FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Brown, D Sloan, J Manoli, I Venditti, CP AF Brown, Donna Sloan, Jennifer Manoli, Irini Venditti, Charles P. TI Three pregnancies complicated by methylmalonic acidemia (MMA) and cesarean deliveries SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 35th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 31-APR 03, 2012 CL Charlotte, NC SP Soc Inherited Metabol Disorders (SIMD), Abbott Nutr (Abbott Metabol), Pfizer Inc, Shire, Actel Pharmaceut (ACTELION), Cytonet LLC, GeneDx, Genzyme, Hyper Therapeut, Inc, Mead Johnson Nutr, Orphan Europe Recordati Grp, Rare Dis Therapeut, Inc, Ucyclyd Pharma, Vitaflo, Appl Nutr Corp, ARUP Labs, BioMarin Pharmaceut, Inc, Cambrooke Foods, Inc, Emory Genet Lab, Hitachi High Technol Amer, Inc, Prevent Genet, Transgenom, Inc, Canadian PKU & Allied Disorders Inc, Natl PKU Alliance, Natl Urea Cycle Disorders Fdn, Propion Acidemia Fdn, United Mitochondrial Dis Fdn C1 [Brown, Donna; Sloan, Jennifer; Manoli, Irini; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Brown, Donna] Washington Hosp Ctr, Dept Obstet & Gynecol, Washington, DC 20010 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 MAR PY 2012 VL 105 IS 3 BP 306 EP 306 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 913VV UT WOS:000301906400047 ER PT J AU Camp, KM Lloyd-Puryear, MA Coates, PM Groft, SC AF Camp, K. M. Lloyd-Puryear, M. A. Coates, P. M. Groft, S. C. TI Nutrition and dietary supplement interventions for inborn errors of metabolism: Building a framework for evidence-based research results of a stakeholder workshop SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 35th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 31-APR 03, 2012 CL Charlotte, NC SP Soc Inherited Metabol Disorders (SIMD), Abbott Nutr (Abbott Metabol), Pfizer Inc, Shire, Actel Pharmaceut (ACTELION), Cytonet LLC, GeneDx, Genzyme, Hyper Therapeut, Inc, Mead Johnson Nutr, Orphan Europe Recordati Grp, Rare Dis Therapeut, Inc, Ucyclyd Pharma, Vitaflo, Appl Nutr Corp, ARUP Labs, BioMarin Pharmaceut, Inc, Cambrooke Foods, Inc, Emory Genet Lab, Hitachi High Technol Amer, Inc, Prevent Genet, Transgenom, Inc, Canadian PKU & Allied Disorders Inc, Natl PKU Alliance, Natl Urea Cycle Disorders Fdn, Propion Acidemia Fdn, United Mitochondrial Dis Fdn C1 [Camp, K. M.; Coates, P. M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Lloyd-Puryear, M. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Groft, S. C.] NIH, Off Rare Dis Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 MAR PY 2012 VL 105 IS 3 BP 308 EP 308 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 913VV UT WOS:000301906400050 ER PT J AU Estrada-Veras, J Manoli, I Sloan, J Venditti, CP AF Estrada-Veras, Juvianee Manoli, Irini Sloan, Jennifer Venditti, C. P. TI Central line sepsis caused by mycobacterium fortuitum in methylmalonic acidemia (MMA) SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 35th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 31-APR 03, 2012 CL Charlotte, NC SP Soc Inherited Metabol Disorders (SIMD), Abbott Nutr (Abbott Metabol), Pfizer Inc, Shire, Actel Pharmaceut (ACTELION), Cytonet LLC, GeneDx, Genzyme, Hyper Therapeut, Inc, Mead Johnson Nutr, Orphan Europe Recordati Grp, Rare Dis Therapeut, Inc, Ucyclyd Pharma, Vitaflo, Appl Nutr Corp, ARUP Labs, BioMarin Pharmaceut, Inc, Cambrooke Foods, Inc, Emory Genet Lab, Hitachi High Technol Amer, Inc, Prevent Genet, Transgenom, Inc, Canadian PKU & Allied Disorders Inc, Natl PKU Alliance, Natl Urea Cycle Disorders Fdn, Propion Acidemia Fdn, United Mitochondrial Dis Fdn C1 [Manoli, Irini; Sloan, Jennifer; Venditti, C. P.] NHGRI, Genet & Mol Biol Branch, 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 MAR PY 2012 VL 105 IS 3 BP 316 EP 317 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 913VV UT WOS:000301906400065 ER PT J AU Estrada-Veras, J Gahl, W Gochuico, B AF Estrada-Veras, Juvianee Gahl, William Gochuico, Bernadette TI Erdheim Chester Disease (ECD): Presentation and natural history SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 35th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 31-APR 03, 2012 CL Charlotte, NC SP Soc Inherited Metabol Disorders (SIMD), Abbott Nutr (Abbott Metabol), Pfizer Inc, Shire, Actel Pharmaceut (ACTELION), Cytonet LLC, GeneDx, Genzyme, Hyper Therapeut, Inc, Mead Johnson Nutr, Orphan Europe Recordati Grp, Rare Dis Therapeut, Inc, Ucyclyd Pharma, Vitaflo, Appl Nutr Corp, ARUP Labs, BioMarin Pharmaceut, Inc, Cambrooke Foods, Inc, Emory Genet Lab, Hitachi High Technol Amer, Inc, Prevent Genet, Transgenom, Inc, Canadian PKU & Allied Disorders Inc, Natl PKU Alliance, Natl Urea Cycle Disorders Fdn, Propion Acidemia Fdn, United Mitochondrial Dis Fdn C1 [Estrada-Veras, Juvianee; Gahl, William; Gochuico, Bernadette] NHGRI, Med Genet Branch, Off Clin Director, NIH, Bethesda, MD USA. NR 0 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2012 VL 105 IS 3 BP 317 EP 317 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 913VV UT WOS:000301906400066 ER PT J AU McGuire, PJ Gramignoli, R Tarasenko, T Wang, T Levy, E Diaz, GA Strom, SC AF McGuire, Peter J. Gramignoli, Roberto Tarasenko, Tatiana Wang, Tony Levy, Ezra Diaz, George A. Strom, Stephen C. TI Cytokine depression of urea cycle function: A focus on ornithine transcarbamylase SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 35th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 31-APR 03, 2012 CL Charlotte, NC SP Soc Inherited Metabol Disorders (SIMD), Abbott Nutr (Abbott Metabol), Pfizer Inc, Shire, Actel Pharmaceut (ACTELION), Cytonet LLC, GeneDx, Genzyme, Hyper Therapeut, Inc, Mead Johnson Nutr, Orphan Europe Recordati Grp, Rare Dis Therapeut, Inc, Ucyclyd Pharma, Vitaflo, Appl Nutr Corp, ARUP Labs, BioMarin Pharmaceut, Inc, Cambrooke Foods, Inc, Emory Genet Lab, Hitachi High Technol Amer, Inc, Prevent Genet, Transgenom, Inc, Canadian PKU & Allied Disorders Inc, Natl PKU Alliance, Natl Urea Cycle Disorders Fdn, Propion Acidemia Fdn, United Mitochondrial Dis Fdn C1 [McGuire, Peter J.; Tarasenko, Tatiana] NHGRI, NIH, Bethesda, MD 20892 USA. [Gramignoli, Roberto; Strom, Stephen C.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. [Wang, Tony; Levy, Ezra; Diaz, George A.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. NR 0 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2012 VL 105 IS 3 BP 338 EP 339 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 913VV UT WOS:000301906400107 ER PT J AU Pearl, PL Theodore, WH McCarter, R McGavin, C Sweetman, L Gibson, KM AF Pearl, P. L. Theodore, W. H. McCarter, R. McGavin, C. Sweetman, L. Gibson, K. M. TI Taurine intervention in succinic semialdehyde dehydrogenase (SSADH) deficiency: An open label trial SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 35th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD) CY MAR 31-APR 03, 2012 CL Charlotte, NC SP Soc Inherited Metabol Disorders (SIMD), Abbott Nutr (Abbott Metabol), Pfizer Inc, Shire, Actel Pharmaceut (ACTELION), Cytonet LLC, GeneDx, Genzyme, Hyper Therapeut, Inc, Mead Johnson Nutr, Orphan Europe Recordati Grp, Rare Dis Therapeut, Inc, Ucyclyd Pharma, Vitaflo, Appl Nutr Corp, ARUP Labs, BioMarin Pharmaceut, Inc, Cambrooke Foods, Inc, Emory Genet Lab, Hitachi High Technol Amer, Inc, Prevent Genet, Transgenom, Inc, Canadian PKU & Allied Disorders Inc, Natl PKU Alliance, Natl Urea Cycle Disorders Fdn, Propion Acidemia Fdn, United Mitochondrial Dis Fdn C1 [Pearl, P. L.; McCarter, R.; McGavin, C.] George Washington Univ, Childrens Natl Med Ctr, Sch Med, Washington, DC USA. [Theodore, W. H.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Sweetman, L.] Baylor Univ, Med Ctr, Inst Metab Dis, Dallas, TX USA. [Gibson, K. M.] Michigan Technol Univ, Houghton, MI 49931 USA. NR 0 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2012 VL 105 IS 3 BP 346 EP 346 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 913VV UT WOS:000301906400118 ER PT J AU Markello, TC Han, T Carlson-Donohoe, H Ahaghotu, C Harper, U Jones, M Chandrasekharappa, S Anikster, Y Adams, DR Gahl, WA Boerkoel, CF AF Markello, Thomas C. Han, Ted Carlson-Donohoe, Hannah Ahaghotu, Chidi Harper, Ursula Jones, MaryPat Chandrasekharappa, Settara Anikster, Yair Adams, David R. Gahl, William A. Boerkoel, Cornelius F. CA NISC Comparative Sequencing Progra TI Recombination mapping using Boolean logic and high-density SNP genotyping for exome sequence filtering SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Linkage; Recombination; Mapping; Exome sequencing; Single nucleotide variants ID LINKAGE ANALYSIS; PEDIGREE ANALYSIS; HUMAN GENOME; IDENTIFICATION; GENE; MAP AB Whole genome sequence data for small pedigrees has been shown to provide sufficient information to resolve detailed haplotypes in small pedigrees. Using such information, recombinations can be mapped onto chromosomes, compared with the segregation of a disease of interest and used to filter genome sequence variants. We now show that relatively inexpensive SNP array data from small pedigrees can be used in a similar manner to provide a means of identifying regions of interest in exome sequencing projects. We demonstrate that in those situations where one can assume complete penetrance and parental DNA is available, SNP recombination mapping using Boolean logic identifies chromosomal regions identical to those detected by multipoint linkage using microsatellites but with much less computation. We further show that this approach is successful because the probability of a double crossover between informative SNP loci is negligible. Our observations provide a rationale for using SNP arrays and recombination mapping as a rapid and cost-effective means of incorporating chromosome segregation information into exome sequencing projects intended for disease-gene identification. Published by Elsevier Inc. C1 [Markello, Thomas C.; Han, Ted; Ahaghotu, Chidi; Anikster, Yair; Adams, David R.; Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Markello, Thomas C.; Adams, David R.; Gahl, William A.; Boerkoel, Cornelius F.] NIH, NIH Undiag Dis Program, Off Director, Bethesda, MD 20892 USA. [Carlson-Donohoe, Hannah] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Harper, Ursula; Jones, MaryPat; Chandrasekharappa, Settara] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Anikster, Yair] Tel Aviv Univ, Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, IL-69978 Tel Aviv, Israel. [Anikster, Yair] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [NISC Comparative Sequencing Progra] Natl Intramural Sequencing Ctr, Rockville, MD 20852 USA. RP Markello, TC (reprint author), NHGRI, NIH, Bldg 10-10C107,10 Ctr Dr, Bethesda, MD 20892 USA. EM markellot@mail.nih.gov FU NIH(Office of Rare Disease Research, Office of the Director, NIH; NHGRI; and NIH Clinical Center); NHGRI FX The authors appreciate the advice and assistance of the Genomics Core of the NHGRI. This work was supported by the NIH Undiagnosed Diseases Program (Office of Rare Disease Research, Office of the Director, NIH; NHGRI; and NIH Clinical Center) and by the Intramural Research Program of the NHGRI. NR 26 TC 7 Z9 7 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 MAR PY 2012 VL 105 IS 3 BP 382 EP 389 DI 10.1016/j.ymgme.2011.12.014 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 913VV UT WOS:000301906400160 PM 22264778 ER PT J AU Rao, M AF Rao, Mahendra TI The NIH and the regenerative medicine field SO REGENERATIVE MEDICINE LA English DT Editorial Material DE adult stem cell; embryonic stem cell; ESC; induced pluripotent stem cell; mesenchymal stem cell; MSC; personalized therapy; regenerative medicine; regulatory standards; stem cell; translational ID CELL-BASED THERAPY C1 NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Rao, M (reprint author), NIH, Ctr Regenerat Med, 50 Ctr Dr,Room 1140, Bethesda, MD 20892 USA. EM mahendra.rao@nih.gov NR 5 TC 2 Z9 2 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0751 J9 REGEN MED JI Regen. Med. PD MAR PY 2012 VL 7 IS 2 BP 129 EP 131 DI 10.2217/RME.12.8 PG 3 WC Cell & Tissue Engineering; Engineering, Biomedical SC Cell Biology; Engineering GA 906EH UT WOS:000301327200001 PM 22397601 ER PT J AU Sizemore, CF Fauci, AS AF Sizemore, Christine F. Fauci, Anthony S. TI Transforming Biomedical Research to Develop Effective TB Vaccines: The Next Ten Years SO TUBERCULOSIS LA English DT Editorial Material C1 [Sizemore, Christine F.] NIAID, TB Leprosy & Other Mycobacterial Dis Sect, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Sizemore, CF (reprint author), NIAID, TB Leprosy & Other Mycobacterial Dis Sect, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD MAR PY 2012 VL 92 SU 1 BP S2 EP S3 PG 2 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA 914LM UT WOS:000301951500002 PM 22441154 ER PT J AU Das, S Singh, S Chigurupati, S Mughal, MR Kumar, A Patra, CR Oommen, S Vlahakis, NE Mukhopadhyay, D Self, WT Mattson, MP Seal, S AF Das, S. Singh, S. Chigurupati, S. Mughal, M. R. Kumar, A. Patra, C. R. Oommen, S. Vlahakis, N. E. Mukhopadhyay, D. Self, W. T. Mattson, M. P. Seal, S. TI CERIUM OXIDE NANOPARTICLES CAN INDUCE PRO-ANGIOGENESIS AND FACILITATE WOUND HEALING SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Das, S.; Kumar, A.; Seal, S.] Adv Mat Proc Anal Ctr, Orlando, FL USA. [Chigurupati, S.; Mughal, M. R.; Mattson, M. P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. [Singh, S.; Self, W. T.] Burnett Sch Biomed Sci, Dept Mol Biol & Microbiol, Orlando, FL USA. [Patra, C. R.; Mukhopadhyay, D.] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN USA. [Oommen, S.] Mayo Clin, Div Pulm & Crit Care, Rochester, MN USA. [Vlahakis, N. E.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RI Self, William/A-6704-2008; Mattson, Mark/F-6038-2012; Kumar, Amit/E-9483-2011 NR 0 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2012 VL 20 IS 2 BP A20 EP A20 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 901DY UT WOS:000300943100034 ER PT J AU Anixt, JS Copeland-Linder, N Haynie, D Cheng, TL AF Anixt, Julia S. Copeland-Linder, Nikeea Haynie, Denise Cheng, Tina L. TI Burden of Unmet Mental Health Needs in Assault-Injured Youths Presenting to the Emergency Department SO ACADEMIC PEDIATRICS LA English DT Article DE aggression; assault; emergency department; gender; mental health ID INTERPERSONAL VIOLENCE; PSYCHOSOCIAL NEEDS; ADOLESCENTS; EXPOSURE; INTERVENTION; BEHAVIORS; CHILDREN; TRAUMA; RISK AB OBJECTIVES: To determine if there is a gap between behavioral symptoms and previously recognized mental health conditions in youth victims of peer assault injuries and to describe gender differences in psychological symptoms. METHODS: A cross-sectional comparison of rates of previously diagnosed mental health conditions and clinical range behavioral symptoms as measured by the Child Behavior Checklist (CBCL) in 168 youths (range, 10-15 years old) presenting to the emergency department (ED) after an interpersonal assault injury. The Fisher exact test was used for comparisons. RESULTS: Mental health symptoms were common among assault-injured youths. More than half of the youths demonstrating clinical range symptoms on the attention problems or anxious/depressed scales of the CBCL had no prior diagnosis of these conditions. Girls were more likely than boys to exhibit clinical range aggressive behavior symptoms (odds ratio [OR], 3.61; 95% confidence interval [CI], 1.64-7.97). Aggressive behavior was associated with clinical range scores on the other problem scales of the CBCL. CONCLUSIONS: After an ED visit for an assault-related injury, less than half of 10 to 15 year olds with significant symptoms of common mental conditions reported having a previously diagnosed disorder, reflecting a burden of unmet psychological needs. An ED visit for an assault injury provides an opportunity to screen for emotional/behavioral symptoms and to refer to appropriate follow-up mental health care. C1 [Anixt, Julia S.] Univ Cincinnati, Cincinnati Childrens Hosp, Med Ctr, Div Dev & Behav Pediat, Cincinnati, OH 45229 USA. [Copeland-Linder, Nikeea; Cheng, Tina L.] Johns Hopkins Univ, Sch Med, Div Gen Pediat & Adolescent Med, Baltimore, MD USA. [Haynie, Denise] Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. RP Anixt, JS (reprint author), Univ Cincinnati, Cincinnati Childrens Hosp, Med Ctr, Div Dev & Behav Pediat, 3333 Bumet Ave,MLC 4002, Cincinnati, OH 45229 USA. EM julia.anixt@cchmc.org OI Haynie, Denise/0000-0002-8270-6079 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Maternal and Child Health Bureau, Health Resources and Services Administration, Department of Health and Human Services [R40MC00174]; DC-Baltimore Research Center on Child Health Disparities from the National Center on Minority Health and Health Disparities [P20 MD00165]; Robert Wood Johnson Clinical Scholars Program FX This project was supported by intramural and extramural research programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, (D.L.H. and T.L.C.), the Maternal and Child Health Bureau (Title V Social Security Act), Health Resources and Services Administration, Department of Health and Human Services, R40MC00174. This publication was supported by the DC-Baltimore Research Center on Child Health Disparities Grant P20 MD00165 from the National Center on Minority Health and Health Disparities. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the funding agency. Support for this analysis was provided by the Robert Wood Johnson Clinical Scholars Program. The authors would like to thank Alan Simon and David Schonfeld for their help with this project. NR 19 TC 4 Z9 4 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1876-2859 J9 ACAD PEDIATR JI Acad. Pediatr. PD MAR-APR PY 2012 VL 12 IS 2 BP 125 EP 130 PG 6 WC Pediatrics SC Pediatrics GA 910HE UT WOS:000301627000009 PM 22112395 ER PT J AU Cole, NB Donaldson, JG AF Cole, Nelson B. Donaldson, Julie G. TI Releasable SNAP-tag Probes for Studying Endocytosis and Recycling SO ACS CHEMICAL BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; MEDIATED ENDOCYTOSIS; IN-VIVO; TRAFFICKING; ARRESTIN; RESENSITIZATION; ENDOSOMES; LYSOSOMES; GPCRS; FRET AB Site-specific labeling of cellular proteins with chemicals probes is a powerful tool for live cell imaging of biological processes. One popular system, known as the SNAP tag is based on an engineered variant of the 20-kDa DNA-repair protein O(6-)alkylguanine-DNA-alkyltransferase (AGT) that covalent reacts with O-6 benzylguanine (BG) and can be derivated with a number of reporter groups For studying the endocytosis and recycling of cell surface proteins, the covalent nature of BG binding to the SNAP tag is problematic, since removing excess noninternalized probe from the cell surface is not feasible. Here we describe a modification of the SNAP tag technology that permits the rapid release of fluorescently labeled probes from the cell surface without affective of fluorescently labeled probes from the cell surface without affecting the population of labelled molecules sequested within endosomes. This simple yet effective approach allows quantitative measurements of endocytosis and recycling in both imaging and biochemical assay and is especially useful when studying endosomal dynamics in live cells. C1 [Cole, Nelson B.; Donaldson, Julie G.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov FU National Heart, Lung, and Blood Institute at NIH FX We thank G. Griffiths and A. Dulcey at the Imaging Probe Development Center, NHLBI/NIH for help during the initial phases of this work and thank C. Combs of the Light Microscopy Core Facility/NHLBI for help with image quantitation. We acknowledge the Biochemistry Core Facility (NHLBI) and especially D.-Y. Lee and R Levine for help with compound synthesis and mass spectrometry analysis. We also thank C. Waterman and L. Greene (both NHLBI) and G. Patterson (NIBIB) for comments on the manuscript. The Intramural Research Program in the National Heart, Lung, and Blood Institute at the NIH supported this work. NR 24 TC 14 Z9 15 U1 1 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD MAR PY 2012 VL 7 IS 3 BP 464 EP 469 DI 10.1021/cb2004252 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 908TQ UT WOS:000301515800003 PM 22216966 ER PT J AU Brown, D Pipe, ME Lewis, C Lamb, ME Orbach, Y AF Brown, Deirdre Pipe, Margaret-Ellen Lewis, Charlie Lamb, Michael E. Orbach, Yael TI How Do Body Diagrams Affect the Accuracy and Consistency of Children's Reports of Bodily Touch Across Repeated Interviews? SO APPLIED COGNITIVE PSYCHOLOGY LA English DT Article ID SEXUAL-ABUSE; QUESTIONS; MEMORIES; REMEMBER; EVENTS AB We examined the amount, accuracy, and consistency of information reported by 58 5- to 7-year-old children about a staged event that included physical contact/touching. Both 1 and 7months following the event, children were asked both open and yes/no questions about touch [i] when provided with human body diagrams (HBDs), [ii] following instruction and practice using the HBDs, or [iii] without HBDs. Children interviewed with HBDs reported more information at 7months, but a high proportion of inaccurate touches. Children seldom repeated touch-related information across the two interviews and did not incorporate errors made in the 1-month interview into their open-ended accounts 6months later. Asking children to talk about innocuous touch may lead them to report unreliable information, especially when HBDs are used as aids and repeated interviews are conducted across delays that resemble those typical of forensic contexts. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Lamb, Michael E.] Univ Cambridge, Cambridge CB2 3RQ, England. [Brown, Deirdre] Univ Victoria, Wellington, New Zealand. [Pipe, Margaret-Ellen] CUNY Brooklyn Coll, New York, NY USA. [Lewis, Charlie] Univ Lancaster, Lancaster, England. [Orbach, Yael] NICHHD, Bethesda, MD 20892 USA. RP Lamb, ME (reprint author), Univ Cambridge, Free Sch Lane, Cambridge CB2 3RQ, England. EM mel37@cam.ac.uk NR 29 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0888-4080 J9 APPL COGNITIVE PSYCH JI Appl. Cogn. Psychol. PD MAR-APR PY 2012 VL 26 IS 2 BP 174 EP 181 DI 10.1002/acp.1828 PG 8 WC Psychology, Experimental SC Psychology GA 901MM UT WOS:000300971000002 ER PT J AU Willis, JR Jefferys, JL Vitale, S Ramulu, PY AF Willis, Jeffrey R. Jefferys, Joan L. Vitale, Susan Ramulu, Pradeep Y. TI Visual Impairment, Uncorrected Refractive Error, and Accelerometer-Defined Physical Activity in the United States SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; OLDER-ADULTS; MACULAR DEGENERATION; POSTURAL STABILITY; RISK-FACTORS; VISION LOSS; MORTALITY; MOBILITY; BALANCE; DISEASE AB Objective: To examine how accelerometer-measured physical activity is affected by visual impairment (VI) and uncorrected refractive error (URE). Design: Cross-sectional study using data from the 2003-2004/2005-2006 National Health and Nutritional Examination Survey. Visual impairment was defined as better-eye postrefraction visual acuity worse than 20/40. Uncorrected refractive error was defined as better-eye presenting visual acuity of 20/50 or worse, improving to 20/40 or better with refraction. Adults older than 20 years with normal sight, URE, and VI were analyzed. The main outcome measures were steps per day and daily minutes of moderate or vigorous physical activity (MVPA). Results: Five thousand seven hundred twenty-two participants (57.1%) had complete visual acuity and accelerometer data. Individuals with normal sight took an average of 9964 steps per day and engaged in an average of 23.5 minutes per day of MVPA, as compared with 9742 steps per day and 23.1 minutes per day of MVPA in individuals with URE (P>.50 for both) and 5992 steps per day and 9.3 minutes/d of MVPA in individuals with VI (P<.01 for both). In multivariable models, individuals with VI took 26% fewer steps per day (P<.01; 95% CI, 18%-34%) and spent 48% less time in MVPA (P<.01; 95% CI, 37%-57%) than individuals with normal sight. The decrement in steps and MVPA associated with VI equaled or exceeded that associated with self-reported chronic obstructive pulmonary disease, diabetes mellitus, arthritis, stroke, or congestive heart failure. Conclusions: Visual impairment, but not URE, impacts physical activity equal to or greater than other serious medical conditions. The substantial decrement in physical activity observed in nonrefractive vision loss highlights a need for better strategies to safely improve mobility and increase physical activity in this group. C1 [Willis, Jeffrey R.; Jefferys, Joan L.; Vitale, Susan; Ramulu, Pradeep Y.] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Ramulu, PY (reprint author), Johns Hopkins Univ Hosp, 600 N Wolfe St,Maumenee B110, Baltimore, MD 21287 USA. EM pramulu1@jhmi.edu FU National Center for Health Statistics, Centers for Disease Control and Prevention; National Eye Institute, National Institutes of Health [Z01EY000402]; National Cancer Institute; National Eye Institute [EY018595]; Research to Prevent Blindness FX NHANES is sponsored by the National Center for Health Statistics, Centers for Disease Control and Prevention. Additional funding for the NHANES Vision Component was provided by the National Eye Institute, National Institutes of Health (Intramural Re-search Program grant Z01EY000402) and funding for the accelerometry data was provided by the National Cancer Institute. The work was also sponsored by National Eye Institute grant EY018595 and a Research to Prevent Blindness Robert & Helen Schaub Special Scholar Award. NR 54 TC 25 Z9 25 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAR PY 2012 VL 130 IS 3 BP 329 EP 335 PG 7 WC Ophthalmology SC Ophthalmology GA 906NW UT WOS:000301353400008 PM 22411662 ER PT J AU Urusova, DV Isupov, MN Antonyuk, S Kachalova, GS Obmolova, G Vagin, AA Lebedev, AA Burenkov, GP Dauter, Z Bartunik, HD Lamzin, VS Melik-Adamyan, WR Mueller, TD Schnackerz, KD AF Urusova, Darya V. Isupov, Michail N. Antonyuk, Svetlana Kachalova, Galina S. Obmolova, Galina Vagin, Alexei A. Lebedev, Andrey A. Burenkov, Gleb P. Dauter, Zbigniew Bartunik, Hans D. Lamzin, Victor S. Melik-Adamyan, William R. Mueller, Thomas D. Schnackerz, Klaus D. TI Crystal structure of D-serine dehydratase from Escherichia coli SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article DE D-Serine dehydratase; Pyridoxal 5 '-phosphate; Type II fold; Open and closed conformation; alpha,beta elimination ID O-ACETYLSERINE SULFHYDRYLASE; PHOSPHATE BINDING-SITE; D-AMINO ACIDS; PYRIDOXAL 5'-PHOSPHATE; SALMONELLA-TYPHIMURIUM; ACTIVE-SITE; 3-DIMENSIONAL STRUCTURE; CONFORMATIONAL-CHANGE; ALANINE RACEMASE; PROTEIN MODELS AB D-Serine dehydratase from Escherichia coli is a member of the beta-family (fold-type II) of the pyridoxal 5'-phosphate-dependent enzymes, catalyzing the conversion of D-serine to pyruvate and ammonia. The crystal structure of monomeric D-serine dehydratase has been solved to 1.97 angstrom-resolution for an orthorhombic data set by molecular replacement. In addition, the structure was refined in a monoclinic data set to 1.55 angstrom resolution. The structure of DSD reveals a larger pyridoxal 5'-phosphate-binding domain and a smaller domain. The active site of DSD is very similar to those of the other members of the beta-family. Lys118 forms the Schiff base to PLP, the cofactor phosphate group is liganded to a tetraglycine cluster Gly279-Gly283, and the 3-hydroxyl group of PLP is liganded to Asn170 and N1 to Thr424, respectively. In the closed conformation the movement of the small domain blocks the entrance to active site of DSD. The domain movement plays an important role in the formation of the substrate recognition site and the catalysis of the enzyme. Modeling of D-serine into the active site of DSD suggests that the hydroxyl group of D-serine is coordinated to the carboxyl group of Asp238. The carboxyl oxygen of D-serine is coordinated to the hydroxyl group of Ser167 and the amide group of Leu171 (O1), whereas the O2 of the carboxyl group of D-serine is hydrogen-bonded to the hydroxyl group of Ser167 and the amide group of Thr168. A catalytic mechanism very similar to that proposed for L-serine dehydratase is discussed. (c) 2011 Elsevier B.V. All rights reserved. C1 [Schnackerz, Klaus D.] Univ Wurzburg, Theodor Boveri Inst Biowissensch, D-97074 Wurzburg, Germany. [Urusova, Darya V.; Melik-Adamyan, William R.] Russian Acad Sci, Inst Crystallog, Moscow 119333, Russia. [Isupov, Michail N.] Univ Exeter, Biosci Coll Life & Environm Sci, Exeter EX4 4QD, Devon, England. [Antonyuk, Svetlana] Univ Liverpool, Fac Hlth & Life Sci, Inst Integrat Biol, Mol Biophys Grp, Liverpool L69 7ZB, Merseyside, England. [Obmolova, Galina] Centocor R&D, Radnor, PA 19087 USA. [Kachalova, Galina S.; Bartunik, Hans D.] Max Planck Unit Struct Mol Biol, MPG ASMB DESY, D-22603 Hamburg, Germany. [Vagin, Alexei A.; Lebedev, Andrey A.] Univ York, Dept Chem, Struct Biol Lab, York YO10 5YW, N Yorkshire, England. [Burenkov, Gleb P.; Lamzin, Victor S.] DESY, European Mol Biol Lab, Hamburg Unit, D-22607 Hamburg, Germany. [Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, NCI, MCL,Biosci Div, Argonne, IL 60439 USA. [Mueller, Thomas D.] Univ Wurzburg, Julius von Sachs Inst, Lehrstuhl Pflanzenphysiol & Biophys, D-97082 Wurzburg, Germany. RP Schnackerz, KD (reprint author), Univ Wurzburg, Theodor Boveri Inst Biowissensch, D-97074 Wurzburg, Germany. EM schnacke@biozentrum.uni-wuerzburg.de OI Antonyuk, Svetlana/0000-0002-2779-9946; Lamzin, Victor/0000-0002-6058-7793; Bourenkov, Gleb/0000-0002-2617-5920; Isupov, Michail/0000-0001-6842-4289 NR 53 TC 6 Z9 7 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD MAR PY 2012 VL 1824 IS 3 BP 422 EP 432 DI 10.1016/j.bbapap.2011.10.017 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 909JV UT WOS:000301561700003 PM 22197591 ER PT J AU Zarate, C Furey, M AF Zarate, C. Furey, M. TI A translational perspective in the search for improved treatments for bipolar disorder SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 5th Biennial Conference of the International-Society-for-Bipolar-Disorders CY MAR 14-17, 2012 CL Istanbul, TURKEY SP Int Soc Bipolar Disorders DE biomarkers; bipolar; cholinergic; glutamate; novel treatments C1 [Zarate, C.; Furey, M.] NIMH, Expt Therapeut & Pathophysiol Branch & Sect Neuro, Div Intramural Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2012 VL 14 SU 1 SI SI BP 15 EP 15 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 908ZG UT WOS:000301531000010 ER PT J AU Selvaraj, S Arnone, D Job, D Stanfield, A Farrow, TFD Nugent, AC Scherk, H Gruber, O Chen, XH Sachdev, PS Dickstein, DP Malhi, GS Ha, TH Ha, K Phillips, ML McIntosh, AM AF Selvaraj, Sudhakar Arnone, Danilo Job, Dominic Stanfield, Andrew Farrow, Tom F. D. Nugent, Allison C. Scherk, Harald Gruber, Oliver Chen, Xiaohua Sachdev, Perminder S. Dickstein, Daniel P. Malhi, Gin S. Ha, Tae H. Ha, Kyooseob Phillips, Mary L. McIntosh, Andrew M. TI Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies SO BIPOLAR DISORDERS LA English DT Review DE bipolar disorder; grey matter; magnetic resonance imaging; meta-analysis; voxel-based morphometry ID ORBITOFRONTAL CORTEX; FACIAL EXPRESSIONS; VOLUME DIFFERENCES; MAJOR DEPRESSION; CORPUS-CALLOSUM; MOOD DISORDERS; I DISORDER; SCHIZOPHRENIA; ACTIVATION; ABNORMALITIES AB Objective: Several neuroimaging studies have reported structural brain differences in bipolar disorder using automated methods. While these studies have several advantages over those using region of interest techniques, no study has yet estimated a summary effect size or tested for between-study heterogeneity. We sought to address this issue using metaanalytic techniques applied for the first time in bipolar disorder at the level of the individual voxel. Methods: A systematic review identified 16 voxel-based morphometry (VBM) studies comparing individuals with bipolar disorder with unaffected controls, of which eight were included in the meta-analysis. In order to take account of heterogeneity, summary effect sizes were computed using a random-effects model with appropriate correction for multiple testing. Results: Compared with controls, subjects with bipolar disorder had reduced grey matter in a single cluster encompassing the right ventral prefrontal cortex, insula, temporal cortex, and claustrum. Study heterogeneity was widespread throughout the brain; though the significant cluster of grey matter reduction remained once these extraneous voxels had been removed. We found no evidence of publication bias (Eggers p = 0.63). Conclusions: Bipolar disorder is consistently associated with reductions in right prefrontal and temporal lobe grey matter. Reductions elsewhere may be obscured by clinical and methodological heterogeneity. C1 [Selvaraj, Sudhakar] Kings Coll London, Inst Psychiat, Dept Psychosis Studies, London SE5 7AF, England. [Arnone, Danilo] Inst Psychiat, Dept Psychol Med, Affect Disorder Res Grp, London SE5 8AF, England. [Job, Dominic; Stanfield, Andrew; McIntosh, Andrew M.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Farrow, Tom F. D.] Univ Sheffield, Sheffield, S Yorkshire, England. [Nugent, Allison C.] NIMH, Sect Neuroimaging, Mood Anxiety Disorders Program, Bethesda, MD 20892 USA. [Scherk, Harald; Gruber, Oliver] Univ Gottingen, Dept Psychiat & Psychotherapy, Gottingen, Germany. [Chen, Xiaohua; Sachdev, Perminder S.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Dickstein, Daniel P.] Brown Univ, Bradley Hasbro Childrens Res Ctr, Providence, RI 02912 USA. [Malhi, Gin S.] Univ Sydney, Dept Psychiat, CADE Clin, Sydney, NSW 2006, Australia. [Malhi, Gin S.] Univ Sydney, Discipline Psychol Med, Sydney, NSW 2006, Australia. [Ha, Tae H.; Ha, Kyooseob] Seoul Natl Univ, Bundang Hosp, Dept Psychiat, Seoul, South Korea. [Phillips, Mary L.] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA USA. RP Selvaraj, S (reprint author), Kings Coll London, Inst Psychiat, Dept Psychosis Studies, 16 De Crespigny Pk, London SE5 7AF, England. EM sudhakar.selvaraj@kcl.ac.uk RI Arnone, Danilo/A-3974-2012; Ha, Kyooseob/J-5698-2012; McIntosh, Andrew/B-9379-2008; selvaraj, sudhakar/J-4295-2014; Dickstein, Daniel/L-3210-2016; Farrow, Tom/B-5003-2009 OI Nugent, Allison/0000-0003-2569-2480; Sachdev, Perminder/0000-0002-9595-3220; McIntosh, Andrew/0000-0002-0198-4588; selvaraj, sudhakar/0000-0002-9494-172X; Dickstein, Daniel/0000-0003-1647-5329; Stanfield, Andrew/0000-0003-2459-1434; Arnone, Danilo/0000-0003-3831-2301; Job, Dominic/0000-0002-7829-7217; Farrow, Tom/0000-0001-5096-6370 FU UK Medical Research Council; Health Foundation; NHMRC [510135]; NIMH [K22MH074945]; American Foundation; AstraZeneca; Eli Lilly Co.; Jansen-Cilag; Organon; Pfizer; Wyeth; Janssen; Otsuka; Servier; GlaxoSmithKline; TMRI FX DA is currently supported by the UK Medical Research Council, and AMM is supported by the Health Foundation through a Clinician Scientist Fellowship. GSM is supported by an NHMRC Program Grant 510135. DPD is currently supported by an NIMH career development award (K22MH074945) and an American Foundation for Suicide Prevention Young Investigator Award.; TFDF has received honoraria for talks from Jansen-Cilag, AstraZeneca, and Cambian Healthcare. GSM has, in the past three years, served on a number of international and national pharmaceutical advisory boards, received funding for research, and received honoraria for talks at sponsored meetings worldwide involving AstraZeneca, Eli Lilly & Co., Jansen-Cilag, Organon, Pfizer, and Wyeth. KH has received grants and/or honoraria from Pfizer, Eli Lilly & Co., Janssen, Otsuka, Servier, AstraZeneca, and GlaxoSmithKline. AMM has received funding from TMRI, a collaboration between the Scottish Universities and Wyeth Pharmaceuticals. SS, DA, DJ, AS, ACN, HS, OG, XC, PSS, DPD, THH, and MLP have no competing interests to report. NR 65 TC 90 Z9 90 U1 1 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2012 VL 14 IS 2 BP 135 EP 145 DI 10.1111/j.1399-5618.2012.01000.x PG 11 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 908ZE UT WOS:000301530800002 PM 22420589 ER PT J AU Fagundes, CP Glaser, R Alfano, CM Bennett, JM Povoski, SP Lipari, AM Agnese, DM Yee, LD Carson, WE Farrar, WB Malarkey, WB Kiecolt-Glaser, JK AF Fagundes, Christopher P. Glaser, Ronald Alfano, Catherine M. Bennett, Jeanette M. Povoski, Stephen P. Lipari, Adele M. Agnese, Doreen M. Yee, Lisa D. Carson, William E., III Farrar, William B. Malarkey, William B. Kiecolt-Glaser, Janice K. TI Fatigue and herpesvirus latency in women newly diagnosed with breast cancer SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Cancer survivorship; Quality of life; Cytomegalovirus; Sickness behaviors; Inflammation ID EPSTEIN-BARR-VIRUS; QUALITY-OF-LIFE; CORONARY-ARTERY-DISEASE; INSOMNIA SEVERITY INDEX; LONG-TERM; PERSISTENT FATIGUE; CYTOMEGALOVIRUS REACTIVATION; INFLAMMATORY BIOMARKERS; DEPRESSIVE SYMPTOMS; PROSTATE-CANCER AB Fatigue is a notable clinical problem in cancer survivors, and understanding its pathophysiology is important. The current study sought to determine biomarkers of fatigue that exist before cancer treatment. Relationships between the expression of latent Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and fatigue were examined in 158 women newly diagnosed with breast cancer or awaiting a positive diagnostic result. Higher CMV antibody titers, but not EBV antibody titers, were associated with a greater likelihood of being fatigued. Associations between fatigue and higher CMV antibody titers remained after controlling for alcohol use, smoking, comorbidities, depressive symptoms, age, BMI, cancer stage, and sleep problems. More sleep problems and higher levels of depressive symptoms were also associated with a greater likelihood of being fatigued. CMV antibody titers, but not EBV antibody titers, were associated with higher levels of C-reactive protein (CRP), but CRP was not associated with fatigue. When the cellular immune system is compromised, reactivation of latent herpesviruses may fuel chronic inflammatory responses. Prior work has suggested that fatigue may be related to inflammation and its associated sickness behaviors; accordingly, our findings may be tapping into this same physiological substrate. (C) 2011 Elsevier Inc. All rights reserved. C1 [Fagundes, Christopher P.; Glaser, Ronald; Bennett, Jeanette M.; Malarkey, William B.; Kiecolt-Glaser, Janice K.] Ohio State Univ, Inst Behav Med Res, Coll Med, Columbus, OH 43210 USA. [Glaser, Ronald; Carson, William E., III; Malarkey, William B.] Ohio State Univ, Coll Med, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Glaser, Ronald; Malarkey, William B.] Ohio State Univ, Coll Med, Dept Internal Med, Columbus, OH 43210 USA. [Glaser, Ronald; Povoski, Stephen P.; Agnese, Doreen M.; Yee, Lisa D.; Carson, William E., III; Farrar, William B.; Malarkey, William B.; Kiecolt-Glaser, Janice K.] Ohio State Univ, Coll Med, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, NIH, Bethesda, MD 20892 USA. [Bennett, Jeanette M.] Ohio State Univ, Div Oral Biol, Coll Dent, Columbus, OH 43210 USA. [Povoski, Stephen P.; Agnese, Doreen M.; Yee, Lisa D.; Carson, William E., III; Farrar, William B.] Ohio State Univ, Dept Surg, Coll Med, Columbus, OH 43210 USA. [Lipari, Adele M.] Ohio State Univ, Dept Radiol, Coll Med, Columbus, OH 43210 USA. [Malarkey, William B.; Kiecolt-Glaser, Janice K.] Ohio State Univ, Dept Psychiat, Coll Med, Columbus, OH 43210 USA. RP Fagundes, CP (reprint author), Ohio State Univ, Inst Behav Med Res, Coll Med, 460 Med Ctr Dr, Columbus, OH 43210 USA. EM christopher.fagundes@osumc.edu RI Kiecolt-Glaser, Janice/A-3236-2009; Agnese, Doreen/I-1351-2012; Povoski, Stephen/E-3887-2011; Carson, William/E-2846-2011; Glaser, Ronald/E-3124-2011; OI Kiecolt-Glaser, Janice/0000-0003-4900-9578; Bennett, Jeanette M./0000-0002-8487-9774 FU NIH [CA131029, CA126857, DE014320, UL1RR025755, CA016058]; S. Robert Davis endowment; Kathryn & Gilbert Mitchell endowment; American Cancer Society [PF-11-007-01-CPPB] FX Work on this project was supported in part by NIH Grants CA131029, CA126857, DE014320, UL1RR025755, CA016058, the S. Robert Davis endowment, the Kathryn & Gilbert Mitchell endowment, and an American Cancer Society Postdoctoral Fellowship Grant PF-11-007-01-CPPB. We appreciate the helpful assistance of Arenda Nolan and Cathie Atkinson. We also thank Min Chen who performed the antibody assays. NR 65 TC 15 Z9 15 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAR PY 2012 VL 26 IS 3 BP 394 EP 400 DI 10.1016/j.bbi.2011.09.014 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 906GD UT WOS:000301332000005 PM 21988771 ER PT J AU Memarzadeh, F Xu, WR AF Memarzadeh, Farhad Xu, Weiran TI Role of air changes per hour (ACH) in possible transmission of airborne infections SO BUILDING SIMULATION LA English DT Article DE infection transmission and control; risk assessment; air change rate (ACH); computational fluid dynamics (CFD); patient room; ventilation system design ID INDOOR ENVIRONMENTS; ISOLATION ROOM; TRANSPORT CHARACTERISTICS; EXPIRATORY DROPLETS; VENTILATION; AEROSOLS; FLOW; DISPERSION; REMOVAL; SPREAD AB The cost of nosocomial infections in the United States is estimated to be $4 billion to $5 billion annually. Applying a scientifically based analysis to disease transmission and performing a site specific risk analysis to determine the design of the ventilation system can provide real and long term cost savings. Using a scientific approach and convincing data, this paper hypothetically illustrates how a ventilation system design can be optimized to potentially reduce infection risk to occupants in an isolation room based on a thorough risk assessment without necessarily increasing ventilation airflow rate. A computational fluid dynamics (CFD) analysis was performed to examine the transport mechanism, particle path and a suggested control strategy for reducing airborne infectious disease agents. Most studies on the transmission of infectious disease particles have concentrated primarily on air changes per hour (ACH) and how ACH provides a dilution factor for possible infectious agents. Although increasing ventilation airflow rate does dilute concentrations better when the contaminant source is constant, it does not increase ventilation effectiveness. Furthermore, an extensive literature review indicates that not every exposure to an infectious agent will necessarily cause a recipient infection. The results of this study suggest a hypothesis that in an enclosed and mechanically ventilated room (e.g., an isolation room), the dominant factor that affects the transmission and control of contaminants is the path between the contaminant source and exhaust. Contaminants are better controlled when this path is uninterrupted by an air stream. This study illustrates that the ventilation system design, i.e., when it conforms with the hypothesized path principle, may be a more important factor than flow rate (i.e., ACH). A secondary factor includes the distance from the contaminant source. This study provides evidence and supports previous studies that moving away from the patient generally reduces the infection risk in a transient (coughing) situation, although the effect is more pronounced under higher flow rate. It is noted that future research is needed to determine the exact mode of transmission for most recently identified organisms. C1 [Memarzadeh, Farhad; Xu, Weiran] NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Memarzadeh, F (reprint author), NIH, Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM fm30c@nih.gov NR 64 TC 8 Z9 8 U1 1 U2 19 PU TSINGHUA UNIV PRESS PI BEIJING PA TSINGHUA UNIV, RM A703, XUEYAN BLDG, BEIJING, 10084, PEOPLES R CHINA SN 1996-3599 J9 BUILD SIMUL-CHINA JI Build. Simul. PD MAR PY 2012 VL 5 IS 1 BP 15 EP 28 DI 10.1007/s12273-011-0053-4 PG 14 WC Thermodynamics; Construction & Building Technology SC Thermodynamics; Construction & Building Technology GA 909LW UT WOS:000301567000004 ER PT J AU Pazmino, PA AF Pazmino, Patricio A. TI Dabigatran SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Letter C1 Nephrol Internal Med & Hypertens NIH Ctr, El Paso, TX USA. RP Pazmino, PA (reprint author), Nephrol Internal Med & Hypertens NIH Ctr, El Paso, TX USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD MAR PY 2012 VL 79 IS 3 BP 166 EP 166 DI 10.3949/ccjm.79c:03003 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 907FK UT WOS:000301403000004 ER PT J AU Chapman, AB Bost, JE Torres, VE Guay-Woodford, L Bae, KT Landsittel, D Li, J King, BF Martin, D Wetzel, LH Lockhart, ME Harris, PC Moxey-Mims, M Flessner, M Bennett, WM Grantham, JJ AF Chapman, Arlene B. Bost, James E. Torres, Vicente E. Guay-Woodford, Lisa Bae, Kyongtae Ty Landsittel, Douglas Li, Jie King, Bernard F. Martin, Diego Wetzel, Louis H. Lockhart, Mark E. Harris, Peter C. Moxey-Mims, Marva Flessner, Mike Bennett, William M. Grantham, Jared J. TI Kidney Volume and Functional Outcomes in Autosomal Dominant Polycystic Kidney Disease SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID DIETARY-PROTEIN RESTRICTION; RENAL-DISEASE; COMPUTED-TOMOGRAPHY; PROGRESSION; GROWTH; ADPKD; DETERMINANTS; SIROLIMUS; COHORT; RISK AB Background and objectives Autosomal dominant polycystic kidney disease (ADPKD) is characterized by increased total kidney volume (TKV) and renal failure. This study aimed to determine if height-adjusted TKV (htTKV) predicts the onset of renal insufficiency. Design, setting, participants, & measurements This prospective, observational, longitudinal, multicenter study included 241 adults with ADPKD and preserved renal function. Magnetic resonance imaging and iothalamate clearance were used to measure htTKV and GFR, respectively. The association between baseline htTKV and the attainment of stage 3 CKD (GFR <60 ml /min per 1.73 m(2)) during follow-up was determined. Results After a mean follow-up of 7.9 years, stage 3 CKD was attained in 30.7% of the enrollees. Using baseline htTKV, negative correlations with GFR increased from -0.22 at baseline to -0.65 at year 8. In multivariable analysis, a baseline htTKV increase of 100 cc/m significantly predicted the development of CKD within 8 years with an odds ratio of 1.48 (95% confidence interval: 1.29, 1.70). In receiver operator characteristic curve analysis, baseline htTKV of 600 cc/m most accurately defined the risk of developing stage 3 CKD within 8 years with an area under the curve of 0.84 (95% confidence interval: 0.79, 0.90). htTKV was a better predictor than baseline age, serum creatinine, BUN, urinary albumin, or monocyte chemotactic protein-1 excretion (P<0.05). Conclusions Baseline htTKV 600 cc/m predicted the risk of developing renal insufficiency in ADPKD patients at high risk for renal disease progression within 8 years of follow-up, qualifying htTKV as a prognostic biomarker in ADPKD. Clin J Am Soc Nephrol 7: 479-486, 2012. doi: 10.2215/CJN.09500911 C1 [Chapman, Arlene B.; Martin, Diego] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Bost, James E.; Bae, Kyongtae Ty; Landsittel, Douglas; Li, Jie] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Torres, Vicente E.; King, Bernard F.; Harris, Peter C.] Mayo Coll Med, Rochester, MN USA. [Guay-Woodford, Lisa; Lockhart, Mark E.] Univ Alabama Birmingham, Birmingham, AL USA. [Wetzel, Louis H.; Grantham, Jared J.