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. Future activities: Plans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care. Summary: By combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data-driven approaches to incorporate genomic information into routine healthcare delivery. C1 [McCarty, Catherine A.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI 54449 USA. [Chisholm, Rex L.; Wolf, Wendy A.] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA. [Chute, Christopher G.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Li, Rongling; Struewing, Jeffery P.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Masys, Daniel R.] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37232 USA. [Ritchie, Marylyn D.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37231 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA. RP McCarty, CA (reprint author), Marshfield Clin Res Fdn, Ctr Human Genet, 1000 N Oak Ave MLR, Marshfield, WI 54449 USA. EM mccarty.catherine@mcrf.mfldclin.edu RI Crawford, Dana/C-1054-2012; Ritchie, Marylyn/C-1114-2012; Haines, Jonathan/C-3374-2012; Jarvik, Gail/N-6476-2014; Darbar, Dawood/C-9079-2015; Struewing, Jeffery/I-7502-2013; Kibbe, Warren/B-2106-2010 OI Jarvik, Gail/0000-0002-6710-8708; Darbar, Dawood/0000-0002-4103-5977; Struewing, Jeffery/0000-0002-4848-3334; Kibbe, Warren/0000-0001-5622-7659 FU NHGRI; NIGMS [U01-HG-004610, U01-HG-004608, U01-HG-04599, U01HG004609, U01-HG-04603]; State of Washington Life Sciences FX The eMERGE Network was initiated and funded by NHGRI, with additional funding from NIGMS through the following grants: U01-HG-004610 (Group Health Cooperative); U01-HG-004608 (Marshfield Clinic); U01-HG-04599 (Mayo Clinic); U01HG004609 (Northwestern University); U01-HG-04603 (Vanderbilt University, also serving as the Coordinating Center), and the State of Washington Life Sciences Discovery Fund award to the Northwest Institute of Medical Genetics. NR 25 TC 230 Z9 233 U1 8 U2 34 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD JAN 26 PY 2011 VL 4 AR 13 DI 10.1186/1755-8794-4-13 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 720ZF UT WOS:000287320500001 PM 21269473 ER PT J AU Reichart, DL Hinkle, RT Lefever, FR Dolan, ET Dietrich, JA Sibley, DR Isfort, RJ AF Reichart, Deborah L. Hinkle, Richard T. Lefever, Frank R. Dolan, Elizabeth T. Dietrich, Jeffrey A. Sibley, David R. Isfort, Robert J. TI Activation of the dopamine 1 and dopamine 5 receptors increase skeletal muscle mass and force production under non-atrophying and atrophying conditions SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID NUCLEOTIDE-BINDING-PROTEINS; CHRONIC HEART-FAILURE; MOLECULAR-BIOLOGY; RAT DIAPHRAGM; DOUBLE-BLIND; D1; D-2; CLENBUTEROL; EXPRESSION; CARBIDOPA AB Background: Control of skeletal muscle mass and force production is a complex physiological process involving numerous regulatory systems. Agents that increase skeletal muscle cAMP levels have been shown to modulate skeletal muscle mass and force production. The dopamine 1 receptor and its closely related homolog, the dopamine 5 receptor, are G-protein coupled receptors that are expressed in skeletal muscle and increase cAMP levels when activated. Thus we hypothesize that activation of the dopamine 1 and/or 5 receptor will increase skeletal muscle cAMP levels thereby modulating skeletal muscle mass and force production. Methods: We treated isolated mouse tibialis anterior (TA) and medial gastrocnemius (MG) muscles in tissue bath with the selective dopamine 1 receptor and dopamine 5 receptor agonist SKF 81297 to determine if activation of skeletal muscle dopamine 1 and dopamine 5 receptors will increase cAMP. We dosed wild-type mice, dopamine 1 receptor knockout mice and dopamine 5 receptor knockout mice undergoing casting-induced disuse atrophy with SKF 81297 to determine if activation of the dopamine 1 and dopamine 5 receptors results in hypertrophy of non-atrophying skeletal muscle and preservation of atrophying skeletal muscle mass and force production. Results: In tissue bath, isolated mouse TA and MG muscles responded to SKF 81297 treatment with increased cAMP levels. Treating wild-type mice with SKF 81297 reduced casting-induced TA and MG muscle mass loss in addition to increasing the mass of non-atrophying TA and MG muscles. In dopamine 1 receptor knockout mice, extensor digitorum longus (EDL) and soleus muscle mass and force was not preserved during casting with SKF 81297 treatment, in contrast to significant preservation of casted wild-type mouse EDL and soleus mass and EDL force with SKF 81297 treatment. Dosing dopamine 5 receptor knockout mice with SKF 81297 did not significantly preserve EDL and soleus muscle mass and force although wild-type mouse EDL mass and force was significantly preserved SKF 81297 treatment. Conclusions: These data demonstrate for the first time that treatment with a dopamine 1/5 receptor agonist results in (1) significant preservation of EDL, TA, MG and soleus muscle mass and EDL muscle force production during periods of atrophy and (2) hypertrophy of TA and MG muscle. These effects appear to be mainly mediated by both the dopamine 1 and dopamine 5 receptors. C1 [Reichart, Deborah L.; Hinkle, Richard T.; Lefever, Frank R.; Dolan, Elizabeth T.; Dietrich, Jeffrey A.; Isfort, Robert J.] Procter & Gamble, Div Res, Mason, OH 45040 USA. [Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Isfort, RJ (reprint author), Procter & Gamble, Div Res, Mason, OH 45040 USA. EM isfort.rj@pg.com FU Procter Gamble Company FX This work was supported by the Procter & Gamble Company. DLR, RTH, FRL, ETD, JAD and RJI are, or were at the time these studies were performed, employees of the Procter & Gamble Company. NR 45 TC 1 Z9 1 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD JAN 26 PY 2011 VL 12 AR 27 DI 10.1186/1471-2474-12-27 PG 8 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 719WV UT WOS:000287243100001 PM 21269506 ER PT J AU Iannuzzi, MC Fontana, JR AF Iannuzzi, Michael C. Fontana, Joseph R. TI Sarcoidosis Clinical Presentation, Immunopathogenesis, and Therapeutics SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PROGRESSIVE PULMONARY SARCOIDOSIS; POSITRON-EMISSION-TOMOGRAPHY; LUNG LYMPHOCYTES-T; ALVEOLAR MACROPHAGES; AFRICAN-AMERICANS; PENTOXIFYLLINE; SUSCEPTIBILITY; NEUROSARCOIDOSIS; HYPERTENSION; METHOTREXATE AB Sarcoidosis is a multisystem granulomatous disorder that most often affects the lungs and may cause significant morbidity. Sarcoidosis can manifest as neurological disease, uveitis, blindness, end-stage pulmonary fibrosis, pulmonary hypertension, dysrhythmias, cardiomyopathy, hypercalcemia, and renal failure. Sarcoidosis persists as chronic disease in approximately one-third of those affected. Clinical pitfalls and misconceptions about the course of disease place this population at risk for delayed or inadequate care. While noncaseating granulomas are the histopathological hallmark of sarcoidosis, they also are nonspecific. No pathognomonic diagnostic test exists for sarcoidosis, so the diagnosis remains one of exclusion. While the etiology of sarcoidosis is still unknown, recent insights into its immunopathogenesis have moved investigators closer to finding more effective treatments. Corticosteroids remain the standard of care when treatment is indicated, despite their adverse effect profile. Clinical investigations of novel drugs and biological agents targeting mechanisms involving CD4 type 1 helper T cells may provide more effective, better tolerated therapies. JAMA. 2011;305(4):391-399 www.jama.com C1 [Fontana, Joseph R.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Iannuzzi, Michael C.] SUNY Syracuse, Dept Med, Syracuse, NY USA. [Iannuzzi, Michael C.] Upstate Med Univ, Syracuse, NY USA. RP Fontana, JR (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, 9000 Rockville Pike,CRC,Room 5-1421,MSC 1507, Bethesda, MD 20892 USA. EM fontanaj@nhlbi.nih.gov FU National Institutes of Health FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and Dr Iannuzzi reported none. Dr Fontana reported receiving funding from the National Institutes of Health for research on 2 of the pharmacological agents discussed in this article. NR 50 TC 100 Z9 103 U1 0 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 26 PY 2011 VL 305 IS 4 BP 391 EP 399 DI 10.1001/jama.2011.10 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 711MH UT WOS:000286595200024 PM 21266686 ER PT J AU Lin, L Sun, W Kung, F Dell'Acqua, ML Hoffman, DA AF Lin, Lin Sun, Wei Kung, Faith Dell'Acqua, Mark L. Hoffman, Dax A. TI AKAP79/150 Impacts Intrinsic Excitability of Hippocampal Neurons through Phospho-Regulation of A-type K+ Channel Trafficking SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; CA1 PYRAMIDAL NEURONS; DEPENDENT PROTEIN-KINASE; NMDA RECEPTOR ACTIVATION; ANCHORING PROTEIN; AMPA RECEPTORS; SYNAPTIC PLASTICITY; POTASSIUM CHANNELS; DENDRITIC EXCITABILITY; SCAFFOLD PROTEIN AB Kv4.2, as the primary alpha-subunit of rapidly inactivating, A-type voltage-gated K+ (Kv) channels expressed in hippocampal CA1 pyramidal dendrites, plays a critical role in regulating their excitability. Activity-dependent trafficking of Kv4.2 relies on C-terminal protein kinase A (PKA) phosphorylation. A-kinase-anchoring proteins (AKAPs) target PKA to glutamate receptor and ion channel complexes to allow for discrete, local signaling. As part of a previous study, we showed that AKAP79/150 interacts with Kv4.2 complexes and that the two proteins colocalize in hippocampal neurons. However, the nature and functional consequence of their interaction has not been previously explored. Here, we report that the C-terminal domain of Kv4.2 interacts with an internal region of AKAP79/150 that overlaps with its MAGUK (membrane-associated guanylate kinase)-binding domain. We show that AKAP79/150-anchored PKA activity controls Kv4.2 surface expression in heterologous cells and hippocampal neurons. Consistent with these findings, disrupting PKA anchoring led to a decrease in neuronal excitability, while preventing dephosphorylation by the phosphatase calcineurin resulted in increased excitability. These results demonstrate that AKAP79/150 provides a platform for dynamic PKA regulation of Kv4.2 expression, fundamentally impacting CA1 excitability. C1 [Lin, Lin; Sun, Wei; Kung, Faith; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. [Sun, Wei] Peking Univ, Hlth Sci Ctr, Neurosci Res Inst, Beijing 100191, Peoples R China. [Sun, Wei] Peking Univ, Hlth Sci Ctr, Dept Neurobiol, Beijing 100191, Peoples R China. [Dell'Acqua, Mark L.] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. RP Hoffman, DA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, Lab Cellular & Synapt Neurophysiol, NIH, 35 Lincoln Dr,MSC 3715,Bldg 35,Room 3C-905, Bethesda, MD 20892 USA. EM hoffmand@mail.nih.gov RI Hoffman, Dax/E-5155-2011; OI Hoffman, Dax/0000-0001-6999-2157; Dell'Acqua, Mark/0000-0003-3798-3461 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank Begum Choudhury for excellent technical support. NR 59 TC 19 Z9 19 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 26 PY 2011 VL 31 IS 4 BP 1323 EP 1332 DI 10.1523/JNEUROSCI.5383-10.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 712GZ UT WOS:000286655600018 PM 21273417 ER PT J AU Hirano, Y Stefanovic, B Silva, AC AF Hirano, Yoshiyuki Stefanovic, Bojana Silva, Afonso C. TI Spatiotemporal Evolution of the Functional Magnetic Resonance Imaging Response to Ultrashort Stimuli SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CEREBRAL-BLOOD-FLOW; RAT SOMATOSENSORY CORTEX; BOLD RESPONSE; NEURONAL-ACTIVITY; CBV CONTRAST; MRI; BRAIN; OXYGENATION; ACTIVATION; FREQUENCY AB The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. The stimulus duration has additional influence on the spatiotemporal evolution of the HRF, as brief stimuli elicit responses that engage only the local vasculature, whereas long stimuli lead to the involvement of remote vascular supply and drainage. Here, we used functional magnetic resonance imaging to investigate the spatiotemporal evolution of the blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF), and cerebral blood volume (CBV) HRF to ultrashort forelimb stimulation in an anesthetized rodent model. The HRFs to a single 333-mu s-long stimulus were robustly detected and consisted of a rapid response in both CBF and CBV, with an onset time (OT) of 350 ms and a full width at half-maximum of 1 s. In contrast, longer stimuli elicited a dispersive transit of oxygenated blood across the cortical microvasculature that significantly prolonged the evolution of the CBV HRF, but not the CBF. The CBF and CBV OTs suggest that vasoactive messengers are synthesized, released, and effective within 350 ms. However, the difference between the BOLD and CBV OT (similar to 100 ms) was significantly smaller than the arteriolar-venular transit time (similar to 500 ms), indicating an arterial contribution to the BOLD HRF. Finally, the rapid rate of growth of the active region with stimulus elongation suggests that functional hyperemia is an integrative process that involves the entire functional cortical depth. These findings offer a new view into the spatiotemporal dynamics of functional hemodynamic regulation in the brain. C1 [Hirano, Yoshiyuki; Stefanovic, Bojana; Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Silva, AC (reprint author), Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,MSC 1065,Bldg 10,Room B1D106, Bethesda, MD 20892 USA. EM silvaa@ninds.nih.gov RI Silva, Afonso/A-7129-2009 FU National Institutes of Health-National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of National Institutes of Health-National Institute of Neurological Disorders and Stroke (Alan P. Koretsky, Scientific Director). We are deeply indebted to Dr. Alan P. Koretsky and Dr. Fernando F. Paiva for enlightening scientific discussions and to Xianfeng (Lisa) Zhang for her invaluable help in animal preparation and surgery. NR 39 TC 43 Z9 43 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 26 PY 2011 VL 31 IS 4 BP 1440 EP 1447 DI 10.1523/JNEUROSCI.3986-10.2011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 712GZ UT WOS:000286655600029 PM 21273428 ER PT J AU Takayama, Y Schwieters, CD Grishaev, A Ghirlando, R Clore, GM AF Takayama, Yuki Schwieters, Charles D. Grishaev, Alexander Ghirlando, Rodolfo Clore, G. Marius TI Combined Use of Residual Dipolar Couplings and Solution X-ray Scattering To Rapidly Probe Rigid-Body Conformational Transitions in a Non-phosphorylatable Active-Site Mutant of the 128 kDa Enzyme I Dimer SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SUGAR PHOSPHOTRANSFERASE SYSTEM; N-TERMINAL DOMAIN; ESCHERICHIA-COLI; NMR STRUCTURES; PROTEIN; HPR; MACROMOLECULES; ALIGNMENT; COMPLEX; PACKING AB The first component of the bacterial phosphotransferase system, enzyme I (El), is a multidomain 128 kDa dimer that undergoes large rigid-body conformational transitions during the course of its catalytic cycle. Here we investigate the solution structure of a non-phosphorylatable active-site mutant in which the active-site histidine is substituted by glutamine. We show that perturbations in the relative orientations and positions of the domains and subdomains can be rapidly and reliably determined by conjoined rigid-body/torsion angle/Cartesian simulated annealing calculations driven by orientational restraints from residual dipolar couplings and shape and translation information afforded by small-and wide-angle X-ray scattering. Although histidine and glutamine are isosteric, the conformational space available to a Gln side chain is larger than that for the imidazole ring of His. An additional hydrogen bond between the side chain of GIn189 located on the E subdomain and an aspartate (Asp129) on the EIN(alpha) subdomain results in a small (similar to 9 degrees) reorientation of the EIN(alpha) and EIN(alpha/beta) subdomains that is in turn propagated to a larger reorientation (similar to 26) of the EIN domain relative to the EIC dimerization domain, illustrating the positional sensitivity of the EIN domain and its constituent subdomains to small structural perturbations. C1 [Takayama, Yuki; Grishaev, Alexander; Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat & Technol, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008; Ghirlando, Rodolfo/A-8880-2009 OI Clore, G. Marius/0000-0003-3809-1027; FU NIDDK; CIT; Office of the Director of the NIH FX This work was supported by the intramural program of NIDDK (G.M.C.) and CIT (C.D.S.) and the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (G.M.C.). Use of the shared scattering beamline resource allocated under the PUP-77 agreement between NCI, NIH and the Argonne National Laboratory, is acknowledged. NR 26 TC 20 Z9 20 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JAN 26 PY 2011 VL 133 IS 3 BP 424 EP 427 DI 10.1021/ja109866w PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 724CF UT WOS:000287553000012 PM 21162528 ER PT J AU Guenaga, J Dosenovic, P Ofek, G Baker, D Schief, WR Kwong, PD Hedestam, GBK Wyatt, RT AF Guenaga, Javier Dosenovic, Pia Ofek, Gilad Baker, David Schief, William R. Kwong, Peter D. Hedestam, Gunilla B. Karlsson Wyatt, Richard T. TI Heterologous Epitope-Scaffold Prime:Boosting Immuno-Focuses B Cell Responses to the HIV-1 gp41 2F5 Neutralization Determinant SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; V3-SPECIFIC ANTIBODIES; STRUCTURAL ELEMENTS; GP120 GLYCOPROTEIN; ENVELOPE PROTEIN; IMMUNOGENICITY; BROAD; IMMUNIZATION; INDUCTION AB The HIV-1 envelope glycoproteins (Env) gp120 and gp41 mediate entry and are the targets for neutralizing antibodies. Within gp41, a continuous epitope defined by the broadly neutralizing antibody 2F5, is one of the few conserved sites accessible to antibodies on the functional HIV Env spike. Recently, as an initial attempt at structure-guided design, we transplanted the 2F5 epitope onto several non-HIV acceptor scaffold proteins that we termed epitope scaffolds (ES). As immunogens, these ES proteins elicited antibodies with exquisite binding specificity matching that of the 2F5 antibody. These novel 2F5 epitope scaffolds presented us with the opportunity to test heterologous prime: boost immunization strategies to selectively boost antibody responses against the engrafted gp41 2F5 epitope. Such strategies might be employed to target conserved but poorly immunogenic sites on the HIV-1 Env, and, more generally, other structurally defined pathogen targets. Here, we assessed ES prime: boosting by measuring epitope specific serum antibody titers by ELISA and B cell responses by ELISpot analysis using both free 2F5 peptide and an unrelated ES protein as probes. We found that the heterologous ES prime: boosting immunization regimen elicits cross-reactive humoral responses to the structurally constrained 2F5 epitope target, and that incorporating a promiscuous T cell helper epitope in the immunogens resulted in higher antibody titers against the 2F5 graft, but did not result in virus neutralization. Interestingly, two epitope scaffolds (ES1 and ES2), which did not elicit a detectable 2F5 epitope-specific response on their own, boosted such responses when primed with the ES5. Together, these results indicate that heterologous ES prime: boost immunization regimens effectively focus the humoral immune response on the structurally defined and immunogen-conserved HIV-1 2F5 epitope. C1 [Guenaga, Javier; Ofek, Gilad; Kwong, Peter D.; Wyatt, Richard T.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Dosenovic, Pia; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Baker, David; Schief, William R.] Univ Washington, Seattle, WA 98195 USA. RP Guenaga, J (reprint author), Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA USA. EM wyatt@scripps.edu RI Baker, David/K-8941-2012 OI Baker, David/0000-0001-7896-6217 FU National Institutes of Health; Bill and Melinda Gates Foundation, International AIDS Vaccine Initiative; Swedish Research Council [K2008-56X-20666-01-3]; Karolinska Institutet FX This work was supported by National Institutes of Health intramural funds, The Bill and Melinda Gates Foundation (www.gatesfoundation.org) International AIDS Vaccine Initiative (www.iavi.org), The Swedish Research Council (project No. K2008-56X-20666-01-3), and a Karolinska Institutet doctoral grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 54 Z9 54 U1 0 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 26 PY 2011 VL 6 IS 1 AR e16074 DI 10.1371/journal.pone.0016074 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JL UT WOS:000286662800016 PM 21297864 ER PT J AU Huang, Y Morozov, A AF Huang, Ying Morozov, Alexei TI Hippocampal Deletion of BDNF Gene Attenuates Gamma Oscillations in Area CA1 by Up-Regulating 5-HT3 Receptor SO PLOS ONE LA English DT Article ID NEUROTROPHIC FACTOR; IN-VITRO; GABAERGIC TRANSMISSION; INTERNEURON NETWORKS; PREFRONTAL CORTEX; CA2+ OSCILLATIONS; MESSENGER-RNA; BEHAVING RAT; BRAIN; SEROTONIN AB Background: Pyramidal neurons in the hippocampal area CA3 express high levels of BDNF, but how this BDNF contributes to oscillatory properties of hippocampus is unknown. Methodology/Principal Findings: Here we examined carbachol-induced gamma oscillations in hippocampal slices lacking BDNF gene in the area CA3. The power of oscillations was reduced in the hippocampal area CA1, which coincided with increases in the expression and activity of 5-HT3 receptor. Pharmacological block of this receptor partially restored power of gamma oscillations in slices from KO mice, but had no effect in slices from WT mice. Conclusion/Significance: These data suggest that BDNF facilitates gamma oscillations in the hippocampus by attenuating signaling through 5-HT3 receptor. Thus, BDNF modulates hippocampal oscillations through serotonergic system. C1 [Huang, Ying; Morozov, Alexei] NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Huang, Ying] Fudan Univ, Shanghai Med Coll, Dept Physiol & Pathophysiol, Shanghai 200433, Peoples R China. RP Huang, Y (reprint author), NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. EM morozova@mail.nih.gov FU National Institutes of Health National Institute of Mental Health FX The work was supported by the National Institutes of Health National Institute of Mental Health Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 6 Z9 6 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 26 PY 2011 VL 6 IS 1 AR e16480 DI 10.1371/journal.pone.0016480 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JL UT WOS:000286662800046 PM 21298058 ER PT J AU Ma, XJ Lin, LG Qin, GJ Lu, XP Fiorotto, M Dixit, VD Sun, YX AF Ma, Xiaojun Lin, Ligen Qin, Guijun Lu, Xinping Fiorotto, Marta Dixit, Vishwa D. Sun, Yuxiang TI Ablations of Ghrelin and Ghrelin Receptor Exhibit Differential Metabolic Phenotypes and Thermogenic Capacity during Aging SO PLOS ONE LA English DT Article ID BROWN ADIPOSE-TISSUE; HORMONE SECRETAGOGUE RECEPTOR; DES-ACYL GHRELIN; GROWTH-HORMONE; FOOD-INTAKE; ENERGY-EXPENDITURE; ADAPTIVE THERMOGENESIS; BODY-COMPOSITION; ACTIVE GHRELIN; HUMAN OBESITY AB Background: Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin (Ghrl), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that Ghrl(-/-) mice have impaired thermoregulatory responses to cold and fasting stresses, while Ghsr(-/-) mice are adaptive. Methodology/Principal Findings: To elucidate the mechanism, we analyzed the complete metabolic profiles of younger (3-4 months) and older (10-12 months) Ghrl(-/-) and Ghsr(-/-) mice. Food intake and locomotor activity were comparable for both null mice and their wild-type (WT) counterparts, regardless of age. There was also no difference in body composition between younger null mice and their WT counterparts. As the WT mice aged, as expected, the fat/lean ratio increased and energy expenditure (EE) decreased. Remarkably, however, older Ghsr(-/-) mice exhibited reduced fat/lean ratio and increased EE when compared to older WT mice, thus retaining a youthful lean and high EE phenotype; in comparison, there was no significant difference with EE in Ghrl(-/-) mice. In line with the EE data, the thermogenic regulator, uncoupling protein 1 (UCP1), was significantly up-regulated in brown adipose tissue (BAT) of Ghsr(-/-) mice, but not in Ghrl(-/-) mice. Conclusions: Our data therefore suggest that GHS-R ablation activates adaptive thermogenic function(s) in BAT and increases EE, thereby enabling the retention of a lean phenotype. This is the first direct evidence that the ghrelin signaling pathway regulates fat-burning BAT to affect energy balance during aging. This regulation is likely mediated through an as-yet-unidentified new ligand of GHS-R. C1 [Ma, Xiaojun; Qin, Guijun] Zhengzhou Univ, Affiliated Hosp 1, Dept Internal Med, Div Endocrinol, Zhengzhou, Peoples R China. [Ma, Xiaojun; Lin, Ligen; Fiorotto, Marta; Sun, Yuxiang] Baylor Univ, USDA ARS, Childrens Nutr Res Ctr, Dept Pediat,Baylor Coll Med, Houston, TX 77030 USA. [Lu, Xinping] NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Dixit, Vishwa D.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Lab Neuroendocrine Immunol, Baton Rouge, LA USA. [Sun, Yuxiang] Baylor Coll Med, Huffington Ctr Aging, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Ma, XJ (reprint author), Zhengzhou Univ, Affiliated Hosp 1, Dept Internal Med, Div Endocrinol, Zhengzhou, Peoples R China. EM yuxiangs@bcm.edu FU USDA/ARS CRIS [6250-51000-055]; NIH/NIA [1R03AG029641-01]; NIH-Diabetes and Endocrinology Research Center at Baylor College of Medicine [P30DK079638] FX The authors are very grateful to the agencies which supported this work: USDA/ARS CRIS fund ARS 6250-51000-055 (YS), NIH/NIA grant 1R03AG029641-01 (YS) and the NIH-Diabetes and Endocrinology Research Center (P30DK079638) at Baylor College of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 27 Z9 30 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2011 VL 6 IS 1 AR e16391 DI 10.1371/journal.pone.0016391 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JL UT WOS:000286662800038 PM 21298106 ER PT J AU Lee, GS Simons, SS AF Lee, Geun-Shik Simons, S. Stoney, Jr. TI Ligand Binding Domain Mutations of the Glucocorticoid Receptor Selectively Modify the Effects with, but Not Binding of, Cofactors SO BIOCHEMISTRY LA English DT Article ID INDUCTION PROPERTIES; COACTIVATOR INTERACTIONS; GENE INDUCTION; TRANSACTIVATION; PHOSPHORYLATION; TRANSCRIPTION; MODULATION; REPRESSION; COMPLEXES; AGONISTS AB We previously reported that several point mutations in the ligand binding domain (LBD) of glucocorticoid receptors (GRs) marginally affect the binding affinity of the synthetic glucocorticoids dexamethasone (Dex) and deacylcortivazol (DAC). However, these mutations dramatically alter the efficacy (A(max)) and potency (EC(50)) of agonists, along with the partial agonist activity (PAA) of the antisteroid Dex-mesylate (DM), for gene induction and repression in a steroid-dependent manner. This was proposed to result, in part, from altered protein protein interactions in the complex of GR with the coactivator TIF2 despite normal TIF2 binding. To explore the generality of this phenomenon, we now ask whether these mutations also affect the transactivation properties, but not binding, of other GR-bound factors. We find that an elevated concentration of GR, to probe unidentified cofactors, or of the comodulator Ubc9 does not reverse the effects of GR LBD mutations that increase the EC(50) and lower the PAA with the GREtkLUC reporter in both CV-1 and U2OS cells. This behavior is more dramatic with Ubc9 and the isolated GR LBD fused to the GAL4 DNA binding domain, despite normal binding of Ubc9 to the mutant GRs. Similar effects, albeit gene, steroid, and transcriptional property-specific, are seen with full-length GRs and three endogenous genes in U2OS cells. Thus, changes in simple steady-state binding capacities of mutant receptors for factors cannot account for the modified transcriptional properties. In all cases, the nuclear translocation of Dex- and DAC-bound wild-type and mutant receptors is the same. These results are consistent with the earlier results with TIF2 and support the hypothesis that small changes in the GR LBD can alter the activities of the bound cofactor without modifying cofactor binding. We propose that this separation of binding and the modulation of transactivation parameters occurs for a wide variety of GR-associated cofactors. C1 [Lee, Geun-Shik; Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, CEB, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, CEB, NIH, Bldg 10,Room 8N-307B, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 33 TC 11 Z9 12 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 25 PY 2011 VL 50 IS 3 BP 356 EP 366 DI 10.1021/bi101792d PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705TN UT WOS:000286160900005 PM 21142156 ER PT J AU Manor, U Disanza, A Grati, M Andrade, L Lin, H Di Fiore, PP Scita, G Kachar, B AF Manor, Uri Disanza, Andrea Grati, M'Hamed Andrade, Leonardo Lin, Harrison Di Fiore, Pier Paolo Scita, Giorgio Kachar, Bechara TI Regulation of Stereocilia Length by Myosin XVa and Whirlin Depends on the Actin-Regulatory Protein Eps8 SO CURRENT BIOLOGY LA English DT Article ID HAIR-CELL STEREOCILIA; UNCONVENTIONAL MYOSIN; DEAFNESS; ELONGATION; LOCALIZATION; ASSOCIATION; FILAMENTS; NETWORK; DFNB31; SHAPE AB Myosin XVa (MyoXVa) and its cargo whirlin are implicated in deafness and vestibular dysfunction and have been shown to localize at stereocilia tips and to be essential for the elongation of these actin protrusions [1-4]. Given that whirlin has no known actin-regulatory activity, it remains unclear how these proteins work together to influence stereocilia length. Here we show that the actin-regulatory protein Eps8 [5] interacts with MyoXVa and that mice lacking Eps8 show short stereocilia compared to MyoXVa- and whirlin-deficient mice. We show that Eps8 fails to accumulate at the tips of stereocilia in the absence of MyoXVa, that overexpression of MyoXVa results in both elongation of stereocilia and increased accumulation of Eps8 at stereocilia tips, and that the exogenous expression of MyoXVa in MyoXVa-deficient hair cells rescues Eps8 tip localization. We find that Eps8 also interacts with whirlin and that the expression of both Eps8 and MyoXVa at stereocilia tips is reduced in whirlin-deficient mice. We conclude that MyoXVa, whirlin, and Eps8 are integral components of the stereocilia tip complex, where Eps8 is a central actin-regulatory element for elongation of the stereocilia actin core. C1 [Disanza, Andrea; Di Fiore, Pier Paolo; Scita, Giorgio] FIRC Inst Mol Oncol Fdn, IFOM, I-20139 Milan, Italy. [Manor, Uri; Grati, M'Hamed; Andrade, Leonardo; Lin, Harrison; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cell Struct & Dynam, NIH, Bethesda, MD 20892 USA. [Manor, Uri] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Di Fiore, Pier Paolo; Scita, Giorgio] Univ Milan, Dipartimento Med Chirurgia & Odontoiatria, I-20142 Milan, Italy. RP Scita, G (reprint author), FIRC Inst Mol Oncol Fdn, IFOM, Via Adamello 16, I-20139 Milan, Italy. EM giorgio.scita@ifom-ieo-campus.it; kacharb@nidcd.nih.gov RI Grati, M'hamed/C-9563-2011; Andrade, Leonardo/C-9554-2011; Di Fiore, Pier Paolo/K-2130-2012; OI Andrade, Leonardo/0000-0002-0004-5677; Di Fiore, Pier Paolo/0000-0002-2252-0950; Scita, Giorgio/0000-0001-7984-1889 FU National Institutes of Health [Z01-DC000002-22]; Associazione Italiana per la Ricerca sul Cancro; Italian Ministries of Education; International Association for Cancer Research FX We would like to thank Nina Offenhauser for discussion, Charlotte Blanche Ekalle Soppo for technical assistance, and Agnieszka Rzadzinska and Mark Schneider for the early MyoXVa hair cell transfections. This work was supported by National Institutes of Health Intramural Research Fund Z01-DC000002-22 (B.K.) and by grants from the Associazione Italiana per la Ricerca sul Cancro (A.D., P.P.D.F., and G.S.), the Italian Ministries of Education (P.P.D.F. and G.S.), and the International Association for Cancer Research (G.S.). NR 26 TC 62 Z9 65 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 25 PY 2011 VL 21 IS 2 BP 167 EP 172 DI 10.1016/j.cub.2010.12.046 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 712QH UT WOS:000286680800029 PM 21236676 ER PT J AU Vickrey, BG Koroshetz, WJ AF Vickrey, Barbara G. Koroshetz, Walter J. TI Ensuring that the fruits of clinical trial research translate to equitable care SO NEUROLOGY LA English DT Editorial Material C1 [Vickrey, Barbara G.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Vickrey, Barbara G.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. RP Vickrey, BG (reprint author), Univ Calif Los Angeles, Dept Neurol, C-109 RNRC,Box 951769, Los Angeles, CA 90095 USA. EM bvickrey@ucla.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 25 PY 2011 VL 76 IS 4 BP 314 EP 315 DI 10.1212/WNL.0b013e31820c7509 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 711IA UT WOS:000286581500006 PM 21209371 ER PT J AU Mattsson, N Zetterberg, H Bianconi, S Yanjanin, NM Fu, R Mansson, JE Porter, FD Blennow, K AF Mattsson, N. Zetterberg, H. Bianconi, S. Yanjanin, N. M. Fu, R. Mansson, J. -E. Porter, F. D. Blennow, K. TI gamma-Secretase-dependent amyloid-beta is increased in Niemann-Pick type C A cross-sectional study SO NEUROLOGY LA English DT Article ID DISEASE TYPE-C; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; CEREBROSPINAL-FLUID; CELL BIOLOGY; LIPID RAFTS; CHOLESTEROL; NEURONS; ENZYME; CONSEQUENCES AB Objective: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by intracellular accumulation of lipids such as cholesterol and glycosphingolipids in endosomes and lysosomes. This accumulation induces progressive degeneration of the nervous system. NPC shows some intriguing similarities with Alzheimer disease (AD), including neurofibrillary tangles, but patients with NPC generally lack amyloid-beta (A beta) plaques. Lipids affect gamma-secretase-dependent amyloid precursor protein (APP) metabolism that generates A beta in vitro, but this has been difficult to prove in vivo. Our aim was to assess the effect of altered lipid constituents in neuronal membranes on amyloidogenic APP processing in humans. Methods: We examined A beta in CSF from patients with NPC (n = 38) and controls (n = 14). CSF was analyzed for A beta(38), A beta(40), A beta(42), alpha-cleaved soluble APP, beta-cleaved soluble APP, total-tau, and phospho-tau. Results: A beta release was markedly increased in NPC, with a shift toward the A beta(42) isoform. Levels of alpha(-) and beta-cleaved soluble APP were similar in patients and controls. Patients with NPC had increased total-tau. Patients on treatment with miglustat (n = 18), a glucosylceramide synthase blocker, had lower A beta(42) and total-tau than untreated patients. Conclusion: Increased CSF levels of A beta(38), A beta(40), and A beta(42) and unaltered levels of beta-cleaved soluble APP are consistent with increased gamma-secretase-dependent A beta release in the brains of patients with NPC. These results provide the first in vivo evidence that neuronal lipid accumulation facilitates gamma-secretase-dependent A beta production in humans and may be of relevance to AD pathogenesis. Neurology (R) 2011;76:366-372 C1 [Mattsson, N.; Zetterberg, H.; Mansson, J. -E.; Blennow, K.] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden. [Bianconi, S.; Yanjanin, N. M.; Fu, R.; Porter, F. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, DHHS, Bethesda, MD USA. RP Mattsson, N (reprint author), Sahlgrenska Univ Hosp Molndal, Clin Neurochem Lab, S-43180 Molndal, Sweden. EM niklas.mattsson@neuro.gu.se FU Swedish Research Council [14002, 2006-6227, 2006-2740, 2006-3505]; Alzheimer's Association [NIRG-08-90356]; cNEUPRO; Royal Swedish Academy of Sciences; Sahlgrenska University Hospital; Soderberg Foundation; Gothenburg Medical Society; Swedish Medical Society; Swedish Brain Power; Stiftelsen Gamla Tjanarinnor; Lundbeck Foundation; Gun och Bertil Stohnes stiftelse; Ahlen-stiftelsen; Swedish Brain Fund; Alzheimer Foundation, Sweden; Dementia Association, Sweden; NIH Office of Rare Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Gamla Tjanarinnor; Pfannenstills stiftelse; Demensfonden; Thureus stiftelse; Anna-Lisa och Bror Bjornssons stiftelse; Hjarnfonden; Svenska Lakaresallskapet; Neurologiskt handikappades riksforbund; Goteborgs lakaresallskap; Swedish Research Council; Alzheimer's Association; NIH/NICHD; Ara Parseghian Medical Research Foundation; Dana's Angels Research Trust; NIH; Ara Paseghian Medical Research Foundation; Innogenetics; Bristol-Myers Squibb; Swedish Brain Power project; Swedish Council for Working Life and Social Research; Swedish Alzheimer Foundation; Stiftelsen for Gamla Tjanarinnor; King Gustaf V's and Queen Victoria's Foundation FX Supported by the Swedish Research Council (projects 14002, 2006-6227, 2006-2740, and 2006-3505), the Alzheimer's Association (NIRG-08-90356), cNEUPRO, the Royal Swedish Academy of Sciences, Sahlgrenska University Hospital, the Soderberg Foundation, the Gothenburg Medical Society, the Swedish Medical Society, Swedish Brain Power, Stiftelsen Gamla Tjanarinnor, the Lundbeck Foundation, Gun och Bertil Stohnes stiftelse, Ahlen-stiftelsen, The Swedish Brain Fund, Alzheimer Foundation, Sweden, The Dementia Association, Sweden, a Bench to Bedside grant from the NIH Office of Rare Diseases, and the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.; Dr. Mattsson receives research support from Sahlgrenska University Hospital, Gamla Tjanarinnor, Pfannenstills stiftelse, Demensfonden, Thureus stiftelse, Anna-Lisa och Bror Bjornssons stiftelse, Hjarnfonden, Svenska Lakaresallskapet, Neurologiskt handikappades riksforbund, Goteborgs lakaresallskap. Dr. Zetterberg has served on a scientific advisory board for GlaxoSmithKline; serves as an Associate Editor of the Journal of Alzheimer's Disease; and receives research support from the Swedish Research Council, the Alzheimer's Association, and the Royal Swedish Academy of Sciences. Dr. Bianconi receives intramural research support from the NIH/NICHD. Dr. Yanjanin receives salary support from the Ara Parseghian Medical Research Foundation and Dana's Angels Research Trust. Dr. Fu has received fellowship support from the NIH. Dr. Mansson has served on a scientific advisory board for Genzyme Corp. Dr. Porter receives intramural research support from the NIH/NICHD; receives research support from Ara Paseghian Medical Research Foundation and Autism Speaks; and holds/has held stock in Pfizer Inc, Curis, Human Genome Sciences, and Genzyme Corporation. Dr. Blennow has served on scientific advisory boards for Innogenetics, AdLyfe Corporation, Bayer Schering Pharma, Bristol-Myers Squibb, Merz Pharmaceuticals, LLC, AstraZeneca, and sanofi-aventis; has received speaker honoraria from Janssen Immunotherapy; serves as a consultant for AstraZeneca and Pfizer Inc; and receives research support from Innogenetics, Bristol-Myers Squibb, the Swedish Research Council, the Swedish Brain Power project, the Swedish Council for Working Life and Social Research, the Swedish Alzheimer Foundation, Stiftelsen for Gamla Tjanarinnor, and the King Gustaf V's and Queen Victoria's Foundation. NR 40 TC 42 Z9 44 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 25 PY 2011 VL 76 IS 4 BP 366 EP 372 DI 10.1212/WNL.0b013e318208f4ab PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 711IA UT WOS:000286581500015 PM 21205675 ER PT J AU Fontainhas, AM Wang, MH Liang, KJ Chen, S Mettu, P Damani, M Fariss, RN Li, W Wong, WT AF Fontainhas, Aurora M. Wang, Minhua Liang, Katharine J. Chen, Shan Mettu, Pradeep Damani, Mausam Fariss, Robert N. Li, Wei Wong, Wai T. TI Microglial Morphology and Dynamic Behavior Is Regulated by Ionotropic Glutamatergic and GABAergic Neurotransmission SO PLOS ONE LA English DT Article ID IN-VIVO; PANNEXIN HEMICHANNELS; CULTURED MICROGLIA; CELL COMMUNICATION; RETINAL MICROGLIA; EXTRACELLULAR ATP; P2Y RECEPTORS; MOUSE RETINA; TASTE-BUDS; BRAIN AB Purpose: Microglia represent the primary resident immune cells in the CNS, and have been implicated in the pathology of neurodegenerative diseases. Under basal or "resting'' conditions, microglia possess ramified morphologies and exhibit dynamic surveying movements in their processes. Despite the prominence of this phenomenon, the function and regulation of microglial morphology and dynamic behavior are incompletely understood. We investigate here whether and how neurotransmission regulates "resting'' microglial morphology and behavior. Methods: We employed an ex vivo mouse retinal explant system in which endogenous neurotransmission and dynamic microglial behavior are present. We utilized live-cell time-lapse confocal imaging to study the morphology and behavior of GFP-labeled retinal microglia in response to neurotransmitter agonists and antagonists. Patch clamp electrophysiology and immunohistochemical localization of glutamate receptors were also used to investigate direct-versus-indirect effects of neurotransmission by microglia. Results: Retinal microglial morphology and dynamic behavior were not cell-autonomously regulated but are instead modulated by endogenous neurotransmission. Morphological parameters and process motility were differentially regulated by different modes of neurotransmission and were increased by ionotropic glutamatergic neurotransmission and decreased by ionotropic GABAergic neurotransmission. These neurotransmitter influences on retinal microglia were however unlikely to be directly mediated; local applications of neurotransmitters were unable to elicit electrical responses on microglia patch-clamp recordings and ionotropic glutamatergic receptors were not located on microglial cell bodies or processes by immunofluorescent labeling. Instead, these influences were mediated indirectly via extracellular ATP, released in response to glutamatergic neurotransmission through probenecid-sensitive pannexin hemichannels. Conclusions: Our results demonstrate that neurotransmission plays an endogenous role in regulating the morphology and behavior of "resting'' microglia in the retina. These findings illustrate a mode of constitutive signaling between the neural and immune compartments of the CNS through which immune cells may be regulated in concert with levels of neural activity. C1 [Fontainhas, Aurora M.; Wang, Minhua; Liang, Katharine J.; Mettu, Pradeep; Damani, Mausam; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Chen, Shan; Li, Wei] NEI, Unit Retinal Neurophysiol, Bethesda, MD 20892 USA. [Fariss, Robert N.] NEI, Off Sci Director, NIH, Bethesda, MD 20892 USA. RP Fontainhas, AM (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute; Prevention of Blindness Society of Metropolitan Washington FX This work has been supported by the National Eye Institute Intramural Research Program and a grant from the Prevention of Blindness Society of Metropolitan Washington (www.youreyes.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 84 Z9 88 U1 2 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 25 PY 2011 VL 6 IS 1 AR e15973 DI 10.1371/journal.pone.0015973 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712IZ UT WOS:000286661400019 PM 21283568 ER PT J AU Keller, MJ Madan, RP Torres, NM Fazzari, MJ Cho, S Kalyoussef, S Shust, G Mesquita, PMM Louissaint, N Chen, JM Cohen, HW Diament, EC Lee, AC Soto-Torres, L Hendrix, CW Herold, BC AF Keller, Marla J. Madan, Rebecca P. Torres, N. Merna Fazzari, Melissa J. Cho, Sylvia Kalyoussef, Sabah Shust, Gail Mesquita, Pedro M. M. Louissaint, Nicolette Chen, Jianmeng Cohen, Hillel W. Diament, Erin C. Lee, Anna C. Soto-Torres, Lydia Hendrix, Craig W. Herold, Betsy C. TI A Randomized Trial to Assess Anti-HIV Activity in Female Genital Tract Secretions and Soluble Mucosal Immunity Following Application of 1% Tenofovir Gel SO PLOS ONE LA English DT Article ID SIMPLEX-VIRUS INFECTION; VAGINAL FLUID; MICROBICIDE; TRANSMISSION; LAMIVUDINE; ADHERENCE; SAFETY; ASSAY AB Background: Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition. Methods: 30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood. Results: A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p, 0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators. Conclusions: Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy. C1 [Keller, Marla J.; Diament, Erin C.; Lee, Anna C.] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Keller, Marla J.; Herold, Betsy C.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, New York, NY USA. [Madan, Rebecca P.; Torres, N. Merna; Cho, Sylvia; Kalyoussef, Sabah; Shust, Gail; Herold, Betsy C.] Albert Einstein Coll Med, Dept Pediat, New York, NY USA. [Fazzari, Melissa J.; Cohen, Hillel W.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Mesquita, Pedro M. M.; Herold, Betsy C.] Albert Einstein Coll Med, Dept Microbiol & Immunol, New York, NY USA. [Louissaint, Nicolette; Chen, Jianmeng; Hendrix, Craig W.] Johns Hopkins Univ, Sch Med, Dept Med Clin Pharmacol, Baltimore, MD USA. [Soto-Torres, Lydia] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Keller, MJ (reprint author), Albert Einstein Coll Med, Dept Med, New York, NY USA. EM marla.keller@einstein.yu.edu RI Hendrix, Craig/G-4182-2014; OI Hendrix, Craig/0000-0002-5696-8665; Cohen, Hillel/0000-0002-4524-0898; Mesquita, Pedro/0000-0002-6591-4896 FU National Institutes of Health [U01 AI069551, UL1 RR025750, UL1 RR025005, U01 AI068633, P60 MD00514]; Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center [NIH AI-51519] FX This work was supported by grants from the National Institutes of Health (U01 AI069551, UL1 RR025750, UL1 RR025005, U01 AI068633, and P60 MD00514) and the Center for AIDS Research at the Albert Einstein College of Medicine and Montefiore Medical Center (NIH AI-51519). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 50 Z9 50 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2011 VL 6 IS 1 AR e16475 DI 10.1371/journal.pone.0016475 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712IZ UT WOS:000286661400055 PM 21283552 ER PT J AU Liu, Z Kim, W Chen, ZK Shin, YK Carlson, OD Fiori, JL Xin, L Napora, JK Short, R Odetunde, JO Lao, QZ Egan, JM AF Liu, Zhuo Kim, Wook Chen, Zhike Shin, Yu-Kyong Carlson, Olga D. Fiori, Jennifer L. Xin, Li Napora, Joshua K. Short, Ryan Odetunde, Juliana O. Lao, Qizong Egan, Josephine M. TI Insulin and Glucagon Regulate Pancreatic alpha-Cell Proliferation SO PLOS ONE LA English DT Article ID DIABETES-MELLITUS; GLUCOSE-HOMEOSTASIS; GENE-EXPRESSION; CANCER-CELLS; BETA-CELLS; IN-VIVO; RECEPTOR; GROWTH; MICE; HYPERGLUCAGONEMIA AB Type 2 diabetes mellitus (T2DM) results from insulin resistance and beta-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic alpha cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if alpha-cell numbers increase in T2DM and what factor (s) regulate alpha-cell turnover. Lepr(db)/Lepr(db) (db/db) mice were used as a T2DM model and alpha TC1 cells were used to study potential alpha-cell trophic factors. Here, we demonstrate that in db/db mice alpha-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of alpha cells significantly increased alpha-cell proliferation in a concentration-dependent manner compared to non-insulin-treated alpha cells. Insulin up-regulated alpha-cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in alpha TC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened alpha-cell proliferation, and increased intraislet insulin content in beta cells in db/db mice. These studies illustrate that pancreatic alpha-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to alpha-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting alpha cells and glucagon. C1 [Liu, Zhuo; Kim, Wook; Chen, Zhike; Shin, Yu-Kyong; Carlson, Olga D.; Fiori, Jennifer L.; Xin, Li; Napora, Joshua K.; Short, Ryan; Odetunde, Juliana O.; Lao, Qizong; Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. RP Liu, Z (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM eganj@grc.nia.nih.gov FU NIH, National Institute on Aging FX Research was supported by the Intramural Research Program of the NIH, National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 30 Z9 30 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2011 VL 6 IS 1 AR e16096 DI 10.1371/journal.pone.0016096 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712IZ UT WOS:000286661400024 PM 21283589 ER PT J AU Fu, D Wakabayashi, Y Lippincott-Schwartz, J Arias, IM AF Fu, Dong Wakabayashi, Yoshiyuki Lippincott-Schwartz, Jennifer Arias, Irwin M. TI Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE primary hepatocytes; occludin; P-glycoprotein ID ACTIVATED PROTEIN-KINASE; SIGNAL-TRANSDUCTION; SANDWICH CONFIGURATION; EPITHELIAL-CELLS; RAT HEPATOCYTES; CAMP PRODUCTION; IN-VITRO; LKB1; PHOSPHORYLATION; MAINTENANCE AB This study describes a unique function of taurocholate in bile canalicular formation involving signaling through a cAMP-Epac-MEK-Rap1-LKB1-AMPK pathway. In rat hepatocyte sandwich cultures, polarization was manifested by sequential progression of bile canaliculi from small structures to a fully branched network. Taurocholate accelerated canalicular network formation and concomitantly increased cAMP, which were prevented by adenyl cyclase inhibitor. The cAMP-dependent PKA inhibitor did not prevent the taurocholate effect. In contrast, activation of Epac, another cAMP downstream kinase, accelerated canalicular network formation similar to the effect of taurocholate. Inhibition of Epac downstream targets, Rap1 and MEK, blocked the taurocholate effect. Taurocholate rapidly activated MEK, LKB1, and AMPK, which were prevented by inhibition of adenyl cyclase or MEK. Our previous study showed that activated-LKB1 and AMPK participate in canalicular network formation. Linkage between bile acid synthesis, hepatocyte polarization, and regulation of energy metabolism is likely important in normal hepatocyte development and disease. C1 [Fu, Dong; Wakabayashi, Yoshiyuki; Lippincott-Schwartz, Jennifer; Arias, Irwin M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov; ariasi@mail.nih.gov RI Fu, Dong /J-1426-2012 NR 49 TC 56 Z9 60 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 25 PY 2011 VL 108 IS 4 BP 1403 EP 1408 DI 10.1073/pnas.1018376108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711MD UT WOS:000286594800039 PM 21220320 ER PT J AU Fujita, KI Maeda, D Xiao, Q Srinivasula, SM AF Fujita, Ken-ichi Maeda, Daisuke Xiao, Qi Srinivasula, Srinivasa M. TI Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTOR NRF2; SELECTIVE AUTOPHAGY; PROTEINS; MACROPHAGES; ACTIVATION; MECHANISM; GENES; KEAP1; IMMUNITY; ELEMENTS AB Toll-like receptors (TLRs) play a crucial role in several innate immune responses by regulating autophagy, but little is known about how TLR signaling controls autophagy. Here we demonstrate that p62/SQSTM1 is required for TLR4-mediated autophagy, which we show as selective autophagy of aggresome-like induced structures (ALIS). Treatment with LPS or Escherichia coli induced LC3(+) dot-like structures, and their assembly, but not lysosomal degradation, occurred independently of classic autophagic machinery. Microscopic and ultrastructural analyses showed that p62 is a component of the induced LC3(+) dots and these TLR4-induced p62(+) structures resemble ALIS. The levels of p62 mRNA and protein were increased in TLR4-activated cells and knockdown of p62 suppressed the ALIS formation and LC3-II conversion. The accumulation of p62 and ALIS required activation of Nrf2 by reactive oxygen species-p38 axis-dependent TLR4/MyD88 signaling, suggesting a link between innate immune and oxidative-stress responses. These findings indicate that TLR4-driven induction of p62 plays an essential role in the formation and the autophagic degradation of ALIS, which might be critical for regulating host defense. C1 [Fujita, Ken-ichi; Maeda, Daisuke; Xiao, Qi; Srinivasula, Srinivasa M.] NIH, Lab Immune Cell Biol, NCI, Bethesda, MD 20892 USA. RP Srinivasula, SM (reprint author), NIH, Lab Immune Cell Biol, NCI, Bldg 10, Bethesda, MD 20892 USA. EM srinivsr@mail.nih.gov FU National Institutes of Health, Center for Cancer Research, National Cancer Institute FX We thank Drs. T. Kitamura for providing retrovirus vector, B. Taylor for cell sorting, S. Garfield for confocal analysis, K. Hartman for sequencing, K. Nagashima for electron microscopic analysis, and J. Ashwell and R. Bosselut for critical review of the manuscript. This work was supported by the intramural research program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. NR 32 TC 94 Z9 97 U1 0 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 25 PY 2011 VL 108 IS 4 BP 1427 EP 1432 DI 10.1073/pnas.1014156108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711MD UT WOS:000286594800043 PM 21220332 ER PT J AU Aggarwal, M Sommers, JA Shoemaker, RH Brosh, RM AF Aggarwal, Monika Sommers, Joshua A. Shoemaker, Robert H. Brosh, Robert M., Jr. TI Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genomic instability; human disease ID RECQ HELICASES; CANCER-THERAPY; POLY(ADP-RIBOSE) POLYMERASE; SUBSTRATE-SPECIFICITY; IN-VITRO; CELLS; REPAIR; TELOMESTATIN; FORK; DISSOCIATION AB Modulation of DNA repair proteins by small molecules has attracted great interest. An in vitro helicase activity screen was used to identify molecules that modulate DNA unwinding by Werner syndrome helicase (WRN), mutated in the premature aging disorder Werner syndrome. A small molecule from the National Cancer Institute Diversity Set designated NSC 19630 [1-(propoxymethyl)-maleimide] was identified that inhibited WRN helicase activity but did not affect other DNA helicases [Bloom syndrome (BLM), Fanconi anemia group J (FANCJ), RECQ1, RecQ, UvrD, or DnaB). Exposure of human cells to NSC 19630 dramatically impaired growth and proliferation, induced apoptosis in a WRN-dependent manner, and resulted in elevated gamma-H2AX and proliferating cell nuclear antigen (PCNA) foci. NSC 19630 exposure led to delayed S-phase progression, consistent with the accumulation of stalled replication forks, and to DNA damage in a WRN-dependent manner. Exposure to NSC 19630 sensitized cancer cells to the G-quadruplex-binding compound telomestatin or a poly(ADP ribose) polymerase (PARP) inhibitor. Sublethal dosage of NSC 19630 and the chemotherapy drug topotecan acted synergistically to inhibit cell proliferation and induce DNA damage. The use of this WRN helicase inhibitor molecule may provide insight into the importance of WRN-mediated pathway(s) important for DNA repair and the replicational stress response. C1 [Aggarwal, Monika; Sommers, Joshua A.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU National Institutes of Health; National Institute on Aging; National Cancer Institute FX We thank Dr. Bob Wersto and Jade Scheers of the National Institute on Aging Flow Cytometry Unit for assistance, Dr. Ian Hickson for providing purified recombinant BLM protein and BLM-/- (PSNG13) and BLM+/+ (PSNF5) cells, Dr. Daniel Kaplan for purified recombinant DnaB helicase, and Dr. Kazuo Shin-ya and Dr. Bernardo Reina San-Martin for TMS and for the PARP inhibitor KU0058948, respectively. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and National Cancer Institute. NR 28 TC 60 Z9 60 U1 1 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 25 PY 2011 VL 108 IS 4 BP 1525 EP 1530 DI 10.1073/pnas.1006423108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711MD UT WOS:000286594800060 PM 21220316 ER PT J AU Franco, AT Malaguarnera, R Refetoff, S Liao, XH Lundsmith, E Kimura, S Pritchard, C Marais, R Davies, TF Weinstein, LS Chen, M Rosen, N Ghossein, R Knauf, JA Fagin, JA AF Franco, Aime T. Malaguarnera, Roberta Refetoff, Samuel Liao, Xiao-Hui Lundsmith, Emma Kimura, Shioko Pritchard, Catrin Marais, Richard Davies, Terry F. Weinstein, Lee S. Chen, Min Rosen, Neal Ghossein, Ronald Knauf, Jeffrey A. Fagin, James A. TI Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Ras; G protein; pax8 ID GROWTH-FACTOR-I; RAS MUTATIONS; DEVELOPMENTAL DEFECTS; BRAF(V600E) MUTATION; TARGETED EXPRESSION; CRE RECOMBINASE; TRANSGENIC MICE; HIGH PREVALENCE; DNA-SYNTHESIS; CANCER AB Mutations of BRAF are found in similar to 45% of papillary thyroid cancers and are enriched in tumors with more aggressive properties. We developed mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf(V600E)/TPO-Cre) to explore the role of endogenous expression of this oncoprotein on tumor initiation and progression. In contrast to other Braf-induced mouse models of tumorigenesis (i.e., melanomas and lung), in which knock-in of Braf(V600E) induces mostly benign lesions, Braf-expressing thyrocytes become transformed and progress to invasive carcinomas with a very short latency, a process that is dampened by treatment with an allosteric MEK inhibitor. These mice also become profoundly hypothyroid due to deregulation of genes involved in thyroid hormone biosynthesis and consequently have high TSH levels. To determine whether TSH signaling cooperates with oncogenic Braf in this process, we first crossed LSL-Braf(V600E)/TPO-Cre with TshR knockout mice. Although oncogenic Braf was appropriately activated in thyroid follicular cells of these mice, they had a lower mitotic index and were not transformed. Thyroid-specific deletion of the Gs alpha gene in LSL-Braf(V600E)/TPO-Cre/Gnas-E1(fl/fl) mice also resulted in an attenuated cancer phenotype, indicating that the cooperation of TshR with oncogenic Braf is mediated in part by cAMP signaling. Once tumors were established in mice with wild-type TshR, suppression of TSH did not revert the phenotype. These data demonstrate the key role of TSH signaling in Braf-induced papillary thyroid cancer initiation and provide experimental support for recent observations in humans pointing to a strong association between TSH levels and thyroid cancer incidence. C1 [Franco, Aime T.; Malaguarnera, Roberta; Lundsmith, Emma; Knauf, Jeffrey A.; Fagin, James A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Rosen, Neal; Fagin, James A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Ghossein, Ronald] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Rosen, Neal] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY 10065 USA. [Refetoff, Samuel; Liao, Xiao-Hui] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Refetoff, Samuel; Liao, Xiao-Hui] Univ Chicago, Genet Program, Chicago, IL 60637 USA. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Pritchard, Catrin] Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. [Marais, Richard] Inst Canc Res, London SW3 6JB, England. [Davies, Terry F.] Mt Sinai Sch Med, Div Endocrinol & Metab, New York, NY 10468 USA. [Weinstein, Lee S.; Chen, Min] NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Fagin, JA (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. EM faginj@mskcc.org OI Knauf, Jeffrey/0000-0003-4456-8792; Marais, Richard/0000-0001-7484-4183; Weinstein, Lee/0000-0002-1899-5152 FU National Institutes of Health (NIH) [CA50706, CA72597, DK17050, F32CA136178, P50-CA92629]; Margot Rosenberg Pulitzer Foundation; National Institute of Diabetes and Digestive and Kidney Diseases; Small Animal Imaging Research Program [R24 CA83084]; NIH Center [P30 CA08748] FX We thank Miriam Benezra for technical assistance. We thank the following Memorial Sloan-Kettering Cancer Center Cores for assistance: Molecular Cytology, Genetically Engineered Mouse Genotyping Service, Laboratory of Comparative Pathology, and Small Animal Imaging. This project was supported by National Institutes of Health (NIH) Grants CA50706, CA72597, and DK17050; the Margot Rosenberg Pulitzer Foundation; and partially supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. A.F. was supported by NIH Grant F32CA136178. The Small Imaging Core is supported by Small Animal Imaging Research Program Grant R24 CA83084, NIH Center Grant P30 CA08748, and NIH Prostate Specialized Program of Research Excellence Grant P50-CA92629. NR 48 TC 77 Z9 82 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 25 PY 2011 VL 108 IS 4 BP 1615 EP 1620 DI 10.1073/pnas.1015557108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711MD UT WOS:000286594800075 PM 21220306 ER PT J AU Wang, Y Park, S Bajpayee, NS Nagaoka, Y Boulay, G Birnbaumer, L Jiang, MS AF Wang, Ying Park, Sangeun Bajpayee, Neil S. Nagaoka, Yoshiko Boulay, Guylain Birnbaumer, Lutz Jiang, Meisheng TI Augmented glucose-induced insulin release in mice lacking G(o2), but not G(o1) or G(i) proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE somatostatin; exocytosis; islet activating protein; signal transduction; G-protein-coupled receptor ID ISLET-ACTIVATING PROTEIN; GTP-BINDING PROTEIN; PANCREATIC BETA-CELLS; ADENYLATE-CYCLASE; ALPHA-SUBUNIT; BORDETELLA-PERTUSSIS; MOLECULAR-MECHANISMS; DEPENDENT INHIBITION; CHROMAFFIN CELLS; LIGHT RESPONSE AB Insulin secretion by pancreatic beta cells is a complex and highly regulated process. Disruption of this process can lead to diabetes mellitus. One of the various pathways involved in the regulation of insulin secretion is the activation of heterotrimeric G proteins. Bordetella pertussis toxin (PTX) promotes insulin secretion, suggesting the involvement of one or more of three G(i) and/or two Go proteins as suppressors of insulin secretion from beta cells. However, neither the mechanism of this inhibitory modulation of insulin secretion nor the identity of the G(i/o) proteins involved has been elucidated. Here we show that one of the two splice variants of G(o), G(o2), is a key player in the control of glucose-induced insulin secretion by beta cells. Mice lacking G(o2)alpha, but not those lacking a subunits of either G(o1) or any G(i) proteins, handle glucose loads more efficiently than wild-type (WT) mice, and do so by increased glucose-induced insulin secretion. We thus provide unique genetic evidence that the G(o2) protein is a transducer in an inhibitory pathway that prevents damaging oversecretion of insulin. C1 [Boulay, Guylain; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Wang, Ying; Park, Sangeun; Bajpayee, Neil S.; Nagaoka, Yoshiko; Jiang, Meisheng] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. RP Birnbaumer, L (reprint author), NIEHS, Neurobiol Lab, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov; jm@ucla.edu FU National Institutes of Health (NIH) [DK 069771, DK19319, Z01- ES101643] FX We are especially indebted to Susanne Ullrich (Institute of Neurophysiology, University of Cologne) for her help in establishing the mouse pancreatic islet isolation technique in the laboratory. We thank MingHua Chai and Diana Vi for technical assistance. This work is supported by National Institutes of Health (NIH) Grants DK 069771 (to M.J.) and DK19319 (to L.B.) and in part by Intramural Research Program, NIH Project Z01- ES101643 (to L.B.). NR 50 TC 11 Z9 12 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 25 PY 2011 VL 108 IS 4 BP 1693 EP 1698 DI 10.1073/pnas.1018903108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711MD UT WOS:000286594800088 PM 21220323 ER PT J AU Hurle, B Marques-Bonet, T Antonacci, F Hughes, I Ryan, JF Eichler, EE Ornitz, DM Green, ED AF Hurle, Belen Marques-Bonet, Tomas Antonacci, Francesca Hughes, Inna Ryan, Joseph F. Eichler, Evan E. Ornitz, David M. Green, Eric D. CA NISC Comparative Sequencing TI Lineage-specific evolution of the vertebrate Otopetrin gene family revealed by comparative genomic analyses SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID PAROXYSMAL POSITIONAL VERTIGO; SEGMENTAL DUPLICATIONS; USHER-SYNDROME; INVERSION POLYMORPHISMS; ZEBRAFISH; PROTEIN; MUTATIONS; OTOCONIA; EXPRESSION; SEQUENCES AB Background: Mutations in the Otopetrin 1 gene (Otop1) in mice and fish produce an unusual bilateral vestibular pathology that involves the absence of otoconia without hearing impairment. The encoded protein, Otop1, is the only functionally characterized member of the Otopetrin Domain Protein (ODP) family; the extended sequence and structural preservation of ODP proteins in metazoans suggest a conserved functional role. Here, we use the tools of sequence-and cytogenetic-based comparative genomics to study the Otop1 and the Otop2-Otop3 genes and to establish their genomic context in 25 vertebrates. We extend our evolutionary study to include the gene mutated in Usher syndrome (USH) subtype 1G (Ush1g), both because of the head-to-tail clustering of Ush1g with Otop2 and because Otop1 and Ush1g mutations result in inner ear phenotypes. Results: We established that OTOP1 is the boundary gene of an inversion polymorphism on human chromosome 4p16 that originated in the common human-chimpanzee lineage more than 6 million years ago. Other lineage-specific evolutionary events included a three-fold expansion of the Otop genes in Xenopus tropicalis and of Ush1g in teleostei fish. The tight physical linkage between Otop2 and Ush1g is conserved in all vertebrates. To further understand the functional organization of the Ushg1-Otop2 locus, we deduced a putative map of binding sites for CCCTC-binding factor (CTCF), a mammalian insulator transcription factor, from genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) data in mouse and human embryonic stem (ES) cells combined with detection of CTCF-binding motifs. Conclusions: The results presented here clarify the evolutionary history of the vertebrate Otop and Ush1g families, and establish a framework for studying the possible interaction(s) of Ush1g and Otop in developmental pathways. C1 [Hurle, Belen; Ryan, Joseph F.; Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Marques-Bonet, Tomas] UPF CSIC, Dept Inst Biol Evolutiva, Barcelona 08003, Spain. [Marques-Bonet, Tomas; Antonacci, Francesca; Eichler, Evan E.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Marques-Bonet, Tomas; Antonacci, Francesca; Eichler, Evan E.] Univ Washington, Sch Med, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Hughes, Inna] Univ Rochester, Med Ctr, Dept Child Neurol, Rochester, NY 14642 USA. [Green, Eric D.; NISC Comparative Sequencing] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20852 USA. [Ornitz, David M.] Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA. RP Green, ED (reprint author), NHGRI, Genome Technol Branch, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM egreen@nhgri.nih.gov RI Antonacci, Francesca/F-5457-2013; Marques-Bonet, Tomas/I-4618-2014; OI Antonacci, Francesca/0000-0002-5833-6186; Marques-Bonet, Tomas/0000-0002-5597-3075; Ornitz, David/0000-0003-1592-7629 FU NHGRI [HG002385, HG0058815]; NIDCD [DC02236] FX We thank Mariano Rocchi and Mario Ventura (University of Bari) for providing chimpanzee and macaque samples used in the tri-color interphase FISH analyses; Laura Elnitski (NHGRI) for advice about analyzing non-coding conserved sequences; Zhaoshi Jiang (University of Washington) for advice about analyzing the evolutionary breakpoints on chromosome 4p16; Bechara Kachar (NIDCD) for critically reading the manuscript and for insightful discussions; Julia Fekecs and Darryl Leja, Rebecca Chodroff, and Shurjo Sen (NHGRI) for input about figure generation; Jacquelyn K. Beals for the editing; and the three anonymous reviewers for their helpful feedback. We also thank numerous people associated with the NISC Comparative Sequencing Program, in particular Robert Blakesley, Gerry Bouffard, Jennifer McDowell, Baishali Maskeri, Nancy Hansen, Morgan Park, Pamela Thomas, Alice Young, and the many dedicated technicians. This work was supported by the NHGRI Intramural Research Program, NIDCD grant DC02236 (DMO); and NHGRI grants HG002385 and HG0058815 (EEE). EEE is an investigator of the Howard Hughes Medical Institute. NR 64 TC 3 Z9 4 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD JAN 24 PY 2011 VL 11 AR 23 DI 10.1186/1471-2148-11-23 PG 18 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 748RK UT WOS:000289408300001 PM 21261979 ER PT J AU Kumar, M Zhao, XL Wang, XW AF Kumar, Mia Zhao, Xuelian Wang, Xin Wei TI Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? SO CELL AND BIOSCIENCE LA English DT Review ID PRIMARY SCLEROSING CHOLANGITIS; TUMOR-SUPPRESSOR GENE; HEPATITIS-C VIRUS; COMPARATIVE GENOMIC HYBRIDIZATION; BIPOTENTIAL PROGENITOR CELLS; PRIMARY LIVER-CANCER; BILIARY-TRACT; P53 GENE; MICROSATELLITE INSTABILITY; MICRORNA EXPRESSION AB Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine. C1 [Kumar, Mia; Zhao, Xuelian; Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 FU Intramural Research Program of the Center for Cancer Research, the National Cancer Institute [Z01 BC 010313, Z01 BC 010876] FX We would like to thank Junfang Ji for her critical review of this manuscript and helpful suggestions and Karen Yarrick for her bibliographical assistance. This work was supported by the Intramural Research Program of the Center for Cancer Research, the National Cancer Institute (Z01 BC 010313 and Z01 BC 010876). NR 134 TC 27 Z9 30 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD JAN 24 PY 2011 VL 1 AR 5 DI 10.1186/2045-3701-1-5 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982NL UT WOS:000307051900001 PM 21711594 ER PT J AU Myers, KA Applegate, KT Danuser, G Fischer, RS Waterman, CM AF Myers, Kenneth A. Applegate, Kathryn T. Danuser, Gaudenz Fischer, Robert S. Waterman, Clare M. TI Distinct ECM mechanosensing pathways regulate microtubule dynamics to control endothelial cell branching morphogenesis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID MYOSIN-II INHIBITOR; EXTRACELLULAR-MATRIX; NEURITE INITIATION; EPITHELIAL-CELLS; AXON GUIDANCE; GROWTH; SUBSTRATE; ANGIOGENESIS; ACTIN; INSTABILITY AB During angiogenesis, cytoskeletal dynamics that mediate endothelial cell branching morphogenesis during vascular guidance are thought to be regulated by physical attributes of the extracellular matrix (ECM) in a process termed mechanosensing. Here, we tested the involvement of microtubules in linking mechanosensing to endothelial cell branching morphogenesis. We used a recently developed microtubule plus end tracking program to show that specific parameters of microtubule assembly dynamics, growth speed and growth persistence, are globally and regionally modified by, and contribute to, ECM mechanosensing. We demonstrated that engagement of compliant two-dimensional or three-dimensional ECMs induces local differences in microtubule growth speed that require myosin II contractility. Finally, we found that microtubule growth persistence is modulated by myosin II mediated compliance mechanosensing when cells are cultured on two-dimensional ECMs, whereas three-dimensional ECM engagement makes microtubule growth persistence insensitive to changes in ECM compliance. Thus, compliance and dimensionality ECM mechanosensing pathways independently regulate specific and distinct microtubule dynamics parameters in endothelial cells to guide branching morphogenesis in physically complex ECMs. C1 [Myers, Kenneth A.; Fischer, Robert S.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Applegate, Kathryn T.; Danuser, Gaudenz] Scripps Res Inst, Lab Computat Cell Biol, Dept Cell Biol, La Jolla, CA 92037 USA. [Danuser, Gaudenz] Harvard Univ, Sch Med, Dept Cell Biol, Lab Computat Cell Biol, Boston, MA 02115 USA. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Gaudenz_Danuser@hms.harvard.edu; fischerr2@nhlbi.nih.gov; watermancm@nhlbi.nih.gov OI Waterman, Clare/0000-0001-6142-6775 FU National Heart, Lung and Blood Institute; National Institute of General Medical Sciences [U01 GM067230] FX This work was initiated as a project in the Physiology Course at the Marine Biological Laboratory in Woods Hole, MA, and we thank student Julie Janvore (Institute Curie, Paris, Prance) for her work at early stages of the study. C.M. Waterman, R.S. Fischer, and K.A. Myers are supported by the National Heart, Lung and Blood Institute, and G. Danuser and K.T. Applegate are supported by National Institute of General Medical Sciences (U01 GM067230). NR 40 TC 50 Z9 51 U1 1 U2 17 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 24 PY 2011 VL 192 IS 2 BP 321 EP 334 DI 10.1083/jcb.201006009 PG 14 WC Cell Biology SC Cell Biology GA 727DW UT WOS:000287778800012 PM 21263030 ER PT J AU Horiuchi, M Itoh, A Pleasure, D Ozato, K Itoh, T AF Horiuchi, Makoto Itoh, Aki Pleasure, David Ozato, Keiko Itoh, Takayuki TI Cooperative contributions of Interferon regulatory factor 1 (IRF1) and IRF8 to interferon-gamma-mediated cytotoxic effects on oligodendroglial progenitor cells SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID SEQUENCE-BINDING-PROTEIN; CENTRAL-NERVOUS-SYSTEM; IFN-GAMMA; MYELOID CELLS; MULTIPLE-SCLEROSIS; GENE-TRANSCRIPTION; FACTOR FAMILY; HOST-DEFENSE; TNF-ALPHA; IN-VITRO AB Background: Administration of exogenous interferon-gamma (IFN gamma) aggravates the symptoms of multiple sclerosis (MS), whereas interferon-beta (IFN beta) is used for treatment of MS patients. We previously demonstrated that IFN gamma induces apoptosis of oligodendroglial progenitor cells (OPCs), suggesting that IFN gamma is more toxic to OPCs than IFN beta. Thus we hypothesized that a difference in expression profiles between IFN gamma-inducible and IFN beta-inducible genes in OPCs would predict the genes responsible for IFN gamma-mediated cytotoxic effects on OPCs. We have tested this hypothesis particularly focusing on the interferon regulatory factors (IRFs) well-known transcription factors up-regulated by IFNs. Methods: Highly pure primary rat OPC cultures were treated with IFN gamma and IFN beta. Cell death and proliferation were assessed by MTT reduction, caspse-3-like proteinase activity, Annexin-V binding, mitochondrial membrane potential, and BrdU-incorporation. Induction of all nine IRFs was comprehensively compared by quantitative PCR between IFN gamma-treated and IFN beta-treated OPCs. IRFs more strongly induced by IFN gamma than by IFN beta were selected, and tested for their ability to induce OPC apoptosis by overexpression and by inhibition by dominant-negative proteins or small interference RNA either in the presence or absence of IFN gamma. Results: Unlike IFN gamma, IFN beta did not induce apoptosis of OPCs. Among nine IRFs, IRF1 and IRF8 were preferentially up-regulated by IFN gamma. In contrast, IRF7 was more robustly induced by IFN beta than by IFN gamma. Overexpressed IRF1 elicited apoptosis of OPCs, and a dominant negative IRF1 protein partially protected OPCs from IFN gamma-induced apoptosis, indicating a substantial contribution of IRF1 to IFN gamma-induced OPC apoptosis. On the other hand, overexpression of IRF8 itself had only marginal proapoptotic effects. However, overexpressed IRF8 enhanced the IFNg-induced cytotoxicity and the proapoptotic effect of overexpressed IRF1, and down-regulation of IRF8 by siRNA partially but significantly reduced preapoptotic cells after treatment with IFN gamma, suggesting that IRF8 cooperatively enhances IFN gamma-induced OPC apoptosis. Conclusions: This study has identified that IRF1 and IRF8 mediate IFN gamma-signaling leading to OPC apoptosis. Therapies targeting at these transcription factors and their target genes could reduce IFN gamma induced OPC loss and thereby enhance remyelination in MS patients. C1 [Horiuchi, Makoto; Itoh, Aki; Pleasure, David; Itoh, Takayuki] Univ Calif Davis, Dept Neurol, Sch Med, Sacramento, CA 95817 USA. [Horiuchi, Makoto; Itoh, Aki; Pleasure, David; Itoh, Takayuki] Shriners Hosp Children No Calif, Inst Pediat Regenerat Med, Sacramento, CA USA. [Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Itoh, T (reprint author), Univ Calif Davis, Dept Neurol, Sch Med, Sacramento, CA 95817 USA. EM takito@ucdavis.edu RI Horiuchi, Makoto/M-5344-2014 FU Shriners Hospitals for Children [85400]; US National Institute of Health [NS025044] FX This work was supported by Research Grant of Shriners Hospitals for Children (No. 85400 to TI), Research fellowships of Shriners Hospitals for Children (to AI and MH) and US National Institute of Health grant NS025044 (to DP and TI). NR 59 TC 9 Z9 10 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JAN 24 PY 2011 VL 8 AR 8 DI 10.1186/1742-2094-8-8 PG 16 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 721LE UT WOS:000287355100001 PM 21261980 ER PT J AU Ganusov, VV Barber, DL De Boer, RJ AF Ganusov, Vitaly V. Barber, Daniel L. De Boer, Rob J. TI Killing of Targets by CD8(+) T Cells in the Mouse Spleen Follows the Law of Mass Action SO PLOS ONE LA English DT Article ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; MEDIATED CYTO-TOXICITY; IN-VIVO; IMMUNODEFICIENCY-VIRUS; VIRAL-INFECTION; CUTTING EDGE; EFFECTOR FUNCTION; RHESUS-MONKEYS; CTL ACTIVITY; LYMPH-NODES AB It has been difficult to correlate the quality of CD8(+) T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8(+) effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8(+) T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8(+) T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8(+) T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8(+) T cell response. C1 [Ganusov, Vitaly V.] Univ Tennessee, Dept Microbiol, Knoxville, TN 37996 USA. [Barber, Daniel L.] NIH, Bethesda, MD 20892 USA. [De Boer, Rob J.] Univ Utrecht, Utrecht, Netherlands. RP Ganusov, VV (reprint author), Univ Tennessee, Dept Microbiol, Knoxville, TN 37996 USA. EM vitaly.ganusov@gmail.com RI De Boer, Rob/B-6050-2011; OI De Boer, Rob/0000-0002-2130-691X; Ganusov, Vitaly/0000-0001-6572-1691 FU NWO [016.048.603]; Marie Curie Incoming International Fellowship (FP6); U.S. Department of Energy; University of Tennessee; Russian Ministry of Education [NK-550P/2] FX This work was supported by the VICI grant 016.048.603 from NWO, Marie Curie Incoming International Fellowship (FP6), the U.S. Department of Energy through the LANL/LDRD Program, start-up funds from the University of Tennessee and in part by a grant from the Russian Ministry of Education (NK-550P/2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 18 Z9 18 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 24 PY 2011 VL 6 IS 1 AR e15959 DI 10.1371/journal.pone.0015959 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710PJ UT WOS:000286523400009 PM 21283669 ER PT J AU Mattera, R Boehm, M Chaudhuri, R Prabhu, Y Bonifacino, JS AF Mattera, Rafael Boehm, Markus Chaudhuri, Rittik Prabhu, Yogikala Bonifacino, Juan S. TI Conservation and Diversification of Dileucine Signal Recognition by Adaptor Protein (AP) Complex Variants SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLARIZED EPITHELIAL-CELLS; LINKED MENTAL-RETARDATION; VIRUS TYPE-1 NEF; CD4 DOWN-REGULATION; CLATHRIN ADAPTER; SORTING SIGNALS; GAMMA-ADAPTIN; HIV-1 NEF; STRUCTURAL EXPLANATION; APPENDAGE DOMAIN AB The clathrin-associated, heterotetrameric adaptor protein (AP) complexes, AP-1, AP-2, and AP-3, recognize signals in the cytosolic domains of transmembrane proteins, leading to their sorting to endosomes, lysosomes, lysosome-related organelles, and/or the basolateral membrane of polarized epithelial cells. One type of signal, referred to as "dileucine-based," fits the consensus motif (D/E)XXXL(L/I). Previous biochemical analyses showed that (D/E)XXXL(L/I) signals bind to a combination of two subunits of each AP complex, namely the AP-1 gamma-sigma 1, AP-2 alpha-sigma 2, and AP-3 delta-sigma 3 hemicomplexes, and structural studies revealed that an imperfect variant of this motif lacking the (D/E) residue binds to a site straddling the interface of alpha and sigma 2. Herein, we report mutational and binding analyses showing that canonical (D/E)XXXL(L/I) signals bind to this same site on AP-2, and to similar sites on AP-1 and AP-3. The strength and amino acid requirements of different interactions depend on the specific signals and AP complexes involved. We also demonstrate the occurrence of diverse AP-1 heterotetramers by combinatorial assembly of various gamma and sigma 1 subunit isoforms encoded by different genes. These AP-1 variants bind (D/E)XXXL(L/I) signals with marked preferences for certain sequences, implying that they are not functionally equivalent. Our results thus demonstrate that different AP complexes share a conserved binding site for (D/E)XXXL(L/I) signals. However, the characteristics of the binding site on each complex vary, providing for the specific recognition of a diverse repertoire of (D/E)XXXL(L/I) signals. C1 [Mattera, Rafael; Boehm, Markus; Chaudhuri, Rittik; Prabhu, Yogikala; Bonifacino, Juan S.] NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 56 TC 43 Z9 43 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 JAN 21 PY 2011 VL 286 IS 3 BP 2022 EP 2030 DI 10.1074/jbc.M110.197178 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 706BV UT WOS:000286191500044 PM 21097499 ER PT J AU Wu, KM Jiao, XM Li, ZM Katiyar, S Casimiro, MC Yang, WC Zhang, QO Willmarth, NE Chepelev, I Crosariol, M Wei, Z Hu, JB Zhao, K Pestell, RG AF Wu, Kongming Jiao, Xuanmao Li, Zhaoming Katiyar, Sanjay Casimiro, Mathew C. Yang, Wancai Zhang, Qiong Willmarth, Nicole E. Chepelev, Iouri Crosariol, Marco Wei, Zhang Hu, Junbo Zhao, Keji Pestell, Richard G. TI Cell Fate Determination Factor Dachshund Reprograms Breast Cancer Stem Cell Function SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DETERMINATION FACTOR DACH1; EPITHELIAL-MESENCHYMAL TRANSITION; CYCLIN D1; ANDROGEN RECEPTOR; EXPRESSION; GROWTH; BINDING; IDENTIFICATION; ACETYLATION; COACTIVATOR AB The cell fate determination factor Dachshund was cloned as a dominant inhibitor of the hyperactive epidermal growth factor receptor ellipse. The expression of Dachshund is lost in human breast cancer associated with poor prognosis. Breast tumor-initiating cells (TIC) may contribute to tumor progression and therapy resistance. Here, endogenous DACH1 was reduced in breast cancer cell lines with high expression of TIC markers and in patient samples of the basal breast cancer phenotype. Re-expression of DACH1 reduced new tumor formation in serial transplantations in vivo, reduced mammosphere formation, and reduced the proportion of CD44(high)/CD24(low) breast tumor cells. Conversely, lentiviral shRNA to DACH1 increased the breast (B) TIC population. Genome-wide expression studies of mammary tumors demonstrated DACH1 repressed a molecular signature associated with stem cells (SOX2, Nanog, and KLF4) and genome-wide ChIP-seq analysis identified DACH1 binding to the promoter of the Nanog, KLF4, and Lin28 genes. KLF4/c-Myc and Oct4/Sox2 antagonized DACH1 repression of BTIC. Mechanistic studies demonstrated DACH1 directly repressed the Nanog and Sox2 promoters via a conserved domain. Endogenous DACH1 regulates BTIC in vitro and in vivo. C1 [Wu, Kongming; Zhang, Qiong; Willmarth, Nicole E.; Crosariol, Marco; Wei, Zhang; Pestell, Richard G.] