; Wei, Ke; Hong, Jau-Shyong] Natl Inst Environm Hlth Sci, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. [Lo, Yi-Ching] Kaohsiung Med Univ, Dept Pharmacol, Kaohsiung 807, Taiwan. [Crews, Fulton Tim] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. [Liu, Yuxin] Hebei Univ, Sch Pharmaceut Sci, Lab Cell Pharmacol, Baoding, Peoples R China. [Chen, Hui-Ling; Wu, Hung-Ming; Chen, Shih-Heng; Lu, Ru-Band] Natl Cheng Kung Univ & Hosp, Dept Psychiat, Tainan, Taiwan. [Ali, Syed] Neurochem Lab NCTR, Jefferson, AR USA. RP Hong, JS (reprint author), Natl Inst Environm Hlth Sci, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. EM hong3@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences, U.S.A.; NIAAA; UNC Bowles Center for Alcohol Studies, U.S.A.; National Science Council, Taiwan [NSC-96-2320-B-037-039-MY3] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, U.S.A.; the Extramural grants from NIAAA (FTC) as well as The UNC Bowles Center for Alcohol Studies (YL and FTC), U.S.A.; and the National Science Council (grant NSC-96-2320-B-037-039-MY3), Taiwan. NR 34 TC 12 Z9 12 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB-MAR PY 2011 VL 60 IS 2-3 BP 373 EP 380 DI 10.1016/j.neuropharm.2010.10.002 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 717NL UT WOS:000287054600021 PM 20950631 ER PT J AU Helfinstein, SM Benson, B Perez-Edgar, K Bar-Haim, Y Detloff, A Pine, DS Fox, NA Ernst, M AF Helfinstein, Sarah M. Benson, Brenda Perez-Edgar, Koraly Bar-Haim, Yair Detloff, Allison Pine, Daniel S. Fox, Nathan A. Ernst, Monique TI Striatal responses to negative monetary outcomes differ between temperamentally inhibited and non-inhibited adolescents SO NEUROPSYCHOLOGIA LA English DT Article DE fMRI; Striatum; vmPFC; Reward; Motivation; Temperament ID HUMAN ORBITOFRONTAL CORTEX; NUCLEUS-ACCUMBENS SHELL; EVENT-RELATED FMRI; BEHAVIORAL-INHIBITION; PREFRONTAL CORTEX; PREDICTION ERROR; REWARD; DISORDERS; VISUALIZATION; ANTICIPATION AB The present study compared blood oxygen level dependent (BOLD) response in behaviorally inhibited and behaviorally non-inhibited adolescents to positive and negative feedback following their choice in a reward task. Previous data in these same subjects showed enhanced activation in striatal areas in behaviorally inhibited subjects to cues predicting gain or a loss. However, no analyses had examined responses following actual gains or losses. Relative to non-inhibited subjects, behaviorally inhibited subjects in the current study showed enhanced caudate response to negative but not positive feedback, indicating that striatal sensitivity to feedback may be specific to aversive information. In addition, compared to non-inhibited subjects, behaviorally inhibited subjects exhibited reduced differentiation between positive and negative feedback in ventromedial prefrontal cortex (vmPFC). This suggests a perturbed ability to encode reward value. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Helfinstein, Sarah M.; Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. [Benson, Brenda; Detloff, Allison; Pine, Daniel S.; Ernst, Monique] NIMH, Bethesda, MD 20892 USA. [Perez-Edgar, Koraly] George Mason Univ, Fairfax, VA 22030 USA. [Bar-Haim, Yair] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. RP Helfinstein, SM (reprint author), Univ Maryland, 3304 Benjamin Bldg, College Pk, MD 20742 USA. EM shelfins@umd.edu OI Perez-Edgar, Koraly/0000-0003-4051-9563 FU National Institute of Mental Health [R01 MH 074454]; National Institute of Child Health and Development [5R37 HD 017899-20]; National Institutes of Health-National Institute of Mental Health; National Science Foundation FX This work was supported in part by the National Institute of Mental Health Grant R01 MH 074454 (N.A.F.), the National Institute of Child Health and Development Grant 5R37 HD 017899-20 (N.A.F.), the Intramural Research Program of the National Institutes of Health-National Institute of Mental Health, and by a National Science Foundation Graduate Research Fellowship (S.M.H.). NR 39 TC 34 Z9 34 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD FEB PY 2011 VL 49 IS 3 BP 479 EP 485 DI 10.1016/j.neuropsychologia.2010.12.015 PG 7 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 728YH UT WOS:000287909900020 PM 21167189 ER PT J AU Yadav, PN Abbas, AI Farrell, MS Setola, V Sciaky, N Huang, XP Kroeze, WK Crawford, LK Piel, DA Keiser, MJ Irwin, JJ Shoichet, BK Deneris, ES Gingrich, J Beck, SG Roth, BL AF Yadav, Prem N. Abbas, Atheir I. Farrell, Martilias S. Setola, Vincent Sciaky, Noah Huang, Xi-Ping Kroeze, Wesley K. Crawford, LaTasha K. Piel, David A. Keiser, Michael J. Irwin, John J. Shoichet, Brian K. Deneris, Evan S. Gingrich, Jay Beck, Sheryl G. Roth, Bryan L. TI The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE serotonin; schizophrenia; clozapine; pet1; antipsychotic drugs ID ATYPICAL ANTIPSYCHOTIC AGENTS; PROTEIN-KINASE; PREFRONTAL CORTEX; COMMON VARIANTS; NMDA RECEPTOR; IN-VIVO; SCHIZOPHRENIA; DRUGS; BINDING; BEHAVIOR AB Clozapine, by virtue of its absence of extrapyramidal side effects and greater efficacy, revolutionized the treatment of schizophrenia, although the mechanisms underlying this exceptional activity remain controversial. Combining an unbiased cheminformatics and physical screening approach, we evaluated clozapine's activity at 42350 distinct molecular targets. Clozapine, and the closely related atypical antipsychotic drug olanzapine, interacted potently with a unique spectrum of molecular targets. This distinct pattern, which was not shared with the typical antipsychotic drug haloperidol, suggested that the serotonergic neuronal system was a key determinant of clozapine's actions. To test this hypothesis, we used pet1(-/-) mice, which are deficient in serotonergic presynaptic markers. We discovered that the antipsychotic-like properties of the atypical antipsychotic drugs clozapine and olanzapine were abolished in a pharmacological model that mimics NMDA-receptor hypofunction in pet1(-/-) mice, whereas haloperidol's efficacy was unaffected. These results show that clozapine's ability to normalize NMDA-receptor hypofunction, which is characteristic of schizophrenia, depends on an intact presynaptic serotonergic neuronal system. Neuropsychopharmacology (2011) 36, 638-651; doi:10.1038/npp.2010.195; published online 3 November 2010 C1 [Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Natl Inst Mental Heath Psychoact Drug Screening P, Chapel Hill, NC 27516 USA. [Abbas, Atheir I.] Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. [Crawford, LaTasha K.; Piel, David A.; Beck, Sheryl G.] Childrens Hosp Philadelphia, Res Inst, Dept Anesthesiol, Philadelphia, PA 19104 USA. [Keiser, Michael J.; Irwin, John J.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Deneris, Evan S.] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. [Gingrich, Jay] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY USA. [Roth, Bryan L.] Univ N Carolina, Lineberger Canc Ctr, Dept Pharmacol, Chapel Hill, NC 27516 USA. [Roth, Bryan L.] Univ N Carolina, Lineberger Canc Ctr, Dept Med Chem, Chapel Hill, NC 27516 USA. [Roth, Bryan L.] Univ N Carolina, Lineberger Canc Ctr, Dept Psychiat, Chapel Hill, NC 27516 USA. RP Roth, BL (reprint author), Univ N Carolina, Dept Pharmacol, Natl Inst Mental Heath Psychoact Drug Screening P, Chapel Hill, NC 27516 USA. EM becks@email.chop.edu; bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010; Keiser, Michael/F-2825-2016; Crawford, LaTasha/H-7981-2016; OI Keiser, Michael/0000-0002-1240-2192; Crawford, LaTasha/0000-0002-8553-9894; Irwin, John/0000-0002-1195-6417 FU NIMH Psychoactive Drug Screening [U19MH82441, RO1MH61887, RO1MH075047]; Michael Hooker Distinguished; Rogers Family Foundation; UNC; Case Western Reserve University; [GM71896]; [MH075047]; [MH082611] FX This study was supported by U19MH82441, RO1MH61887, RO1MH075047, the NIMH Psychoactive Drug Screening Program Contract, and the Michael Hooker Distinguished Professorship to BLR. Additional support was from GM71896 (to JJI and BKS) MH075047 to SGB, MH082611 to LKC and the Rogers Family Foundation (to MJK, JJI, and BKS). BKS thanks Tudor Oprea for a gift of the WOMBAT database and John Overington for early access to ChEMBL.; Dr Roth in the past 24 months has been a consultant for Bristol Myers Squibb, Otsuka Pharmaceuticals, Merck, Medivation, Galenea Pharmaceuticals, the National Institutes of Health, Invitrogen, and Albany Molecular Researech, and has received royalty payments from licensing of 5-HT receptor patents (which are owned by UNC and Case Western Reserve University) to Galena Pharmaceuticals. Drs Shoichet and Irwin are co-founders of SeaChange, and Dr Keiser is an employee of SeaChange. The other authors declare no conflict of interest. NR 65 TC 36 Z9 36 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2011 VL 36 IS 3 BP 638 EP 651 DI 10.1038/npp.2010.195 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 705YM UT WOS:000286176700009 PM 21048700 ER PT J AU Heremans, E Feys, P Nieuwboer, A Vercruysse, S Vandenberghe, W Sharma, N Helsen, W AF Heremans, Elke Feys, Peter Nieuwboer, Alice Vercruysse, Sarah Vandenberghe, Wim Sharma, Nikhil Helsen, Werner TI Motor Imagery Ability in Patients With Early- and Mid-Stage Parkinson Disease SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE mental practice; visual imagery; motor imagery; imagery ability; Parkinson disease ID RANDOMIZED CONTROLLED-TRIAL; MENTAL PRACTICE; SIMULATED MOVEMENTS; ARM MOVEMENTS; STROKE; PEOPLE; REAL; REHABILITATION; INTERVENTIONS; METAANALYSIS AB Background. Motor imagery has recently gained attention as a promising new rehabilitation method for patients with neurological disorders. Up to now, however, it has been unclear whether this practice method can also be successfully applied in the rehabilitation of patients with Parkinson disease (PD). Objective. This study aimed to investigate whether the motor imagery ability of patients with PD is still intact despite basal ganglia dysfunctioning. Methods. A total of 14 patients with early- and mid-stage PD (Hoehn and Yahr 1-3) and 14 healthy controls were evaluated by means of an extensive imagery ability assessment battery, consisting of 2 questionnaires, the Chaotic Motor Imagery Assessment battery, and a test based on mental chronometry. Results. PD patients performed the imagery tasks more slowly than controls, but the motor imagery vividness and accuracy of most patients were well preserved. Conclusions. These results are promising regarding the potential use of motor imagery practice in the rehabilitation of patients with PD. C1 [Heremans, Elke; Feys, Peter; Nieuwboer, Alice; Vercruysse, Sarah; Vandenberghe, Wim; Helsen, Werner] Katholieke Univ Leuven, Leuven, Belgium. [Feys, Peter] PHL Univ Coll, Hasselt, Belgium. [Feys, Peter] Univ Hasselt, Hasselt, Belgium. [Sharma, Nikhil] NINDS, NIH, HCPS, Bethesda, MD 20892 USA. [Vandenberghe, Wim] Univ Hosp Leuven, Leuven, Belgium. RP Helsen, W (reprint author), Katholieke Univ Leuven, Tervuursevest 101, B-3001 Heverlee, Belgium. EM werner.helsen@faber.kuleuven.be RI Nieuwboer, Alice/F-5643-2013; OI Nieuwboer, Alice/0000-0003-1193-6229; Sharma, Nikhil/0000-0001-8903-2938 FU Research Foundation - Flanders (FWO) FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: Elke Heremans is a Research Assistant and Wim Vandenberghe a Senior Clinical Investigator at the Research Foundation - Flanders (FWO). NR 53 TC 29 Z9 29 U1 3 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD FEB PY 2011 VL 25 IS 2 BP 168 EP 177 DI 10.1177/1545968310370750 PG 10 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 706AR UT WOS:000286184900007 PM 21239707 ER PT J AU Li, LY Wang, XX Fei, XF Xia, LP Qin, ZH Liang, ZQ AF Li, Lingyun Wang, Xiaoxia Fei, Xifeng Xia, Liping Qin, Zhenghong Liang, Zhongqin TI Parkinson's disease involves autophagy and abnormal distribution of cathepsin L SO NEUROSCIENCE LETTERS LA English DT Article DE Parkinson's disease; Autophagy; Cathepsin L; 6-Hydroxydopamine; Neurodegeneration ID NF-KAPPA-B; DOPAMINERGIC-NEURONS; UP-REGULATION; CELL-DEATH; IN-VITRO; NEURODEGENERATION; APOPTOSIS; STRESS; ACTIVATION; INJURY AB Accumulating evidences suggest that the related autophagy-lysosomal mechanism plays a critical role in many neurodegenerative disorders. In this study, we examined postmortem Parkinson's disease (PD) substantia nigra for evidence of cathepsin L by immunofluorescent staining, and found increased expression of cathepsin L in dopamine neurons of PD patients. We confirmed 6-OHDA induced nuclear translocation of cathepsin L in rat substantia nigral neurons as well. Furthermore, we observed autophagic vacuoles and lysosomes were accumulated in the 6-hydroxydopamine (6-OHDA) injured rat substantia nigra neurons with electron microscopy. Immunofluorescent staining showed that LC3 was enriched in dopamine neurons after 6-OHDA treatment. When pretreated with 3-methyladenine (3-MA), dopaminergic neurons were protected from cell death induced by 6-OHDA, associated with the suppression of LC3 and cathepsin L Our results demonstrate that activation of autophagy and abnormal distribution of cathepsin L may be responsible for dopamine neuron death, involved in the pathogenic cascade event for the development of Parkinson's disease. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Li, Lingyun; Fei, Xifeng; Xia, Liping; Qin, Zhenghong; Liang, Zhongqin] Soochow Univ, Coll Med, Dept Pharmacol, Suzhou 215123, Peoples R China. [Li, Lingyun] Soochow Univ, Affiliated Hosp 2, Ctr Med Expt, Suzhou 215004, Peoples R China. [Wang, Xiaoxia] NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Liang, ZQ (reprint author), Soochow Univ, Coll Med, Dept Pharmacol, 199 Renai Rd, Suzhou 215123, Peoples R China. EM liangzhongqin@suda.edu.cn FU Natural Science Foundation of China [30873052]; National Basic Research Program of China/973 Program [2011CB510003]; Medical Science and Technology Development Planning of Yancheng [YK2006130] FX This work was supported by grants from "Natural Science Foundation of China (30873052)", "National Basic Research Program of China/973 Program (2011CB510003)" and "Medical Science and Technology Development Planning of Yancheng (YK2006130)". NR 23 TC 27 Z9 27 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 1 PY 2011 VL 489 IS 1 BP 62 EP 67 DI 10.1016/j.neulet.2010.11.068 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 717BM UT WOS:000287017200014 PM 21134415 ER PT J AU McPherson, CA Kraft, AD Harry, GJ AF McPherson, Christopher A. Kraft, Andrew D. Harry, G. Jean TI Injury-Induced Neurogenesis: Consideration of Resident Microglia as Supportive of Neural Progenitor Cells SO NEUROTOXICITY RESEARCH LA English DT Article DE Microglia; Neural progenitor cell; Subgranular zone; Inflammation; Neurogenesis ID TUMOR-NECROSIS-FACTOR; TRAUMATIC BRAIN-INJURY; INDUCED HIPPOCAMPAL NEUROGENESIS; DENTATE GRANULE CELLS; PRECURSOR CELLS; MESSENGER-RNA; FACTOR-ALPHA; SUBVENTRICULAR ZONE; ADULT HIPPOCAMPUS; FACTOR RECEPTOR AB The induction of neurogenesis in the adult subgranular zone (SGZ) by injury is often accompanied by changes in the extracellular environment that can have significant impacts on neural progenitor cells (NPCs). We examined the induction of neurogenesis in the SGZ at 72 h following an injection of the hippocampal toxicant, trimethyltin (TMT; 2 mg/kg, ip) inducing apoptosis in dentate granule neurons. BrdU+ incorporation during the active period of neuronal death indicated NPC proliferation and migration of newly generated cells into the granule cell layer (GCL). BrdU+ cells were transiently in contact with process bearing microglia within the inner SGZ layer. Contact with GFAP+ astrocyte processes occurred once cells were within the GCL. A small percentage of the BrdU+ cells within the SGZ region showed immunoreactivity for tumor necrosis factor (TNF) p75 receptor (TNFp75R). In mice deficient for TNFp75R, TMT injection produced an equivalent level of dentate granule cell death however; BrdU+ cells were localized at the SGZ as compared to the presence of cells within the GCL in the WT mice dosed with TMT. These data suggest that cells generated by NPCs in the SGZ induced with a focal lesion to the dentate granule neurons of adolescent mice maintain the capacity to utilize the neuroinflammation and microglia responses within their environment for migration into the GCL. C1 [McPherson, Christopher A.; Kraft, Andrew D.; Harry, G. Jean] NIEHS, Neurotoxicol Grp, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), NIEHS, Neurotoxicol Grp, Mol Toxicol Lab, NIH, MD C1-04,POB 12233, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU division of intramural research of the National Institute of Environmental Health Science, National Institutes of Health; Department of Health and Human Services FX This study was supported by the division of intramural research of the National Institute of Environmental Health Science, National Institutes of Health, and Department of Health and Human Services. The authors wish to thank Drs Mary Gilbert and Susan McGuire for their review of the manuscript, and Mr. Robert Wine for technical expertise. NR 50 TC 16 Z9 16 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD FEB PY 2011 VL 19 IS 2 BP 341 EP 352 DI 10.1007/s12640-010-9199-6 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 721QK UT WOS:000287369500011 PM 20524106 ER PT J AU Kim, HS Wilce, MCJ Yoga, YMK Pendini, NR Gunzburg, MJ Cowieson, NP Wilson, GM Williams, BRG Gorospe, M Wilce, JA AF Kim, Henry S. Wilce, Matthew C. J. Yoga, Yano M. K. Pendini, Nicole R. Gunzburg, Menachem J. Cowieson, Nathan P. Wilson, Gerald M. Williams, Bryan R. G. Gorospe, Myriam Wilce, Jacqueline A. TI Different modes of interaction by TIAR and HuR with target RNA and DNA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID AU-RICH ELEMENT; BINDING PROTEINS TIA-1; ALPHA MESSENGER-RNA; STRESS GRANULES; 3'-UNTRANSLATED REGION; RECOGNITION MOTIFS; TRANSLATIONAL REPRESSION; TISSUE DISTRIBUTION; SPLICING REGULATION; MAMMALIAN-CELLS AB TIAR and HuR are mRNA-binding proteins that play important roles in the regulation of translation. They both possess three RNA recognition motifs (RRMs) and bind to AU-rich elements (AREs), with seemingly overlapping specificity. Here we show using SPR that TIAR and HuR bind to both U-rich and AU-rich RNA in the nanomolar range, with higher overall affinity for U-rich RNA. However, the higher affinity for U-rich sequences is mainly due to faster association with U-rich RNA, which we propose is a reflection of the higher probability of association. Differences between TIAR and HuR are observed in their modes of binding to RNA. TIAR is able to bind deoxy-oligonucleotides with nanomolar affinity, whereas HuR affinity is reduced to a micromolar level. Studies with U-rich DNA reveal that TIAR binding depends less on the 2'-hydroxyl group of RNA than HuR binding. Finally we show that SAXS data, recorded for the first two domains of TIAR in complex with RNA, are more consistent with a flexible, elongated shape and not the compact shape that the first two domains of Hu proteins adopt upon binding to RNA. We thus propose that these triple-RRM proteins, which compete for the same binding sites in cells, interact with their targets in fundamentally different ways. C1 [Kim, Henry S.; Wilce, Matthew C. J.; Yoga, Yano M. K.; Pendini, Nicole R.; Gunzburg, Menachem J.; Cowieson, Nathan P.; Wilce, Jacqueline A.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. [Cowieson, Nathan P.] Monash Univ, Ctr Synchrotron Sci, Clayton, Vic 3800, Australia. [Wilson, Gerald M.] Univ Maryland, Dept Biochem & Mol Biol, Sch Med, Baltimore, MD 21201 USA. [Williams, Bryan R. G.] Monash Univ, Monash Inst Med Res, Clayton, Vic 3168, Australia. [Gorospe, Myriam] NIA, Lab Cellular & Mol Biol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wilce, JA (reprint author), Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. EM jackie.wilce@med.monash.edu.au RI Williams, Bryan/A-5021-2009 OI Wilce, Jacqueline/0000-0002-8344-2626; Williams, Bryan/0000-0002-4969-1151 FU Australian Research Council [DP0879279]; National Health and Medical Research Council of Australia; National Institute on Aging, National Institutes of Health; Department of Biochemistry and Molecular Biology, Monash University; National Cancer Institute, National Institutes of Health [R01 CA102428] FX Australian Research Council (DP0879279 awarded to M.C.J.W., J.A.W., M. G. and B. R. G. W.); National Health and Medical Research Council of Australia fellowship (to M.C.J.W.); National Institute on Aging-Intramural Research Program, National Institutes of Health (to M. G.); National Cancer Institute, National Institutes of Health (R01 CA102428 to G. M. W.). Funding for open access charge: Department of Biochemistry and Molecular Biology, Monash University. NR 67 TC 31 Z9 31 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2011 VL 39 IS 3 BP 1117 EP 1130 DI 10.1093/nar/gkq837 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 720CJ UT WOS:000287257500036 PM 21233170 ER PT J AU Gluck, ME Venti, CA Salbe, AD Votruba, SB Krakoff, J AF Gluck, Marci E. Venti, Colleen A. Salbe, Arline D. Votruba, Susanne B. Krakoff, Jonathan TI Higher 24-h Respiratory Quotient and Higher Spontaneous Physical Activity in Nighttime Eaters SO OBESITY LA English DT Article ID X-RAY ABSORPTIOMETRY; LIBITUM FOOD-INTAKE; EATING SYNDROME; ENERGY-EXPENDITURE; CARBOHYDRATE OXIDATION; METABOLIC CONSEQUENCES; SLEEP-DEPRIVATION; WEIGHT-GAIN; BODY-WEIGHT; OBESITY AB We have previously shown that a higher 24-h respiratory quotient (24-h RQ) predicts greater ad-libitum food intake and that nighttime eaters (NE) ingested more calories during an in-patient food intake study and gained more weight over time. We investigated whether 24-h RQ was higher in individuals who exhibited nighttime eating behavior. Healthy nondiabetic Pima Indians (PI; n = 97, 54 male/43 female) and whites (W; n = 32, 22 male/10 female) were admitted to our Clinical Research Unit. After 3 days of a weight maintaining diet, 24-h energy expenditure (24-h EE), 24-h RQ, rates of carbohydrate (CHOX) and lipid oxidation (LIPOX), and spontaneous physical activity (SPA) were measured in a metabolic chamber whereas volunteers were in energy balance and unable to consume excess calories. Individuals subsequently ate ad libitum from a computerized vending machine for 3 days with amount and timing of food intake recorded. Fifty-five individuals (36%; 39 PI, 16 W) were NE, who ate between 11 pm and 5 am on at least one of the 3 days on the vending machines. There were no differences in BMI or percentage body fat between NE and non-NE. After adjusting for age, sex, race, fat-free mass, fat mass, and energy balance, NE had a higher 24-h RQ (P = 0.01), higher CHOX (P = 0.009), and lower LIPOX (P = 0.03) and higher 24-h SPA (P = 0.04) compared to non-NE. There were no differences in adjusted 24-h EE or sleep RQ between the groups. Individuals with nighttime eating behavior have higher 24-h RQ, higher CHOX and lower LIPOX, a phenotype associated with increased food intake and weight gain. C1 [Gluck, Marci E.; Venti, Colleen A.; Salbe, Arline D.; Votruba, Susanne B.; Krakoff, Jonathan] NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Gluck, ME (reprint author), NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM gmarci@niddk.nih.gov FU NIDDK FX The authors thank Mr John Graves and the dietary staff and Ms Carol Massengill and the nursing staff of the NIH Clinical Unit and the staff of the Diabetes Epidemiology and Clinical Research Section, NIDDK. This study was supported by the Intramural Research Program of the NIDDK. Most of all, we thank the volunteers for their participation in the study. NR 36 TC 16 Z9 16 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD FEB PY 2011 VL 19 IS 2 BP 319 EP 323 DI 10.1038/oby.2010.206 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 712FW UT WOS:000286651400014 PM 20864947 ER PT J AU Tita, ATN Lai, YL Landon, MB Spong, CY Leveno, KJ Varner, MW Caritis, SN Meis, PJ Wapner, RJ Sorokin, Y Peaceman, AM O'Sullivan, MJ Sibai, BM Thorp, JM Ramin, SM Mercer, BM AF Tita, Alan T. N. Lai, Yinglei Landon, Mark B. Spong, Catherine Y. Leveno, Kenneth J. Varner, Michael W. Caritis, Steve N. Meis, Paul J. Wapner, Ronald J. Sorokin, Yoram Peaceman, Alan M. O'Sullivan, Mary J. Sibai, Baha M. Thorp, John M. Ramin, Susan M. Mercer, Brian M. CA Eunice Kennedy Shriver Natl Inst TI Timing of Elective Repeat Cesarean Delivery at Term and Maternal Perioperative Outcomes SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID NEONATAL RESPIRATORY MORBIDITY; SECTION; LABOR; RISK; INFANTS; TRIAL; MODE AB OBJECTIVE: Elective repeat cesarean delivery at 37 or 38 weeks compared with 39 completed weeks of gestation is associated with adverse neonatal outcomes. We assessed whether delivery before 39 weeks is justifiable on the basis of decreased adverse maternal outcomes. METHODS: We conducted a cohort study of women with live singleton pregnancies delivered by prelabor elective repeat cesarean delivery from 1999 through 2002 at 19 U. S. academic centers. Gestational age was examined by completed weeks (eg, 37 completed weeks = 37 0/7-37 6/7 weeks). Maternal outcomes included a primary composite of death, hysterectomy, uterine rupture or dehiscence, blood transfusion, uterine atony, thromboembolic complications, anesthetic complications, surgical injury or need for arterial ligation, intensive care unit admission, wound complications, or endometritis. RESULTS: Of 13,258 elective repeat cesareans performed at 37 weeks of gestation or later, 11,255 (84.9%) were between 37 0/7 and 39 6/7 weeks (6.3% at 37, 29.5% at 38, and 49.1% at 39 completed weeks), and 15.1% were at 40 0/7 weeks or more. The primary outcome occurred in 7.43% at 37 weeks, 7.47% at 38 weeks and 6.56% at 39 weeks (P for trend test=.09). Delivery before 39 weeks was not associated with a decrease in the primary outcome when compared with delivery at 39 weeks (adjusted odds ratio 1.16; 95% confidence interval 1.00-1.34). Early delivery was associated with increased maternal hospitalization of 5 days or more [1.96 (1.54, 2.49)] but not with a composite of death or hysterectomy or with individual maternal morbidities. CONCLUSION: Elective repeat cesarean delivery at 37 or 38 weeks is not associated with decreased maternal morbidity. (Obstet Gynecol 2011;117:280-6) DOI: 10.1097/AOG.0b013e3182078115 C1 [Tita, Alan T. N.] Univ Alabama, Dept Obstet & Gynecol, Ctr Womens Reprod Hlth, Div Maternal Fetal Med, Birmingham, AL 35233 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ Utah, Salt Lake City, UT USA. Wake Forest Univ Hlth Sci, Winston Salem, NC USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Wayne State Univ, Detroit, MI USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Miami, Miami, FL USA. Univ Tennessee, Memphis, TN USA. Univ N Carolina, Chapel Hill, NC USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Tita, ATN (reprint author), Univ Alabama, Dept Obstet & Gynecol, Ctr Womens Reprod Hlth, Div Maternal Fetal Med, 618 20th St S, Birmingham, AL 35233 USA. EM alan.tita@obgyn.uab.edu RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) [HD21410, HD21414, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD36801] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) [HD21410, HD21414, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, and HD36801] and its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NICHD or NIH. NR 21 TC 35 Z9 35 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2011 VL 117 IS 2 BP 280 EP 286 DI 10.1097/AOG.0b013e3182078115 PN 1 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 709SB UT WOS:000286460600012 PM 21252740 ER PT J AU Incerti, M Toso, L Vink, J Roberson, R Nold, C Abebe, D Spong, CY AF Incerti, Maddalena Toso, Laura Vink, Joy Roberson, Robin Nold, Christopher Abebe, Daniel Spong, Catherine Y. TI Prevention of Learning Deficit in a Down Syndrome Model SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; FETAL ALCOHOL SYNDROME; MOUSE MODEL; TS65DN MICE; NEUROPROTECTIVE PEPTIDE; MEMORY; ABNORMALITIES; NEUROPEPTIDES; RECEPTOR; PROTEIN AB OBJECTIVE: To evaluate whether peptides given to adult mice with Down syndrome prevent learning deficits, and to delineate the mechanisms behind the protective effect. METHODS: Ts65Dn mice were treated for 9 days with peptides D-NAPVSIPQ (NAP) + D-SALLRSIPA (SAL) or placebo, and wild-type animals were treated with placebo. Beginning on treatment day 4, the mice were tested for learning using the Morris watermaze. Probe tests for long-term memory were performed on treatment day 9 and 10 days after treatment stopped. Open-field testing was performed before and after the treatment. Calibrator-normalized relative real-time polymerase chain reaction (PCR) with glyceraldehyde-3-phosphate dehydrogenase (GAPD) standardization was performed on the whole brain and hippocampus for activity-dependent neuroprotective protein, vasoactive intestinal peptide (VIP), glial fibrillary acidic protein (GFAP), NR2B, NR2A, and gamma-aminobutyric acid type A (GABA(A))-alpha 5. Statistics included analysis of variance and the Fisher protected least significant difference, with P<.05 significant. RESULTS: The Ts65Dn plus placebo animals did not learn over the 5-day period compared with the controls (P<.001). The Ts65Dn + (D-NAP + D-SAL) learned significantly better than the Ts65Dn plus placebo (P<.05), and they retained learning similar to controls on treatment day 9, but not after 10 days of no treatment. Treatment with D-NAP + D-SAL prevented the Ts65Dn hyperactivity. Adult administration of D-NAP + D-SAL prevented changes in activity-dependent neuroprotective protein, intestinal peptide, and NR2B with levels similar to controls (all P<.05). CONCLUSION: Adult treatment with D-NAP + D-SAL prevented learning deficit in Ts65Dn, a model of Down syndrome. Possible mechanisms of action include reversal of vasoactive intestinal peptide and activity-dependent neuroprotective protein dysregulation, as well as increasing expression of NR2B, thus facilitating learning. (Obstet Gynecol 2011;117:354-61) DOI: 10.1097/AOG.0b013e3182051ca5 C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Perinatal & Dev Neurobiol, NIH, Bethesda, MD USA. George Washington Univ, Dept Obstet Gynecol, Washington, DC USA. Columbia Univ, Med Ctr, Div Maternal Fetal Med, New York, NY USA. Univ Connecticut, Ctr Hlth, Dept Obstet Gynecol, Storrs, CT 06269 USA. RP Incerti, M (reprint author), NICHD, Unit Perinatal & Dev Neurobiol, NIH, Bldg 9 Room 1W125,9 Mem Dr, Bethesda, MD 20892 USA. EM maddalena.incerti@gmail.com FU DIR of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH) FX Supported by the DIR of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institutes of Health (NIH). NR 34 TC 20 Z9 20 U1 0 U2 4 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 FEB PY 2011 VL 117 IS 2 BP 354 EP 361 DI 10.1097/AOG.0b013e3182051ca5 PN 1 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 709SB UT WOS:000286460600023 PM 21252750 ER PT J AU Martin-Montalvo, A Villalba, JM Navas, P de Cabo, R AF Martin-Montalvo, A. Villalba, J. M. Navas, P. de Cabo, R. TI NRF2, cancer and calorie restriction SO ONCOGENE LA English DT Review DE calorie restriction; carcinogenesis; NRF2; phytochemicals ID ANTIOXIDANT-RESPONSE ELEMENT; TRANSCRIPTION FACTOR NRF2; GLUTATHIONE-S-TRANSFERASE; DIETARY ENERGY RESTRICTION; SKIN TUMOR PROMOTION; SMALL MAF PROTEINS; CHEMICALLY-INDUCED MAMMARY; TRANSGENIC MOUSE MODEL; CENTRAL-NERVOUS-SYSTEM; CUL3-BASED E3 LIGASE AB The transcription factor NF-E2-related factor (NRF2) is a key regulator of several enzymatic pathways, including cytoprotective enzymes in highly metabolic organs. In this review, we summarize the ongoing research related to NRF2 activity in cancer development, focusing on in vivo studies using NRF2 knockout (KO) mice, which have helped in defining the crucial role of NRF2 in chemoprevention. The lower cancer protection observed in NRF2 KO mice under calorie restriction (CR) suggests that most of the beneficial effects of CR on the carcinogenesis process are likely mediated by NRF2. We propose that future interventions in cancer treatment would be carried out through the activation of NRF2 in somatic cells, which will lead to a delay or prevention of the onset of some forms of human cancers, and subsequently an extension of health-and lifespan. Oncogene (2011) 30, 505-520; doi: 10.1038/onc.2010.492; published online 8 November 2010 C1 [Martin-Montalvo, A.; de Cabo, R.] NIA, Aging Metab & Nutr Unit, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Villalba, J. M.] Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Cordoba, Spain. [Navas, P.] Univ Pablo Olavide, CSIC, Ctr Andaluz Biol Desarrollo, Seville, Spain. [Navas, P.] ISCIII, Ctr Biomed Res Rare Dis CIBERER, Seville, Spain. RP de Cabo, R (reprint author), NIA, Aging Metab & Nutr Unit, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. EM decabora@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; , rafael/0000-0003-2830-5693 FU National Institute on Aging, National Institutes of Health; Junta de Andalucia [CVI 4887, CVI-276]; NIH [1R01AG028125-01A1]; Ministry of Health, Spain [PI080500] FX AM-M and RdC are supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The work was partially supported by Junta de Andalucia International Projects, CVI 4887 and CVI-276, NIH Grant 1R01AG028125-01A1 and FIS Grant PI080500 of the Ministry of Health, Spain. We thank Alex Sossong and Andrew Levette for critiquing the manuscript. NR 263 TC 18 Z9 20 U1 3 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB PY 2011 VL 30 IS 5 BP 505 EP 520 DI 10.1038/onc.2010.492 PG 16 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 715WG UT WOS:000286922300001 ER PT J AU Booth, BW Boulanger, CA Anderson, LH Smith, GH AF Booth, B. W. Boulanger, C. A. Anderson, L. H. Smith, G. H. TI The normal mammary microenvironment suppresses the tumorigenic phenotype of mouse mammary tumor virus-neu-transformed mammary tumor cells SO ONCOGENE LA English DT Article DE erbB2/HER2; mammary; microenvironment; regeneration; suppression of tumorigenesis ID ESTROGEN-RECEPTOR-ALPHA; HUMAN-BREAST-CANCER; TRANSGENIC MICE; GLAND DEVELOPMENT; TERATOCARCINOMA CELLS; METASTATIC-DISEASE; EPITHELIAL-CELLS; STEM-CELLS; IN-VIVO; ONCOGENE AB The microenvironment of the mammary gland has been shown to exert a deterministic control over cells from different normal organs during murine mammary gland regeneration in transplantation studies. When mouse mammary tumor virus (MMTV)-neu-induced tumor cells were mixed with normal mammary epithelial cells (MECs) in a dilution series and inoculated into epithelium-free mammary fat pads, they were redirected to noncarcinogenic cell fates by interaction with untransformed MECs during regenerative growth. In the presence of non-transformed MECs (50:1), tumor cells interacted with MECs to generate functional chimeric outgrowths. When injected alone, tumor cells invariably produced tumors. Here, the normal microenvironment redirects MMTV-neu-transformed tumorigenic cells to participate in the regeneration of a normal, functional mammary gland. In addition, the redirected tumor cells show the capacity to differentiate into normal mammary cell types, including luminal, myoepithelial and secretory. The results indicate that signals emanating from a normal mammary microenvironment, comprised of stromal, epithelial and host-mediated signals, combine to suppress the cancer phenotype during glandular regeneration. Clarification of these signals offers improved therapeutic possibilities for the control of mammary cancer growth. Oncogene (2011) 30, 679-689; doi:10.1038/onc.2010.439; published online 4 October 2010 C1 [Booth, B. W.; Boulanger, C. A.; Anderson, L. H.; Smith, G. H.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bldg 10,Room 5B56,9000 Rockville Pike, Bethesda, MD 20892 USA. EM gs4d@nih.gov FU Center for Cancer Research, NCI; NIH; Institute for Biological Interfaces of Engineering of Clemson University FX We thank KU Wagner for the gift of the triple transgenic WAP-Cre/Rosa26/MMTV-neu cell lines and for providing paraffin blocks from WAP-Cre/Rosa26R/MMTV-neu mouse mammary tissues. BK Vonderhaar, DS Salomon, R Callahan and GW Robinson for critical evaluation of the manuscript. The intramural research program of the Center for Cancer Research, NCI, NIH and the Institute for Biological Interfaces of Engineering of Clemson University contributed support to this work. NR 32 TC 35 Z9 35 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB PY 2011 VL 30 IS 6 BP 679 EP 689 DI 10.1038/onc.2010.439 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 719GY UT WOS:000287192000005 PM 20890308 ER PT J AU Wang, D Taboas, JM Tuan, RS AF Wang, D. Taboas, J. M. Tuan, R. S. TI PTHrP overexpression partially inhibits a mechanical strain-induced arthritic phenotype in chondrocytes SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Articular cartilage; Parathyroid hormone-related peptide; Chondroprotection; Tensile strain; Hypertrophy ID HORMONE-RELATED PROTEIN; GROWTH-PLATE; ARTICULAR CHONDROCYTES; OSTEOARTHRITIC CARTILAGE; GENE-EXPRESSION; HYPERTROPHIC CHONDROCYTES; TERMINAL DIFFERENTIATION; SYNOVIAL FIBROBLASTS; SKELETAL DEVELOPMENT; NITRIC-OXIDE AB Objective: Cell-based tissue engineering strategies are currently in clinical use and continue to be developed at a rapid pace for the repair of cartilage defects. Regardless of the repair methodology, chondrocytes within newly regenerated cartilage remain susceptible to the abnormal inflammatory and mechanical environments that underlie osteoarthritic disease, likely compromising the implant's integration, function, and longevity. The present study investigates the use of parathyroid hormone-related peptide (PTHrP) overexpression for chondroprotection. Design: Bovine articular chondrocytes were transfected with human PTHrP (hPTHrP) constructs (1-141 or 1-173) and subjected to injurious cyclic tensile strain (CTS; 0.5 Hz and 16% elongation) for 48 h. mRNA expression of matrix remodeling, inflammatory signaling, hypertrophic, and apoptotic genes were examined with real-time reverse transcription polymerase chain reaction. Nitric oxide (NO) and prostaglandin E-2 (PGE(2)) production were measured using the Griess assay and enzyme immunoassay (EIA), respectively. Results: CTS-induced an arthritic phenotype in articular chondrocytes as indicated by increased gene expression of collagenases and aggrecanases and increased production of NO and PGE(2). Additionally, CTS increased collagen type X (Col10a1) mRNA expression, whereas overexpression of either hPTHrP isoform inhibited CTS-induced Col10a1 gene expression. However, hPTHrP 1-141 augmented CTS-induced NO and PGE(2) production, and neither hPTHrP isoform had any significant effect on apoptotic genes. Conclusions: Our results suggest that chondrocytes overexpressing PTHrP resist mechanical strain-induced hypertrophic-like changes. Therapeutic PTHrP gene transfer may be considered for chondroprotection applications in newly regenerated cartilage. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Taboas, J. M.; Tuan, R. S.] Univ Pittsburgh, Sch Med, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Pittsburgh, PA 15219 USA. [Wang, D.; Taboas, J. M.; Tuan, R. S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv Bethesda, Bethesda, MD 20892 USA. [Wang, D.] NIH, Howard Hughes Med Inst, Res Scholars Program Bethesda, Bethesda, MD 20814 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Sch Med, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu OI Wang, Dean/0000-0002-3005-1154 FU NIH [Z01 AR41131]; Commonwealth of Pennsylvania Department of Health FX We thank Dr Leonard J. Deftos for providing the hPTHrP constructs. This research was supported by the NIH Intramural Research Program (Z01 AR41131) and the Commonwealth of Pennsylvania Department of Health. D.W. was a Howard Hughes Medical Institute-NIH Research Scholar. NR 50 TC 9 Z9 10 U1 3 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD FEB PY 2011 VL 19 IS 2 BP 213 EP 221 DI 10.1016/j.joca.2010.11.003 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 722YG UT WOS:000287470600011 PM 21087676 ER PT J AU Widemann, BC Arceci, RJ Jayaprakash, N Fox, E Zannikos, P Goodspeed, W Goodwin, A Wright, JJ Blaney, SM Adamson, PC Balis, FM AF Widemann, Brigitte C. Arceci, Robert J. Jayaprakash, Nalini Fox, Elizabeth Zannikos, Peter Goodspeed, Wendy Goodwin, Anne Wright, John J. Blaney, Susan M. Adamson, Peter C. Balis, Frank M. TI Phase 1 Trial and Pharmacokinetic Study of the Farnesyl Transferase Inhibitor Tipifarnib in Children and Adolescents With Refractory Leukemias: A Report From the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE pharmacodynamics; pharmacokinetics; phase I trial; refractory childhood leukemia; toxicity ID JUVENILE MYELOMONOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; SOLID TUMORS; R115777; CANCER; THERAPY; RISK AB Background. The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies. Procedure. Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m(2)/dose. Pharmacokinetic sampling was performed for 36 hr after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity. Results. Of 29 patients enrolled, 18 were fully evaluable for toxicity, and 23 for response; 26 had pharmacokinetic and pharmacodynamic sampling. The recommended dose is 300 mg/m(2)/dose and toxicities included skin rash, mucositis, nausea, vomiting, and diarrhea. Neurotoxicity, which was dose-limiting in adults at doses exceeding 600 mg/dose, was infrequent and mild. The plasma pharmacokinetics of tipifarnib were highly variable but comparable to adults with acute leukemia and children with solid tumors. The median apparent clearance of tipifarnib was 630 ml/min/m(2) and the median half-life was 4.7 hr. At steady state on 300 mg/m(2)/dose, FTase activity was inhibited by 82% in leukemic blasts. No objective responses were observed. Conclusions. Oral tipifarnib is well tolerated in children with leukemia on a twice daily for 21days schedule at 300 mg/m(2)/dose. Pediatr Blood Cancer 2011;56:226-233. (C) 2010 Wiley-Liss, Inc. C1 [Widemann, Brigitte C.; Jayaprakash, Nalini; Fox, Elizabeth; Goodspeed, Wendy; Goodwin, Anne; Balis, Frank M.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Arceci, Robert J.] Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA. [Zannikos, Peter] Johnson & Johnson Pharmaceut Res & Dev LLC, Titusville, NJ USA. [Wright, John J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Blaney, Susan M.] Texas Childrens Canc Ctr, Houston, TX USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, POB,10 Ctr Dr,Bldg 10 CRC Rm 1-5750, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; Phase I/Pilot Consortium of the Children's Oncology Group from the NCI, NIH, Bethesda, MD, USA [U01 CA97452] FX This research was in part supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Phase I/Pilot Consortium Grant U01 CA97452 of the Children's Oncology Group from the NCI, NIH, Bethesda, MD, USA. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. The views expressed do not necessarily represent views of the National Institutes of Health or the U.S. government. NR 20 TC 12 Z9 12 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2011 VL 56 IS 2 BP 226 EP 233 DI 10.1002/pbc.22775 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 703YI UT WOS:000286017500010 PM 20860038 ER PT J AU Kang, MH Smith, MA Morton, CL Keshelava, N Houghton, PJ Reynolds, CP AF Kang, Min H. Smith, Malcolm A. Morton, Christopher L. Keshelava, Nino Houghton, Peter J. Reynolds, C. Patrick TI National Cancer Institute Pediatric Preclinical Testing Program: Model Description for In Vitro Cytotoxicity Testing SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cell line models; childhood cancer; cytotoxicity; DIMSCAN; NCI PPTP ID NEUROBLASTOMA-CELL-LINES; ACUTE MYELOID-LEUKEMIA; TOPOISOMERASE-I; GROWTH-FACTOR; RHABDOMYOSARCOMA; XENOGRAFTS; TUMORS; TRANSLOCATION; RESISTANCE; INHIBITORS AB Background. The National Cancer Institute (NCI) has established the Pediatric Preclinical Testing Program (PPTP) for testing drugs against in vitro and in vivo childhood cancer models to aid in the prioritization of drugs considered for early phase pediatric clinical trials. Procedures. In vitro cytotoxicity testing employs a semi-automated fluorescence-based digital imaging cytotoxicity assay (DIMSCAN) that has a 4-log dynamic range of detection. Curve fitting of the fractional survival data of the cell lines in response to various concentrations of the agents was used to calculate relative IC(50), absolute IC(50), and Y(min) values. The panel of 23 pediatric cancer cell lines included leukemia (n = 6), lymphoma (n = 2), rhabdomyosarcoma (n = 4), brain tumors (n = 31, Ewing family of tumors (EFT, n = 4), and neuroblastoma In = 4). The doubling times obtained using DIMSCAN were incorporated into data analyses to estimate the relationship between input cell numbers and final cell number. Results. We report in vitro activity data for three drugs (vincristine, melphalan, and etoposide) that are commonly used for pediatric cancer and for the mTOR inhibitor rapamycin, an agent that is currently under preclinical investigation for cancer. To date, the PPTP has completed in vitro testing of 39 investigational and approved agents for single drug activity and two investigational agents in combination with various "standard" chemotherapy drugs. Conclusions. This robust in vitro cytotoxicity testing system for pediatric cancers will enable comparisons to response data for novel agents obtained from xenograft studies and from clinical trials. Pediatr Blood Cancer 2011;56:239-249. (C) 2010 Wiley-Liss, Inc. C1 [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Sch Med, Ctr Canc, Lubbock, TX 79430 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Morton, Christopher L.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Keshelava, Nino] Univ So Calif, Childrens Hosp Los Angeles, Sch Med, Los Angeles, CA USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. RP Reynolds, CP (reprint author), Texas Tech Univ, Hlth Sci Ctr, Sch Med, Ctr Canc, 3601 4th St STOP 9445, Lubbock, TX 79430 USA. EM patrick.reynolds@ttuhsc.edu RI Houghton, Peter/E-3265-2011; OI Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786, CA82830] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786, CA82830. NR 46 TC 41 Z9 41 U1 2 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2011 VL 56 IS 2 BP 239 EP 249 DI 10.1002/pbc.22801 PG 11 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 703YI UT WOS:000286017500012 PM 20922763 ER PT J AU Gemmill, JAL Brown, RJ Nandagopal, R Rodriguez, LM Rother, KI AF Gemmill, Julie Anne L. Brown, Rebecca J. Nandagopal, Radha Rodriguez, Luisa M. Rother, Kristina I. TI Clinical trials in youth with type 2 diabetes SO PEDIATRIC DIABETES LA English DT Article DE adolescent; clinical trials; pediatric; type 2 diabetes; youth ID BETA-CELL FAILURE; GLUCOSE-TOLERANCE; INSULIN SENSITIVITY; PEDIATRIC-PATIENTS; SINGLE-BLIND; OBESE YOUTH; ADOLESCENTS; MELLITUS; CHILDREN; METFORMIN AB Type 2 diabetes in youth was almost unheard of only two decades ago. However, tracking the recent dramatic rise in childhood obesity, type 2 diabetes has become increasingly prevalent. Thus, there is an urgent need for high-quality clinical trials to increase in-depth knowledge about pathophysiology, optimal treatment, and prevention. We therefore systematically reviewed published and ongoing clinical trials of type 2 diabetes in children and adolescents. The results demonstrate that (i) few randomized clinical trials have been completed and published in children with type 2 diabetes; (ii) ongoing trials in type 1 diabetes clearly outnumber trials in type 2 diabetes; and (iii) recruitment and enrollment into the latter trials are challenging, however once achieved, drop-out rates are not excessively high. We conclude that type 2 diabetes in youth is an important but difficult new field of clinical research, and we discuss the existing barriers to successful recruitment, conduct, and support of these clinical trials. C1 [Gemmill, Julie Anne L.; Brown, Rebecca J.; Nandagopal, Radha; Rother, Kristina I.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Nandagopal, Radha] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Genet & Endocrinol, NIH, Bethesda, MD 20892 USA. [Rodriguez, Luisa M.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. RP Rother, KI (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bldg 10,Rm 8C 432A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kr58q@nih.gov FU Intramural NIH HHS [ZIA DK075052-01, Z01 DK047049-01, Z99 DK999999, ZIA DK047049-03, ZIA DK047049-04, Z01 DK047049-02] NR 43 TC 5 Z9 5 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD FEB PY 2011 VL 12 IS 1 BP 50 EP 57 DI 10.1111/j.1399-5448.2010.00657.x PG 8 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 711UT UT WOS:000286617600009 PM 20456085 ER PT J AU Alexander, DF AF Alexander, Duane F. TI Why Should There Be an NICHD? SO PEDIATRICS LA English DT Review DE research; pediatric research; pediatric disease; history AB In its nearly 5 decades of existence, the Eunice Kennedy Shriver National Institute of Child Health and Human Development has expended $23 billion in conducting and supporting research and translating discoveries to practice. The resulting dramatic impact on peoples' lives and improved health for children and families, chronicled herein, are a testament to the benefits of having this institute at the National Institutes of Health. Pediatrics 2011;127:325-333 C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Alexander, DF (reprint author), NIH, Fogarty Int Ctr, Bldg 16,Room 217,MSC 6705, Bethesda, MD 20892 USA. EM duane.alexander@nih.gov FU National Institutes of Health (NIH) FX Funded by the National Institutes of Health (NIH). NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2011 VL 127 IS 2 BP 325 EP 333 DI 10.1542/peds.2010-2029 PG 9 WC Pediatrics SC Pediatrics GA 714JF UT WOS:000286805200050 PM 21199851 ER PT J AU McCrae, RR Kurtz, JE Yamagata, S Terracciano, A AF McCrae, Robert R. Kurtz, John E. Yamagata, Shinji Terracciano, Antonio TI Internal Consistency, Retest Reliability, and Their Implications for Personality Scale Validity SO PERSONALITY AND SOCIAL PSYCHOLOGY REVIEW LA English DT Article DE reliability; validity; cross-national; five-factor model; personality traits ID NEO-PI-R; INDIVIDUAL-DIFFERENCES; COEFFICIENT-ALPHA; SELF-REPORTS; ENVIRONMENTAL-INFLUENCES; CONSENSUAL VALIDATION; MEASUREMENT ERROR; SPOUSE RATINGS; FACET SCALES; TRAITS AB The authors examined data (N = 34,108) on the differential reliability and validity of facet scales from the NEO Inventories. They evaluated the extent to which (a) psychometric properties of facet scales are generalizable across ages, cultures, and methods of measurement, and, (b) validity criteria are associated with different forms of reliability. Composite estimates of facet scale stability, heritability, and cross-observer validity were broadly generalizable. Two estimates of retest reliability were independent predictors of the three validity criteria; none of three estimates of internal consistency was. Available evidence suggests the same pattern of results for other personality inventories. Internal consistency of scales can be useful as a check on data quality but appears to be of limited utility for evaluating the potential validity of developed scales, and it should not be used as a substitute for retest reliability. Further research on the nature and determinants of retest reliability is needed. C1 [McCrae, Robert R.; Terracciano, Antonio] NIA, NIH, US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Kurtz, John E.; Yamagata, Shinji] Villanova Univ, Villanova, PA 19085 USA. RP McCrae, RR (reprint author), 809 Evesham Ave, Baltimore, MD 21212 USA. EM RRMcCrae@gmail.com RI terracciano, antonio/B-1884-2008 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000183-22, ZIA AG000183-23] NR 101 TC 126 Z9 126 U1 12 U2 59 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1088-8683 J9 PERS SOC PSYCHOL REV JI Pers. Soc. Psychol. Rev. PD FEB PY 2011 VL 15 IS 1 BP 28 EP 50 DI 10.1177/1088868310366253 PG 23 WC Psychology, Social SC Psychology GA 702US UT WOS:000285922000002 PM 20435807 ER PT J AU Farrell, D Ptak, K Panaro, NJ Grodzinski, P AF Farrell, Dorothy Ptak, Krzysztof Panaro, Nicholas J. Grodzinski, Piotr TI Nanotechnology-Based Cancer Therapeutics-Promise and Challenge-Lessons Learned Through the NCI Alliance for Nanotechnology in Cancer SO PHARMACEUTICAL RESEARCH LA English DT Article DE drug delivery; multi-functional nanoparticle carriers; nanoparticle; toxicity ID ALBUMIN-BOUND PACLITAXEL; IN-VIVO; POLYMERIC NANOPARTICLES; DRUG-DELIVERY; BREAST-CANCER; TUMOR; SIRNA; PHARMACOKINETICS; MODULATION; RESISTANCE AB The new generation of nanotechnology-based drug formulations is challenging the accepted ways of cancer treatment. Multi-functional nanomaterial constructs have the capability to be delivered directly to the tumor site and eradicate cancer cells selectively, while sparing healthy cells. Tailoring of the nano-construct design can result in enhanced drug efficacy at lower doses as compared to free drug treatment, wider therapeutic window, and lower side effects. Nanoparticle carriers can also address several drug delivery problems which could not be effectively solved in the past and include reduction of multi-drug resistance effects, delivery of siRNA, and penetration of the blood-brain-barrier. Although challenges in understanding toxicity, biodistribution, and paving an effective regulatory path must be met, nanoscale devices carry a formidable promise to change ways cancer is diagnosed and treated. This article summarizes current developments in nanotechnology-based drug delivery and discusses path forward in this field. The discussion is done in context of research and development occurring within the NCI Alliance for Nanotechnology in Cancer program. C1 [Farrell, Dorothy; Ptak, Krzysztof; Grodzinski, Piotr] NCI, Ctr Strateg Sci Initiat, Off Director, NIH, Bethesda, MD 20892 USA. [Panaro, Nicholas J.] NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Grodzinski, P (reprint author), NCI, Ctr Strateg Sci Initiat, Off Director, NIH, Bethesda, MD 20892 USA. EM grodzinp@mail.nih.gov FU NCI, NIH [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the NCI, NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 32 TC 29 Z9 29 U1 4 U2 18 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES-DORDR JI Pharm. Res. PD FEB PY 2011 VL 28 IS 2 BP 273 EP 278 DI 10.1007/s11095-010-0214-7 PG 6 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 711OT UT WOS:000286602000007 PM 20814720 ER PT J AU Lemos, C Giovannetti, E Zucali, PA Assaraf, YG Scheffer, GL van der Straaten, T D'Incecco, A Falcone, A Guchelaar, HJ Danesi, R Santoro, A Giaccone, G Tibaldi, C Peters, GJ AF Lemos, Clara Giovannetti, Elisa Zucali, Paolo A. Assaraf, Yehuda G. Scheffer, George L. van der Straaten, Tahar D'Incecco, Armida Falcone, Alfredo Guchelaar, Henk-Jan Danesi, Romano Santoro, Armando Giaccone, Giuseppe Tibaldi, Carmelo Peters, Godefridus J. TI Impact of ABCG2 polymorphisms on the clinical outcome and toxicity of gefitinib in non-small-cell lung cancer patients SO PHARMACOGENOMICS LA English DT Article DE ABCG2; gefitinib; lung cancer; pharmacogenetics; toxicity ID SINGLE NUCLEOTIDE POLYMORPHISMS; TYROSINE KINASE INHIBITORS; MULTIDRUG TRANSPORTER ABCG2; DRUG-RESISTANCE; PROTEIN; EXPRESSION; BCRP; PHARMACOKINETICS; GENE; LOCALIZATION AB Aims: The current study investigates whether or not functional polymorphisms in the ATP-binding cassette transporter gene ABCG2 might affect gefitinib activity and/or toxicity in non-small-cell lung cancer (NSCLC) patients. Materials & methods: Towards this end, ABCG2 polymorphisms and expression were assessed in DNA and tumors from 94 NSCLC patients treated with gefitinib, whereas their associations with toxicity/response and time-to-progression/overall survival were evaluated using Pearson-chi(2) and log-rank-test, respectively. Results: Patients carrying an ABCG2-15622T/T genotype or harboring at least one IT copy in the ABCG2 (1143C/T, -15622C/T) haplotype developed significantly more grade 2/3 diarrhea (p < 0.01). No associations were found between polymorphisms and outcome. Consistently, ABCG2 protein levels in tumors were not significantly different between patients harboring different ABCG2 variants. Conclusion: The ABCG2 -15622C/T polymorphism and ABCG2 (1143C/T, -15622C/T) haplotype resulted in a gefitinib-dependent, moderate-to-severe diarrhea suggesting that these pharmacogenetic markers should be considered to optimize NSCLC treatment. C1 [Lemos, Clara; Giovannetti, Elisa; Peters, Godefridus J.] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands. [Giovannetti, Elisa; Danesi, Romano] Univ Pisa, Dept Internal Med, I-56100 Pisa, Italy. [Zucali, Paolo A.; Santoro, Armando] Ist Clin Humanitas, Dept Med Oncol & Hematol, Milan, Italy. [Assaraf, Yehuda G.] Technion Israel Inst Technol, Fred Wyszkowski Canc Res Lab, Dept Biol, IL-32000 Haifa, Israel. [Scheffer, George L.] Vrije Univ Amsterdam Med Ctr, Dept Pathol, NL-1081 HV Amsterdam, Netherlands. [van der Straaten, Tahar; Guchelaar, Henk-Jan] Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, NL-2333 ZA Leiden, Netherlands. [D'Incecco, Armida; Falcone, Alfredo; Tibaldi, Carmelo] Azienda USL 6 Livorno, Dept Oncol, I-57100 Livorno, Italy. [Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Giovannetti, E (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Giovannetti, Elisa/0000-0002-7565-7504 NR 40 TC 26 Z9 29 U1 1 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD FEB PY 2011 VL 12 IS 2 BP 159 EP 170 DI 10.2217/PGS.10.172 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 741RE UT WOS:000288881000009 PM 21332310 ER PT J AU Breese, GR Sinha, R Heilig, M AF Breese, George R. Sinha, Rajita Heilig, Markus TI Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Alcoholism; Alcohol; Adaptation; Stress; Corticotropin releasing factor; Cytokines; Brain sites; Substance P; Relapse; Brain imaging ID CORTICOTROPIN-RELEASING-FACTOR; ANXIETY-LIKE BEHAVIOR; WITHDRAWAL-INDUCED ANXIETY; PREFERRING P-RATS; SUBSTANCE USE DISORDERS; PITUITARY-ADRENAL AXIS; ETHANOL-DEPENDENT RATS; RECEPTOR ANTAGONIST ANTALARMIN; NATIONAL EPIDEMIOLOGIC SURVEY; VENTRAL TEGMENTAL AREA AB Alcoholism is a chronic relapsing disorder. Major characteristics observed in alcoholics during an initial period of alcohol abstinence are altered physiological functions and a negative emotional state. Evidence suggests that a persistent, cumulative adaptation involving a kindling/allostasis-like process occurs during the course of repeated chronic alcohol exposures that is critical for the negative symptoms observed during alcohol withdrawal. Basic studies have provided evidence for specific neurotransmitters within identified brain sites being responsible for the negative emotion induced by the persistent cumulative adaptation following intermittent-alcohol exposures. After an extended period of abstinence, the cumulative alcohol adaptation increases susceptibility to stress- and alcohol cue-induced negative symptoms and alcohol seeking, both of which can facilitate excessive ingestion of alcohol. In the alcoholic, stressful imagery and alcohol cues alter physiological responses, enhance negative emotion, and induce craving. Brain fMRI imaging following stress and alcohol cues has documented neural changes in specific brain regions of alcoholics not observed in social drinkers. Such altered activity in brain of abstinent alcoholics to stress and alcohol cues is consistent with a continuing ethanol adaptation being responsible. Therapies in alcoholics found to block responses to stress and alcohol cues would presumably be potential treatments by which susceptibility for continued alcohol abuse can be reduced. By continuing to define the neurobiological basis of the sustained alcohol adaptation critical for the increased susceptibility of alcoholics to stress and alcohol cues that facilitate craving, a new era is expected to evolve in which the high rate of relapse in alcoholism is minimized. (C) 2010 Elsevier Inc. All rights reserved. C1 [Breese, George R.] UNC Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. [Breese, George R.] UNC Sch Med, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA. [Sinha, Rajita] Yale Univ, Sch Med, Stress Ctr, New Haven, CT 06519 USA. [Heilig, Markus] NIAAA, Clin Div, Bethesda, MD 20892 USA. RP Breese, GR (reprint author), UNC Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. EM george_breese@med.unc.edu; rajita.sinha@yale.edu; mheilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482 FU NIAAA; Bowles Center for Alcohol Studies FX The authors have no conflicts. The preparation of this review was supported by funds from NIAAA and from the Bowles Center for Alcohol Studies. NR 333 TC 84 Z9 87 U1 15 U2 39 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD FEB PY 2011 VL 129 IS 2 BP 149 EP 171 DI 10.1016/j.pharmthera.2010.09.007 PG 23 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 729LA UT WOS:000287949900003 PM 20951730 ER PT J AU Ramamoorthy, S Shippenberg, TS Jayanthi, LD AF Ramamoorthy, Sammanda Shippenberg, Toni S. Jayanthi, Lankupalle D. TI Regulation of monoamine transporters: Role of transporter phosphorylation SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Biogenic amines; Transporters; Regulation; Phosphorylation; Mental illness ID PROTEIN-KINASE-C; HUMAN DOPAMINE TRANSPORTER; HUMAN SEROTONIN TRANSPORTER; HUMAN NOREPINEPHRINE TRANSPORTER; INDUCED REVERSE TRANSPORT; CELL-SURFACE EXPRESSION; KNOCK-OUT MICE; DEPENDENT NEUROTRANSMITTER TRANSPORTERS; TRAFFICKING-INDEPENDENT REGULATION; DEFICIT HYPERACTIVITY DISORDER AB Presynaptic biogenic amine transporters mediate reuptake of released amines from the synapse, thus regulating serotonin, dopamine and norepinephrine neurotransmission. Medications utilized in the treatment of depression, attention deficit-hyperactivity disorder and other psychiatric disorders possess high affinity for amine transporters. In addition, amine transporters are targets for psychostimulants. Altered expression of biogenic amine transporters has long been implicated in several psychiatric and degenerative disorders. Therefore, appropriate regulation and maintenance of biogenic amine transporter activity is critical for the maintenance of normal amine homoeostasis. Accumulating evidence suggests that cellular protein kinases and phosphatases regulate amine transporter expression, activity, trafficking and degradation. Amine transporters are phosphoproteins that undergo dynamic control under the influence of various kinase and phosphatase activities. This review presents a brief overview of the role of amine transporter phosphorylation in the regulation of amine transport in the normal and diseased brain. Understanding the molecular mechanisms by which phosphorylation events affect amine transporter activity is essential for understanding the contribution of transporter phosphorylation to the regulation of monoamine neurotransmission and for identifying potential new targets for the treatment of various brain diseases. (C) 2010 Elsevier Inc. All rights reserved. C1 [Ramamoorthy, Sammanda; Jayanthi, Lankupalle D.] Med Univ S Carolina, Div Neurosci Res, Dept Neurosci, Charleston, SC 29425 USA. [Shippenberg, Toni S.] Natl Inst Drug Abuse, Integrat Neurosci Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Ramamoorthy, S (reprint author), Med Univ S Carolina, Div Neurosci Res, Dept Neurosci, 173 Ashley Ave,BSB 403, Charleston, SC 29425 USA. EM rama@musc.edu; jayanthi@musc.edu FU National Institutes of Health [MH062612, MH083928, MH091633, GM081054]; NIDA IRP FX The support from the National Institutes of Health (MH062612, MH083928, MH091633 to SR) (GM081054 to LDJ) and (NIDA IRP to TSS) is greatly acknowledged. NR 271 TC 54 Z9 57 U1 2 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD FEB PY 2011 VL 129 IS 2 BP 220 EP 238 DI 10.1016/j.pharmthera.2010.09.009 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 729LA UT WOS:000287949900008 PM 20951731 ER PT J AU Lee, JSH Wirtz, D AF Lee, Jerry S. H. Wirtz, Denis TI Physical oncology PREFACE SO PHYSICAL BIOLOGY LA English DT Editorial Material C1 [Lee, Jerry S. H.] NCI, Ctr Strateg Sci Initiat, Off Director, Bethesda, MD 20892 USA. [Wirtz, Denis] Johns Hopkins Univ, Phys Sci Oncol Ctr, Baltimore, MD 21218 USA. RP Lee, JSH (reprint author), NCI, Ctr Strateg Sci Initiat, Off Director, Bethesda, MD 20892 USA. RI Lee, Jerry/A-3189-2008; Wirtz, Denis/A-3257-2010; Lee, Jerry/K-4553-2014 OI Lee, Jerry/0000-0003-1515-0952; NR 0 TC 0 Z9 0 U1 1 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 J9 PHYS BIOL JI Phys. Biol. PD FEB PY 2011 VL 8 IS 1 AR 010301 DI 10.1088/1478-3975/8/1/010301 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 717LE UT WOS:000287044600002 PM 21368347 ER PT J AU Sun, MX Kawamura, R Marko, JF AF Sun, Mingxuan Kawamura, Ryo Marko, John F. TI Micromechanics of human mitotic chromosomes SO PHYSICAL BIOLOGY LA English DT Article ID CHROMATIN ORGANIZATION; CONDENSIN-II; LAMIN-A; PROTEIN; ARCHITECTURE; DNA; ELASTICITY; REVEALS; COHESIN; FORCE AB Eukaryote cells dramatically reorganize their long chromosomal DNAs to facilitate their physical segregation during mitosis. The internal organization of folded mitotic chromosomes remains a basic mystery of cell biology; its understanding would likely shed light on how chromosomes are separated from one another as well as into chromosome structure between cell divisions. We report biophysical experiments on single mitotic chromosomes from human cells, where we combine micromanipulation, nano-Newton-scale force measurement and biochemical treatments to study chromosome connectivity and topology. Results are in accord with previous experiments on amphibian chromosomes and support the 'chromatin network' model of mitotic chromosome structure. Prospects for studies of chromosome-organizing proteins using siRNA expression knockdowns, as well as for differential studies of chromosomes with and without mutations associated with genetic diseases, are also discussed. C1 [Sun, Mingxuan; Marko, John F.] Northwestern Univ, Dept Mol Biosci, Dept Phys & Astron, Evanston, IL 60208 USA. [Kawamura, Ryo] Univ Illinois, Dept Phys & Astron, Chicago, IL 60607 USA. [Marko, John F.] Northwestern Univ, NCI, Phys Sci & Oncol Ctr, Evanston, IL 60208 USA. RP Sun, MX (reprint author), Northwestern Univ, Dept Mol Biosci, Dept Phys & Astron, Evanston, IL 60208 USA. EM john-marko@northwestern.edu FU NSF [DMR-0715099, MCB-1022117]; NIH [1U54CA143869-01]; American Heart Association FX This work was supported by NSF grants DMR-0715099 and MCB-1022117, by NIH grant 1U54CA143869-01 (NU-PS-OC), and by a predoctoral fellowship from the American Heart Association (MS). NR 42 TC 12 Z9 12 U1 1 U2 10 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 EI 1478-3975 J9 PHYS BIOL JI Phys. Biol. PD FEB PY 2011 VL 8 IS 1 AR 015003 DI 10.1088/1478-3975/8/1/015003 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 717LE UT WOS:000287044600006 PM 21301072 ER PT J AU Wu, PH Hung, SH Ren, TN Shih, IM Tseng, Y AF Wu, Pei-Hsun Hung, Shen-Hsiu Ren, Tina Shih, Ie-Ming Tseng, Yiider TI Cell cycle-dependent alteration in NAC1 nuclear body dynamics and morphology SO PHYSICAL BIOLOGY LA English DT Article ID BTB/POZ DOMAIN; BODIES; ONCOPROTEIN; PML; ARCHITECTURE; SURVIVAL; PROTEIN; GROWTH; CANCER AB NAC1, a BTB/POZ family member, has been suggested to participate in maintaining the stemness of embryonic stem cells and has been implicated in the pathogenesis of human cancer. In ovarian cancer, NAC1 upregulation is associated with disease aggressiveness and with the development of chemoresistance. Like other BTB/POZ proteins, NAC1 forms discrete nuclear bodies in non-dividing cells. To investigate the biological role of NAC1 nuclear bodies, we characterized the expression dynamics of NAC1 nuclear bodies during different phases of the cell cycle. Fluorescence recovery after photobleaching assays revealed that NAC1 was rapidly exchanged between the nucleoplasm and NAC1 nuclear bodies in interphase cells. The number of NAC1 bodies significantly increased and their size decreased in the S phase as compared to the G(0)/G(1) and G(2) phases. NAC1 nuclear bodies disappeared and NAC1 became diffuse during mitosis. NAC1 nuclear bodies reappeared immediately after completion of mitosis. These results indicate that a cell cycle-dependent regulatory mechanism controls NAC1 body formation in the nucleus and suggest that NAC1 body dynamics are associated with mitosis or cytokinesis. C1 [Wu, Pei-Hsun; Hung, Shen-Hsiu; Ren, Tina; Tseng, Yiider] Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. [Wu, Pei-Hsun; Tseng, Yiider] NCI, Phys Sci Oncol Ctr, Gainesville, FL 32611 USA. [Shih, Ie-Ming] Johns Hopkins Med Inst, Dept Pathol & Oncol, Baltimore, MD 21231 USA. RP Tseng, Y (reprint author), Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. EM ytseng@che.ufl.edu FU NIH/NCI [CA103937, U54CA143868]; NIH/NIBIB [R01EB004416] FX This study was supported in part by grants from NIH/NCI CA103937, NIH/NCI U54CA143868, and NIH/NIBIB R01EB004416. NR 26 TC 10 Z9 10 U1 1 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 J9 PHYS BIOL JI Phys. Biol. PD FEB PY 2011 VL 8 IS 1 AR 015005 DI 10.1088/1478-3975/8/1/015005 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 717LE UT WOS:000287044600008 PM 21301057 ER PT J AU Bharti, K Miller, SS Arnheiter, H AF Bharti, Kapil Miller, Sheldon S. Arnheiter, Heinz TI The new paradigm: retinal pigment epithelium cells generated from embryonic or induced pluripotent stem cells SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Review DE ES cells; induced pluripotent stem cells; age-related macular degeneration; retinitis pigmentosa; cell-based therapy; retinal pigment epithelium ID RECESSIVE RETINITIS-PIGMENTOSA; LIGHT-EVOKED RESPONSES; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; EYE DEVELOPMENT; CONE PHOTORECEPTORS; VISUAL FUNCTION; IN-VITRO; DIRECTED DIFFERENTIATION; REGENERATIVE MEDICINE AB P>Compared with neural crest-derived melanocytes, retinal pigment epithelium (RPE) cells in the back of the eye are pigment cells of a different kind. They are a part of the brain, form an epithelial monolayer, respond to distinct extracellular signals, and provide functions that far exceed those of a light-absorbing screen. For instance, they control nutrient and metabolite flow to and from the retina, replenish 11-cis-retinal by re-isomerizing all-trans-retinal generated during photoconversion, phagocytose daily a portion of the photoreceptors' outer segments, and secrete cytokines that locally control the innate and adaptive immune systems. Not surprisingly, RPE cell damage is a major cause of human blindness worldwide, with age-related macular degeneration a prevalent example. RPE replacement therapies using RPE cells generated from embryonic or induced pluripotent stem cells provide a novel approach to a rational treatment of such forms of blindness. In fact, RPE-like cells can be obtained relatively easily when stem cells are subjected to a two-step induction protocol, a first step that leads to a neuroectodermal fate and a second to RPE differentiation. Here, we discuss the characteristics of such cells, propose criteria they should fulfill in order to be considered authentic RPE cells, and point out the challenges one faces when using such cells in attempts to restore vision. C1 [Bharti, Kapil; Arnheiter, Heinz] Natl Inst Neurol Disorders & Stroke, Mammalian Dev Sect, Bethesda, MD USA. [Miller, Sheldon S.] NEI, Sect Epithelial & Retinal Physiol & Dis, NIH, Bethesda, MD 20892 USA. RP Bharti, K (reprint author), Natl Inst Neurol Disorders & Stroke, Mammalian Dev Sect, Bethesda, MD USA. EM kapilbharti@ninds.nih.gov FU NIH; NINDS; NEI FX We would like to express our gratitude to Drs Sally Temple, Jeffrey Stern, Ronald McKay, Christine Curcio, Monique Dubois-Dalcq and Polly Matzinger for invaluable comments on the manuscript, and Vinish Saini for help with the artwork in Fig. 1. This work was supported by the intramural program of the NIH, NINDS and NEI. NR 112 TC 38 Z9 39 U1 4 U2 23 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD FEB PY 2011 VL 24 IS 1 BP 21 EP 34 DI 10.1111/j.1755-148X.2010.00772.x PG 14 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 706IA UT WOS:000286210400012 PM 20846177 ER PT J AU Miyamura, Y Coelho, SG Schlenz, K Batzer, J Smuda, C Choi, W Brenner, M Passeron, T Zhang, GF Kolbe, L Wolber, R Hearing, VJ AF Miyamura, Yoshinori Coelho, Sergio G. Schlenz, Kathrin Batzer, Jan Smuda, Christoph Choi, Wonseon Brenner, Michaela Passeron, Thierry Zhang, Guofeng Kolbe, Ludger Wolber, Rainer Hearing, Vincent J. TI The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE ultraviolet; skin; pigmentation; DNA damage; photoprotection ID ULTRAVIOLET-RADIATION; DNA-DAMAGE; MOLECULAR-MECHANISMS; ACTIN CYTOSKELETON; MALIGNANT-MELANOMA; HUMAN-EPIDERMIS; IN-VIVO; PIGMENTATION; RESPONSES; PHOTOCARCINOGENESIS AB P>The relationship between human skin pigmentation and protection from ultraviolet (UV) radiation is an important element underlying differences in skin carcinogenesis rates. The association between UV damage and the risk of skin cancer is clear, yet a strategic balance in exposure to UV needs to be met. Dark skin is protected from UV-induced DNA damage significantly more than light skin owing to the constitutively higher pigmentation, but an as yet unresolved and important question is what photoprotective benefit, if any, is afforded by facultative pigmentation (i.e. a tan induced by UV exposure). To address that and to compare the effects of various wavelengths of UV, we repetitively exposed human skin to suberythemal doses of UVA and/or UVB over 2 weeks after which a challenge dose of UVA and UVB was given. Although visual skin pigmentation (tanning) elicited by different UV exposure protocols was similar, the melanin content and UV-protective effects against DNA damage in UVB-tanned skin (but not in UVA-tanned skin) were significantly higher. UVA-induced tans seem to result from the photooxidation of existing melanin and its precursors with some redistribution of pigment granules, while UVB stimulates melanocytes to up-regulate melanin synthesis and increases pigmentation coverage, effects that are synergistically stimulated in UVA and UVB-exposed skin. Thus, UVA tanning contributes essentially no photoprotection, although all types of UV-induced tanning result in DNA and cellular damage, which can eventually lead to photocarcinogenesis. C1 [Miyamura, Yoshinori; Coelho, Sergio G.; Choi, Wonseon; Brenner, Michaela; Passeron, Thierry; Hearing, Vincent J.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. [Schlenz, Kathrin; Batzer, Jan; Smuda, Christoph; Kolbe, Ludger; Wolber, Rainer] Beiersdorf AG, R&D, Skin Res, Hamburg, Germany. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM hearingv@nih.gov OI Passeron, Thierry/0000-0002-0797-6570 FU National Cancer Institute at NIH FX This research was supported in part by the Intramural Research Program of the National Cancer Institute at NIH. NR 67 TC 37 Z9 38 U1 2 U2 14 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD FEB PY 2011 VL 24 IS 1 BP 136 EP 147 DI 10.1111/j.1755-148X.2010.00764.x PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 706IA UT WOS:000286210400022 PM 20979596 ER PT J AU Camilli, TC Xu, M O'Connell, MP Chien, B Frank, BP Subaran, S Indig, FE Morin, PJ Hewitt, SM Weeraratna, AT AF Camilli, Tura C. Xu, Mai O'Connell, Michael P. Chien, Bonnie Frank, Brittany P. Subaran, Sarah Indig, Fred E. Morin, Patrice J. Hewitt, Stephen M. Weeraratna, Ashani T. TI Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE Klotho; Wnt5A; melanoma; syndecan; sialidase ID TRPV5 CHANNEL; PROTEIN; CANCER; CALPAIN; PHOSPHORYLATION; SUPPRESSION; METASTASIS; SENESCENCE; SIALIDASE; MEMBRANE AB P>We have previously shown that Wnt5A-mediated signaling can promote melanoma metastasis. It has been shown that Wnt signaling is antagonized by the protein Klotho, which has been implicated in aging. We show here that in melanoma cells, expressions of Wnt5A and Klotho are inversely correlated. In the presence of recombinant Klotho (rKlotho), we show that Wnt5A internalization and signaling is decreased in high Wnt5A-expressing cells. Moreover, in the presence of rKlotho, we observe an increase in Wnt5A remaining in the medium, coincident with an increase in sialidase activity, and decrease in syndecan expression. These effects can be inhibited using a sialidase inhibitor. In addition to its effects on Wnt5A internalization, we also demonstrate that Klotho decreases melanoma cell invasive potential by a second mechanism that involves the inhibition of calpain and a resultant decrease in filamin cleavage, which we demonstrate is critical for melanoma cell motility. C1 [Camilli, Tura C.; Xu, Mai; O'Connell, Michael P.; Chien, Bonnie; Frank, Brittany P.; Morin, Patrice J.; Weeraratna, Ashani T.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Subaran, Sarah; Indig, Fred E.] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. [Hewitt, Stephen M.] NIA, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Weeraratna, AT (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM weerarat@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU National Institute on Aging, Baltimore, MD, USA FX We thank Dr. Dan Longo (National Institute on Aging, Baltimore, MD, USA) for helpful discussions on this manuscript. We also thank Dr. Michel Bernier (National Institute on Aging, Baltimore, MD, USA) for the M2 cells, and full-length, wild-type pRep4-Filamin A construct, and Dr. Akiko Mammoto (Childrens Hospital, Boston, MA, USA) for the pEGFP-Filamin-del2 CR Filamin A construct. This work was funded by the Intramural Research Program of the National Institute on Aging, Baltimore, MD, USA. NR 36 TC 30 Z9 31 U1 2 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD FEB PY 2011 VL 24 IS 1 BP 175 EP 186 DI 10.1111/j.1755-148X.2010.00792.x PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 706IA UT WOS:000286210400025 PM 20955350 ER PT J AU Lettre, G Palmer, CD Young, T Ejebe, KG Allayee, H Benjamin, EJ Bennett, F Bowden, DW Chakravarti, A Dreisbach, A Farlow, DN Folsom, AR Fornage, M Forrester, T Fox, E Haiman, CA Hartiala, J Harris, TB Hazen, SL Heckbert, SR Henderson, BE Hirschhorn, JN Keating, BJ Kritchevsky, SB Larkin, E Li, M Rudock, ME McKenzie, CA Meigs, JB Meng, YA Mosley, TH Newman, AB Newton-Cheh, CH Paltoo, DN Papanicolaou, GJ Patterson, N Post, WS Psaty, BM Qasim, AN Qu, L Rader, DJ Redline, S Reilly, MP Reiner, AP Rich, SS Rotter, JI Liu, Y Shrader, P Siscovick, DS Tang, WHW Taylor, HA Tracy, RP Vasan, RS Waters, KM Wilks, R Wilson, JG Fabsitz, RR Gabriel, SB Kathiresan, S Boerwinkle, E AF Lettre, Guillaume Palmer, Cameron D. Young, Taylor Ejebe, Kenechi G. Allayee, Hooman Benjamin, Emelia J. Bennett, Franklyn Bowden, Donald W. Chakravarti, Aravinda Dreisbach, Al Farlow, Deborah N. Folsom, Aaron R. Fornage, Myriam Forrester, Terrence Fox, Ervin Haiman, Christopher A. Hartiala, Jaana Harris, Tamara B. Hazen, Stanley L. Heckbert, Susan R. Henderson, Brian E. Hirschhorn, Joel N. Keating, Brendan J. Kritchevsky, Stephen B. Larkin, Emma Li, Mingyao Rudock, Megan E. McKenzie, Colin A. Meigs, James B. Meng, Yang A. Mosley, Tom H., Jr. Newman, Anne B. Newton-Cheh, Christopher H. Paltoo, Dina N. Papanicolaou, George J. Patterson, Nick Post, Wendy S. Psaty, Bruce M. Qasim, Atif N. Qu, Liming Rader, Daniel J. Redline, Susan Reilly, Muredach P. Reiner, Alexander P. Rich, Stephen S. Rotter, Jerome I. Liu, Yongmei Shrader, Peter Siscovick, David S. Tang, W. H. Wilson Taylor, Herman A., Jr. Tracy, Russell P. Vasan, Ramachandran S. Waters, Kevin M. Wilks, Rainford Wilson, James G. Fabsitz, Richard R. Gabriel, Stacey B. Kathiresan, Sekar Boerwinkle, Eric TI Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project SO PLOS GENETICS LA English DT Article ID ARTERY-DISEASE; MYOCARDIAL-INFARCTION; LOCI; VARIANTS; METAANALYSIS; TRAITS AB Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture-and SNP-association to maximize power for genetic discovery in even larger African-American consortia. C1 [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Palmer, Cameron D.; Young, Taylor; Ejebe, Kenechi G.; Farlow, Deborah N.; Hirschhorn, Joel N.; Meng, Yang A.; Newton-Cheh, Christopher H.; Patterson, Nick; Gabriel, Stacey B.; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Allayee, Hooman; Haiman, Christopher A.; Hartiala, Jaana; Henderson, Brian E.; Waters, Kevin M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Epidemiol, Boston, MA 02118 USA. [Benjamin, Emelia J.; Newton-Cheh, Christopher H.; Vasan, Ramachandran S.; Kathiresan, Sekar] NHLBI, Framingham Heart Study, Framingham, MA USA. [Benjamin, Emelia J.; Newton-Cheh, Christopher H.; Vasan, Ramachandran S.; Kathiresan, Sekar] Boston Univ, Framingham, MA USA. [Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Dreisbach, Al; Fox, Ervin; Mosley, Tom H., Jr.; Taylor, Herman A., Jr.; Wilson, James G.] Univ Mississipi, Med Ctr, Dept Med, Jackson, MS USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Sch Publ Hlth, Houston, TX USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hazen, Stanley L.; Tang, W. H. Wilson] Cleveland Clin, Dept Cell Biol, Cleveland, OH 44106 USA. [Hazen, Stanley L.; Tang, W. H. Wilson] Cleveland Clin, Dept Cardiovasc Med, Ctr Cardiovasc Diagnost & Prevent, Cleveland, OH 44106 USA. [Heckbert, Susan R.