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Moxey-Mims, Marva; Flessner, Mike] NIDDK, NIH, Bethesda, MD USA. [Bennett, William M.] Legacy Good Samaritan Hosp, Portland, OR USA. RP Chapman, AB (reprint author), Emory Univ, Sch Med, 1364 Clifton Rd,Suite GG23, Atlanta, GA 30322 USA. EM Arlene_chapman@emory.org FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [DK056943, DK056956, DK056957, DK056961]; National Center for Research Resources General Clinical Research Centers [RR000039, RR00585, R1223940, RR000052]; Otsuka Corporation; National Center for Research Resources [RR025008, RR024150, RR033179, R12025777, R12024153] FX The CRISP study is supported by cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (DK056943, DK056956, DK056957, DK056961) and by the National Center for Research Resources General Clinical Research Centers at each institution (RR000039, Emory University; RR00585, Mayo College of Medicine; R1223940, Kansas University Medical Center; RR000052, University of Alabama at Birmingham) and the National Center for Research Resources Clinical and Translational Science Awards at each institution (RR025008, Emory; RR024150, Mayo College of Medicine; RR033179, Kansas University Medical Center; R12025777, University of Alabama at Birmingham; R12024153, University of Pittsburgh School of Medicine).; A.B.C. and J.J.G. are consultants to Otsuka Corporation, and V.E.T. received research support from Otsuka Corporation. NR 35 TC 98 Z9 99 U1 0 U2 11 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAR PY 2012 VL 7 IS 3 BP 479 EP 486 DI 10.2215/CJN.09500911 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 904TZ UT WOS:000301222100017 PM 22344503 ER PT J AU Ghiorzo, P Pensotti, V Fornarini, G Sciallero, S Battistuzzi, L Belli, F Bonelli, L Borgonovo, G Bruno, W Gozza, A Gargiulo, S Mastracci, L Nasti, S Palmieri, G Papadia, F Pastorino, L Russo, A Savarino, V Varesco, L Bernard, L Scarra, GB AF Ghiorzo, P. Pensotti, V. Fornarini, G. Sciallero, S. Battistuzzi, L. Belli, F. Bonelli, L. Borgonovo, G. Bruno, W. Gozza, A. Gargiulo, S. Mastracci, L. Nasti, S. Palmieri, G. Papadia, F. Pastorino, L. Russo, A. Savarino, V. Varesco, L. Bernard, L. Scarra, G. Bianchi CA Genoa Pancreatic Canc Study Grp TI Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy SO FAMILIAL CANCER LA English DT Article DE Pancreatic cancer susceptibility; BRCA; PALB2; Hereditary breast ovarian cancer syndrome (HBOC); Germline mutation ID ADENOCARCINOMA; POLYMERASE; INHIBITOR; FAMILIES; BREAST; RISK AB Pancreatic adenocarcinoma (PC) is the third most common cancer associated with BRCA mutations. Most notice has been given to BRCA2, while the association between BRCA1 and PC is less widely reported. Recently, PALB2 has been implicated in both PC and breast cancer (BC) susceptibility. We selected 29 Italian PC patients from a case-control study of PC according to their personal and family history of both PC and breast/ovarian cancer (BC/OC) and tested them for presence of germline mutations in BRCA1, BRCA2 and PALB2. We identified no germline mutations or deletions in PALB2, but detected 7 BRCA mutations (4 in BRCA1 and 3 in BRCA2). These findings suggest that PALB2 does not play a major role in PC susceptibility in our population. As we found an almost equal frequency of germline mutations in BRCA1 and BRCA2, germline alterations in either of these genes may explain a subset of Italian families presenting both PC and BC/OC. Moreover, as we began the observation of these families from probands who are affected by PC, we provide here a direct assessment of the role of PALB2 and BRCA mutations in PC susceptibility. C1 [Ghiorzo, P.; Bruno, W.; Gargiulo, S.; Nasti, S.; Pastorino, L.; Scarra, G. Bianchi] Univ Genoa, Dept Oncol Biol & Genet, I-16129 Genoa, Italy. [Pensotti, V.] FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy. [Fornarini, G.; Sciallero, S.] San Martino Hosp, Med Oncol Unit, Genoa, Italy. [Battistuzzi, L.] Univ Genoa, Dept Hlth Sci, I-16129 Genoa, Italy. [Belli, F.] Galliera Hosp, Gen & Biliopancreat Surg Unit, Genoa, Italy. [Bonelli, L.] Natl Canc Inst, I-20133 Milan, Italy. [Borgonovo, G.; Papadia, F.] Univ Genoa, Dept Surg, I-16129 Genoa, Italy. [Gozza, A.] Galliera Hosp, Med Oncol Unit, Genoa, Italy. [Mastracci, L.] Univ Genoa, Dept Anat Pathol, I-16129 Genoa, Italy. [Palmieri, G.] CNR, Inst Biomol Chem, Sassari, Italy. [Russo, A.] Univ Palermo, Dept Surg & Oncol, Palermo, Italy. [Savarino, V.] Univ Genoa, Dept Internal Med, I-16129 Genoa, Italy. [Varesco, L.] Natl Canc Inst, Ctr Hereditary Tumors, Genoa, Italy. [Bernard, L.] European Inst Oncol, Dept Expt Oncol, Milan, Italy. [Scarra, G. Bianchi] San Martino Hosp, Lab Rare Hereditary Canc, Genoa, Italy. RP Ghiorzo, P (reprint author), Univ Genoa, Dept Oncol Biol & Genet, Vle Benedetto 15,6, I-16129 Genoa, Italy. EM paola.ghiorzo@unige.it RI Bianchi Scarra, Giovanna/G-8933-2014; Bernard, Loris/K-5953-2014; Bruno, William/N-7477-2013; OI Bianchi Scarra, Giovanna/0000-0002-6127-1192; Bruno, William/0000-0002-0337-0168; Mastracci, Luca/0000-0003-0193-5281; Palmieri, Giuseppe/0000-0002-4350-2276 FU IRCSS Italian Ministry of Health [DGRST.4/4235-P1.9.A.B]; Fondazione CARIGE FX We are grateful to Chiara Baldo at the Galliera Genetic Bank-Network of Telethon Genetic Biobanks (project GTB07001) for providing lymphoblastoid cell-lines. This study was funded by IRCSS 2007 Italian Ministry of Health DGRST.4/4235-P1.9.A.B, Fondazione CARIGE, PRIN 2008 to G.B.-S. NR 31 TC 13 Z9 13 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD MAR PY 2012 VL 11 IS 1 BP 41 EP 47 DI 10.1007/s10689-011-9483-5 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 908RR UT WOS:000301508300007 PM 21989927 ER PT J AU Schoen, RE Pinsky, PF Weissfeld, JL Yokochi, LA Church, T Laiyemo, AO Bresalier, R Hickey, T Riley, T Prorok, PC AF Schoen, Robert E. Pinsky, Paul F. Weissfeld, Joel L. Yokochi, Lance A. Church, Timothy Laiyemo, Adeyinka O. Bresalier, Robert Hickey, Tom Riley, Thomas Prorok, Philip C. TI Colorectal cancers not detected by screening flexible sigmoidoscopy in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID NEGATIVE COLONOSCOPY; ADENOMA DETECTION; SURVEILLANCE; RISK; PROTECTION; PREDICTORS; COLON; RATES; SITE; AGE AB Background and Objective: Diagnosis of colorectal cancer after negative findings on endoscopic evaluation raises concern about the effectiveness of endoscopic screening. We contrast screening-detected cancers with cancers not detected by screening among participants assigned to flexible sigmoidoscopy (FSG) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to determine the reasons for the lack of detection of prevalent lesions. Design: Cancers detected within 1 year of a screening FSG with abnormal findings were classified as screening detected. All other cancers were categorized, based on cancer stage and years until detection, as either not detectable or prevalent but not detected at the time of screening. Setting/Patients: A total of 77,447 subjects in the multicenter PLCO trial. Main Outcome Measurements: A total of 977 colorectal cancers were diagnosed with a mean follow-up of 11.5 years. Results: A total of 243 (24.9%) cancers were screening detected, 470 (48.1%) were not detectable at screening, and 264 (27.0%) were considered prevalent but not detected. Among prevalent nondetected lesions, 35.6% (n = 94) were attributed to problems in patient compliance (58 never screened, 34 delayed colonoscopy follow-up, and 2 inadequate bowel preparation), 43.9% (n = 116) were attributable to a limitation in the FSG procedure (97 beyond the reach of the sigmoidoscope and 19 inadequate depth of insertion on FSG), and 20.5% (n = 54) were caused by endoscopist limitation (33 missed on FSG, 21 missed at initial colonoscopy) (P < .0001). Had colonoscopy instead of FSG been used for screening, an additional 15.6% and as many as 19.0% of cancers may have been screening-detected. Limitations: These estimates are reasonable approximations, but biological variability precludes precise determinations. Conclusions: Prevalent nondetected cancers were more often attributable to problems with patient compliance or limitations in the FSG procedure than to missed lesions. Colonoscopy instead of FSG could have moderately increased the detection of cancer via screening. (Gastrointest Endosc 2012;75:612-20.) C1 [Schoen, Robert E.] Univ Pittsburgh, Inst Canc, Dept Med, Div Gastroenterol Hepatol & Nutr,PUH, Pittsburgh, PA 15213 USA. [Schoen, Robert E.; Weissfeld, Joel L.] Univ Pittsburgh, Inst Canc, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Pinsky, Paul F.; Prorok, Philip C.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Yokochi, Lance A.] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. [Church, Timothy] Univ Minnesota, Dept Hlth Studies Environm Hlth Sci, Minneapolis, MN USA. [Laiyemo, Adeyinka O.] Howard Univ, Washington, DC 20059 USA. [Bresalier, Robert] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hickey, Tom; Riley, Thomas] Informat Management Serv Inc, Rockville, MD USA. RP Schoen, RE (reprint author), Univ Pittsburgh, Inst Canc, Dept Med, Div Gastroenterol Hepatol & Nutr,PUH, C Wing,200 Lothrop St, Pittsburgh, PA 15213 USA. EM rschoen@pitt.edu OI Church, Timothy R./0000-0003-3292-5035 FU National Cancer Institute [N01-CN-25511, N01-CN-25513, N01-CN-25515] FX The authors disclosed no financial relationships relevant to this publication. Supported by contracts from the National Cancer Institute: N01-CN-25511 to University of Pittsburgh Cancer Institute (RES, JLW), N01-CN-25513 to University of Minnesota School of Public Health (TG), N01-CN-25515 to Pacific Health Research & Education Institute (LAY). NR 35 TC 14 Z9 15 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAR PY 2012 VL 75 IS 3 BP 612 EP 620 DI 10.1016/j.gie.2011.10.024 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 906BM UT WOS:000301319900024 PM 22341106 ER PT J AU Yu, CH Bonaduce, MJ Klar, AJS AF Yu, Chuanhe Bonaduce, Michael J. Klar, Amar J. S. TI Going in the Right Direction: Mating-Type Switching of Schizosaccharomyces pombe Is Controlled by Judicious Expression of Two Different swi2 Transcripts SO GENETICS LA English DT Article ID DOUBLE-STRAND BREAKS; FISSION YEAST; CENP-B; S-POMBE; CHROMOSOME SEGREGATION; SEX DETERMINATION; DNA STRANDS; RECOMBINATION; PROTEIN; HETEROCHROMATIN AB Schizosaccharomyces pombe, the fission yeast, cells alternate between P-and M-mating type, controlled by the alternate alleles of the mating-type locus (mat1). The mat1 switching occurs by replacing mat1 with a copy derived from a silenced "donor locus," mat2P or mat3M. The mechanism of donor choice ensuring that switching occurs primarily and productively to the opposite type, called directionality, is largely unknown. Here we identified the mat1-Mc gene, a mammalian sex-determination gene (SRY) homolog, as the primary gene that dictates directionality in M cells. A previously unrecognized, shorter swi2 mRNA, a truncated form of the swi2, was identified, and its expression requires the mat1-Mc function. We also found that the abp1 gene (human CENPB homolog) controls directionality through swi2 regulation. In addition, we implicated a cis-acting DNA sequence in mat2 utilization. Overall, we showed that switching directionality is controlled by judicious expression of two swi2 transcripts through a cell-type-regulated dual promoter. In this respect, this regulation mechanism resembles that of the Drosophila sex-determination Slx gene. C1 [Yu, Chuanhe; Bonaduce, Michael J.; Klar, Amar J. S.] NCI, Dev Genet Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Dev Genet Sect, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. EM klara@mail.nih.gov FU National Cancer Institute of the National Institutes of Health FX We thank Sharon Moore, Ken Ishikawa, Stephan Sauer, and Jeff Strathern's laboratory members for discussions and advice. We also thank Drs. Fernando Azorin and Hiroshi Iwasaki for providing yeast strains. The Intramural Research Program of the National Cancer Institute of the National Institutes of Health supported this work. C.Y. and A. K. designed and performed the experiments, analyzed the data, and wrote the manuscript; M. B. provided technical support for this work. The authors declare that they have no conflict of interest. NR 52 TC 4 Z9 4 U1 1 U2 9 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD MAR PY 2012 VL 190 IS 3 BP 977 EP U182 DI 10.1534/genetics.111.137109 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 908ZP UT WOS:000301531900010 PM 22209903 ER PT J AU Diao, FQ White, BH AF Diao, Fengqiu White, Benjamin H. TI A Novel Approach for Directing Transgene Expression in Drosophila: T2A-Gal4 In-Frame Fusion SO GENETICS LA English DT Article ID COURTSHIP BEHAVIOR; MELANOGASTER; VERSATILE; RECEPTOR; INSERTION; PROTEINS; RESOURCE; VECTORS; DISEASE; CELLS AB In Drosophila, the Gal4-UAS system permits a transgene to be expressed in the same pattern as a gene of interest by placing the Gal4 transcription factor under control of the gene's DNA regulatory elements. If these regulatory elements are not known, however, expression of Gal4 in the desired pattern may be difficult or impossible. To solve this problem, we have developed a method for co-expressing Gal4 with the endogenous gene by exploiting the "ribosomal skipping" mechanism of the viral T2A peptide. This method requires explicit knowledge only of the endogenous gene's open reading frame and not its regulatory elements. C1 [Diao, Fengqiu; White, Benjamin H.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP White, BH (reprint author), NIMH, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM benjaminwhite@mail.nih.gov FU National Institute of Mental Health [1ZIA-MH-002800-07] FX We thank Bruce Paterson and Chi-hon Lee for the pPacPL and pC-attB plasmids, respectively; Randall Hewes for UAS-dnc flies; and the National Institute of Neurological Disorders and Stroke DNA sequencing facility for sequencing services. We also thank Grace Gray for comments on the manuscript. This research was supported by the Intramural Research Program of the National Institute of Mental Health (Project 1ZIA-MH-002800-07). NR 23 TC 23 Z9 23 U1 0 U2 7 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAR PY 2012 VL 190 IS 3 BP 1139 EP U356 DI 10.1534/genetics.111.136291 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 908ZP UT WOS:000301531900022 PM 22209908 ER PT J AU Bush, LW Rothenberg, KH AF Bush, Lynn W. Rothenberg, Karen H. TI Dialogues, dilemmas, and disclosures: genomic research and incidental findings SO GENETICS IN MEDICINE LA English DT Editorial Material ID PARTICIPANTS C1 [Bush, Lynn W.] Columbia Univ, Dept Pediat, Div Clin Genet, New York, NY 10027 USA. [Rothenberg, Karen H.] Univ Maryland, Francis King Carey Sch Law, Baltimore, MD 21201 USA. [Rothenberg, Karen H.] NHGRI, Bethesda, MD 20892 USA. [Rothenberg, Karen H.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Bush, LW (reprint author), Columbia Univ, Dept Pediat, Div Clin Genet, New York, NY 10027 USA. EM lwb25@columbia.edu NR 10 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD MAR PY 2012 VL 14 IS 3 BP 293 EP 295 DI 10.1038/gim.2011.72 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 908FF UT WOS:000301475100002 PM 22391780 ER PT J AU Handel, EM Gellhaus, K Khan, K Bednarski, C Cornu, TI Muller-Lerch, F Kotin, RM Heilbronn, R Cathomen, T AF Haendel, Eva-Maria Gellhaus, Katharina Khan, Kafaitullah Bednarski, Christien Cornu, Tatjana I. Mueller-Lerch, Felix Kotin, Robert M. Heilbronn, Regine Cathomen, Toni TI Versatile and Efficient Genome Editing in Human Cells by Combining Zinc-Finger Nucleases With Adeno-Associated Viral Vectors SO HUMAN GENE THERAPY LA English DT Article ID DOUBLE-STRAND BREAKS; TARGETED GENE ADDITION; IN-VIVO; VIRUS VECTORS; STEM-CELLS; HOMOLOGOUS RECOMBINATION; MAJOR DETERMINANT; INSECT CELLS; TRANSDUCTION; SPECIFICITY AB Zinc-finger nucleases (ZFNs) have become a valuable tool for targeted genome engineering. Based on the enzyme's ability to create a site-specific DNA double-strand break, ZFNs promote genome editing by activating the cellular DNA damage response, including homology-directed repair (HDR) and nonhomologous end-joining. The goal of this study was (i) to demonstrate the versatility of combining the ZFN technology with a vector platform based on adeno-associated virus (AAV), and (ii) to assess the toxicity evoked by this platform. To this end, human cell lines that harbor enhanced green fluorescence protein (EGFP) reporters were generated to easily quantify the frequencies of gene deletion, gene disruption, and gene correction. We demonstrated that ZFN-encoding AAV expression vectors can be employed to induce large chromosomal deletions or to disrupt genes in up to 32% of transduced cells. In combination with AAV vectors that served as HDR donors, the AAV-ZFN platform was utilized to correct a mutation in EGFP in up to 6% of cells. Genome editing on the DNA level was confirmed by genotyping. Although cell cycle profiling revealed a modest G2/M arrest at high AAV-ZFN vector doses, platform-induced apoptosis could not be detected. In conclusion, the combined AAV-ZFN vector technology is a useful tool to edit the human genome with high efficiency. Because AAV vectors can transduce many cell types relevant for gene therapy, the ex vivo and in vivo delivery of ZFNs via AAV vectors will be of great interest for the treatment of inherited disorders. C1 [Haendel, Eva-Maria; Khan, Kafaitullah; Bednarski, Christien; Cathomen, Toni] Hannover Med Sch, Inst Expt Hematol, D-30625 Hannover, Germany. [Haendel, Eva-Maria; Gellhaus, Katharina; Khan, Kafaitullah; Bednarski, Christien; Cornu, Tatjana I.; Mueller-Lerch, Felix; Heilbronn, Regine; Cathomen, Toni] Charite, Inst Virol, D-12203 Berlin, Germany. [Kotin, Robert M.] NHLBI, Mol Virol & Gene Delivery Sect, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Cathomen, T (reprint author), Hannover Med Sch, Inst Expt Hematol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM cathomen.toni@mh-hannover.de RI Heilbronn, Regine/E-1349-2013; OI Cathomen, Toni/0000-0002-7757-4630 FU German Ministry of Education and Research [ITCF-01GU0618]; European Commission [PERSIST-222878]; German Research Foundation [SFB/TR19-TPC5]; German Academic Exchange Service (DAAD) FX We thank Jessica Wenzl and Eva Guhl for technical assistance, Shamim H. Rahman and Sylwia Bobis-Wozowicz for help with experiments and critical discussions, and Nicholas Muzyczka for plasmids. This work was supported by grants ITCF-01GU0618 of the German Ministry of Education and Research, PERSIST-222878 of the European Commission's 7th Framework Programme, and SFB/TR19-TPC5 of the German Research Foundation to T.C., and a fellowship of the German Academic Exchange Service (DAAD) to K.K. NR 55 TC 37 Z9 37 U1 0 U2 8 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD MAR PY 2012 VL 23 IS 3 BP 321 EP 329 DI 10.1089/hum.2011.140 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 906PO UT WOS:000301359100010 PM 21980922 ER PT J AU Kaess, BM Pedley, A Massaro, JM Larson, MG Corsini, E Hoffmann, U Smith, HM Sawyer, DB Vasan, RS Fox, CS AF Kaess, Bernhard M. Pedley, Alison Massaro, Joseph M. Larson, Martin G. Corsini, Erin Hoffmann, Udo Smith, Holly M. Sawyer, Douglas B. Vasan, Ramachandran S. Fox, Caroline S. TI Relation of Vascular Growth Factors with CT-Derived Measures of Body Fat Distribution: The Framingham Heart Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; SOLUBLE RECEPTOR SFLT-1; DISEASE RISK-FACTORS; ADIPOSE-TISSUE; GENE-EXPRESSION; BREAST-CANCER; PLASMA-LEVELS; OBESITY; ASSOCIATION; ADIPOCYTES AB Background: Visceral adiposity is associated with metabolic risk. Given that angiogenesis is a key feature of adipogenesis, variation in the association of levels of circulating vascular growth factors (and their soluble receptors) with distinct body fat compartments may explain differences in the systemic pathogenicity of regional fat depots. Methods and Results: Four body fat compartments [visceral adipose tissue (VAT), sc adipose tissue (SAT), thoracic periaortic fat, and pericardial fat] derived from computed tomography were related to serum concentrations of vascular endothelial growth factor (VEGF), the soluble VEGF receptor (fms-like tyrosine kinase-1), hepatocyte growth factor (HGF), and angiopoietin-2 and its soluble receptor (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2 sTie-2) in 1806 Framingham Heart Study participants (mean age 44.9 yr, 44.5% women). In multivariable models, we observed positive associations between several fat compartments and VEGF and HGF levels. The magnitude of the associations were similar for VAT, SAT, and periaortic fat. We observed effect modification by sex. A stronger association was observed between VAT and HGF levels in women; higher VAT and periaortic fat were jointly associated with higher HGF concentrations (P = 0.02 and P = 0.051, respectively). In women within the highest tertile of VAT, HGF levels significantly increased with higher periaortic fat (P = 0.0005). Conclusions: In our large community-based sample, greater adiposity was associated with higher circulating growth factor levels in general. Additional studies are warranted to confirm the stronger association of VAT and periaortic fat with HGF in women and to examine its potential contribution to the sex-related differences in cardiometabolic risk. (J Clin Endocrinol Metab 97: 987-994, 2012) C1 [Kaess, Bernhard M.; Pedley, Alison; Larson, Martin G.; Vasan, Ramachandran S.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Kaess, Bernhard M.] Univ Regensburg, Dept Internal Med 2, D-93053 Regensburg, Germany. [Massaro, Joseph M.; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Dept Med, Cardiol Sect, Boston, MA 02215 USA. [Corsini, Erin; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA. [Smith, Holly M.; Sawyer, Douglas B.] Vanderbilt Univ, Div Cardiovasc, Nashville, TN 37232 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health National Heart, Lung, and Blood Institute [N01-HC-25195, RO1-HL-077477] FX This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute Contract N01-HC-25195 and RO1-HL-077477 (to R.S.V.). NR 48 TC 8 Z9 8 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 MAR PY 2012 VL 97 IS 3 BP 987 EP 994 DI 10.1210/jc.2011-2310 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904WM UT WOS:000301229600065 PM 22170711 ER PT J AU Patronas, Y Horvath, A Greene, E Tsang, K Bimpaki, E Haran, M Nesterova, M Stratakis, CA AF Patronas, Yianna Horvath, Anelia Greene, Elizabeth Tsang, Kitman Bimpaki, Eirini Haran, Michelle Nesterova, Maria Stratakis, Constantine A. TI In Vitro Studies of Novel PRKAR1A Mutants that Extend the Predicted RI alpha Protein Sequence into the 3 '-Untranslated Open Reading Frame: Proteasomal Degradation Leads to RI alpha Haploinsufficiency and Carney Complex SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ABERRANT MESSENGER-RNAS; REGULATORY SUBUNIT; MUTATIONS; GENE; PHENOTYPE; DISEASE; PATIENT AB Background: Carney complex (CNC) is a multiple endocrine neoplasia syndrome due to inactivating mutations in the PRKAR1A gene that codes for type I alpha regulatory (RI alpha) subunit of protein kinase A. Most PRKAR1A mutations are subject to nonsense mRNA decay (NMD) and, thus, lead to haploinsufficiency. Methods and Setting: Patient phenotyping for CNC features and DNA, RNA, protein, and transfection studies were carried out at a research center. Results: We describe in unrelated kindreds with CNC four naturally occurring PRKAR1A mutations (1055del4, 1067del4ins5, 1076delTTins13, and1142del4) that are predicted to escape NMD because they are located in the last coding exon of the gene. The phenotype of CNC was not different from that in other patients with the condition, although the number of patients was small. Each of the mutations caused a frameshift that led to a new stop codon into the 3' untranslated open reading frame, predicting an elongated protein that, however, was absent in patient-derived cells. After site-directed mutagenesis, in vitro transcription, and cell-free translation experiments, the expected size mutant proteins were present. However, when the mutant constructs were transfected in adrenal (NCI-295), testicular (N-TERA), and embryonic (HEK293) cells and despite the presence of the mutant mRNA, Western blot analysis indicated that there were no longer proteins. The subsequent application of proteasome inhibitors to cells transfected with the mutant constructs led to the detection of the aberrant proteins, although a compound that affects protein folding had no effect. The wild-type protein was also decreased in both patient-derived cells and/or tissues as well as in the in vitro systems used in this study. Conclusions: This was the first demonstration of proteasomal degradation of RI alpha protein variants leading to PRKAR1A haploinsufficiency and CNC, adding protein surveillance to NMD in the cellular mechanisms overseeing RI alpha synthesis. In agreement with the molecular data, CNC patients bearing PRKAR1A defects that extend the open reading frame did not have a different phenotype, although this has to be confirmed in a larger number of patients. (J Clin Endocrinol Metab 97: E496-E502, 2012) C1 [Patronas, Yianna; Horvath, Anelia; Greene, Elizabeth; Tsang, Kitman; Bimpaki, Eirini; Haran, Michelle; Nesterova, Maria; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol Genet, Program Dev Endocrinol & Genet, NIH,Clin Ctr, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol Genet, Program Dev Endocrinol & Genet, NIH,Clin Ctr, Bldg 10,CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Leyla, Sozaeva/C-7231-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, Intramural National Institutes of Health [Z01-HD-000642-04] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Intramural National Institutes of Health Project Z01-HD-000642-04 to C.A.S. NR 19 TC 9 Z9 9 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 MAR PY 2012 VL 97 IS 3 BP E496 EP E502 DI 10.1210/jc.2011-2220 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904WM UT WOS:000301229600024 PM 22205709 ER PT J AU Xekouki, P Pacak, K Almeida, M Wassif, CA Rustin, P Nesterova, M Sierra, MD Matro, J Ball, E Azevedo, M Horvath, A Lyssikatos, C Quezado, M Patronas, N Ferrando, B Pasini, B Lytras, A Tolis, G Stratakis, CA AF Xekouki, Paraskevi Pacak, Karel Almeida, Madson Wassif, Christopher A. Rustin, Pierre Nesterova, Maria Sierra, Maria de la Luz Matro, Joey Ball, Evan Azevedo, Monalisa Horvath, Anelia Lyssikatos, Charalampos Quezado, Martha Patronas, Nicholas Ferrando, Barbara Pasini, Barbara Lytras, Aristides Tolis, George Stratakis, Constantine A. TI Succinate Dehydrogenase (SDH) D Subunit (SDHD) Inactivation in a Growth-Hormone-Producing Pituitary Tumor: A New Association for SDH? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARNEY-STRATAKIS-SYNDROME; GERMLINE MUTATIONS; COMPLEX-II; HEREDITARY PARAGANGLIOMA; MOLECULAR-GENETICS; PHEOCHROMOCYTOMA; TUMORIGENESIS; EXPRESSION; VARIANTS; GENES AB Background: Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD). Aim: Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma. Patients and Methods: A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors. Conclusion: We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis. (J Clin Endocrinol Metab 97: E357-E366, 2012) C1 [Xekouki, Paraskevi; Almeida, Madson; Nesterova, Maria; Sierra, Maria de la Luz; Ball, Evan; Azevedo, Monalisa; Horvath, Anelia; Lyssikatos, Charalampos; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. [Wassif, Christopher A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Dysmorphol, Bethesda, MD 20892 USA. [Pacak, Karel; Matro, Joey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Pacak, Karel; Matro, Joey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. [Pacak, Karel; Matro, Joey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Bethesda, MD 20892 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Patronas, Nicholas] NIH, Dept Diagnost Radiol, Clin Res Ctr, Bethesda, MD 20892 USA. [Xekouki, Paraskevi; Lytras, Aristides; Tolis, George] Hippocrate Gen Hosp, Div Endocrinol & Metab, Athens 11527, Greece. [Rustin, Pierre] INSERM, U676, Fac Med Denis Diderot, IFR02 Paris, F-75654 Paris 13, France. [Rustin, Pierre] Univ Paris 07, Fac Med Denis Diderot, IFR02 Paris, F-75221 Paris 05, France. [Ferrando, Barbara; Pasini, Barbara] Univ Turin, Dept Genet Biol & Biochem, I-10126 Turin, Italy. [Lytras, Aristides] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Cellular & Mol Physiol, Boston, MA 02215 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 10,CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU NICHD, NIH [Z01 HD000642-04]; Agence National de la Recherche; Hellenic Endocrine Society, Athens, Greece FX This work was supported by the intramural program of the NICHD, NIH (Project Z01 HD000642-04; principal investigator C.A.S.), by the Agence National de la Recherche (Project MitOxy; principal investigator P.R.), and in part, by a 1-yr grant to P.X. on the molecular investigation of pituitary tumors by the Hellenic Endocrine Society, Athens, Greece. NR 39 TC 47 Z9 48 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 MAR PY 2012 VL 97 IS 3 BP E357 EP E366 DI 10.1210/jc.2011-1179 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904WM UT WOS:000301229600005 PM 22170724 ER PT J AU Zhang, LS He, M Zhang, YQ Nilubol, N Shen, M Kebebew, E AF Zhang, Lisa He, Mei Zhang, Yaqin Nilubol, Naris Shen, Min Kebebew, Electron TI Quantitative High-Throughput Drug Screening Identifies Novel Classes of Drugs with Anticancer Activity in Thyroid Cancer Cells: Opportunities for Repurposing SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ACTIVATED-RECEPTOR-BETA/DELTA; CHEMICAL LIBRARIES; NA+/K+-ATPASE; INHIBITION; CYCLOOXYGENASE-2; CHEMOPREVENTION; PROSTATE; LINES; RISK; LUNG AB Context: Despite increased understanding of the pathogenesis and targets for thyroid cancer and other cancers, developing a new anticancer chemical agent remains an expensive and long process. An alternative approach is the exploitation of clinically used and/or bioactive compounds. Objective: Our objective was to identify agents with an anticancer effect in thyroid cancer cell lines using quantitative high-throughput screening (qHTS). Design: We used the newly assembled National Institutes of Health Chemical Genomic Center's pharmaceutical collection, which contains 2816 clinically approved drugs and bioactive compounds to perform qHTS. Results: Multiple agents, across a variety of therapeutic categories and with different modes of action, were found to have an antiproliferative effect. We found the following therapeutic categories were the most enriched categories with antiproliferative activity: cardiotonic and anti-obesity agents. Sixteen agents had an efficacy of greater than 60% and a 50% inhibitory concentration (IC50) in the nanomolar range. We validated the results of the qHTS using two agents (bortezomib and ouabain) in additional cell lines representing different histological subtypes of thyroid cancer and with different mutations (BRAF V600E, RET/PTC1, p53, PTEN). Both agents induced apoptosis, and ouabain also caused cell cycle arrest. Conclusions: To our knowledge, this is the first study to use qHTS of a large drug library to identify candidate drugs for anticancer therapy. Our results indicate such a screening approach can lead to the discovery of novel agents in different therapeutic categories and drugs with nonclassic chemotherapy mode of action. Our approach could lead to drug repurposing and accelerate clinical trials of compounds with well-established pharmacokinetics and toxicity profiles. (J Clin Endocrinol Metab 97: E319-E328, 2012) C1 [Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, Clin Res Ctr, Bethesda, MD 20892 USA. [Zhang, Yaqin; Shen, Min] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, Clin Res Ctr, Bldg 10 CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 34 TC 13 Z9 14 U1 0 U2 7 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 MAR PY 2012 VL 97 IS 3 BP E319 EP E328 DI 10.1210/jc.2011-2671 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 904WM UT WOS:000301229600001 PM 22170715 ER PT J AU Ozturk, F Park, PJ Tellez, J Colletti, E Eiden, MV Almeida-Porada, G Porada, CD AF Ozturk, Ferhat Park, Paul J. Tellez, Joseph Colletti, Evan Eiden, Maribeth V. Almeida-Porada, Graca Porada, Christopher D. TI Expression levels of the PiT-2 receptor explain, in part, the gestational age-dependent alterations in transduction efficiency after in utero retroviral-mediated gene transfer SO JOURNAL OF GENE MEDICINE LA English DT Article DE fetal gene therapy; retroviral vector; transduction; developmental regulation; PiT-2 receptor ID APE LEUKEMIA-VIRUS; BONE-MARROW-CELLS; MURINE; VECTORS; ENGRAFTMENT; INFECTION; THERAPY; PROTEIN; BLOOD; ENTRY AB Background A fundamental obstacle to using retroviral-mediated gene transfer (GT) to treat human diseases is the relatively low transduction levels that have been achieved in clinically relevant human cells. We previously showed that performing GT in utero overcomes this obstacle and results in significant levels of transduction within multiple fetal organs, with different tissues exhibiting optimal transduction at different developmental stages. We undertook the present study aiming to elucidate the mechanism for this age-dependent transduction, testing the two factors that we hypothesized could be responsible: (i) the proliferative status of the tissue at the time of GT and (ii) the expression level of the amphotropic PiT-2 receptor. Methods Immunofluorescence was performed on tissues from sheep of varying developmental stages to assess the proliferative status of the predominant cells within each organ as a function of age. After developing an enzyme-linked immunosorbent assay (ELISA) and a quantitative reverse transcription chain reaction (qRT-PCR) assay, we then quantified PiT-2 expression at the protein and mRNA levels, respectively. Results The results obtained indicate that the proliferative status of organs at the time of fetal GT is not the major determinant governing transduction efficiency. By contrast, our ELISA and qRT-PCR analyses demonstrated that PiT-2 mRNA and protein levels vary with gestational age, correlating with the observed differences in transduction efficiency. Conclusions The findings of the present study explain the age-related differences that we previously observed in transduction efficiency after in utero GT. They also suggest it may be possible to achieve relatively selective GT to specific tissues by performing in utero GT when levels of PiT-2 are maximal in the desired target organ. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Ozturk, Ferhat; Park, Paul J.; Tellez, Joseph; Colletti, Evan; Almeida-Porada, Graca; Porada, Christopher D.] Univ Nevada, Dept Anim Biotechnol, Reno, NV 89557 USA. [Eiden, Maribeth V.] NIMH, Sect Mol Virol, LCMR, Bethesda, MD 20892 USA. RP Porada, CD (reprint author), Wake Forest Inst Regenerat Med, Richard H Dean Biomed Bldg,4th Floor,391 Tecnol W, Winston Salem, NC 27157 USA. EM cporada@wfubmc.edu RI Ozturk, Ferhat/F-9983-2013 OI Ozturk, Ferhat/0000-0003-3066-1638 FU National Institutes of Health [HD43038] FX This work was supported by grant #HD43038 from the National Institutes of Health. NR 22 TC 1 Z9 1 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD MAR PY 2012 VL 14 IS 3 BP 169 EP 181 DI 10.1002/jgm.2607 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 911IL UT WOS:000301710400005 PM 22262359 ER PT J AU Lohith, TG Zoghbi, SS Morse, CL Araneta, MF Barth, VN Goebl, NA Tauscher, JT Pike, VW Innis, RB Fujita, M AF Lohith, Talakad G. Zoghbi, Sami S. Morse, Cheryl L. Araneta, Maria F. Barth, Vanessa N. Goebl, Nancy A. Tauscher, Johannes T. Pike, Victor W. Innis, Robert B. Fujita, Masahiro TI Brain and Whole-Body Imaging of Nociceptin/Orphanin FQ Peptide Receptor in Humans Using the PET Ligand C-11-NOP-1A SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE NOP receptors; nociceptin; opioid receptor; PET; receptor imaging ID POSITRON-EMISSION-TOMOGRAPHY; ALCOHOL-DRINKING; MESSENGER-RNA; RADIOLIGAND; BINDING; AGONIST; ACTIVATION; EXPRESSION; ORL1 AB Nociceptin/orphanin FQ peptide (NOP) receptor is a new class of opioid receptor that may play a pathophysiologic role in anxiety and drug abuse and is a potential therapeutic target in these disorders. We previously developed a high-affinity PET ligand, C-11-NOP-1A, which yielded promising results in monkey brain. Here, we assessed the ability of C-11-NOP-1A to quantify NOP receptors in human brain and estimated its radiation safety profile. Methods: After intravenous injection of C-11-NOP-1A, 7 healthy subjects underwent brain PET for 2 h and serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (V-T; a measure of receptor density) was determined by compartmental (1- and 2-tissue) and noncompartmental (Logan analysis and Ichise's bilinear analysis [MA1]) methods. A separate group of 9 healthy subjects underwent whole-body PET to estimate whole-body radiation exposure (effective dose). Results: After 11C-NOP-1A injection, the peak concentration of radioactivity in brain was high (similar to 5-7 standardized uptake values), occurred early (similar to 10 min), and then washed out quickly. The unconstrained 2-tissue-compartment model gave excellent V-T identifiability (similar to 1.1% SE) and fitted the data better than a 1-tissue-compartment model. Regional V-T values (mL.cm(-3)) ranged from 10.1 in temporal cortex to 5.6 in cerebellum. VT was well identified in the initial 70 min of imaging and remained stable for the remaining 50 min, suggesting that brain radioactivity was most likely parent radioligand, as supported by the fact that all plasma radiometabolites of C-11-NOP-1A were less lipophilic than the parent radioligand. Voxel-based MA1 V-T values correlated well with results from the 2-tissue-compartment model, showing that parametric methods can be used to compare populations. Whole-body scans showed radioactivity in brain and in peripheral organs expressing NOP receptors, such as heart, pancreas, and spleen. C-11-NOP-1A was significantly metabolized and excreted via the hepatobiliary route. Gallbladder had the highest radiation exposure (21 mu Sv/MBq), and the effective dose was 4.3 mu Sv/MBq. Conclusion: C-11-NOP-1A is a promising radioligand that reliably quantifies NOP receptors in human brain. The effective dose in humans is low and similar to that of other C-11-labeled radioligands, allowing multiple scans in 1 subject. C1 [Lohith, Talakad G.; Zoghbi, Sami S.; Morse, Cheryl L.; Araneta, Maria F.; Pike, Victor W.; Innis, Robert B.; Fujita, Masahiro] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Barth, Vanessa N.; Goebl, Nancy A.; Tauscher, Johannes T.] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM robert.innis@nih.gov RI Tauscher, Johannes/M-5976-2016 FU National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); Cooperative Research and Development Agreement; Eli Lilly Co. FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH), and by a Cooperative Research and Development Agreement with Eli Lilly & Co. We thank Denise Rallis-Frutos, Gerald L. Hodges, Kimberly Jenko, David Clark, Jeih-San Liow, Robert L. Gladding, and the staff of the PET Department for assistance in successful completion of the studies, and PMOD Technologies (Zurich, Switzerland) for providing its image analysis and modeling software. Ioline Henter provided invaluable editorial assistance. No other potential conflict of interest relevant to this article was reported. NR 26 TC 21 Z9 21 U1 1 U2 7 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAR 1 PY 2012 VL 53 IS 3 BP 385 EP 392 DI 10.2967/jnumed.111.097162 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 904KL UT WOS:000301194300034 PM 22312136 ER PT J AU Coleman, CN Lurie, N AF Coleman, C. Norman Lurie, Nicole TI Emergency medical preparedness for radiological/nuclear incidents in the United States SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article AB The Office of the Assistant Secretary for Preparedness and Response in the Department of Health and Human Services develops health and medical response plans for all hazards-natural and human caused. While a nuclear power plant (NPP) incident will take time to evolve, a terrorist incident will have 'no-notice' so that extensive preparation and planning are essential. For radiological/nuclear (rad/nuc) incidents we have developed and continue to refine detailed plans and tools for medical responders for a nuclear detonation and a radiological dispersal device, which also serve for any type of rad/nuc incident. The plans are based on the best available basic science with the goal of providing planners and responders with just-in-time information and tools. There is much in common across the range of hazards, so that the products developed for rad/nuc incidents have helped overall preparedness. A major consideration in the development of new diagnostics, medical treatment and countermeasures for radiation injury is that of 'dual utility' with potential for routine medical use for cancer care. Participation and collaboration among nations helping the Japanese response to the Fukushima earthquake, tsunami and NPP disaster demonstrated the benefit of preparation and ongoing worldwide cooperation among experts. C1 [Coleman, C. Norman] NCI, Off Assistant Secretary Preparedness & Response A, Washington, DC USA. NCI, DHHS, Washington, DC USA. RP Coleman, CN (reprint author), NCI, Off Assistant Secretary Preparedness & Response A, Washington, DC USA. EM ccoleman@mail.nih.gov NR 16 TC 2 Z9 2 U1 0 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 J9 J RADIOL PROT JI J. Radiol. Prot. PD MAR PY 2012 VL 32 IS 1 BP N27 EP N32 DI 10.1088/0952-4746/32/1/N27 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 906ND UT WOS:000301351200009 PM 22395159 ER PT J AU Tronko, M Mabuchi, K Bogdanova, T Hatch, M Likhtarev, I Bouville, A Oliynik, V McConnell, R Shpak, V Zablotska, L Tereshchenko, V Brenner, A Zamotayeva, G AF Tronko, Mykola Mabuchi, Kiyohiko Bogdanova, Tetiana Hatch, Maureen Likhtarev, Ilya Bouville, Andre Oliynik, Valeriy McConnell, Robert Shpak, Viktor Zablotska, Lydia Tereshchenko, Valeriy Brenner, Alina Zamotayeva, Galyna TI Thyroid cancer in Ukraine after the Chernobyl accident (in the framework of the Ukraine-US Thyroid Project) SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article ID DISEASES; COHORT AB As a result of the accident at the Chernobyl Nuclear Power Plant, millions of residents of Belarus, Russia, and Ukraine were exposed to large doses of radioactive iodine isotopes, mainly I-131. The purpose of the Ukraine-American (UkrAm) and Belarus-American (BelAm) projects are to quantify the risks of thyroid cancer in the framework of a classical cohort study, comprising subjects who were aged under 18 years at the time of the accident, had direct measurements of thyroid I-131 radioactivity taken within two months after the accident, and were residents of three heavily contaminated northern regions of Ukraine (Zhitomir, Kiev, and Chernigov regions). Four two-year screening examination cycles were implemented from 1998 until 2007 to study the risks associated with thyroid cancer due to the iodine exposure caused during the Chernobyl accident. A standardised procedure of clinical examinations included: thyroid palpation, ultrasound examination, blood collection followed by a determination of thyroid hormone levels, urinary iodine content test, and fine-needle aspiration if required. Among the 110 cases of thyroid cancer diagnosed in UkrAm as the result of four screening examinations, 104 cases (94.5%) of papillary carcinomas, five cases (4.6%) of follicular carcinomas, and one case (0.9%) of medullary carcinoma were diagnosed. C1 [Tronko, Mykola; Bogdanova, Tetiana; Oliynik, Valeriy; Shpak, Viktor; Tereshchenko, Valeriy; Zamotayeva, Galyna] Ukraine Acad Med Sci, State Inst, VP Komisarenko Inst Endocrinol & Metab, UA-04114 Kiev, Ukraine. [Mabuchi, Kiyohiko; Hatch, Maureen; Bouville, Andre; Brenner, Alina] Natl Canc Inst USA, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Rockville, MD USA. [Likhtarev, Ilya] Natl Acad Med Sci Ukraine, Res Ctr Radiat Med, Kiev, Ukraine. [McConnell, Robert] Columbia Univ, Coll Phys & Surg, Thyroid Clin, Dept Med, New York, NY USA. [Zablotska, Lydia] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco Sch Med, San Francisco, CA 94143 USA. RP Tronko, M (reprint author), Ukraine Acad Med Sci, State Inst, VP Komisarenko Inst Endocrinol & Metab, Vyshgorodska 69, UA-04114 Kiev, Ukraine. EM m.tronko@dccie.kiev.ua FU Intramural NIH HHS [ZIA CP010132-18] NR 9 TC 6 Z9 6 U1 1 U2 7 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 J9 J RADIOL PROT JI J. Radiol. Prot. PD MAR PY 2012 VL 32 IS 1 BP N65 EP N69 DI 10.1088/0952-4746/32/1/N65 PG 5 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 906ND UT WOS:000301351200016 PM 22394669 ER PT J AU Ayres, EJ Hoggle, LB AF Ayres, Elaine J. Hoggle, Lindsey B. TI 2011 Nutrition Informatics Member Survey SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article C1 [Ayres, Elaine J.] NIH, Lab Informat Dev, Ctr Clin, Bethesda, MD 20892 USA. [Hoggle, Lindsey B.] Acad Nutr & Dietet, Washington, DC USA. RP Ayres, EJ (reprint author), NIH, Lab Informat Dev, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. FU Laboratory for Informatics Development, NIH Clinical Center, National Institutes of Health FX This work was supported by the Laboratory for Informatics Development, NIH Clinical Center, National Institutes of Health. The 2010-2011 Nutrition Informatics Committee: Martin Yadrick, MBA, MS, RD, FADA; Margaret Dittloff, MS, RD; Nancy Collins, PhD, RD, LDN; Phyllis McShane, MS, RD, LDN; and Amy Miller, RD, provided excellent assistance with content and testing. Academy staff support was provided by Diane Juskelis, MS, RD, LDN, and Harold Holler, RD, LDN. The HIMSS Analytics collaborator was Jennifer Horowitz. NR 3 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD MAR PY 2012 VL 112 IS 3 BP 360 EP + DI 10.1016/j.jand.2012.01.003 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 905VU UT WOS:000301305100003 PM 22709663 ER PT J AU Habbema, D de Kok, IMCM Brown, ML AF Habbema, Dik de Kok, Inge M. C. M. Brown, Martin L. TI Cervical Cancer Screening in the United States and the Netherlands: A Tale of Two Countries SO MILBANK QUARTERLY LA English DT Article DE Cancer; screening; pap testing; comparative effectiveness; clinical guidelines; cross-country study; preventive services; health care policy; economic efficiency ID EARLY-DETECTION PROGRAM; HUMAN-PAPILLOMAVIRUS; COST-EFFECTIVENESS; NATIONAL BREAST; HEALTH; WOMEN; RISK; PAP; US; PREVALENCE AB Context: This article compares cervical cancer screening intensity and cervical cancer mortality trends in the United States and the Netherlands to illustrate the potential of cross-national comparative studies. We discuss the lessons that can be learned from the comparison as well as the challenges in each country to effective and efficient screening. Methods: We used nationally representative data sources in the United States and the Netherlands to estimate the number of Pap smears and the cervical cancer mortality rate since 1950. The following questions are addressed: How do differences in intensity of Pap smear use between the countries translate into differences in mortality trends? Can population coverage rates ( the proportion of eligible women who had a Pap smear within a specified period) explain the mortality trends better than the total intensity of Pap smear use? Findings: Even though three to four times more Pap smears per woman were conducted in the United States than in the Netherlands over a period of three decades, the two countries' mortality trends were quite similar. The five-year coverage rates for women aged thirty to sixty-four were quite comparable at 80 to 90 percent. Because screening in the Netherlands was limited to ages thirty to sixty, screening rates for women under thirty and over sixty were much higher in the United States. These differences had consequences for age-specific mortality trends. The relatively good coverage rate in the Netherlands can be traced back to a nationwide invitation system based on municipal population registries. While both countries followed a "policy cycle" involving evidence review, surveillance of screening practices and outcomes, clinical guidelines, and reimbursement policies, the components of this cycle were more systematically linked and implemented nationwide in the Netherlands than in the United States. To a large extent, this was facilitated by a public health model of screening in the Netherlands, rather than a medical services model. Conclusions: Cross-country studies like ours are natural experiments that can produce insights not easily obtained from other types of study. The cervical cancer screening system in the Netherlands seems to have been as effective as the U. S. system but used much less screening. Adequate coverage of the female population at risk seems to be of central importance. C1 [Brown, Martin L.] NCI, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. [Habbema, Dik; de Kok, Inge M. C. M.] Erasmus MC Univ, Med Ctr, Rotterdam, Netherlands. RP Brown, ML (reprint author), NCI, Hlth Serv & Econ Branch, 6130 Execut Blvd,EPN 4005, Bethesda, MD 20892 USA. EM mb53o@nih.gov NR 74 TC 32 Z9 32 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-378X J9 MILBANK Q JI Milbank Q. PD MAR PY 2012 VL 90 IS 1 BP 5 EP 37 DI 10.1111/j.1468-0009.2011.00652.x PG 33 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 910OO UT WOS:000301649300002 PM 22428690 ER PT J AU Kelly, RJ Sharon, E Pastan, I Hassan, R AF Kelly, Ronan J. Sharon, Elad Pastan, Ira Hassan, Raffit TI Mesothelin-Targeted Agents in Clinical Trials and in Preclinical Development SO MOLECULAR CANCER THERAPEUTICS LA English DT Review ID MONOCLONAL-ANTIBODY MORAB-009; PANCREATIC-CANCER; OVARIAN-CANCER; ANTITUMOR-ACTIVITY; IMMUNOTOXIN SS1P; IN-VITRO; T-CELLS; PHASE-I; RECOMBINANT IMMUNOTOXIN; TUMOR XENOGRAFTS AB Mesothelin is a tumor differentiation antigen that is highly expressed in several malignant diseases in humans, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissues and its high expression in many common cancers make it an attractive candidate for cancer therapy. Several agents, including an immunotoxin, monoclonal antibody, antibody drug conjugate, and tumor vaccine, are in various stages of development to treat patients with mesothelin-expressing tumors. This review highlights ongoing clinical trials, as well as other approaches to exploit mesothelin for cancer therapy, that are in preclinical development. Mol Cancer Ther; 11(3); 517-25. (C) 2012 AACR. C1 [Pastan, Ira; Hassan, Raffit] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kelly, Ronan J.; Sharon, Elad] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Rm 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 56 TC 49 Z9 50 U1 3 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2012 VL 11 IS 3 BP 517 EP 525 DI 10.1158/1535-7163.MCT-11-0454 PG 9 WC Oncology SC Oncology GA 904WL UT WOS:000301229500001 PM 22351743 ER PT J AU Yong, KJ Milenic, DE Baidoo, KE Brechbiel, MW AF Yong, Kwon Joong Milenic, Diane E. Baidoo, Kwamena E. Brechbiel, Martin W. TI Pb-212-Radioimmunotherapy Induces G(2) Cell-Cycle Arrest and Delays DNA Damage Repair in Tumor Xenografts in a Model for Disseminated Intraperitoneal Disease SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ALPHA-PARTICLE RADIOIMMUNOTHERAPY; DISSEMINATED PERITONEAL DISEASE; CANCER CELLS; IN-VITRO; IONIZING-RADIATION; CLINICAL-TRIALS; TARGETING HER2; APOPTOSIS; INDUCTION; TRASTUZUMAB AB In preclinical studies, targeted radioimmunotherapy using (212)pb-TCMC-trastuzumab as an in vivo generator of the high-energy a-particle emitting radionuclide Bi-212 is proving an efficacious modality for the treatment of disseminated peritoneal cancers. To elucidate mechanisms associated with this therapy, mice bearing human colon cancer LS-174T intraperitoneal xenografts were treated with (212)pb-TCMC-trastuzumab and compared with the nonspecific control (212)pb-TCMC-HuIgG, unlabeled trastuzumab, and HuIgG, as well as untreated controls. (212)pb-TCMC-trastuzumab treatment induced significantly more apoptosis and DNA double-strand breaks (DSB) at 24 hours. Rad51 protein expression was downregulated, indicating delayed DNA double-strand damage repair compared with (212)pb-TCMC-HuIgG, the nonspecific control. (212)pb-TCMC-trastuzumab treatment also caused G2-M arrest, depression of the S phase fraction, and depressed DNA synthesis that persisted beyond 120 hours. In contrast, the effects produced by (212)pb-TCMC-HuIgG seemed to rebound by 120 hours. In addition, (212)pb-TCMC-trastuzumab treatment delayed open chromatin structure and expression of p21 until 72 hours, suggesting a correlation between induction of p21 protein and modification in chromatin structure of p21 in response to (212)pb-TCMC-trastuzumab treatment. Taken together, increased DNA DSBs, impaired DNA damage repair, persistent G(2)-M arrest, and chromatin remodeling were associated with (212)pb-TCMC-trastuzumab treatment and may explain its increased cell killing efficacy in the LS-174T intraperitoneal xenograft model for disseminated intraperitoneal disease. Mol Cancer Ther; 11(3); 639-48. (C) 2012 AACR. C1 [Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bldg 10,Room B3B69,10 Ctr Dr, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 48 TC 21 Z9 21 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2012 VL 11 IS 3 BP 639 EP 648 DI 10.1158/1535-7163.MCT-11-0671 PG 10 WC Oncology SC Oncology GA 904WL UT WOS:000301229500012 PM 22238365 ER PT J AU Chu, C Hsu, AL Chou, KH Bandettini, P Lin, CP AF Chu, Carlton Hsu, Ai-Ling Chou, Kun-Hsien Bandettini, Peter Lin, ChingPo CA Alzheimer's Dis Neuroimaging TI Does feature selection improve classification accuracy? Impact of sample size and feature selection on classification using anatomical magnetic resonance images SO NEUROIMAGE LA English DT Article DE Feature selection; Support vector machine (SVM); Diseases classification; Recursive feature elimination (RFE) ID MILD COGNITIVE IMPAIRMENT; VOXEL-BASED MORPHOMETRY; SUPPORT VECTOR MACHINES; FMRI ACTIVITY PATTERNS; ALZHEIMERS-DISEASE; FUNCTIONAL MRI; MATTER LOSS; PREDICTION; REGRESSION; NETWORKS AB There are growing numbers of studies using machine learning approaches to characterize patterns of anatomical difference discernible from neuroimaging data. The high-dimensionality of image data often raises a concern that feature selection is needed to obtain optimal accuracy. Among previous studies, mostly using fixed sample sizes, some show greater predictive accuracies with feature selection, whereas others do not. In this study, we compared four common feature selection methods. 