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Wu, Kongming; Li, Zhaoming; Hu, Junbo] Huazhong Univ Sci & Technol, Tongji Med Sch, Tongji Hosp, Wuhan 430030, Peoples R China. [Yang, Wancai] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA. [Chepelev, Iouri; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Wu, KM (reprint author), Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, 233 S 10th St, Philadelphia, PA 19107 USA. EM kmwu2005@gmail.com; director@kimmelcancercenter.org RI Zhang, Qiong/F-8172-2015 FU National Institutes of Health [R01CA70896, R01CA75503, R01CA86072, P30CA56036]; Dr. Ralph and Marian C. Falk Medical Research Trust; Margaret Q. Landenberger Research Foundation; Pennsylvania Department of Health; National Natural Science Foundation of China [81072169] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01CA70896, R01CA75503, and R01CA86072 (to R. G. P.) and Grant P30CA56036 (Kimmel Cancer Center Core grant to R. G. P.).; This work was also supported by a grant from Dr. Ralph and Marian C. Falk Medical Research Trust (to R. G. P.), Margaret Q. Landenberger Research Foundation (to K. W.), in part by a grant from the Pennsylvania Department of Health (to R. G. P.), and in part by National Natural Science Foundation of China Grant 81072169 (to K. W.). NR 44 TC 44 Z9 47 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 21 PY 2011 VL 286 IS 3 BP 2132 EP 2142 DI 10.1074/jbc.M110.148395 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 706BV UT WOS:000286191500055 PM 20937839 ER PT J AU Wu, LM Ma, CA Zhao, YG Jain, A AF Wu, Liming Ma, Chi A. Zhao, Yongge Jain, Ashish TI Aurora B Interacts with NIR-p53, Leading to p53 Phosphorylation in Its DNA-binding Domain and Subsequent Functional Suppression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRAND BREAKS; CHROMOSOMAL PASSENGERS; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; IN-VIVO; KINASE; ACETYLATION; ACTIVATION; APOPTOSIS; DEGRADATION AB NIR (novel INHAT repressor) is a transcriptional co-repressor with inhibitor of histone acetyltransferase (INHAT) activity and has previously been shown to physically interact with and suppress p53 transcriptional activity and function. However, the mechanism by which NIR suppresses p53 is not completely understood. Using a proteomic approach, we have identified the Aurora kinase B as a novel binding partner of NIR. We show that Aurora B, NIR and p53 exist in a protein complex in which Aurora B binds to NIR, thus also indirectly associates with p53. Functionally, overexpression of Aurora B or NIR suppresses p53 transcriptional activity, and depletion of Aurora B or NIR causes p53-dependent apoptosis and cell growth arrest, due to the up-regulation of p21 and Bax. We then demonstrate that Aurora B phosphorylates multiple sites in the p53 DNA-binding domain in vitro, and this phosphorylation probably also occurs in cells. Importantly, the Aurora B-mediated phosphorylation on Ser(269) or Thr(284) significantly compromises p53 transcriptional activity. Taken together, these results provide novel insight into NIR-mediated p53 suppression and also suggest an additional way for p53 regulation. C1 [Wu, Liming; Ma, Chi A.; Zhao, Yongge; Jain, Ashish] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Jain, A (reprint author), NIAID, Host Def Lab, NIH, 10 Ctr Dr,CRC,Rm 5W3950, Bethesda, MD 20892 USA. EM ajain@niaid.nih.gov RI Wu, Liming/C-4004-2011 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health FX This work was supported, in whole or in part, by the intramural Research Program from National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. NR 38 TC 26 Z9 29 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 21 PY 2011 VL 286 IS 3 BP 2236 EP 2244 DI 10.1074/jbc.M110.174755 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 706BV UT WOS:000286191500064 PM 20959462 ER PT J AU Mahler, B Doddapaneni, K Kleckner, I Yuan, CH Wistow, G Wu, ZR AF Mahler, Bryon Doddapaneni, Kiran Kleckner, Ian Yuan, Chunhua Wistow, Graeme Wu, Zhengrong TI Characterization of a Transient Unfolding Intermediate in a Core Mutant of gamma S-Crystallin SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE relaxation dispersion; gamma S-crystallin; protein unfolding; cataract ID RELAXATION DISPERSION NMR; TIME-SCALE DYNAMICS; FIBRILS IN-VITRO; X-RAY-ANALYSIS; EYE LENS; CATARACT FORMATION; FOLDING PATHWAY; II-CRYSTALLIN; PROTEIN; DOMAIN AB In many age-related and neurological diseases, formerly native proteins aggregate via formation of a partially unfolded intermediate. gamma S-Crystallin is a highly stable structural protein of the eye lens. In the mouse Opj cataract, a non-conservative F9S mutation in the N-terminal domain core of gamma S allows the adoption of a native fold but renders the protein susceptible to temperature- and concentration-dependent aggregation, including fibril formation. Hydrogen/deuterium exchange and denaturant unfolding studies of this mutant protein (Opj) have suggested the existence of a partially unfolded intermediate in its aggregation pathway. Here, we used NMR and fluorescence spectroscopy to obtain evidence for this intermediate. In 3.5 M urea, Opj forms a stable and partially unfolded entity that is characterized by an unstructured N-terminal domain and a largely intact C-terminal domain. Under physiologically relevant conditions, Carr-Purcell-Meiboom-Gill T(2)-relaxation dispersion experiments showed that the N-terminal domain residues were in conformational exchange with a loosely structured intermediate with a population of 1-2%, which increased with temperature. This provides direct evidence for a model in which proteins of native fold can explore an intermediate state with an increased propensity for formation of aggregates, such as fibrils. For the crystallins, this shows how inherited sequence variants or environmentally induced modifications can destabilize a well-folded protein, allowing the formation of intermediates able to act as nucleation sites for aggregation and the accumulation of light-scattering centers in the cataractous lens. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Mahler, Bryon; Doddapaneni, Kiran; Kleckner, Ian; Wu, Zhengrong] Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA. [Yuan, Chunhua] Ohio State Univ, Campus Chem Instrument Ctr, Columbus, OH 43210 USA. [Wistow, Graeme] NEI, Sect Mol Struct & Funct Genom, Bethesda, MD 20892 USA. RP Wu, ZR (reprint author), Ohio State Univ, Dept Biochem, 484 W 12Th Ave, Columbus, OH 43210 USA. EM wu.473@osu.edu FU NIH [R21EY018423, R016M077234]; NET intramural program FX We are very grateful for useful discussion with Dr Lewis Kay and the software support from his laboratory. Z.W. is funded by NIH R21EY018423, G.W. is funded by the NET intramural program, and I.K. is supported by NIH R016M077234 (for Dr Mark Foster). NR 39 TC 16 Z9 16 U1 1 U2 20 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 21 PY 2011 VL 405 IS 3 BP 840 EP 850 DI 10.1016/j.jmb.2010.11.005 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 714DR UT WOS:000286788200018 PM 21108948 ER PT J AU Hoppins, S Edlich, F Cleland, MM Banerjee, S McCaffery, JM Youle, RJ Nunnari, J AF Hoppins, Suzanne Edlich, Frank Cleland, Megan M. Banerjee, Soojay McCaffery, J. Michael Youle, Richard J. Nunnari, Jodi TI The Soluble Form of Bax Regulates Mitochondrial Fusion via MFN2 Homotypic Complexes SO MOLECULAR CELL LA English DT Article ID M-AAA PROTEASE; MITOFUSIN 2; MAMMALIAN-CELLS; IN-VITRO; OPA1; APOPTOSIS; DYNAMICS; FISSION; ACTIVATION; MUTATIONS AB In mammals, fusion of the mitochondrial outer membrane is controlled by two DRPs, MFN1 and MFN2, that function in place of a single outer membrane DRP, Fzo1 in yeast. We addressed the significance of two mammalian outer membrane fusion DRPs using an in vitro mammalian mitochondrial fusion assay. We demonstrate that heterotypic MFN1-MFN2 trans complexes possess greater efficacy in fusion as compared to homotypic MFN1 or MFN2 complexes. In addition, we show that the soluble form of the proapoptotic Bcl2 protein, Bax, positively regulates mitochondrial fusion exclusively through homotypic MFN2 trans complexes. Together, these data demonstrate functional and regulatory distinctions between MFN1 and MFN2 and provide insight into their unique physiological roles. C1 [Hoppins, Suzanne; Nunnari, Jodi] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. [Edlich, Frank; Cleland, Megan M.; Banerjee, Soojay; Youle, Richard J.] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [McCaffery, J. Michael] Johns Hopkins Univ, Integrated Imaging Ctr, Baltimore, MD 21218 USA. RP Nunnari, J (reprint author), Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. EM jmnunnari@ucdavis.edu OI Harwig, Megan/0000-0003-2140-5739 FU NIH [2R01GM062942] FX We are grateful to members of the Nunnari lab for discussions and comments on the manuscript. This work was supported by an NIH 2R01GM062942 grant to J.N. NR 36 TC 80 Z9 83 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 21 PY 2011 VL 41 IS 2 BP 150 EP 160 DI 10.1016/j.molcel.2010.11.030 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 713AV UT WOS:000286708300006 PM 21255726 ER PT J AU Moskwa, P Buffa, FM Pan, YF Panchakshari, R Gottipati, P Muschel, RJ Beech, J Kulshrestha, R Abdelmohsen, K Weinstock, DM Gorospe, M Harris, AL Helleday, T Chowdhury, D AF Moskwa, Patryk Buffa, Francesca M. Pan, Yunfeng Panchakshari, Rohit Gottipati, Ponnari Muschel, Ruth J. Beech, John Kulshrestha, Ritu Abdelmohsen, Kotb Weinstock, David M. Gorospe, Myriam Harris, Adrian L. Helleday, Thomas Chowdhury, Dipanjan TI miR-182-Mediated Downregulation of BRCA1 Impacts DNA Repair and Sensitivity to PARP Inhibitors SO MOLECULAR CELL LA English DT Article ID CANCER-CELL-LINES; SPORADIC BREAST-CANCER; MICRORNA TARGETS; GENE-EXPRESSION; MESSENGER-RNA; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; PROMOTER-REGION; TUMORS; IDENTIFICATION AB Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 downregulates BRCA1 expression. Antagonizing miR-182 enhances BRCA1 protein levels and protects them from IR-induced cell death, while overexpressing miR-182 reduces BRCA1 protein, impairs homologous recombination-mediated repair, and render cells hypersensitive to IR. The impaired DNA repair phenotype induced by mill 182 overexpression can be fully rescued by overexpressing miR-182-insensitive BRCA1. Consistent with a BRCA1-deficiency phenotype, miR-182-over-expressing breast tumor cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). Conversely, antagonizing miR-182 enhances BRCA1 levels and induces resistance to PARP1 inhibitor. Finally, a clinical-grade PARP1 inhibitor impacts outgrowth of miR-182-expressing tumors in animal models. Together these results suggest that miR-182-mediated downregulation of BRCA1 impedes DNA repair and may impact breast cancer therapy. C1 [Gottipati, Ponnari; Muschel, Ruth J.; Beech, John; Helleday, Thomas] Univ Oxford, Canc Res UK Med Res Council, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England. [Moskwa, Patryk; Pan, Yunfeng; Panchakshari, Rohit; Kulshrestha, Ritu; Chowdhury, Dipanjan] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Weinstock, David M.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. [Buffa, Francesca M.; Harris, Adrian L.] Univ Oxford, Canc Res UK Dept Med Oncol, Weatherall Inst Mol Med, John Radcliffe Hosp, Oxford OX3 9DS, England. [Abdelmohsen, Kotb; Gorospe, Myriam] NIA IRP, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Helleday, Thomas] Stockholm Univ, Dept Genet Microbiol & Toxicol, S-10691 Stockholm, Sweden. [Helleday, Thomas] Stockholm Univ, Sci Life Lab, SE-17121 Solna, Sweden. RP Helleday, T (reprint author), Univ Oxford, Canc Res UK Med Res Council, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England. EM helleday@gmt.su.se; dipanjan_chowdhury@dfci.harvard.edu RI Buffa, Francesca/D-2574-2013; Helleday, Thomas/D-5224-2013; OI Buffa, Francesca/0000-0003-0409-406X; Helleday, Thomas/0000-0002-7384-092X; abdelmohsen, Kotb/0000-0001-6240-5810; Harris, Adrian/0000-0003-1376-8409 FU NCI [R01CA142698]; JCRT; Barr Award; Medical Research Council; NIHR Biomedical Research Centre, Oxford; NIA-IRP, NIH FX This work was supported by R01CA142698 (NCI), JCRT and a Barr Award (D.C.); by the Medical Research Council (T.H.); and by the NIHR Biomedical Research Centre, Oxford (A.L.H.). M.G. and K.A. were supported by the NIA-IRP, NIH. Dr. Mark O'Connor (AstraZeneca) kindly provided olaparib. We thank members of the Harris, Helleday, and Chowdhury laboratories for useful discussions. NR 63 TC 196 Z9 206 U1 4 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 21 PY 2011 VL 41 IS 2 BP 210 EP 220 DI 10.1016/j.molcel.2010.12.005 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 713AV UT WOS:000286708300011 PM 21195000 ER PT J AU Malinouski, M Zhou, Y Belousov, VV Hatfield, DL Gladyshev, VN AF Malinouski, Mikalai Zhou, You Belousov, Vsevolod V. Hatfield, Dolph L. Gladyshev, Vadim N. TI Hydrogen Peroxide Probes Directed to Different Cellular Compartments SO PLOS ONE LA English DT Article ID OXYGEN SPECIES PRODUCTION; DISULFIDE RELAY SYSTEM; GLUTATHIONE-PEROXIDASE; MITOCHONDRIAL-MEMBRANE; INTERMEMBRANE SPACE; FLUORESCENT-PROBES; RESPIRATORY-CHAIN; ESCHERICHIA-COLI; OXIDATIVE STRESS; MAMMALIAN-CELLS AB Background: Controlled generation and removal of hydrogen peroxide play important roles in cellular redox homeostasis and signaling. We used a hydrogen peroxide biosensor HyPer, targeted to different compartments, to examine these processes in mammalian cells. Principal Findings: Reversible responses were observed to various redox perturbations and signaling events. HyPer expressed in HEK 293 cells was found to sense low micromolar levels of hydrogen peroxide. When targeted to various cellular compartments, HyPer occurred in the reduced state in the nucleus, cytosol, peroxisomes, mitochondrial intermembrane space and mitochondrial matrix, but low levels of the oxidized form of the biosensor were also observed in each of these compartments, consistent with a low peroxide tone in mammalian cells. In contrast, HyPer was mostly oxidized in the endoplasmic reticulum. Using this system, we characterized control of hydrogen peroxide in various cell systems, such as cells deficient in thioredoxin reductase, sulfhydryl oxidases or subjected to selenium deficiency. Generation of hydrogen peroxide could also be monitored in various compartments following signaling events. Conclusions: We found that HyPer can be used as a valuable tool to monitor hydrogen peroxide generated in different cellular compartments. The data also show that hydrogen peroxide generated in one compartment could translocate to other compartments. Our data provide information on compartmentalization, dynamics and homeostatic control of hydrogen peroxide in mammalian cells. C1 [Malinouski, Mikalai; Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68583 USA. [Malinouski, Mikalai; Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE USA. [Malinouski, Mikalai; Gladyshev, Vadim N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Zhou, You] Univ Nebraska, Ctr Biotechnol, Lincoln, NE USA. [Belousov, Vsevolod V.] Russian Acad Sci, Inst Bioorgan Chem, Moscow, Russia. [Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Malinouski, M (reprint author), Univ Nebraska, Dept Biochem, Lincoln, NE 68583 USA. EM vgladyshev@rics.bwh.harvard.edu RI Gladyshev, Vadim/A-9894-2013; Belousov, Vsevolod/G-5562-2016 FU National Institutes of Health; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Russian Federation [DoeDs.-3567.2009.4]; Russian Foundation for Basic Research [10-04-01561] FX This study was supported by National Institutes of Health grants (to VNG), the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to DLH), a grant of the President of Russian Federation (DoeDs.-3567.2009.4) and the Russian Foundation for Basic Research (10-04-01561) (VVB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 72 Z9 75 U1 4 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 21 PY 2011 VL 6 IS 1 AR e14564 DI 10.1371/journal.pone.0014564 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710OY UT WOS:000286522300004 PM 21283738 ER PT J AU Hinrichs, CS Borman, ZA Gattinoni, L Yu, ZY Burns, WR Huang, JP Klebanoff, CA Johnson, LA Kerkar, SP Yang, SC Muranski, P Palmer, DC Scott, CD Morgan, RA Robbins, PF Rosenberg, SA Restifo, NP AF Hinrichs, Christian S. Borman, Zachary A. Gattinoni, Luca Yu, Zhiya Burns, William R. Huang, Jianping Klebanoff, Christopher A. Johnson, Laura A. Kerkar, Sid P. Yang, Shicheng Muranski, Pawel Palmer, Douglas C. Scott, Christopher D. Morgan, Richard A. Robbins, Paul F. Rosenberg, Steven A. Restifo, Nicholas P. TI Human effector CD8(+) T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy SO BLOOD LA English DT Article ID CHIMERIC ANTIGEN RECEPTOR; ANTITUMOR IMMUNITY; TUMOR-REGRESSION; ENGINEERED LYMPHOCYTES; TRANSCRIPTION FACTOR; TELOMERE LENGTH; CORD BLOOD; CANCER; THERAPY; DIFFERENTIATION AB Cluster of differentiation (CD)8(+) T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered in to tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8(+) T cells for patient treatments is controversial and understudied. We investigated human CD8(+) T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or "exhaustion," maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy. (Blood.2011;117(3):808-814) C1 [Restifo, Nicholas P.] NCI, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, NIH, Clin Res Ctr, Rm 3-5816,10 Ctr Dr, Bethesda, MD 20892 USA. EM restifo@nih.gov RI Restifo, Nicholas/A-5713-2008; Gattinoni, Luca/A-2281-2008; Klebanoff, Christopher/D-9581-2011; Johnson, Laura/H-4861-2013; Palmer, Douglas/B-9454-2008; OI Gattinoni, Luca/0000-0003-2239-3282; Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 NR 50 TC 112 Z9 115 U1 1 U2 14 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 20 PY 2011 VL 117 IS 3 BP 808 EP 814 DI 10.1182/blood-2010-05-286286 PG 7 WC Hematology SC Hematology GA 709GM UT WOS:000286426300012 PM 20971955 ER PT J AU Reiss, S Rebhan, I Backes, P Romero-Brey, I Erfle, H Matula, P Kaderali, L Poenisch, M Blankenburg, H Hiet, MS Longerich, T Diehl, S Ramirez, F Balla, T Rohr, K Kaul, A Buhler, S Pepperkok, R Lengauer, T Albrecht, M Eils, R Schirmacher, P Lohmann, V Bartenschlager, R AF Reiss, Simon Rebhan, Ilka Backes, Perdita Romero-Brey, Ines Erfle, Holger Matula, Petr Kaderali, Lars Poenisch, Marion Blankenburg, Hagen Hiet, Marie-Sophie Longerich, Thomas Diehl, Sarah Ramirez, Fidel Balla, Tamas Rohr, Karl Kaul, Artur Buehler, Sandra Pepperkok, Rainer Lengauer, Thomas Albrecht, Mario Eils, Roland Schirmacher, Peter Lohmann, Volker Bartenschlager, Ralf TI Recruitment and Activation of a Lipid Kinase by Hepatitis C Virus NS5A Is Essential for Integrity of the Membranous Replication Compartment SO CELL HOST & MICROBE LA English DT Article ID RNA REPLICATION; PHOSPHATIDYLINOSITOL 4-KINASES; CELLULAR COFACTORS; CORE PROTEIN; HOST FACTORS; HUH-7 CELLS; INFECTION; COMPLEX; IDENTIFICATION; SCREEN AB Hepatitis C virus (HCV) is a major causative agent of chronic liver disease in humans. To gain insight into host factor requirements for HCV replication, we performed a siRNA screen of the human kinome and identified 13 different kinases, including phosphatidylinositol-4-kinase III alpha (PI4KIIIa), as being required for HCV replication. Consistent with elevated levels of the PI4KIII alpha product phosphatidylinositol-4-phosphate (PI4P) detected in HCV-infected cultured hepatocytes and liver tissue from chronic hepatitis C patients, the enzymatic activity of PI4KIII alpha was critical for HCV replication. Viral nonstructural protein 5A (NS5A) was found to interact with PI4KIII alpha and stimulate its kinase activity. The absence of PI4KIII alpha activity induced a dramatic change in the ultrastructural morphology of the membranous HCV replication complex. Our analysis suggests that the direct activation of a lipid kinase by HCV NS5A contributes critically to the integrity of the membranous viral replication complex. C1 [Reiss, Simon; Rebhan, Ilka; Backes, Perdita; Romero-Brey, Ines; Poenisch, Marion; Hiet, Marie-Sophie; Kaul, Artur; Buehler, Sandra; Lohmann, Volker; Bartenschlager, Ralf] Univ Heidelberg, Dept Infect Dis, D-69120 Heidelberg, Germany. [Erfle, Holger] Univ Heidelberg, ViroQuant CellNetworks RNAi Screening Facil, D-69120 Heidelberg, Germany. [Matula, Petr; Rohr, Karl] Univ Heidelberg, Biomed Comp Vis Grp, Inst Pharm & Mol Biotechnol, Dept Bioinformat & Funct Genom, D-69120 Heidelberg, Germany. [Matula, Petr] Masaryk Univ, Fac Informat, Ctr Biomed Image Anal, CZ-60200 Brno, Czech Republic. [Kaderali, Lars] Univ Heidelberg, ViroQuant Res Grp Modeling, D-69120 Heidelberg, Germany. [Blankenburg, Hagen; Diehl, Sarah; Ramirez, Fidel; Lengauer, Thomas; Albrecht, Mario] Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, D-66123 Saarbrucken, Germany. [Longerich, Thomas; Schirmacher, Peter] Univ Heidelberg, Dept Pathol, D-69121 Heidelberg, Germany. [Balla, Tamas] NICHHD, Sect Mol Signal Transduct, NIH, Bethesda, MD 20892 USA. [Pepperkok, Rainer] European Mol Biol Lab, Cell Biol & Cell Biophys Unit, D-69117 Heidelberg, Germany. [Matula, Petr; Rohr, Karl; Eils, Roland] German Canc Res Ctr, Dept Theoret Bioinformat, D-69120 Heidelberg, Germany. [Eils, Roland] Univ Heidelberg, Inst Pharm & Mol Biotechnol BioQuant, D-69120 Heidelberg, Germany. RP Lohmann, V (reprint author), Univ Heidelberg, Dept Infect Dis, D-69120 Heidelberg, Germany. EM volker_lohmann@med.uni-heidelberg.de; ralf_bartenschlager@med.uni-heidelberg.de RI Albrecht, Mario/B-6694-2008; Matula, Petr/L-2119-2013; Bartenschlager, Ralf/L-2582-2015; Eils, Roland/B-6121-2009; OI Albrecht, Mario/0000-0002-3103-9624; Matula, Petr/0000-0003-4125-1597; Lohmann, Volker/0000-0001-8719-7608; Romero Brey, Ines/0000-0002-9073-9612; Eils, Roland/0000-0002-0034-4036; Pepperkok, Rainer/0000-0002-9762-3583; Balla, Tamas/0000-0002-9077-3335 FU Landesstiftung Baden-Wurttemberg [P-LS-RNS/30]; FORSYS (BMBF) [FKZ 0313923]; German Research Foundation DFG [SFB/TRR77, Lo 1556/1-1, KFO 129/1-2]; CellNetworks-Cluster of Excellence [EXC81]; German National Genome Research Network NGFN (BMBF) [01GR0453]; DFG; FORSYS; Ministry of Education of the Czech Republic [2B06052, MSM0021622419]; Medical Faculty of the University of Heidelberg; EU (EI-HCV); Tissue bank of the National Center for Tumor Diseases Heidelberg FX We are grateful to Ulrike Herian, Stephanie Kallis, Rahel Klein, Jurgen Beneke, and Nina Beil for excellent technical assistance. We thank Wolfgang Fischl for providing the DENV reporter construct and Charles M. Rice for the Huh7.5 cells and the NS5A monoclonal antibody 9E10. We are grateful to Kai Lin and Brigitte Wiedmann for providing purified PI4KIII alpha. and PIK93. We thank Jeremy Luban and Thomas Pertel for stable knockdown vector and Mark Harris for the NS5A polyclonal sheep serum. We thank Rossella Pellegrino for her assistance with IHC. We are grateful to the Nikon Imaging Center at the University of Heidelberg for providing access to their facility. This work was supported in part by the research program RNS/RNAi of the Landesstiftung Baden-Wurttemberg (P-LS-RNS/30 to R.B.), a grant from the FORSYS ViroQuant project (BMBF, FKZ 0313923 to R.B. and V.L.), and the German Research Foundation DFG (SFB/TRR77, Teilprojekt A1 to R.B. and V.L., Teilprojekt B5 to T.L. and P.S.; grant Lo 1556/1-1 to V.L and KFO 129/1-2 to T.L. and M.A.). The ViroQuant-CellNetworks RNAi Screening core facility was supported by CellNetworks-Cluster of Excellence (EXC81). The work directed by M.A. was supported by the German National Genome Research Network NGFN (BMBF, contract number 01GR0453) and the DFG-funded Cluster of Excellence for Multimodal Computing and Interaction. The work of P.M. was funded by the FORSYS ViroQuant project and The Ministry of Education of the Czech Republic, grant numbers 2B06052 and MSM0021622419. M.P. is supported by an intramural grant of the Medical Faculty of the University of Heidelberg, and M.-S.H. is supported by a Marie-Curie fellowship from the EU (EI-HCV). The work related to liver biopsy analysis was supported by the Tissue bank of the National Center for Tumor Diseases Heidelberg. R.B. and members of the Molecular Virology unit in Heidelberg would like to dedicate this study to the memory of Professor Heinz Schaller, a wonderful mentor and colleague and a generous sponsor, who made this unit and the work conducted therein possible and who shaped Heidelberg Life Sciences so much. NR 41 TC 241 Z9 246 U1 5 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JAN 20 PY 2011 VL 9 IS 1 BP 32 EP 45 DI 10.1016/j.chom.2010.12.002 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 721HP UT WOS:000287344500006 PM 21238945 ER PT J AU Warren, KE Goldman, S Pollack, IF Fangusaro, J Schaiquevich, P Stewart, CF Wallace, D Blaney, SM Packer, R MacDonald, T Jakacki, R Boyett, JM Kun, LE AF Warren, Katherine E. Goldman, Stewart Pollack, Ian F. Fangusaro, Jason Schaiquevich, Paula Stewart, Clinton F. Wallace, Dana Blaney, Susan M. Packer, Roger MacDonald, Tobey Jakacki, Regina Boyett, James M. Kun, Larry E. TI Phase I Trial of Lenalidomide in Pediatric Patients With Recurrent, Refractory, or Progressive Primary CNS Tumors: Pediatric Brain Tumor Consortium Study PBTC-018 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RENAL-CELL CARCINOMA; NERVOUS-SYSTEM TUMORS; MULTIPLE-MYELOMA; THALIDOMIDE ANALOG; CC-5013; SAFETY AB Purpose A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics. Patients and Methods Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m(2)/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21). Results Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m(2)/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m(2)/d. Twenty-three patients, representing all dose levels, received > six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied. Conclusion Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m(2)/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas. C1 [Warren, Katherine E.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. St Jude Childrens Hosp, Memphis, TN 38105 USA. Operat & Biostat Ctr Pediat Brain Tumor Consortiu, Memphis, TN USA. Texas Childrens Canc Ctr, Houston, TX USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Warren, KE (reprint author), NCI, Pediat Oncol Branch, Bldg 10 CRC,Rm 1-5750, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov RI MacDonald, Tobey/D-4554-2013 FU National Institutes of Health (NIH) [U01 CA81457, 5M01RR000188]; American Lebanese Syrian Associated Charities FX Supported in part by National Institutes of Health (NIH) Grant No. U01 CA81457 for the Pediatric Brain Tumor Consortium, NIH Grant No. 5M01RR000188, and the American Lebanese Syrian Associated Charities. NR 27 TC 33 Z9 33 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2011 VL 29 IS 3 BP 324 EP 329 DI 10.1200/JCO.2010.31.3601 PG 6 WC Oncology SC Oncology GA 707VU UT WOS:000286319000023 PM 21149652 ER PT J AU Lopez-Novoa, JM Rodriguez-Pena, AB Ortiz, A Martinez-Salgado, C Hernandez, FJL AF Lopez-Novoa, Jose M. Rodriguez-Pena, Ana B. Ortiz, Alberto Martinez-Salgado, Carlos Lopez Hernandez, Francisco J. TI Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID CHRONIC KIDNEY-DISEASE; CHRONIC-RENAL-FAILURE; GROWTH-FACTOR-BETA; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; MESANGIAL CELL-PROLIFERATION; EPITHELIAL-MESENCHYMAL TRANSFORMATION; MONOCYTE CHEMOATTRACTANT PROTEIN-1; PLATELET-ACTIVATING-FACTOR; MEMBRANE ATTACK COMPLEX; FAS-INDUCED APOPTOSIS AB Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed. C1 [Martinez-Salgado, Carlos; Lopez Hernandez, Francisco J.] IECSCYL, Soria, Spain. [Martinez-Salgado, Carlos; Lopez Hernandez, Francisco J.] Hosp Univ Salamanca, Unidad Invest, Salamanca, Spain. [Lopez-Novoa, Jose M.; Martinez-Salgado, Carlos; Lopez Hernandez, Francisco J.] Univ Salamanca, Dept Fisiol & Farmacol, Unidad Fisiopatol Renal & Cardiovasc, E-37008 Salamanca, Spain. [Lopez-Novoa, Jose M.; Ortiz, Alberto] IIS Fdn Jimenez Diaz, Renal & Vasc Res Lab, Madrid, Spain. [Rodriguez-Pena, Ana B.] NIH, Bethesda, MD 20892 USA. [Lopez-Novoa, Jose M.; Ortiz, Alberto] Univ Autonoma Madrid, Madrid, Spain. [Ortiz, Alberto; Martinez-Salgado, Carlos; Lopez Hernandez, Francisco J.] Fdn Inigo Alvarez de Toledo, Inst Reina Sofia Invest Nefrol, Madrid, Spain. RP Hernandez, FJL (reprint author), IECSCYL, Soria, Spain. EM flopezher@usal.es RI 2011, Secribsal/D-9425-2012; Martinez-Salgado, Carlos/E-7299-2012; OI Lopez-Novoa, Jose M./0000-0002-6211-7269 NR 284 TC 39 Z9 40 U1 3 U2 12 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 20 PY 2011 VL 9 AR 13 DI 10.1186/1479-5876-9-13 PG 26 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 718TC UT WOS:000287148100001 PM 21251296 ER PT J AU Ewens, KG Jones, MR Ankener, W Stewart, DR Urbanek, M Dunaif, A Legro, RS Chua, A Azziz, R Spielman, RS Goodarzi, MO Strauss, JF AF Ewens, Kathryn G. Jones, Michelle R. Ankener, Wendy Stewart, Douglas R. Urbanek, Margrit Dunaif, Andrea Legro, Richard S. Chua, Angela Azziz, Ricardo Spielman, Richard S. Goodarzi, Mark O. Strauss, Jerome F., III TI FTO and MC4R Gene Variants Are Associated with Obesity in Polycystic Ovary Syndrome SO PLOS ONE LA English DT Article ID DIABETES-MELLITUS; CHILDHOOD OBESITY; FAT MASS; POLYMORPHISMS; PREVALENCE; LINKAGE; TRAITS; REGION; ADULT; WOMEN AB Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (chi(2) = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism. C1 [Ewens, Kathryn G.; Ankener, Wendy; Spielman, Richard S.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Stewart, Douglas R.] NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, Rockville, MD USA. [Urbanek, Margrit; Dunaif, Andrea] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Legro, Richard S.] Penn State Hershey Coll Med, Dept Obstet & Gynecol, Hershey, PA USA. [Jones, Michelle R.; Chua, Angela; Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Azziz, Ricardo] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Los Angeles, CA 90048 USA. [Strauss, Jerome F., III] Virginia Commonwealth Univ, Dept Obstet & Gynecol, Richmond, VA USA. RP Ewens, KG (reprint author), Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. EM mark.goodarzi@cshs.org; jfstrauss@vcu.edu RI Azziz, Ricardo/N-7229-2014 OI Azziz, Ricardo/0000-0002-3917-0483 FU National Institutes of Health (NIH) [U54HD034449]; Division of Intramural Research of the National Human Genome Research Institute; NCRR [M01-RR00425]; Winnick Clinical Scholars Award; Pennsylvania Department of Health [RSL- SAP 41-000-26343]; [P50 HD44405]; [U54 HD34449]; [RR10732]; [C06 RR016499]; [M01 RR00048]; [M01 RR10732]; [M01 RR02635]; [R01-HD29364]; [K24-HD01346]; [R01-DK79888] FX This research was supported by National Institutes of Health (NIH) Grants U54HD034449 (to J.F.S. and R.S.S.); Division of Intramural Research of the National Human Genome Research Institute (D.R.S.); P50 HD44405 (A.D.); U54 HD34449 (to M.U. and A.D.); RR10732 and C06 RR016499 (to Pennsylvania State University General Clinical Research Center (GCRC)); M01 RR00048 (to Northwestern University GCRC); M01 RR10732 and M01 RR02635 (to Brigham and Women's Hospital GCRC); R01-HD29364 and K24-HD01346 (to RA); R01-DK79888 (to M.O.G.); and M01-RR00425 (General Clinical Research Center Grant from the NCRR); the Winnick Clinical Scholars Award (to M.O.G.); and an endowment from the Helping Hand of Los Angeles, Inc. This project is funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco Settlement Funds (RSL- SAP 41-000-26343). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 45 Z9 46 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2011 VL 6 IS 1 AR e16390 DI 10.1371/journal.pone.0016390 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710OX UT WOS:000286522200057 PM 21283731 ER PT J AU Wei, J Wu, A Kong, LY Wang, YT Fuller, G Fokt, I Melillo, G Priebe, W Heimberger, AB AF Wei, Jun Wu, Adam Kong, Ling-Yuan Wang, Yongtao Fuller, Gregory Fokt, Isabella Melillo, Giovanni Priebe, Waldemar Heimberger, Amy B. TI Hypoxia Potentiates Glioma-Mediated Immunosuppression SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; REGULATORY T-CELLS; TUMOR-ASSOCIATED MACROPHAGES; IMMUNE-RESPONSE; STEM-CELLS; SIGNAL TRANSDUCERS; INDUCIBLE FACTORS; TISSUE-DAMAGE; CANCER; EXPRESSION AB Glioblastoma multiforme (GBM) is a lethal cancer that exerts potent immune suppression. Hypoxia is a predominant feature of GBM, but it is unclear to the degree in which tumor hypoxia contributes to this tumor-mediated immunosuppression. Utilizing GBM associated cancer stem cells (gCSCs) as a treatment resistant population that has been shown to inhibit both innate and adaptive immune responses, we compared immunosuppressive properties under both normoxic and hypoxic conditions. Functional immunosuppression was characterized based on production of immunosuppressive cytokines and chemokines, the inhibition of T cell proliferation and effector responses, induction of FoxP3+ regulatory T cells, effect on macrophage phagocytosis, and skewing to the immunosuppressive M2 phenotype. We found that hypoxia potentiated the gCSC-mediated inhibition of T cell proliferation and activation and especially the induction of FoxP3+T cells, and further inhibited macrophage phagocytosis compared to normoxia condition. These immunosuppressive hypoxic effects were mediated by signal transducer and activator of transcription 3 (STAT3) and its transcriptionally regulated products such as hypoxia inducible factor (HIF)-1 alpha and vascular endothelial growth factor (VEGF). Inhibitors of STAT3 and HIF-1 alpha down modulated the gCSCs' hypoxia-induced immunosuppressive effects. Thus, hypoxia further enhances GBM-mediated immunosuppression, which can be reversed with therapeutic inhibition of STAT3 and HIF-1 alpha and also helps to reconcile the disparate findings that immune therapeutic approaches can be used successfully in model systems but have yet to achieve generalized successful responses in the vast majority of GBM patients by demonstrating the importance of the tumor hypoxic environment. C1 [Wei, Jun; Wu, Adam; Kong, Ling-Yuan; Wang, Yongtao; Heimberger, Amy B.] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. [Fuller, Gregory] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Fokt, Isabella; Priebe, Waldemar] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Melillo, Giovanni] NCI, Frederick, MD 21701 USA. RP Wei, J (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. EM aheimber@mdanderson.org OI Fuller, Gregory/0000-0001-9447-2647 FU Anthony Bullock III Foundation; Mitchell Foundation; Dr. Marnie Rose Foundation; U.S. National Institutes of Health [CA120813-03, A177225-01, P50 CA093459] FX This work was supported by the Anthony Bullock III Foundation (ABH), the Mitchell Foundation (ABH), the Dr. Marnie Rose Foundation (ABH), and the U.S. National Institutes of Health grants CA120813-03, A177225-01, P50 CA093459 (ABH), and P50 CA093459 (WP). The funding organizations had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 64 Z9 66 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2011 VL 6 IS 1 AR e16195 DI 10.1371/journal.pone.0016195 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710OX UT WOS:000286522200035 PM 21283755 ER PT J AU Li, XJ Zhang, XA Cmarik, JL Ruscetti, S AF Li, Xiujie Zhang, Xiang Cmarik, Joan L. Ruscetti, Sandra TI Importance of macrophage inflammatory protein-la and splenic macrophages in neurodegeneration induced by PVC-211 murine leukemia virus SO VIROLOGY LA English DT Article DE Retrovirus; PVC-211 MuLV; Neuropathogenesis; Chemokine; MIP-1 alpha; Microglia; Splenectomy ID T-CELLS; MIP-1-ALPHA; ACTIVATION; MICROGLIA; DISEASE; STROKE; PROTEIN-1-ALPHA; TROPISM; VARIANT; SYSTEM AB We recently reported that infection of rats with the neurodegenerative disease-causing retrovirus PVC-211 MuLV results in elevated levels of the chemokine MIP-1 alpha followed by the accumulation of activated microglia in the brain. To investigate the importance of MIP-1 alpha in recruitment of microglia to the brain, we treated rats with MIP-1 alpha antibodies before and after PVC-211 MuLV infection. This caused a delay in the development of paralysis which was associated with a decrease in activated microglia without affecting virus expression. To determine the source of activated microglia, rats were splenectomized 4 days after virus infection. Splenectomized rats showed a delay in disease development that was associated with decreased numbers of activated microglia without affecting virus expression. Together, these results suggest that MIP-1 alpha is directly involved in the neurodegeneration induced in rats by PVC-211 MuLV by recruiting macrophages/microglia from the periphery into regions of the brain that eventually become diseased. Published by Elsevier Inc. C1 [Li, Xiujie; Zhang, Xiang; Cmarik, Joan L.; Ruscetti, Sandra] NCI, Lab Canc Prevent, Frederick, MD 21702 USA. RP Ruscetti, S (reprint author), NCI, Lab Canc Prevent, Bldg 567,Room 152, Frederick, MD 21702 USA. EM ruscetts@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 23 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 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2011 VL 409 IS 2 BP 198 EP 203 DI 10.1016/j.virol.2010.10.012 PG 6 WC Virology SC Virology GA 708MV UT WOS:000286366800007 PM 21051067 ER PT J AU Chen, NH Bellone, CJ Schriewer, J Owens, G Fredrickson, T Parker, S Buller, RML AF Chen, Nanhai Bellone, Clifford J. Schriewer, Jill Owens, Gelita Fredrickson, Torgny Parker, Scott Buller, R. Mark L. TI Poxvirus interleukin-4 expression overcomes inherent resistance and vaccine-induced immunity: Pathogenesis, prophylaxis, and antiviral therapy SO VIROLOGY LA English DT Article DE Immunosuppression; Poxvirus; Ectromelia virus; Lethal infection; IL-4 ID SIMPLEX-VIRUS TYPE-1; ACYCLIC NUCLEOSIDE PHOSPHONATES; RESPIRATORY SYNCYTIAL VIRUS; LETHAL MOUSEPOX MODEL; ECTROMELIA VIRUS; MURINE INTERLEUKIN-4; LYMPHOCYTE-RESPONSES; GENETIC-RESISTANCE; PROTECTS MICE; RECOMBINANT AB In 2001, Jackson et al. reported that murine IL-4 expression by a recombinant ectromelia virus caused enhanced morbidity and lethality in resistant C57BL/6 mice as well as overcame protective immune memory responses. To achieve a more thorough understanding of this phenomenon and to assess a variety of countermeasures, we constructed a series of ECTV recombinants encoding murine IL-4 under the control of promoters of different strengths and temporal regulation. We showed that the ECTV-IL-4 recombinant expressing the highest level of IL-4 was uniformly lethal for C57BL/6 mice even when previously immunized. The lethality of the ECTV-IL-4 recombinants resulted from virus-expressed IL-4 signaling through the IL-4 receptor but was not due to IL-4 toxicity. A number of treatment approaches were evaluated against the most virulent IL-4 encoding virus. The most efficacious therapy was a combination of two antiviral drugs (CMX001 (R) and ST-246 (R)) that have different mechanisms of action. (C) 2010 Elsevier Inc. All rights reserved. C1 [Bellone, Clifford J.; Schriewer, Jill; Parker, Scott; Buller, R. Mark L.] Doisy Res Ctr, Dept Mol Microbiol & Immunol, St Louis, MO 63104 USA. [Chen, Nanhai] Genelux Corp, San Diego Sci Ctr, San Diego, CA 92109 USA. [Owens, Gelita] Nestle Purina PetCare PTC, St Joseph, MO USA. [Fredrickson, Torgny] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Buller, RML (reprint author), Doisy Res Ctr, Dept Mol Microbiol & Immunol, 1100 S Grand Blvd, St Louis, MO 63104 USA. EM mark.buller@gmail.com FU NIAID [NOI-AI-15436, 25XS065] FX This work was supported by NIAID NOI-AI-15436 and subcontract 25XS065. We thank Ed Hembrador for assaying virus infectivity and Elsa Taricone and Christina Oberle for technical assistance. We also thank Drs. Michael Bray, Heather Greenstone, Dennis Dixon, Denis Hruby, Guna Karupiah, Peter Jahrling, Cliff Lane, George Painter, and Jorge Tavel for helpful discussions. NR 57 TC 17 Z9 17 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2011 VL 409 IS 2 BP 328 EP 337 DI 10.1016/j.virol.2010.10.021 PG 10 WC Virology SC Virology GA 708MV UT WOS:000286366800020 PM 21071055 ER PT J AU Maltsev, AV Maltsev, VA Mikheev, M Maltseva, LA Sirenko, SG Lakatta, EG Stern, MD AF Maltsev, Anna V. Maltsev, Victor A. Mikheev, Maxim Maltseva, Larissa A. Sirenko, Syevda G. Lakatta, Edward G. Stern, Michael D. TI Synchronization of Stochastic Ca2+ Release Units Creates a Rhythmic Ca2+ Clock in Cardiac Pacemaker Cells SO BIOPHYSICAL JOURNAL LA English DT Article ID SINOATRIAL NODAL CELLS; RYANODINE RECEPTOR; DIASTOLIC DEPOLARIZATION; SARCOPLASMIC-RETICULUM; CALCIUM-RELEASE; RABBIT; OSCILLATIONS; AUTOMATICITY; STIMULATION; INITIATION AB In sinoatrial node cells of the heart, beating rate is controlled, in part, by local Ca2+ releases (LCRs) from the sarcoplasmic reticulum, which couple to the action potential via electrogenic Na+/Ca2+ exchange. We observed persisting, roughly periodic LCRs in depolarized rabbit sinoatrial node cells (SANCs). The features of these LCRs were reproduced by a numerical model consisting of a two-dimensional array of stochastic, diffusively coupled Ca2+ release units (CRUs) with fixed refractory period. Because previous experimental studies showed that beta-adrenergic receptor stimulation increases the rate of Ca2+ release through each CRU (dubbed I-spark), we explored the link between LCRs and I-spark in our model. Increasing the CRU release current I-spark facilitated Ca2+-induced-Ca2+ release and local recruitment of neighboring CRUs to fire more synchronously. This resulted in a progression in simulated LCR size (from sparks to wavelets to global waves), LCR rhythmicity, and decrease of LCR period that parallels the changes observed experimentally with beta-adrenergic receptor stimulation. The transition in LCR characteristics was steeply nonlinear over a narrow range of I-spark, resembling a phase transition. We conclude that the (partial) periodicity and rate regulation of the "Calcium clock" in SANCs are emergent properties of the diffusive coupling of an ensemble of interacting stochastic CRUs. The variation in LCR period and size with I-spark is sufficient to account for beta-adrenergic regulation of SANC beating rate. C1 [Maltsev, Anna V.; Maltsev, Victor A.; Mikheev, Maxim; Maltseva, Larissa A.; Sirenko, Syevda G.; Lakatta, Edward G.; Stern, Michael D.] Natl Inst Aging, Intramural Res Program, NIH, Baltimore, MD 20892 USA. RP Stern, MD (reprint author), Natl Inst Aging, Intramural Res Program, NIH, Baltimore, MD 20892 USA. EM sternm@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health, Bethesda, MD FX This work is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, MD. NR 33 TC 31 Z9 31 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JAN 19 PY 2011 VL 100 IS 2 BP 271 EP 283 DI 10.1016/j.bpj.2010.11.081 PG 13 WC Biophysics SC Biophysics GA 710UX UT WOS:000286543600004 PM 21244823 ER PT J AU Husain, FT Medina, RE Davis, CW Szymko-Bennett, Y Simonyan, K Pajor, NM Horwitz, B AF Husain, Fatima T. Medina, Roberto E. Davis, Caroline W. Szymko-Bennett, Yvonne Simonyan, Kristina Pajor, Nathan M. Horwitz, Barry TI Neuroanatomical changes due to hearing loss and chronic tinnitus: A combined VBM and DTI study SO BRAIN RESEARCH LA English DT Article DE Voxel-based morphometry; VBM; Diffusion tensor imaging; DTI; MRI; Brain; Structure; Tinnitus; Hearing loss; Hearing impairment; Gray matter; Grey matter; White matter ID VOXEL-BASED MORPHOMETRY; PRIMARY AUDITORY-CORTEX; MEDIAL GENICULATE-BODY; DIFFUSION ANISOTROPY; INFERIOR COLLICULUS; NEURAL PLASTICITY; COCHLEAR NUCLEUS; GRAY-MATTER; HUMAN BRAIN; PERCEPTION AB Subjective tinnitus is the perception of sound in the absence of an external source. Tinnitus is often accompanied by hearing loss but not everyone with hearing loss experiences tinnitus. We examined neuroanatomical alterations associated with hearing loss and tinnitus in three groups of subjects: those with hearing loss with tinnitus, those with hearing loss without tinnitus and normal hearing controls without tinnitus. To examine changes in gray matter we used structural MRI scans and voxel-based morphometry (VBM) and to identify changes in white matter tract orientation we used diffusion tensor imaging (DTI). A major finding of our study was that there were both gray and white matter changes in the vicinity of the auditory cortex for subjects with hearing loss alone relative to those with tinnitus and those with normal hearing. We did not find significant changes in gray or white matter in subjects with tinnitus and hearing loss compared to normal hearing controls. VBM analysis revealed that individuals with hearing loss without tinnitus had gray matter decreases in anterior cingulate and superior and medial frontal gyri relative to those with hearing loss and tinnitus. Region-of-interest analysis revealed additional decreases in superior temporal gyrus for the hearing loss group compared to the tinnitus group. Investigating effects of hearing loss alone, we found gray matter decreases in superior and medial frontal gyri in participants with hearing loss compared to normal hearing controls. DTI analysis showed decreases in fractional anisotropy values in the right superior and inferior longitudinal fasciculi, corticospinal tract, inferior fronto-occipital tract, superior occipital fasciculus, and anterior thalamic radiation for the hearing loss group relative to normal hearing controls. In attempting to dissociate the effect of tinnitus from hearing loss, we observed that hearing loss rather than tinnitus had the greatest influence on gray and white matter alterations. (C) 2010 Elsevier B.V. All rights reserved. C1 [Husain, Fatima T.; Medina, Roberto E.; Davis, Caroline W.] Univ Illinois, Dept Speech & Hearing Sci, Champaign, IL 61820 USA. [Husain, Fatima T.; Szymko-Bennett, Yvonne; Pajor, Nathan M.; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD USA. [Simonyan, Kristina] Natl Inst Neurol Disorders & Stroke, Laryngeal & Speech Sect, NIH, Bethesda, MD USA. RP Husain, FT (reprint author), Univ Illinois, Dept Speech & Hearing Sci, 901 S 6th St,MC-482, Champaign, IL 61820 USA. EM husainf@illinois.edu OI Simonyan, Kristina/0000-0001-7444-0437 FU NIH-NIDCD; Tinnitus Research Consortium FX The research was supported by the NIH-NIDCD Intramural Research Program and a grant from the Tinnitus Research Consortium to FTH. We are grateful to Dr. Allen Braun of the Language Section and the Audiology clinic staff of NIDCD-NIH: Dr. H. J. Kim, Dr. C. Brewer, Nurse Practitioner S. Rudy, audiologist C. Zalewski, for their diligent efforts in screening the participants in the study. We thank Kathy Xu for her help in the initial stages of the DTI analysis and Christopher Grindrod for his comments on earlier drafts of this manuscript. NR 65 TC 57 Z9 60 U1 2 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 19 PY 2011 VL 1369 BP 74 EP 88 DI 10.1016/j.brainres.2010.10.095 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 714GE UT WOS:000286794700007 PM 21047501 ER PT J AU Jin, QH Yu, LR Wang, LF Zhang, ZJ Kasper, LH Lee, JE Wang, CC Brindle, PK Dent, SYR Ge, K AF Jin, Qihuang Yu, Li-Rong Wang, Lifeng Zhang, Zhijing Kasper, Lawryn H. Lee, Ji-Eun Wang, Chaochen Brindle, Paul K. Dent, Sharon Y. R. Ge, Kai TI Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation SO EMBO JOURNAL LA English DT Article DE CBP and p300; GCN5 and PCAF; histone acetylation; nuclear receptor ID HISTONE H3; GENE-EXPRESSION; TRANSCRIPTIONAL REGULATION; HUMAN GENOME; CHROMATIN; ACETYLATION; COMPLEX; P300; ACETYLTRANSFERASE; ACTIVATION AB Histone acetyltransferases (HATs) GCN5 and PCAF (GCN5/PCAF) and CBP and p300 (CBP/p300) are transcription co-activators. However, how these two distinct families of HATs regulate gene activation remains unclear. Here, we show deletion of GCN5/PCAF in cells specifically and dramatically reduces acetylation on histone H3K9 (H3K9ac) while deletion of CBP/p300 specifically and dramatically reduces acetylations on H3K18 and H3K27 (H3K18/27ac). A ligand for nuclear receptor (NR) PPAR delta induces sequential enrichment of H3K18/27ac, RNA polymerase II (Pol H) and H3K9ac on PPAR delta target gene Angptl4 promoter, which correlates with a robust Angptl4 expression. Inhibiting transcription elongation blocks ligand-induced H3K9ac, but not H3K18/27ac, on the Angptl4 promoter. Finally, we show GCN5/PCAF and GCN5/PCAF-mediated H3K9ac correlate with, but are surprisingly dispensable for, NR target gene activation. In contrast, CBP/p300 and their HAT activities are essential for ligand-induced Pol II recruitment on, and activation of, NR target genes. These results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF- and CBP/p300-mediated histone acetylations in gene activation, and suggest an important role of CBP/p300-mediated H3K18/27ac in NR-dependent transcription. The EMBO Journal (2011) 30, 249-262. doi:10.1038/emboj.2010.318; Published online 3 December 2010 C1 [Jin, Qihuang; Wang, Lifeng; Lee, Ji-Eun; Wang, Chaochen; Ge, Kai] NIDDK, Nucl Receptor Biol Sect, CEB, NIH, Bethesda, MD 20892 USA. [Yu, Li-Rong] US FDA, Ctr Excellence Prote, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Zhang, Zhijing; Dent, Sharon Y. R.] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Kasper, Lawryn H.] St Jude Childrens Hosp, Dept Biochem, Memphis, TN 38105 USA. RP Ge, K (reprint author), NIDDK, Nucl Receptor Biol Sect, CEB, NIH, Bldg 10,Room 8N307C,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kaig@niddk.nih.gov RI Lee, Ji-Eun/F-7891-2011; Wang, Lifeng/I-4888-2012; OI Lee, Ji-Eun/0000-0002-3768-7016; Wang, Lifeng/0000-0003-4752-6547; Ge, Kai/0000-0002-7442-5138 FU NIDDK, NIH; NIH [R01GM067718, DE018183] FX We thank Y Barak and R Evans for providing PPAR deltaflox/flox mice, Z Wang and K Zhao for validated histone modification antibodies, R Roeder for Ada2b, SPT3 and Ada2a antibodies, and D Mendrick for critical reading of the paper. This work was supported by the Intramural Research Program of the NIDDK, NIH to KG, NIH R01GM067718 to SYRD and NIH DE018183 to PKB. NR 55 TC 209 Z9 214 U1 5 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 19 PY 2011 VL 30 IS 2 BP 249 EP 262 DI 10.1038/emboj.2010.318 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 719DE UT WOS:000287179100004 PM 21131905 ER PT J AU Park, EH Walker, SE Lee, JM Rothenburg, S Lorsch, JR Hinnebusch, AG AF Park, Eun-Hee Walker, Sarah E. Lee, Joseph M. Rothenburg, Stefan Lorsch, Jon R. Hinnebusch, Alan G. TI Multiple elements in the eIF4G1 N-terminus promote assembly of elF4G1 center dot PABP mRNPs in vivo SO EMBO JOURNAL LA English DT Article DE elF4G; initiation; translation; PABP; yeast ID TRANSLATION INITIATION-FACTOR; POLY(A) BINDING-PROTEIN; SACCHAROMYCES-CEREVISIAE; RNA-BINDING; POLY(A)-BINDING PROTEIN; DEPENDENT TRANSLATION; MESSENGER-RNA; FACTOR 4F; FACTOR 4G; YEAST AB eIF4G is the scaffold subunit of the eIF4F complex, whose binding domains for eIF4E and poly(A)-binding protein (PABP) are thought to enhance formation of activated eIF4F center dot mRNA center dot PABP complexes competent to recruit 43S pre-initiation complexes. We found that the RNA-binding region (RNA1) in the N-terminal domain (NTD) of yeast eIF4G1 can functionally substitute for the PABP-binding segment to rescue the function of an eIF4G1-459 mutant impaired for eIF4E binding. Assaying RNA-dependent PABP-eIF4G association in cell extracts suggests that RNA1, the PABP-binding domain, and two conserved elements (Box1 and Box2) between these segments have overlapping functions in forming native eIF4G center dot mRNA center dot PABP complexes. In vitro experiments confirm the role of RNA1 in stabilizing eIF4G-mRNA association, and further indicate that RNA1 and Box1 promote PABP binding, in addition to RNA binding, by the eIF4G1 NTD. Our findings indicate that PABP-eIF4G association is only one of several interactions that stabilize eIF4F center dot mRNA complexes, and emphasize that closed-loop mRNP formation via PABP-eIF4G interaction is non-essential in vivo. Interestingly, two other RNA-binding regions in eIF4G1 have critical functions downstream of eIF4F center dot mRNA assembly. The EMBO Journal (2011) 30, 302-316. doi:10.1038/emboj.2010.312; Published online 7 December 2010 C1 [Walker, Sarah E.; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. [Park, Eun-Hee; Rothenburg, Stefan; Hinnebusch, Alan G.] Eunice K Shriver Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Lee, Joseph M.] NCI, Mammary Biol & Inmorigenesis Lab, NIH, Bethesda, MD 20892 USA. RP Lorsch, JR (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. EM jlorsch@jhmi.edu; ahinnebusch@nih.gov RI Rothenburg, Stefan/A-8340-2008 FU NIH [GM62128]; American Heart Association FX We thank Alan Sachs, John McCarthy, and Jon Warner for generous gifts of strains, plasmids, or antibodies, and Byung-Sik Shin for excellent technical advice. This work was supported in part by the Intramural Research Program of the NIH, an NIH grant to JRL (GM62128), and an American Heart Association award (SEW). NR 42 TC 32 Z9 32 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 19 PY 2011 VL 30 IS 2 BP 302 EP 316 DI 10.1038/emboj.2010.312 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 719DE UT WOS:000287179100008 PM 21139564 ER PT J AU Bergmann, JH Rodriguez, MG Martins, NMC Kimura, H Kelly, DA Masumoto, H Larionov, V Jansen, LET Earnshaw, WC AF Bergmann, Jan H. Rodriguez, Mariluz Gomez Martins, Nuno M. C. Kimura, Hiroshi Kelly, David A. Masumoto, Hiroshi Larionov, Vladimir Jansen, Lars E. T. Earnshaw, William C. TI Epigenetic engineering shows H3K4me2 is required for HJURP targeting and CENP-A assembly on a synthetic human kinetochore SO EMBO JOURNAL LA English DT Article DE CENP-A; centromere; chromatin; kinetochore; non-coding RNA ID EMBRYONIC STEM-CELLS; HISTONE LYSINE METHYLATION; CENTROMERIC CHROMATIN; MOLECULAR ARCHITECTURE; MICROTUBULE INTERFACE; MAMMALIAN CHROMATIN; NONCODING RNAS; COMPLEX; TRANSCRIPTION; PROTEINS AB Kinetochores assemble on distinct 'centrochromatin' containing the histone 113 variant CENP-A and interspersed nucleosomes dimethylated on H3K4 (H3K4me2). Little is known about how the chromatin environment at active centromeres governs centromeric structure and function. Here, we report that centrochromatin resembles K4-K36 domains found in the body of some actively transcribed housekeeping genes. By tethering the lysine-specific demethylase 1 (LSD1), we specifically depleted H3K4me2, a modification thought to have a role in transcriptional memory, from the kinetochore of a synthetic human artificial chromosome (HAC). H3K4me2 depletion caused kinetochores to suffer a rapid loss of transcription of the underlying CL-satellite DNA and to no longer efficiently recruit HJURP, the CENP-A chaperone. Kinetochores depleted of H3K4me2 remained functional in the short term, but were defective in incorporation of CENP-A, and were gradually inactivated. Our data provide a functional link between the centromeric chromatin, a-satellite transcription, maintenance of CENP-A levels and kinetochore stability. The EMBO Journal (2011) 30, 328-340: doi:10.1038/emboj.2010.329; Published online 14 December 2010 C1 [Bergmann, Jan H.; Martins, Nuno M. C.; Kelly, David A.; Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [Rodriguez, Mariluz Gomez; Jansen, Lars E. T.] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Kimura, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Biomol Networks Labs Grp, Osaka, Japan. [Masumoto, Hiroshi] Kazusa DNA Res Inst, Lab Cell Engn, Chiba, Japan. [Larionov, Vladimir] NIH, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Earnshaw, WC (reprint author), Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Mayfield Rd, Edinburgh EH9 3JR, Midlothian, Scotland. EM bill.earnshaw@ed.ac.uk OI Jansen, Lars/0000-0002-2158-0345; Martins, Nuno/0000-0003-3953-9313 FU Wellcome Trust; Fundacao para a Ciencia e a Tecnologia (FCT); Fundacao Calouste Gulbenkian, FCT [BIA-PRO/100537/2008]; European Commission; EMBO; NIH, National Cancer Institute, Center for Cancer Research; Ministry of Education, Science, Sports and Culture of Japan; MEXT of Japan FX We thank Graham Johnson for letting us use the nucleosome drawings shown in Figure 8, and Natalay Kouprina, Alison L Pidoux and Irina Stancheva for critical reading of the paper. JHB was funded by a PhD studentship from The Wellcome Trust and NMCM and MGR by studentships from the Fundacao para a Ciencia e a Tecnologia (FCT). This work was supported by the Fundacao Calouste Gulbenkian, FCT grant BIA-PRO/100537/2008, the European Commission FP7 programme and an EMBO installation grant (LETJ); the intramural research program of the NIH, National Cancer Institute, Center for Cancer Research (VL); a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (HM) and the Genome Network project and Grants-in-aid from the MEXT of Japan (FIR). Work in the WCE laboratory is funded by The Wellcome Trust, of which he is a Principal Research Fellow. NR 60 TC 113 Z9 114 U1 0 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 19 PY 2011 VL 30 IS 2 BP 328 EP 340 DI 10.1038/emboj.2010.329 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 719DE UT WOS:000287179100010 PM 21157429 ER PT J AU Yaffe, K Weston, A Graff-Radford, NR Satterfield, S Simonsick, EM Younkin, SG Younkin, LH Kuller, L Ayonayon, HN Ding, JZ Harris, TB AF Yaffe, Kristine Weston, Andrea Graff-Radford, Neill R. Satterfield, Suzanne Simonsick, Eleanor M. Younkin, Steven G. Younkin, Linda H. Kuller, Lewis Ayonayon, Hilsa N. Ding, Jingzhong Harris, Tamara B. TI Association of Plasma beta-Amyloid Level and Cognitive Reserve With Subsequent Cognitive Decline SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ALZHEIMERS-DISEASE; CARDIOVASCULAR HEALTH; OLDER PERSONS; RISK; IMPAIRMENT; DEMENTIA; PROTEIN; EDUCATION; LITERACY; MEMORY AB Context Lower plasma beta-amyloid 42 and 42/40 levels have been associated with incident dementia, but results are conflicting and few have investigated cognitive decline among elders without dementia. Objective To determine if plasma beta-amyloid is associated with cognitive decline and if this association is modified by measures of cognitive reserve. Design, Setting, and Participants We studied 997 black and white community-dwelling older adults from Memphis, Tennessee, and Pittsburgh, Pennsylvania, who were enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998 with 10-year follow-up in 2006-2007. Participant mean age was 74.0 (SD, 3.0) years; 55.2% (n=550) were female; and 54.0% (n=538) were black. Main Outcome Measures Association of near-baseline plasma beta-amyloid levels (42 and 42/40 measured in 2010) and repeatedly measured Modified Mini-Mental State Examination (3MS) results. Results Low beta-amyloid 42/40 level was associated with greater 9-year 3MS cognitive decline (lowest beta-amyloid tertile: mean change in 3MS score, -6.59 [95% confidence interval [CI], -5.21 to -7.67] points; middle tertile: -6.16 [95% CI, -4.92 to -7.32] points; and highest tertile: -3.60 [95% CI, -2.27 to -4.73] points; P<.001). Results were similar after multivariate adjustment for age, race, education, diabetes, smoking, and apolipoprotein E [APOE] e4 status and after excluding the 72 participants with incident dementia. Measures of cognitive reserve modified this association whereby among those with high reserve (at least a high school diploma, higher than sixth-grade literacy, or no APOE e4 allele), beta-amyloid 42/40 was less associated with multivariate adjusted 9-year decline. For example, among participants with less than a high school diploma, the 3MS score decline was -8.94 (95% CI, -6.94 to -10.94) for the lowest tertile compared with -4.45 (95% CI, -2.31 to -6.59) for the highest tertile, but for those with at least a high school diploma, 3MS score decline was -4.60 (95% CI, -3.07 to -6.13) for the lowest tertile and -2.88 (95% CI, -1.41 to -4.35) for the highest tertile (P=.004 for interaction). Interactions were also observed for literacy (P=.005) and for APOE e4 allele (P=.02). Conclusion Lower plasma beta-amyloid 42/40 is associated with greater cognitive decline among elderly persons without dementia over 9 years, and this association is stronger among those with low measures of cognitive reserve. JAMA. 2011; 305(3): 261-266 C1 [Yaffe, Kristine; Weston, Andrea] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine; Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Graff-Radford, Neill R.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Younkin, Steven G.; Younkin, Linda H.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Kuller, Lewis] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ding, Jingzhong] Wake Forest Univ, Med Ctr, Dept Gerontol & Geriatr Med, Winston Salem, NC USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, Box 181,4150 Clement St, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu FU National Institute on Aging [N01-AG62101, N01-AG62103, N01-AG62106, K24AG031155] FX This study was funded by National Institute on Aging contracts N01-AG62101, N01-AG62103, and N01-AG62106. This research was supported in part by the Intramural Research Program of the National Institute on Aging. Dr Yaffe is supported in part by National Institute on Aging grant K24AG031155 and by an anonymous foundation. NR 33 TC 93 Z9 96 U1 3 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 19 PY 2011 VL 305 IS 3 BP 261 EP 266 DI 10.1001/jama.2010.1995 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 707YY UT WOS:000286328700021 PM 21245181 ER PT J AU Freeman, EW Guthrie, KA Caan, B Sternfeld, B Cohen, LS Joffe, H Carpenter, JS Anderson, GL Larson, JC Ensrud, KE Reed, SD Newton, KM Sherman, S Sammel, MD LaCroix, AZ AF Freeman, Ellen W. Guthrie, Katherine A. Caan, Bette Sternfeld, Barbara Cohen, Lee S. Joffe, Hadine Carpenter, Janet S. Anderson, Garnet L. Larson, Joseph C. Ensrud, Kristine E. Reed, Susan D. Newton, Katherine M. Sherman, Sheryl Sammel, Mary D. LaCroix, Andrea Z. TI Efficacy of Escitalopram for Hot Flashes in Healthy Menopausal Women A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PLACEBO-CONTROLLED TRIAL; VASOMOTOR SYMPTOMS; CLINICAL-TRIAL; NEWER ANTIDEPRESSANTS; POSTMENOPAUSAL WOMEN; HORMONE-THERAPY; DOUBLE-BLIND; CITALOPRAM; GABAPENTIN; DEPRESSION AB Context Concerns regarding the risks associated with estrogen and progesterone to manage menopausal symptoms have resulted in its declining use and increased interest in nonhormonal treatments with demonstrated efficacy for hot flashes. Objective To determine the efficacy and tolerability of 10 to 20 mg/d escitalopram, a selective serotonin reuptake inhibitor, in alleviating the frequency, severity, and bother of menopausal hot flashes. Design, Setting, and Patients A multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel group trial that enrolled 205 women (95 African American; 102 white; 8 other) between July 2009 and June 2010. Intervention Women received 10 to 20 mg/d of escitalopram or a matching placebo for 8 weeks. Main Outcome Measures Primary outcomes were the frequency and severity of hot flashes assessed by prospective daily diaries at weeks 4 and 8. Secondary outcomes were hot flash bother, recorded on daily diaries, and clinical improvement (defined as hot flash frequency >= 50% decrease from baseline). Results Mean (SD) daily hot flash frequency was 9.78 (5.60) at baseline. In a modified intent-to-treat analysis that included all randomized participants who provided hot flash diary data, the mean difference in hot flash frequency reduction was 1.41 (95% CI, 0.13-2.69) fewer hot flashes per day at week 8 among women taking escitalopram (P<.001), with mean reductions of 4.60 (95% CI, 3.74-5.47) and 3.20 (95% CI, 2.24-4.15) hot flashes per day in the escitalopram and placebo groups, respectively. Fifty-five percent of women in the escitalopram group vs 36% in the placebo group reported a decrease of at least 50% in hot flash frequency (P=.009) at the 8-week follow-up. Reductions in hot flash severity scores were significantly greater in the escitalopram group (-0.52; 95% CI, -0.64 to -0.40 vs -0.30; 95% CI, -0.42 to -0.17 for placebo; P<.001). Race did not significantly modify the treatment effect (P=.62). Overall discontinuation due to adverse events was 4% (7 in the active group, 2 in the placebo group). Three weeks after treatment ended, women in the escitalopram group reported a mean 1.59 (95% CI, 0.55-2.63; P=.02) more hot flashes per day than women in the placebo group. Conclusion Among healthy women, the use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up. C1 [Freeman, Ellen W.] Univ Penn, Sch Med, Dept Obstet, Philadelphia, PA 19104 USA. [Freeman, Ellen W.] Univ Penn, Sch Med, Dept Gynecol & Psychiat, Philadelphia, PA 19104 USA. [Sammel, Mary D.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Stat, Philadelphia, PA 19104 USA. [Guthrie, Katherine A.; Anderson, Garnet L.; Larson, Joseph C.; LaCroix, Andrea Z.] Fred Hutchinson Canc Res Ctr, Data Coordinating Ctr, Seattle, WA 98104 USA. [Reed, Susan D.] Univ Washington, Sch Med, Seattle, WA USA. [Newton, Katherine M.] Grp Hlth Res Inst, Seattle, WA USA. [Caan, Bette; Sternfeld, Barbara] Kaiser Permanente, Div Res, Oakland, CA USA. [Cohen, Lee S.; Joffe, Hadine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Carpenter, Janet S.] Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. [Ensrud, Kristine E.] Univ Minnesota, VA Med Ctr, Minneapolis, MN USA. [Sherman, Sheryl] NIA, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Freeman, EW (reprint author), 3701 Market St,Ste 820 Mudd, Philadelphia, PA 19104 USA. EM freemane@mail.med.upenn.edu FU Forest Laboratories, Inc; Wyeth; Pfizer; Xanodyne Pharmaceuticals; National Alliance for Research on Schizophrenia and Depression; Astra-Zeneca Pharmaceuticals; Sepracor, Inc; Bayer HealthCare; Bristol-Myers; Stanley Foundation; Ortho-McNeill Jansen; Pfizer, Inc.; Eli Lilly; GlaxoSmithKline; Sanofi-Events; Wyeth-Ayerst Pharmaceuticals; National Institute of Aging [U01 AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, U01AG032700]; Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD); National Center for Complementary and Alternative Medicine (NCCAM); Indiana Clinical and Translational Sciences Institute; National Institutes of Health, National Center for Research Resources [UL1 RR025761] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Freeman reported research support from Forest Laboratories, Inc, Wyeth, Pfizer and Xanodyne Pharmaceuticals; honoraria for consulting and presentations from Wyeth, Forest Laboratories, Inc, Pherin Pharmaceuticals and Bayer Health Care. Dr Cohen reported research support from National Alliance for Research on Schizophrenia and Depression; Astra-Zeneca Pharmaceuticals; Sepracor, Inc; Bayer HealthCare; Bristol-Myers; Stanley Foundation; Ortho-McNeill Jansen; Pfizer, Inc. Advisory/Consulting: Eli Lilly; GlaxoSmithKline; JDS/Noven Pharmaceuticals; Wyeth-Ayerst Pharmaceuticals; Honoraria, Eli Lilly, Forest Laboratories, Inc; GlaxosmithKline; Pfizer, Inc, and Wyeth-Ayerst Pharmaceuticals. Dr Joffe reported research support from AstraZeneca Pharmaceuticals, Bayer HealthCare, Eli Lilly, Forest Laboratories, Inc, GlaxoSmithKline, Sanofi-Events (product support only), Sepracor, Inc, and Wyeth-Ayerst Pharmaceuticals; speaking honoraria, Eli Lilly, GlaxoSmithKline; Advisory/Consulting, Abbott Laboratories, Eli Lilly, Forest Laboratories, Inc, JDS-Noven Pharmaceuticals, Sanofi-Events, Sepracor Inc, and Wyeth-Ayerst Pharmaceuticals. No other authors reported having a financial conflict of interest.; The study was supported by a cooperative agreement issued by the National Institute of Aging (NIA), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Research and Women's Health (ORWH), and grants U01 AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, U01AG032700 from the NIA. At the Indiana University site, the project was funded in part with support from the Indiana Clinical and Translational Sciences Institute, funded in part by grant UL1 RR025761 from the National Institutes of Health, National Center for Research Resources, Clinical and Translational Sciences Award. Escitalopram and matching placebo pills were provided by Forest Research Institute. NR 29 TC 87 Z9 91 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 19 PY 2011 VL 305 IS 3 BP 267 EP 274 DI 10.1001/jama.2010.2016 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 707YY UT WOS:000286328700022 PM 21245182 ER PT J AU Gao, HM Zhou, H Zhang, F Wilson, BC Kam, W Hong, JS AF Gao, Hui-Ming Zhou, Hui Zhang, Feng Wilson, Belinda C. Kam, Wayneho Hong, Jau-Shyong TI HMGB1 Acts on Microglia Mac1 to Mediate Chronic Neuroinflammation That Drives Progressive Neurodegeneration SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NECROSIS-FACTOR-ALPHA; MOBILITY GROUP BOX-1; PARKINSONS-DISEASE; DOPAMINERGIC NEURODEGENERATION; MPTP MODEL; ALZHEIMERS-DISEASE; SUBSTANTIA-NIGRA; NITRIC-OXIDE; REACTIVE MICROGLIA; IMMUNE-RESPONSES AB What drives the gradual degeneration of dopamine neurons in Parkinson's disease (PD), the second most common neurodegenerative disease, remains elusive. Here, we demonstrated, for the first time, that persistent neuroinflammation was indispensible for such a neurodegenerative process. 1-Methyl-4-phenylpyridinium, lipopolysaccharide (LPS), and rotenone, three toxins often used to create PD models, produced acute but nonprogressive neurotoxicity in neuron-enriched cultures. In the presence of microglia (brain immune cells), these toxins induced progressive dopaminergic neurodegeneration. More importantly, such neurodegeneration was prevented by removing activated microglia. Collectively, chronic neuroinflammation may be a driving force of progressive dopaminergic neurodegeneration. Conversely, ongoing neurodegeneration sustained microglial activation. Microglial activation persisted only in the presence of neuronal damage in LPS-treated neuron-glia cultures but not in LPS-treated mixed-glia cultures. Thus, activated microglia and damaged neurons formed a vicious cycle mediating chronic, progressive neurodegeneration. Mechanistic studies indicated that HMGB1 (high-mobility group box 1), released from inflamed microglia and/or degenerating neurons, bound to microglial Mac1 (macrophage antigen complex 1) and activated nuclear factor-kappa B pathway and NADPH oxidase to stimulate production of multiple inflammatory and neurotoxic factors. The treatment of microglia with HMGB1 led to membrane translocation of p47(phox) (a cytosolic subunit of NADPH oxidase) and consequent superoxide release, which required the presence of Mac1. Neutralization of HMGB1 and genetic ablation of Mac1 and gp91(phox) (the catalytic submit of NADPH oxidase) blocked the progressive neurodegeneration. Our findings indicated that HMGB1-Mac1- NADPH oxidase signaling axis bridged chronic neuroinflammation and progressive dopaminergic neurodegeneration, thus identifying a mechanistic basis for chronic PD progression. C1 [Gao, Hui-Ming; Zhou, Hui; Zhang, Feng; Wilson, Belinda C.; Kam, Wayneho; Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM gao2@niehs.nih.gov RI gao, huiming/C-8454-2012 FU National Institutes of Health; National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences. We thank Anthony Lockhart for assistance with animal colony management and maintenance of the timed pregnant mice. NR 67 TC 104 Z9 113 U1 2 U2 19 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 19 PY 2011 VL 31 IS 3 BP 1081 EP 1092 DI 10.1523/JNEUROSCI.3732-10.