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Heckbert, Susan R.; Psaty, Bruce M.; Reiner, Alexander P.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Hirschhorn, Joel N.; Meigs, James B.; Newton-Cheh, Christopher H.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Keating, Brendan J.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sch Med, Div Gerontol & Geriatr Med, J Paul Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Larkin, Emma] Case Western Reserve Univ, Ctr Clin Investigat, Cleveland, OH 44106 USA. [Qasim, Atif N.; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Rudock, Megan E.; Liu, Yongmei] Wake Forest Univ, Div Publ Hlth Sci, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [McKenzie, Colin A.] Univ W Indies, Res Inst Trop Med, Trop Metab Res Unit, Kingston 7, Jamaica. [Meigs, James B.; Shrader, Peter] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Newton-Cheh, Christopher H.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher H.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher H.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Paltoo, Dina N.; Papanicolaou, George J.; Fabsitz, Richard R.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Post, Wendy S.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Taylor, Herman A., Jr.] Jackson State Univ, Jackson, MS USA. [Taylor, Herman A., Jr.] Tougaloo Coll, Tougaloo, MS USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, VT USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Colchester, VT USA. [Wilks, Rainford] Univ W Indies, Res Inst Trop Med, Epidemiol Res Unit, Kingston 7, Jamaica. [Wilson, James G.] GV Sonny Montgomery Vet Affairs Med Ctr, Jackson, MS USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. RP Lettre, G (reprint author), Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. EM Eric.Boerwinkle@uth.tmc.edu RI Tang, Wai Hong/I-1238-2013; Newman, Anne/C-6408-2013; Ejebe, Kenechi/I-9238-2016; OI Newman, Anne/0000-0002-0106-1150; Ejebe, Kenechi/0000-0002-6090-8657; Ramachandran, Vasan/0000-0001-7357-5970; Kritchevsky, Stephen/0000-0003-3336-6781; Benjamin, Emelia/0000-0003-4076-2336 FU ADB [HHSN268200625226C, N01-HC-65226]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, 1P01HL098055-01, P01HL087018, P01HL076491, R01DK080732, R01HL103931-01]; NIH, National Institute on Aging; National Center for Research Resources [C06, RR10600-01, CA62528-01, RR14514-01] FX The grants and contracts that have supported CARe are listed at http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx, including HHSN268200625226C (ADB No. N01-HC-65226). Additional support for this work was provided by: the Fondation de l'Institut de Cardiologie de Montreal and the Centre of Excellence in Personalized Medicine (CEPMed) (to GL), NIDDK K24 DK080140 (to JBM). The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The Health ABC 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 Health ABC research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The Cleveland Clinic GeneBank study was supported through NIH grants 1P01HL098055-01, P01HL087018, P01HL076491, R01DK080732, and R01HL103931-01. A portion of analyses for the Cleveland Clinic GeneBank was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 (RR10600-01, CA62528-01, RR14514-01) from the National Center for Research Resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 135 Z9 140 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2011 VL 7 IS 2 AR e1001300 DI 10.1371/journal.pgen.1001300 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 726CV UT WOS:000287697300015 PM 21347282 ER PT J AU Smith, JG Magnani, JW Palmer, C Meng, YA Soliman, EZ Musani, SK Kerr, KF Schnabel, RB Lubitz, SA Sotoodehnia, N Redline, S Pfeufer, A Muller, M Evans, DS Nalls, MA Liu, YM Newman, AB Zonderman, AB Evans, MK Deo, R Ellinor, PT Paltoo, DN Newton-Cheh, C Benjamin, EJ Mehra, R Alonso, A Heckbert, SR Fox, ER AF Smith, J. Gustav Magnani, Jared W. Palmer, Cameron Meng, Yan A. Soliman, Elsayed Z. Musani, Solomon K. Kerr, Kathleen F. Schnabel, Renate B. Lubitz, Steven A. Sotoodehnia, Nona Redline, Susan Pfeufer, Arne Mueller, Martina Evans, Daniel S. Nalls, Michael A. Liu, Yongmei Newman, Anne B. Zonderman, Alan B. Evans, Michele K. Deo, Rajat Ellinor, Patrick T. Paltoo, Dina N. Newton-Cheh, Christopher Benjamin, Emelia J. Mehra, Reena Alonso, Alvaro Heckbert, Susan R. Fox, Ervin R. CA CARe Consortium TI Genome-Wide Association Studies of the PR Interval in African Americans SO PLOS GENETICS LA English DT Article ID HEART-RATE; ATHEROSCLEROSIS RISK; GENETIC-ANALYSIS; COMMON VARIANTS; DESIGN; POPULATIONS; OBJECTIVES; CONDUCTION; DISEASE; TWINS AB The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p < 2.5 > 10(-8)) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta = 5.1 msec per minor allele, 95% CI = 4.1-6.1, p = 3 x 10(-23)). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8-3.0, p = 3 x 10(-16)) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity < 0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans. C1 [Smith, J. Gustav] Lund Univ, Fac Med, Dept Cardiol, Lund, Sweden. [Smith, J. Gustav; Palmer, Cameron; Meng, Yan A.; Newton-Cheh, Christopher] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Smith, J. Gustav; Palmer, Cameron; Meng, Yan A.; Newton-Cheh, Christopher] MIT, Cambridge, MA 02139 USA. [Magnani, Jared W.] Boston Univ, Sch Med, Cardiovasc Sect, Boston, MA 02118 USA. [Magnani, Jared W.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Soliman, Elsayed Z.] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Ctr EPICARE, Winston Salem, NC 27109 USA. [Musani, Solomon K.; Fox, Ervin R.] Univ Mississippi, Med Ctr, Jackson Heart Study, Dept Med,Div Cardiovasc Dis, Jackson, MS 39216 USA. [Kerr, Kathleen F.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Schnabel, Renate B.] Johannes Gutenberg Univ Mainz, Med Clin Cardiol 2, Mainz, Germany. [Lubitz, Steven A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Lubitz, Steven A.; Ellinor, Patrick T.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steven A.; Ellinor, Patrick T.; Newton-Cheh, Christopher] Harvard Univ, Sch Med, Boston, MA USA. [Sotoodehnia, Nona] Univ Washington, Dept Med, Div Cardiol, Seattle, WA 98195 USA. [Redline, Susan] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Pfeufer, Arne] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Pfeufer, Arne] Helmholtz Cent Munchen, Inst Human Genet, Neuherberg, Germany. [Mueller, Martina] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Mueller, Martina] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany. [Mueller, Martina] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Evans, Daniel S.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Zonderman, Alan B.; Evans, Michele K.] NIA, NIH, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Deo, Rajat] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Ellinor, Patrick T.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Paltoo, Dina N.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Div Prevent Med, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. [Mehra, Reena] Case Sch Med, Dept Med, Cleveland, OH USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Smith, JG (reprint author), Lund Univ, Fac Med, Dept Cardiol, Lund, Sweden. EM gustav.smith@med.lu.se RI Kerr, Kathleen/A-2893-2013; Pfeufer, Arne/B-6634-2013; Alonso, Alvaro/A-4917-2010; Schnabel, Renate/F-6527-2014; Newman, Anne/C-6408-2013; Soliman, Elsayed/D-8124-2011 OI Alonso, Alvaro/0000-0002-2225-8323; Newman, Anne/0000-0002-0106-1150; Mehra, Reena/0000-0002-6222-2675; Benjamin, Emelia/0000-0003-4076-2336; Zonderman, Alan B/0000-0002-6523-4778; Soliman, Elsayed/0000-0001-5632-8150 FU National Heart, Lung, and Blood Institute [N01-HC-55015, 268200900055C-0-0-1]; Baylor Medical College [N01-HC-55016]; University of Mississippi Medical Center [N01-HC-55021]; University of Minnesota [N01-HC-55019, N01-HC-95163]; Johns Hopkins University [N01-HC-55020, N01-HC-95162, N01-HC-95168]; University of Texas, Houston [N01-HC-55022]; University of North Carolina, Forsyth County [N01-HC-55018]; Cleveland Family Study (CFS): Case Western Reserve University (NIH) [HL 46380, M01RR00080]; Jackson Heart Study (JHS): Jackson State University [N01-HC-95170]; University of Mississippi [N01-HC-95171]; Tougaloo College [N01-HC-95172]; Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington [N01-HC-95159]; Regents of the University of California [N01-HC-95160]; Columbia University [N01-HC-95161]; Northwestern University [N01-HC-95164]; Wake Forest University [N01-HC-95165]; University of Vermont [N01-HC-95166]; New England Medical Center [N01-HC-95167]; Harbor-UCLA Research and Education Institute [N01-HC-95169]; Cedars-Sinai Medical Center [R01-HL-071205]; University of Virginia [R01-HL-071205]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, T32HL007575, 1K23HL080025, 1R01HL098283, 1R01HL092577, 1R01HL102214, 1R01 AG028321, K23 HL079114, 1RC1HL099452, 1RC1HL101056]; NIH, National Institute on Aging; National Center for Minority Health and Health Disparities; NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; Swedish Heart Lung Foundation; American Heart Association [09FTF2190028, 0530188N, 09SDG2280087]; NHLBI [268200900055C-0-0-1]; German National Genome Research Network [NGFN 01GR0803]; German Federal Ministry of Research BMBF [01EZ0874]; National Center for Research Resources [KL2RR024132]; Doris Duke Charitable Foundation; Burroughs Wellcome Fund; Central Society of Clinical Research Award; NCI [1U54CA116867]; [1R21DA027021] FX The following four parent studies have contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology - Broad Institute (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community. Atherosclerosis Risk in Communities (ARIC): The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts to the University of North Carolina at Chapel Hill (N01-HC-55015), Baylor Medical College (N01-HC-55016), University of Mississippi Medical Center (N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas, Houston (N01-HC-55022), University of North Carolina, Forsyth County (N01-HC-55018); Cleveland Family Study (CFS): Case Western Reserve University (NIH HL 46380, M01RR00080); Jackson Heart Study (JHS): Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172); Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL-071205). The Health, Aging, and Body Composition Study (Health ABC) was supported by 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. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS) study was in part supported by the intramural research program of the National Institute on Aging and the National Center for Minority Health and Health Disparities, National Institutes of Health. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (contract # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). JGS was supported by the Swedish Heart Lung Foundation. JWM was supported by American Heart Association grant 09FTF2190028. KFK was supported by NHLBI contract 268200900055C-0-0-1. SAL was supported by NIH T32HL007575. AP was supported by the German National Genome Research Network grants NGFN 01GR0803 and the German Federal Ministry of Research BMBF 01EZ0874. RD was supported by Grant Number KL2RR024132 from the National Center for Research Resources. PTE was supported by 1R01HL092577, 1R21DA027021.; CN-C was supported by NIH 1K23HL080025, 1R01HL098283, Doris Duke Charitable Foundation Clinical Scientist Development Award, and Burrougs Wellcome Fund Career Award for Medical Scientists. EJB was supported by NIH awards 1R01HL092577, 1R01HL092577, 1R01HL102214, 1R01 AG028321. RM was supported by NIH K23 HL079114, American Heart Association National Scientist Development Award 0530188N, Central Society of Clinical Research Award, and NCI 1U54CA116867. AA was supported by NIH awards 1RC1HL099452 and 1RC1HL101056 and American Heart Association grant 09SDG2280087. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 50 Z9 51 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2011 VL 7 IS 2 AR e1001304 DI 10.1371/journal.pgen.1001304 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 726CV UT WOS:000287697300019 PM 21347284 ER PT J AU Snitkin, ES Segre, D AF Snitkin, Evan S. Segre, Daniel TI Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes SO PLOS GENETICS LA English DT Article ID GENETIC INTERACTION; SACCHAROMYCES-CEREVISIAE; PROTEIN EVOLUTION; YEAST; NETWORKS; ROBUSTNESS; MUTATIONS; PATHWAY AB An epistatic interaction between two genes occurs when the phenotypic impact of one gene depends on another gene, often exposing a functional association between them. Due to experimental scalability and to evolutionary significance, abundant work has been focused on studying how epistasis affects cellular growth rate, most notably in yeast. However, epistasis likely influences many different phenotypes, affecting our capacity to understand cellular functions, biochemical networks adaptation, and genetic diseases. Despite its broad significance, the extent and nature of epistasis relative to different phenotypes remain fundamentally unexplored. Here we use genome-scale metabolic network modeling to investigate the extent and properties of epistatic interactions relative to multiple phenotypes. Specifically, using an experimentally refined stoichiometric model for Saccharomyces cerevisiae, we computed a three-dimensional matrix of epistatic interactions between any two enzyme gene deletions, with respect to all metabolic flux phenotypes. We found that the total number of epistatic interactions between enzymes increases rapidly as phenotypes are added, plateauing at approximately 80 phenotypes, to an overall connectivity that is roughly 8-fold larger than the one observed relative to growth alone. Looking at interactions across all phenotypes, we found that gene pairs interact incoherently relative to different phenotypes, i.e. antagonistically relative to some phenotypes and synergistically relative to others. Specific deletion-deletion-phenotype triplets can be explained metabolically, suggesting a highly informative role of multiphenotype epistasis in mapping cellular functions. Finally, we found that genes involved in many interactions across multiple phenotypes are more highly expressed, evolve slower, and tend to be associated with diseases, indicating that the importance of genes is hidden in their total phenotypic impact. Our predictions indicate a pervasiveness of nonlinear effects in how genetic perturbations affect multiple metabolic phenotypes. The approaches and results reported could influence future efforts in understanding metabolic diseases and the role of biochemical regulation in the cell. C1 [Snitkin, Evan S.; Segre, Daniel] Boston Univ, Program Bioinformat, Boston, MA 02215 USA. [Snitkin, Evan S.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Segre, Daniel] Boston Univ, Dept Biol, Boston, MA 02215 USA. [Segre, Daniel] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP Snitkin, ES (reprint author), Boston Univ, Program Bioinformat, Boston, MA 02215 USA. EM dsegre@bu.edu RI Segre, Daniel/A-1993-2009 FU National Institute of Health [1RC2GM092602-01, 1R01GM089978, 1R01GM078209] FX This work was supported by grants from the National Institute of Health (1RC2GM092602-01, 1R01GM089978, and 1R01GM078209). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 27 Z9 27 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2011 VL 7 IS 2 AR e1001294 DI 10.1371/journal.pgen.1001294 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 726CV UT WOS:000287697300009 PM 21347328 ER PT J AU Zhernakova, A Stahl, EA Trynka, G Raychaudhuri, S Festen, EA Franke, L Westra, HJ Fehrmann, RSN Kurreeman, FAS Thomson, B Gupta, N Romanos, J McManus, R Ryan, AW Turner, G Brouwer, E Posthumus, MD Remmers, EF Tucci, F Toes, R Grandone, E Mazzilli, MC Rybak, A Cukrowska, B Coenen, MJH Radstake, TRDJ van Riel, PLCM Li, YH de Bakker, PIW Gregersen, PK Worthington, J Siminovitch, KA Klareskog, L Huizinga, TWJ Wijmenga, C Plenge, RM AF Zhernakova, Alexandra Stahl, Eli A. Trynka, Gosia Raychaudhuri, Soumya Festen, Eleanora A. Franke, Lude Westra, Harm-Jan Fehrmann, Rudolf S. N. Kurreeman, Fina A. S. Thomson, Brian Gupta, Namrata Romanos, Jihane McManus, Ross Ryan, Anthony W. Turner, Graham Brouwer, Elisabeth Posthumus, Marcel D. Remmers, Elaine F. Tucci, Francesca Toes, Rene Grandone, Elvira Mazzilli, Maria Cristina Rybak, Anna Cukrowska, Bozena Coenen, Marieke J. H. Radstake, Timothy R. D. J. van Riel, Piet L. C. M. Li, Yonghong de Bakker, Paul I. W. Gregersen, Peter K. Worthington, Jane Siminovitch, Katherine A. Klareskog, Lars Huizinga, Tom W. J. Wijmenga, Cisca Plenge, Robert M. TI Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci SO PLOS GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; SUSCEPTIBILITY LOCI; RISK LOCUS; TYROSINE-PHOSPHATASE; AUTOIMMUNE-DISEASES; GENETIC-VARIANTS; CROHNS-DISEASE; COMMON; ACTIVATION; EXPRESSION AB Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P < 5 x 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) = 1.2 x 10(-12)), rs864537 near CD247 (P(combined) = 2.2 x 10(-11)), rs2298428 near UBE2L3 (P(combined) = 2.5 x 10(-10)), and rs11203203 near UBASH3A (P(combined) = 1.1 x 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 x 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases. C1 [Zhernakova, Alexandra; Kurreeman, Fina A. S.; Toes, Rene; Huizinga, Tom W. J.] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands. [Zhernakova, Alexandra] Univ Med Ctr Utrecht, Complex Genet Sect, Dept Med Genet, Utrecht, Netherlands. [Zhernakova, Alexandra; Stahl, Eli A.; Raychaudhuri, Soumya; Kurreeman, Fina A. S.; de Bakker, Paul I. W.; Plenge, Robert M.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Stahl, Eli A.; Raychaudhuri, Soumya; Kurreeman, Fina A. S.; Thomson, Brian; Gupta, Namrata; de Bakker, Paul I. W.; Plenge, Robert M.] Broad Inst, Cambridge, MA USA. [Trynka, Gosia; Festen, Eleanora A.; Franke, Lude; Westra, Harm-Jan; Fehrmann, Rudolf S. N.; Romanos, Jihane; Wijmenga, Cisca] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Trynka, Gosia; Festen, Eleanora A.; Franke, Lude; Westra, Harm-Jan; Fehrmann, Rudolf S. N.; Romanos, Jihane; Brouwer, Elisabeth; Posthumus, Marcel D.; Wijmenga, Cisca] Univ Groningen, Groningen, Netherlands. [Raychaudhuri, Soumya] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Raychaudhuri, Soumya; Plenge, Robert M.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Franke, Lude] Queen Mary Univ London, Blizard Inst Cell & Mol Sci, Barts & London Sch Med & Dent, London, England. [McManus, Ross; Ryan, Anthony W.; Turner, Graham] St James Hosp, Trinity Coll, Dept Clin Med, Trinity Ctr Hlth Sci, Dublin, Ireland. [McManus, Ross; Ryan, Anthony W.; Turner, Graham] St James Hosp, Trinity Coll, Inst Mol Med, Trinity Ctr Hlth Sci, Dublin, Ireland. [Brouwer, Elisabeth; Posthumus, Marcel D.] Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9713 AV Groningen, Netherlands. [Remmers, Elaine F.] NIAMSD, Genet & Genom Branch, NIH, Bethesda, MD 20892 USA. [Tucci, Francesca] Univ Naples Federico 2, European Lab Food Induced Dis, Naples, Italy. [Grandone, Elvira] IRCCS Casa Sollievo Sofferenza, Unita Aterosclerosi & Trombosi, Foggia, Italy. [Mazzilli, Maria Cristina] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy. [Rybak, Anna] Childrens Mem Hlth Inst, Dept Gastroenterol Hepatol & Immunol, Warsaw, Poland. [Cukrowska, Bozena] Childrens Mem Hlth Inst, Dept Pathol, Warsaw, Poland. [Coenen, Marieke J. H.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Radstake, Timothy R. D. J.; van Riel, Piet L. C. M.] Radboud Univ Nijmegen, Dept Rheumatol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Li, Yonghong] Celera, Alameda, CA USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Div Genet, Dept Med,Med Sch, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Gregersen, Peter K.] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Worthington, Jane] Univ Manchester, Arthrit Res Campaign Epidemiol Unit, Manchester, Lancs, England. [Siminovitch, Katherine A.] Univ Toronto, Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada. [Siminovitch, Katherine A.] Univ Hlth Network, Toronto, ON, Canada. [Klareskog, Lars] Karolinska Inst, Rheumatol Unit, Dept Med, Karolinska Univ Hosp Solna, Stockholm, Sweden. RP Zhernakova, A (reprint author), Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands. EM rplenge@partners.org RI Coenen, Marieke/A-2159-2010; Fehrmann, Rudolf/E-2551-2011; Ryan, Anthony/A-1336-2010; Romanos, Jihane/F-7372-2012; de Bakker, Paul/B-8730-2009; Brouwer, Elisabeth/A-3198-2015; Franke, Lude/P-7036-2016; Wijmenga, Cisca/D-2173-2009; Festen, Eleonora/S-3557-2016; Siminovitch, Katherine/K-1475-2013; Riel, P.L.C.M./H-8082-2014; Worthington, Jane/M-9770-2014 OI Zhernakova, Alexandra/0000-0002-4574-0841; Trynka, Gosia/0000-0002-6955-9529; Wijmenga, Cisca/0000-0002-5635-1614; McManus, Ross/0000-0002-0529-9617; Klareskog, Lars/0000-0001-9601-6186; Fehrmann, Rudolf/0000-0002-7516-315X; de Bakker, Paul/0000-0001-7735-7858; Franke, Lude/0000-0002-5159-8802; Worthington, Jane/0000-0003-0544-042X FU NIH [R01-AR057108, R01-AR056768, U01-GM092691, 1K08AR055688-01A1]; Burroughs Wellcome Fund; European Community [PIOF-GA-2009-237280, HEALTH-F2-2008-223404]; National Center for Research Resources [U54 RR020278]; Coeliac Disease Consortium; Dutch Government [BSIK03009]; Netherlands Organisation for Scientific Research (NWO) [918.66.620, 916.10.135, 825.10.002]; Netherlands Genomics Initiative [93519031]; Royal Netherlands Academy of Arts and Sciences (KNAW); Science Foundation Ireland [09/IN.1/B2640]; Canada Research Chair; Sherman Family Chair in Genomic Medicine; CIHR [MOP79321, IIN84042]; ORF [RE01061]; EU; National Institute of Arthritis and Musculoskeletal and Skin Diseases FX RMP was supported by grants from the NIH (R01-AR057108, R01-AR056768, U01-GM092691) and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. SR is supported by an NIH Career Development Award (1K08AR055688-01A1). FK is supported by a Marie Curie International Outgoing Fellowship for Career Development from the European Community's FP7 (Grant Agreement number PIOF-GA-2009-237280). The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The work presented is made possible by grants from the Coeliac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative, and partially funded by the Dutch Government (BSIK03009 to CW) and by the Netherlands Organisation for Scientific Research (NWO, VICI grant 918.66.620 to CW). LF received a Horizon Breakthrough grant from the Netherlands Genomics Initiative (93519031) and a VENI grant from NWO (ZonMW grant 916.10.135). AZ received a Rubicon grant from NWO (825.10.002). GT received a Ter Meulen Fund grant from the Royal Netherlands Academy of Arts and Sciences (KNAW). RMcM is supported by a Science Foundation Ireland Grant 09/IN.1/B2640. KAS is supported by a Canada Research Chair, Sherman Family Chair in Genomic Medicine, CIHR grants MOP79321 and IIN84042, and ORF grant RE01061. This work is partly supported by Coordination Theme 1 (Health) of the European Community's FP7, Grant Agreement number HEALTH-F2-2008-223404 (MASTERSWITCH project); by the EU FP6 supported AutoCure; and by the intramural program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 165 Z9 166 U1 1 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD FEB PY 2011 VL 7 IS 2 AR e1002004 DI 10.1371/journal.pgen.1002004 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 726CV UT WOS:000287697300036 PM 21383967 ER PT J AU Ferrari, G Korber, B Goonetilleke, N Liu, MKP Turnbull, EL Salazar-Gonzalez, JF Hawkins, N Self, S Watson, S Betts, MR Gay, C McGhee, K Pellegrino, P Williams, I Tomaras, GD Haynes, BF Gray, CM Borrow, P Roederer, M McMichael, AJ Weinhold, KJ AF Ferrari, Guido Korber, Bette Goonetilleke, Nilu Liu, Michael K. P. Turnbull, Emma L. Salazar-Gonzalez, Jesus F. Hawkins, Natalie Self, Steve Watson, Sydeaka Betts, Michael R. Gay, Cynthia McGhee, Kara Pellegrino, Pierre Williams, Ian Tomaras, Georgia D. Haynes, Barton F. Gray, Clive M. Borrow, Persephone Roederer, Mario McMichael, Andrew J. Weinhold, Kent J. TI Relationship between Functional Profile of HIV-1 Specific CD8 T Cells and Epitope Variability with the Selection of Escape Mutants in Acute HIV-1 Infection SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; LYMPHOCYTE RESPONSE; MATHEMATICAL-THEORY; RHESUS-MONKEYS; AIDS VACCINE; VIREMIA; REPLICATION; GAG; ASSOCIATION; VARIANTS AB In the present study, we analyzed the functional profile of CD8(+) T-cell responses directed against autologous transmitted/founder HIV-1 isolates during acute and early infection, and examined whether multifunctionality is required for selection of virus escape mutations. Seven anti-retroviral therapy-naive subjects were studied in detail between 1 and 87 weeks following onset of symptoms of acute HIV-1 infection. Synthetic peptides representing the autologous transmitted/ founder HIV-1 sequences were used in multiparameter flow cytometry assays to determine the functionality of HIV-1-specific CD8(+) T memory cells. In all seven patients, the earliest T cell responses were predominantly oligofunctional, although the relative contribution of multifunctional cell responses increased significantly with time from infection. Interestingly, only the magnitude of the total and not of the poly-functional T-cell responses was significantly associated with the selection of escape mutants. However, the high contribution of MIP-1 beta-producing CD8(+) T-cells to the total response suggests that mechanisms not limited to cytotoxicity could be exerting immune pressure during acute infection. Lastly, we show that epitope entropy, reflecting the capacity of the epitope to tolerate mutational change and defined as the diversity of epitope sequences at the population level, was also correlated with rate of emergence of escape mutants. C1 [Ferrari, Guido; Tomaras, Georgia D.; Weinhold, Kent J.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Korber, Bette; Watson, Sydeaka] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM USA. [Goonetilleke, Nilu; Liu, Michael K. P.; McMichael, Andrew J.] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [Turnbull, Emma L.; Borrow, Persephone] Univ Oxford, Jenner Inst, Nuffield Dept Clin Med, Newbury, Berks, England. [Salazar-Gonzalez, Jesus F.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Hawkins, Natalie; Self, Steve] VID Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Watson, Sydeaka] Baylor Univ, Dept Stat Sci, Waco, TX 76798 USA. [Betts, Michael R.] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Gay, Cynthia] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [McGhee, Kara; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Pellegrino, Pierre; Williams, Ian] Mortimer Market Ctr, Ctr Sexual Hlth & HIV Res, London, England. [Tomaras, Georgia D.; Haynes, Barton F.; Weinhold, Kent J.] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Gray, Clive M.] Natl Inst Communicable Dis, AIDS Res Unit, Johannesburg, South Africa. [Borrow, Persephone; Roederer, Mario] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Ferrari, G (reprint author), Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. EM gflmp@duke.edu RI Ferrari, Guido/A-6088-2015; Tomaras, Georgia/J-5041-2016; OI Korber, Bette/0000-0002-2026-5757 FU Center for HIV/AIDS Vaccine Immunology [A1067854-03]; Duke University Center for AIDS Research (CFAR), an NIH [P30 AI 64518]; Bill and Melinda Gates Foundation [37874]; Senior Jenner Fellowship; UK Medical Research Council; UK National Institute for Health Research (NIHR) Biomedical Research Centre; Bristol Myers Squibb; Gilead Sciences; Abbott; Tibotec Therapeutics; [5R01AI050483-09] FX This publication was made possible with the support from the Center for HIV/AIDS Vaccine Immunology (A1067854-03) and from the Duke University Center for AIDS Research (CFAR), an NIH funded program (P30 AI 64518). Additional support came from the Gates Grand Challenges in Global Health Program of the Bill and Melinda Gates Foundation (grant #37874). G.F. received partial support from 5R01AI050483-09; P.B. received salary support from a Senior Jenner Fellowship; P.B. and A.J.McM. are Jenner Institute Investigators. A.J.McM. received partial support from the UK Medical Research Council and the UK National Institute for Health Research (NIHR) Biomedical Research Centre Programme. C.G. has received research support from Bristol Myers Squibb, Gilead Sciences, Abbott and Tibotec Therapeutics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 52 Z9 52 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2011 VL 7 IS 2 AR e1001273 DI 10.1371/journal.ppat.1001273 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 726DE UT WOS:000287698200011 PM 21347345 ER PT J AU Graf, EH Mexas, AM Yu, JQJ Shaheen, F Liszewski, MK Di Mascio, M Migueles, SA Connors, M O'Doherty, U AF Graf, Erin H. Mexas, Angela M. Yu, Jianqing J. Shaheen, Farida Liszewski, Megan K. Di Mascio, Michele Migueles, Stephen A. Connors, Mark O'Doherty, Una TI Elite Suppressors Harbor Low Levels of Integrated HIV DNA and High Levels of 2-LTR Circular HIV DNA Compared to HIV plus Patients On and Off HAART SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; BLOOD MONONUCLEAR-CELLS; TERMINAL REPEAT CIRCLES; PERIPHERAL-BLOOD; IN-VIVO; RNA LEVELS; HIV-1-INFECTED PATIENTS; QUANTITATIVE ASSAY AB Elite suppressors (ES) are a rare population of HIV-infected individuals that are capable of naturally controlling the infection without the use of highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods to measure viral burden are needed to elucidate important differences between these two patient populations in order to better understand their mechanisms of control. Viral burden quantification in ES patients has been limited to measurements of total DNA in PBMC, and estimates of Infectious Units per Million cells (IUPM). There appears to be no significant difference in the level of total HIV DNA between cells from ES patients and patients on HAART. However, recovering infectious virus from ES patient samples is much more difficult, suggesting their reservoir size should be much smaller than that in patients on HAART. Here we find that there is a significant difference in the level of integrated HIV DNA in ES patients compared to patients on HAART, providing an explanation for the previous results. When comparing the level of total to integrated HIV DNA in these samples we find ES patients have large excesses of unintegrated HIV DNA. To determine the composition of unintegrated HIV DNA in these samples, we measured circular 2-LTR HIV DNA forms and found ES patients frequently have high levels of 2-LTR circles in PBMC. We further show that these high levels of 2-LTR circles are not the result of inefficient integration in ES cells, since HIV integrates with similar efficiency in ES and normal donor cells. Our findings suggest that measuring integration provides a better surrogate of viral burden than total HIV DNA in ES patients. Moreover, they add significantly to our understanding of the mechanisms that allow viral control and reservoir maintenance in this unique patient population. C1 [Graf, Erin H.; Mexas, Angela M.; Yu, Jianqing J.; Liszewski, Megan K.; O'Doherty, Una] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Shaheen, Farida] Univ Penn, Sch Med, Ctr AIDS Res, Philadelphia, PA 19104 USA. [Di Mascio, Michele] Biostat Res Branch, Bethesda, MD USA. [Migueles, Stephen A.; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Graf, EH (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM unao@mail.med.upenn.edu FU NIH [5K02AI078766-03, 1R21AI087461-01] FX This work was supported by NIH grants 5K02AI078766-03 and 1R21AI087461-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 67 Z9 67 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2011 VL 7 IS 2 AR e1001300 DI 10.1371/journal.ppat.1001300 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 726DE UT WOS:000287698200038 PM 21383972 ER PT J AU Nawaz, F Cicala, C Van Ryk, D Block, KE Jelicic, K McNally, JP Ogundare, O Pascuccio, M Patel, N Wei, DL Fauci, AS Arthos, J AF Nawaz, Fatima Cicala, Claudia Van Ryk, Donald Block, Katharine E. Jelicic, Katija McNally, Jonathan P. Ogundare, Olajumoke Pascuccio, Massimiliano Patel, Nikita Wei, Danlan Fauci, Anthony S. Arthos, James TI The Genotype of Early-Transmitting HIV gp120s Promotes alpha(4)beta(7) -Reactivity, Revealing alpha(4)beta(+)(7)/CD4(+) T cells As Key Targets in Mucosal Transmission SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; N-LINKED GLYCOSYLATION; HAMSTER OVARY CELLS; SUBTYPE-C; HETEROSEXUAL TRANSMISSION; INTEGRIN ALPHA(4)BETA(7); ANTIBODY NEUTRALIZATION; VARIABLE REGIONS; HOMING RECEPTOR; EARLY INFECTION AB Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4(+) T cells. Low-level viral replication occurs initially in mucosal CD4(+) T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary alpha(4)beta(+)(7)/CD4(+) T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin- alpha(4)beta(7). High-affinity for integrin alpha(4)beta(7), although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased alpha(4)beta(7) affinity is mediated by sequences encoded in gp120 V1/V2. alpha(4)beta(7)-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of alpha(4)beta(+)(7)/CD4(+) T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s derived from chronically replicating viruses. Understanding the structural features that characterize early-transmitting gp120s may aid in the design of an effective gp120-based subunit vaccine. C1 [Nawaz, Fatima; Cicala, Claudia; Van Ryk, Donald; Block, Katharine E.; Jelicic, Katija; McNally, Jonathan P.; Ogundare, Olajumoke; Pascuccio, Massimiliano; Patel, Nikita; Wei, Danlan; Fauci, Anthony S.; Arthos, James] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Nawaz, Fatima] NYU, Sch Med, Sackler Inst Grad Biomed Sci, New York, NY USA. RP Nawaz, F (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jarthos@niaid.nih.gov FU National Institutes of Health FX Support for this work was provided by the Intramural Research Program of 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 66 TC 85 Z9 86 U1 5 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2011 VL 7 IS 2 AR e1001301 DI 10.1371/journal.ppat.1001301 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 726DE UT WOS:000287698200039 PM 21383973 ER PT J AU Zhou, S Potts, EN Cuttitta, F Foster, WM Sunday, ME AF Zhou, Shutang Potts, Erin N. Cuttitta, Frank Foster, W. Michael Sunday, Mary E. TI Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma (Retracted article. See vol. 112, pg. E1813, 2015) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Retracted Publication DE gastrin-releasing peptide receptor phosphorylation; mouse models; bombesin ID BOMBESIN-LIKE PEPTIDE; PULMONARY NEUROENDOCRINE SYSTEM; INDUCED OXIDATIVE STRESS; CELL LUNG-CANCER; BRONCHOPULMONARY DYSPLASIA; PROTEIN-KINASE; GUINEA-PIG; SENSORY NEUROPEPTIDES; RECEPTOR SUBTYPES; AIRWAY DISEASE AB Gastrin-releasing peptide (GRP) is synthesized by pulmonary neuroendocrine cells in inflammatory lung diseases, such as bronchopulmonary dysplasia (BPD). Many BPD infants develop asthma, a serious disorder of intermittent airway obstruction. Despite extensive research, early mechanisms of asthma remain controversial. The incidence of asthma is growing, now affecting >300 million people worldwide. To test the hypothesis that GRP mediates asthma, we used two murine models: ozone exposure for air pollution-induced airway hyperreactivity (AHR), and ovalbumin (OVA)-induced allergic airway disease. BALB/c mice were given small molecule GRP blocking agent 77427, or GRP blocking antibody 2A11, before exposure to ozone or OVA challenge. In both models, GRP blockade abrogated AHR and bronchoalveolar lavage (BAL) macrophages and granulocytes, and decreased BAL cytokines implicated in asthma, including those typically derived from Th1 (e.g., IL-2, TNF alpha), Th2 (e g., IL-5, IL-13), Th17 (IL-17), macrophages (e. g., MCP-1, IL-1), and neutrophils (KC = IL-8). Dexamethasone generally had smaller effects on all parameters. Macrophages, T cells, and neutrophils express GRP receptor (GRPR). GRP blockade diminished serine phosphorylation of GRPR with ozone or OVA. Thus, GRP mediates AHR and airway inflammation in mice, suggesting that GRP blockade is promising as a broad-spectrum therapeutic approach to treat and/or prevent asthma in humans. C1 [Zhou, Shutang; Sunday, Mary E.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Potts, Erin N.; Foster, W. Michael; Sunday, Mary E.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Cuttitta, Frank] NCI, Angiogenesis Core Facil, Radiat Oncol Branch, NIH, Gaithersburg, MD 20877 USA. RP Zhou, S (reprint author), Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. EM shutang.zhou@duke.edu; mary.sunday@duke.edu RI Cuttitta, Frank/B-4758-2016 FU American Asthma Foundation; National Institutes of Health [AI081672, ES016347] FX We thank Dr. Robert P. Orange and Prof. Baruj Benacerraf for invaluable discussions. This work was supported by an Established Investigator Award (to M. E. S.) from the American Asthma Foundation. Mouse model development and airway physiology were supported by National Institutes of Health Grants AI081672 and ES016347 (to W.M.F.). NR 58 TC 17 Z9 18 U1 0 U2 7 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 FEB 1 PY 2011 VL 108 IS 5 BP 2100 EP 2105 DI 10.1073/pnas.1014792108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714JA UT WOS:000286804700066 PM 21252304 ER PT J AU Zhou, QF Lau, ST Wu, DW Shung, K AF Zhou, Qifa Lau, Sienting Wu, Dawei Shung, Kirk TI Piezoelectric films for high frequency ultrasonic transducers in biomedical applications SO PROGRESS IN MATERIALS SCIENCE LA English DT Review ID LEAD-ZIRCONATE-TITANATE; AEROSOL DEPOSITION METHOD; PZT THICK-FILMS; RESOLVED ACOUSTIC MICROSCOPY; MEDICAL IMAGING APPLICATIONS; ELECTRICAL-PROPERTIES; SINGLE-CRYSTALS; VINYLIDENE FLUORIDE; HYDROTHERMAL METHOD; DIELECTRIC-PROPERTIES AB Piezoelectric films have recently attracted considerable attention in the development of various sensor and actuator devices such as nonvolatile memories, tunable microwave circuits and ultrasound transducers. In this paper, an overview of the state of art in piezoelectric films for high frequency transducer applications is presented. Firstly, the basic principles of piezoelectric materials and design considerations for ultrasound transducers will be introduced. Following the review, the current status of the piezoelectric films and recent progress in the development of high frequency ultrasonic transducers will be discussed. Then details for preparation and structure of the materials derived from piezoelectric thick film technologies will be described. Both chemical and physical methods are included in the discussion, namely, the sol-gel approach, aerosol technology and hydrothermal method. The electric and piezoelectric properties of the piezoelectric films, which are very important for transducer applications, such as permittivity and electromechanical coupling factor, are also addressed. Finally, the recent developments in the high frequency transducers and arrays with piezoelectric ZnO and PZT thick film using MEMS technology are presented. In addition, current problems and further direction of the piezoelectric films for very high frequency ultrasound application (up to GHz) are also discussed. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Zhou, Qifa] Univ So Calif, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. RP Zhou, QF (reprint author), Univ So Calif, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu RI Lau, Sien-Ting/B-6091-2013; wu, dawei/D-3158-2014 FU NIH [P41-EB2182, 1R43CA110214-01, 1R43 RR014127-01A1] FX We would like to acknowledge Dr. B.P. Zhu, Dr. C.G. Liu, Dr. F.T. Diuth, Dr. G.H. Feng, Dr. J. Cannata, Dr. C. Hu. Dr. M. Ishikawa, D.Y. Huang, Dr. J. Lee, Ms. A. Jakob, Mr. J. William, Mr. L Xiang, Mr. R. Chen and Mr. H. Chabok. Without their significant contributions, the overview cannot be finished. Special thanks are extended to Prof. Susan Trolier-McKinstry at Penn State University, Prof. E.S. Kim at USC MEMS group, Prof. Takamuta at Toin University of Yokohama in Japan, Dr. J.H. Ryu at Korea Institute of Materials Science (KIMS), Prof. W. Ren at Xi'an Jian Tong University in China. This work is financially supported by NIH P41-EB2182, 1R43CA110214-01 and 1R43 RR014127-01A1. NR 151 TC 74 Z9 75 U1 9 U2 133 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6425 J9 PROG MATER SCI JI Prog. Mater. Sci. PD FEB PY 2011 VL 56 IS 2 BP 139 EP 174 DI 10.1016/j.pmatsci.2010.09.001 PG 36 WC Materials Science, Multidisciplinary SC Materials Science GA 692BJ UT WOS:000285126200002 PM 21720451 ER PT J AU Clore, GM AF Clore, G. Marius TI Exploring sparsely populated states of macromolecules by diamagnetic and paramagnetic NMR relaxation SO PROTEIN SCIENCE LA English DT Review DE high energy states; paramagnetic NMR; relaxation dispersion; paramagnetic relaxation enhancement; transient species ID PROTEIN-PROTEIN ASSOCIATION; CYTOCHROME-C PEROXIDASE; TRANSIENT ENCOUNTER COMPLEXES; MALTODEXTRIN-BINDING-PROTEIN; NUCLEAR-MAGNETIC-RESONANCE; DIHYDROFOLATE-REDUCTASE CATALYSIS; GLOBAL FOLD DETERMINATION; INVISIBLE EXCITED-STATES; SITE-DIRECTED SPIN; DNA COGNATE SITES AB Sparsely populated states of macromolecules, characterized by short lifetimes and high free-energies relative to the predominant ground state, often play a key role in many biological, chemical, and biophysical processes. In this review, we briefly summarize various new developments in NMR spectroscopy that permit these heretofore invisible, sparsely populated states to be detected, characterized, and in some instances visualized. Relaxation dispersion spectroscopy yields detailed kinetic information on processes involving species characterized by distinct chemical shifts with lifetimes in the similar to 50 mu s-10 ms range and populations as low as 0.5%. In the fast exchange regime (time scale less than similar to 250-500 mu s), the footprint of sparsely populated states can be observed on paramagnetic relaxation enhancement profiles measured on the resonances of the major species, thereby yielding structural information that is directly related to paramagnetic center-nuclei distances from which it is possible, under suitable circumstances, to compute a structure or ensemble of structures for the minor species. Finally, differential transverse relaxation measurements can be used to detect lifetime broadening effects that directly reflect the unidirectional rates for the conversion of NMR-visible into high-molecular weight NMR-invisible species. Examples of these various approaches are presented. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU NIDDK, NIH; Office of the Director of the NIH FX Grant sponsors: The intramural program of the NIDDK, NIH; The Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH NR 94 TC 38 Z9 38 U1 1 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2011 VL 20 IS 2 BP 229 EP 246 DI 10.1002/pro.576 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716IW UT WOS:000286963300001 PM 21280116 ER PT J AU Ell, K Xie, B Kapetanovic, S Quinn, DI Lee, PJ Wells, A Chou, CP AF Ell, Kathleen Xie, Bin Kapetanovic, Suad Quinn, David I. Lee, Pey-Jiuan Wells, Anjanette Chou, Chih-Ping TI One-Year Follow-Up of Collaborative Depression Care for Low-Income, Predominantly Hispanic Patients With Cancer SO PSYCHIATRIC SERVICES LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; HEALTH QUESTIONNAIRE; BREAST-CANCER; FUNCTIONAL ASSESSMENT; MAJOR DEPRESSION; SERVICE USE; PRIME-MD; SURVIVORS; PHQ-9 AB Objective: This study assessed longer-term outcomes of low-income patients with cancer (predominantly female and Hispanic) after treatment in a collaborative model of depression care or in enhanced usual care. Methods: The randomized controlled trial, conducted in safety-net oncology clinics, recruited 472 patients with major depression symptoms. Patients randomly assigned to a 12-month intervention (a depression care manager and psychiatrist provided problem-solving therapy, antidepressants, and symptom monitoring and relapse prevention) or enhanced usual care (control group) were interviewed at 18 and 24 months after enrollment. Results: At 24 months, 46% of patients in the intervention group and 32% in the control group had a >= 50% decrease in depression score over baseline (odds ratio=2.09, 95% confidence interval=1.13-3.86; p=.02); intervention patients had significantly better social (p=.03) and functional (p=.01) well-being. Treatment receipt among intervention patients declined (72%, 21%, and 18% at 12, 18, and 24 months, respectively); few control group patients reported treatment receipt (10%, 6%, and 13%, respectively). Significant differences in receipt of counseling or antidepressants disappeared at 24 months. Depression recurrence was similar between groups (intervention, 36%; control, 39%). Among patients with depression recurrence, intervention patients were more likely to receive treatment after 12 months (34% versus 10%; p=.03). At 24 months, attrition (262 patients, 56%) did not vary by group; 22% were deceased, 20% declined further participation, and 14% could not be located. Conclusions: Collaborative care reduced depression symptoms and enhanced quality of life; however, results call for ongoing depression symptom monitoring and treatment for low-income cancer survivors. (Psychiatric Services 62:162-170, 2011) C1 [Ell, Kathleen; Lee, Pey-Jiuan] Univ So Calif, Sch Social Work, Los Angeles, CA 90089 USA. [Xie, Bin] Claremont Grad Univ, Sch Community & Global Hlth, San Dimas, CA USA. [Kapetanovic, Suad] NIMH, Bethesda, MD 20892 USA. [Quinn, David I.; Chou, Chih-Ping] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA. [Wells, Anjanette] Washington Univ, George Warren Brown Sch Social Work, St Louis, MO 63130 USA. RP Ell, K (reprint author), Univ So Calif, Sch Social Work, 669 W 34th St, Los Angeles, CA 90089 USA. EM ell@usc.edu RI Quinn, David/F-4343-2015 OI Quinn, David/0000-0002-1411-0417 FU National Cancer Institute [R01-CA105269] FX This study was funded by grant R01-CA105269 from the National Cancer Institute. The views expressed are those of the authors and do not necessarily represent the views of the National Institutes of Health or the federal government. NR 65 TC 34 Z9 34 U1 2 U2 10 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD FEB PY 2011 VL 62 IS 2 BP 162 EP 170 DI 10.1176/appi.ps.62.2.162 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 714KW UT WOS:000286809500009 PM 21285094 ER PT J AU Reimold, M Knobel, A Rapp, MA Batra, A Wiedemann, K Strohle, A Zimmer, A Schonknecht, P Smolka, MN Weinberger, DR Goldman, D Machulla, HJ Bares, R Heinz, A AF Reimold, Matthias Knobel, Astrid Rapp, Michael A. Batra, Anil Wiedemann, Klaus Stroehle, Andreas Zimmer, Anke Schoenknecht, Peter Smolka, Michael N. Weinberger, Daniel R. Goldman, David Machulla, Hans-Juergen Bares, Roland Heinz, Andreas TI Central serotonin transporter levels are associated with stress hormone response and anxiety SO PSYCHOPHARMACOLOGY LA English DT Article DE Stress hormones; Serotonin transporter; Negative mood states; PET; Dex-CRH-Test ID POSITRON-EMISSION-TOMOGRAPHY; OBSESSIVE-COMPULSIVE DISORDER; MAJOR DEPRESSIVE DISORDER; BIPOLAR DISORDER; MESSENGER-RNA; SEX-DIFFERENCES; HUMAN BRAIN; AVAILABILITY; BINDING; CORTISOL AB Negative mood states are characterized by both stress hormone dysregulation and serotonergic dysfunction, reflected by altered thalamic serotonin transporter (5-HTT) levels. However, so far, no study examined the individual association between cortisol response and cerebral in vivo 5-HTT levels in patients suffering from negative mood states. The objective of this cross-sectional study was to assess the interrelation of cortisol response, thalamic 5-HTT levels, and anxiety in healthy subjects and two previously published samples of patients with unipolar major depression (UMD) and obsessive-compulsive disorder (OCD), controlling for age, gender, 5-HTT genotype, smoking, and seasonality. Regional 5-HTT levels and cortisol response to dexamethasone-corticotropin (Dex-CRH) challenge were assessed in consecutive samples of medication-free patients suffering from UMD (N = 10) and OCD (N = 10), and 20 healthy volunteers. The intervention used was combined Dex-CRH test and [(11)C]DASB positron emission tomography. The main outcome measures were: 5-HTT binding potential (BP(ND)) in a predefined thalamic ROI, cortisol response defined as the maximum cortisol increase in the combined Dex-CRH-test, and state of anxiety from the state-trait-anxiety inventory. Reduced thalamic 5-HTT BP(ND) was associated with increased cortisol response (r = -0.35, p < 0.05; in patients: r = -0.53, p < 0.01) and with increased state anxiety (r = -0.46, p < 0.01), surviving correction for age, gender, 5-HTT genotype, smoking, and seasonality (p < 0.05). The 5-HTT genotype, on the contrary, was not significantly associated with cortisol response (p = 0.19) or negative mood (p = 0.23). The association between stress hormone response, thalamic 5-HTT levels, and anxiety in patients suffering from negative mood states suggests an interaction between two major mechanisms implicated in negative mood states in humans. C1 [Knobel, Astrid; Rapp, Michael A.; Stroehle, Andreas; Heinz, Andreas] Charite Campus Mitte, Dept Psychiat & Psychotherapy, D-10117 Berlin, Germany. [Reimold, Matthias; Machulla, Hans-Juergen; Bares, Roland] Univ Tubingen, Dept Nucl Med, PET Ctr, Tubingen, Germany. [Batra, Anil] Univ Tubingen Hosp, Dept Psychiat & Psychotherapy, Tubingen, Germany. [Wiedemann, Klaus] Univ Hamburg, Dept Psychiat & Psychotherapy, Hamburg, Germany. [Zimmer, Anke] Univ Heidelberg, Dept Addict Res, ZI Mannheim, D-6800 Mannheim, Germany. [Schoenknecht, Peter] Univ Hosp Leipzig, Dept Psychiat, Leipzig, Germany. [Smolka, Michael N.] Tech Univ Dresden, Dept Psychiat & Psychotherapy, Sect Syst Neurosci, Dresden, Germany. [Weinberger, Daniel R.] NIMH, Bethesda, MD 20892 USA. [Goldman, David] NIAAA, Bethesda, MD USA. RP Heinz, A (reprint author), Charite Campus Mitte, Dept Psychiat & Psychotherapy, Charitepl 1, D-10117 Berlin, Germany. EM andreas.heinz@charite.de RI Smolka, Michael/B-4865-2011; Goldman, David/F-9772-2010 OI Smolka, Michael/0000-0001-5398-5569; Goldman, David/0000-0002-1724-5405 FU Deutsche Forschungsgemeinschaft [He 2597/7-3, Sm 80/2-2, Re 1472/6-2]; German Ministry for Education and Research [01GS08159]; National Genome Research Network [NGFN 01GS08148] FX The study was supported by grants from the Deutsche Forschungsgemeinschaft (He 2597/7-3, Sm 80/2-2, and Re 1472/6-2) and supported in part by the German Ministry for Education and Research (01GS08159), and the National Genome Research Network (NGFN 01GS08148). We would like to thank Professors Florian Holsboer and Jeff Meyer for their helpful comments on an earlier version of this manuscript. NR 56 TC 27 Z9 27 U1 4 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2011 VL 213 IS 2-3 BP 563 EP 572 DI 10.1007/s00213-010-1903-y PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 716AT UT WOS:000286938000029 PM 20585760 ER PT J AU Koffarnus, MN Katz, JL AF Koffarnus, Mikhail N. Katz, Jonathan L. TI Response requirement and increases in accuracy produced by stimulant drugs in a 5-choice serial reaction-time task in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE 5-Choice serial reaction time task; Sustained attention; Attention deficit hyperactivity disorder; Fixed ratio; Psychostimulants; Rats ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; FUNCTIONAL NEUROCHEMISTRY; SUSTAINED ATTENTION; ANIMAL-MODELS; NICOTINE; METHYLPHENIDATE; AMPHETAMINE; IMPULSIVITY; ATOMOXETINE AB Rationale Increased signal-detection accuracy on the 5-choice serial reaction time (5-CSRT) task has been shown with drugs that are useful clinically in treating attention deficit hyperactivity disorder (ADHD), but these increases are often small and/or unreliable. By reducing the reinforcer frequency, it may be possible to increase the sensitivity of this task to pharmacologically induced improvements in accuracy. Methods Rats were trained to respond on the 5-CSRT task on a fixed ratio (FR) 1, FR 3, or FR 10 schedule of reinforcement. Drugs that were and were not expected to enhance performance were then administered before experimental sessions. Results Significant increases in accuracy of signal detection were not typically obtained under the FR 1 schedule with any drug. However, d-amphetamine, methylphenidate, and nicotine typically increased accuracy under the FR 3 and FR 10 schedules. Conclusions Increasing the FR requirement in the 5-CSRT task increases the likelihood of a positive result with clinically effective drugs, and may more closely resemble conditions in children with attention deficits. C1 [Koffarnus, Mikhail N.] Johns Hopkins Univ Sch Med, Dept Psychiat, Baltimore, MD 21224 USA. [Katz, Jonathan L.] Natl Inst Drug Abuse, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Koffarnus, MN (reprint author), Johns Hopkins Univ Sch Med, Dept Psychiat, 5200 Eastern Ave,Suite 142W, Baltimore, MD 21224 USA. EM mkoffar1@jhmi.edu OI Katz, Jonathan/0000-0002-1068-1159 FU National Institute on Drug Abuse FX The authors would like to express their gratitude to Bettye Campbell and Dawn French for their expert technical assistance. This research was supported by the National Institute on Drug Abuse Intramural Research Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. NR 28 TC 7 Z9 7 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2011 VL 213 IS 4 BP 723 EP 733 DI 10.1007/s00213-010-2027-0 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 726YV UT WOS:000287764500007 PM 20924752 ER PT J AU Yang, W AF Yang, Wei TI Nucleases: diversity of structure, function and mechanism SO QUARTERLY REVIEWS OF BIOPHYSICS LA English DT Review ID SINGLE-STRANDED-DNA; SITE-SPECIFIC RECOMBINATION; GAMMA-DELTA-RESOLVASE; AICARDI-GOUTIERES-SYNDROME; PANCREATIC DEOXYRIBONUCLEASE-I; HOLLIDAY JUNCTION RESOLVASE; NUCLEOTIDE EXCISION-REPAIR; METALLO-BETA-LACTAMASE; X-RAY-STRUCTURE; STRUCTURE-SPECIFIC ENDONUCLEASE AB Nucleases cleave the phosphodiester bonds of nucleic acids and may be endo or exo, DNase or RNase, topoisomerases, recombinases, ribozymes, or RNA splicing enzymes. In this review, 1 survey nuclease activities with known structures and catalytic machinery and classify them by reaction mechanism and metal-ion dependence and by their biological function ranging from DNA replication, recombination, repair, RNA maturation, processing, interference, to defense, nutrient regeneration or cell death. Several general principles emerge from this analysis. There is little correlation between catalytic mechanism and biological function. A single catalytic mechanism can be adapted in a variety of reactions and biological pathways. Conversely, a single biological process can often be accomplished by multiple tertiary and quaternary folds and by more than one catalytic mechanism. Two-metal-ion-dependent nucleases comprise the largest number of different tertiary folds and mediate the most diverse set of biological functions. Metal-ion-dependent cleavage is exclusively associated with exonucleases producing mononucleotides and endonucleases that cleave double- or single-stranded substrates in helical and base-stacked conformations. All metal-ion-independent RNases generate 2',3'-cyclic phosphate products, and all metal-ion-independent DNases form phospho-protein intermediates. I also find several previously unnoted relationships between different nucleases and shared catalytic configurations. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, 9000 Rockville Pike,Bldg 5,Rm B1-03, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU NIH, NIDDK FX W.Y. is supported by NIH, NIDDK intramural research fund. The author thanks Dr C. Biertuempfel for initially collecting nucleases deposited with PDB database, and Drs R. Craigie and D. Leahy for reading and editing the manuscript. NR 471 TC 116 Z9 118 U1 6 U2 98 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-5835 EI 1469-8994 J9 Q REV BIOPHYS JI Q. Rev. Biophys. PD FEB PY 2011 VL 44 IS 1 BP 1 EP 93 DI 10.1017/S0033583510000181 PG 93 WC Biophysics SC Biophysics GA 721GN UT WOS:000287341700001 PM 20854710 ER PT J AU Dickey, JS Zemp, FJ Altamirano, A Sedelnikova, OA Bonner, WM Kovalchuk, O AF Dickey, Jennifer S. Zemp, Franz J. Altamirano, Alvin Sedelnikova, Olga A. Bonner, William M. Kovalchuk, Olga TI H2AX PHOSPHORYLATION IN RESPONSE TO DNA DOUBLE-STRAND BREAK FORMATION DURING BYSTANDER SIGNALLING: EFFECT OF MICRORNA KNOCKDOWN SO RADIATION PROTECTION DOSIMETRY LA English DT Article; Proceedings Paper CT 15th International Symposium on Microdosimetry CY OCT 25-30, 2009 CL Verona, ITALY SP INFN Lab Nazl Legnaro, NASA Johnson Space Ctr, CERN, Univ Oxford, Gray Inst Radiat Oncol & Biol ID RADIATION-INDUCED BYSTANDER; INDUCED GENOMIC INSTABILITY; PRIMARY HUMAN FIBROBLASTS; IONIZING-RADIATION; IN-VIVO; INTERCELLULAR COMMUNICATION; EPIGENETIC EFFECTORS; HISTONE H2AX; EXPOSURE; CELLS AB Upon DNA double-strand break (DSB) formation, hundreds of H2AX molecules in the chromatin flanking the break site are phosphorylated on serine residue 139, termed gamma-H2AX, so that virtually every DSB site in a nucleus can be visualised within 10 min of its formation using an antibody to gamma-H2AX. One application of this sensitive assay is to examine the induction of DNA double-strand damage in subtle non-targeted cellular effects such as the bystander effect. Here whether microRNA (miRNA) serve as a primary signalling mechanism for bystander effect propagation by comparing matched human colon carcinoma cell lines with wild-type or depleted levels of mature miRNAs was investigated. No major differences were found in the levels of induced gamma-H2AX foci in the tested cell lines, indicating that though miRNAs play a role in bystander effect manifestation, they appear not to be the primary bystander signalling molecules in the formation of bystander effect-induced DSBs. C1 [Dickey, Jennifer S.; Sedelnikova, Olga A.; Bonner, William M.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zemp, Franz J.; Altamirano, Alvin; Kovalchuk, Olga] Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada. RP Bonner, WM (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bonnerw@mail.nih.gov FU Intramural NIH HHS NR 28 TC 16 Z9 18 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD FEB PY 2011 VL 143 IS 2-4 BP 264 EP 269 DI 10.1093/rpd/ncq470 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 730GR UT WOS:000288022300026 PM 21183548 ER PT J AU Miglioretti, DL Walker, R Weaver, DL Buist, DSM Taplin, SH Carney, PA Rosenberg, RD Dignan, MB Zhang, Z White, E AF Miglioretti, Diana L. Walker, Rod Weaver, Donald L. Buist, Diana S. M. Taplin, Stephen H. Carney, Patricia A. Rosenberg, Robert D. Dignan, Mark B. Zhang, Zhuo (Tracy) White, Emily TI Accuracy of Screening Mammography Varies by Week of Menstrual Cycle SO RADIOLOGY LA English DT Article ID SERVICES TASK-FORCE; CONTRAST-MEDIUM ENHANCEMENT; AGED 40-49 YEARS; BREAST DENSITY; UNITED-STATES; DATA SYSTEM; CANCER; PHASE; METAANALYSIS; VARIABILITY AB Purpose: To investigate sensitivity, specificity, and cancer detection rate of screening mammography according to week of menstrual cycle among premenopausal women. Materials and Methods: In this institutional review board-approved HIPAA-compliant study, sensitivity, specificity, and cancer detection rate of 387 218 screening mammograms linked to 1283 breast cancers in premenopausal women according to week of menstrual cycle were studied by using prospectively collected information from the Breast Cancer Surveillance Consortium. Logistic regression analysis was used to test for differences in mammography performance according to week of menstrual cycle, adjusting for age and registry. Results: Overall, screening mammography performance did not differ according to week of menstrual cycle. However, when analyses were subdivided according to prior mammography, different patterns emerged. For the 66.6% of women who had undergone regular screening (mammography had been performed within the past 2 years), sensitivity was higher in week 1 (79.5%) than in subsequent weeks (week 2, 70.3%; week 3, 67.4%; week 4, 73.0%; P = .041). In the 17.8% of women who underwent mammography for the first time in this study, sensitivity tended to be lower during the follicular phase (week 1, 72.1%; week 2, 80.4%; week 3, 84.6%; week 4, 93.8%; P = .051). Sensitivity did not vary significantly by week in menstrual cycle in women who had undergone mammography more than 3 years earlier. There were no clinically meaningful differences in specificity or cancer detection rate. Conclusion: Premenopausal women who undergo regular screening may benefit from higher sensitivity of mammography if they schedule screening mammography during the 1st week of their menstrual cycle. (C)RSNA, 2010 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100974/-/DC1 C1 [Miglioretti, Diana L.; Walker, Rod; Buist, Diana S. M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Miglioretti, Diana L.; Zhang, Zhuo (Tracy)] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Buist, Diana S. M.; White, Emily] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Miglioretti, Diana L.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Buist, Diana S. M.; White, Emily] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Taplin, Stephen H.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Rosenberg, Robert D.] Univ New Mexico, Dept Radiol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Dignan, Mark B.] Univ Kentucky, Dept Internal Med, Lexington, KY USA. RP Miglioretti, DL (reprint author), Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM miglioretti.d@ghc.org FU National Institutes of Health [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040]; National Cancer Institute (NCI); American Cancer Society; AMC Cancer Research Center; National Institutes of Health/NCI FX This research was supported by the National Institutes of Health (grants U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040).; D.L.M. Financial activities related to the present article: institution received a grant from National Cancer Institute (NCI). Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. R.W. Financial activities related to the present article: institution received a grant from NCI. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. D.L.W. Financial activities related to the present article: institution received a grant from NCI; consultant for and received reimbursement for attending meetings from Group Health. Financial activities not related to the present article: institution received a grant or has a grant pending from NCI. Other relationships: none to disclose. D.S.M.B. Financial activities related to the present article: institution received a grant and support for travel to meetings for the study or for other purposes from National Institutes of Health. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. S.H.T. No potential conflicts of interest to disclose. P.A.C. Financial activities related to the present article: institution received a grant from NCI. Financial activities not related to the present article: institution received a grant or has a grant pending from NCI. Other relationships: none to disclose. R.D.R. Financial activities related to the present article: institution received a grant from American Cancer Society and NCI; received support for travel to a meeting for the study or other purposes from American Cancer Society and NCI. Financial activities not related to the present article: institution received a grant or has a grant pending from NCI. Other relationships: none to disclose. M.B.D. Financial activities related to the present article: institution received a grant from AMC Cancer Research Center. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. Z.Z. No potential conflicts of interest to disclose. E.W. Financial activities related to the present article: institution received Group Health subcontract from National Institutes of Health/NCI grant; received Group Health consulting fee from National Institutes of Health/NCI grant. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. NR 49 TC 6 Z9 6 U1 2 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2011 VL 258 IS 2 BP 372 EP 379 DI 10.1148/radiol.10100974 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 712GH UT WOS:000286653700005 PM 21131584 ER PT J AU Turkbey, B Shah, VP Pang, YX Bernardo, M Xu, S Kruecker, J Locklin, J Baccala, AA Rastinehad, AR Merino, MJ Shih, JH Wood, BJ Pinto, PA Choyke, PL AF Turkbey, Baris Shah, Vijay P. Pang, Yuxi Bernardo, Marcelino Xu, Sheng Kruecker, Jochen Locklin, Julia Baccala, Angelo A., Jr. Rastinehad, Ardeshir R. Merino, Maria J. Shih, Joanna H. Wood, Bradford J. Pinto, Peter A. Choyke, Peter L. TI Is Apparent Diffusion Coefficient Associated with Clinical Risk Scores for Prostate Cancers that Are Visible on 3-T MR Images ? SO RADIOLOGY LA English DT Article ID RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; PERIPHERAL ZONE; GLEASON SCORE; WEIGHTED MRI; TUMOR VOLUME; ANTIGEN ERA; 3 T; LOCALIZATION; ARRAY AB Purpose: To investigate whether apparent diffusion coefficients (ADCs) derived from diffusion-weighted (DW) magnetic resonance (MR) imaging at 3 T correlate with the clinical risk of prostate cancer in patients with tumors that are visible on MR images, with MR imaging/transrectal ultrasonography (US) fusion-guided biopsy as a reference. Materials and Methods: Forty-eight consecutive patients (median age, 60 years; median serum prostate-specific antigen value, 6.3 ng/mL) who underwent DW imaging during 3-T MR imaging with an endorectal coil were included in this retrospective institutional review board-approved study, and informed consent was obtained from each patient. Patients underwent targeted MR imaging/transrectal US fusion-guided prostate biopsy. Mean ADCs of cancerous target tumors were correlated with Gleason and D'Amico clinical risk scores. The true risk group rate and predictive value of the mean ADC for classifying a tumor by its D'Amico clinical risk score was determined by using linear discriminant and receiver operating characteristic analyses. Results: A significant negative correlation was found between mean ADCs of tumors in the peripheral zone and their Gleason scores (P = .003; Spearman rho = -0.60) and D'Amico clinical risk scores (P < .0001; Spearman rho = -0.69). ADC was found to distinguish tumors in the peripheral zone with intermediate to high clinical risk from those with low clinical risk with a correct classification rate of 0.73. Conclusion: There is a significant negative correlation between ADCs and Gleason and D'Amico clinical risk scores. ADCs may therefore be useful in predicting the aggressiveness of prostate cancer. (C)RSNA, 2010 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100667/-/DC1 C1 [Turkbey, Baris; Shah, Vijay P.; Bernardo, Marcelino; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Locklin, Julia; Wood, Bradford J.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Locklin, Julia; Wood, Bradford J.] NCI, Dept Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Baccala, Angelo A., Jr.; Rastinehad, Ardeshir R.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Shah, Vijay P.; Bernardo, Marcelino] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Xu, Sheng; Kruecker, Jochen] Philips Res N Amer, New York, NY USA. [Pang, Yuxi] Philips Healthcare, Cleveland, OH USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B69F, Bethesda, MD 20892 USA. EM pchoyke@mail.nih.gov RI Shah, Vijay/D-4083-2014 OI Shah, Vijay/0000-0003-3856-156X FU Intramural NIH HHS [ZID BC011242-02] NR 43 TC 186 Z9 197 U1 1 U2 9 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2011 VL 258 IS 2 BP 488 EP 495 DI 10.1148/radiol.10100667 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 712GH UT WOS:000286653700018 PM 21177390 ER PT J AU Haseman, JK Strickland, J Allen, D Salicru, E Paris, M Tice, RR Stokes, WS AF Haseman, Joseph K. Strickland, Judy Allen, David Salicru, Eleni Paris, Michael Tice, Raymond R. Stokes, William S. TI Safety assessment of allergic contact dermatitis hazards: An analysis supporting reduced animal use for the murine local lymph node assay SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE Local lymph node assay; Skin sensitization; Alternative test method; Animal reduction; Sample size; OECD test guideline 429 ID ICCVAM EVALUATION; CLASSIFICATION AB The original Organisation for Economic Co-operation and Development Test Guideline 429 (OECD TG 429) for the murine local lymph node assay (LLNA) required five mice/group if mice were processed individually. We used data from 83 LLNA tests (275 treated groups) to determine the impact on the LLNA outcome of reducing the group size from five to four. From DPM measurements, we formed all possible four- and five-mice combinations for the treated and control groups. Stimulation index (SI) values from each four-mice combination were compared with those from five-mice combinations, and agreement (both SI <3 or both SI >= 3) determined. Average agreement between group sizes was 97.5% for the 275 treated groups. Compared test-by-test, 90% (75/83) of the tests had 100% agreement: agreement was 83% for the remaining eight tests. Disagreement was due primarily to variability in animal responses and closeness of the SI to three (positive response threshold) rather than to group size reduction. We conclude that using four rather than five mice per group would reduce animal use by 20% without adversely impacting LLNA performance. This analysis supported the recent update to OECD TG 429 allowing a minimum of four mice/group when each mouse is processed individually. Published by Elsevier Inc. C1 [Haseman, Joseph K.] JK Haseman Consulting, Raleigh, NC 27614 USA. [Strickland, Judy; Allen, David; Salicru, Eleni; Paris, Michael] Integrated Lab Syst Inc, Res Triangle Pk, NC 27709 USA. [Tice, Raymond R.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Biomol Screening Branch, Res Triangle Pk, NC 27709 USA. [Stokes, William S.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Interagcy Ctr Evaluat Alternat Toxicol Methods, Res Triangle Pk, NC 27709 USA. RP Stokes, WS (reprint author), 530 Davis Dr,POB 12233,K2-16, Res Triangle Pk, NC 27709 USA. EM stokes@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences; NIEHS [N01-ES 35504] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. ILS staff are supported by NIEHS contract N01-ES 35504. The views expressed in this manuscript do not necessarily represent the official position of any US Federal agency. NR 14 TC 2 Z9 3 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD FEB PY 2011 VL 59 IS 1 BP 191 EP 196 DI 10.1016/j.yrtph.2010.10.004 PG 6 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 727BM UT WOS:000287772300020 PM 20974208 ER PT J AU Martinez-Hernandez, MG Baiza-Gutman, LA Castillo-Trapala, A Armant, DR AF Martinez-Hernandez, M. G. Baiza-Gutman, L. A. Castillo-Trapala, A. Armant, D. Randall TI Regulation of proteinases during mouse peri-implantation development: urokinase-type plasminogen activator expression and cross talk with matrix metalloproteinase 9 SO REPRODUCTION LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; EXTRACELLULAR-MATRIX DEGRADATION; CELL-SURFACE RECEPTOR; IV COLLAGENASE; EMBRYO IMPLANTATION; BASEMENT-MEMBRANE; TROPHOBLAST CELLS; ENDOTHELIAL-CELLS; TISSUE-TYPE; IN-VITRO AB Trophoblast cells express urokinase-type plasminogen activator (PLAU) and may depend on its activity for endometrial invasion and tissue remodeling during peri-implantation development. However, the developmental regulation, tissue distribution, and function of PLAU are not completely understood. In this study, the expression of PLAU and its regulation by extracellular matrix proteins was examined by RT-PCR, immunocytochemistry, and plasminogen-casein zymography in cultured mouse embryos. There was a progressive increase in Plau mRNA expression in blastocysts cultured on gestation days 4-8. Tissue-type plasminogen activator (55 kDa) and PLAU (a triplet of 40, 37, and 31 kDa) were present in conditioned medium and embryo lysates, and were adsorbed to the culture plate surface. The temporal expression pattern of PLAU, according to semi-quantitative gel zymography, was similar in non-adhering embryos and embryos cultured on fibronectin, laminin, or type IV collagen, although type IV collagen and laminin upregulated Plau mRNA expression. Immunofluorescence revealed PLAU on the surface of the mural trophectoderm and in non-spreading giant trophoblast cells. Exogenous human plasminogen was transformed to plasmin by cultured embryos and activated endogenous matrix metalloproteinase 9 (MMP9). Indeed, the developmental expression profile of MMP9 was similar to that of PLAU. Our data suggest that the intrinsic developmental program predominantly regulates PLAU expression during implantation, and that PLAU could be responsible for activation of MMP9, leading to localized matrix proteolysis as trophoblast invasion commences. Reproduction (2011) 141 227-239 C1 [Martinez-Hernandez, M. G.; Baiza-Gutman, L. A.; Armant, D. Randall] Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Martinez-Hernandez, M. G.; Baiza-Gutman, L. A.; Armant, D. Randall] Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Martinez-Hernandez, M. G.; Baiza-Gutman, L. A.; Castillo-Trapala, A.] Univ Nacl Autonoma Mexico, FES Iztacala, UMF, Lab Biol Desarrollo, Tlalnepantla 54090, Estado Mexico, Mexico. [Armant, D. Randall] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, Bethesda, MD 20892 USA. RP Armant, DR (reprint author), Wayne State Univ, Sch Med, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, 275 E Hancock Ave, Detroit, MI 48201 USA. EM d.armant@wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; DHHS; NIH [HD36764, HD045966, AA12057, ES06639, CA22453]; PAPIIT-DGAPA-UNAM [IN 230611]; PAPCA; FES-Iztacala FX Supported, in part, by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, NIH grants HD36764, HD045966, and AA12057 to D R Armant and by PAPIIT-DGAPA-UNAM, grant IN 230611 and PAPCA 2006-2007, FES-Iztacala to L A Baiza-Gutman and M G Martinez-Hernandez. Confocal microscopy was supported by center grants ES06639 and CA22453 from the NIH. NR 91 TC 14 Z9 14 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD FEB PY 2011 VL 141 IS 2 BP 227 EP 239 DI 10.1530/REP-10-0334 PG 13 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 707GG UT WOS:000286273900009 PM 21075828 ER PT J AU Hatch, EE Troisi, R Wise, LA Titus-Ernstoff, L Hyer, M Palmer, JR Strohsnitter, WC Robboy, SJ Anderson, D Kaufman, R Adam, E Hoover, RN AF Hatch, Elizabeth E. Troisi, Rebecca Wise, Lauren A. Titus-Ernstoff, Linda Hyer, Marianne Palmer, Julie R. Strohsnitter, William C. Robboy, Stanley J. Anderson, Diane Kaufman, Raymond Adam, Ervin Hoover, Robert N. TI Preterm birth, fetal growth, and age at menarche among women exposed prenatally to diethylstilbestrol (DES) SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Diethylstilbestrol; Early life factors; Birth weight; Small for gestational age; Gestational length; Menarche; Endocrine disruptors ID IN-UTERO; GESTATIONAL-AGE; PLACENTAL CLOCK; YOUNG-WOMEN; PREGNANCY; FEMALE; EXPOSURES; WEIGHT; RECALL; RISK AB Diethylstilbestrol (DES), a synthetic estrogen used in pregnancy during the 1950s and 1960s, provides a model for potential health effects of endocrine disrupting compounds in the environment. We evaluated prenatal exposure to DES, based on medical record review, in relation to gestational length, fetal growth, and age at menarche in 4429 exposed and 1427 unexposed daughters. DES exposure was associated with an increase in preterm birth (odds ratio (OR) = 2.97; 95% CI = 2.27, 3.87), and a higher risk of small for gestational age (SGA) (OR = 1.61; 95% CI = 1.31, 1.98). The association between DES exposure and early menarche was borderline, with stronger effects when early menarche was defined as <= 10 years (OR = 1.41 95% CI = 0.97, 2.03) than defined as <= 11 years (OR = 1.16; 95% CI = 0.97, 1.39). This study provides evidence that prenatal DES exposure was associated with fetal growth and gestational length, which may mediate associations between DES and health outcomes in later life. (c) 2010 Elsevier Inc. All rights reserved. C1 [Hatch, Elizabeth E.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Troisi, Rebecca; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wise, Lauren A.; Palmer, Julie R.] Boston Univ, Sch Publ Hlth, Slone Epidemiol Ctr, Boston, MA 02118 USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Titus-Ernstoff, Linda] Norris Cotton Canc Ctr, Lebanon, NH USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Pediat, Lebanon, NH USA. [Titus-Ernstoff, Linda] Hood Ctr Children & Families, Lebanon, NH USA. [Hyer, Marianne] Informat Management Serv Inc, Rockville, MD USA. [Strohsnitter, William C.] Tufts Med Ctr, Dept Obstet & Gynecol, Boston, MA USA. [Robboy, Stanley J.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Anderson, Diane] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Kaufman, Raymond] Methodist Hosp, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Adam, Ervin] Baylor Coll Med, Dept Virol & Epidemiol, Houston, TX 77030 USA. RP Hatch, EE (reprint author), Boston Univ, Sch Publ Hlth, Dept Epidemiol, 715 Albany St,Talbot 318 E, Boston, MA 02118 USA. EM eehatch@bu.edu OI Palmer, Julie/0000-0002-6534-335X; Hatch, Elizabeth/0000-0001-7901-3928; Wise, Lauren/0000-0003-2138-3752 FU National Cancer Institute [N01-CP-51010] FX This work was supported by the National Cancer Institute, N01-CP-51010. NR 45 TC 16 Z9 17 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD FEB PY 2011 VL 31 IS 2 BP 151 EP 157 DI 10.1016/j.reprotox.2010.11.006 PG 7 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 735LX UT WOS:000288417200005 PM 21130156 ER PT J AU Bloom, MS Louis, GMB Sundaram, R Kostyniak, PJ Jain, J AF Bloom, Michael S. Louis, Germaine M. Buck Sundaram, Rajeshwari Kostyniak, Paul J. Jain, Jinesh TI Associations between blood metals and fecundity among women residing in New York State SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Arsenic (As); Cadmium (Cd); Fecundity; Lead (Pb); Magnesium (Mg); Nickel (Ni); Selenium (Se); Zinc (Zn) ID IN-VITRO FERTILIZATION; TIME-TO-PREGNANCY; DRINKING-WATER; FOLLICULAR-FLUID; MENSTRUAL-CYCLE; LONG-TERM; ARSENIC EXPOSURE; LIFE-STYLE; MAGNESIUM; SERUM AB Trace exposures to metals may affect female reproductive health. To assess the relation between trace concentrations of blood metals and female fecundity, 99 non-pregnant women discontinuing contraception for the purpose of becoming pregnant were prospectively followed. Participants completed a baseline interview and daily diaries until pregnant, or up to 12 menstrual cycles at risk for pregnancy; home pregnancy test kits were used. For 80 women, whole blood specimens were analyzed for arsenic, cadmium, lead, magnesium, nickel, selenium and zinc using inductively coupled plasma mass spectrometry (ICP-MS). Time to pregnancy was estimated using Cox proportional hazards models for discrete time. Metal concentrations were generally within population reference intervals. Adjusted models suggest a 51.5% increase in the probability for pregnancy per 3.60 mu g/L increase in Mg (P=0.062), and a 27.7% decrease per 0.54 mu g/L increase in Zn (P=0.114). Findings indicate that Mg and Zn may impact female fecundity, but in varying directions. (c) 2010 Elsevier Inc. All rights reserved. C1 [Bloom, Michael S.] SUNY Albany, Dept Environm Hlth Sci, Sch Publ Hlth, Rensselaer, NY 12144 USA. [Louis, Germaine M. Buck; Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Kostyniak, Paul J.] SUNY Buffalo, Dept Biotech & Clin Lab Sci, Buffalo, NY 14260 USA. [Jain, Jinesh] Univ Notre Dame, Dept Civil Engn & Geol Sci, Notre Dame, IN 46556 USA. RP Bloom, MS (reprint author), SUNY Albany, Dept Environm Hlth Sci, Sch Publ Hlth, Rm 153,1 Univ Pl, Rensselaer, NY 12144 USA. EM mbloom@uamail.albany.edu OI Buck Louis, Germaine/0000-0002-1774-4490; Sundaram, Rajeshwari/0000-0002-6918-5002; Bloom, Michael/0000-0002-0028-5494 FU Great Lakes Protection Fund [RM791-3021]; Agency for Toxic Substances and Disease Registry [H751 ATH 298338]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported in part with funding from the Great Lakes Protection Fund (RM791-3021), the Agency for Toxic Substances and Disease Registry (H751 ATH 298338) and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 61 TC 16 Z9 16 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD FEB PY 2011 VL 31 IS 2 BP 158 EP 163 DI 10.1016/j.reprotox.2010.09.013 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 735LX UT WOS:000288417200006 PM 20933593 ER PT J AU Chen, K Chen, XY AF Chen, Kai Chen, Xiaoyuan TI Positron Emission Tomography Imaging of Cancer Biology: Current Status and Future Prospects SO SEMINARS IN ONCOLOGY LA English DT Review ID GROWTH-FACTOR RECEPTOR; INTEGRIN ALPHA(V)BETA(3) EXPRESSION; SQUAMOUS-CELL CARCINOMA; GLUCOSE METABOLIC-RATE; PROLIFERATION IN-VIVO; BREAST-CANCER; TUMOR HYPOXIA; RGD PEPTIDE; NEUROENDOCRINE TUMORS; CLINICAL-APPLICATIONS C1 [Chen, Kai] Univ So Calif, Keck Sch Med, Mol Imaging Ctr, Dept Radiol, Los Angeles, CA 90033 USA. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Chen, K (reprint author), Univ So Calif, Keck Sch Med, Mol Imaging Ctr, Dept Radiol, 2250 Alcazar St,CSC 103, Los Angeles, CA 90033 USA. EM chenkai@usc.edu; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering FX The authors would like to acknowledge the intramural research program at the National Institute of Biomedical Imaging and Bioengineering for financial support. NR 125 TC 47 Z9 48 U1 3 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 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2011 VL 38 IS 1 BP 70 EP 86 DI 10.1053/j.seminoncol.2010.11.005 PG 17 WC Oncology SC Oncology GA 730MW UT WOS:000288038400007 PM 21362517 ER PT J AU Gooding, JS Cooper, LG Blaine, AI Franck, LS Howse, JL Berns, SD AF Gooding, Judith S. Cooper, Liza G. Blaine, Arianna I. Franck, Linda S. Howse, Jennifer L. Berns, Scott D. TI Family Support and Family-Centered Care in the Neonatal Intensive Care Unit: Origins, Advances, Impact SO SEMINARS IN PERINATOLOGY LA English DT Review DE family-centered care; FCC; NICU; family support ID LOW-BIRTH-WEIGHT; INDIVIDUALIZED DEVELOPMENTAL CARE; TO-SKIN KANGAROO; LENGTH-OF-STAY; PREMATURE-INFANTS; PRETERM INFANTS; CONTROLLED-TRIAL; CHILD-ABUSE; PARENTS; NICU C1 [Gooding, Judith S.] March Dimes Fdn, NICU Initiat & Chapter Program Strategy, White Plains, NY 10605 USA. [Blaine, Arianna I.] NICHD, NIH, Bethesda, MD USA. [Franck, Linda S.] Univ Calif San Francisco, Dept Family Hlth Care Nursing, San Francisco, CA 94143 USA. [Berns, Scott D.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Cooper, Liza G.] March Dimes Fdn, NICU Family Support, White Plains, NY 10605 USA. [Berns, Scott D.] March Dimes Fdn, Chapter Programs, White Plains, NY 10605 USA. RP Gooding, JS (reprint author), March Dimes Fdn, NICU Initiat & Chapter Program Strategy, 1275 Mamaroneck Ave, White Plains, NY 10605 USA. EM JGooding@marchofdimes.com NR 82 TC 105 Z9 114 U1 3 U2 31 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 J9 SEMIN PERINATOL JI Semin. Perinatol. PD FEB PY 2011 VL 35 IS 1 BP 20 EP 28 DI 10.1053/j.semperi.2010.10.004 PG 9 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 718KZ UT WOS:000287121400004 PM 21255703 ER PT J AU Thoma, ME Gray, RH Kiwanuka, N Aluma, S Wang, MC Sewankambo, N Wawer, MJ AF Thoma, Marie E. Gray, Ronald H. Kiwanuka, Noah Aluma, Simon Wang, Mei-Cheng Sewankambo, Nelson Wawer, Maria J. TI The Short-term Variability of Bacterial Vaginosis Diagnosed by Nugent Gram Stain Criteria Among Sexually Active Women in Rakai, Uganda SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID VAGINAL FLORA; MENSTRUAL-CYCLE; PREGNANCY; THERAPY; BEHAVIORS; SMEARS; HEALTH AB Background: Studies evaluating clinical and behavioral factors related to short-term fluctuations in vaginal microbiota are limited. We sought to describe changes in vaginal microbiota evaluated by Gram stain and assess factors associated with progression to and resolution of bacterial vaginosis (BV) at weekly intervals. Methods: A cohort of 255 sexually experienced, postmenarcheal women provided self-collected vaginal swabs to assess vaginal microbiota by Nugent score criteria at weekly visits for up to 2 years contributing 16,757 sequential observations. Absolute differences in Nugent scores (0-10) and transition probabilities of vaginal microbiota states classified by Nugent score into normal (0-3), intermediate (4-6), and BV (7-10) between visits were estimated. Allowing each woman to serve as her own control, weekly time-varying factors associated with progression from normal microbiota to BV and resolution of BV to normal microbiota were estimated using conditional logistic regression. Results: The distribution of absolute difference in Nugent scores was fairly symmetric with a mode of 0 (no change) and a standard deviation of 2.64. Transition probabilities showed weekly persistence, was highest for normal (76.1%) and BV (73.6%) states; whereas, intermediate states had similar probabilities of progression (36.6%), resolution 36.0%), and persistence (27.4%). Weekly fluctuation between normal and BV states was associated with menstrual cycle phase, recency of sex, treatment for vaginal symptoms, pregnancy, and prior Nugent score. Conclusions: Weekly changes in vaginal microbiota were common in this population. Clinical and behavioral characteristics were associated with vaginal microbiota transitioning, which may be used to inform future studies and clinical management of BV. C1 [Thoma, Marie E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. [Kiwanuka, Noah] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Kiwanuka, Noah; Aluma, Simon] Rakai Hlth Sci Program, Rakai, Uganda. [Wang, Mei-Cheng] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Sewankambo, Nelson] Makerere Univ, Coll Hlth Sci, Kampala, Uganda. RP Thoma, ME (reprint author), NICHD, DESPR, NIH, 6100 Execut Blvd,Room 7B13E, Bethesda, MD 20892 USA. EM thomame@mail.nih.gov OI Sewankambo, Nelson/0000-0001-9362-053X FU National Institutes of Health (NIH) [T32AI050056]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH [R01AI47608]; NIH, National Institute for Allergy and Infectious Diseases (NIAID); Center for Disease Control and Prevention (CDC) [R36PS001104] FX Supported in part by the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH grant R01AI47608 (to M.J.W.); the Intramural Research and Training Award from the NIH, NICHD (to M. E. T.); the NIH, National Institute for Allergy and Infectious Diseases (NIAID), NIH grant T32AI050056 (to J.M.Z.), the Cooperative Agreement number R36PS001104 (to M.E.T.) from the Center for Disease Control and Prevention (CDC). NR 29 TC 17 Z9 17 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD FEB PY 2011 VL 38 IS 2 BP 111 EP 116 DI 10.1097/OLQ.0b013e3181f0bdd0 PG 6 WC Infectious Diseases SC Infectious Diseases GA 705YJ UT WOS:000286176400009 PM 20921931 ER PT J AU Ghosh, D Guha, R AF Ghosh, Debarchana Guha, Rajarshi TI Using a neural network for mining interpretable relationships of West Nile risk factors SO SOCIAL SCIENCE & MEDICINE LA English DT Article; Proceedings Paper CT 13th International Symposium on Medical Geography CY JUL, 2009 CL Hamilton, CANADA DE West Nile virus; Risk factors; Nonlinear; Neural network; Urban morphology; USA ID UNITED-STATES; VIRUS ACTIVITY; TRANSMISSION; DISEASE; EPIDEMIC; PATTERNS; MODEL; USA; CALIFORNIA; CULICIDAE AB The West Nile Virus (WNV) is an infectious disease spreading rapidly throughout the United States, causing illness among thousands of birds, animals, and humans. Yet, we only have a rudimentary understanding of how the mosquito-borne virus operates in complex avian human environmental systems. The four broad categories of risk factors underlying WNV incidences are: environmental (temperature, precipitation, wetlands), socioeconomic (housing age), built-environment (catch basins, ditches), and existing mosquito abatement policies. This research first built a model incorporating the non-linear relationship between WNV incidences and hypothesized risk factors and second, identified important factor(s) whose management would result in effective disease prevention and containment. The research was conducted in the Metropolitan area of Minnesota, which had experienced significant WNV outbreaks from 2002. Computational neural network (CNN) modeling was used to understand the occurrence of WNV infected dead birds because of their ability to capture complex relationships with higher accuracy than linear models. Further a detailed interpretation technique, based on weights and biases of the network, provided a means for extracting relationships between risk factors and disease occurrence. Five risk factors: proximity to bogs, lakes, temperature, housing age, and developed medium density land cover class, were selected by the model. The detailed interpretation indicated that temperature, age of houses, and developed medium density land cover were positively related, and distance to bogs and lakes were negatively related to the incidence of WNV. This paper provides both applied and methodological contributions to the field of health geography. The relationships between the risk factors and disease occurrence could contribute to vector control strategies such as targeted insecticide spraying near bogs and lakes, mosquito control treatments for older houses, and extensive mapping, inspection, and treatments of catch basins. The proposed interpretation technique expanded the role of CNN models in health sciences as both predictive and explanatory tools. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Ghosh, Debarchana] Kent State Univ, Dept Geog Kent State, Kent, OH 44242 USA. [Guha, Rajarshi] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Ghosh, D (reprint author), Kent State Univ, Dept Geog Kent State, 413 McGilvery Hall, Kent, OH 44242 USA. EM dghosh@kent.edu OI Guha, Rajarshi/0000-0001-7403-8819 NR 53 TC 6 Z9 6 U1 0 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD FEB PY 2011 VL 72 IS 3 SI SI BP 418 EP 429 DI 10.1016/j.socscimed.2010.09.014 PG 12 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 755FA UT WOS:000289911400013 PM 20950908 ER PT J AU Kuznetsov, SA Cherman, N Robey, PG AF Kuznetsov, Sergei A. Cherman, Natasha Robey, Pamela Gehron TI In Vivo Bone Formation by Progeny of Human Embryonic Stem Cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID MARROW STROMAL CELLS; TISSUE-ENGINEERED BONE; OSTEOGENIC DIFFERENTIATION; GENE-EXPRESSION; VITRO; CULTURE; TRANSPLANTATION; DEXAMETHASONE; FIBROBLASTS; COLLAGEN AB The derivation of osteogenic cells from human embryonic stem cells (hESCs) or from induced pluripotent stem cells for bone regeneration would be a welcome alternative to the use of adult stem cells. In an attempt to promote hESC osteogenic differentiation, cells of the HSF-6 line were cultured in differentiating conditions in vitro for prolonged periods of time ranging from 7 to 14.5 weeks, followed by in vivo transplantation into immunocompromised mice in conjunction with hydroxyapatite/tricalcium phosphate ceramic powder. Twelve different medium compositions were tested, along with a number of other variables in culture parameters. In differentiating conditions, HSF-6-derived cells demonstrated an array of diverse phenotypes reminiscent of multiple tissues, but after a few passages, acquired amore uniform, fibroblast-like morphology. Eight to 16 weeks post-transplantation, a group of transplants revealed the formation of histologically proven bone of human origin, including broad areas of multiple intertwining trabeculae, which represents by far the most extensive in vivo bone formation by the hESC-derived cells described to date. Knockout-Dulbecco's modified Eagle's medium-based media with fetal bovine serum, dexamethasone, and ascorbate promoted more frequent bone formation, while media based on alpha-modified minimum essential medium promoted teratoma formation in 12- to 20-week-old transplants. Transcription levels of pluripotency-related (octamer binding protein 4, Nanog), osteogenesis-related (collagen type I, Runx2, alkaline phosphatase, and bone sialoprotein), and chondrogenesis-related (collagen types II and X, and aggrecan) genes were not predictive of either bone or teratoma formation. The most extensive bone was formed by the strains that, following 4 passages in monolayer conditions, were cultured for 23 to 25 extra days on the surface of hydroxyapatite/tricalcium phosphate particles, suggesting that coculturing of hESC-derived cells with osteo-conductive material may increase their osteogenic potential. While none of the conditions tested in this study, and elsewhere, ensured consistent bone formation by hESC-derived cells, our results may elucidate further directions toward the construction of bone on the basis of hESCs or an individual's own induced pluripotent stem cells. C1 [Kuznetsov, Sergei A.; Cherman, Natasha; Robey, Pamela Gehron] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kuznetsov, SA (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 228,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM skuznets@mail.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU National Institute of Dental and Craniofacial Research, NIH, DHHS FX The authors are deeply indebted to Dr. Barbara Mallon and Dr. Ron McKay (NIH Stem Cell Unit, NINDS, NIH) for guiding us through the treacherous techniques of hESC cultivation, and to Dr. Marian F. Young and Dr. Agnes D. Berendsen (CSDB, NIDCR, NIH) for their help with Q-RT-PCR. We are grateful to Dr. Emmanuel Olivier (Einstein Center for Human Embryonic Stem Cell Research, Albert Einstein College of Medicine, Bronx, NY) for his advice and valuable suggestions; to Ms. Vicky Fellowes (Cell Processing Section, Department of Transfusion Medicine, NIH) for hPL; to Zimmer for its gift of HA/TCP particles; and to Ms. Joanne Shi and Ms. Li Li (CSDB, NIDCR, NIH) for excellent technical assistance. This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, DHHS. NR 77 TC 38 Z9 38 U1 0 U2 18 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD FEB PY 2011 VL 20 IS 2 BP 269 EP 287 DI 10.1089/scd.2009.0501 PG 19 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 709RV UT WOS:000286460000009 PM 20590404 ER PT J AU Rajan, A Giaccone, G AF Rajan, Arun Giaccone, Giuseppe TI Chemotherapy for Thymic Tumors: Induction, Consolidation, Palliation SO THORACIC SURGERY CLINICS LA English DT Article DE Thymoma; Thymic carcinoma; Chemotherapy ID PHASE-II TRIAL; SINGLE-INSTITUTION EXPERIENCE; DOSE-DENSE CHEMOTHERAPY; INVASIVE THYMOMA; MULTIMODALITY TREATMENT; METASTATIC THYMOMA; RADIATION-THERAPY; INTERGROUP TRIAL; MULTIDISCIPLINARY APPROACH; NEOADJUVANT CHEMOTHERAPY AB Although thymoma and thymic carcinoma are rare malignancies, they constitute a large proportion of tumors of the anterior mediastinum. Surgery forms the mainstay of therapy; however, thymic malignancies are sensitive to chemotherapy and radiation therapy also. Systemic chemotherapy is primarily used for treatment of metastatic or recurrent disease. Chemotherapy is also used as a component of multimodality treatment in the neoadjuvant setting with the aim of increasing the chances of achieving a complete surgical resection. In this article we outline various clinical trials that have been performed to evaluate the role of chemotherapy in the treatment of thymic malignancies. C1 [Rajan, Arun; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 31 TC 10 Z9 10 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1547-4127 J9 THORAC SURG CLIN JI Thorac. Surg. Clin. PD FEB PY 2011 VL 21 IS 1 BP 107 EP + DI 10.1016/j.thorsurg.2010.08.003 PG 9 WC Respiratory System; Surgery SC Respiratory System; Surgery GA 045AB UT WOS:000311665200012 PM 21070992 ER PT J AU Aschebrook-Kilfoy, B Ward, MH Sabra, MM Devesa, SS AF Aschebrook-Kilfoy, Briseis Ward, Mary H. Sabra, Mona M. Devesa, Susan S. TI Thyroid Cancer Incidence Patterns in the United States by Histologic Type, 1992-2006 SO THYROID LA English DT Article ID DISEASE RATES; TRENDS; PAPILLARY; GENDER; WOMEN; CARE AB Background: The increasing incidence of thyroid cancer in the United States is well documented. In this study, we assessed the incidence patterns by histologic type according to demographic and tumor characteristics to further our understanding of these cancers. Methods: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for cases diagnosed during 1992-2006 to investigate patterns for the four major histologic types of thyroid cancer by gender, race/ethnicity, and age as well as registry, tumor stage, and size. Results: Among women, papillary thyroid cancer rates were highest among Asians (10.96 per 100,000 woman-years) and lowest among blacks (4.90 per 100,000 woman-years); follicular cancer rates did not vary substantially by race/ethnicity (p-values >0.05), medullary cancer rates were highest among Hispanics (0.21 per 100,000 woman-years) and whites (0.22 per 100,000 woman-years), and anaplastic rates were highest among Hispanics (0.17 per 100,000 woman-years). Among men, both papillary and follicular thyroid cancer rates were highest among whites (3.58 and 0.58 per 100,000 man-years, respectively), medullary cancer rates were highest among Hispanics (0.18 per 100,000 man-years), and anaplastic rates were highest among Asians (0.11 per 100,000 man-years). Racial/ethnic-specific rates did not vary notably across registries. In contrast to age-specific rates of papillary thyroid cancer that peaked in midlife (age 50), especially pronounced among women, rates for follicular, medullary, and anaplastic types continued to rise across virtually the entire age range, especially for anaplastic carcinomas. Female-to-male incidence rate ratios among whites decreased with age most steeply for the follicular type and least steeply for the medullary type; it was <1 until the very oldest ages for the anaplastic type. Conclusion: We conclude that the similar age-specific patterns and lack of geographical variation across the SEER racial/ethnic groups indicate that detection effects cannot completely explain the observed thyroid cancer incidence patterns as variation in the amount or quality of healthcare provided has been shown to vary by SEER racial/ethnic groups, gender, and age. We find that the variations in age-specific patterns by gender and across histologic types are intriguing and recommend that future etiologic investigation focus on exogenous and endogenous exposures that are experienced similarly by racial/ethnic groups, more strongly among women, and distinctively by age. C1 [Aschebrook-Kilfoy, Briseis; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Rockville, MD USA. [Sabra, Mona M.] Univ Maryland, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Sabra, Mona M.] Baltimore Vet Hlth Adm Med Ctr, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD USA. [Devesa, Susan S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH, Rockville, MD USA. RP Aschebrook-Kilfoy, B (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS,NIH,EPS, Room 8,6120 Execut Blvd, Bethesda, MD 20852 USA. EM kilfoyb@mail.nih.gov RI Aschebrook-Kilfoy, Briseis/A-2537-2012 FU National Institutes of Health/National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health/National Cancer Institute. NR 23 TC 136 Z9 148 U1 1 U2 13 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD FEB PY 2011 VL 21 IS 2 BP 125 EP 134 DI 10.1089/thy.2010.0021 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 712IN UT WOS:000286660200006 PM 21186939 ER PT J AU Irrechukwu, ON Lin, PC Fritton, K Doty, S Pleshko, N Spencer, RG AF Irrechukwu, Onyi N. Lin, Ping-Chang Fritton, Kate Doty, Steve Pleshko, Nancy Spencer, Richard G. TI Magnetic Resonance Studies of Macromolecular Content in Engineered Cartilage Treated with Pulsed Low-Intensity Ultrasound SO TISSUE ENGINEERING PART A LA English DT Article ID HUMAN ARTICULAR CHONDROCYTES; HOLLOW-FIBER BIOREACTOR; IN-VITRO; GENE-EXPRESSION; MATRIX METALLOPROTEINASES; MECHANICAL STIMULATION; PROTEOGLYCAN SYNTHESIS; DYNAMIC COMPRESSION; CHONDROITIN-SULFATE; COLLAGEN SCAFFOLDS AB Noninvasive monitoring of matrix development in tissue-engineered cartilage constructs would permit ongoing assessment with the ability to modify culture conditions during development to optimize tissue characteristics. In this study, chondrocytes seeded in a collagen hydrogel were exposed for 20 min/day to pulsed low-intensity ultrasound (PLIUS) at 30 mWcm(-2) and cultured for up to 5 weeks. Biochemical assays, histology, immunohistochemistry, Fourier transform infrared spectroscopy, and magnetic resonance imaging (MRI) were performed at weeks 3 and 5 after initiation of growth. The noninvasive MRI measurements were correlated with those from the invasive studies. In particular, MRI transverse relaxation time (T2) and magnetization transfer rate (km) correlated with macromolecular content, which was increased by application of PLIUS. This indicates the sensitivity of MR techniques to PLIUS-induced changes in matrix development, and highlights the potential for noninvasive assessment of the efficacy of anabolic interventions for engineered tissue. C1 [Irrechukwu, Onyi N.; Lin, Ping-Chang; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, Gerontol Res Ctr 4D 06, NIH, Baltimore, MD 21224 USA. [Fritton, Kate] Exponent, Philadelphia, PA USA. [Doty, Steve] Hosp Special Surg, New York, NY 10021 USA. [Pleshko, Nancy] Temple Univ, Philadelphia, PA 19122 USA. RP Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, Gerontol Res Ctr 4D 06, NIH, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov OI Lin, Ping-Chang/0000-0003-0918-4072 FU NIH, National Institute on Aging [NIH R01 EB000744, AR056145, NIH AR046121] FX This work was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and by NIH R01 EB000744 and AR056145 (NP). We would also like to acknowledge the Hospital for Special Surgery (New York, NY) for providing histology and immunohistochemistry services (NIH AR046121). NR 64 TC 12 Z9 12 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD FEB PY 2011 VL 17 IS 3-4 BP 407 EP 415 DI 10.1089/ten.tea.2010.0187 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 712JB UT WOS:000286661600015 PM 20807015 ER PT J AU Dunnick, JK Singh, B Nyska, A Peckham, J Kissling, GE Sanders, JM AF Dunnick, June K. Singh, Bhanu Nyska, Abraham Peckham, John Kissling, Grace E. Sanders, J. Michael TI Investigating the Potential for Toxicity from Long-Term Use of the Herbal Products, Goldenseal and Milk Thistle SO TOXICOLOGIC PATHOLOGY LA English DT Article DE herbal products; milk thistle; goldenseal ID SILYBUM-MARIANUM; HEPATOCELLULAR-CARCINOMA; DIETARY-SUPPLEMENTS; ANTIOXIDANT STATUS; MASS-SPECTROMETRY; PROSTATE-CANCER; TUMOR-INCIDENCE; SILYMARIN; BERBERINE; MICE AB Two-year toxicity studies were conducted on the widely used herbal products, goldenseal and milk thistle, in male and female F344/N rats and B6C3F1 mice. With goldenseal root powder, the primary finding was an increase in liver tumors in rats and mice, and with milk thistle extract, a decrease in spontaneous background tumors including mammary gland tumors in female rats and liver tumors in male mice. Increased tumorigenicity in rodents exposed to goldenseal root powder may be due in part to the topoisomerase inhibition properties of berberine, a major alkaloid constituent in goldenseal, or its metabolite, berberrubine. In the clinic, use of topoisomerase-inhibiting agents has been associated with secondary tumor formation and inhibition in DNA repair processes. In contrast, the radical-scavenging and antioxidant properties of silibinin and other flavonolignans in milk thistle extract may have contributed to the decrease in background tumors in rodents in the present studies. The fate of the active constituents of goldenseal and milk thistle is similar in humans and rodents; therefore, the modes of action may translate across species. Further studies are needed to extrapolate the findings to humans. C1 [Dunnick, June K.; Kissling, Grace E.; Sanders, J. Michael] NIEHS, Res Triangle Pk, NC 27709 USA. [Singh, Bhanu] DuPont Haskell Global Ctr Hlth & Environm Sci, Newark, DC USA. [Nyska, Abraham] Tel Aviv Univ, Timrat & Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Dunnick, JK (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences; Southern Research Laboratory (NTP) [N01-ES-15463] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The animals for the goldenseal and milk thistle study were dosed and housed at Southern Research Laboratory (NTP contract N01-ES-15463). We gratefully acknowledge the expert review of Dr. R. Irwin and Dr. A. Brix, NIEHS, RTP, NC. This paper is dedicated in memory of Dr. John Peckham, a great colleague with extensive knowledge and expertise in pathology. NR 64 TC 8 Z9 9 U1 1 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD FEB PY 2011 VL 39 IS 2 BP 398 EP 409 DI 10.1177/0192623310394211 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA 800QW UT WOS:000293380000009 PM 21300790 ER PT J AU Steele-Mortimer, O AF Steele-Mortimer, Olivia TI Exploitation of the Ubiquitin System by Invading Bacteria SO TRAFFIC LA English DT Article DE effector; intracellular; Listeria; Salmonella; type III secretion system ID RECEPTOR TYROSINE KINASE; NF-KAPPA-B; SALMONELLA-CONTAINING VACUOLE; III SECRETION EFFECTORS; DOMAIN BINDING-SITE; LISTERIA-MONOCYTOGENES; E-CADHERIN; EPITHELIAL-CELLS; INVASION PROTEIN; MAMMALIAN-CELLS AB A variety of bacterial intracellular pathogens target the host cell ubiquitin system during invasion, a process that involves transient but fundamental changes in the actin cytoskeleton and plasma membrane. These changes are induced by bacterial proteins, which can be surface associated, secreted or injected directly into the host cell. Here, the invasion strategies of two extensively studied intracellular bacteria, Salmonella enterica serovar Typhimurium and Listeria monocytogenes, are used to illustrate some of the diverse ways by which bacterial pathogens intersect the host cell ubiquitin pathway. C1 NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Steele-Mortimer, O (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM omortimer@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The work in the Steele-Mortimer laboratory is funded by the Intramural Research Program (DIR) of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. I would like to thank the members of the laboratory and the anonymous reviewer for their constructive criticism and suggestions. NR 88 TC 11 Z9 11 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD FEB PY 2011 VL 12 IS 2 BP 162 EP 169 DI 10.1111/j.1600-0854.2010.01137.x PG 8 WC Cell Biology SC Cell Biology GA 704LK UT WOS:000286054300004 PM 20977569 ER PT J AU Hong, JH Li, Q Kim, MS Shin, DM Feske, S Birnbaumer, L Cheng, KT Ambudkar, IS Muallem, S AF Hong, Jeong Hee Li, Qin Kim, Min Seuk Shin, Dong Min Feske, Stefan Birnbaumer, Lutz Cheng, Kwong Tai Ambudkar, Indu S. Muallem, Shmuel TI Polarized but Differential Localization and Recruitment of STIM1, Orai1 and TRPC Channels in Secretory Cells SO TRAFFIC LA English DT Article DE epithelial cells; Orai1; polarized; recruitment; STIM1; TRPC1 ID OPERATED CA2+ ENTRY; PROTEIN-COUPLED RECEPTORS; PANCREATIC ACINAR-CELLS; SALIVARY-GLAND CELLS; PLASMA-MEMBRANE; CRAC CHANNELS; INOSITOL 1,4,5-TRISPHOSPHATE; STORE DEPLETION; HCO3-SECRETION; CALCIUM INFLUX AB Polarized Ca2+ signals in secretory epithelial cells are determined by compartmentalized localization of Ca2+ signaling proteins at the apical pole. Recently the ER Ca2+ sensor STIM1 (stromal interaction molecule 1) and the Orai channels were shown to play a critical role in store-dependent Ca2+ influx. STIM1 also gates the transient receptor potential-canonical (TRPC) channels. Here, we asked how cell stimulation affects the localization, recruitment and function of the native proteins in polarized cells. Inhibition of Orai1, STIM1, or deletion of TRPC1 reduces Ca2+ influx and frequency of Ca2+ oscillations. Orai1 localization is restricted to the apical pole of the lateral membrane. Surprisingly, cell stimulation does not lead to robust clustering of native Orai1, as is observed with expressed Orai1. Unexpectedly, cell stimulation causes polarized recruitment of native STIM1 to both the apical and lateral regions, thus to regions with and without Orai1. Accordingly, STIM1 and Orai1 show only 40% colocalization. Consequently, STIM1 shows higher colocalization with the basolateral membrane marker E-cadherin than does Orai1, while Orai1 showed higher colocalization with the tight junction protein ZO1. TRPC1 is expressed in both apical and basolateral regions of the plasma membrane. Co-IP of STIM1/Orai1/IP(3) receptors (IP(3)Rs)/TRPCs is enhanced by cell stimulation and disrupted by 2-aminoethoxydiphenyl borate (2APB). The polarized localization and recruitment of these proteins results in preferred Ca2+ entry that is initiated at the apical pole. These findings reveal that in addition to Orai1, STIM1 likely regulates other Ca2+ permeable channels, such as the TRPCs. Both channels contribute to the frequency of [Ca2+] oscillations and thus impact critical cellular functions. C1 [Hong, Jeong Hee; Li, Qin; Kim, Min Seuk; Muallem, Shmuel] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA. [Hong, Jeong Hee; Kim, Min Seuk; Cheng, Kwong Tai; Ambudkar, Indu S.; Muallem, Shmuel] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Shin, Dong Min] Yonsei Univ, Coll Dent, Dept Oral Biol, Brain Korea Project 21, Seoul 120752, South Korea. [Feske, Stefan] NYU, Langone Med Ctr, New York, NY 10016 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. RP Muallem, S (reprint author), Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA. EM Shmuel.muallem@nih.gov OI Feske, Stefan/0000-0001-5431-8178 FU National Institutes of Health [DE12309, DK38938]; NIH [Z01-ES-101684] FX This work was supported in part by a grant from the National Institutes of Health Grants DE12309 and DK38938 and by the NIH Intramural Research grants to S. M., I. S. A. and Z01-ES-101684 to L. B. NR 53 TC 46 Z9 46 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD FEB PY 2011 VL 12 IS 2 BP 232 EP 245 DI 10.1111/j.1600-0854.2010.01138.x PG 14 WC Cell Biology SC Cell Biology GA 704LK UT WOS:000286054300009 PM 21054717 ER PT J AU Zimring, JC Welniak, L Semple, JW Ness, PM Slichter, SJ Spitalnik, SL AF Zimring, James C. Welniak, Lis Semple, John W. Ness, Paul M. Slichter, Sherrill J. Spitalnik, Steven L. CA NHLBI Alloimmunization Working Grp TI Current problems and future directions of transfusion-induced alloimmunization: summary of an NHLBI working group SO TRANSFUSION LA English DT Editorial Material ID ALLOANTIBODIES; REDUCTION; PLATELETS; DISEASE AB In April 2010, a working group sponsored by the National Heart, Lung, and Blood Institute was assembled to identify research strategies to improve our understanding of alloimmunization caused by the transfusion of allogeneic blood components and to evaluate potential approaches to both reduce its occurrence and manage its effects. Significant sequelae of alloimmunization were discussed and identified, including difficulties in maintaining chronic transfusion of red blood cells and platelets, hemolytic disease of the newborn, neonatal alloimmune thrombocytopenia, and rejection of transplanted cells and tissues. The discussions resulted in a consensus that identified key areas of future research and developmental areas, including genetic and epigenetic recipient factors that regulate alloimmunization, biochemical specifics of transfused products that affect alloimmunization, and novel technologies for high-throughput genotyping to facilitate extensive and efficient antigen matching between donor and recipient. Additional areas of importance included analysis of unappreciated medical sequelae of alloimmunization, such as cellular immunity and its effect upon transplant and autoimmunity. In addition, support for research infrastructure was discussed, with an emphasis on encouraging collaboration and synergy of animal models biology and human clinical research. Finally, training future investigators was identified as an area of importance. In aggregate, this communication provides a synopsis of the opinions of the working group on the above issues and presents both a list of suggested priorities and the rationale for the topics of focus. The areas of research identified in this report represent potential fertile ground for the medical advancement of preventing and managing alloimmunization in its different forms and mitigating the clinical problems it presents to multiple patient populations. C1 [Zimring, James C.] Emory Univ, Sch Med, Ctr Transfus & Cellular Therapies, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Aflac Canc Ctr & Blood Disorders Serv, Div Pediat Hematol Oncol,Childrens Healthcare Atl, Atlanta, GA 30322 USA. NHLBI, Bethesda, MD 20892 USA. Univ Toronto, Li Ka Shing Knowledge Inst, Canadian Blood Serv, Keenan Res Ctr,St Michaels Hosp,Dept Pharmacol, Toronto, ON, Canada. Johns Hopkins Med Inst, Dept Pathol, Transfus Med Div, Baltimore, MD 21205 USA. Puget Sound Blood Ctr, Seattle, WA 98104 USA. Univ Washington, Sch Med, Seattle, WA USA. Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. RP Zimring, JC (reprint author), Emory Univ, Sch Med, Ctr Transfus & Cellular Therapies, Dept Pathol & Lab Med, Woodruff Mem Bldg Suite 7301,101 Woodruff Circle, Atlanta, GA 30322 USA. EM jzimrin@emory.edu OI Zimring, James/0000-0002-1063-4010; Spitalnik, Steven/0000-0002-8528-4561 FU NHLBI NIH HHS [R21 HL097350] NR 23 TC 25 Z9 27 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD FEB PY 2011 VL 51 IS 2 BP 435 EP 441 DI 10.1111/j.1537-2995.2010.03024.x PG 7 WC Hematology SC Hematology GA 719IW UT WOS:000287199400028 PM 21251006 ER PT J AU Flegel, WA AF Flegel, Willy A. TI Molecular genetics and clinical applications for RH SO TRANSFUSION AND APHERESIS SCIENCE LA English DT Article DE Rhesus; Blood group; Molecular genetics; Molecular diagnostic; Transfusion ID WEAK-D-TYPES; POLYMERASE-CHAIN-REACTION; AMINO-ACID SUBSTITUTIONS; ANTI-D ALLOIMMUNIZATION; TIME QUANTITATIVE PCR; BLOOD-GROUP ANTIGENS; MATERNAL PLASMA; FETAL DNA; HEMOLYTIC-DISEASE; RED-CELLS AB Rhesus is the clinically most important protein-based blood group system. It represents the largest number of antigens and the most complex genetics of the 30 known blood group systems. The RHO and RHCE genes are strongly homologous. Some genetic complexity is explained by their close chromosomal proximity and unusual orientation, with their tail ends facing each other. The antigens are expressed by the RhD and the RhCE proteins. Rhesus exemplifies the correlation of genotype and phenotype, facilitating the understanding of general genetic mechanisms. For clinical purposes, genetic diagnostics of Rhesus antigens will improve the cost-effective development of transfusion medicine. Published by Elsevier Ltd. C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov OI Flegel, Willy Albrecht/0000-0002-1631-7198 FU Intramural NIH HHS [Z99 CL999999] NR 114 TC 53 Z9 59 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1473-0502 J9 TRANSFUS APHER SCI JI Transfus. Apher. Sci. PD FEB PY 2011 VL 44 IS 1 BP 81 EP 91 DI 10.1016/j.transci.2010.12.013 PG 11 WC Hematology SC Hematology GA 736FY UT WOS:000288477400014 PM 21277262 ER PT J AU de Azua, IR Gautam, D Guettier, JM Wess, J AF de Azua, Inigo Ruiz Gautam, Dinesh Guettier, Jean-Marc Wess, Juergen TI Novel insights into the function of beta-cell M-3 muscarinic acetylcholine receptors: therapeutic implications SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID PROTEIN-COUPLED RECEPTORS; PHASIC INSULIN RELEASE; IN-VIVO; GLUCOSE-HOMEOSTASIS; RGS PROTEINS; SECRETION; REGULATOR; ACTIVATION; MECHANISMS; MICE AB Impaired function of pancreatic beta-cells is one of the hallmarks of type 2 diabetes. beta-cell function is regulated by the activity of many hormones and neurotransmitters, which bind to specific cell surface receptors. The M-3 muscarinic acetylcholine receptor (M3R) belongs to the superfamily of G protein-coupled receptors and, following ligand dependent activation, selectively activates G proteins of the G(q/11) family. Recent studies with M3R mutant mice strongly suggest that beta-cell M3Rs play a central role in promoting insulin release and maintaining correct glucose homeostasis. In this review, we highlight recent studies indicating that beta-cell M3Rs and components of downstream signaling pathways might represent promising new targets for the treatment of type 2 diabetes. C1 [de Azua, Inigo Ruiz; Gautam, Dinesh; Guettier, Jean-Marc; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov FU NIH, NIDDK FX The authors' own research covered in this review was supported by the Intramural Research Program of the NIH, NIDDK. NR 49 TC 16 Z9 16 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD FEB PY 2011 VL 22 IS 2 BP 74 EP 80 DI 10.1016/j.tem.2010.10.004 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 725EV UT WOS:000287628900005 ER PT J AU Ekins, S Freundlich, JS Choi, I Sarker, M Talcott, C AF Ekins, Sean Freundlich, Joel S. Choi, Inhee Sarker, Malabika Talcott, Carolyn TI Computational databases, pathway and cheminformatics tools for tuberculosis drug discovery SO TRENDS IN MICROBIOLOGY LA English DT Review ID MONOPHOSPHATE KINASE INHIBITORS; STRUCTURAL GENOMICS CONSORTIUM; MYCOBACTERIUM-TUBERCULOSIS; ANTITUBERCULOSIS AGENTS; METABOLIC PATHWAYS; PHYSICOCHEMICAL PROPERTIES; ANTIMYCOBACTERIAL DRUGS; IN-VITRO; 3D-QSAR; DESIGN AB We are witnessing the growing menace of both increasing cases of drug-sensitive and drug-resistant Mycobacterium tuberculosis strains and the challenge to produce the first new tuberculosis (TB) drug in well over 40 years. The TB community, having invested in extensive high-throughput screening efforts, is faced with the question of how to optimally leverage these data to move from a hit to a lead to a clinical candidate and potentially, a new drug. Complementing this approach, yet conducted on a much smaller scale, cheminformatic techniques have been leveraged and are examined in this review. We suggest that these computational approaches should be optimally integrated within a workflow with experimental approaches to accelerate TB drug discovery. C1 [Ekins, Sean] Collaborat Chem, Jenkintown, PA 19046 USA. [Ekins, Sean] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Ekins, Sean] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. [Ekins, Sean] Collaborat Drug Discovery, Burlingame, CA 94010 USA. [Freundlich, Joel S.] Texas A&M Univ, Dept Biochem & Biophys, Coll Stn, College Stn, TX 77843 USA. [Choi, Inhee] NIAID, NIH, Lab Clin Infect Dis, TB Res Sect, Bethesda, MD 20892 USA. [Sarker, Malabika; Talcott, Carolyn] SRI Int, Menlo Pk, CA 94025 USA. RP Ekins, S (reprint author), Collaborat Chem, 601 Runnymede Ave, Jenkintown, PA 19046 USA. EM eltinssean@yahoo.com OI Ekins, Sean/0000-0002-5691-5790 FU Bill and Melinda Gates Foundation [49852]; National Institute of Allergy and Infectious Diseases [R41AI088893] FX S.E. acknowledges Dr Barry A. Bunin and colleagues for developing the CDD TB database as well as the many TB research collaborators. The CDD TB database along with introductory training was provided freely to Mtb researchers until the end of October 2010 thanks to funding from the Bill and Melinda Gates Foundation (Grant number 49852 Collaborative Drug Discovery for TB Through a Novel Database of SAR Data Optimized to Promote Data Archiving and Sharing). The project described was supported by Award Number R41AI088893 from the National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. We sincerely apologize to any authors whose papers we had to omit because of space restrictions. NR 100 TC 33 Z9 34 U1 1 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD FEB PY 2011 VL 19 IS 2 BP 65 EP 74 DI 10.1016/j.tim.2010.10.005 PG 10 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 728VT UT WOS:000287903300005 PM 21129975 ER PT J AU Evans, NS Liu, K Criqui, MH Ferrucci, L Guralnik, JM Tian, L Liao, YH McDermott, MM AF Evans, Natalie S. Liu, Kiang Criqui, Michael H. Ferrucci, Luigi Guralnik, Jack M. Tian, Lu Liao, Yihua McDermott, Mary M. TI Associations of calf skeletal muscle characteristics and peripheral nerve function with self-perceived physical functioning and walking ability in persons with peripheral artery disease SO VASCULAR MEDICINE LA English DT Article DE calf muscle characteristics; peripheral artery disease; peripheral nerve function; quality of life ID RANDOMIZED CONTROLLED-TRIAL; LOWER-EXTREMITY ISCHEMIA; ANKLE-BRACHIAL INDEX; QUALITY-OF-LIFE; INTERMITTENT CLAUDICATION; EXERCISE REHABILITATION; CARDIOVASCULAR HEALTH; LEG SYMPTOMS; RISK-FACTORS; ARM INDEX AB We determined whether more adverse calf muscle characteristics and poorer peripheral nerve function were associated with impairments in self-perceived physical functioning and walking ability in persons with lower extremity peripheral artery disease (PAD). Participants included 462 persons with PAD; measures included the ankle-brachial index (ABI), medical history, electrophysiologic characteristics of nerves, and computed tomography of calf muscle. Self-perceived physical functioning and walking ability were assessed using the 36-Item Short Form Health Survey (SF-36) and the Walking Impairment Questionnaire (WIQ). Results were adjusted for age, sex, race, ABI, body mass index, comorbidities, and other confounders. Lower calf muscle area was associated with a poorer SF-36 physical function (PF) score (overall p-trend < 0.001, 33.76 PF score for the lowest quartile versus 59.74 for the highest, pairwise p < 0.001) and a poorer WIQ walking distance score (p-trend = 0.001, 29.71 WIQ score for the lowest quartile versus 48.43 for the highest, pairwise p < 0.001). Higher calf muscle percent fat was associated with a poorer SF-36 PF score (p-trend < 0.001, 53.76 PF score for the lowest quartile versus 40.28 for the highest, pairwise p = 0.009). Slower peroneal nerve conduction velocity was associated with a poorer WIQ speed score ( p-trend = 0.023, 30.49 WIQ score for the lowest quartile versus 40.48 for the highest, pairwise p = 0.031). In summary, adverse calf muscle characteristics and poorer peripheral nerve function are associated significantly and independently with impairments in self-perceived physical functioning and walking ability in PAD persons. C1 [Evans, Natalie S.] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Gen Internal Med, Chicago, IL 60611 USA. [Liu, Kiang; Liao, Yihua; McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Criqui, Michael H.] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Ferrucci, Luigi; Guralnik, Jack M.] NIA, Bethesda, MD 20892 USA. [Tian, Lu] Stanford Univ, San Francisco, CA USA. RP Evans, NS (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, Div Gen Internal Med, 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM natalie-evans@md.northwestern.edu FU National Heart, Lung and Blood Institute [R01-HL58099, R01-HL64739, R01-HL071223, R01-HL076298, K12-HL083790]; National Center for Research Resources, NIH [RR-00048]; National Institute on Aging, NIH FX Supported by R01-HL58099, R01-HL64739, R01-HL071223, R01-HL076298, and K12-HL083790 from the National Heart, Lung and Blood Institute and by RR-00048 from the National Center for Research Resources, NIH. Supported in part by the Intramural Research Program, National Institute on Aging, NIH. NR 33 TC 6 Z9 6 U1 1 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD FEB PY 2011 VL 16 IS 1 BP 3 EP 11 DI 10.1177/1358863X10395656 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 745VQ UT WOS:000289198700001 PM 21471147 ER PT J AU Simmons, HE Holmes, EC Stephenson, AG AF Simmons, Heather E. Holmes, Edward C. Stephenson, Andrew G. TI Rapid turnover of intra-host genetic diversity in Zucchini yellow mosaic virus SO VIRUS RESEARCH LA English DT Article DE Evolution; Intra-host diversity; Zucchini yellow mosaic virus; Plant RNA virus; Potyvirus; Complementation ID TRANSGENIC TOBACCO PLANTS; LONG-DISTANCE MOVEMENT; COAT PROTEIN; EVOLUTIONARY DYNAMICS; PURIFYING SELECTION; INFLUENZA-VIRUS; RNA VIRUS; POPULATION; TRANSMISSION; BOTTLENECKS AB Genetic diversity in RNA viruses is shaped by a variety of evolutionary processes, including the bottlenecks that may occur at inter-host transmission. However, how these processes structure genetic variation at the scale of individual hosts is only partly understood. We obtained intra-host sequence data for the coat protein (CP) gene of Zucchini yellow mosaic virus (ZYMV) from two horizontally transmitted populations - one via aphid, the other without - and with multiple samples from individual plants. We show that although mutations are generated relatively frequently within infected plants, attaining similar levels of genetic diversity to that seen in some animal RNA viruses (mean intra-sample diversity of 0.02%), most mutations are likely to be transient, deleterious, and purged rapidly. We also observed more population structure in the aphid transmitted viral population, including the same mutations in multiple clones, the presence of a sub-lineage, and evidence for the short-term complementation of defective genomes. (C) 2010 Elsevier B.V. All rights reserved. C1 [Holmes, Edward C.] Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Holmes, Edward/0000-0001-9596-3552 FU USDA National Institute of Food and Agriculture [2009-33120-20093]; National Institutes of Health [R01 GM080533] FX This work was supported by Biotechnology Risk Assessment Program Grant No. 2009-33120-20093 from the USDA National Institute of Food and Agriculture. ECH is supported in part by Grant R01 GM080533 from the National Institutes of Health. We are grateful to Joseph Dunham for his invaluable advice and assistance, and thank Melinda Bothe, Sarah Scanlon and James Parker for their help performing mini-preps. NR 59 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD FEB PY 2011 VL 155 IS 2 BP 389 EP 396 DI 10.1016/j.virusres.2010.11.007 PG 8 WC Virology SC Virology GA 723YX UT WOS:000287544400002 PM 21138748 ER PT J AU Lonser, RR AF Lonser, Russell R. TI Neurosurgeon of the Year SO WORLD NEUROSURGERY LA English DT Editorial Material C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 J9 WORLD NEUROSURG JI World Neurosurg. PD FEB PY 2011 VL 75 IS 2 BP 197 EP 197 DI 10.1016/j.wneu.2010.12.044 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 793JG UT WOS:000292816700021 ER PT J AU Pang, XY Cheng, J Krausz, KW Guo, DA Gonzalez, FJ AF Pang, Xiaoyan Cheng, Jie Krausz, Kristopher W. Guo, De-an Gonzalez, Frank J. TI Pregnane X receptor-mediated induction of Cyp3a by black cohosh SO XENOBIOTICA LA English DT Article ID DRUG-INTERACTIONS; NUCLEAR RECEPTORS; BOTANICAL SUPPLEMENTATION; DEPENDENT REGULATION; MENOPAUSAL SYMPTOMS; GENE-EXPRESSION; IN-VITRO; PXR; MICE; MOUSE AB Black cohosh (BC) has been widely applied for the treatment of menopausal symptoms. However, increasing concerns about herb-drug interactions demand the need for studies on the influence of BC on cytochrome 450. Cyp3a11 in liver was induced by 7-fold in wild-type mice treated with 500 mg/kg black cohosh for 28 days compared with the control group as assessed by quantitative real-time PCR; no difference was found in small intestine and kidney, suggesting that up-regulation of Cyp3a11 by black cohosh was liver-specific. Western blot, activity assays, and pharmacokinetic analyses established dose- and time-dependent induction of Cyp3a11. To determine the mechanism of Cyp3a11 induction, including the role of pregnane X receptor (PXR) in vivo and in vitro, respectively, in Pxr-null, PXR-humanized, and double transgenic CYP3A4/hPXR mice, cell-based luciferase assays were employed revealing that mouse PXR played a direct role in the induction of Cyp3a11; human PXR was not activated by black cohosh. Overall, these findings demonstrate that induction of Cyp3a11 is liver-specific and involved only mouse PXR, not the human counterpart. Thus, the incidence of herb-drug interaction in patients administered black cohosh may not be mediated by human PXR and CYP3A4. T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads. The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0.004), and that risk increased linearly from low to high activity haplotypes (P = 0.003). In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor "T'' allele interact to increase preeclampsia risk (p = 0.022). We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0.052) and the fetal risk alleles in combination with a maternal balancing allele (P, 0.001). This non-random distribution was not observed in controls (P = 0.341 and P = 0.219, respectively). Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR. C1 [Hill, Lori D.; Strauss, Jerome F., III] Virginia Commonwealth Univ, Dept Obstet & Gynecol, Sch Med, Richmond, VA 23284 USA. [York, Timothy P.; Eaves, Lindon J.] Virginia Commonwealth Univ, Sch Med, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [York, Timothy P.; Eaves, Lindon J.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Sch Med, Richmond, VA USA. [Kusanovic, Juan P.; Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kusanovic, Juan P.; Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Kusanovic, Juan P.; Gomez, Ricardo] Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Santiago, Chile. [Kusanovic, Juan P.; Gomez, Ricardo] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. RP Hill, LD (reprint author), Virginia Commonwealth Univ, Dept Obstet & Gynecol, Sch Med, Richmond, VA 23284 USA. EM jfstrauss@vcu.edu FU NCMHD [P60 MD002256]; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS [N01 HD-2-3342] FX This research was supported in part by grants from the NCMHD P60 MD002256 (JFS) and the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, N01 HD-2-3342 (JFS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 26 Z9 31 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 31 PY 2011 VL 6 IS 1 AR e16681 DI 10.1371/journal.pone.0016681 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714UK UT WOS:000286834300120 PM 21304959 ER PT J AU Xiang, XR Phung, Y Feng, MQ Nagashima, K Zhang, JL Broaddus, VC Hassan, R FitzGerald, D Ho, M AF Xiang, Xinran Phung, Yen Feng, Mingqian Nagashima, Kunio Zhang, Jingli Broaddus, V. Courtney Hassan, Raffit FitzGerald, David Ho, Mitchell TI The Development and Characterization of a Human Mesothelioma In Vitro 3D Model to Investigate Immunotoxin Therapy SO PLOS ONE LA English DT Article ID E-CADHERIN; MALIGNANT MESOTHELIOMA; MULTICELLULAR SPHEROIDS; APOPTOTIC RESISTANCE; SOLID TUMORS; LUNG-CANCER; CELL-LINES; TAXOL; ADENOCARCINOMA; CHEMOTHERAPY AB Background: Tumor microenvironments present significant barriers to penetration by antibodies and immunoconjugates. Tumor microenvironments, however, are difficult to study in vitro. Cells cultured as monolayers exhibit less resistance to therapy than those grown in vivo and an alternative research model more representative of the in vivo tumor is more desirable. SS1P is an immunotoxin composed of the Fv portion of a mesothelin-specific antibody fused to a bacterial toxin that is presently undergoing clinical trials in mesothelioma. Methodology/Principal Findings: Here, we examined how the tumor microenvironment affects the penetration and killing activity of SS1P in a new three-dimensional (3D) spheroid model cultured in vitro using the human mesothelioma cell line (NCI-H226) and two primary cell lines isolated from the ascites of malignant mesothelioma patients. Mesothelioma cells grown as monolayers or as spheroids expressed comparable levels of mesothelin; however, spheroids were at least 100 times less affected by SS1P. To understand this disparity in cytotoxicity, we made fluorescence-labeled SS1P molecules and used confocal microscopy to examine the time course of SS1P penetration within spheroids. The penetration was limited after 4 hours. Interestingly, we found a significant increase in the number of tight junctions in the core area of spheroids by electron microscopy. Expression of E-Cadherin, a protein involved in the assembly and sealing of tight junctions and highly expressed in malignant mesothelioma, was found significantly increased in spheroids as compared to monolayers. Moreover, we found that siRNA silencing and antibody inhibition targeting E-Cadherin could enhance SS1P immunotoxin therapy in vitro. Conclusion/Significance: This work is one of the first to investigate immunotoxins in 3D tumor spheroids in vitro. This initial description of an in vitro tumor model may offer a simple and more representative model of in vivo tumors and will allow for further investigations of the microenvironmental effects on drug penetration and tumor cell killing. We believe that the methods developed here may apply to the studies of other tumor-targeting antibodies and immunoconjugates in vitro. C1 [Xiang, Xinran; Phung, Yen; Feng, Mingqian; Zhang, Jingli; Hassan, Raffit; FitzGerald, David; Ho, Mitchell] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nagashima, Kunio] Sci Applicat Int Corp Frederick Inc, Frederick, MD USA. [Broaddus, V. Courtney] Univ Calif San Francisco, Lung Biol Ctr, San Francisco, CA 94143 USA. RP Xiang, XR (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU National Institutes of Health (NIH); National Cancer Institute (NCI); Center for Cancer Research; Mesothelioma Applied Research Foundation; NCI, NIH [HHSN26120080001E] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research, in part by the NCI Director's Intramural Innovation Award for Principal Investigators (MH), in part by a Mesothelioma Applied Research Foundation Grant in Honor of Craig Kozicki (MH), and in part with federal funds from the NCI, NIH, under contract HHSN26120080001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 18 Z9 18 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 31 PY 2011 VL 6 IS 1 AR e14640 DI 10.1371/journal.pone.0014640 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714UK UT WOS:000286834300021 PM 21305058 ER PT J AU Shriner, D Vaughan, LK AF Shriner, Daniel Vaughan, Laura Kelly TI A unified framework for multi-locus association analysis of both common and rare variants SO BMC GENOMICS LA English DT Article ID LINKAGE DISEQUILIBRIUM; PARKINSON-DISEASE; LOGIC REGRESSION; GENOMIC CONTROL; GENES; SUSCEPTIBILITY; POWER AB Background: Common, complex diseases are hypothesized to result from a combination of common and rare genetic variants. We developed a unified framework for the joint association testing of both types of variants. Within the framework, we developed a union-intersection test suitable for genome-wide analysis of single nucleotide polymorphisms (SNPs), candidate gene data, as well as medical sequencing data. The union-intersection test is a composite test of association of genotype frequencies and differential correlation among markers. Results: We demonstrated by computer simulation that the false positive error rate was controlled at the expected level. We also demonstrated scenarios in which the multi-locus test was more powerful than traditional single marker analysis. To illustrate use of the union-intersection test with real data, we analyzed a publically available data set of 319,813 autosomal SNPs genotyped for 938 cases of Parkinson disease and 863 neurologically normal controls for which no genome-wide significant results were found by traditional single marker analysis. We also analyzed an independent follow-up sample of 183 cases and 248 controls for replication. Conclusions: We identified a single risk haplotype with a directionally consistent effect in both samples in the gene GAK, which is involved in clathrin-mediated membrane trafficking. We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes SYN3 and NGLY1, which are involved in neurotransmitter release and proteasomal degradation, respectively. These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases. C1 [Shriner, Daniel] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Vaughan, Laura Kelly] Univ Alabama, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. RP Shriner, D (reprint author), NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. EM shrinerda@mail.nih.gov FU National Institute on Aging; National Institute of Neurological Disorders and Stroke; Robert P. & Judith N. Goldberg Foundation; Bumpus Foundation; Harvard NeuroDiscovery Center; Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362]; National Institutes of Health [K01DK080188] FX We dedicate this manuscript to Allan Morris and Fern Vaughan. We thank David T. Redden and Charles Rotimi for discussion and critical review of this manuscript. Funding support was provided by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Robert P. & Judith N. Goldberg Foundation, the Bumpus Foundation, and the Harvard NeuroDiscovery Center. Samples were provided by the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. Genotyping services were provided by the Center for Inherited Disease Research and the National Institute of Neurological Disorders and Stroke (Foroud/Myers, PI). The discovery sample used for the analyses described in this manuscript was obtained from the NINDS Database found at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id-phs000126. v1.p1 through dbGaP accession number phs000126.v1.p1. The replication sample used for the analyses described in this manuscript was obtained from the Coriell Queue, now available from the NINDS Database found at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id-phs0 00003.v1.p1. The contents of this publication are solely the responsibility of the authors and do not necessarily reflect the official view of the National Institutes of Health. This research was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH), which is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362) and National Institutes of Health grant K01DK080188. The funding bodies had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript. NR 26 TC 9 Z9 9 U1 0 U2 0 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 JAN 31 PY 2011 VL 12 AR 89 DI 10.1186/1471-2164-12-89 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 722OS UT WOS:000287444300002 PM 21281506 ER PT J AU Balwit, JM Hwu, P Urba, WJ Marincola, FM AF Balwit, James M. Hwu, Patrick Urba, Walter J. Marincola, Francesco M. TI The iSBTc/SITC primer on tumor immunology and biological therapy of cancer: a summary of the 2010 program SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID IMMUNOTHERAPY; MELANOMA AB The Society for Immunotherapy of Cancer, SITC (formerly the International Society for Biological Therapy of Cancer, iSBTc), aims to improve cancer patient outcomes by advancing the science, development and application of biological therapy and immunotherapy. The society and its educational programs have become premier destinations for interaction and innovation in the cancer biologics community. For over a decade, the society has offered the Primer on Tumor Immunology and Biological Therapy of Cancer T in conjunction with its Annual Scientific Meeting. This report summarizes the 2010 Primer that took place October 1, 2010 in Washington, D. C. as part of the educational offerings associated with the society's 25th anniversary. The target audience was basic and clinical investigators from academia, industry and regulatory agencies, and included clinicians, post-doctoral fellows, students, and allied health professionals. Attendees were provided a review of basic immunology and educated on the current status and most recent advances in tumor immunology and clinical/translational caner immunology. Ten prominent investigators presented on the following topics: innate immunity and inflammation; an overview of adaptive immunity; dendritic cells; tumor microenvironment; regulatory immune cells; immune monitoring; cytokines in cancer immunotherapy; immune modulating antibodies; cancer vaccines; and adoptive T cell therapy. Presentation slides, a Primer webinar and additional program information are available online on the society's website. C1 [Balwit, James M.; Marincola, Francesco M.] Soc Immunotherapy Canc, Milwaukee, WI USA. [Hwu, Patrick] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Urba, Walter J.] Providence Portland Med Ctr, Earle A Chiles Res Inst, Portland, OR USA. [Marincola, Francesco M.] NIH, IDIS, Dept Translat Med, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), Soc Immunotherapy Canc, Milwaukee, WI USA. EM FMarincola@mail.cc.nih.gov NR 9 TC 8 Z9 8 U1 0 U2 1 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 JAN 31 PY 2011 VL 9 AR 18 DI 10.1186/1479-5876-9-18 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 720DX UT WOS:000287261500001 PM 21281484 ER PT J AU Larremore, DB Shew, WL Restrepo, JG AF Larremore, Daniel B. Shew, Woodrow L. Restrepo, Juan G. TI Predicting Criticality and Dynamic Range in Complex Networks: Effects of Topology SO PHYSICAL REVIEW LETTERS LA English DT Article ID NEURONAL AVALANCHES; CORTICAL NETWORKS; STABILITY AB The collective dynamics of a network of coupled excitable systems in response to an external stimulus depends on the topology of the connections in the network. Here we develop a general theoretical approach to study the effects of network topology on dynamic range, which quantifies the range of stimulus intensities resulting in distinguishable network responses. We find that the largest eigenvalue of the weighted network adjacency matrix governs the network dynamic range. When the largest eigenvalue is exactly one, the system is in a critical state and its dynamic range is maximized. Further, we examine higher order behavior of the steady state system, which predicts that networks with more homogeneous degree distributions should have higher dynamic range. Our analysis, confirmed by numerical simulations, generalizes previous studies in terms of the largest eigenvalue of the adjacency matrix. C1 [Larremore, Daniel B.; Restrepo, Juan G.] Univ Colorado, Dept Appl Math, Boulder, CO 80309 USA. [Shew, Woodrow L.] NIMH, NIH, Bethesda, MD 20892 USA. RP Larremore, DB (reprint author), Univ Colorado, Dept Appl Math, Boulder, CO 80309 USA. EM larremor@colorado.edu OI Shew, Woodrow/0000-0003-0679-1766 FU National Institute of Mental Health; NSF [DMS-0908221] FX We thank Ed Ott and Dietmar Plenz for useful discussions. The work of W. L. S. was supported by the Intramural Research Program of the National Institute of Mental Health. J. G. R. was supported by NSF Grant No. DMS-0908221. NR 18 TC 52 Z9 52 U1 2 U2 14 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD JAN 31 PY 2011 VL 106 IS 5 AR 058101 DI 10.1103/PhysRevLett.106.058101 PG 4 WC Physics, Multidisciplinary SC Physics GA 713IZ UT WOS:000286733000009 PM 21405438 ER PT J AU Catalan, MA Scott-Anne, K Klein, MI Koo, H Bowen, WH Melvin, JE AF Catalan, Marcelo A. Scott-Anne, Kathleen Klein, Marlise I. Koo, Hyun Bowen, William H. Melvin, James E. TI Elevated Incidence of Dental Caries in a Mouse Model of Cystic Fibrosis SO PLOS ONE LA English DT Article ID SUBMANDIBULAR SALIVA; ELECTROLYTE CONCENTRATIONS; KNOCKOUT MICE; ORAL-HEALTH; DUCT CELLS; CFTR; GLAND; RATS; HETEROZYGOTES; HOMOZYGOTES AB Background: Dental caries is the single most prevalent and costly infectious disease worldwide, affecting more than 90% of the population in the U. S. The development of dental cavities requires the colonization of the tooth surface by acid-producing bacteria, such as Streptococcus mutans. Saliva bicarbonate constitutes the main buffering system which neutralizes the pH fall generated by the plaque bacteria during sugar metabolism. We found that the saliva pH is severely decreased in a mouse model of cystic fibrosis disease (CF). Given the close relationship between pH and caries development, we hypothesized that caries incidence might be elevated in the mouse CF model. Methodology/Principal Findings: We induced carious lesions in CF and wildtype mice by infecting their oral cavity with S. mutans, a well-studied cariogenic bacterium. After infection, the mice were fed a high-sucrose diet for 5 weeks (diet 2000). The mice were then euthanized and their jaws removed for caries scoring and bacterial counting. A dramatic increase in caries and severity of lesions scores were apparent in CF mice compared to their wildtype littermates. The elevated incidence of carious lesions correlated with a striking increase in the S. mutans viable population in dental plaque (20-fold increase in CF vs. wildtype mice; p value, <.003; t test). We also found that the pilocarpine-stimulated saliva bicarbonate concentration was significantly reduced in CF mice (16 +/- 2 mM vs. 31 +/- 2 mM, CF and wildtype mice, respectively; p value <0.01; t test). Conclusions/Significance: Considering that bicarbonate is the most important pH buffering system in saliva, and the adherence and survival of aciduric bacteria such as S. mutans are enhanced at low pH values, we speculate that the decrease in the bicarbonate content and pH buffering of the saliva is at least partially responsible for the increased severity of lesions observed in the CF mouse. C1 [Catalan, Marcelo A.; Melvin, James E.] Univ Rochester, Med Ctr, Dept Physiol & Pharmacol, Rochester, NY 14642 USA. [Scott-Anne, Kathleen; Klein, Marlise I.; Koo, Hyun; Bowen, William H.] Univ Rochester, Med Ctr, Ctr Oral Biol, Rochester, NY 14642 USA. RP Catalan, MA (reprint author), Natl Inst Dent & Craniofacial Res, Secretory Mech & Dysfunct Sect, Div Intramural Res, NIH, Bethesda, MD USA. EM james.melvin@nih.gov RI Klein, Marlise/A-2550-2014; OI Klein, Marlise/0000-0002-7916-1557; Catalan, Marcelo/0000-0003-3544-2821 FU National Institutes of Health [DE09692, DE08921] FX This work was funded by grants to JEM from the National Institutes of Health (DE09692 and DE08921). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 17 Z9 17 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 31 PY 2011 VL 6 IS 1 AR e16549 DI 10.1371/journal.pone.0016549 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714UK UT WOS:000286834300083 PM 21304986 ER PT J AU Nestor, MW Cai, X Stone, MR Bloch, RJ Thompson, SM AF Nestor, Michael W. Cai, Xiang Stone, Michele R. Bloch, Robert J. Thompson, Scott M. TI The Actin Binding Domain of beta I-Spectrin Regulates the Morphological and Functional Dynamics of Dendritic Spines SO PLOS ONE LA English DT Article ID LONG-TERM POTENTIATION; PROTEIN-KINASE-C; F-ACTIN; NMDA RECEPTORS; POSTSYNAPTIC DENSITY; HIPPOCAMPAL-NEURONS; AMPA RECEPTORS; MOLECULAR-MECHANISMS; GLUTAMATE RECEPTORS; SYNAPTIC PLASTICITY AB Actin microfilaments regulate the size, shape and mobility of dendritic spines and are in turn regulated by actin binding proteins and small GTPases. The beta I isoform of spectrin, a protein that links the actin cytoskeleton to membrane proteins, is present in spines. To understand its function, we expressed its actin-binding domain (ABD) in CA1 pyramidal neurons in hippocampal slice cultures. The ABD of beta I-spectrin bundled actin in principal dendrites and was concentrated in dendritic spines, where it significantly increased the size of the spine head. These effects were not observed after expression of homologous ABDs of utrophin, dystrophin, and alpha-actinin. Treatment of slice cultures with latrunculin-B significantly decreased spine head size and decreased actin-GFP fluorescence in cells expressing the ABD of alpha-actinin, but not the ABD of beta I-spectrin, suggesting that its presence inhibits actin depolymerization. We also observed an increase in the area of GFP-tagged PSD-95 in the spine head and an increase in the amplitude of mEPSCs at spines expressing the ABD of beta I-spectrin. The effects of the beta I-spectrin ABD on spine size and mEPSC amplitude were mimicked by expressing wild-type Rac3, a small GTPase that co-immunoprecipitates specifically with beta I-spectrin in extracts of cultured cortical neurons. Spine size was normal in cells co-expressing a dominant negative Rac3 construct with the beta I-spectrin ABD. We suggest that beta I-spectrin is a synaptic protein that can modulate both the morphological and functional dynamics of dendritic spines, perhaps via interaction with actin and Rac3. C1 [Nestor, Michael W.; Cai, Xiang; Stone, Michele R.; Bloch, Robert J.; Thompson, Scott M.] Univ Maryland, Dept Physiol, Sch Med, Baltimore, MD 21201 USA. [Nestor, Michael W.; Bloch, Robert J.; Thompson, Scott M.] Univ Maryland, Program Neurosci, Sch Med, Baltimore, MD 21201 USA. [Nestor, Michael W.; Bloch, Robert J.; Thompson, Scott M.] Univ Maryland, Training Program Integrat Membrane Biol, Sch Med, Baltimore, MD 21201 USA. RP Nestor, MW (reprint author), Natl Inst Child Hlth & Dev, NIH, Bethesda, MD USA. EM sthom003@umaryland.edu FU Muscular Dystrophy Association [T32 GM08181, T32 NS07375]; National Institutes of Health [R01 HL75106, R01 MH65488] FX Supported by stipends to MWN from T32 GM08181, to MRS from T32 NS07375, and from grants from the Muscular Dystrophy Association (RJB) and the National Institutes of Health (R01 HL75106 to RJB and R01 MH65488 to SMT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 17 Z9 17 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 31 PY 2011 VL 6 IS 1 AR e16197 DI 10.1371/journal.pone.0016197 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714UK UT WOS:000286834300040 PM 21297961 ER PT J AU Hamel, AF Meyer, JS Henchey, E Dettmer, AM Suomi, SJ Novak, MA AF Hamel, Amanda F. Meyer, Jerrold S. Henchey, Elizabeth Dettmer, Amanda M. Suomi, Stephen J. Novak, Melinda A. TI Effects of shampoo and water washing on hair cortisol concentrations SO CLINICA CHIMICA ACTA LA English DT Article DE Hair; Cortisol; Hypothalamic-pituitary-adrenocortical axis; Rhesus monkey; Shampoo ID BIOMARKER; MONKEY; STRESS AB Background: Measurement of cortisol in hair is an emerging biomarker for chronic stress in human and nonhuman primates. Currently unknown, however, is the extent of potential cortisol loss from hair that has been repeatedly exposed to shampoo and/or water. Methods: Pooled hair samples from 20 rhesus monkeys were subjected to five treatment conditions: 10, 20, or 30 shampoo washes, 20 water-only washes, or a no-wash control. For each wash, hair was exposed to a dilute shampoo solution or tap water for 45 s, rinsed 4 times with tap water, and rapidly dried. Samples were then processed for cortisol extraction and analysis using previously published methods. Results: Hair cortisol levels were significantly reduced by washing, with an inverse relationship between number of shampoo washes and the cortisol concentration. This effect was mainly due to water exposure, as cortisol levels following 20 water-only washes were similar to those following 20 shampoo treatments. Conclusions: Repeated exposure to water with or without shampoo appears to leach cortisol from hair, yielding values that underestimate the amount of chronic hormone deposition within the shaft. Collecting samples proximal to the scalp and obtaining hair washing frequency data may be valuable when conducting human hair cortisol studies. (C) 2010 Elsevier B.V. All rights reserved. C1 [Hamel, Amanda F.] Univ Massachusetts, Neurosci & Behav Grad Program, Amherst, MA 01003 USA. [Meyer, Jerrold S.; Henchey, Elizabeth; Novak, Melinda A.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Dettmer, Amanda M.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, Poolesville, MD 20837 USA. RP Hamel, AF (reprint author), Univ Massachusetts, Neurosci & Behav Grad Program, 529 Tobin Hall,135 Hicks Way, Amherst, MA 01003 USA. EM afhamel@cns.umass.edu OI Meyer, Jerrold/0000-0002-8382-7075 FU National Institutes of Health [RR11122]; Division of Intramural Research, NICHD; [RR000168] FX Support for this work was provided by a grant RR11122 awarded to M.A.N. from the National Institutes of Health and by the Division of Intramural Research, NICHD and grant RR000168 awarded to the New England Primate Research Center. NR 11 TC 39 Z9 39 U1 2 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD JAN 30 PY 2011 VL 412 IS 3-4 BP 382 EP 385 DI 10.1016/j.cca.2010.10.019 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 718IV UT WOS:000287115400029 PM 21034727 ER PT J AU Carli, V Roy, A Bevilacqua, L Maggi, S Cesaro, C Sarchiapone, M AF Carli, Vladimir Roy, Alec Bevilacqua, Laura Maggi, Stefania Cesaro, Caterina Sarchiapone, Marco TI Insomnia and suicidal behaviour in prisoners SO PSYCHIATRY RESEARCH LA English DT Article DE Insomnia; Suicide attempt; Prisoners ID ANTISOCIAL PERSONALITY-DISORDER; QUALITY-OF-LIFE; MAJOR DEPRESSION; PSYCHIATRIC-DISORDERS; CHILDHOOD TRAUMA; SLEEP QUALITY; RISK-FACTORS; RATING-SCALE; POPULATION; DISTURBANCES AB Insomnia has been associated with suicidality. Prisoners have an increased risk of both insomnia and suicidal behaviour. Therefore, it was decided to examine for a relationship between insomnia and suicidal behaviour in a large group of 1420 prisoners. Prisoners had a semi-structured psychiatric interview, which included the Hamilton Depression Rating Scale (HDRS), and completed the Childhood Trauma Questionnaire, Eysenck Personality Questionnaire, Spielberg Anger Expression Inventory and Connor-Davidson Resilience Scale. It was found that 568 (61.2%) of the prisoners scored in the insomnia cluster of the HDRS and that 183 (12.8%) had attempted suicide. Regression analyses showed that insomnia was significantly and independently associated with a lifetime history of attempting suicide. Insomnia was also significantly related to actual suicidality. After controlling for confounders, axis 1 psychiatric disorder, childhood trauma, neuroticism, low resilience, and anger were significantly associated with insomnia in male prisoners. These data suggest the possibility of a relationship between insomnia and suicidality in prisoners. Assessing insomnia may be helpful when evaluating the risk of suicidality in prisoners. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Carli, Vladimir; Cesaro, Caterina; Sarchiapone, Marco] Univ Molise, Dept Hlth Sci, I-86100 Campobasso, Italy. [Carli, Vladimir] Karolinska Inst, Natl Prevent Suicide & Mental Hlth NASP 3, Stockholm, Sweden. [Bevilacqua, Laura] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Maggi, Stefania] Fdn Leonardo Sci Med, Padua, Italy. RP Sarchiapone, M (reprint author), Univ Molise, Dept Hlth Sci, I-86100 Campobasso, Italy. EM marco.sarchiapone@gmail.com RI Carli, Vladimir/G-4728-2012; OI Sarchiapone, Marco/0000-0001-9583-3117 NR 53 TC 22 Z9 22 U1 3 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JAN 30 PY 2011 VL 185 IS 1-2 BP 141 EP 144 DI 10.1016/j.psychres.2009.10.001 PG 4 WC Psychiatry SC Psychiatry GA 718HY UT WOS:000287113000024 PM 20510461 ER PT J AU Nugent, AC Bain, EE Thayer, JF Sollers, JJ Drevets, WC AF Nugent, Allison Carol Bain, Earle Eugene Thayer, Julian Francis Sollers, John James, III Drevets, Wayne Curtis TI Heart rate variability during motor and cognitive tasks in females with major depressive disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Autonomic; PET; MRI; Depression; Brain ID MEDIAL PREFRONTAL CORTEX; N-BACK TASK; SPECTRAL-ANALYSIS; WORKING-MEMORY; ANTIDEPRESSIVE TREATMENT; MYOCARDIAL-INFARCTION; TRYPTOPHAN DEPLETION; ANESTHETIZED RABBITS; GLUCOSE-METABOLISM; MOOD DISORDERS AB Research indicates that major depressive disorder (MDD) is associated with alterations in autonomic control, particularly cardiac control as measured by heart rate variability (HRV). In this preliminary study, we investigated the neural correlates of autonomic control by measuring both HRV and associated brain activity during the performance of mildly stressful tasks. Medically healthy female subjects with MDD (N = 10) and healthy controls (N = 7) underwent H(2)(15)O-positron emission tomography (PET) and electrocardiographic ECG recording while performing a handgrip motor task and an n-back task. Indices of HRV were calculated and correlated with regional cerebral blood flow (rCBF). Differences in the rCBF and HRV correlations between depressed and healthy subjects were evident in both the medial and lateral orbital cortices. In addition, these areas appeared to be involved in different facets of autonomic control with regard to sympathetic or parasympathetic dominance of cardiac control. These results are consistent with the known roles of networks within the orbital cortex in both autonomic control and the pathophysiology of MDD. Published by Elsevier Ireland Ltd. C1 [Nugent, Allison Carol] NIMH, Sect Neuroimaging Mood Disorders, NIH, Bethesda, MD 20892 USA. [Bain, Earle Eugene] Abbott Labs, Neurosci & Anesthesia Dev, Abbott Pk, IL 60064 USA. [Thayer, Julian Francis] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Sollers, John James, III] Univ Auckland, Dept Psychol Med, Auckland 1, New Zealand. [Drevets, Wayne Curtis] Laureate Inst Brain Res, Tulsa, OK USA. RP Nugent, AC (reprint author), NIMH, Sect Neuroimaging Mood Disorders, NIH, 10 Ctr Dr,MSC 1030, Bethesda, MD 20892 USA. EM nugenta@mail.nih.gov OI Nugent, Allison/0000-0003-2569-2480 FU Intramural NIH HHS [Z99 MH999999] NR 61 TC 16 Z9 17 U1 5 U2 15 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 JAN 30 PY 2011 VL 191 IS 1 BP 1 EP 8 DI 10.1016/j.pscychresns.2010.08.013 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 737TM UT WOS:000288591100001 PM 21129936 ER PT J AU Corrado, C Raimondo, S Flugy, AM Fontana, S Santoro, A Stassi, G Marfia, A Iovino, F Arlinghaus, R Kohn, EC De Leo, G Alessandro, R AF Corrado, Chiara Raimondo, Stefania Flugy, Anna Maria Fontana, Simona Santoro, Alessandra Stassi, Giorgio Marfia, Anna Iovino, Flora Arlinghaus, Ralph Kohn, Elise C. De Leo, Giacomo Alessandro, Riccardo TI Carboxyamidotriazole inhibits cell growth of imatinib-resistant chronic myeloid leukaemia cells including T3151 Bcr-Abl mutant by a redox-mediated mechanism SO CANCER LETTERS LA English DT Article DE Chronic myelogenous leukemia (CML); Carboxy amidotriazole (CAI); Drug resistance; Reactive-oxygen species (ROS) ID CHRONIC MYELOGENOUS LEUKEMIA; REACTIVE OXYGEN; CANCER-CELLS; IN-VITRO; TYROSINE KINASE; TRANSFORMED-CELLS; INDUCED APOPTOSIS; OXIDATIVE STRESS; OVARIAN-CANCER; CML CELLS AB Mutation of the Bcr-Abl oncoprotein is one of most frequent mechanisms by which chronic myelogenous leukemia (CML) cells become resistant to imatinib Here we show that treatment of cell lines harbouring wild type or mutant BCR-ABL with carboxyamidotriazole (CAI) a calcium influx and signal transduction inhibitor inhibits cell growth the expression of Bcr-Abl and its downstream signalling and Induces apoptosis Moreover we show that CAI acts by increasing intracellular ROS Clinically ignificant CAI has also inhibitory effects on T315I Bcr-Abl mutant a mutation that causes CML cells to become insensitive to imatinib and second generation abl kinase inhibitors (C) 2010 Elsevier Ireland Ltd All rights reserved C1 [Corrado, Chiara; Raimondo, Stefania; Flugy, Anna Maria; Fontana, Simona; De Leo, Giacomo; Alessandro, Riccardo] Univ Palermo, Dipartimento Biopatol & Biotecnol Med & Forensi, Sez Biol & Genet, I-90133 Palermo, Italy. [Santoro, Alessandra; Marfia, Anna] AO V Cervello, Lab Ematol, Dipartimento Ric Clin & Biotecnol, Palermo, Italy. [Stassi, Giorgio; Iovino, Flora] Dipartimento Sci Chirurg & Oncol, Palermo, Italy. [Arlinghaus, Ralph] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kohn, Elise C.] NCI, Mol Signaling Sect, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Alessandro, R (reprint author), Univ Palermo, Dipartimento Biopatol & Biotecnol Med & Forensi, Sez Biol & Genet, Via Divisi 83, I-90133 Palermo, Italy. RI Iovino, Flora/K-8834-2016 OI Iovino, Flora/0000-0002-6374-5582 FU Italian Association for Cancer Research (AIRC); University of Palermo (International Cooperation); Center for Cancer Research National Cancer Institute National Institutes of Health USA FX This work was supported by Italian Association for Cancer Research (AIRC) to G D L and RA University of Palermo (International Cooperation) to R A ex 60% MURST to R A A M F S F and to G D L Dr Kohn is supported by the Intramural Program of the Center for Cancer Research National Cancer Institute National Institutes of Health USA NR 43 TC 3 Z9 3 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 28 PY 2011 VL 300 IS 2 BP 205 EP 214 DI 10.1016/j.canlet.2010.10.007 PG 10 WC Oncology SC Oncology GA 701JJ UT WOS:000285813900012 PM 21041018 ER PT J AU Daniel, CR Prabhakaran, D Kapur, K Graubard, BI Devasenapathy, N Ramakrishnan, L George, PS Shetty, H Ferrucci, LM Yurgalevitch, S Chatterjee, N Reddy, KS Rastogi, T Gupta, PC Mathew, A Sinha, R AF Daniel, Carrie R. Prabhakaran, Dorairaj Kapur, Kavita Graubard, Barry I. Devasenapathy, Niveditha Ramakrishnan, Lakshmy George, Preethi S. Shetty, Hemali Ferrucci, Leah M. Yurgalevitch, Susan Chatterjee, Nilanjan Reddy, K. S. Rastogi, Tanuja Gupta, Prakash C. Mathew, Aleyamma Sinha, Rashmi TI A cross-sectional investigation of regional patterns of diet and cardio-metabolic risk in India SO NUTRITION JOURNAL LA English DT Article ID CORONARY-HEART-DISEASE; NUTRITION TRANSITION; CARDIOVASCULAR-DISEASE; CARBOHYDRATE INTAKE; INSULIN-RESISTANCE; PRIMARY PREVENTION; DIABETES-MELLITUS; PHYSICAL-ACTIVITY; ASIAN INDIANS; SOUTH ASIANS AB Background: The role of diet in India's rapidly progressing chronic disease epidemic is unclear; moreover, diet may vary considerably across North-South regions. Methods: The India Health Study was a multicenter study of men and women aged 35-69, who provided diet, lifestyle, and medical histories, as well as blood pressure, fasting blood, urine, and anthropometric measurements. In each region (Delhi, n = 824; Mumbai, n = 743; Trivandrum, n = 2,247), we identified two dietary patterns with factor analysis. In multiple logistic regression models adjusted for age, gender, education, income, marital status, religion, physical activity, tobacco, alcohol, and total energy intake, we investigated associations between regional dietary patterns and abdominal adiposity, hypertension, diabetes, and dyslipidemia. Results: Across the regions, more than 80% of the participants met the criteria for abdominal adiposity and 10 to 28% of participants were considered diabetic. In Delhi, the "fruit and dairy" dietary pattern was positively associated with abdominal adiposity [highest versus lowest tertile, multivariate-adjusted OR and 95% CI: 2.32 (1.03-5.23); P(trend) = 0.008] and hypertension [2.20 (1.47-3.31); P(trend) < 0.0001]. In Trivandrum, the "pulses and rice" pattern was inversely related to diabetes [0.70 (0.51-0.95); P(trend) = 0.03] and the "snacks and sweets" pattern was positively associated with abdominal adiposity [2.05 (1.34-3.14); P(trend) = 0.03]. In Mumbai, the "fruit and vegetable" pattern was inversely associated with hypertension [0.63 (0.40-0.99); P(trend) = 0.05] and the "snack and meat" pattern appeared to be positively associated with abdominal adiposity. Conclusions: Cardio-metabolic risk factors were highly prevalent in this population. Across all regions, we found little evidence of a Westernized diet; however, dietary patterns characterized by animal products, fried snacks, or sweets appeared to be positively associated with abdominal adiposity. Conversely, more traditional diets in the Southern regions were inversely related to diabetes and hypertension. Continued investigation of diet, as well as other environmental and biological factors, will be needed to better understand the risk profile in this population and potential means of prevention. C1 [Daniel, Carrie R.; Graubard, Barry I.; Ferrucci, Leah M.; Chatterjee, Nilanjan; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Prabhakaran, Dorairaj; Devasenapathy, Niveditha] Ctr Chron Dis Control, New Delhi 110016, India. [Kapur, Kavita] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Ramakrishnan, Lakshmy; Reddy, K. S.] All India Inst Med Sci, Dept Cardiac Biochem, New Delhi 110029, India. [George, Preethi S.; Gupta, Prakash C.] Reg Canc Ctr, Trivandrum 695011, Kerala, India. [Shetty, Hemali; Gupta, Prakash C.] Healis Sekhsaria Inst Publ Hlth, Navi Mumbai 400614, India. [Yurgalevitch, Susan] WESTAT Corp, Rockville, MD 20850 USA. [Rastogi, Tanuja] UN World Food Programme, I-00148 Rome, Italy. RP Daniel, CR (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM danielc3@mail.nih.gov RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Prabhakaran, Dorairaj/0000-0002-3172-834X FU NIH, National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. We are indebted to the participants of the IHS as well as Sriram Hariharan, Puneet Chadda, Mary McAdams, Eric Berger, and Sujata Dixit-Joshi. NR 76 TC 22 Z9 23 U1 1 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PD JAN 28 PY 2011 VL 10 AR 12 DI 10.1186/1475-2891-10-12 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 724WK UT WOS:000287606900001 PM 21276235 ER PT J AU Ho, J Moir, S Wang, W Posada, JG Gu, WJ Rehman, MT Dewar, R Kovacs, C Sneller, MC Chun, TW Follmann, DA Fauci, AS AF Ho, Jason Moir, Susan Wang, Wei Posada, Jacqueline G. Gu, Wenjuan Rehman, Muhammad T. Dewar, Robin Kovacs, Colin Sneller, Michael C. Chun, Tae-Wook Follmann, Dean A. Fauci, Anthony S. TI Enhancing effects of adjuvanted 2009 pandemic H1N1 influenza A vaccine on memory B-cell responses in HIV-infected individuals SO AIDS LA English DT Article DE adjuvants; antibody response; HIV infection; memory B-cell response; pandemic influenza; vaccination ID ACTIVE ANTIRETROVIRAL THERAPY; ANTIBODY-RESPONSES; ADULTS; IMMUNITY; TRIAL; IMMUNOGENICITY; MORTALITY; SAFETY AB Objective: To assess the humoral immune response to low-dose AS03-adjuvanted and standard-dose nonadjuvanted 2009 pandemic H1N1 influenza A vaccine in HIV-infected aviremic individuals receiving antiretroviral therapy and in uninfected individuals. Design: A three-arm study. Setting: Two clinics: one at the National Institutes of Health in Bethesda, Maryland, USA; and the other at the Maple Leaf Medical Clinic in Toronto, Ontario, Canada. Participants: HIV-infected and HIV-uninfected adults. Intervention: Single intramuscular 15 mu g dose of the monovalent inactivated 2009 pandemic H1N1 influenza A vaccine without adjuvant or 3.75 mu g dose of the same strain with adjuvant AS03. Main outcomes: Immunogenicity, as measured by hemagglutination inhibition (HAI) antibody titers and vaccine-specific memory B-cell responses. Results: A total of 74 participants were enrolled. Twenty-one HIV-infected individuals received the low-dose adjuvanted 2009 pandemic H1N1 influenza A vaccine. Twenty-nine HIV-infected and 24 HIV-uninfected individuals received the standard-dose nonadjuvanted vaccine. There were no significant differences in antibody responses at 9 weeks postvaccination among the three groups studied. However, the IgG memory B-cell response against the vaccine was significantly higher in the HIV-infected group that received the low-dose adjuvanted vaccine when compared to the HIV-infected and uninfected groups that received the standard-dose nonadjuvanted vaccine. Conclusions remained unchanged after regression adjustment for age, gender, CD4(+) T-cell count, and baseline HAI titer. Conclusion: These data suggest that adjuvants could be used to expand coverage through dose sparing and improve humoral immune responses in immunocompromised individuals. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Moir, Susan] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Gu, Wenjuan; Follmann, Dean A.] Natl Canc Inst Frederick, Biostat Res Branch, Frederick, MD USA. [Rehman, Muhammad T.; Dewar, Robin] Natl Canc Inst Frederick, Appl & Dev Res Directorate, Sci Applicat Int Corp Frederick, Frederick, MD USA. [Kovacs, Colin] Maple Leaf Med HIV Res Collaborat Inc, Toronto, ON, Canada. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A02,9000 Rockville Pike, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU NIAID at the NIH; National Cancer Institute, NIH [HHSN261200800001E] FX We thank the volunteers for their participation in this study. We thank Catherine A. Rehm, Erika Benko, Marie A. O'Shea, and Laura Heytens for their assistance with participant recruitment and sample processing. We thank J. Shawn Justement, Danielle Murray, and Clarisa M. Buckner for technical assistance. This work was funded by the Intramural Research Program of NIAID at the NIH, and in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 34 TC 19 Z9 19 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 28 PY 2011 VL 25 IS 3 BP 295 EP 302 DI 10.1097/QAD.0b013e328342328b PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 706DO UT WOS:000286197900003 PM 21157297 ER PT J AU Wang, JL Han, XM Saha, S Xu, T Rai, R Zhang, FL Wolf, YI Wolfson, A Yates, JR Kashina, A AF Wang, Junling Han, Xuemei Saha, Sougata Xu, Tao Rai, Reena Zhang, Fangliang Wolf, Yuri. I. Wolfson, Alexey Yates, John R., III Kashina, Anna TI Arginyltransferase Is an ATP-Independent Self-Regulating Enzyme that Forms Distinct Functional Complexes In Vivo SO CHEMISTRY & BIOLOGY LA English DT Article ID ARGINYL-TRANSFER-RNA; END RULE PATHWAY; N-TERMINAL ARGINYLATION; ACIDIC NH2 TERMINI; PROTEIN TRANSFERASE; IDENTIFICATION; PURIFICATION; COMPONENT; SYSTEM; RGS4 AB Posttranslational arginylation mediated by arginyltransferase (ATE1) plays an important role in cardiovascular development, cell motility, and regulation of cytoskeleton and metabolic enzymes. This protein modification was discovered decades ago, however, the arginylation reaction and the functioning of ATE1 remained poorly understood because of the lack of good biochemical models. Here, we report the development of an in vitro arginylation system, in which ATE1 function and molecular requirements can be tested using purified recombinant ATE1 isoforms supplemented with a controlled number of components. Our results show that arginylation reaction is a self-sufficient, ATP-independent process that can affect different sites in a polypeptide and that arginyltransferases form different molecular complexes in vivo, associate with components of the translation machinery, and have distinct, partially overlapping subsets of substrates, suggesting that these enzymes play different physiological functions. C1 [Wang, Junling; Saha, Sougata; Rai, Reena; Zhang, Fangliang; Kashina, Anna] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. [Han, Xuemei; Xu, Tao; Yates, John R., III] Scripps Res Inst, La Jolla, CA 92037 USA. [Wolf, Yuri. I.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Wolfson, Alexey] Univ Colorado, Boulder, CO 80309 USA. RP Kashina, A (reprint author), Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. EM akashina@vet.upenn.edu RI Xu, Tao/A-9353-2009 FU National Institutes of Health [5R01HL084419, P41 RR011823]; W.W. Smith Charitable Trust; Philip Morris Research Management Group; American Heart Association [0560027Z] FX We are grateful to Dr. Roberto Dominguez and Dr. Francois Ferron for their help in developing the purification and expression systems for ATE1 and E. coli RRS; Kendrick Laboratories, Inc. for performing the 2D gel analysis of the ATE1 isoform substrates; Dr. Claire Mitchell and Jason Lim for help with ATP detection assays; Chao-Xing Yuan and the University of Pennsylvania proteomics core facility for the mass spectrometry analysis of Arg-tRNA preparations; Dr. J. Pehrson and Dr. S. Kurosaka for helpful discussions throughout the project; and Dr. N. G. Avadhani and Dr. S.Y. Fuchs for critical reading of the manuscript. This work was supported by National Institutes of Health grant 5R01HL084419, W.W. Smith Charitable Trust, and Philip Morris Research Management Group (support to A.K.); American Heart Association (award 0560027Z to A.W.); and National Institutes of Health grant P41 RR011823 to J.R.Y. NR 26 TC 21 Z9 21 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JAN 28 PY 2011 VL 18 IS 1 BP 121 EP 130 DI 10.1016/j.chembiol.2010.10.016 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 723XI UT WOS:000287540300017 PM 21276945 ER PT J AU Wan, XP Dennis, AT Obejero-Paz, C Overholt, JL Heredia-Moya, J Kirk, KL Ficker, E AF Wan, Xiaoping Dennis, Adrienne T. Obejero-Paz, Carlos Overholt, Jeffrey L. Heredia-Moya, Jorge Kirk, Kenneth L. Ficker, Eckhard TI Oxidative Inactivation of the Lipid Phosphatase Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) as a Novel Mechanism of Acquired Long QT Syndrome SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; PROTEIN-TYROSINE PHOSPHATASES; TUMOR-SUPPRESSOR PTEN; GROWTH-FACTOR-I; ARSENIC TRIOXIDE; PHOSPHATIDYLINOSITOL 3-KINASE; CARDIAC REPOLARIZATION; CA2+ CHANNEL; KINASE-C; CELLS AB The most common cause of cardiac side effects of pharmaco-therapy is acquired long QT syndrome, which is characterized by abnormal cardiac repolarization and most often caused by direct blockade of the cardiac potassium channel human ether a-go-go-related gene (hERG). However, little is known about therapeutic compounds that target ion channels other than hERG. We have discovered that arsenic trioxide (As(2)O(3)), a very potent antineoplastic compound for the treatment of acute promyelocytic leukemia, is proarrhythmic via two separate mechanisms: a well characterized inhibition of hERG/I(Kr) trafficking and a poorly understood increase of cardiac calcium currents. We have analyzed the latter mechanism in the present study using biochemical and electrophysiological methods. We find that oxidative inactivation of the lipid phosphatase PTEN by As(2)O(3) enhances cardiac calcium currents in the therapeutic concentration range via a PI3K alpha-dependent increase in phosphatidylinositol 3,4,5-triphosphate (PIP(3)) production. In guinea pig ventricular myocytes, even a modest reduction in PTEN activity is sufficient to increase cellular PIP(3) levels. Under control conditions, PIP(3) levels are kept low by PTEN and do not affect calcium current amplitudes. Based on pharmacological experiments and intracellular infusion of PIP(3), we propose that in guinea pig ventricular myocytes, PIP(3) regulates calcium currents independently of the protein kinase Akt along a pathway that includes a secondary oxidation-sensitive target. Overall, our report describes a novel form of acquired long QT syndrome where the target modified by As(2)O(3) is an intracellular signaling cascade. C1 [Wan, Xiaoping; Dennis, Adrienne T.; Ficker, Eckhard] Case Western Reserve Univ, Rammelkamp Ctr Educ & Res, Cleveland, OH 44109 USA. [Obejero-Paz, Carlos] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Overholt, Jeffrey L.] Winston Salem State Univ, Dept Life Sci, Winston Salem, NC 27110 USA. [Heredia-Moya, Jorge; Kirk, Kenneth L.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ficker, E (reprint author), Metrohlth Med Ctr, Rammelkamp Ctr, 2500 Metrohlth Dr, Cleveland, OH 44109 USA. EM eficker@metrohealth.org FU National Institutes of Health [HL71789]; NIDDK, National Institutes of Health; American Heart Association FX This work was supported, in whole or in part, by National Institutes of Health Grant HL71789 (to E. F.) and intramural funds of NIDDK, National Institutes of Health (to J. H.-M. and K. L. K.). This work was also supported by a grant from the American Heart Association (to J. L. O.). NR 45 TC 19 Z9 20 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 28 PY 2011 VL 286 IS 4 BP 2843 EP 2852 DI 10.1074/jbc.M110.125526 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 709TM UT WOS:000286464300050 PM 21097842 ER PT J AU Noben-Trauth, K Latoche, JR AF Noben-Trauth, Konrad Latoche, Joseph R. TI Ectopic Mineralization in the Middle Ear and Chronic Otitis Media with Effusion Caused by RPL38 Deficiency in the Tail-short (Ts) Mouse SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; SENSORINEURAL HEARING-LOSS; RIBOSOMAL-PROTEIN S19; INNER-EAR; LABYRINTHITIS OSSIFICANS; CHOLESTEROL GRANULOMA; EXTRARIBOSOMAL FUNCTIONS; PLANAR POLARITY; EUSTACHIAN-TUBE; OTIC CAPSULE AB Inflammation of the middle ear cavity (otitis media) and the abnormal deposition of bone at the otic capsule are common causes of conductive hearing impairment in children and adults. Although a host of environmental factors can contribute to these conditions, a genetic predisposition has an important role as well. Here, we analyze the Tail-short (Ts) mouse, which harbors a spontaneous semi-dominant mutation that causes skeletal defects and hearing loss. By genetic means, we show that the Ts phenotypes arise from an 18-kb deletion/insertion of the Rpl38 gene, encoding a ribosomal protein of the large subunit. We show that Ts mutants exhibit significantly elevated auditory-brain stem response thresholds and reduced distortion-product otoacoustic emissions, in the presence of normal endocochlear potentials and typical inner ear histology suggestive of a conductive hearing impairment. We locate the cause of the hearing impairment to the middle ear, demonstrating over-ossification at the round window ridge, ectopic deposition of cholesterol crystals in the middle ear cavity, enlarged Eustachian tube, and chronic otitis media with effusion all beginning at around 3 weeks after birth. Using specific antisera, we demonstrate that Rpl38 is an similar to 8-kDa protein that is predominantly expressed in mature erythrocytes. Finally, using an Rpl38 cDNA transgene, we rescue the Ts phenotypes. Together, these data present a previously uncharacterized combination of interrelated middle ear pathologies and suggest Rpl38 deficiency as a model to dissect the causative relationships between neo-ossification, cholesterol crystal deposition, and Eustachian tubes in the etiology of otitis media. C1 [Noben-Trauth, Konrad; Latoche, Joseph R.] NIDCD, Neurogenet Sect, Mol Biol Lab, NIH, Rockville, MD 20850 USA. RP Noben-Trauth, K (reprint author), 5 Res Ct, Rockville, MD 20850 USA. EM nobentk@nidcd.nih.gov FU National Institutes of Health Division of Intramural Research FX This work was supported, in whole or in part, by National Institutes of Health Division of Intramural Research. NR 62 TC 10 Z9 10 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 JAN 28 PY 2011 VL 286 IS 4 BP 3079 EP 3093 DI 10.1074/jbc.M110.184598 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 709TM UT WOS:000286464300070 PM 21062742 ER PT J AU Davis, MI Puhl, HL AF Davis, Margaret I. Puhl, Henry L., III TI Nr4a1-eGFP Is a Marker of Striosome-Matrix Architecture, Development and Activity in the Extended Striatum SO PLOS ONE LA English DT Article ID MESSENGER-RNA EXPRESSION; MU-OPIOID RECEPTOR; MEF2 TRANSCRIPTION FACTORS; RAT CAUDATE-PUTAMEN; COMPARTMENTAL ORGANIZATION; NGFI-B; NUCLEUS-ACCUMBENS; SUBSTANCE-P; DOPAMINE D1; IMMUNOCYTOCHEMICAL LOCALIZATION AB Transgenic mice expressing eGFP under population specific promoters are widely used in neuroscience to identify specific subsets of neurons in situ and as sensors of neuronal activity in vivo. Mice expressing eGFP from a bacterial artificial chromosome under the Nr4a1 promoter have high expression within the basal ganglia, particularly within the striosome compartments and striatal-like regions of the extended amygdala (bed nucleus of the stria terminalis, striatal fundus, central amygdaloid nucleus and intercalated cells). Grossly, eGFP expression is inverse to the matrix marker calbindin 28K and overlaps with mu-opioid receptor immunoreactivity in the striatum. This pattern of expression is similar to Drd1, but not Drd2, dopamine receptor driven eGFP expression in structures targeted by medium spiny neuron afferents. Striosomal expression is strong developmentally where Nr4a1-eGFP expression overlaps with Drd1, TrkB, tyrosine hydroxylase and phospho-ERK, but not phospho-CREB, immunoreactivity in "dopamine islands''. Exposure of adolescent mice to methylphenidate resulted in an increase in eGFP in both compartments in the dorsolateral striatum but eGFP expression remained brighter in the striosomes. To address the role of activity in Nr4a1-eGFP expression, primary striatal cultures were prepared from neonatal mice and treated with forskolin, BDNF, SKF-83822 or high extracellular potassium and eGFP was measured fluorometrically in lysates. eGFP was induced in both neurons and contaminating glia in response to forskolin but SKF-83822, brain derived neurotrophic factor and depolarization increased eGFP in neuronal-like cells selectively. High levels of eGFP were primarily associated with Drd1+ neurons in vitro detected by immunofluorescence; however similar to 15% of the brightly expressing cells contained punctate met-enkephalin immunoreactivity. The Nr4a1-GFP mouse strain will be a useful model for examining the connectivity, physiology, activity and development of the striosome system. C1 [Davis, Margaret I.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD USA. [Puhl, Henry L., III] NIAAA, Lab Mol Physiol, NIH, Bethesda, MD USA. RP Davis, MI (reprint author), NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD USA. EM midavis@mail.nih.gov RI Davis, Margaret/F-4165-2010; OI Puhl, Henry/0000-0003-3095-7201; Davis, Margaret/0000-0002-0489-8351 FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural and Biomedical Research FX This work was supported by the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural and Biomedical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 13 Z9 13 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 28 PY 2011 VL 6 IS 1 AR e16619 DI 10.1371/journal.pone.0016619 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JX UT WOS:000286664100051 PM 21305052 ER PT J AU Johnson, TR Johnson, CN Corbett, KS Edwards, GC Graham, BS AF Johnson, Teresa R. Johnson, Christina N. Corbett, Kizzmekia S. Edwards, Gretchen C. Graham, Barney S. TI Primary Human mDC1, mDC2, and pDC Dendritic Cells Are Differentially Infected and Activated by Respiratory Syncytial Virus SO PLOS ONE LA English DT Article ID INTERFERON-PRODUCING CELLS; ALLERGIC AIRWAY DISEASE; CD4 T-CELLS; VIRAL-INFECTION; CYTOKINE PRODUCTION; PERIPHERAL-BLOOD; IMMUNE-RESPONSES; EPITHELIAL-CELLS; ADAPTIVE IMMUNITY; INFLUENZA-VIRUS AB Respiratory syncytial virus (RSV) causes recurrent infections throughout life. Vaccine development may depend upon understanding the molecular basis for induction of ineffective immunity. Because dendritic cells (DCs) are critically involved in early responses to infection, their interaction with RSV may determine the immunological outcome of RSV infection. Therefore, we investigated the ability of RSV to infect and activate primary mDCs and pDCs using recombinant RSV expressing green fluorescent protein (GFP). At a multiplicity of infection of 5, initial studies demonstrated similar to 6.8% of mDC1 and similar to 0.9% pDCs were infected. We extended these studies to include CD1c(-)CD141(+) mDC2, finding mDC2 infected at similar frequencies as mDC1. Both infected and uninfected cells upregulated phenotypic markers of maturation. Divalent cations were required for infection and maturation, but maturation did not require viral replication. There is evidence that attachment and entry/replication processes exert distinct effects on DC activation. Cell-specific patterns of RSV-induced maturation and cytokine production were detected in mDC1, mDC2, and pDC. We also demonstrate for the first time that RSV induces significant TIMP-2 production in all DC subsets. Defining the influence of RSV on the function of selected DC subsets may improve the likelihood of achieving protective vaccine-induced immunity. C1 [Johnson, Teresa R.; Johnson, Christina N.; Corbett, Kizzmekia S.; Edwards, Gretchen C.; Graham, Barney S.] NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, Natl Inst Hlth Bethesda, Bethesda, MD 20892 USA. RP Johnson, TR (reprint author), NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, Natl Inst Hlth Bethesda, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM teresaj@nih.gov FU NIH FX The work was supported by NIH intramural funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 30 Z9 30 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 28 PY 2011 VL 6 IS 1 AR e16458 DI 10.1371/journal.pone.0016458 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JX UT WOS:000286664100033 PM 21297989 ER PT J AU Smits, M Mir, SE Nilsson, RJA van der Stoop, PM Niers, JM Marquez, VE Cloos, J Breakefield, XO Krichevsky, AM Noske, DP Tannous, BA Wurdinger, T AF Smits, Michiel Mir, Shahryar E. Nilsson, R. Jonas A. van der Stoop, Petra M. Niers, Johanna M. Marquez, Victor E. Cloos, Jacqueline Breakefield, Xandra O. Krichevsky, Anna M. Noske, David P. Tannous, Bakhos A. Wuerdinger, Thomas TI Down-Regulation of miR-101 in Endothelial Cells Promotes Blood Vessel Formation through Reduced Repression of EZH2 SO PLOS ONE LA English DT Article ID HISTONE METHYLTRANSFERASE ACTIVITY; H3 LYSINE-27 METHYLATION; GROUP PROTEIN EZH2; GENE-EXPRESSION; TUMOR-GROWTH; ANGIOGENESIS; CANCER; MICRORNAS; COMPLEX; OVEREXPRESSION AB Angiogenesis is a balanced process controlled by pro-and anti-angiogenic molecules of which the regulation is not fully understood. Besides classical gene regulation, miRNAs have emerged as post-transcriptional regulators of angiogenesis. Furthermore, epigenetic changes caused by histone-modifying enzymes were shown to modulate angiogenesis as well. However, a possible interplay between miRNAs and histone-modulating enzymes during angiogenesis has not been described. Here we show that VEGF-mediated down-regulation of miR-101 caused pro-angiogenic effects. We found that the pro-angiogenic effects are partly mediated through reduced repression by miR-101 of the histone-methyltransferase EZH2, a member of the Polycomb group family, thereby increasing methylation of histone H3 at lysine 27 and transcriptome alterations. In vitro, the sprouting and migratory properties of primary endothelial cell cultures were reduced by inhibiting EZH2 through up-regulation of miR-101, siRNA-mediated knockdown of EZH2, or treatment with 3-Deazaneplanocin-A (DZNep), a small molecule inhibitor of EZH2 methyltransferase activity. In addition, we found that systemic DZNep administration reduced the number of blood vessels in a subcutaneous glioblastoma mouse model, without showing adverse toxicities. Altogether, by identifying a pro-angiogenic VEGF/miR-101/EZH2 axis in endothelial cells we provide evidence for a functional link between growth factor-mediated signaling, post-transcriptional silencing, and histone-methylation in the angiogenesis process. Inhibition of EZH2 may prove therapeutic in diseases in which aberrant vascularization plays a role. C1 [Smits, Michiel; Mir, Shahryar E.; Nilsson, R. Jonas A.; van der Stoop, Petra M.; Niers, Johanna M.; Cloos, Jacqueline; Noske, David P.; Wuerdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp,Dept Neurosurg, Amsterdam, Netherlands. [Smits, Michiel; Mir, Shahryar E.; Nilsson, R. Jonas A.; van der Stoop, Petra M.; Niers, Johanna M.; Cloos, Jacqueline; Noske, David P.; Wuerdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp,Dept Pediat Oncol Hematol, Amsterdam, Netherlands. [Niers, Johanna M.; Breakefield, Xandra O.; Tannous, Bakhos A.; Wuerdinger, Thomas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Mol Neurogenet Unit, Boston, MA USA. [Niers, Johanna M.; Breakefield, Xandra O.; Tannous, Bakhos A.; Wuerdinger, Thomas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Mol Neurogenet Unit, Boston, MA USA. [Niers, Johanna M.; Breakefield, Xandra O.; Tannous, Bakhos A.; Wuerdinger, Thomas] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Marquez, Victor E.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Krichevsky, Anna M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Smits, M (reprint author), Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp,Dept Neurosurg, Amsterdam, Netherlands. EM t.wurdinger@vumc.nl FU Dutch Cancer Society/KWF; Lions Cancer Research Foundation; Umea University, Sweden; Stichting Translational Research CCA/VU University Medical Center; Swedish Research Counsil; National Cancer Institute (NCI) [CA069246, CA86355]; American Brain Tumor Association FX This work was supported by the Dutch Cancer Society/KWF (S. E. M.), Lions Cancer Research Foundation, Umea University, Sweden; Stichting Translational Research CCA/VU University Medical Center; Swedish Research Counsil (R.J.A.N.), National Cancer Institute (NCI) CA069246 and CA86355 (X.O.B.), and the American Brain Tumor Association (T. W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 42 Z9 45 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 28 PY 2011 VL 6 IS 1 AR e16282 DI 10.1371/journal.pone.0016282 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JX UT WOS:000286664100018 PM 21297974 ER PT J AU Parsons, DW Li, M Zhang, XS Jones, S Leary, RJ Lin, JCH Boca, SM Carter, H Samayoa, J Bettegowda, C Gallia, GL Jallo, GI Binder, ZA Nikolsky, Y Hartigan, J Smith, DR Gerhard, DS Fults, DW VandenBerg, S Berger, MS Marie, SKN Shinjo, SMO Clara, C Phillips, PC Minturn, JE Biegel, JA Judkins, AR Resnick, AC Storm, PB Curran, T He, YP Rasheed, BA Friedman, HS Keir, ST McLendon, R Northcott, PA Taylor, MD Burger, PC Riggins, GJ Karchin, R Parmigiani, G Bigner, DD Yan, H Papadopoulos, N Vogelstein, B Kinzler, KW Velculescu, VE AF Parsons, D. Williams Li, Meng Zhang, Xiaosong Jones, Sian Leary, Rebecca J. Lin, Jimmy Cheng-Ho Boca, Simina M. Carter, Hannah Samayoa, Josue Bettegowda, Chetan Gallia, Gary L. Jallo, George I. Binder, Zev A. Nikolsky, Yuri Hartigan, James Smith, Doug R. Gerhard, Daniela S. Fults, Daniel W. VandenBerg, Scott Berger, Mitchel S. Marie, Suely Kazue Nagahashi Shinjo, Sueli Mieko Oba Clara, Carlos Phillips, Peter C. Minturn, Jane E. Biegel, Jaclyn A. Judkins, Alexander R. Resnick, Adam C. Storm, Phillip B. Curran, Tom He, Yiping Rasheed, B. Ahmed Friedman, Henry S. Keir, Stephen T. McLendon, Roger Northcott, Paul A. Taylor, Michael D. Burger, Peter C. Riggins, Gregory J. Karchin, Rachel Parmigiani, Giovanni Bigner, Darell D. Yan, Hai Papadopoulos, Nick Vogelstein, Bert Kinzler, Kenneth W. Velculescu, Victor E. TI The Genetic Landscape of the Childhood Cancer Medulloblastoma SO SCIENCE LA English DT Article ID MYELOID-LEUKEMIA GENOME; SOMATIC MUTATIONS; COLORECTAL CANCERS; HUMAN BREAST; AMPLIFICATION; METHYLATION; PROGRESSION; CARCINOMA; SEQUENCES; COMPLEX AB Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis. C1 [Parsons, D. Williams; Li, Meng; Zhang, Xiaosong; Jones, Sian; Leary, Rebecca J.; Lin, Jimmy Cheng-Ho; Bettegowda, Chetan; Riggins, Gregory J.; Papadopoulos, Nick; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.] Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA. [Parsons, D. Williams; Li, Meng; Zhang, Xiaosong; Jones, Sian; Leary, Rebecca J.; Lin, Jimmy Cheng-Ho; Bettegowda, Chetan; Riggins, Gregory J.; Papadopoulos, Nick; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD 21231 USA. [Parsons, D. Williams] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Parsons, D. Williams] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Parsons, D. Williams] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Boca, Simina M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Carter, Hannah; Samayoa, Josue; Karchin, Rachel] Johns Hopkins Med Inst, Dept Biomed Engn, Inst Computat Med, Baltimore, MD 21218 USA. [Bettegowda, Chetan; Gallia, Gary L.; Jallo, George I.; Binder, Zev A.; Riggins, Gregory J.] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21231 USA. [Nikolsky, Yuri] GeneGo Inc, St Joseph, MI 49085 USA. [Hartigan, James; Smith, Doug R.] Beckman Coulter Genom Inc, Danvers, MA 01923 USA. [Gerhard, Daniela S.] NCI, Off Canc Genom, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fults, Daniel W.] Univ Utah, Sch Med, Dept Neurosurg, Salt Lake City, UT 84132 USA. [VandenBerg, Scott] Univ Calif San Diego, Dept Pathol, Div Neuropathol, San Diego, CA 92103 USA. [Berger, Mitchel S.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Marie, Suely Kazue Nagahashi; Shinjo, Sueli Mieko Oba] Univ Sao Paulo, Sch Med, Dept Neurol, Sao Paulo, Brazil. [Clara, Carlos] Barretos Canc Hosp, Pio XII Fdn, Sao Paulo, Brazil. [Phillips, Peter C.; Minturn, Jane E.; Biegel, Jaclyn A.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Resnick, Adam C.; Storm, Phillip B.] Childrens Hosp Philadelphia, Div Neurosurg, Philadelphia, PA 19104 USA. [Judkins, Alexander R.; Curran, Tom] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [He, Yiping; Rasheed, B. Ahmed; Friedman, Henry S.; Keir, Stephen T.; McLendon, Roger; Bigner, Darell D.; Yan, Hai] Duke Univ, Med Ctr, Pediat Brain Tumor Fdn Inst, Preston Robert Tisch Brain Tumor Ctr,Dept Pathol, Durham, NC 27710 USA. [He, Yiping; Rasheed, B. Ahmed; Friedman, Henry S.; Keir, Stephen T.; McLendon, Roger; Bigner, Darell D.; Yan, Hai] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Northcott, Paul A.; Taylor, Michael D.] Univ Toronto, Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1L7, Canada. [Burger, Peter C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA. [Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Vogelstein, B (reprint author), Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA. EM vogelbe@gmail.com; kinzlke@jhmi.edu; velculescu@jhmi.edu RI Karchin, Rachel/A-3385-2010; Jones, Sian/A-5050-2012; Oba-Shinjo, Sueli /C-4017-2012; Marie, Suely/D-1870-2012; Papadopoulos, Nickolas/K-7272-2012; Curran, Tom/C-1164-2008; Curran, Tom/D-7515-2011 OI Curran, Tom/0000-0003-1444-7551; FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Virginia and D. K. Ludwig Fund for Cancer Research; Alex's Lemonade Stand Foundation; American Brain Tumor Association; Brain Tumor Research Fund at Johns Hopkins; Hoglund Foundation; Ready or Not Foundation; Children's Brain Tumor Foundation; Pediatric Brain Tumor Foundation Institute; David and Barbara B. Hirschhorn Foundation; American Association for Cancer Research; Johns Hopkins Sommer Scholar Program; NIH [CA121113, CA096832, CA057345, CA118822, CA135877, GM074906-01A1/B7BSCW]; NSF [DBI 0845275]; DOD NDSEG [32 CFR 168a] FX We thank J. Ptak, N. Silliman, L. Dobbyn, and M. Whalen for technical assistance with sequencing analyses, and M. Ehinger, D. Satterfield, E. Lipp, D. Lister, and M. J. Dougherty for help with sample preparation and data collection. This project has been funded in part by the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This work was supported by the Virginia and D. K. Ludwig Fund for Cancer Research, Alex's Lemonade Stand Foundation, the American Brain Tumor Association, the Brain Tumor Research Fund at Johns Hopkins, the Hoglund Foundation, the Ready or Not Foundation, the Children's Brain Tumor Foundation, the Pediatric Brain Tumor Foundation Institute, the David and Barbara B. Hirschhorn Foundation, American Association for Cancer Research Stand Up To Cancer Dream Team Translational Cancer Research Grant, Johns Hopkins Sommer Scholar Program, NIH grants CA121113, CA096832, CA057345, CA118822, CA135877, and GM074906-01A1/B7BSCW, NSF grant DBI 0845275, and DOD NDSEG Fellowship 32 CFR 168a. D. W. P. is a Graham Cancer Research Scholar at Texas Children's Cancer Center. Under licensing agreements between the Johns Hopkins University and Beckman Coulter, B.V., K.W.K., and V.E.V. are entitled to a share of royalties received by the university on sales of products related to research described in this paper. N.P., B.V., K.W.K., and V.E.V are cofounders of Inostics and Personal Genome Diagnostics and are members of their Scientific Advisory Boards. N.P., B.V., K.W.K., and V.E.V. own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under university policy. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict-of-interest policies. NR 43 TC 378 Z9 383 U1 3 U2 47 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 JAN 28 PY 2011 VL 331 IS 6016 BP 435 EP 439 DI 10.1126/science.1198056 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712BB UT WOS:000286635900045 PM 21163964 ER PT J AU Badea, TC Nathans, J AF Badea, Tudor Constantin Nathans, Jeremy TI Morphologies of mouse retinal ganglion cells expressing transcription factors Brn3a, Brn3b, and Brn3c: Analysis of wild type and mutant cells using genetically-directed sparse labeling SO VISION RESEARCH LA English DT Article; Proceedings Paper CT 13th Annual Vision Research Conference on Retinal Ganglion Cells - Development, Function, and Disease CY APR 30-MAY 01, 2010 CL Ft Lauderdale, FL DE Mouse; Retina development; Retinal ganglion cell; Brn3 transcription factors; Dendritic arbor ID LATERAL GENICULATE-NUCLEUS; MAMMALIAN RETINA; PRIMATE RETINA; BIPOLAR CELLS; CATS RETINA; DENDRITIC MORPHOLOGIES; RECEPTIVE-FIELDS; AXON OUTGROWTH; VISUAL-SYSTEM; FACTOR BRN-3B AB The mammalian retina contains more than 50 distinct neuronal types, which are broadly classified into several major classes: photoreceptor, bipolar, horizontal, amacrine, and ganglion cells. Although some of the developmental mechanisms involved in the differentiation of retinal ganglion cells (RGCs) are beginning to be understood, there is little information regarding the genetic and molecular determinants of the distinct morphologies of the 15-20 mammalian RGC cell types. Previous work has shown that the transcription factor Brn3b/Pou4f2 plays a major role in the development and survival of many RGCs. The roles of the closely related family members, Brn3a/Pou4f1 and Brn3c/Pou4f3 in RGC development are less clear. Using a genetically-directed method for sparse cell labeling and sparse conditional gene ablation in mice, we describe here the sets of RGC types in which each of the three Brn3/Pou4f transcription factors are expressed and the consequences of ablating these factors on the development of RGC morphologies. Published by Elsevier Ltd. C1 [Badea, Tudor Constantin; Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Neurosci, Baltimore, MD 21205 USA. [Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Ophthalmol, Baltimore, MD 21205 USA. [Badea, Tudor Constantin] NEI, Retinal Circuit Dev & Genet Unit, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. RP Badea, TC (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. EM tbadea@mail.jhmi.edu; badeatc@mail.nih.gov FU Howard Hughes Medical Institute; Intramural NIH HHS [Z99 EY999999] NR 73 TC 33 Z9 34 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 EI 1878-5646 J9 VISION RES JI Vision Res. PD JAN 28 PY 2011 VL 51 IS 2 SI SI BP 269 EP 279 DI 10.1016/j.visres.2010.08.039 PG 11 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 713DV UT WOS:000286716100008 PM 20826176 ER PT J AU Moitra, K Scally, M Mcgee, K Lancaster, G Gold, B Dean, M AF Moitra, Karobi Scally, Mark McGee, Kate Lancaster, Germaine Gold, Bert Dean, Michael TI Molecular Evolutionary Analysis of ABCB5: The Ancestral Gene Is a Full Transporter with Potentially Deleterious Single Nucleotide Polymorphisms SO PLOS ONE LA English DT Article ID BINDING CASSETTE TRANSPORTER; HUMAN-MALIGNANT MELANOMA; CANCER STEM-CELLS; PROTEIN SEQUENCES; CODON ALIGNMENTS; LEUKEMIA-CELLS; PREDICTION; MODEL; CHEMORESISTANCE; RESISTANCE AB Background: ABCB5 is a member of the ABC protein superfamily, which includes the transporters ABCB1, ABCC1 and ABCG2 responsible for causing drug resistance in cancer patients and also several other transporters that have been linked to human disease. The ABCB5 full transporter (ABCB5.ts) is expressed in human testis and its functional significance is presently unknown. Another variant of this transporter, ABCB5 beta posses a "half-transporter-like'' structure and is expressed in melanoma stem cells, normal melanocytes, and other types of pigment cells. ABCB5 beta has important clinical implications, as it may be involved with multidrug resistance in melanoma stem cells, allowing these stem cells to survive chemotherapeutic regimes. Methodology/Principal Findings: We constructed and examined in detail topological structures of the human ABCB5 protein and determined in-silico the cSNPs (coding single nucleotide polymorphisms) that may affect its function. Evolutionary analysis of ABCB5 indicated that ABCB5, ABCB1, ABCB4, and ABCB11 share a common ancestor, which began duplicating early in the evolutionary history of chordates. This suggests that ABCB5 has evolved as a full transporter throughout its evolutionary history. Conclusions/Significance: From our in-silco analysis of cSNPs we found that a large number of non-synonymous cSNPs map to important functional regions of the protein suggesting that these SNPs if present in human populations may play a role in diseases associated with ABCB5. From phylogenetic analyses, we have shown that ABCB5 evolved as a full transporter throughout its evolutionary history with an absence of any major shifts in selection between the various lineages suggesting that the function of ABCB5 has been maintained during mammalian evolution. This finding would suggest that ABCB5 beta may have evolved to play a specific role in human pigment cells and/or melanoma cells where it is predominantly expressed. C1 [Moitra, Karobi; Scally, Mark; McGee, Kate; Lancaster, Germaine; Gold, Bert; Dean, Michael] NCI, Expt Immunol Lab, Human Genet Sect, Canc & Inflammat Program, Frederick, MD 21701 USA. RP Moitra, K (reprint author), NCI, Expt Immunol Lab, Human Genet Sect, Canc & Inflammat Program, Frederick, MD 21701 USA. EM deanm@mail.nih.gov RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU National Institutes of Health, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 11 Z9 11 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 27 PY 2011 VL 6 IS 1 AR e16318 DI 10.1371/journal.pone.0016318 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JV UT WOS:000286663900032 PM 21298007 ER PT J AU Mukhopadhyay, S Varin, A Chen, YY Liu, BY Tryggvason, K Gordon, S AF Mukhopadhyay, Subhankar Varin, Audrey Chen, Yunying Liu, Baoying Tryggvason, Karl Gordon, Siamon TI SR-A/MARCO-mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens SO BLOOD LA English DT Article ID CLASS-A; RECEPTOR MARCO; NALP3 INFLAMMASOME; INNATE IMMUNITY; NEISSERIA-MENINGITIDIS; MACROPHAGES; RECOGNITION; ACTIVATION; ATP; PHAGOCYTOSIS AB Phagocytic and pathogen sensing receptors are responsible for particle uptake and inflammation. It is unclear how these receptors' systems influence each other's function to shape an innate response. The class-A scavenger receptors SR-A (scavenger receptor A) and MARCO (macrophage receptor with collagenous structure) are 2 well-characterized phagocytic receptors that are unable to initiate inflammatory responses by themselves, yet are implicated in the pathogenesis of various inflammatory disorders. However, the mechanism for such an apparent discrepancy is still unclear. We utilized SR-A(-/-), MARCO(-/-), and SR-A(-/-)-MARCO(-/-) mice, along with microbe-derived, environmental, and synthetic polyanions to assess the inflammatory responses following combinatorial ligation of SR-A/MARCO and selected Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) by their shared ligands. In addition to ligating SR-A and MARCO, these agonists also selectively activated the cell-surface sensor TLR4, endosomal TLR3, and the cytosolic NOD2 and NALP3 (NACHT domain-, leucine-rich repeat-, and pyrin domain-containing protein 3). We show that, following recognition of common ligands, SR-A and MARCO attenuate TLR4-mediated responses while enhancing responses by the intracellular TLR3, NOD2, and NALP3. We conclude that SR-A/MARCO-mediated rapid ligand internalization prevented sensing by surface TLRs while increasing ligand availability in intracellular compartments, thus allowing sensing and robust responses by intracellular sensors. (Blood. 