1) Pre-selected region of interests (ROIs) that are based on prior knowledge. 2) Univariate t-test filtering. 3) Recursive feature elimination (RFE), and 4) t-test filtering constrained by ROIs. The predictive accuracies achieved from different sample sizes, with and without feature selection, were compared statistically. To demonstrate the effect, we used grey matter segmented from the T1-weighted anatomical scans collected by the Alzheimer's disease Neuroimaging Initiative (ADNI) as the input features to a linear support vector machine classifier. The objective was to characterize the patterns of difference between Alzheimer's disease (AD) patients and cognitively normal subjects, and also to characterize the difference between mild cognitive impairment (MCI) patients and normal subjects. In addition, we also compared the classification accuracies between MCI patients who converted to AD and MCI patients who did not convert within the period of 12 months. Predictive accuracies from two data-driven feature selection methods (t-test filtering and RFE) were no better than those achieved using whole brain data. We showed that we could achieve the most accurate characterizations by using prior knowledge of where to expect neurodegeneration (hippocampus and parahippocampal gyrus). Therefore, feature selection does improve the classification accuracies, but it depends on the method adopted. In general, larger sample sizes yielded higher accuracies with less advantage obtained by using knowledge from the existing literature. (C) 2011 Elsevier Inc. All rights reserved. C1 [Chou, Kun-Hsien; Lin, ChingPo] Natl Yang Ming Univ, Inst Neurosci, Brain Connect Lab, Taipei 112, Taiwan. [Chu, Carlton; Bandettini, Peter] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Hsu, Ai-Ling; Lin, ChingPo] Natl Yang Ming Univ, Inst Brain Sci, Taipei 112, Taiwan. RP Lin, CP (reprint author), Natl Yang Ming Univ, Inst Neurosci, Brain Connect Lab, 155 Nong St,Sec 2, Taipei 112, Taiwan. EM cplin@ym.edu.tw RI Bandettini, Peter/F-5871-2012; Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007 OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532 FU NIH; NIMH; National Science Council of Taiwan [NSC 100-2628-E-010-002-MY3, NSC 100-2627-B-010-004-]; National Health Research Institute [NHRI-EX100-9813EC]; Wellcome Trust; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering (NIBIB) FX This research was supported in part by the Intramural Research Program of the NIH, NIMH, National Science Council of Taiwan (NSC 100-2628-E-010-002-MY3, NSC 100-2627-B-010-004-) and National Health Research Institute (NHRI-EX100-9813EC). JA is funded by the Wellcome Trust. 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).; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co.,Medpace, Inc.,Merck and Co., Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., as well as non-profit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the U.S. Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. NR 48 TC 75 Z9 79 U1 5 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2012 VL 60 IS 1 BP 59 EP 70 DI 10.1016/j.neuroimage.2011.11.066 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 904SR UT WOS:000301218700007 PM 22166797 ER PT J AU Robinson, OJ Charney, DR Overstreet, C Vytal, K Grillon, C AF Robinson, Oliver J. Charney, Danielle R. Overstreet, Cassie Vytal, Katherine Grillon, Christian TI The adaptive threat bias in anxiety: Amygdala-dorsomedial prefrontal cortex coupling and aversive amplification SO NEUROIMAGE LA English DT Article DE Amygdala; DMPFC; Functional connectivity; Prelimbic; Anxiety; Threat bias ID ANTERIOR CINGULATE CORTEX; COGNITIVE CONTROL; CONDITIONED FEAR; HUMANS; EXTINCTION; MECHANISMS; EXPRESSION; BRAIN; DEPRESSION; ACTIVATION AB Functionally, anxiety serves to increase vigilance towards aversive stimuli and improve the ability to detect and avoid danger. We have recently shown, for instance, that anxiety increases the ability to a) detect and b) instigate defensive responses towards aversive and not appetitive face stimuli in healthy individuals. This is arguably the key adaptive function of anxiety, yet the neural circuitry underlying this valence-specific effect is unknown. In the present translational study, we sought evidence for the proposition that dorsomedial regions of the prefrontal (DMPFC) and cingulate cortex constitute the human homologue of the rodent prelimbic and are thus associated with increased amygdala responding during this adaptive threat bias in anxiety. To this end, we applied a novel functional connectivity analysis to healthy subjects (N=20) identifying the emotion of fearful and happy faces in an fMRI scanner under anxious (threat of unpredictable foot shock) and non-anxious (safe) conditions. We showed that anxiety significantly increased positive DMPFC-amygdala connectivity during the processing of fearful faces. This effect was a) valence-specific (it was not seen for happy faces), b) paralleled by faster behavioral response to fearful faces, and c) correlated positively with trait anxiety. As such we provide the first experimental support for an anxiety-mediated, valence-specific, DMPFC-amygdala aversive amplification mechanism in healthy humans. This may be homologous to the rodent prelimbic-amygdala circuit and may, given the relationship with trait anxiety, underlie vulnerability to anxiety disorders. This study thus pinpoints a key neural mechanism in adaptive anxiety and highlights its potential link to maladaptive anxiety. Published by Elsevier Inc. C1 [Robinson, Oliver J.] NIMH, MAP, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. RP Robinson, OJ (reprint author), NIMH, MAP, Sect Neurobiol Fear & Anxiety, NIH, 15K North Dr,Room 203,MSC 2670, Bethesda, MD 20892 USA. EM oliver.j.robinson@gmail.com RI Robinson, Oliver/B-3646-2011 OI Robinson, Oliver/0000-0002-3100-1132 FU National Institutes of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Mental Health. We would like to thank Angie Wu and Jeannette Black for the invaluable participation and technical support and Stephen Fromm for fMRI analysis discussions. This work was presented in part at the Society for Psychophysiological Research in Boston, September 2011. NR 37 TC 59 Z9 61 U1 1 U2 37 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 MAR PY 2012 VL 60 IS 1 BP 523 EP 529 DI 10.1016/j.neuroimage.2011.11.096 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 904SR UT WOS:000301218700053 PM 22178453 ER PT J AU Bulte, DP Kelly, M Germuska, M Xie, J Chappell, MA Okell, TW Bright, MG Jezzard, P AF Bulte, D. P. Kelly, M. Germuska, M. Xie, J. Chappell, M. A. Okell, T. W. Bright, M. G. Jezzard, P. TI Quantitative measurement of cerebral physiology using respiratory-calibrated MRI SO NEUROIMAGE LA English DT Article DE FMRI; Hyperoxia; Hypercapnia; CMRO2 ID OXYGEN EXTRACTION FRACTION; SPIN-LABELING MRI; POSITRON-EMISSION-TOMOGRAPHY; BLOOD-FLOW; BOLD-FMRI; CEREBROVASCULAR REACTIVITY; OXIDATIVE-METABOLISM; CARBON-DIOXIDE; FUNCTIONAL MRI; HUMAN BRAIN AB Functional magnetic resonance imaging typically measures signal increases arising from changes in the transverse relaxation rate over small regions of the brain and associates these with local changes in cerebral blood flow, blood volume and oxygen metabolism. Recent developments in pulse sequences and image analysis methods have improved the specificity of the measurements by focussing on changes in blood flow or changes in blood volume alone. However. FMRI is still unable to match the physiological information obtainable from positron emission tomography (PET), which is capable of quantitative measurements of blood flow and volume, and can indirectly measure resting metabolism. The disadvantages of PET are its cost, its availability, its poor spatial resolution and its use of ionising radiation. The MRI techniques introduced here address some of these limitations and provide physiological data comparable with PET measurements. We present an 18-minute MRI protocol that produces multi-slice whole-brain coverage and yields quantitative images of resting cerebral blood flow, cerebral blood volume, oxygen extraction fraction, CMRO2, arterial arrival time and cerebrovascular reactivity of the human brain in the absence of any specific functional task. The technique uses a combined hyperoxia and hypercapnia paradigm with a modified arterial spin labelling sequence. (C) 2011 Elsevier Inc. All rights reserved. C1 [Bulte, D. P.; Kelly, M.; Germuska, M.; Xie, J.; Chappell, M. A.; Okell, T. W.; Bright, M. G.; Jezzard, P.] Univ Oxford, FMRIB Ctr, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England. [Chappell, M. A.] Univ Oxford, Dept Engn Sci, Inst Biomed Engn, Oxford OX3 9DU, England. [Bright, M. G.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. [Bright, M. G.] Cardiff Univ, Sch Psychol, Brain Res Imaging Ctr, Cardiff, S Glam, Wales. RP Bulte, DP (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, FMRIB Ctr, Oxford OX3 9DU, England. EM bulte@fmrib.ox.ac.uk RI Bright, Molly/F-6394-2010; OI Bright, Molly/0000-0001-7257-9646; Okell, Thomas/0000-0001-8258-0659; Jezzard, Peter/0000-0001-7912-2251; Chappell, Michael/0000-0003-1802-4214 FU Engineering and Physical Research Council of the United Kingdom; UK Medical Research Council; Dunhill Medical Trust; Wellcome Trust; NIHR Oxford Biomedical Research Centre FX This research was supported by the Engineering and Physical Research Council of the United Kingdom, the UK Medical Research Council, the Dunhill Medical Trust, the Wellcome Trust, and the NIHR Oxford Biomedical Research Centre. NR 67 TC 64 Z9 64 U1 2 U2 15 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 MAR PY 2012 VL 60 IS 1 BP 582 EP 591 DI 10.1016/j.neuroimage.2011.12.017 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 904SR UT WOS:000301218700060 PM 22209811 ER PT J AU Weise, CM Thiyyagura, P Reiman, EM Chen, KW Krakoff, J AF Weise, Christopher M. Thiyyagura, Pradeep Reiman, Eric M. Chen, Kewei Krakoff, Jonathan TI Postprandial plasma PYY concentrations are associated with increased regional gray matter volume and rCBF declines in caudate nuclei - A combined MRI and (H2O)-O-15 PET study SO NEUROIMAGE LA English DT Article DE PYY; Caudate nucleus; Striatum; Gray matter; VBM; MRI; PET; rCBF ID NEUROPEPTIDE-Y; PEPTIDE-YY; FOOD-INTAKE; OBESE SUBJECTS; GUT HORMONE; RAT-BRAIN; PREFRONTAL CORTEX; RECEPTOR SUBTYPES; DECISION-MAKING; DOPAMINE AB The anorexigenic gastrointestinal hormone Peptide YY plays an important role in the communication between the gastrointestinal tract and the central nervous system. PYY has been shown to modulate brain activity in regions implicated in reward and food related behavior. Its effects on brain structure however, remain unknown. Voxel-based morphometry was used to investigate the relationship between fasting and postprandial plasma PYY concentrations and regional gray matter volume (GMV). For this analysis twenty adult, non diabetic Caucasians were included (18 F/2 M, age 31 +/- 9 y, percentage of body fat [PFAT] 32 +/- 8%) who had volumetric brain magnetic resonance images and underwent (H2O)-O-15 positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF), a marker of local neuronal activity, and measurements of plasma total PYY, prior to (fasting) and following a satiating liquid meal. Voxel-wise analysis revealed a regional positive association between postprandial PYY and gray matter volume bilaterally in the caudate nuclei. These associations remained significant (p<0.05) after small volume correction for multiple comparisons. Based on these findings we investigated whether postprandial PYY is associated with PET measured rCBF of the caudate nucleus. We found a significant negative association between average postprandial caudate rCBF and postprandial plasma PYY concentrations (r = -0.60, p<0.02, age, sex and PFAT adjusted). Average postprandial caudate rCBF was also negatively associated with rCBF in the right medial orbitofrontal cortex and the right hippocampal formation (p<0.05, corrected for multiple comparisons). Total PYY is positively associated with gray matter but negatively with postprandial activity in the caudate nuclei while caudate activity is negatively associated with rCBF in prefrontal and paralimbic regions implicated in reward behavior. Thus, PYY may act centrally to modulate eating behavior via striatal networks. Published by Elsevier Inc. C1 [Weise, Christopher M.] NIDDK, NIH, PECRB, Obes & Diabet Clin Res Sect,DHHS, Phoenix, AZ 85016 USA. [Thiyyagura, Pradeep; Reiman, Eric M.; Chen, Kewei] Banner Alzheimers Inst, Dept Psychiat, Phoenix, AZ USA. [Reiman, Eric M.] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA. RP Weise, CM (reprint author), NIDDK, NIH, PECRB, Obes & Diabet Clin Res Sect,DHHS, 4212 N 16th St, Phoenix, AZ 85016 USA. EM christopher.weise@nih.gov RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 FU Intramural NIH HHS [Z99 DK999999] NR 68 TC 4 Z9 4 U1 2 U2 7 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 MAR PY 2012 VL 60 IS 1 BP 592 EP 600 DI 10.1016/j.neuroimage.2011.12.023 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 904SR UT WOS:000301218700061 PM 22206963 ER PT J AU Chen, G Saad, ZS Nath, AR Beauchamp, MS Cox, RW AF Chen, Gang Saad, Ziad S. Nath, Audrey R. Beauchamp, Michael S. Cox, Robert W. TI FMRI group analysis combining effect estimates and their variances SO NEUROIMAGE LA English DT Article DE FMRI group analysis; Effect estimate precision or reliability; Mixed-effects multilevel analysis (MEMA); Weighted least squares (WLS); Restricted maximum likelihood (REML); Outliers; AFNI ID EFFECTS META-REGRESSION; RANDOM-EFFECTS MODEL; METAANALYSIS; INFERENCE; HETEROGENEITY; TESTS; BIAS AB Conventional functional magnetic resonance imaging (FMRI) group analysis makes two key assumptions that are not always justified. First, the data from each subject is condensed into a single number per voxel, under the assumption that within-subject variance for the effect of interest is the same across all subjects or is negligible relative to the cross-subject variance. Second, it is assumed that all data values are drawn from the same Gaussian distribution with no outliers. We propose an approach that does not make such strong assumptions, and present a computationally efficient frequentist approach to FMRI group analysis, which we term mixed-effects multilevel analysis (MEMA), that incorporates both the variability across subjects and the precision estimate of each effect of interest from individual subject analyses. On average, the more accurate tests result in higher statistical power, especially when conventional variance assumptions do not hold, or in the presence of outliers. In addition, various heterogeneity measures are available with MEMA that may assist the investigator in further improving the modeling. Our method allows group effect t-tests and comparisons among conditions and among groups. In addition, it has the capability to incorporate subject-specific covariates such as age, IQ or behavioral data. Simulations were performed to illustrate power comparisons and the capability of controlling type I errors among various significance testing methods, and the results indicated that the testing statistic we adopted struck a good balance between power gain and type I error control. Our approach is instantiated in an open-source, freely distributed program that may be used on any dataset stored in the universal neuroimaging file transfer (NIfTI) format. To date, the main impediment for more accurate testing that incorporates both within- and cross-subject variability has been the high computational cost. Our efficient implementation makes this approach practical. We recommend its use in lieu of the less accurate approach in the conventional group analysis. Published by Elsevier Inc. C1 [Chen, Gang; Saad, Ziad S.; Cox, Robert W.] NIMH, NIH, DHHS, Bethesda, MD 20892 USA. [Nath, Audrey R.; Beauchamp, Michael S.] Univ Texas Med Sch Houston, Dept Neurobiol & Anat, Houston, TX 77030 USA. RP Chen, G (reprint author), NIMH, NIH, DHHS, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gangchen@mail.nih.gov OI Beauchamp, Michael/0000-0002-7599-9934 FU NIMH; NIH [R01N5065395]; NSF [642532] FX We are indebted to Wolfgang Viechtbauer for theoretical consultation and programming support, to Xiang-Gui Qu for the help in mathematical derivation, to Rick Reynolds for assisting in data analysis, and to anonymous reviewers for simulation suggestions. Writing of this paper was supported by the NIMH and NINDS Intramural Research Programs of the NIH. This research was also supported by NSF 642532 and NIH R01N5065395 to MSB. NR 40 TC 50 Z9 50 U1 2 U2 15 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 MAR PY 2012 VL 60 IS 1 BP 747 EP 765 DI 10.1016/j.neuroimage.2011.12.060 PG 19 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 904SR UT WOS:000301218700076 PM 22245637 ER PT J AU Ross, OA Singleton, AB AF Ross, Owen A. Singleton, Andrew B. TI Does trans size matter in Huntington disease? SO NEUROLOGY LA English DT Editorial Material ID REPEAT; ONSET; AGE C1 [Ross, Owen A.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Ross, OA (reprint author), Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. EM ross.owen@mayo.edu RI Singleton, Andrew/C-3010-2009; Ross, Owen/D-7573-2013 FU NIA NIH HHS [Z01 AG000957-09]; NINDS NIH HHS [1RC2NS070276, P50 NS072187] NR 7 TC 0 Z9 0 U1 1 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 MAR PY 2012 VL 78 IS 10 BP 686 EP 687 DI 10.1212/WNL.0b013e3182494d77 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 904YR UT WOS:000301236400002 PM 22323751 ER PT J AU Bandmann, O Cookson, MR AF Bandmann, Oliver Cookson, Mark R. TI Parkinson disease, cancer, and LRRK2 Causation or association? SO NEUROLOGY LA English DT Editorial Material ID MUTATIONS C1 [Bandmann, Oliver] Univ Sheffield, SITraN, Dept Neurosci, Sheffield, S Yorkshire, England. [Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Bandmann, O (reprint author), Univ Sheffield, SITraN, Dept Neurosci, Sheffield, S Yorkshire, England. EM o.bandmann@sheffield.ac.uk FU Parkinson's UK [G-1007, G-1202, G-0715] NR 11 TC 6 Z9 6 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 MAR PY 2012 VL 78 IS 11 BP 772 EP 773 DI 10.1212/WNL.0b013e318249f744 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 907VW UT WOS:000301448300003 PM 22323745 ER PT J AU Chanyshev, B Shainberg, A Isak, A Litinsky, A Chepurko, Y Tosh, DK Phan, K Gao, ZG Hochhauser, E Jacobson, KA AF Chanyshev, Bella Shainberg, Asher Isak, Ahuva Litinsky, Alexandra Chepurko, Yelena Tosh, Dilip K. Khai Phan Gao, Zhan-Guo Hochhauser, Edith Jacobson, Kenneth A. TI Anti-ischemic effects of multivalent dendrimeric A(3) adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart SO PHARMACOLOGICAL RESEARCH LA English DT Article DE Dendrimer; Cardiomyocyte; Adenosine receptor; Ischemia; Isolated heart; Rat ID ISCHEMIA/REPERFUSION INJURY; MYOCARDIAL INFARCT; CARDIAC MYOCYTES; CLICK CHEMISTRY; SIZE; CARDIOPROTECTION; ACTIVATION; PROTECTS; A(1); RESPONSES AB Adenosine released during myocardial ischemia mediates cardioprotective preconditioning. Multivalent drugs covalently bound to nanocarriers may differ greatly in chemical and biological properties from the corresponding monomeric agents. Here, we conjugated chemically functionalized nucleosides to poly(amidoamine) (PAMAM) dendrimeric polymers and investigated their effects in rat primary cardiac cell cultures and in the isolated heart. Three conjugates of A(3) adenosine receptor (AR) agonists, chain-functionalized at the C2 or N-6 position, were cardioprotective, with greater potency than monomeric agonist Cl-IB-MECA. Multivalent amide-linked MRS5216 was selective for A(1) and A(3)ARs, and triazole-linked MR55246 and MRS5539 (optionally containing fluorescent label) were A(3)AR-selective. The conjugates protected ischemic rat cardiomyocytes, an effect blocked by an A(3)AR antagonist MRS1523, and isolated hearts with significantly improved infarct size, rate of pressure product, and rate of contraction and relaxation. Thus, strategically derivatized nucleosides tethered to biocompatible polymeric carriers display enhanced cardioprotective potency via activation of A(3)AR on the cardiomyocyte surface. Published by Elsevier Ltd. C1 [Tosh, Dilip K.; Khai Phan; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, LBC, NIH, Bethesda, MD 20892 USA. [Chanyshev, Bella; Shainberg, Asher; Isak, Ahuva; Litinsky, Alexandra] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. [Chepurko, Yelena; Hochhauser, Edith] Tel Aviv Univ, Dept Cardiothorac Surg, Rabin Med Ctr, Felsenstein Med Res Ctr,Cardiac Res Lab, Petah Tiqwa, Israel. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, LBC, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH, NIDDK; Adar Program for the Advancement of Research in Heart Function; Horowitz Foundation at Bar-Ilan University FX This research was supported by the Intramural Research Program of the NIH, NIDDK. This work was also in part supported by The Adar Program for the Advancement of Research in Heart Function and the Horowitz Foundation at Bar-Ilan University. NR 43 TC 8 Z9 9 U1 0 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD MAR PY 2012 VL 65 IS 3 BP 338 EP 346 DI 10.1016/j.phrs.2011.11.013 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 909II UT WOS:000301557800009 PM 22154845 ER PT J AU Wen, R Tao, W Li, YW Sieving, PA AF Wen, Rong Tao, Weng Li, Yiwen Sieving, Paul A. TI CNTF and retina SO PROGRESS IN RETINAL AND EYE RESEARCH LA English DT Article DE CNTF; Photoreceptors; Retinal ganglion cells; Retinal degeneration; Neuroprotection; Photoreceptor plasticity ID CILIARY NEUROTROPHIC FACTOR; LEUKEMIA INHIBITORY FACTOR; AMYOTROPHIC-LATERAL-SCLEROSIS; ACUTE-PHASE RESPONSE; CHOLINERGIC NEURONOTROPHIC FACTORS; LENTIVIRAL-MEDIATED TRANSFER; RHODOPSIN MUTATION S334TER; CELL INTRAOCULAR IMPLANTS; PERIPHERAL-NERVE GRAFTS; IL-6 SIGNAL TRANSDUCER AB Ciliary neurotrophic factor (CNTF) is one of the most studied neurotrophic factors for neuroprotection of the retina. A large body of evidence demonstrates that CNTF promotes rod photoreceptor survival in almost all animal models. Recent studies indicate that CNTF also promotes cone photoreceptor survival and cone outer segment regeneration in the degenerating retina and improves cone function in dogs with congenital achromotopsia. In addition, CNTF is a neuroprotective factor and an axogenesis factor for retinal ganglion cells (RGCs). This review focuses on the effects of exogenous CNTF on photoreceptors and RGCs in the mammalian retina and the potential clinical application of CNTF for retinal degenerative diseases. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Wen, Rong; Li, Yiwen] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Tao, Weng] Neurotech USA, Lincoln, RI 02865 USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. RP Wen, R (reprint author), Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, McKnight Bldg,RM 506,1638 NW 10th Ave, Miami, FL 33136 USA. EM rwen@med.miami.edu FU National Institutes of Health [R01EY12727, R01EY018586, P30EY14801]; Hope for Vision; State of Florida; Department of Defense [W81XWH-09-1-0674]; Research to Prevent Blindness; National Institutes of Health, National Eye Institute, and National Institute on Deafness and Other Communication Disorders FX We thank Dr. Andras Komaromy for allowing us to discuss his unpublished data and for critically reading the manuscript; and Dr. Byron Lam for critically reading the manuscript. This work was supported by grants from National Institutes of Health (R01EY12727, R01EY018586 to RW, P30EY14801 to Bascom Palmer Eye Institute), Hope for Vision (RW), the James and Esther King Biomedical Research Program of the State of Florida (YL), the Department of Defense (W81XWH-09-1-0674 to RW), an unrestricted grant from Research to Prevent Blindness to Bascom Palmer Eye Institute; and by the intramural research program of National Institutes of Health, National Eye Institute, and National Institute on Deafness and Other Communication Disorders. NR 145 TC 69 Z9 72 U1 0 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-9462 J9 PROG RETIN EYE RES JI Prog. Retin. Eye Res. PD MAR PY 2012 VL 31 IS 2 BP 136 EP 151 DI 10.1016/j.preteyeres.2011.11.005 PG 16 WC Ophthalmology SC Ophthalmology GA 910GC UT WOS:000301624200002 PM 22182585 ER PT J AU Tie, YF Wang, YF Boross, PI Chiu, TY Ghosh, AK Tozser, J Louis, JM Harrison, RW Weber, IT AF Tie, Yunfeng Wang, Yuan-Fang Boross, Peter I. Chiu, Ting-Yi Ghosh, Arun K. Tozser, Jozsef Louis, John M. Harrison, Robert W. Weber, Irene T. TI Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors SO PROTEIN SCIENCE LA English DT Article DE HIV; AIDS; drug resistance; aspartic protease; antiviral inhibitors; molecular recognition ID RESOLUTION CRYSTAL-STRUCTURES; IMMUNODEFICIENCY-VIRUS PROTEASE; AMINO-ACID PREFERENCES; DRUG-RESISTANT MUTANTS; RETROVIRAL PROTEASES; LIGAND SPECIFICITY; CLEAVAGE SITES; SUSCEPTIBILITY; PROTEINASES; COMPLEXES AB Clinical inhibitor amprenavir (APV) is less effective on HIV-2 protease (PR2) than on HIV-1 protease (PR1). We solved the crystal structure of PR2 with APV at 1.5 angstrom resolution to identify structural changes associated with the lowered inhibition. Furthermore, we analyzed the PR1 mutant (PR1M) with substitutions V32I, I47V, and V82I that mimic the inhibitor binding site of PR2. PR1M more closely resembled PR2 than PR1 in catalytic efficiency on four substrate peptides and inhibition by APV, whereas few differences were seen for two other substrates and inhibition by saquinavir (SQV) and darunavir (DRV). High resolution crystal structures of PR1M with APV, DRV, and SQV were compared with available PR1 and PR2 complexes. Val/Ile32 and Ile/Val47 showed compensating interactions with SQV in PR1M and PR1, however, Ile82 interacted with a second SQV bound in an extension of the active site cavity of PR1M. Residues 32 and 82 maintained similar interactions with DRV and APV in all the enzymes, whereas Val47 and Ile47 had opposing effects in the two subunits. Significantly diminished interactions were seen for the aniline of APV bound in PR1M and PR2 relative to the strong hydrogen bonds observed in PR1, consistent with 15- and 19-fold weaker inhibition, respectively. Overall, PR1M partially replicates the specificity of PR2 and gives insight into drug resistant mutations at residues 32, 47, and 82. Moreover, this analysis provides a structural explanation for the weaker antiviral effects of APV on HIV-2. C1 [Tie, Yunfeng; Wang, Yuan-Fang; Chiu, Ting-Yi; Harrison, Robert W.; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Boross, Peter I.; Tozser, Jozsef] Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, Debrecen, Hungary. [Ghosh, Arun K.] Purdue Univ, Dept Chem & Med Chem, W Lafayette, IN 47907 USA. [Louis, John M.] NIDDK, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Harrison, Robert W.] Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA. [Weber, Irene T.] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. RP Weber, IT (reprint author), Georgia State Univ, Dept Biol, POB 4010, Atlanta, GA 30302 USA. EM iweber@gsu.edu RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 FU Hungarian Science and Research Fund (OTKA) [K68288, K101591]; NIDDK, National Institutes of Health (NIH); Office of the Director, NIH [GM062920, GM53386]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This research was authored, in whole or in part, by National Institutes of Health staff. This research was supported, in whole or in part, by the Hungarian Science and Research Fund (OTKA K68288, K101591), the Intramural Research Program of the NIDDK, National Institutes of Health (NIH), Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH, and grants GM062920 (ITW) and GM53386 (AKG) from the NIH. The authors thank the staff at the SER-CAT beam-line at the Advanced Photon Source, Argonne National Laboratory, for assistance during X-ray data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. NR 47 TC 11 Z9 14 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD MAR PY 2012 VL 21 IS 3 BP 339 EP 350 DI 10.1002/pro.2019 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 895NY UT WOS:000300504300005 PM 22238126 ER PT J AU Scott, TW Takken, W AF Scott, Thomas W. Takken, Willem TI Feeding strategies of anthropophilic mosquitoes result in increased risk of pathogen transmission SO TRENDS IN PARASITOLOGY LA English DT Review DE blood feeding; Anopheles gambiae; malaria; Aedes aegypti; dengue; mosquito; multiple bloodmeals; sugar; fitness; reproduction; disease transmission; pathogen transmission ID AEDES-AEGYPTI DIPTERA; ANOPHELES-GAMBIAE DIPTERA; IDEAL FREE DISTRIBUTION; SENSU-STRICTO DIPTERA; PUERTO-RICO; HUMAN-BLOOD; BODY-SIZE; PLASMODIUM-FALCIPARUM; DENGUE VECTOR; DEFENSIVE BEHAVIOR AB Vector-borne disease specialists have traditionally assumed that in each egg-laying cycle mosquitoes take a single bloodmeal that is used for egg development and feed on plant sugars for flight and production of energy reserves. Here we review research showing that for two of the most important vectors of human pathogens (Anopheles gambiae and Aedes aegypti) imbibing multiple bloodmeals during a gonotrophic cycle while foregoing sugar feeding is a common behaviour, not an exception. By feeding preferentially and frequently on human blood these species increase their fitness and exponentially boost the basic reproduction rate of pathogens they transmit. Although the epidemiological outcome is similar, there are important differences in processes underlying frequent human contact by these species that merit more detailed investigation. C1 [Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Takken, Willem] Wageningen Univ, Entomol Lab, Wageningen, Netherlands. RP Scott, TW (reprint author), Univ Calif Davis, Dept Entomol, 1 Shields Ave, Davis, CA 95616 USA. EM twscott@ucdavis.edu; willem.takken@wur.nl FU Wageningen University FX We thank L.C. Harrington for helpful discussions and review of an earlier draft of this manuscript. J.D. Charlwood, C.J.M. Koenraadt, J.J.A. van Loon, T.A. Perkins and R.C. Reiner are thanked for their useful comments while developing this paper. Content of this manuscript benefited from discussions with working group members in the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Centre, National Institutes of Health. Wageningen University provided financial support for a sabbatical to W.T., which allowed for collaborative work between the authors. Owing to space constraints imposed by the journal, we were not able to cite all the references we would have liked. NR 76 TC 55 Z9 55 U1 4 U2 51 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD MAR PY 2012 VL 28 IS 3 BP 114 EP 121 DI 10.1016/j.pt.2012.01.001 PG 8 WC Parasitology SC Parasitology GA 910KK UT WOS:000301635400006 PM 22300806 ER PT J AU Beedie, SA Benson, PJ Giegling, I Rujescu, D St Clair, DM AF Beedie, Sara A. Benson, Philip J. Giegling, Ina Rujescu, Dan St Clair, David M. TI Smooth pursuit and visual scanpaths: Independence of two candidate oculomotor risk markers for schizophrenia SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Article DE Schizophrenia; psychosis; genetics; biomarkers; eye movements ID DORSOLATERAL PREFRONTAL CORTEX; EYE-TRACKING DYSFUNCTION; OCULAR MOTOR BEHAVIOR; SCAN PATHS; 1ST-DEGREE RELATIVES; MOVEMENT DYSFUNCTION; 1ST-EPISODE SCHIZOPHRENIA; FIELD LESIONS; PERFORMANCE; TRAIT AB Objectives. Smooth pursuit and visual scanpath deficits are candidate trait markers for schizophrenia. It is not clear whether eye tracking dysfunction (ETD) and atypical scanpath behaviour are the product of the same underlying neurobiological processes. We have examined co-occurrence of ETD and scanpath disturbance in individuals with schizophrenia and healthy volunteers. Methods. Eye movements of individuals with schizophrenia (N = 96) and non-clinical age-matched comparison participants (N = 100) were recorded using non-invasive infrared oculography during smooth pursuit in both predictable (horizontal sinusoid) and less predictable (Lissajous sinusoid) conditions and a free viewing scanpath task. Results. Individuals with schizophrenia demonstrated scanning deficits in both tasks. There was no association between performance measures of smooth pursuit and scene scanpaths in patient or control groups. Odds ratios comparing the likelihood of scanpath dysfunction when ETD was present, and the likelihood of finding scanpath dysfunction when ETD was absent were not significant in patients or controls in either pursuit variant, suggesting that ETD and scanpath dysfunction are independent anomalies in schizophrenia. Conclusion. ETD and scanpath disturbance appear to reflect independent oculomotor or neurocognitive deficits in schizophrenia. Each task may confer unique information about the pathophysiology of psychosis. C1 [Beedie, Sara A.] Univ Aberdeen, Coll Life Sci & Med, Sch Psychol, Univ London Kings Coll, Aberdeen AB24 3FX, Scotland. [Giegling, Ina; Rujescu, Dan] Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, D-8000 Munich, Germany. [St Clair, David M.] Univ Aberdeen, Dept Mental Hlth, Royal Cornhill Hosp, Aberdeen AB24 3FX, Scotland. [St Clair, David M.] NIMH, Bethesda, MD 20892 USA. RP Beedie, SA (reprint author), Univ Aberdeen, Coll Life Sci & Med, Sch Psychol, Univ London Kings Coll, William Guild Bldg, Aberdeen AB24 3FX, Scotland. EM s.beedie@abdn.ac.uk FU Royal Society of London; Millar-MacKenzie Trust; University of Aberdeen; Chief Scientists Office [CZB-4-734]; European Commission FX This manuscript is partly based on a doctoral dissertation completed by SAB under the supervision of PJB and DSC. We are grateful to our participants for their time. We are also grateful to Drs Nicholas Walker and Sheila Gilfillan for facilitating patient recruitment in Scotland. Data collection was supported by the Royal Society of London, Millar-MacKenzie Trust, and the University of Aberdeen. During the preparation of this manuscript, salary support for SAB has been provided by the Chief Scientists Office (CZB-4-734, awarded to PJB) and previously by the European Commission (SGENE, awarded to DSC). Preliminary findings from this study were presented at the 2nd Biennial Schizophrenia International Research Society Conference, 2010, Florence, Italy. NR 78 TC 3 Z9 3 U1 2 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD MAR PY 2012 VL 13 IS 3 BP 200 EP 210 DI 10.3109/15622975.2011.566628 PG 11 WC Psychiatry SC Psychiatry GA 908BC UT WOS:000301464200005 PM 21545243 ER PT J AU Siberry, GK Li, H Jacobson, D AF Siberry, George K. Li, Hong Jacobson, Denise CA Pediat AIDS Clinical Trials Grp PA TI Short Communication: Fracture Risk by HIV Infection Status in Perinatally HIV-Exposed Children SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID BONE-MINERAL DENSITY; NAIVE PATIENTS; THERAPY; ADOLESCENTS; TENOFOVIR; HEALTH; IMPACT; RATES AB The objective of this study was to examine the incidence of fractures in HIV-infected children and comparable HIV-exposed, uninfected (HEU) children in a multicenter, prospective cohort study (PACTG 219/219C) in the United States. The main outcome was first fracture during the risk period. Nine fractures occurred in 7 of 1326 HIV-infected and 2 of 649 HEU children, corresponding to incidence rates of 1.2 per 1000 person-years and 1.1 per 1000 person-years, respectively. The incidence rate ratio was 1.1 (95% CI 0.2, 5.5). There was no evidence of a substantially increased risk of fracture in HIV-infected compared to HEU children. C1 [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS PAMA Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. [Li, Hong] Rush Univ, Dept Prevent Med, Chicago, IL 60612 USA. [Jacobson, Denise] Harvard Univ, Sch Publ Hlth, Dept Biostat, Ctr Biostat AIDS Res CBAR, Boston, MA 02115 USA. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS PAMA Branch, Ctr Res Mothers & Children, NIH, 6100 Execut Blvd,Room 4B11H, Bethesda, MD 20892 USA. EM siberryg@mail.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; Statistical and Data Analysis Center at Harvard School of Public Health under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG) [1 U01 AI068616]; National Institute of Allergy and Infectious Diseases (NIAID); NICHD [N01-DK-9-001/HHSN267200800001C] FX We thank the children and families for their participation in PACTG 219C, and the individuals and institutions involved in the conduct of 219C as well as the leadership and participants of the P219/219C protocol team. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632], the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) [AI068632]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement # 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and # 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). We also thank the individual staff members and sites who have participated in the conduct of this study. NR 19 TC 7 Z9 7 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2012 VL 28 IS 3 BP 247 EP 250 DI 10.1089/aid.2011.0064 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 904VK UT WOS:000301226100004 PM 22471877 ER PT J AU Prushik, SG Farber, A Gona, P Shrader, P Pencina, MJ D'Agostino, RB Murabito, JM AF Prushik, Scott G. Farber, Alik Gona, Philimon Shrader, Peter Pencina, Michael J. D'Agostino, Ralph B., Sr. Murabito, Joanne M. TI Parental Intermittent Claudication as Risk Factor for Claudication in Adults SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; ABDOMINAL AORTIC-ANEURYSM; GENOME-WIDE ASSOCIATION; ANKLE-BRACHIAL INDEX; MIDDLE-AGED ADULTS; CARDIOVASCULAR-DISEASE; CHROMOSOME 9P21.3; SEQUENCE VARIANT; MYOCARDIAL-INFARCTION; FAMILY-HISTORY AB Little is known about the familial aggregation of intermittent claudication (IC). Our objective was to examine whether parental IC increased the risk of IC in adult offspring, independent of the established cardiovascular risk factors. We evaluated the Offspring Cohort Participants of the Framingham Heart Study who were >= 30 years old, cardiovascular disease free, and had both parents enrolled in the Framingham Heart Study (n = 2,970 unique participants, 53% women). Pooled proportional hazards regression analysis was used to examine whether the 12-year risk of incident IC in offspring participants was associated with parental IC, adjusting for age, gender, diabetes, smoking, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, and antihypertensive and lipid treatment. Of the 909 person-examinations in the parental IC history group and 5,397 person-examinations in the no-parental IC history group, there were 101 incident IC events (29 with parental IC history and 72 without a parental IC history) during follow-up. The age- and gender-adjusted 12-year cumulative incidence rate per 1,000 person-years was 5.08 (95% confidence interval [CI] 2.74 to 7.33) and 2.34 (95% CI 1.46 to 3.19) in participants with and without a parental IC history. A parental history of IC significantly increased the risk of incident IC in the offspring (multivariable adjusted hazard ratio 1.81,95% CI 1.14 to 2.88). The hazard ratio was unchanged, with an adjustment for the occurrence of cardiovascular disease (hazard ratio 1.83, 95% CI 1.15 to 2.91). In conclusion, IC in parents increases the risk of IC in adult offspring, independent of the established risk factors. These data suggest a genetic component of peripheral artery disease and support future research into genetic causes. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:736-741) C1 [Gona, Philimon; Pencina, Michael J.; D'Agostino, Ralph B., Sr.; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Prushik, Scott G.] Univ Massachusetts, Dept Vasc Surg, Worcester, MA USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Farber, Alik] Boston Univ, Sch Med, Dept Vasc Surg, Boston, MA 02118 USA. [Gona, Philimon; Shrader, Peter; Pencina, Michael J.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Gona, Philimon; Shrader, Peter; Pencina, Michael J.; D'Agostino, Ralph B., Sr.] New England Res Inst, Watertown, MA 02172 USA. RP Murabito, JM (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM murabito@bu.edu OI Murabito, Joanne/0000-0002-0192-7516 FU National Heart, Lung, and Blood Institute's Framingham Heart Study (Bethesda, Maryland) [N01-HC-25195] FX This work was supported by grant N01-HC-25195 from the National Heart, Lung, and Blood Institute's Framingham Heart Study (Bethesda, Maryland). NR 30 TC 4 Z9 4 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 1 PY 2012 VL 109 IS 5 BP 736 EP 741 DI 10.1016/j.amjcard.2011.10.032 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 907CA UT WOS:000301394200023 PM 22154319 ER PT J AU Davis, BM Aiello, AE Dawid, S Rohani, P Shrestha, S Foxman, B AF Davis, Brian M. Aiello, Allison E. Dawid, Suzanne Rohani, Pejman Shrestha, Sourya Foxman, Betsy TI Influenza and Community-acquired Pneumonia Interactions: The Impact of Order and Time of Infection on Population Patterns SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE community-acquired infections; influenza, human; pneumococcal infections; pneumonia ID STREPTOCOCCUS-PNEUMONIAE; BACTERIAL PNEUMONIA; STAPHYLOCOCCUS-AUREUS; PANDEMIC INFLUENZA; UNITED-STATES; VIRUS; DISEASE; DEATH; SUSCEPTIBILITY; COLONIZATION AB Discoveries made during the 1918 influenza A pandemic and reports of severe disease associated with coinfection during the 2009 hemagglutinin type 1 and neuraminidase type 1 (commonly known as H1N1 or swine flu) pandemic have renewed interest in the role of coinfection in disease pathogenesis. The authors assessed how various timings of coinfection with influenza virus and pneumonia-causing bacteria could affect the severity of illness at multiple levels of interaction, including the biologic and population levels. Animal studies most strongly support a single pathway of coinfection with influenza inoculation occurring approximately 7 days before inoculation with Streptococcus pneumoniae, but less-examined pathways of infection also may be important for human disease. The authors discussed the implications of each pathway for disease prevention and what they would expect to see at the population level if there were sufficient data available. Lastly, the authors identified crucial gaps in the study of timing of coinfection and proposed related research questions. C1 [Aiello, Allison E.; Foxman, Betsy] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ctr Mol & Clin Epidemiol Infect Dis, Ann Arbor, MI 48109 USA. [Davis, Brian M.; Aiello, Allison E.] Univ Michigan, Sch Publ Hlth, Ctr Social Epidemiol & Populat Hlth, Ann Arbor, MI 48109 USA. [Dawid, Suzanne] Univ Michigan, Sch Med, Dept Pediat & Communicable Dis, Ann Arbor, MI USA. [Dawid, Suzanne] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Rohani, Pejman; Shrestha, Sourya] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman; Shrestha, Sourya] Univ Michigan, Coll Literature Sci & Arts, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Foxman, B (reprint author), Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ctr Mol & Clin Epidemiol Infect Dis, 1415 Washington Hts, Ann Arbor, MI 48109 USA. EM bfoxman@umich.edu OI Shrestha, Sourya/0000-0002-6106-6834; Foxman, Betsy/0000-0001-6682-238X NR 37 TC 6 Z9 7 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 1 PY 2012 VL 175 IS 5 BP 363 EP 367 DI 10.1093/aje/kwr402 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 898GT UT WOS:000300728800001 PM 22247048 ER PT J AU Gaskins, AJ Wilchesky, M Mumford, SL Whitcomb, BW Browne, RW Wactawski-Wende, J Perkins, NJ Schisterman, EF AF Gaskins, Audrey J. Wilchesky, Machelle Mumford, Sunni L. Whitcomb, Brian W. Browne, Richard W. Wactawski-Wende, Jean Perkins, Neil J. Schisterman, Enrique F. TI Endogenous Reproductive Hormones and C-reactive Protein Across the Menstrual Cycle SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE estrogens; inflammation; menstrual cycle ID MARGINAL STRUCTURAL MODELS; CORONARY HEART-DISEASE; CARDIOVASCULAR-DISEASE; TRANSDERMAL ESTRADIOL; GENE-EXPRESSION; WOMEN; ESTROGEN; INFLAMMATION; MARKERS; 17-BETA-ESTRADIOL AB Creactive protein (CRP) is one of the most commonly used markers of acute phase reaction in clinical settings and predictors of cardiovascular risk in healthy women; however, data on its physiologic regulation in premenopausal women are sparse. The objective of this study was to evaluate the association between endogenous reproductive hormones and CRP in the BioCycle Study (2005-2007). Women aged 18-44 years from western New York were followed prospectively for up to 2 menstrual cycles (n = 259). Serum levels of CRP, estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to 8 times per cycle, timed by fertility monitors. CRP levels varied significantly across the cycle (P < 0.001). More women were classified as being at elevated risk of cardiovascular disease (CRP, >3 mg/L) during menses compared with other phases (12.3% vs. 7.4%; P < 0.001). A 10-fold increase in estradiol was associated with a 24.3% decrease in CRP (95% confidence interval: 19.3, 29.0). A 10-fold increase in luteal progesterone was associated with a 19.4% increase in CRP (95% confidence interval: 8.4, 31.5). These results support the hypothesis that endogenous estradiol might have antiinflammatory effects and highlight the need for standardization of CRP measurement to menstrual cycle phase in reproductive-aged women. C1 [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Wilchesky, Machelle] McGill Univ, Montreal Childrens Hosp, Res Inst, Montreal, PQ H3H 1P3, Canada. [Whitcomb, Brian W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Browne, Richard W.] SUNY Buffalo, Dept Biotech & Clin Lab Sci, Buffalo, NY 14260 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Preventat Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03M, Rockville, MD 20852 USA. EM schistee@mail.nih.gov 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 40 TC 28 Z9 29 U1 4 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 1 PY 2012 VL 175 IS 5 BP 423 EP 431 DI 10.1093/aje/kwr343 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 898GT UT WOS:000300728800009 PM 22306563 ER PT J AU McBride, CM Bryan, AD Bray, MS Swan, GE Green, ED AF McBride, Colleen M. Bryan, Angela D. Bray, Molly S. Swan, Gary E. Green, Eric D. TI Health Behavior Change: Can Genomics Improve Behavioral Adherence? SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID GENETIC INFORMATION; RISK-FACTORS; TOBACCO USE; EXERCISE; WEIGHT; INTERVENTIONS; MANAGEMENT; GENOTYPES; MEDICINE; SMOKING C1 [McBride, Colleen M.; Green, Eric D.] NHGRI, Bethesda, MD 20892 USA. [Bryan, Angela D.