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 708OS UT WOS:000286373700033 PM 21248133 ER PT J AU Ellis, RD Fay, MP Sagara, I Dicko, A Miura, K Guindo, MA Guindo, A Sissoko, MS Doumbo, OK Diallo, D AF Ellis, Ruth D. Fay, Michael P. Sagara, Issaka Dicko, Alassane Miura, Kazutoyo Guindo, Merepen A. Guindo, Aldiouma Sissoko, Mahamadou S. Doumbo, Ogobara K. Diallo, Dapa TI Anaemia in a phase 2 study of a blood stage falciparum malaria vaccine SO MALARIA JOURNAL LA English DT Article ID CHILDREN; MALI AB Background: A Phase 1-2b study of the blood stage malaria vaccine AMA1-C1/Alhydrogel was conducted in 336 children in Doneguebougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300), no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin < 8.5 g/dL) compared to those who received the comparator vaccine (Hiberix). This effect was one of many tested and was not significant after adjusting for multiple comparisons. Methods: To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis. Results: A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix)]= 2.01, 95% confidence interval [1.26,3.20]) was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect. Conclusions: While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria-associated anaemia should be closely evaluated in clinical trials of AMA1 and other blood stage vaccines in malaria-exposed populations. C1 [Ellis, Ruth D.; Miura, Kazutoyo] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Sagara, Issaka; Dicko, Alassane; Guindo, Merepen A.; Guindo, Aldiouma; Sissoko, Mahamadou S.; Doumbo, Ogobara K.; Diallo, Dapa] Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali. RP Ellis, RD (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. EM ellisru@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU NIAID/NIH FX This work was supported by the Intramural Program of NIAID/NIH. Thanks to the study team and coordinators at MRTC and LMIV, and to volunteers at the study sites for their participation. NR 26 TC 4 Z9 4 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JAN 19 PY 2011 VL 10 AR 13 DI 10.1186/1475-2875-10-13 PG 7 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 740QX UT WOS:000288810600001 PM 21247484 ER PT J AU Zarin, DA Tse, T AF Zarin, Deborah A. Tse, Tony TI The Effect of Funding Source on Outcome Reporting Among Drug Trials SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID CLINICALTRIALS.GOV C1 [Zarin, Deborah A.; Tse, Tony] NIH, Natl Lib Med, Bethesda, MD 20894 USA. RP Zarin, DA (reprint author), NIH, Natl Lib Med, Bethesda, MD 20894 USA. NR 4 TC 2 Z9 2 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 18 PY 2011 VL 154 IS 2 BP 137 EP + DI 10.7326/0003-4819-154-2-201101180-00020 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 706MW UT WOS:000286223500011 PM 21242372 ER PT J AU Erlich, RL Jia, XM Anderson, S Banks, E Gao, XJ Carrington, M Gupta, N DePristo, MA Henn, MR Lennon, NJ de Bakker, PIW AF Erlich, Rachel L. Jia, Xiaoming Anderson, Scott Banks, Eric Gao, Xiaojiang Carrington, Mary Gupta, Namrata DePristo, Mark A. Henn, Matthew R. Lennon, Niall J. de Bakker, Paul I. W. TI Next-generation sequencing for HLA typing of class I loci SO BMC GENOMICS LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; EXTENDED HUMAN MHC; DISEASE ASSOCIATION; HIGH-RESOLUTION; HIGH-THROUGHPUT; GENE MAP; NOMENCLATURE; SYSTEM; ALIGNMENT; IMGT/HLA AB Background: Comprehensive sequence characterization across the MHC is important for successful organ transplantation and genetic association studies. To this end, we have developed an automated sample preparation, molecular barcoding and multiplexing protocol for the amplification and sequence-determination of class I HLA loci. We have coupled this process to a novel HLA calling algorithm to determine the most likely pair of alleles at each locus. Results: We have benchmarked our protocol with 270 HapMap individuals from four worldwide populations with 96.4% accuracy at 4-digit resolution. A variation of this initial protocol, more suitable for large sample sizes, in which molecular barcodes are added during PCR rather than library construction, was tested on 95 HapMap individuals with 98.6% accuracy at 4-digit resolution. Conclusions: Next-generation sequencing on the 454 FLX Titanium platform is a reliable, efficient, and scalable technology for HLA typing. C1 [Erlich, Rachel L.; Jia, Xiaoming; Anderson, Scott; Banks, Eric; Gupta, Namrata; DePristo, Mark A.; Henn, Matthew R.; Lennon, Niall J.; de Bakker, Paul I. W.] MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA. [Jia, Xiaoming] Harvard MIT Div Hlth Sci & Technol, Boston, MA USA. [Gao, Xiaojiang; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Gao, Xiaojiang; Carrington, Mary] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [de Bakker, Paul I. W.] Harvard Univ, Div Genet, Dept Med, Brigham & Womens Hosp,Med Sch, Boston, MA 02114 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. RP de Bakker, PIW (reprint author), MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA. EM pdebakker@rics.bwh.harvard.edu RI Sincan, Murat /A-3794-2010; de Bakker, Paul/B-8730-2009 OI de Bakker, Paul/0000-0001-7735-7858 FU Bill & Melinda Gates Foundation; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded [in part] through the Collaboration for AIDS Vaccine Discovery with support from the Bill & Melinda Gates Foundation (MRH & PIWDB). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 28 TC 54 Z9 57 U1 0 U2 3 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 18 PY 2011 VL 12 AR 42 DI 10.1186/1471-2164-12-42 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 717YA UT WOS:000287083500003 PM 21244689 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI If you organize, they will join SO CELL AND BIOSCIENCE LA English DT Editorial Material AB This Editorial briefly introduces the Society of Chinese Bioscientists in America (SCBA) to readers of Cell & Bioscience. C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov NR 3 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD JAN 18 PY 2011 VL 1 AR 2 DI 10.1186/2045-3701-1-2 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982NH UT WOS:000307051500002 PM 21711588 ER PT J AU Ji, JF Yamashita, T Wang, XW AF Ji, Junfang Yamashita, Taro Wang, Xin W. TI Wnt/beta-catenin signaling activates microRNA-181 expression in hepatocellular carcinoma SO CELL AND BIOSCIENCE LA English DT Article ID BETA-CATENIN; HEPATITIS-B; STEM-CELLS; CANCER; EPCAM; IDENTIFICATION; APC AB Background: Hepatocellular carcinoma (HCC) is a malignant cancer with an observable heterogeneity and microRNAs are functionally associated with the tumorigenesis of HCC. We recently identified that EpCAM (CD326)positive cells isolated from alpha-fetoprotein (AFP)-positive HCC samples are hepatic cancer stem cells (HepCSCs). EpCAM(+)AFP(+) HepCSCs have an activated Wnt/beta-catenin signaling with a parallel increased expression of all four microRNA-181 family members. We hypothesized that Wnt/beta-catenin signaling transcriptionally activates microRNA-181s in HCC. Results: Using both western blot and quantitative reverse transcriptase-PCR analyses, we found that the expression of all four microRNA-181 family members was positively correlated with beta-catenin expression in HCC cell lines. MicroRNA-181 expression could be directly induced upon an activation of Wnt/beta-catenin signaling, which includes Wnt10B overexpression, inhibition of GSK3 beta signaling by LiCl, or forced expression of beta-catenin/Tcf4. Moreover, microRNA-181 expression was inhibited upon an inactivation of Wnt/beta-catenin signaling by an induction of adenomatosis polyposis coli (APC) expression or silencing beta-catenin via RNA interference. In addition, seven putative beta-catenin/Tcf4 binding sites were identified in the promoter region of the microRNA-181a-2 and microRNA-181b-2 transcripts. Consistently, we found that Tcf4 interacted with these regions in vivo using chromatin immunoprecipitation assay. Conclusions: Taken together, our results demonstrate that microRNA-181s are transcriptionally activated by the Wnt/beta-catenin signaling pathway in HCC. C1 [Ji, Junfang; Yamashita, Taro; Wang, Xin W.] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Yamashita, Taro] Kanazawa Univ, Kanazawa Univ Hosp, Kanazawa, Ishikawa, Japan. [Yamashita, Taro] Kanazawa Univ, Liver Dis Ctr, Kanazawa, Ishikawa, Japan. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 FU Center for Cancer Research, the National Cancer Institute [Z01 BC 010876] FX We thank Dr. Bert Vogelstein and Dr. Toren Finkel for invaluable reagents, Karen Yarrick for bibliographic assistance, and the NIH Fellows Editorial Board for editing the manuscript. This work was supported by the Intramural Research Program of the Center for Cancer Research, the National Cancer Institute (Z01 BC 010876). NR 20 TC 44 Z9 54 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD JAN 18 PY 2011 VL 1 AR 4 DI 10.1186/045-3701-1-4 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982NH UT WOS:000307051500004 PM 21711587 ER PT J AU Shi, YB AF Shi, Yun-Bo TI The right journal for the right time - Cell & Bioscience SO CELL AND BIOSCIENCE LA English DT Editorial Material AB Cell & Bioscience welcomes the submission of your best work for rapid open access publication. This is the official journal of the Society of Chinese Bioscientists in America (SCBA). C1 NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 1 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD JAN 18 PY 2011 VL 1 AR 1 DI 10.1186/2045-3701-1-1 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982NH UT WOS:000307051500001 PM 21711586 ER PT J AU Lehky, TJ Iwamoto, FM Kreisl, TN Floeter, MK Fine, HA AF Lehky, T. J. Iwamoto, F. M. Kreisl, T. N. Floeter, M. K. Fine, H. A. TI Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome SO NEUROLOGY LA English DT Article ID KINASE INHIBITORS; FLT3; GLIOBLASTOMA; AUTOIMMUNE; LEUKEMIA; IMATINIB; RECEPTOR; GRAVIS AB Background: Tandutinib (MLN 518, Millennium Pharmaceuticals, Cambridge, MA) is an orally active multitargeted tyrosine kinase inhibitor that is currently under evaluation for the treatment of glioblastoma and has been used in the treatment of leukemia. In prior clinical and animal studies, a dose-dependent muscular weakness has been observed with this drug, though the etiology of the weakness has not been defined. Methods: Standard neurophysiologic techniques, including repetitive nerve stimulation, needle EMG, and single-fiber EMG, were used to evaluate patients who developed weakness while being treated with tandutinib and bevacizumab (Avastin, Genentech, South San Francisco, CA) for glioblastoma (NCT00667394). Results: Six patients were observed to develop a reversible weakness that correlated with the administration of the tandutinib. The onset of weakness after starting tandutinib occurred within 3 to 112 days and in less than 15 days in 3 patients. Electrophysiologic studies showed that all patients developed abnormal repetitive nerve stimulation studies. Four patients had short duration motor unit potentials. Two of these patients also had abnormal single-fiber EMG, as did a third patient who did not have standard needle EMG. The clinical and electrophysiologic abnormalities improved with the termination or reduction in the dose of tandutinib. Conclusion: These observations suggest that tandutinib is toxic to the neuromuscular junction, possibly by reversibly binding to a molecule on the postsynaptic acetylcholine receptor complex. Classification of evidence: This study provides Class III evidence that tandutinib 500 mg twice daily induces reversible muscle weakness and electrophysiologic changes consistent with neuromuscular junction dysfunction. Neurology (R) 2011; 76:236-241 C1 [Lehky, T. J.; Floeter, M. K.] NINDS, EMG Sect, OCD, NIH, Bethesda, MD 20892 USA. [Iwamoto, F. M.; Kreisl, T. N.; Fine, H. A.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. RP Lehky, TJ (reprint author), NINDS, EMG Sect, OCD, NIH, 8900 Wisconsin Ave, Bethesda, MD 20892 USA. EM lehkyt@ninds.nih.gov FU NIH/NCI; NIH/NINDS FX Trial NCT00667394 was sponsored by NIH/NCI. This research was also supported by the Intramural Research Program of the NIH/NINDS. NR 13 TC 8 Z9 9 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 18 PY 2011 VL 76 IS 3 BP 236 EP 241 DI 10.1212/WNL.0b013e3182074a69 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 708OG UT WOS:000286371900009 PM 21242491 ER PT J AU Jakacki, RI Dombi, E Potter, DM Goldman, S Allen, JC Pollack, IF Widemann, BC AF Jakacki, R. I. Dombi, E. Potter, D. M. Goldman, S. Allen, J. C. Pollack, I. F. Widemann, B. C. TI Phase I trial of pegylated interferon-alpha-2b in young patients with plexiform neurofibromas SO NEUROLOGY LA English DT Article ID ALPHA; THERAPY; CHILDREN; TYPE-1; NF1 AB Objective: Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-alpha-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN). Methods: PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity. Results: Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 mu g/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 mu g/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 mu g/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 mu g/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage. Conclusions: The RP2D of PI for pediatric patients with PN is 1 mu g/kg/wk. Clinical and radiographic improvement and cessation of growth can occur. Classification of evidence: This study provides Class III evidence that pegylated interferon-alpha-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size. Neurology (R) 2011; 76:265-272 C1 [Jakacki, R. I.; Pollack, I. F.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15224 USA. [Dombi, E.; Widemann, B. C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Goldman, S.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Allen, J. C.] NYU, New York, NY USA. [Potter, D. M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Potter, D. M.] Univ Pittsburgh, Inst Canc, Biostat Facil, Pittsburgh, PA USA. RP Jakacki, RI (reprint author), Childrens Hosp Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224 USA. EM regina.jakacki@chp.edu FU NIH; Brain Tumor Society; Children's Brain Tumor Foundation; Children's Oncology Group; Schering-Plough Corp. FX Dr. Jakacki serves as a consultant for OSI Pharmaceuticals, Inc. and receives research support from the NIH and the Brain Tumor Society. Dr. Dombi, Dr. Potter, Dr. Goldman, and Dr. Allen report no disclosures. Dr. Pollack serves on the editorial board of Journal of Neurosurgery and Pediatric Blood and Cancer; receives royalties from the publication of Principles and Practice of Pediatric Neurosurgery (Thieme, 2008); and receives research support from the NIH, the Brain Tumor Society, Children's Brain Tumor Foundation, and Children's Oncology Group. Dr. Wideman serves on the editorial board of The Oncologist.; Supported by Schering-Plough Corp., who supplied the pegylated interferon-alpha-2b. NR 22 TC 26 Z9 26 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 18 PY 2011 VL 76 IS 3 BP 265 EP 272 DI 10.1212/WNL.0b013e318207b031 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 708OG UT WOS:000286371900014 PM 21242495 ER PT J AU Cortese, I Chaudhry, V So, YT Cantor, F Cornblath, DR Rae-Grant, A AF Cortese, I. Chaudhry, V. So, Y. T. Cantor, F. Cornblath, D. R. Rae-Grant, A. TI Evidence-based guideline update: Plasmapheresis in neurologic disorders Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology SO NEUROLOGY LA English DT Article ID GUILLAIN-BARRE-SYNDROME; INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY; PROGRESSIVE MULTIPLE-SCLEROSIS; PLASMA-EXCHANGE THERAPY; INTRAVENOUS IMMUNOGLOBULIN; DOUBLE-BLIND; RANDOMIZED-TRIAL; IMMUNE GLOBULIN; CROSS-OVER; POLYNEUROPATHY AB Objective: To reassess the role of plasmapheresis in the treatment of neurologic disorders. Methods: We evaluated the available evidence based on a structured literature review for relevant articles from 1995 through September 2009. In addition, due to revision of the definitions of classification of evidence since the publication of the previous American Academy of Neurology assessment in 1996, the evidence cited in that manuscript was reviewed and reclassified. Results and Recommendations: Plasmapheresis is established as effective and should be offered in severe acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain-Barre syndrome (GBS) and in the short-term management of chronic inflammatory demyelinating polyneuropathy (Class I studies, Level A). Plasmapheresis is established as ineffective and should not be offered for chronic or secondary progressive multiple sclerosis (MS) (Class I studies, Level A). Plasmapheresis is probably effective and should be considered for mild AIDP/GBS, as second-line treatment of steroid-resistant exacerbations in relapsing forms of MS, and for neuropathy associated with immunoglobulin A or immunoglobulin G gammopathy, based on at least one Class I or 2 Class II studies (Level B). Plasmapheresis is probably not effective and should not be considered for neuropathy associated with immunoglobulin M gammopathy, based on one Class I study (Level B). Plasmapheresis is possibly effective and may be considered for acute fulminant demyelinating CNS disease (Level C). There is insufficient evidence to support or refute the use of plasmapheresis for myasthenia gravis, pediatric autoimmune neuropsychiatric disorders associated with streptococcus infection, and Sydenham chorea (Class III evidence, Level U). Neurology (R) 2011; 76:294-300 C1 [Cortese, I.; Cantor, F.] NIH, Bethesda, MD 20892 USA. [Chaudhry, V.; Cornblath, D. R.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [So, Y. T.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Rae-Grant, A.] Cleveland Clin, Cleveland, OH 44106 USA. RP Cortese, I (reprint author), Amer Acad Neurol, 1080 Montreal Ave, St Paul, MN 55116 USA. EM guidelines@aan.com FU Neuropathy Association; Nutricia; Insmed Inc.; NIH (NIEHS, NINDS); NINDS FX Dr. Cortese reports no disclosures. Dr. Chaudhry serves on the editorial board of Neurologist; is an inventor on patent(s) re: Total Neuropathy Score (TNS)-a score for evaluating peripheral neuropathies, for which he receives technology royalties from Abbott, Johnson & Johnson, and sanofi-aventis; receives publishing royalties for Harrison's Principles of Internal Medicine, 17th ed. (McGraw Hill Companies, Inc., 2008); estimates that 40% of his clinical effort is spent on nerve conduction studies; has given expert testimony for the Department of Health and Human Services Vaccine Injury Compensation program; and receives research support from the Neuropathy Association, Nutricia, and Insmed Inc. Dr. So receives publishing royalties for Occupational & Environmental Medicine (Appleton & Lange, 2007), Occupational & Environmental Medicine (Appleton & Lange, 2007), and contributions to UpToDate; receives research support from the NIH (NIEHS, NINDS) and holds stock in Sartoris, Inc. Dr. Cantor has received honoraria from Elsevier and research support from NINDS Intramural Research Funds. Dr. Cornblath has served on a scientific advisory board or as a consultant for Merck Serono, Sun Pharmaceutical Industries Ltd., DP Clinical, Inc., Geron Corporation, Schwarz Biosciences, Avigen, Inc., Pfizer Inc, Johnson & Johnson, GlaxoSmithKline, Abbott, Acorda Therapeutics Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Baxter International Inc., Bionevia Pharmaceuticals Inc., Bristol-Myers Squibb, Cebix Incorporated, CSL Behring, Eisai Inc., Exelixis Inc., FoldRx Pharmaceuticals, Genzyme Corporation, Neryx Biopharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation, Octapharma AG, Sangamo BioSciences, sanofi-aventis, and Talecris Biotherapeutics; is an inventor on patent(s) re: Total Neuropathy Score (TNS)-a score for evaluating peripheral neuropathies, for which he receives technology royalties from Abbott, Johnson & Johnson, and sanofi-aventis; receives publishing royalties for Diagnosis and Management of Peripheral Nerve Disorders (Oxford University Press, 2001); and has given expert testimony, prepared affidavits, and acted as a witness or consult with regard to legal proceedings. Dr. Rae-Grant has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., and EMD Serono, Inc.; receives publishing royalties for Handbook of Multiple Sclerosis (Springer Healthcare, 2010); and has served on the speakers' bureau for Biogen Idec. NR 28 TC 111 Z9 118 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 18 PY 2011 VL 76 IS 3 BP 294 EP 300 DI 10.1212/WNL.0b013e318207b1f6 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 708OG UT WOS:000286371900019 PM 21242498 ER PT J AU Waisberg, M Tarasenko, T Vickers, BK Scott, BL Willcocks, LC Molina-Cruz, A Pierce, MA Huang, CY Torres-Velez, FJ Smith, KGC Barillas-Mury, C Miller, LH Pierce, SK Bolland, S AF Waisberg, Michael Tarasenko, Tatyana Vickers, Brandi K. Scott, Bethany L. Willcocks, Lisa C. Molina-Cruz, Alvaro Pierce, Matthew A. Huang, Chiung-yu Torres-Velez, Fernando J. Smith, Kenneth G. C. Barillas-Mury, Carolina Miller, Louis H. Pierce, Susan K. Bolland, Silvia TI Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-NECROSIS-FACTOR; CENTRAL-NERVOUS-SYSTEM; AUTOIMMUNE-DISEASE; T-CELLS; DEFICIENT MICE; GAMMA; POLYMORPHISM; EXPRESSION; PATHOGENESIS; INFLAMMATION AB Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in Fc gamma RIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease. C1 [Molina-Cruz, Alvaro; Barillas-Mury, Carolina; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Waisberg, Michael; Tarasenko, Tatyana; Vickers, Brandi K.; Scott, Bethany L.; Pierce, Matthew A.; Pierce, Susan K.; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Willcocks, Lisa C.; Smith, Kenneth G. C.] Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Cambridge CB2 2OY, England. [Willcocks, Lisa C.; Smith, Kenneth G. C.] Univ Cambridge, Sch Clin Med, Dept Med, Addenbrookes Hosp, Cambridge CB2 2OY, England. [Huang, Chiung-yu] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20817 USA. [Torres-Velez, Fernando J.] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM lmiller@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 35 TC 28 Z9 29 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 JAN 18 PY 2011 VL 108 IS 3 BP 1122 EP 1127 DI 10.1073/pnas.1017996108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 707TF UT WOS:000286310300045 PM 21187399 ER PT J AU Chen, GL Lau, YF Lamirande, EW McCall, AW Subbarao, K AF Chen, Grace L. Lau, Yuk-Fai Lamirande, Elaine W. McCall, Amber W. Subbarao, Kanta TI Seasonal influenza infection and live vaccine prime for a response to the 2009 pandemic H1N1 vaccine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CD8(+) T-CELLS; CELLULAR IMMUNE-RESPONSES; A VIRUS; B-CELLS; PROTECTION; MICE; CHALLENGE; CLEARANCE; CHILDREN; ANTIBODY AB The robust immune response to a single dose of pandemic 2009 H1N1 vaccine suggests that a large segment of the population has been previously primed. We evaluated the effect of seasonal (s) H1N1 infection, s-trivalent inactivated vaccine (s-TIV), and trivalent s-live attenuated influenza vaccine (s-LAIV) before immunization with a pandemic live attenuated influenza vaccine (p-LAIV) in mice. We compared serum and mucosal antibody and pulmonary CD8 and CD4 responses and the virologic response to challenge with a wild-type 2009 pandemic H1N1 (p-H1N1) virus. Two doses of p-LAIV induced cellular immune and robust ELISA and neutralizing antibody responses that were associated with complete protection from p-H1N1 challenge. A single dose of p-LAIV induced a cellular response and ELISA but not a neutralizing antibody response, and incomplete protection from p-H1N1 virus challenge. Primary infection with s-H1N1 influenza virus followed by a dose of p-LAIV resulted in cross-reactive ELISA antibodies and a robust cellular immune response that was also associated with complete protection from p-H1N1 virus challenge. A lower-magnitude but similar response associated with partial protection was seen in mice that received a dose of s-LAIV followed by p-LAIV. Mice that received a dose of s-TIV followed by p-LAIV did not show any evidence of priming. In summary, prior infection with a seasonal influenza virus or s-LAIV primed mice for a robust response to a single dose of pLAIV that was associated with protection equivalent to two doses of the matched pandemic vaccine. C1 [Chen, Grace L.; Lau, Yuk-Fai; Lamirande, Elaine W.; McCall, Amber W.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Lau, Yuk-Fai] Def Med & Environm Res Inst, DSO Natl Labs, Med Countermeasures Biol Lab, Singapore 117510, Singapore. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU National Institutes of Health; National Institute of Allergy and Infectious Diseases FX We thank Jadon Jackson for technical support. We also thank Drs. Ruben Donis and Alexander Klimov from the Centers for Disease Control and Prevention for providing the 2009 pandemic H1N1 viruses, Drs. Hong Jin and George Kemble at MedImmune for the 2009 pandemic H1N1 live attenuated vaccine, and Dr. Derek O'Hagan and Kathryn Patton at Novartis for the 2008-2009 seasonal trivalent inactivated influenza vaccine used in this study. This work was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. NR 49 TC 36 Z9 37 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 18 PY 2011 VL 108 IS 3 BP 1140 EP 1145 DI 10.1073/pnas.1009908108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 707TF UT WOS:000286310300048 PM 21199945 ER PT J AU Kim, TH Jiang, HH Youn, YS Park, CW Tak, KK Lee, S Kim, H Jon, S Chen, XY Lee, KC AF Kim, Tae Hyung Jiang, Hai Hua Youn, Yu Seok Park, Chan Woong Tak, Kyung Kook Lee, Seulki Kim, Hyungjun Jon, Sangyong Chen, Xiaoyuan Lee, Kang Choon TI Preparation and characterization of water-soluble albumin-bound curcumin nanoparticles with improved antitumor activity SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Curcumin; Solubility; Nanoparticle; Human serum albumin; Antitumor ID ENDOTHELIAL-CELLS; IN-VIVO; CONTRAST AGENT; CREMOPHOR-FREE; DRUG-DELIVERY; PHASE-I; PACLITAXEL; TRANSPORT; EFFICACY; ABI-007 AB Curcumin (CCM), a yellow natural polyphenol extracted from turmeric (Curcuma longa), has potent anticancer properties as has been demonstrated in various human cancer cells. However, the widespread clinical application of this efficient agent in cancer and other diseases has been limited by its poor aqueous solubility and bioavailability. In this study, we prepared novel CCM-loaded human serum albumin (HSA) nanoparticles (CCM-HSA-NPs) for intravenous administration using albumin bound technology. Field emission scanning electron microscopy (FE-SEM) and dynamic light scattering (DLS) investigation confirmed a narrow size distribution in the 130-150 nm range. Furthermore, CCM-HSA-NPs showed much greater water solubility (300-fold) than free CCM, and on storage, the biological activity of CCM-HSA-NPs was preserved with negligible activity loss. In vivo distributions and vascular endothelial cells transport studies demonstrated the superiority of CCM-HSA-NPs over CCM. Amounts of CCM in tumors after treatment with CCM-HSA-NPs were about 14 times higher at 1 h after injection than that achieved by CCM. Furthermore, vascular endothelial cell binding of CCM increased 5.5-fold, and transport of CCM across a vascular endothelial cell monolayer by Transwell testing was 7.7-fold greater for CCM-HSA-NPs than CCM. Finally, in vivo antitumor tests revealed that CCM-HSA-NPs (10 or 20 mg/kg) had a greater therapeutic effect (50% or 66% tumor growth inhibition vs. PBS-treated controls) than CCM (18% inhibition vs. controls) in tumor xenograft HCT116 models without inducing toxicity. We attribute this potent antitumor activity of CCM-HSA-NPs to enhanced water solubility, increased accumulation in tumors, and an ability to traverse vascular endothelial cell. (C) 2010 Elsevier B.V. All rights reserved. C1 [Kim, Tae Hyung; Jiang, Hai Hua; Park, Chan Woong; Tak, Kyung Kook; Lee, Kang Choon] Sungkyunkwan Univ, Drug Targeting Lab, Coll Pharm, Suwon 440746, South Korea. [Youn, Yu Seok] Pusan Natl Univ, Coll Pharm, Pusan 609735, South Korea. [Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Kim, Hyungjun; Jon, Sangyong] Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju 500712, South Korea. RP Lee, KC (reprint author), Sungkyunkwan Univ, Drug Targeting Lab, Coll Pharm, 300 Chonchon Dong, Suwon 440746, South Korea. EM kclee@skku.edu RI Jon, Sangyong/C-3725-2012 FU Ministry of Education, Science and Technology [2009-0081871] FX This work was supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0081871). NR 36 TC 95 Z9 101 U1 1 U2 63 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD JAN 17 PY 2011 VL 403 IS 1-2 BP 285 EP 291 DI 10.1016/j.ijpharm.2010.10.041 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 711AG UT WOS:000286557500035 PM 21035530 ER PT J AU Wrammert, J Koutsonanos, D Li, GM Edupuganti, S Sui, JH Morrissey, M McCausland, M Skountzou, I Hornig, M Lipkin, WI Mehta, A Razavi, B Del Rio, C Zheng, NY Lee, JH Huang, M Ali, Z Kaur, K Andrews, S Amara, RR Wang, YL Das, SR O'Donnell, CD Yewdell, JW Subbarao, K Marasco, WA Mulligan, MJ Compans, R Ahmed, R Wilson, PC AF Wrammert, Jens Koutsonanos, Dimitrios Li, Gui-Mei Edupuganti, Srilatha Sui, Jianhua Morrissey, Michael McCausland, Megan Skountzou, Ioanna Hornig, Mady Lipkin, W. Ian Mehta, Aneesh Razavi, Behzad Del Rio, Carlos Zheng, Nai-Ying Lee, Jane-Hwei Huang, Min Ali, Zahida Kaur, Kaval Andrews, Sarah Amara, Rama Rao Wang, Youliang Das, Suman Ranjan O'Donnell, Christopher David Yewdell, Jon W. Subbarao, Kanta Marasco, Wayne A. Mulligan, Mark J. Compans, Richard Ahmed, Rafi Wilson, Patrick C. TI Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; A VIRUS; IMMUNE-RESPONSE; VACCINATION; VACCINES; MEMORY; SWINE; MICE; NEUTRALIZATION; GENERATION AB The 2009 pandemic H1N1 influenza pandemic demonstrated the global health threat of reassortant influenza strains. Herein, we report a detailed analysis of plasmablast and monoclonal antibody responses induced by pandemic H1N1 infection in humans. Unlike antibodies elicited by annual influenza vaccinations, most neutralizing antibodies induced by pandemic H1N1 infection were broadly cross-reactive against epitopes in the hemagglutinin (HA) stalk and head domain of multiple influenza strains. The antibodies were from cells that had undergone extensive affinity maturation. Based on these observations, we postulate that the plasmablasts producing these broadly neutralizing antibodies were predominantly derived from activated memory B cells specific for epitopes conserved in several influenza strains. Consequently, most neutralizing antibodies were broadly reactive against divergent H1N1 and H5N1 influenza strains. This suggests that a pan-influenza vaccine may be possible, given the right immunogen. Antibodies generated potently protected and rescued mice from lethal challenge with pandemic H1N1 or antigenically distinct influenza strains, making them excellent therapeutic candidates. C1 [Wrammert, Jens; Li, Gui-Mei; McCausland, Megan; Amara, Rama Rao; Wang, Youliang; Compans, Richard; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Wrammert, Jens; Koutsonanos, Dimitrios; Li, Gui-Mei; McCausland, Megan; Skountzou, Ioanna; Amara, Rama Rao; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Mehta, Aneesh; Del Rio, Carlos] Emory Univ, Sch Med, Div Infect Dis, Dept Med, Atlanta, GA 30322 USA. [Edupuganti, Srilatha; Del Rio, Carlos; Mulligan, Mark J.] Emory Vaccine Ctr, Hope Clin, Sch Med, Div Infect Dis, Decatur, GA 30030 USA. [Edupuganti, Srilatha; Razavi, Behzad] Emory Univ, Dept Internal Med, Atlanta, GA 30322 USA. [Sui, Jianhua; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Morrissey, Michael; Zheng, Nai-Ying; Lee, Jane-Hwei; Huang, Min; Ali, Zahida; Kaur, Kaval; Andrews, Sarah; Wilson, Patrick C.] Univ Chicago, Dept Med, Rheumatol Sect, Comm Immunol,Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. [Hornig, Mady; Lipkin, W. Ian] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Del Rio, Carlos] Emory Univ, Sch Med, Hubert Dept Global Hlth, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Del Rio, Carlos] Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA. [Das, Suman Ranjan; Yewdell, Jon W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [O'Donnell, Christopher David; Subbarao, Kanta] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM rahmed@emory.edu; wilsonp@uchicago.edu RI yewdell, jyewdell@nih.gov/A-1702-2012; Mehta, Aneesh/B-8054-2012; Das, Suman/C-8760-2009; Compans, Richard/I-4087-2013; Skountzou, Ioanna/A-4454-2010; del Rio, Carlos/B-3763-2012; Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Mehta, Aneesh/0000-0002-6552-9162; Compans, Richard/0000-0003-2360-335X; Skountzou, Ioanna/0000-0002-6429-244X; del Rio, Carlos/0000-0002-0153-3517; Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) [U19-AI057266, U19 AI057266-06S2, HHSN266200500026C, 5U19AI062629-05, U01 AI074518]; NIH/NIAID, Center of Excellence for Influenza Research and Surveillance [HHSN266200700006C]; Northeast Biodefense Center [U54-AI057158-Lipkin]; National Foundation for Cancer Research; Center of Excellence for Influenza Research and Surveillance; NIAID; [U01-AI074579] FX This work was funded in parts by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) U19-AI057266 with ARRA supplement funding U19 AI057266-06S2 (R. Ahmed and P.C. Wilson), by NIH/NIAID HHSN266200700006C Center of Excellence for Influenza Research and Surveillance (R. Ahmed, R. Compans, and P.C. Wilson), by the Northeast Biodefense Center U54-AI057158-Lipkin (R. Ahmed, W.I. Lipkin, and P.C. Wilson), by NIH/NIAID HHSN266200500026C (P.C. Wilson), by NIH/NIAID 5U19AI062629-05 (P.C. Wilson), and by NIH/NIAID U01 AI074518 (W.A. Marasco) and the National Foundation for Cancer Research (W.A.M.). J. Wrammert was supported by a training fellowship through the Center of Excellence for Influenza Research and Surveillance and D. Koutsonanos by U01-AI074579 (R. Compans). This research was supported in part by the Intramural Research Program of the NIAID. NR 40 TC 349 Z9 353 U1 2 U2 37 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 17 PY 2011 VL 208 IS 1 BP 181 EP 193 DI 10.1084/jem.20101352 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 707SV UT WOS:000286309300015 PM 21220454 ER PT J AU Gonzalez-Bosquet, J Calcei, J Wei, JS Garcia-Closas, M Sherman, ME Hewitt, S Vockley, J Lissowska, J Yang, HP Khan, J Chanock, S AF Gonzalez-Bosquet, Jesus Calcei, Jacob Wei, Jun S. Garcia-Closas, Montserrat Sherman, Mark E. Hewitt, Stephen Vockley, Joseph Lissowska, Jolanta Yang, Hannah P. Khan, Javed Chanock, Stephen TI Detection of Somatic Mutations by High-Resolution DNA Melting (HRM) Analysis in Multiple Cancers SO PLOS ONE LA English DT Article ID CELL LUNG-CANCER; PARAFFIN-EMBEDDED TISSUES; BREAST-CANCER; ACTIVATING MUTATIONS; AMPLICON ANALYSIS; GENE-MUTATIONS; SINGLE CELLS; RISK-FACTORS; GENOME; AMPLIFICATION AB Identification of somatic mutations in cancer is a major goal for understanding and monitoring the events related to cancer initiation and progression. High resolution melting (HRM) curve analysis represents a fast, post-PCR high-throughput method for scanning somatic sequence alterations in target genes. The aim of this study was to assess the sensitivity and specificity of HRM analysis for tumor mutation screening in a range of tumor samples, which included 216 frozen pediatric small rounded blue-cell tumors as well as 180 paraffin-embedded tumors from breast, endometrial and ovarian cancers (60 of each). HRM analysis was performed in exons of the following candidate genes known to harbor established commonly observed mutations: PIK3CA, ERBB2, KRAS, TP53, EGFR, BRAF, GATA3, and FGFR3. Bi-directional sequencing analysis was used to determine the accuracy of the HRM analysis. For the 39 mutations observed in frozen samples, the sensitivity and specificity of HRM analysis were 97% and 87%, respectively. There were 67 mutation/variants in the paraffin-embedded samples, and the sensitivity and specificity for the HRM analysis were 88% and 80%, respectively. Paraffin-embedded samples require higher quantity of purified DNA for high performance. In summary, HRM analysis is a promising moderate-throughput screening test for mutations among known candidate genomic regions. Although the overall accuracy appears to be better in frozen specimens, somatic alterations were detected in DNA extracted from paraffin-embedded samples. C1 [Gonzalez-Bosquet, Jesus; Calcei, Jacob; Chanock, Stephen] NCI, Lab Translat Genom, DHHS, NIH, Bethesda, MD 20892 USA. [Wei, Jun S.; Khan, Javed] NCI, Adv Technol Ctr, Pediat Oncol Branch, Ctr Canc Res,DHHS,NIH, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat; Sherman, Mark E.; Yang, Hannah P.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20892 USA. [Hewitt, Stephen] NCI, Tissue Array Res Program, DHHS, NIH, Bethesda, MD 20892 USA. [Vockley, Joseph] NCI, Off Canc Genom, DHHS, NIH, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol & Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. RP Gonzalez-Bosquet, J (reprint author), NCI, Lab Translat Genom, DHHS, NIH, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Khan, Javed/P-9157-2014; Garcia-Closas, Montserrat /F-3871-2015; OI Khan, Javed/0000-0002-5858-0488; Garcia-Closas, Montserrat /0000-0003-1033-2650; Hewitt, Stephen/0000-0001-8283-1788; Lissowska, Jolanta/0000-0003-2695-5799 NR 50 TC 25 Z9 26 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 17 PY 2011 VL 6 IS 1 AR e14522 DI 10.1371/journal.pone.0014522 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710ND UT WOS:000286517600006 PM 21264207 ER PT J AU Micoli, F Rondini, S Pisoni, I Proietti, D Berti, F Costantino, P Rappuoli, R Szu, S Saul, A Martin, LB AF Micoli, F. Rondini, S. Pisoni, I. Proietti, D. Berti, F. Costantino, P. Rappuoli, R. Szu, S. Saul, A. Martin, L. B. TI Vi-CRM197 as a new conjugate vaccine against Salmonella Typhi SO VACCINE LA English DT Article DE Vi; Conjugate vaccine; Salmonella Typhi ID VI CAPSULAR POLYSACCHARIDE; ANION-EXCHANGE CHROMATOGRAPHY; PULSED-AMPEROMETRIC DETECTION; INFLUENZAE TYPE-B; O-ACETYL; IMMUNOLOGICAL-PROPERTIES; UNITED-STATES; FEVER; IMMUNOGENICITY; CHILDREN AB An efficacious, low cost vaccine against typhoid fever, especially for young children, would make a major impact on disease burden in developing countries. The virulence capsular polysaccharide of Salmonella Typhi (Vi) coupled to recombinant mutant Pseudomonas aeruginosa exoprotein A (Vi-rEPA) has been shown to be highly efficacious. We investigated the use of carrier proteins included in infant vaccines, standardized the conjugation process and developed key assays required for routine lot release at production scale. Vi from a BSL1 organism, Citrobacter freundii, strain WR7011, was used as an alternative to Vi from S. Typhi. We showed that Vi conjugated to CRM197, a non-toxic mutant of diphtheria toxin, widely used in commercial vaccines, was produced at high yield. Vi-CRM197 proved immunogenic in animal studies, even without adjuvant. Thus. Vi-CRM197 appears to be a suitable candidate for the development of a commercially viable, effective typhoid vaccine for developing countries. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Micoli, F.; Rondini, S.; Pisoni, I.; Saul, A.; Martin, L. B.] Novartis Vaccines Inst Global Hlth, I-53100 Siena, Italy. [Proietti, D.; Berti, F.; Costantino, P.; Rappuoli, R.] Novartis Vaccines & Diagnost Res Ctr, I-53100 Siena, Italy. [Szu, S.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Micoli, F (reprint author), Novartis Vaccines Inst Global Hlth, Via Fiorentina 1, I-53100 Siena, Italy. EM francesca.micoli@novartis.com RI Saul, Allan/I-6968-2013; Rondini, Simona/N-1780-2013; Martin, Laura/N-1789-2013 OI Saul, Allan/0000-0003-0665-4091; Rondini, Simona/0000-0002-7993-9656; Martin, Laura/0000-0002-4431-4381 FU Associazione A. Sclavo from Regione Toscana; Fondazione Monte Dei Paschi di Siena FX The authors would like to thank Nathalie Norais for performing MALDI analysis; Mariagrazia Pizza and Vega Masignani for their comments and suggestions on this manuscript; and the Novartis Animal Resources Center for conducting in vivo studies. This study was funded in part by grants received by Associazione A. Sclavo from Regione Toscana and Fondazione Monte Dei Paschi di Siena. This manuscript is dedicated to the memory of Angela Bardotti who provided exceptional contribution in the HPAEC-PAD method development. NR 48 TC 31 Z9 31 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 17 PY 2011 VL 29 IS 4 BP 712 EP 720 DI 10.1016/j.vaccine.2010.11.022 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 715AT UT WOS:000286853500017 PM 21115057 ER PT J AU Mumford, SL Schisterman, EF VanderWeele, TJ AF Mumford, Sunni L. Schisterman, Enrique F. VanderWeele, Tyler J. TI Mumford et al. Respond to "Dietary Fiber, Estradiol, and Cholesterol" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material C1 [Mumford, Sunni L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Executive Blvd 7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X NR 9 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2011 VL 173 IS 2 BP 160 EP 161 DI 10.1093/aje/kwq393 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 698XF UT WOS:000285627500005 ER PT J AU Mumford, SL Schisterman, EF Siega-Riz, AM Gaskins, AJ Wactawski-Wende, J VanderWeele, TJ AF Mumford, Sunni L. Schisterman, Enrique F. Siega-Riz, Anna Maria Gaskins, Audrey J. Wactawski-Wende, Jean VanderWeele, Tyler J. TI Effect of Dietary Fiber Intake on Lipoprotein Cholesterol Levels Independent of Estradiol in Healthy Premenopausal Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cholesterol; dietary fiber; estradiol; lipoproteins; menstrual cycle ID MARGINAL STRUCTURAL MODELS; SERUM ESTROGEN CONCENTRATIONS; FOOD FREQUENCY QUESTIONNAIRE; CARDIOVASCULAR-DISEASE RISK; CORONARY-HEART-DISEASE; SEX-HORMONE LEVELS; MENSTRUAL-CYCLE; OXIDATIVE STRESS; BREAST-CANCER; PLASMA AB High-fiber diets are associated with improved lipid profiles. However, pre- and postmenopausal women respond differently to fiber intake, suggesting that endogenous estradiol mediates the effect. The authors' objective was to determine the direct effect of fiber intake on lipoprotein cholesterol levels independent of estradiol among premenopausal women. The BioCycle Study, a prospective cohort study conducted at the State University of New York at Buffalo from 2005 to 2007, followed 259 healthy women for up to 2 complete menstrual cycles. Serum lipoprotein and hormone levels were measured at 16 visits timed using fertility monitors. Fiber intake was assessed by 8 24-hour recalls. Marginal structural models with inverse probability weights for both lipoprotein and estradiol levels were used to estimate controlled direct effects of the highest category of fiber intake (>= 22 g/day vs. < 22 g/day) while accounting for age, body mass index, total energy, vitamin E intake, physical activity, luteinizing hormone, follicle-stimulating hormone, and progesterone. Reductions were observed in total and low density lipoprotein cholesterol in women with higher fiber intakes. Direct effects were greater than total effects. These analyses suggested that estradiol mediates at least part of the association between fiber and cholesterol among premenopausal women. More research is needed to elucidate the biologic mechanisms driving these associations. C1 [Mumford, Sunni L.; Schisterman, Enrique F.; Gaskins, Audrey J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Mumford, Sunni L.; Siega-Riz, Anna Maria] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Siega-Riz, Anna Maria] Univ N Carolina, Dept Nutr, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [1R03HD060696-01] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Tyler J. VanderWeele was supported by National Institutes of Health grant 1R03HD060696-01. NR 54 TC 9 Z9 9 U1 3 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2011 VL 173 IS 2 BP 145 EP 156 DI 10.1093/aje/kwq388 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 698XF UT WOS:000285627500003 PM 21148240 ER PT J AU Youn, A Simon, R AF Youn, Ahrim Simon, Richard TI Identifying cancer driver genes in tumor genome sequencing studies SO BIOINFORMATICS LA English DT Article ID COLORECTAL CANCERS; SOMATIC MUTATIONS; SUPPRESSOR GENES; HUMAN BREAST; LUNG-CANCER; 3P21.3; BLU; CARCINOMA; REGION; KINASE AB Motivation: Major tumor sequencing projects have been conducted in the past few years to identify genes that contain 'driver' somatic mutations in tumor samples. These genes have been defined as those for which the non-silent mutation rate is significantly greater than a background mutation rate estimated from silent mutations. Several methods have been used for estimating the background mutation rate. Results: We propose a new method for identifying cancer driver genes, which we believe provides improved accuracy. The new method accounts for the functional impact of mutations on proteins, variation in background mutation rate among tumors and the redundancy of the genetic code. We reanalyzed sequence data for 623 candidate genes in 188 non-small cell lung tumors using the new method. We found several important genes like PTEN, which were not deemed significant by the previous method. At the same time, we determined that some genes previously reported as drivers were not significant by the new analysis because mutations in these genes occurred mainly in tumors with large background mutation rates. C1 [Youn, Ahrim; Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9000 Rockville Pike,MSC 7434, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov NR 16 TC 71 Z9 72 U1 1 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JAN 15 PY 2011 VL 27 IS 2 BP 175 EP 181 DI 10.1093/bioinformatics/btq630 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 706JR UT WOS:000286215200005 PM 21169372 ER PT J AU Riddick, G Song, H Ahn, S Walling, J Borges-Rivera, D Zhang, W Fine, HA AF Riddick, Gregory Song, Hua Ahn, Susie Walling, Jennifer Borges-Rivera, Diego Zhang, Wei Fine, Howard A. TI Predicting in vitro drug sensitivity using Random Forests SO BIOINFORMATICS LA English DT Article ID CELL-LINES; GENE-EXPRESSION; CHEMOSENSITIVITY; PROFILES AB Motivation: Panels of cell lines such as the NCI-60 have long been used to test drug candidates for their ability to inhibit proliferation. Predictive models of in vitro drug sensitivity have previously been constructed using gene expression signatures generated from gene expression microarrays. These statistical models allow the prediction of drug response for cell lines not in the original NCI-60. We improve on existing techniques by developing a novel multistep algorithm that builds regression models of drug response using Random Forest, an ensemble approach based on classification and regression trees (CART). Results: This method proved successful in predicting drug response for both a panel of 19 Breast Cancer and 7 Glioma cell lines, outperformed other methods based on differential gene expression, and has general utility for any application that seeks to relate gene expression data to a continuous output variable. Implementation: Software was written in the R language and will be available together with associated gene expression and drug response data as the package ivDrug at http://r-forge.r-project.org. C1 [Riddick, Gregory; Song, Hua; Ahn, Susie; Walling, Jennifer; Zhang, Wei; Fine, Howard A.] NCI, Neurooncol Branch, NINDS, NIH, Bethesda, MD 20892 USA. [Borges-Rivera, Diego] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. RP Riddick, G (reprint author), NCI, Neurooncol Branch, NINDS, NIH, Bethesda, MD 20892 USA. EM riddickgp@mail.nih.gov RI Exarchos, Konstantinos/B-5978-2008 FU National Institutes of Health; National Cancer Institute FX Intramural Research Program of the National Institutes of Health; National Cancer Institute. NR 14 TC 33 Z9 33 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JAN 15 PY 2011 VL 27 IS 2 BP 220 EP 224 DI 10.1093/bioinformatics/btq628 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 706JR UT WOS:000286215200011 PM 21134890 ER PT J AU Deep-Soboslay, A Benes, FM Haroutunian, V Ellis, JK Kleinman, JE Hyde, TM AF Deep-Soboslay, Amy Benes, Francine M. Haroutunian, Vahram Ellis, Justin K. Kleinman, Joel E. Hyde, Thomas M. TI Psychiatric Brain Banking: Three Perspectives on Current Trends and Future Directions SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Brain banks; brain collections; postmortem human brain; psychiatric; psychosis; schizophrenia ID PLURIPOTENT STEM-CELLS; POSTMORTEM HUMAN BRAIN; GENE-EXPRESSION; PREFRONTAL CORTEX; SCHIZOPHRENIA; TISSUE; DIAGNOSIS; FIBROBLASTS; AUTOPSY; DISEASE AB Postmortem human brain tissue is critical for advancing neurobiological studies of psychiatric illness, particularly for identifying brain-specific transcripts and isoforms. State-of-the-art methods and recommendations for maintaining psychiatric brain banks are discussed in three disparate collections, the National Institute of Mental Health Brain Tissue Collection, the Harvard Brain Tissue Resource Center, and the Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank. While the National Institute of Mental Health Brain Tissue Collection obtains donations from medical examiners and focuses on clinical diagnosis, toxicology, and building life span control cohorts, the Harvard Brain Tissue Resource Center is designed as a repository to collect large-volume, high-quality brain tissue from community-based donors across a nationwide network, placing emphasis on the accessibility of tissue and related data to research groups worldwide. The Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank has shown that prospective recruitment is a successful approach to tissue donation, placing particular emphasis on clinical diagnosis through antemortem contact with donors, as well as stereological tissue sampling methods for neuroanatomical studies and frozen tissue sampling approaches that enable multiple assessments (e.g., RNA, DNA, protein, enzyme activity, binding) of the same tissue block. Promising scientific approaches for elucidating the molecular and cellular pathways in brain that may contribute to schizophrenia are briefly discussed. Despite different perspectives from three established brain collections, there is consensus that varied networking strategies, rigorous tissue and clinical characterization, sample and data accessibility, and overall adaptability are integral to the success of psychiatric brain banking. C1 [Deep-Soboslay, Amy; Ellis, Justin K.; Kleinman, Joel E.; Hyde, Thomas M.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Benes, Francine M.] McLean Hosp, Harvard Brain Tissue Resource Ctr, Program Struct & Mol Neurosci, Belmont, MA 02178 USA. Harvard Univ, Sch Med, Boston, MA USA. [Haroutunian, Vahram] Mt Sinai Sch Med, Alzheimers Dis & Schizophrenia Brain Bank, New York, NY USA. RP Hyde, TM (reprint author), NIMH, Sect Neuropathol, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,MSC 1385, Bethesda, MD 20892 USA. EM hydet@mail.nih.gov FU National Institutes of Health National Institute of Mental Health; National Institutes of Health [R24 MH/NS 077550-06, R01 MH/NS 31862-28, MH066392, AG02219, AG05138] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Mental Health (AD-S JKE, JEK, TMH); National Institutes of Health Grant R24 MH/NS 077550-06 (R01 MH/NS 31862-28) (FMB); and National Institutes of Health Grants MH066392, AG02219, and AG05138 (VH). NR 50 TC 15 Z9 15 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2011 VL 69 IS 2 BP 104 EP 112 DI 10.1016/j.biopsych.2010.05.025 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 704FN UT WOS:000286036600002 PM 20673875 ER PT J AU Kleinman, JE Law, AJ Lipska, BK Hyde, TM Ellis, JK Harrison, PJ Weinberger, DR AF Kleinman, Joel E. Law, Amanda J. Lipska, Barbara K. Hyde, Thomas M. Ellis, Justin K. Harrison, Paul J. Weinberger, Daniel R. TI Genetic Neuropathology of Schizophrenia: New Approaches to an Old Question and New Uses for Postmortem Human Brains SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alternative splicing; gene expression; genetics; human brain; neuropathology; schizophrenia ID CATECHOL-O-METHYLTRANSFERASE; DORSOLATERAL PREFRONTAL CORTEX; MESSENGER-RNA EXPRESSION; AMINO-ACID OXIDASE; D2 RECEPTOR GENE; BIPOLAR DISORDER; ENZYME-ACTIVITY; SUSCEPTIBILITY GENE; CONVERGENT EVIDENCE; RGS4 POLYMORPHISMS AB Human postmortem brain studies are critical for elucidating the pathophysiology and etiology of schizophrenia and other major mental illnesses. The traditional approach compares patients and control subjects but is potentially confounded by a number of artifacts, including medication, substance misuse, and other secondary effects of illness. Genetic advances now make possible a novel approach that focuses on how allelic variation in risk-associated genes affects expression and function of transcripts and proteins. These questions can be addressed in normal brain, overcoming to some extent the confounding effects of studying brains from subjects with schizophrenia; equally, extension of the studies to include cases also has advantages. Conceptually, the approach may be seen as the neuropathologic counterpart of genetic neuroimaging, representing a potentially powerful intermediate phenotype. For several schizophrenia susceptibility genes, the data show that risk-associated polymorphisms do affect gene expression or the function of the encoded protein; in some instances, expression of downstream or interacting partners of the gene are also altered. A further striking finding is that the implicated transcripts often appear to be enriched in, or specific to, human brain. Some also show enhanced expression in fetal brain. These considerations give unique importance to postmortem human brain tissue in elucidating the genetic mechanisms underlying schizophrenia and probably other neurodevelopmental disorders as well. Studies of this kind can provide clues as to the biological mechanisms of genetic association, especially when carried out in conjunction with experimental studies. Moreover, the data, interpreted judiciously, can strengthen the plausibility of the association itself. C1 [Kleinman, Joel E.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, GCAP NIMH,NIH, Bethesda, MD 20892 USA. [Harrison, Paul J.] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford, England. RP Kleinman, JE (reprint author), NIMH, Sect Neuropathol, Clin Brain Disorders Branch, GCAP NIMH,NIH, MSC 1379, Bethesda, MD 20892 USA. EM joel.kleinman@mail.nih.gov RI Law, Amanda/G-6372-2012; OI Law, Amanda/0000-0002-2574-1564 FU National Institutes of Health, National Institute of Mental Health; Medical Research Council; Wellcome Trust; Stanley Medical Research Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health. PJH receives grant support from the Medical Research Council, Wellcome Trust, and Stanley Medical Research Institute. NR 75 TC 41 Z9 41 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2011 VL 69 IS 2 BP 140 EP 145 DI 10.1016/j.biopsych.2010.10.032 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 704FN UT WOS:000286036600006 PM 21183009 ER PT J AU He, YP Long, J Zhang, SS Li, C Lai, CC Zhang, CS Li, DX Zhang, DH Wang, H Cai, QQ Zheng, YT AF He, Yan-Ping Long, Jin Zhang, Shui-Shuan Li, Cong Lai, Christopher Cong Zhang, Chun-Sheng Li, Da-Xiong Zhang, De-Hua Wang, Hua Cai, Qing-Qing Zheng, Yong-Tang TI Synthesis and biological evaluation of novel dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines (S-DACOs) as high active anti-HIV agents SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE NNRTIs; S-DABOs; S-DACOs; Anti HIV-1 activity ID REVERSE-TRANSCRIPTASE INHIBITORS; NONNUCLEOSIDE INHIBITORS; ANTI-HIV-1 AGENTS; ANTIVIRAL ACTIVITY; DRUG-RESISTANT; DABO SERIES; POTENT; DERIVATIVES; DESIGN; HEPT AB A novel dihydro-aryl/alkylsulfanyl-cyclohexylmethyl-oxopyrimidines (S-DACOs) combinatory library was synthesized and evaluated with C8166 cells infected by the HIV-1(IIIB) in vitro, using Nevirapine (NVP) and Zidovudine (AZT) as positive control. The anti-HIV screening results revealed that C-6-cyclohexylmethyl substituted pyrimidinones possessed higher selective index than its 6-arylmethyl counterparts. Compounds 1g, 1c, 1e and 1b showed potent anti-HIV activities with EC(50) values of 0.012, 0.025, 0.088 and 0.162 nM, respectively. (C) 2010 Elsevier Ltd. All rights reserved. C1 [He, Yan-Ping; Zhang, Shui-Shuan; Li, Cong; Zhang, Chun-Sheng; Li, Da-Xiong; Zhang, De-Hua; Wang, Hua; Cai, Qing-Qing] Yunnan Univ, Sch Chem Sci & Technol, Minist Educ, Key Lab Med Chem Nat Resource, Kunming 650091, Peoples R China. [Long, Jin; Zheng, Yong-Tang] Chinese Acad Sci, Kunming Inst Zool, Key Lab Anim Models & Human Dis Mech, Lab Mol Immunopharmacol, Kunming 650223, Peoples R China. [Lai, Christopher Cong] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP He, YP (reprint author), Yunnan Univ, Sch Chem Sci & Technol, Minist Educ, Key Lab Med Chem Nat Resource, Kunming 650091, Peoples R China. EM yphe@ynu.edu.cn; zhengyt@mail.kiz.ac.cn FU National Natural Science Foundation of China [30560179, 30960459]; Science Foundation of Chinese academy science [W8090303]; Science Foundation of Yunnan province [2009BC018, 2010CI019]; Chinese Academy of Sciences [KSCX1-YW-R-24]; 973 Program [2006CB504200]; Key Scientific and Technological projects of Yunnan [2004NG12] FX This research was supported by the National Natural Science Foundation of China (Grant No. 30560179 and 30960459), the Science Foundation of Chinese academy science (Grant No. W8090303) and the Science Foundation of Yunnan province (Grant Nos. 2009BC018 and 2010CI019) and to Dr. Y. P. He, the knowledge Innovation Program of Chinese Academy of Sciences (KSCX1-YW-R-24), 973 Program (2006CB504200), Key Scientific and Technological projects of Yunnan (2004NG12) to Dr. Y. T. Zheng. We would like to acknowledge MRC AIDS Research Project (UK) for providing cell lines and virus. NR 22 TC 21 Z9 24 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 15 PY 2011 VL 21 IS 2 BP 694 EP 697 DI 10.1016/j.bmcl.2010.12.003 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 703RC UT WOS:000285998000015 PM 21194939 ER PT J AU Bollo, S Nunez-Vergara, LJ Kang, S Zhang, LA Boshoff, HI Barry, CE Squella, JA Dowd, CS AF Bollo, Soledad Nunez-Vergara, Luis J. Kang, Sunhee Zhang, Liang Boshoff, Helena I. Barry, Clifton E., III Squella, Juan A. Dowd, Cynthia S. TI The effect of 5-substitution on the electrochemical behavior and antitubercular activity of PA-824 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Nitro radical anion; Cyclic voltammetry; PA-824; Mycobacterium tuberculosis ID STATIONARY ELECTRODE POLAROGRAPHY; MYCOBACTERIUM-TUBERCULOSIS; NITROIMIDAZOPYRAN PA-824 AB Nitroimidazole PA-824 is part of an exciting new class of compounds currently undergoing clinical evaluation as novel TB therapeutics. The recently elucidated mechanism of action of PA-824 involves reduction of the nitroimidazole ring and subsequent nitric oxide release. The importance of this compound and its unique activity prompted us to explore how substitution of the nitroimidazole ring would affect electrochemical reduction and antitubercular activity. We prepared analogs of PA-824 with bromo, chloro, cyano, and amino substituents in the 5-position of the aromatic ring. We found that substitution of the imidazole ring greatly influences reduction and the stability of the corresponding nitro radical anion. Further, the antitubercular activities of the bromo and chloro analogs may indicate that an alternate nitroreductase pathway within Mycobacterium tuberculosis exists. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Bollo, Soledad; Nunez-Vergara, Luis J.; Squella, Juan A.] Univ Chile, Chem & Pharmaceut Sci Fac, Bioelectrochem Lab, Santiago 1, Chile. [Kang, Sunhee; Zhang, Liang; Boshoff, Helena I.; Barry, Clifton E., III; Dowd, Cynthia S.] NIAID, TB Res Sect, LCID, NIH, Bethesda, MD 20892 USA. RP Squella, JA (reprint author), George Washington Univ, Dept Chem, 725 21st St NW, Washington, DC 20052 USA. EM asquella@ciq.uchile.cl; cdowd@gwu.edu RI Bollo, Soledad/B-5257-2011; Barry, III, Clifton/H-3839-2012; Squella, Juan/A-5093-2009 OI Squella, Juan/0000-0003-0362-4399 FU Intramural Research Division of the NIAID; NIH; FONDECYT [1090120] FX This study was funded by the Intramural Research Division of the NIAID, NIH, and FONDECYT (Project No. 1090120). NR 20 TC 10 Z9 10 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 15 PY 2011 VL 21 IS 2 BP 812 EP 817 DI 10.1016/j.bmcl.2010.11.093 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 703RC UT WOS:000285998000043 PM 21168331 ER PT J AU Biegstraaten, M van Schaik, IN Aerts, JMFG Langeveld, M Mannens, MMAM Bour, LJ Sidransky, E Tayebi, N Fitzgibbon, E Hollak, CEM AF Biegstraaten, M. van Schaik, I. N. Aerts, J. M. F. G. Langeveld, M. Mannens, M. M. A. M. Bour, L. J. Sidransky, E. Tayebi, N. Fitzgibbon, E. Hollak, C. E. M. TI A monozygotic twin pair with highly discordant Gaucher phenotypes SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Gaucher disease; Monozygotic twins; Glucocerebrosidase; Seizures ID DISEASE; GLUCOCEREBROSIDASE; COMPLEXITY; MUTATIONS AB We describe monozygotic twin sisters, born to consanguineous Moroccan parents, who are highly discordant for the manifestations of Gaucher disease. Both carry Gaucher genotype N188S/N188S. One has severe visceral involvement, epilepsy, and a cerebellar syndrome. Her twin does not manifest any symptoms or signs of Gaucher disease but suffers from type 1 diabetes mellitus. The concurrence of a mild Gaucher mutation with a severe phenotype, as well as the occurrence of highly discordant phenotypes in a pair of monozygotic twins, is discussed. (C) 2010 Elsevier Inc. All rights reserved. C1 [Langeveld, M.; Hollak, C. E. M.] Univ Amsterdam, Acad Med Ctr, Div Endocrinol & Metab, Dept Internal Med, NL-1100 DD Amsterdam, Netherlands. [Biegstraaten, M.; van Schaik, I. N.] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands. [Aerts, J. M. F. G.] Univ Amsterdam, Acad Med Ctr, Dept Biochem, NL-1105 AZ Amsterdam, Netherlands. [Mannens, M. M. A. M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Bour, L. J.] Univ Amsterdam, Acad Med Ctr, Dept Neurophysiol, NL-1105 AZ Amsterdam, Netherlands. [Sidransky, E.; Tayebi, N.] NHGRI, NIH, Bethesda, MD 20892 USA. [Fitzgibbon, E.] NEI, NIH, Bethesda, MD 20892 USA. RP Hollak, CEM (reprint author), Univ Amsterdam, Acad Med Ctr, Div Endocrinol & Metab, Dept Internal Med, F5-170,POB 22660, NL-1100 DD Amsterdam, Netherlands. EM c.e.hollak@amc.uva.nl RI Aerts, Johannes/A-1028-2009 FU Intramural NIH HHS [ZIA HG200336-06] NR 9 TC 20 Z9 21 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JAN 15 PY 2011 VL 46 IS 1 SI SI BP 39 EP 41 DI 10.1016/j.bcmd.2010.10.007 PG 3 WC Hematology SC Hematology GA 709CJ UT WOS:000286412600009 PM 21056933 ER PT J AU Gupta, N Oppenheim, IM Kauvar, EF Tayebi, N Sidransky, E AF Gupta, N. Oppenheim, I. M. Kauvar, E. F. Tayebi, N. Sidransky, E. TI Type 2 Gaucher disease: Phenotypic variation and genotypic heterogeneity SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Review DE Gaucher disease; Glucocerebrosidase; Neuronopathic Gaucher disease; Hydrops fetalis; Genotype-phenotype correlation ID HUMAN GLUCOCEREBROSIDASE GENE; ENZYME REPLACEMENT THERAPY; LYSOSOMAL STORAGE DISEASES; PERINATAL LETHAL FORM; BRAIN-STEM RESPONSE; BETA-GLUCOSIDASE; MUTANT ALLELES; INTERMEDIATE PHENOTYPE; TARGETED DISRUPTION; COLLODION BABIES AB Gaucher disease (GD), the most common lysosomal storage disease, results from a deficiency of the lysosomal enzyme glucocerebrosidase. GD has been classified into 3 types, of which type 2 (the acute neuronopathic form) is the most severe, presenting pre- or perinatally, or in the first few months of life. Traditionally, type 2 GD was considered to have the most uniform clinical phenotype when compared to other GD subtypes. However, case studies over time have demonstrated that type 2 GD, like types 1 and 3, manifests with a spectrum of phenotypes. This review includes case reports that illustrate the broad range of clinical presentations encountered in type 2 GD, as well as a discussion of associated manifestations, pathological findings, diagnostic techniques, and a review of current therapies. While type 2 GD is generally associated with severe mutations in the glucocerebrosidase gene, there is also significant genotypic heterogeneity. Published by Elsevier Inc. C1 [Sidransky, E.] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Kauvar, E. F.] Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20817 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Division of Intramural Research of the National Human Genome Research Institute; National Institutes of Health FX Special thanks to Dr. Ehud Goldin for his constructive suggestions. This research was supported by the Division of Intramural Research of the National Human Genome Research Institute, and the National Institutes of Health. NR 118 TC 24 Z9 25 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JAN 15 PY 2011 VL 46 IS 1 SI SI BP 75 EP 84 DI 10.1016/j.bcmd.2010.08.012 PG 10 WC Hematology SC Hematology GA 709CJ UT WOS:000286412600016 PM 20880730 ER PT J AU Miri-Moghaddam, E Velayati, A Naderi, M Tayebi, N Sidransky, E AF Miri-Moghaddam, Ebrahim Velayati, Arash Naderi, Majid Tayebi, Nahid Sidransky, Ellen TI Coinheritance of Gaucher disease and alpha-thalassemia resulting in confusion between two inherited hematologic diseases SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Gaucher disease; alpha-Thalassemia; Splenomegaly; Hemoglobinopathies ID GLUCOCEREBROSIDASE GENE; MUTATIONS AB Gaucher type 1 disease has a wide spectrum of phenotypes ranging from asymptomatic individuals to patients with massive hepatosplenomegaly and bone involvement. In most, anemia, thrombocytopenia and splenomegaly are the primary manifestations at diagnosis, findings shared by the hemoglobinopathies. Here we report the co-inheritance of alpha-thalassemia and Gaucher disease in a consanguineous family followed in Iran, which resulted in confusion regarding the diagnosis. This report emphasizes the need to independently establish the diagnosis of every affected member of a family to ensure appropriate management and therapeutic decisions. (C) 2010 Published by Elsevier Inc. C1 [Velayati, Arash; Tayebi, Nahid; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Miri-Moghaddam, Ebrahim] Zahedan Univ Med Sci, Dept Immunohematol, Fac Med, Zahedan, Iran. [Naderi, Majid] Zahedan Univ Med Sci, Res Ctr Children & Adolescent, Zahedan, Iran. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov OI Miri-Moghaddam, Ebrahim/0000-0001-9435-2450 FU Intramural NIH HHS [ZIA HG200336-06] NR 15 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JAN 15 PY 2011 VL 46 IS 1 SI SI BP 88 EP 91 DI 10.1016/j.bcmd.2010.08.007 PG 4 WC Hematology SC Hematology GA 709CJ UT WOS:000286412600018 PM 20846888 ER PT J AU Jung, SC Eun, SY Kim, J Hoffman, DA AF Jung, Sung-Cherl Eun, Su-Yong Kim, Jinhyun Hoffman, Dax A. TI Kv4.2 block of long-term potentiation is partially dependent on synaptic NMDA receptor remodeling SO BRAIN RESEARCH BULLETIN LA English DT Article DE Synaptic plasticity; A-type K(+) channel; Kv4.2; LIP; NMDA receptor; CaMKII ID CA1 PYRAMIDAL NEURONS; SUBUNIT COMPOSITION; K+ CURRENT; HIPPOCAMPAL; PLASTICITY; INDUCTION; DENDRITES; CHANNELS; CAMKII; LTP AB Proper expression of synaptic NMDA receptors (NMDARs) is necessary to regulate synaptic Ca2(+) influx and the induction the long-term potentiation (LTP) in the mammalian hippocampus. Previously we reported that expressing the A-type K(+) channel subunit Kv4.2 in CA1 neurons of organotypic slice cultures reduced synaptic NR2B-containing NMDAR expression and completely blocked LTP induced by a pairing protocol. As pretreatment with an NMDAR antagonist (APV) overnight blocked the reduction of NR2B-containing receptors in neurons expressing EGFP-labeled Kv4.2 (Kv4.2g), we hypothesized that LTP would be rescued in Kv4.2g neurons by overnight treatment with APV. We report here that the overnight APV pretreatment in Kv4.2g-expressing neurons only partially restored potentiation. This partial potentiation was completely blocked by inhibition of the CAMKII kinase. These results indicate that A-type K(+) channels must regulate synaptic integration and plasticity through another mechanism in addition to their regulation of synaptic NR2 subunit composition. We suggest that dendritic excitability, which is regulated by Kv4.2 expression, also contributes to synaptic plasticity. (c) 2010 Elsevier Inc. All rights reserved. C1 [Jung, Sung-Cherl; Eun, Su-Yong] Cheju Natl Univ, Sch Med, Dept Physiol, Cheju 690756, South Korea. [Kim, Jinhyun] Howard Hughes Med Inst, Ashburn, VA USA. [Jung, Sung-Cherl; Kim, Jinhyun; Hoffman, Dax A.] NICHHD, Mol Neurophysiol & Biophys Unit, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Jung, SC (reprint author), Cheju Natl Univ, Sch Med, Dept Physiol, Rm 118,1753-3,Ara 1 Dong, Cheju 690756, South Korea. EM jungsc@jejunu.ac.kr RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Ministry of Education, Science and Technology [2009-0076404] FX The research was funded through the Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural research program and supported by Basic Science Research Program through the Korea NRF funded by the Ministry of Education, Science and Technology (2009-0076404). NR 19 TC 6 Z9 6 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JAN 15 PY 2011 VL 84 IS 1 BP 17 EP 21 DI 10.1016/j.brainresbull.2010.09.012 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 714YQ UT WOS:000286848000004 PM 20920553 ER PT J AU Vriens, MR Moses, W Weng, J Peng, MA Griffin, A Bleyer, A Pollock, BH Indelicato, DJ Hwang, J Kebebew, E AF Vriens, Menno R. Moses, Willieford Weng, Julie Peng, Miao Griffin, Ann Bleyer, Archie Pollock, Brad H. Indelicato, Daniel J. Hwang, Jimmy Kebebew, Electron TI Clinical and Molecular Features of Papillary Thyroid Cancer in Adolescents and Young Adults SO CANCER LA English DT Article DE thyroid cancer; adolescents; young adults; genomics; oncogenes ID PROGNOSTIC VALUE; INCREASING INCIDENCE; EXPRESSION PROFILES; BRAF MUTATION; CARCINOMA; NEOPLASMS; GENES; PREVALENCE; CHILDREN; RET/PTC AB BACKGROUND: Age disparities in thyroid cancer incidence and outcome among adolescents and young adults (AYAs) with thyroid cancer are under reported. In this study, the authors compared the molecular and clinical features of papillary thyroid cancer (PTC) in AYAs with the same features among patients in other age groups. METHODS: One thousand eleven patients underwent initial treatment for PTC at the University of California at San Francisco. Patients were subdivided into 2 age groups: ages 15 to 39 years (the AYA group) and aged >= 40 years. Demographic, clinical, and survival data in the cohort also were compared with data from the National Cancer Instsitute's Surveillance, Epidemiology, and End Results (SEER) Program. In a subset of the study cohort, the primary tumors were analyzed by genome-wide expression analyses, genotyping for common somatic mutations, and path-way-specific gene expression arrays between the age groups. RESULTS: The percentage of women and the lymph node metastasis rate were significantly higher in the AYA group. In the AYA group, the rate of distant metastasis was lower. Disease-free survival and median overall survival were significantly higher in the AYA group. The better survival in AYA patients also was apparent in the national SEER data. An unsupervised cluster analysis of gene expression data revealed no distinct clustering by age in 96 PTC samples. The frequency and type of somatic mutations in the primary tumors did not differ significantly between age groups (the AYA group vs the group aged >= 40 years). Six genes (extracellular matrix protein 1 [ECM1], v-erb-2 erythroblastic leukemia viral oncogene homolog 2 [ERBB2], urinary plasminogen activator [UPA], 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 [PFKFB2], meis homeobox 2 [MEIS2], and carbonic anhydrase II [CA2]) had significant differential expression between age groups. CONCLUSIONS: The extent of disease at presentation and the survival of patients with PTC differed between AYAs and older patients. The current results indicated that these differences may be caused by several candidate genes and that these genes are expressed differentially and may play an important role in tumor cell biology. However, no distinct gene expression profiles exist for patients with PTC that distinguish between AYAs and patients aged >= 40 years. Cancer 2011; 117: 259-67. (C) 2010 American Cancer Society. C1 [Vriens, Menno R.; Moses, Willieford; Weng, Julie; Peng, Miao; Kebebew, Electron] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Hwang, Jimmy; Kebebew, Electron] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Griffin, Ann] Univ Calif San Francisco, Canc Registry, San Francisco, CA 94143 USA. [Bleyer, Archie] Univ Oregon, St Charles Med Ctr, Dept Pediat Oncol, Bend, OR USA. [Pollock, Brad H.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Indelicato, Daniel J.] Univ Florida, Proton Therapy Inst, Jacksonville, FL USA. RP Kebebew, E (reprint author), NCI, Ctr Canc Res, Surg Branch, CRC Room 4-5952,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov OI Indelicato, Daniel/0000-0001-5765-1873 FU Lance Armstrong Foundation through the LIVESTRONG Young Adult Alliance FX This research was supported in part by a grant from the Lance Armstrong Foundation through the LIVESTRONG Young Adult Alliance. NR 26 TC 30 Z9 32 U1 0 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2011 VL 117 IS 2 BP 259 EP 267 DI 10.1002/cncr.25369 PG 9 WC Oncology SC Oncology GA 703KF UT WOS:000285976100004 PM 20824721 ER PT J AU Niesvizky, R Ely, S Mark, T Aggarwal, S Gabrilove, JL Wright, JJ Chen-Kiang, S Sparano, JA AF Niesvizky, Ruben Ely, Scott Mark, Tomer Aggarwal, Sangeeta Gabrilove, Janice L. Wright, John J. Chen-Kiang, Selina Sparano, Joseph A. TI Phase 2 Trial of the Histone Deacetylase Inhibitor Romidepsin for the Treatment of Refractory Multiple Myeloma SO CANCER LA English DT Article DE romidepsin; myeloma; recurrent/refractory; histone deacetylase; inhibitor; phase 2 ID T-CELL LYMPHOMA; SUBEROYLANILIDE HYDROXAMIC ACID; DEPSIPEPTIDE FR901228; CLINICAL-TRIAL; I TRIAL; BORTEZOMIB; METHYLATION; COMBINATION; VORINOSTAT; INDUCTION AB BACKGROUND: Epigenetic dysregulation is a hallmark of cancer, including multiple myeloma. Inhibitors of histone deacetylases (HDACs) induce DNA hyperacetylation by inhibiting removal of acetyl groups from amino tails on histone proteins, thereby uncoiling condensed chromatin favoring transcription of silenced genes, including tumor suppressor genes. Romidepsin is an HDAC inhibitor that exhibits antiproliferative and apoptotic effects against multiple myeloma cell lines. METHODS: A phase 2 trial was performed of romidepsin in patients with multiple myeloma who were refractory to standard therapy. Treatment was comprised of romidepsin (13 mg/m(2)) given as a 4-hour intravenous infusion on Days 1, 8, and 15 every 28 days). Thirteen patients received a median of 2 cycles of therapy (range, 1-7 cycles). RESULTS: Although no patients had an objective response, 4 of 12 patients with secretory myeloma exhibited evidence of M-protein stabilization, and several other patients experienced improvement in bone pain and resolution of hypercalcemia. CONCLUSIONS: The results of the current study demonstrate that romidepsin, as a single agent, is unlikely to be associated with a response rate of >= 30% in patients with refractory myeloma, although there was some clinical evidence suggesting a biological effect associated with therapy. Cancer 2011; 117:336-42. Published 2010 by the American Cancer Society.* C1 [Niesvizky, Ruben; Mark, Tomer] New York Presbyterian Hosp, Weill Cornell Med Coll, Ctr Excellence Lymphoma & Myeloma, Dept Med,Div Hematol Oncol, New York, NY USA. [Ely, Scott] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [Aggarwal, Sangeeta] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Gabrilove, Janice L.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Wright, John J.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. [Chen-Kiang, Selina] Weill Cornell Med Coll, Dept Pathol & Lab Med & Microbiol & Immunol, New York, NY USA. RP Niesvizky, R (reprint author), 520 E 70th St,Starr 341, New York, NY 10021 USA. EM run9001@med.cornell.edu FU National Institute of Health, National Cancer Institute (NCI) [N01-CM-62204]; Leukemia and Lymphoma Society [RFP S03-058]; NCI [K24 CA100287-02, K23 CA109260-01] FX Supported by a contract from the National Institute of Health, National Cancer Institute (NCI) (N01-CM-62204 [Principal Investigator: Joseph A. Sparano]) and by the Leukemia and Lymphoma Society SCOR grant RFP S03-058 SAIC-Frederick, NCI K24 CA100287-02 (to J.G.), and NCI K23 CA109260-01. NR 29 TC 62 Z9 64 U1 2 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2011 VL 117 IS 2 BP 336 EP 342 DI 10.1002/cncr.25584 PG 7 WC Oncology SC Oncology GA 703KF UT WOS:000285976100013 PM 20862746 ER PT J AU Varghese, S Chen, ZR Bartlett, DL Pingpank, JF Libutti, SK Steinberg, SM Wunderlich, J Alexander, HR AF Varghese, Sheelu Chen, Zhaorong Bartlett, David L. Pingpank, James F. Libutti, Steven K. Steinberg, Seth M. Wunderlich, John Alexander, H. Richard, Jr. TI Activation of the Phosphoinositide-3-Kinase and Mammalian Target of Rapamycin Signaling Pathways Are Associated With Shortened Survival in Patients With Malignant Peritoneal Mesothelioma SO CANCER LA English DT Article DE microarray; peritoneal mesothelioma; cancer pathways; patient survival ID EXPANDED ACCESS PROGRAM; INTRAPERITONEAL CHEMOTHERAPY; ONCOGENIC TRANSFORMATION; CYTOREDUCTIVE SURGERY; P110-ALPHA ISOFORM; POOR-PROGNOSIS; MEK INHIBITORS; LUNG CANCERS; PI3K; COMBINATION AB BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignancy of the serosal membranes of the abdominal cavity. This cancer is ultimately fatal in almost all afflicted individuals; however, there is marked variability in its clinical behavior: Some patients die rapidly, and others survive for many years. In the current study, the authors investigated the molecular nature of MPM to obtain insights into the heterogeneity of its clinical behavior and to identify new therapeutic targets for intervention. METHODS: Fresh pretreatment tumor samples were collected from 41 patients with MPM who underwent surgical cytoreduction and received regional intraoperative chemotherapy perfusion. From those samples, gene expression analyses were performed. The major cellular pathways that were identified in this cancer were inhibited using a pathway-specific inhibitor. RESULTS: Unsupervised clustering of genes identified 2 distinct groups of patients with significantly different survivals (Group A: median survival, 24 months; Group B: median survival, 69.5 months; P = .035). Phosphoinositide-3-kinase (PI3K) and the closely interacting mammalian target of rapamycin (mTOR) signaling pathways were overexpressed predominantly in the poor survival group; and the genes of these pathways, phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) and rapamycin- insensitive companion of mammalian target of rapamycin (RICTOR), were highly significantly predictive of shortened patient survival in Group A. The role of these pathways in MPM tumor progression was also investigated by treating 2 MPM cell lines with BEZ235, a dual-class PI3K and mTOR inhibitor, and the authors observed significant inhibition of downstream cell signaling and cell proliferation. CONCLUSIONS: Taken together, the results from this study revealed that, based on gene expression profiles, there were 2 distinct patient groups with significantly different survival and that targeting the PI3K and mTOR signaling pathways may have significant therapeutic value in patients with MPM. Cancer 2011; 117:361-71. (C) 2010 American Cancer Society. C1 [Varghese, Sheelu; Chen, Zhaorong; Alexander, H. Richard, Jr.] Univ Maryland, Sch Med, Dept Surg, Div Surg Oncol, Baltimore, MD 21201 USA. [Varghese, Sheelu; Chen, Zhaorong; Alexander, H. Richard, Jr.