2011; 117(4):1319-1328) C1 [Mukhopadhyay, Subhankar; Varin, Audrey; Gordon, Siamon] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. [Varin, Audrey] Univ Tours, Fac Med, Tours, France. [Chen, Yunying] Karolinska Inst, Dept Med Solna, Clin Allergy Res Unit, Stockholm, Sweden. [Liu, Baoying] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Tryggvason, Karl] Karolinska Inst, Dept Med Biochem & Biophys, Div Matrix Biol, Stockholm, Sweden. RP Gordon, S (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England. EM siamon.gordon@path.ox.ac.uk FU Wellcome Trust; Fondation pour la Recherche Medicale; Medical Research Council, United Kingdom FX S.M. was supported by the E. P. Abraham Trust, Oxford, and is presently funded by a Wellcome Trust Flexible Travel Award Fellowship. A.V. was supported by the Fondation pour la Recherche Medicale. S.G. was supported by a program grant from the Medical Research Council, United Kingdom. NR 50 TC 38 Z9 40 U1 0 U2 13 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 27 PY 2011 VL 117 IS 4 BP 1319 EP 1328 DI 10.1182/blood-2010-03-276733 PG 10 WC Hematology SC Hematology GA 711WZ UT WOS:000286623400031 PM 21098741 ER PT J AU Cho, J Shen, HM Yu, H Li, HJ Cheng, T Lee, SB Lee, BC AF Cho, Joonseok Shen, Hongmei Yu, Hui Li, Hongjie Cheng, Tao Lee, Sean Bong Lee, Byeong Chel TI Ewing sarcoma gene Ews regulates hematopoietic stem cell senescence SO BLOOD LA English DT Article ID PROGENITOR CELLS; AGE; EXPRESSION; FAMILY; MOUSE; P16; ACTIVATION; QUIESCENCE; LEUKEMIA; TUMORS AB The longevity of organisms is maintained by stem cells. If an organism loses the ability to maintain a balance between quiescence and differentiation in the stem/progenitor cell compartment due to aging and/or stress, this may result in death or age-associated diseases, including cancer. Ewing sarcoma is the most lethal bone tumor in young patients and arises from primitive stem cells. Here, we demonstrated that endogenous Ewing sarcoma gene (Ews) is indispensable for stem cell quiescence, and that the ablation of Ews promotes the early onset of senescence in hematopoietic stem progenitor cells. The phenotypic and functional changes in Ews-deficient stem cells were accompanied by an increase in senescence-associated beta-galactosidase staining and a marked induction of p16(INK4a) compared with wild-type counterparts. With its relevance to cancer and possibly aging, EWS is likely to play a significant role in maintaining the functional capacity of stem cells and may provide further insight into the complexity of Ewing sarcoma in the context of stem cells. (Blood. 2011;117(4):1156-1166) C1 [Lee, Byeong Chel] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Sch Med, Pittsburgh, PA 15213 USA. [Cho, Joonseok; Lee, Byeong Chel] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol & Oncol, Pittsburgh, PA 15213 USA. [Shen, Hongmei] Univ Pittsburgh, Sch Med, Dept Surg, Thomas E Starzl Transplantat Inst, Pittsburgh, PA 15213 USA. [Yu, Hui; Cheng, Tao] Univ Pittsburgh, Sch Med, Dept Radiat Oncol, Pittsburgh, PA 15213 USA. [Li, Hongjie; Lee, Sean Bong] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Cheng, Tao] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China. [Cheng, Tao] Chinese Acad Med Sci, Blood Dis Hosp, Ctr Stem Cell Med, Tianjin, Peoples R China. [Cheng, Tao] Peking Union Med Coll, Tianjin, Peoples R China. RP Lee, BC (reprint author), Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Sch Med, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM leeb4@upmc.edu OI Cho, Joonseok/0000-0001-7268-5748 FU Department of Defense [W81XWH-09-1-0364]; University of Pittsburgh Cancer Institute; National Institutes of Health [R01HL070561]; National Basic Research Program of China [2011CB964801]; Tianjin International Co-operation Science Foundation [09ZC-ZDSF03800]; Hillman Foundation; Leukemia & Lymphoma Society; National Natural Science Foundation of China (NSFC) [30825017] FX This work was supported in part by the Department of Defense (W81XWH-09-1-0364) and the University of Pittsburgh Cancer Institute to B. L.; and by the National Institutes of Health (R01HL070561), the National Basic Research Program of China (2011CB964801), and the Tianjin International Co-operation Science Foundation (09ZC-ZDSF03800) to T. C. B. L. is a recipient of the Hillman Foundation Research Scholar Grant. T. C. is a recipient of the Scholar Award from the Leukemia & Lymphoma Society (1027-08) and the Outstanding Young Scholar Award from the National Natural Science Foundation of China (NSFC; no. 30825017). NR 48 TC 27 Z9 28 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 27 PY 2011 VL 117 IS 4 BP 1156 EP 1166 DI 10.1182/blood-2010-04-279349 PG 11 WC Hematology SC Hematology GA 711WZ UT WOS:000286623400013 PM 21030557 ER PT J AU Zhang, SL Readinger, JA DuBois, W Janka-Junttila, M Robinson, R Pruitt, M Bliskovsky, V Wu, JZ Sakakibara, K Patel, J Parent, CA Tessarollo, L Schwartzberg, PL Mock, BA AF Zhang, Shuling Readinger, Julie A. DuBois, Wendy Janka-Junttila, Mirkka Robinson, Richard Pruitt, Margaret Bliskovsky, Val Wu, Julie Z. Sakakibara, Kaori Patel, Jyoti Parent, Carole A. Tessarollo, Lino Schwartzberg, Pamela L. Mock, Beverly A. TI Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production SO BLOOD LA English DT Article ID TUMOR-SUPPRESSOR GENE; B-CELLS; TRANSLATION INITIATION; MAMMALIAN TARGET; KINASE INHIBITOR; REGULATORY CELLS; LYMPHOID ORGANS; RAPAMYCIN; MIGRATION; ACTIVATION AB Mammalian TOR (mTOR) regulates cell growth, proliferation, and migration. Because mTOR knock-outs are embryonic lethal, we generated a viable hypomorphic mouse by neo-insertion that partially disrupts mTOR transcription and creates a potential physiologic model of mTORC1/TORC2 inhibition. Homozygous knock-in mice exhibited reductions in body, organ, and cell size. Although reductions in most organ sizes were proportional to decreased body weight, spleens were disproportionately smaller. Decreases in the total number of T cells, particularly memory cells, and reduced responses to chemokines suggested alterations in T-cell homing/homeostasis. T-cell receptor-stimulated T cells proliferated less, produced lower cytokine levels, and expressed FoxP3. Decreased neutrophil numbers were also observed in the spleen, despite normal development and migration in the bone marrow. However, B-cell effects were most pronounced, with a partial block in B-cell development in the bone marrow, altered splenic populations, and decreases in proliferation, antibody production, and migration to chemokines. Moreover, increased AKT(Ser473) phosphorylation was observed in activated B cells, reminiscent of cancers treated with rapamycin, and was reduced by a DNA-pk inhibitor. Thus, mTOR is required for the maturation and differentiation of multiple immune cell lineages. These mice provide a novel platform for studying the consequences of constitutively reduced mTORC1/TORC2 activity. (Blood. 2011;117(4):1228-1238) C1 [Mock, Beverly A.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Readinger, Julie A.; Wu, Julie Z.; Schwartzberg, Pamela L.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Janka-Junttila, Mirkka; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Mock, BA (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bldg 37,Rm 3146,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. EM bev@helix.nih.gov FU National Institutes of Health, National Cancer Institute; Center for Cancer Research; National Human Genome Research Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the National Human Genome Research Institute. NR 50 TC 54 Z9 56 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 27 PY 2011 VL 117 IS 4 BP 1228 EP 1238 DI 10.1182/blood-2010-05-287821 PG 11 WC Hematology SC Hematology GA 711WZ UT WOS:000286623400020 PM 21079150 ER PT J AU Bolton, EE Kim, S Bryant, SH AF Bolton, Evan E. Kim, Sunghwan Bryant, Stephen H. TI PubChem3D: Conformer generation SO JOURNAL OF CHEMINFORMATICS LA English DT Article ID MOLECULAR-FORCE FIELD; PROTEIN DATA-BANK; ENTREZS 3D-STRUCTURE DATABASE; CONFORMATIONAL ENERGIES; MMFF94; PERFORMANCE; GEOMETRIES; OMEGA; INFORMATION; VALIDATION AB Background: PubChem, an open archive for the biological activities of small molecules, provides search and analysis tools to assist users in locating desired information. Many of these tools focus on the notion of chemical structure similarity at some level. PubChem3D enables similarity of chemical structure 3-D conformers to augment the existing similarity of 2-D chemical structure graphs. It is also desirable to relate theoretical 3-D descriptions of chemical structures to experimental biological activity. As such, it is important to be assured that the theoretical conformer models can reproduce experimentally determined bioactive conformations. In the present study, we investigate the effects of three primary conformer generation parameters (the fragment sampling rate, the energy window size, and force field variant) upon the accuracy of theoretical conformer models, and determined optimal settings for PubChem3D conformer model generation and conformer sampling. Results: Using the software package OMEGA from OpenEye Scientific Software, Inc., theoretical 3-D conformer models were generated for 25,972 small-molecule ligands, whose 3-D structures were experimentally determined. Different values for primary conformer generation parameters were systematically tested to find optimal settings. Employing a greater fragment sampling rate than the default did not improve the accuracy of the theoretical conformer model ensembles. An ever increasing energy window did increase the overall average accuracy, with rapid convergence observed at 10 kcal/mol and 15 kcal/mol for model building and torsion search, respectively; however, subsequent study showed that an energy threshold of 25 kcal/mol for torsion search resulted in slightly improved results for larger and more flexible structures. Exclusion of coulomb terms from the 94s variant of the Merck molecular force field (MMFF94s) in the torsion search stage gave more accurate conformer models at lower energy windows. Overall average accuracy of reproduction of bioactive conformations was remarkably linear with respect to both non-hydrogen atom count ("size") and effective rotor count ("flexibility"). Using these as independent variables, a regression equation was developed to predict the RMSD accuracy of a theoretical ensemble to reproduce bioactive conformations. The equation was modified to give a minimum RMSD conformer sampling value to help ensure that 90% of the sampled theoretical models should contain at least one conformer within the RMSD sampling value to a "bioactive" conformation. Conclusion: Optimal parameters for conformer generation using OMEGA were explored and determined. An equation was developed that provides an RMSD sampling value to use that is based on the relative accuracy to reproduce bioactive conformations. The optimal conformer generation parameters and RMSD sampling values determined are used by the PubChem3D project to generate theoretical conformer models. C1 [Bolton, Evan E.; Kim, Sunghwan; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Bolton, EE (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Dept Hlth & Human Serv, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov RI Kim, Sunghwan/A-6738-2008 OI Kim, Sunghwan/0000-0001-9828-2074 FU National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services FX We are grateful to the NCBI Systems staff, especially Ron Patterson, Charlie Cook, and Don Preuss, whose efforts helped make the PubChem3D project possible. This research was supported in part by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). NR 33 TC 15 Z9 15 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD JAN 27 PY 2011 VL 3 AR 4 DI 10.1186/1758-2946-3-4 PG 16 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 891NQ UT WOS:000300224300001 PM 21272340 ER PT J AU Ghosh, AK Chapsal, BD Baldridge, A Steffey, MP Walters, DE Koh, Y Amano, M Mitsuya, H AF Ghosh, Arun K. Chapsal, Bruno D. Baldridge, Abigail Steffey, Melinda P. Walters, D. Eric Koh, Yasuhiro Amano, Masayuki Mitsuya, Hiroaki TI Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived High Affinity P-2 Ligands: Structure-Activity Studies and Biological Evaluation SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID COMBAT DRUG-RESISTANCE; VIRUS IN-VITRO; GENERATION; THERAPY; TMC114; INFECTION; DARUNAVIR; HALIDES; COPPER; AIDS AB The design, synthesis, and evaluation of a new series of hexahydrofuropyranol-derived HIV-1 protease inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of la-bound HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol, (-)-7, was carried out in optically active form. Incorporation of this ligand provided inhibitor 35a, which has shown excellent enzyme inhibitory activity and antiviral potency. Our structure activity studies have indicated that the stereochemistry and the position of oxygens in the ligand are important to the observed potency of the inhibitor. Inhibitor 35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand. C1 [Ghosh, Arun K.; Chapsal, Bruno D.; Baldridge, Abigail; Steffey, Melinda P.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Walters, D. Eric] Rosalind Franklin Univ Med & Sci, Dept Biochem & Mol Biol, N Chicago, IL 60064 USA. [Koh, Yasuhiro; Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 8608556, Japan. [Koh, Yasuhiro; Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU National Institutes of Health [GM 53386]; Center for Cancer Research, National Cancer Institute, National Institutes of Health; Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho); Ministry of Health, Welfare, and Labor of Japan (Kosei Rohdosho); Monbu-Kagakusho FX The research was supported by the National Institutes of Health (Grant GM 53386). This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and in part by a Grant-in-Aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan (Kosei Rohdosho), and a Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho. NR 37 TC 34 Z9 35 U1 0 U2 7 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 JAN 27 PY 2011 VL 54 IS 2 BP 622 EP 634 DI 10.1021/jm1012787 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 707SN UT WOS:000286306400018 PM 21194227 ER PT J AU Cicala, C Arthos, J Fauci, AS AF Cicala, Claudia Arthos, James Fauci, Anthony S. TI HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; MACROPHAGE-TROPIC HIV; VIROLOGICAL SYNAPSE FORMATION; SUBTYPE-C INFECTION; GASTROINTESTINAL-TRACT; NEUTRALIZING ANTIBODY; CHLAMYDIA-TRACHOMATIS; CHEMOKINE RECEPTORS; SIGNAL-TRANSDUCTION AB It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in similar to 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a "genetic bottleneck", and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4(+) T cells express high levels of CCR5, and a subset of these CD4(+)/CCR5(high) cells express the integrin alpha(4)beta(7), the gut homing receptor. CD4(+)/CCR5(high)/alpha 4 beta 7(high) T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to alpha(4)beta(7) on CD4(+) T cells. On CD4(+)/CCR5(high)/alpha 4 beta 7(high) T cells, alpha(4)beta(7) is closely associated with CD4 and CCR5. Furthermore, alpha(4)beta(7) is similar to 3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-alpha(4)beta(7) interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell-to-cell spread of HIV-1. gp120 binding to alpha(4)beta, is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-alpha(4)beta(7) interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-alpha(4)beta(7) interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infection C1 [Cicala, Claudia; Arthos, James; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Cicala, C (reprint author), NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM CCICALA@niaid.nih.gov NR 97 TC 42 Z9 43 U1 4 U2 16 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 JAN 27 PY 2011 VL 9 SU 1 AR S2 DI 10.1186/1479-5876-9-S1-S2 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 759XA UT WOS:000290280800003 PM 21284901 ER PT J AU Grivel, JC Shattock, RJ Margolis, LB AF Grivel, Jean-Charles Shattock, Robin J. Margolis, Leonid B. TI Selective transmission of R5 HIV-1 variants: where is the gatekeeper? SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN LYMPHOID-TISSUE; DUAL-TROPIC HIV-1; CD4(+) T-CELLS; LYMPHADENOPATHY-ASSOCIATED VIRUS; CHEMOKINE RECEPTOR EXPRESSION; SYNCYTIUM-INDUCING PHENOTYPE; INFECTIOUS MOLECULAR CLONES; DEFICIENCY-SYNDROME VIRUS; FEMALE GENITAL-TRACT AB To enter target cells HIV-1 uses CD4 and a coreceptor. In vivo the coreceptor function is provided either by CCR5 (for R5) or CXCR4 (for X4 HIV-1). Although both R5 and X4 HIV-1 variants are present in body fluids (semen, blood, cervicovaginal and rectal secretions), R5 HIV-1 appears to transmit infection and dominates early stages of HIV disease. Moreover, recent sequence analysis of virus in acute infection shows that, in the majority of cases of transmission, infection is initiated by a single virus. Therefore, the existence of a "gatekeeper" that selects R5 over X4 HIV-1 and that operates among R5 HIV-1 variants has been suggested. In the present review we consider various routes of HIV-transmission and discuss potential gatekeeping mechanisms associated with each of these routes. Although many mechanisms have been identified none of them explains the almost perfect selection of R5 over X4 in HIV-1 transmission. We suggest that instead of one strong gatekeeper there are multiple functional gatekeepers and that their superimposition is sufficient to protect against X4 HIV-1 infection and potentially select among R5 HIV-1 variants. In conclusion, we propose that the principle of multiple barriers is more general and not restricted to protection against X4 HIV-1 but rather can be applied to other phenomena when one factor has a selective advantage over the other(s). In the case of gatekeepers for HIV-1 transmission, the task is to identify them and to decipher their molecular mechanisms. Knowledge of the gatekeepers` localization and function may enable us to enhance existing barriers against R5 transmission and to erect the new ones against all HIV-1 variants. C1 [Grivel, Jean-Charles; Margolis, Leonid B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Shattock, Robin J.] Univ London, London, England. RP Margolis, LB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM margolis@helix.nih.gov FU NICHD; EUROPRISE, EC [LSHP-CT-2006-037611] FX The work of J-C.G. and LM was supported by the Intramural NICHD Program. RJS contribution to this manuscript was supported by FP-6-funded EUROPRISE, EC grant LSHP-CT-2006-037611. NR 192 TC 53 Z9 53 U1 2 U2 11 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 JAN 27 PY 2011 VL 9 SU 1 AR S6 DI 10.1186/1479-5876-9-S1-S6 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 759XA UT WOS:000290280800007 PM 21284905 ER PT J AU Schuitemaker, H van 't Wout, AB Lusso, P AF Schuitemaker, Hanneke van 't Wout, Angelique B. Lusso, Paolo TI Clinical significance of HIV-1 coreceptor usage SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; SYNCYTIUM-INDUCING PHENOTYPE; GP120 ENVELOPE GLYCOPROTEIN; CHEMOKINE RECEPTOR USE; IN-VIVO EVOLUTION; DUAL-TROPIC HIV-1; SUBTYPE-C; DISEASE PROGRESSION; TYPE-1 INFECTION AB The identification of phenotypically distinct HIV-1 variants with different prevalence during the progression of the disease has been one of the earliest discoveries in HIV-1 biology, but its relevance to AIDS pathogenesis remains only partially understood. The physiological basis for the phenotypic variability of HIV-1 was elucidated with the discovery of distinct coreceptors employed by the virus to infect susceptible cells. The role of the viral phenotype in the variable clinical course and treatment outcome of HIV-1 infection has been extensively investigated over the past two decades. In this review, we summarize the major findings on the clinical significance of the HIV-1 coreceptor usage. C1 [Schuitemaker, Hanneke; van 't Wout, Angelique B.] Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, NL-1105 AZ Amsterdam, Netherlands. [Lusso, Paolo] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Schuitemaker, Hanneke; van 't Wout, Angelique B.] Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, Dept Expt Immunol, NL-1105 AZ Amsterdam, Netherlands. RP Schuitemaker, H (reprint author), Crucell Holland BV, Leiden, Netherlands. EM H.Schuitemaker@amc.uva.nl; plusso@niaid.nih.gov FU NIAID, NIH, Bethesda, Maryland FX This work was supported in part by the Intramural Research Program of the NIAID, NIH, Bethesda, Maryland. We wish to thank all the individuals who ever worked in the Department of Clinical Viro- Immunology at the Sanquin Blood Supply Foundation and/or at the Laboratory for Viral Immune Pathogenesis at the Academic Medical Center for their helpful discussion on the topic of HIV-1 variability in AIDS pathogenesis. We thank Dr Andrew Leigh-Brown for his helpful suggestion on the different ages of the HIV-1 subtype epidemics. NR 174 TC 33 Z9 34 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 27 PY 2011 VL 9 SU 1 AR S5 DI 10.1186/1479-5876-9-S1-S5 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 759XA UT WOS:000290280800006 PM 21284904 ER PT J AU Zaidi, MR Davis, S Noonan, FP Graff-Cherry, C Hawley, TS Walker, RL Feigenbaum, L Fuchs, E Lyakh, L Young, HA Hornyak, TJ Arnheiter, H Trinchieri, G Meltzer, PS De Fabo, EC Merlino, G AF Zaidi, M. Raza Davis, Sean Noonan, Frances P. Graff-Cherry, Cari Hawley, Teresa S. Walker, Robert L. Feigenbaum, Lionel Fuchs, Elaine Lyakh, Lyudmila Young, Howard A. Hornyak, Thomas J. Arnheiter, Heinz Trinchieri, Giorgio Meltzer, Paul S. De Fabo, Edward C. Merlino, Glenn TI Interferon-gamma links ultraviolet radiation to melanomagenesis in mice SO NATURE LA English DT Article ID HLA-E; MONOCLONAL-ANTIBODIES; MALIGNANT-MELANOMA; MOUSE; MACROPHAGES; MELANOCYTES; EXPRESSION; CELLS; SKIN; SEQUENCE AB Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood(1,2). We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA(3,4). However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-gamma (IFN-gamma), but not type-I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-enhanced melanoma growth and survival. IFN-gamma-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients. C1 [Zaidi, M. Raza; Merlino, Glenn] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Davis, Sean; Walker, Robert L.; Meltzer, Paul S.] NCI, Genet Branch, Bethesda, MD 20892 USA. [Noonan, Frances P.; De Fabo, Edward C.] George Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Lab Photobiol & Photoimmunol, Washington, DC 20037 USA. [Graff-Cherry, Cari; Feigenbaum, Lionel] NCI, Lab Anim Sci Program, Frederick, MD 21702 USA. [Fuchs, Elaine] Rockefeller Univ, New York, NY 10021 USA. [Lyakh, Lyudmila; Young, Howard A.; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Hornyak, Thomas J.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Arnheiter, Heinz] NINDS, Bethesda, MD 20892 USA. RP Merlino, G (reprint author), NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM drmecd@gwumc.edu; gmerlino@helix.nih.gov RI Zaidi, M. Raza/H-1386-2016 OI Zaidi, M. Raza/0000-0003-0480-3188 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute; National Institutes of Health [CA53765, CA92258]; Melanoma Research Foundation FX We would like to thank the following individuals for their support: S. Yuspa for primary keratinocytes; C. Toniatti and H. Bujard for the rtTA2sM2 construct; V. Hearing for melan-c cell line; S. Hewitt for the human melanoma tissue microarray; M. Anver for immunohistochemical staining and production/analysis of mouse melanoma tissue microarray; K. Blas and E. Vega-Valle for technical help; N. Restifo and A. Hurwitz for suggestions and discussions. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. M.R.Z. was supported by a National Cancer Institute Director's Innovation Career Development Award. E.C.D. and F.P.N. were supported by grants from the National Institutes of Health (awards CA53765 and CA92258), and the Melanoma Research Foundation. NR 43 TC 107 Z9 110 U1 3 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 27 PY 2011 VL 469 IS 7331 BP 548 EP U129 DI 10.1038/nature09666 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711MU UT WOS:000286596500036 PM 21248750 ER PT J AU Assisi, C Stopfer, M Bazhenov, M AF Assisi, Collins Stopfer, Mark Bazhenov, Maxim TI Using the Structure of Inhibitory Networks to Unravel Mechanisms of Spatiotemporal Patterning SO NEURON LA English DT Article ID OSCILLATING NEURAL ASSEMBLIES; LOCUST ANTENNAL LOBE; COMPLEX NETWORKS; FEEDFORWARD INHIBITION; OLFACTORY NETWORK; NEURONAL NETWORKS; FIRING PATTERNS; MUSHROOM BODY; SYNCHRONIZATION; DYNAMICS AB Neuronal networks exhibit a rich dynamical repertoire, a consequence of both the intrinsic properties of neurons and the structure of the network. It has been hypothesized that inhibitory interneurons corral principal neurons into transiently synchronous ensembles that encode sensory information and subserve behavior. How does the structure of the inhibitory network facilitate such spatiotemporal patterning? We established a relationship between an important structural property of a network, its colorings, and the dynamics it constrains. Using a model of the insect antennal lobe, we show that our description allows the explicit identification of the groups of inhibitory interneurons that switch, during odor stimulation, between activity and quiescence in a coordinated manner determined by features of the network structure. This description optimally matches the perspective of the downstream neurons looking for synchrony in ensembles of presynaptic cells and allows a low-dimensional description of seemingly complex high-dimensional network activity. C1 [Assisi, Collins; Bazhenov, Maxim] Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. [Stopfer, Mark] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Assisi, C (reprint author), Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. EM collinsa@ucr.edu RI Assisi, Collins/R-7467-2016 OI Assisi, Collins/0000-0003-0108-582X FU US National Institute of Deafness and other Communication Disorders; US National Institute of Neurological Disorders and Stroke; US National Institute of Child Health and Human Development FX This work was supported by grants from the US National Institute of Deafness and other Communication Disorders (C.A. and M.B.), the US National Institute of Neurological Disorders and Stroke (M.B.) and a US National Institute of Child Health and Human Development intramural award (M.S.). The authors would like to thank Professor Gilles Laurent for many stimulating discussions and insightful suggestions and Stacey Brown Daffron for providing examples of recordings from LNs made in vivo. C.A and M.B. would also like to thank Professor Terrence Sejnowski and members of the Computational Neurobiology Laboratory at the Salk Institute for Biological Studies for hospitality and a number of fruitful discussions. C.A. would like to thank Dr. Suhita Nadkarni for discussions and comments about the manuscript. NR 71 TC 16 Z9 16 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN 27 PY 2011 VL 69 IS 2 BP 373 EP 386 DI 10.1016/j.neuron.2010.12.019 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 714FM UT WOS:000286792900018 PM 21262473 ER PT J AU Davis, JL Huang, L Worodria, W Masur, H Cattamanchi, A Huber, C Miller, C Conville, PS Murray, P Kovacs, JA AF Davis, J. Lucian Huang, Laurence Worodria, William Masur, Henry Cattamanchi, Adithya Huber, Charles Miller, Cecily Conville, Patricia S. Murray, Patrick Kovacs, Joseph A. TI Nucleic Acid Amplification Tests for Diagnosis of Smear-Negative TB in a High HIV-Prevalence Setting: A Prospective Cohort Study SO PLOS ONE LA English DT Article ID POLYMERASE-CHAIN-REACTION; PULMONARY TUBERCULOSIS; COST-EFFECTIVENESS; MICROSCOPY; UGANDA; SPUTUM; SECA1; PCR AB Background: Nucleic acid amplification tests are sensitive for identifying Mycobacterium tuberculosis in populations with positive sputum smears for acid-fast bacilli, but less sensitive in sputum-smear-negative populations. Few studies have evaluated the clinical impact of these tests in low-income countries with high burdens of TB and HIV. Methods: We prospectively enrolled 211 consecutive adults with cough >= 2 weeks and negative sputum smears at Mulago Hospital in Kampala, Uganda. We tested a single early-morning sputum specimen for Mycobacterium tuberculosis DNA using two nucleic acid amplification tests: a novel in-house polymerase chain reaction targeting the mycobacterial secA1 gene, and the commercial Amplified (R) Mycobacterium tuberculosis Direct (MTD) test (Gen-Probe Inc, San Diego, CA). We calculated the diagnostic accuracy of these index tests in reference to a primary microbiologic gold standard (positive mycobacterial culture of sputum or bronchoalveolar lavage fluid), and measured their likely clinical impact on additional tuberculosis cases detected among those not prescribed initial TB treatment. Results: Of 211 patients enrolled, 170 (81%) were HIV-seropositive, with median CD4+ T-cell count 78 cells/mL (interquartile range 29-203). Among HIV-seropositive patients, 94 (55%) reported taking co-trimoxazole prophylaxis and 29 (17%) reported taking antiretroviral therapy. Seventy-five patients (36%) had culture-confirmed TB. Sensitivity of MTD was 39% (95% CI 28-51) and that of secA1 was 24% (95% CI 15-35). Both tests had specificities of 95% (95% CI 90-98). The MTD test correctly identified 18 (24%) TB patients not treated at discharge and led to a 72% relative increase in the smear-negative case detection rate. Conclusions: The secA1 and MTD nucleic acid amplification tests had moderate sensitivity and high specificity for TB in a predominantly HIV-seropositive population with negative sputum smears. Although newer, more sensitive nucleic acid assays may enhance detection of Mycobacterium tuberculosis in sputum, even currently available tests can provide substantial clinical impact in smear-negative populations. C1 [Davis, J. Lucian; Huang, Laurence; Cattamanchi, Adithya; Miller, Cecily] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Huang, Laurence] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div HIV AIDS, San Francisco, CA 94143 USA. [Davis, J. Lucian; Cattamanchi, Adithya] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Francis J Curry Int TB Ctr, San Francisco, CA 94143 USA. [Masur, Henry; Kovacs, Joseph A.] Natl Inst Hlth Clin Ctr, Dept Crit Care Med, Bethesda, MD USA. [Huber, Charles; Conville, Patricia S.; Murray, Patrick] Natl Inst Hlth Clin Ctr, Dept Lab Med, Bethesda, MD USA. [Worodria, William] Makerere Univ, Mulago Hosp, Dept Med, Kampala, Uganda. [Davis, J. Lucian; Huang, Laurence; Worodria, William; Cattamanchi, Adithya] Makerere Univ, Univ Calif San Francisco Res Collaborat, Kampala, Uganda. RP Davis, JL (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. EM Lucian.Davis@ucsf.edu OI Davis, J. Lucian/0000-0002-8629-9992 FU National Institutes of Health [NIH T32HL007185, NIH P30AI027763, NIH K23AI080147, NIH K23HL094141, NIH K24HL087713, NIH R01HL090335]; NIH Bench-to-Bedside; National Center for Research Resources [KL2RR024130]; National Institutes of Health Clinical Center; National Institute of Allergy and Infectious Diseases FX This work was funded by the following grants from the National Institutes of Health (to individual authors whose initials are noted in parentheses): NIH T32HL007185 (JLD), NIH P30AI027763 (JLD), NIH K23AI080147 (JLD), NIH K23HL094141 (AC), NIH K24HL087713 (LH), NIH R01HL090335 (LH), and NIH Bench-to-Bedside (JAK and LH). This work was also supported in part by the National Center for Research Resources (KL2RR024130) and by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 18 Z9 18 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 27 PY 2011 VL 6 IS 1 AR e16321 DI 10.1371/journal.pone.0016321 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JV UT WOS:000286663900035 PM 21298001 ER PT J AU Ng, OT Lin, L Laeyendecker, O Quinn, TC Sun, YJ Lee, CC Leo, YS AF Ng, Oon Tek Lin, Li Laeyendecker, Oliver Quinn, Thomas C. Sun, Yong Jiang Lee, Cheng Chuan Leo, Yee Sin TI Increased Rate of CD4+T-Cell Decline and Faster Time to Antiretroviral Therapy in HIV-1 Subtype CRF01_AE Infected Seroconverters in Singapore SO PLOS ONE LA English DT Article ID DISEASE PROGRESSION; VIRAL SUBTYPE; THAILAND; UGANDA; HEALTH; IMPACT AB Background: It remains controversial as to whether HIV-1 subtypes influence disease progression. Singapore offers a unique opportunity to address this issue due to the presence of co-circulating subtypes. We compared subtype CRF01_AE and non-CRF01_AE infected patients, with regards to estimated annual rate of CD4+ T-cell loss and time from estimated data of seroconversion (EDS) to antiretroviral therapy (ART). Methods: We recruited ART-naive patients with known dates of seroconversion between October 2002 and December 2007 at the Singapore Communicable Disease Centre, the national reference treatment centre. Multilevel mixed-effects models were used to analyse the rate of CD4+ T-cell decline. Time from EDS to ART was analyzed with the Kaplan-Meier survival method and compared with Cox proportional hazards models. Results: 54 patients with previously assigned HIV-1 subtypes (24 CRF01_AE, 17 B, 8 B', 1 CRF33_01B, 3 CRF34_01B and 1 G) were observed for 89 patient-years. Subtype CRF01_AE and non-CRF01_AE infected patients did not differ in age, gender, risk factor, rate of symptomatic seroconversion, baseline CD4+ T-cell count, log(10) viral load or haemoglobin concentration. The estimated annual rate of CD4+ T-cell loss was 58 cells/mm(3)/year (95% CI: 7 to 109; P = 0.027) greater in subtype CRF01_AE infected patients compared to non-CRF01_AE patients, after adjusting for age, baseline CD4+ T-cell count and baseline log(10) viral load. The median time from EDS to ART was 1.8 years faster comparing CRF01_AE to non-CRF01_AE infected patient with a 2.5 times (95% CI: 1.2-5.0; P = 0.013) higher hazard for ART initiation, after controlling for age, baseline CD4+ T-cell count and baseline log(10) viral load. Conclusions: Infecting subtype significantly impacted the rate of CD4+ T-cell loss and time to treatment in this cohort. Studies to understand the biological basis for this difference could further our understanding of HIV pathogenesis. C1 [Ng, Oon Tek; Laeyendecker, Oliver; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Ng, Oon Tek; Lin, Li; Sun, Yong Jiang; Lee, Cheng Chuan; Leo, Yee Sin] Tan Tock Seng Hosp, Dept Infect Dis, Singapore, Singapore. [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. RP Ng, OT (reprint author), Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. EM oong@jhsph.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Singapore National Medical Research Training Fellowship [MH 95:03/8-169] FX A Singapore National Medical Research Training Fellowship grant (MH 95:03/8-169) provided salary support for OT Ng. Additional support was provided by the Division of Intramural Research, 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 18 TC 21 Z9 23 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 27 PY 2011 VL 6 IS 1 AR e15738 DI 10.1371/journal.pone.0015738 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JV UT WOS:000286663900017 PM 21298051 ER PT J AU Park, EH Zhang, F Warringer, J Sunnerhagen, P Hinnebusch, AG AF Park, Eun-Hee Zhang, Fan Warringer, Jonas Sunnerhagen, Per Hinnebusch, Alan G. TI Depletion of eIF4G from yeast cells narrows the range of translational efficiencies genome-wide SO BMC GENOMICS LA English DT Article ID MESSENGER-RNA; SACCHAROMYCES-CEREVISIAE; INITIATION-FACTORS; EXPRESSION; RIBOSOMES; PROMOTE; PROTEIN; STRESS; CLN3; PROGRESSION AB Background: Eukaryotic translation initiation factor 4G (eIF4G) is thought to influence the translational efficiencies of cellular mRNAs by its roles in forming an eIF4F mRNA PABP mRNP that is competent for attachment of the 43S preinitiation complex, and in scanning through structured 5' UTR sequences. We have tested this hypothesis by determining the effects of genetically depleting eIF4G from yeast cells on global translational efficiencies (TEs), using gene expression microarrays to measure the abundance of mRNA in polysomes relative to total mRNA for similar to 5900 genes. Results: Although depletion of eIF4G is lethal and reduces protein synthesis by similar to 75%, it had small effects (less than a factor of 1.5) on the relative TE of most genes. Within these limits, however, depleting eIF4G narrowed the range of translational efficiencies genome-wide, with mRNAs of better than average TE being translated relatively worse, and mRNAs with lower than average TE being translated relatively better. Surprisingly, the fraction of mRNAs most dependent on eIF4G display an average 5' UTR length at or below the mean for all yeast genes. Conclusions: This finding suggests that eIF4G is more critical for ribosome attachment to mRNAs than for scanning long, structured 5' UTRs. Our results also indicate that eIF4G, and the closed-loop mRNP it assembles with the m(7) G cap- and poly(A)-binding factors (eIF4E and PABP), is not essential for translation of most (if not all) mRNAs but enhances the differentiation of translational efficiencies genome-wide. C1 [Park, Eun-Hee; Zhang, Fan; Hinnebusch, Alan G.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Warringer, Jonas; Sunnerhagen, Per] Univ Gothenburg, Lundberg Lab, Dept Cell & Mol Biol, S-40530 Gothenburg, Sweden. RP Hinnebusch, AG (reprint author), Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov RI Sunnerhagen, Per/G-1696-2012; Warringer, Jonas/B-8520-2013 OI Sunnerhagen, Per/0000-0002-0967-8729; Warringer, Jonas/0000-0001-6144-2740 FU NIH; Swedish Research Council [2007-5460] FX This research was supported by the Intramural Research Program of the NIH, and by a grant from the Swedish Research Council (2007-5460). NR 35 TC 26 Z9 26 U1 0 U2 0 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 JAN 26 PY 2011 VL 12 AR 68 DI 10.1186/1471-2164-12-68 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 723TP UT WOS:000287530300001 PM 21269496 ER PT J AU McCarty, CA Chisholm, RL Chute, CG Kullo, IJ Jarvik, GP Larson, EB Li, RL Masys, DR Ritchie, MD Roden, DM Struewing, JP Wolf, WA AF McCarty, Catherine A. Chisholm, Rex L. Chute, Christopher G. Kullo, Iftikhar J. Jarvik, Gail P. Larson, Eric B. Li, Rongling Masys, Daniel R. Ritchie, Marylyn D. Roden, Dan M. Struewing, Jeffery P. Wolf, Wendy A. CA eMERGE Team TI The eMERGE Network: A consortium of biorepositories linked to electronic medical records data for conducting genomic studies SO BMC MEDICAL GENOMICS LA English DT Article ID PROSPECTIVE COHORT; PERSONALIZED MEDICINE; ALZHEIMER-DISEASE; DEMENTIA; RISK; PARTICIPANTS; BIOBANK; UPDATE; OLDER AB Introduction: The eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors. Organization: The five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel. Current progress: The primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in approximate to 2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross-network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site.