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Swan, Gary E.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Bray, Molly S.] Univ Alabama, Sch Publ Hlth, Birmingham, AL USA. RP McBride, CM (reprint author), NHGRI, 31 Ctr Dr,Bldg 31,Room B1B54B, Bethesda, MD 20892 USA. EM cmcbride@mail.nih.gov FU NIDDK NIH HHS [R01 DK062148] NR 46 TC 26 Z9 28 U1 2 U2 22 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2012 VL 102 IS 3 BP 401 EP 405 DI 10.2105/AJPH.2011.300513 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 893EN UT WOS:000300338500010 PM 22390502 ER PT J AU Driscoll, JJ Burris, J Annunziata, CM AF Driscoll, James J. Burris, Jason Annunziata, Christina M. TI Targeting the Proteasome With Bortezomib in Multiple Myeloma: Update on Therapeutic Benefit as an Upfront Single Agent, Induction Regimen for Stem-Cell Transplantation and as Maintenance Therapy SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Article DE multiple myeloma; bortezomib; monotherapy; stem-cell transplantation induction; maintenance therapy ID PHASE-II; INCORPORATING BORTEZOMIB; NEDD8-ACTIVATING ENZYME; COMBINATION THERAPY; PLUS DEXAMETHASONE; CLINICAL-OUTCOMES; TRIAL; EXPRESSION; LENALIDOMIDE; CHEMOTHERAPY AB Bortezomib is the first therapeutic inhibitor of the proteasome that has demonstrated a significant clinical response in patients with otherwise refractory or rapidly advancing disease. Bortezomib has received US Federal Drug Administration approval for the treatment of the hematologic malignancies such as multiple myeloma and mantle cell lymphoma. Herein, the use of bortezomib as an upfront therapy, as an induction regimen before stem-cell transplantation and as maintenance therapy in the treatment of multiple myeloma is discussed. C1 [Driscoll, James J.; Burris, Jason; Annunziata, Christina M.] NCI, Med Oncol Branch, Magnuson Canc Ctr, NIH,Translat Genom Sect, Bethesda, MD 20892 USA. [Burris, Jason] Walter Reed Army Med Ctr, Dept Med, Hematol Oncol Serv, Washington, DC 20307 USA. RP Driscoll, JJ (reprint author), NCI, Med Oncol Branch, Magnuson Canc Ctr, NIH,Translat Genom Sect, 10 Ctr Dr,Bldg 10,Room 12N-226, Bethesda, MD 20892 USA. EM driscollj@mail.nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU Intramural NIH HHS [ZIA BC011312-02] NR 64 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1075-2765 EI 1536-3686 J9 AM J THER JI Am. J. Ther. PD MAR PY 2012 VL 19 IS 2 BP 133 EP 144 DI 10.1097/MJT.0b013e3181ff7a9e PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 906GW UT WOS:000301333900017 PM 21248621 ER PT J AU Murphy, SC Prentice, JL Williamson, K Wallis, CK Fang, FC Fried, M Pinzon, C Wang, RB Talley, AK Kappe, SHI Duffy, PE Cookson, BT AF Murphy, Sean C. Prentice, Jennifer L. Williamson, Kathryn Wallis, Carolyn K. Fang, Ferric C. Fried, Michal Pinzon, Cris Wang, Ruobing Talley, Angela K. Kappe, Stefan H. I. Duffy, Patrick E. Cookson, Brad T. TI Real-Time Quantitative Reverse Transcription PCR for Monitoring of Blood-Stage Plasmodium falciparum Infections in Malaria Human Challenge Trials SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID POLYMERASE-CHAIN-REACTION; SEQUENCE-BASED AMPLIFICATION; VACCINIA VIRUS ANKARA; RIBOSOMAL-RNA GENES; RAPID DIAGNOSTIC-TESTS; ERYTHROCYTIC STAGES; CLINICAL-DIAGNOSIS; ENDEMIC AREA; NESTED PCR; ASSAY AB To detect pre-patent parasitemia, we developed a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for the asexual 18S ribosomal RNA (rRNAs) of Plasmodium falciparum. Total nucleic acids extracted from whole blood were combined with control RNA and tested by qRT-PCR. The assay quantified > 98.7% of parasite-containing samples to +/- 0.5 log(10) parasites/mL of the nominal value without false positives. The analytical sensitivity was >= 20 parasites/mL. The coefficient of variation was 0.6% and 1.8% within runs and 1.6% and 4.0% between runs for high and low parasitemia specimens, respectively. Using this assay, we determined that A-type 18S rRNAs are stably expressed at 1 x 10(4) copies per ring-stage parasite. When used to monitor experimental P. falciparum infection of human volunteers, the assay detected blood-stage infections 3.7 days earlier on average than thick blood smears. This validated, internally controlled qRT-PCR method also uses a small (50 mu L) sample volume requiring minimal pre-analytical handling, making it useful for clinical trials. C1 Univ Washington, Med Ctr, Dept Lab Med Microbiol & Med, Div Allergy & Infect Dis, Seattle, WA 98195 USA. Seattle Biomed Res Inst, Malaria Clin Trials Ctr, Seattle, WA 98109 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Murphy, SC (reprint author), Univ Washington, Med Ctr, Dept Lab Med, 1959 NE Pacific St,Box 357110, Seattle, WA 98195 USA. EM murphysc@u.washington.edu OI Fang, Ferric/0000-0002-3243-110X FU PATH Malaria Vaccine Initiative; U.S. Department of Defense [W81XWH-09-1-0531]; U.S. Army Medical Research Acquisition Activity FX Funding in support of the human challenge trial was provided by the PATH Malaria Vaccine Initiative and the U.S. Department of Defense (award no. W81XWH-09-1-0531; the U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office). NR 51 TC 25 Z9 26 U1 0 U2 5 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAR PY 2012 VL 86 IS 3 BP 383 EP 394 DI 10.4269/ajtmh.2012.10-0658 PG 12 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 904AM UT WOS:000301166000003 PM 22403305 ER PT J AU Alkhalil, A Hong, L Nguitragool, W Desai, SA AF Alkhalil, Abdulnaser Hong, Liang Nguitragool, Wang Desai, Sanjay A. TI Voltage-dependent inactivation of the plasmodial surface anion channel via a cleavable cytoplasmic component SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE PSAC; Voltage-dependent inactivation; Patch-clamp; Malaria; Antimalarial drug targets; Clag genes ID RED-BLOOD-CELLS; MALARIA PARASITE; HUMAN ERYTHROCYTES; CHLORIDE CHANNEL; NUTRIENT-UPTAKE; SODIUM-CHANNEL; SQUID AXONS; FALCIPARUM; MEMBRANE; CONDUCTANCE AB Erythrocytes infected with malaria parasites have increased permeability to ions and various nutrient solutes, mediated by a parasite ion channel known as the plasmodial surface anion channel (PSAC). The parasite clag3 gene family encodes PSAC activity, but there may also be additional unidentified components of this channel. Consistent with a lack of clag3 homology to genes of other ion channels. PSAC has a number of unusual functional properties. Here, we report that PSAC exhibits an unusual form of voltage-dependent inactivation. Inactivation was readily detected in the whole-cell patch-clamp configuration after steps to negative membrane potentials. The fraction of current that inactivates, its kinetics, and the rate of recovery were all voltage-dependent, though with a modest effective valence (0.7 +/- 0.1 elementary charges). These properties were not affected by solution composition or charge carrier, suggesting inactivation intrinsic to the channel protein. Intriguingly, inactivation was absent in cell-attached recordings and took several minutes to appear after obtaining the whole-cell configuration, suggesting interactions with soluble cytosolic components. Inactivation could also be largely abolished by application of intracellular, but not extracellular protease. The findings implicate inactivation via a charged cytoplasmic channel domain. This domain may be tethered to one or more soluble intracellular components under physiological conditions. Published by Elsevier B.V. C1 [Alkhalil, Abdulnaser; Hong, Liang; Nguitragool, Wang; Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Room 3W-01,12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM sdesai@niaid.nih.gov RI Hong, Liang/C-4251-2008 OI Hong, Liang/0000-0001-8152-5631 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank Ajay D. Pillai for comments on the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 36 TC 5 Z9 5 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD MAR PY 2012 VL 1818 IS 3 BP 367 EP 374 DI 10.1016/j.bbamem.2011.11.010 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 903XI UT WOS:000301155600003 PM 22115742 ER PT J AU Cooper-Knock, J Hewitt, C Highley, JR Brockington, A Milano, A Man, S Martindale, J Hartley, J Walsh, T Gelsthorpe, C Baxter, L Forster, G Fox, M Bury, J Mok, K McDermott, CJ Traynor, BJ Kirby, J Wharton, SB Ince, PG Hardy, J Shaw, PJ AF Cooper-Knock, Johnathan Hewitt, Christopher Highley, J. Robin Brockington, Alice Milano, Antonio Man, Somai Martindale, Joanne Hartley, Judith Walsh, Theresa Gelsthorpe, Catherine Baxter, Lynne Forster, Gillian Fox, Melanie Bury, Joanna Mok, Kin McDermott, Christopher J. Traynor, Bryan J. Kirby, Janine Wharton, Stephen B. Ince, Paul G. Hardy, John Shaw, Pamela J. TI Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72 SO BRAIN LA English DT Article DE amyotrophic lateral sclerosis; C9ORF72; dementia; neurodegeneration ID FRONTOTEMPORAL DEMENTIA; MUTATIONS; TDP-43; ALS; PATHOLOGY; OPTINEURIN; INCLUSIONS; DISEASES AB Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status. C1 [Cooper-Knock, Johnathan; Hewitt, Christopher; Highley, J. Robin; Brockington, Alice; Hartley, Judith; Walsh, Theresa; Gelsthorpe, Catherine; Baxter, Lynne; Forster, Gillian; Fox, Melanie; Bury, Joanna; McDermott, Christopher J.; Kirby, Janine; Wharton, Stephen B.; Ince, Paul G.; Shaw, Pamela J.] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield S10 2HQ, S Yorkshire, England. [Milano, Antonio; Man, Somai; Martindale, Joanne] Sheffield Childrens NHS Fdn Trust, Sheffield Diagnost Genet Serv, Western Bank, Sheffield S10 2TH, S Yorkshire, England. [Mok, Kin; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N IPJ, England. [Mok, Kin; Hardy, John] UCL, Inst Neurol, Reta Lila Weston Labs, London WC1N IPJ, England. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Brain Sci Inst, Dept Neurol, Baltimore, MD 21287 USA. RP Shaw, PJ (reprint author), Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, 385A Glossop Rd, Sheffield S10 2HQ, S Yorkshire, England. EM pamela.shaw@sheffield.ac.uk RI Hardy, John/C-2451-2009; Mok, Kin/F-5860-2012; Traynor, Bryan/G-5690-2010; Brockington, Alice/B-5122-2009; OI Highley, Robin/0000-0002-4969-6526; Kirby, Janine/0000-0002-7468-5917; Cooper-Knock, Johnathan/0000-0002-0873-8689 FU European Community [259867]; MND Association [Shaw/Nov02/6700/3]; Wellcome Trust [WT070122MF]; MND Association/Medical Research Council [G0 800380]; Wellcome Trust/MRC [WT 089698/Z/09/Z]; NIH, National Institute on Aging [Z01-AG000949-02]; National Institute for Neurological Disorders and Stroke FX European Community's Health 7th Framework Programme (FP 7 2007-2013 under grant agreement no. 259867 to P.J.S. and J.K.). MND Association (Shaw/Nov02/6700/3 to P.J.S.); Wellcome Trust (WT070122MF to P.J.S.); MND Association/Medical Research Council Lady Edith Wolfson Fellowship award (G0 800380 to J.R.H.); Wellcome Trust/MRC Strategic Neurodegeneration Award (WT 089698/Z/09/Z to J.H.) and Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02 to B.J.T.) and National Institute for Neurological Disorders and Stroke (to B.J.T.). NR 36 TC 124 Z9 127 U1 3 U2 35 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD MAR PY 2012 VL 135 BP 751 EP 764 DI 10.1093/brain/awr365 PN 3 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 898JI UT WOS:000300738300009 PM 22366792 ER PT J AU Chio, A Borghero, G Restagno, G Mora, G Drepper, C Traynor, BJ Sendtner, M Brunetti, M Ossola, I Calvo, A Pugliatti, M Sotgiu, MA Murru, MR Marrosu, MG Marrosu, F Marinou, K Mandrioli, J Sola, P Caponnetto, C Mancardi, G Mandich, P La Bella, V Spataro, R Conte, A Monsurro, MR Tedeschi, G Pisano, F Bartolomei, I Salvi, F Pinter, GL Simone, I Logroscino, G Gambardella, A Quattrone, A Lunetta, C Volanti, P Zollino, M Penco, S Battistini, S Renton, AE Majounie, E Abramzon, Y Conforti, FL Giannini, F Corbo, M Sabatelli, M AF Chio, Adriano Borghero, Giuseppe Restagno, Gabriella Mora, Gabriele Drepper, Carsten Traynor, Bryan J. Sendtner, Michael Brunetti, Maura Ossola, Irene Calvo, Andrea Pugliatti, Maura Sotgiu, Maria Alessandra Murru, Maria Rita Marrosu, Maria Giovanna Marrosu, Francesco Marinou, Kalliopi Mandrioli, Jessica Sola, Patrizia Caponnetto, Claudia Mancardi, Gianluigi Mandich, Paola La Bella, Vincenzo Spataro, Rossella Conte, Amelia Monsurro, Maria Rosaria Tedeschi, Gioacchino Pisano, Fabrizio Bartolomei, Ilaria Salvi, Fabrizio Pinter, Giuseppe Lauria Simone, Isabella Logroscino, Giancarlo Gambardella, Antonio Quattrone, Aldo Lunetta, Christian Volanti, Paolo Zollino, Marcella Penco, Silvana Battistini, Stefania Renton, Alan E. Majounie, Elisa Abramzon, Yevgeniya Conforti, Francesca Luisa Giannini, Fabio Corbo, Massimo Sabatelli, Mario CA ITALSGEN Consortium TI Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72 SO BRAIN LA English DT Article DE amyotrophic lateral sclerosis; familial ALS; C9ORF72 gene; phenotype-genotype correlation ID TARDBP MUTATIONS; ALS; POPULATION; DISEASE; DEMENTIA; FTD AB A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for similar to 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for similar to 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis. C1 [Chio, Adriano; Calvo, Andrea] Univ Turin, Dept Neurosci, I-10126 Turin, Italy. [Chio, Adriano; Calvo, Andrea] Azienda Osped Univ San Giovanni Battista Turin, I-10126 Turin, Italy. [Borghero, Giuseppe; Marrosu, Francesco] Azienda Univ Osped Cagliari, I-09100 Cagliari, Italy. [Borghero, Giuseppe] Univ Cagliari, I-09100 Cagliari, Italy. [Restagno, Gabriella; Brunetti, Maura; Ossola, Irene] ASO OIRM St Anna, Mol Genet Unit, Dept Clin Pathol, I-10126 Turin, Italy. [Drepper, Carsten; Sendtner, Michael] Univ Wurzburg, Inst Clin Neurobiol, D-97018 Wurzburg, Germany. [Traynor, Bryan J.; Renton, Alan E.; Abramzon, Yevgeniya] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20894 USA. [Pugliatti, Maura] Univ Sassari, Dept Neurosci, I-07100 Sassari, Italy. [Sotgiu, Maria Alessandra] Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy. [Murru, Maria Rita; Marrosu, Maria Giovanna] Univ Cagliari, Ctr Sclerosi Multipla, Osped Binaghi, I-09100 Cagliari, Italy. [Mandrioli, Jessica; Sola, Patrizia] Univ Modena, St Agostino Estense Hosp, Dept Neurosci, I-41126 Modena, Italy. [Mora, Gabriele; Marinou, Kalliopi] Salvatore Maugeri Fdn IRCSS, Sci Inst Milan, I-20138 Milan, Italy. [Caponnetto, Claudia; Mancardi, Gianluigi; Mandich, Paola] Univ Genoa, Dept Neurosci Ophthalmol & Genet, I-16132 Genoa, Italy. [La Bella, Vincenzo; Spataro, Rossella] Univ Palermo, Dept Neurosci, ALS Clin Res Ctr, Bio Ne C, I-90100 Palermo, Italy. [Conte, Amelia; Sabatelli, Mario] Catholic Univ, Neurol Inst, I-00168 Rome, Italy. [Conte, Amelia; Sabatelli, Mario] I CO MM Assoc ALS Res, I-00168 Rome, Italy. [Monsurro, Maria Rosaria; Tedeschi, Gioacchino] Univ Naples 2, Dept Neurol Sci, I-80138 Naples, Italy. [Pisano, Fabrizio] Salvatore Maugeri Fdn IRCSS, Sci Inst Veruno, I-28010 Veruno, NO, Italy. [Bartolomei, Ilaria; Salvi, Fabrizio] Bellaria Hosp, Dept Neurol, Ctr Diag & Cure Rare Dis, I-40139 Bologna, Italy. [Pinter, Giuseppe Lauria] Natl Neurol Inst Besta, Dept Neurol, I-20133 Milan, Italy. [Simone, Isabella; Logroscino, Giancarlo] Univ Bari, Dept Neurosci, I-70100 Bari, Italy. [Gambardella, Antonio; Quattrone, Aldo; Conforti, Francesca Luisa] CNR, Inst Neurol Sci, I-87050 Cosenza, Italy. [Lunetta, Christian; Corbo, Massimo] Serena Fdn, Neuromuscular OnmiCtr, I-20162 Milan, Italy. [Volanti, Paolo] Salvatore Maugeri Fdn IRCSS, Sci Inst Mistretta, I-98073 Mistretta, ME, Italy. [Zollino, Marcella] Catholic Univ, Dept Lab Med, Mol Genet Lab, I-00168 Rome, Italy. [Penco, Silvana] Osped Niguarda Ca Granda, Dept Lab Med, I-20162 Milan, Italy. [Battistini, Stefania; Giannini, Fabio] Univ Siena, Neurol Sect, Dept Neurosci, I-53100 Siena, Italy. [Majounie, Elisa] NIA, Neurogenet Lab, Mol Genet Unit, Bethesda, MD 20892 USA. RP Chio, A (reprint author), Univ Turin, Dept Neurosci, Via Cherasco 15, I-10126 Turin, Italy. EM achio@usa.net RI MANDRIOLI, JESSICA/K-7235-2016; Conforti, Francesca Luisa/K-8877-2016; mancardi, giovanni luigi/K-8656-2016; Traynor, Bryan/G-5690-2010; Battistini, Stefania/N-2596-2015; QUATTRONE, Aldo/A-6734-2016; Calvo, Andrea/K-4141-2016; LOGROSCINO, GIANCARLO/K-5148-2016; Spataro, Rossella/B-3656-2016; Lunetta, Christian/K-9214-2016; Sendtner, Michael/J-1542-2012; La Bella, Vincenzo/H-4532-2012; Moglia, Cristina/K-4142-2016 OI MANDRIOLI, JESSICA/0000-0002-9244-9782; Sabatelli, Mario/0000-0001-6635-4985; Conforti, Francesca Luisa/0000-0001-8364-1783; mancardi, giovanni luigi/0000-0001-8427-118X; Chio, Adriano/0000-0001-9579-5341; Cammarosano, Stefania/0000-0002-0981-5252; Penco, Silvana/0000-0003-1050-095X; SOLINAS, GIULIANA/0000-0003-2174-0983; Marrosu, Maria Giovanna/0000-0003-2334-2081; Gambardella , Antonio/0000-0001-7384-3074; Battistini, Stefania/0000-0003-2887-7624; QUATTRONE, Aldo/0000-0003-2001-957X; Calvo, Andrea/0000-0002-5122-7243; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Spataro, Rossella/0000-0002-8910-3131; Lunetta, Christian/0000-0002-4788-1875; Sendtner, Michael/0000-0002-4737-2974; Mandich, Paola/0000-0003-3123-3512; Moglia, Cristina/0000-0001-7377-7222 FU Federazione Italiana Giuoco Calcio; Fondazione Vialli e Mauro per la Sclerosi Laterale Amiotrofica onlus; Ministero della Salute (Ricerca Sanitaria Finalizzata); European Community [FP7/2007-2013, 259867]; National Institutes of Health (NIH); National Institute on Aging [Z01-AG000949-02]; National Institute on Neurological Disorders and Stroke (NINDS); Packard Centre for ALS Research at Hopkins; ALS Association; Microsoft Research; Deutsche Forschungsgemeinschaft [SFB 581, TP B1] FX Federazione Italiana Giuoco Calcio (Grant 2010 #1 to M.S. and A.C.); Fondazione Vialli e Mauro per la Sclerosi Laterale Amiotrofica onlus (to A.C.); Ministero della Salute (Ricerca Sanitaria Finalizzata, 2007) (to A.C. and G.R.); European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867 (to A.C.); The Intramural Research Programmes of the National Institutes of Health (NIH); National Institute on Aging (Z01-AG000949-02); and National Institute on Neurological Disorders and Stroke (NINDS); The Packard Centre for ALS Research at Hopkins (to B.J.T.); the ALS Association (to B.J.T. and A.C.); Microsoft Research (to B.J.T.); the Deutsche Forschungsgemeinschaft (SFB 581 and TP B1 to C.D. and M.S.). NR 25 TC 102 Z9 105 U1 3 U2 34 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD MAR PY 2012 VL 135 BP 784 EP 793 DI 10.1093/brain/awr366 PN 3 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 898JI UT WOS:000300738300011 PM 22366794 ER PT J AU Harford, JB AF Harford, Joe B. TI Viral infections and human cancers: the legacy of Denis Burkitt SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE viral infections; human cancers; Burkitt lymphoma; Africa ID EPSTEIN-BARR-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; T-CELL LEUKEMIA; HUMAN-PAPILLOMAVIRUS; HEPATOCELLULAR-CARCINOMA; CERVICAL-CANCER; NASOPHARYNGEAL CARCINOMA; GEOGRAPHICAL-DISTRIBUTION; PARTICLE VACCINE AB Denis Parsons Burkitt was born in 1911, and in the late 1950s, described the disease that has come to be known as Burkitt lymphoma based on cases he observed in Uganda. Subsequently, Burkitt lymphoma was recognized as the first human tumour associated with an infectious agent when Epstein- Barr virus was isolated from samples supplied by Burkitt. It is now recognized that over one- quarter of cancers worldwide are tied to infections. Notably, liver cancer is linked to hepatitis B virus and hepatitis C virus infections, and cervical cancer to infections involving the human papilloma viruses. In addition, immunocompromise arising from infection with the human immunodeficiency virus allows tumours (e.g., Kaposi sarcoma) caused by other viruses to arise. More than 50 years after the seminal paper by Burkitt based on his work in Africa, it is appreciated that the contribution of viral infections to cancers remains considerably higher in sub- Saharan Africa than in the rest of the world. C1 NCI, Bethesda, MD 20892 USA. RP Harford, JB (reprint author), NCI, Bethesda, MD 20892 USA. EM harfordj@nih.gov NR 104 TC 4 Z9 4 U1 3 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2012 VL 156 IS 6 BP 709 EP 718 DI 10.1111/j.1365-2141.2011.09017.x PG 10 WC Hematology SC Hematology GA 901MY UT WOS:000300972200004 PM 22233526 ER PT J AU Magrath, I AF Magrath, Ian TI Epidemiology: clues to the pathogenesis of Burkitt lymphoma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE epidemiology; Burkitt; lymphoma; malaria; Epstein-Barr ID EPSTEIN-BARR-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; T-CELL LEUKEMIA; HUMAN-PAPILLOMAVIRUS; HEPATOCELLULAR-CARCINOMA; CERVICAL-CANCER; NASOPHARYNGEAL CARCINOMA; GEOGRAPHICAL-DISTRIBUTION; INFECTIOUS AGENTS AB The two major epidemiological clues to the pathogenesis of Burkitt lymphoma (BL) are the geographical association with malaria - BL incidence relates to the malaria transmission rate - and early infection by Epstein- Barr virus (EBV). Both agents cause B cell hyperplasia, which is almost certainly an essential component of lymphomagenesis in BL. The critical event in lymphomagenesis is the creation of a MYC translocation, bringing the MYC gene into juxtaposition with immunoglobulin genes and causing its ectopic expression, thereby driving the proliferation of BL cells. It is highly likely that such translocations are mediated by the activation- induced cytidine deaminase (AID) gene, which is responsible for hypervariable region mutations as well as class switching. Stimulation of the Toll- like receptor 9 by malaria- associated agonists induces AID, providing a mechanism whereby malaria could directly influence BL pathogenesis. EBV- containing cells must reach the memory cell compartment in order to survive throughout the life of the individual, which probably requires traversal of the germinal centre. Normally, cells that do not produce high affinity antibodies do not survive this passage, and are induced to undergo apoptosis. EBV, however, prevents this, and in doing so may also enhance the likelihood of survival of rare translocation- containing cells. C1 [Magrath, Ian] Int Network Canc Treatment & Res, B-1180 Brussels, Belgium. [Magrath, Ian] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Magrath, Ian] NCI, Bethesda, MD 20892 USA. RP Magrath, I (reprint author), Int Network Canc Treatment & Res, Rue Engeland 642, B-1180 Brussels, Belgium. EM imagrath@inctr.be NR 104 TC 37 Z9 40 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2012 VL 156 IS 6 BP 744 EP 756 DI 10.1111/j.1365-2141.2011.09013.x PG 13 WC Hematology SC Hematology GA 901MY UT WOS:000300972200007 PM 22260300 ER PT J AU Han, SS Sue, LY Berndt, SI Selhub, J Burdette, LA Rosenberg, PS Ziegler, RG AF Han, Summer S. Sue, Laura Y. Berndt, Sonja I. Selhub, Jacob Burdette, Laurie A. Rosenberg, Philip S. Ziegler, Regina G. TI Associations between Genes in the One-Carbon Metabolism Pathway and Advanced Colorectal Adenoma Risk in Individuals with Low Folate Intake SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM; ADENOSINE-DEAMINASE; CANCER-RISK; POLYPS; SURVEILLANCE; GUIDELINE; TISSUES; SCAN AB Background: Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer. Methods: We genotyped 882 single nucleotide polymorphisms (SNP) in 82 one-carbon metabolism genes for 1,331 cases of advanced colorectal adenoma, identified by sigmoidoscopy at baseline, and 1,501 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We evaluated associations between one-carbon genes and adenoma risk in all subjects and stratified by folate intake. We applied the Adaptive Rank Truncated Product (ARTP) method to assess statistical significance at the gene and pathway levels. Results: Folate intake was inversely associated with advanced colorectal adenoma risk [odds ratio (OR) by quartile = 0.85, P = 1.9 x 10(-5)]. We found no statistically significant associations between one-carbon genes and adenoma risk in all subjects. As hypothesized, we observed a statistically significant pathway-level association (P = 0.038) in the lowest quartile of folate; no significant associations were found in higher quartiles. Several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) contributed to this signal (gene-level P = 0.001 and 0.0073, respectively). The most statistically significant SNP was rs244072 in ADA (P = 2.37 x 10(-5)). Conclusions and Impact: Stratification by dietary folate and application of the ARTP method revealed statistically significant pathway-and gene-level associations between one-carbon metabolism genes and risk of advanced colorectal adenoma, which were not apparent in analysis of the entire population. Folate intake may interact with associations between common variants in one-carbon metabolism genes and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev; 21(3); 417-27. (C) 2012 AACR. C1 [Han, Summer S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program,NIH, Bethesda, MD 20892 USA. [Selhub, Jacob] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Burdette, Laurie A.] NCI, Core Genotyping Facil, Adv Technol Ctr, Div Canc Epidemiol & Genet,NIH, Gaithersburg, MD USA. RP Han, SS (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program,NIH, 6120 Execut Blvd,EPS 8089, Bethesda, MD 20892 USA. EM summer.han@nih.gov NR 39 TC 11 Z9 11 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2012 VL 21 IS 3 BP 417 EP 427 DI 10.1158/1055-9965.EPI-11-0782 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 905PG UT WOS:000301284100005 PM 22253295 ER PT J AU Lindstrom, S Schumacher, FR Cox, D Travis, RC Albanes, D Allen, NE Andriole, G Berndt, SI Boeing, H Bueno-de-Mesquita, HB Crawford, ED Diver, WR Gaziano, JM Giles, GG Giovannucci, E Gonzalez, CA Henderson, B Hunter, DJ Johansson, M Kolonel, LN Ma, J Le Marchand, L Pala, V Stampfer, M Stram, DO Thun, MJ Tjonneland, A Trichopoulos, D Virtamo, J Weinstein, SJ Willett, WC Yeager, M Hayes, RB Severi, G Haiman, CA Chanock, SJ Peter, K AF Lindstroem, Sara Schumacher, Fredrick R. Cox, David Travis, Ruth C. Albanes, Demetrius Allen, Naomi E. Andriole, Gerald Berndt, Sonja I. Boeing, Heiner Bueno-de-Mesquita, H. Bas Crawford, E. David Diver, W. Ryan Gaziano, J. Michael Giles, Graham G. Giovannucci, Edward Gonzalez, Carlos A. Henderson, Brian Hunter, David J. Johansson, Mattias Kolonel, Laurence N. Ma, Jing Le Marchand, Loic Pala, Valeria Stampfer, Meir Stram, Daniel O. Thun, Michael J. Tjonneland, Anne Trichopoulos, Dimitrios Virtamo, Jarmo Weinstein, Stephanie J. Willett, Walter C. Yeager, Meredith Hayes, Richard B. Severi, Gianluca Haiman, Christopher A. Chanock, Stephen J. Kraft, Peter TI Common Genetic Variants in Prostate Cancer Risk Prediction-Results from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GROWTH-FACTOR-I; BINDING PROTEIN-3; MARKER; RECLASSIFICATION; SUSCEPTIBILITY; STATISTICS; PREVENTION; ANTIGEN; LUNG AB Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age. Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data. Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile). Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening. Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited. Cancer Epidemiol Biomarkers Prev; 21(3); 437-44. (C) 2012 AACR. C1 [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Dept Biostat, Boston, MA 02115 USA. [Lindstroem, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward; Stampfer, Meir; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Dept Med, Boston, MA 02115 USA. [Giovannucci, Edward; Hunter, David J.; Ma, Jing; Stampfer, Meir] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Giovannucci, Edward; Hunter, David J.; Ma, Jing; Stampfer, Meir] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Boston Vet Affairs Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr MA, Boston, MA USA. [Gaziano, J. Michael] Boston Vet Affairs Healthcare Syst, Geriatr Res Educ & Clin Ctr GRECC, Boston, MA USA. [Schumacher, Fredrick R.; Henderson, Brian; Stram, Daniel O.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cox, David] INSERM, U1052, Ctr Leon Berard, Canc Res Ctr Lyon, F-75654 Paris 13, France. [Johansson, Mattias] Int Agcy Res Canc, Lyon, France. [Cox, David] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Med, London SW7 2AZ, England. [Cox, David] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Travis, Ruth C.; Allen, Naomi E.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Albanes, Demetrius; Berndt, Sonja I.; Weinstein, Stephanie J.; Yeager, Meredith; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Andriole, Gerald] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Boeing, Heiner] Deutsch Inst Ernahrungsforsch, Dept Epidemiol, Potsdam, Germany. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht UMCU, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Crawford, E. David] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Diver, W. Ryan; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Canc Epidemiol Ctr, Canc Council Victoria, Melbourne, Vic 3010, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Ctr Mol Genet Environm & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Gonzalez, Carlos A.] Catalan Inst Oncol IDIBELL RETICC RD06 0020, Unit Nutr Environm & Canc, Barcelona, Spain. [Johansson, Mattias] Umea Univ, Dept Surg & Perioperat Sci, Umea, Sweden. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Pala, Valeria] Ist Nazl Tumori, Fdn IRCCS, Nutr Epidemiol Unit, Dept Predict Med, I-20133 Milan, Italy. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Hayes, Richard B.] NYU, Div Epidemiol, Langone Med Ctr, New York, NY USA. RP Peter, K (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Dept Biostat, 655 Huntington Ave,Bldg 2,Room 207, Boston, MA 02115 USA. EM pkraft@hsph.harvard.edu RI Cox, David/A-2023-2009; Gonzalez, Carlos A/O-4651-2014; Albanes, Demetrius/B-9749-2015; OI Cox, David/0000-0002-2152-9259; Gonzalez, Carlos A/0000-0003-2822-9715; Giles, Graham/0000-0003-4946-9099 FU U.S. NIH, National Cancer Institute (NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics) [U01-CA98233-07, U01-CA98710-06, U01-CA98216-06, U01-CA98758-07] FX This work was supported by the U.S. NIH, National Cancer Institute (cooperative agreements U01-CA98233-07 to D.J. Hunter, U01-CA98710-06 to M.J. Thun, U01-CA98216-06 to E. Riboli and R. Kaaks, and U01-CA98758-07 to B. E. Henderson and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). NR 37 TC 34 Z9 34 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2012 VL 21 IS 3 BP 437 EP 444 DI 10.1158/1055-9965.EPI-11-1038 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 905PG UT WOS:000301284100007 PM 22237985 ER PT J AU Zheng, YL Amr, S Saleh, DA Dash, C Ezzat, S Mikhail, NN Gouda, I Loay, I Hifnawy, T Abdel-Hamid, M Khaled, H Wolpert, B Abdel-Aziz, MA Loffredo, CA AF Zheng, Yun-Ling Amr, Sania Saleh, Doa'a A. Dash, Chiranjeev Ezzat, Sameera Mikhail, Nabiel N. Gouda, Iman Loay, Iman Hifnawy, Tamer Abdel-Hamid, Mohamed Khaled, Hussein Wolpert, Beverly Abdel-Aziz, Mohamed A. Loffredo, Christopher A. TI Urinary Bladder Cancer Risk Factors in Egypt: A Multicenter Case-Control Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ENVIRONMENTAL TOBACCO-SMOKE; CIGARETTE-SMOKING; SCHISTOSOMIASIS; EPIDEMIOLOGY; CARCINOMA; ALEXANDRIA; MECHANISMS; DISEASE; GENDER AB Background: We investigated associations between tobacco exposure, history of schistosomiasis, and bladder cancer risk in Egypt. Methods: We analyzed data from a case-control study (1,886 newly diagnosed and histologically confirmed cases and 2,716 age-, gender-, and residence-matched, population-based controls). Using logistic regression, we estimated the covariate-adjusted ORs and 95% confidence interval (CI) of the associations. Results: Among men, cigarette smoking was associated with an increased risk of urothelial carcinoma (OR = 1.8; 95% CI, 1.4-2.2) but not squamous cell carcinoma (SCC); smoking both water pipes and cigarettes was associated with an even greater risk for urothelial carcinoma (OR = 2.9; 95% CI, 2.1-3.9) and a statistically significant risk for SCC (OR = 1.8; 95% CI, 1.2-2.6). Among nonsmoking men and women, environmental tobacco smoke exposure was associated with an increased risk of urothelial carcinoma. History of schistosomiasis was associated with increased risk of both urothelial carcinoma (OR = 1.9; 95% CI, 1.2-2.9) and SCC (OR = 1.9; 95% CI, 1.2-3.0) in women and to a lesser extent (OR = 1.4; 95% CI, 1.2-1.7 and OR = 1.4; 95% CI, 1.1-1.7, for urothelial carcinoma and SCC, respectively) in men. Conclusions: The results suggest that schistosomiasis and tobacco smoking increase the risk of both SCC and urothelial carcinoma. Impact: This study provides new evidence for associations between bladder cancer subtypes and schistosomiasis and suggests that smoking both cigarettes and water pipes increases the risk for SCC and urothelial carcinoma in Egyptian men. Cancer Epidemiol Biomarkers Prev; 21(3); 537-46. (C) 2011 AACR. C1 [Zheng, Yun-Ling; Dash, Chiranjeev; Loffredo, Christopher A.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Carcinogenesis Biomarkers & Epidemiol Program, Washington, DC 20057 USA. [Amr, Sania; Wolpert, Beverly] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Saleh, Doa'a A.] Cairo Univ, Dept Community Med, Cairo, Egypt. [Gouda, Iman; Loay, Iman; Khaled, Hussein] Natl Canc Inst, Bethesda, MD 20892 USA. [Abdel-Hamid, Mohamed] Menia Univ, Dept Microbiol, Cairo, Egypt. [Abdel-Hamid, Mohamed] Natl Hepatol & Trop Med Res Inst, Cairo, Egypt. [Ezzat, Sameera] Menoufiya Univ, Natl Liver Inst, Shibin Al Kawm, Egypt. [Mikhail, Nabiel N.; Abdel-Aziz, Mohamed A.] Assiut Univ, S Egypt Canc Inst, Assiut, Egypt. [Hifnawy, Tamer] Beni Suif Univ, Dept Publ Hlth, Beni Suif, Egypt. RP Loffredo, CA (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Carcinogenesis Biomarkers & Epidemiol Program, 3800 Reservoir Rd NW,LL Room 153, Washington, DC 20057 USA. EM cal9@georgetown.edu FU Ministry of Health and Population of Egypt; Cancer Center in Cairo; Cancer Center in Minia; Cancer Center in Assiut; National Cancer Institute of the U.S. NIH [R01-CA115618, R01-CA132996] FX The authors thank the Ministry of Health and Population of Egypt and the Cancer Centers in Cairo, Minia, and Assiut for supporting the study. We are also indebted to the many interviewers, translators, drivers, and other support personnel who made the study possible through their dedicated work. The greatest gratitude goes to all the individuals who participated in our study.; This work was supported by grants from the National Cancer Institute of the U.S. NIH (R01-CA115618 to C.A. Loffredo and R01-CA132996 to Y.-L. Zheng). NR 36 TC 21 Z9 21 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2012 VL 21 IS 3 BP 537 EP 546 DI 10.1158/1055-9965.EPI-11-0589 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 905PG UT WOS:000301284100019 PM 22147365 ER PT J AU Hou, NQ Zheng, YL Gamazon, ER Ogundiran, TO Adebamowo, C Nathanson, KL Domchek, SM Rebbeck, TR Simon, MS John, EM Hennis, A Nemesure, B Wu, SY Leske, MC Ambs, S Niu, Q Zhang, J Pierce, B Cox, NJ Olopade, OI Huo, DZ AF Hou, Ningqi Zheng, Yonglan Gamazon, Eric R. Ogundiran, Temidayo O. Adebamowo, Clement Nathanson, Katherine L. Domchek, Susan M. Rebbeck, Timothy R. Simon, Michael S. John, Esther M. Hennis, Anselm Nemesure, Barbara Wu, Suh-Yuh Leske, M. Cristina Ambs, Stefan Niu, Qun Zhang, Jing Pierce, Brandon Cox, Nancy J. Olopade, Olufunmilayo I. Huo, Dezheng TI Genetic Susceptibility to Type 2 Diabetes and Breast Cancer Risk in Women of European and African Ancestry SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; OBESITY AB Background: Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight. Methods: We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2,651 breast cancer cases and 2,520 controls of African or European ancestry that were pooled from seven studies. Results: We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk. Conclusion: The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist. Impact: The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 21(3); 552-6. (C) 2012 AACR. C1 [Hou, Ningqi; Pierce, Brandon; Huo, Dezheng] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Zheng, Yonglan; Gamazon, Eric R.; Niu, Qun; Zhang, Jing; Cox, Nancy J.; Olopade, Olufunmilayo I.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ogundiran, Temidayo O.] Univ Ibadan, Dept Surg, Coll Med, Ibadan, Nigeria. [Adebamowo, Clement] Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Simon, Michael S.] Wayne State Univ, Dept Oncol, Karmanos Canc Inst, Detroit, MI USA. [John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [John, Esther M.] Stanford Canc Inst, Stanford, CA USA. [Hennis, Anselm] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm] Univ W Indies, Res Inst Trop Med, Bridgetown, Barbados. [Nemesure, Barbara; Wu, Suh-Yuh; Leske, M. Cristina] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Ambs, Stefan] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Huo, DZ (reprint author), Univ Chicago, Dept Hlth Studies, 5841 S Maryland Ave,MC 2007, Chicago, IL 60637 USA. EM dhuo@health.bsd.uchicago.edu OI Adebamowo, Clement/0000-0002-6571-2880; Nathanson, Katherine/0000-0002-6740-0901; Pierce, Brandon/0000-0002-7829-952X; Gamazon, Eric/0000-0003-4204-8734 FU National Cancer Institute (NCI) [R01CA141712, P01CA82707]; Breast Cancer Research Foundation; U.S. NCI, NIH [RFA-CA-06-503]; BCFR; Northern California Cancer Center [U01CA69417]; Georgetown University Medical Center Informatics Support Center [HHSN261200900010C] FX This work was supported by National Cancer Institute (NCI) grant R01CA141712 and P01CA82707; support also was given by the Breast Cancer Research Foundation. The Northern California site of the Breast Cancer Family Registry (BCFR) was supported by the U.S. NCI, NIH under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators, including the Northern California Cancer Center (U01CA69417) and Georgetown University Medical Center Informatics Support Center (HHSN261200900010C). NR 10 TC 3 Z9 3 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2012 VL 21 IS 3 BP 552 EP 556 DI 10.1158/1055-9965.EPI-11-0979 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 905PG UT WOS:000301284100021 PM 22237986 ER PT J AU Dewdney, SB Kizer, NT Andaya, AA Babb, SA Luo, JQ Mutch, DG Schmidt, AP Brinton, LA Broaddus, RR Ramirez, NC Huettner, PC McMeekin, DS Darcy, K Ali, S Judson, PL Mannel, RS Lele, SB O'Malley, DM Goodfellow, PJ AF Dewdney, Summer B. Kizer, Nora T. Andaya, Abegail A. Babb, Sheri A. Luo, Jingqin Mutch, David G. Schmidt, Amy P. Brinton, Louise A. Broaddus, Russell R. Ramirez, Nilsa C. Huettner, Phyllis C. McMeekin, Donald Scott Darcy, Kathleen Ali, Shamshad Judson, Patricia L. Mannel, Robert S. Lele, Shashikant B. O'Malley, David M. Goodfellow, Paul J. TI Uterine Serous Carcinoma: Increased Familial Risk for Lynch-Associated Malignancies SO CANCER PREVENTION RESEARCH LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; ENDOMETRIAL CANCER; PANCREATIC-CANCER; PAPILLARY CARCINOMA; GERMLINE MUTATIONS; BRCA2 MUTATIONS; BREAST-CANCER; HER-2/NEU OVEREXPRESSION; JEWISH PATIENTS; WOMEN AB Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for patients with serous uterine carcinoma, focusing on Lynch syndrome malignancies. Fifty serous or mixed serous endometrial carcinoma cases were prospectively enrolled. Pedigrees were developed for 29 probands and tumors were assessed for DNA mismatch repair (MMR) abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second-stage analysis was undertaken using data from Gynecologic Oncology Group (GOG)-210. Incidence data for cancers reported in relatives of 348 patients with serous and mixed epithelial and 624 patients with endometrioid carcinoma were compared. Nineteen of 29 (65.5%) patients in the single-institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly overrepresented and a high number of probands (6 of 29, 20.7%) reported pancreatic cancers. None of the probands' tumors had DNA MMR abnormalities. There was no difference in endometrial or ovarian cancer incidence in relatives of serous and endometrioid cancer probands in the case-control study. Pancreatic cancers were, however, significantly more common in relatives of patients with serous cancer [OR, 2.39; 95% confidence interval (CI), 1.06-5.38]. We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of patients with serous cancer in a single-institution study. Follow-up studies suggest that only pancreatic cancers are overrepresented in relatives. DNA MMR defects in familial clustering of pancreatic and other Lynch-associated malignancies are unlikely. The excess of pancreatic cancers in relatives may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers. Cancer Prev Res; 5(3); 435-43. (C) 2012 AACR. C1 [Schmidt, Amy P.; Goodfellow, Paul J.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Dewdney, Summer B.; Kizer, Nora T.; Babb, Sheri A.; Mutch, David G.; Goodfellow, Paul J.] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. [Huettner, Phyllis C.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Luo, Jingqin] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Andaya, Abegail A.; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Broaddus, Russell R.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Ramirez, Nilsa C.] Nationwide Childrens Hosp, Res Inst, Dept Pathol & Lab Med, Columbus, OH USA. [O'Malley, David M.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [O'Malley, David M.] James Graham Brown Canc Ctr, Columbus, OH USA. [McMeekin, Donald Scott; Mannel, Robert S.] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. [Darcy, Kathleen; Ali, Shamshad] Roswell Pk Canc Inst, Gynecol Oncol Grp, Stat & Data Ctr, Buffalo, NY 14263 USA. [Lele, Shashikant B.] Roswell Pk Canc Inst, Dept Gynecol, Buffalo, NY 14263 USA. [Judson, Patricia L.] Univ Minnesota, Sch Med, Dept Obstet Gynecol & Womens Hlth, Minneapolis, MN 55455 USA. RP Goodfellow, PJ (reprint author), Washington Univ, Sch Med, Dept Surg, 660 S Euclid,Box 8109, St Louis, MO 63110 USA. EM goodfellowp@wudosis.wustl.edu RI OMalley, David/E-3789-2011; Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU National Cancer Institute [CA134254]; Gynecologic Oncology Group (GOG) Administrative Office [CA 27469]; Gynecologic Oncology Group Statistical Office [CA 37517]; GOG Cooperative Group [U10CA027469]; [CA071754] FX This study was supported by a National Cancer Institute P50 SPORE PJG award (CA134254), grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517), the GOG Cooperative Group (U10CA027469), and RO1 funding to P.J. Goodfellow (CA071754). NR 50 TC 4 Z9 4 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2012 VL 5 IS 3 BP 435 EP 443 DI 10.1158/1940-6207.CAPR-11-0499 PG 9 WC Oncology SC Oncology GA 901ST UT WOS:000300987800010 PM 22246618 ER PT J AU Adoro, S Park, JH Singer, A AF Adoro, Stanley Park, Jung-Hyun Singer, Alfred TI Coreceptor gene "imprinting" A genetic solution to a developmental dilemma in T cells SO CELL CYCLE LA English DT Editorial Material ID LINEAGE COMMITMENT; DIFFERENTIATION; CD8; THYMOCYTES; SELECTION; CHOICE C1 [Adoro, Stanley; Park, Jung-Hyun; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM singera@mail.nih.gov RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 NR 11 TC 3 Z9 3 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 MAR 1 PY 2012 VL 11 IS 5 BP 833 EP 834 DI 10.4161/cc.11.5.19596 PG 2 WC Cell Biology SC Cell Biology GA 901TM UT WOS:000300989700004 PM 22333594 ER PT J AU Pobezinskaya, YL Liu, ZG AF Pobezinskaya, Yelena L. Liu, Zhenggang TI The role of TRADD in death receptor signaling SO CELL CYCLE LA English DT Article DE death receptor; TRADD; apoptosis; necrosis; MAP kinase ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; DOMAIN-CONTAINING RECEPTOR; TNF-LIKE LIGAND; APOPTOSIS-MEDIATING RECEPTOR; PEYERS PATCH ORGANOGENESIS; P75 NEUROTROPHIN RECEPTOR; FADD-DEPENDENT APOPTOSIS; T-CELL PROLIFERATION; TOLL-LIKE-RECEPTORS AB TRADD (TNFR1-associated death domain protein) was initially identified as an adaptor molecule that transduces the signal downstream of the TNFR1 (tumor necrosis factor receptor 1). TNFR1 belongs to the so-called death receptor (DR) family of receptors that, depending on the context, can induce either apoptosis or proliferation, as well as NF kappa B and MAP kinase activation. The receptors of this group contain death domain (DD), which is necessary for the induction of apoptosis. This review summarizes the recent advances in the field of DR signaling and in particular the role of TRADD. C1 [Pobezinskaya, Yelena L.; Liu, Zhenggang] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zgliu@helix.nih.gov NR 83 TC 20 Z9 21 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 1 PY 2012 VL 11 IS 5 BP 871 EP 876 DI 10.4161/cc.11.5.19300 PG 6 WC Cell Biology SC Cell Biology GA 901TM UT WOS:000300989700016 PM 22333735 ER PT J AU Murphy, RF Komlodi-Pasztor, E Robey, R Balis, FM Farrell, NP Fojo, T AF Murphy, Robert F. Komlodi-Pasztor, Edina Robey, Rob Balis, Frank M. Farrell, Nicholas P. Fojo, Tito TI Retained platinum uptake and indifference to p53 status make novel transplatinum agents active in platinum-resistant cells compared with cisplatin and oxaliplatin SO CELL CYCLE LA English DT Article DE transplatinum compounds; drug resistance; p53; cell cycle; apoptosis; DNA platination; platinum uptake ID ANTICANCER DRUG SCREEN; OVARIAN-CANCER CELLS; CELLULAR ACCUMULATION; COLORECTAL-CANCER; AMINE COMPLEXES; MOLECULAR-BASIS; LUNG-CANCER; DONOR SETS; PHASE-II; CYTOTOXICITY AB Despite the clinical success of platinum-containing drugs in the treatment of solid tumors, acquired resistance remains a major obstacle. We previously identified a group of novel transplanaramine or transplatinum compounds based on distinct activity profiles in the NCI-60 panel. In the present study, parental KB-3.1 cells with wild-type p53 and its cisplatin-and oxaliplatin-resistant sublines harboring mutant p53 proteins were used to contrast several transplatinum compounds with cisplatin and oxaliplatin. The transplatinum compounds retained cytotoxic activity in the resistant cell lines. While intracellular accumulation and DNA platination of cisplatin and oxaliplatin was decreased in the resistant cells, the transplatinum compounds both accumulated intracellularly and platinated DNA at comparable levels in all cell lines. Cytoflow analysis confirmed that cisplatin and oxaliplatin alter the cell cycle distribution and result in apoptosis; however, at comparably toxic concentrations, the transplatinum compounds did not alter the cell cycle distribution. Analysis of the cytoplasmic fraction treated with acetone showed that cisplatin and oxaliplatin readily bound to macromolecules in the pellet, whereas a larger percentage of the transplatinum compounds remained in the supernatant. We concluded that, distinct from platinum compounds currently in use, transplatinum compounds accumulate intracellularly in resistant cells at levels comparable to those in drug-sensitive cells, do not affect the cell cycle and, thus, retain cytotoxicity independent of p53 status and likely have cytoplasmic targets that are important in their activity. C1 [Murphy, Robert F.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Komlodi-Pasztor, Edina; Robey, Rob; Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Balis, Frank M.