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Bartlett, David L.; Pingpank, James F.; Libutti, Steven K.; Wunderlich, John] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), Univ Maryland, Sch Med, Dept Surg, Div Surg Oncol, 22 S Greene St S4B05A, Baltimore, MD 21201 USA. EM hralexander@smail.umaryland.edu FU Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland FX Funding support was received from the Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, and the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. NR 37 TC 24 Z9 24 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2011 VL 117 IS 2 BP 361 EP 371 DI 10.1002/cncr.25555 PG 11 WC Oncology SC Oncology GA 703KF UT WOS:000285976100016 PM 20839315 ER PT J AU Tandon, P Farahani, K AF Tandon, Pushpa Farahani, Keyvan TI NCI Image-Guided Drug Delivery Summit SO CANCER RESEARCH LA English DT Editorial Material ID IN-VIVO; NANOPARTICLES; CAVEOLAE; CELLS AB On April 17, 2010, scientists from academia, the National Cancer Institute (NCI), and the Food and Drug Administration (FDA) assembled at "The NCI Image Guided Drug Delivery Summit," in Washington D.C., to discuss recent advances,barriers, opportunities, and regulatory issues related to the field. The meeting included a scientific session and an NCI/FDA session, followed by a panel discussion of speakers from both sessions. Image-guided drug delivery (IGDD) in cancer is a form of individualized therapy where imaging methods are used in guidance and monitoring of localized and targeted delivery of therapeutics to the tumor. So, a systematic approach to IGDD requires mechanisms for targeting, delivery, activation, and monitoring of the process. Although the goal in IGDD is to optimize the therapeutic ratio through personalized image-guided treatments, a major challenge is in overcoming the biological barriers to the delivery of therapeutics into tumors and cells. Speakers discussed potential challenges to clinical translation of nano-based drug delivery systems including in vivo characterization of nanocarriers, preclinical validation of targeting and delivery, studies of biodistribution, pharmacokinetics, pharmacodynamics, and toxicity as well as scale-up manufacturing of delivery systems. Physiologic and quantitative imaging techniques may serve as enabling tools that could potentially transform many existing challenges into opportunities for advancement of the field. Cancer Res; 71(2); 314-7. (c) 2011 AACR. C1 [Tandon, Pushpa; Farahani, Keyvan] Natl Canc Inst, NIH, Div Canc Treatment & Diag, Canc Imaging Program, Bethesda, MD 20892 USA. RP Farahani, K (reprint author), Natl Canc Inst, NIH, Div Canc Treatment & Diag, Canc Imaging Program, 6130 Execut Blvd, MSC 7412,Suite 6000, Bethesda, MD 20892 USA. EM farahank@mail.nih.gov RI Farahani, Keyvan/G-9069-2012 FU Intramural NIH HHS [Z99 CA999999] NR 14 TC 13 Z9 13 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2011 VL 71 IS 2 BP 314 EP 317 DI 10.1158/0008-5472.CAN-10-2629 PG 4 WC Oncology SC Oncology GA 706CI UT WOS:000286193900036 PM 21224356 ER PT J AU Wang, Y Ozawa, A Zaman, S Prasad, NB Chandrasekharappa, SC Agarwal, SK Marx, SJ AF Wang, Yan Ozawa, Atsushi Zaman, Shadia Prasad, Nijaguna B. Chandrasekharappa, Settara C. Agarwal, Sunita K. Marx, Stephen J. TI The Tumor Suppressor Protein Menin Inhibits AKT Activation by Regulating Its Cellular Localization SO CANCER RESEARCH LA English DT Article ID MULTIPLE-ENDOCRINE-NEOPLASIA; TYPE-1 GENE; PRODUCT; EXPRESSION; GROWTH; IDENTIFICATION; INTERACTS; PATHWAY AB Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder associated mainly with tumors of multiple endocrine organs. Mutations in the MEN1 gene that encodes for the menin protein are the predominant cause for hereditary MEN1 syndrome. Though menin is a tumor suppressor, its molecular mechanism of action has not been defined. Here, we report that menin interacts with AKT1 in vitro and in vivo. Menin downregulates the level of active AKT and its kinase activity. Through interaction with AKT1, menin suppresses both AKT1-induced proliferation and antiapoptosis in nonendocrine and endocrine cells. Confocal microscopy analysis revealed that menin regulates AKT1 in part by reducing the translocation of AKT1 from the cytoplasm to the plasma membrane during growth factor stimulation. Our findings may be generalizable to other cancers, insofar as we found that loss of menin expression was also associated with AKT activation in a mouse model of pancreatic islet adenoma. Together, our results suggest menin as an important novel negative regulator of AKT kinase activity. Cancer Res; 71(2); 371-82. (C) 2010 AACR. C1 [Wang, Yan; Ozawa, Atsushi; Zaman, Shadia; Agarwal, Sunita K.; Marx, Stephen J.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Ozawa, Atsushi] Gunma Univ, Grad Sch Med, Dept Med & Mol Sci, Gunma, Japan. [Prasad, Nijaguna B.; Chandrasekharappa, Settara C.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Prasad, Nijaguna B.] Johns Hopkins Univ, Dept Surg, Baltimore, MD USA. RP Wang, Y (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Room 9C-103,9000 Rockville, Bethesda, MD 20892 USA. EM wangyan@mail.nih.gov; marxs@mail.nih.gov RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU National Institute of Diabetes and Digestive and Kidney Diseases FX These studies were supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 28 TC 28 Z9 30 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2011 VL 71 IS 2 BP 371 EP 382 DI 10.1158/0008-5472.CAN-10-3221 PG 12 WC Oncology SC Oncology GA 706CI UT WOS:000286193900009 PM 21127195 ER PT J AU Wu, LM Ma, CA Jain, A AF Wu, Liming Ma, Chi A. Jain, Ashish TI When Aurora B met p53 Newly revealed regulatory phosphorylation in an old protein SO CELL CYCLE LA English DT Editorial Material ID CANCER C1 [Wu, Liming; Ma, Chi A.; Jain, Ashish] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Jain, A (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ajain@niaid.nih.gov RI Wu, Liming/C-4004-2011 FU Intramural NIH HHS NR 12 TC 4 Z9 4 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JAN 15 PY 2011 VL 10 IS 2 BP 171 EP 172 DI 10.4161/cc.10.2.14349 PG 2 WC Cell Biology SC Cell Biology GA 709SL UT WOS:000286461600001 PM 21212738 ER PT J AU Movsas, B Vikram, B Hauer-Jensen, M Moulder, JE Basch, E Brown, SL Kachnic, LA Dicker, AP Coleman, CN Okunieff, P AF Movsas, Benjamin Vikram, Bhadrasain Hauer-Jensen, Martin Moulder, John E. Basch, Ethan Brown, Stephen L. Kachnic, Lisa A. Dicker, Adam P. Coleman, C. Norman Okunieff, Paul TI Decreasing the Adverse Effects of Cancer Therapy: National Cancer Institute Guidance for the Clinical Development of Radiation Injury Mitigators SO CLINICAL CANCER RESEARCH LA English DT Review ID PATIENT-REPORTED OUTCOMES; RENIN-ANGIOTENSIN SYSTEM; CELL LUNG-CANCER; NORMAL-TISSUE; MEDICAL COUNTERMEASURES; RANDOMIZED-TRIAL; NECK-CANCER; IRRADIATION; AMIFOSTINE; MICE AB Recently, many agents have been identified that target molecular pathways that can mitigate radiation toxicity. To date, no drugs have been approved as radiation injury mitigators, which are defined as agents administered after irradiation but before toxicity is manifest. In order to accelerate the application of potential mitigators for cancer patients, a meeting sponsored by the National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID) was held in January 2010. This article presents an algorithm to guide clinical trials for such agents in patients receiving radiotherapy or radiochemotherapy. It reviews the mechanisms of radiation injury, the clinical problem, the preclinical and clinical development of candidate agents, and the design and conduct of clinical trials. The central role of patient reported outcomes is outlined, as well as key lessons learned from prior clinical trials. Ultimately, the goal is to be able to apply such promising agents to improve the quality of life for patients receiving radiotherapy or chemoradiotherapy for cancer. Clin Cancer Res; 17(2); 222-28. (C)2010 AACR. C1 [Movsas, Benjamin; Brown, Stephen L.] Henry Ford Hosp, Dept Radiat Oncol, Detroit, MI 48202 USA. [Vikram, Bhadrasain; Coleman, C. Norman] NCI, Rockville, MD USA. [Hauer-Jensen, Martin] Univ Arkansas Med Sci, Div Radiat Hlth, Little Rock, AR 72205 USA. [Moulder, John E.] Med Coll Wisconsin, Dept Radiat Oncol, Milwaukee, WI 53226 USA. [Basch, Ethan] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kachnic, Lisa A.] Boston Med Ctr, Dept Radiat Oncol, Boston, MA USA. [Dicker, Adam P.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Okunieff, Paul] Univ Florida, Shands Canc Ctr, Dept Radiat Oncol, Gainesville, FL USA. RP Movsas, B (reprint author), Henry Ford Hosp, Dept Radiat Oncol, 2799 W Grand Blvd, Detroit, MI 48202 USA. EM bmovsas1@hfhs.org RI Moulder, John/E-6799-2012; OI Dicker, Adam/0000-0003-0733-3337 FU NIH; Small Business Innovation Research grants; Small Business Technology Transfer Research grants FX Funding for such studies may be available, among other sources, from the NIH as research project grants, Small Business Innovation Research grants, and/or Small Business Technology Transfer Research grants. NR 52 TC 21 Z9 21 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2011 VL 17 IS 2 BP 222 EP 228 DI 10.1158/1078-0432.CCR-10-1402 PG 7 WC Oncology SC Oncology GA 706ME UT WOS:000286221700004 PM 21047979 ER PT J AU Zacharias, AL Lewandoski, M Rudnicki, MA Gage, PJ AF Zacharias, Amanda L. Lewandoski, Mark Rudnicki, Michael A. Gage, Philip J. TI Pitx2 is an upstream activator of extraocular myogenesis and survival SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Extraocular muscles; Myogenesis; Pitx2; Eye development; Inducible knockout ID MUSCLE PROGENITOR CELLS; DISTINCT REGULATORY CASCADES; NEURAL CREST; GENE-EXPRESSION; MESODERM; MOUSE; PAX7; DIFFERENTIATION; MORPHOGENESIS; PITUITARY AB The transcription factors required to initiate myogenesis in branchial arch- and somite-derived muscles are known, but the comparable upstream factors required during extraocular muscle development have not been identified. We show Pax7 is dispensable for extraocular muscle formation, whereas Pitx2 is cell-autonomously required to prevent apoptosis of the extraocular muscle primordia. The survival requirement for Pitx2 is stage-dependent and ends following stable activation of genes for the muscle regulatory factors (e.g. Myf5,MyoD), which is reduced in the absence of Pitx2. Further, PITX2 binds and activates transcription of the Myf5 and MyoD promoters, indicating these genes are direct targets. Collectively, these data demonstrate that PITX2 is required at several steps in the development of extraocular muscles, acting first as an anti-apoptotic factor in pre-myogenic mesoderm, and subsequently to activate the myogenic program in these cells. Thus, Pitx2 is the first demonstrated upstream activator of myogenesis in the extraocular muscles. (C) 2010 Elsevier Inc. All rights reserved. C1 [Zacharias, Amanda L.; Gage, Philip J.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Gage, Philip J.] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI 48105 USA. [Lewandoski, Mark] NCI, Canc & Dev Biol Lab, Ft Detrick, MD 21702 USA. [Rudnicki, Michael A.] Ottawa Hosp, Res Inst, Regenerat Med Program, Sprott Ctr Stem Cell Res, Ottawa, ON K1H 8L6, Canada. [Rudnicki, Michael A.] Univ Ottawa, Dept Med, Ottawa, ON K1H 8L6, Canada. RP Gage, PJ (reprint author), Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. EM philgage@umich.edu OI Gage, Philip/0000-0001-5536-6702 FU NEI/NIH [EY014126, EY007003, EY013934] FX The authors wish to thank those noted for their gifts of reagents; Peter Hitchcock and Deneen Wellik for critical reading of this manuscript; Christopher Momont and David Lingenfelter for help with sectioning and staining; Amy Moran and Faisal Siddiqui for mouse colony maintenance; and Ivan Maillard and Min Qian for technical advice. This work was supported by NEI/NIH (EY014126 (PJG), EY007003 (PJG), EY013934 (ALZ)). NR 53 TC 24 Z9 26 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JAN 15 PY 2011 VL 349 IS 2 BP 395 EP 405 DI 10.1016/j.ydbio.2010.10.028 PG 11 WC Developmental Biology SC Developmental Biology GA 709CK UT WOS:000286412800027 PM 21035439 ER PT J AU Tasevska, N Cross, AJ Dodd, KW Ziegler, RG Caporaso, NE Sinha, R AF Tasevska, Natasa Cross, Amanda J. Dodd, Kevin W. Ziegler, Regina G. Caporaso, Neil E. Sinha, Rashmi CA PLCO Canc Screening Trial Project TI No effect of meat, meat cooking preferences, meat mutagens or heme iron on lung cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE meat; diet; lung cancer; meat mutagens; heme iron; PLCO ID POLYCYCLIC AROMATIC-HYDROCARBONS; FOOD FREQUENCY QUESTIONNAIRE; HETEROCYCLIC AMINE CONTENT; RED MEAT; NITROSO-COMPOUNDS; VARYING DEGREES; WOMENS HEALTH; UNITED-STATES; DIETARY-FAT; COHORT AB Recent epidemiological studies have suggested that red and processed meat may increase the risk of lung cancer. Possible underlying mechanisms include mutagens produced during high-temperature cooking or preservation, or formed endogenously from heme iron in meat. We used data from 99,579 participants of both screened and nonscreened arms of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, aged 55-74 years, to investigate whether meat type, cooking method, doneness level, intake of specific meat mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline] (DiMeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and benzo(a)pyrene (B(a)P)] and heme iron are associated with lung cancer. Participants' diet was assessed prospectively using a 124-item food frequency questionnaire and an additional meat-cooking module. Dietary data were used in conjunction with a database to estimate intake of MeIQx, DiMeIQx, PhIP, B(a)P and heme iron. After up to 8 years of follow-up, 782 incident lung cancer cases were ascertained. Lung cancer risk was not associated with the consumption of either red (men: HRQ5 (vs.) (Q1) = 1.11, 95% CI = 0.79-1.56, P-trend = 0.42; women: HRQ5 vs. Q1 = 1.30, 95% CI = 0.87-1.95, P-trend = 0.65) or processed meat (men: HRQ5 vs. Q1 = 1.12, 95% CI = 0.83-1.53, P-trend (=) 0.22; women: HRQ5 vs. Q1 = 0.98, 95% CI = 0.68-1.41, P-trend = 0.32) in multivariable models. High-temperature cooking methods, level of meat doneness, meat mutagens and heme iron had no effect on lung cancer risk. In this population, we found no association between meat type, cooking method, doneness level or intake of specific meat mutagens or heme iron and lung cancer risk. C1 [Tasevska, Natasa; Cross, Amanda J.; Ziegler, Regina G.; Caporaso, Neil E.; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Dodd, Kevin W.] NCI, Biometry Res Grp, Canc Prevent Div, NIH,Dept Hlth & Human Serv, Rockville, MD USA. RP Tasevska, N (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 3121, Bethesda, MD 20892 USA. EM tasevskan@mail.nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health, National Cancer Institute FX Grant sponsors: Division of Cancer Prevention, National Cancer Institute, NIH, DHHS, Intramural Research Program of the National Institutes of Health, National Cancer Institute NR 46 TC 14 Z9 14 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2011 VL 128 IS 2 BP 402 EP 411 DI 10.1002/ijc.25327 PG 10 WC Oncology SC Oncology GA 693ZE UT WOS:000285263100016 PM 20232386 ER PT J AU Chinnasamy, N Wargo, JA Yu, Z Rao, M Frankel, TL Riley, JP Hong, JJ Parkhurst, MR Feldman, SA Schrump, DS Restifo, NP Robbins, PF Rosenberg, SA Morgan, RA AF Chinnasamy, Nachimuthu Wargo, Jennifer A. Yu, Zhiya Rao, Mahadev Frankel, Timothy L. Riley, John P. Hong, Jenny J. Parkhurst, Maria R. Feldman, Steven A. Schrump, David S. Restifo, Nicholas P. Robbins, Paul F. Rosenberg, Steven A. Morgan, Richard A. TI A TCR Targeting the HLA-A*0201-Restricted Epitope of MAGE-A3 Recognizes Multiple Epitopes of the MAGE-A Antigen Superfamily in Several Types of Cancer SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOLYTIC T-LYMPHOCYTES; TISSUE MICROARRAY EVALUATION; TUMOR-CELL RECOGNITION; MELANOMA PATIENTS; METASTATIC MELANOMA; DENDRITIC CELLS; LUNG-CANCER; ENGINEERED LYMPHOCYTES; POTENTIAL INDICATIONS; PROGNOSTIC RELEVANCE AB Adoptive immunotherapy using TCR-engineered PBLs against melanocyte differentiation Ags mediates objective tumor regression but is associated with on-target toxicity. To avoid toxicity to normal tissues, we targeted cancer testis Ag (CTA) MAGE-A3, which is widely expressed in a range of epithelial malignancies but is not expressed in most normal tissues. To generate high-avidity TCRs against MAGE-A3, we employed a transgenic mouse model that expresses the human HLA-A*0201 molecule. Mice were immunized with two HLA-A*0201-restricted peptides of MAGE-A3: 112-120 (KVAELVHFL) or MAGE-A3: 271-279 (FLWGPRALV), and T cell clones were generated. MAGE-A3-specific TCR alpha-and beta-chains were isolated and cloned into a retroviral vector. Expression of both TCRs in human PBLs demonstrated Ag-specific reactivity against a range of melanoma and nonmelanoma tumor cells. The TCR against MAGE-A3: 112-120 was selected for further development based on superior reactivity against tumor target cells. Interestingly, peptide epitopes from MAGE-A3 and MAGE-A12 (and to a lesser extent, peptides from MAGE-A2 and MAGE-A6) were recognized by PBLs engineered to express this TCR. To further improve TCR function, single amino acid variants of the CDR3 alpha-chain were generated. Substitution of alanine to threonine at position 118 of the alpha-chain in the CDR3 region of the TCR improved its functional avidity in CD4 and CD8 cells. On the basis of these results, a clinical trial is planned in which patients bearing a variety of tumor histologies will receive autologous PBLs that have been transduced with this optimized anti-MAGE-A3 TCR. The Journal of Immunology, 2011, 186: 685-696. C1 [Chinnasamy, Nachimuthu; Wargo, Jennifer A.; Yu, Zhiya; Rao, Mahadev; Frankel, Timothy L.; Riley, John P.; Hong, Jenny J.; Parkhurst, Maria R.; Feldman, Steven A.; Schrump, David S.; Restifo, Nicholas P.; Robbins, Paul F.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, NIH, Bldg 10,CRC Room 3-5940,10 Ctr Dr, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 63 TC 71 Z9 76 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2011 VL 186 IS 2 BP 685 EP 696 DI 10.4049/jimmunol.1001775 PG 12 WC Immunology SC Immunology GA 702TB UT WOS:000285917700008 PM 21149604 ER PT J AU Subleski, JJ Hall, VL Wolfe, TB Scarzello, AJ Weiss, JM Chan, T Hodge, DL Back, TC Ortaldo, JR Wiltrout, RH AF Subleski, Jeff J. Hall, Veronica L. Wolfe, Thomas B. Scarzello, Anthony J. Weiss, Jonathan M. Chan, Tim Hodge, Deborah L. Back, Timothy C. Ortaldo, John R. Wiltrout, Robert H. TI TCR-Dependent and -Independent Activation Underlie Liver-Specific Regulation of NKT Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID KILLER T-CELLS; NATURAL-KILLER; CYTOKINE PRODUCTION; EXTRATHYMIC DEVELOPMENT; ANTIGEN PRESENTATION; IMMUNE REGULATION; ANERGY INDUCTION; DENDRITIC CELLS; VIRUS-INFECTION; SELECTIVE LOSS AB The fate of invariant NKT (iNKT) cells following activation remains controversial and unclear. We systemically examined how iNKT cells are regulated following TCR-dependent and -independent activation with alpha-galactosylceramide (alpha GC) or IL-18 plus IL-12, respectively. Our studies reveal activation by alpha GC or IL-18 plus IL-12 induced transient depletion of iNKT cells exclusively in the liver that was independent of caspase 3-mediated apoptosis. The loss of iNKT cells was followed by repopulation and expansion of phenotypically distinct cells via different mechanisms. Liver iNKT cell expansion following alpha GC, but not IL-18 plus IL-12, treatment required an intact spleen and IFN-gamma. Additionally, IL-18 plus IL-12 induced a more prolonged expansion of liver iNKT cells compared with alpha GC. iNKT cells that repopulate the liver following alpha GC had higher levels of suppressive receptors PD-1 and Lag3, whereas those that repopulate the liver following IL-18 plus IL-12 had increased levels of TCR and ICOS. In contrast to acute treatment that caused a transient loss of iNKT cells, chronic alpha GC or IL-18 plus IL-12 treatment caused long-term systemic loss requiring an intact thymus for repopulation of the liver. This report reveals a previously undefined role for the liver in the depletion of activated iNKT cells. Additionally, TCR-dependent and -independent activation differentially regulate iNKT cell distribution and phenotype. These results provide new insights for understanding how iNKT cells are systemically regulated following activation. The Journal of Immunology, 2011, 186: 838-847. C1 [Wiltrout, Robert H.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Wiltrout, RH (reprint author), NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM wiltrour@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 55 TC 10 Z9 10 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2011 VL 186 IS 2 BP 838 EP 847 DI 10.4049/jimmunol.1001735 PG 10 WC Immunology SC Immunology GA 702TB UT WOS:000285917700023 PM 21148802 ER PT J AU Gabryszewski, SJ Bachar, O Dyer, KD Percopo, CM Killoran, KE Domachowske, JB Rosenberg, HF AF Gabryszewski, Stanislaw J. Bachar, Ofir Dyer, Kimberly D. Percopo, Caroline M. Killoran, Kristin E. Domachowske, Joseph B. Rosenberg, Helene F. TI Lactobacillus-Mediated Priming of the Respiratory Mucosa Protects against Lethal Pneumovirus Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYNCYTIAL VIRUS-INFECTION; MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA; TOLL-LIKE RECEPTOR-4; PNEUMONIA VIRUS; IN-VIVO; CHEMOKINE RECEPTOR; IMMUNE-RESPONSE; DENDRITIC CELLS; BOWEL-DISEASE; HOST-DEFENSE AB The inflammatory response to respiratory virus infection can be complex and refractory to standard therapy. Lactobacilli, when targeted to the respiratory epithelium, are highly effective at suppressing virus-induced inflammation and protecting against lethal disease. Specifically, wild-type mice primed via intranasal inoculation with live or heat-inactivated Lactobacillus plantarum or Lactobacillus reuteri were completely protected against lethal infection with the virulent rodent pathogen, pneumonia virus of mice; significant protection (60% survival) persisted for at least 13 wk. Protection was not unique to Lactobacillus species, and it was also observed in response to priming with nonpathogenic Gram-positive Listeria innocua. Priming with live lactobacilli resulted in diminished granulocyte recruitment, diminished expression of multiple proinflammatory cytokines (CXCL10, CXCL1, CCL2, and TNF), and reduced virus recovery, although we have demonstrated clearly that absolute virus titer does not predict clinical outcome. Lactobacillus priming also resulted in prolonged survival and protection against the lethal sequelae of pneumonia virus of mice infection in MyD88 gene-deleted (MyD88(-/-)) mice, suggesting that the protective mechanisms may be TLR-independent. Most intriguing, virus recovery and cytokine expression patterns in Lactobacillus-primed MyD88(-/-) mice were indistinguishable from those observed in control-primed MyD88(-/-) counterparts. In summary, we have identified and characterized an effective Lactobacillus-mediated innate immune shield, which may ultimately serve as critical and long-term protection against infection in the absence of specific antiviral vaccines. The Journal of Immunology, 2011, 186: 1151-1161. C1 [Gabryszewski, Stanislaw J.; Bachar, Ofir; Dyer, Kimberly D.; Percopo, Caroline M.; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Eosinophil Biol Sect, Bethesda, MD 20892 USA. [Killoran, Kristin E.] NIAID, Lymphocyte Biol Unit, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Domachowske, Joseph B.] SUNY Syracuse, Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, Eosinophil Biol Sect, Bldg 10,Room 11C215,MSC 1883,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases Division of Intramural Research Project [Z01-AI000943]; Children's Miracle Network of Central New York FX This work was supported by funds from the National Institute of Allergy and Infectious Diseases Division of Intramural Research Project Z01-AI000943 (to H. F. R.) and the Children's Miracle Network of Central New York (to J.B.D.). NR 59 TC 36 Z9 39 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2011 VL 186 IS 2 BP 1151 EP 1161 DI 10.4049/jimmunol.1001751 PG 11 WC Immunology SC Immunology GA 702TB UT WOS:000285917700054 PM 21169550 ER PT J AU Yu, M Lam, J Rada, B Leto, TL Levine, SJ AF Yu, Man Lam, Jonathan Rada, Balazs Leto, Thomas L. Levine, Stewart J. TI Double-Stranded RNA Induces Shedding of the 34-kDa Soluble TNFR1 from Human Airway Epithelial Cells via TLR3-TRIF-RIP1-Dependent Signaling: Roles for Dual Oxidase 2-and Caspase-Dependent Pathways SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; FACTOR-BINDING-PROTEIN; IMPROVES ENDOTHELIAL DYSFUNCTION; HYDROGEN-PEROXIDE PRODUCTION; EXOSOME-LIKE VESICLES; RHEUMATOID-ARTHRITIS; MOLECULAR-MECHANISMS; ANTIVIRAL RESPONSE; IMMUNE-RESPONSES AB TNF, an important mediator of inflammatory and innate immune responses, can be regulated by binding to soluble TNF receptors. The 55-kDa type 1 TNFR (TNFR1), the key receptor for TNF signaling, is released to the extracellular space by two mechanisms, the inducible cleavage and shedding of 34-kDa soluble TNFR1 (sTNFR1) ectodomains and the constitutive release of full-length 55-kDa TNFR1 within exosome-like vesicles. The aim of this study was to identify and characterize TLR signaling pathways that mediate TNFR1 release to the extracellular space. To our knowledge, we demonstrate for the first time that polyinosinic-polycytidylic acid [poly (I:C)], a synthetic dsRNA analogue that signals via TLR3, induces sTNFR1 shedding from human airway epithelial (NCI-H292) cells, whereas ligands for other microbial pattern recognition receptors, including TLR4, TLR7, and nucleotide-binding oligomerization domain containing 2, do not. Furthermore, poly (I:C) selectively induces the cleavage of 34-kDa sTNFR1 ectodomains but does not enhance the release of full-length 55-kDa TNFR1 within exosome-like vesicles. RNA interference experiments demonstrated that poly (I:C)-induced sTNFR1 shedding is mediated via activation of TLR3-TRIF-RIP1 signaling, with subsequent activation of two downstream pathways. One pathway involves the dual oxidase 2-mediated generation of reactive oxygen species, and the other pathway is via the caspase-mediated activation of apoptosis. Thus, the ability of dsRNA to induce the cleavage and shedding of the 34-kDa sTNFR1 from human bronchial epithelial cells represents a novel mechanism by which innate immune responses to viral infections are modulated. The Journal of Immunology, 2011, 186: 1180-1188. C1 [Yu, Man; Lam, Jonathan; Levine, Stewart J.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Rada, Balazs; Leto, Thomas L.] NIAID, Host Def Lab, NIH, Rockville, MD 20852 USA. RP Levine, SJ (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, 10 Ctr Dr,Room 6D03, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health. NR 69 TC 30 Z9 31 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2011 VL 186 IS 2 BP 1180 EP 1188 DI 10.4049/jimmunol.1001499 PG 9 WC Immunology SC Immunology GA 702TB UT WOS:000285917700057 PM 21148036 ER PT J AU Ishmael, FT Fang, X Houser, KR Pearce, K Abdelmohsen, K Zhan, M Gorospe, M Stellato, C AF Ishmael, Faoud T. Fang, Xi Houser, Kenneth R. Pearce, Kenneth Abdelmohsen, Kotb Zhan, Ming Gorospe, Myriam Stellato, Cristiana TI The Human Glucocorticoid Receptor as an RNA-Binding Protein: Global Analysis of Glucocorticoid Receptor-Associated Transcripts and Identification of a Target RNA Motif SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RICH SIGNATURE MOTIF; MESSENGER-RNA; GENE-EXPRESSION; POSTTRANSCRIPTIONAL REGULATION; T-CELLS; EOSINOPHILIC ESOPHAGITIS; NUCLEOLIN; STABILITY; NF90; HUR AB Posttranscriptional regulation is emerging as a key factor in glucocorticoid (GC)-mediated gene regulation. We investigated the role of the human GC receptor (GR) as an RNA-binding protein and its effect on mRNA turnover in human airway epithelial cells. Cell treatment with the potent GC budesonide accelerated the decay of CCL2 mRNA (t(1/2) = 8 +/- 1 min versus 62 +/- 17 min in DMSO-treated cells) and CCL7 mRNA (t(1/2) = 15 +/- 4 min versus 114 +/- 37 min), but not that of CCL5 mRNA (t(1/2) = 231 +/- 8 min versus 266 +/- 5 min) in the BEAS-2B cell line. This effect was inhibited by preincubation with an anti-GR Ab, indicating that GR itself plays a role in the turnover of these transcripts. Coimmunoprecipitation and biotin pulldown experiments showed that GR associates with CCL2 and CCL7 mRNAs, but not CCL5 mRNA. These methods confirmed CCL2 mRNA targeting by GR in human primary airway epithelial cells. Association of the GR was localized to the 59 untranslated region of CCL2 mRNA and further mapped to nt 44-60. The collection of transcripts associated with GR, identified by immunoprecipitation of GR-mRNA complexes followed by microarray analysis, revealed 479 transcripts that associated with GR. Computational analysis of the primary sequence and secondary structures of these transcripts yielded a GC-rich motif, which was shown to bind to GR in vitro. This motif was used to predict binding of GR to an additional 7889 transcripts. These results indicate that cytoplasmic GR interacts with a subset of mRNA through specific sequences and can regulate turnover rates, suggesting a novel posttranscriptional role for GR as an RNA-binding protein. The Journal of Immunology, 2011, 186: 1189-1198. C1 [Ishmael, Faoud T.; Fang, Xi; Stellato, Cristiana] Johns Hopkins Asthma & Allergy Ctr, Div Clin Immunol & Allergy, Baltimore, MD 21224 USA. [Ishmael, Faoud T.; Houser, Kenneth R.] Penn State Univ, Coll Med, Dept Med, Hershey, PA 17033 USA. [Ishmael, Faoud T.; Houser, Kenneth R.] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. [Pearce, Kenneth] GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA. [Abdelmohsen, Kotb; Zhan, Ming; Gorospe, Myriam] NIA, NIH, Baltimore, MD 21224 USA. RP Stellato, C (reprint author), Johns Hopkins Asthma & Allergy Ctr, Div Clin Immunol & Allergy, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM fishmael@hmc.psu.edu; stellato@jhmi.edu RI Stellato, Cristiana/P-3001-2015; OI Stellato, Cristiana/0000-0002-1294-8355; abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institutes of Health [R01 AI060990-01A1]; American Academy of Allergy, Asthma, and Immunology/Glaxo-Smith Kline; National Institute on Aging, National Institutes of Health FX This work was supported by National Institutes of Health Grant R01 AI060990-01A1 (to C. S.) and by the American Academy of Allergy, Asthma, and Immunology/Glaxo-Smith Kline Fellows Career Development Award (to F. T. I.). K. A., M.Z., and M. G. are supported by the National Institute on Aging Intramural Research Program, National Institutes of Health. NR 55 TC 21 Z9 21 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2011 VL 186 IS 2 BP 1189 EP 1198 DI 10.4049/jimmunol.1001794 PG 10 WC Immunology SC Immunology GA 702TB UT WOS:000285917700058 PM 21148795 ER PT J AU Ghedin, E Laplante, J DePasse, J Wentworth, DE Santos, RP Lepow, ML Porter, J Stellrecht, K Lin, XD Operario, D Griesemer, S Fitch, A Halpin, RA Stockwell, TB Spiro, DJ Holmes, EC St George, K AF Ghedin, Elodie Laplante, Jennifer DePasse, Jay Wentworth, David E. Santos, Roberto P. Lepow, Martha L. Porter, Joanne Stellrecht, Kathleen Lin, Xudong Operario, Darwin Griesemer, Sara Fitch, Adam Halpin, Rebecca A. Stockwell, Timothy B. Spiro, David J. Holmes, Edward C. St George, Kirsten TI Deep Sequencing Reveals Mixed Infection with 2009 Pandemic Influenza A (H1N1) Virus Strains and the Emergence of Oseltamivir Resistance SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNOCOMPROMISED PATIENT; MOLECULAR MARKERS; GENOME ANALYSIS; PROPHYLAXIS; EVOLUTION; THERAPY AB Mixed infections with seasonal influenza A virus strains are a common occurrence and an important source of genetic diversity. Prolonged viral shedding, as observed in immunocompromised individuals, can lead to mutational accumulation over extended periods. Recently, drug resistance was reported in immunosuppressed patients infected with the 2009 pandemic influenza A (H1N1) virus within a few days after oseltamivir treatment was initiated. To better understand the evolution and emergence of drug resistance in these circumstances, we used a deep sequencing approach to survey the viral population from an immunosuppressed patient infected with H1N1/2009 influenza and treated with neuraminidase inhibitors. This patient harbored 3 genetic variants from 2 phylogenetically distinct viral clades of pandemic H1N1/2009, strongly suggestive of mixed infection. Strikingly, one of these variants also developed drug resistance de novo in response to oseltamivir treatment. Immunocompromised individuals may, therefore, constitute an important source of genetic and phenotypic diversity, both through mixed infection and de novo mutation. C1 [Ghedin, Elodie; DePasse, Jay; Fitch, Adam] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Dept Computat & Syst Biol, Pittsburgh, PA 15261 USA. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Laplante, Jennifer; Wentworth, David E.; Lin, Xudong; Operario, Darwin; Griesemer, Sara; St George, Kirsten] SUNY Albany, Wadsworth Ctr, New York State Dept Hlth, Albany, NY 12222 USA. [Wentworth, David E.] SUNY Albany, Sch Publ Hlth, Dept Biomed Sci, Albany, NY 12222 USA. [Santos, Roberto P.; Lepow, Martha L.; Porter, Joanne; Stellrecht, Kathleen] Albany Med Ctr, Albany, NY USA. [Ghedin, Elodie; Halpin, Rebecca A.; Stockwell, Timothy B.; Spiro, David J.] J Craig Venter Inst, Rockville, MD USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ghedin, E (reprint author), Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Dept Computat & Syst Biol, 3501 5th Ave,BST3 Rm 9043B, Pittsburgh, PA 15261 USA. EM elg21@pitt.edu OI Wentworth, David/0000-0002-5190-980X; Holmes, Edward/0000-0001-9596-3552 FU National Institutes of Health [HHSN272200900007, R01 GM080533-03] FX This work was supported by National Institutes of Health (HHSN272200900007 to E.G., E.C.H., R.A.H., T.B.S., D.J.S., and R01 GM080533-03 to E.C.H.). NR 37 TC 56 Z9 59 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2011 VL 203 IS 2 BP 168 EP 174 DI 10.1093/infdis/jiq040 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 705XB UT WOS:000286172900006 PM 21288815 ER PT J AU Tanaka, NK Dye, L Stopfer, M AF Tanaka, Nobuaki K. Dye, Louis Stopfer, Mark TI Dual-labeling method for electron microscopy to characterize synaptic connectivity using genetically encoded fluorescent reporters in Drosophila SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Olfactory circuit; Olfaction; Synapse; GFP; DAB; Antennal lobe ID ANTENNAL LOBE GLOMERULI; IDENTIFIED NEURON TYPES; PERIPLANETA-AMERICANA; OLFACTORY SYSTEM; MAP; REPRESENTATION; INTERNEURONS; COCKROACH; CIRCUITS; BRAIN AB Light and electron microscopy (LM and EM) both offer important advantages for characterizing neuronal circuitry in intact brains: LM can reveal the general patterns neurons trace between brain areas, and EM can confirm synaptic connections between identified neurons within a small area. In a few species, genetic labeling with fluorescent proteins has been used with LM to visualize many kinds of neurons and to analyze their morphologies and projection patterns. However, combining these large-scale patterns with the fine detail available in EM analysis has been a technical challenge. To analyze the synaptic connectivity of neurons expressing fluorescent markers with EM, we developed a dual-labeling method for use with pre-embedded brains. In Drosophila expressing genetic labels and also injected with markers we visualized synaptic connections among two populations of neurons in the AL, one of which has been shown to mediate a specific function, odor evoked neural oscillation. Published by Elsevier B.V. C1 [Tanaka, Nobuaki K.; Dye, Louis; Stopfer, Mark] NICHHD, NIH, Bethesda, MD 20892 USA. RP Stopfer, M (reprint author), NICHHD, NIH, 35 Lincoln Dr,Msc 3715, Bethesda, MD 20892 USA. EM nktanaka@cp.kyoto-u.ac.jp; dyel@mail.nih.gov; stopferm@mail.nih.gov FU JSPS; National Institutes of Health; National Institute of Child Health and Human Development FX We are grateful to Ian Meinertzhagen and his lab members for technical advice, Joby Joseph for technical suggestions, Yuko Shimada, Emiko Suzuki, Shuying Gao, Chun-Yuan Ting, Friedrich-Wilhelm Schurmann, and Sakiko Shiga for helpful discussions, and Kei Ito for supplying fly strains. N.K.T. was supported by the JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH and the JST PRESTO program. This work was funded by art intramural grant from the National Institutes of Health, the National Institute of Child Health and Human Development to M.S. NR 20 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JAN 15 PY 2011 VL 194 IS 2 BP 312 EP 315 DI 10.1016/j.jneumeth.2010.10.020 PG 4 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 755IQ UT WOS:000289923100015 PM 21074556 ER PT J AU Wawer, MJ Tobian, AAR Kigozi, G Kong, XR Gravitt, PE Serwadda, D Nalugoda, F Makumbi, F Ssempiija, V Sewankambo, N Watya, S Eaton, KP Oliver, AE Chen, MZ Reynolds, SJ Quinn, TC Gray, RH AF Wawer, Maria J. Tobian, Aaron A. R. Kigozi, Godfrey Kong, Xiangrong Gravitt, Patti E. Serwadda, David Nalugoda, Fred Makumbi, Frederick Ssempiija, Victor Sewankambo, Nelson Watya, Stephen Eaton, Kevin P. Oliver, Amy E. Chen, Michael Z. Reynolds, Steven J. Quinn, Thomas C. Gray, Ronald H. TI Effect of circumcision of HIV-negative men on transmission of human papillomavirus to HIV-negative women: a randomised trial in Rakai, Uganda SO LANCET LA English DT Article ID RISK HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; FEMALE PARTNERS; YOUNG MEN; PREVENTION; INFECTION; METAANALYSIS; PREVALENCE; DNA; ACQUISITION AB Background Randomised trials show that male circumcision reduces the prevalence and incidence of high-risk human papillomavirus (HPV) infection in men. We assessed the efficacy of male circumcision to reduce prevalence and incidence of high-risk HPV in female partners of circumcised men. Methods In two parallel but independent randomised controlled trials of male circumcision, we enrolled HIV-negative men and their female partners between 2003 and 2006, in Rakai, Uganda. With a computer-generated random number sequence in blocks of 20, men were assigned to undergo circumcision immediately (intervention) or after 24 months (control). HIV-uninfected female partners (648 of men from the intervention group, and 597 of men in the control group) were simultaneously enrolled and provided interview information and self-collected vaginal swabs at baseline, 12 months, and 24 months. Vaginal swabs were tested for high-risk HPV by Roche HPV Linear Array. Female HPV infection was a secondary endpoint of the trials, assessed as the prevalence of high-risk HPV infection 24 months after intervention and the incidence of new infections during the trial. Analysis was by intention-to-treat. An as-treated analysis was also done to account for study-group crossovers. The trials were registered, numbers NCT00425984 and NCT00124878. Findings During the trial, 18 men in the control group underwent circumcision elsewhere, and 31 in the intervention group did not undergo circumcision. At 24-month follow-up, data were available for 544 women in the intervention group and 488 in the control group; 151 (27.8%) women in the intervention group and 189 (38.7%) in the control group had high-risk HPV infection (prevalence risk ratio=0.72, 95% CI 0.60-0.85, p=0.001). During the trial, incidence of high-risk HPV infection in women was lower in the intervention group than in the control group (20.7 infections vs 26.9 infections per 100 person-years; incidence rate ratio=0.77, 0.63-0.93, p=0.008). Interpretation Our findings indicate that male circumcision should now be accepted as an efficacious intervention for reducing the prevalence and incidence of HPV infections in female partners. However, protection is only partial; the promotion of safe sex practices is also important. C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21287 USA. [Wawer, Maria J.; Tobian, Aaron A. R.; Kong, Xiangrong; Chen, Michael Z.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD 21287 USA. [Eaton, Kevin P.; Oliver, Amy E.; Reynolds, Steven J.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Kong, Xiangrong] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21287 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21287 USA. [Wawer, Maria J.; Kigozi, Godfrey; Serwadda, David; Nalugoda, Fred; Makumbi, Frederick; Ssempiija, Victor; Sewankambo, Nelson; Gray, Ronald H.] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David; Nalugoda, Fred; Makumbi, Frederick] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Sewankambo, Nelson] Makerere Univ, Sch Allied Med Sci, Kampala, Uganda. [Sewankambo, Nelson] Makerere Univ, Dept Med, Kampala, Uganda. [Watya, Stephen] Makerere Univ, Dept Urol, Kampala, Uganda. [Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 667,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu OI Sewankambo, Nelson/0000-0001-9362-053X FU The Bill & Melinda Gates Foundation [22006.02]; National Institutes of Health [U1AI51171]; Fogarty International Center [5D43TW001508, 2D43TW00001049-AITRP]; National Institute of Allergy and Infectious Diseases (NIAID), NIH [U01-A1-068613, 3U01-AI075115-03S1]; NIAID; Johns Hopkins University FX The Bill & Melinda Gates Foundation, National Institutes of Health, and Fogarty International Center.; The study was funded by the Bill & Melinda Gates Foundation (22006.02) and the National Institutes of Health (U1AI51171). The Fogarty International Center (5D43TW001508 and 2D43TW00001049-AITRP) contributed to training. National Institute of Allergy and Infectious Diseases (NIAID), NIH grants (U01-A1-068613 and 3U01-AI075115-03S1) and NIAID Intramural Program provided laboratory support. AART was supported by the Johns Hopkins University Clinician Scientist Award. We thank the study participants and the Rakai Community Advisory Board whose commitment and cooperation made this study possible. We thank Edward M'bidde, Director, Uganda Virus Research Institute, for his continuing support, and Renee Ridzon of the Bill & Melinda Gates Foundation and Melanie Bacon of National Institutes of Health for their assistance with the trial. NR 30 TC 79 Z9 83 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JAN 15 PY 2011 VL 377 IS 9761 BP 209 EP 218 DI 10.1016/S0140-6736(10)61967-8 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 712WG UT WOS:000286696400028 PM 21216000 ER PT J AU Weng, JC Chuang, KH Goloshevsky, A Dodd, SJ Sharer, K AF Weng, Jun-Cheng Chuang, Kai-Hsiang Goloshevsky, Artem Dodd, Stephen J. Sharer, Kathryn TI Mapping plasticity in the forepaw digit barrel subfield of rat brains using functional MRI SO NEUROIMAGE LA English DT Article DE Functional MRI; High resolution; Forepaw digit barrel subfield; Electrical stimulation ID PRIMARY SOMATOSENSORY CORTEX; HIGH MAGNETIC-FIELDS; ECHO BOLD FMRI; SPIN-ECHO; LAYER-IV; RECEPTIVE-FIELDS; INTRINSIC SIGNAL; CEREBRAL-CORTEX; GRADIENT-ECHO; VIBRISSAL INFORMATION AB The topographic organization of the forepaw barrel subfield in layer IV of rat primary somatosensory cortex (Si) is a good model for studying neural function and plasticity. The goal of this study was to test the feasibility of functional MRI (fMRI) to map the forepaw digit representations in the Si of the rat and its plasticity after digit amputation. Three dimensional echo-planar imaging with 300 micron isotropic resolution at 11.7T was used to achieve high signal-to-noise ratios and laminar layer resolution. By alternating electrical stimulation of the 2nd (D2) and 4th (D4) digits, functional activation in layer IV of the barrel subfields could be distinguished using a differential analysis. Furthermore, 2 and a half months after the amputation of the 3rd digit in baby rats, the overlapping area between D2 and D4 representations was increased. This indicates that the forepaw barrel subfield previously associated with the ablated digit is now associated with the representation of nearby digits, which is consistent with studies using electrophysiology and cytochrome oxidase staining. (C) 2010 Elsevier Inc. All rights reserved. C1 [Chuang, Kai-Hsiang] ASTAR, Singapore Bioimaging Consortium, Lab Mol Imaging, Singapore 138667, Singapore. [Weng, Jun-Cheng; Chuang, Kai-Hsiang; Goloshevsky, Artem; Dodd, Stephen J.; Sharer, Kathryn] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Weng, Jun-Cheng] Chung Shan Med Univ, Sch Med Imaging & Radiol Sci, Taichung, Taiwan. [Weng, Jun-Cheng] Chung Shan Med Univ Hosp, Dept Med Imaging, Taichung, Taiwan. RP Chuang, KH (reprint author), ASTAR, Singapore Bioimaging Consortium, Lab Mol Imaging, 11 Biopolis Way,Helios 02-02, Singapore 138667, Singapore. EM chuang_kai_hsiang@sbic.a-star.edu.sg OI Chuang, Kai-Hsiang/0000-0002-8356-0657 FU NINDS, NIH, USA; National Science Council, Taipei, Taiwan [NSC99-2314-B-040-001] FX This study was supported in part by the intramural research program of the NINDS, NIH, USA and research program NSC99-2314-B-040-001, National Science Council, Taipei, Taiwan. The authors would like to thank Dr. Alan Koretsky and Dr. Afonso Silva for helpful discussions and Nadia Bouraoud for her assistance in the animal preparation. NR 62 TC 5 Z9 5 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2011 VL 54 IS 2 BP 1122 EP 1129 DI 10.1016/j.neuroimage.2010.08.046 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 697AW UT WOS:000285486000037 PM 20804851 ER PT J AU Yuan, ZJ Luo, ZC Volkow, ND Pan, YT Du, CW AF Yuan, Zhijia Luo, Zhongchi Volkow, Nora D. Pan, Yingtian Du, Congwu TI Imaging separation of neuronal from vascular effects of cocaine on rat cortical brain in vivo SO NEUROIMAGE LA English DT Article DE Cocaine; Cerebral blood flow; Calcium [Ca]; Optical imaging; Drug abuse and addiction; fMRI ID CEREBRAL-BLOOD-FLOW; OPTICAL COHERENCE TOMOGRAPHY; NEAR-INFRARED SPECTROSCOPY; LASER SPECKLE; SENSORY STIMULATION; FOCAL CHANGES; OXYGENATION; CORTEX; MICROVASCULATURE; HEMODYNAMICS AB MRI techniques to study brain function assume coupling between neuronal activity, metabolism and flow. However, recent evidence of physiological uncoupling between neuronal and cerebrovascular events highlights the need for methods to simultaneously measure these three properties. We report a multimodality optical approach that integrates dual-wavelength laser speckle imaging (measures changes in blood flow, blood volume and hemoglobin oxygenation), digital-frequency-ramping optical coherence tomography (images quantitative 3D vascular network) and Rhod(2) fluorescence (images intracellular calcium for measure of neuronal activity) at high spatiotemporal resolutions (30 mu m, 10 Hz) and over a large field of view (3 x 5 mm(2)). We apply it to assess cocaine's effects in rat cortical brain and show an immediate decrease (3.5 +/- 0.9 min, phase 1) in the oxygen content of hemoglobin and the cerebral blood flow followed by an overshoot (7.1 +/- 0.2 min, phase 2) lasting over 20 min whereas Ca(2+) increased immediately (peaked at t = 4.1 +/- 0.4 min) and remained elevated. This enabled us to identify a delay (2.9 +/- 0.5 min) between peak neuronal and vascular responses in phase 2. The ability of this multimodality optical approach for simultaneous imaging at high spatiotemporal resolutions permits us to distinguish the vascular versus cellular changes of the brain, thus complimenting other neuroimaging modalities for brain functional studies (e. g., PET, fMRI). (C) 2010 Elsevier Inc. All rights reserved. C1 [Yuan, Zhijia; Luo, Zhongchi; Pan, Yingtian] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Volkow, Nora D.] Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD 20892 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. [Du, Congwu] SUNY Stony Brook, Dept Anesthesiol, Stony Brook, NY 11794 USA. [Du, Congwu] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. RP Pan, YT (reprint author), SUNY Stony Brook, Dept Biomed Engn, Bioengineer Bldg,Rm G06, Stony Brook, NY 11794 USA. EM Yingtian.Pan@sunysb.edu; congwu@bnl.gov RI yuan, zhijia/F-4314-2011 FU National Institutes of Health (NIH) [K25-DA021200, 2R01-DK059265, 1RC1DA028534]; Department of Energy (DOE) [LDRD 10-023] FX The authors thank Rubing Pan for cryosectioning and fluorescence microscope imaging and analysis of the rat brain specimens. The work was supported in part by National Institutes of Health (NIH) grants K25-DA021200 (CD), 2R01-DK059265 (YP) and 1RC1DA028534 (CD and YP), and by a Department of Energy (DOE) grant LDRD 10-023 (CD). NR 47 TC 18 Z9 18 U1 0 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 JAN 15 PY 2011 VL 54 IS 2 BP 1130 EP 1139 DI 10.1016/j.neuroimage.2010.08.045 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 697AW UT WOS:000285486000038 PM 20804849 ER PT J AU Walker, L Chang, LC Koay, CG Sharma, N Cohen, L Verma, R Pierpaoli, C AF Walker, Lindsay Chang, Lin-Ching Koay, Cheng Guan Sharma, Nik Cohen, Leonardo Verma, Ragini Pierpaoli, Carlo TI Effects of physiological noise in population analysis of diffusion tensor MRI data SO NEUROIMAGE LA English DT Article ID INDUCED B-0 FLUCTUATIONS; HUMAN BRAIN; IMAGES; DISTORTION; UNCERTAINTY; ORIENTATION; ACQUISITION; FRAMEWORK; MOTION; ECHO AB The goal of this study is to characterize the potential effect of artifacts originating from physiological noise on statistical analysis of diffusion tensor MRI (DTI) data in a population. DTI derived quantities including mean diffusivity (Trace(D)), fractional anisotropy (FA), and principal eigenvector (epsilon(1)) are computed in the brain of 40 healthy subjects from tensors estimated using two different methods: conventional nonlinear least-squares, and robust fitting (RESTORE). RESTORE identifies artifactual data points as outliers and excludes them on a voxel-by-voxel basis. We found that outlier data points are localized in specific spatial clusters in the population, indicating a consistency in brain regions affected across subjects. In brain parenchyma RESTORE slightly reduces inter-subject variance of FA and Trace(D). The dominant effect of artifacts, however, is bias. Voxel-wise analysis indicates that inclusion of outlier data points results in clusters of under- and over-estimation of FA, while Trace(D) is always over-estimated. Removing outliers affects epsilon(1) mostly in low anisotropy regions. It was found that brain regions known to be affected by cardiac pulsation - cerebellum and genu of the corpus callosum, as well as regions not previously reported, splenium of the corpus callosum-show significant effects in the population analysis. It is generally assumed that statistical properties of DTI data are homogenous across the brain. This assumption does not appear to be valid based on these results. The use of RESTORE can lead to a more accurate evaluation of a population, and help reduce spurious findings that may occur due to artifacts in DTI data. Published by Elsevier Inc. C1 [Walker, Lindsay; Chang, Lin-Ching; Koay, Cheng Guan; Pierpaoli, Carlo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD USA. [Chang, Lin-Ching] Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. [Sharma, Nik; Cohen, Leonardo] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Verma, Ragini] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Walker, L (reprint author), NICHD, Sect Tissue Biophys & Biomimet, NIH, Bldg 13,Room 3W16,13 South Dr, Bethesda, MD 20892 USA. EM walkerlin@mail.nih.gov RI Pierpaoli, Carlo/E-1672-2011; Walker, Lindsay/A-7122-2012; OI Sharma, Nikhil/0000-0001-8903-2938 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke as part of the NIH; NIH Neuroscience Blueprint; NICHD FX We would like to thank Gary Hui Zhang for use of and help with the software DTI-TK (http://www.nitrc.org/projects/dtitk). This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NICHD Intramural Program, the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke as part of the NIH MRI Study of Normal Pediatric Brain Development with supplemental funding from the NIH Neuroscience Blueprint. NR 39 TC 38 Z9 38 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2011 VL 54 IS 2 BP 1168 EP 1177 DI 10.1016/j.neuroimage.2010.08.048 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 697AW UT WOS:000285486000042 PM 20804850 ER PT J AU Moll, J Zahn, R de Oliveira-Souza, R Bramati, IE Krueger, F Tura, B Cavanagh, AL Grafman, J AF Moll, Jorge Zahn, Roland de Oliveira-Souza, Ricardo Bramati, Ivanei E. Krueger, Frank Tura, Bernardo Cavanagh, Alyson L. Grafman, Jordan TI Impairment of prosocial sentiments is associated with frontopolar and septal damage in frontotemporal dementia SO NEUROIMAGE LA English DT Article DE Frontopolar cortex; Prefrontal cortex; Subgenual; Septal area; Amygdala; Orbitofrontal cortex; Moral sentiment; Emotion ID ECONOMIC DECISION-MAKING; HUMAN PREFRONTAL CORTEX; NEURAL BASIS; LOBAR DEGENERATION; MORAL EMOTIONS; BEHAVIORAL-DISORDERS; FUNCTIONAL MRI; ULTIMATUM GAME; FMRI; COGNITION AB Poets and philosophers have long acknowledged moral sentiments as key motivators of human social behavior. Prosocial sentiments, which include guilt, pity and embarrassment, enable us to care about others and to be concerned about our mistakes. Functional imaging studies have implicated frontopolar, ventromedial frontal and basal forebrain regions in the experience of prosocial sentiments. Patients with lesions of the frontopolar and ventromedial frontal areas were observed to behave inappropriately and less prosocially, which could be attributed to a generalized emotional blunting. Direct experimental evidence for brain regions distinctively associated with moral sentiment impairments is lacking, however. We investigated this issue in patients with the behavioral variant of frontotemporal dementia, a disorder in which early and selective impairments of social conduct are consistently observed. Using a novel moral sentiment task, we show that the degree of impairment of prosocial sentiments is associated with the degree of damage to frontopolar cortex and septal area, as assessed with 18-Fluoro-Deoxy-Glucose-Positron Emission Tomography, an established measure of neurodegenerative damage. This effect was dissociable from impairment of other-critical feelings (anger and disgust), which was in turn associated with dorsomedial prefrontal and amygdala dysfunction. Our findings suggest a critical role of the frontopolar cortex and septal region in enabling prosocial sentiments, a fundamental component of moral conscience. Published by Elsevier Inc. C1 [Moll, Jorge; Zahn, Roland; Krueger, Frank; Cavanagh, Alyson L.; Grafman, Jordan] NINDS, NIH, Cognit Neurosci Sect, Bethesda, MD 20892 USA. [Moll, Jorge; Zahn, Roland; de Oliveira-Souza, Ricardo; Bramati, Ivanei E.; Tura, Bernardo] DOr Inst Res & Educ IDOR, Cognit & Behav Neurosci Unit, Rio De Janeiro, Brazil. [Zahn, Roland] Univ Manchester, Sch Psychol Sci, Neurosci & Aphasia Res Unit NARU, Manchester M13 9PL, Lancs, England. [de Oliveira-Souza, Ricardo] Gaffree & Guinle Univ Hosp, Rio De Janeiro, Brazil. [Krueger, Frank] George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. RP Grafman, J (reprint author), NINDS, NIH, Cognit Neurosci Sect, 10 Ctr Dr,Room 7D43, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov RI Zahn, Roland/C-4665-2008; Moll, Jorge/B-2654-2013; Neurociencia, Inct/I-1011-2013; Inbeb, Inct/K-2317-2013; OI Zahn, Roland/0000-0002-8447-1453; Grafman, Jordan H./0000-0001-8645-4457; Moll, Jorge/0000-0002-4297-591X FU NINDS; D'Or Institute for Research and Education, Rio de Janeiro, Brazil; Stepping Stone Fellowship at The University of Manchester, UK FX This study was supported by NINDS intramural funding to JG and in part by the D'Or Institute for Research and Education, Rio de Janeiro, Brazil, to JM, RO-S, IEB and BT. RZ was supported by a Stepping Stone Fellowship at The University of Manchester, UK. We thank Eric Wassermann for the neurological exams, Kris Knutson and Griselda Garrido for imaging analysis advice, Michael Tierney and Karen DeTucci for testing patients, and Vijeth lyengar for help with data preprocessing and management. NR 79 TC 49 Z9 51 U1 4 U2 27 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2011 VL 54 IS 2 BP 1735 EP 1742 DI 10.1016/j.neuroimage.2010.08.026 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 697AW UT WOS:000285486000097 PM 20728544 ER PT J AU Corsini, E Avogadro, A Galbiati, V dell'Agli, M Marinovich, M Galli, CL Germolec, DR AF Corsini, Emanuela Avogadro, Anna Galbiati, Valentina dell'Agli, Mario Marinovich, Marina Galli, Corrado L. Germolec, Dori R. TI In vitro evaluation of the immunotoxic potential of perfluorinated compounds (PFCs) SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Perfluorinated compounds; Immunosuppression; PPAR-alpha receptor; Cytokine; MMP-9; Whole blood assay ID NF-KAPPA-B; PROLIFERATOR-ACTIVATED RECEPTORS; PEROXISOME PROLIFERATOR; PERFLUOROOCTANOIC ACID; PPAR-ALPHA; HUMORAL IMMUNITY; P65 SUBUNIT; CD RATS; MICE; EXPOSURE AB There is evidence from both epidemiology and laboratory studies that perfluorinated compounds may be immunotoxic, affecting both cell-mediated and humoral immunity. The overall goal of this study was to investigate the mechanisms underlying the immunotoxic effects of perfluorooctane sulfonate (PFOS) and perfluorooctane acid (PFOA), using in vitro assays. The release of the pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha was evaluated in lipolysaccharide (LPS)-stimulated human peripheral blood leukocytes and in the human promyelocytic cell line THP-1, while the release of IL-4, IL-10 and IFN-gamma was evaluated in phytohaemagglutinin (PHA)-stimulated peripheral blood leukocytes. PFOA and PFOS suppressed LPS-induced TNF-a production in primary human cultures and THP-1 cells, while IL-8 was suppressed only in THP-1 cells. IL-6 release was decreased only by PFOS. Both PFOA and PFOS decreased T-cell derived, PHA-induced IL-4 and IL-10 release, while IFN-gamma release was affected only by PFOS. In all instances. PFOS was more potent than PFOA. Mechanistic investigations carried out in THP-1 cells demonstrated that the effect on cytokine release was pre-transcriptional, as assessed by a reduction in LPS-induced TNF-a mRNA expression. Using siRNA, a role for PPAR-a could be demonstrated for PFOA-induced immunotoxicity, while an inhibitory effect on LPS-induced I-NB degradation could explain the immunomodulatory effect of PFOS. The dissimilar role of PPAR-a in PFOA and PFOS-induced immunotoxicity was consistent with the differing effects observed on LPS-induced MMP-9 release: PFOA, as the PPAR-a agonist fenofibrate, modulated the release, while PFOS had no effect. Overall, these studies suggest that PFCs directly suppress cytokine secretion by immune cells, and that PFOA and PFOS have different mechanisms of action. (C) 2010 Elsevier Inc. All rights reserved. C1 [Corsini, Emanuela; Avogadro, Anna; Galbiati, Valentina; Marinovich, Marina; Galli, Corrado L.] Univ Milan, Toxicol Lab, Dept Pharmacol Sci, I-20133 Milan, Italy. [dell'Agli, Mario] Univ Milan, Lab Pharmacognosy, Dept Pharmacol Sci, I-20133 Milan, Italy. [Germolec, Dori R.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. RP Corsini, E (reprint author), Univ Milan, Toxicol Lab, Dept Pharmacol Sci, Via Balzaretti 9, I-20133 Milan, Italy. EM emanuela.corsini@unimi.it RI Corsini, Emanuela/B-5602-2011; Dell'Agli, Mario/E-5253-2011; OI Dell'Agli, Mario/0000-0001-5378-402X; Galli, Corrado Lodovico/0000-0003-0078-5488; Marinovich, Marina/0000-0003-0625-8101 FU National Institute of Environmental Health Sciences; National Institutes of Health FX We would like to thank Dr. Chad Blystone and Dr. Andrew Rooney for their review and helpful suggestions. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, and the National Institutes of Health. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), and the National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. NR 42 TC 41 Z9 44 U1 4 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JAN 15 PY 2011 VL 250 IS 2 BP 108 EP 116 DI 10.1016/j.taap.2010.11.004 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 705KZ UT WOS:000286128600003 PM 21075133 ER PT J AU Lo, DJ Weaver, TA Kleiner, DE Mannon, RB Jacobson, LM Becker, BN Swanson, SJ Hale, DA Kirk, AD AF Lo, Denise J. Weaver, Tim A. Kleiner, David E. Mannon, Roslyn B. Jacobson, Lynn M. Becker, Bryan N. Swanson, S. John Hale, Douglas A. Kirk, Allan D. TI Chemokines and Their Receptors in Human Renal Allotransplantation SO TRANSPLANTATION LA English DT Article DE Chemokines; Renal transplantation; RT-PCR ID T-CELL RECRUITMENT; ALLOGRAFT-REJECTION; TRANSPLANT REJECTION; DIFFERENTIAL EXPRESSION; ISCHEMIA-REPERFUSION; CARDIAC ALLOGRAFTS; DENDRITIC CELL; IFN-GAMMA; KIDNEY; INJURY AB Background. Chemokines and their receptors play a critical role in leukocyte trafficking, and inhibition of select chemokines has been shown to attenuate kidney disease and allograft rejection in animal models. Therefore, we evaluated chemokine and chemokine receptor transcripts in human renal allograft biopsies, correlating transcript levels with clinical course and immunohistochemical analysis to relate chemokine expression to relevant clinical human disease phenotypes. Methods. Renal biopsies were grouped as postreperfusion (n=10), stable function (n=10), subclinical (n=10) or acute rejection (n=17), or calcineurin inhibitor nephrotoxicity (n=9) based on clinical presentation and histopathologic assessment. Using quantitative real-time polymerase chain reaction analysis, chemokine transcripts were assessed relative to transcript levels in preprocurement biopsies from live donor kidneys (n=15). Results. Transcripts from several inflammatory chemokines (CCL3, CCL5, CXCL9, CXCL10, and CXCL11) and chemokine receptors (CCR5, CCR7, and CXCR3) were significantly increased in allografts with subclinical and clinical acute rejection, indicating a strong polarization toward a T-helper 1 effector phenotype during rejection. These transcripts also distinguished acutely rejecting allografts from allografts with nonrejection causes of renal dysfunction. Biopsies from patients with stable function without histologic evidence of rejection had increased chemokine transcript levels that were qualitatively similar but quantitatively reduced compared with rejecting allografts. Conclusions. This comprehensive evaluation of chemokines and their receptors in human renal transplantation defines associations between chemokine expression and clinical phenotypes, may have diagnostic utility, and highlights relevant pathways for therapeutic intervention. C1 [Lo, Denise J.; Weaver, Tim A.; Kirk, Allan D.] Emory Univ, Emory Transplant Ctr, Dept Surg, Atlanta, GA 30322 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Mannon, Roslyn B.; Swanson, S. John; Hale, Douglas A.; Kirk, Allan D.] NIDDK, Transplantat Branch, NIH, DHHS, Bethesda, MD USA. [Jacobson, Lynn M.; Becker, Bryan N.] Univ Wisconsin, Dept Med, Madison, WI USA. RP Kirk, AD (reprint author), Emory Univ, Emory Transplant Ctr, Dept Surg, 101 Woodruff Circle,5105 WMB, Atlanta, GA 30322 USA. EM ADKirk@emory.edu RI Kirk, Allan/B-6905-2012; OI Kleiner, David/0000-0003-3442-4453 FU Division of Intramural Research, NIDDK, NCI, NIH; NIH [RO1 AI49285-04, 1K24 DK616962-02, 2P01AI044644-10]; Georgia Research Alliance FX This work was supported in part by the Division of Intramural Research, NIDDK, NCI, NIH; in part by NIH grants RO1 AI49285-04 and 1K24 DK616962-02 (B.N.B.) and 2P01AI044644-10 (A.D.K.); and by the Georgia Research Alliance (A.D.K.). NR 39 TC 30 Z9 37 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 15 PY 2011 VL 91 IS 1 BP 70 EP 77 DI 10.1097/TP.0b013e3181fe12fc PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 700CI UT WOS:000285709700012 PM 21441854 ER PT J AU Shlipak, MG Li, YM Fox, C Coresh, J Grunfeld, C Whooley, M AF Shlipak, Michael G. Li, Yongmei Fox, Caroline Coresh, Josef Grunfeld, Carl Whooley, Mary TI Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease SO BMC NEPHROLOGY LA English DT Article ID TAMM-HORSFALL PROTEIN; SERUM CREATININE; CYSTATIN-C; RISK AB Background: A common variant of the UMOD gene was linked with prevalent chronic kidney disease (CKD) in large, genomics consortia. One community-based study found that urine concentrations of the uromodulin protein forecast risk of incident CKD. This study within persons with known coronary artery disease (CAD) evaluated whether uromodulin concentrations could distinguish CKD risk. Methods: In the Heart and Soul Study, the UMOD snp (12917707) was genotyped in 879 individuals with baseline creatinine clearance (CrCl) measured from a 24-hour urine collection. Uromodulin protein was measured from stored urine specimens among a subset of 120 participants, balanced by genotype. Incident CKD cases (N = 102) were defined by an initial CrCl > 70 ml/min and a 5-year follow-up CrCl < 60 ml/min; controls (N = 94) were matched on age, sex, and race. Results: Among 527 self-described White participants with DNA, 373 (71%) were homozygous for the dominant allele (G/G), 133 (25%) were heterozygous (G/T) and only 21 (4%) were homozygous for the minor allele (T/T). The T/T genotype had an approximately 11 ml/min higher CrCl than the other 2 groups, but this difference did not reach statistical significance (p = 0.20). The T/T genotype had significantly lower uromodulin levels than the common G/G genotype, and the G/T genotype had intermediate levels. However, uromodulin concentrations were similar between cases and controls (44 vs. 48 mg/dL, p = 0.88). Conclusions: This study among a cohort of persons with established CAD found no association between urine uromodulin and incident CKD, although UMOD genotype was associated with urine uromodulin concentrations. C1 [Shlipak, Michael G.; Li, Yongmei; Whooley, Mary] San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA USA. [Shlipak, Michael G.; Grunfeld, Carl; Whooley, Mary] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Fox, Caroline] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline] Brigham & Womens Hosp, Div Endocrinol Metab & Diabet, Dept Med, Boston, MA 02115 USA. [Fox, Caroline] Harvard Univ, Sch Med, Boston, MA USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Grunfeld, Carl] San Francisco VA Med Ctr, Div Metab & Endocrine Sect, San Francisco, CA USA. RP Shlipak, MG (reprint author), San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA USA. EM michael.shlipak@ucsf.edu FU [R01 HL079235]; [R01 DK066488] FX This work was supported by R01 HL079235 (PI: M.W) and R01 DK066488 (PI: M.S.). NR 14 TC 9 Z9 9 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JAN 14 PY 2011 VL 12 AR 2 DI 10.1186/1471-2369-12-2 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 946MF UT WOS:000304355100002 PM 21235779 ER PT J AU Palmer, MT Lee, YK Maynard, CL Oliver, JR Bikle, DD Jetten, AM Weaver, CT AF Palmer, Matthew T. Lee, Yun Kyung Maynard, Craig L. Oliver, James R. Bikle, Daniel D. Jetten, Anton M. Weaver, Casey T. TI Lineage-specific Effects of 1,25-Dihydroxyvitamin D-3 on the Development of Effector CD4 T Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VITAMIN-D-RECEPTOR; INFLAMMATORY-BOWEL-DISEASE; GROWTH-FACTOR-BETA; ROR-GAMMA; TGF-BETA; IN-VITRO; TRANSCRIPTIONAL REGULATION; INTESTINAL INFLAMMATION; MEDIATED PATHOLOGY; SKIN INFLAMMATION AB Vitamin D deficiency is implicated in autoimmune disease. We therefore evaluated the effects of 1 alpha,25-dihydroxyvitamin D-3 (1,25-D-3), the active form of vitamin D, on the development of T helper 1 (Th1), Th17, and Th9 cells, which are implicated in the pathogenesis of different types of autoimmunity. 1,25-D-3 compromised the development of Th17 and Th9 cells, including IL-22-expressing cells while simultaneously increasing the frequency of IL-10-competent cells. Relative to Th17 and Th9 cells, the effects of 1,25-D-3 on Th1 cells were modest, reflecting the significantly reduced levels of the receptor for vitamin D in this lineage. The use of cells deficient in IL-10 or antibodies that block IL-10 signaling abolished the inhibitory effect of 1,25-D-3 on Th9 cells but had no effect on inhibition of Th17 cell frequencies. Thus, the induction of IL-10 in cultures of Th9 cells is an important mechanism by which 1,25-D-3 compromises Th9 development but does not explain inhibition of Th17 cells. A survey of select representatives of the Th17 transcriptome revealed that the levels of mRNA that encode ROR gamma t, IL-17A, IL-17F, IL-23R, and IL-22, were reduced by 1,25-D-3, whereas IL-21 and aryl hydrocarbon receptor mRNA remained unchanged. These data suggest that vitamin D deficiency may promote autoimmunity by favoring the inordinate production of Th17 and Th9 cells at the expense of regulatory IL-10-producing T cells. C1 [Palmer, Matthew T.; Lee, Yun Kyung; Maynard, Craig L.; Oliver, James R.; Weaver, Casey T.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Bikle, Daniel D.] Univ Calif San Francisco, Ctr Vet Med, Dept Med, San Francisco, CA 94121 USA. [Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Weaver, CT (reprint author), Univ Alabama, Dept Pathol, BBRB 870,845 19th St S, Birmingham, AL 35294 USA. EM cweaver@uab.edu OI Weaver, Casey/0000-0002-2180-1793; Jetten, Anton/0000-0003-0954-4445 FU National Institutes of Health [AI035783, AI057956, DK064400]; Crohn's and Colitis Foundation of America; [AR053458] FX This work was supported, in whole or in part, by National Institutes of Health Grants AI035783, AI057956, and DK064400 (to C. T. W.) and Postdoctoral Training Grant AR053458. This work was also supported by a Crohn's and Colitis Foundation of America fellowship (to M. T. P.). NR 63 TC 62 Z9 64 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 14 PY 2011 VL 286 IS 2 BP 997 EP 1004 DI 10.1074/jbc.M110.163790 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 703TU UT WOS:000286005000010 PM 21047796 ER PT J AU Sasaki, CY Ghosh, P Longo, DL AF Sasaki, Carl Y. Ghosh, Paritosh Longo, Dan L. TI Recruitment of RelB to the Csf2 Promoter Enhances RelA-mediated Transcription of Granulocyte-Macrophage Colony-stimulating Factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; CHROMATIN IMMUNOPRECIPITATION; NF-KAPPA-B2 P100; IKK-ALPHA; ACTIVATION; GENE; PHOSPHORYLATION; KINASE; SERINE-536 AB Tumor necrosis factor (TNF) induces expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) but lymphotoxin beta (LT beta) does not. Here we report that priming of cells with agonistic LT beta receptor antibody synergistically enhanced TNF-induced GM-CSF expression. The LT beta priming process was not due to an increase in TNF-mediated nuclear translocation of p65, p65 DNA binding, or NF-kappa B transactivational activity. The synergistic effect of LT beta priming was not observed with other TNF-responsive genes such as Ccl2 or RelB, which suggested that this effect was not a general increase in TNF signaling. Furthermore, RelB and p65 were both independently recruited to the GM-CSF promoter when cells were primed with LT beta followed by TNF treatment. As a consequence, an increase in both chromatin accessibility and the recruitment of RNA polymerase II were observed to the GMCSF promoter. Taken together, these findings suggested that LT beta signaling amplified TNF-mediated GM-CSF expression by facilitating chromatin access and the co-recruitment of RNA polymerase II to increase gene transcription. Moreover, the novel priming process described here underscores the complexity of the interactions between the classical and alternative NF-kappa B signaling pathways. C1 [Sasaki, Carl Y.; Ghosh, Paritosh; Longo, Dan L.] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Sasaki, CY (reprint author), NIA, Immunol Lab, NIH, 251 Bay View Blvd,Suite 100, Baltimore, MD 21224 USA. EM sasakic@grc.nia.nih.gov FU NIA, National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of the NIA, National Institutes of Health. NR 35 TC 7 Z9 7 U1 0 U2 1 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 14 PY 2011 VL 286 IS 2 BP 1093 EP 1102 DI 10.1074/jbc.M110.119438 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 703TU UT WOS:000286005000020 PM 21071440 ER PT J AU Mitra, PS Basu, NK Basu, M Chakraborty, S Saha, T Owens, IS AF Mitra, Partha S. Basu, Nikhil K. Basu, Mousumi Chakraborty, Sunit Saha, Tapas Owens, Ida S. TI Regulated Phosphorylation of a Major UDP-glucuronosyltransferase Isozyme by Tyrosine Kinases Dictates Endogenous Substrate Selection for Detoxification SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER PATIENTS; COMET ASSAY; DNA-DAMAGE; CELLS; SRC; ESTRADIOL; EXPRESSION; METABOLITES; ESTROGENS; ESTRONE AB Whereas UDP-glucuronosyltransferase-2B7 is widely distributed in different tissues, it preferentially detoxifies genotoxic 4-OH-estradiol and 4-OH-estrone (4-OHE1) with barely detectable 17 beta-estradiol (E-2) conversion following expression in COS-1 cells. Consistent with the UDP-glucuronosyltransferase requirement for regulated phosphorylation, we discovered that 2B7 requires Src-dependent tyrosine phosphorylation. Y236F-2B7 and Y438F-2B7 mutants were null and 90% inactive, respectively, when expressed in COS-1. We demonstrated that 2B7 incorporated immunoprecipitable [P-33] orthophosphate and that 2B7His, previously expressed in SYF-(Src, Yes, Fyn)(-/-) cells, was Src-supported or phosphorylated under in vitro conditions. Unexpectedly, 2B7 expressed in SYF-/- and SYF+/- cells metabolized 4-OHE1 at 10- and 3-fold higher rates, respectively, than that expressed in COS-1, and similar analysis showed that E-2 metabolism was 16- and 9-fold higher than in COS-1. Because anti-Tyr(P)-438-2B7 detected Tyr(P)-438-2B7 in each cell line, results indicated that unidentified tyrosine kinase(s) (TKs) phosphorylated 2B7 in SYF-/-. 2B7-transfected COS-1 treated with increasing concentrations of the Src-specific inhibitor PP2 down-regulated 4-OHE1 glucuronidation reaching 60% maximum while simultaneously increasing E-2 metabolism linearly. This finding indicated that increasing PP2 inhibition of Src allows increasing E-2 metabolism caused by 2B7 phosphorylation by unidentified TK(s). Importantly, 2B7 expressed in SYF-/- is more competent at metabolizing E-2 in cellulo than 2B7 expressed in COS-1. To confirm Src-controlled 2B7 prevents toxicity, we showed that 2B7-transfected COS-1 efficiently protected against 4-OH-E-1-mediated depurination. Finally, our results indicate that Src-dependent phosphorylation of 2B7 allows metabolism of 4-OHE1, but not E-2, in COS-1, whereas non-Src-phosphorylated 2B7 metabolizes both chemicals. Importantly, we determined that 2B7 substrate selection is not fixed but varies depending upon the TK(s) that carry out its required phosphorylation. C1 [Mitra, Partha S.; Basu, Nikhil K.; Basu, Mousumi; Chakraborty, Sunit; Owens, Ida S.] NICHHD, Sect Genet Disorders Drug Metab, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Saha, Tapas] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Basu, M (reprint author), NICHHD, Sect Genet Disorders Drug Metab, Program Dev Endocrinol & Genet, NIH, Bldg 10,Rm 9D-42, Bethesda, MD 20892 USA. EM basun@mail.nih.gov; owens@mail.nih.gov FU National Institutes of Health NICHD FX This work was supported, in whole or in part, by the National Institutes of Health NICHD Intramural Research Program. NR 36 TC 8 Z9 9 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 14 PY 2011 VL 286 IS 2 BP 1639 EP 1648 DI 10.1074/jbc.M110.165126 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 703TU UT WOS:000286005000076 PM 21056984 ER PT J AU Weiss, GE Clark, EH Li, SP Traore, B Kayentao, K Ongoiba, A Hernandez, JN Doumbo, OK Pierce, SK Branch, OH Crompton, PD AF Weiss, Greta E. Clark, Eva H. Li, Shanping Traore, Boubacar Kayentao, Kassoum Ongoiba, Aissata Hernandez, Jean N. Doumbo, Ogobara K. Pierce, Susan K. Branch, OraLee H. Crompton, Peter D. TI A Positive Correlation between Atypical Memory B Cells and Plasmodium falciparum Transmission Intensity in Cross-Sectional Studies in Peru and Mali SO PLOS ONE LA English DT Article ID MALARIA-ENDEMIC AREA; INDIVIDUALS; EXPRESSION; ANTIGENS; IMMUNITY AB Background: Antibodies that protect against Plasmodium falciparum (Pf) malaria are only acquired after years of repeated infections. The B cell biology that underlies this observation is poorly understood. We previously reported that "atypical'' memory B cells are increased in children and adults exposed to intense Pf transmission in Mali, similar to what has been observed in individuals infected with HIV. In this study we examined B cell subsets of Pf-infected adults in Peru and Mali to determine if Pf transmission intensity correlates with atypical memory B cell expansion. Methodology/Principal Findings: In this cross-sectional study venous blood was collected from adults in areas of zero (U. S., n = 10), low (Peru, n = 18) and high (Mali, n = 12) Pf transmission. Adults in Peru and Mali were infected with Pf at the time of blood collection. Thawed lymphocytes were analyzed by flow cytometry to quantify B cell subsets, including atypical memory B cells, defined by the cell surface markers CD19(+) CD20(+) CD21(-) CD27(-) CD10(-). In Peru, the mean level of atypical memory B cells, as a percent of total B cells, was higher than U. S. adults (Peru mean: 5.4% [95% CI: 3.61-7.28]; U. S. mean: 1.4% [95% CI: 0.92-1.81]; p<0.0001) but lower than Malian adults (Mali mean 13.1% [95% CI: 10.68-15.57]; p = 0.0001). In Peru, individuals self-reporting >= 1 prior malaria episodes had a higher percentage of atypical memory B cells compared to those reporting no prior episodes (>= 1 prior episodes mean: 6.6% [95% CI: 4.09-9.11]; no prior episodes mean: 3.1% [95% CI: 1.52-4.73]; p = 0.028). Conclusions/Significance: Compared to Pf-naive controls, atypical memory B cells were increased in Peruvian adults exposed to low Pf transmission, and further increased in Malian adults exposed to intense Pf transmission. Understanding the origin, function and antigen specificity of atypical memory B cells in the context of Pf infection could contribute to our understanding of naturally-acquired malaria immunity. C1 [Weiss, Greta E.; Li, Shanping; Pierce, Susan K.; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Clark, Eva H.; Branch, OraLee H.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Clark, Eva H.; Hernandez, Jean N.; Branch, OraLee H.] Univ Nacl Amazonia Peruana, LIPNAA, Iquitos, Loreto, Peru. [Traore, Boubacar; Kayentao, Kassoum; Ongoiba, Aissata; Doumbo, Ogobara K.] Univ Bamako, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Fac Med Pharm & Odontostomatol, Bamako, Mali. [Branch, OraLee H.] NYU, Dept Med Parasitol, New York, NY USA. RP Weiss, GE (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM pcrompton@niaid.nih.gov RI Crompton, Peter/N-1130-2016 FU NIAID/NIH [R01AI064831] FX This research was supported by NIAID/NIH grant No. R01AI064831 and the Intramural Research Program of the NIAID/NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 37 Z9 37 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 14 PY 2011 VL 6 IS 1 AR e15983 DI 10.1371/journal.pone.0015983 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710MS UT WOS:000286516500021 PM 21264245 ER PT J AU Ou, XA Chae, HD Wang, RH Shelley, WC Cooper, S Taylor, T Kim, YJ Deng, CX Yoder, MC Broxmeyer, HE AF Ou, Xuan Chae, Hee-Don Wang, Rui-Hong Shelley, William C. Cooper, Scott Taylor, Tammi Kim, Young-June Deng, Chu-Xia Yoder, Mervin C. Broxmeyer, Hal E. TI SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse SO BLOOD LA English DT Article ID IN-VITRO DIFFERENTIATION; ENDOTHELIAL-CELLS; COMMON PRECURSOR; YOLK-SAC; GROWTH; HEMANGIOBLAST; PROGENITORS; DEACETYLASE; EXPRESSION; MESODERM AB SIRT1 is a founding member of a sirtuin family of 7 proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1(-/-) mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1(-/-) mouse embryonic stem cells (ESCs) in vitro, and hematopoietic progenitors in SIRT1(-/-), (+/-), and (-/-) mice. SIRT1(-/-) ESCs formed fewer mature blast cell colonies. Replated SIRT1(-/-) blast colony-forming cells demonstrated defective hematopoietic potential. Endothelial cell production was unaltered, but there were defects in formation of a primitive vascular network from SIRT1(-/-) derived embryoid bodies. Development of primitive and definitive progenitors derived from SIRT1(-/-) ESCs were also delayed and/or defective. Differentiation delay/defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5 expression, decreased beta-H1 globin, beta-major globin, and Scl gene expression, and reduced activation of Erk1/2. Ectopic expression of SIRT1 rescued SIRT1(-/-) ESC differentiation deficiencies. SIRT1(-/-) yolk sacs manifested fewer primitive erythroid precursors. SIRT1(-/-) and SIRT1(-/-) adult marrow had decreased numbers and cycling of hematopoietic progenitors, effects more apparent at 5%, than at 20%, oxygen tension, and these progenitors survived less well in vitro under conditions of delayed growth factor addition. This suggests a role for SIRT1 in ESC differentiation and mouse hematopoiesis. (Blood. 2011; 117(2):440-450) C1 [Ou, Xuan; Chae, Hee-Don; Cooper, Scott; Taylor, Tammi; Kim, Young-June; Broxmeyer, Hal E.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Wang, Rui-Hong; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Shelley, William C.; Yoder, Mervin C.] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN USA. [Shelley, William C.; Yoder, Mervin C.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN USA. RP Broxmeyer, HE (reprint author), Indiana Univ Sch Med, Dept Microbiol & Immunol, 950 W Walnut St R2-302, Indianapolis, IN 46202 USA. EM hbroxmey@iupui.edu RI Chae, Hee-Don/D-2620-2011; Ou, Xuan/C-4871-2012; Ou, Xuan/F-4026-2012; deng, chuxia/N-6713-2016 FU US Public Health Service [RO1 HL56416, RO1 HL67384]; National Institutes of Health [PO1 HL53586, R01 AI080759] FX These studies were supported by US Public Health Service grant nos. RO1 HL56416, RO1 HL67384, and a project in PO1 HL53586 to H. E. B., and R01 AI080759 to M.C.Y. from the National Institutes of Health. NR 48 TC 44 Z9 45 U1 0 U2 6 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 13 PY 2011 VL 117 IS 2 BP 440 EP 450 DI 10.1182/blood-2010-03-273011 PG 11 WC Hematology SC Hematology GA 705ZD UT WOS:000286178700014 PM 20966168 ER PT J AU Perez-Galan, P Mora-Jensen, H Weniger, MA Shaffer, AL Rizzatti, EG Chapman, CM Mo, CC Stennett, LS Rader, C Liu, PC Raghavachari, N Stetler-Stevenson, M Yuan, C Pittaluga, S Maric, I Dunleavy, KM Wilson, WH Staudt, LM Wiestner, A AF Perez-Galan, Patricia Mora-Jensen, Helena Weniger, Marc A. Shaffer, Arthur L., III Rizzatti, Edgar G. Chapman, Colby M. Mo, Clifton C. Stennett, Lawrence S. Rader, Christoph Liu, Poching Raghavachari, Nalini Stetler-Stevenson, Maryalice Yuan, Constance Pittaluga, Stefania Maric, Irina Dunleavy, Kieron M. Wilson, Wyndham H. Staudt, Louis M. Wiestner, Adrian TI Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation SO BLOOD LA English DT Article ID MULTIPLE-MYELOMA CELLS; PROTEASOME INHIBITOR BORTEZOMIB; UNFOLDED PROTEIN RESPONSE; NATIONAL-CANCER-INSTITUTE; CLINICAL-TRIALS GROUP; NON-HODGKINS-LYMPHOMA; PHASE-II; REGULATORY FACTOR-4; B-CELLS; GENE AB Bortezomib induces remissions in 30%-50% of patients with relapsed mantle cell lymphoma (MCL). Conversely, more than half of patients' tumors are intrinsically resistant to bortezomib. The molecular mechanism of resistance has not been defined. We generated a model of bortezomib-adapted subclones of the MCL cell lines JEKO and HBL2 that were 40- to 80-fold less sensitive to bortezomib than the parental cells. Acquisition of bortezomib resistance was gradual and reversible. Bortezomib-adapted subclones showed increased proteasome activity and tolerated lower proteasome capacity than the parental lines. Using gene expression profiling, we discovered that bortezomib resistance was associated with plasmacytic differentiation, including up-regulation of IRF4 and CD38 and expression of CD138. In contrast to plasma cells, plasmacytic MCL cells did not increase immunoglobulin secretion. Intrinsically bortezomib-resistant MCL cell lines and primary tumor cells from MCL patients with inferior clinical response to bortezomib also expressed plasmacytic features. Knockdown of IRF4 was toxic for the subset of MCL cells with plasmacytic differentiation, but only slightly sensitized cells to bortezomib. We conclude that plasmacytic differentiation in the absence of an increased secretory load can enable cells to withstand the stress of proteasome inhibition. Expression of CD38 and IRF4 could serve as markers of bortezomib resistance in MCL. This study has been registered at http://clinicaltrials.gov as NCT00131976. (Blood. 2011; 117(2):542-552) C1 [Perez-Galan, Patricia; Mora-Jensen, Helena; Weniger, Marc A.; Rizzatti, Edgar G.; Chapman, Colby M.; Mo, Clifton C.; Stennett, Lawrence S.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Shaffer, Arthur L., III; Dunleavy, Kieron M.; Wilson, Wyndham H.; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rader, Christoph] NCI, Metab Branch, Expt Transplantat & Immunol, NIH, Bethesda, MD 20892 USA. [Liu, Poching; Raghavachari, Nalini] NHLBI, Gene Express Core Facil, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice; Yuan, Constance; Pittaluga, Stefania] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov FU National, Heart, Lung and Blood Institute; National Cancer Institute of the NIH; NIH FX This research was supported by the Intramural Research Program, National, Heart, Lung and Blood Institute, and National Cancer Institute of the NIH, and by a Bench-to-Bedside award from the NIH. NR 57 TC 46 Z9 46 U1 0 U2 10 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 13 PY 2011 VL 117 IS 2 BP 542 EP 552 DI 10.1182/blood-2010-02-269514 PG 11 WC Hematology SC Hematology GA 705ZD UT WOS:000286178700024 PM 20956803 ER PT J AU Herishanu, Y Perez-Galan, P Liu, DL Biancotto, A Pittaluga, S Vire, B Gibellini, F Njuguna, N Lee, E Stennett, L Raghavachari, N Liu, PC McCoy, JP Raffeld, M Stetler-Stevenson, M Yuan, C Sherry, R Arthur, DC Maric, I White, T Marti, GE Munson, P Wilson, WH Wiestner, A AF Herishanu, Yair Perez-Galan, Patricia Liu, Delong Biancotto, Angelique Pittaluga, Stefania Vire, Berengere Gibellini, Federica Njuguna, Ndegwa Lee, Elinor Stennett, Lawrence Raghavachari, Nalini Liu, Poching McCoy, J. Philip Raffeld, Mark Stetler-Stevenson, Maryalice Yuan, Constance Sherry, Richard Arthur, Diane C. Maric, Irina White, Therese Marti, Gerald E. Munson, Peter Wilson, Wyndham H. Wiestner, Adrian TI The lymph node microenvironment promotes B-cell receptor signaling, NF-kappa B activation, and tumor proliferation in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID TOLL-LIKE RECEPTORS; GENE-EXPRESSION; ZAP-70 EXPRESSION; GENOMIC ABERRATIONS; DISEASE PROGRESSION; ANTIGEN RECEPTOR; MUTATION STATUS; CROSS-LINKING; SURVIVAL; IGM AB Chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes, involves blood, bone marrow, and secondary lymphoid organs such as the lymph nodes (LN). A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations, but its contribution in vivo remains ill-defined. To elucidate the effects of tumor-host interactions in vivo, we purified tumor cells from 24 treatment-naive patients. Samples were obtained concurrently from blood, bone marrow, and/or LN and analyzed by gene expression profiling. We identified the LN as a key site in CLL pathogenesis. CLL cells in the LN showed up-regulation of gene signatures, indicating B-cell receptor (BCR) and nuclear factor-kappa B activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-kappa B activation, we detected phosphorylation of SYK and I kappa B alpha, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the LN and was correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370. (Blood. 2011;117(2):563-574) C1 [Herishanu, Yair; Perez-Galan, Patricia; Vire, Berengere; Gibellini, Federica; Njuguna, Ndegwa; Lee, Elinor; Stennett, Lawrence; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Liu, Delong; Munson, Peter] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Biancotto, Angelique; McCoy, J. Philip] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Raffeld, Mark; Stetler-Stevenson, Maryalice; Yuan, Constance; Arthur, Diane C.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Sherry, Richard] NCI, Surg Branch, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [White, Therese] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Marti, Gerald E.; Wilson, Wyndham H.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov FU American Physician Fellowship (APF); NIH, the National Heart, Lung, and Blood Institute; National Cancer Institute FX Foremost we thank our patients for their willingness to undergo additional or more extensive procedures to make this research possible. We thank Dr Lou Staudt for lymphochip microarrays, the NCI surgery team for performing excisional lymph node biopsies, and Theresa Davies-Hill for assistance in processing biopsy specimens. We thank Drs Lou Staudt, Neal Young, Cindy Dunbar, and Clifton Mo for helpful discussions and critical reading of the manuscript. We gratefully acknowledge the American Physician Fellowship (APF) for support of Y.H.; This research was also supported by the Intramural Research Program of the NIH, the National Heart, Lung, and Blood Institute, and the National Cancer Institute. NR 50 TC 327 Z9 336 U1 4 U2 23 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 13 PY 2011 VL 117 IS 2 BP 563 EP 574 DI 10.1182/blood-2010-05-284984 PG 12 WC Hematology SC Hematology GA 705ZD UT WOS:000286178700026 PM 20940416 ER PT J AU Savan, R McFarland, AP Reynolds, DA Feigenbaum, L Ramakrishnan, K Karwan, M Shirota, H Klinman, DM Dunleavy, K Pittaluga, S Anderson, SK Donnelly, RP Wilson, WH Young, HA AF Savan, Ram McFarland, Adelle P. Reynolds, Della A. Feigenbaum, Lionel Ramakrishnan, Karthika Karwan, Megan Shirota, Hidekazu Klinman, Dennis M. Dunleavy, Kieron Pittaluga, Stefania Anderson, Stephen K. Donnelly, Raymond P. Wilson, Wyndham H. Young, Howard A. TI A novel role for IL-22R1 as a driver of inflammation SO BLOOD LA English DT Article ID LARGE-CELL LYMPHOMA; EFFECTIVE THERAPY; NPM-ALK; CHAIN; ACTIVATION; EXPRESSION; KINASE; TRANSLOCATION; CONTRIBUTES; ANTIBODY AB The interleukin (IL)-22R1 chain of the heterodimeric IL-22 receptor is not expressed on normal leukocytes, but this receptor is expressed on T cells from anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large cell lymphoma (ALCL) patients. To investigate the consequences of aberrant expression of this receptor on lymphocytes, we generated transgenic mice that express IL-22R1 on lymphocytes. The health of these animals progressively deteriorated at 8 to 12 weeks of age, as they displayed respiratory distress, rough coat and sluggish movement, and subsequent lethality due to multiorgan inflammation. The IL-22R1 transgenic animals developed neutrophilia that correlated with increased levels of circulating IL-17 and granulocyte colony-stimulating factor. In addition, these mice had increased serum IL-22 levels, suggesting that T cells expressing IL-22R1 generate IL-22 in a positive autoregulatory loop. As a result of the mouse model findings, we analyzed circulating cytokine levels in ALK(+)ALCL patients and detected elevated levels of IL-22, IL-17, and IL-8 in untreated patient samples. Importantly, IL-22 and IL-17 were undetectable in all patients who were in complete remission after chemotherapy. This study documents a previously unknown role of IL-22R1 in inflammation and identifies the involvement of IL-22R1/IL-22 in ALK(+)ALCL. (Blood. 2011;117(2):575-584) C1 [Savan, Ram; McFarland, Adelle P.; Reynolds, Della A.; Ramakrishnan, Karthika; Shirota, Hidekazu; Klinman, Dennis M.; Anderson, Stephen K.; Young, Howard A.] Ctr Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. [Feigenbaum, Lionel; Karwan, Megan] NCI, Lab Anim Sci Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Dunleavy, Kieron; Wilson, Wyndham H.] NCI, Metab Branch, Lymphoma Therapeut Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, Hematopathol Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Young, HA (reprint author), Ctr Canc Res, Canc & Inflammat Program, POB B,Bldg 560, Frederick, MD 21702 USA. EM savanr@mail.nih.gov; YoungHow@mail.nih.gov RI Anderson, Stephen/B-1727-2012 OI Anderson, Stephen/0000-0002-7856-4266 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. NR 28 TC 27 Z9 28 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 13 PY 2011 VL 117 IS 2 BP 575 EP 584 DI 10.1182/blood-2010-05-285908 PG 10 WC Hematology SC Hematology GA 705ZD UT WOS:000286178700027 PM 20971950 ER PT J AU Chen, YT Zheng, TZ Lan, Q Foss, F Kim, C Chen, XZ Dai, M Li, YM Holford, T Leaderer, B Boyle, P Chanock, SJ Rothman, N Zhang, YW AF Chen, Yingtai Zheng, Tongzhang Lan, Qing Foss, Francine Kim, Christopher Chen, Xuezhong Dai, Min Li, Yumin Holford, Theodore Leaderer, Brian Boyle, Peter Chanock, Stephen J. Rothman, Nathaniel Zhang, Yawei TI Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index, and risk of non-Hodgkin lymphoma SO BLOOD LA English DT Article ID CANCER-RISK; INTERLEUKIN-7 RECEPTOR; INTERLYMPH-CONSORTIUM; ADAPTIVE IMMUNITY; PHYSICAL-ACTIVITY; OBESITY; MEN; INFLAMMATION; ASSOCIATION; LYMPHOCYTES AB We conducted a population-based, case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared with those with BMI less than 25 kg/m(2), women with BMI more than or equal to 25 kg/m2 had 50% to 90% increased risk of NHL among women who carried IFNGR2 (rs9808753) AA, IL5 (rs2069812) CT/TT, IL7R (rs1494555) AA, and TNF (rs1799724) CC genotypes, but no increased risk among women with IFNGR2 AG/GG, IL5 CC, IL7R AG/GG, and TNF CT/TT genotypes. A significant interaction with BMI was only observed for IFNGR2 (rs9808753 P(forinteraction) = .034) and IL7R (rs1494555 P(forinteraction) = .016) for NHL overall; IL7R (rs1494555 P(forinteraction) = .016) and TNF (1799724 P(forinteraction) = .031) for B-cell lymphoma; and IL5 (rs2069812 P(forinteraction) = .034) for T-cell lymphoma. After stratification by common B-cell lymphoma subtypes, a significant interaction was observed for IFNGR2 (rs9808753 P(forinteraction) = .006), IL13 (rs20541 P(forinteraction) = .019), and IL7R (rs1494555 P(forinteraction) = .012) for marginal zone B-cell lymphoma; IL7R (rs1494555 P(forinteraction) = .017) for small lymphocytic lymphoma/chronic lymphocytic leukemia; and IL12A (rs568408 P(forinteraction) = .013) and TNF (1799724 P(forinteraction) = .04) for follicular lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between BMI and NHL risk. (Blood. 2011;117(2):585-590) C1 [Chen, Yingtai; Zheng, Tongzhang; Kim, Christopher; Holford, Theodore; Leaderer, Brian; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Chen, Yingtai; Li, Yumin] Lanzhou Univ, Hosp 2, Lanzhou 730000, Peoples R China. [Lan, Qing; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Foss, Francine] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Chen, Xuezhong] Gansu Prov Acad Med Sci, Gansu Prov Tumor Hosp, Lanzhou, Peoples R China. [Dai, Min] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100037, Peoples R China. [Boyle, Peter] Int Prevent Res Inst, Lyon, France. [Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,Dept Hlth & Human Serv, Gaithersburg, MD USA. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, 60 Coll St,LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Boyle, Peter/A-4380-2014 OI Boyle, Peter/0000-0001-6251-0610 FU National Institutes of Health [CA62006]; National Institutes of Health, National Cancer Institute; National Institutes of Health Fogarty [1D43TW008323-01, 1D43TW007864-01]; National Center for Research Resources, a component of the National Institutes of Health, and NHL roadmap for medical Research [UL1 RR024139] FX This work was supported by the National Institutes of Health (grant CA62006), the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the National Institutes of Health Fogarty (training grants 1D43TW008323-01 and 1D43TW007864-01).; This publication was made possible by a Clinical and Translational Science Award (grant UL1 RR024139) from the National Center for Research Resources, a component of the National Institutes of Health, and NHL roadmap for medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of National Center for Research Resources. NR 49 TC 24 Z9 24 U1 0 U2 9 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 13 PY 2011 VL 117 IS 2 BP 585 EP 590 DI 10.1182/blood-2010-07-295097 PG 6 WC Hematology SC Hematology GA 705ZD UT WOS:000286178700028 PM 20952689 ER PT J AU Chmelar, J Oliveira, CJ Rezacova, P Francischetti, IMB Kovarova, Z Pejler, G Kopacek, P Ribeiro, JMC Mares, M Kopecky, J Kotsyfakis, M AF Chmelar, Jindrich Oliveira, Carlo J. Rezacova, Pavlina Francischetti, Ivo M. B. Kovarova, Zuzana Pejler, Gunnar Kopacek, Peter Ribeiro, Jose M. C. Mares, Michael Kopecky, Jan Kotsyfakis, Michail TI A tick salivary protein targets cathepsin G and chymase and inhibits host inflammation and platelet aggregation SO BLOOD LA English DT Article ID IXODES-RICINUS; SERPIN SUPERFAMILY; MODEL; NEUTROPHILS; REFINEMENT; SCAPULARIS; CLONING AB Platelet aggregation and acute inflammation are key processes in vertebrate defense to a skin injury. Recent studies uncovered the mediation of 2 serine proteases, cathepsin G and chymase, in both mechanisms. Working with a mouse model of acute inflammation, we revealed that an exogenous salivary protein of Ixodes ricinus, the vector of Lyme disease pathogens in Europe, extensively inhibits edema formation and influx of neutrophils in the inflamed tissue. We named this tick salivary gland secreted effector as I ricinus serpin-2 (IRS-2), and we show that it primarily inhibits cathepsin G and chymase, while in higher molar excess, it affects thrombin activity as well. The inhibitory specificity was explained using the crystal structure, determined at a resolution of 1.8 angstrom. Moreover, we disclosed the ability of IRS-2 to inhibit cathepsin G-induced and thrombin-induced platelet aggregation. For the first time, an ectoparasite protein is shown to exhibit such pharmacological effects and target specificity. The stringent specificity and biological activities of IRS-2 combined with the knowledge of its structure can be the basis for the development of future pharmaceutical applications. (Blood. 2011;117(2):736-744) C1 [Chmelar, Jindrich; Kopacek, Peter; Kopecky, Jan; Kotsyfakis, Michail] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, CR-37005 Ceske Budejovice, Czech Republic. [Chmelar, Jindrich] Univ S Bohemia, Fac Sci, Ceske Budejovice, Czech Republic. [Oliveira, Carlo J.] Univ Sao Paulo, Dept Biochem & Immunol, Sch Med Ribeirao Preto, BR-14049 Ribeirao Preto, Brazil. [Rezacova, Pavlina; Kovarova, Zuzana; Mares, Michael] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Prague, Czech Republic. [Francischetti, Ivo M. B.; Ribeiro, Jose M. C.] NIAID, NIH, Rockville, MD USA. [Pejler, Gunnar] Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Biomed Ctr, Uppsala, Sweden. RP Kotsyfakis, M (reprint author), Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, Branisovska 31, CR-37005 Ceske Budejovice, Czech Republic. EM kotsyfakis@paru.cas.cz RI Mares, Michael/B-2413-2009; Maloy Rezacova, Pavlina/G-3600-2014; Kopacek, Petr/G-8414-2014; Kotsyfakis, Michail/G-9525-2014; Kopecky, Jan/G-9347-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Ribeiro, Jose/0000-0002-9107-0818 FU Swedish Research Council; Grant Agency of the Academy of Sciences of the Czech Republic [IAA600960811]; Ministry of Education, Youth and Sports of the Czech Republic; Academy of Sciences of the Czech Republic [Z60220518]; Grant Agency of the Czech Republic [P207/10/2183]; [Z40550506] FX We thank Ida Waern and Elin Ronnberg from the Swedish University of Agricultural Sciences for help with mast cell experiments and the Swedish Research Council for financial support. We also thank Jan Erhart (Institute of Parasitology, Biology Center of the Academy of Sciences of Czech Republic) for providing ticks; Anderson Sa-Nunes (Institute of Biomedical Sciences, University of Sao Paulo) for discussions and help with the experimental design; and NIAID intramural editor Brenda Rae Marshall for assistance. We also thank the anonymous reviewers for critical and constructive comments and the editorial team of Blood for efficiently processing the manuscript.; This work was supported by grant no. IAA600960811 from the Grant Agency of the Academy of Sciences of the Czech Republic, Research Center no. LC06009 from the Ministry of Education, Youth and Sports of the Czech Republic, and by grant no. Z60220518 of the Academy of Sciences of the Czech Republic. The structural element was supported by grant no. P207/10/2183 from the Grant Agency of the Czech Republic and research project Z40550506. Diffraction data were collected at beam line X12, EMBL-Hamburg outstation at DESY (Hamburg, Germany). I.M.B.F., J.M.C.R., and M.K. were supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, and M.K. by a Jan Evengelista Purkyne fellowship of the Academy of Sciences of the Czech Republic. NR 41 TC 53 Z9 54 U1 0 U2 7 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 13 PY 2011 VL 117 IS 2 BP 736 EP 744 DI 10.1182/blood-2010-06-293241 PG 9 WC Hematology SC Hematology GA 705ZD UT WOS:000286178700045 PM 20940421 ER PT J AU Krebs, NF Hambidge, KM Mazariegos, M Westcott, J Goco, N Wright, LL Koso-Thomas, M Tshefu, A Bose, C Pasha, O Goldenberg, R Chomba, E Carlo, W Kindem, M Das, A Hartwell, T McClure, E AF Krebs, Nancy F. Hambidge, K. Michael Mazariegos, Manolo Westcott, Jamie Goco, Norman Wright, Linda L. Koso-Thomas, Marion Tshefu, Antoinette Bose, Carl Pasha, Omrana Goldenberg, Robert Chomba, Elwyn Carlo, Waldemar Kindem, Mark Das, Abhik Hartwell, Ty McClure, Elizabeth CA Complementary Feeding Study Grp TI Complementary feeding: a Global Network cluster randomized controlled trial SO BMC PEDIATRICS LA English DT Article ID KENYAN SCHOOL-CHILDREN; DIETARY QUALITY; YOUNG-CHILDREN; NUTRITION; GROWTH; INTERVENTION; HEALTH; FOODS; ADAPTATION; DESIGN AB Background: Inadequate and inappropriate complementary feeding are major factors contributing to excess morbidity and mortality in young children in low resource settings. Animal source foods in particular are cited as essential to achieve micronutrient requirements. The efficacy of the recommendation for regular meat consumption, however, has not been systematically evaluated. Methods/Design: A cluster randomized efficacy trial was designed to test the hypothesis that 12 months of daily intake of beef added as a complementary food would result in greater linear growth velocity than a micronutrient fortified equi-caloric rice-soy cereal supplement. The study is being conducted in 4 sites of the Global Network for Women's and Children's Health Research located in Guatemala, Pakistan, Democratic Republic of the Congo (DRC) and Zambia in communities with toddler stunting rates of at least 20%. Five clusters per country were randomized to each of the food arms, with 30 infants in each cluster. The daily meat or cereal supplement was delivered to the home by community coordinators, starting when the infants were 6 months of age and continuing through 18 months. All participating mothers received nutrition education messages to enhance complementary feeding practices delivered by study coordinators and through posters at the local health center. Outcome measures, obtained at 6, 9, 12, and 18 months by a separate assessment team, included anthropometry; dietary variety and diversity scores; biomarkers of iron, zinc and Vitamin B(12) status (18 months); neurocognitive development (12 and 18 months); and incidence of infectious morbidity throughout the trial. The trial was supervised by a trial steering committee, and an independent data monitoring committee provided oversight for the safety and conduct of the trial. Discussion: Findings from this trial will test the efficacy of daily intake of meat commencing at age 6 months and, if beneficial, will provide a strong rationale for global efforts to enhance local supplies of meat as a complementary food for young children. C1 [Krebs, Nancy F.; Hambidge, K. Michael; Westcott, Jamie] Univ Colorado Denver, Aurora, CO USA. [Mazariegos, Manolo] San Carlos Univ, Guatemala City, Guatemala. [Goco, Norman; Kindem, Mark; Das, Abhik; Hartwell, Ty; McClure, Elizabeth] RTI Int, Res Triangle Pk, NC USA. [Wright, Linda L.; Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Tshefu, Antoinette] Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Bose, Carl] Univ N Carolina, Chapel Hill, NC USA. [Pasha, Omrana] Aga Khan Univ, Karachi, Pakistan. [Goldenberg, Robert] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Carlo, Waldemar] Univ Alabama, Birmingham, AL USA. RP Krebs, NF (reprint author), Univ Colorado Denver, Aurora, CO USA. EM nancy.krebs@ucdenver.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD040657, HD043464, HD040607, HD043475, HD040636]; Office of Dietary Supplements; NIDDK [9K24 DK083772]; National Cattlemen's Beef Association FX Funded by grants from Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD040657 (UCD), HD043464 (UAB), HD040607 (Drexel), HD043475 (UNC), HD040636 (RTI)), Office of Dietary Supplements, and NIDDK 9K24 DK083772. The National Cattlemen's Beef Association partially supported the analyses of the biomarkers for this project. NR 37 TC 10 Z9 12 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2431 J9 BMC PEDIATR JI BMC Pediatr. PD JAN 13 PY 2011 VL 11 AR 4 DI 10.1186/1471-2431-11-4 PG 10 WC Pediatrics SC Pediatrics GA 718AW UT WOS:000287093000001 PM 21232139 ER PT J AU Pike, VW Taliani, S Lohith, TG Owen, DRJ Pugliesi, I Da Pozzo, E Hong, JS Zoghbi, SS Gunn, RN Parker, CA Rabiner, EA Fujita, M Innis, RB Martini, C Da Settimo, F AF Pike, Victor W. Taliani, Sabrina Lohith, Talakad G. Owen, David R. J. Pugliesi, Isabella Da Pozzo, Eleonora Hong, Jinsoo Zoghbi, Sami S. Gunn, Roger N. Parker, Christine A. Rabiner, Eugenii A. Fujita, Masahiro Innis, Robert B. Martini, Claudia Da Settimo, Federico TI Evaluation of Novel N-1-Methyl-2-phenylindol-3-ylglyoxylamides as a New Chemotype of 18 kDa Translocator Protein-Selective Ligand Suitable for the Development of Positron Emission Tomography Radioligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PERIPHERAL BENZODIAZEPINE-RECEPTOR; NEUROSTEROID BIOSYNTHESIS; BINDING-SITES; IN-VIVO; BRAIN; PROBES; VISUALIZATION; INFLAMMATION; DISORDERS; BIOMARKER AB A novel series of N-1-methyl-(2-phenylindol-3-yl)glyoxylamides, 19-31, designed in accordance with our previously reported pharmacophore/topological model, showed high affinity for the 18 kDa translocator protein (TSPO) and paved the way for developing a new radiolabeled probe Thus ligand 31, N,N-di-n-propyl-(N-1-methyl-2-(4'-nitrophenyl)indol-3-yl)glyoxylamide, featuring the best combination of affinity and lipophilicity, was labeled with carbon-11 for evaluation with positron emission tomography (PET) in monkey After intravenous injection, [C-11]31 entered brain to give a high proportion of TSPO-specific binding These findings augur well for the future application of [C-11]31 in humans Consequently, the binding of 31 to human TSPO was tested on samples of brain membranes from deceased subjects who through ethically approved in vitro study had previously been established to be high-affinity binders (HABs), mixed-affinity binders (MABs), or low-affinity binders (LABs) for the known TSPO ligand, PBR28 (2) 31 showed high affinity for HABs, MABs, and LABs In conclusion, [C-11]31 represents a promising new chemotype for developing novel TSPO radioligands as biomarkers of neuroinflammation C1 [Pike, Victor W.; Lohith, Talakad G.; Hong, Jinsoo; Zoghbi, Sami S.; Fujita, Masahiro; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Taliani, Sabrina; Pugliesi, Isabella; Da Settimo, Federico] Univ Pisa, Dipartimento Sci Farmaceut, I-56126 Pisa, Italy. [Owen, David R. J.; Rabiner, Eugenii A.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Expt Med & Toxicol, London, England. [Da Pozzo, Eleonora; Martini, Claudia] Univ Pisa, Dipartimento Psichiatria Neurobiol Farmacol & Bio, I-56126 Pisa, Italy. [Gunn, Roger N.; Parker, Christine A.; Rabiner, Eugenii A.] GlaxoSmitlKline, Clin Imaging Ctr, London, England. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3,C346A,10 Ctr Dr, Bethesda, MD 20892 USA. RI Gunn, Roger/H-1666-2012; Da Settimo, Federico/M-1451-2015; Da Pozzo, Eleonora/M-2215-2015; Rabiner, Eugenii/G-6263-2012 OI TALIANI, SABRINA/0000-0001-8675-939X; Martini, Claudia/0000-0001-9379-3027; Gunn, Roger/0000-0003-1181-5769; Da Settimo, Federico/0000-0002-7897-7917; Da Pozzo, Eleonora/0000-0003-4762-8949; Rabiner, Eugenii/0000-0003-3612-6687 FU National Institutes of Health (NIH); National Institute of Mental Health (NIMH); Tuscan Cancer Institute (Istituto Toscano Tumori, ITT) [2007] FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), specifically the National Institute of Mental Health (NIMH), and the Tuscan Cancer Institute (Istituto Toscano Tumori, ITT, grant 2007) We thank the UK Multiple Sclerosis Tissue Bank (Director, Prof Richard Reynolds) for providing human brain tissue samples used in this study We also thank the NIH PET Department for radioisotope production and Kimberley J Jenko and Kacey B Anderson for assistance with blood analysis NR 42 TC 11 Z9 11 U1 1 U2 9 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 13 PY 2011 VL 54 IS 1 BP 366 EP 373 DI 10.1021/jm101230g PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 701KY UT WOS:000285818000030 PM 21133364 ER PT J AU Zhang, D Hu, XM Qian, L Chen, SH Zhou, H Wilson, B Miller, DS Hong, JS AF Zhang, Dan Hu, Xiaoming Qian, Li Chen, Shih-Heng Zhou, Hui Wilson, Belinda Miller, David S. Hong, Jau-Shyong TI Microglial MAC1 receptor and PI3K are essential in mediating beta-amyloid peptide-induced microglial activation and subsequent neurotoxicity SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID ALZHEIMERS-DISEASE; NADPH OXIDASE; DOPAMINERGIC NEURODEGENERATION; PHOSPHOINOSITIDE 3-KINASE; MPTP MODEL; COMPLEMENT RECEPTOR-3; PARKINSONS-DISEASE; SIGNALING PATHWAYS; SCAVENGER RECEPTOR; KNOCKOUT MICE AB Background: beta-Amyloid peptide (A beta) is a major protein in the brain associated with Alzheimer's and Parkinson's diseases. The purpose of this study was to investigate the role of macrophage antigen-1 (MAC1) receptor, an integrin scavenger receptor in microglia, and subsequent signaling events in mediating A beta-induced neurotoxicity. We have previously reported that NADPH oxidase (PHOX) on microglia and superoxide produced by PHOX are critical for A beta-induced loss of dopaminergic neurons. However, the upstream signaling pathway of superoxide production remains unclear. Methods: For the in vitro study, mesencephalic neuron-glia cultures and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1(-/-)) and wild type controls were used to investigate the role of MAC1 receptor in A beta-induced neurotoxicity and the role of phosphoinositide-3 kinase (PI3K) in the signal pathway between MAC1 receptor and PHOX. For the in vivo study, A beta was injected into the substantia nigra of MAC1(-/-) mice and wild type mice to confirm the role of MAC1 receptor. Results: We found that A beta-induced activation of microglia, activation of PHOX, generation of superoxide and other reactive oxygen species, and loss of dopaminergic neurons were decreased in MAC1(-/-) cultures compared to MAC1(+/+) cultures. In MAC1(-/-) mice, dopaminergic neuron loss in response to Ab injection into the substantia nigra was reduced relative to MAC1(+/+) mice. Thus, MAC1 receptor-mediated PHOX activation and increased superoxide production are associated with A beta-induced neurotoxicity. PI3K activation was one downstream step in MAC1 signaling to PHOX and played an important role in A beta-induced neurotoxicity. In microglia-enriched cultures from MAC1(-/-) mice, A beta-induced activation of PI3K (phosphorylation of target proteins and PIP(3) production) was reduced relative to MAC1(+/+) cultures. Conclusions: Taken together, our data demonstrate that A beta activates MAC1 receptor to increase the activity of PI3K, which in turn phosphorylates p47(phox), triggers the translocation of cytosolic subunits of PHOX to microglia membrane, increases PHOX activation and the subsequent production of superoxide and causes neurotoxicity. C1 [Zhang, Dan; Hu, Xiaoming; Qian, Li; Chen, Shih-Heng; Zhou, Hui; Wilson, Belinda; Miller, David S.; Hong, Jau-Shyong] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Zhang, Dan] Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China. [Zhang, Dan] Peking Union Med Coll, Beijing 100050, Peoples R China. [Hu, Xiaoming] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Hu, Xiaoming] Univ Pittsburgh, Sch Med, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15261 USA. [Qian, Li] Univ N Carolina, Comprehens Ctr Inflammatory Disorders, Chapel Hill, NC 27599 USA. [Chen, Shih-Heng] Natl Cheng Kung Univ, Coll Med, Inst Behav Med, Tainan 70101, Taiwan. RP Zhang, D (reprint author), NIEHS, Pharmacol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM danzhang@imm.ac.cn FU National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. We thank Anthony Lockhart for assistance with animal colony management and maintenance of the timed pregnant mice. NR 52 TC 32 Z9 35 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JAN 13 PY 2011 VL 8 AR 3 DI 10.1186/1742-2094-8-3 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 711XO UT WOS:000286625300001 PM 21232086 ER PT J AU Chew, EY Ambrosius, WT AF Chew, Emily Y. Ambrosius, Walter T. TI Update of the ACCORD Eye Study SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. [Ambrosius, Walter T.] Wake Forest Univ, Winston Salem, NC 27109 USA. RP Chew, EY (reprint author), NEI, Bethesda, MD 20892 USA. EM echew@nei.nih.gov NR 2 TC 7 Z9 9 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 13 PY 2011 VL 364 IS 2 BP 188 EP 189 DI 10.1056/NEJMc1011499 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 705NJ UT WOS:000286142900033 PM 21226603 ER PT J AU Pollock, CB Yin, YZ Yuan, HY Zeng, XA King, S Li, X Kopelovich, L Albanese, C Glazer, RI AF Pollock, Claire B. Yin, Yuzhi Yuan, Hongyan Zeng, Xiao King, Sruthi Li, Xin Kopelovich, Levy Albanese, Chris Glazer, Robert I. TI PPAR delta Activation Acts Cooperatively with 3-Phosphoinositide-Dependent Protein Kinase-1 to Enhance Mammary Tumorigenesis SO PLOS ONE LA English DT Article ID HUMAN BREAST-CANCER; ATP CITRATE LYASE; RECEPTOR-DELTA; EPITHELIAL-CELLS; GENE-EXPRESSION; TRANSCRIPTIONAL CONTROL; SKELETAL-MUSCLE; GROWTH-FACTOR; PDK1; PHOSPHORYLATION AB Peroxisome proliferator-activated receptor delta (PPAR delta) is a transcription factor that is associated with metabolic gene regulation and inflammation. It has been implicated in tumor promotion and in the regulation of 3-phosphoinositide-dependent kinase-1 (PDK1). PDK1 is a key regulator of the AGC protein kinase family, which includes the proto-oncogene AKT/PKB implicated in several malignancies, including breast cancer. To assess the role of PDK1 in mammary tumorigenesis and its interaction with PPAR delta, transgenic mice were generated in which PDK1 was expressed in mammary epithelium under the control of the MMTV enhancer/promoter region. Transgene expression increased pT308AKT and pS9GSK3 beta, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKC alpha. The transgenic mammary gland also expressed higher levels of PPAR delta and a gene expression profile resembling wild-type mice maintained on a diet containing the PPAR delta agonist, GW501516. Both wild-type and transgenic mice treated with GW501516 exhibited accelerated rates of tumor formation that were more pronounced in transgenic animals. GW501516 treatment was accompanied by a distinct metabolic gene expression and metabolomic signature that was not present in untreated animals. GW501516-treated transgenic mice expressed higher levels of fatty acid and phospholipid metabolites than treated wild-type mice, suggesting the involvement of PDK1 in enhancing PPAR delta-driven energy metabolism. These results reveal that PPAR delta activation elicits a distinct metabolic and metabolomic profile in tumors that is in part related to PDK1 and AKT signaling. C1 [Pollock, Claire B.; Yin, Yuzhi; Yuan, Hongyan; Zeng, Xiao; Albanese, Chris; Glazer, Robert I.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Pollock, Claire B.; Yin, Yuzhi; Yuan, Hongyan; Zeng, Xiao; Albanese, Chris; Glazer, Robert I.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [King, Sruthi] Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. [Li, Xin] Georgetown Univ, Med Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC 20007 USA. [Kopelovich, Levy] NCI, Chemoprevent Agent Dev & Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Pollock, CB (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. EM glazerr@georgetown.edu FU National Institutes of Health, Bethesda, MD [R01 CA111482, N01 CN43309]; National Cancer Institute [1P30-CA-51008] FX This work was supported by grant R01 CA111482 and contract N01 CN43309 from the National Institutes of Health, Bethesda, MD. This investigation was conducted using the Animal Research, Histopathology and Tissue, Genomics and Epigenomics, Preclinical Imaging, and Proteomics and Metabolomics Shared Resources supported in part by Cancer Center Support Grant 1P30-CA-51008 from the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 11 Z9 11 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 13 PY 2011 VL 6 IS 1 AR e16215 DI 10.1371/journal.pone.0016215 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710ME UT WOS:000286515000033 PM 21297860 ER PT J AU Zhang, DD Qian, YD Akula, N Alliey-Rodriguez, N Tang, JS Gershon, ES Liu, CY AF Zhang, Dandan Qian, Yudong Akula, Nirmala Alliey-Rodriguez, Ney Tang, Jinsong Gershon, Elliot S. Liu, Chunyu CA Bipolar Genome Study TI Accuracy of CNV Detection from GWAS Data SO PLOS ONE LA English DT Article ID COPY-NUMBER VARIATION; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; HUMAN GENOME; BIPOLAR DISORDER; INCREASE RISK; SCHIZOPHRENIA; POLYMORPHISM; ASSOCIATION; ABERRATIONS AB Several computer programs are available for detecting copy number variants (CNVs) using genome-wide SNP arrays. We evaluated the performance of four CNV detection software suites-Birdsuite, Partek, HelixTree, and PennCNV-Affy-in the identification of both rare and common CNVs. Each program's performance was assessed in two ways. The first was its recovery rate, i.e., its ability to call 893 CNVs previously identified in eight HapMap samples by paired-end sequencing of whole-genome fosmid clones, and 51,440 CNVs identified by array Comparative Genome Hybridization (aCGH) followed by validation procedures, in 90 HapMap CEU samples. The second evaluation was program performance calling rare and common CNVs in the Bipolar Genome Study (BiGS) data set (1001 bipolar cases and 1033 controls, all of European ancestry) as measured by the Affymetrix SNP 6.0 array. Accuracy in calling rare CNVs was assessed by positive predictive value, based on the proportion of rare CNVs validated by quantitative real-time PCR (qPCR), while accuracy in calling common CNVs was assessed by false positive/false negative rates based on qPCR validation results from a subset of common CNVs. Birdsuite recovered the highest percentages of known HapMap CNVs containing >20 markers in two reference CNV datasets. The recovery rate increased with decreased CNV frequency. In the tested rare CNV data, Birdsuite and Partek had higher positive predictive values than the other software suites. In a test of three common CNVs in the BiGS dataset, Birdsuite's call was 98.8% consistent with qPCR quantification in one CNV region, but the other two regions showed an unacceptable degree of accuracy. We found relatively poor consistency between the two "gold standards,'' the sequence data of Kidd et al., and aCGH data of Conrad et al. Algorithms for calling CNVs especially common ones need substantial improvement, and a "gold standard'' for detection of CNVs remains to be established. C1 [Zhang, Dandan] Zhejiang Univ, Sch Med, Dept Pathol, Hangzhou 310003, Zhejiang, Peoples R China. [Zhang, Dandan; Qian, Yudong; Alliey-Rodriguez, Ney; Gershon, Elliot S.; Liu, Chunyu] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Akula, Nirmala] NIMH, Intramural Res Programs, Bethesda, MD 20892 USA. [Tang, Jinsong] Cent S Univ, Xiangya Hosp 2, Inst Mental Hlth, Changsha, Hunan, Peoples R China. RP Zhang, DD (reprint author), Zhejiang Univ, Sch Med, Dept Pathol, Hangzhou 310003, Zhejiang, Peoples R China. EM egershon@yoda.bsd.uchicago.edu; cliu@yoda.bsd.uchicago.edu RI Liu, Chunyu/G-7561-2012; Smith, Erin/E-5933-2011; OI Liu, Chunyu/0000-0002-5986-4415; McMahon, Francis/0000-0002-9469-305X FU National Institute of Mental Health [R01MH080425, 1R01MH081804]; National Alliance for Research on Schizophrenia and Depression [R01MH081804]; Eklund family; Geraldi Norton Foundation FX This work was supported by grants from The National Institute of Mental Health, R01MH080425 and 1R01MH081804, The National Alliance for Research on Schizophrenia and Depression, R01MH081804, the Eklund family, and the Geraldi Norton Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 37 Z9 39 U1 1 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 13 PY 2011 VL 6 IS 1 AR e14511 DI 10.1371/journal.pone.0014511 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710ME UT WOS:000286515000001 PM 21249187 ER PT J AU Strasak, AM Kim, AY Lauer, GM de Sousa, PS Ginuino, CF Fernandes, CA Velloso, CE de Almeida, AJ de Oliveira, JM Yoshida, CF zur Wiesch, JS Paranhos-Baccala, G Lang, S Brant, LJ Ulmer, H Strohmaier, S Kaltenbach, L Lampe, E Lewis-Ximenez, LL AF Strasak, Alexander M. Kim, Arthur Y. Lauer, Georg M. de Sousa, Paulo S. Ginuino, Cleber F. Fernandes, Carlos A. Velloso, Carlos E. de Almeida, Adilson J. de Oliveira, Jaqueline M. Yoshida, Clara F. zur Wiesch, Julian Schulze Paranhos-Baccala, Glaucia Lang, Stefan Brant, Larry J. Ulmer, Hanno Strohmaier, Susanne Kaltenbach, Lalit Lampe, Elisabeth Lewis-Ximenez, Lia L. TI Antibody dynamics and spontaneous viral clearance in patients with acute hepatitis C infection in Rio de Janeiro, Brazil SO BMC INFECTIOUS DISEASES LA English DT Article ID CELLULAR IMMUNE-RESPONSES; VIRUS-INFECTION; HCV; SEROCONVERSION; POPULATION; DISEASE; VIREMIA; COHORT; LOAD AB Background: The anti-HCV antibody response has not been well characterized during the early phase of HCV infection and little is known about its relationship to the clinical course during this period. Methods: We analyzed serial anti-HCV antibodies longitudinally obtained from a prospective cohort of 65 patients with acute HCV infection by using a microparticle enzyme immunoassay AxSYM HCV 3.0 (Abbott Diagnostics) during the first 12 months from HCV acquisition in Rio de Janeiro, Brazil. Spontaneous viral clearance (SVC) was defined as undetectable HCV RNA in serum, in the absence of treatment, for three consecutive HCV PCR tests within 12-months of follow-up. Results: Baseline antibody values were similar among patient groups with self-limiting HCV evolution (n = 34) and persistent viremia (n = 31) [median (interquartile range) signal/cut-off ratio (s/co) 78.7 (60.7-93.8) vs. 93.9 (67.8-111.9), p = 0.26]. During 12-months follow-up, patients with acute spontaneous resolving HCV infection showed significantly lower serial antibody response in comparison to individuals progressing to chronic infection [median (interquartile range) s/co 62.7 (35.2-85.0) vs. 98.4 (70.4-127.4), p < 0.0001]. In addition, patients with self-limiting HCV evolution exhibited an expeditious, sharp decline of serial antibody values after SVC in comparison to those measured before SVC [median (interquartile range) s/co 56.0 (25.4-79.3) vs. 79.4 (66.3-103.0), p < 0.0001]. Conclusion: Our findings indicate a rapid short-term decline of antibody values in patients with acute spontaneous resolving HCV infection. C1 [de Sousa, Paulo S.; Ginuino, Cleber F.; Velloso, Carlos E.; de Almeida, Adilson J.; Yoshida, Clara F.; Lampe, Elisabeth; Lewis-Ximenez, Lia L.] Fiocruz MS, Inst Oswaldo Cruz, Viral Hepatitis Lab, BR-21045900 Rio De Janeiro, Brazil. [Strasak, Alexander M.; Ulmer, Hanno; Strohmaier, Susanne; Kaltenbach, Lalit] Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Innsbruck, Austria. [Kim, Arthur Y.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Kim, Arthur Y.; Lauer, Georg M.] Harvard Univ, Sch Med, Boston, MA USA. [Lauer, Georg M.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Fernandes, Carlos A.] Cent Publ Hlth Lab Noel Nutels, Hepatitis Div, Rio De Janeiro, Brazil. [de Almeida, Adilson J.] Fed Univ State Rio de Janeiro, Gaffree & Guinle Univ Hosp, Hematol Unit, Rio De Janeiro, Brazil. [de Oliveira, Jaqueline M.] Fiocruz MS, Inst Oswaldo Cruz, Viral Technol Lab, BR-21045900 Rio De Janeiro, Brazil. [zur Wiesch, Julian Schulze] Univ Klinikum Eppendorf, Med Klin 1, Hamburg, Germany. [Paranhos-Baccala, Glaucia] Fdn Merieux, Emerging Pathogens Lab, Lyon, France. [Lang, Stefan] Univ Innsbruck, Inst Stat, A-6020 Innsbruck, Austria. [Brant, Larry J.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Lewis-Ximenez, LL (reprint author), Fiocruz MS, Inst Oswaldo Cruz, Viral Hepatitis Lab, BR-21045900 Rio De Janeiro, Brazil. EM lialewis.fiocruz@gmail.com RI Lang, Stefan/E-7500-2010; Ulmer, Hanno/C-3488-2011; Fernandes, Carlos/F-9968-2012 OI Lang, Stefan/0000-0003-0739-3858; Ulmer, Hanno/0000-0001-5911-1002; Fernandes, Carlos/0000-0003-2941-4744 FU National Institute of Health (NIH) [AI066345-05]; CGLAB/Ministry of Health, Brazil FX Our research was supported by National Institute of Health (NIH) grant AI066345-05, and CGLAB/Ministry of Health, Brazil. NR 28 TC 6 Z9 6 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JAN 12 PY 2011 VL 11 AR 15 DI 10.1186/1471-2334-11-15 PG 5 WC Infectious Diseases SC Infectious Diseases GA 717YU UT WOS:000287086000003 PM 21226945 ER PT J AU Shen, H Harvey, BK Chiang, YH Pick, CG Wang, Y AF Shen, Hui Harvey, Brandon K. Chiang, Yung-Hsiao Pick, Chaim G. Wang, Yun TI Methamphetamine potentiates behavioral and electrochemical responses after mild traumatic brain injury in mice SO BRAIN RESEARCH LA English DT Article DE Head trauma; mTBI; Dopamine; Methamphetamine; Behavior ID TYROSINE-HYDROXYLASE; ISCHEMIC-STROKE; RAT; IMPAIRMENT; PREVALENCE; INHALATION; SYSTEM AB We previously demonstrated that high doses of methamphetamine (MA) exacerbate damage induced by severe brain trauma. The purpose of the present study was to examine if MA, at low dosage, affected abnormalities in locomotor activity and dopamine turnover in a mouse model of mild traumatic brain injury (mTBI). Adult male CD1 mice were treated with MA (5 mg/kg i.p.) or vehicle 30-min prior to mTBI, conducted by dropping a 30 g metal weight onto the temporal skull, anterior the right ear. At 15 min after mTBI, animals were put into locomotor activity chambers for up to 72 h. During the first 3 h, mTBI alone, compared with vehicle control, did not alter total distance travelled. Treatment with MA significantly increased locomotor activity in the control animals during the first 3 h; mTBI reduced MA-induced hyperactivity. In contrast, at 2 and 3 days after injury, mTBI or MA alone reduced locomotor activity. Co-treatment with MA and mTBI further reduced this activity, suggesting a differential and temporal behavioral interaction between MA and mTBI during acute and subacute phases after injury. Dopamine and DOPAC levels in striatal tissue were analyzed using HPLC-ECD. At 1 h after mTBI or injection, DA was not altered but DOPAC level and DOPAC/DA turnover ratios were significantly reduced. Co-treatment with MA further reduced the DOPAC/DA ratio. At 36 h after injury, mTBI increased tissue DA levels, but reduced DOPAC levels and DOPAC/DA ratios. Co-treatment with MA further reduced DOPAC/DA ratios in striatum. In conclusion, our data suggest that low dosage of MA worsens the suppression of locomotor responses and striatal dopamine turnover after mTBI. Published by Elsevier B.V. C1 [Wang, Yun] NIDA, Neural Protect & Regenerat Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Chiang, Yung-Hsiao] Taipei Med Univ, Taipei, Taiwan. [Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, Tel Aviv, Israel. RP Wang, Y (reprint author), NIDA, Neural Protect & Regenerat Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov FU National Institute on Drug Abuse, IRP, U.S.A.; National Science Council of Taiwan [NSC98-2314-B-038-011-MY3] FX This study was supported by the National Institute on Drug Abuse, IRP, U.S.A. and National Science Council of Taiwan (NSC98-2314-B-038-011-MY3). NR 22 TC 2 Z9 2 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 12 PY 2011 VL 1368 BP 248 EP 253 DI 10.1016/j.brainres.2010.10.014 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 714ZJ UT WOS:000286849900026 PM 20950593 ER PT J AU Rider, LG Miller, FW AF Rider, Lisa G. Miller, Frederick W. TI Deciphering the Clinical Presentations, Pathogenesis, and Treatment of the Idiopathic Inflammatory Myopathies SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID INTERSTITIAL LUNG-DISEASE; INCLUSION-BODY MYOSITIS; ULTRAVIOLET-RADIATION INTENSITY; JUVENILE DERMATOMYOSITIS; POLYMYOSITIS-DERMATOMYOSITIS; ENVIRONMENTAL-FACTORS; AUTOANTIBODIES; EXPRESSION; ARTHRITIS; RISK AB The idiopathic inflammatory myopathies or myositis syndromes (the most common forms are polymyositis, dermatomyositis, and inclusion body myositis) are systemic autoimmune diseases defined by chronic muscle weakness and inflammation of unknown etiology and result in significant morbidity and mortality. Research suggests that categorizing heterogeneous myositis syndromes into mutually exclusive and stable phenotypes by using clinical and immune response features is useful for predicting clinical signs and symptoms, associated genetic and environmental risk factors, and responses to therapy and prognosis. Knowledge of myositis phenotypes should enhance clinicians' ability to recognize and manage these rare disorders. JAMA. 2011; 305(2): 183-190 C1 [Rider, Lisa G.; Miller, Frederick W.] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Program Clin Res, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Rider, LG (reprint author), Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Program Clin Res, NIH,US Dept Hlth & Human Serv, CRC 4-2352,MSC 1301,10 Ctr Dr, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU National Institute of Environmental Health Sciences, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 50 TC 46 Z9 49 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 12 PY 2011 VL 305 IS 2 BP 183 EP 190 DI 10.1001/jama.2010.1977 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 705BM UT WOS:000286103400024 PM 21224460 ER PT J AU Berman, RA Wurtz, RH AF Berman, Rebecca A. Wurtz, Robert H. TI Signals Conveyed in the Pulvinar Pathway from Superior Colliculus to Cortical Area MT SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VISUAL RESPONSE PROPERTIES; BEHAVING RHESUS-MONKEY; SACCADIC SUPPRESSION; SINGLE NEURONS; MACAQUE MONKEY; AFFERENT BASIS; MODULATION; ATTENTION; CORTEX; SELECTIVITY AB We previously established a functional pathway extending from the superficial layers of the superior colliculus (SC) through the inferior pulvinar (PI) to cortical area MT in the primate (Macaca mulatta). Here, we characterized the signals that this pathway conveys to cortex by recording from pulvinar neurons that we identified by microstimulation as receiving input from SC and/or projecting to MT. The basic properties of these ascending-path PI neurons resembled those of SC visual neurons. Namely, they had brisk responses to spots of light, inhibitory surrounds, and relatively large receptive fields that increased with eccentricity, as well as minimal presaccadic activity. Beyond these basic properties, there were two salient results regarding the modulatory and motion signals conveyed by this ascending pathway. First, the PI neurons appeared to convey only a subset of the modulations found in the SC: they exhibited saccadic suppression, the inhibition of activity at the time of the saccade, but did not clearly show the attentional enhancement of the visual response seen in SC. Second, directional selectivity was minimal in PI neurons belonging to the ascending path but was significantly more prominent in PI neurons receiving input from MT. This finding casts doubt on earlier assumptions that PI provides directionally selective signals to MT and instead suggests that PI derives its selectivity from MT. The identification of this pathway and its transmitted activity establishes the first functional pathway from brainstem to cortex through pulvinar and makes it possible to examine its contribution to cortical visual processing, perception, and action. C1 [Berman, Rebecca A.; Wurtz, Robert H.] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Berman, RA (reprint author), NEI, Sensorimotor Res Lab, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. EM bermanr@nei.nih.gov FU National Eye Institute Intramural Research Program at the National Institutes of Health FX This work was supported by the National Eye Institute Intramural Research Program at the National Institutes of Health. We are grateful to Drs. David Leopold, David McMahon, and Michael Schmid for helpful discussions and comments on this manuscript, and to Mitchell Smith, Altah Nichols, Tom Ruffner, and John McClurkin for technical support. NR 48 TC 51 Z9 53 U1 2 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 12 PY 2011 VL 31 IS 2 BP 373 EP 384 DI 10.1523/JNEUROSCI.4738-10.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 705MR UT WOS:000286139100002 PM 21228149 ER PT J AU Forni, PE Fornaro, M Guenette, S Wray, S AF Forni, Paolo E. Fornaro, Michele Guenette, Suzanne Wray, Susan TI A Role for FE65 in Controlling GnRH-1 Neurogenesis SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; HORMONE-RELEASING HORMONE; NEURAL PROGENITOR CELLS; ADAPTER PROTEIN; EXPLANT CULTURES; DEVELOPING MOUSE; LHRH NEURONS; INTRACELLULAR DOMAIN; ALZHEIMERS-DISEASE; OLFACTORY PLACODE AB Gonadotropin-releasing hormone-1 (GnRH-1) neurons migrate from the nasal placode to the forebrain where they control gonadal function via the hypothalamic-pituitary-gonadal axis. The birth of GnRH-1-expressing neurons is one of the first neurogenic events in the developing nasal placode. By gene expression screening on single GnRH-1 neurons, amyloid precursor binding protein-1 (FE65) was identified in migratory GnRH-1 neurons. FE65 has been shown to modulate beta 1-integrin dynamics, actin cytoskeleton, cell motility, and FE65/amyloid precursor protein signaling has been described in neuro/glial cell fate determination as well as in modulating neurogenesis. Analysis of two mouse lines, one deficient for the 97 kDa FE65 isoform and a second deficient for the 97 and 60 kDa forms of FE65, showed overlapping phenotypes. In both lines, no migratory defects of the GnRH-1 neurons were observed, but a 25% increase in GnRH-1 neuronal number during embryonic development was found. Bromodeoxyuridine birth tracing and spatiotemporal tracking of GnRH-1 cell precursors demonstrated that the lack of the N-terminal portion of FE65, which includes part of the functional nuclear translocation/gene transcription domain of FE65 (WW domain), extends the timing of GnRH-1 neurogenesis in the developing nasal placode without affecting proliferation of GnRH-1 neuronal progenitors or cell death. The observed changes in the dynamics of GnRH-1 neurogenesis highlight a unique role for the 97 kDa isoform of FE65 and suggest that GnRH-1 cells, which have a short neurogenic window, originate from multipotent progenitors able to generate distinct cell types as GnRH-1 neurogenesis declines in response to environmental changes. C1 [Forni, Paolo E.; Fornaro, Michele; Wray, Susan] Natl Inst Neurol Disorders & Stroke, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Fornaro, Michele] Univ Turin, Dept Clin & Biol Sci, I-10129 Turin, Italy. [Guenette, Suzanne] Massachusetts Gen Inst Neurodegenerat Dis, Genet & Aging Res Unit, Charlestown, MA 02129 USA. RP Wray, S (reprint author), Natl Inst Neurol Disorders & Stroke, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov RI FORNI, PAOLO /C-3533-2011; OI Fornaro, Michele/0000-0003-1852-9167; wray, susan/0000-0001-7670-3915 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. We thank Drs. H. Arnheiter for critical review of this manuscript and G. M. Martins for providing p97FE65 animals. NR 57 TC 13 Z9 13 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 12 PY 2011 VL 31 IS 2 BP 480 EP 491 DI 10.1523/JNEUROSCI.4698-10.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 705MR UT WOS:000286139100011 PM 21228158 ER PT J AU Krueger, F Pardini, M Huey, ED Raymont, V Solomon, J Lipsky, RH Hodgkinson, CA Goldman, D Grafman, J AF Krueger, Frank Pardini, Matteo Huey, Edward D. Raymont, Vanessa Solomon, Jeffrey Lipsky, Robert H. Hodgkinson, Colin A. Goldman, David Grafman, Jordan TI The Role of the Met66 Brain-Derived Neurotrophic Factor Allele in the Recovery of Executive Functioning after Combat-Related Traumatic Brain Injury SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BDNF VAL66MET POLYMORPHISM; ACTIVITY-DEPENDENT SECRETION; FAMILY-BASED ASSOCIATION; PENETRATING HEAD-INJURY; CARD SORTING TEST; FACTOR GENE; ALZHEIMERS-DISEASE; NEURONAL DEVELOPMENT; MEMORY PERFORMANCE; RECEPTOR SORTILIN AB Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the recovery of executive functioning after TBI. We genotyped a sample of male Vietnam combat veterans consisting of a frontal lobe lesion group with focal penetrating head injuries and a non-head-injured control group for the Val66Met BDNF polymorphism. The Delis-Kaplan Executive Function System as a standardized psychometric battery was administrated to examine key domains of executive functions. The results revealed that the Met allele but not the hypothesized Val allele promotes recovery of executive functioning. Overall, the Met66 carriers in the lesion group performed as well as the Met66 carriers in the control group. The Met66 allele accounted for 6.2% of variance for executive functioning independently of other significant predictors including preinjury intelligence, left hemisphere volume loss, and dorsolateral PFC volume loss. The findings point to different mechanisms of the Val66Met BDNF gene in complex phenotypes under normal and pathological conditions. Abetter understanding of these mechanisms could be instrumental in the development and application of effective therapeutic strategies to facilitate recovery from TBI. C1 [Krueger, Frank] George Mason Univ, Dept Mol Neurosci, Fairfax, VA 22030 USA. [Krueger, Frank; Raymont, Vanessa; Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Pardini, Matteo] Univ Genoa, Dept Neurosci Ophthalmol & Genet, I-16132 Genoa, Italy. [Huey, Edward D.] Study Alzheimers Dis & Memory Disorders, Litwin Zucker Res Ctr, Manhasset, NY 11030 USA. [Raymont, Vanessa] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21287 USA. [Lipsky, Robert H.] Inova Fairfax Hosp, Dept Neurosci, Falls Church, VA 22042 USA. RP Krueger, F (reprint author), George Mason Univ, Dept Mol Neurosci, Fairfax, VA 22030 USA. EM fkrueger@gmu.edu; grafmanj@ninds.nih.gov RI Pardini, Matteo/F-8414-2010; Goldman, David/F-9772-2010; OI Pardini, Matteo/0000-0002-4740-1982; Goldman, David/0000-0002-1724-5405; Grafman, Jordan H./0000-0001-8645-4457; Lipsky, Robert/0000-0001-7753-1473 FU National Institute of Neurological Disorders and Stroke; U.S. Army Medical Research and Material Command FX This work was supported by the National Institute of Neurological Disorders and Stroke intramural research program and a project grant from the U.S. Army Medical Research and Material Command administrated by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30 year postinjury follow-up study). We are grateful to all the Vietnam veterans who participated in this study. Without their long-term commitment to improving the health care of veterans, this study could not have been completed. We thank the National Naval Medical Center for their support and provision of their facilities. We are grateful to S. Bonifant, B. Cheon, C. Ngo, A. Greathouse, K. Reding, and G. Tasick for their invaluable help with the testing of participants and organization of this study. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, or the U. S. Government. NR 70 TC 41 Z9 44 U1 5 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 12 PY 2011 VL 31 IS 2 BP 598 EP 606 DI 10.1523/JNEUROSCI.1399-10.2011 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 705MR UT WOS:000286139100021 PM 21228168 ER PT J AU Hongpaisan, J Sun, MK Alkon, DL AF Hongpaisan, Jarin Sun, Miao-Kun Alkon, Daniel L. TI PKC epsilon Activation Prevents Synaptic Loss, A beta Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROTEIN-KINASE-C; AMYLOID-BETA; NEUROTROPHIC FACTOR; MOUSE MODEL; PRECURSOR PROTEIN; MEMORY DEFICITS; ALPHA-SECRETASE; TG2576 MICE; IN-VIVO; BRAIN AB Among the pathologic hallmarks of Alzheimer's disease (AD) neurodegeneration, only synaptic loss in the brains of AD patients closely correlates with the degree of dementia in vivo. Here, we describe a molecular basis for this AD loss of synapses: pathological reduction of synaptogenic PKC isozymes and their downstream synaptogenic substrates, such as brain-derived neurotrophic factor. This reduction, particularly of PKC alpha and epsilon, occurs in association with elevation of soluble beta amyloid protein (A beta), but before the appearance of the amyloid plaques or neuronal loss in the Tg2576 AD transgenic mouse strain. Conversely, treatment of the Tg2576 mouse brain with the PKC activator, bryostatin-1, restores normal or supranormal levels of PKC alpha and epsilon, reduces the level of soluble A beta, prevents and/or reverses the loss of hippocampal synapses, and prevents the memory impairment observed at 5 months postpartum. Similarly, the PKC epsilon-specific activator, DCP-LA, effectively prevents synaptic loss, amyloid plaques, and cognitive deficits (also prevented by bryostatin-1) in the much more rapidly progressing 5XFAD transgenic strain. These results suggest that synaptic loss and the resulting cognitive deficits depend on the balance between the lowering effects of A beta on PKC alpha and epsilon versus the lowering effects of PKC on A beta in AD transgenic mice. C1 [Hongpaisan, Jarin; Sun, Miao-Kun; Alkon, Daniel L.] W Virginia Univ, Blanchette Rockefeller Neurosci Inst, Morgantown, WV 26505 USA. [Hongpaisan, Jarin] Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Hongpaisan, J (reprint author), W Virginia Univ, Blanchette Rockefeller Neurosci Inst, 8 Med Ctr Dr, Morgantown, WV 26505 USA. EM jhongpaisan@brni.org NR 51 TC 81 Z9 85 U1 3 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 12 PY 2011 VL 31 IS 2 BP 630 EP 643 DI 10.1523/JNEUROSCI.5209-10.2011 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 705MR UT WOS:000286139100025 PM 21228172 ER PT J AU Qiu, XY Rau, DC Parsegian, VA Fang, LT Knobler, CM Gelbart, WM AF Qiu, Xiangyun Rau, Donald C. Parsegian, V. Adrian Fang, Li Tai Knobler, Charles M. Gelbart, William M. TI Salt-Dependent DNA-DNA Spacings in Intact Bacteriophage lambda Reflect Relative Importance of DNA Self-Repulsion and Bending Energies SO PHYSICAL REVIEW LETTERS LA English DT Article ID EJECTION FORCES; GENOME LENGTH; PORTAL MOTOR; PHAGE; HELICES; PHI-29 AB Using solution synchrotron x-ray scattering, we measure the variation of DNA-DNA d spacings in bacteriophage lambda with mono-, di-, and polyvalent salt concentrations, for wild-type [48.5 x 10(3) base pairs (bp)] and short-genome-mutant (37.8 kbp) strains. From the decrease in d spacings with increasing salt, we deduce the relative contributions of DNA self-repulsion and bending to the energetics of packaged phage genomes. We quantify the DNA-DNA interaction energies within the intact phage by combining the measured d spacings in the capsid with measurements of osmotic pressure in DNA assemblies under the same salt conditions in bulk solution. In the commonly used Tris-Mg buffer, the DNA-DNA interaction energies inside the phage capsids are shown to be about 1kT/bp, an order of magnitude larger than the bending energies. C1 [Qiu, Xiangyun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Rau, Donald C.] NIH, Lab Phys & Struct Biol, Program Phys Biol, Bethesda, MD 20892 USA. [Parsegian, V. Adrian] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. [Fang, Li Tai; Knobler, Charles M.; Gelbart, William M.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. RP Qiu, XY (reprint author), George Washington Univ, Dept Phys, Washington, DC 20052 USA. RI Fang, Li Tai/D-4760-2011 FU NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NSF [CHE07-14411] FX We thank Drs. Lin Yang, Sankar Adhya, and Rotem Edgar for helpful advice and discussions. This research was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and by NSF Grant No. CHE07-14411. NR 26 TC 31 Z9 31 U1 2 U2 24 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 12 PY 2011 VL 106 IS 2 AR 028102 DI 10.1103/PhysRevLett.106.028102 PG 4 WC Physics, Multidisciplinary SC Physics GA 713NX UT WOS:000286745800005 PM 21405253 ER PT J AU Rozycki, B Kim, YC Hummer, G AF Rozycki, Bartosz Kim, Young C. Hummer, Gerhard TI SAXS Ensemble Refinement of ESCRT-III CHMP3 Conformational Transitions SO STRUCTURE LA English DT Article ID X-RAY-SCATTERING; SMALL-ANGLE SCATTERING; STRUCTURAL BASIS; BIOLOGICAL MACROMOLECULES; PROTEIN; COMPLEXES; DOMAIN; AUTOINHIBITION; BINDING; NMR AB We developed and implemented an ensemble-refinement method to study dynamic biomolecular assemblies with intrinsically disordered segments. Data from small angle X-ray scattering (SAXS) experiments and from coarse-grained molecular simulations were combined by using a maximum-entropy approach. The method was applied to CHMP3 of ESCRT-III, a protein with multiple helical domains separated by flexible linkers. Based on recent SAXS data by Lata et al. (J. Mol. Biol. 378, 818, 2008), we constructed ensembles of CHMP3 at low- and high-salt concentration to characterize its closed autoinhibited state and open active state. At low salt, helix alpha(5) is bound to the tip of helices alpha(1) and alpha(2), in excellent agreement with a recent crystal structure. Helix alpha(6) remains free in solution and does not appear to be part of the autoinhibitory complex. The simulation-based ensemble refinement is general and effectively increases the resolution of SAXS beyond shape information to atomically detailed structures. C1 [Rozycki, Bartosz; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Kim, Young C.] USN, Res Lab, Ctr Computat Mat Sci, Washington, DC 20375 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov RI Rozycki, Bartosz/B-7005-2009; Hummer, Gerhard/A-2546-2013 OI Rozycki, Bartosz/0000-0001-5938-7308; Hummer, Gerhard/0000-0001-7768-746X FU NIH, NIDDK; European Community FX We thank Dr. James Hurley and Dr. Alexander Grishaev for many helpful discussions. This work used the Biowulf computing cluster at the NIH. The research was supported by the Intramural Research Program of the NIH, NIDDK, and by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (to B.R.). NR 47 TC 95 Z9 96 U1 2 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JAN 12 PY 2011 VL 19 IS 1 BP 109 EP 116 DI 10.1016/j.str.2010.10.006 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 708FP UT WOS:000286348000014 PM 21220121 ER PT J AU Nathan, AA Mohan, V Babu, SS Bairagi, S Dixit, M AF Nathan, Abel A. Mohan, Viswanathan Babu, Subash S. Bairagi, Soumi Dixit, Madhulika TI Glucose challenge increases circulating progenitor cells in Asian Indian male subjects with normal glucose tolerance which is compromised in subjects with pre-diabetes: A pilot study SO BMC ENDOCRINE DISORDERS LA English DT Article ID TYPE-2 DIABETES-MELLITUS; CARDIOVASCULAR-DISEASE; PERIPHERAL-BLOOD; STEM-CELL; NATURAL-HISTORY; RISK; TRANSPLANTATION; DYSFUNCTION; ENGRAFTMENT; POPULATION AB Background: Haematopoietic stem cells undergo mobilization from bone marrow to blood in response to physiological stimuli such as ischemia and tissue injury. The aim of study was to determine the kinetics of circulating CD34(+) and CD133(+)CD34(+) progenitor cells in response to 75 g glucose load in subjects with normal and impaired glucose metabolism. Methods: Asian Indian male subjects (n = 50) with no prior history of glucose imbalance were subjected to 2 hour oral glucose tolerance test (OGTT). 24 subjects had normal glucose tolerance (NGT), 17 subjects had impaired glucose tolerance (IGT) and 9 had impaired fasting glucose (IFG). The IGT and IFG subjects were grouped together as pre-diabetes group (n = 26). Progenitor cell counts in peripheral circulation at fasting and 2 hour post glucose challenge were measured using direct two-color flow cytometry. Results: The pre-diabetes group was more insulin resistant (p < 0.0001) as measured by homeostasis assessment model (HOMA-IR) compared to NGT group. A 2.5-fold increase in CD34(+) cells (p = 0.003) and CD133(+)CD34(+) (p = 0.019) cells was seen 2 hours post glucose challenge in the NGT group. This increase for both the cell types was attenuated in subjects with IGT. CD34(+) cell counts in response to glucose challenge inversely correlated with neutrophil counts (r = -0.330, p = 0.019), while post load counts of CD133(+)CD34(+) cells inversely correlated with serum creatinine (r = -0.312, p = 0.023). Conclusion: There is a 2.5-fold increase in the circulating levels of haematopoietic stem cells in response to glucose challenge in healthy Asian Indian male subjects which is attenuated in subjects with pre-diabetes. C1 [Nathan, Abel A.; Bairagi, Soumi; Dixit, Madhulika] Indian Inst Technol Madras IIT Madras, Dept Biotechnol, Lab Vasc Biol, Madras, Tamil Nadu, India. [Mohan, Viswanathan] MDRF, Dept Diabetol, Madras, Tamil Nadu, India. [Mohan, Viswanathan] WHO Collaborating Ctr Noncommunicable Dis Prevent, Dr Mohans Diabet Special Ctr, Madras, Tamil Nadu, India. [Mohan, Viswanathan] IDF Ctr Educ, Madras, Tamil Nadu, India. [Babu, Subash S.] Int Ctr Excellence Res, Natl Inst Hlth, Chennai, Tamil Nadu, India. [Babu, Subash S.