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Farrell, Nicholas P.] Virginia Commonwealth Univ, Dept Chem, Richmond, VA 23284 USA. RP Murphy, RF (reprint author), NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM murphyb@mail.nih.gov; fojot@mail.nih.gov NR 51 TC 9 Z9 9 U1 1 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 1 PY 2012 VL 11 IS 5 BP 963 EP 973 DI 10.4161/cc.11.5.19447 PG 11 WC Cell Biology SC Cell Biology GA 901TM UT WOS:000300989700025 PM 22333583 ER PT J AU Bagci, U Bray, M Caban, J Yao, JH Mollura, DJ AF Bagci, Ulas Bray, Mike Caban, Jesus Yao, Jianhua Mollura, Daniel J. TI Computer-assisted detection of infectious lung diseases: A review (vol 36, pg 72, 2012) SO COMPUTERIZED MEDICAL IMAGING AND GRAPHICS LA English DT Correction C1 [Bagci, Ulas; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Bray, Mike] NIAID, NIH, Bethesda, MD 20892 USA. [Caban, Jesus] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Bagci, U (reprint author), NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. EM ulasbagci@gmail.com RI Bagci, Ulas/A-4225-2012; OI Bagci, Ulas/0000-0001-7379-6829 NR 1 TC 0 Z9 0 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-6111 J9 COMPUT MED IMAG GRAP JI Comput. Med. Imaging Graph. PD MAR PY 2012 VL 36 IS 2 BP 169 EP 169 DI 10.1016/j.compmedimag.2011.12.003 PG 1 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 902KA UT WOS:000301035800008 ER PT J AU Peters-Lawrence, MH Bell, MC Hsu, LL Osunkwo, I Seaman, P Blackwood, M Guillaume, E Bellevue, R Krishnamurti, L Smith, WR Dampier, CD Minniti, CP AF Peters-Lawrence, Marlene H. Bell, Margaret C. Hsu, Lewis L. Osunkwo, Ifeyinwa Seaman, Phillip Blackwood, Miren Guillaume, Edouard Bellevue, Rita Krishnamurti, Lakshmanan Smith, Wally R. Dampier, Carlton D. Minniti, Caterina P. CA SCDCRN TI Clinical trial implementation and recruitment: Lessons learned from the early closure of a randomized clinical trial SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Recruitment; Clinical trial; Sickle cell disease; Minority; Pain; Protocol development ID RESEARCH PARTICIPATION; STRATEGIES; PAIN AB Background: The NHLBI-sponsored Sickle Cell Disease Clinical Research Network (SCDCRN) conducted a multi-center, acute intervention randomized clinical trial of two methods of Patient Controlled Analgesia for acute pain. This trial was terminated early due to low enrollment. We analyzed the perceived barriers and recruitment difficulties as reported by the coordinators and principal investigators. Methods: Participating sites completed a missed eligibility log of subjects admitted in pain crisis throughout the study and a survey at the end of the trial. The survey covered site-specific factors, policies, and procedures in study implementation, recruitment strategies, and eligibility factors. The New England Research Institutes (NERI) collected de-identified surveys from 31 respondents at 29 of 31 participating sites. Results: From December 2009 to June 2010, 1116 patient encounters for SCD and pain occurred at participating institutions: 38 subjects were enrolled (14 pediatric and 24 adults) and 34 completed the trial, below the projected 278 subjects. Fourteen sites enrolled subjects and seventeen did not. Recruitment barriers included insufficient staff, subject ineligibility or in too much pain to consent, competing protocols, and concerns regarding pain control. Recruitment methods were referrals from urgent care. SCD clinics and in house databases. No use of media or outside physicians was reported. Conclusion: We identified multiple barriers to patient accrual including short duration of enrollment period, protocol design, complex dosing schedule, requirement for staff availability during week-end and after hours, multiple departments' involvement, protocol acceptance, eligibility criteria, competing protocols, and limited staff. Each of these areas should be targeted for intervention in order to plan and conduct successful future clinical trials. Published by Elsevier Inc. C1 [Peters-Lawrence, Marlene H.; Minniti, Caterina P.] NIH, Cardiovasc & Pulm Med Branch, Bethesda, MD 20892 USA. [Bell, Margaret C.] New England Res Inst, Watertown, MA 02172 USA. [Hsu, Lewis L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Osunkwo, Ifeyinwa] Emory Univ, Sch Med, Aflac Canc Ctr, Atlanta, GA USA. [Osunkwo, Ifeyinwa] Emory Univ, Sch Med, Blood Disorders Serv, Atlanta, GA USA. [Osunkwo, Ifeyinwa; Dampier, Carlton D.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Seaman, Phillip] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Blackwood, Miren; Guillaume, Edouard] Interfaith Med Ctr, Brooklyn, NY USA. [Bellevue, Rita] New York Methodist Hosp, Dept Med, New York, NY USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Smith, Wally R.] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA USA. RP Minniti, CP (reprint author), NHLBI, NIH, Cardiovasc & Pulm Branch, Bldg 10CRC Room 5-5140, Bethesda, MD 20892 USA. EM minnitic@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health [U10HL083721, M01-RR02172, ULl-RR-024134, U54 RR026076, UL1RR031988, UL1RR025747] FX This publication was made possible by Grant Number U10HL083721, M01-RR02172, ULl-RR-024134, U54 RR026076, UL1RR031988, UL1RR025747, and intramural funding from the National Heart, Lung, and Blood Institute, National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 16 TC 24 Z9 24 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2012 VL 33 IS 2 BP 291 EP 297 DI 10.1016/j.cct.2011.11.018 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 901JA UT WOS:000300962000007 PM 22155024 ER PT J AU Campbell, ANC Nunes, EV Miele, GM Matthews, A Polsky, D Ghitza, UE Turrigiano, E Bailey, GL VanVeldhuisen, P Chapdelaine, R Froias, A Stitzer, ML Carroll, KM Winhusen, T Clingerman, S Perez, L McClure, E Goldman, B Crowell, AR AF Campbell, Aimee N. C. Nunes, Edward V. Miele, Gloria M. Matthews, Abigail Polsky, Daniel Ghitza, Udi E. Turrigiano, Eva Bailey, Genie L. VanVeldhuisen, Paul Chapdelaine, Rita Froias, Autumn Stitzer, Maxine L. Carroll, Kathleen M. Winhusen, Theresa Clingerman, Sara Perez, Livangelie McClure, Erin Goldman, Bruce Crowell, A. Rebecca TI Design and methodological considerations of an effectiveness trial of a computer-assisted intervention: An example from the NIDA Clinical Trials Network SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Substance use disorders; Computer-assisted treatment; Effectiveness research; Clinical trial design; Randomized trials ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; COMMUNITY-REINFORCEMENT APPROACH; WEB-BASED INTERVENTIONS; SUBSTANCE USE DISORDERS; COCAINE DEPENDENCE; MOTIVATIONAL INCENTIVES; ADDICTION TREATMENT; METAANALYSIS; ANXIETY AB Computer-assisted interventions hold the promise of minimizing two problems that are ubiquitous in substance abuse treatment: the lack of ready access to treatment and the challenges to providing empirically-supported treatments. Reviews of research on computer-assisted treatments for mental health and substance abuse report promising findings, but study quality and methodological limitations remain an issue. In addition, relatively few computer-assisted treatments have been tested among illicit substance users. This manuscript describes the methodological considerations of a multi-site effectiveness trial conducted within the National Institute on Drug Abuse's (NIDA's) National Drug Abuse Treatment Clinical Trials Network (CTN). The study is evaluating a web-based version of the Community Reinforcement Approach, in addition to prize-based contingency management, among 500 participants enrolled in 10 outpatient substance abuse treatment programs. Several potential effectiveness trial designs were considered and the rationale for the choice of design in this study is described. The study uses a randomized controlled design (with independent treatment arm allocation), intention-to-treat primary outcome analysis, biological markers for the primary outcome of abstinence, long-term follow-up assessments, precise measurement of intervention dose, and a cost-effectiveness analysis. Input from community providers during protocol development highlighted potential concerns and helped to address issues of practicality and feasibility. Collaboration between providers and investigators supports the utility of infrastructures that enhance research partnerships to facilitate effectiveness trials and dissemination of promising, technologically innovative treatments. Outcomes from this study will further the empirical knowledge base on the effectiveness and cost-effectiveness of computer-assisted treatment in clinical treatment settings. (C) 2011 Elsevier Inc. All rights reserved. C1 [Campbell, Aimee N. C.; Nunes, Edward V.; Miele, Gloria M.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY 10032 USA. [Matthews, Abigail; VanVeldhuisen, Paul] EMMES Corp, Rockville, MD 20850 USA. [Polsky, Daniel] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Ghitza, Udi E.] NIDR, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Bailey, Genie L.; Chapdelaine, Rita; Froias, Autumn] Stanley St Treatment & Resources Inc, Fall River, MA 02720 USA. [Bailey, Genie L.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Stitzer, Maxine L.; McClure, Erin] Johns Hopkins Univ, Sch Med, Baltimore, MD 21224 USA. [Carroll, Kathleen M.] Yale Univ, Sch Med, West Haven, CT 06516 USA. [Winhusen, Theresa] Univ Cincinnati, Dept Psychiat, Cincinnati, OH 45220 USA. [Clingerman, Sara; Perez, Livangelie] Ctr Drug Free Living Inc, Orlando, FL 32806 USA. [Goldman, Bruce] N Shore Long Isl Jewish Hlth Syst, Hempstead, NY 11552 USA. [Crowell, A. Rebecca] Nexus Recovery Inc, Dallas, TX 75228 USA. RP Campbell, ANC (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, 1051 Riverside Dr,Unit 120,Room 3732, New York, NY 10032 USA. EM anc2002@columbia.edu OI Winhusen, Theresa/0000-0002-3364-0739; Carroll, Kathleen/0000-0003-3263-3374 FU National Drug Abuse Treatment Clinical Trials Network (CTN), National Institute on Drug Abuse (NIDA) [U10 DA13035, U10 DA015831, U10 DA013034, U10 DA013732, U10 DA013720, K24 DA022412]; Titan Pharmaceuticals, Inc.; Alkermes, Inc. FX This work was supported by grants from the National Drug Abuse Treatment Clinical Trials Network (CTN), National Institute on Drug Abuse (NIDA): U10 DA13035 (Edward V. Nunes and John Rotrosen), U10 DA015831 (Kathleen M. Carroll and Roger D. Weiss), U10 DA013034 (Maxine L Stitzer and Robert P. Schwartz), U10 DA013732 (Eugene C. Somoza), U10 DA013720 (Jose Szapocznik and Lisa R. Metsch), and K24 DA022412 (Edward V. Nunes). Staff from NIDA's Center for the Clinical Trials Network collaborated in the design of the study, contributed to writing this manuscript, and provided editorial comments.; Dr. Genie Bailey has been on the speaker's bureau of Forest Pharmaceuticals and Pfizer and has received research support from Titan Pharmaceuticals, Inc. and Alkermes, Inc. NR 49 TC 23 Z9 23 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2012 VL 33 IS 2 BP 386 EP 395 DI 10.1016/j.cct.2011.11.001 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 901JA UT WOS:000300962000018 PM 22085803 ER PT J AU Bornstein, MH Putnick, DL AF Bornstein, Marc H. Putnick, Diane L. TI Stability of Language in Childhood: A Multiage, Multidomain, Multimeasure, and Multisource Study SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE language development; stability; preschool ID YOUNG-CHILDREN; FIT INDEXES; COMMUNICATIVE DEVELOPMENT; INDIVIDUAL-DIFFERENCES; PRESCHOOL-CHILDREN; EARLY VOCABULARY; PRODUCTIVE VOCABULARY; EXPRESSIVE LANGUAGE; PREDICTIVE-VALIDITY; CONSISTENCY AB The stability of language across childhood is traditionally assessed by exploring longitudinal relations between individual language measures. However, language encompasses many domains and varies with different sources (child speech, parental report, experimenter assessment). This study evaluated individual variation in multiple age-appropriate measures of child language derived from multiple sources and stability between their latent variables in 192 young children across more than 2 years. Structural equation modeling demonstrated the loading of multiple measures of child language from different sources on single latent variables of language at ages 20 months and 48 months. A large stability coefficient (r = .84) obtained between the 2 language latent variables. This stability obtained even when accounting for family socioeconomic status, maternal verbal intelligence, education, speech, tendency to respond in a socially desirable fashion, and child social competence. Stability was also equivalent for children in diverse childcare situations and for girls and boys. Across age, from the beginning of language acquisition to just before school entry, aggregating multiple age-appropriate methods and measures at each age and multiple reporters, children show a strong stability of individual differences in general language development. C1 [Bornstein, Marc H.; Putnick, Diane L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockledge 1,Suite 8030,6705 Rockledge Dr,MSC 7971, Bethesda, MD 20892 USA. EM marc_h_bornstein@nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural NIH HHS [Z01 HD001119-20] NR 129 TC 15 Z9 16 U1 5 U2 18 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD MAR PY 2012 VL 48 IS 2 BP 477 EP 491 DI 10.1037/a0025889 PG 15 WC Psychology, Developmental SC Psychology GA 901IU UT WOS:000300961400018 PM 22004343 ER PT J AU Andersen, SD Keijzers, G Rampakakis, E Engels, K Luhn, P El-Shemerly, M Nielsen, FC Du, YH May, A Bohr, VA Ferrari, S Zannis-Hadjopoulos, M Fu, HA Rasmussen, LJ AF Andersen, Sofie Dabros Keijzers, Guido Rampakakis, Emmanouil Engels, Kim Luhn, Patricia El-Shemerly, Mahmoud Nielsen, Finn Cilius Du, Yuhong May, Alfred Bohr, Vilhelm A. Ferrari, Stefano Zannis-Hadjopoulos, Maria Fu, Haian Rasmussen, Lene Juel TI 14-3-3 checkpoint regulatory proteins interact specifically with DNA repair protein human exonuclease 1 (hEXO1) via a semi-conserved motif SO DNA REPAIR LA English DT Article DE hEXO1; 14-3-3; DNA repair; Cell cycle control; DNA damage; Protein phosphorylation ID HUMAN MISMATCH REPAIR; DOUBLE-STRAND BREAKS; ASSOCIATES IN-VIVO; SUBCELLULAR-LOCALIZATION; REPLICATION FORKS; STRUCTURAL BASIS; BINDING PROTEIN; END RESECTION; RAF-1 KINASE; EXOENZYME-S AB Human exonuclease 1 (hEXO1) acts directly in diverse DNA processing events, including replication, mismatch repair (MMR), and double strand break repair (DSBR), and it was also recently described to function as damage sensor and apoptosis inducer following DNA damage. In contrast, 14-3-3 proteins are regulatory phosphorserine/threonine binding proteins involved in the control of diverse cellular events, including cell cycle checkpoint and apoptosis signaling. hEXO1 is regulated by post-translation Ser/Thr phosphorylation in a yet not fully clarified manner, but evidently three phosphorylation sites are specifically induced by replication inhibition leading to protein ubiquitination and degradation. We demonstrate direct and robust interaction between hEXO1 and six of the seven 14-3-3 isoforms in vitro, suggestive of a novel protein interaction network between DNA repair and cell cycle control. Binding experiments reveal weak affinity of the more selective isoform 14-3-3 sigma but both 14-3-3 isoforms eta and sigma significantly stimulate hEXO1 activity, indicating that these regulatory proteins exert a common regulation mode on hEXO1. Results demonstrate that binding involves the phosphorable amino acid S746 in hEXO1 and most likely a second unidentified binding motif. 14-3-3 associations do not appear to directly influence hEXO1 in vitro nuclease activity or in vitro DNA replication initiation. Moreover, specific phosphorylation variants, including hEXO1 S746A, are efficiently imported to the nucleus; to associate with PCNA in distinct replication foci and respond to DNA double strand breaks (DSBs), indicating that 14-3-3 binding does not involve regulating the subcellular distribution of hEXO1. Altogether, these results suggest that association may be related to regulation of hEXO1 availability during the DNA damage response to plausibly prevent extensive DNA resection at the damage site, as supported by recent studies. (C) 2011 Elsevier B.V. All rights reserved. C1 [Rasmussen, Lene Juel] Univ Copenhagen, Ctr Hlth Aging, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark. [Andersen, Sofie Dabros] Roskilde Univ Ctr, Dept Sci Syst & Models, Roskilde, Denmark. [Rampakakis, Emmanouil; Zannis-Hadjopoulos, Maria] Rosalind & Morris Goodman Canc Ctr, Montreal, PQ, Canada. [Rampakakis, Emmanouil; Zannis-Hadjopoulos, Maria] Dept Biochem, Montreal, PQ, Canada. [Engels, Kim; El-Shemerly, Mahmoud; Ferrari, Stefano] Univ Zurich, Inst Mol Canc Res, CH-8006 Zurich, Switzerland. [Luhn, Patricia; Du, Yuhong; Fu, Haian] Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. [Nielsen, Finn Cilius] Univ Copenhagen Hosp, Dept Clin Biochem, Copenhagen, Denmark. [May, Alfred; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Bethesda, MD 20892 USA. RP Rasmussen, LJ (reprint author), Univ Copenhagen, Ctr Hlth Aging, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark. EM lenera@sund.ku.dk RI Ferrari, Stefano/I-7357-2016 OI Ferrari, Stefano/0000-0002-6607-215X FU EU [LSHC-CT-2005-018754]; NORDEA-fonden; Cancer Research Society, Inc. (Montreal, Canada); Swiss National Science Foundation [31003A-112080]; Promedica-Stiftung (UBS-AG) FX LJR was supported by EU grant LSHC-CT-2005-018754 and NORDEA-fonden. MZH was funded by the Cancer Research Society, Inc. (Montreal, Canada). SF was supported by the Swiss National Science Foundation grant 31003A-112080 and by a grant from the Promedica-Stiftung (UBS-AG). NR 57 TC 10 Z9 11 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAR 1 PY 2012 VL 11 IS 3 BP 267 EP 277 DI 10.1016/j.dnarep.2011.11.007 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 905MN UT WOS:000301276400005 PM 22222486 ER PT J AU Covo, S Westmoreland, JW Reddy, AK Gordenin, DA Resnick, MA AF Covo, Shay Westmoreland, James W. Reddy, Amit K. Gordenin, Dmitry A. Resnick, Michael A. TI RAD53 is limiting in double-strand break repair and in protection against toxicity associated with ribonucleotide reductase inhibition SO DNA REPAIR LA English DT Article DE RAD53; Hydroxyurea; Rnr1; Double strand breaks ID S-PHASE CHECKPOINT; DNA-DAMAGE CHECKPOINT; SACCHAROMYCES-CEREVISIAE; REPLICATION FORKS; HOMOLOGOUS RECOMBINATION; DNTP POOLS; YEAST; RESISTANCE; KINASE; ADAPTATION AB The yeast Chk2/Chk1 homolog Rad53 is a central component of the DNA damage checkpoint system. While it controls genotoxic stress responses such as cell cycle arrest, replication fork stabilization and increase in dNTP pools, little is known about the consequences of reduced Rad53 levels on the various cellular endpoints or about its roles in dealing with chronic vs. acute genotoxic challenges. Using a tetraploid gene dosage model in which only one copy of the yeast RAD53 is functional (simplex), we found that the simplex strain was not sensitive to acute UV radiation or chronic MMS exposure. However, the simplex strain was sensitized to chronic exposure of the ribonucleotide reductase inhibitor hydroxyurea (HU). Surprisingly, reduced RAD53 gene dosage did not affect sensitivity to HU acute exposure, indicating that immediate checkpoint responses and recovery from HU-induced stress were not compromised. Interestingly, cells of most of the colonies that arise after chronic HU exposure acquired heritable resistance to HU. We also found that short HU exposure before and after treatment of G(2) cells with ionizing radiation (IR) reduced the capability of RAD53 simplex cells to repair DSBs, in agreement with sensitivity of RAD53 simplex strain to high doses of IR. We propose that a modest reduction in Rad53 activity can impact the activation of the ribonucleotide reductase catalytic subunit Rnr1 following stress, reducing the ability to generate nucleotide pools sufficient for DNA repair and replication. At the same time, reduced Rad53 activity may lead to genome instability and to the acquisition of drug resistance before and/or during the chronic exposure to HU. These results have implications for developing drug enhancers as well as for understanding mechanisms of drug resistance in cells compromised for DNA damage checkpoint. Published by Elsevier B.V. C1 [Covo, Shay; Westmoreland, James W.; Reddy, Amit K.; Gordenin, Dmitry A.; Resnick, Michael A.] NIEHS, Chromosome Stabil Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Gordenin, DA (reprint author), NIEHS, Chromosome Stabil Grp, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU NIEHS (NIH, DHHS) [1Z01ES065073] FX We greatly appreciate the critical evaluation of the manuscript by Drs. Jeffrey Stumpf, Kin Chan, and Anders Clausen. This work was supported by the Intramural Research Program of the NIEHS (NIH, DHHS) under project 1Z01ES065073 to MAR. NR 47 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAR 1 PY 2012 VL 11 IS 3 BP 317 EP 323 DI 10.1016/j.dnarep.2011.12.008 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 905MN UT WOS:000301276400011 PM 22277748 ER PT J AU Tyagi, M Hashimoto, K Shoemaker, BA Wuchty, S Panchenko, AR AF Tyagi, Manoj Hashimoto, Kosuke Shoemaker, Benjamin A. Wuchty, Stefan Panchenko, Anna R. TI Large-scale mapping of human protein interactome using structural complexes SO EMBO REPORTS LA English DT Article DE protein interactions; protein structures; protein complexes; IBIS ID INTERACTION NETWORKS; GENOME; EVOLUTIONARY; SIMILARITIES; SOFTWARE; BIOLOGY; SERVER AB Although the identification of protein interactions by high-throughput (HTP) methods progresses at a fast pace, 'interactome' data sets still suffer from high rates of false positives and low coverage. To map the human protein interactome, we describe a new framework that uses experimental evidence on structural complexes, the atomic details of binding interfaces and evolutionary conservation. The structurally inferred interaction network is highly modular and more functionally coherent compared with experimental interaction networks derived from multiple literature citations. Moreover, structurally inferred and high-confidence HTP networks complement each other well, allowing us to construct a merged network to generate testable hypotheses and provide valuable experimental leads. C1 [Tyagi, Manoj; Hashimoto, Kosuke; Shoemaker, Benjamin A.; Wuchty, Stefan; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, US Natl Lib Med, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, US Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov RI Tyagi, Manoj/K-8438-2014 FU National Institutes of Health/Department of Health and Human Service (National Library of Medicine) FX This work was supported by National Institutes of Health/Department of Health and Human Service (Intramural Research program of the National Library of Medicine). NR 22 TC 22 Z9 22 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD MAR PY 2012 VL 13 IS 3 BP 266 EP 271 DI 10.1038/embor.2011.261 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 902SX UT WOS:000301061800019 PM 22261719 ER PT J AU Hoang, A Drew, BG Low, H Remaley, AT Nestel, P Kingwell, BA Sviridov, D AF Hoang, Anh Drew, Brian G. Low, Hann Remaley, Alan T. Nestel, Paul Kingwell, Bronwyn A. Sviridov, Dmitri TI Mechanism of cholesterol efflux in humans after infusion of reconstituted high-density lipoprotein SO EUROPEAN HEART JOURNAL LA English DT Article DE Lipids; Lipoproteins; Cholesterol ID TRANSPORT; MACROPHAGES; CAPACITY; PLASMA; CELLS; SIZE AB Infusion of reconstituted HDL (rHDL) leads to changes in HDL metabolism as well as to an increased capacity of plasma to support cholesterol efflux providing an opportunity to investigate mechanisms linking cholesterol efflux to changes in plasma HDL. Patient plasmas after infusion of rHDL were tested ex vivo for their capacity to stimulate cholesterol efflux. Reconstituted HDL enhanced mobilization of cholesterol from tissues in vivo as shown by rising HDL cholesterol concentrations over the infusion period. Infusion of rHDL in vivo led to increased cholesterol efflux ex vivo; surprisingly, removing apoB-containing lipoproteins while preserving all HDL subfractions eliminated this increase. Infusion of rHDL led to the remodelling of plasma HDL; however, the capacity of plasma to support cholesterol efflux did not correlate with changes in the concentrations of any of HDL subfractions. Unmodified rHDL accounted for only a proportion of the increment in cholesterol efflux capacity. Furthermore, studies using HeLa and BHK cells overexpressing ABCA1, ABCG1, and SR-B1 showed that the contribution of these cellular mediators of cholesterol efflux to the enhanced capacity of plasma for the efflux was minimal. Enhanced cholesterol efflux from tissues requires the presence of apoB-containing lipoproteins and may involve enhanced flow of cholesterol through multiple components of the reverse cholesterol transport pathway rather than being determined by a specific HDL subfraction. C1 [Hoang, Anh; Drew, Brian G.; Low, Hann; Nestel, Paul; Kingwell, Bronwyn A.; Sviridov, Dmitri] Baker Heart & Diabet Inst, Melbourne, Vic 8008, Australia. [Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Sviridov, D (reprint author), Baker Heart & Diabet Inst, POB 6492,St Kilda Rd Cent, Melbourne, Vic 8008, Australia. EM dmitri.sviridov@bakeridi.edu.au RI Kingwell, Bronwyn/B-1183-2009; Sviridov, Dmitri/E-7943-2010 FU National Health and Medical Research Council of Australia [526614, 418920] FX This study was supported by grants #526614 (to D. S.) and #418920 (to B. K.) from the National Health and Medical Research Council of Australia. D. S. and B. K. are Fellows of the National Health and Medical Research Council of Australia. B. G. D. is a Post-Doctoral Training Fellow of the National Health and Medical Research Council of Australia. rHDL for the original clinical trial was supplied by CSL Behring. NR 17 TC 38 Z9 39 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD MAR PY 2012 VL 33 IS 5 BP 657 EP 665 DI 10.1093/eurheartj/ehr103 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 901YE UT WOS:000301004400023 PM 21498847 ER PT J AU Martinez-Gonzalez, C Wang, HL Micklem, BR Bolam, JP Mena-Segovia, J AF Martinez-Gonzalez, Cristina Wang, Hui-Ling Micklem, Benjamin R. Bolam, J. Paul Mena-Segovia, Juan TI Subpopulations of cholinergic, GABAergic and glutamatergic neurons in the pedunculopontine nucleus contain calcium-binding proteins and are heterogeneously distributed SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE brainstem; calbindin; calretinin; in situ hybridization; rat; stereology ID LATERODORSAL TEGMENTAL NUCLEI; NITRIC-OXIDE SYNTHASE; BRAIN-STEM CORE; PONTOMESENCEPHALIC TEGMENTUM; NONCHOLINERGIC NEURONS; RAT HIPPOCAMPUS; SQUIRREL-MONKEY; MACAQUE MONKEY; BASAL GANGLIA; PARVALBUMIN AB Neurons in the pedunculopontine nucleus (PPN) are highly heterogeneous in their discharge properties, their neurochemical markers, their pattern of connectivity and the behavioural processes in which they participate. Three main transmitter phenotypes have been described, cholinergic, GABAergic and glutamatergic, and yet electrophysiological evidence suggests heterogeneity within these subtypes. To gain further insight into the molecular composition of these three populations in the rat, we investigated the pattern of expression of calcium binding proteins (CBPs) across distinct regions of the PPN and in relation to the presence of other neurochemical markers. Calbindin- and calretinin-positive neurons are as abundant as cholinergic neurons, and their expression follows a rostro-caudal gradient, whereas parvalbumin is expressed by a low number of neurons. We observed a high degree of expression of CBPs by GABAergic and glutamatergic neurons, with a large majority of calbindin- and calretinin-positive neurons expressing GAD or VGluT2 mRNA. Notably, CBP-positive neurons expressing GAD mRNA were more concentrated in the rostral PPN, whereas the caudal PPN was characterized by a higher density of CBP-positive neurons expressing VGluT2 mRNA. In contrast to these two large populations, in cholinergic neurons expression of calretinin is observed only in low numbers and expression of calbindin is virtually non-existent. These findings thus identify novel subtypes of cholinergic, GABAergic and glutamatergic neurons based on their expression of CBPs, and further contribute to the notion of the PPN as a highly heterogeneous structure, an attribute that is likely to underlie its functional complexity. C1 [Martinez-Gonzalez, Cristina; Micklem, Benjamin R.; Bolam, J. Paul; Mena-Segovia, Juan] Univ Oxford, Dept Pharmacol, Med Res Council Anat Neuropharmacol Unit, Oxford OX1 3TH, England. [Wang, Hui-Ling] NIDA, Intramural Res Program, Biomed Res Ctr, Baltimore, MD USA. RP Mena-Segovia, J (reprint author), Univ Oxford, Dept Pharmacol, Med Res Council Anat Neuropharmacol Unit, Mansfield Rd, Oxford OX1 3TH, England. EM juan.mena-segovia@pharm.ox.ac.uk OI Mena-Segovia, Juan/0000-0002-9991-8254; Bolam, J Paul/0000-0002-5008-8405 FU Medical Research Council UK; National Institute on Drug Abuse; CONACyT FX This work was supported by the Medical Research Council UK and by the Intramural Research Program of the National Institute on Drug Abuse. C.M.-G. is in receipt of a CONACyT studentship. We thank E. Norman and K. Whitworth for their technical assistance. NR 49 TC 21 Z9 21 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD MAR PY 2012 VL 35 IS 5 BP 723 EP 734 DI 10.1111/j.1460-9568.2012.08002.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 903LW UT WOS:000301119000009 PM 22356461 ER PT J AU Bodelon, C Madeleine, MM Johnson, LG Du, Q Malkki, M Petersdorf, EW Schwartz, SM AF Bodelon, Clara Madeleine, Margaret M. Johnson, Lisa G. Du, Qin Malkki, Mari Petersdorf, Effie W. Schwartz, Stephen M. TI Genetic variation in CD83 and risks of cervical and vulvar cancers: A population-based case-control study SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Human papillomavirus; Cervix; Vulva; Epidemiology; Genetics ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; DENDRITIC CELLS; INTRAEPITHELIAL NEOPLASIA; VARIANTS; ADENOCARCINOMA; METAANALYSIS; MATURATION; PROGRAM; MARKER AB Objectives. The CD83 glycoprotein is a marker of dendritic cell maturation that may contribute to the T cell response to oncogenic human papillomavirus (HPV) infection. Whether single nucleotide polymorphisms (SNPs) in CD83 influence the risk of HPV-related genital cancers has not been adequately studied. We investigated whether the common genetic variation of the CD83 region was associated with the risks of cervical and vulvar cancers in a population-based case-control study conducted in the Seattle-Puget Sound Region. Methods. A total of 17 tagSNPs were genotyped in the CD83 region of 886 cervical cases, 517 vulvar cases and 1100 controls. Odds ratio (OR) and 95% confidence intervals (Cl) were computed to assess the risk of cervical and vulvar cancers. The interaction between the tagSNPs and cigarette smoking was also explored. Results. TagSNPs in the CD83 chromosomal region were not associated with risk of either cervical or vulvar cancer. TagSNP rs853360 was associated with a decreased risk of cervical squamous cell carcinoma (SCC) (OR=0.80; 95% Cl: 0.66-0.98). Conclusions. Our results do not suggest that the common genetic variation of CD83 is related to cervical or vulvar cancers. The association between tagSNP rs853360 and risk of cervical SCC is likely to be due to chance. If larger or pooled studies confirm our results, CD83 has little or no influence in the risk of HPV-related cancers. Published by Elsevier Inc. C1 [Bodelon, Clara; Madeleine, Margaret M.; Johnson, Lisa G.; Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Bodelon, Clara; Madeleine, Margaret M.; Schwartz, Stephen M.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Du, Qin; Malkki, Mari; Petersdorf, Effie W.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. RP Bodelon, C (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7003, Rockville, MD 20852 USA. EM clara.bodelon@nih.gov OI Schwartz, Stephen/0000-0001-7499-8502 FU National Cancer Institute [R01CA112512, P01CA042792, NO1-CN-67009, NO1-PC-35142, T32CA009168]; Fred Hutchinson Cancer Research Center FX This work was supported by the research grants (R01CA112512, P01CA042792), contracts (NO1-CN-67009, NO1-PC-35142) and a training grant (T32CA009168 to CB) from the National Cancer Institute, as well as institutional funding from the Fred Hutchinson Cancer Research Center. NR 25 TC 5 Z9 5 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2012 VL 124 IS 3 BP 525 EP 528 DI 10.1016/j.ygyno.2011.11.017 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 898OO UT WOS:000300751900026 PM 22134374 ER PT J AU Glasgow, RE Kaplan, RM Ockene, JK Fisher, EB Emmons, KM AF Glasgow, Russell E. Kaplan, Robert M. Ockene, Judith K. Fisher, Edwin B. Emmons, Karen M. TI Patient-Reported Measures Of Psychosocial Issues And Health Behavior Should Be Added To Electronic Health Records SO HEALTH AFFAIRS LA English DT Article ID CENTERED MEDICAL HOME; PRIMARY-CARE; PHYSICAL-ACTIVITY; CONTROLLED-TRIAL; FIELD-TEST; DEPRESSION; SATISFACTION; MANAGEMENT AB Recent legislation and delivery system reform efforts are greatly expanding the use of electronic health records. For these efforts to reach their full potential, they must actively involve patients and include patient-reported information about such topics as health behavior, preferences, and psychosocial functioning. We offer a plan for including standardized, practical patient-reported measures as part of electronic health records, quality and performance indexes, the primary care medical home, and research collaborations. These measures must meet certain criteria, including being valid, reliable, sensitive to change, and available in multiple languages. Clinicians, patients, and policy makers also must be able to understand the measures and take action based on them. Including more patient-reported items in electronic health records would enhance health, patient-centered care, and the capacity to undertake population-based research. C1 [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kaplan, Robert M.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Ockene, Judith K.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Fisher, Edwin B.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC USA. [Fisher, Edwin B.] Univ N Carolina, Gillings Sch Global Publ Hlth, Amer Acad Family Phys Fdn, Chapel Hill, NC USA. [Fisher, Edwin B.] Amer Acad Family Phys Fdn, Peers Progress Program, Leawood, KS USA. [Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM russ.glasgow@nih.gov FU Society of Behavioral Medicine Health Policy Committee and Executive Committee FX The opinions expressed in this article do not necessarily represent those of the National Cancer Institute. The authors thank the members of the Society of Behavioral Medicine Health Policy Committee and Executive Committee for their support, comments on earlier versions, and work on the health policy brief that prompted this article. NR 50 TC 51 Z9 51 U1 8 U2 20 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD MAR PY 2012 VL 31 IS 3 BP 497 EP 504 DI 10.1377/hlthaff.2010.1295 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 904UQ UT WOS:000301223800006 PM 22392660 ER PT J AU Wang, T Rowland, JG Parmar, J Nesterova, M Seki, T Rainey, WE AF Wang, T. Rowland, J. G. Parmar, J. Nesterova, M. Seki, T. Rainey, W. E. TI Comparison of Aldosterone Production Among Human Adrenocortical Cell Lines SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE aldosterone; adrenocortical carcinoma; steroidogenesis ID ACUTE REGULATORY PROTEIN; ANGIOTENSIN-II; STEROIDOGENIC ENZYMES; SYNTHASE CYTOCHROME-P-450; EXPRESSION PROFILES; GLOMERULOSA CELLS; ADRENAL ZONATION; GENE-EXPRESSION; CARCINOMA; 11-BETA-HYDROXYLASE AB Several human adrenocortical cell lines have been used as model systems for aldosterone production. However, these cell lines have not been directly compared with each other. Human adrenal cell lines SW13, CAR47, the NCI-H295 and its sub-strains and sub-clones were compared with regard to aldosterone production and aldosterone synthase (CYP11B2) expression. Culture media was collected 48 h after incubation, aldosterone secretion was measured and the data were normalized to the amount of cell protein. RNA was isolated for microarray analysis and quantitative RT-PCR (qPCR). The cell lines with the highest aldosterone production were further tested with regard to angiotensin II (Ang II) stimulation. Neither aldosterone nor CYP11B2 tran-script were detected in SW13 or CAR47 cells. The aldosterone production by the NCI-H295, H295A, H295R-S1, H295R-S2, H295R-S3, HAC13, HAC15 and HAC50 were 119, 1, 6, 826, 18, 139, 412, and 1 334 (pmol/mg protein/48 h), respectively. H295A and H295R-S1 expressed less CYP11B2 than the commonly used H295R-S3 cells; while NCI-H295, H295R-S2, HAC13, HAC15 and HAC50 expressed 24-, 14-, 3-, 10-, and 35-fold higher CYP11B2 compared with the H295R-S3 cells. When treated with Ang II, NCI-H295, H295RS2, HAC13, HAC15 and HAC50 showed signifi cantly higher aldosterone production than the basal level (p < 0.05). A comparison of the available human adrenal cell lines indicates that the H295R-S2 and the clonal cell lines, HAC13, HAC15 and HAC50 produced the highest levels of aldosterone and responded well to Ang II. C1 [Wang, T.; Rowland, J. G.; Parmar, J.; Seki, T.; Rainey, W. E.] Georgia Hlth Sci Univ, Dept Physiol, Augusta, GA 30912 USA. [Wang, T.] Wuhan Univ, Renmin Hosp, Dept Cardiol, Wuhan 430072, Peoples R China. [Nesterova, M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol Genet, NIH, Ctr Clin, Bethesda, MD USA. RP Rainey, WE (reprint author), Georgia Hlth Sci Univ, Dept Physiol, 1120 15th St, Augusta, GA 30912 USA. EM wrainey@georgiahealth.edu RI WANG, TAO/B-1888-2013 FU National Institutes of Health [DK-43140, DK-069950]; Cardiovascular Discovery Institute, Georgia Health Sciences University FX This work was also supported by National Institutes of Health Grants DK-43140 and DK-069950 (to WER), a Synergy Award from the Cardiovascular Discovery Institute, Georgia Health Sciences University (to WER). NR 39 TC 23 Z9 24 U1 0 U2 4 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAR PY 2012 VL 44 IS 3 BP 245 EP 250 DI 10.1055/s-0031-1298019 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 905PP UT WOS:000301285000016 PM 22266826 ER PT J AU Fanchiang, SS Cojocaru, R Othman, M Khanna, R Brooks, MJ Smith, T Tang, XL Maricic, I Swaroop, A Kumar, V AF Fanchiang, Shaohsuan S. Cojocaru, Radu Othman, Mohammad Khanna, Ritu Brooks, Matthew J. Smith, Trevor Tang, Xiaolei Maricic, Igor Swaroop, Anand Kumar, Vipin TI Global expression profiling of peripheral Qa-1-restricted CD8 alpha alpha plus TCR alpha beta plus regulatory T cells reveals innate-like features: Implications for immune-regulatory repertoire SO HUMAN IMMUNOLOGY LA English DT Article DE CD8(+) Treg; Experimental autoimmune encephalomyelitis; Microarray; Innate cells; Qa-1; HLA-E ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HERPESVIRUS ENTRY MEDIATOR; MULTIPLE-SCLEROSIS; POSITIVE SELECTION; NEGATIVE REGULATOR; NONCLASSICAL MHC; SELF-TOLERANCE; ROR-ALPHA; IN-VIVO; RESPONSES AB Among peripheral regulatory T cells, CD8(+) T cells also play an important role in the maintenance of immune homeostasis. A subset of CD8(+) Treg that express alpha beta T cell receptor (TCR) and CD8 alpha alpha homodimers can recognize TCR-derived peptides in the context of the class Ib MHC molecule Qa-1. To gain a better understanding of the nature and phenotype of CD8 alpha alpha+TCR alpha beta+ Treg, a global gene expression profiling using microarray, real-time quantitative polymerase chain reaction, and flow-cytometric analysis was performed using functional Treg clones and lines. The study findings show that CD8(+) Treg shared gene profile expressed by innate-like lymphocytes, including murine intraepithelial lymphocytes and thymic CD8 alpha alpha+TCR alpha beta+ T-cell populations. In addition, this subset displays differential expression of several key regulatory molecules, including CD200. CD8 alpha alpha(+) Treg expressed higher levels of a number of natural killer cell related receptors and molecules belonging to the TNF superfamily. Collectively, peripheral class Ib-reactive CD8 alpha alpha+TCR alpha beta+ T cells represent a unique regulatory population different from class la major histocompatibility complex restricted conventional T cells. These studies have important implications for the regulatory mechanisms mediated by the CD8(+) Treg population in general. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. C1 [Fanchiang, Shaohsuan S.; Smith, Trevor; Tang, Xiaolei; Maricic, Igor; Kumar, Vipin] Torrey Pines Inst Mol Studies, Lab Autoimmun, San Diego, CA 92121 USA. [Cojocaru, Radu; Brooks, Matthew J.; Swaroop, Anand] NEI, NIH, N NRL, Bethesda, MD 20892 USA. [Othman, Mohammad; Khanna, Ritu; Brooks, Matthew J.; Swaroop, Anand] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Othman, Mohammad; Khanna, Ritu; Brooks, Matthew J.; Swaroop, Anand] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Kumar, V (reprint author), Torrey Pines Inst Mol Studies, Lab Autoimmun, San Diego, CA 92121 USA. EM vkumar@tpims.org FU National Institutes of Health [R01AI05227]; MSNRI; DNRG FX The authors thank Dr Randle Ware for critical reading of the manuscript, and other members of the Laboratory of Autoimmunity for their kind help. This work was supported by the National Institutes of Health (R01AI05227), MSNRI, and DNRG (to V.K.). NR 60 TC 6 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD MAR PY 2012 VL 73 IS 3 BP 214 EP 222 DI 10.1016/j.humimm.2011.07.306 PG 9 WC Immunology SC Immunology GA 901JY UT WOS:000300964400002 PM 21889557 ER PT J AU Han, S Koo, HH Lan, Q Lee, KM Park, AK Park, SK Sung, H Ahn, HS Shin, HY Kang, HJ Seo, JJ Ahn, YO Kim, H Rothman, N Kang, D AF Han, Sohee Koo, Hong Hoe Lan, Qing Lee, Kyoung-Mu Park, Ae Kyung Park, Sue K. Sung, Hyuna Ahn, Hyo Seop Shin, Hee Young Kang, Hyoung Jin Seo, Jong Jin Ahn, Yoon-Ok Kim, Ho Rothman, Nathaniel Kang, Daehee TI Common variation in genes related to immune response and risk of childhood leukemia SO HUMAN IMMUNOLOGY LA English DT Article DE Childhood leukemia; Immune response; Single nucleotide polymorphism ID ACUTE LYMPHOBLASTIC-LEUKEMIA; POLYMORPHISMS; CANCER; NOTCH; IDENTIFICATION; CHROMOSOME-11; PROTEIN; CELLS; ACID; 11Q AB An abnormal immune response to common infection(s) may be a plausible etiological mechanism in childhood leukemia. We investigated whether 931 tagging single nucleotide polymorphisms (SNPs) selected in gene regions related to immune response are associated with childhood leukemia susceptibility in a hospital-based case control study (63 cases and 148 controls) conducted among Korean children. The AT or IT genotype of rs7939734 in Fas-associated protein with death domain (FADD) was associated with increased risk of childhood leukemia compared with the AA genotype (odds ratio [OR] = 2.26, 95% confidence interval [95% CI] = 1.20-4.25, p(trend) = 0.0007, min p = 0.002, false discovery rate [FDR] p = 0.17). The CG or GG genotype of rs2301696 in TRPM5 was associated with decreased risk of childhood leukemia compared with the CC genotype (OR = 0.30, 95% CI = 0.14 0.63, P-trend = 0.002, min p = 0.004, FDR p = 0.17). Our findings suggest that genetic polymorphisms in immune response genes might play a role in childhood leukemia development with limited biologic evidence. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. C1 [Han, Sohee; Park, Sue K.; Ahn, Yoon-Ok; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Koo, Hong Hoe] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pediat, Seoul 110799, South Korea. [Lan, Qing; Rothman, Nathaniel] NCI, NIH, Dept Hlth, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lan, Qing; Rothman, Nathaniel] NCI, NIH, Dept Hlth, Human Serv, Bethesda, MD 20892 USA. [Lee, Kyoung-Mu] Korea Natl Open Univ, Dept Environm Hlth, Seoul 110799, South Korea. [Park, Ae Kyung] Sunchon Natl Univ, Coll Pharm, Sunchon 540742, Jeonnam, South Korea. [Park, Sue K.; Ahn, Hyo Seop; Shin, Hee Young; Kang, Hyoung Jin; Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea. [Sung, Hyuna; Kang, Daehee] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul 110799, South Korea. [Ahn, Hyo Seop; Shin, Hee Young; Kang, Hyoung Jin] Seoul Natl Univ, Coll Med, Dept Pediat, Seoul 110799, South Korea. [Seo, Jong Jin] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pediat, Seoul 110799, South Korea. [Kim, Ho] Sch Publ Hlth, Div Epidemiol & Biostat, Seoul 110799, South Korea. [Kang, Daehee] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Seoul 110799, South Korea. [Kang, Daehee] Seoul Natl Univ, Coll Med, Seoul 110799, South Korea. [Kang, Daehee] Seoul Natl Univ, Coll Pharm, Seoul 110799, South Korea. RP Kang, D (reprint author), Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. EM dhkang@snu.ac.kr RI Kang, Hyoung Jin/J-2730-2012; Kang, Dae Hee/E-8631-2012; Ahn, Yoon-Ok/J-5530-2012; Shin, Hee Young/J-2766-2012; Park, Sue Kyung/J-2757-2012 FU Ministry of Health and Welfare, Republic of Korea [AO030001, 0520290] FX The authors thank all patients and their parents who consented to participate in a genetics study related to leukemia. This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (Grant AO030001) and by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (Grant 0520290). NR 28 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD MAR PY 2012 VL 73 IS 3 BP 316 EP 319 DI 10.1016/j.humimm.2011.12.018 PG 4 WC Immunology SC Immunology GA 901JY UT WOS:000300964400017 PM 22244917 ER PT J AU Wildfire, JJ Gergen, PJ Sorkness, CA Mitchell, HE Calatroni, A Kattan, M Szefler, SJ Teach, SJ Bloomberg, GR Wood, RA Liu, AH Pongracic, JA Chmiel, JF Conroy, K Rivera-Sanchez, Y Busse, WW Morgan, WJ AF Wildfire, Jeremy J. Gergen, Peter J. Sorkness, Christine A. Mitchell, Herman E. Calatroni, Agustin Kattan, Meyer Szefler, Stanley J. Teach, Stephen J. Bloomberg, Gordon R. Wood, Robert A. Liu, Andrew H. Pongracic, Jacqueline A. Chmiel, James F. Conroy, Kathleen Rivera-Sanchez, Yadira Busse, William W. Morgan, Wayne J. TI Development and validation of the Composite Asthma Severity Index-an outcome measure for use in children and adolescents SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; composite score; morbidity; treatment; exacerbations; symptoms; severity ID INNER-CITY CHILDREN; CLINICAL-TRIAL; END-POINTS; EXACERBATIONS; MANAGEMENT; PROGRAM; PANEL AB Background: Asthma severity is reflected in many aspects of the disease, including impairment and future risks, particularly for exacerbations. According to the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, however, to assess more comprehensively the severity of asthma the level of current treatment needed to maintain a level of control should be included. Objective: Development and validation of a new instrument, the Composite Asthma Severity Index (CASI), which can quantify disease severity by taking into account impairment, risk, and the amount of medication needed to maintain control. At present, there is no instrument available to measure and assess the multidimensional nature of asthma. Methods: Twenty-six established asthma investigators, who are part of the National Institutes of Health-supported Inner City Asthma Consortium, participated in a modified Delphi consensus process to identify and weight the dimensions of asthma. Factor analysis was performed to identify independent domains of asthma by using the Asthma Control Evaluation trial. CASI was validated by using the Inner City Anti-IgE Therapy for Asthma trial. Results: CASI scores include 5 domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. At Asthma Control Evaluation trial enrollment, CASI ranged from 0 to 17, with a mean of 6.2. CASI was stable, with minimal change in variance after 1 year of treatment. In external validation, CASI detected a 32% larger improvement than did symptoms alone. Conclusion: CASI retained its discriminatory ability even with low levels of symptoms reported after months of guidelines-directed care. Thus, CASI has the ability to determine the level of asthma severity and provide a composite clinical characterization of asthma. (J Allergy Clin Immunol 2012; 129: 694-701.) C1 [Wildfire, Jeremy J.; Mitchell, Herman E.; Calatroni, Agustin] Rho Fed Syst Div Inc, Chapel Hill, NC 27517 USA. [Gergen, Peter J.] NIAID, Bethesda, MD 20892 USA. [Sorkness, Christine A.; Busse, William W.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Kattan, Meyer] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Szefler, Stanley J.; Liu, Andrew H.] Natl Jewish Hlth, Denver, CO USA. [Szefler, Stanley J.; Liu, Andrew H.] Univ Colorado, Sch Med, Denver, CO USA. [Teach, Stephen J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Bloomberg, Gordon R.] Washington Univ, St Louis, MO USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Pongracic, Jacqueline A.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Chmiel, James F.] Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. [Conroy, Kathleen] Boston Univ, Sch Med, Boston, MA 02118 USA. [Rivera-Sanchez, Yadira] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Morgan, Wayne J.] Univ Arizona, Coll Med, Tucson, AZ USA. RP Wildfire, JJ (reprint author), Rho Fed Syst Div Inc, 6330 Quadrangle Dr, Chapel Hill, NC 27517 USA. EM jeremy_wildfire@rhoworld.com FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [NO1-AI-25496, NO1-JAI-25482]; National Center for Research Resources, National Institutes of Health [RR00052, M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, 5UL1RR024992-02, 5M01RR020359-04]; GlaxoSmithKline; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Environmental Health Sciences (NIEHS; NIAID; NIH; Environmental Protection Agency; Novartis; NIAID/NHLBI/NIH FX This project was funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract nos. NO1-AI-25496 and NO1-JAI-25482. Additional funds were provided by the National Center for Research Resources, National Institutes of Health, under grants RR00052, M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, 5UL1RR024992-02, and 5M01RR020359-04.; M. Kattan and G. R. Bloomberg have received research support from the National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH). S. J. Szefer has consulted for GlaxoSmithKline, Genentech, Merck, Boehringer-Ingelheim, Novartis, and Schering-Plough and has received research support from GlaxoSmithKline, the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Environmental Health Sciences (NIEHS), the NIAID, the NIH, and the Environmental Protection Agency. R. A. Wood has consulted for the Asthma and Allergy Foundation of America, received research support from the NIH, and served on the medical advisory board for the Food Allergy and Anaphylaxis Network. A. H. Liu has received a speaker honorarium from Merck. J. A. Pongracic has received research support from the NIAID. J. F. Chmiel has received research support from the NIH. W. J. Morgan has consulted for the Cystic Fibrosis Foundation, Genentech, and Novartis and has received research support from the NIH and Novartis. W. W. Busse has served on advisory boards for Centocor and Merck; has consulted for Amgen, AstraZeneca, Novartis, GlaxoSmithKline, Med-Immune, and Genentech; and has received research support from the NIAID/NHLBI/NIH. The rest of the authors declare that they have no relevant conflicts of interest. NR 22 TC 24 Z9 24 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 MAR PY 2012 VL 129 IS 3 BP 694 EP 701 DI 10.1016/j.jaci.2011.12.962 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 904IW UT WOS:000301189300013 PM 22244599 ER PT J AU Kesserwan, C Sokolic, R Cowen, EW Garabedian, E Heselmeyer-Haddad, K Lee, CCR Pittaluga, S Ortiz, C Baird, K Lopez-Terrada, D Bridge, J Wayne, AS Candotti, F AF Kesserwan, Chimene Sokolic, Robert Cowen, Edward W. Garabedian, Elizabeth Heselmeyer-Haddad, Kerstin Lee, Chyi-Chia Richard Pittaluga, Stefania Ortiz, Clarymar Baird, Kristin Lopez-Terrada, Dolores Bridge, Julia Wayne, Alan S. Candotti, Fabio TI Multicentric dermatofibrosarcoma protuberans in patients with adenosine deaminase-deficient severe combined immune deficiency SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Severe combined immunodeficiency; adenosine deaminase; dermatofibrosarcoma; adenosine; fibrosis ID GIANT-CELL FIBROBLASTOMA; BONE-MARROW TRANSPLANTATION; MICE; CHILDHOOD; GENETICS; FIBROSIS; CHILDREN; FUSION; TUMORS AB Background: Dermatofibrosarcoma protuberans (DFSP) is a rare malignant skin tumor associated with a characteristic chromosomal translocation (t[17; 22][q22;q13]) resulting in the COL1A1-platelet-derived growth factor beta (PDGFB) fusion gene. This malignancy is rarely diagnosed in childhood. Objective: We observed an unexpected high incidence of this DFSP in children affected with adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) and set out to evaluate the association of these 2 clinical entities. Methods: Twelve patients with ADA-SCID were evaluated with a complete dermatologic examination and skin biopsy when indicated. Conventional cytogenetic and molecular analyses (fluorescence in situ hybridization, RT-PCR, or both) were performed when possible. Results: Eight patients were found to have DFSP. Six patients had multicentric involvement (4-15 lesions), primarily of the trunk and extremities. Most lesions presented as 2- to 15-mm, round atrophic plaques. Nodular lesions were present in 3 patients. In all cases CD34 expression was diffusely positive, and diagnosis was confirmed either by means of cytogenetic analysis, molecular testing, or both. The characteristic DFSP-associated translocation, t(17; 22)(q22; q13), was identified in 6 patients; results of fluorescence in situ hybridization were positive for fusion of the COL1A1 and PDGFB loci in 7 patients; and RTPCR showed the COL1A1-PDGFB fusion transcript in 6 patients. Conclusions: We describe a previously unrecognized association between ADA-SCID and DFSP with unique features, such as multicentricity and occurrence in early age. We hypothesize that the t(17; 22)(q22; q13) translocation that results in dermal overexpression of PDGFB and favors the development of fibrotic tumors might arise because of the known DNA repair defect in patients with ADA-SCID. Although the natural course of DFSP in the setting of ADA-SCID is unknown, this observation should prompt regular screening for DFSP in patients with ADA-SCID. (J Allergy Clin Immunol 2012; 129: 762-9.) C1 [Candotti, Fabio] NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Kesserwan, Chimene; Sokolic, Robert; Garabedian, Elizabeth; Candotti, Fabio] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Heselmeyer-Haddad, Kerstin; Ortiz, Clarymar] NCI, Sect Canc Genom, NIH, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard; Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Baird, Kristin; Wayne, Alan S.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lopez-Terrada, Dolores] Texas Childrens Hosp, Dept Pathol, Houston, TX 77030 USA. [Bridge, Julia] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. RP Candotti, F (reprint author), NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Bldg 49,Rm 3A04,MSC 4442, Bethesda, MD 20892 USA. EM fabio@nhgri.nih.gov RI Sokolic, Robert/I-6072-2012; Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 FU National Institutes of Health, National Human Genome Research Institute; National Cancer Institute FX Supported by the Intramural Research Program of the National Institutes of Health, National Human Genome Research Institute and National Cancer Institute. NR 28 TC 13 Z9 13 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 MAR PY 2012 VL 129 IS 3 BP 762 EP U240 DI 10.1016/j.jaci.2011.10.028 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 904IW UT WOS:000301189300023 PM 22153773 ER PT J AU Granada, M Wilk, JB Tuzova, M Strachan, DP Weidinger, S Albrecht, E Gieger, C Heinrich, J Himes, BE Hunninghake, GM Celedon, JC Weiss, ST Cruikshank, WW Farrer, LA Center, DM O'Connor, GT AF Granada, Mark Wilk, Jemma B. Tuzova, Marina Strachan, David P. Weidinger, Stephan Albrecht, Eva Gieger, Christian Heinrich, Joachim Himes, Blanca E. Hunninghake, Gary M. Celedon, Juan C. Weiss, Scott T. Cruikshank, William W. Farrer, Lindsay A. Center, David M. O'Connor, George T. TI A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Total IgE; atopy; asthma; genome-wide association study ID IMMUNOGLOBULIN-E; ALLERGIC DISEASES; CHILDHOOD ASTHMA; HLA ANTIGENS; GENE; POPULATION; LINKAGE; STAT6; RISK; SUSCEPTIBILITY AB Background: Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation. Objective: We sought to ascertain the genetic risk factors that lead to IgE dysregulation. Methods: A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS). Seventy of the top single nucleotide polymorphisms (SNPs) were selected based on P values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with 5 independent populations from the Cooperative Health Research in the Region of Augsburg cohort, the British 1958 Birth Cohort, and the Childhood Asthma Management Program cohort. Results: Thirteen SNPs located in the region of 3 genes, FCER1A, signal transducer and activator of transcription 6 (STAT6), and IL13, were found to have genome-wide significance in the FHS cohort GWAS. The most significant SNPs from the 3 regions were rs2251746 (FCER1A, P = 2.11 x 10(-12)), rs1059513 (STAT6, P = 2.87 x 10(-8)), and rs1295686 (IL13, P = 3.55 x 10(-8)). Four additional gene regions, HLA-G, HLA-DQA2, HLA-A, and Duffy blood group, chemokine receptor (DARC), reached genome-wide statistical significance in a meta-analysis combining the FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene. Conclusion: This GWAS of the FHS cohort has identified genetic loci in HLA genes that might have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of the known susceptibility loci FCER1A, STAT6, and IL13 for the dysregulation of total IgE. (J Allergy Clin Immunol 2012;129:840-5.) C1 [Granada, Mark; Tuzova, Marina; Cruikshank, William W.; Center, David M.; O'Connor, George T.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Wilk, Jemma B.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Strachan, David P.] Univ London, Div Community Hlth Sci, London WC1E 7HU, England. [Weidinger, Stephan] Univ Kiel, Dept Dermatol, D-24098 Kiel, Germany. [Albrecht, Eva; Gieger, Christian] German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Heinrich, Joachim] German Res Ctr Environm Hlth, Inst Epidemiol 1, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Himes, Blanca E.; Hunninghake, Gary M.; Weiss, Scott T.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Himes, Blanca E.; Hunninghake, Gary M.; Weiss, Scott T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Celedon, Juan C.] Univ Pittsburgh, Div Pediat Pulm Med Allergy & Immunol, Childrens Hosp Pittsburgh, UPMC,Sch Med, Pittsburgh, PA 15260 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Genet & Genom, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. RP O'Connor, GT (reprint author), Boston Univ, Sch Med, Ctr Pulm, 72 E Concord St R-304, Boston, MA 02118 USA. EM goconnor@bu.edu RI Weidinger, Stephan/C-8461-2011; OI Farrer, Lindsay/0000-0001-5533-4225; O'Connor, George/0000-0002-6476-3926; Gieger, Christian/0000-0001-6986-9554 FU Flight Attendant Medical Research Institute; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02]; DFG [WE 2678/6-1]; German Ministry of Education and Research (BMBF) [01GS 0818]; Helmholtz Center Munich; German National Genome Research Network [01GS0823]; National Library of Medicine [K08 HL092222, 2T15LM007092-16]; National Institutes of Health/National Heart, Lung, and Blood Institute [U01 HL075419, U01 HL65899, P01 HL083069, N01 HR16049, T32 HL07427]; [N01 HC 25195]; [P01 AI 050516] FX G.T.O. and J.B.W. were supported by N01 HC 25195 and P01 AI 050516. J.B.W. was supported by the Flight Attendant Medical Research Institute. D. P. S. was supported by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02. S. W. was supported by the DFG (grant WE 2678/6-1) and the German Ministry of Education and Research (BMBF) as part of the National Genome Research Network (NGFN grant 01GS 0818). C. G., J.H., and E. A. were supported by Helmholtz Center Munich, German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823) and MC Health as part of LMUinnovativ. G. M. H. was supported by K08 HL092222. B. E. H. was supported by 2T15LM007092-16 from the National Library of Medicine. The Childhood Asthma Management Program Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, N01 HR16049, and T32 HL07427 from the National Institutes of Health/National Heart, Lung, and Blood Institute. NR 38 TC 63 Z9 65 U1 2 U2 8 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 MAR PY 2012 VL 129 IS 3 BP 840 EP U371 DI 10.1016/j.jaci.2011.09.029 PG 27 WC Allergy; Immunology SC Allergy; Immunology GA 904IW UT WOS:000301189300033 PM 22075330 ER PT J AU Venditti, V Fawzi, NL Clore, GM AF Venditti, Vincenzo Fawzi, Nicolas L. Clore, G. Marius TI An efficient protocol for incorporation of an unnatural amino acid in perdeuterated recombinant proteins using glucose-based media SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Site-specific labeling; Isotopic labeling; Unnatural amino acids; Spin-labeling ID ESCHERICHIA-COLI; PHOSPHOTRANSFERASE SYSTEM; GENETIC INCORPORATION; ENZYME-I; NMR; DYNAMICS; SPECTROSCOPY; PROBE; CODE AB The in vivo incorporation of unnatural amino acids into proteins is a well-established technique requiring an orthogonal tRNA/aminoacyl-tRNA synthetase pair specific for the unnatural amino acid that is incorporated at a position encoded by a TAG amber codon. Although this technology provides unique opportunities to engineer protein structures, poor protein yields are usually obtained in deuterated media, hampering its application in the protein NMR field. Here, we describe a novel protocol for incorporating unnatural amino acids into fully deuterated proteins using glucose-based media (which are relevant to the production, for example, of amino acid-specific methyl-labeled proteins used in the study of large molecular weight systems). The method consists of pre-induction of the pEVOL plasmid encoding the tRNA/aminoacyl-tRNA synthetase pair in a rich, H2O-based medium prior to exchanging the culture into a D2O-based medium. Our protocol results in high level of isotopic incorporation (similar to 95%) and retains the high expression level of the target protein observed in Luria-Bertani medium. C1 [Venditti, Vincenzo; Fawzi, Nicolas L.; Clore, G. Marius] 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@mail.nih.gov RI Venditti, Vincenzo/A-9411-2013; Fawzi, Nicolas/E-2555-2013; Clore, G. Marius/A-3511-2008 OI Fawzi, Nicolas/0000-0001-5483-0577; Clore, G. Marius/0000-0003-3809-1027 FU NIH, NIDDK; Office of the Director of the NIH FX We thank Drs. Mark Fleissner and Wayne Hubbell for generously providing pAcF and the Scripps Research Institute for the pEVOL plasmid. This work was supported by funds from the Intramural Program of the NIH, NIDDK, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 24 TC 7 Z9 7 U1 2 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD MAR PY 2012 VL 52 IS 3 BP 191 EP 195 DI 10.1007/s10858-012-9606-9 PG 5 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 905VD UT WOS:000301303100001 PM 22350951 ER PT J AU Shen, Y Bax, A AF Shen, Yang Bax, Ad TI Identification of helix capping and beta-turn motifs from NMR chemical shifts SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Artificial neural network; Backbone chemical shift; Helix capping; beta-turn; CS-Rosetta; MCC score; Protein structure prediction; Rosetta; Secondary structure prediction ID PROTEIN SECONDARY STRUCTURE; NEURAL-NETWORK; STRUCTURE GENERATION; SEQUENCE HOMOLOGY; ANGLE RESTRAINTS; TORSION ANGLE; WEB SERVER; AB-INITIO; C-13 NMR; C-ALPHA AB We present an empirical method for identification of distinct structural motifs in proteins on the basis of experimentally determined backbone and C-13(beta) chemical shifts. Elements identified include the N-terminal and C-terminal helix capping motifs and five types of beta-turns: I, II, I', II' and VIII. Using a database of proteins of known structure, the NMR chemical shifts, together with the PDB-extracted amino acid preference of the helix capping and beta-turn motifs are used as input data for training an artificial neural network algorithm, which outputs the statistical probability of finding each motif at any given position in the protein. The trained neural networks, contained in the MICS (motif identification from chemical shifts) program, also provide a confidence level for each of their predictions, and values ranging from ca 0.7-0.9 for the Matthews correlation coefficient of its predictions far exceed those attainable by sequence analysis. MICS is anticipated to be useful both in the conventional NMR structure determination process and for enhancing on-going efforts to determine protein structures solely on the basis of chemical shift information, where it can aid in identifying protein database fragments suitable for use in building such structures. C1 [Shen, Yang; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 126, Bethesda, MD 20892 USA. EM bax@nih.gov RI Shen, Yang/C-3064-2008 OI Shen, Yang/0000-0003-1408-8034 FU NIDDK; Office of the Director, NIH FX We thank Frank Delaglio for helpful comments and suggestions. This work was funded by the Intramural Research Program of the NIDDK and by the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 68 TC 38 Z9 38 U1 1 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD MAR PY 2012 VL 52 IS 3 BP 211 EP 232 DI 10.1007/s10858-012-9602-0 PG 22 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 905VD UT WOS:000301303100003 PM 22314702 ER PT J AU Li, XL Murray, F Koide, N Goldstone, J Dann, SM Chen, JZ Bertin, S Fu, G Weinstein, LS Chen, M Corr, M Eckmann, L Insel, PA Raz, E AF Li, Xiangli Murray, Fiona Koide, Naoki Goldstone, Jonathan Dann, Sara M. Chen, Jianzhong Bertin, Samuel Fu, Guo Weinstein, Lee S. Chen, Min Corr, Maripat Eckmann, Lars Insel, Paul A. Raz, Eyal TI Divergent requirement for G alpha s and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GROWTH-FACTOR RECEPTOR; CELL-DIFFERENTIATION; ADENYLATE-CYCLASE; G-PROTEIN; STIMULATION; CHANNELS; PHOSPHORYLATION; PATHOGENESIS; ACTIVATION; GENERATION AB cAMP, the intracellular signaling molecule produced in response to GPCR signaling, has long been recognized as an immunosuppressive agent that inhibits T cell receptor activation and T cell function. However, recent studies show that cAMP also promotes T cell-mediated immunity. Central to cAMP production downstream of GPCR activation is the trimeric G protein Gs. In order to reconcile the reports of divergent effects of cAMP in T cells and to define the direct effect of cAMP in T cells, we engineered mice in which the stimulatory G alpha subunit of Gs (G alpha s) could be deleted in T cells using CD4-Cre (Gnas(Delta CD4)). Gnas(Delta CD4) CD4(+) T cells had reduced cAMP accumulation and Ca2+ influx. In vitro and in vivo, Gnas(Delta cD4) CD4(+) T cells displayed impaired differentiation to specific Th subsets: Th17 and Th1 cells were reduced or absent, but Th2 and regulatory T cells were unaffected. Furthermore, Gnas(Delta CD4) CD4(+) T cells failed to provoke colitis in an adoptive transfer model, indicating reduced inflammatory function. Restoration of cAMP levels rescued the impaired phenotype of Gnas(Delta CD4) CD4(+) T cells, reinstated the PKA-dependent influx of Ca2+, and enhanced the ability of these cells to induce colitis. Our findings thus define an important role for cAMP in the differentiation of Th subsets and their subsequent inflammatory responses, and provide evidence that altering cAMP levels in CD4(+) T cells could provide an immunomodulatory approach targeting specific Th subsets. C1 [Li, Xiangli; Murray, Fiona; Koide, Naoki; Goldstone, Jonathan; Dann, Sara M.; Chen, Jianzhong; Bertin, Samuel; Corr, Maripat; Eckmann, Lars; Insel, Paul A.; Raz, Eyal] UCSD, Dept Med, La Jolla, CA USA. [Murray, Fiona; Insel, Paul A.] UCSD, Dept Pharmacol, La Jolla, CA USA. [Dann, Sara M.] Univ Texas Med Branch, Dept Microbiol, Dept Internal Med, Galveston, TX USA. [Fu, Guo] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Weinstein, Lee S.; Chen, Min] NIDDK, Metab Dis Branch, NIH, Bethesda, MD USA. RP Raz, E (reprint author), Univ Calif San Diego, Dept Med 0663, La Jolla, CA 92093 USA. EM eraz@ucsd.edu FU NIH [AI068685, AI095623, AI077989, DK35108, DK080506, T32 AI7469]; Crohn's and Colitis Foundation of America FX We thank Liang Zhou, Dianel Mucida, Jongdae Lee, and Nakon Aroonsakool for technical help and discussion. This study was supported by NIH grants AI068685, AI095623, AI077989, DK35108, DK080506, and T32 AI7469 and a grant from the Crohn's and Colitis Foundation of America. NR 37 TC 18 Z9 20 U1 2 U2 6 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 MAR PY 2012 VL 122 IS 3 BP 963 EP 973 DI 10.1172/JCI59097 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 902EN UT WOS:000301021500021 PM 22326954 ER PT J AU Brown-Elliott, BA Biehle, J Conville, PS Cohen, S Saubolle, M Sussland, D Wengenack, N Kriel, K Bridge, L McNulty, S Vasireddy, R Wallace, RJ AF Brown-Elliott, Barbara A. Biehle, Jon Conville, Patricia S. Cohen, Samuel Saubolle, Michael Sussland, Den Wengenack, Nancy Kriel, Kimberly Bridge, Linda McNulty, Steven Vasireddy, Ravikiran Wallace, Richard J., Jr. TI Sulfonamide Resistance in Isolates of Nocardia spp. from a US Multicenter Survey SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID IDENTIFICATION; SUSCEPTIBILITY; EXPERIENCE; FEATURES AB Recent reports of increasing in vitro sulfonamide resistance in Nocardia prompted us to investigate the findings. Despite the reports, there is a paucity of clinical reports of sulfonamide failure in treatment of nocardia disease. We reviewed 552 recent susceptibilities of clinical isolates of Nocardia from six major laboratories in the United States, and only 2% of the isolates were found to have resistant MICs of trimethoprim-sulfamethoxazole and/or sulfamethoxazole. We hypothesize that the discrepancies in the apparent sulfonamide resistance between our study and the previous findings may be associated with difficulty in the laboratory interpretation of in vitro MICs for trimethoprim-sulfamethoxazole and sulfamethoxazole and the lack of quality controls for Nocardia for these agents. C1 [Brown-Elliott, Barbara A.; Kriel, Kimberly; Bridge, Linda; McNulty, Steven; Vasireddy, Ravikiran; Wallace, Richard J., Jr.] Univ Texas Hlth Sci Ctr Tyler, Tyler, TX USA. [Biehle, Jon] Creighton Univ, Med Ctr, Omaha, NE USA. [Conville, Patricia S.] NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Cohen, Samuel] Associated & Reg Univ Pathologists, Salt Lake City, UT USA. [Saubolle, Michael; Sussland, Den] Banner Good Samaritan Med Ctr, Lab Sci Arizona, Phoenix, AZ USA. [Wengenack, Nancy] Mayo Clin, Rochester, MN USA. RP Brown-Elliott, BA (reprint author), Univ Texas Hlth Sci Ctr Tyler, Tyler, TX USA. EM barbara.elliott@uthct.edu NR 21 TC 26 Z9 28 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2012 VL 50 IS 3 BP 670 EP 672 DI 10.1128/JCM.06243-11 PG 3 WC Microbiology SC Microbiology GA 901WB UT WOS:000300997800021 PM 22170936 ER PT J AU Sharma-Kuinkel, BK Ahn, SH Rude, TH Zhang, YR Tong, SYC Ruffin, F Genter, FC Braughton, KR DeLeo, FR Barriere, SL Fowler, VG AF Sharma-Kuinkel, Batu K. Ahn, Sun H. Rude, Thomas H. Zhang, Yurong Tong, Steven Y. C. Ruffin, Felicia Genter, Fredric C. Braughton, Kevin R. DeLeo, Frank R. Barriere, Steven L. Fowler, Vance G., Jr. TI Presence of Genes Encoding Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome in Patients with Hospital-Acquired Pneumonia Due to Staphylococcus aureus SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID METHICILLIN-RESISTANT; VIRULENCE DETERMINANT; NECROTIZING PNEUMONIA; TREATMENT OPTIONS; ALPHA-HEMOLYSIN; UNITED-STATES; AGR LOCUS; STRAINS; INFECTIONS; DISEASE AB The impact of Panton-Valentine leukocidin (PVL) on the outcome in Staphylococcus aureus pneumonia is controversial. We genotyped S. aureus isolates from patients with hospital-acquired pneumonia (HAP) enrolled in two registrational multinational clinical trials for the genetic elements carrying pvl and 30 other virulence genes. A total of 287 isolates (173 methicillin-resistant S. aureus [MRSA] and 114 methicillin-susceptible S. aureus [MSSA] isolates) from patients from 127 centers in 34 countries for whom clinical outcomes of cure or failure were available underwent genotyping. Of these, pvl was detected by PCR and its product confirmed in 23 isolates (8.0%) (MRSA, 18/173 isolates [10.4%]; MSSA, 5/114 isolates [4.4%]). The presence of pvl was not associated with a higher risk for clinical failure (4/23 [17.4%] versus 48/264 [18.2%]; P = 1.00) or mortality. These findings persisted after adjustment for multiple potential confounding variables. No significant associations between clinical outcome and (i) presence of any of the 30 other virulence genes tested, (ii) presence of specific bacterial clone, (iii) levels of alpha-hemolysin, or (iv) delta-hemolysin production were identified. This study suggests that neither pvl presence nor in vitro level of alpha-hemolysin production is the primary determinant of outcome among patients with HAP caused by S. aureus. C1 [Sharma-Kuinkel, Batu K.; Ahn, Sun H.; Rude, Thomas H.; Zhang, Yurong; Tong, Steven Y. C.; Ruffin, Felicia; Fowler, Vance G., Jr.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Genter, Fredric C.; Barriere, Steven L.] Theravance Inc, San Francisco, CA USA. [Braughton, Kevin R.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. [Fowler, Vance G., Jr.] Duke Clin Res Inst, Durham, NC USA. [Tong, Steven Y. C.] Menzies Sch Hlth Res, Darwin, NT, Australia. RP Fowler, VG (reprint author), Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. EM fowle003@mc.duke.edu OI Tong, Steven/0000-0002-1368-8356; DeLeo, Frank/0000-0003-3150-2516 FU Theravance, Inc., South San Francisco, CA; National Institutes of Health [K24 AI093969]; National Institute of Allergy and Infectious Diseases, National Institutes of Health; Australian National Health and Medical Research Council [508829]; Australian-American Fulbright Scholarship; Royal Australasian College of Physicians Bayer Australia Medical Research FX This study was supported by a grant from Theravance, Inc., South San Francisco, CA. V.G. Fowler was supported in part by K24 AI093969 from the National Institutes of Health. This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. S. Y. C. Tong is supported by an Australian National Health and Medical Research Council Postdoctoral Training Fellowship (508829), an Australian-American Fulbright Scholarship, and a Royal Australasian College of Physicians Bayer Australia Medical Research Fellowship. NR 49 TC 16 Z9 17 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2012 VL 50 IS 3 BP 848 EP 856 DI 10.1128/JCM.06219-11 PG 9 WC Microbiology SC Microbiology GA 901WB UT WOS:000300997800045 PM 22205797 ER PT J AU Zeller, M Patton, JT Heylen, E De Coster, S Ciarlet, M Van Ranst, M Matthijnssens, J AF Zeller, Mark Patton, John T. Heylen, Elisabeth De Coster, Sarah Ciarlet, Max Van Ranst, Marc Matthijnssens, Jelle TI Genetic Analyses Reveal Differences in the VP7 and VP4 Antigenic Epitopes between Human Rotaviruses Circulating in Belgium and Rotaviruses in Rotarix and RotaTeq SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID VACCINE-INTRODUCTION; CHILDHOOD DIARRHEA; GLOBAL SPREAD; UNITED-STATES; DOUBLE-BLIND; CHILDREN; STRAINS; GASTROENTERITIS; EFFICACY; GENOTYPES AB Two live-attenuated rotavirus group A (RVA) vaccines, Rotarix (G1P[8]) and RotaTeq (G1-G4, P[8]), have been successfully introduced in many countries worldwide, including Belgium. The parental RVA strains used to generate the vaccines were isolated more than 20 years ago in France (G4 parental strain in RotaTeq) and the United States (all other parental strains). At present, little is known about the relationship between currently circulating human RVAs and the vaccine strains. In this study, we determined sequences for the VP7 and VP4 outer capsid proteins of representative G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and G12P[8] RVAs circulating in Belgium during 2007 to 2009. The analyses showed that multiple amino acid differences existed between the VP7 and VP4 antigenic epitopes of the vaccine viruses and the Belgian isolates, regardless of their G and P genotypes. However, the highest variability was observed among the circulating G1P[8] RVA strains and the G1 and P[8] components of both RVA vaccines. In particular, RVA strains of the P[8] lineage 4 (OP354-like) showed a significant number of amino acid differences with the P[8] VP4 of both vaccines. In addition, the circulating Belgian G3 RVA strains were found to possibly possess an extra N-linked glycosylation site compared to the G3 RVA vaccine strain of RotaTeq. These results indicate that the antigenic epitopes of RVA strains contained in the vaccines differ substantially from those of the currently circulating RVA strains in Belgium. Over time, these differences might result in selection for strains that escape the RVA neutralizing-antibody pressure induced by vaccines. C1 [Zeller, Mark; Heylen, Elisabeth; De Coster, Sarah; Van Ranst, Marc; Matthijnssens, Jelle] Univ Louvain, Lab Clin & Epidemiol Virol, Dept Microbiol & Immunol, Rega Inst Med Res, Louvain, Belgium. [Patton, John T.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Ciarlet, Max] Novartis Vaccines & Diagnost Inc, Clin Res & Dev, Cambridge, MA USA. RP Matthijnssens, J (reprint author), Univ Louvain, Lab Clin & Epidemiol Virol, Dept Microbiol & Immunol, Rega Inst Med Res, Louvain, Belgium. EM jelle.matthijnssens@uz.kuleuven.be RI Patton, John/P-1390-2014; Matthijnssens, Jelle/A-6770-2015; Matthijnssens, Jelle/B-8634-2016; OI Van Ranst, Marc/0000-0002-1674-4157 FU Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT Vlaanderen); FWO (Fonds voor Wetenschappelijk Onderzoek); National Institute of Allergy and Infectious Diseases, National Institutes of Health FX M.Z. was supported by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT Vlaanderen). J.M. was supported by an FWO (Fonds voor Wetenschappelijk Onderzoek) postdoctoral fellowship. J.T.P. was supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 67 TC 52 Z9 53 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2012 VL 50 IS 3 BP 966 EP 976 DI 10.1128/JCM.05590-11 PG 11 WC Microbiology SC Microbiology GA 901WB UT WOS:000300997800062 PM 22189107 ER PT J AU Nakagawa, K Tanaka, N Morita, M Sugioka, A Miyagawa, S Gonzalez, FJ Aoyama, T AF Nakagawa, Kan Tanaka, Naoki Morita, Miwa Sugioka, Atsushi Miyagawa, Shin-ichi Gonzalez, Frank J. Aoyama, Toshifumi TI PPAR alpha is down-regulated following liver transplantation in mice SO JOURNAL OF HEPATOLOGY LA English DT Article DE Oxidative stress; Mitochondrial beta-oxidation; Early graft dysfunction; Liver transplantation; PPAR alpha ID PROLIFERATOR-ACTIVATED RECEPTORS; ISCHEMIA-REPERFUSION INJURY; HEPATIC STEATOSIS; FATTY LIVER; T-CELLS; NONALCOHOLIC STEATOHEPATITIS; PERMEABILITY TRANSITION; TOLERANCE INDUCTION; GRAFT ACCEPTANCE; GENE-EXPRESSION AB Background & Aims: Graft dysfunction is one of the major complications after liver transplantation, but its precise mechanism remains unclear. Since steatotic liver grafts are susceptible to post-transplant dysfunction, and peroxisome proliferator-activated receptor (PPAR) alpha plays an important role in the maintenance of hepatic lipid homeostasis, we examined the role of PPAR alpha in liver transplantation. Methods: Livers were harvested from Sv/129 wild-type (Ppara(+/+)) mice and PPAR alpha-null (Ppara(-/-)) mice and transplanted orthotopically into syngeneic Ppara(+/+) mice. Results: Hepatocellular damage was unexpectedly milder in transplanted Ppara(-/-) livers compared with Ppara(+/+) ones. This was likely due to decreased lipid peroxides in the Ppara(-/-) livers, as revealed by the lower levels of fatty acid oxidation (FAO) enzymes, which are major sources of reactive oxygen species. Hepatic PPAR alpha and its target genes, such as FAO enzymes and pyruvate dehydrogenase kinase 4, were strongly down-regulated after transplantation, which was associated with increases in hepatic tumor necrosis factor-alpha expression and nuclear factor-kappa B activity. Inhibiting post-transplant PPAR alpha down-regulation by clofibrate treatment markedly augmented oxidative stress and hepatocellular injury. Conclusions: Down-regulation of PPAR alpha seemed to be an adaptive response to metabolic alterations following liver transplantation. These results provide novel information to the understanding of the pathogenesis of early post-transplant events. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Nakagawa, Kan; Tanaka, Naoki; Aoyama, Toshifumi] Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. [Nakagawa, Kan; Miyagawa, Shin-ichi] Shinshu Univ, Sch Med, Dept Surg, Matsumoto, Nagano 3908621, Japan. [Tanaka, Naoki] Shinshu Univ, Sch Med, Dept Gastroenterol, Matsumoto, Nagano 3908621, Japan. [Morita, Miwa; Sugioka, Atsushi] Fujita Hlth Univ, Sch Med, Dept Surg, Toyoake, Aichi, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tanaka, N (reprint author), Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Asahi 3-1-1, Matsumoto, Nagano 3908621, Japan. EM tanakan@mail.nih.gov RI Ji, Haofeng/G-6206-2012 NR 47 TC 4 Z9 4 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2012 VL 56 IS 3 BP 586 EP 594 DI 10.1016/j.jhep.2011.08.021 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 904TQ UT WOS:000301221200014 PM 22037025 ER PT J AU DiGiovanna, JJ Kraemer, KH AF DiGiovanna, John J. Kraemer, Kenneth H. TI Shining a Light on Xeroderma Pigmentosum SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Review ID DNA-REPAIR GENE; NUCLEOTIDE-EXCISION-REPAIR; UV-SENSITIVE SYNDROME; COCKAYNE-SYNDROME; SKIN-CANCER; COMPLEMENTATION GROUP; GROUP-A; MICE LACKING; GROUP-C; POLYMERASE-ETA AB Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair characterized by sun sensitivity and UV radiation-induced skin and mucous membrane cancers. Initially described in 1874 by Moriz Kaposi in Vienna, nearly 100 years later, James Cleaver in San Francisco reported defective DNA repair in XP cells. This eventually provided the basis for a mechanistic link between sun exposure, DNA damage, somatic mutations, and skin cancer. XP cells were found to have defects in seven of the proteins of the nucleotide excision repair pathway and in DNA polymerase eta. XP cells are hypersensitive to killing by UV radiation, and XP cancers have characteristic "UV signature" mutations. Clinical studies at the National Institutes of Health found a nearly 10,000-fold increase in skin cancer in XP patients under the age of 20 years, demonstrating the substantial importance of DNA repair in cancer prevention in the general population. Approximately 25% of XP patients have progressive neurological degeneration with progressive loss of neurons, probably from DNA damage induced by oxidative metabolism, which kills nondividing cells in the nervous system. Interestingly, patients with another disorder, trichothiodystrophy, have defects in some of the same genes as XP, but they have primary developmental abnormalities without an increase in skin cancer. C1 [DiGiovanna, John J.; Kraemer, Kenneth H.] NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res, Bldg 37,Room 4002,MSC 4258, Bethesda, MD 20892 USA. EM kraemerk@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank the patients for participating in our studies, and the XP patient support groups for helping people with XP and their families. NR 95 TC 139 Z9 143 U1 4 U2 61 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 MAR PY 2012 VL 132 IS 3 BP 785 EP 796 DI 10.1038/jid.2011.426 PN 2 PG 12 WC Dermatology SC Dermatology GA 893RW UT WOS:000300374100006 PM 22217736 ER PT J AU Mascia, F Denning, M Kopan, R Yuspa, SH AF Mascia, Francesca Denning, Mitchell Kopan, Raphael Yuspa, Stuart H. TI The Black Box Illuminated: Signals and Signaling SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Review ID PROTEIN-KINASE-C; GROWTH-FACTOR RECEPTOR; NF-KAPPA-B; HUMAN EPIDERMAL-KERATINOCYTES; SQUAMOUS-CELL CARCINOMAS; CALCIUM-SENSING RECEPTOR; TRANSGENIC MICE; CHEMOKINE EXPRESSION; MOUSE KERATINOCYTES; TUMOR PROMOTION AB Unraveling the signaling pathways that transmit information from the cell surface to the nucleus has been a major accomplishment of modern cell and molecular biology. The benefit to humans is seen in the multitude of new therapeutics based on the illumination of these pathways. Although considerable insight has been gained in understanding homeostatic and pathological signaling in the epidermis and other skin compartments, the translation into therapy has been lacking. This review will outline advances made in understanding fundamental signaling in several of the most prominent pathways that control cutaneous development, cell-fate decisions, and keratinocyte growth and differentiation with the anticipation that this insight will contribute to new treatments for troubling skin diseases. C1 [Mascia, Francesca; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Denning, Mitchell] Loyola Univ Chicago, Dept Pathol, Maywood, IL USA. [Kopan, Raphael] Washington Univ, Sch Med, St Louis, MO USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, Bldg 37,Room 4068,37 Convent Dr, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov NR 100 TC 11 Z9 12 U1 0 U2 1 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 MAR PY 2012 VL 132 IS 3 BP 811 EP 819 DI 10.1038/jid.2011.406 PN 2 PG 9 WC Dermatology SC Dermatology GA 893RW UT WOS:000300374100008 PM 22170487 ER PT J AU Kong, HH Segre, JA AF Kong, Heidi H. Segre, Julia A. TI Skin Microbiome: Looking Back to Move Forward SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Review ID STAPHYLOCOCCUS-EPIDERMIDIS; BACTERIAL BIOTA; BODY HABITATS; DIVERSITY; INFECTIONS; DEFENSE; DISEASE; PROJECT; LESIONS; FOOT AB Trillions of bacteria, fungi, viruses, archaea, and small arthropods colonize the skin surface, collectively comprising the skin microbiome. Generations of researchers have classified these microbes as transient versus resident, beneficial versus pathogenic, and collaborators versus adversaries. Culturing and direct sequencing of microbial inhabitants identified distinct populations present at skin surface sites. Herein, we explore the history of this field, describe findings from the current molecular sequencing era, and consider the future of investigating how microbes and antimicrobial therapy contribute to human health. C1 [Kong, Heidi H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Segre, Julia A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Kong, HH (reprint author), NCI, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov; jsegre@nhgri.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU Intramural NIH HHS [ZIA BC010938-03, ZIA HG000180-11] NR 37 TC 78 Z9 83 U1 4 U2 74 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 MAR PY 2012 VL 132 IS 3 BP 933 EP 939 DI 10.1038/jid.2011.417 PN 2 PG 7 WC Dermatology SC Dermatology GA 893RW UT WOS:000300374100022 PM 22189793 ER PT J AU Millum, J AF Millum, Joseph TI Introduction: Case Studies in the Ethics of Mental Health Research SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Research ethics; international; case studies; mental health ID PLACEBO-CONTROLLED TRIALS; CLINICAL-TRIALS; RISPERIDONE; COUNTRIES; DISORDERS; EQUIPOISE AB This collection presents six case studies on the ethics of mental health research, written by scientific researchers and ethicists from around the world. We publish them here as a resource for teachers of research ethics and as a contribution to several ongoing ethical debates. Each consists of a description of a research study that was proposed or carried out and an in-depth analysis of the ethics of the study. C1 NIH, Ctr Clin, Dept Bioeth, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Millum, J (reprint author), NIH, Ctr Clin, Dept Bioeth, Fogarty Int Ctr, 10-1C118,10 Ctr Dr, Bethesda, MD 20892 USA. EM millumj@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 39 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD MAR PY 2012 VL 200 IS 3 BP 230 EP 235 DI 10.1097/NMD.0b013e318247cb5b PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 900PX UT WOS:000300901600008 PM 22373760 ER PT J AU Igarashi, M Kim, HW Chang, LS Ma, KZ Rapoport, SI AF Igarashi, Miki Kim, Hyung-Wook Chang, Lisa Ma, Kaizong Rapoport, Stanley I. TI Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachidonic; brain; docosahexaenoic; kinetics; linoleic acid; turnover ID ALPHA-LINOLENIC ACID; THIN-LAYER CHROMATOGRAPHY; PHOSPHOLIPASE A(2); SIGNAL-TRANSDUCTION; PUFA DEPRIVATION; NUTRITIONAL DEPRIVATION; UNANESTHETIZED RATS; GENE-TRANSCRIPTION; LIVER CONVERSION; MAMMALIAN BRAIN AB Dietary n-6 polyunsaturated fatty acid (PUFA) deprivation in rodents reduces brain arachidonic acid (20:4n-6) concentration and 20:4n-6-preferring cytosolic phospholipase A2 (cPLA2-IVA) and cyclooxygenase (COX)-2 expression, while increasing brain docosahexaenoic acid (DHA, 22:6n-3) concentration and DHA-selective calcium-independent phospholipase A2 (iPLA2)-VIA expression. We hypothesized that these changes are accompanied by up-regulated brain DHA metabolic rates. Using a fatty acid model, brain DHA concentrations and kinetics were measured in unanesthetized male rats fed, for 15 weeks post-weaning, an n-6 PUFA adequate (31.4 wt% linoleic acid) or deficient (2.7 wt% linoleic acid) diet, each lacking 20:4n-6 and DHA. [1-14C]DHA was infused intravenously, arterial blood was sampled, and the brain was microwaved at 5 min and analyzed. Rats fed the n-6 PUFA deficient compared with adequate diet had significantly reduced n-6 PUFA concentrations in brain phospholipids but increased eicosapentaenoic acid (EPA, 20:5n-3), docosapentaenoic acid n-3 (DPAn-3, 22:5n-3), and DHA (by 9.4%) concentrations, particularly in ethanolamine glycerophospholipid (EtnGpl). Incorporation rates of unesterified DHA from plasma, which represent DHA metabolic loss from brain, were increased 45% in brain phospholipids, as was DHA turnover. Increased DHA metabolism following dietary n-6 PUFA deprivation may increase brain concentrations of antiinflammatory DHA metabolites, which with a reduced brain n-6 PUFA content, likely promotes neuroprotection and alters neurotransmission. C1 [Igarashi, Miki; Kim, Hyung-Wook; Chang, Lisa; Ma, Kaizong; Rapoport, Stanley I.] NIA, NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. RP Igarashi, M (reprint author), Univ Calif Irvine, 2205 McGaugh Hall, Irvine, CA 92697 USA. EM miki.i@uci.edu FU National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging. The authors thank the NIH Fellows Editorial Board for editorial assistance. No author has a conflict of interest with regard to this manuscript. NR 83 TC 13 Z9 13 U1 0 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2012 VL 120 IS 6 BP 985 EP 997 DI 10.1111/j.1471-4159.2011.07597.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 903JL UT WOS:000301112500012 PM 22117540 ER PT J AU Yu, PP Santiago, LY Katagiri, Y Geller, HM AF Yu, Panpan Santiago, Lizzie Y. Katagiri, Yasuhiro Geller, Herbert M. TI Myosin II activity regulates neurite outgrowth and guidance in response to chondroitin sulfate proteoglycans SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE blebbistatin; cerebellar granule neuron; CSPG ID NEURONAL GROWTH CONES; ACTIN-FILAMENT; REGENERATION; DRIVES; RHO; RECEPTOR; MICE; FLOW; CUES; PHOSPHATASE AB Chondroitin sulfate proteoglycans (CSPGs) are major components of the extracellular matrix in the CNS that inhibit axonal regeneration after CNS injury. Signaling pathways in neurons triggered by CSPGs are still largely unknown. In this study, using well-characterized in vitro assays for neurite outgrowth and neurite guidance, we demonstrate a major role for myosin II in the response of neurons to CSPGs. We found that the phosphorylation of myosin II regulatory light chains is increased by CSPGs. Specific inhibition of myosin II activity with blebbistatin allows growing neurites to cross onto CSPG-rich areas and increases the length of neurites of neurons growing on CSPGs. Using specific gene knockdown, we demonstrate selective roles for myosin IIA and IIB in these processes. Time lapse microscopy and immunocytochemistry demonstrated that CSPGs also inhibit cell adhesion and cell spreading. Inhibition of myosin II selectively accelerated neurite initiation without altering cell adhesion and spreading on CSPGs. C1 [Yu, Panpan; Santiago, Lizzie Y.; Katagiri, Yasuhiro; Geller, Herbert M.] NHLBI, NIH, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, Bethesda, MD 20892 USA. RP Geller, HM (reprint author), NHLBI, NIH, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM geller@helix.nih.gov RI Yu, Panpan/A-4962-2013; OI Geller, Herbert/0000-0002-7048-6144 FU Intramural NIH HHS [ZIA HL006021-02] NR 38 TC 15 Z9 16 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2012 VL 120 IS 6 BP 1117 EP 1128 DI 10.1111/j.1471-4159.2011.07638.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 903JL UT WOS:000301112500023 PM 22191382 ER PT J AU Miller, AC Odenkirchen, J Duhaime, AC Hicks, R AF Miller, A. Cate Odenkirchen, Joanne Duhaime, Ann-Christine Hicks, Ramona TI Common Data Elements for Research on Traumatic Brain Injury: Pediatric Considerations SO JOURNAL OF NEUROTRAUMA LA English DT Article DE assessment tools; bioinformatics; CDE; clinical trials; database; meta-analysis; pediatrics; rehabilitation; research; TBI ID PSYCHOLOGICAL HEALTH; OUTCOME MEASURES; WORKING GROUP; RECOMMENDATIONS AB Traumatic brain injury (TBI) is a significant global health problem, with a notably high incidence in children and adolescents. Despite the prevalence of TBI and the disabilities that often follow, research on which to base effective treatment is limited by several challenges, including but not limited to the complexity and heterogeneity of TBI. Even when rigorous methods are employed, the utility of the research may be limited by difficulties in comparing findings across studies resulting from the use of different measures to assess similar TBI study variables. Standardization of definitions and data elements is an important step toward accelerating the process of data sharing that will ultimately lead to a stronger evidence base for treatment advances. To address this need, recommendations for common data elements (CDEs) for research on TBI were developed through a 2009 national initiative. To ensure that the TBI CDE recommendations are relevant to pediatric populations, the National Institute on Disability and Rehabilitation Research (NIDRR) and the National Institute of Neurological Disorders and Stroke (NINDS) called for a review of the original recommendations. Following the process used for the original initiative, multidisciplinary work groups composed of pediatric TBI experts were formed (Demographics and Clinical Assessment; Biomarkers; Neuroimaging; and Outcomes Assessment). Recommendations for modifications and additions to the original CDEs were developed by the work groups, vetted at a 2010 workshop and further refined in preparation for publication. The pediatric considerations for TBI CDEs are described in a series of articles in this journal. This article describes the efforts leading to this pediatric CDE initiative and the CDE review and development process. It concludes with general recommendations for future iterations of the CDE initiative. C1 [Miller, A. Cate] US Dept Educ, Natl Inst Disabil & Rehabil Res, Washington, DC 20202 USA. [Odenkirchen, Joanne; Hicks, Ramona] NINDS, NIH, Bethesda, MD 20892 USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Miller, AC (reprint author), US Dept Educ, Natl Inst Disabil & Rehabil Res, 400 Maryland Ave SW, Washington, DC 20202 USA. EM cate.miller@ed.gov FU National Institute for Disability and Rehabilitation Research of the United States Department of Education (NIDRR/DoE); National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS/NIH) FX We gratefully acknowledge the working group members and chairpersons for their dedication of time and expertise to this initiative. Support for the workshop came from the National Institute for Disability and Rehabilitation Research of the United States Department of Education (NIDRR/DoE) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS/NIH) NR 14 TC 6 Z9 6 U1 1 U2 5 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 MAR PY 2012 VL 29 IS 4 BP 634 EP 638 DI 10.1089/neu.2011.1932 PG 5 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 901SQ UT WOS:000300987500003 PM 22091862 ER PT J AU Han, PKJ Lee, M Reeve, BB Mariotto, AB Wang, ZQ Hays, RD Yabroff, KR Topor, M Feuer, EJ AF Han, Paul K. J. Lee, Minjung Reeve, Bryce B. Mariotto, Angela B. Wang, Zhuoqiao Hays, Ron D. Yabroff, K. Robin Topor, Marie Feuer, Eric J. TI Development of a Prognostic Model for Six-Month Mortality in Older Adults With Declining Health SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Prognosis; clinical prediction model; elderly; health-related quality of life ID QUALITY-OF-LIFE; NURSING-HOME RESIDENTS; ILL CANCER-PATIENTS; MEDICARE MANAGED CARE; HOSPITALIZED-PATIENTS; SURVIVAL PREDICTION; UNITED-STATES; HOSPICE USE; ADVANCED DEMENTIA; PALLIATIVE-CARE AB Context. Estimation of six-month prognosis is essential in hospice referral decisions, but accurate, evidence-based tools to assist in this task are lacking. Objectives. To develop a new prognostic model, the Patient-Reported Outcome Mortality Prediction Tool (PROMPT), for six-month mortality in community-dwelling elderly patients. Methods. We used data from the Medicare Health Outcomes Survey linked to vital status information. Respondents were 65 years old or older, with self-reported declining health over the past year (n = 21,870), identified from four Medicare Health Outcomes Survey cohorts (1998-2000, 1999-2001, 2000-2002, and 2001-2003). A logistic regression model was derived to predict six-month mortality, using sociodemographic characteristics, comorbidities, and health-related quality of life (HRQOL), ascertained by measures of activities of daily living and the Medical Outcomes Study Short Form-36 Health Survey; k-fold cross-validation was used to evaluate model performance, which was compared with existing prognostic tools. Results. The PROMPT incorporated 11 variables, including four HRQOL domains: general health perceptions, activities of daily living, social functioning, and energy/fatigue. The model demonstrated good discrimination (c-statistic = 0.75) and calibration. Overall diagnostic accuracy was superior to existing tools. At cut points of 10%-70%, estimated six-month mortality risk sensitivity and specificity ranged from 0.8% to 83.4% and 51.1% to 99.9%, respectively, and positive likelihood ratios at all mortality risk cut points >= 40% exceeded 5.0. Corresponding positive and negative predictive values were 23.1%-64.1% and 85.3%-94.5%. Over 50% of patients with estimated six-month mortality risk >= 30% died within 12 months. Conclusion. The PROMPT, a new prognostic model incorporating HRQOL, demonstrates promising performance and potential value for hospice referral decisions. More work is needed to evaluate the model. J Pain Symptom Manage 2012;43:527-539. (C) 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04105 USA. [Lee, Minjung; Reeve, Bryce B.; Mariotto, Angela B.; Yabroff, K. Robin; Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Wang, Zhuoqiao; Topor, Marie] Informat Management Serv Inc, Silver Spring, MD USA. [Hays, Ron D.] Univ Calif Los Angeles, Div Gen Internal Med, Los Angeles, CA USA. RP Han, PKJ (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, 39 Forest Ave, Portland, ME 04105 USA. EM hanp@mmc.org RI Hays, Ronald/D-5629-2013; OI Yabroff, K. Robin/0000-0003-0644-5572; Han, Paul/0000-0003-0165-1940 FU National Cancer Institute, National Institutes of Health; National Institute on Aging [P30AG021684, P30-AG028748]; National Center on Minority Health and Health Disparities [2P20MD000182] FX This study was supported by intramural research funds from the National Cancer Institute, National Institutes of Health. Ron Hays was supported in part by National Institute on Aging grants (P30AG021684 and P30-AG028748) and a National Center on Minority Health and Health Disparities grant (2P20MD000182). The authors declare no conflicts of interest. NR 83 TC 18 Z9 18 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAR PY 2012 VL 43 IS 3 BP 527 EP 539 DI 10.1016/j.jpainsymman.2011.04.015 PG 13 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 903NY UT WOS:000301125200008 PM 22071167 ER PT J AU Wiktorowicz, JE English, RD Wu, Z Kurosky, A AF Wiktorowicz, John E. English, Robert D. Wu, Zheng Kurosky, Alexander TI Model Studies on iTRAQ Modification of Peptides: Sequence-dependent Reaction Specificity SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE quantitative proteomics; iTRAQ; sequence-specific modification; peptide O-acylation; mass spectrometry; hydroxyl amino acid reactivity ID ISOBARIC TAGGING REAGENTS; ESCHERICHIA-COLI-CELLS; PROTEIN-PHOSPHORYLATION; QUANTITATION; TAGS AB A multiplexed peptide quantification strategy using the iTRAQ reagent has been described for relative measurements of peptides in digested protein mixtures. To validate the chemical specificity of the iTRAQ reaction, we have performed a detailed study of iTRAQ reactivity with two sets of synthetic peptides. The first set of peptides had sequences of Tyr-Xaa-Ser-Glu-Gly-Leu-Ser-Lys and Tyr-Xaa-Ser-Glu-Tyr-Leu-Ser-Lys where Xaa = Ala, Pro, Trp, Tyr, or Glu and was designed to study the extent of O-acylation by iTRAQ, especially hydroxyl-containing residues in different positions. The second set of peptides included Ala-Ser-Glu-His-Ala-Xaa-Tyr-Gly where Xaa = Ser, Thr, or Tyr and was selected to investigate the effect of histidyl residues separated by one amino acid residue from seryl, tyrosyl, or threonyl residues. Our findings indicated that, in addition to variable levels of O-acylation of nonsequence-specific hydroxyl-containing residues, significant sequence-specific O-acylation of seryl, threonyl, and tyrosyl hydroxyls occurred when separated one residue removed from a histidyl residue, that is, (Tyr/Ser)-Xaa-His or His-Xaa-(Tyr/Ser/Thr). This behavior was verified by a separate spiking experiment of one of the first set of peptides into Escherichia coli protein extracts, followed by retention time targeted LC-MS/MS to demonstrate the occurrence of modifications in a complex mixture. These sequence-dependent O-acylation modifications can be confounding factors to accurate MS quantification. Reversal of peptide O-acylation by the iTRAQ reagent can be accomplished by reaction with hydroxylamine with virtually no cleavage of N-acylation and is a recommended modification of the iTRAQ protocol for many applications. C1 [Wiktorowicz, John E.; Wu, Zheng; Kurosky, Alexander] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Wiktorowicz, John E.; English, Robert D.; Wu, Zheng; Kurosky, Alexander] Univ Texas Med Branch, NHLBI Prote Ctr Airway Inflammat, Galveston, TX 77555 USA. RP Kurosky, A (reprint author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. EM akurosky@utmb.edu FU National Heart, Lung, and Blood Institute's Proteomics Initiative [NO1-HV-00245]; National Institute for Environmental Health Sciences Center [P30-ES006676]; National Institute of Allergy and Infectious Diseases [P01-AI062885] FX This work was supported in part by the National Heart, Lung, and Blood Institute's Proteomics Initiative NO1-HV-00245 (A.K.), National Institute for Environmental Health Sciences Center grant P30-ES006676 (C. Elferink), and the National Institute of Allergy and Infectious Diseases grant P01-AI062885 (A. Brasier). We acknowledge Steven Serabin for peptide synthesis, Drs. Anthony Haag for his MS consultation, and Kizhake Soman for his assistance in quantifying the frequency of triplet sequences in the human genome. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC Section 1734 solely to indicate this fact. NR 15 TC 5 Z9 5 U1 3 U2 19 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 MAR PY 2012 VL 11 IS 3 BP 1512 EP 1520 DI 10.1021/pr2003165 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 900UH UT WOS:000300916200007 PM 22335824 ER PT J AU Wei, BR Simpson, RM Johann, DJ Dwyer, JE Prieto, DA Kumar, M Ye, X Luke, B Shive, HR Webster, JD Hoover, SB Veenstra, TD Blonder, J AF Wei, Bih-Rong Simpson, R. Mark Johann, Donald J., Jr. Dwyer, Jennifer E. Prieto, DaRue A. Kumar, Mia Ye, Xiaoying Luke, Brian Shive, Heather R. Webster, Joshua D. Hoover, Shelley B. Veenstra, Timothy D. Blonder, Josip TI Proteomic Profiling of H-Ras-G12V Induced Hypertrophic Cardiomyopathy in Transgenic Mice Using Comparative LC-MS Analysis of Thin Fresh-Frozen Tissue Sections SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE H-Ras; hypertrophic cardiomyopathy; fresh frozen tissue; methanol-based solubilization/digestion; comparative proteomic profiling; pathway analysis; method development ID CANCER BIOMARKER DISCOVERY; TANDEM MASS-SPECTROMETRY; BETA-CATENIN; CARDIAC-HYPERTROPHY; DILATED CARDIOMYOPATHY; THERAPEUTIC TARGET; SAMPLE PREPARATION; CELL-ADHESION; EXPRESSION; PROTEINS AB Determination of disease-relevant proteomic profiles from limited tissue specimens, such as pathological biopsies and tissues from small model organisms, remains an analytical challenge and a much needed clinical goal. In this study, a transgenic mouse disease model of cardiac-specific H-Ras-G12V induced hypertrophic cardiomyopathy provided a system to explore the potential of using mass spectrometry (MS)-based proteomics to obtain a disease-relevant molecular profile from amount-limited specimens that are routinely used in pathological diagnosis. Our method employs a two-stage methanol-assisted solubilization to digest lysates prepared from 8-mu m-thick fresh-frozen histological tissue sections of diseased/experimental and normal/control hearts. Coupling this approach with a nanoflow reversed-phase liquid chromatography (LC) and a hybrid linear ion trap/Fourier transform-ion cyclotron resonance MS resulted in the identification of 704 and 752 proteins in hypertrophic and wild-type (control) myocardium, respectively. The disease driving H-Ras protein along with vimentin were unambiguously identified by LC-MS in hypertrophic myocardium and cross-validated by immunohistochemistry and western blotting. The pathway analysis involving proteins identified by MS showed strong association of proteomic data with cardiovascular disease. More importantly, the MS identification and subsequent cross-validation of Wnt3a and beta-catenin, in conjunction with IHC identification of phosphorylated GSK-3 beta and nuclear localization of beta-catenin, provided evidence of Wnt/beta-catenin canonical pathway activation secondary to Ras activation in the course of pathogenic myocardial hypertrophic transformation. Our method yields results indicating that the described proteomic approach permits molecular discovery and assessment of differentially expressed proteins regulating H-Ras induced hypertrophic cardiomyopathy. Selected proteins and pathways can be further investigated using immunohistochemical techniques applied to serial tissue sections of similar or different origin. C1 [Prieto, DaRue A.; Ye, Xiaoying; Veenstra, Timothy D.; Blonder, Josip] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Wei, Bih-Rong; Simpson, R. Mark; Dwyer, Jennifer E.; Kumar, Mia; Shive, Heather R.; Webster, Joshua D.; Hoover, Shelley B.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Johann, Donald J., Jr.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Luke, Brian] NCI, Adv Biomed Comp Ctr, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Blonder, J (reprint author), NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM blonderj@mail.nih.gov FU Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD; National Cancer Institute, National Institutes of Health [N01-CO-12400]; National Cancer Institute FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD. Additional support was provided with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. H.R.S. was a molecular pathology fellow in the NIH Comparative Biomedical Scientist Training Program supported by the National Cancer Institute in partnership with the University of 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 organizations imply endorsement by the United States Government. NR 42 TC 5 Z9 6 U1 1 U2 10 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 MAR PY 2012 VL 11 IS 3 BP 1561 EP 1570 DI 10.1021/pr200612y PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 900UH UT WOS:000300916200011 PM 22214408 ER PT J AU Olsavsky, AK Brotman, MA Rutenberg, JG Muhrer, EJ Deveney, CM Fromm, SJ Towbin, K Pine, DS Leibenluft, E AF Olsavsky, Aviva K. Brotman, Melissa A. Rutenberg, Julia G. Muhrer, Eli J. Deveney, Christen M. Fromm, Stephen J. Towbin, Kenneth Pine, Daniel S. Leibenluft, Ellen TI Amygdala Hyperactivation During Face Emotion Processing in Unaffected Youth at Risk for Bipolar Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE bipolar; anxiety; endophenotype; fMRI; faces ID FACIAL EXPRESSIONS; PSYCHIATRIC-DISORDERS; ANXIETY DISORDER; RATING-SCALE; CHILDREN; DEPRESSION; CONNECTIVITY; ADOLESCENTS; COMMUNITY; RELATIVES AB Objective: Youth at familial risk for bipolar disorder (BD) show deficits in face emotion processing, but the neural correlates of these deficits have not been examined. This preliminary study tests the hypothesis that, relative to healthy comparison (HC) subjects, both BD subjects and youth at risk for BD (i.e., those with a first-degree BD relative) will demonstrate amygdala hyperactivation when viewing fearful and happy faces. The at-risk youth were unaffected, in that they had no history of mood disorder. Method: Amygdala activity was examined in 101 unrelated participants, 8 to 18 years old. Age, gender, and IQ-matched groups included BD (N = 32), unaffected at-risk (N = 13), and HC (N = 56). During functional magnetic resonance imaging, participants attended to emotional and nonemotional aspects of fearful and happy faces. Results: While rating their fear of fearful faces, both BD and unaffected at-risk subjects exhibited amygdala hyperactivity versus HC. There were no between-group differences in amygdala activity in response to happy faces. Post-hoc comparisons revealed that, in at-risk youth, familial risk status (offspring versus sibling), presence of Axis I diagnosis (n = 1 attention-deficit/hyperactivity disorder [ADHD], n = 1 social phobia), and history of medication exposure (n = 1) did not influence imaging findings. Conclusions: We found amygdala hyperactivation in both unaffected at-risk and BD youth while rating their fear of fearful faces. These pilot data suggest that both face emotion labeling deficits and amygdala hyperactivity during face processing should receive further study as potential BD endophenotypes. Longitudinal studies should test whether amygdala hyperactivity to fearful faces predicts conversion to BD in at-risk youth. J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(3): 294-303. C1 [Olsavsky, Aviva K.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Olsavsky, Aviva K.; Brotman, Melissa A.; Rutenberg, Julia G.; Muhrer, Eli J.; Deveney, Christen M.; Fromm, Stephen J.; Towbin, Kenneth; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Olsavsky, AK (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Box 951720,12-159 CHS, Los Angeles, CA 90095 USA. EM aolsavsky@mednet.ucla.edu RI Brotman, Melissa/H-7409-2013 FU National Institute of Mental Health; NIH; Pfizer Inc.; Foundation for NIH from Pfizer Inc. FX This study was supported by the Intramural Research Program of the National Institute of Mental Health. Ms. Olsavsky's research was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). NR 36 TC 31 Z9 31 U1 0 U2 15 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 MAR PY 2012 VL 51 IS 3 BP 294 EP 303 DI 10.1016/j.jaac.2011.12.008 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 902IG UT WOS:000301031200008 PM 22365465 ER PT J AU Duan, Q van Gelderen, P Duyn, J AF Duan, Qi van Gelderen, Peter Duyn, Jeff TI Tailored excitation using nonlinear B0-shims SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE high-field MRI; flip angle; wavelength effects; B1 shimming; transmit sense ID REDUCED B-1 INHOMOGENEITY; RF PULSE DESIGN; PARALLEL EXCITATION; 7 TESLA; SELECTIVE EXCITATION; HUMAN BRAIN; COIL; TRANSMIT; NMR AB In high-field MRI, RF flip angle inhomogeneity due to wavelength effects can lead to spatial variations in contrast and sensitivity. Improved flip angle homogeneity can be achieved through multidimensional excitation, but long RF pulse durations limit practical application. A recent approach to reduce RF pulse duration is based on parallel excitation through multiple RF channels. Here, an alternative approach to shorten multidimensional excitation is proposed that makes use of nonlinear spatial variations in the stationary (B0) magnetic field during a B0-sensitive excitation pulse. As initial demonstration, the method was applied to 2D gradient echo (GE) MRI of human brain at 7 T. Using B0 shims with up to second-order spatial dependence, it is demonstrated that root-mean-squared flip angle variation can be reduced from 20 to 11% with RF pulse lengths that are practical for general GE imaging applications without requiring parallel excitation. The method is expected to improve contrast and sensitivity in GE MRI of human brain at high field. Magn Reson Med, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Duan, Qi; van Gelderen, Peter; Duyn, Jeff] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. RP Duyn, J (reprint author), 10 Ctr Dr,Room B1D724,Bldg 10, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov RI Duan, Qi/J-7916-2016 OI Duan, Qi/0000-0002-2407-6611 FU NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. NR 33 TC 4 Z9 4 U1 0 U2 2 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 MAR PY 2012 VL 67 IS 3 BP 601 EP 608 DI 10.1002/mrm.23278 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 897UO UT WOS:000300683900002 PM 22222623 ER PT J AU Saito, K Matsumoto, S Devasahayam, N Subramanian, S Munasinghe, JP Morris, HD Lizak, MJ Ardenkjaer-Larsen, JH Mitchell, JB Krishna, MC AF Saito, Keita Matsumoto, Shingo Devasahayam, Nallathamby Subramanian, Sankaran Munasinghe, Jeeva P. Morris, H. Douglas Lizak, Martin J. Ardenkjaer-Larsen, Jan Henrik Mitchell, James B. Krishna, Murali C. TI Transient decrease in tumor oxygenation after intravenous administration of pyruvate SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE electron paramagnetic resonance imaging; hyperpolarized 13C MRI; tumor hypoxia; radiotherapy ID CANCER; HYPOXIA; THERAPY; CELLS; MICE AB MRI using hyperpolarized 13C-labeled pyruvate is a promising tool to biochemically profile tumors and monitor their response to therapy. This technique requires injection of pyruvate into tumor-bearing animals. Pyruvate is an endogenous entity but the influence of exogenously injected bolus doses of pyruvate on tumor microenvironment is not well understood. In this study, the effect of injecting a bolus of pyruvate on tumor oxygen status was investigated. EPR oxygen imaging revealed that the partial pressure of oxygen (pO2) in squamous cell carcinoma implanted in mice decreased significantly 30 min after [1-13C]pyruvate injection, but recovered to preinjection levels after 5 h. Dynamic contrast-enhanced-MRI studies showed that, at the dose of pyruvate used, no changes in tumor perfusion were noticed. Immunohistochemical analysis of hypoxic marker pimonidazole independently verified that the squamous cell carcinoma tumor transiently became more hypoxic by pyruvate injection. Efficacy of radiotherapy was suppressed when X-irradiation was delivered during the period of pyruvate-induced transient hypoxia. These results suggest importance of taking into account the transient decrease in tumor pO2 after pyruvate injection in hyperpolarized 13C MRI, because tumor oxygen status is an important factor in determining outcomes of therapies. Magn Reson Med, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Saito, Keita; Matsumoto, Shingo; Devasahayam, Nallathamby; Subramanian, Sankaran; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva P.; Morris, H. Douglas; Lizak, Martin J.] NINDS, NIH, Bethesda, MD 20892 USA. [Ardenkjaer-Larsen, Jan Henrik] Grove Ctr GC 18, GE Healthcare, Amersham HP7 9LL, England. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM murali@helix.nih.gov RI Ardenkjar-Larsen, Jan Henrik/B-5765-2017 OI Ardenkjar-Larsen, Jan Henrik/0000-0001-6167-6926 FU Intramural NIH HHS [ZIA BC010476-08] NR 21 TC 12 Z9 12 U1 1 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 MAR PY 2012 VL 67 IS 3 BP 801 EP 807 DI 10.1002/mrm.23065 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 897UO UT WOS:000300683900026 PM 22006570 ER PT J AU Rahimi, Z Ahmadian, Z Akramipour, R Vaisi-Raygani, A Rahimi, Z Parsian, A AF Rahimi, Zohreh Ahmadian, Zainab Akramipour, Reza Vaisi-Raygani, Asad Rahimi, Ziba Parsian, Abbas TI Thymidylate synthase and methionine synthase polymorphisms are not associated with susceptibility to childhood acute lymphoblastic leukemia in Kurdish population from Western Iran SO MOLECULAR BIOLOGY REPORTS LA English DT Article DE ALL; Gene polymorphism; MS A2756G; TS 28-bp repeat; Western Iran ID METHYLENETETRAHYDROFOLATE REDUCTASE MTHFR; FOLATE METABOLIC PATHWAY; GENETIC POLYMORPHISMS; RISK; LYMPHOMA; HAPLOTYPES; CHILDREN; ADULTS AB In order to determine the influence of polymorphism in thymidylate synthase (TS 28-bp repeat) and methionine synthase (MS A2756G) genes on the susceptibility to acute lymphoblastic leukemia (ALL), 73 children with ALL and 128 age and sex matched unrelated healthy individuals from the Kermanshah Province of Iran were screened. The genotyping of TS 28-bp repeat and MS A2756G polymorphisms were performed by polymerase chain reaction (PCR) and PCR-RFLP, respectively. The frequency of TS 2R allele in patients and controls were 41.5 and 38%, respectively (Odds ratios (OR) = 1.13, 95% CI 0.73-1.74, P = 0.56). The allelic frequency of G allele of MS was higher (25%) in patients compared with healthy subjects (23%) (OR = 1.09, 95% CI 0.67-1.75, P = 0.71). Considering MS AA and TS 3R3R genotypes as reference indicated that individuals with MS GG + TS 2R2R genotypes have 1.3-fold increase in the risk of ALL (OR = 1.3, 95% CI 0.6-2.7, P = 0.5). Our results showed that neither TS 28-bp repeat nor MS A2756G polymorphisms are risk factors for susceptibility to ALL in Western Iran. C1 [Rahimi, Zohreh; Vaisi-Raygani, Asad] Med Biol Res Ctr, Dept Biochem, Sch Med, Kermanshah 6714869914, Iran. [Rahimi, Zohreh; Ahmadian, Zainab; Rahimi, Ziba] Kermanshah Univ Med Sci, Med Biol Res Ctr, Kermanshah, Iran. [Ahmadian, Zainab] Kermanshah Univ Med Sci, Dept Pharmacol, Sch Pharm, Kermanshah, Iran. [Akramipour, Reza] Kermanshah Univ Med Sci, Dept Pediat Hematol Oncol, Sch Med, Kermanshah, Iran. [Parsian, Abbas] NIAAA, Div Neurosci & Behav, NIH, Rockville, MD 20852 USA. RP Rahimi, Z (reprint author), Med Biol Res Ctr, Dept Biochem, Sch Med, Daneshgah Ave, Kermanshah 6714869914, Iran. EM zrahimi@kums.ac.ir; zrahimi@kums.ac.ir OI Rahimi, Zohreh/0000-0001-7589-3307; Vaisi-Raygani, Asad/0000-0002-3042-2832 FU Kermanshah University of Medical Sciences, Kermanshah, Iran FX This work was financially supported by a grant from Vice Chancellor for Research of Kermanshah University of Medical Sciences, Kermanshah, Iran. NR 27 TC 8 Z9 11 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-4851 J9 MOL BIOL REP JI Mol. Biol. Rep. PD MAR PY 2012 VL 39 IS 3 BP 2195 EP 2200 DI 10.1007/s11033-011-0968-y PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 903HS UT WOS:000301107800016 PM 21643952 ER PT J AU Patri, AK Simanek, E AF Patri, Anil K. Simanek, Eric TI Biological Applications of Dendrimers SO MOLECULAR PHARMACEUTICS LA English DT Editorial Material C1 [Patri, Anil K.] SAIC Frederick Inc, Nanotechnol Characterizat Lab, Natl Canc Inst Frederick, Frederick, MD 21702 USA. [Simanek, Eric] Texas Christian Univ, Dept Chem, Ft Worth, TX 76129 USA. RP Patri, AK (reprint author), SAIC Frederick Inc, Nanotechnol Characterizat Lab, Natl Canc Inst Frederick, Frederick, MD 21702 USA. EM patria@mail.nih.gov; e.simanek@tcu.edu RI Nanotechnology Characterization Lab, NCL/K-8454-2012 NR 0 TC 6 Z9 7 U1 3 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD MAR PY 2012 VL 9 IS 3 BP 341 EP 341 DI 10.1021/mp300057m PG 1 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 902DG UT WOS:000301018200001 PM 22384975 ER PT J AU Nwe, K Milenic, DE Ray, GL Kim, YS Brechbiel, MW AF Nwe, Kido Milenic, Diane E. Ray, Geoffrey L. Kim, Young-Seung Brechbiel, Martin W. TI Preparation of Cystamine Core Dendrimer and Antibody-Dendrimer Conjugates for MRI Angiography SO MOLECULAR PHARMACEUTICS LA English DT Article DE magnetic resonance imaging (MRI); cystamine core dendrimer; F(ab ')(2); antibody ID GROWTH-FACTOR RECEPTOR; NEUTRON-CAPTURE THERAPY; SINGLE-CHAIN FV; MONOCLONAL-ANTIBODY; CONTRAST AGENTS; MAGNETIC-RESONANCE; POLYAMIDOAMINE DENDRIMER; ENHANCEMENT PATTERNS; GADOLINIUM-DENDRIMER; CETUXIMAB IMC-C225 AB Herein we report the preparation along with the in vivo and in vitro MRI characterization of two generation four and five cystamine core dendrimers loaded with thirty and fifty-eight derivatized Gd-DOTA (G4SS30, GSSS58) respectively. Likewise the development and characterization of two half-dendrimers conjugated to the F(ab')(2) fragment of the monoclonal antibody (mAb) panitumumab functionalized with a maleimide conjugation functional group site (Ab-(G4S15)(4), Ab-(G5S29)(4)) are also described. The in vitro molar relaxivity of the Ab-(G4S15)(4) conjugate, measured at pH 7.4, 22 degrees C, and 3T showed a moderate increase in relaxivity as compared to Magnevist (6.7 vs 4.0 mM(-1) s(-1)) while the Ab-(G5S29)(4) conjugate was 2-fold higher (9.1 vs 4.0 mM(-1) s(-1)). The data showed that only a high injection dose (0.050 mmol Gd3+/kg) produced a detectable contrast enhanced contrast for the Ab-(G4S15)(4) conjugate while a lower dose (0.035 mmol Gd3+/kg) was sufficient for the Ab-(G5S29)(4) conjugate. The antibody-SMCC conjugate was purified by a Sephadex G-100 column, and the antibody-dendrimer-based agents were purified by spin filtration using a Centricon filter (50,000 MCO). The protein assay coupled with cysteine and Ellman's assay indicated an antibody to dendrimer ratio of 1:4. The in vivo blood clearance half-lives of the four agents measured at the jugular vein were similar to 12-22 min. C1 [Nwe, Kido; Milenic, Diane E.; Ray, Geoffrey L.; Kim, Young-Seung; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Bldg 10,Room B3B69,10 Ctr Dr MSC 1088, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; United States Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research and the United States Department of Health and Human Services. We thank Dr. L. Henry Bryant, Jr., Laboratory of Diagnostic Radiology Research (LDRR), National Institutes of Health, for his help with the instrumentation for photon correlation spectroscopy (PCS) and relaxometry. NR 45 TC 7 Z9 7 U1 3 U2 44 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD MAR PY 2012 VL 9 IS 3 BP 374 EP 381 DI 10.1021/mp2003219 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 902DG UT WOS:000301018200004 PM 21882823 ER PT J AU Dobrovolskaia, MA Patri, AK Simak, J Hall, JB Semberova, J Lacerda, SHDP McNeil, SE AF Dobrovolskaia, Marina A. Patri, Anil K. Simak, Jan Hall, Jennifer B. Semberova, Jana Lacerda, Silvia H. De Paoli McNeil, Scott E. TI Nanoparticle Size and Surface Charge Determine Effects of PAMAM Dendrimers on Human Platelets in Vitro SO MOLECULAR PHARMACEUTICS LA English DT Article DE PAMAM dendrimers; platelets; aggregation; activation; nanomaterials; thrombogenicity; coagulation; nanoparticles; thrombocyte; dendrimers; blood; nanomedicine ID SUPPORTED LIPID-BILAYERS; COARSE-GRAINED MODEL; POLY(AMIDOAMINE) DENDRIMERS; THROMBUS FORMATION; LATEX-PARTICLES; PROTEIN CORONA; HOLE FORMATION; AGGREGATION; CELLS; MICROPARTICLES AB Blood platelets are essential in maintaining hemostasis. Various materials can activate platelets and cause them to aggregate. Platelet aggregation in vitro is often used as a marker for materials thrombogenic properties, and studying nanomaterial interaction with platelets is an important step toward understanding their hematocompatibility. Here we report evaluation of 12 formulations of PAMAM dendrimers varying in size and surface charge. Using a cell counter based method, light transmission aggregometry and scanning electron microscopy, we show that only large cationic dendrimers, but not anionic, neutral or small cationic dendrimers, induce aggregation of human platelets in plasma in vitro. The aggregation caused by large cationic dendrimers was proportional to the number of surface amines. The observed aggregation was not associated with membrane microparticle release, and was insensitive to a variety of chemical and biological inhibitors known to interfere with various pathways of platelet activation. Taken in context with previously reported studies, our data suggest that large cationic PAMAM dendrimers induce platelet aggregation through disruption of membrane integrity. C1 [Dobrovolskaia, Marina A.; Patri, Anil K.; Hall, Jennifer B.; McNeil, Scott E.] SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA. [Simak, Jan; Semberova, Jana; Lacerda, Silvia H. De Paoli] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Dobrovolskaia, MA (reprint author), Lab SAIC Frederick Inc, Nanotechnol Characterizat, NCI Frederick, 1050 Boyles St,Bldg 469, Frederick, MD 21702 USA. EM marina@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [N01-CO-12400, HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400 and 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. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. We thank Nader Ayub, Kent Worthington, Barry Neun, David Parmiter and Jamie Rodriguez for excellent technical support. NR 45 TC 74 Z9 74 U1 4 U2 47 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD MAR PY 2012 VL 9 IS 3 BP 382 EP 393 DI 10.1021/mp200463e PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 902DG UT WOS:000301018200005 PM 22026635 ER PT J AU Kohno, T Ichikawa, H Totoki, Y Yasuda, K Hiramoto, M Nammo, T Sakamoto, H Tsuta, K Furuta, K Shimada, Y Iwakawa, R Ogiwara, H Oike, T Enari, M Schetter, AJ Okayama, H Haugen, A Skaug, V Chiku, S Yamanaka, I Arai, Y Watanabe, SI Sekine, I Ogawa, S Harris, CC Tsuda, H Yoshida, T Yokota, J Shibata, T AF Kohno, Takashi Ichikawa, Hitoshi Totoki, Yasushi Yasuda, Kazuki Hiramoto, Masaki Nammo, Takao Sakamoto, Hiromi Tsuta, Koji Furuta, Koh Shimada, Yoko Iwakawa, Reika Ogiwara, Hideaki Oike, Takahiro Enari, Masato Schetter, Aaron J. Okayama, Hirokazu Haugen, Aage Skaug, Vidar Chiku, Suenori Yamanaka, Itaru Arai, Yasuhito Watanabe, Shun-ichi Sekine, Ikuo Ogawa, Seishi Harris, Curtis C. Tsuda, Hitoshi Yoshida, Teruhiko Yokota, Jun Shibata, Tatsuhiro TI KIF5B-RET fusions in lung adenocarcinoma SO NATURE MEDICINE LA English DT Article ID CANCER; RET; IDENTIFICATION; THERAPY AB We identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs) from people from Japan and the United States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells. C1 [Kohno, Takashi; Shimada, Yoko; Ogiwara, Hideaki] Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, Tokyo 104, Japan. [Ichikawa, Hitoshi; Sakamoto, Hiromi; Yoshida, Teruhiko] Natl Canc Ctr, Res Inst, Div Genet, Chuo Ku, Tokyo 104, Japan. [Totoki, Yasushi; Shibata, Tatsuhiro] Natl Canc Ctr, Res Inst, Div Canc Genom, Chuo Ku, Tokyo 104, Japan. [Yasuda, Kazuki; Hiramoto, Masaki; Nammo, Takao] Natl Ctr Global Hlth & Med, Dept Metab Disorder, Diabet Res Ctr, Res Inst,Shinjuku Ku, Tokyo, Japan. [Tsuta, Koji; Furuta, Koh; Tsuda, Hitoshi] Natl Canc Ctr, Div Pathol & Clin Labs, Chuo Ku, Tokyo, Japan. [Iwakawa, Reika; Oike, Takahiro; Okayama, Hirokazu; Yokota, Jun] Natl Canc Ctr, Res Inst, Div Multistep Carcinogenesis, Chuo Ku, Tokyo 104, Japan. [Enari, Masato] Natl Canc Ctr, Res Inst, Div Refractory Canc Res, Tokyo 104, Japan. [Schetter, Aaron J.; Okayama, Hirokazu; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Haugen, Aage; Skaug, Vidar] Natl Inst Occupat Hlth, Sect Toxicol, Dept Chem & Biol Working Environm, Oslo, Norway. [Chiku, Suenori] Mizuho Informat & Res Inst, Sci Solut Div, Chiyoda Ku, Tokyo, Japan. [Yamanaka, Itaru] StaGen, Stat Genet Anal Div, Taito Ku, Tokyo, Japan. [Watanabe, Shun-ichi] Natl Canc Ctr, Div Thorac Surg, Chuo Ku, Tokyo, Japan. [Sekine, Ikuo] Natl Canc Ctr, Div Thorac Oncol, Chuo Ku, Tokyo, Japan. [Ogawa, Seishi] Univ Tokyo, Bunkyo Ku, Canc Genom Project, Tokyo 113, Japan. RP Kohno, T (reprint author), Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, Tokyo 104, Japan. EM tkkohno@ncc.go.jp RI Enari, Masato/E-5507-2014 OI Enari, Masato/0000-0003-4293-3848 FU National Institute of Biomedical Innovation (NiBio); Ministry of Health, Labour and Welfare; National Cancer Center; Norwegian Cancer Society; National Cancer Center, Japan FX This work was supported in part by the program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio), Grants-in-Aid from the Ministry of Health, Labour and Welfare for the 3rd-term Comprehensive 10-year Strategy for Cancer Control, the National Cancer Center Research and Development Fund and the Norwegian Cancer Society. National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan. We thank T. Urushidate, S. Ohashi, S. Mitani, K. Yokozawa, S. Wakai, C. Otsubo and H. Isomura of the National Cancer Center and D. Suzuki and K. Nagase of the National Center for Global Health and Medicine for technical assistance. We also thank J.D. Minna and L. Girard of the University of Texas Southwestern Medical Center, K. Kumamoto of Saitama Medical University and A. Okamoto of Jikei University for RET fusion screening, N. Morii of the National Institute of Advanced Industrial Science and Technology (AIST) for thermodynamic characterization of the KIF5B protein and M. Maekawa of the GSP laboratory for rapid preparation of the FISH probes. NR 19 TC 298 Z9 317 U1 5 U2 36 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 MAR PY 2012 VL 18 IS 3 BP 375 EP 377 DI 10.1038/nm.2644 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905IF UT WOS:000301264800036 PM 22327624 ER PT J AU Thu, MS Bryant, LH Coppola, T Jordan, EK Budde, MD Lewis, BK Chaudhry, A Ren, JQ Varma, NRS Arbab, AS Frank, JA AF Thu, Mya S. Bryant, L. Henry Coppola, Tiziana Jordan, E. Kay Budde, Matthew D. Lewis, Bobbi K. Chaudhry, Aneeka Ren, Jiaqiang Varma, Nadimpalli Ravi S. Arbab, Ali S. Frank, Joseph A. TI Self-assembling nanocomplexes by combining ferumoxytol, heparin and protamine for cell tracking by magnetic resonance imaging SO NATURE MEDICINE LA English DT Article ID STEM-CELLS; DELIVERY-SYSTEM; LABELED CELLS; IRON; NANOPARTICLES; MRI; OPTIMIZATION; FERUMOXIDES; EXPRESSION; DRUGS AB We report on a new straightforward magnetic cell-labeling approach that combines three US Food and Drug Administration (FDA)-approved drugs-ferumoxytol, heparin and protamine-in serum-free medium to form self-assembling nanocomplexes that effectively label cells for in vivo magnetic resonance imaging (MRI). We observed that the ferumoxytol-heparin-protamine (HPF) nanocomplexes were stable in serum-free cell culture medium. HPF nanocomplexes show a threefold increase in T2 relaxivity compared to ferumoxytol. Electron microscopy showed internalized HPF in endosomes, which we confirmed by Prussian blue staining of labeled cells. There was no long-term effect or toxicity on cellular physiology or function of HPF-labeled hematopoietic stem cells, bone marrow stromal cells, neural stem cells or T cells when compared to controls. In vivo MRI detected 1,000 HPF-labeled cells implanted in rat brains. This HPF labeling method should facilitate the monitoring by MRI of infused or implanted cells in clinical trials. C1 [Thu, Mya S.; Bryant, L. Henry; Coppola, Tiziana; Jordan, E. Kay; Budde, Matthew D.; Lewis, Bobbi K.; Chaudhry, Aneeka; Frank, Joseph A.] NIH, Frank Lab, Bethesda, MD 20892 USA. [Thu, Mya S.; Bryant, L. Henry; Coppola, Tiziana; Jordan, E. Kay; Budde, Matthew D.; Lewis, Bobbi K.; Chaudhry, Aneeka; Frank, Joseph A.] NIH, Lab Diagnost Radiol Res, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Ren, Jiaqiang] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Varma, Nadimpalli Ravi S.; Arbab, Ali S.] Henry Ford Hosp, Dept Radiol, Cellular & Mol Imaging Lab, Detroit, MI 48202 USA. [Frank, Joseph A.] NIH, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. RP Frank, JA (reprint author), NIH, Frank Lab, Bldg 10, Bethesda, MD 20892 USA. EM jafrank@helix.nih.gov FU Clinical Center of the US National Institutes of Health (NIH); NIH [R01CA122031] FX This work was supported by and performed in part in the intramural research program at the Clinical Center of the US National Institutes of Health (NIH). BMSCs were provided from the Center for Bone Marrow Stromal Cell Transplantation at the NIH. NSCs were provided as part of a material transfer agreement with K. Aboody (City of Hope Medical Center). The authors would like to acknowledge the Clinical Image Processing Section at the NIH. This work was also supported by NIH grant R01CA122031. NR 38 TC 81 Z9 83 U1 7 U2 54 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 MAR PY 2012 VL 18 IS 3 BP 463 EP U165 DI 10.1038/nm.2666 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905IF UT WOS:000301264800051 PM 22366951 ER PT J AU Almering, J Tsvilovskyy, V Mannebach, S Kriebs, U Weissgerber, P Flockerzi, V Birnbaumer, L Freichel, M AF Almering, J. Tsvilovskyy, V. Mannebach, S. Kriebs, U. Weissgerber, P. Flockerzi, V. Birnbaumer, L. Freichel, M. TI Regulation of mast cell activation by TRP protein-mediated Ca2+ entry SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 78th Annual Congress of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT) CY MAR 19-22, 2012 CL Dresden, GERMANY SP German Soc Expt & Clin Pharmacol & Toxicol (DGPT) C1 [Almering, J.; Tsvilovskyy, V.; Kriebs, U.; Freichel, M.] Univ Heidelberg, Inst Pharmakol, D-69120 Heidelberg, Germany. [Mannebach, S.; Weissgerber, P.; Flockerzi, V.] Univ Saarlandes Expt & Klin Pharmakol & Toxikol, D-66421 Homburg, Germany. [Birnbaumer, L.] NIEHS Transmembrane Signaling, Res Triangle Pk, NC 27709 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2012 VL 385 SU 1 MA 009 BP 4 EP 4 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898YY UT WOS:000300779500010 ER PT J AU Devanathan, V Hagedorn, I Kohler, D Pexa, K Piekorz, R Kraft, P Stoll, G Birnbaumer, L Rosenberger, P Nieswandt, B Nurnberg, B AF Devanathan, V Hagedorn, I Koehler, D. Pexa, K. Piekorz, R. Kraft, P. Stoll, G. Birnbaumer, L. Rosenberger, P. Nieswandt, B. Nuernberg, B. TI Different roles for G alpha(i2) and G alpha(i3) in myocardial and cerebral ischemia SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 78th Annual Congress of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT) CY MAR 19-22, 2012 CL Dresden, GERMANY SP German Soc Expt & Clin Pharmacol & Toxicol (DGPT) C1 [Devanathan, V; Nuernberg, B.] Univ Tubingen, Inst Pharmakol, D-72074 Tubingen, Germany. [Hagedorn, I; Nieswandt, B.] Univ Wurzburg, Rudolf Virchow Zentrum Expt Biomed, D-97080 Wurzburg, Germany. [Koehler, D.] Univ Tubingen, Zentrum Hypoxie & Inflammat, D-72074 Tubingen, Germany. [Pexa, K.; Piekorz, R.] Univ Dusseldorf, Inst Biochem & Mol Biol 2, D-40225 Dusseldorf, Germany. [Kraft, P.; Stoll, G.] Univ Wurzburg, Neurol Klin & Poliklin, D-97080 Wurzburg, Germany. [Birnbaumer, L.] NIH, Transmembrane Signaling Grp, Res Triangle Pk, NC 27709 USA. [Rosenberger, P.] Goethe Univ Frankfurt, Anasthesiol Klin, D-60590 Frankfurt, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2012 VL 385 SU 1 MA 085 BP 21 EP 21 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898YY UT WOS:000300779500086 ER PT J AU Mathar, I Vennekens, R Mannebach, S Londono, JEC Uhl, S Birnbaumer, L Voets, T Freichel, M AF Mathar, I Vennekens, R. Mannebach, S. Londono, Camacho J. E. Uhl, S. Birnbaumer, L. Voets, T. Freichel, M. TI Transient receptor potential channels as mediators of catecholamine release SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 78th Annual Congress of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT) CY MAR 19-22, 2012 CL Dresden, GERMANY SP German Soc Expt & Clin Pharmacol & Toxicol (DGPT) C1 [Mathar, I; Londono, Camacho J. E.; Uhl, S.; Freichel, M.] Univ Heidelberg, Inst Pharmakol, D-69120 Heidelberg, Germany. [Vennekens, R.; Voets, T.] KU Leuven Lab Ion Channel Res, B-3000 Louvain, Belgium. [Mannebach, S.] Univ Saarlandes Expt, D-66421 Homburg, Germany. [Mannebach, S.] Klin Pharmakol & Toxikol, D-66421 Homburg, Germany. [Birnbaumer, L.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2012 VL 385 SU 1 MA 246 BP 57 EP 57 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898YY UT WOS:000300779500247 ER PT J AU Schneider, E Gao, JL Holmes, G Peiper, SC Murphy, PM AF Schneider, E. Gao, J-L Holmes, G. Peiper, S. C. Murphy, P. M. TI The Duffy Antigen Receptor for Chemokines modulates balance, locomotion and anxiety-like behavior in mice under homeostatic conditions SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 78th Annual Congress of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT) CY MAR 19-22, 2012 CL Dresden, GERMANY SP German Soc Expt & Clin Pharmacol & Toxicol (DGPT) C1 [Schneider, E.; Gao, J-L; Murphy, P. M.] NIAID, NIH, Mol Signaling Sect, Bethesda, MD 20892 USA. [Holmes, G.] NIAID, NIH, Inflammat Biol Sect, Bethesda, MD 20892 USA. [Peiper, S. C.] Jefferson Med Coll Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2012 VL 385 SU 1 MA 369 BP 84 EP 84 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898YY UT WOS:000300779500370 ER PT J AU Warren, KE Killian, K Suuriniemi, M Wang, YH Quezado, M Meltzer, PS AF Warren, Katherine E. Killian, Keith Suuriniemi, Miia Wang, Yonghong Quezado, Martha Meltzer, Paul S. TI Genomic aberrations in pediatric diffuse intrinsic pontine gliomas SO NEURO-ONCOLOGY LA English DT Article DE brainstem glioma; DIPG; genomics; microarray; pontine glioma ID BRAIN-STEM GLIOMA; PHASE-I TRIAL; GROWTH-FACTOR; GENETIC ALTERATIONS; HYBRIDIZATION; GRADE; GLIOBLASTOMA; TUMOR; ABNORMALITIES; EXPRESSION AB Diagnostic biopsy is not routinely performed for children with diffuse intrinsic pontine glioma (DIPG). Consequently, our understanding of DIPG biology is hindered by limited tissue availability. We performed comparative genomic hybridization (CGH) on autopsy specimens to examine the feasibility of determining DNA genomic copy number aberrations on formalin-fixed, paraffin-embedded (FFPE) blocks. Histology on FFPE blocks obtained from autopsy of pediatric patients with DIPG was reviewed. Regions were marked for processing, and DNA was extracted from the tissue core, labeled by chemical coupling with Cy5, and hybridized to 105K oligonucleotide CGH arrays. After hybridization and washing, arrays were scanned, and data segmented and processed with Nexus software. Twenty-two samples from 13 subjects were obtained. Histologic variability was noted. CGH was successfully performed on 18 of 22 samples, representing 11 of 13 subjects. All demonstrated DNA copy number abnormalities. High copy number amplification of known oncogenes and homozygous deletions of known tumor suppressor genes were observed. Additional regions of high copy number amplification and homozygous deletion and geographical variations in the CGH patterns were found. CGH performed on FFPE tissue obtained from autopsy yields satisfactory results. This sample set from patients with DIPG was highly informative, with the majority of specimens showing >= 1 abnormality related to a known cancer gene. Aberrations in candidate drug targets were observed. This study establishes the feasibility of genomic DNA analysis from DIPG autopsy material, identifies several targets for which molecular targeted therapy exists, and suggests significant heterogeneity among patients with DIPG. C1 [Killian, Keith; Suuriniemi, Miia; Wang, Yonghong; Meltzer, Paul S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Warren, Katherine E.] NCI, Pediat Oncol Branch, Pediat Neurooncol Sect, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Warren, KE (reprint author), NCI, Pediat Oncol Branch, Pediat Neurooncol Sect, Ctr Canc Res,NIH, Bldg 10 CRC,Rm 1W-5750, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research 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. NR 24 TC 21 Z9 22 U1 0 U2 6 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 MAR PY 2012 VL 14 IS 3 BP 326 EP 332 DI 10.1093/neuonc/nor190 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 900VF UT WOS:000300918900009 PM 22064882 ER PT J AU Yabroff, KR Harlan, L Zeruto, C Abrams, J Mann, B AF Yabroff, K. Robin Harlan, Linda Zeruto, Christopher Abrams, Jeffrey Mann, Bhupinder TI Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006 SO NEURO-ONCOLOGY LA English DT Article DE brain cancer; glioblastoma; practice patterns; SEER; temozolomide ID CLINICAL-TRIAL; UNITED-STATES; CANCER; ADULTS; PARTICIPATION; RADIOTHERAPY; TEMOZOLOMIDE; GLIOMA; TRENDS AB Standard treatment for glioblastoma multi forme (GBM) changed in 2005 when addition of temozolomide (TMZ) to maximal surgical resection followed by radiation therapy (RT) was shown to prolong survival in a clinical trial. In this study, we assessed treatment patterns and survival of patients with GBM in community settings in the United States. Patients with newly diagnosed GBM who were aged >= 20 years in 2006 (n = 1202) were identified as part of the National Cancer Institute 's Patterns of Care Studies. We assessed treatment patterns, and in the subset of patients who received total or partial surgical resection, we used multivariable regression analysis to assess patient, clinical, and health system factors associated with receipt of adjuvant chemotherapy and RT and survival through 2008. Approximately 65% of patients with GBM received total or partial surgical resection, and approximately 70% of these patients received adjuvant TMZ and RT. Receipt of adjuvant therapy was associated with patient age, marital status, health insurance, and tumor location. Median survival in all patients was 10 months (95% confidence interval [CI], 9-11 months). Receipt of adjuvant therapy following resection was associated with a lower risk of dying in adjusted analyses for patients who received TMZ and RT (hazard ratio [HR], 0.25; 95% CI, 0.18-0.35) and other adjuvant therapies (HR, 0.55; 95% CI, 0.37-0.81), compared with no adjuvant therapy. We observed rapid diffusion of a new standard of treatment, adjuvant and concurrent TMZ with RT, among adult patients with newly diagnosed GBM in the community setting following publication of a pivotal clinical trial. C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Zeruto, Christopher] Informat Management Serv Inc, Silver Spring, MD USA. [Abrams, Jeffrey; Mann, Bhupinder] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Rm 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU National Cancer Institute [N01-PC35133, N01-PC-35135, N01-PC-35141, N01-PC35136, N01-PC-35137, N01-PC-35138, N01-PC35139, N01-PC-35142, N01-PC-35143, N01-PC35145, N01-PC-54402, N01-PC-54403, N01-PC54404, N01-PC-54405] FX This work was supported by the following grants provided by the National Cancer Institute N01-PC35133, N01-PC-35135, N01-PC-35141, N01-PC35136, N01-PC-35137, N01-PC-35138, N01-PC35139, N01-PC-35142, N01-PC-35143, N01-PC35145, N01-PC-54402, N01-PC-54403, N01-PC54404, and N01-PC-54405. NR 28 TC 27 Z9 29 U1 0 U2 2 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 MAR PY 2012 VL 14 IS 3 BP 351 EP 359 DI 10.1093/neuonc/nor218 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 900VF UT WOS:000300918900012 PM 22241797 ER PT J AU Chen, MF Huang, YC Long, C Yang, HI Lee, HC Chen, PY Hoffer, BJ Lee, TJF AF Chen, Mei-Fang Huang, Yi-Chiao Long, Cheng Yang, Hui-I Lee, Hui-Chao Chen, Po-Yi Hoffer, Barry J. Lee, Tony Jer-Fu TI Bimodal effects of fluoxetine on cerebral nitrergic neurogenic vasodilation in porcine large cerebral arteries SO NEUROPHARMACOLOGY LA English DT Article DE Fluoxetine; Antidepressant; Neurogenic nitrergic vasodilation; Porcine basilar artery; Nicotinic acetylcholine receptor; Nitric oxide ID NICOTINIC ACETYLCHOLINE-RECEPTORS; NITRIC OXIDERGIC INNERVATION; LIQUID-CHROMATOGRAPHY; UPTAKE INHIBITORS; CALCIUM-CHANNELS; MONOAMINE UPTAKE; BLOOD-FLOW; SEROTONIN; MUSCLE; NORFLUOXETINE AB Fluoxetine-induced relaxation of the smooth muscle of small cerebral arteries is thought beneficial in treating mental disorders. The present study was designed to examine effect of fluoxetine on neurogenic nitrergic vasodilation in large cerebral arteries, using in vitro tissue myography, techniques of electrophysiology, calcium imaging and biochemistry. In isolated porcine endothelium-denuded basilar arteries in the presence of U-46619-induced active muscle tone, fluoxetine in low concentration (<0.03 mu M) significantly enhanced nicotine- and choline-induced relaxations. The vasorelaxation, however, was blocked by higher concentration of fluoxetine (>0.3 mu M) with maximum inhibition at 3 mu M. At this concentration, fluoxetine did not affect the basal tone or vasorelaxations induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, fluoxetine exclusively blocked nicotine-induced inward currents and calcium influx in cultured neurons of rat superior cervical ganglion and Xenopus oocytes expressing human alpha 7-, alpha 3 beta 2-, or alpha 4 beta 2-nicotinic acetylcholine receptors (nAChRs). In addition, fluoxetine at 0.03 mu M and 3 mu M significantly enhanced and blocked, respectively, nicotine-induced norepinephrine (NE) release from cerebral perivascular sympathetic nerves. These results indicate that fluoxetine via axo-axonal interaction mechanism exhibits bimodal effects on nAChR-mediated neurogenic nitrergic dilation of basilar arteries. Fluoxetine in high concentrations decreases while in low concentrations it increases neurogenic vasodilation. These results from in vitro experimentation suggest that optimal concentrations of fluoxetine which increase or minimally affect neurogenic vasodilation indicative of regional cerebral blood flow may be important consideration in treating mental disorders. (c) 2011 Elsevier Ltd. All rights reserved. C1 [Lee, Tony Jer-Fu] Tzu Chi Univ, Coll Life Sci, Dept Life Sci, Hualien 970, Taiwan. [Chen, Mei-Fang; Yang, Hui-I; Chen, Po-Yi] Buddhist Tzu Chi Gen Hosp, Dept Res, Hualien, Taiwan. [Chen, Mei-Fang] Tzu Chi Coll Technol, Hualien, Taiwan. [Lee, Hui-Chao; Lee, Tony Jer-Fu] Tzu Chi Univ, Inst Med Sci, Hualien 970, Taiwan. [Huang, Yi-Chiao; Chen, Po-Yi; Lee, Tony Jer-Fu] Tzu Chi Univ, Coll Med, Inst Pharmacol & Toxicol, Hualien 970, Taiwan. [Chen, Mei-Fang; Lee, Hui-Chao; Chen, Po-Yi; Lee, Tony Jer-Fu] Tzu Chi Univ, Ctr Vasc Med, Hualien 970, Taiwan. [Hoffer, Barry J.] NIDA, NIH, Baltimore, MD USA. [Long, Cheng; Lee, Tony Jer-Fu] So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA. RP Lee, TJF (reprint author), Tzu Chi Univ, Coll Life Sci, Dept Life Sci, 701 Sec 3,Chung Yang Rd, Hualien 970, Taiwan. EM tlee@mail.tcu.edu.tw OI Lee, Reggie/0000-0001-6099-8333 FU Taiwan National Science Council [NSC 95-2314-B-303-014-MY3, NSC-95-2320-B-320-013-MY2, NSC-96-2320-B-320-005-MY3, NSC 100-2320-B-320-007-MY2]; Tzu Chi University [TCRPP99006, TCIRP98005-01Y1, TCIRP98005-01Y2] FX We thank Dr. J. Michael McIntosh of university of Utah for the generous gift of alpha 3 beta 2-nAChR plasmids, Dr. Jon-Son Kuo for reading the manuscript, Mr. Wen-Hao Lan and Ms. Wan-Rong Lin for technical assistance, and Fong-Ling packing company for supplying porcine brains. This work was supported by the grants from Taiwan National Science Council [NSC 95-2314-B-303-014-MY3, NSC-95-2320-B-320-013-MY2, NSC-96-2320-B-320-005-MY3 and NSC 100-2320-B-320-007-MY2], and Tzu Chi University (TCRPP99006, TCIRP98005-01Y1, and TCIRP98005-01Y2). NR 46 TC 3 Z9 3 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 MAR PY 2012 VL 62 IS 4 BP 1651 EP 1658 DI 10.1016/j.neuropharm.2011.11.011 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 904TT UT WOS:000301221500006 PM 22155207 ER PT J AU Guo, JD Hazra, R Dabrowska, J Muly, EC Wess, J Rainnie, DG AF Guo, Ji-Dong Hazra, Rimi Dabrowska, Joanna Muly, E. Chris Wess, Juergen Rainnie, Donald G. TI Presynaptic muscarinic M-2 receptors modulate glutamatergic transmission in the bed nucleus of the stria terminalis SO NEUROPHARMACOLOGY LA English DT Article DE Acetylcholine; Eserine; Carbachol; Muscarinic receptor knockout mice; EPSCs ID LONG-TERM POTENTIATION; SYNAPTIC-TRANSMISSION; ACETYLCHOLINE-RECEPTORS; RAT-BRAIN; CHOLINERGIC MODULATION; PREFRONTAL CORTEX; BASAL FOREBRAIN; KNOCKOUT MICE; IN-VIVO; HIPPOCAMPAL ACETYLCHOLINE AB The anterolateral cell group of the bed nucleus of the stria terminalis (BNSTALG) serves as an important relay station in stress circuitry. Limbic inputs to the BNSTALG are primarily glutamatergic and activity-dependent changes in this input have been implicated in abnormal behaviors associated with chronic stress and addiction. Significantly, local infusion of acetylcholine (ACh) receptor agonists into the BNST trigger stress-like cardiovascular responses, however, little is known about the effects of these agents on glutamatergic transmission in the BNSTALG. Here, we show that glutamate- and ACh-containing fibers are found in close association in the BNSTALG. Moreover, in the presence of the acetylcholinesterase inhibitor, eserine, endogenous ACh release evoked a long-lasting reduction of the amplitude of stimulus-evoked EPSCs. This effect was mimicked by exogenous application of the ACh analog, carbachol, which caused a reversible, dose-dependent, reduction of the evoked EPSC amplitude, and an increase in both the paired-pulse ratio and coefficient of variation, suggesting a presynaptic site of action. Uncoupling of postsynaptic G-proteins with intracellular GDP-beta-S, or application of the nicotinic receptor antagonist, tubocurarine, failed to block the carbachol effect. In contrast, the carbachol effect was blocked by prior application of atropine or M-2 receptor-preferring antagonists, and was absent in M-2/M-4 receptor knockout mice, suggesting that presynaptic M-2 receptors mediate the effect of ACh. Immunoelectron microscopy studies further revealed the presence of M-2 receptors on axon terminals that formed asymmetric synapses with BNST neurons. Our findings suggest that presynaptic M-2 receptors might be an important modulator of the stress circuit and hence a novel target for drug development. (c) 2011 Elsevier Ltd. All rights reserved. C1 [Guo, Ji-Dong; Hazra, Rimi; Dabrowska, Joanna; Rainnie, Donald G.] Yerkes Natl Primate Res Ctr, Div Behav Neurosci & Psychiat Disorders, Atlanta, GA 30329 USA. [Guo, Ji-Dong; Hazra, Rimi; Dabrowska, Joanna; Muly, E. Chris; Rainnie, Donald G.