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Dixit, M (reprint author), Indian Inst Technol Madras IIT Madras, Dept Biotechnol, Lab Vasc Biol, Madras, Tamil Nadu, India. EM mdixit@iitm.ac.in FU Department of Biotechnology (DBT), Government of India FX This work was supported by the Innovative Young Biotechnologist Award (IYBA) program of the Department of Biotechnology (DBT), Government of India awarded to Dr. Madhulika Dixit. Authors acknowledge Mrs. N. Alamelu, Proprietress, ANSI Techniques, Chennai, for extending her help in statistical analysis. Help rendered by Dr. V. Kumaraswamy, Director, Tuberculosis Research Center (TRC), Dr. M. Deepa and Dr. H. Ranjani of Dr. Mohan's Diabetes Specialties Centre and Madras Diabetes Research Foundation, Gopalapuram, Chennai is acknowledged. NR 27 TC 4 Z9 4 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6823 J9 BMC ENDOCR DISORD JI BMC Endocr. Disord. PD JAN 11 PY 2011 VL 11 AR 2 DI 10.1186/1472-6823-11-2 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 851RL UT WOS:000297288500001 PM 21219665 ER PT J AU Clark, WF Na, YB Rosansky, SJ Sontrop, JM Macnab, JJ Glassock, RJ Eggers, PW Jackson, K Moist, L AF Clark, William F. Na, Yingbo Rosansky, Steven J. Sontrop, Jessica M. Macnab, Jennifer J. Glassock, Richard J. Eggers, Paul W. Jackson, Kirby Moist, Louise TI Association between estimated glomerular filtration rate at initiation of dialysis and mortality SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Article ID SUDDEN CARDIAC DEATH; QUALITY-OF-LIFE; STARTING DIALYSIS; UNITED-STATES; HEMODIALYSIS; GUIDELINES; SURVIVAL; COMORBIDITY; IMPACT AB Background: Recent studies have reported a trend toward earlier initiation of dialysis (i.e., at higher levels of glomerular filtration rate) and an association between early initiation and increased risk of death. We examined trends in initiation of hemodialysis within Canada and compared the risk of death between patients with early and late initiation of dialysis. Methods: The analytic cohort consisted of 25 910 patients at least 18 years of age who initiated hemodialysis, as identified from the Canadian Organ Replacement Register (2001-2007). We defined the initiation of dialysis as early if the estimated glomerular filtration rate was greater than 10.5 mL/min per 1.73 m(2). We fitted time-dependent proportional-hazards Cox models to compare the risk of death between patients with early and late initiation of dialysis. Results: Between 2001 and 2007, mean estimated glomerular filtration rate at initiation of dialysis increased from 9.3 (standard deviation [SD] 5.2) to 10.2 (SD 7.1) (p < 0.001), and the proportion of early starts rose from 28% (95% confidence interval [CI] 27%-30%) to 36% (95% CI 34%-37%). Mean glomerular filtration rate was 15.5 (SD 7.7) mL/min per 1.73 m(2) among those with early initiation and 7.1 (SD 2.0) mL/min per 1.73 m(2) among those with late initiation. The unadjusted hazard ratio (HR) for mortality with early relative to late initiation was 1.48 (95% CI 1.43-1.54). The HR decreased to 1.18 (95% CI 1.13-1.23) after adjustment for demographic characteristics, serum albumin, primary cause of end-stage renal disease, vascular access type, comorbidities, late referral and transplant status. The mortality differential between early and late initiation per 1000 patient-years narrowed after one year of follow-up, but never crossed and began widening again after 24 months of follow-up. The differences were significant at 6, 12, 30 and 36 months. Interpretation: In Canada, dialysis is being initiated at increasingly higher levels of glomerular filtration rate. A higher glomerular filtration rate at initiation of dialysis is associated with an increased risk of death that is not fully explained by differences in baseline characteristics. C1 [Clark, William F.; Moist, Louise] Univ Western Ontario, Div Nephrol, London, ON, Canada. [Sontrop, Jessica M.; Macnab, Jennifer J.; Moist, Louise] Univ Western Ontario, Dept Med, London, ON, Canada. [Sontrop, Jessica M.; Macnab, Jennifer J.; Moist, Louise] Univ Western Ontario, Dept Epidemiol & Biostat, London, ON, Canada. [Na, Yingbo] Canadian Inst Hlth Informat, Toronto, ON, Canada. [Rosansky, Steven J.] William Jennings Bryan Dorn VA Hosp, Dorn Res Inst, Columbia, MO USA. [Rosansky, Steven J.; Jackson, Kirby] Univ S Carolina, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Glassock, Richard J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Eggers, Paul W.] NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD USA. RP Clark, WF (reprint author), Univ Western Ontario, Div Nephrol, London, ON, Canada. EM William.Clark@lhsc.on.ca OI Sontrop, Jessica M./0000-0001-7784-2028 FU American Renal Associates; Program in Experimental Medicine [RO5 22A04]; Department of Medicine, University of Western Ontario, London, Ont. FX Richard Glassock has received consultancy fees and payment for development of education presentations from American Renal Associates. None declared for other authors.; Funding for this study was provided by a grant to William Clark from the Program in Experimental Medicine (RO5 22A04), Department of Medicine, University of Western Ontario, London, Ont. NR 35 TC 50 Z9 56 U1 0 U2 2 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD JAN 11 PY 2011 VL 183 IS 1 BP 47 EP 53 DI 10.1503/cmaj.100349 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 716JO UT WOS:000286965100010 PM 21135082 ER PT J AU Lewandoski, M Mackem, S AF Lewandoski, Mark Mackem, Susan TI Developmental Biology: Extending the Limb and Body with Vectors and Scalars SO CURRENT BIOLOGY LA English DT Editorial Material ID VERTEBRATE EMBRYO; CELL MOTILITY; MORPHOGENESIS; ELONGATION; GENITALIA; GRADIENT AB Outgrowth of the embryonic limb in vertebrates is driven by a proximodistal gradient of cell movement, with WNT and FGF activities controlling direction and velocity, respectively. A similar gradient, though without a directional bias, drives caudal body axis extension. C1 [Lewandoski, Mark; Mackem, Susan] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Lewandoski, M (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM lewandom@mail.nih.gov; mackems@mail.nih.gov NR 20 TC 2 Z9 2 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 11 PY 2011 VL 21 IS 1 BP R34 EP R36 DI 10.1016/j.cub.2010.11.023 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 710BH UT WOS:000286485200017 PM 21215936 ER PT J AU Harrison, DM Caffo, BS Shiee, N Farrell, JAD Bazin, PL Farrell, SK Ratchford, JN Calabresi, PA Reich, DS AF Harrison, D. M. Caffo, B. S. Shiee, N. Farrell, J. A. D. Bazin, P. -L. Farrell, S. K. Ratchford, J. N. Calabresi, P. A. Reich, D. S. TI Longitudinal changes in diffusion tensor-based quantitative MRI in multiple sclerosis SO NEUROLOGY LA English DT Article ID RAT SPINAL-CORD; CORTICOSPINAL TRACT; BRAIN ATROPHY; WHITE-MATTER; DISABILITY; AXOTOMY; DAMAGE AB Objective: To estimate longitudinal changes in a quantitative whole-brain and tract-specific MRI study of multiple sclerosis (MS), with the intent of assessing the feasibility of this approach in clinical trials. Methods: A total of 78 individuals with MS underwent a median of 3 scans over 2 years. Diffusion tensor imaging indices, magnetization transfer ratio, and T2 relaxation time were analyzed in supratentorial brain, corpus callosum, optic radiations, and corticospinal tracts by atlas-based tractography. Linear mixed-effect models estimated annualized rates of change for each index, and sample size estimates for potential clinical trials were determined. Results: There were significant changes over time in fractional anisotropy and perpendicular diffusivity in the supratentorial brain and corpus callosum, mean diffusivity in the supratentorial brain, and magnetization transfer ratio in all areas studied. Changes were most rapid in the corpus callosum, where fractional anisotropy decreased 1.7% per year, perpendicular diffusivity increased 1.2% per year, and magnetization transfer ratio decreased 0.9% per year. The T2 relaxation time changed more rapidly than diffusion tensor imaging indices and magnetization transfer ratio but had higher within-participant variability. Magnetization transfer ratio in the corpus callosum and supratentorial brain declined at an accelerated rate in progressive MS relative to relapsing-remitting MS. Power analysis yielded reasonable sample sizes (on the order of 40 participants per arm or fewer) for 1- or 2-year trials. Conclusions: Longitudinal changes in whole-brain and tract-specific diffusion tensor imaging indices and magnetization transfer ratio can be reliably quantified, suggesting that small clinical trials using these outcome measures are feasible. Neurology (R) 2011;76:179-186 C1 [Harrison, D. M.; Farrell, S. K.; Ratchford, J. N.; Calabresi, P. A.; Reich, D. S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Shiee, N.; Farrell, J. A. D.; Bazin, P. -L.; Reich, D. S.] Johns Hopkins Univ, Sch Med, Neuroradiol Div, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Caffo, B. S.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Shiee, N.] Johns Hopkins Univ, Dept Elect Engn, Baltimore, MD USA. [Farrell, J. A. D.] Kennedy Krieger Inst, FM Kirby Res Ctr Funct Brain Imaging, Baltimore, MD USA. [Reich, D. S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Harrison, DM (reprint author), 600 N Wolfe St,Pathol 627, Baltimore, MD 21287 USA. EM dharri90@jhmi.edu RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU NINDS [K99NS064098]; National MS Society [TR3760A3]; EMD Serono, Inc.; Partners Multiple Sclerosis Center; Bayer Schering Pharma; Sapphire Consulting, Creative Business Strategies International; NIH; Novartis; Biogen Idec; Partners Multiple Sclerosis Clinical Research; Teva Pharmaceutical Industries Ltd.; Vertex Pharmaceuticals; Novo Nordisk; Genentech, Inc.; National Multiple Sclerosis Society; NINDS FX Supported by NINDS (grant K99NS064098 and the Intramural Research Program). The MRI data were acquired through the National MS Society Tissue Repair Grant TR3760A3 and through a grant from EMD Serono, Inc.; Dr. Harrison has received support from a Partners Multiple Sclerosis Center Clinical Research Training Fellowship Award and from Bayer Schering Pharma. Dr. Caffo receives support from Sapphire Consulting, Creative Business Strategies International, and the NIH. N. Shiee, Dr. Farrell, Dr. Bazin, and S.K. Farrell report no disclosures. Dr. Ratchford serves as a consultant for Sun Pharmaceutical Industries Ltd.; receives research support from Novartis and Biogen Idec; has received support from a Partners Multiple Sclerosis Clinical Research Training Fellowship Award; and holds stock in Merck & Co., Inc. Dr. Calabresi serves on scientific advisory boards for Biogen Idec, Teva Pharmaceutical Industries Ltd., Vertex Pharmaceuticals, and Novartis; has received funding for travel from Biogen Idec, Teva Pharmaceutical Industries Ltd., Vertex Pharmaceuticals, EMD Serono, Inc., Novartis, and Novo Nordisk; serves on the editorial board of Neurology (R); is an author on a patent re: Role of Kv1.3 as neuroprotective; serves/has served as a consultant for Biogen Idec, Teva Pharmaceutical Industries Ltd., Vertex Pharmaceuticals, Novartis, Amplimmune, Inc., Centocor Ortho Biotech Inc. DioGenix, Inc., and Eisai Inc.; and receives research support from Vertex Pharmaceuticals, Bayer Schering Pharma, EMD Serono, Inc., Teva Pharmaceutical Industries Ltd., Genentech, Inc., Biogen Idec, the NIH, and the National Multiple Sclerosis Society. Dr. Reich has received a speaker honorarium from Teva Pharmaceutical Industries Ltd. and has received research support from the Extramural and Intramural Research Programs of the NINDS. NR 26 TC 30 Z9 32 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 11 PY 2011 VL 76 IS 2 BP 179 EP 186 DI 10.1212/WNL.0b013e318206ca61 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 704ZZ UT WOS:000286098400016 PM 21220722 ER PT J AU Chertov, O Zhang, N Chen, X Oppenheim, JJ Lubkowski, J McGrath, C Sowder, RC Crise, BJ Malyguine, A Kutzler, MA Steele, AD Henderson, EE Rogers, TJ AF Chertov, Oleg Zhang, Ning Chen, Xin Oppenheim, Joost J. Lubkowski, Jacek McGrath, Connor Sowder, Raymond C., II Crise, Bruce J. Malyguine, Anatoli Kutzler, Michele A. Steele, Amber D. Henderson, Earl E. Rogers, Thomas J. TI Novel Peptides Based on HIV-1 gp120 Sequence with Homology to Chemokines Inhibit HIV Infection in Cell Culture SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN; V3 LOOP; RECEPTOR-BINDING; LIGAND-BINDING; CC-CHEMOKINE; R5 HIV-1; CXCR4; CORECEPTOR; IDENTIFICATION AB The sequential interaction of the envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) with CD4 and certain chemokine coreceptors initiates host cell entry of the virus. The appropriate chemokines have been shown to inhibit viral replication by blocking interaction of the gp120 envelope protein with the coreceptors. We considered the possibility that this interaction involves a motif of the gp120 that may be structurally homologous to the chemokines. In the amino acid sequences of most chemokines there is a Trp residue located at the beginning of the C-terminal a-helix, which is separated by six residues from the fourth Cys residue. The gp120 of all HIV-1 isolates have a similar motif, which includes the C-terminal part of a variable loop 3 (V3) and N-terminal part of a conserved region 3 (C3). Two synthetic peptides, derived from the relevant gp120 sequence inhibited HIV-1 replication in macrophages and T lymphocytes in sequence-dependent manner. The peptides also prevented binding of anti-CXCR4 antibodies to CXCR4, and inhibited the intracellular Ca(2+) influx in response to CXCL12/SDF-1 alpha. Thus these peptides can be used to dissect gp120 interactions with chemokine receptors and could serve as leads for the design of new inhibitors of HIV-1. C1 [Chertov, Oleg] NCI, Prot Chem Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Zhang, Ning; Chen, Xin; Oppenheim, Joost J.] NCI, Mol Immunoregulat Lab, Frederick, MD 21701 USA. [Lubkowski, Jacek] NCI, Ctr Macromol Crystallog, Frederick, MD 21701 USA. [McGrath, Connor] Target Struct Based Drug Discovery Grp, Frederick, MD USA. [Sowder, Raymond C., II; Crise, Bruce J.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD USA. [Malyguine, Anatoli] SAIC Frederick Inc, Clin Serv Program, Frederick, MD USA. [Kutzler, Michele A.; Steele, Amber D.; Henderson, Earl E.; Rogers, Thomas J.] Temple Univ, Sch Med, Ctr Subst Abuse Res, Fels Inst Canc Res & Mol Biol,Dept Pharmacol, Philadelphia, PA 19122 USA. RP Chertov, O (reprint author), NCI, Prot Chem Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. EM rogerst@temple.edu RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 FU National Cancer Institute, National Institutes of Health (NIH) [N01-CO-12400]; NIH, National Cancer Institute, Center for Cancer Research; United States Public Health Service [DA-14230, DA-25532, P01DA-23860, P30DA-13429, F31 DA-05894]; National Institute on Drug Abuse [DA-06650] FX This project was funded with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract N01-CO-12400. It was also supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work was also supported by United States Public Health Service Grants DA-14230, DA-25532, P01DA-23860, P30DA-13429, and F31 DA-05894 (to M. K.), and grant DA-06650 from the National Institute on Drug Abuse. 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 United States government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 3 Z9 3 U1 0 U2 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 11 PY 2011 VL 6 IS 1 AR e14474 DI 10.1371/journal.pone.0014474 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710LU UT WOS:000286514000001 PM 21264298 ER PT J AU Orru, M Bakesova, J Brugarolas, M Quiroz, C Beaumont, V Goldberg, SR Lluis, C Cortes, A Franco, R Casado, V Canela, EI Ferre, S AF Orru, Marco Bakesova, Jana Brugarolas, Marc Quiroz, Cesar Beaumont, Vahri Goldberg, Steven R. Lluis, Carme Cortes, Antoni Franco, Rafael Casado, Vicent Canela, Enric I. Ferre, Sergi TI Striatal Pre- and Postsynaptic Profile of Adenosine A(2A) Receptor Antagonists SO PLOS ONE LA English DT Article ID PARKINSONS-DISEASE; DOPAMINE-D-2 RECEPTORS; BASAL GANGLIA; D2 DOPAMINE; HETEROMERS; NEUROTRANSMISSION; PHOSPHORYLATION; DISORDERS AB Striatal adenosine A(2A) receptors (A(2A)Rs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D-2 receptors (D(2)Rs). A(2A)Rs are also localized presynaptically in corticostriatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1) receptors (A(1)Rs). It has been hypothesized that postsynaptic A(2A)R antagonists should be useful in Parkinson's disease, while presynaptic A(2A)R antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2A)R antagonists may be subdivided according to a preferential pre-versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre-and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2A)R-D2R and A(1)R-A(2A)R heteromers to determine possible differences in the affinity of these compounds for different A(2A)R heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2A)R when co-expressed with D2R than with A(1)R. KW-6002 showed the best relative affinity for A(2A)R coexpressed with D2R than co-expressed with A(1)R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre-and postsynaptic profile. On the basis of their preferential pre-versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively. C1 [Orru, Marco; Quiroz, Cesar; Goldberg, Steven R.; Ferre, Sergi] NIDA, IRP, NIH, DHHS, Baltimore, MD USA. [Bakesova, Jana; Brugarolas, Marc; Lluis, Carme; Cortes, Antoni; Franco, Rafael; Casado, Vicent; Canela, Enric I.] Univ Barcelona, Fac Biol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain. [Beaumont, Vahri] CHDI Fdn, CHDI Management, Los Angeles, CA USA. RP Orru, M (reprint author), NIDA, IRP, NIH, DHHS, Baltimore, MD USA. EM sferre@intra.nida.nih.gov RI Canela, Enric I./M-8726-2013; Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; OI Canela, Enric I./0000-0003-4992-7440; Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Casado, Vicent/0000-0002-1764-3825 FU National Institute on Drug Abuse; CHDI Foundation; Spanish Ministerio de Ciencia y Tecnologia [SAF2008-00146, SAF2008-03229-E] FX Work supported by the National Institute on Drug Abuse, Intramural Research Program, CHDI Foundation and by the Spanish Ministerio de Ciencia y Tecnologia (grant numbers SAF2008-00146 and SAF2008-03229-E). The co-author Vahri Baumont, scientific manager from CHDI Foundation, participated in the design of the experiments. The other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 44 Z9 44 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 11 PY 2011 VL 6 IS 1 AR e16088 DI 10.1371/journal.pone.0016088 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710LU UT WOS:000286514000020 PM 21264319 ER PT J AU Johnson, ME Hummer, G AF Johnson, Margaret E. Hummer, Gerhard TI Nonspecific binding limits the number of proteins in a cell and shapes their interaction networks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protein-protein binding; proteome size; interactome; contact potentials; Hamming bound ID PAIR POTENTIALS; GENE NUMBER; COMPLEXES; PROTEOME; SIMULATIONS; CONSTRAINTS; STABILITY; SELECTION; SCALE; MAP AB Multicellular organisms, from Caenorhabditis elegans to humans, have roughly the same number of protein encoding genes. We show that the need to prevent disease-causing nonspecific interactions between proteins provides a simple physical reason why organism complexity is not reflected in the number of distinct proteins. By collective evolution of the amino acid sequences of protein binding interfaces we estimate the degree of misbinding as a function of the number of distinct proteins. Protein interaction energies are calculated with an empirical, residue-specific energy function tuned for protein binding. We show that the achievable energy gap favoring specific over nonspecific binding decreases with protein number in a power-law fashion. From the fraction of proteins involved in nonspecific complexes as a function of increasing protein number and decreasing energy gap, we predict the limits these binding requirements place on the number of different proteins that can function effectively in a given cellular compartment. Remarkably, the optimization of binding interfaces favors networks in which a few proteins have many partners, and most proteins have few partners, consistent with a scale-free network topology. We conclude that nonspecific binding adds to the evolutionary pressure to develop scale-free protein-protein interaction networks. C1 [Johnson, Margaret E.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM Gerhard.Hummer@NIH.GOV RI Hummer, Gerhard/A-2546-2013; Johnson, Margaret/M-4708-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Johnson, Margaret/0000-0001-9881-291X FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). The research used the Biowulf Linux cluster at the NIH. NR 34 TC 32 Z9 32 U1 0 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 11 PY 2011 VL 108 IS 2 BP 603 EP 608 DI 10.1073/pnas.1010954108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZU UT WOS:000286097700035 PM 21187424 ER PT J AU Chen, ZC Schneerson, R Lovchik, J Lyons, CR Zhao, HY Dai, ZD Kubler-Kielb, J Leppla, SH Purcell, RH AF Chen, Zhaochun Schneerson, Rachel Lovchik, Julie Lyons, C. Rick Zhao, Huaying Dai, Zhongdong Kubler-Kielb, Joanna Leppla, Stephen H. Purcell, Robert H. TI Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GLUTAMIC ACID CAPSULE; PULMONARY ANTHRAX; VACCINIA VIRUS; MURINE MODEL; ANTIGEN; TOXIN; LETHAL; NEUTRALIZATION; DISSEMINATION; IMMUNIZATION AB One of the two essential virulence factors of Bacillus anthracis is the poly-gamma-D-glutamic acid (gamma DPGA) capsule. Five gamma DPGA-specific antibody antigen-binding fragments (Fabs) were generated from immunized chimpanzees. The two selected for further study, Fabs 11D and 4C, were both converted into full-length IgG1 and IgG3 mAbs having human IgG1 or IgG3 constant regions. These two mAbs had similar binding affinities, in vitro opsonophagocytic activities, and in vivo efficacies, with the IgG1 and IgG3 subclasses reacting similarly. The mAbs bound to gamma DPGA specifically with estimated binding affinities (K-d) of 35-70 nM and effective affinities (effective K-d) of 0.1-0.3 nM. The LD50 in an opsonophagocytic bactericidal assay was approximate to 10 ng/mL of 11D or 4C. A single 30-mu g dose of either mAb given to BALB/c mice 18 h before challenge conferred about 50% protection against a lethal intratracheal spore challenge by the virulent B. anthracis Ames strain. More importantly, either mAb given 8 h or 20 h after challenge provided significant protection against lethal infection. Thus, these anti gamma DPGA mAbs should be useful, alone or in combination with antitoxin mAbs, for achieving a safe and efficacious postexposure therapy for anthrax. C1 [Chen, Zhaochun; Purcell, Robert H.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Leppla, Stephen H.] NIAID, Lab Bacterial Dis, Bethesda, MD 20892 USA. [Schneerson, Rachel; Dai, Zhongdong; Kubler-Kielb, Joanna] NICHHD, Program Dev & Mol Immun, Bethesda, MD 20892 USA. [Zhao, Huaying] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Lovchik, Julie; Lyons, C. Rick] Univ New Mexico, Hlth Sci Ctr, Dept Internal Med, Albuquerque, NM 87131 USA. RP Chen, ZC (reprint author), NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. EM zc20a@nih.gov; rpurcelL@niaid.nih.gov RI Zhao, Huaying/F-5716-2012 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank Dr. Mahtab Moayeri for helpful discussions and Dr. Haijing Hu for preparing B. anthracis spores for opsonophagocytosis work. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 33 TC 12 Z9 13 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 11 PY 2011 VL 108 IS 2 BP 739 EP 744 DI 10.1073/pnas.1017677108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 704ZU UT WOS:000286097700058 PM 21187383 ER PT J AU Fields, RD AF Fields, R. Douglas TI Signaling by Neuronal Swelling SO SCIENCE SIGNALING LA English DT Editorial Material ID ADAPTED SQUID RETINA; MECHANICAL CHANGES; ACTION-POTENTIALS; LIGHT-PULSES; NERVE-FIBERS; SPINAL-CORD; STIMULATION; EXCITATION; IMPULSE; AXONS AB Several physical phenomena accompany the firing of electrical impulses by axons. Some of these, such as the microscopic swelling of axons, alter the transmission of light through axons. This produces what are called "intrinsic optical signals" because optical methods can be used to see axons fire without adding voltage-sensitive dyes or using electronic amplifiers. These physical changes allow neurons to communicate through nonsynaptic signals to adjacent cells, such as other neurons or glia. Two of the three videos in this Teaching Resource show the optical manifestations of the microscopic swelling of axons that accompanies the firing of action potentials in cultured neurons, and one shows the nonsynaptic release of ATP that occurs through membrane channels that are stimulated by neuronal swelling. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), NICHHD, NIH, Bldg 35,Room 2A211,MSC3713, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 37 TC 7 Z9 7 U1 0 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JAN 11 PY 2011 VL 4 IS 155 AR tr1 DI 10.1126/scisignal.4155tr1 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 705BD UT WOS:000286102200003 PM 21224445 ER PT J AU Kuipers, MA Stasevich, TJ Sasaki, T Wilson, KA Hazelwood, KL McNally, JG Davidson, MW Gilbert, DM AF Kuipers, Marjorie A. Stasevich, Timothy J. Sasaki, Takayo Wilson, Korey A. Hazelwood, Kristin L. McNally, James G. Davidson, Michael W. Gilbert, David M. TI Highly stable loading of Mcm proteins onto chromatin in living cells requires replication to unload SO JOURNAL OF CELL BIOLOGY LA English DT Article ID ORIGIN RECOGNITION COMPLEX; DNA-REPLICATION; S-PHASE; DECISION POINT; TRANSCRIPTIONAL ACTIVATION; NUCLEAR-DYNAMICS; MAMMALIAN-CELLS; BIND CHROMATIN; IFN-GAMMA; ASSOCIATION AB The heterohexameric minichromosome maintenance protein complex (Mcm2-7) functions as the eukaryotic helicase during DNA replication. Mcm2-7 loads onto chromatin during early G1 phase but is not converted into an active helicase until much later during S phase. Hence, inactive Mcm complexes are presumed to remain stably bound from early G1 through the completion of S phase. Here, we investigated Mcm protein dynamics in live mammalian cells. We demonstrate that Mcm proteins are irreversibly loaded onto chromatin cumulatively throughout G1 phase, showing no detectable exchange with a gradually diminishing soluble pool. Eviction of Mcm requires replication; during replication arrest, Mcm proteins remained bound indefinitely. Moreover, the density of immobile Mcms is reduced together with chromatin decondensation within sites of active replication, which provides an explanation for the lack of colocalization of Mcm with replication fork proteins. These results provide in vivo evidence for an exceptionally stable lockdown mechanism to retain all loaded Mcm proteins on chromatin throughout prolonged cell cycles. C1 [Kuipers, Marjorie A.; Sasaki, Takayo; Wilson, Korey A.; Gilbert, David M.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Stasevich, Timothy J.; McNally, James G.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Hazelwood, Kristin L.; Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32310 USA. [Hazelwood, Kristin L.; Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. RP Gilbert, DM (reprint author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. EM gilbert@bio.fsu.edu FU National Institute for General Medical Sciences [RO1GM083337] FX We thank R. Didier for assistance with flow cytometry, H. Kimura for helpful comments on the manuscript and for mouse cDNA plasmids for Mcm2-7, C. Cardoso for GFP and RP human PCNA plasmids, H. Masai for mouse Mcm4 mutant 6AA plasmid, J. Schimenti for Mcm4 mutant Chaos3 plasmid, and A. Schwacha and I Misteli for helpful discussions. This work was supported by National Institute for General Medical Sciences grant RO1GM083337 to D.M. Gilbert. NR 68 TC 34 Z9 34 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 10 PY 2011 VL 192 IS 1 BP 29 EP 41 DI 10.1083/jcb.201007111 PG 13 WC Cell Biology SC Cell Biology GA 727DU UT WOS:000287778600005 PM 21220507 ER PT J AU Du, XM Kumar, J Ferguson, C Schulz, TA Ong, YS Hong, WJ Prinz, WA Parton, RG Brown, AJ Yang, HY AF Du, Ximing Kumar, Jaspal Ferguson, Charles Schulz, Timothy A. Ong, Yan Shan Hong, Wanjin Prinz, William A. Parton, Robert G. Brown, Andrew J. Yang, Hongyuan TI A role for oxysterol-binding protein-related protein 5 in endosomal cholesterol trafficking SO JOURNAL OF CELL BIOLOGY LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; STEROL-SENSING DOMAIN; PICK C1 PROTEIN; TRANS-GOLGI NETWORK; ENDOPLASMIC-RETICULUM; PLASMA-MEMBRANE; NPC1; ER; CELLS; REVEALS AB Oxysterol-binding protein (OSBP) and its related proteins (ORPs) constitute a large and evolutionarily conserved family of lipid-binding proteins that target organelle membranes to mediate sterol signaling and/or transport. Here we characterize ORP5, a tail-anchored ORP protein that localizes to the endoplasmic reticulum. Knocking down ORP5 causes cholesterol accumulation in late endosomes and lysosomes, which is reminiscent of the cholesterol trafficking defect in Niemann Pick C (NPC) fibroblasts. Cholesterol appears to accumulate in the limiting membranes of endosomal compartments in ORP5-depleted cells, whereas depletion of NPC1 or both ORP5 and NPC1 results in luminal accumulation of cholesterol. Moreover, trans-Golgi resident proteins mislocalize to endosomal compartments upon ORP5 depletion, which depends on a functional NPC1. Our results establish the first link between NPC1 and a cytoplasmic sterol carrier, and suggest that ORP5 may cooperate with NPC1 to mediate the exit of cholesterol from endosomes/lysosomes. C1 [Du, Ximing; Brown, Andrew J.; Yang, Hongyuan] Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia. [Kumar, Jaspal] Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore. [Ferguson, Charles; Parton, Robert G.] Univ Queensland, Inst Mol Biosci, Mol Cell Biol Div, Brisbane, Qld 4072, Australia. [Schulz, Timothy A.; Prinz, William A.] NIDDK, NIH, Bethesda, MD 20892 USA. [Ong, Yan Shan; Hong, Wanjin] Inst Mol & Cell Biol, Singapore 138673, Singapore. RP Yang, HY (reprint author), Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia. EM h.rob.yang@unsw.edu.au RI HONG, Wanjin/E-9927-2010; ASTAR, IMCB/E-2320-2012; OI Yang, Hongyuan/0000-0002-8482-6031; Parton, Robert/0000-0002-7494-5248 FU Ara Parseghian Medical Research Foundation; National Health and Medical Research Council of Australia [510271]; National Institute of Diabetes and Digestive and Kidney Diseases FX This work is jointly supported by research grants from the Ara Parseghian Medical Research Foundation and the National Health and Medical Research Council of Australia (No. 510271). The Institute for Molecular Bioscience is a Special Research Centre of the Australian Research Council. W.A. Prinz and T.A. Schulz were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 61 TC 93 Z9 96 U1 3 U2 16 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 10 PY 2011 VL 192 IS 1 BP 121 EP 135 DI 10.1083/jcb.201004142 PG 15 WC Cell Biology SC Cell Biology GA 727DU UT WOS:000287778600012 PM 21220512 ER PT J AU Kupchik, YM Barchad-Avitzur, O Wess, J Ben-Chaim, Y Parnas, I Parnas, H AF Kupchik, Yonatan M. Barchad-Avitzur, Ofra Wess, Juergen Ben-Chaim, Yair Parnas, Itzchak Parnas, Hanna TI A novel fast mechanism for GPCR-mediated signal transduction-control of neurotransmitter release SO JOURNAL OF CELL BIOLOGY LA English DT Article ID MUSCARINIC ACETYLCHOLINE-RECEPTORS; FROG NEUROMUSCULAR-JUNCTION; PROTEIN-COUPLED RECEPTORS; VOLTAGE-DEPENDENT INTERACTION; EVOKED TRANSMITTER RELEASE; SYNAPTIC-TRANSMISSION; MOLECULAR-MECHANISMS; PRESYNAPTIC CALCIUM; BINDING-SITES; KNOCKOUT MICE AB Reliable neuronal communication depends on accurate temporal correlation between the action potential and neurotransmitter release. Although a requirement for Ca2+ in neurotransmitter release is amply documented, recent studies have shown that voltage-sensitive G protein coupled receptors (GPCRs) are also involved in this process. However, how slow-acting GPCRs control fast neurotransmitter release is an unsolved question. Here we examine whether the recently discovered fast depolarization-induced charge movement in the M-2-muscarinic receptor (M2R) is responsible for M2R-mediated control of acetylcholine release. We show that inhibition of the M2R charge movement in Xenopus oocytes correlated well with inhibition of acetylcholine release at the mouse neuromuscular junction. Our results suggest that, in addition to Ca2+ influx, charge movement in GPCRs is also necessary for release control. C1 [Kupchik, Yonatan M.; Barchad-Avitzur, Ofra; Ben-Chaim, Yair; Parnas, Itzchak; Parnas, Hanna] Hebrew Univ Jerusalem, Inst Life Sci, Dept Neurobiol, IL-91904 Jerusalem, Israel. [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Wess, Juergen] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Parnas, H (reprint author), Hebrew Univ Jerusalem, Inst Life Sci, Dept Neurobiol, Edmond Safra campus, IL-91904 Jerusalem, Israel. EM hannap@huji.ac.il OI Kupchik, Yonatan/0000-0003-3732-4933 FU Goldie-Anna fund FX We thank Professor Micha Spiro for his insightful suggestions and comments. We are grateful to Dr. Kenneth Stein and the Goldie-Anna fund for their support. NR 62 TC 13 Z9 14 U1 1 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 10 PY 2011 VL 192 IS 1 BP 137 EP 151 DI 10.1083/jcb.201007053 PG 15 WC Cell Biology SC Cell Biology GA 727DU UT WOS:000287778600013 PM 21200029 ER PT J AU Meyer, PN Fu, K Greiner, TC Smith, LM Delabie, J Gascoyne, RD Ott, G Rosenwald, A Braziel, RM Campo, E Vose, JM Lenz, G Staudt, LM Chan, WC Weisenburger, DD AF Meyer, Paul N. Fu, Kai Greiner, Timothy C. Smith, Lynette M. Delabie, Jan Gascoyne, Randy D. Ott, German Rosenwald, Andreas Braziel, Rita M. Campo, Elias Vose, Julie M. Lenz, Georg Staudt, Louis M. Chan, Wing C. Weisenburger, Dennis D. TI Immunohistochemical Methods for Predicting Cell of Origin and Survival in Patients With Diffuse Large B-Cell Lymphoma Treated With Rituximab SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GERMINAL CENTER; MOLECULAR SUBTYPES; TISSUE MICROARRAY; PROGNOSTIC IMPACT; CHEMOTHERAPY; CLASSIFICATION; IMPROVES AB Purpose Patients with diffuse large B-cell lymphoma (DLBCL) can be divided into prognostic groups based on the cell of origin of the tumor as determined by microarray analysis. Various immunohistochemical algorithms have been developed to replicate these microarray results and/or stratify patients according to survival. This study compares some of those algorithms and also proposes some modifications. Patients and Methods Two-hundred and sixty-two cases of de novo DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy were examined. Results The Choi algorithm and Hans algorithm had high concordance with the microarray results. Modifications of the Choi and Hans algorithms for ease of use still retained high concordance with the microarray results. Although the Nyman and Muris algorithms had high concordance with the microarray results, each had a low value for either sensitivity or specificity. The use of LMO2 alone showed the lowest concordance with the microarray results. A new algorithm (Tally) using a combination of antibodies, but without regard to the order of examination, showed the greatest concordance with microarray results. All of the algorithms divided patients into groups with significantly different overall and event-free survivals, but with different hazard ratios. With the exception of the Nyman algorithm, this survival prediction was independent of the International Prognostic Index. Although the Muris algorithm had prognostic significance, it misclassified a large number of cases with activated B-cell type DLBCL. Conclusion The Tally algorithm showed the best concordance with the microarray data while maintaining prognostic significance and ease of use. J Clin Oncol 29:200-207. (C) 2010 by American Society of Clinical Oncology C1 [Meyer, Paul N.] Univ Nebraska, Med Ctr, Nebraska Med Ctr 983135, Omaha, NE 68198 USA. Univ Oslo, Rikshosp, Radiumhosp Med Ctr, N-0027 Oslo, Norway. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Robert Bosch Krankenhaus, Stuttgart, Germany. Univ Wurzburg, Wurzburg, Germany. Charite, D-13353 Berlin, Germany. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Barcelona, Barcelona, Spain. NCI, Div Canc Treatment & Diag, Ctr Canc Res, Bethesda, MD USA. RP Meyer, PN (reprint author), Univ Nebraska, Med Ctr, Nebraska Med Ctr 983135, Omaha, NE 68198 USA. EM pnm105@hotmail.com RI Lenz, Georg/I-6844-2012; OI Delabie, Jan/0000-0001-5023-0689; Campo, elias/0000-0001-9850-9793 FU National Cancer Institute [U01-CA114778-01, CA36727] FX Supported by National Cancer Institute Grants No. U01-CA114778-01 and CA36727. NR 16 TC 205 Z9 216 U1 2 U2 6 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 JAN 10 PY 2011 VL 29 IS 2 BP 200 EP 207 DI 10.1200/JCO.2010.30.0368 PG 8 WC Oncology SC Oncology GA 703GC UT WOS:000285965400024 PM 21135273 ER PT J AU Thill, M Berna, MJ Kunst, F Wege, H Strunnikova, NV Gordiyenko, N Grierson, R Richard, G Csaky, KG AF Thill, Michelle Berna, Marc J. Kunst, Frank Wege, Henning Strunnikova, Natalya V. Gordiyenko, Natalya Grierson, Rebecca Richard, Gisbert Csaky, Karl G. TI SU5416 induces premature senescence in endothelial progenitor cells from patients with age-related macular degeneration SO MOLECULAR VISION LA English DT Article ID EXPERIMENTAL CHOROIDAL NEOVASCULARIZATION; HEMATOPOIETIC STEM-CELLS; FIBROBLAST GROWTH FACTOR-2; RECEPTOR 2 INHIBITOR; SMOOTH-MUSCLE-CELLS; PROTEIN-KINASE-C; IN-VIVO; REPLICATIVE SENESCENCE; TELOMERASE INACTIVATION; DIFFERENTIAL REGULATION AB Purpose: We recently demonstrated increased frequency and growth potential of late outgrowth endothelial progenitor cells (OECs) in patients with neovascular age-related macular degeneration (nvAMD). This study investigated the effects of short-and long-term in vitro inhibition of vascular endothelial growth factor (VEGF) Receptor-2 (VEGFR-2) signaling by SU5416 and other inhibitors of the VEGF signaling pathway in OECs. Methods: OECs, from the peripheral blood of patients with nvAMD, and human umbilical vein endothelial cells were grown in the presence of SU5416, other VEGFR-2 tyrosine kinase inhibitors (TKIs), and inhibitors of phosphatidylinositol 3'-Kinase (PI3K)/protein kinase B (Akt) and protein kinase C (PKC) in complete angiogenic medium. Apotosis was assessed after 48 h using the fluorescein isothiocyanate Annexin V method. Cell counts were performed for 10 days, and features of senescence were analyzed using senescence-associated beta-galactosidase staining, the telomeric repeat amplification protocol for telomerase activity, Southern blot analysis for mean telomere length, flow cytometric analysis for cell-cycle arrest, and western blot for p53 and p21. Control OECs, cells treated for 7 days with inhibitors, as well as naturally senescent OECs were analyzed for expression of different endothelial antigens, including VEGFR-2 and the receptor for stromal cell-derived factor 1, chemokine receptor 4 (CXCR-4). Migration in vitro to VEGF and stromal cell-derived factor 1 of OECs was assessed. Results: SU5416, other VEGFR-2 TKIs, and inhibitors of PI3K, Akt, and PKC induced apoptosis, inhibited long-term proliferation, reduced telomerase activity, and induced premature senescence and cell-cycle arrest in OECs as well as in human umbilical vein endothelial cells. Naturally senescent cells and cells rendered senescent by VEGFR-2 TKIs had reduced VEGFR-2 and CXCR-4 expression and demonstrated reduced migratory ability to VEGF. Conclusions: This study demonstrates apoptosis upon short-term inhibition and inhibition of long-term survival of OECs from patients with nvAMD by SU5416, presumably via PI3K/Akt and/or PKC-mediated reduction in telomerase activity and subsequent induction of premature senescence, which is accompanied by impaired endothelial activity. Therefore, induction of premature senescence in endothelial cells may represent a potential therapeutic target in nvAMD. C1 [Thill, Michelle; Kunst, Frank; Grierson, Rebecca; Richard, Gisbert] Univ Hosp Hamburg Eppendorf, Klin & Poliklin Augenheilkunde, D-20246 Hamburg, Germany. [Berna, Marc J.; Wege, Henning] Univ Hosp Hamburg Eppendorf, Med Klin 1, D-20246 Hamburg, Germany. [Strunnikova, Natalya V.; Gordiyenko, Natalya] NEI, NIH, Bethesda, MD 20892 USA. [Csaky, Karl G.] Duke Univ, Duke Univ Eye Ctr, Durham, NC USA. RP Thill, M (reprint author), Univ Hosp Hamburg Eppendorf, Klin & Poliklin Augenheilkunde, Martinistr 52, D-20246 Hamburg, Germany. EM mthill@uke.de FU Ministry of Culture, Higher Education and Research of Luxembourg [BFR 04/109] FX This work was partly supported by a grant (BFR 04/109) from the Ministry of Culture, Higher Education and Research of Luxembourg to M. Thill. We thank the nurses and staff of the NIH Eye Clinic and we are grateful to the patients who participated in this study. NR 68 TC 4 Z9 4 U1 1 U2 3 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JAN 10 PY 2011 VL 17 IS 11-12 BP 85 EP 98 PG 14 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 707VH UT WOS:000286316800002 PM 21245959 ER PT J AU Lederle, L Weber, S Wright, T Feyder, M Brigman, JL Crombag, HS Saksida, LM Bussey, TJ Holmes, A AF Lederle, Lauren Weber, Susanna Wright, Tara Feyder, Michael Brigman, Jonathan L. Crombag, Hans S. Saksida, Lisa M. Bussey, Timothy J. Holmes, Andrew TI Reward-Related Behavioral Paradigms for Addiction Research in the Mouse: Performance of Common Inbred Strains SO PLOS ONE LA English DT Article ID REPEATED MATERNAL SEPARATION; GOAL-DIRECTED BEHAVIOR; KNOCK-OUT MICE; HABIT FORMATION; PREFRONTAL CORTEX; AMPA RECEPTOR; STRESS; ANXIETY; EXTINCTION; REINFORCER AB The mouse has emerged as a uniquely valuable species for studying the molecular and genetic basis of complex behaviors and modeling neuropsychiatric disease states. While valid and reliable preclinical assays for reward-related behaviors are critical to understanding addiction-related processes, and various behavioral procedures have been developed and characterized in rats and primates, there have been relatively few studies using operant-based addiction-relevant behavioral paradigms in the mouse. Here we describe the performance of the C57BL/6J inbred mouse strain on three major reward-related paradigms, and replicate the same procedures in two other commonly used inbred strains (DBA/2J, BALB/cJ). We examined Pavlovian-instrumental transfer (PIT) by measuring the ability of an auditory cue associated with food reward to promote an instrumental (lever press) response. In a separate experiment, we assessed the acquisition and extinction of a simple stimulus-reward instrumental behavior on a touchscreen-based task. Reinstatement of this behavior was then examined following either continuous exposure to cues (conditioned reinforcers, CRs) associated with reward, brief reward and CR exposure, or brief reward exposure followed by continuous CR exposure. The third paradigm examined sensitivity of an instrumental (lever press) response to devaluation of food reward (a probe for outcome insensitive, habitual behavior) by repeated pairing with malaise. Results showed that C57BL/6J mice displayed robust PIT, as well as clear extinction and reinstatement, but were insensitive to reinforcer devaluation. DBA/2J mice showed good PIT and (rewarded) reinstatement, but were slow to extinguish and did not show reinforcer devaluation or significant CR-reinstatement. BALB/cJ mice also displayed good PIT, extinction and reinstatement, and retained instrumental responding following devaluation, but, unlike the other strains, demonstrated reduced Pavlovian approach behavior (food magazine head entries). Overall, these assays provide robust paradigms for future studies using the mouse to elucidate the neural, molecular and genetic factors underpinning reward-related behaviors relevant to addiction research. C1 [Lederle, Lauren; Weber, Susanna; Wright, Tara; Feyder, Michael; Brigman, Jonathan L.; Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. [Crombag, Hans S.] Univ Sussex, Sch Psychol, Behav & Clin Neurosci Res Grp, Brighton, E Sussex, England. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, Med Res Council, Cambridge, England. [Saksida, Lisa M.; Bussey, Timothy J.] Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England. RP Lederle, L (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. EM holmesan@mail.nih.gov RI Brigman, Jonathan/O-4978-2016; Saksida, Lisa/M-2753-2016; Bussey, Timothy/M-2758-2016 OI Saksida, Lisa/0000-0002-8416-8171; Bussey, Timothy/0000-0001-7518-4041 FU National Institute on Alcohol Abuse and Alcoholism FX Research supported by National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 24 Z9 24 U1 2 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 10 PY 2011 VL 6 IS 1 AR e15536 DI 10.1371/journal.pone.0015536 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710LL UT WOS:000286513100006 PM 21249214 ER PT J AU Pluta, RM Oldfield, EH Bakhtian, KD Fathi, AR Smith, RK DeVroom, HL Nahavandi, M Woo, S Figg, WD Lonser, RR AF Pluta, Ryszard M. Oldfield, Edward H. Bakhtian, Kamran D. Fathi, Ali Reza Smith, Rene K. DeVroom, Hetty L. Nahavandi, Masoud Woo, Sukyung Figg, William D. Lonser, Russell R. TI Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers SO PLOS ONE LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; SUBARACHNOID HEMORRHAGE; CEREBRAL VASOSPASM; IN-VIVO; HUMAN CIRCULATION; CEREBROSPINAL-FLUID; OXIDE METABOLITES; PLASMA NITRITE; PRIMATE MODEL; BLOOD-FLOW AB Background: Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. Methodology: Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8 +/- 9.2 years (range, 21-56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 mu g/kg/hr; maximal dose of 533.8 mu g/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. Findings: The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 mu g/kg/hr. Dose limiting toxicity occurred at 446 mu g/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. Conclusion: Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. Information: C1 [Pluta, Ryszard M.; Oldfield, Edward H.; Bakhtian, Kamran D.; Fathi, Ali Reza; Smith, Rene K.; DeVroom, Hetty L.; Nahavandi, Masoud; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Univ Virginia, Hlth Sci Ctr, Dept Neurol Surg, Charlottesville, VA 22908 USA. [Fathi, Ali Reza] Kantonsspital Aarau AG, Dept Neurosurg, Aarau, Switzerland. [Woo, Sukyung; Figg, William D.] NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. [Woo, Sukyung; Figg, William D.] NCI, Clin Pharmacol Program, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Pluta, RM (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM rysiek@ninds.nih.gov RI Figg Sr, William/M-2411-2016 FU National Institute of Neurological Disorders and Stroke at the NIH; Swiss National Science Foundation [PBSKP3-123454] FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the NIH. Ali Reza Fathi, M.D. was supported by a grant from the Swiss National Science Foundation (PBSKP3-123454). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 48 Z9 50 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 10 PY 2011 VL 6 IS 1 AR e14504 DI 10.1371/journal.pone.0014504 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710LL UT WOS:000286513100001 PM 21249218 ER PT J AU Steffen, C Diop, OM Gessner, BD Hacen, MM Hassar, M Katz, MA Miller, MA Paget, WJ Schoub, BD Vernet, G Ndumbe, PM AF Steffen, C. Diop, O. M. Gessner, B. D. Hacen, M. M. Hassar, M. Katz, M. A. Miller, M. A. Paget, W. J. Schoub, B. D. Vernet, G. Ndumbe, P. M. TI Afriflu-International conference on influenza disease burden in Africa, 1-2 June 2010, Marrakech, Morocco SO VACCINE LA English DT Article DE Influenza; Africa; Conference report; Epidemiology; Disease burden AB The burden of influenza disease is to a large extent unknown for the African continent. Moreover, the interaction of influenza with common infectious diseases in Africa remains poorly described. Solid scientific evidence on the influenza disease burden in Africa is critical for the development of effective influenza vaccine policies. On 1st and 2nd June 2010 in Marrakech, Morocco, over eighty surveillance and influenza experts from 22 African countries as well as Europe and America met at the 'Afriflu' conference to discuss influenza challenges and solutions for the continent. During the meeting, participants exchanged their experiences and discussed a wide variety of topics related to influenza in Africa, including diagnosis, surveillance, epidemiology, and interventions. The meeting concluded with a pledge to improve influenza knowledge and awareness in Africa, with an emphasis on accurate determination of disease burden to help orient public health policies. C1 [Steffen, C.] Agence Med Prevent AMP, F-01210 Ferney Voltaire, France. [Diop, O. M.] Inst Pasteur, Dakar, Senegal. [Gessner, B. D.] Agence Med Prevent, Paris, France. [Hacen, M. M.] Mauritanian Assoc Publ Hlth, Nouakchott, Mauritania. [Hassar, M.] Inst Pasteur, Casablanca, Morocco. [Katz, M. A.] Ctr Dis Control & Prevent, Nairobi, Kenya. [Miller, M. A.] NIH, Fogarty Ctr, Bethesda, MD 20892 USA. [Paget, W. J.] Netherlands Inst Hlth Serv Res NIVEL, Utrecht, Netherlands. [Schoub, B. D.] Natl Inst Communicable Dis, Johannesburg, South Africa. [Vernet, G.] Fdn Merieux, Lyon, France. [Ndumbe, P. M.] Univ Buea, Buea, Cameroon. RP Steffen, C (reprint author), Agence Med Prevent AMP, 13 Chemin Levant, F-01210 Ferney Voltaire, France. EM csteffen@aamp.org FU Pfizer; Merck; GlaxoSmithKline; AstraZeneca; Sanofi Pasteur FX Disclosure statement: B.D. Gessner and C. Steffen work for Agence de Medecine Preventive (AMP) which receives substantial support for all activities from Sanofi-Aventis and research support from Pfizer, Merck and GlaxoSmithKline. B.D. Gessner also served as speaker for GlaxoSmithKline. W.J. Paget has received lecture fees from AstraZeneca and has served on an expert advisory board on matters relating to the surveillance of influenza for GlaxoSmithKline. Conflicts of interest: All other authors declared that they had no conflict of interest. Funding: The 'Afriflu' Conference was funded through an unrestricted grant from Sanofi Pasteur. Sanofi Pasteur did not have any control over the conference agenda (which was determined by an Independent Scientific Committee) or the conference content (which was determined by the authors of the various presentations). Sanofi Pasteur did not have any editorial control over the contents of the current manuscript, which is solely the work of the authors. NR 14 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 10 PY 2011 VL 29 IS 3 BP 363 EP 369 DI 10.1016/j.vaccine.2010.11.029 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 715AQ UT WOS:000286853200001 PM 21111779 ER PT J AU Frazao-Teixeira, E Sundar, N Dubey, JP Grigg, ME de Oliveira, FCR AF Frazao-Teixeira, E. Sundar, N. Dubey, J. P. Grigg, M. E. de Oliveira, F. C. R. TI Multi-locus DNA sequencing of Toxoplasma gondii isolated from Brazilian pigs identifies genetically divergent strains SO VETERINARY PARASITOLOGY LA English DT Article DE Toxoplasma gondii; Pigs; Isolation; Genetic typing; Brazil ID FREE-RANGE CHICKENS; RIO-DE-JANEIRO; SAO-PAULO; OCULAR TOXOPLASMOSIS; POPULATION-STRUCTURE; UNEXPECTED FINDINGS; CLONAL LINEAGES; PCR-RFLP; GENOTYPES; STATE AB Five Toxoplasma gondii isolates (TgPgBr1-5) were isolated from hearts and brains of pigs freshly purchased at the market of Campos dos Goytacazes, Northern Rio de Janeiro State, Brazil. Four of the five isolates were highly pathogenic in mice. Four genotypes were identified. Multi-locus PCR-DNA sequencing showed that each strain possessed a unique combination of archetypal and novel alleles not previously described in South America. The data suggest that different strains circulate in pigs destined for human consumption from those previously isolated from cats and chickens in Brazil. Further, multi-locus PCR-RFLP analyses failed to accurately genotype the Brazilian isolates due to the high presence of atypical alleles. This is the first report of multi-locus DNA sequencing of T. gondii isolates in pigs from Brazil. Published by Elsevier B.V. C1 [Sundar, N.; Grigg, M. E.] NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Frazao-Teixeira, E.; de Oliveira, F. C. R.] Univ Estadual Norte Fluminense, Ctr Ciencias & Tecnol Agropecuarias, Lab Sanidade Anim, BR-28013602 Campos Dos Goytacazes, RJ, Brazil. [Dubey, J. P.] ARS, USDA, Anim & Nat Resources Inst, Anim Parasit Dis Lab, Beltsville, MD 20705 USA. RP Grigg, ME (reprint author), NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM griggm@niaid.nih.gov RI Frazao-Teixeira, Edwards/A-9542-2015 OI Frazao-Teixeira, Edwards/0000-0001-7505-4765 FU Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [BEX 3409/08-2]; Universidade Estadual do Norte Fluminense Darcy Ribeiro (UENF); United States Department of Agriculture (USDA); NIH; NIAID FX This study was supported by Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, process # BEX 3409/08-2), Universidade Estadual do Norte Fluminense Darcy Ribeiro (UENF), United States Department of Agriculture (USDA), and by the Intramural Research Program of the NIH and NIAID. MEG is a scholar of the Canadian Institute for Advanced Research (CIFAR) Program for Integrated Microbial Biodiversity. NR 33 TC 16 Z9 18 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 J9 VET PARASITOL JI Vet. Parasitol. PD JAN 10 PY 2011 VL 175 IS 1-2 BP 33 EP 39 DI 10.1016/j.vetpar.2010.09.030 PG 7 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA 704FR UT WOS:000286037000006 PM 21051148 ER PT J AU Sambuughin, N Yau, KS Olive, M Duff, RM Bayarsaikhan, M Lu, SJ Gonzalez-Mera, L Sivadorai, P Nowak, KJ Ravenscroft, G Mastaglia, FL North, KN Ilkovski, B Kremer, H Lammens, M van Engelen, BGM Fabian, V Lamont, P Davis, MR Laing, NG Goldfarb, LG AF Sambuughin, Nyamkhishig Yau, Kyle S. Olive, Montse Duff, Rachael M. Bayarsaikhan, Munkhuu Lu, Shajia Gonzalez-Mera, Laura Sivadorai, Padma Nowak, Kristen J. Ravenscroft, Gianina Mastaglia, Frank L. North, Kathryn N. Ilkovski, Biljana Kremer, Hannie Lammens, Martin van Engelen, Baziel G. M. Fabian, Vicki Lamont, Phillipa Davis, Mark R. Laing, Nigel G. Goldfarb, Lev G. TI Dominant Mutations in KBTBD13, a Member of the BTB/Kelch Family, Cause Nemaline Myopathy with Cores (vol 87, pg 842, 2010) SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Correction C1 [Sambuughin, Nyamkhishig; Bayarsaikhan, Munkhuu] Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. [Yau, Kyle S.; Duff, Rachael M.; Nowak, Kristen J.; Ravenscroft, Gianina; Laing, Nigel G.] Univ Western Australia, Med Res Ctr, Western Australian Inst Med Res, QEII Med Ctr, Nedlands, WA 6009, Australia. [Olive, Montse; Gonzalez-Mera, Laura] IDIBELL Hosp Bellvitge, Dept Neurol, Dept Pathol & Neuromuscular Unit, Inst Neuropatol, Barcelona 08907, Spain. [Olive, Montse; Gonzalez-Mera, Laura] CIBERNED, Barcelona 08907, Spain. [Lu, Shajia] NIAMSD, NIH, Bethesda, MD 20892 USA. [Sivadorai, Padma; Fabian, Vicki; Davis, Mark R.] Royal Perth Hosp, Dept Anat Pathol, Perth, WA 6000, Australia. [Mastaglia, Frank L.] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Nedlands, WA 6009, Australia. [North, Kathryn N.; Ilkovski, Biljana] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Westmead, NSW 2145, Australia. [Kremer, Hannie] Radboud Univ Nijmegen, Med Ctr, Dept Otorhinolaryngol, NL-6500 Nijmegen, Netherlands. [Kremer, Hannie] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 Nijmegen, Netherlands. [Lammens, Martin; van Engelen, Baziel G. M.] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6500 Nijmegen, Netherlands. [Lamont, Phillipa] Royal Perth Hosp, Div Neurosci, Perth, WA 6000, Australia. [Goldfarb, Lev G.] NINDS, NIH, Bethesda, MD 20892 USA. RP Sambuughin, N (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. EM nsambuughin@usuhs.mil RI Engelen, B.G.M./H-8027-2014; Ravenscroft, Gina/H-5695-2014 NR 1 TC 0 Z9 0 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 7 PY 2011 VL 88 IS 1 BP 122 EP 122 DI 10.1016/j.ajhg.2010.12.013 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 710HJ UT WOS:000286501500014 ER PT J AU Lanktree, MB Guo, YR Murtaza, M Glessner, JT Bailey, SD Onland-Moret, NC Lettre, G Ongen, H Rajagopalan, R Johnson, T Shen, HQ Nelson, CP Klopp, N Baumert, J Padmanabhan, S Pankratz, N Pankow, JS Shah, S Taylor, K Barnard, J Peters, BJ Maloney, CM Lobmeyer, MT Stanton, A Zafarmand, MH Romaine, SPR Mehta, A van Iperen, EPA Gong, Y Price, TS Smith, EN Kim, CE Li, YR Asselbergs, FW Atwood, LD Bailey, KM Bhatt, D Bauer, F Behr, ER Bhangale, T Boer, JMA Boehm, BO Bradfield, JP Brown, M Braund, PS Burton, PR Carty, C Chandrupatla, HR Chen, W Connell, J Dalgeorgou, C de Boer, A Drenos, F Elbers, CC Fang, JC Fox, CS Frackelton, EC Fuchs, B Furlong, CE Gibson, Q Gieger, C Goe, A Grobbee, DE Hastie, C Howard, PJ Huang, GH Johnson, WC Li, Q Kleber, ME Klein, BEK Klein, R Kooperberg, C Ky, B LaCroix, A Lanken, P Lathrop, M Li, MY Marshal, V Melander, O Mentch, FD Meyer, NJ Monda, KL Montpetit, A Murugesan, G Nakayama, K Nondah, D Onipinla, A Rafelt, S Newhouse, SJ Otieno, FG Patel, SR Putt, ME Rodriguez, S Safa, RN Sawyer, DB Schreiner, PJ Simpson, C Sivapalaratnam, S Srinivasan, SR Suver, C Swergold, G Sweitzer, NK Thomas, KA Thorand, B Timpson, NJ Tischfield, S Tobin, M Tomaszweski, M Verschuren, WMM Wallace, C Winkelmann, B Zhang, HT Zheng, DL Zhang, L Zmuda, JM Clarke, R Balmforth, AJ Danesh, J Day, IN Schork, NJ de Bakker, PIW Delles, C Duggan, D Hingorani, AD Hirschhorn, JN Hofker, MH Humphries, SE Kivimaki, M Lawlor, DA Kottke-Marchant, K Mega, JL Mitchell, BD Morrow, DA Palmen, J Redline, S Shields, DC Shuldiner, AR Sleiman, PM Smith, GD Farrall, M Jamshidi, Y Christiani, DC Casas, JP Hall, AS Doevendans, PA Christie, JD Berenson, GS Murray, SS Illig, T Dorn, GW Cappola, TP Boerwinkle, E Sever, P Rader, DJ Reilly, MP Caulfield, M Talmud, PJ Topol, E Engert, JC Wang, K Dominiczak, A Hamsten, A Curtis, SP Silverstein, RL Lange, LA Sabatine, MS Trip, M Saleheen, D Peden, JF Cruickshanks, KJ Marz, W O'Connell, JR Klungel, OH Wijmenga, C Maitland-van der Zee, AH Schadt, EE Johnson, JA Jarvik, GP Papanicolaou, GJ Watkins, H Grant, SFA Munroe, PB North, KE Samani, NJ Koenig, W Gaunt, TR Anand, SS van der Schouw, YT Kumari, M Soranzo, N FitzGerald, GA Reiner, A Hegele, RA Hakonarson, H Keating, BJ AF Lanktree, Matthew B. Guo, Yiran Murtaza, Muhammed Glessner, Joseph T. Bailey, Swneke D. Onland-Moret, N. Charlotte Lettre, Guillaume Ongen, Halit Rajagopalan, Ramakrishnan Johnson, Toby Shen, Haiqing Nelson, Christopher P. Klopp, Norman Baumert, Jens Padmanabhan, Sandosh Pankratz, Nathan Pankow, James S. Shah, Sonia Taylor, Kira Barnard, John Peters, Bas J. Maloney, Cliona M. Lobmeyer, Maximilian T. Stanton, Alice Zafarmand, M. Hadi Romaine, Simon P. R. Mehta, Amar van Iperen, Erik P. A. Gong, Yan Price, Tom S. Smith, Erin N. Kim, Cecilia E. Li, Yun R. Asselbergs, Folkert W. Atwood, Larry D. Bailey, Kristian M. Bhatt, Deepak Bauer, Florianne Behr, Elijah R. Bhangale, Tushar Boer, Jolanda M. A. Boehm, Bernhard O. Bradfield, Jonathan P. Brown, Morris Braund, Peter S. Burton, Paul R. Carty, Cara Chandrupatla, Hareesh R. Chen, Wei Connell, John Dalgeorgou, Chrysoula de Boer, Anthonius Drenos, Fotios Elbers, Clara C. Fang, James C. Fox, Caroline S. Frackelton, Edward C. Fuchs, Barry Furlong, Clement E. Gibson, Quince Gieger, Christian Goe, Anuj Grobbee, Diederik E. Hastie, Claire Howard, Philip J. Huang, Guan-Hua Johnson, W. Craig Li, Qing Kleber, Marcus E. Klein, Barbara E. K. Klein, Ronald Kooperberg, Charles Ky, Bonnie LaCroix, Andrea Lanken, Paul Lathrop, Mark Li, Mingyao Marshal, Vanessa Melander, Olle Mentch, Frank D. Meyer, Nuala J. Monda, Keri L. Montpetit, Alexandre Murugesan, Gurunathan Nakayama, Karen Nondah, Dave Onipinla, Abiodun Rafelt, Suzanne Newhouse, Stephen J. Otieno, F. George Patel, Sanjey R. Putt, Mary E. Rodriguez, Santiago Safa, Radwan N. Sawyer, Douglas B. Schreiner, Pamela J. Simpson, Claire Sivapalaratnam, Suthesh Srinivasan, Sathanur R. Suver, Christine Swergold, Gary Sweitzer, Nancy K. Thomas, Kelly A. Thorand, Barbara Timpson, Nicholas J. Tischfield, Sam Tobin, Martin Tomaszweski, Maciej Verschuren, W. M. Monique Wallace, Chris Winkelmann, Bernhard Zhang, Haitao Zheng, Dongling Zhang, Li Zmuda, Joseph M. Clarke, Robert Balmforth, Anthony J. Danesh, John Day, Ian N. Schork, Nicholas J. de Bakker, Paul I. W. Delles, Christian Duggan, David Hingorani, Aroon D. Hirschhorn, Joel N. Hofker, Marten H. Humphries, Steve E. Kivimaki, Mika Lawlor, Debbie A. Kottke-Marchant, Kandice Mega, Jessica L. Mitchell, Braxton D. Morrow, David A. Palmen, Jutta Redline, Susan Shields, Denis C. Shuldiner, Alan R. Sleiman, Patrick M. Smith, George Davey Farrall, Martin Jamshidi, Yalda Christiani, David C. Casas, Juan P. Hall, Alistair S. Doevendans, Pieter A. Christie, Jason D. Berenson, Gerald S. Murray, Sarah S. Illig, Thomas Dorn, Gerald W., II Cappola, Thomas P. Boerwinkle, Eric Sever, Peter Rader, Daniel J. Reilly, Muredach P. Caulfield, Mark Talmud, Philippa J. Topol, Eric Engert, James C. Wang, Kai Dominiczak, Anna Hamsten, Anders Curtis, Sean P. Silverstein, Roy L. Lange, Leslie A. Sabatine, Marc S. Trip, Mieke Saleheen, Danish Peden, John F. Cruickshanks, Karen J. Maerz, Winfried O'Connell, Jeffrey R. Klungel, Olaf H. Wijmenga, Cisca Maitland-van der Zee, Anke Hilse Schadt, Eric E. Johnson, Julie A. Jarvik, Gail P. Papanicolaou, George J. Watkins, Hugh Grant, Struan F. A. Munroe, Patricia B. North, Kari E. Samani, Nilesh J. Koenig, Wolfgang Gaunt, Tom R. Anand, Sonia S. van der Schouw, Yvonne T. Kumari, Meena Soranzo, Nicole FitzGerald, Garret A. Reiner, Alex Hegele, Robert A. Hakonarson, Hakon Keating, Brendan J. CA PROCARDIS Whitehall II Study WHII 50K Grp TI Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BIOLOGICAL PATHWAYS; ADULT HEIGHT; LOCI; POPULATION; INTERLEUKIN-11; IDENTIFICATION; HERITABILITY; TRAITS; MICE AB Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 x 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait. C1 [Guo, Yiran; Glessner, Joseph T.; Kim, Cecilia E.; Li, Yun R.; Bradfield, Jonathan P.; Frackelton, Edward C.; Mentch, Frank D.; Otieno, F. George; Thomas, Kelly A.; Zhang, Haitao; Sleiman, Patrick M.; Wang, Kai; Grant, Struan F. A.; Hakonarson, Hakon] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Lanktree, Matthew B.; Hegele, Robert A.] Univ Western Ontario, Dept Med & Biochem, London, ON N6A 5C1, Canada. [Guo, Yiran] Beijing Genom Inst Shenzhen, Shenzhen, Peoples R China. [Murtaza, Muhammed; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Bailey, Swneke D.; Engert, James C.] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. [Hingorani, Aroon D.; Kivimaki, Mika; Kumari, Meena; Whitehall II Study; WHII 50K Grp] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London WC1E 6BT, England. [Ongen, Halit; Goe, Anuj; Farrall, Martin; Peden, John F.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Johnson, Toby; Howard, Philip J.; Onipinla, Abiodun; Newhouse, Stephen J.; Caulfield, Mark; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London EC1M 6BQ, England. [Rajagopalan, Ramakrishnan; Furlong, Clement E.; Nakayama, Karen; Jarvik, Gail P.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Shen, Haiqing; Gibson, Quince; Mitchell, Braxton D.; Shuldiner, Alan R.; O'Connell, Jeffrey R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Klopp, Norman; Baumert, Jens; Gieger, Christian; Thorand, Barbara; Illig, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, D-85764 Neuherberg, Germany. [Taylor, Kira; North, Kari E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Barnard, John; Zhang, Li] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Nelson, Christopher P.; Braund, Peter S.; Rafelt, Suzanne; Tomaszweski, Maciej; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Lobmeyer, Maximilian T.; Gong, Yan; Johnson, Julie A.] Univ Florida, Coll Pharm, Ctr Pharmacogenom, Gainesville, FL 32610 USA. [Klein, Barbara E. K.; Klein, Ronald; Nondah, Dave; Cruickshanks, Karen J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53705 USA. [Zafarmand, M. Hadi; Asselbergs, Folkert W.; Doevendans, Pieter A.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands. [Carty, Cara; Kooperberg, Charles; LaCroix, Andrea; Reiner, Alex] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Price, Tom S.] Inst Psychiat, MRC SGDP Ctr, London SE5 8AF, England. [Onland-Moret, N. Charlotte; Asselbergs, Folkert W.; Bauer, Florianne; Elbers, Clara C.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, DBG, Complex Genet Sect, Utrecht, Netherlands. [van Iperen, Erik P. A.] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Romaine, Simon P. R.; Bailey, Kristian M.; Balmforth, Anthony J.; Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. [Pankratz, Nathan] Indiana Univ, Dept Med & Mol Genet, Sch Med, Indianapolis, IN 46202 USA. [Mehta, Amar; Christiani, David C.] Harvard Univ, Environm & Occupat Med & Epidemiol Program, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Sivapalaratnam, Suthesh; Trip, Mieke] Univ Amsterdam, Acad Med Ctr, Dept Cardiol & Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Drenos, Fotios; Humphries, Steve E.; Palmen, Jutta; Talmud, Philippa J.] UCL, Dept Med, Ctr Cardiovasc Genet, London WC1E 6JF, England. [Boer, Jolanda M. A.; Verschuren, W. M. Monique] Natl Inst Publ Hlth & Environm RIVM, NL-3720 BA Bilthoven, Netherlands. [Chandrupatla, Hareesh R.; Li, Mingyao; Rader, Daniel J.; Reilly, Muredach P.; Keating, Brendan J.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Maloney, Cliona M.; Suver, Christine] Rosetta Inpharmat, Dept Genet, Seattle, WA 98109 USA. [Smith, Erin N.; Schork, Nicholas J.; Murray, Sarah S.] Scripps Genom Med & Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Burton, Paul R.; Tobin, Martin] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England. [Murugesan, Gurunathan] Cleveland Clin, Pathol & Lab Med Inst, Dept Clin Pathol, Cleveland, OH 44106 USA. [Johnson, W. Craig] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Atwood, Larry D.; Fox, Caroline S.] Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02118 USA. [Fuchs, Barry; Lanken, Paul; Meyer, Nuala J.; Christie, Jason D.] Univ Penn, Med Ctr, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. [Zmuda, Joseph M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Connell, John] Univ Dundee, Ninewells Hosp & Med Sch, Sch Med, Dundee DD1 9SY, Scotland. [Schreiner, Pamela J.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Monda, Keri L.; Lange, Leslie A.] Univ N Carolina, Dept Genet, Sch Med Chapel Hill, Chapel Hill, NC 27514 USA. [Patel, Sanjey R.; Redline, Susan] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Montpetit, Alexandre] McGill Univ, Montreal, PQ H3A 1A4, Canada. [Montpetit, Alexandre] Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada. [Bhangale, Tushar] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA USA. [Tischfield, Sam; de Bakker, Paul I. W.; Hirschhorn, Joel N.] Broad Inst MIT & Harvard, Cambridge, MA 02115 USA. [Behr, Elijah R.] St Georges Univ London, Div Cardiovasc Sci, London SW17 0RE, England. [Dalgeorgou, Chrysoula; Zheng, Dongling; Jamshidi, Yalda] St Georges Univ London, Div Clin Dev Sci, London SW17 0RE, England. [Sweitzer, Nancy K.] Univ Wisconsin, Madison, WI 53792 USA. [Sawyer, Douglas B.] Vanderbilt Univ, Med Ctr, Div Cardiovasc, Nashville, TN 37232 USA. [Safa, Radwan N.] Boston Univ, Dept Mol Med, Boston, MA 02118 USA. [Ky, Bonnie; Cappola, Thomas P.] Univ Penn, Penn Cardiovasc Inst, Sch Med, Philadelphia, PA 19104 USA. [Fang, James C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Huang, Guan-Hua] Natl Chiao Tung Univ, Inst Stat, Hsinchu 30010, Taiwan. [Rodriguez, Santiago; Timpson, Nicholas J.; Day, Ian N.; Lawlor, Debbie A.; Smith, George Davey; Gaunt, Tom R.] Univ Bristol, Sch Social & Community Med, MRC, Ctr Causal Anal Translat Epidemiol, Bristol BS8 2BN, Avon, England. [Padmanabhan, Sandosh; Hastie, Claire; Delles, Christian] Univ Glasgow, Western Infirm, Div Cardiovasc & Med Sci, BHP Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Melander, Olle] Malmo Univ Hosp, CRC, SE-20502 Malmo, Sweden. [Dominiczak, Anna] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. [Shields, Denis C.] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland. [Stanton, Alice] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Mega, Jessica L.; Morrow, David A.; Sabatine, Marc S.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Silverstein, Roy L.] Case Western Reserve Univ, Dept Cell Biol, Lerner Res Inst,Cleveland Clin Fdn, Dept Mol Med,Cleveland Clin,Lerner Coll Med, Cleveland, OH 44195 USA. [de Bakker, Paul I. W.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Johnson, Julie A.] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32610 USA. [Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Murtaza, Muhammed; Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Engert, James C.] McGill Univ, Dept Med, Montreal, PQ H3A 1B1, Canada. [Boerwinkle, Eric] Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Div Epidemiol, Houston, TX 77030 USA. [Wijmenga, Cisca] Univ Groningen, NL-9700 RB Groningen, Netherlands. [Wijmenga, Cisca] Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Papanicolaou, George J.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Hingorani, Aroon D.] UCL, Dept Med, Ctr Clin Pharmacol, London WC1E 6JF, England. [Goe, Anuj; Farrall, Martin; Peden, John F.; Watkins, Hugh; PROCARDIS] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Anand, Sonia S.] McMaster Univ, Dept Med & Clin Epidemiol & Biostat, Populat Genom Program, Hamilton Gen Hosp, Hamilton, ON L8L 2X2, Canada. [Rader, Daniel J.; Reilly, Muredach P.; FitzGerald, Garret A.; Keating, Brendan J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Grant, Struan F. A.; Hakonarson, Hakon] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. [North, Kari E.] Univ N Carolina, Sch Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC 27514 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Cruickshanks, Karen J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53705 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA. [Christiani, David C.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Pulm & Crit Care Unit, Boston, MA 02114 USA. [van Iperen, Erik P. A.] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1007 MB Amsterdam, Netherlands. [Pankratz, Nathan; Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Schadt, Eric E.] Sage Bionetworks, Seattle, WA 98109 USA. [Dorn, Gerald W., II] Washington Univ, Ctr Pharmacogenet, St Louis, MO 63110 USA. [Nelson, Christopher P.; Braund, Peter S.; Rafelt, Suzanne; Tomaszweski, Maciej; Samani, Nilesh J.] Glenfield Hosp, Leicester Natl Inst Hlth Res, Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England. [Shah, Sonia] UCL, UCL Genet Inst, London WC1E 6BT, England. [Kleber, Marcus E.] LURIC Nonprofit LLC, Freiburg, Germany. [Maerz, Winfried] Synlab Ctr Lab Diagnost Heidelberg, D-58509 Heidelberg, Germany. [Maerz, Winfried] Univ Heidelberg, Inst Publ Hlth, Social Med & Epidemiol Med Fac, D-68167 Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagriost, A-8036 Graz, Austria. [Boehm, Bernhard O.] Univ Ulm, Ctr Excellence Baden Wuerttemberg, Div Endocrinol Diabet & Metab, D-89081 Ulm, Germany. [Winkelmann, Bernhard] Cardiol Grp Frankfurt Sachsenhausen, Frankfurt, Germany. [Marshal, Vanessa] Drug Safety Res Unit, Southampton SO31 1AA, Hants, England. [Brown, Morris] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol & Cambridge Inst Med Res, Cambridge CB2 0SP, England. [Lathrop, Mark] Ctr Natl Genotypage, F-91057 Evry, France. [Wallace, Chris] Addenbrookes Hosp, JDRF WT Diabet & Inflammat Lab, Cambridge Inst Med Res, Cambridge CB2 0XY, England. [Topol, Eric] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Kottke-Marchant, Kandice] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44195 USA. [Sever, Peter] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Int Ctr Circulatory Hlth, London W2 1NY, England. [Putt, Mary E.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-5050 Ulm Konto Nr, Germany. [Zafarmand, M. Hadi; Asselbergs, Folkert W.; Grobbee, Diederik E.; van der Schouw, Yvonne T.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3508 GA Utrecht, Netherlands. [Chen, Wei; Srinivasan, Sathanur R.; Berenson, Gerald S.] Tulane Univ, Dept Epidemiol, New Orleans, LA 70112 USA. [Hamsten, Anders] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, SE-17177 Stockholm, Sweden. [Clarke, Robert] Clin Trial Serv Unit, Oxford OX3 7LF, England. [Peters, Bas J.; de Boer, Anthonius; Klungel, Olaf H.; Maitland-van der Zee, Anke Hilse] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, NL-3508 TC Utrecht, Netherlands. [Casas, Juan P.] Univ London London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1E 7HT, England. [Li, Qing; Simpson, Claire] NHGRI, NIH, Baltimore, MD 21224 USA. [Swergold, Gary] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. [Curtis, Sean P.] Merck Res Labs, Rahway, NJ 07065 USA. RP Hakonarson, H (reprint author), Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA. EM hakonarson@chop.edu; bkeating@chop.edu RI Guo, Yiran/H-4120-2011; Kivimaki, Mika/B-3607-2012; Grobbee, Diederick/C-7651-2014; Wijmenga, Cisca/D-2173-2009; Smith, Erin/E-5933-2011; Carty, Cara/B-8683-2013; Thorand, Barbara/B-5349-2014; Price, Thomas/B-7372-2008; Jarvik, Gail/N-6476-2014; Murtaza, Muhammed/A-4188-2011; Stanton, Alice/F-4697-2012; de Bakker, Paul/B-8730-2009; Gaunt, Tom/O-3918-2014; Boehm, Bernhard/F-8750-2015; Onland-Moret, N. Charlotte/G-9185-2011; Hegele, Robert/G-3301-2011; Burton, Paul/H-7527-2016; Newhouse, Stephen/C-9330-2011; Klungel, Olaf/I-9563-2016; Fox, Laura /C-6249-2016; Padmanabhan, Sandosh/S-3963-2016; Davey Smith, George/A-7407-2013; OI Wallace, Chris/0000-0001-9755-1703; van Iperen, Erik/0000-0001-7107-3168; Topol, Eric/0000-0002-1478-4729; Mitchell, Braxton/0000-0003-4920-4744; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262; Pankow, James/0000-0001-7076-483X; Kleber, Marcus/0000-0003-0663-7275; Talmud, Philippa/0000-0002-5560-1933; Monsalve, Beatriz Elena/0000-0002-5994-866X; Johnson, Toby/0000-0002-5998-3270; Padmanabhan, Sandosh/0000-0003-3869-5808; Murtaza, Muhammed/0000-0001-7557-2861; Jamshidi, Yalda/0000-0003-0151-6482; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Patel, Sanjay/0000-0002-9142-5172; Klein, Ronald/0000-0002-4428-6237; Guo, Yiran/0000-0002-6549-8589; Grobbee, Diederick/0000-0003-4472-4468; Thorand, Barbara/0000-0002-8416-6440; Price, Thomas/0000-0001-7356-2109; Jarvik, Gail/0000-0002-6710-8708; de Bakker, Paul/0000-0001-7735-7858; Gaunt, Tom/0000-0003-0924-3247; Newhouse, Stephen/0000-0002-1843-9842; Davey Smith, George/0000-0002-1407-8314; Lanktree, Matthew/0000-0002-5750-6286; Suver, Christine/0000-0002-2986-385X; Kivimaki, Mika/0000-0002-4699-5627 FU Canadian Institutes of Health Research (CIHR) [79533]; Genome Canada through the Ontario Genomics Institute FX We thank the researchers, staff, and participants of all of the studies that contributed data. Specific cohort acknowledgements are cited in the Supplemental Acknowledgments. Matthew B. Lanktree is supported by a Canadian Institutes of Health Research (CIHR) M.D.-Ph.D. Studentship Award. Robert A. Hegele is funded by CIHR grant 79533 and by Genome Canada through the Ontario Genomics Institute. NR 36 TC 74 Z9 74 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 7 PY 2011 VL 88 IS 1 BP 6 EP 18 DI 10.1016/j.ajhg.2010.11.007 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 710HJ UT WOS:000286501500001 PM 21194676 ER PT J AU Ahmed, ZM Yousaf, R Lee, BC Khan, SN Lee, S Lee, K Husnain, T Rehman, AU Bonneux, S Ansar, M Ahmad, W Leal, SM Gladyshev, VN Belyantseva, IA Van Camp, G Riazuddin, S Friedman, TB Riazuddin, S AF Ahmed, Zubair M. Yousaf, Rizwan Lee, Byung Cheon Khan, Shaheen N. Lee, Sue Lee, Kwanghyuk Husnain, Tayyab Rehman, Atteeq Ur Bonneux, Sarah Ansar, Muhammad Ahmad, Wasim Leal, Suzanne M. Gladyshev, Vadim N. Belyantseva, Inna A. Van Camp, Guy Riazuddin, Sheikh Friedman, Thomas B. Riazuddin, Saima TI Functional Null Mutations of MSRB3 Encoding Methionine Sulfoxide Reductase Are Associated with Human Deafness DFNB74 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID NONSYNDROMIC HEARING IMPAIRMENT; OXIDATIVE STRESS; INNER-EAR; MACULAR DEGENERATION; GAMMA-ACTIN; AGE; GENE; CELLS; APOPTOSIS; DYSTONIA AB The DFNB74 locus for autosomal-recessive, nonsyndromic deafness segregating in three families was previously mapped to a 5.36 Mb interval on chromosome 12q14.2-q15. Subsequently, we ascertained five additional consanguineous families in which deafness segregated with markers at this locus and refined the critical interval to 2.31 Mb. We then sequenced the protein-coding exons of 18 genes in this interval. The affected individuals of six apparently unrelated families were homozygous for the same transversion (c.265T>G) in MSRB3, which encodes a zinc-containing methionine sulfoxide reductase B3. c.265T>G results in a substitution of glycine for cysteine (p.Cys89Gly), and this substitution cosegregates with deafness in the six DFNB74 families. This cysteine residue of MSRB3 is conserved in orthologs from yeast to humans and is involved in binding structural zinc. In vitro, p.Cys89Gly abolished zinc binding and MSRB3 enzymatic activity, indicating that p.Cys89Gly is a loss-of-function allele. The affected individuals in two other families were homozygous for a transition mutation (c.55T>C), which results in a nonsense mutation (p.Arg19X) in alternatively spliced exon 3, encoding a mitochondrial localization signal. This finding suggests that DFNB74 deafness is due to a mitochondrial dysfunction. In a cohort of 1,040 individuals (aged 53-67 years) of European ancestry, we found no association between 17 tagSNPs for MSRB3 and age-related hearing loss. Mouse Msrb3 is expressed widely. In the inner ear, it is found in the sensory epithelium of the organ of Corti and vestibular end organs as well as in cells of the spiral ganglion. Taken together, MSRB3-catalyzed reduction of methionine sulfoxides to methionine is essential for hearing. C1 [Ahmed, Zubair M.; Yousaf, Rizwan; Riazuddin, Saima] Cincinnati Childrens Hosp Res Fdn, Div Pediat Otolaryngol Head & Neck Surg, Mol Genet Lab, Cincinnati, OH 45229 USA. [Ahmed, Zubair M.; Yousaf, Rizwan; Riazuddin, Saima] Univ Cincinnati, Coll Med, Dept Otolaryngol, Cincinnati, OH 45229 USA. [Ahmed, Zubair M.; Riazuddin, Saima] Cincinnati Childrens Hosp Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH 45229 USA. [Ahmed, Zubair M.; Riazuddin, Saima] Univ Cincinnati, Coll Med, Dept Ophthalmol, Cincinnati, OH 45229 USA. [Lee, Byung Cheon; Gladyshev, Vadim N.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Lee, Byung Cheon; Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Yousaf, Rizwan; Khan, Shaheen N.; Husnain, Tayyab; Rehman, Atteeq Ur] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 54500, Pakistan. [Lee, Sue; Rehman, Atteeq Ur; Belyantseva, Inna A.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Lee, Kwanghyuk; Leal, Suzanne M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Bonneux, Sarah; Van Camp, Guy] Univ Antwerp, Dept Med Genet, B-2610 Antwerp, Belgium. [Ansar, Muhammad; Ahmad, Wasim] Quaid I Azam Univ, Fac Biol Sci, Dept Biochem, Islamabad 45320, Pakistan. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Jinnah Hosp Complex, Lahore 54500, Pakistan. RP Riazuddin, S (reprint author), Cincinnati Childrens Hosp Res Fdn, Div Pediat Otolaryngol Head & Neck Surg, Mol Genet Lab, Cincinnati, OH 45229 USA. EM saima.riazuddin@cchmc.org; saima.riazuddin@cchmc.org RI Ansar, Muhammad/H-5967-2011; Gladyshev, Vadim/A-9894-2013; Van Camp, Guy/F-3386-2013; Nasim Khan, Shaheen/F-2135-2015; Ansar, Muhammad/F-4808-2015; Husnain, Tayyab/G-3805-2015; Ahmad, Wasim/E-9713-2015; OI Ansar, Muhammad/0000-0001-5891-7063; Van Camp, Guy/0000-0001-5105-9000; Lee, Kwanghyuk/0000-0001-7781-9696 FU Cincinnati Children's Hospital Research Foundation (CCHMC); National Institute on Deafness and Other Communication Disorders, National Institutes of Health (NIDCD/NIH) [R00-DC009287-03, DC03594, DC00039-14]; National Institute on Aging, NIH [AG021518]; Higher Education Commission; World Health Organization Regional Office for the Eastern Mediterranean (EMRO); COMSTECH (Organization of the Islamic Conference [OIC] Standing Committee on Scientific and Technological Cooperation); Ministry of Science and Technology (MOST); International Center for Genetic Engineering and Biotechnology, Trieste, Italy [CRP/PAK08-01, 08/009]; Higher Education Commission (HEC), Government of Pakistan; Center for Inherited Disease Research (CIDR); NIH [N01-HG-65403] FX We wish to thank all participants in this study. We thank Shannon Bell for technical assistance and Dennis Drayna and Karen Friderici for critiques of the manuscript. This work was supported by Cincinnati Children's Hospital Research Foundation (CCHMC) intramural research funds to SR and ZA, the National Institute on Deafness and Other Communication Disorders, National Institutes of Health (NIDCD/NIH) research grant R00-DC009287-03, a Career Development Award from Research to Prevent Blindness (to Z.A.), and National Institute on Aging, NIH grant AG021518 (to V.N.G.). S. B. is a fellow of the Research Foundation Flanders (FWO-Vlaanderen). Work in Pakistan was supported by the Higher Education Commission to S.R. (Lahore); funding from World Health Organization Regional Office for the Eastern Mediterranean (EMRO) and COMSTECH (Organization of the Islamic Conference [OIC] Standing Committee on Scientific and Technological Cooperation) and from the Ministry of Science and Technology (MOST) to S.R. (Lahore); the International Center for Genetic Engineering and Biotechnology, Trieste, Italy under project CRP/PAK08-01 contract no. 08/009 to SR., (Islamabad). Part of the work was funded by the Higher Education Commission (HEC), Government of Pakistan, and the NIH National Institute of Deafness and other Communication Disorders grant DC03594 to S.M.L. Genotyping services were partially provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number N01-HG-65403. Work at NIDCD/NIH was supported by intramural funds DC00039-14 to T.B.F. NR 49 TC 32 Z9 36 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 7 PY 2011 VL 88 IS 1 BP 19 EP 29 DI 10.1016/j.ajhg.2010.11.010 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 710HJ UT WOS:000286501500002 PM 21185009 ER PT J AU Klopocki, E Lohan, S Brancati, F Koll, R Brehm, A Seemann, P Dathe, K Stricker, S Hecht, J Bosse, K Betz, RC Garaci, FG Dallapiccola, B Jain, M Muenke, M Ng, VCW Chan, W Chan, D Mundlos, S AF Klopocki, Eva Lohan, Silke Brancati, Francesco Koll, Randi Brehm, Anja Seemann, Petra Dathe, Katarina Stricker, Sigmar Hecht, Jochen Bosse, Kristin Betz, Regina C. Garaci, Francesco Giuseppe Dallapiccola, Bruno Jain, Mahim Muenke, Maximilian Ng, Vivian C. W. Chan, Wilson Chan, Danny Mundlos, Stefan TI Copy-Number Variations Involving the IHH Locus Are Associated with Syndactyly and Craniosynostosis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MOUSE MUTANT DOUBLEFOOT; INDIAN-HEDGEHOG; TRIPHALANGEAL THUMB; PHILADELPHIA TYPE; HUMAN GENOME; LIMB; MUTATIONS; DIFFERENTIATION; GLI3; PROLIFERATION AB Indian hedgehog (IHH) is a secreted signaling molecule of the hedgehog family known to play important roles in the regulation of chondrocyte differentiation, cortical bone formation, and the development of joints. Here, we describe that copy-number variations of the IHH locus involving conserved noncoding elements (CNEs) are associated with syndactyly and craniosynostosis. These CNEs are able to drive reporter gene expression in a pattern highly similar to wild-type Ihh expression. We postulate that the observed duplications lead to a misexpression and/or overexpression of IHH and by this affect the complex regulatory signaling network during digit and skull development. C1 [Klopocki, Eva; Lohan, Silke; Koll, Randi; Brehm, Anja; Dathe, Katarina; Stricker, Sigmar; Mundlos, Stefan] Charite, Inst Med Genet, D-13353 Berlin, Germany. [Klopocki, Eva; Lohan, Silke; Brehm, Anja; Dathe, Katarina; Stricker, Sigmar; Mundlos, Stefan] Max Planck Inst Mol Genet, Res Grp Dev & Dis, D-14195 Berlin, Germany. [Lohan, Silke; Brehm, Anja] Free Univ Berlin, D-14195 Berlin, Germany. [Brancati, Francesco] San Giovanni Rotondo & CSS Mendel Inst, IRCCS, I-00198 Rome, Italy. [Seemann, Petra; Hecht, Jochen; Mundlos, Stefan] Berlin Brandenburg Ctr Regenerat Therapies BCRT, D-13353 Berlin, Germany. [Bosse, Kristin] Univ Hosp Cologne, Dept Obstet & Gynecol, Div Mol Gynecol, D-50924 Cologne, Germany. [Betz, Regina C.] Univ Bonn, Inst Human Genet, D-53105 Bonn, Germany. [Garaci, Francesco Giuseppe] Univ Roma Tor Vergata, Dept Diagnost Imaging & Intervent Radiol, I-00133 Rome, Italy. [Dallapiccola, Bruno] Bambino Gesu Children Hosp, IRCCS, I-00198 Rome, Italy. [Jain, Mahim; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Ng, Vivian C. W.; Chan, Wilson; Chan, Danny] Univ Hong Kong, Dept Biochem, Pokfulam, Hong Kong, Peoples R China. [Brancati, Francesco] Univ Roma Tor Vergata, Dept Biopathol, I-00198 Rome, Italy. [Brancati, Francesco] Gabriele DAnnunzio Univ, Dept Biomed Sci, I-66013 Chieti, Italy. RP Klopocki, E (reprint author), Charite, Inst Med Genet, D-13353 Berlin, Germany. EM eva.klopocki@charite.de RI Dallapiccola, Bruno/K-8692-2016; Betz, Regina/E-8591-2011; Seemann, Petra/G-3606-2011; Stricker, Sigmar/B-9169-2009; Lohan, Silke/N-8917-2013; Klopocki, Eva/B-6823-2017; OI Dallapiccola, Bruno/0000-0002-5031-1013; Betz, Regina/0000-0001-5024-3623; Seemann, Petra/0000-0002-6056-6669; Stricker, Sigmar/0000-0002-7174-5363; Klopocki, Eva/0000-0003-1438-2081; Dathe, Katarina/0000-0002-8674-5817 FU Deutsche Forschungsgemeinschaft [KL 2158/2-1]; University Grants Council of Hong Kong [AoE 04/04]; General Research Grant of Hong Kong [HKU760608M] FX This work was supported by a grant from the Deutsche Forschungsgemeinschaft to E.K., K.D., and S.M. (KL 2158/2-1) and by funding from the University Grants Council (AoE 04/04) and the General Research Grant (HKU760608M) of Hong Kong. We thank Douglas P. Mortlock for generously providing us with the vector pSfi-Hsp68lacZ. We acknowledge Fabienne Trotier for excellent technical assistance. NR 32 TC 35 Z9 35 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 7 PY 2011 VL 88 IS 1 BP 70 EP 75 DI 10.1016/j.ajhg.2010.11.006 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 710HJ UT WOS:000286501500006 PM 21167467 ER PT J AU Guelly, C Zhu, PP Leonardis, L Papic, L Zidar, J Schabhuttl, M Strohmaier, H Weis, J Strom, TM Baets, J Willems, J De Jonghe, P Reilly, MM Frohlich, E Hatz, M Trajanoski, S Pieber, TR Janecke, AR Blackstone, C Auer-Grumbach, M AF Guelly, Christian Zhu, Peng-Peng Leonardis, Lea Papic, Lea Zidar, Janez Schabhuettl, Maria Strohmaier, Heimo Weis, Joachim Strom, Tim M. Baets, Jonathan Willems, Jan De Jonghe, Peter Reilly, Mary M. Froehlich, Eleonore Hatz, Martina Trajanoski, Slave Pieber, Thomas R. Janecke, Andreas R. Blackstone, Craig Auer-Grumbach, Michaela TI Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SERINE PALMITOYLTRANSFERASE; SPASTIC PARAPLEGIA; GTPASE ATLASTIN; MORPHOGENESIS; GENERATION; FAMILY AB Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders. C1 [Papic, Lea; Schabhuettl, Maria; Pieber, Thomas R.; Auer-Grumbach, Michaela] Med Univ Graz, Dept Internal Med, Div Endocrinol & Metab, A-8036 Graz, Austria. [Guelly, Christian; Strohmaier, Heimo; Froehlich, Eleonore; Hatz, Martina; Trajanoski, Slave] Med Univ Graz, Med Res Ctr, A-8010 Graz, Austria. [Zhu, Peng-Peng; Blackstone, Craig] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Leonardis, Lea; Zidar, Janez] Univ Clin Ctr, Inst Clin Neurophysiol, Ljubljana 1000, Slovenia. [Weis, Joachim] Univ Aachen, Rhein Westfal TH, Fac Med, Inst Neuropathol, D-52074 Aachen, Germany. [Strom, Tim M.] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany. [Baets, Jonathan; De Jonghe, Peter] Univ Antwerp VIB, Dept Mol Genet, Neurogenet Grp, B-2610 Antwerp, Belgium. [Baets, Jonathan; De Jonghe, Peter] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2610 Antwerp, Belgium. [Baets, Jonathan; De Jonghe, Peter] Univ Antwerp Hosp, Div Neurol, B-2650 Antwerp, Belgium. [Willems, Jan] Hosp Network Antwerp Middelheim, Dept Phys & Rehabil Med, B-2020 Antwerp, Belgium. [Reilly, Mary M.] UCL, Inst Neurol, Med Res Ctr Neuromuscular Dis, London WC1N 3BG, England. [Janecke, Andreas R.] Innsbruck Med Univ, Dept Pediat 2, A-6020 Innsbruck, Austria. [Janecke, Andreas R.] Innsbruck Med Univ, Div Human Genet, A-6020 Innsbruck, Austria. RP Auer-Grumbach, M (reprint author), Med Univ Graz, Dept Internal Med, Div Endocrinol & Metab, A-8036 Graz, Austria. EM michaela.auergrumbach@medunigraz.at RI Weis, Joachim/G-1984-2014; OI Weis, Joachim/0000-0003-3280-6773; Janecke, Andreas/0000-0001-7155-0315; Frohlich, Eleonore/0000-0002-6056-6829 FU Austrian Science Fund (FWF) [P19455-B05]; Oesterreichische Nationalbank (ONB) [13010]; National Institute of Neurological Disorders and Stroke, US National Institutes of Health; University of Antwerp; Fund for Scientific Research (FWO-Flanders); Medical Foundation Queen Elisabeth (GSKE); Association Beige contre les Maladies Neuromusculaires (ABMM); Interuniversity Attraction Poles Program of the Belgian Federal Science Policy Office (BELSPO) [P6/43]; Deutsche Forschungsgemeinschaft [WE 1406 13/1] FX We are grateful for the participation of the patients and families, and we thank C. Fischer, H. Knausz, J. Nagle, and T. Deconinck for expert technical assistance. This work was supported by the Austrian Science Fund (FWF, P19455-B05), the Oesterreichische Nationalbank (ONB, project 13010), and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, US National Institutes of Health. This project was in part funded by a Methusalem grant of the University of Antwerp, the Fund for Scientific Research (FWO-Flanders), the Medical Foundation Queen Elisabeth (GSKE), the Association Beige contre les Maladies Neuromusculaires (ABMM), and the Interuniversity Attraction Poles P6/43 Program of the Belgian Federal Science Policy Office (BELSPO). J.B. is supported by a PhD fellowship of the FWO-Flanders, and J.W. is supported by Deutsche Forschungsgemeinschaft grant WE 1406 13/1. NR 23 TC 60 Z9 62 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 7 PY 2011 VL 88 IS 1 BP 99 EP 105 DI 10.1016/j.ajhg.2010.12.003 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 710HJ UT WOS:000286501500010 PM 21194679 ER PT J AU Pan, DD Li, QZ Jiang, NN Liu, AY Yu, K AF Pan, Dongdong Li, Qizhai Jiang, Ningning Liu, Aiyi Yu, Kai TI Robust joint analysis allowing for model uncertainty in two-stage genetic association studies SO BMC BIOINFORMATICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SAMPLE-SIZE; DESIGNS; TESTS; COSTS AB Background: The cost efficient two-stage design is often used in genome-wide association studies (GWASs) in searching for genetic loci underlying the susceptibility for complex diseases. Replication- based analysis, which considers data from each stage separately, often suffers from loss of efficiency. Joint test that combines data from both stages has been proposed and widely used to improve efficiency. However, existing joint analyses are based on test statistics derived under an assumed genetic model, and thus might not have robust performance when the assumed genetic model is not appropriate. Results: In this paper, we propose joint analyses based on two robust tests, MERT and MAX3, for GWASs under a two-stage design. We developed computationally efficient procedures and formulas for significant level evaluation and power calculation. The performances of the proposed approaches are investigated through the extensive simulation studies and a real example. Numerical results show that the joint analysis based on the MAX3 test statistic has the best overall performance. Conclusions: MAX3 joint analysis is the most robust procedure among the considered joint analyses, and we recommend using it in a two-stage genome-wide association study. C1 [Pan, Dongdong; Li, Qizhai; Jiang, Ningning] Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100190, Peoples R China. [Pan, Dongdong] Yunnan Univ, Dept Stat, Kunming 650091, Peoples R China. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD 20892 USA. [Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Li, QZ (reprint author), Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100190, Peoples R China. EM liqz@amss.ac.cn OI Liu, Aiyi/0000-0002-6618-5082 FU National Young Science Foundation of China [10901155] FX We would like to thank the editor and three anonymous reviewers for their very constructive comments and suggestions, which significantly improved our presentation. This work is partially support by the National Young Science Foundation of China, No. 10901155. NR 27 TC 4 Z9 5 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JAN 7 PY 2011 VL 12 AR 9 DI 10.1186/1471-2105-12-9 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 711NN UT WOS:000286598800001 PM 21211060 ER PT J AU Luco, RF Allo, M Schor, IE Kornblihtt, AR Misteli, T AF Luco, Reini F. Allo, Mariano Schor, Ignacio E. Kornblihtt, Alberto R. Misteli, Tom TI Epigenetics in Alternative Pre-mRNA Splicing SO CELL LA English DT Review ID CARBOXY-TERMINAL DOMAIN; SR PROTEIN FAMILY; POLYMERASE-II; IN-VIVO; PREMESSENGER RNA; INTRON REMOVAL; TRANSCRIPTIONAL ELONGATION; 3'-END FORMATION; DNA METHYLATION; GENE-EXPRESSION AB Alternative splicing plays critical roles in differentiation, development, and disease and is a major source for protein diversity in higher eukaryotes. Analysis of alternative splicing regulation has traditionally focused on RNA sequence elements and their associated splicing factors, but recent provocative studies point to a key function of chromatin structure and histone modifications in alternative splicing regulation. These insights suggest that epigenetic regulation determines not only what parts of the genome are expressed but also how they are spliced. C1 [Luco, Reini F.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Allo, Mariano; Schor, Ignacio E.; Kornblihtt, Alberto R.] Univ Buenos Aires, Fac Ciencias Exactas Nat, LFBM, Dept Fisiol Biol Mol, Buenos Aires, DF, Argentina. [Allo, Mariano; Schor, Ignacio E.; Kornblihtt, Alberto R.] Univ Buenos Aires, Fac Ciencias Exactas Nat, IFIBYNE CONICET, Buenos Aires, DF, Argentina. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Allo, Mariano/0000-0002-3617-6126; Kornblihtt, Alberto/0000-0003-4322-0831 FU Agencia Nacional de Promocion de Ciencia y Tecnologia of Argentina; Universidad de Buenos Aires; European Alternative Splicing Network (EURASNET); Consejo Nacional de Investigaciones Cientificas y Tecnicas of Argentina (CONICET); National Institutes of Health (NIH), NCI, Center for Cancer Research FX This work was supported by grants to A.R.K. from the Agencia Nacional de Promocion de Ciencia y Tecnologia of Argentina, the Universidad de Buenos Aires, and the European Alternative Splicing Network (EURASNET). I.E.S. is a recipient of a postdoctoral fellowships, and A.R.K. is a career investigator from the Consejo Nacional de Investigaciones Cientificas y Tecnicas of Argentina (CONICET). A.R.K. is an international research scholar of the Howard Hughes Medical Institute. Work in the Misteli laboratory is supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research. NR 94 TC 324 Z9 340 U1 9 U2 126 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 7 PY 2011 VL 144 IS 1 BP 16 EP 26 DI 10.1016/j.cell.2010.11.056 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 703QF UT WOS:000285993600004 PM 21215366 ER PT J AU Leonard, TA Rozycki, B Saidi, LF Hummer, G Hurley, JH AF Leonard, Thomas A. Rozycki, Bartosz Saidi, Layla F. Hummer, Gerhard Hurley, James H. TI Crystal Structure and Allosteric Activation of Protein Kinase C beta II SO CELL LA English DT Article ID RAY SOLUTION SCATTERING; SMALL-ANGLE SCATTERING; MEMBRANE-BINDING; CATALYTIC DOMAIN; BIOLOGICAL MACROMOLECULES; MULTIPROTEIN COMPLEXES; PHOSPHORYLATION SITES; INDUCED TRANSLOCATION; NIH 3T3-CELLS; PHORBOL ESTER AB Protein kinase C (PKC) isozymes are the paradigmatic effectors of lipid signaling. PKCs translocate to cell membranes and are allosterically activated upon binding of the lipid diacylglycerol to their C1A and C1B domains. The crystal structure of full-length protein kinase C beta II was determined at 4.0 angstrom, revealing the conformation of an unexpected intermediate in the activation pathway. Here, the kinase active site is accessible to substrate, yet the conformation of the active site corresponds to a low-activity state because the ATP-binding side chain of Phe629 of the conserved NFD motif is displaced. The C1B domain clamps the NFD helix in a low-activity conformation, which is reversed upon membrane binding. A low-resolution solution structure of the closed conformation of PKC beta II was derived from small-angle X-ray scattering. Together, these results show how PKC beta II is allosterically regulated in two steps, with the second step defining a novel protein kinase regulatory mechanism. C1 [Leonard, Thomas A.; Saidi, Layla F.; Hurley, James H.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Rozycki, Bartosz; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov RI Rozycki, Bartosz/B-7005-2009; Hummer, Gerhard/A-2546-2013; Leonard, Thomas/A-5143-2013 OI Rozycki, Bartosz/0000-0001-5938-7308; Hummer, Gerhard/0000-0001-7768-746X; Leonard, Thomas/0000-0001-6853-666X FU NCI [Y1-CO-1020]; NIGMS [Y1-GM-1104]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; Department of Energy, Office of Biological and Environmental Research; National Institutes of Health, National Center for Research Resources; EMBO; Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank J. Chang for technical assistance, J. Lloyd and D. E. Anderson for assistance with mass spectrometry, J. F. Mushinski and A. Toker for DNAs, E. Boura for assistance with SAXS data collection, H. Tsuruta and T. Weiss for user support at BL4-2, SSRL, M. Becker for user support at GM/CA-CAT, APS, H. Mischak and M. Pearson for early efforts, A. Newton for discussions, and A. Brunger for a prerelease version of CNS 1.3. GM/CA-CAT has been funded in whole or in part with Federal funds from the NCI (Y1-CO-1020) and the NIGMS (Y1-GM-1104). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357. SAXS data were collected at the Stanford Synchrotron Radiation Laboratory, a national user facility operated by Stanford University on behalf of the U.S. Department of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program. T.A.L. was supported in part by an EMBO long term fellowship. B.R. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme. This research was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health to J.H.H. and G.H. NR 56 TC 98 Z9 99 U1 1 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 7 PY 2011 VL 144 IS 1 BP 55 EP 66 DI 10.1016/j.cell.2010.12.013 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 703QF UT WOS:000285993600007 PM 21215369 ER PT J AU Misteli, T AF Misteli, Tom TI HGPS-Derived iPSCs For The Ages SO CELL STEM CELL LA English DT Editorial Material ID PROGERIA-SYNDROME AB In this issue of Cell Stem Cell, Zhang et al. (2011) generate patient-derived iPSCs for one of the major premature aging diseases, Hutchinson-Gilford Progeria Syndrome (HGPS). These cells are a much-needed new tool to study HGPS, and their use may lead to novel insights into mechanisms of aging. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov NR 7 TC 2 Z9 2 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD JAN 7 PY 2011 VL 8 IS 1 BP 4 EP 6 DI 10.1016/j.stem.2010.12.014 PG 3 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 714CX UT WOS:000286786200003 PM 21211775 ER PT J AU Kuehn, HS Jung, MY Beaven, MA Metcalfe, DD Gilfillan, AM AF Kuehn, Hye Sun Jung, Mi-Yeon Beaven, Michael A. Metcalfe, Dean D. Gilfillan, Alasdair M. TI Prostaglandin E-2 Activates and Utilizes mTORC2 as a Central Signaling Locus for the Regulation of Mast Cell Chemotaxis and Mediator Release SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FC-EPSILON-RI; NF-KAPPA-B; REACTIVE OXYGEN; RAC ACTIVATION; PROTEIN-KINASE; RESPONSES; RECEPTORS; DEGRANULATION; PATHWAYS; PHOSPHORYLATION AB Prostaglandin (PG) E-2, a potent mediator produced in inflamed tissues, can substantially influence mast cell responses including adhesion to basement membrane proteins, chemotaxis, and chemokine production. However, the signaling pathways by which PGE(2) induces mast cell chemotaxis and chemokine production remains undefined. In this study, we identified the downstream target of phosphatidylinositol 3-kinase, mammalian target of rapamycin (mTOR), as a key regulator of these responses. In mouse bone marrow-derived mast cells, PGE(2) was found to induce activation of mTORC1 (mTOR complexed to raptor) as indicated by increased p70S6K and 4E-BP1 phosphorylation, and activation of mTORC2 (mTOR complexed to rictor), as indicated by increased phosphorylation of AKT at position Ser(473). Selective inhibition of the mTORC1 cascade by rapamycin or by the use of raptor-targeted shRNA failed to decrease PGE(2)-mediated chemotaxis or chemokine generation. However, inhibition of the mTORC2 cascade through the dual mTORC1/mTORC2 inhibitor Torin, or through rictor-targeted shRNA, resulted in a significant attenuation in PGE2-mediated chemotaxis, which was associated with a comparable decrease in actin polymerization. Furthermore, mTORC2 down-regulation decreased PGE(2)-induced production of the chemokine monocyte chemoattractant protein-1 (CCL2), which was linked to a significant reduction in ROS production. These findings are consistent with the conclusion that activation of mTORC2, downstream of PI3K, represents a critical signaling locus for chemotaxis and chemokine release from PGE(2)-activated mast cells. C1 [Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Rm 11C206,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov FU NIAID; NHLBI within the National Institutes of Health FX Financial support was provided by the Division of Intramural Research of NIAID and NHLBI within the National Institutes of Health. NR 54 TC 39 Z9 40 U1 0 U2 1 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 7 PY 2011 VL 286 IS 1 BP 391 EP 402 DI 10.1074/jbc.M110.164772 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 700YZ UT WOS:000285782800042 PM 20980255 ER PT J AU Sajid, W Kulahin, N Schluckebier, G Ribel, U Henderson, HR Tatar, M Hansen, BF Svendsen, AM Kiselyov, VV Norgaard, P Wahlund, PO Brandt, J Kohanski, RA Andersen, AS De Meyts, P AF Sajid, Waseem Kulahin, Nikolaj Schluckebier, Gerd Ribel, Ulla Henderson, Hope Rosalind Tatar, Marc Hansen, Bo Falck Svendsen, Angela Manegold Kiselyov, Vladislav V. Norgaard, Per Wahlund, Per-Olof Brandt, Jakob Kohanski, Ronald A. Andersen, Asser Sloth De Meyts, Pierre TI Structural and Biological Properties of the Drosophila Insulin-like Peptide 5 Show Evolutionary Conservation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR-BINDING REGION; NEGATIVE COOPERATIVITY; LIFE-SPAN; SACCHAROMYCES-CEREVISIAE; SIGNAL-TRANSDUCTION; BOMBYX-MORI; GROWTH; PROTEIN; CELLS; EXPRESSION AB We report the crystal structure of two variants of Drosophila melanogaster insulin-like peptide 5 (DILP5) at a resolution of 1.85 angstrom. DILP5 shares the basic fold of the insulin peptide family (T conformation) but with a disordered B-chain C terminus. DILP5 dimerizes in the crystal and in solution. The dimer interface is not similar to that observed in vertebrates, i.e. through an anti-parallel beta-sheet involving the B-chain C termini but, in contrast, is formed through an anti-parallel beta-sheet involving the B-chain N termini. DILP5 binds to and activates the human insulin receptor and lowers blood glucose in rats. It also lowers trehalose levels in Drosophila. Reciprocally, human insulin binds to the Drosophila insulin receptor and induces negative cooperativity as in the human receptor. DILP5 also binds to insect insulin-binding proteins. These results show high evolutionary conservation of the insulin receptor binding properties despite divergent insulin dimerization mechanisms. C1 [Sajid, Waseem; Kulahin, Nikolaj; Svendsen, Angela Manegold; Kiselyov, Vladislav V.; De Meyts, Pierre] Hagedorn Res Inst, Receptor Syst Biol Lab, DK-2820 Gentofte, Denmark. [Schluckebier, Gerd; Ribel, Ulla; Hansen, Bo Falck; Norgaard, Per; Wahlund, Per-Olof; Brandt, Jakob; Andersen, Asser Sloth] Novo Nordisk AS, Diabet Res Unit, DK-2760 Malov, Denmark. [Henderson, Hope Rosalind; Tatar, Marc] Brown Univ, Dept Ecol & Evolutionary Biol, Providence, RI 02912 USA. [Kohanski, Ronald A.] NIA, NIH, Bethesda, MD 20892 USA. RP Sajid, W (reprint author), Hagedorn Res Inst, Receptor Syst Biol Lab, DK-2820 Gentofte, Denmark. EM wsaj@hagedorn.dk RI Schluckebier, Gerd/A-5045-2009 NR 70 TC 20 Z9 21 U1 0 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 7 PY 2011 VL 286 IS 1 BP 661 EP 673 DI 10.1074/jbc.M110.156018 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 700YZ UT WOS:000285782800067 PM 20974844 ER PT J AU Ghoshal, S Trivedi, DB Graf, GA Loftin, CD AF Ghoshal, Sarbani Trivedi, Darshini B. Graf, Gregory A. Loftin, Charles D. TI Cyclooxygenase-2 Deficiency Attenuates Adipose Tissue Differentiation and Inflammation in Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INHIBITS ADIPOCYTE DIFFERENTIATION; ACTIVATED RECEPTOR-GAMMA; PPAR-GAMMA; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); UP-REGULATION; 3T3-L1 CELLS; IN-VIVO; PROSTAGLANDIN; EXPRESSION; OBESITY AB Obesity is associated with a variety of disorders and is a significant health problem in developed countries. One factor controlling the level of adiposity is the differentiation of cells into adipocytes. Adipocyte differentiation requires expression of peroxisome proliferator-activated receptor gamma (PPAR gamma), which is activated by ligands to regulate expression of genes involved in adipocyte differentiation. Although 15-deoxy-Delta(12,14)-prostaglandin (PG) J(2) (15d-PGJ(2)) has long been known to be a potent activator of PPAR gamma, the importance of its synthesis in adipose tissue in vivo is not clear. The current study utilized mice deficient in cyclooxygenase-2 (COX-2) to examine the role of COX-2-derived PGs as in vivo modulators of adiposity. As compared with strain- and age-matched wildtype controls, the genetic deficiency of COX-2 resulted in a significant reduction in total body weight and percent body fat. Although there were no significant differences in food consumption between groups, COX-2-deficient mice showed increased metabolic activity. Epididymal adipose tissue from wild-type mice produced a significantly greater level of 15d-PGJ(2), as compared with adipose tissue isolated from mice deficient in COX-2. Furthermore, production of the precursor required for 15d-PGJ(2) formation, PGD(2), was also significantly reduced in COX-2-deficient adipose tissue. The expression of markers for differentiated adipocytes was significantly reduced in adipose tissue from COX-2-deficient mice, whereas preadipocyte marker expression was increased. Macrophage-dependent inflammation was also significantly reduced in adipose tissue of COX-2-deficient mice. These findings suggest that reduced adiposity in COX-2-deficient mice results from attenuated PPAR gamma ligand production and adipocyte differentiation. C1 [Ghoshal, Sarbani; Graf, Gregory A.; Loftin, Charles D.] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA. [Trivedi, Darshini B.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Loftin, CD (reprint author), Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Bio Pharm Complex,Rm 347,789 S Limestone St, Lexington, KY 40536 USA. EM cdloft2@email.uky.edu FU NCRR NIH HHS [S10 RR024598]; NIDDK NIH HHS [R01 DK080874-03, R01 DK080874-01A2, R01 DK080874-02, R01 DK080874]; NIGMS NIH HHS [P20 GM103527] NR 51 TC 37 Z9 39 U1 2 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 7 PY 2011 VL 286 IS 1 BP 889 EP 898 DI 10.1074/jbc.M110.139139 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 700YZ UT WOS:000285782800088 PM 20961858 ER PT J AU Berdygulova, Z Westblade, LF Florens, L Koonin, EV Chait, BT Ramanculov, E Washburn, MP Darst, SA Severinov, K Minakhin, L AF Berdygulova, Zhanna Westblade, Lars F. Florens, Laurence Koonin, Eugene V. Chait, Brian T. Ramanculov, Erlan Washburn, Michael P. Darst, Seth A. Severinov, Konstantin Minakhin, Leonid TI Temporal Regulation of Gene Expression of the Thermus thermophilus Bacteriophage P23-45 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Thermus thermophilus; thermophage; phage promoters; RNA polymerase; RNAP-binding proteins ID RNA-POLYMERASE HOLOENZYME; PROTEIN IDENTIFICATION TECHNOLOGY; ANGSTROM RESOLUTION; PROTEOMIC ANALYSIS; STRUCTURAL BASIS; TRANSCRIPTION INITIATION; STRUCTURE PREDICTION; CRYSTAL-STRUCTURE; SEQUENCE; GENOME AB Regulation of gene expression during infection of the thermophilic bacterium Thermus thermophilus HB8 with the bacteriophage P23-45 was investigated. Macroarray analysis revealed host transcription shut-off and identified three temporal classes of phage genes; early, middle and late. Primer extension experiments revealed that the 5` ends of P23-45 early transcripts are preceded by a common sequence motif that likely defines early viral promoters. T. thermophilus HB8 RNA polymerase (RNAP) recognizes middle and late phage promoters in vitro but does not recognize early promoters. In vivo experiments revealed the presence of rifampicin-resistant RNA polymerizing activity in infected cells responsible for early transcription. The product of the P23-45 early gene 64 shows a distant sequence similarity with the largest, catalytic subunits of multisubunit RNAPs and contains the conserved metal-binding motif that is diagnostic of these proteins. We hypothesize that ORF64 encodes rifampicin-resistant phage RNAP that recognizes early phage promoters. Affinity isolation of T. thermophilus HB8 RNAP from P23-45-infected cells identified two phage-encoded proteins, gp39 and gp76, that bind the host RNAP and inhibit in vitro transcription from host promoters, but not from middle or late phage promoters, and may thus control the shift from host to viral gene expression during infection. To our knowledge, gp39 and gp76 are the first characterized bacterial RNAP-binding proteins encoded by a thermophilic phage. (c) 2010 Elsevier Ltd. All rights reserved. C1 [Berdygulova, Zhanna; Severinov, Konstantin; Minakhin, Leonid] Waksman Inst Microbiol, Piscataway, NJ 08854 USA. [Westblade, Lars F.; Chait, Brian T.; Darst, Seth A.] Rockefeller Univ, New York, NY 10065 USA. [Florens, Laurence; Washburn, Michael P.] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Koonin, Eugene V.] NCBI, NLM, NIH, Bethesda, MD 20894 USA. [Washburn, Michael P.] Univ Kansas, Dept Pathol & Lab Med, Med Ctr, Kansas City, KS 66160 USA. [Severinov, Konstantin] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. RP Severinov, K (reprint author), Waksman Inst Microbiol, Piscataway, NJ 08854 USA. EM severik@waksman.rutgers.edu; minakhin@waksman.rutgers.edu RI Ramanculov, Erlan/E-2823-2013; Severinov, Konstantin/C-8545-2016; OI Florens, Laurence/0000-0002-9310-6650; Washburn, Michael/0000-0001-7568-2585 FU NIH [R21 AI074769, R01 GM61898, RR00862, RR022220, R01 GM59295]; Federal Program "Scientific and scientific-pedagogical personnel of innovative Russia [02.740.11.5132]; Stowers Institute for Medical Research; Presidium of Russian Academy of Sciences, Russian Foundation [07-04-00366-a]; Federal Program "Scientific and scientific-pedagogical personnel of innovative Russia" [02.740.11.0771]; National Center for Biotechnology of the Republic of Kazakhstan; US Department of Health and Human Resources (National Library of Medicine, National Institutes of Health) FX Bacteriophage P23-45 was generously provided by Dr Michael Slater from Promega Corporation. We thank Dr E. Peter Geiduschek for critical reading of the manuscript and helpful advice. This work was supported by NIH grant R21 AI074769 and Federal Program "Scientific and scientific-pedagogical personnel of innovative Russia 2009-2013", state contract 02.740.11.5132 (to L.M.), by NIH grant R01 GM61898 (to S.A.D.), by NIH grants RR00862 and RR022220 (to B.T.C.), by the Stowers Institute for Medical Research (to L.F. and M.P.W.) by NIH grant R01 GM59295, by Molecular and Cell Biology grant from the Presidium of Russian Academy of Sciences, Russian Foundation for Basis Research grant 07-04-00366-a, by Federal Program "Scientific and scientific-pedagogical personnel of innovative Russia 2009-2013", state contract 02.740.11.0771, and by a National Center for Biotechnology of the Republic of Kazakhstan grant (to K.S.); E.V.K. is supported by the US Department of Health and Human Resources (National Library of Medicine, National Institutes of Health). NR 45 TC 11 Z9 12 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 7 PY 2011 VL 405 IS 1 BP 125 EP 142 DI 10.1016/j.jmb.2010.10.049 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 712XY UT WOS:000286700800013 PM 21050864 ER PT J AU Je, HS Ji, YY Wang, Y Yang, F Wu, W Lu, B AF Je, H. Shawn Ji, Yuanyuan Wang, Ying Yang, Feng Wu, Wei Lu, Bai TI Presynaptic protein synthesis required for NT-3-induced long-term synaptic modulation SO MOLECULAR BRAIN LA English DT Article ID DEVELOPING NEUROMUSCULAR SYNAPSES; GREEN FLUORESCENT PROTEIN; GENE-EXPRESSION; KINASE PKR; NEUROTROPHINS; MEMORY; POTENTIATION; MECHANISMS; PHOSPHORYLATION; DIMERIZATION AB Background: Neurotrophins elicit both acute and long-term modulation of synaptic transmission and plasticity. Previously, we demonstrated that the long-term synaptic modulation requires the endocytosis of neurotrophin-receptor complex, the activation of PI3K and Akt, and mTOR mediated protein synthesis. However, it is unclear whether the long-term synaptic modulation by neurotrophins depends on protein synthesis in pre- or postsynaptic cells. Results: Here we have developed an inducible protein translation blocker, in which the kinase domain of protein kinase R (PKR) is fused with bacterial gyrase B domain (GyrB-PKR), which could be dimerized upon treatment with a cell permeable drug, coumermycin. By genetically targeting GyrB-PKR to specific cell types, we show that NT-3 induced long-term synaptic modulation requires presynaptic, but not postsynaptic protein synthesis. Conclusions: Our results provide mechanistic insights into the cell-specific requirement for protein synthesis in the long-term synaptic modulation by neurotrophins. The GyrB-PKR system may be useful tool to study protein synthesis in a cell-specific manner. C1 [Je, H. Shawn; Ji, Yuanyuan; Yang, Feng; Lu, Bai] NIMH, Genes Cognit & Psychosis Program GCAP, NIH, Bethesda, MD 20892 USA. [Je, H. Shawn] DUKE NUS Grad Med Sch, Program Neurosci & Behav Disorders, Singapore 169857, Singapore. [Ji, Yuanyuan; Lu, Bai] GlaxoSmithKline, R&D China, Shanghai 201203, Peoples R China. [Wang, Ying; Wu, Wei; Lu, Bai] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. [Wang, Ying; Wu, Wei] Tsinghua Univ, Minist Educ, Prot Sci Lab, Beijing 100084, Peoples R China. RP Lu, B (reprint author), NIMH, Genes Cognit & Psychosis Program GCAP, NIH, Bethesda, MD 20892 USA. EM bai.b.lu@gsk.com OI Je, hyunsoo/0000-0002-2924-5621 NR 27 TC 6 Z9 6 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-6606 J9 MOL BRAIN JI Mol. Brain PD JAN 7 PY 2011 VL 4 AR 1 DI 10.1186/1756-6606-4-1 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 007VO UT WOS:000308916700001 PM 21211057 ER PT J AU Yamane, K Mizuguchi, T Cui, BW Zofall, M Noma, K Grewal, SIS AF Yamane, Kenichi Mizuguchi, Takeshi Cui, Bowen Zofall, Martin Noma, Ken-ichi Grewal, Shiv I. S. TI Asf1/HIRA Facilitate Global Histone Deacetylation and Associate with HP1 to Promote Nucleosome Occupancy at Heterochromatic Loci SO MOLECULAR CELL LA English DT Article ID FISSION YEAST; DNA-REPLICATION; SACCHAROMYCES-CEREVISIAE; EPIGENETIC CONTROL; HIR PROTEINS; CHROMATIN; COMPLEX; GENOME; RNAI; MAINTENANCE AB Heterochromatin impacts various nuclear processes by providing a recruiting platform for diverse chromosomal proteins. In fission yeast, HP1 proteins Chp2 and Swi6, which bind to methylated histone H3 lysine 9, associate with SHREC (Snf2/HDAC repressor complex) and Clr6 histone deacetylases (HDACs) involved in heterochromatic silencing. However, heterochromatic silencing machinery is not fully defined. We describe a histone chaperone complex containing Ast1 and HIRA that spreads across silenced domains via its association with Swi6 to enforce transcriptional silencing. Asf1 functions in concert with a Clr6 HDAC complex to silence heterochromatic repeats, and it suppresses antisense transcription by promoting histone deacetylation. Furthermore, we demonstrate that Ast1 and SHREC facilitate nucleosome occupancy at heterochromatic regions but TFIIIC transcription factor binding sites within boundary elements are refractory to these factors. These analyses uncover a role for Asf1 in global histone deacetylation and suggest that HP1-associated histone chaperone promotes nucleosome occupancy to assemble repressive heterochromatin. C1 [Yamane, Kenichi; Mizuguchi, Takeshi; Cui, Bowen; Zofall, Martin; Noma, Ken-ichi; Grewal, Shiv I. S.] NCI, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. RP Grewal, SIS (reprint author), NCI, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov RI Cui, Bowen/F-1038-2011 FU National Institutes of Health, National Cancer Institute FX We thank K. Zhang and T. Fischer for their helpful contributions, F. Reyes-Turcu and O. Aygun for critical reading of the manuscript, M. Zhou and T. Veenstra for mass spectrometry, and members of the Grewal laboratory for discussions. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 47 TC 44 Z9 44 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 7 PY 2011 VL 41 IS 1 BP 56 EP 66 DI 10.1016/j.molcel.2010.12.009 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 712US UT WOS:000286692400009 PM 21211723 ER PT J AU Cui, F Sirotin, MV Zhurkin, VB AF Cui, Feng Sirotin, Michael V. Zhurkin, Victor B. TI Impact of Alu repeats on the evolution of human p53 binding sites SO BIOLOGY DIRECT LA English DT Article ID POLYMERASE-III TRANSCRIPTION; CELL-SPECIFIC ENHANCER; ACID RESPONSE ELEMENT; TUMOR-SUPPRESSOR; TRANSPOSABLE ELEMENTS; REPETITIVE ELEMENTS; GENE-REGULATION; P53-INDUCIBLE GENE; P53-BINDING SITES; REPBASE UPDATE AB Background: The p53 tumor suppressor protein is involved in a complicated regulatory network, mediating expression of similar to 1000 human genes. Recent studies have shown that many p53 in vivo binding sites (BSs) reside in transposable repeats. The relationship between these BSs and functional p53 response elements (REs) remains unknown, however. We sought to understand whether the p53 REs also reside in transposable elements and particularly in the most-abundant Alu repeats. Results: We have analyzed similar to 160 functional p53 REs identified so far and found that 24 of them occur in repeats. More than half of these repeat-associated REs reside in Alu elements. In addition, using a position weight matrix approach, we found similar to 400,000 potential p53 BSs in Alu elements genome-wide. Importantly, these putative BSs are located in the same regions of Alu repeats as the functional p53 REs - namely, in the vicinity of Boxes A/A' and B of the internal RNA polymerase III promoter. Earlier nucleosome-mapping experiments showed that the Boxes A/A' and B have a different chromatin environment, which is critical for the binding of p53 to DNA. Here, we compare the Alu-residing p53 sites with the corresponding Alu consensus sequences and conclude that the p53 sites likely evolved through two different mechanisms - the sites overlapping with the Boxes A/A' were generated by CG -> TG mutations; the other sites apparently pre-existed in the progenitors of several Alu subfamilies, such as AluJo and AluSq. The binding affinity of p53 to the Alu-residing sites generally correlates with the age of Alu subfamilies, so that the strongest sites are embedded in the 'relatively young' Alu repeats. Conclusions: The primate-specific Alu repeats play an important role in shaping the p53 regulatory network in the context of chromatin. One of the selective factors responsible for the frequent occurrence of Alu repeats in introns may be related to the p53-mediated regulation of Alu transcription, which, in turn, influences expression of the host genes. C1 [Cui, Feng; Sirotin, Michael V.; Zhurkin, Victor B.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Zhurkin, VB (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM zhurkin@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We are grateful to Drs. J. Jurka, V. Kapitonov, A. Kondrashov, R. Maraia and I. Rogozin for valuable discussions and to G. Leiman for text editing. Funding of this research was provided by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 81 TC 38 Z9 41 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JAN 6 PY 2011 VL 6 AR 2 DI 10.1186/1745-6150-6-2 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 716LM UT WOS:000286970100001 PM 21208455 ER PT J AU Barrett, AJJ AF Barrett, A. J. John TI Fighting the flu in multiple myeloma SO BLOOD LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; B-CELL; LYMPHODEPLETION; VACCINATION; EFFICACY; VACCINES C1 Natl Inst Hlth, Bethesda, MD 20892 USA. RP Barrett, AJJ (reprint author), Natl Inst Hlth, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 1 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 6 PY 2011 VL 117 IS 1 BP 1 EP 2 DI 10.1182/blood-2010-10-311217 PG 2 WC Hematology SC Hematology GA 703FO UT WOS:000285963900003 PM 21212286 ER PT J AU Perez-Galan, P Dreyling, M Wiestner, A AF Perez-Galan, Patricia Dreyling, Martin Wiestner, Adrian TI Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era SO BLOOD LA English DT Review ID NF-KAPPA-B; PROTEASOME INHIBITOR BORTEZOMIB; MULTIPLE-MYELOMA CELLS; REFRACTORY HEMATOLOGIC MALIGNANCIES; CHRONIC LYMPHOCYTIC-LEUKEMIA; PHASE-2 CLINICAL-TRIAL; NUCLEAR CYCLIN D1; V-H GENES; HUMAN CANCER; MAMMALIAN TARGET AB Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma of which at least a subset arises from antigen-experienced B cells. However, what role antigen stimulation plays in its pathogenesis remains ill defined. The genetic hallmark is the chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. Secondary genetic events increase the oncogenic potential of cyclin D1 and frequently inactivate DNA damage response pathways. In combination these changes drive cell-cycle progression and give rise to pronounced genetic instability. Several signaling pathways contribute to MCL pathogenesis, including the often constitutively activated PI3K/AKT/mTOR pathway, which promotes tumor proliferation and survival. WNT, Hedgehog, and NF-kappa B pathways also appear to be important. Although MCL typically responds to frontline chemotherapy, it remains incurable with standard approaches. Proteasome inhibitors (bortezomib), mTOR inhibitors (temsirolimus), and immunomodulatory drugs (lenalidomide) have recently been added to the treatment options in MCL. The molecular basis for the antitumor activity of these agents is an area of intense study that hopefully will lead to further improvements in the near future. Given its unique biology, relative rarity, and the difficulty in achieving long-lasting remissions with conventional approaches, patients with MCL should be encouraged to participate in clinical trials. (Blood. 2011;117(1):26-38) C1 [Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Perez-Galan, Patricia] Univ Barcelona, IDIBAPS, Barcelona, Spain. [Dreyling, Martin] Klinikum Univ Munchen, Dept Med 3, Munich, Germany. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov FU National Institutes of Health, the National, Heart, Lung and Blood Institute; Amgen; Bayer; Celgene; Janssen; Mundipharma; Pfizer; Roche; GSK; Lilly; Roche Glycart FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National, Heart, Lung and Blood Institute (P.P.-G. and A.W.).; M.D. received speakers' honoraria from Bayer, Mundiopharma/Cephalon, Pfizer, and Roche, clinical research support from Amgen, Bayer, Celgene, Janssen, Mundipharma, Pfizer, and Roche, and preclinical research support from GSK, Lilly, and Roche Glycart; and served on the scientific advisory boards of Calistoga, Celgene, Janssen, Mundipharma/Cephalon, Pfizer, and Roche. The remaining authors declare no competing financial interests. NR 136 TC 162 Z9 166 U1 3 U2 26 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 6 PY 2011 VL 117 IS 1 BP 26 EP 38 DI 10.1182/blood-2010-04-189977 PG 13 WC Hematology SC Hematology GA 703FO UT WOS:000285963900011 PM 20940415 ER PT J AU Martinez-Garcia, E Popovic, R Min, DJ Sweet, SMM Thomas, PM Zamdborg, L Heffner, A Will, C Lamy, L Staudt, LM Levens, DL Kelleher, NL Licht, JD AF Martinez-Garcia, Eva Popovic, Relja Min, Dong-Joon Sweet, Steve M. M. Thomas, Paul M. Zamdborg, Leonid Heffner, Aaron Will, Christine Lamy, Laurence Staudt, Louis M. Levens, David L. Kelleher, Neil L. Licht, Jonathan D. TI The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells SO BLOOD LA English DT Article ID DOMAIN-CONTAINING GENE; SOMATIC MUTATIONS; FGFR3 EXPRESSION; VARIANT H3.3; CANCER; METHYLTRANSFERASE; LEUKEMIA; T(4/14)(P16,Q32); TRANSLOCATION; FUSION AB The multiple myeloma SET domain (MMSET) protein is overexpressed in multiple myeloma (MM) patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/Wolf-Hirschhorn syndrome candidate 1 in development, its mode of action in the pathogenesis of MM is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth, and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation, and integrin signaling. Regulation of many of these genes required functional histone methyltransferase activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM. (Blood. 2011;117(1):211-220) C1 [Martinez-Garcia, Eva; Popovic, Relja; Min, Dong-Joon; Will, Christine; Licht, Jonathan D.] Northwestern Univ, Div Hematol Oncol, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Sweet, Steve M. M.; Thomas, Paul M.; Zamdborg, Leonid; Kelleher, Neil L.] Northwestern Univ, Dept Chem, Weinberg Coll Arts & Sci, Evanston, IL USA. [Heffner, Aaron; Levens, David L.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Lamy, Laurence; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Licht, JD (reprint author), Northwestern Univ, Div Hematol Oncol, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Lurie 5-123,303 E Super St, Chicago, IL 60611 USA. EM j-licht@northwestern.edu RI Thomas, Paul/A-6233-2011; Levens, David/C-9216-2009; Sweet, Steve/B-5528-2008 OI Thomas, Paul/0000-0003-2887-4765; Levens, David/0000-0002-7616-922X; Sweet, Steve/0000-0002-3962-0421 FU Multiple Myeloma Research Foundation (MMRF); European Hematology Association; Government of Navarra, Spain; Ruth Kirschstein National Research Service Awards [T32CA070085, F32HL099177, RO1CA123204]; Leukemia & Lymphoma Society; Physical Sciences Oncology Center [1U54CA143869-01] FX This work was supported by a Multiple Myeloma Research Foundation (MMRF) award, a European Hematology Association fellowship, a fellowship from the Government of Navarra, Spain (E.M.-G.), Ruth Kirschstein National Research Service Awards T32CA070085 and F32HL099177 (R.P.), RO1CA123204, and a Leukemia & Lymphoma Society Specialized Center for Research Award and a Physical Sciences Oncology Center Grant 1U54CA143869-01 (J.D.L.). NR 50 TC 139 Z9 146 U1 0 U2 9 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 6 PY 2011 VL 117 IS 1 BP 211 EP 220 DI 10.1182/blood-2010-07-298349 PG 10 WC Hematology SC Hematology GA 703FO UT WOS:000285963900031 PM 20974671 ER PT J AU Wassel, CL Lange, LA Keating, BJ Taylor, KC Johnson, AD Palmer, C Ho, LA Smith, NL Lange, EM Li, Y Yang, QO Delaney, JA Tang, WH Tofler, G Redline, S Taylor, HA Wilson, JG Tracy, RP Jacobs, DR Folsom, AR Green, D O'Donnell, CJ Reiner, AP AF Wassel, Christina L. Lange, Leslie A. Keating, Brendan J. Taylor, Kira C. Johnson, Andrew D. Palmer, Cameron Ho, Lindsey A. Smith, Nicholas L. Lange, Ethan M. Li, Yun Yang, Qiong Delaney, Joseph A. Tang, Weihong Tofler, Geoffrey Redline, Susan Taylor, Herman A., Jr. Wilson, James G. Tracy, Russell P. Jacobs, David R., Jr. Folsom, Aaron R. Green, David O'Donnell, Christopher J. Reiner, Alexander P. TI Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe) SO BLOOD LA English DT Article ID ARTERY RISK DEVELOPMENT; INDIVIDUAL PARTICIPANT METAANALYSIS; CORONARY-HEART-DISEASE; YOUNG-ADULTS CARDIA; PLASMA-FIBRINOGEN; WIDE ASSOCIATION; IMMUNONEPHELOMETRIC ASSAYS; THR312ALA POLYMORPHISM; HEMOSTATIC FACTORS; ISCHEMIC-STROKE AB Several common genomic loci, involving various immunity-and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23 634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47 539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk. (Blood. 2011;117(1):268-275) C1 [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Wassel, Christina L.] Univ Calif San Diego, San Diego, CA 92103 USA. [Lange, Leslie A.; Taylor, Kira C.; Ho, Lindsey A.; Lange, Ethan M.; Li, Yun] Univ N Carolina, Chapel Hill, NC USA. [Keating, Brendan J.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Bethesda, MD 20892 USA. [Palmer, Cameron] Broad Inst, Cambridge, MA USA. [Smith, Nicholas L.] Off Res & Dev, Dept Vet Affairs, Epidemiol Res & Informat Ctr, Seattle, WA USA. [Yang, Qiong] Boston Univ, Boston, MA 02215 USA. [Delaney, Joseph A.] Univ Florida, Gainesville, FL USA. [Tang, Weihong; Jacobs, David R., Jr.; Folsom, Aaron R.] Univ Minnesota, Minneapolis, MN USA. [Tofler, Geoffrey] Harvard Univ, Cambridge, MA 02138 USA. [Redline, Susan] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Taylor, Herman A., Jr.; Wilson, James G.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Tracy, Russell P.] Univ Vermont, Burlington, VT USA. [Green, David] Northwestern Univ, Evanston, IL USA. RP Reiner, AP (reprint author), Univ Washington, Dept Epidemiol, Box 357236, Seattle, WA 98195 USA. EM apreiner@u.washington.edu RI Johnson, Andrew/G-6520-2013; Yang, Qiong/G-5438-2014 FU NHLBI [HL073410, HL095080]; National Institutes of Health/NHLBI; [R01 HL71862-06]; [HHSN268200625226C]; [5215810-55000000041] FX A.P.R., C.L.W., L.A.L., and E.M.L. are supported by R01 HL71862-06, "Thrombosis Genetics, MI, and Stroke in Older Adults." N.L.S. is supported by NHLBI grant nos. HL073410 and HL095080. CARe is supported by contract no. HHSN268200625226C and from the National Institutes of Health/NHLBI, and subcontract no. 5215810-55000000041 to C.L.W. A full listing of the grants and contracts that have supported CARe is provided at http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx. NR 53 TC 23 Z9 23 U1 0 U2 6 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 6 PY 2011 VL 117 IS 1 BP 268 EP 275 DI 10.1182/blood-2010-06-289546 PG 8 WC Hematology SC Hematology GA 703FO UT WOS:000285963900038 PM 20978265 ER PT J AU George, JF Roederer, M AF George, James F. Roederer, Mario TI Data quality in the study of the mechanisms of extracorporeal photochemotherapy SO BLOOD LA English DT Letter ID COMPENSATION C1 [George, James F.] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. [Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP George, JF (reprint author), Univ Alabama, Dept Surg, 1530 3rd Ave S,LHRB 780, Birmingham, AL 35294 USA. EM jgeorge@uab.edu NR 4 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 6 PY 2011 VL 117 IS 1 BP 366 EP 367 DI 10.1182/blood-2010-09-306662 PG 2 WC Hematology SC Hematology GA 703FO UT WOS:000285963900050 PM 21212292 ER PT J AU Hancock, DB London, SJ AF Hancock, Dana B. London, Stephanie J. CA CHARGE Pulm Function Working Grp TI Determinants of Lung Function, COPD, and Asthma. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hancock, Dana B.; London, Stephanie J.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Hancock, DB (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM london2@niehs.nih.gov RI Hancock, Dana/D-8577-2012; cicardi, marco/K-9219-2016; OI cicardi, marco/0000-0003-1251-225X; Hancock, Dana/0000-0003-2240-3604; London, Stephanie/0000-0003-4911-5290 NR 4 TC 1 Z9 1 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 6 PY 2011 VL 364 IS 1 BP 86 EP 87 DI 10.1056/NEJMc1011921 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 702UY UT WOS:000285922600025 PM 21208119 ER PT J AU Studenski, S Perera, S Patel, K Rosano, C Faulkner, K Inzitari, M Brach, J Chandler, J Cawthon, P Connor, EB Nevitt, M Visser, M Kritchevsky, S Badinelli, S Harris, T Newman, AB Cauley, J Ferrucci, L Guralnik, J AF Studenski, Stephanie Perera, Subashan Patel, Kushang Rosano, Caterina Faulkner, Kimberly Inzitari, Marco Brach, Jennifer Chandler, Julie Cawthon, Peggy Connor, Elizabeth Barrett Nevitt, Michael Visser, Marjolein Kritchevsky, Stephen Badinelli, Stefania Harris, Tamara Newman, Anne B. Cauley, Jane Ferrucci, Luigi Guralnik, Jack TI Gait Speed and Survival in Older Adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PHYSICAL PERFORMANCE-MEASURES; LOWER-EXTREMITY FUNCTION; LOWER-BODY FUNCTION; WALKING SPEED; MUSCLE STRENGTH; MOBILITY LIMITATIONS; 5-YEAR MORTALITY; LIFE EXPECTANCY; ELDERLY PERSONS; HEALTH AB Context Survival estimates help individualize goals of care for geriatric patients, but life tables fail to account for the great variability in survival. Physical performance measures, such as gait speed, might help account for variability, allowing clinicians to make more individualized estimates. Objective To evaluate the relationship between gait speed and survival. Design, Setting, and Participants Pooled analysis of 9 cohort studies (collected between 1986 and 2000), using individual data from 34 485 community-dwelling older adults aged 65 years or older with baseline gait speed data, followed up for 6 to 21 years. Participants were a mean (SD) age of 73.5 (5.9) years; 59.6%, women; and 79.8%, white; and had a mean (SD) gait speed of 0.92 (0.27) m/s. Main Outcome Measures Survival rates and life expectancy. Results There were 17 528 deaths; the overall 5-year survival rate was 84.8% (confidence interval [CI], 79.6%-88.8%) and 10-year survival rate was 59.7% (95% CI, 46.5%-70.6%). Gait speed was associated with survival in all studies (pooled hazard ratio per 0.1 m/s, 0.88; 95% CI, 0.87-0.90; P<.001). Survival increased across the full range of gait speeds, with significant increments per 0.1 m/s. At age 75, predicted 10-year survival across the range of gait speeds ranged from 19% to 87% in men and from 35% to 91% in women. Predicted survival based on age, sex, and gait speed was as accurate as predicted based on age, sex, use of mobility aids, and self-reported function or as age, sex, chronic conditions, smoking history, blood pressure, body mass index, and hospitalization. Conclusion In this pooled analysis of individual data from 9 selected cohorts, gait speed was associated with survival in older adults. JAMA. 2011;305(1):50-58 www.jama.com C1 [Studenski, Stephanie; Perera, Subashan] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr Med, Pittsburgh, PA 15260 USA. [Rosano, Caterina; Newman, Anne B.; Cauley, Jane] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Brach, Jennifer] Univ Pittsburgh, Sch Hlth & Rehabil, Dept Phys Therapy, Pittsburgh, PA 15260 USA. [Faulkner, Kimberly] Natl Personal Protect Technol Lab, Pittsburgh, PA USA. [Patel, Kushang; Harris, Tamara; Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Inzitari, Marco] Autonomous Univ Barcelona, Pere Virgili Hosp, Barcelona, Spain. [Inzitari, Marco] Autonomous Univ Barcelona, Inst Aging, Barcelona, Spain. [Chandler, Julie] Merck Res Labs, N Wales, PA USA. [Nevitt, Michael] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Connor, Elizabeth Barrett] Univ Calif San Diego, La Jolla, CA 92093 USA. [Kritchevsky, Stephen] Wake Forest Univ, Winston Salem, NC 27109 USA. [Badinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. RP Studenski, S (reprint author), Kaufmann Bldg,Ste 500,3471 5th Ave, Pittsburgh, PA 15143 USA. EM sas33@pitt.edu RI Newman, Anne/C-6408-2013; Perera, Subashan/D-7603-2014; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Cauley, Jane A/0000-0003-0752-4408 FU Merck; Novartis; GTX; Merck Research Lab; Amgen; National Institute on Aging, NIH NIA Professional Services Contract Health and Human Services [11200800292P]; [AG023641]; [AG024827] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Studenski reported receiving institutional grant support, travel expenses, and consultancy fees from Merck; consultlancy fees from Novartis and GTX; and royalties from Hazzart Text McGraw Hill. Dr Perera reported receiving institutional grant support from Merck Research Lab. Dr Inzitari reported receiving insitutional grant support from Merck. Dr Brach reported receiving institutional grant support from Merck. Dr Cawthon reported receiving consultancy fees from Amgen and Merck. Dr Cauley reported receiving consultancy fees and institutional grant support from Novartis. Drs Patel, Faulkner, Barett-Connor, Nevitt, Visser, Bandellini, Harris, Newman, Ferrucci, and Gurlanik reported no disclosures.; Additional support for the pooled analyses was provided by grants AG023641, AG024827 and the Intramural Research Program, National Institute on Aging, NIH NIA Professional Services Contract Health and Human Services number 11200800292P. Dr Studenski received grant support from Merck to perform this work. NR 67 TC 917 Z9 939 U1 17 U2 121 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 5 PY 2011 VL 305 IS 1 BP 50 EP 58 DI 10.1001/jama.2010.1923 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 702VN UT WOS:000285924100024 PM 21205966 ER PT J AU Frio, TR Bahubeshi, A Kanellopoulou, C Hamel, N Niedziela, M Sabbaghian, N Pouchet, C Gilbert, L O'Brien, PK Serfas, K Broderick, P Houlston, RS Lesueur, F Bonora, E Muljo, S Schimke, RN Bouron-Dal Soglio, D Arseneau, J Schultz, KA Priest, JR Nguyen, VH Harach, HR Livingston, DM Foulkes, WD Tischkowitz, M AF Frio, Thomas Rio Bahubeshi, Amin Kanellopoulou, Chryssa Hamel, Nancy Niedziela, Marek Sabbaghian, Nelly Pouchet, Carly Gilbert, Lucy O'Brien, Paul K. Serfas, Kim Broderick, Peter Houlston, Richard S. Lesueur, Fabienne Bonora, Elena Muljo, Stefan Schimke, R. Neil Bouron-Dal Soglio, Dorothee Arseneau, Jocelyne Schultz, Kris Ann Priest, John R. Nguyen, Van-Hung Ruben Harach, H. Livingston, David M. Foulkes, William D. Tischkowitz, Marc TI DICER1 Mutations in Familial Multinodular Goiter With and Without Ovarian Sertoli-Leydig Cell Tumors SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PLEUROPULMONARY BLASTOMA; THYROID-CARCINOMA; DOMINANT FORM; CANCER; GERMLINE; DISEASE; ARRHENOBLASTOMA; DISORDERS; MICRORNAS; FEMALE AB Context Nontoxic multinodular goiter (MNG) is frequently observed in the general population, but little is known about the underlying genetic susceptibility to this disease. Familial cases of MNG have been reported, and published reports describe 5 families that also contain at least 1 individual with a Sertoli-Leydig cell tumor of the ovary (SLCT). Germline mutations in DICER1, a gene that codes for an RNase III endoribonuclease, have been identified in families affected by pleuropulmonary blastoma (PPB), some of whom include cases of MNG and gonadal tumors such as SLCTs. Objective To determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1. Design, Setting, and Patients From September 2009 to September 2010, we screened 53 individuals from 2 MNG and 3 MNG/SLCT families at McGill University for mutations in DICER1. We investigated blood lymphocytes and MNG and SLCT tissue from family members for loss of the wild-type DICER1 allele (loss of heterozygosity), DICER1 expression, and microRNA (miRNA) dysregulation. Main Outcome Measure Detection of germline DICER1 gene mutations in familial MNG with and without SLCT. Results We identified and characterized germline DICER1 mutations in 37 individuals from 5 families. Two mutations were predicted to be protein truncating, 2 resulted in inframe deletions, and 1 was a missense mutation. Molecular analysis of the 3 SLCTs showed no loss of heterozygosity of DICER1, and immunohistochemical analysis in 2 samples showed strong expression of DICER1 in Sertoli cells but weak staining of Leydig cells. miRNA profiling of RNA from lymphoblastoid cell lines from both affected and unaffected members of the familial MNG cases revealed miRNA perturbations in DICER1 mutation carriers. Conclusions DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns. JAMA. 2011;305(1):68-77 www.jama.com C1 [Foulkes, William D.] McGill Univ, Ctr Hlth, Gerald Bronfman Ctr Clin Res Oncol, Program Canc Genet,Dept Oncol, Montreal, PQ H2W 1S6, Canada. [Gilbert, Lucy] McGill Univ, Ctr Hlth, Dept Obstet & Gynecol, Montreal, PQ H2W 1S6, Canada. [Arseneau, Jocelyne; Nguyen, Van-Hung] McGill Univ, Ctr Hlth, Dept Pathol, Montreal, PQ H2W 1S6, Canada. [Frio, Thomas Rio; Hamel, Nancy; Foulkes, William D.] McGill Univ, Ctr Hlth, Dept Med Genet, Montreal, PQ H2W 1S6, Canada. [Frio, Thomas Rio; Hamel, Nancy; Foulkes, William D.] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H2W 1S6, Canada. [Bahubeshi, Amin; Sabbaghian, Nelly; Pouchet, Carly; Foulkes, William D.; Tischkowitz, Marc] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Segal Canc Ctr, Montreal, PQ H2W 1S6, Canada. [Kanellopoulou, Chryssa; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Niedziela, Marek] Poznan Univ Med Sci, Dept Pediat Endocrinol & Rheumatol, Poznan, Poland. [O'Brien, Paul K.] Etobicoke Gen Hosp, Dept Pathol, Toronto, ON, Canada. [Serfas, Kim] Hlth Sci Ctr Winnipeg, Hereditary Breast Hlth Clin, Winnipeg, MB, Canada. [Broderick, Peter; Houlston, Richard S.] Inst Canc Res, Sect Canc Genet, Surrey, England. [Lesueur, Fabienne] Int Agcy Res Canc, Genet Canc Susceptibil Grp, F-69372 Lyon, France. [Bonora, Elena] Univ Bologna, S Orsola M Malpighi Hosp, Dept Gynaecol, Med Genet Unit, Bologna, Italy. [Muljo, Stefan] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Schimke, R. Neil] Univ Kansas, Med Ctr, Dept Internal Med, Div Endocrinol Metab & Genet, Kansas City, KS 66103 USA. [Bouron-Dal Soglio, Dorothee] CHU St Justine, Dept Pathol, Montreal, PQ, Canada. [Schultz, Kris Ann] Childrens Hosp & Clin Minnesota, St Paul, MN USA. [Priest, John R.] Int Pleuropulm Blastoma Registry, St Paul, MN USA. [Ruben Harach, H.] Hosp Dr A Onativia, Sector Patol, Salta, Argentina. [Frio, Thomas Rio; Bahubeshi, Amin; Hamel, Nancy; Sabbaghian, Nelly; Pouchet, Carly; Foulkes, William D.; Tischkowitz, Marc] McGill Univ, Ctr Hlth, Program Canc Genet, Dept Human Genet, Montreal, PQ H2W 1S6, Canada. RP Foulkes, WD (reprint author), McGill Univ, Ctr Hlth, Gerald Bronfman Ctr Clin Res Oncol, Program Canc Genet,Dept Oncol, 546 Ave Pins, Montreal, PQ H2W 1S6, Canada. EM william.foulkes@mcgill.ca RI Muljo, Stefan/F-5671-2015; OI Muljo, Stefan/0000-0003-1013-446X; Broderick, Peter/0000-0002-8348-5829; Bonora, Elena/0000-0001-6132-7734; Houlston, Richard/0000-0002-5268-0242 FU Jewish General Hospital; Turner Family Cancer Research Fund; Fonds de la Recherche en Sante du Quebec (FRSQ); Canadian Institutes of Health Research/FRSQ [FRN53888]; Research Institute of the McGill University Health Centre; Cedars Cancer Institute; Pine Tree Apple Tennis Classic; Theodora H. Lang Charitable trust FX The work was funded by the Jewish General Hospital Weekend to End Women's Cancers, the Turner Family Cancer Research Fund, and les Fonds de la Recherche en Sante du Quebec (FRSQ). Mr Bahubeshi is funded by the Canadian Institutes of Health Research/FRSQ training grant in cancer research (FRN53888) of the McGill Integrated Cancer Research Training Program. Dr Rio Frio was funded by the Research Institute of the McGill University Health Centre and by the Henry R. Shibata Fellowship of the Cedars Cancer Institute. Dr Priest receives funding support from the Pine Tree Apple Tennis Classic and the Theodora H. Lang Charitable trust. Dr Foulkes holds an FRSQ national scientist award and Dr Tischkowitz holds an FRSQ clinician-scientist award. NR 41 TC 59 Z9 59 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 5 PY 2011 VL 305 IS 1 BP 68 EP 77 DI 10.1001/jama.2010.1910 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 702VN UT WOS:000285924100026 ER PT J AU Jaimes, MC Maecker, HT Yan, M Maino, VC Hanley, MB Greer, A Darden, JM D'Souza, MP AF Jaimes, Maria C. Maecker, Holden T. Yan, Ming Maino, Vernon C. Hanley, Mary Beth Greer, Angela Darden, Janice M. D'Souza, M. Patricia TI Quality assurance of intracellular cytokine staining assays: Analysis of multiple rounds of proficiency testing SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Flow cytometry; Intracellular cytokine staining; Quality assurance ID CANCER VACCINE CONSORTIUM; T-LYMPHOCYTE ACTIVITY; HARMONIZATION GUIDELINES; HIV-1 INFECTION; FLOW-CYTOMETRY; VIRAL LOAD; OPTIMIZATION; RESPONSES; PANEL; CELL AB When evaluating candidate prophylactic HIV and cancer vaccines, intracellular cytokine staining (ICS) assays that measure the frequency and magnitude of antigen-specific T-cell subsets are one tool to monitor immunogen performance and make product advancement decisions. To assess the inter-laboratory assay variation among multiple laboratories testing vaccine candidates, the NIH/NIAID/DAIDS in collaboration with BD Biosciences implemented an ICS Quality Assurance Program (QAP). Seven rounds of testing have been conducted in which 16 laboratories worldwide participated. In each round, IFN-gamma, IL-2 and/or TNF-alpha responses in CD4+ and CD8+ T-cells to CEF or CMV pp65 peptide mixes were tested using cryopreserved peripheral blood mononuclear cells (PBMC) from CMV seropositive donors. We found that for responses measured above 0.2%, inter-laboratory %CVs were, on average, 35%. No differences in inter-laboratory variation were observed if a 4-color antibody cocktail or a 7-color combination was used. Moreover, the data allowed identification of important sources of variability for flow cytometry-based assays, including: number of collected events, gating strategy and instrument setup and performance. As a consequence, in this multi-site study we were able to define pass and fail criteria for ICS assays, which will be adopted in the subsequent rounds of testing and could be easily extrapolated to QAP for other flow cytometry-based assays. (C) 2010 Elsevier B.V. All rights reserved. C1 [Jaimes, Maria C.; Yan, Ming; Maino, Vernon C.; Hanley, Mary Beth] BD Biosci, San Jose, CA 95131 USA. [Maecker, Holden T.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Greer, Angela] PPD Inc, Wilmington, NC 28401 USA. [Darden, Janice M.; D'Souza, M. Patricia] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Jaimes, MC (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM maria_jaimes@bd.com FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN26620050022C] FX This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN26620050022C. NR 24 TC 19 Z9 20 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JAN 5 PY 2011 VL 363 IS 2 SI SI BP 143 EP 157 DI 10.1016/j.jim.2010.08.004 PG 15 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 719CD UT WOS:000287176100006 PM 20727897 ER PT J AU Dorner, T Jacobi, AM Lee, J Lipsky, PE AF Doerner, Thomas Jacobi, Annett M. Lee, Jisoo Lipsky, Peter E. TI Abnormalities of B cell subsets in patients with systemic lupus erythematosus SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE B cells; Phenotyping; Systemic lupus erythematosus; Plasma cells ID COMMON VARIABLE IMMUNODEFICIENCY; PRIMARY SJOGRENS-SYNDROME; PERIPHERAL-BLOOD; PLASMA-CELLS; AUTOANTIBODY PRODUCTION; LYMPHOCYTE HOMEOSTASIS; REGION GENES; MURINE LUPUS; MEMORY; ACTIVATION AB The prototypic autoimmune disease, SLE, is known to be associated with polyclonal B cell hyperreactivity. Developing an understanding of the complex nature of human B cell differentiation, largely through the application of multiparameter flow cytometry to an analysis of circulating B cells has permitted an assessment of whether specific stages of B cell maturation are affected by the tendency for polyclonal B cell activation. Moreover, the analysis of perturbations of the specific stages of B cell maturation has generated new information on whether abnormalities in B cell differentiation are primarily involved in autoimmune disease immunopathology or, rather, are secondary to the inflammatory environment characteristic of subjects with this autoimmune disease. Multivariant analysis has begun to document abnormalities in B cell maturation that are primarily associated with lupus, or, alternatively related to disease duration, disease activity and concomitant medication. Together, these analyses have provided new insights on the role of B cell over-reactivity in SLE. (C) 2010 Elsevier B.V. All rights reserved. C1 [Doerner, Thomas] Charite Univ Med Berlin, Dept Med Rheumatol & Clin Immunol, D-10098 Berlin, Germany. [Doerner, Thomas] Deutsch Rheumaforschungszentrum, D-10098 Berlin, Germany. [Jacobi, Annett M.] Univ Munster, Dept Med, D-4400 Munster, Germany. [Lee, Jisoo] Ewha Womans Univ, Sch Med, Dept Internal Med, Div Rheumatol, Seoul, South Korea. [Lipsky, Peter E.] NIAMS, NIH, Bethesda, MD USA. RP Dorner, T (reprint author), Charite Univ Med Berlin, Dept Med Rheumatol & Clin Immunol, Charitepl 10, D-10098 Berlin, Germany. EM thomas.doerner@charite.de NR 85 TC 52 Z9 53 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JAN 5 PY 2011 VL 363 IS 2 SI SI BP 187 EP 197 DI 10.1016/j.jim.2010.06.009 PG 11 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 719CD UT WOS:000287176100010 PM 20598709 ER PT J AU Biancotto, A Fuchs, JC Williams, A Dagur, PK McCoy, JP AF Biancotto, Angelique Fuchs, John C. Williams, Ann Dagur, Pradeep K. McCoy, J. Philip, Jr. TI High dimensional flow cytometry for comprehensive leukocyte immunophenotyping (CLIP) in translational research SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Leukocytes; Immunophenotyping; Polychromatic; Cytometry; Immunome ID CRYOPRESERVATION; IMMUNOLOGY; BLOOD AB New paradigms in translational research are focused on deep understanding of all aspects of the human immune system in response to diseases or perturbations such as vaccination or therapy. To obtain this knowledge, coordinated, comprehensive assessments by genomics, proteomics, and cytomics are necessary. One component of this assessment is comprehensive leukocyte immunophenotyping (CLIP) that not only provides a deep and broad description of the entire immune system at any given moment, but also encompasses all leukocyte lineages, including activation states, functional markers, and signaling molecules. As envisioned, a CLIP panel could study nearly 400 antigens utilizing 17-parameter flow cytometry. The CLIP panel is structured in a manner that tubes are grouped by lineage and, within lineage each of the tubes, while having some redundant markers, characterize distinct populations. To date, a preliminary 10 tube CLIP panel has been developed with the following 17 parameter tubes: T(reg), T(h17), T(h1/2), B(general), B(naive/memory), B(intracellular), NK(1), NK(2), myeloid/monocyte, and dendritic cells (DC). Together these tubes have the potential to identify over 28,000 subsets of leukocytes. The feasibility of developing these tubes has been demonstrated, as well as their utility in describing complex alterations of the immune system in the context of disease and vaccination. The plethora of data accrued in the preliminary CLIP panel highlights the need for novel data analysis and reduction strategies, while at the same time illustrates the power of CLIP. Published by Elsevier B.V. C1 [McCoy, J. Philip, Jr.] NHLBI, CHI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Biancotto, Angelique; Fuchs, John C.; McCoy, J. Philip, Jr.] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. RP McCoy, JP (reprint author), NHLBI, CHI, Hematol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM mccoyj@nhlbi.nih.gov FU NHLBI, NIH, Bethesda, MD; CHI (Center for Human Immunology, Autoimmunity and Inflammation), NIH, Bethesda, MD FX This research was supported by the Intramural Research Program of the NHLBI, NIH, Bethesda, MD and by the CHI (Center for Human Immunology, Autoimmunity and Inflammation), NIH, Bethesda, MD. We thank the following for helpful comments and suggestions: Mario Roederer, Pratip Chattopadhyay, Giorgio Trinchieri, Kristen Tarbell, Franco Marincola, Ron Germain, Pam Schwartzberg, Bruce Bagwell, Don Herbert, Dan Kastner, Robert Nussenblatt, Rick Childs, Andreas Lundqvist, Adrian Wiestner, Matthew Dines and Neal Young. NR 17 TC 18 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JAN 5 PY 2011 VL 363 IS 2 SI SI BP 245 EP 261 DI 10.1016/j.jim.2010.06.010 PG 17 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 719CD UT WOS:000287176100015 PM 20600079 ER PT J AU Shew, WL Yang, HD Yu, S Roy, R Plenz, D AF Shew, Woodrow L. Yang, Hongdian Yu, Shan Roy, Rajarshi Plenz, Dietmar TI Information Capacity and Transmission Are Maximized in Balanced Cortical Networks with Neuronal Avalanches SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LATERAL GENICULATE-NUCLEUS; VISUAL-CORTEX; POPULATIONS; CRITICALITY; MECHANISMS; RESPONSES; CIRCUITS; RANGE; CODES AB The repertoire of neural activity patterns that a cortical network can produce constrains the ability of the network to transfer and process information. Here, we measured activity patterns obtained from multisite local field potential recordings in cortex cultures, urethane-anesthetized rats, and awake macaque monkeys. First, we quantified the information capacity of the pattern repertoire of ongoing and stimulus-evoked activity using Shannon entropy. Next, we quantified the efficacy of information transmission between stimulus and response using mutual information. By systematically changing the ratio of excitation/inhibition (E/I) in vitro and in a network model, we discovered that both information capacity and information transmission are maximized at a particular intermediate E/I, at which ongoing activity emerges as neuronal avalanches. Next, we used our in vitro and model results to correctly predict in vivo information capacity and interactions between neuronal groups during ongoing activity. Close agreement between our experiments and model suggest that neuronal avalanches and peak information capacity arise because of criticality and are general properties of cortical networks with balanced E/I. C1 [Shew, Woodrow L.; Yang, Hongdian; Yu, Shan; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Yang, Hongdian; Roy, Rajarshi] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Shew, WL (reprint author), NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Bethesda, MD 20892 USA. EM sheww@mail.nih.gov RI Yang, Hongdian/D-1450-2015; OI Shew, Woodrow/0000-0003-0679-1766 FU National Institute of Mental Health; Department of Defense Multidisciplinary University Research Initiative [ONR N000140710734] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. R.R. acknowledges support from Department of Defense Multidisciplinary University Research Initiative Grant ONR N000140710734 to the University of Maryland. We thank E. D. Gireesh and C. Stewart for help with the anesthetized rat recordings and preparing the in vitro cortex cultures. We thank A. Mitz and R. Saunders for help with monkey surgery. W.L.S. and H.Y. contributed equally to in vitro and anesthetized rat recordings and all data analysis. S.Y. performed monkey recordings. R.R. and D.P. supervised the work. All authors contributed to the interpretation of the data and manuscript preparation. NR 42 TC 128 Z9 128 U1 1 U2 24 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 5 PY 2011 VL 31 IS 1 BP 55 EP 63 DI 10.1523/JNEUROSCI.4637-10.2011 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 702SH UT WOS:000285915100007 PM 21209189 ER PT J AU Chen, BS Thomas, EV Sanz-Clemente, A Roche, KW AF Chen, Bo-Shiun Thomas, Eleanor V. Sanz-Clemente, Antonio Roche, Katherine W. TI NMDA Receptor-Dependent Regulation of Dendritic Spine Morphology by SAP102 Splice Variants SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HIPPOCAMPAL SYNAPSES; GLUTAMATE RECEPTORS; MENTAL-RETARDATION; GUANYLATE KINASES; IN-VIVO; TRAFFICKING; PLASTICITY; PROTEIN; PSD-95; PHOSPHORYLATION AB Membrane-associated guanylate kinases (MAGUKs) are major components of the postsynaptic density and play important roles in synaptic organization and plasticity. Most excitatory synapses are located on dendritic spines, which are dynamic structures that undergo morphological changes during synapse formation and plasticity. Synapse-associated protein 102 (SAP102) is a MAGUK that is highly expressed early in development and mediates receptor trafficking during synaptogenesis. Mutations in human SAP102 cause mental retardation, which is often accompanied with abnormalities in dendritic spines. However, little is known about the role of SAP102 in regulating synapse formation or spine morphology. We now find that SAP102 contains a novel NMDA receptor binding site in the N-terminal domain, which is specific for the NR2B subunit. The interaction between SAP102 and NR2B is PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain independent and is regulated by alternative splicing of SAP102. We show that SAP102 that possesses an N-terminal insert is developmentally regulated at both mRNA and protein levels. In addition, expression of SAP102 increases synapse formation. Furthermore, the alternative splicing of SAP102 regulates dendritic spine morphology. SAP102 containing the N-terminal insert promotes lengthening of dendritic spines and preferentially promotes the formation of synapses at long spines, whereas a short hairpin RNA knockdown of the same SAP102 splice variant causes spine shrinkage. Finally, blocking NMDA receptor activity prevents the spine lengthening induced by the N-terminal splice variant of SAP102. Thus, our data provide the first evidence that SAP102 links NMDA receptor activation to alterations in spine morphology. C1 [Chen, Bo-Shiun; Thomas, Eleanor V.; Sanz-Clemente, Antonio; Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Chen, BS (reprint author), Med Coll Georgia, Program Dev Neurobiol, Inst Mol Med & Genet, CA3008,1120 15th St, Augusta, GA 30912 USA. EM bochen@mcg.edu RI Chen, Bo-Shiun/H-4633-2012; OI Roche, Katherine/0000-0001-7282-6539 FU National Institute of Neurological Disorders and Stroke (NINDS) FX This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) Intramural Research Program (E.V.T., B.-S.C., K.W.R.) and a NINDS Career Transition Award (E.V.T., B.-S.C.). We thank the NINDS sequencing facility and light imaging facility. NR 37 TC 23 Z9 24 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 5 PY 2011 VL 31 IS 1 BP 89 EP 96 DI 10.1523/JNEUROSCI.1034-10.2011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 702SH UT WOS:000285915100011 PM 21209193 ER PT J AU Kramer, PF Christensen, CH Hazelwood, LA Dobi, A Bock, R Sibley, DR Mateo, Y Alvarez, VA AF Kramer, Paul F. Christensen, Christine H. Hazelwood, Lisa A. Dobi, Alice Bock, Roland Sibley, David R. Mateo, Yolanda Alvarez, Veronica A. TI Dopamine D2 Receptor Overexpression Alters Behavior and Physiology in Drd2-EGFP Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIUM SPINY NEURONS; INHIBITION; MODULATION; PLASTICITY; RELEASE; D1 AB Bacteria artificial chromosome (BAC) transgenic mice expressing the reporter protein enhanced green fluorescent protein (EGFP) under the control of the D1 and D2 dopamine receptor promoters (Drd1-EGFP and Drd2-EGFP) have been widely used to study striatal function and have contributed to our understanding of the physiological and pathological functions of the basal ganglia. These tools were produced and promptly made available to address questions in a cell-specific manner that has transformed the way we frame hypotheses in neuroscience. However, these mice have not been fully characterized until now. We found that Drd2-EGFP mice display an similar to 40% increase in membrane expression of the dopamine D2 receptor (D2R) and a twofold increase in D2R mRNA levels in the striatum when compared with wild-type and Drd1-EGFP mice. D2R overexpression was accompanied by behavioral hypersensitivity to D2R-like agonists, as well as enhanced electrophysiological responses to D2R activation in midbrain dopaminergic neurons. Dopamine (DA) transients evoked by stimulation in the nucleus accumbens showed slower clearance in Drd2-EGFP mice, and cocaine actions on DA clearance were impaired in these mice. Thus, it was not surprising to find that Drd2-EGFP mice were hyperactive when exposed to a novel environment and locomotion was suppressed by acute cocaine administration. All together, this study demonstrates that Drd2-EGFP mice overexpress D2R and have altered dopaminergic signaling that fundamentally differentiates them from wild-type and Drd1-EGFP mice. C1 [Kramer, Paul F.; Christensen, Christine H.; Dobi, Alice; Bock, Roland; Sibley, David R.; Alvarez, Veronica A.] NIAAA, Sect Neuronal Struct, Bethesda, MD 20892 USA. [Mateo, Yolanda] NIAAA, Sect Synapt Pharmacol, Bethesda, MD 20892 USA. [Hazelwood, Lisa A.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Alvarez, VA (reprint author), NIAAA, Sect Neuronal Struct, Bethesda, MD 20892 USA. EM alvarezva@mail.nih.gov RI Alvarez, Veronica /E-9745-2015; Bock, Roland/G-2982-2016; OI Alvarez, Veronica /0000-0003-2611-8675; Bock, Roland/0000-0002-8654-1080; Kramer, Paul/0000-0002-0095-3712 FU National Institute on Alcohol Abuse and Alcoholism; National Institute of Neurological Disorders and Stroke FX This study was funded by the intramural programs of the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Neurological Disorders and Stroke. We thank J. M. Urban and H. Puhl for their valuable technical advice with the qPCR and sequencing, and M. Rubinstein and D. M. Lovinger for their helpful comments and discussions of this manuscript. NR 25 TC 52 Z9 52 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 5 PY 2011 VL 31 IS 1 BP 126 EP 132 DI 10.1523/JNEUROSCI.4287-10.2011 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 702SH UT WOS:000285915100015 PM 21209197 ER PT J AU Morozov, A Sukato, D Ito, W AF Morozov, Alexei Sukato, Daniel Ito, Wataru TI Selective Suppression of Plasticity in Amygdala Inputs from Temporal Association Cortex by the External Capsule SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ANTERIOR CINGULATE; INTERNEURONS; RAT AB GABAergic neurons in the external capsule (EC) provide feedforward inhibition in the lateral amygdala (LA), but how EC affects synaptic transmission and plasticity in inputs from specific cortical areas remains unknown; this is because axonal fibers from different cortical areas are intermingled in the amygdala and cannot be activated selectively using conventional electrical stimulation. Here, we achieved selective activation of fibers from the temporal association cortex (TeA) or the anterior cingulate cortex (ACC) by using channelrhodopsin-2. Long-term potentiation (LTP) in the TeA-LA pathway, which runs through EC, was enabled by cutting connections between EC and LA or by blocking GABA(A) receptor-mediated transmission. In contrast, LTP in the ACC-LA pathway, which bypasses EC, was GABAA receptor independent. The EC transection shifted balance between inhibitory and excitatory responses in the TeA-LA pathway toward excitation, but had no effect on the ACC-LA pathway. Thus, EC provides pathway-specific suppression of amygdala plasticity. C1 [Morozov, Alexei; Sukato, Daniel; Ito, Wataru] NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Morozov, A (reprint author), NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM morozova@mail.nih.gov; itow@mail.nih.gov FU National Institute of Mental Health FX This study was supported by the National Institute of Mental Health Intramural Research Program. We thank Chris McBain and Victor Luna for critical comments on the manuscript, and Jiayang Li for image analysis. NR 14 TC 24 Z9 24 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 5 PY 2011 VL 31 IS 1 BP 339 EP 345 DI 10.1523/JNEUROSCI.5537-10.2011 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 702SH UT WOS:000285915100038 PM 21209220 ER PT J AU Guo, JE Hall, KD AF Guo, Juen Hall, Kevin D. TI Predicting Changes of Body Weight, Body Fat, Energy Expenditure and Metabolic Fuel Selection in C57BL/6 Mice SO PLOS ONE LA English DT Article ID THERMOGENESIS; MASS; OBESITY AB The mouse is an important model organism for investigating the molecular mechanisms of body weight regulation, but a quantitative understanding of mouse energy metabolism remains lacking. Therefore, we created a mathematical model of mouse energy metabolism to predict dynamic changes of body weight, body fat, energy expenditure, and metabolic fuel selection. Based on the principle of energy balance, we constructed ordinary differential equations representing the dynamics of body fat mass (FM) and fat-free mass (FFM) as a function of dietary intake and energy expenditure (EE). The EE model included the cost of tissue deposition, physical activity, diet-induced thermogenesis, and the influence of FM and FFM on metabolic rate. The model was calibrated using previously published data and validated by comparing its predictions to measurements in five groups of male C57/BL6 mice (N = 30) provided ad libitum access to either chow or high fat diets for varying time periods. The mathematical model accurately predicted the observed body weight and FM changes. Physical activity was predicted to decrease immediately upon switching from the chow to the high fat diet and the model coefficients relating EE to FM and FFM agreed with previous independent estimates. Metabolic fuel selection was predicted to depend on a complex interplay between diet composition, the degree of energy imbalance, and body composition. This is the first validated mathematical model of mouse energy metabolism and it provides a quantitative framework for investigating energy balance relationships in mouse models of obesity and diabetes. C1 [Guo, Juen; Hall, Kevin D.] NIDDKD, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Guo, JE (reprint author), NIDDKD, Lab Biol Modeling, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov FU NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 21 Z9 21 U1 0 U2 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 5 PY 2011 VL 6 IS 1 AR e15961 DI 10.1371/journal.pone.0015961 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710KT UT WOS:000286511200029 PM 21246038 ER PT J AU Kenney, J Aravantinou, M Singer, R Hsu, M Rodriguez, A Kizima, L Abraham, CJ Menon, R Seidor, S Chudolij, A Gettie, A Blanchard, J Lifson, JD Piatak, M Fernandez-Romero, JA Zydowsky, TM Robbiani, M AF Kenney, Jessica Aravantinou, Meropi Singer, Rachel Hsu, Mayla Rodriguez, Aixa Kizima, Larisa Abraham, Ciby J. Menon, Radhika Seidor, Samantha Chudolij, Anne Gettie, Agegnehu Blanchard, James Lifson, Jeffrey D. Piatak, Michael, Jr. Fernandez-Romero, Jose A. Zydowsky, Thomas M. Robbiani, Melissa TI An Antiretroviral/Zinc Combination Gel Provides 24 Hours of Complete Protection against Vaginal SHIV Infection in Macaques SO PLOS ONE LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; REVERSE-TRANSCRIPTASE INHIBITORS; PLACEBO-CONTROLLED TRIAL; RHESUS MACAQUES; INTRAVAGINAL INOCULATION; DENDRITIC CELLS; VIRAL LOAD; TRANSIENT VIREMIA; SIV; TRANSMISSION AB Background: Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non-nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application. Methods and Findings: Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 mM MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8-24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h. Conclusions: A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans. C1 [Kenney, Jessica; Aravantinou, Meropi; Singer, Rachel; Hsu, Mayla; Rodriguez, Aixa; Kizima, Larisa; Abraham, Ciby J.; Menon, Radhika; Seidor, Samantha; Chudolij, Anne; Fernandez-Romero, Jose A.; Zydowsky, Thomas M.; Robbiani, Melissa] Populat Council, New York, NY 10021 USA. [Gettie, Agegnehu] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Blanchard, James] Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA USA. [Lifson, Jeffrey D.; Piatak, Michael, Jr.] NCI, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD 21701 USA. RP Kenney, J (reprint author), Populat Council, 1230 York Ave, New York, NY 10021 USA. EM mrobbiani@popcouncil.org FU National Institutes of Health (NIH) [U19 AI065412, RR00164]; United States Agency for International Development (USAID) [GPO-A-00-04-00019-00]; Swedish Ministry of Foreign Affairs; Swedish International Development Cooperation Agency; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported by the National Institutes of Health (NIH) grant U19 AI065412, the United States Agency for International Development (USAID) Cooperative Agreement GPO-A-00-04-00019-00, the Swedish Ministry of Foreign Affairs, the Swedish International Development Cooperation Agency, the NIH base grant RR00164, and in part, with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. This research is made possible by the generous support of the American people through the USAID. The contents of this manuscript are the sole responsibility of the Population Council and do not necessarily reflect the views of USAID or the United States government. MR is a 2002 Elizabeth Glaser Scientist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 57 Z9 58 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 5 PY 2011 VL 6 IS 1 AR e15835 DI 10.1371/journal.pone.0015835 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710KT UT WOS:000286511200018 PM 21246052 ER PT J AU Teterina, NL Lauber, C Jensen, KS Levenson, EA Gorbalenya, AE Ehrenfeld, E AF Teterina, Natalya L. Lauber, Chris Jensen, Kenneth S. Levenson, Eric A. Gorbalenya, Alexander E. Ehrenfeld, Ellie TI Identification of tolerated insertion sites in poliovirus non-structural proteins SO VIROLOGY LA English DT Article DE Poliovirus; Transposon-mediated insertion mutagenesis; Viral protein tags; Protein structure; Enterovirus evolution ID DEPENDENT RNA-POLYMERASE; HEPATITIS-C-VIRUS; CRYSTAL-STRUCTURE; ENDOPLASMIC-RETICULUM; REPLICATION COMPLEX; FLUORESCENT PROTEIN; COXSACKIEVIRUS B3; VIRAL-PROTEINS; 3C PROTEASE; 3A PROTEIN AB Insertion of nucleotide sequences encoding "tags" that can be expressed in specific viral proteins during an infection is a useful strategy for purifying viral proteins and their functional complexes from infected cells and/or for visualizing the dynamics of their subcellular location over time. To identify regions in the poliovirus polyprotein that could potentially accommodate insertion of tags, transposon-mediated insertion mutagenesis was applied to the entire nonstructural protein-coding region of the poliovirus genome, followed by selection of genomes capable of generating infectious, viable viruses. This procedure allowed us to identify at least one site in each viral nonstructural protein, except protein 2C, in which a minimum of five amino acids could be inserted. The distribution of these sites is analyzed from the perspective of their protein structural context and from the perspective of virus evolution. Published by Elsevier Inc. C1 [Teterina, Natalya L.; Jensen, Kenneth S.; Levenson, Eric A.; Ehrenfeld, Ellie] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Lauber, Chris; Gorbalenya, Alexander E.] Leiden Univ, Med Ctr, Dept Med Microbiol, NL-2300 RC Leiden, Netherlands. RP Ehrenfeld, E (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr,Room 6120, Bethesda, MD 20892 USA. EM nteterina@niaid.nih.gov; clauber@lumc.nl; a.e.gorbalenya@lumc.nl; eehrenfeld@niaid.nih.gov RI Levenson, Eric/A-7963-2008; Gorbalenya, Alexander/J-4818-2012 OI Levenson, Eric/0000-0002-3896-3908; Gorbalenya, Alexander/0000-0002-4967-7341 FU NIH; NIAID; Netherlands Bioinformatics Center (NBIC) [SP3.2.2] FX This research was supported in part by the Intramural Research Program of the NIH, NIAID, and by The Netherlands Bioinformatics Center (NBIC Biorange SP3.2.2). We thank Igor Sidorov, Alexander Kravchenko and Dmitry Samborskiy for administering the Viralis software platform. NR 43 TC 13 Z9 13 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2011 VL 409 IS 1 BP 1 EP 11 DI 10.1016/j.virol.2010.09.028 PG 11 WC Virology SC Virology GA 696OO UT WOS:000285450900001 PM 20971490 ER PT J AU Minang, JT Trivett, MT Barsov, EV Del Prete, GQ Trubey, CM Thomas, JA Gorelick, RJ Piatak, M Ott, DE Ohlen, C AF Minang, Jacob T. Trivett, Matthew T. Barsov, Eugene V. Del Prete, Gregory Q. Trubey, Charles M. Thomas, James A. Gorelick, Robert J. Piatak, Michael, Jr. Ott, David E. Ohlen, Claes TI TCR triggering transcriptionally downregulates CCR5 expression on rhesus macaque CD4(+) T-cells with no measurable effect on susceptibility to SIV infection SO VIROLOGY LA English DT Article DE AIDS; CCR5; CD4; SIV; Rhesus macaques ID SIMIAN IMMUNODEFICIENCY VIRUS; HIV-1 DISEASE PROGRESSION; CORECEPTOR USAGE; IN-VIVO; CHEMOKINE CORECEPTORS; CD28 COSTIMULATION; DENDRITIC CELLS; EX-VIVO; RESISTANCE; TYPE-1 AB Studies using transformed human cell lines suggest that most SIV strains use CCR5 as co-receptor. Our analysis of primary rhesus macaque CD4(+) T-cell clones revealed marked differences in susceptibility to SIV(mac)239 infection. We investigated whether different levels of CCR5 expression account for clonal differences in SIV(mac)239 susceptibility. Macaque CD4(+) T-cells showed significant CCR5 downregulation 1-2 days following CD3 mAb stimulation, which gradually recovered at resting state. 7-10 days after activation. Exposure of clones to SIV(mac)239 during their CCR5(low) or CCR5(high) expression states revealed differences in SIV susceptibility independent of surface CCR5 levels. Furthermore, a CCR5 antagonist similarly reduced SIV(mac)239 infection of clones during their CCR5(low) or CCR5(high) expression states. Our data suggest a model where i) very low levels of CCR5 are sufficient for efficient SIV infection, ii) CCR5 levels above this threshold do not enhance infection, and iii) low level infection can occur in the absence of CCR5. (C) 2010 Elsevier Inc. All rights reserved. C1 [Minang, Jacob T.; Trivett, Matthew T.; Barsov, Eugene V.; Del Prete, Gregory Q.; Trubey, Charles M.; Thomas, James A.; Gorelick, Robert J.; Piatak, Michael, Jr.; Ott, David E.; Ohlen, Claes] NCI Frederick, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Ohlen, C (reprint author), NCI Frederick, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM ohlenc@mail.nih.gov RI Del Prete, Gregory/C-2030-2012; OI Thomas, James/0000-0002-2509-490X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors thank Jeffrey D. Lifson for valuable suggestions, Rebecca Shoemaker for help with the cell-associated viral DNA (QPCR) analyzes and Andy Wu for help with sample preparation. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: IL-2 from Hoffman-La Roche Inc., NJ; SIVmac p27 hybridoma (55-2f12) from Dr Niels Pedersen; SIVmac 239 Gag, Pal, Acc (15-mer) Peptides - Complete Sets; Maraviroc (Cat #11580). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. NR 56 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2011 VL 409 IS 1 BP 132 EP 140 DI 10.1016/j.virol.2010.10.005 PG 9 WC Virology SC Virology GA 696OO UT WOS:000285450900016 PM 21035160 ER PT J AU Zablotska, LB Ron, E Rozhko, AV Hatch, M Polyanskaya, ON Brenner, AV Lubin, J Romanov, GN McConnell, RJ O'Kane, P Evseenko, VV Drozdovitch, VV Luckyanov, N Minenko, VF Bouville, A Masyakin, VB AF Zablotska, L. B. Ron, E. Rozhko, A. V. Hatch, M. Polyanskaya, O. N. Brenner, A. V. Lubin, J. Romanov, G. N. McConnell, R. J. O'Kane, P. Evseenko, V. V. Drozdovitch, V. V. Luckyanov, N. Minenko, V. F. Bouville, A. Masyakin, V. B. TI Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident SO BRITISH JOURNAL OF CANCER LA English DT Article DE thyroid neoplasms; iodine radioisotopes; Chernobyl nuclear accident; risk; iodine deficiency ID POWER-STATION ACCIDENT; EXTERNAL RADIATION; IODINE DEFICIENCY; BRYANSK OBLAST; COHORT; CHILDHOOD; DISEASES; RUSSIA; NUTRITION; AREAS AB BACKGROUND: Previous studies showed an increased risk of thyroid cancer among children and adolescents exposed to radioactive iodines released after the Chornobyl (Chernobyl) accident, but the effects of screening, iodine deficiency, age at exposure and other factors on the dose-response are poorly understood. METHODS: We screened 11 970 individuals in Belarus aged 18 years or younger at the time of the accident who had estimated (131)I thyroid doses based on individual thyroid activity measurements and dosimetric data from questionnaires. The excess odds ratio per gray (EOR/Gy) was modelled using linear and linear-exponential functions. RESULTS: For thyroid doses <5 Gy, the dose-response was linear (n = 85; EOR/Gy = 2.15, 95% confidence interval: 0.81-5.47), but at higher doses the excess risk fell. The EOR/Gy was significantly increased among those with prior or screening-detected diffuse goiter, and larger for men than women, and for persons exposed before age 5 than those exposed between 5 and 18 years, although not statistically significant. A somewhat higher EOR/Gy was estimated for validated pre-screening cases. CONCLUSION: 10-15 years after the Chornobyl accident, thyroid cancer risk was significantly increased among individuals exposed to fallout as children or adolescents, but the risk appeared to be lower than in other Chornobyl studies and studies of childhood external irradiation. British Journal of Cancer (2011) 104, 181-187. doi: 10.1038/sj.bjc.6605967 www.bjcancer.com Published online 23 November 2010 (C) 2011 Cancer Research UK C1 [Zablotska, L. B.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA. [Ron, E.; Hatch, M.; Brenner, A. V.; Lubin, J.; Drozdovitch, V. V.; Luckyanov, N.; Bouville, A.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Rozhko, A. V.; Polyanskaya, O. N.; Romanov, G. N.; Evseenko, V. V.; Masyakin, V. B.] Republican Res Ctr Radiat Med & Human Ecol, Gomel 246040, Byelarus. [McConnell, R. J.] Columbia Univ, Thyroid Ctr, New York, NY 10032 USA. [O'Kane, P.] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. [Minenko, V. F.] Belarusian Med Acad Postgrad Educ, Minsk 220714, Byelarus. RP Zablotska, LB (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 3333 Calif St,Suite 280, San Francisco, CA 94118 USA. EM lydia.zablotska@ucsf.edu FU National Cancer Institute, US Department of Health and Human Services; US Department of Energy; Nuclear Regulatory Commission FX We gratefully acknowledge the contributions of the late Dr Gilbert W Beebe and Dr Geoffrey R Howe to the original design of the study and the contributions of Dr Aaron B Brill, Dr Daniel J Fink, Dr Ellen Greenbaum, Dr Ihor J Masnyk, Dr Jacob Robbins, Dr Terry L Thomas and Dr Paul G Voilleque to the setup and execution of the study over the years. We thank the BelAm study staff for their dedication and commitment to the success of this study. We express our deep appreciation of the work of the members of the International Pathology Panel of the Chornobyl Tumor Tissue Bank and the ad hoc international thyroid pathology panel: Dr Alexander Abrosimov, Dr Tatiana I Bogdanova, Dr Ronald A Ghossein, Dr Masahiro Ito, Dr Virginia LiVolsi, Dr Alexander M Nerovnya, Dr Juan Rosai, Dr Geraldine A Thomas Dr and E Dillwyn Williams. We also thank Dr Kiyohiko Mabuchi for careful review and helpful comments on the draft of the article. Funding for this study was provided by the National Cancer Institute, US Department of Health and Human Services. The US Department of Energy provided funding at the earlier stages of the study and the Nuclear Regulatory Commission provided the initial funds for purchase of equipment, but neither of the two agencies had any role in the design and analysis of the study. NR 31 TC 63 Z9 68 U1 4 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 4 PY 2011 VL 104 IS 1 BP 181 EP 187 DI 10.1038/sj.bjc.6605967 PG 7 WC Oncology SC Oncology GA 702SN UT WOS:000285915900026 PM 21102590 ER PT J AU Behnam, AJ Herzka, DA Sheehan, FT AF Behnam, Abrahm J. Herzka, Daniel A. Sheehan, Frances T. TI Assessing the accuracy and precision of musculoskeletal motion tracking using cine-PC MRI on a 3.0T platform SO JOURNAL OF BIOMECHANICS LA English DT Article DE Patella; Knee; Bone; Muscle; Validation; Phantom; Dynamic ID 3-DIMENSIONAL PATELLAR TRACKING; IN-VIVO; KINEMATICS; JOINT; FEASIBILITY; FLUOROSCOPY AB The rising cost of musculoskeletal pathology, disease, and injury creates a pressing need for accurate and reliable methods to quantify 3D musculoskeletal motion, fostering a renewed interest in this area over the past few years. To date, cine-phase contrast (PC) MRI remains the only technique capable of non-invasively tracking in vivo 3D musculoskeletal motion during volitional activity, but current scan times are long on the 1.5T MR platform (similar to 2.5 min or 75 movement cycles). With the clinical availability of higher field strength magnets (3.0T) that have increased signal-to-noise ratios, it is likely that scan times can be reduced while improving accuracy. Therefore, the purpose of this study is to validate cine-PC MRI on a 3.0T platform, in terms of accuracy, precision, and subject-repeatability, and to determine if scan time could be minimized. On the 3.0T platform it is possible to limit scan time to 2 min, with sub-millimeter accuracy (<0.33 mm/0.97 degrees), excellent technique precision (<0.18 degrees), and strong subject-repeatability (<0.73 mm/1.10 degrees). This represents reduction in imaging time by 25% (42 s), a 50% improvement in accuracy, and a 72% improvement in technique precision over the original 1.5T platform. Scan time can be reduced to 1 min (30 movement cycles), but the improvements in accuracy are not as large. Published by Elsevier Ltd. C1 [Behnam, Abrahm J.; Sheehan, Frances T.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Behnam, Abrahm J.; Herzka, Daniel A.] Johns Hopkins Sch Med, Dept Biomed Engn, Baltimore, MD USA. RP Sheehan, FT (reprint author), NIH, Dept Rehabil Med, Bldg 10 CRC RM 1-1469,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov RI sheehan, frances/B-6962-2009; OI Herzka, Daniel/0000-0002-9400-7814 FU NIH; Clinical Center at the NIH; Diagnostic Radiology Department at the National Institutes of Health FX This research was supported by the Intramural Research Program of the NIH, and the Clinical Center at the NIH. We thank Sara Sadeghi, Bonnie Damaska, and the Diagnostic Radiology Department at the National Institutes of Health for their support and research time. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Institutes of Health or the US Public Health Service. NR 24 TC 24 Z9 24 U1 2 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD JAN 4 PY 2011 VL 44 IS 1 BP 193 EP 197 DI 10.1016/j.jbiomech.2010.08.029 PG 5 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 710XO UT WOS:000286550500030 PM 20863502 ER PT J AU Wang, XD Wang, E Marincola, FM AF Wang, Xiangdong Wang, Ena Marincola, Francesco M. TI Translational Medicine is developing in China: A new venue for collaboration SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material AB Translational Medicine is an emerging area comprising multidisciplinary Research from basic sciences to medical applications well summarized by the Bench-to-Beside concept; this entails close collaboration between clinicians and basic scientists across institutes. We further clarified that Translational Medicine should be regarded as a two-way road: Bench-to-Bedside and Bedside-to-Bench, to complement testing of novel therapeutic strategies in humans with feedback understanding of how they respond to them. It is, therefore, critical and important to define and promote Translational Medicine among clinicians, basic Researchers, biotechnologists, politicians, ethicists, sociologists, investors and coordinate these efforts among different Countries, fostering aspects germane only to this type of Research such as, as recently discussed, biotechnology entrepreneurship. Translational Medicine as an inter-disciplinary science is developing rapidly and widely and, in this article, we will place a special emphasis on China. C1 [Wang, Xiangdong] Fudan Univ, Zhongshan Hosp, Biomed Res Ctr, Dept Resp Med, Shanghai 200433, Peoples R China. [Wang, Ena; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Wang, XD (reprint author), Fudan Univ, Zhongshan Hosp, Biomed Res Ctr, Dept Resp Med, Shanghai 200433, Peoples R China. EM xiangdong.wang@telia.com RI Wang, Xiangdong/F-2913-2014 NR 22 TC 11 Z9 16 U1 1 U2 13 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 4 PY 2011 VL 9 AR 3 DI 10.1186/1479-5876-9-3 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 708QZ UT WOS:000286380700002 PM 21205297 ER PT J AU Efroni, S Ben-Hamo, R Edmonson, M Greenblum, S Schaefer, CF Buetow, KH AF Efroni, Sol Ben-Hamo, Rotem Edmonson, Michael Greenblum, Sharon Schaefer, Carl F. Buetow, Kenneth H. TI Detecting Cancer Gene Networks Characterized by Recurrent Genomic Alterations in a Population SO PLOS ONE LA English DT Article ID DNA COPY-NUMBER; UBIQUITIN-PROTEASOME PATHWAY; HIGH-RESOLUTION ANALYSIS; HUMAN BREAST-TUMORS; PATIENT SURVIVAL; P53 STATUS; HYBRIDIZATION; EXPRESSION; MICROARRAYS; REVEALS AB High resolution, system-wide characterizations have demonstrated the capacity to identify genomic regions that undergo genomic aberrations. Such research efforts often aim at associating these regions with disease etiology and outcome. Identifying the corresponding biologic processes that are responsible for disease and its outcome remains challenging. Using novel analytic methods that utilize the structure of biologic networks, we are able to identify the specific networks that are highly significantly, nonrandomly altered by regions of copy number amplification observed in a systems-wide analysis. We demonstrate this method in breast cancer, where the state of a subset of the pathways identified through these regions is shown to be highly associated with disease survival and recurrence. C1 [Efroni, Sol; Ben-Hamo, Rotem] Bar Ilan Univ, Mina & Everard Fac Life Sci, Ramat Gan, Israel. [Schaefer, Carl F.; Buetow, Kenneth H.] NCI, Ctr Biomed Informat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Edmonson, Michael; Greenblum, Sharon; Buetow, Kenneth H.] NIH, Lab Populat Genet, Bethesda, MD 20892 USA. RP Efroni, S (reprint author), Bar Ilan Univ, Mina & Everard Fac Life Sci, Ramat Gan, Israel. EM buetowk@nih.gov RI Efroni, Sol/I-6752-2012 OI Efroni, Sol/0000-0001-7927-6349 FU European Union FX SE is funded by the European Union through its International Reintegration Grants (IRG) program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 10 Z9 10 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 4 PY 2011 VL 6 IS 1 AR e14437 DI 10.1371/journal.pone.0014437 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710KM UT WOS:000286510500003 PM 21283511 ER PT J AU Bok, J Raft, S Kong, KA Koo, SK Drager, UC Wu, DK AF Bok, Jinwoong Raft, Steven Kong, Kyoung-Ah Koo, Soo Kyung Draeger, Ursula C. Wu, Doris K. TI Transient retinoic acid signaling confers anterior-posterior polarity to the inner ear SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE axial specification; developmental compartments; morphogen ID CELL FATE SPECIFICATION; ZEBRAFISH OTIC VESICLE; AXIAL SPECIFICATION; CHICK-EMBRYO; STEM-CELLS; HINDBRAIN; EXPRESSION; HEDGEHOG; MORPHOGENESIS; GENERATION AB Vertebrate hearing and balance are based in complex asymmetries of inner ear structure. Here, we identify retinoic acid (RA) as an extrinsic signal that acts directly on the ear rudiment to affect its compartmentalization along the anterior-posterior axis. A rostrocaudal wave of RA activity, generated by tissues surrounding the nascent ear, induces distinct responses from anterior and posterior halves of the inner ear rudiment. Prolonged response to RA by posterior otic tissue correlates with Tbx1 transcription and formation of mostly nonsensory inner ear structures. By contrast, anterior otic tissue displays only a brief response to RA and forms neuronal elements and most sensory structures of the inner ear. C1 [Bok, Jinwoong; Kong, Kyoung-Ah] Yonsei Univ, Coll Med, Project Med Sci BK21, Dept Anat, Seoul 120752, South Korea. [Raft, Steven; Wu, Doris K.] Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. [Draeger, Ursula C.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Koo, Soo Kyung] Natl Inst Hlth, Dept Biomed Sci, Osong 363951, South Korea. RP Bok, J (reprint author), Yonsei Univ, Coll Med, Project Med Sci BK21, Dept Anat, Seoul 120752, South Korea. EM bokj@yuhs.ac; wud@nidcd.nih.gov RI Bok, Jinwoong/B-8982-2016; OI Bok, Jinwoong/0000-0003-1958-1872; Drager, Ursula C/0000-0003-1815-190X FU Yonsei University College of Medicine [6-2008-0102]; National Research Foundation of Korea [2010-0015354] FX We thank Drs. Robert Morell and Andrew Griffith for critical reading of the manuscript. This work was supported by the National Institute on Deafness and Other Communication Disorders Intramural Program, faculty research Grant 6-2008-0102 from Yonsei University College of Medicine (to J.B.), and Basic Science Research Program Grant 2010-0015354 through the National Research Foundation of Korea (to J.B.). NR 43 TC 36 Z9 37 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 4 PY 2011 VL 108 IS 1 BP 161 EP 166 DI 10.1073/pnas.1010547108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702SG UT WOS:000285915000033 PM 21173260 ER PT J AU Hirai, T Chagin, AS Kobayashi, T Mackem, S Kronenberg, HM AF Hirai, Takao Chagin, Andrei S. Kobayashi, Tatsuya Mackem, Susan Kronenberg, Henry M. TI Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CHONDROCYTE MATURATION; BH3 DOMAIN; CELL-DEATH; PEPTIDE; BONE; CHONDRODYSPLASIA; PHOSPHORYLATION; DIFFERENTIATION; INACTIVATE; APOPTOSIS AB Parathyroid hormone (PTH)-related protein (PTHrP), regulated by Indian hedgehog and acting through the PTH/PTHrP receptor (PPR), is crucial for normal cartilage development. These observations suggest a possible role of PPR signaling in the postnatal growth plate; however, the role of PPR signaling in postnatal chondrocytes is unknown. In this study, we have generated tamoxifen-inducible and cartilage-specific PPR KO mice to evaluate the physiological role of PPR signaling in postnatal chondrocytes. We found that inactivation of the PPR in chondrocytes postnatally leads to accelerated differentiation of chondrocytes, followed by disappearance of the growth plate. We also observed an increase of TUNEL-positive cells and activities of caspase-3 and caspase-9 in the growth plate, along with a decrease in phosphorylation of Bad at Ser155 in postnatal PPR KO mice. Administration of a low-phosphate diet, which prevents apoptosis of chondrocytes, prevented the disappearance of the growth plate. Taken together, these observations suggest that the major consequences of PPR activation are similar in both the fetal and postnatal growth plates. Moreover, chondrocyte apoptosis through the activation of a mitochondrial pathway may be involved in the process of premature disappearance of the growth plate by postnatal inactivation of the PPR in chondrocytes. C1 [Hirai, Takao; Chagin, Andrei S.; Kobayashi, Tatsuya; Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Hirai, Takao; Chagin, Andrei S.; Kobayashi, Tatsuya; Kronenberg, Henry M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mackem, Susan] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kronenberg, HM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM hkronenberg@partners.org RI Chagin, Andrei/F-4080-2014 OI Chagin, Andrei/0000-0002-2696-5850 FU National Institutes of Health [DK56246] FX We thank Marie B. Demay, Shigeki Nishimori, and Makoto Okazaki for helpful suggestions. This work was funded by National Institutes of Health Grant DK56246. NR 23 TC 37 Z9 40 U1 1 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 JAN 4 PY 2011 VL 108 IS 1 BP 191 EP 196 DI 10.1073/pnas.1005011108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702SG UT WOS:000285915000038 PM 21173257 ER PT J AU Kitchen, A Shackelton, LA Holmes, EC AF Kitchen, Andrew Shackelton, Laura A. Holmes, Edward C. TI Family level phylogenies reveal modes of macroevolution in RNA viruses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE emergence; molecular evolution; host jumping ID PAN-TROGLODYTES; FLAVIVIRUSES; EPIDEMIOLOGY; TRANSMISSION; EMERGENCE; EVOLUTION; INFERENCE; DYNAMICS; DISEASES; DECLINE AB Despite advances in understanding the patterns and processes of microevolution in RNA viruses, little is known about the determinants of viral diversification at the macroevolutionary scale. In particular, the processes by which viral lineages assigned as different "species" are generated remain largely uncharacterized. To address this issue, we use a robust phylogenetic approach to analyze patterns of lineage diversification in five representative families of RNA viruses. We ask whether the process of lineage diversification primarily occurs when viruses infect new host species, either through cross-species transmission or codivergence, and which are defined here as analogous to allopatric speciation in animals, or by acquiring new niches within the same host species, analogous to sympatric speciation. By mapping probable primary host species onto family level viral phylogenies, we reveal a strong clustering among viral lineages that infect groups of closely related host species. Although this is consistent with lineage diversification within individual hosts, we argue that this pattern more likely represents strong biases in our knowledge of viral biodiversity, because we also find that better-sampled human viruses rarely cluster together. Hence, although closely related viruses tend to infect related host species, it is unlikely that they often infect the same host species, such that evolutionary constraints hinder lineage diversification within individual host species. We conclude that the colonization of new but related host species may represent the principle mode of macroevolution in RNA viruses. C1 [Kitchen, Andrew; Shackelton, Laura A.; Holmes, Edward C.] Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Shackelton, Laura A.] Bill & Melinda Gates Fdn, Global Hlth Discovery, Seattle, WA 98105 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 National Institutes of Health [R01 GM080533] FX We thank Dr. Scott Weaver (University of Texas Medical Branch, Galveston, TX) for kindly providing an alignment of alphavirus proteins, and Dr. Herve Bourhy for advice concerning rhabdoviruses. Support for this work was provided in part by National Institutes of Health Grant R01 GM080533 (to E.C.H.). NR 33 TC 29 Z9 29 U1 1 U2 22 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 4 PY 2011 VL 108 IS 1 BP 238 EP 243 DI 10.1073/pnas.1011090108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702SG UT WOS:000285915000046 PM 21173251 ER PT J AU Janeway, KA Kim, SY Lodish, M Nose, V Rustin, P Gaal, J Dahia, PLM Liegl, B Ball, ER Raygada, M Lai, AH Kelly, L Hornick, JL O'Sullivan, M de Krijger, RR Dinjens, WNM Demetri, GD Antonescu, CR Fletcher, JA Helman, L Stratakis, CA AF Janeway, Katherine A. Kim, Su Young Lodish, Maya Nose, Vania Rustin, Pierre Gaal, Jose Dahia, Patricia L. M. Liegl, Bernadette Ball, Evan R. Raygada, Margarita Lai, Angela H. Kelly, Lorna Hornick, Jason L. O'Sullivan, Maureen de Krijger, Ronald R. Dinjens, Winand N. M. Demetri, George D. Antonescu, Cristina R. Fletcher, Jonathan A. Helman, Lee Stratakis, Constantine A. CA NIH Pediat Wild Type GIST Clinic TI Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genetic predisposition; sarcoma; pediatric ID APPARENTLY SPORADIC PHEOCHROMOCYTOMAS; SDHD GENE; GERMLINE MUTATIONS; RESPIRATORY-CHAIN; COMPLEX-II; PARAGANGLIOMA; MECHANISMS; GIST; PHENOTYPE; VARIANTS AB Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1-associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis. C1 [Janeway, Katherine A.; Lai, Angela H.] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Janeway, Katherine A.; Lai, Angela H.] Childrens Hosp, Boston, MA 02115 USA. [Kim, Su Young; Helman, Lee] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lodish, Maya; Ball, Evan R.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, NIH, Bethesda, MD 20892 USA. [Nose, Vania] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. [Rustin, Pierre] INSERM, U676, Paris, France. [Rustin, Pierre] Univ Paris 07, Fac Med Denis Diderot, IFR02, Paris, France. [Gaal, Jose; de Krijger, Ronald R.; Dinjens, Winand N. M.] Erasmus MC Univ Med Ctr, Dept Pathol, Josephine Nefkens Inst, NL-3000 CA Rotterdam, Netherlands. [Dahia, Patricia L. M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Dahia, Patricia L. M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Liegl, Bernadette] Med Univ, Inst Pathol, A-8036 Graz, Austria. [Raygada, Margarita] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol Genet, NIH, Bethesda, MD 20892 USA. [Kelly, Lorna; O'Sullivan, Maureen] Our Ladys Childrens Hosp, Natl Childrens Res Ctr, Dublin 12, Ireland. [Hornick, Jason L.; Fletcher, Jonathan A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. St Jude Childrens Res Ctr, Dept Oncol, Memphis, TN 38105 USA. Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [O'Sullivan, Maureen] Our Ladys Childrens Hosp, Histol Lab, Dublin 12, Ireland. [Raygada, Margarita] Dana Farber Harvard Canc Ctr, Dept Med Oncol, Boston, MA 02115 USA. [Demetri, George D.] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA. [Antonescu, Cristina R.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [NIH Pediat Wild Type GIST Clinic] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. RP Janeway, KA (reprint author), Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. EM kjaneway@partners.org FU GIST; St. Baldrick's Foundation; Leduq Foundation; Agence Nationale de la Recherche Mitoxy; Voelcker Fund; Health Research Board of Ireland; American Cancer Society [CCE-106841]; National Institutes of Health (NIH) [P01CA47179]; Life Raft Group; Shuman Family Fund; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Cancer Institute; Office of Rare Diseases of the National Institutes of Health FX This work was supported by the GIST Cancer Research Fund (to K.A.J., C.R.A., and J.A.F.), the St. Baldrick's Foundation (to K.A.J.), the Leduq Foundation (to P.R.), the Agence Nationale de la Recherche Mitoxy (to P.R.), the Voelcker Fund Investigator Award (to P. L. M.D.), a grant from the Health Research Board of Ireland through the Medical Research Charities Group (to M.O.), American Cancer Society Mentored Research Scholar Grant CCE-106841 (to C.R.A.), National Institutes of Health (NIH) P01CA47179 (to C.R.A.), Life Raft Group (to C.R.A.), Shuman Family Fund for GIST Research (to C.R.A.), the Intramural Program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Intramural Program of the National Cancer Institute, and a grant from the Office of Rare Diseases of the National Institutes of Health. NR 42 TC 215 Z9 220 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 4 PY 2011 VL 108 IS 1 BP 314 EP 318 DI 10.1073/pnas.1009199108 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702SG UT WOS:000285915000059 PM 21173220 ER PT J AU Bok, K Parra, GI Mitra, T Abente, E Shaver, CK Boon, D Engle, R Yu, C Kapikian, AZ Sosnovtsev, SV Purcell, RH Green, KY AF Bok, Karin Parra, Gabriel I. Mitra, Tanaji Abente, Eugenio Shaver, Charlene K. Boon, Denali Engle, Ronald Yu, Claro Kapikian, Albert Z. Sosnovtsev, Stanislav V. Purcell, Robert H. Green, Kim Y. TI Chimpanzees as an animal model for human norovirus infection and vaccine development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BLOOD GROUP ANTIGENS; HEPATITIS-A VIRUS; EPIDEMIC VIRAL GASTROENTERITIS; CELLULAR IMMUNE-RESPONSES; NORWALK VIRUS; NONBACTERIAL GASTROENTERITIS; MONOCLONAL-ANTIBODIES; GNOTOBIOTIC PIGS; NONHUMAN-PRIMATES; IN-VITRO AB Noroviruses are global agents of acute gastroenteritis, but the development of control strategies has been hampered by the absence of a robust animal model. Studies in chimpanzees have played a key role in the characterization of several fastidious hepatitis viruses, and we investigated the feasibility of such studies for the noroviruses. Seronegative chimpanzees inoculated i.v. with the human norovirus strain Norwalk virus (NV) did not show clinical signs of gastroenteritis, but the onset and duration of virus shedding in stool and serum antibody responses were similar to that observed in humans. NV RNA was detected in intestinal and liver biopsies concurrent with the detection of viral shedding in stool, and NV antigen expression was observed in cells of the small intestinal lamina propria. Two infected chimpanzees rechallenged 4, 10, or 24 mo later with NV were resistant to reinfection, and the presence of NV-specific serum antibodies correlated with protection. We evaluated the immunogenicity and efficacy of virus-like particles (VLPs) derived from NV (genogroup I, GI) and MD145 (genogroup II, GII) noroviruses as vaccines. Chimpanzees vaccinated intramuscularly with GI VLPs were protected from NV infection when challenged 2 and 18 mo after vaccination, whereas chimpanzees that received GII VLPs vaccine or a placebo were not. This study establishes the chimpanzee as a viable animal model for the study of norovirus replication and immunity, and shows that NV VLP vaccines could induce protective homologous immunity even after extended periods of time. C1 [Bok, Karin; Parra, Gabriel I.; Mitra, Tanaji; Abente, Eugenio; Boon, Denali; Engle, Ronald; Yu, Claro; Kapikian, Albert Z.; Sosnovtsev, Stanislav V.; Purcell, Robert H.; Green, Kim Y.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Shaver, Charlene K.] Bioqual Inc, Rockville, MD 20850 USA. RP Bok, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM bokk@niaid.nih.gov; rpurcell@niaid.nih.gov OI Abente, Eugenio/0000-0002-3390-2786; Parra, Gabriel/0000-0002-1102-4740 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Alicia Brockington FX We thank Dr. Anthony Cook and Jake Yalley-Ogunro for their expert assistance with the animal protocols. We are also very grateful to Alicia Brockington for support in conducting these studies. This research was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 49 TC 91 Z9 93 U1 2 U2 25 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 JAN 4 PY 2011 VL 108 IS 1 BP 325 EP 330 DI 10.1073/pnas.1014577107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 702SG UT WOS:000285915000061 PM 21173246 ER PT J AU Kubler-Kielb, J Lai, WT Schneerson, R Vinogradov, E AF Kubler-Kielb, Joanna Lai, Wen-Tzu Schneerson, Rachel Vinogradov, Evgeny TI The structure of the Escherichia coli O148 lipopolysaccharide core region and its linkage to the O-specific polysaccharide SO CARBOHYDRATE RESEARCH LA English DT Article DE Escherichia coli O148; LPS; O-Specific polysaccharide; Core; Structure ID VACCINE AB Recently it was demonstrated that Shigella dysenteriae type 1, a cause of severe dysentery epidemics, gained its O-specific polysaccharide (O-SP) from Escherichia coli O148. The O-SP5 of these bacteria differ only by a galactose residue in the repeat unit of S. dysenteriae type 1 in place of a glucose residue in E. coli O148. Herein, we analyzed the core structure and its linkage to the O-SP in E. coli O148 LPS. Both were found to be identical to those of S. dysenteriae type 1 structures, further supporting the relatedness of these two bacteria. The following structure of the core with one repeat unit of the O-SP has been assigned (all have D-configuration except L-Rha): alpha-Hepp-7 vertical bar a-Galp-2-alpha-Galp-2-alpha-Glcp-3-alpha-Glcp-3-alpha-Hepp4P-3-alpha-Hepp4P-5-Kdo vertical bar a-Rhap-3-alpha-Rhap-2-alpha-Glcp-3-beta-GlepNAc-6-beta-Galp-4 (C) 2010 Elsevier Ltd. All rights reserved. C1 [Vinogradov, Evgeny] Natl Res Council Canada, Inst Biol Sci, Ottawa, ON K1A 0R6, Canada. [Kubler-Kielb, Joanna; Lai, Wen-Tzu; Schneerson, Rachel] NICHHD, NIH, Bethesda, MD 20892 USA. RP Vinogradov, E (reprint author), Natl Res Council Canada, Inst Biol Sci, 100 Sussex Dr, Ottawa, ON K1A 0R6, Canada. EM Evguenii.Vinogradov@nrc-cnrc.gc.ca OI Vinogradov, Evgeny/0000-0002-5364-1376 FU NIH, NICHD FX This research was supported in part by the Intramural Research Program of the NIH, NICHD. Authors thank J. Stupak (NRC, Canada) for mass spectrometry analysis, Nancy A. Strockbine (CDC, Atlanta, GA) for giving us E. coli O148 strains, and Patrick Murray and Nayana Patel (NIH, Bethesda, MD) for bacterial strain identification. NR 12 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 EI 1873-426X J9 CARBOHYD RES JI Carbohydr. Res. PD JAN 3 PY 2011 VL 346 IS 1 BP 150 EP 152 DI 10.1016/j.carres.2010.10.012 PG 3 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 713DR UT WOS:000286715700020 PM 21074753 ER PT J AU Tolstanova, G Deng, XM Khomenko, T Garg, P Paunovic, B Chen, LC Sitaraman, SV Shiloach, J Szabo, S Sandor, Z AF Tolstanova, Ganna Deng, Xiaoming Khomenko, Tetyana Garg, Pallavi Paunovic, Brankica Chen, Longchuan Sitaraman, Shanthi V. Shiloach, Joseph Szabo, Sandor Sandor, Zsuzsanna TI Role of anti-angiogenic factor endostatin in the pathogenesis of experimental ulcerative colitis SO LIFE SCIENCES LA English DT Article DE Endostatin; Matrix metalloproteinase-9; VEGF; Ulcerative colitis ID INFLAMMATORY-BOWEL-DISEASE; ENDOTHELIAL GROWTH-FACTOR; CANCER IN-VIVO; CROHNS-DISEASE; MATRIX METALLOPROTEINASES; GENE-TRANSFER; MURINE MODEL; SERUM-LEVELS; VEGF; PDGF AB Aims: Vascular endothelial growth factor (VEGF) and pathologic angiogenesis have been demonstrated to play a pathogenic role in the development and progression of inflammatory bowel disease. Thus, we hypothesized that the potent anti-angiogenic factor endostatin might play a beneficial role in experimental ulcerative colitis (UC). Main methods: We used three animal models of UC: (1) induced by 6% iodoacetamide (IA) in rats, or (2) by 3% dextran sulfate sodium (DSS) in matrix metalloproteinase-9 (MMP-9) knockout (KO) and wild-type mice, and (3) interleukin-10 (IL-10) KO mice. Groups of MMP-9 KO mice with DSS-induced UC were treated with endostatin or water for 5 days. Key findings: We found concomitant upregulation of VEGF, PDGF, MMP-9 and endostatin in both rat and mouse models of UC. A positive correlation between the levels of endostatin or VEGF and the sizes of colonic lesions was seen in IA-induced UC. The levels and activities of MMP-9 were also significantly increased during UC induced by IA and IL-10 KO. Deletion of MMP-9 decreased the levels of endostatin in both water- and DSS-treated MMP-9 KO mice. Treatment with endostatin significantly improved DSS-induced UC in MMP-9 KO mice. Significance: 1) Concomitantly increased endostatin is a defensive response to the increased VEGF in UC, 2) MMP-9 is a key enzyme to generate endostatin which may modulate the balance between VEGF and endostatin during experimental UC, and 3) endostatin treatment plays a beneficial role in UC. Thus, antiangiogenesis seems to be a new therapeutic option for UC. Published by Elsevier Inc. C1 [Sandor, Zsuzsanna] Vet Adm Med Ctr, Med Hlth Care Grp, Long Beach, CA 90822 USA. [Tolstanova, Ganna; Deng, Xiaoming; Khomenko, Tetyana; Paunovic, Brankica; Chen, Longchuan; Szabo, Sandor] Vet Adm Med Ctr, Hlth Care Grp, Long Beach, CA 90822 USA. [Deng, Xiaoming; Khomenko, Tetyana; Szabo, Sandor] Univ Calif Irvine, Dept Pathol, Irvine, CA 92717 USA. [Deng, Xiaoming; Khomenko, Tetyana; Szabo, Sandor] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92717 USA. [Sandor, Zsuzsanna] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Garg, Pallavi; Sitaraman, Shanthi V.] Emory Univ, Atlanta, GA 30322 USA. [Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD USA. RP Szabo, S (reprint author), Vet Adm Med Ctr, Med Hlth Care Grp, 05-113,5901 E 7th St, Long Beach, CA 90822 USA. EM sandor.szabo@va.gov; zsuzsanna.sandor@va.gov FU Department of Veterans Affairs, Veterans Health Administration Merit Review [VAMR0710-580] FX We thank Loc Trinh of NIH Biotechnology Unit for producing and purifying recombinant mouse endostatin. This work was supported by the Department of Veterans Affairs, Veterans Health Administration Merit Review [Grant VAMR0710-580]. NR 54 TC 11 Z9 13 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JAN 3 PY 2011 VL 88 IS 1-2 BP 74 EP 81 DI 10.1016/j.lfs.2010.10.026 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 707LR UT WOS:000286288600011 PM 21047522 ER PT J AU Smith, W Grady, C Krohmal, B Lazovski, J Wendler, D AF Smith, William Grady, Christine Krohmal, Benjamin Lazovski, Jaime Wendler, David CA INSIGHT ESPRIT Grp TI Empirical evaluation of the need for 'on-going consent' in clinical research SO AIDS LA English DT Article DE clinical trials; comprehension; informed consent ID INFORMED-CONSENT; INTERLEUKIN-2; TRIALS AB Objective: Some commentators argue that informed consent for clinical research should be an on-going process, which begins, rather than ends, with participants' initial consent. Lacking, however, are empirical data on whether there is a need for 'on-going consent'. Design: Two self-administered surveys - a baseline survey at initial consent and a follow-up survey 2-3 years later - to assess whether participants remain informed over time. Methods: Respondents were adults with HIV disease from Argentina, Brazil and Thailand enrolled in a long-term clinical trial. Results: Respondents overall were well informed at baseline. At follow-up, many reported being not informed about aspects of the study central to their on-going participation. With respect to the possibility of withdrawal, 38.5% of respondents at follow-up reported being 'not at all' informed. At follow-up, 71.1% wanted more information. Yet, 62.8% had not asked any questions during the entire study. Reasons for not asking questions included not having an opportunity (16.4%) and not knowing whom to ask (15.5%). Conclusions: The standard consent process resulted in participants being well informed at enrollment. Yet, this process was not sufficient to keep them informed about aspects of the study central to their on-going participation. In addition, participants who wanted more information often did not ask for it. These findings provide empirical support for recommendations that clinical trials should consider including a process of 'on-going consent'. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Smith, William; Grady, Christine; Krohmal, Benjamin; Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Lazovski, Jaime] Minist Hlth, Buenos Aires, DF, Argentina. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU Intramural NIH HHS [Z99 CL999999]; Medical Research Council [MC_U122886352] NR 20 TC 7 Z9 7 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 2 PY 2011 VL 25 IS 1 BP 107 EP 114 DI 10.1097/QAD.0b013e328340fec7 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 688BM UT WOS:000284823900013 PM 21076272 ER PT J AU Oh, KS Bustin, M Mazur, SJ Appella, E Kraemer, KH AF Oh, Kyu-Seon Bustin, Michael Mazur, Sharlyn J. Appella, Ettore Kraemer, Kenneth H. TI UV-induced histone H2AX phosphorylation and DNA damage related proteins accumulate and persist in nucleotide excision repair-deficient XP-B cells SO DNA REPAIR LA English DT Article DE UV damage; DNA double strand breaks; Xeroderma pigmentosum group B; Comet assay; Immunofluorescence; gamma-H2AX; Wip1 ID DOUBLE-STRAND BREAKS; INDUCED REPLICATION ARREST; XERODERMA-PIGMENTOSUM; COCKAYNE-SYNDROME; ULTRAVIOLET-LIGHT; WIP1 PHOSPHATASE; DEPENDENT PHOSPHORYLATION; HOMOLOGOUS RECOMBINATION; CELLULAR-RESPONSE; COMBINED FEATURES AB DNA double strand breaks (DSB) may be caused by ionizing radiation. In contrast, UV exposure forms dipyrimidine photoproducts and is not considered an inducer of DSB. We found that uniform or localized UV treatment induced phosphorylation of the DNA damage related (DDR) proteins H2AX, ATM and NBS1 and co-localization of gamma-H2AX with the DDR proteins p-ATM, p-NBS1, Rad51 and FANCD2 that persisted for about 6 h in normal human fibroblasts. This post-UV phosphorylation was observed in the absence of nucleotide excision repair (NER), since NER deficient XP-B cells (lacking functional XPB DNA repair helicase) and global genome repair-deficient rodent cells also showed phosphorylation and localization of these DDR proteins. Resolution of the DDR proteins was dependent on NER, since they persisted for 24 h in the XP-B cells. In the normal and XP-B cells p53 and p21 was detected at 6 h and 24 h but Mdm2 was not induced in the XP-B cells. Post-UV induction of Wip1 phosphatase was detected in the normal cells but not in the XP-B cells. DNA DSB were detected with a neutral comet assay at 6 h and 24 h post-UV in the normal and XP-B cells. These results indicate that UV damage can activate the DDR pathway in the absence of NER. However, a later step in DNA damage processing involving induction of Wip1 and resolution of DDR proteins was not observed in the absence of NER. Published by Elsevier ay. C1 [Oh, Kyu-Seon; Kraemer, Kenneth H.] NCI, DNA Repair Sect, Dermatol Branch, CCR, Bethesda, MD 20892 USA. [Bustin, Michael] NCI, Lab Metab, CCR, Bethesda, MD 20892 USA. [Mazur, Sharlyn J.; Appella, Ettore] NCI, Cell Biol Lab, CCR, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, DNA Repair Sect, Dermatol Branch, CCR, Bldg 37,Room 4002,MSC 4258, Bethesda, MD 20892 USA. EM kraemerk@nih.gov RI Bustin, Michael/G-6155-2015 FU U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA FX This research was supported by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA. We thank Dr. Susan Garfield of NCI for assistance with the confocal microscopy and Drs. Yongwei Zhang (NCI) and Jenq-Lin Yang of NIA for comet assay and analysis of comet moment. NR 57 TC 22 Z9 23 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JAN 2 PY 2011 VL 10 IS 1 BP 5 EP 15 DI 10.1016/j.dnarep.2010.09.004 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 710WJ UT WOS:000286547400003 PM 20947453 ER PT J AU Rhee, DB Ghosh, A Lu, JA Bohr, VA Liu, Y AF Rhee, David B. Ghosh, Avik Lu, Jian Bohr, Vilhelm A. Liu, Yie TI Factors that influence telomeric oxidative base damage and repair by DNA glycosylase OGG1 SO DNA REPAIR LA English DT Article DE Base excision repair; DNA glycosylase; Ogg1; Telomere; Oxidative base damage ID ELECTRON-TRANSFER; MAMMALIAN TELOMERES; UNCAPPED TELOMERES; EXCISION-REPAIR; TRF2; CLEAVAGE; SEQUENCE; COMPLEX; PROTEIN; SITE AB Telomeres are nucleoprotein complexes at the ends of linear chromosomes in eukaryotes, and are essential in preventing chromosome termini from being recognized as broken DNA ends. Telomere shortening has been linked to cellular senescence and human aging, with oxidative stress as a major contributing factor. 7,8-Dihydro-8-oxogaunine (8-oxodG) is one of the most abundant oxidative guanine lesions, and 8-oxoguanine DNA glycosylase (OGG1) is involved in its removal. In this study, we examined if telomeric DNA is particularly susceptible to oxidative base damage and if telomere-specific factors affect the incision of oxidized guanines by OGG1. We demonstrated that telomeric TTAGGG repeats were more prone to oxidative base damage and repaired less efficiently than non-telomeric TG repeats in vivo. We also showed that the 8-oxodG-incision activity of OGG1 is similar in telomeric and non-telomeric double-stranded substrates. In addition, telomere repeat binding factors TRF1 and TRF2 do not impair OGG1 incision activity. Yet, 8-oxodG in some telomere structures (e.g., fork-opening, 3'-overhang, and D-loop) were less effectively excised by OGG1, depending upon its position in these substrates. Collectively, our data indicate that the sequence context of telomere repeats and certain telomere configurations may contribute to telomere vulnerability to oxidative DNA damage processing. Published by Elsevier B.V. C1 [Rhee, David B.; Ghosh, Avik; Lu, Jian; Bohr, Vilhelm A.; Liu, Yie] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Liu, Y (reprint author), 251 Bayview Dr,Suite 100,Room 06B121, Baltimore, MD 21224 USA. EM liuyie@mail.nih.gov RI Lu, Jian/G-8391-2011 OI Lu, Jian/0000-0001-6522-8485 FU NIA, National Institutes of Health; UT-ORNL Graduate School of Genome Science and Technology FX We would like to thank Shakima St. Clair for technical assistance, Mary Pfeiffer for editing manuscript, and Drs. Jason Aulds, Brian Berquist, Robert Brosh, Huseyin Saribasak, and David Wilson for comments. This work was supported by funds from the Intramural Research Program of the NIA, National Institutes of Health. DBR was supported by UT-ORNL Graduate School of Genome Science and Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 44 Z9 44 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JAN 2 PY 2011 VL 10 IS 1 BP 34 EP 44 DI 10.1016/j.dnarep.2010.09.008 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 710WJ UT WOS:000286547400006 PM 20951653 ER PT J AU Liberti, SE Andersen, SD Wang, J May, A Miron, S Perderiset, M Keijzers, G Nielsen, FC Charbonnier, JB Bohr, VA Rasmussen, LJ AF Liberti, Sascha E. Andersen, Sofie D. Wang, Jing May, Alfred Miron, Simona Perderiset, Mylene Keijzers, Guido Nielsen, Finn C. Charbonnier, Jean-Baptiste Bohr, Vilhelm A. Rasmussen, Lene J. TI Bi-directional routing of DNA mismatch repair protein human exonuclease 1 to replication foci and DNA double strand breaks SO DNA REPAIR LA English DT Article DE hEXO1; PCNA; Replication foci; Double strand break; DNA mismatch repair ID CELL NUCLEAR ANTIGEN; SACCHAROMYCES-CEREVISIAE MRE11; IN-VIVO; GENETIC-RECOMBINATION; OVERLAPPING FUNCTIONS; IONIZING-RADIATION; INDUCED APOPTOSIS; PCNA; EXO1; INVOLVEMENT AB Human exonuclease 1 (hEXO1) is implicated in DNA metabolism, including replication, recombination and repair, substantiated by its interactions with PCNA, DNA helicases BLM and WRN, and several DNA mismatch repair (MMR) proteins. We investigated the sub-nuclear localization of hEXO1 during S-phase progression and in response to laser-induced DNA double strand breaks (DSBs). We show that hEXO1 and PCNA co-localize in replication foci. This apparent interaction is sustained throughout S-phase. We also demonstrate that hEXO1 is rapidly recruited to DNA DSBs. We have identified a PCNA interacting protein (PIP-box) region on hEXO1 located in its COOH-terminal ((788)QIKLNELW(795)). This motif is essential for PCNA binding and co-localization during S-phase. Recruitment of hEXO1 to DNA DSB sites is dependent on the MMR protein hMLH1. We show that two distinct hMLH1 interaction regions of hEXO1 (residues 390-490 and 787-846) are required to direct the protein to the DNA damage site. Our results reveal that protein domains in hEXO1 in conjunction with specific protein interactions control bi-directional routing of hEXO1 between on-going DNA replication and repair processes in living cells. (C) 2010 Elsevier B.V. All rights reserved. C1 [Liberti, Sascha E.; Keijzers, Guido; Rasmussen, Lene J.] Univ Copenhagen, Dept Cellular & Mol Med, Ctr Healthy Aging, DK-2200 Copenhagen, Denmark. [Andersen, Sofie D.; Wang, Jing] Roskilde Univ Ctr, Dept Sci Syst & Models, Roskilde, Denmark. [May, Alfred; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Bethesda, MD 20892 USA. [Miron, Simona] Inst Curie, INSERM, U759, Integrat Imaging Unit, F-91405 Orsay, France. [Perderiset, Mylene] Inst Curie, Telomeres & Canc Lab, F-91405 Orsay, France. [Nielsen, Finn C.] Copenhagen Univ Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Charbonnier, Jean-Baptiste] CEA, CNRS, URA2096, Lab Struct Biol & Radiobiol,iBiTec S, Saclay, France. RP Rasmussen, LJ (reprint author), Univ Copenhagen, Dept Cellular & Mol Med, Ctr Healthy Aging, DK-2200 Copenhagen, Denmark. EM lenera@sund.ku.dk OI Charbonnier, Jean-Baptiste/0000-0002-5219-1983 FU NORDEA foundation; Danish Cancer Society; EU [FP6-018754]; National Institutes on Aging, National Institutes of Health FX This work was supported in part by grants to LJR from the NORDEA foundation, Danish Cancer Society, and EU (FP6-018754). VB was supported in part by funds from the Intramural Research Program of the National Institutes on Aging, National Institutes of Health. NR 63 TC 23 Z9 23 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JAN 2 PY 2011 VL 10 IS 1 BP 73 EP 86 DI 10.1016/j.dnarep.2010.09.023 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 710WJ UT WOS:000286547400010 PM 20970388 ER PT J AU Nakai, W Westmoreland, J Yeh, E Bloom, K Resnick, MA AF Nakai, Wataru Westmoreland, Jim Yeh, Elaine Bloom, Kerry Resnick, Michael A. TI Chromosome integrity at a double-strand break requires exonuclease 1 and MRX SO DNA REPAIR LA English DT Article DE Double-strand break repair; Chromosome break; Exonuclease 1; MRX; Fluorescent imaging ID SACCHAROMYCES-CEREVISIAE; MISMATCH REPAIR; GENOMIC INSTABILITY; MUTATION AVOIDANCE; NUCLEASE ACTIVITY; DNA-DAMAGE; IN-VIVO; EXO1; COMPLEX; YEAST AB The continuity of duplex DNA is generally considered a prerequisite for chromosome continuity. However, as previously shown in yeast as well as human cells, the introduction of a double-strand break (DSB) does not generate a chromosome break (CRB) in yeast or human cells. The transition from DSB to CRB was found to be under limited control by the tethering function of the RAD50/MRE11/XRS2 (MRX) complex. Using a system for differential fluorescent marking of both sides of an endonuclease-induced DSB in single cells, we found that nearly all DSBs are converted to CRBs in cells lacking both exonuclease 1 (EXO1) activity and MRX complex. Thus, it appears that some feature of exonuclease processing or resection at a DSB is critical for maintaining broken chromosome ends in close proximity. In addition, we discovered a thermal sensitive (cold) component to CRB formation in an MRX mutant that has implications for chromosome end mobility and/or end-processing. Published by Elsevier B.V. C1 [Nakai, Wataru; Westmoreland, Jim; Resnick, Michael A.] NIEHS, NIH, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Yeh, Elaine; Bloom, Kerry; Resnick, Michael A.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27515 USA. RP Resnick, MA (reprint author), NIEHS, NIH, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov OI Bloom, Kerry/0000-0002-3457-004X FU NIEHS [Z01-ES021016] FX We greatly appreciate the statistical analysis provided by Dr. David Umbach as well imaging assistance provided by Dr. Masaki Akita. We thank the Resnick lab for critical comments and suggestions, especially Drs. Shay Covo, Kin Chan, Steven Roberts and Dmitry Gordenin. This work was supported by intramural research funds from NIEHS to MAR, project Z01-ES021016. NR 41 TC 12 Z9 12 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JAN 2 PY 2011 VL 10 IS 1 BP 102 EP 110 DI 10.1016/j.dnarep.2010.10.004 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 710WJ UT WOS:000286547400013 PM 21115410 ER PT S AU Booth, R Wallace, GL Happe, F AF Booth, Rhonda Wallace, Gregory L. Happe, Francesca BE Braddick, O Atkinson, J Innocenti, GM TI Connectivity and the corpus callosum in autism spectrum conditions: Insights from comparison of autism and callosal agenesis SO GENE EXPRESSION TO NEUROBIOLOGY AND BEHAVIOR: HUMAN BRAIN DEVELOPMENT AND DEVELOPMENTAL DISORDERS SE Progress in Brain Research LA English DT Review; Book Chapter DE autism spectrum disorder; Asperger's syndrome; corpus callosum; agenesis of the corpus callosum; callosal agenesis; connectivity; theory of mind; central coherence; social cognition ID HIGH-FUNCTIONING AUTISM; WHITE-MATTER; ASPERGER-SYNDROME; BRAIN-DEVELOPMENT; SOCIAL COGNITION; EARLY-CHILDHOOD; WEAK COHERENCE; DISORDERS; CHILDREN; POPULATION AB Neural models of autism spectrum disorders (ASDs) have moved, in recent years, from a lesion model to a focus on abnormal connectivity. In this chapter, we review this work and summarize findings from our recent research comparing autism and agenesis of the corpus callosum (AgCC). We discuss our findings in the context of the "fractionable triad" account and highlight three main points. First, the social aspects of autism can be found in isolation, not accompanied by the nonsocial features of this disorder, supporting a view of autism as a "compound," rather than "monolithic," condition. Second, many young people with callosal agenesis show theory of mind-and emotion-processing deficits akin to those seen in autism. Diagnostic overshadowing may mean these people do not receive interventions that have proven beneficial in ASD. Last, study of AgCC shows that it is possible, in some cases, to develop good social cognitive skills in the absence of the corpus callosum, presenting a challenge to future connectivity models of autism. C1 [Booth, Rhonda; Happe, Francesca] Kings Coll London, MRC Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. [Wallace, Gregory L.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Happe, F (reprint author), Kings Coll London, MRC Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England. EM francesca.happe@kcl.ac.uk OI Happe, Francesca/0000-0001-9226-4000; Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS NR 83 TC 23 Z9 23 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0079-6123 BN 978-0-44-453885-7 J9 PROG BRAIN RES JI Prog. Brain Res. PY 2011 VL 189 BP 303 EP 317 DI 10.1016/B978-0-444-53884-0.00031-2 PG 15 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA BCR63 UT WOS:000311107200018 PM 21489396 ER PT J AU Puri, PL Sartorelli, V AF Puri, Pier Lorenzo Sartorelli, Vittorio BE Tollefsbol, T TI Epigenetic Basis of Skeletal Muscle Regeneration SO HANDBOOK OF EPIGENETICS: THE NEW MOLECULAR AND MEDICAL GENETICS LA English DT Article; Book Chapter ID MYOGENIC SATELLITE CELLS; GENE-EXPRESSION; STEM-CELLS; DEACETYLASE INHIBITORS; REGULATE EXPRESSION; PROGENITOR CELLS; NETWORK MOTIFS; DIFFERENTIATION; MICRORNA; MYOD C1 [Puri, Pier Lorenzo] Fdn S Lucia, Dulbecco Telethon Inst, Rome, Italy. [Puri, Pier Lorenzo] Burnham Inst Med Res, San Diego, CA USA. [Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Puri, PL (reprint author), Fdn S Lucia, Dulbecco Telethon Inst, Rome, Italy. NR 77 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-375710-4 PY 2011 BP 329 EP 339 DI 10.1016/B978-0-12-375709-8.00020-4 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BCR50 UT WOS:000311100300021 ER PT S AU Jacobson, KA Linden, J AF Jacobson, Kenneth A. Linden, Joel BE Jacobson, KA Linden, J TI PHARMACOLOGY OF PURINE AND PYRIMIDINE RECEPTORS Preface SO PHARMACOLOGY OF PURINE AND PYRIMIDINE RECEPTORS SE Advances in Pharmacology LA English DT Editorial Material; Book Chapter C1 [Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Linden, Joel] La Jolla Inst Allergy & Immunol, Div Inflammat Biol, La Jolla, CA USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 3 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 1054-3589 BN 978-0-12-385533-6 J9 ADV PHARMACOL JI Adv. Pharmacol. PY 2011 VL 61 BP XV EP XVI PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BCS05 UT WOS:000311235800001 PM 21586353 ER PT S AU Jacobson, KA Gao, ZG Goblyos, A IJzerman, AP AF Jacobson, Kenneth A. Gao, Zhan-Guo Goblyos, Aniko IJzerman, Adriaan P. BE Jacobson, KA Linden, J TI Allosteric Modulation of Purine and Pyrimidine Receptors SO PHARMACOLOGY OF PURINE AND PYRIMIDINE RECEPTORS SE Advances in Pharmacology LA English DT Article; Book Chapter ID ADENOSINE A(1) RECEPTOR; PROTEIN-COUPLED RECEPTORS; ENHANCER PD 81,723; P2X(4) RECEPTOR; BIOLOGICAL EVALUATION; AGONIST BINDING; P2Y RECEPTORS; ANTAGONIST BINDING; ION-CHANNEL; ADENOSINE-A1-RECEPTOR BINDING AB Among the purine and pyrimidine receptors, the discovery of small molecular allosteric modulators has been most highly advanced for the A(1) and A(3) adenosine receptors (ARs). These AR modulators have allosteric effects that are structurally separated from the orthosteric effects in SAR studies. The benzoylthiophene derivatives tend to act as allosteric agonists as well as selective positive allosteric modulators (PAMs) of the A(1) AR. A 2-amino-3-aroylthiophene derivative T-62 has been under development as a PAM of the A(1) AR for the treatment of chronic pain. Several structurally distinct classes of allosteric modulators of the human A(3) AR have been reported: 3-(2-pyridinyl)isoquinolines, 2,4-disubstituted quinolines, 1H-imidazo-[4,5-c]quinolin-4-amines, endocannabinoid 2-arachidonylglycerol, and the food dye Brilliant Black BN. Site-directed mutagenesis of A(1) and A(3) ARs has identified residues associated with the allosteric effect, distinct from those that affect orthosteric binding. A few small molecular allosteric modulators have been reported for several of the P2X ligand-gated ion channels and the G protein-coupled P2Y receptor nucleotides. Metal ion modulation of the P2X receptors has been extensively explored. The allosteric approach to modulation of purine and pyrimidine receptors looks promising for development of drugs that are event and site specific in action. C1 [Jacobson, Kenneth A.; Gao, Zhan-Guo] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Goblyos, Aniko; IJzerman, Adriaan P.] Leiden Univ, Div Med Chem, Leiden Amsterdam Ctr Drug Res, Leiden, Netherlands. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; IJzerman, Ad/0000-0002-1182-2259 FU Intramural NIH HHS [ZIA DK031117-22] NR 123 TC 17 Z9 17 U1 1 U2 1 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 1054-3589 BN 978-0-12-385533-6 J9 ADV PHARMACOL JI Adv. Pharmacol. PY 2011 VL 61 BP 187 EP 220 DI 10.1016/B978-0-12-385526-8.00007-2 PG 34 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BCS05 UT WOS:000311235800008 PM 21586360 ER PT S AU Balenga, NAB Henstridge, CM Kargl, J Waldhoer, M AF Balenga, Nariman A. B. Henstridge, Christopher M. Kargl, Julia Waldhoer, Maria BE Neubig, RR TI Pharmacology, Signaling and Physiological Relevance of the G Protein-coupled Receptor 55 SO PHARMACOLOGY OF G PROTEIN COUPLED RECEPTORS SE Advances in Pharmacology LA English DT Article; Book Chapter ID L-ALPHA-LYSOPHOSPHATIDYLINOSITOL; PERIPHERAL CANNABINOID RECEPTOR; CANCER-CELL PROLIFERATION; ENDOGENOUS CANNABINOIDS; MESENTERIC VASODILATION; INTRACELLULAR CALCIUM; SYNAPTIC-TRANSMISSION; ENDOTHELIAL-CELLS; PANCREATIC-ISLETS; SITE DISTINCT AB According to The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), similar to 70 million European adults have consumed cannabis on at least one occasion. Cannabis consumption leads to a variety of psychoactive effects due to the presence of the constituent Delta(9)-tetrahydrocannabinol (Delta(9)-THC). Delta(9)-THC interacts with the endocannabinoid system (ECS), which consists of the seven transmembrane spanning (7TM)/G protein-coupled receptors (GPCRs) CB1 and CB2, their respective ligands (endocannabinoids), and enzymes involved in their biosynthesis and degradation. This system plays a critical role in many physiological processes such as learning and memory, appetite control, pain sensation, motor coordination, lipogenesis, modulation of immune response, and the regulation of bone mass. Therefore, a huge effort has been spent trying to fully elucidate the composition and function of the ECS. The G protein-coupled receptor 55 (GPR55) was recently proposed as a novel component of this system; however, its classification as a cannabinoid receptor has been significantly hampered by its complex pharmacology, signaling, and cellular function. GPR55 is phylogenetically distinct from the traditional cannabinoid receptors, but in some experimental paradigms, it is activated by endocannabinoids, phytocannabinoids, and synthetic cannabinoid ligands. However, the most potent compound appears to be a lysophospholipid known as lysophosphatidylinositol (LPI). Here, we provide a comprehensive evaluation of the current pharmacology and signaling of GPR55 and review the proposed role of this receptor in a number of physiological and pathophysiological processes. C1 [Balenga, Nariman A. B.; Kargl, Julia; Waldhoer, Maria] Med Univ Graz, Inst Expt & Clin Pharmacol, Graz, Austria. [Henstridge, Christopher M.] Hungarian Acad Sci, Inst Expt Med, Budapest, Hungary. RP Balenga, NAB (reprint author), NIAID, Mol & Signal Transduct Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Henstridge, Christopher/0000-0002-0393-180X; Balenga, Nariman/0000-0002-2741-9595 NR 105 TC 14 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1054-3589 BN 978-0-12-385953-2 J9 ADV PHARMACOL JI Adv. Pharmacol. PY 2011 VL 62 BP 251 EP 277 DI 10.1016/B978-0-12-385952-5.00004-X PG 27 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BCS01 UT WOS:000311230400009 PM 21907912 ER PT J AU Reitzel, AM Pang, K Ryan, JF Mullikin, JC Martindale, MQ Baxevanis, AD Tarrant, AM AF Reitzel, Adam M. Pang, Kevin Ryan, Joseph F. Mullikin, James C. Martindale, Mark Q. Baxevanis, Andreas D. Tarrant, Ann M. TI Nuclear receptors from the ctenophore Mnemiopsis leidyi lack a zinc-finger DNA-binding domain: lineage-specific loss or ancestral condition in the emergence of the nuclear receptor superfamily? SO EVODEVO LA English DT Article ID DEVELOPMENTAL EXPRESSION; ESTROGEN-RECEPTOR; ACOEL FLATWORMS; X-RECEPTOR; EVOLUTION; GENE; DAX-1; DIVERSIFICATION; TRICHOPLAX; COMPLEMENT AB Background: Nuclear receptors (NRs) are an ancient superfamily of metazoan transcription factors that play critical roles in regulation of reproduction, development, and energetic homeostasis. Although the evolutionary relationships among NRs are well-described in two prominent clades of animals (deuterostomes and protostomes), comparatively little information has been reported on the diversity of NRs in early diverging metazoans. Here, we identified NRs from the phylum Ctenophora and used a phylogenomic approach to explore the emergence of the NR superfamily in the animal kingdom. In addition, to gain insight into conserved or novel functions, we examined NR expression during ctenophore development. Results: We report the first described NRs from the phylum Ctenophora: two from Mnemiopsis leidyi and one from Pleurobrachia pileus. All ctenophore NRs contained a ligand-binding domain and grouped with NRs from the subfamily NR2A (HNF4). Surprisingly, all the ctenophore NRs lacked the highly conserved DNA-binding domain (DBD). NRs from Mnemiopsis were expressed in different regions of developing ctenophores. One was broadly expressed in the endoderm during gastrulation. The second was initially expressed in the ectoderm during gastrulation, in regions corresponding to the future tentacles; subsequent expression was restricted to the apical organ. Phylogenetic analyses of NRs from ctenophores, sponges, cnidarians, and a placozoan support the hypothesis that expansion of the superfamily occurred in a step-wise fashion, with initial radiations in NR family 2, followed by representatives of NR families 3, 6, and 1/4 originating prior to the appearance of the bilaterian ancestor. Conclusions: Our study provides the first description of NRs from ctenophores, including the full complement from Mnemiopsis. Ctenophores have the least diverse NR complement of any animal phylum with representatives that cluster with only one subfamily (NR2A). Ctenophores and sponges have a similarly restricted NR complement supporting the hypothesis that the original NR was HNF4-like and that these lineages are the first two branches from the animal tree. The absence of a zinc-finger DNA-binding domain in the two ctenophore species suggests two hypotheses: this domain may have been secondarily lost within the ctenophore lineage or, if ctenophores are the first branch off the animal tree, the original NR may have lacked the canonical DBD. Phylogenomic analyses and categorization of NRs from all four early diverging animal phyla compared with the complement from bilaterians suggest the rate of NR diversification prior to the cnidarian-bilaterian split was relatively modest, with independent radiations of several NR subfamilies within the cnidarian lineage. C1 [Reitzel, Adam M.; Tarrant, Ann M.] Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA. [Pang, Kevin; Martindale, Mark Q.] Univ Hawaii, Kewalo Marine Lab, Pacific Biosci Res Ctr, Honolulu, HI 96822 USA. [Ryan, Joseph F.; Mullikin, James C.; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Tarrant, AM (reprint author), Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA. EM atarrant@whoi.edu OI Tarrant, Ann/0000-0002-1909-7899 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [F32HD062178]; NSF; NASA; Tropical Research Initiative of the Woods Hole Oceanographic Institution; National Human Genome Research Institute (NHGRI), National Institutes of Health FX This research was supported by Award Number F32HD062178 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) to AMR, an NSF Graduate Research Fellowship to KP, grants from the NSF and NASA to MQM, the Tropical Research Initiative of the Woods Hole Oceanographic Institution, and the Intramural Research Program of the National Human Genome Research Institute (NHGRI), National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health. NR 52 TC 14 Z9 14 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-9139 J9 EVODEVO JI EvoDevo PY 2011 VL 2 AR 3 DI 10.1186/2041-9139-2-3 PG 12 WC Evolutionary Biology; Developmental Biology SC Evolutionary Biology; Developmental Biology GA 032DY UT WOS:000310693900003 PM 21291545 ER EF