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Muly, E. Chris] Yerkes Natl Primate Res Ctr, Div Neuropharmacol & Neurol Dis, Atlanta, GA 30329 USA. [Muly, E. Chris] Vet Affairs Med Ctr, Atlanta Dept, Decatur, GA 30033 USA. [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP Rainnie, DG (reprint author), Yerkes Natl Primate Res Ctr, Div Behav Neurosci & Psychiat Disorders, Yerkes Neurosci Bldg,Rm 5220 954, Atlanta, GA 30329 USA. EM drainni@emory.edu RI Guo, Jidong/D-5564-2009; Rainnie, Donald/L-3853-2016 OI Rainnie, Donald/0000-0003-0758-0530 FU National Institute of Mental Health [MH-072908]; Yerkes National Primate Research Center [RR-00165]; National Institutes of Health FX The authors want to thank Dr. Allan Levey for constructive comments and help in supplying the knockout mice and Marcelia Maddox for technical assistance in EM studies. This work was supported by National Institute of Mental Health Grant MH-072908 to D. G. Rainnie; and the Yerkes National Primate Research Center Base Grant RR-00165 awarded by the Animal Resources Program of National Institutes of Health. NR 86 TC 7 Z9 7 U1 1 U2 5 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 MAR PY 2012 VL 62 IS 4 BP 1671 EP 1683 DI 10.1016/j.neuropharm.2011.11.013 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 904TT UT WOS:000301221500008 PM 22166222 ER PT J AU Carcillo, JA Dean, JM Holubkov, R Berger, J Meert, KL Anand, KJS Zimmerman, J Newth, CJL Harrison, R Burr, J Willson, DF Nicholson, C AF Carcillo, Joseph A. Dean, J. Michael Holubkov, Richard Berger, John Meert, Kathleen L. Anand, K. J. S. Zimmerman, Jerry Newth, Christopher J. L. Harrison, Rick Burr, Jeri Willson, Douglas F. Nicholson, Carol CA Eunice Kennedy Shriver Natl Inst TI The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE glutamine; nosocomial infection; prolactin; selenium; sepsis; whey protein; zinc ID WHEY-PROTEIN CONCENTRATE; ENRICHED ENTERAL NUTRITION; PLASMA GLUTATHIONE LEVELS; ORAL REHYDRATION THERAPY; HIV-INFECTED PATIENTS; DOUBLE-BLIND; AMINO-ACIDS; ZINC SUPPLEMENTATION; SUCKLING RATS; CHILDREN AB Objectives: Nosocomial infection/sepsis occurs in up to 40% of children requiring long-term intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and/or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein, would reduce the occurrence of nosocomial infection/sepsis in this at-risk population. Design: Randomized, double-blinded, comparative effectiveness trial. Setting: Eight pediatric intensive care units in the National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Patients: Two hundred ninety-three long-term intensive care patients (age 1-17 yrs) expected to require >72 hrs of invasive care. Interventions: Patients were stratified according to immuno-compromised status and center and then were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide (n = 149), or daily enteral whey protein (n = 144) and intravenous saline for up to 28 days of intensive care unit stay. The primary end point was time to development of nosocomial sepsis/infection. The analysis was intention to treat. Measurements and Main Results: There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection/sepsis (median whey protein 13.2 days vs. zinc, selenium, glutamine, and intravenous metoclopramide 12.1 days; p = .29 by log-rank test) or the rate of nosocomial infection/sepsis (4.83/100 days whey protein vs. 4.99/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection/sepsis with zinc, selenium, glutamine, and intravenous metoclopramide in this immunocompromised group (6.09/100 days whey protein vs. 1.57/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .011). Conclusion: Compared with whey protein supplementation, zinc, selenium, glutamine, and intravenous metoclopramide conferred no advantage in the immune-competent population. Further evaluation of zinc, selenium, glutamine, and intravenous metoclopramide supplementation is warranted in the immunocompromised long-term pediatric intensive care unit patient. (Pediatr Crit Care Med 2012; 13: 165-173) C1 [Carcillo, Joseph A.] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [Dean, J. Michael; Holubkov, Richard; Berger, John] Univ Utah, Salt Lake City, UT USA. [Berger, John] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Meert, Kathleen L.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Anand, K. J. S.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Zimmerman, Jerry] Seattle Childrens Hosp, Seattle, WA USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Holubkov, Richard] Mattel Childrens Hosp, Los Angeles, CA USA. [Willson, Douglas F.] Univ Virginia, Childrens Hosp, Charlottesville, VA USA. [Nicholson, Carol] NICHHD, Bethesda, MD 20892 USA. RP Carcillo, JA (reprint author), UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. EM carcilloja@ccm.upmc.edu RI Andrade, Hugo/M-6631-2013; OI Andrade, Hugo/0000-0001-6781-6125; Anand, Kanwaljeet/0000-0001-6498-1483 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS) [U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, U01HD049934] FX Supported, in part, by the following cooperative agreements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services (DHHS; U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, and U01HD049934). NR 30 TC 32 Z9 34 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1529-7535 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD MAR PY 2012 VL 13 IS 2 BP 165 EP 173 DI 10.1097/PCC.0b013e31823896ae PG 9 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA 904WR UT WOS:000301230100019 PM 22079954 ER PT J AU Tykvart, J Sacha, P Barinka, C Knedlik, T Starkova, J Lubkowski, J Konvalinka, J AF Tykvart, J. Sacha, P. Barinka, C. Knedlik, T. Starkova, J. Lubkowski, J. Konvalinka, J. TI Efficient and versatile one-step affinity purification of in vivo biotinylated proteins: Expression, characterization and structure analysis of recombinant human glutamate carboxypeptidase II SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Affinity purification; Biotin acceptor peptide; Recombinant protein expression; Biotin-protein ligase (BirA); Co-localization; PSMA ID LINKED ACIDIC DIPEPTIDASE; MEMBRANE ANTIGEN PSMA; SUBSTRATE-SPECIFICITY; MONOMERIC STREPTAVIDIN; ENZYMATIC SYNTHESIS; PROSTATE-CANCER; TRANSGENIC MICE; STREP-TAG; SITE; HOLOTRANSCARBOXYLASE AB Affinity purification is a useful approach for purification of recombinant proteins. Eukaryotic expression systems have become more frequently used at the expense of prokaryotic systems since they afford recombinant eukaryotic proteins with post-translational modifications similar or identical to the native ones. Here, we present a one-step affinity purification set-up suitable for the purification of secreted proteins. The set-up is based on the interaction between biotin and mutated streptavidin. Drosophila Schneider 2 cells are chosen as the expression host, and a biotin acceptor peptide is used as an affinity tag. This tag is biotinylated by Escherichia coli biotin-protein ligase in vivo. We determined that localization of the ligase within the ER led to the most effective in vivo biotinylation of the secreted proteins. We optimized a protocol for large-scale expression and purification of AviTEV-tagged recombinant human glutamate carboxypeptidase II (Avi-GCPII) with milligram yields per liter of culture. We also determined the 3D structure of Avi-GCPII by X-ray crystallography and compared the enzymatic characteristics of the protein to those of its non-tagged variant. These experiments confirmed that AviTEV tag does not affect the biophysical properties of its fused partner. Purification approach, developed here, provides not only a sufficient amount of highly homogenous protein but also specifically and effectively biotinylates a target protein and thus enables its subsequent visualization or immobilization. (C) 2011 Elsevier Inc. All rights reserved. C1 [Konvalinka, J.] ASCR, Inst Organ Chem & Biochem, Vvi, Gilead Sci & IOCB Res Ctr, Prague 16610 6, Czech Republic. [Tykvart, J.; Sacha, P.; Knedlik, T.; Konvalinka, J.] Charles Univ Prague, Dept Biochem, Fac Nat Sci, Prague 2, Czech Republic. [Barinka, C.] Acad Sci Czech Republic, Inst Biotechnol, Prague 4, Czech Republic. [Lubkowski, J.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. RP Konvalinka, J (reprint author), ASCR, Inst Organ Chem & Biochem, Vvi, Gilead Sci & IOCB Res Ctr, Flemingovo 2, Prague 16610 6, Czech Republic. EM jan.konvalinka@uochb.cas.cz RI Tykvart, Jan/G-6770-2014; Konvalinka, Jan/G-7518-2014; Knedlik, Tomas/G-7955-2014; Sacha, Pavel/G-9729-2014; Barinka, Cyril/G-9803-2014; OI Tykvart, Jan/0000-0002-6938-1513; Sacha, Pavel/0000-0001-6198-9826; Konvalinka, Jan/0000-0003-0695-9266 FU Ministry of Education of Czech Republic [Z4 055 905, 1M0508, LC 512, 1978]; IBT [AV0Z50520701]; Guilford Pharmaceuticals; NIH; National Cancer Institute; Center for Cancer Research; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng38] FX This work (performed under the research project Z4 055 905) was supported by Grants 1M0508 and LC 512 from the Ministry of Education of Czech Republic, EMBO Installation Grant #1978 (C.B), the IBT institutional support (AV0Z50520701), by research support from Guilford Pharmaceuticals, and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (J.L.). Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng38. NR 43 TC 13 Z9 14 U1 0 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2012 VL 82 IS 1 BP 106 EP 115 DI 10.1016/j.pep.2011.11.016 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 900WZ UT WOS:000300923700016 PM 22178733 ER PT J AU Austin, BP Waugh, DS AF Austin, Brian P. Waugh, David S. TI Isolation of Metarhizium anisopliae carboxypeptidase A with native disulfide bonds from the cytosol of Escherichia coli BL21(DE3) SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE MeCPA; Carboxypeptidase; Maltose-binding protein; Polyhistidine tag; Thermolysin; His-tag; DsbC; DsbA; Protein disulfide isomerase; trxB; gor ID MALTOSE-BINDING PROTEIN; HPV E6 ONCOPROTEIN; AFFINITY TAGS; SUBSTRATE-SPECIFICITY; RECOMBINANT PROTEINS; HEXAHISTIDINE-TAG; INCLUSION-BODIES; FUSION PROTEINS; HIS-TAG; EXPRESSION AB The carboxypeptidase A enzyme from Metarhizium anisopliae (MeCPA) has broader specificity than the mammalian A-type carboxypeptidases, making it a more useful reagent for the removal of short affinity tags and disordered residues from the C-termini of recombinant proteins. When secreted from baculovirus-infected insect cells, the yield of pure MeCPA was 0.25 mg per liter of conditioned medium. Here, we describe a procedure for the production of MeCPA in the cytosol of Escherichia coli that yields approximately 0.5 mg of pure enzyme per liter of cell culture. The bacterial system is much easier to scale up and far less expensive than the insect cell system. The expression strategy entails maintaining the proMeCPA zymogen in a soluble state by fusing it to the C-terminus of maltose-binding protein (MBP) while simultaneously overproducing the protein disulfide isomerase DsbC in the cytosol from a separate plasmid. Unexpectedly, we found that the yield of active and properly oxidized MeCPA was highest when coexpressed with DsbC in BL21(DE3) cells that do not also contain mutations in the trxB and gor genes. Moreover, the formation of active MeCPA was only partially dependent on the disulfide-isomerase activity of DsbC. Intriguingly, we observed that most of the active MeCPA was generated after cell lysis and amylose affinity purification of the MBP-proMeCPA fusion protein, during the time that the partially purified protein was held overnight at 4 degrees C prior to activation with thermolysin. Following removal of the MBP-propeptide by thermolysin digestion, active MeCPA (with a C-terminal polyhistidine tag) was purified to homogeneity by immobilized metal affinity chromatography (IMAC), ion exchange chromatography and gel filtration. Published by Elsevier Inc. C1 [Austin, Brian P.; Waugh, David S.] NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. EM waughd@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Dr. Joseph E. Tropea for the suggestion to try co-expression of the MeCPA fusion protein and DsbC in BL-21(DE3) cells lacking the trxB and gor mutations. This project was supported by the Intramural Research Program of the National Institutes of Health, 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 the mention of trade names, commercial products or organizations imply endorsement by the US government. We thank the Biophysics Resource in the Structural Biophysics Laboratory, NCl-Frederick, for use of the LC/ESMS instrument. NR 38 TC 7 Z9 7 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2012 VL 82 IS 1 BP 116 EP 124 DI 10.1016/j.pep.2011.11.015 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 900WZ UT WOS:000300923700017 PM 22197595 ER PT J AU Amos, A Greaves, L Nichter, M Bloch, M AF Amos, Amanda Greaves, Lorraine Nichter, Mimi Bloch, Michele TI Women and tobacco: a call for including gender in tobacco control research, policy and practice SO TOBACCO CONTROL LA English DT Article ID SECONDHAND SMOKE EXPOSURE; COLLEGE-STUDENTS; SEX-DIFFERENCES; YOUNG-PEOPLE; PREGNANCY; CESSATION; NICOTINE; HEALTH; GIRLS; COUNTRIES AB Objectives Female smoking is predicted to double between 2005 and 2025. There have been numerous calls for action on women's tobacco use over the past two decades. In the present work, evidence about female tobacco use, progress, challenges and ways forward for developing gendered tobacco control is reviewed. Methods Literature on girls, women and tobacco was reviewed to identify trends and determinants of tobacco use and exposure, the application of gender analysis, tobacco marketing, the impact of tobacco control on girls and women and ways to address these issues particularly in low-income and middle-income countries. Results Global female tobacco use is increasingly complex, involving diverse products and factors including tobacco marketing, globalisation and changes in women's status. In high-income countries female smoking is declining but is increasingly concentrated among disadvantaged women. In low-income and middle-income countries the pattern is more complex; in several regions the gap between girls' and boys' smoking is narrow. Gendered analyses and approaches to tobacco control are uncommon, especially in low-income and middle-income countries. Conclusions Tobacco control has remained largely gender blind, with little recognition of the importance of understanding the context and challenges of girl's and women's smoking and secondhand smoke exposure. There has been little integration of gender considerations in research, policy and programmes. The present work makes a case for gender and diversity analyses in tobacco control to reflect and identify intersecting factors affecting women's tobacco use. This will help animate the WHO Framework Convention on Tobacco Control's concern for gender specificity and women's leadership, and reduce the impact of tobacco on women. C1 [Amos, Amanda] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, UK Ctr Tobacco Control Studies, Edinburgh EH8 9AG, Midlothian, Scotland. [Greaves, Lorraine] Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, British Columbia Ctr Excellence Womens Hlth, Vancouver, BC, Canada. [Nichter, Mimi] Univ Arizona, Sch Anthropol, Tucson, AZ USA. [Bloch, Michele] US Natl Canc Inst, Tobacco Control Res Branch, Rockville, MD USA. RP Amos, A (reprint author), Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, UK Ctr Tobacco Control Studies, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. EM amanda.amos@ed.ac.uk FU UKCTCS, a UKCRC Public Health Research Centre of Excellence; British Heart Foundation; Cancer Research UK; Economic and Social Research Council; Medical Research Council; Department of Health under UK Clinical Research Collaboration FX We thank Irina Morozova, Svitlana Sydorova, Magdalena Petryniak, Andriy Skipalskyi and Martina Potschke-Langer for providing pictures of tobacco promotions and product. Amanda Amos is part funded by the UKCTCS, a UKCRC Public Health Research Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the Department of Health, under the auspices of the UK Clinical Research Collaboration is gratefully acknowledged. NR 105 TC 64 Z9 65 U1 1 U2 19 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 EI 1468-3318 J9 TOB CONTROL JI Tob. Control PD MAR PY 2012 VL 21 IS 2 BP 236 EP 243 DI 10.1136/tobaccocontrol-2011-050280 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 897CG UT WOS:000300618200038 PM 22166266 ER PT J AU Tucker, JD Chen, AH Glass, RI AF Tucker, Joseph D. Chen, Alice H. Glass, Roger I. TI Foreign Language Assessment and Training in U.S. Medical Education Is a Must SO ACADEMIC MEDICINE LA English DT Letter C1 [Tucker, Joseph D.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Chen, Alice H.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA USA. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD USA. RP Tucker, JD (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA. EM joseph.tucker@post.harvard.edu RI liu, jing/D-9482-2012 NR 3 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD MAR PY 2012 VL 87 IS 3 BP 257 EP 257 DI 10.1097/ACM.0b013e3182447096 PG 1 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 901TK UT WOS:000300989500007 PM 22373612 ER PT J AU Ray, LA Barr, CS Blendy, JA Oslin, D Goldman, D Anton, RF AF Ray, Lara A. Barr, Christina S. Blendy, Julie A. Oslin, David Goldman, David Anton, Raymond F. TI The Role of the Asn40Asp Polymorphism of the Mu Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE OPRM1; Pharmacogenetics; Genetics; Alcoholism; Naltrexone; Asn40Asp ID SINGLE-NUCLEOTIDE POLYMORPHISM; HPA-AXIS ACTIVATION; FUNCTIONAL POLYMORPHISM; SUBSTANCE DEPENDENCE; A118G POLYMORPHISM; HEAVY DRINKERS; DRUG-DEPENDENCE; SUBJECTIVE RESPONSES; NALTREXONE TREATMENT; NATURAL-ENVIRONMENT AB The endogenous opioid system has been implicated in the pathophysiology of alcoholism as it modulates the neurobehavioral effects of alcohol. A variant in the mu opioid receptor gene (OPRM1), the Asn40Asp polymorphism, has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: (i) genetic association studies; (ii) behavioral studies of alcoholism; (iii) neuroimaging studies; (iv) pharmacogenetic studies and clinical trials; and (v) preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response. C1 [Ray, Lara A.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Barr, Christina S.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD USA. [Blendy, Julie A.] Univ Penn, Dept Pharmacol, Sch Med, Philadelphia, PA 19104 USA. [Goldman, David] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Anton, Raymond F.] Med Univ S Carolina, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. RP Ray, LA (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,POB 951563, Los Angeles, CA 90095 USA. EM lararay@psych.ucla.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-09, Z01 AA000301-10, ZIA AA000306-04]; NIAAA NIH HHS [K05 AA017435, R01 AA017633] NR 84 TC 36 Z9 37 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2012 VL 36 IS 3 BP 385 EP 394 DI 10.1111/j.1530-0277.2011.01633.x PG 10 WC Substance Abuse SC Substance Abuse GA 897PC UT WOS:000300663900001 PM 21895723 ER PT J AU Litten, RZ Fertig, JB Falk, DE Ryan, ML Mattson, ME Collins, JF Murtaugh, C Ciraulo, D Green, AI Johnson, B Pettinati, H Swift, R Afshar, M Brunette, MF Tiouririne, NAD Kampman, K Stout, R AF Litten, Raye Z. Fertig, Joanne B. Falk, Daniel E. Ryan, Megan L. Mattson, Margaret E. Collins, Joseph F. Murtaugh, Cristin Ciraulo, Domenic Green, Alan I. Johnson, Bankole Pettinati, Helen Swift, Robert Afshar, Maryam Brunette, Mary F. Tiouririne, Nassima A. -D. Kampman, Kyle Stout, Robert CA NCIG 001 Study Grp TI A Double-Blind, Placebo-Controlled Trial to Assess the Efficacy of Quetiapine Fumarate XR in Very Heavy-Drinking Alcohol-Dependent Patients SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Dependence; Quetiapine; Seroquel (R); Medications Development; Alcohol Use Disorder ID RANDOMIZED CONTROLLED-TRIAL; USE DISORDERS; SCALE; SCHIZOPHRENIA; ARIPIPRAZOLE; CONSUMPTION; DEPRESSION; OLANZAPINE; SLEEP; QUESTIONNAIRE AB Background: Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol-dependent population of very heavy drinkers. Methods: In this double-blind, placebo-controlled trial, 224 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization. Results: No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy-drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%). Conclusions: This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy-drinking alcohol-dependent patients. C1 [Litten, Raye Z.; Fertig, Joanne B.; Falk, Daniel E.; Ryan, Megan L.] NIAAA, Div Treatment & Recovery Res, Bethesda, MD 20892 USA. [Mattson, Margaret E.] SAMHSA, Ctr Behav Hlth Stat & Qual, Rockville, MD USA. [Collins, Joseph F.; Murtaugh, Cristin] VA Maryland Hlth Care Syst, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [Ciraulo, Domenic; Afshar, Maryam] Boston Univ, Sch Med, Boston, MA 02118 USA. [Green, Alan I.] Dartmouth Med Sch DHMC, Dept Psychiat, Lebanon, NH USA. [Johnson, Bankole] Univ Virginia, Dept Psychiat Med, Charlottesville, VA USA. [Pettinati, Helen; Kampman, Kyle] Univ Penn, Treatment Res Ctr, Philadelphia, PA 19104 USA. Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Brunette, Mary F.] Dartmouth Med Sch, Psychopharmacol Res Grp, Concord, NH USA. [Tiouririne, Nassima A. -D.] Univ Virginia, Ctr Addict Res & Educ, Richmond, VA USA. Decis Sci Inst PIRE, Pawtucket, RI USA. RP Falk, DE (reprint author), NIAAA, Div Treatment & Recovery Res, 5635 Fishers Lane,Room 2040, Bethesda, MD 20892 USA. EM falkde@mail.nih.gov RI Leggio, Lorenzo/M-2972-2016; OI Ciraulo, Domenic/0000-0001-7706-8765 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services; AstraZeneca FX This research was supported by the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services. The Veterans Affairs Cooperative Studies Program (VACSP), Perry Point, MD, was the Coordinating Center; this research was supported in part by the Investigator-Sponsored Study Program of AstraZeneca. NR 58 TC 34 Z9 34 U1 3 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2012 VL 36 IS 3 BP 406 EP 416 DI 10.1111/j.1530-0277.2011.01649.x PG 11 WC Substance Abuse SC Substance Abuse GA 897PC UT WOS:000300663900004 PM 21950727 ER PT J AU Agrawal, A Freedman, ND Cheng, YC Lin, P Shaffer, JR Sun, Q Taylor, K Yaspan, B Cole, JW Cornelis, MC DeSensi, RS Fitzpatrick, A Heiss, G Kang, JH O'Connell, J Bennett, S Bookman, E Bucholz, KK Caporaso, N Crout, R Dick, DM Edenberg, HJ Goate, A Hesselbrock, V Kittner, S Kramer, J Nurnberger, JI Qi, L Rice, JP Schuckit, M van Dam, RM Boerwinkle, E Hu, F Levy, S Marazita, M Mitchell, BD Pasquale, LR Bierut, LJ AF Agrawal, Arpana Freedman, Neal D. Cheng, Yu-Ching Lin, Peng Shaffer, John R. Sun, Qi Taylor, Kira Yaspan, Brian Cole, John W. Cornelis, Marilyn C. DeSensi, Rebecca S. Fitzpatrick, Annette Heiss, Gerardo Kang, Jae H. O'Connell, Jeffrey Bennett, Siiri Bookman, Ebony Bucholz, Kathleen K. Caporaso, Neil Crout, Richard Dick, Danielle M. Edenberg, Howard J. Goate, Alison Hesselbrock, Victor Kittner, Steven Kramer, John Nurnberger, John I., Jr. Qi, Lu Rice, John P. Schuckit, Marc van Dam, Rob M. Boerwinkle, Eric Hu, Frank Levy, Steven Marazita, Mary Mitchell, Braxton D. Pasquale, Louis R. Bierut, Laura J. CA GENEVA Consortium TI Measuring alcohol consumption for genomic meta-analyses of alcohol intake: opportunities and challenges SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID U-SHAPED CURVE; WIDE ASSOCIATION; GENETIC INFLUENCES; ENVIRONMENTAL-INFLUENCES; GENOMEWIDE ASSOCIATION; DIETARY PATTERNS; SMOKING-BEHAVIOR; CANCER RISK; DEPENDENCE; MORTALITY AB Whereas moderate drinking may have health benefits, excessive alcohol consumption causes many important acute and chronic diseases and is the third leading contributor to preventable death in the United States. Twin studies suggest that alcohol-consumption patterns are heritable (50%); however, multiple genetic variants of modest effect size are likely to contribute to this heritable variation. Genome-wide association studies provide a tool for discovering genetic loci that contribute to variations in alcohol consumption. Opportunities exist to identify susceptibility loci with modest effect by meta-analyzing together multiple studies. However, existing studies assessed many different aspects of alcohol use, such as typical compared with heavy drinking, and these different assessments can be difficult to reconcile. In addition, many studies lack the ability to distinguish between lifetime and recent abstention or to assess the pattern of drinking during the week, and a variety of such concerns surround the appropriateness of developing a common summary measure of alcohol intake. Combining such measures of alcohol intake can cause heterogeneity and exposure misclassification, cause a reduction in power, and affect the magnitude of genetic association signals. In this review, we discuss the challenges associated with harmonizing alcohol-consumption data from studies with widely different assessment instruments, with a particular focus on large-scale genetic studies. Am J Clin Nutr 2012; 95: 539-47. C1 [Agrawal, Arpana] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Freedman, Neal D.; Caporaso, Neil] NCI, Bethesda, MD 20892 USA. [Cheng, Yu-Ching; Cole, John W.; O'Connell, Jeffrey; Kittner, Steven; Mitchell, Braxton D.] Univ Maryland, Bethesda, MD USA. [Shaffer, John R.; DeSensi, Rebecca S.; Marazita, Mary] Univ Pittsburgh, Pittsburgh, PA USA. [Sun, Qi; Cornelis, Marilyn C.; Qi, Lu; van Dam, Rob M.; Hu, Frank] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Kang, Jae H.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Taylor, Kira] Univ Louisville, Louisville, KY 40292 USA. [Heiss, Gerardo] Univ N Carolina, Chapel Hill, NC USA. [Yaspan, Brian] Vanderbilt Univ, Nashville, TN USA. [Fitzpatrick, Annette; Bennett, Siiri] Univ Washington, GENEVA Coordinating Ctr, Seattle, WA 98195 USA. [Fitzpatrick, Annette; Bennett, Siiri; Bookman, Ebony] NHGRI, Morrisville, NC USA. [Crout, Richard] W Virginia Univ, Morgantown, WV 26506 USA. [Dick, Danielle M.] Virginia Commonwealth Univ, Richmond, VA USA. [Edenberg, Howard J.; Nurnberger, John I., Jr.] Indiana Univ, Indianapolis, IN 46204 USA. [Hesselbrock, Victor] Univ Connecticut, Farmington, CT USA. [Kramer, John; Levy, Steven] Univ Iowa, Iowa City, IA USA. [Schuckit, Marc] Univ Calif San Diego, San Diego, CA 92103 USA. [Boerwinkle, Eric] Univ Texas Houston, Houston, TX USA. [Pasquale, Louis R.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Agrawal, A (reprint author), Washington Univ, Sch Med, Dept Psychiat, 660 S Euclid,CB 8134, St Louis, MO 63110 USA. EM arpana@wustl.edu RI van Dam, Rob/F-9674-2010; Lin, P/G-7702-2014; Freedman, Neal/B-9741-2015; OI van Dam, Rob/0000-0002-7354-8734; Freedman, Neal/0000-0003-0074-1098; Nurnberger, John/0000-0002-7674-1767; Edenberg, Howard/0000-0003-0344-9690; Mitchell, Braxton/0000-0003-4920-4744 FU NIH Genes, Environment and Health Initiative (GEI) [U01 HG004422]; Gene, Environment Association Studies (GENEVA) under GEI; Johns Hopkins University Center for Inherited Disease Research by NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH [HHSN268200782096C]; ABMRF/Foundation for Alcohol Research; Boston Obesity Nutrition Research Center [DK46200, U01HG004399, NIH R01 HL71981, K99HL098459]; American Heart Association Scientist Development Award; Canadian Institutes of Health Research (MCC); National Institutes of Dental and Craniofacial Research (NIDCR) as part of the trans-NIH GEI [U01-DE018903]; NIDCR [R01-DE 014899, R01-DE09551, R01-DE12101]; Iowa Fluoride Study; Iowa Bone Development Study; NIDCR through CIDR's NIH; NHLBI; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; Office of Research and Development; Medical Research Service and the Baltimore Geriatrics Research, Education and Clinical Center of the Department of Veterans Affairs; National Institute of Neurological Disorders and Stroke; NIH Office of Research on Women's Health [R01 NS45012, U01 NS069208-01]; National Human Genome Research Institute [U01 HG004436]; NHGRI [U01HG004728, NEI R01EY015473]; NIH GEI [U01HG04424]; [K02DA21237]; [DA23668]; [T32 AG000262] FX The Study of Addiction: Genetics and Environment (SAGE): supported by the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene, Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning and with the general study coordination was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for the collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). LJB was supported by K02DA21237. AA receives support from the DA23668 and ABMRF/Foundation for Alcohol Research. NHS and HPFS: the Pilot and Feasibility program were sponsored by the Boston Obesity Nutrition Research Center (DK46200; QS), U01HG004399 (FH), NIH R01 HL71981 and K99HL098459 (QS), American Heart Association Scientist Development Award (LQ), and the Canadian Institutes of Health Research (MCC). Dental Caries: Study: "Dental Caries: Whole Genome Association and Gene Environment Studies" 1-U01-DE018903, PI Marazita. (Included in the alcohol cross-study were the Levy (IOWA) and Marazita (PITT) study populations so the acknowledgements below reflect only those studies.) Funding support for the GWAS was provided by the National Institutes of Dental and Craniofacial Research (NIDCR) as part of the trans-NIH GEI (U01-DE018903). Data and samples were provided by the Center for Oral Health Research in Appalachia (a collaboration of the University of Pittsburgh and West Virginia University funded by NIDCR R01-DE 014899) and the Iowa Fluoride Study and the Iowa Bone Development Study, funded by NIDCR R01-DE09551 and R01-DE12101, respectively. Genotyping was done by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to The Johns Hopkins University (contract number HHSN268200782096C). Funds for this project's genotyping were provided by the NIDCR through CIDR's NIH contract. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01-HG004446). Atherosclerosis Risk in Communities Study: supported by NHLBI Cardiovascular Epidemiology Training Grant (UNC) (National Research Service Award) to KT; carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C.; GEOS: supported in part by the Office of Research and Development, Medical Research Service and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs (SK and JWC); the National Institute of Neurological Disorders and Stroke and the NIH Office of Research on Women's Health (R01 NS4512 and U01 NS069208-01) (SK); the National Human Genome Research Institute (U01 HG004436) (BDM, SK, and JO); and grant T32 AG000262 (Y-CC). GLAUGEN: supported by grants NHGRI U01HG004728 and NEI R01EY015473 to LRP (Research to Prevent Blindness Physician Scientist Award). Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424). The GENEVA Coordinating Center (U01HG004446) provided assistance with genotype cleaning. NR 74 TC 16 Z9 16 U1 2 U2 14 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2012 VL 95 IS 3 BP 539 EP 547 DI 10.3945/ajcn.111.015545 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 897HK UT WOS:000300638700003 PM 22301922 ER PT J AU de Souza, RJ Bray, GA Carey, VJ Hall, KD LeBoff, MS Loria, CM Laranjo, NM Sacks, FM Smith, SR AF de Souza, Russell J. Bray, George A. Carey, Vincent J. Hall, Kevin D. LeBoff, Meryl S. Loria, Catherine M. Laranjo, Nancy M. Sacks, Frank M. Smith, Steven R. TI Effects of 4 weight-loss diets differing in fat, protein, and carbohydrate on fat mass, lean mass, visceral adipose tissue, and hepatic fat: results from the POUNDS LOST trial SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; BODY-COMPOSITION; RISK-FACTORS; ENERGY-EXPENDITURE; OBESE WOMEN; CARDIOVASCULAR-DISEASE; LIPID CONCENTRATIONS; COMPUTED-TOMOGRAPHY; OVERWEIGHT SUBJECTS; METABOLIC SYNDROME AB Background: Weight loss reduces body fat and lean mass, but whether these changes are influenced by macronutrient composition of the diet is unclear. Objective: We determined whether energy-reduced diets that emphasize fat, protein, or carbohydrate differentially reduce total, visceral, or hepatic fat or preserve lean mass. Design: In a subset of participants in a randomized trial of 4 weight-loss diets, body fat and lean mass (n = 424; by using dual-energy X-ray absorptiometry) and abdominal and hepatic fat (n = 165; by using computed tomography) were measured after 6 mo and 2 y. Changes from baseline were compared between assigned amounts of protein (25% compared with 15%) and fat (40% compared with 20%) and across 4 carbohydrate amounts (35% through 65%). Results: At 6 mo, participants lost a mean (+/- SEM) of 4.2 +/- 0.3 kg (12.4%) fat and 2.1 +/- 0.3 kg (3.5%) lean mass (both P < 0.0001 compared with baseline values), with no differences between 25% and 15% protein (P > 0.10), 40% and 20% fat (P > 0.34), or 65% and 35% carbohydrate (P >= 0.27). Participants lost 2.3 +/- 0.2 kg (13.8%) abdominal fat: 1.5 +/- 0.2 kg (13.6%) subcutaneous fat and 0.9 +/- 0.1 kg (16.1%) visceral fat (all P, 0.0001 compared with baseline values), with no differences between the diets (P > 0.29). Women lost more visceral fat than did men relative to total-body fat loss. Participants regained; 40% of these losses by 2 y, with no differences between diets (P >= 0.23). Weight loss reduced hepatic fat, but there were no differences between groups (P >= 0.28). Dietary goals were not fully met; self-reported contrasts were closer to 2% protein, 8% fat, and 14% carbohydrate at 6 mo and 1%, 7%, and 10%, respectively, at 2 y. Conclusion: Participants lost more fat than lean mass after consumption of all diets, with no differences in changes in body composition, abdominal fat, or hepatic fat between assigned macronutrient amounts. This trial was registered at clinicaltrials.gov as NCT00072995. Am J Clin Nutr 2012;95:614-25. C1 [de Souza, Russell J.; Sacks, Frank M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Bray, George A.; Smith, Steven R.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Carey, Vincent J.; Laranjo, Nancy M.; Sacks, Frank M.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [LeBoff, Meryl S.] Brigham & Womens Hosp, Div Endocrine, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Hall, Kevin D.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. [Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. RP Bray, GA (reprint author), 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM brayga@pbrc.edu OI de Souza, Russell/0000-0001-8945-513X FU National Heart, Lung, and Blood Institute [HL073286]; General Clinical Research Center, NIH [RR-02635] FX Supported by the National Heart, Lung, and Blood Institute (grant HL073286) and the General Clinical Research Center, NIH (grant RR-02635). NR 62 TC 57 Z9 57 U1 2 U2 15 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2012 VL 95 IS 3 BP 614 EP 625 DI 10.3945/ajcn.111.026328 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 897HK UT WOS:000300638700013 PM 22258266 ER PT J AU Arpadi, SM McMahon, DJ Abrams, EJ Bamji, M Purswani, M Engelson, ES Horlick, M Shane, E AF Arpadi, Stephen M. McMahon, Donald J. Abrams, Elaine J. Bamji, Mahrukh Purswani, Murli Engelson, Ellen S. Horlick, Mary Shane, Elizabeth TI Effect of supplementation with cholecalciferol and calcium on 2-y bone mass accrual in HIV-infected children and adolescents: a randomized clinical trial SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID VITAMIN-D DEFICIENCY; ACTIVE ANTIRETROVIRAL THERAPY; MULTIPLE HEALTH OUTCOMES; B LIGAND RANKL; MINERAL DENSITY; PROTEASE INHIBITORS; FOREARM FRACTURES; 25-HYDROXYVITAMIN-D LEVELS; SERUM 25-HYDROXYVITAMIN-D; PUBERTAL CHANGES AB Background: Skeletal abnormalities have been reported in HIV-infected children and adolescents. Although the etiology is not well understood, vitamin D deficiency may be involved. Objective: The study objective was to evaluate the effect of vitamin D and calcium supplementation on bone mass accrual in HIV-infected youth. Design: Perinatally HIV-infected children were randomly assigned to receive vitamin D (100,000 IU cholecalciferol given every 2 mo) and calcium (1 g/d) (supplemented group) or double placebo (placebo group) for 2 y. The total-body bone mineral content (TBBMC), total-body bone mineral density (TBBMD), spine bone mineral content (SBMC), and spine bone mineral density (SBMD) were assessed by using dual-energy X-ray absorptiometry at baseline and at 2 annual follow-up visits. Results: Fifty-nine participants, aged 6-16 y, were randomly assigned to either the supplemented (n = 30) or the placebo (n = 29) group. At enrollment, supplemented and placebo groups did not differ with respect to age, sex, dietary intakes of vitamin D and calcium, mean baseline serum 25-hydroxyvitamin D [25(OH) D] concentration, TBBMC, TBBMD, SBMC, or SBMD. Significant increases in serum 25(OH) D were observed in the supplemented group but not in the placebo group. TBBMC, TBBMD, SBMC, and SBMD increased significantly at 1 and 2 y in both groups. No between-group differences were observed at any time before or after adjustment for stage of sexual maturation by mixed linear model analysis. Conclusion: One gram of calcium per day and oral cholecalciferol at a dosage of 100,000 IU every 2 mo administered to HIV-infected children and adolescents did not affect bone mass accrual despite significant increases in serum 25(OH) D concentrations. This trial was registered at clinicaltrials.gov as NCT00724178. Am J Clin Nutr 2012;95:678-85. C1 [Arpadi, Stephen M.] Columbia Univ, Coll Phys & Surg, Sergievsky Ctr, New York, NY USA. [Arpadi, Stephen M.; Abrams, Elaine J.] Columbia Univ, Mailman Sch Publ Hlth, Dept Pediat, New York, NY USA. [McMahon, Donald J.; Engelson, Ellen S.; Shane, Elizabeth] Columbia Univ, Mailman Sch Publ Hlth, Dept Med, New York, NY USA. [Arpadi, Stephen M.; Abrams, Elaine J.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Abrams, Elaine J.] Columbia Univ Coll Phys & Surg, Harlem Hosp Ctr, New York, NY 10032 USA. [Arpadi, Stephen M.; Engelson, Ellen S.] St Lukes Roosevelt Hosp, New York, NY USA. [Bamji, Mahrukh] Metropolitan Hosp Ctr, New York, NY 10029 USA. [Purswani, Murli] Bronx Lebanon Hosp Ctr, Bronx, NY 10456 USA. [Horlick, Mary] NIDDK, Bethesda, MD USA. RP Arpadi, SM (reprint author), Coll Phys & Surg, GH Sergievsky Ctr, PH Room 19-114,630 W 168th St, New York, NY 10032 USA. EM sma2@columbia.edu RI Ghartouchent, malek/B-9088-2012 FU NIH [DK63666, RR00645] FX Supported by the NIH (grants DK63666 and RR00645). NR 63 TC 17 Z9 17 U1 0 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2012 VL 95 IS 3 BP 678 EP 685 DI 10.3945/ajcn.111.024786 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 897HK UT WOS:000300638700020 PM 22258265 ER PT J AU Zhang, XH Spiegelman, D Baglietto, L Bernstein, L Boggs, DA van den Brandt, PA Buring, JE Gapstur, SM Giles, GG Giovannucci, E Goodman, G Hankinson, SE Helzlsouer, KJ Horn-Ross, PL Inoue, M Jung, S Khudyakov, P Larsson, SC Lof, M McCullough, ML Miller, AB Neuhouser, ML Palmer, JR Park, Y Robien, K Rohan, TE Ross, JA Schouten, LJ Shikany, JM Tsugane, S Visvanathan, K Weiderpass, E Wolk, A Willett, WC Zhang, SMM Ziegler, RG Smith-Warner, SA AF Zhang, Xuehong Spiegelman, Donna Baglietto, Laura Bernstein, Leslie Boggs, Deborah A. van den Brandt, Piet A. Buring, Julie E. Gapstur, Susan M. Giles, Graham G. Giovannucci, Edward Goodman, Gary Hankinson, Susan E. Helzlsouer, Kathy J. Horn-Ross, Pamela L. Inoue, Manami Jung, Seungyoun Khudyakov, Polyna Larsson, Susanna C. Lof, Marie McCullough, Marjorie L. Miller, Anthony B. Neuhouser, Marian L. Palmer, Julie R. Park, Yikyung Robien, Kim Rohan, Thomas E. Ross, Julie A. Schouten, Leo J. Shikany, James M. Tsugane, Shoichiro Visvanathan, Kala Weiderpass, Elisabete Wolk, Alicja Willett, Walter C. Zhang, Shumin M. Ziegler, Regina G. Smith-Warner, Stephanie A. TI Carotenoid intakes and risk of breast cancer defined by estrogen receptor and progesterone receptor status: a pooled analysis of 18 prospective cohort studies SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; BASE-LINE CHARACTERISTICS; BLACK WOMENS HEALTH; VITAMIN-E; HORMONE-RECEPTOR; BETA-CAROTENE; DIETARY CAROTENOIDS; ANTIOXIDANT INTAKE; REGRESSION-MODELS; PROPENSITY SCORES AB Background: Epidemiologic studies examining associations between carotenoid intakes and risk of breast cancer by estrogen receptor (ER) and progesterone receptor (PR) status are limited. Objective: We investigated these associations in a pooled analysis of 18 cohort studies. Design: Of 1,028,438 participants followed for a maximum follow-up of 26 y across studies, 33,380 incident invasive breast cancers were identified. Study-specific RRs and 95% CIs were estimated by using Cox proportional hazards regression and then pooled by using a random-effects model. Results: alpha-Carotene, beta-carotene, and lutein/zeaxanthin intakes were inversely associated with the risk of ER-negative (ER-) breast cancer (pooled multivariable RRs of the comparison between the highest and lowest quintiles): alpha-carotene (0.87; 95% CI: 0.78, 0.97), beta-carotene (0.84; 95% CI: 0.77, 0.93), and lutein/zeaxanthin (0.87; 95% CI: 0.79, 0.95). These variables were not inversely associated with the risk of ER-positive (ER+) breast cancer (pooled multivariable RRs for the same comparison): a-carotene (1.04; 95% CI: 0.99, 1.09), beta-carotene (1.04; 95% CI: 0.98, 1.10), and lutein/zeaxanthin (1.00; 95% CI: 0.93, 1.07). Although the pooled RRs for quintile 5 for beta-cryptoxanthin were not significant, inverse trends were observed for ER- and ER+ breast cancer (P-trend <= 0.05). Nonsignificant associations were observed for lycopene intake. The associations were largely not appreciably modified by several breast cancer risk factors. Nonsignificant associations were observed for PR-positive and PR-negative breast cancer. Conclusions: Intakes of alpha-carotene, beta-carotene, and lutein/zeaxanthin were inversely associated with risk of ER-, but not ER+, breast cancer. However, the results need to be interpreted with caution because it is unclear whether the observed association is real or due to other constituents in the same food sources. Am J Clin Nutr 2012;95:713-25. C1 [Zhang, Xuehong] Harvard Univ, Sch Publ Hlth, Channing Lab, Landmark Ctr,Dept Nutr, Boston, MA 02115 USA. [Zhang, Xuehong; Spiegelman, Donna; Buring, Julie E.; Giovannucci, Edward; Hankinson, Susan E.; Willett, Walter C.; Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Spiegelman, Donna; Khudyakov, Polyna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Baglietto, Laura; Giles, Graham G.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3010, Australia. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, Duarte, CA 91010 USA. [Boggs, Deborah A.; Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [van den Brandt, Piet A.; Schouten, Leo J.] Maastricht Univ, GROW Sch Oncol & Dev Biol, Dept Epidemiol, Maastricht, Netherlands. [Buring, Julie E.; Zhang, Shumin M.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Giovannucci, Edward; Hankinson, Susan E.; Willett, Walter C.; Zhang, Shumin M.] Harvard Univ, Sch Med, Boston, MA USA. [Gapstur, Susan M.; McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Giovannucci, Edward; Hankinson, Susan E.; Willett, Walter C.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Goodman, Gary; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Helzlsouer, Kathy J.] Mercy Med Ctr, Weinberg Ctr Womens Hlth & Med, Prevent & Res Ctr, Baltimore, MD USA. [Helzlsouer, Kathy J.; Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA USA. [Inoue, Manami; Tsugane, Shoichiro] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Epidemiol & Prevent Div, Tokyo 104, Japan. [Larsson, Susanna C.; Wolk, Alicja] Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. [Lof, Marie] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Miller, Anthony B.; Rohan, Thomas E.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Park, Yikyung; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Robien, Kim; Ross, Julie A.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Shikany, James M.] Univ Alabama, Sch Med, Div Prevent Med, Birmingham, AL USA. [Weiderpass, Elisabete] Univ Tromso, Inst Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Etiol Res, Oslo, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Dept Genet Epidemiol, Helsinki, Finland. RP Zhang, XH (reprint author), Harvard Univ, Sch Publ Hlth, Channing Lab, Landmark Ctr,Dept Nutr, West Wing,401 Pk Dr, Boston, MA 02115 USA. EM pooling@hsphsun2.harvard.edu RI Zhang, Xuehong/E-6219-2012; Schouten, Leo/G-3713-2012; Tsugane, Shocichiro/A-2424-2015; Larsson, Susanna/F-6065-2015; Weiderpass, Elisabete/M-4029-2016; OI Park, Yikyung/0000-0002-6281-489X; Larsson, Susanna/0000-0003-0118-0341; Weiderpass, Elisabete/0000-0003-2237-0128; Palmer, Julie/0000-0002-6534-335X; Robien, Kim/0000-0002-2120-2280; Giles, Graham/0000-0003-4946-9099 FU NIH [CA055075]; Breast Cancer Research Foundation FX Supported by NIH grant CA055075 and a Breast Cancer Research Foundation grant. NR 81 TC 35 Z9 35 U1 0 U2 8 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2012 VL 95 IS 3 BP 713 EP 725 DI 10.3945/ajcn.111.014415 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 897HK UT WOS:000300638700024 PM 22277553 ER PT J AU Cook, CM Subar, AF Troiano, RP Schoeller, DA AF Cook, Chad M. Subar, Amy F. Troiano, Richard P. Schoeller, Dale A. TI Relation between holiday weight gain and total energy expenditure among 40- to 69-y-old men and women (OPEN study) SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID DOUBLY LABELED WATER; OBESITY; EQUATION; CHILDREN; BALANCE; ADULTS; COST AB Background: A significant proportion of the average annual body weight (BW) gain in US adults (similar to 0.5-1 kg/y) may result from modest episodes of positive energy balance during the winter holiday season. Objective: We tested whether holiday BW gain was reduced in participants with high baseline total energy expenditure (TEE) or whether it varied by BMI (in kg/m(2)). Design: In a secondary analysis of previously published data, Delta BW normalized over 90 d from mid-September/mid-October 1999 to mid-January/early March 2000 was analyzed by sex, age, and BMI in 443 men and women (40-69 y of age). TEE was measured by doubly labeled water. High or low energy expenditure was assessed as residual TEE after linear adjustment for age, height, and BW. Results: No correlations between DBW and TEE or TEE residuals were found. Sixty-five percent of men and 58% of women gained >= 0.5 kg BW, with similar to 50% of both groups gaining >= 1% of preholiday BW. Obese men (BMI >= 30) gained more BW than did obese women. Conclusions: A high preholiday absolute TEE or residual TEE did not protect against BW gain during the winter holiday quarter. It is not known whether higher than these typical TEE levels would protect against weight gain or if the observed gain may be attributed to increased food consumption and/or reduced physical activity during the holiday quarter. Am J Clin Nutr 2012;95:726-31. C1 [Schoeller, Dale A.] Univ Wisconsin, Dept Nutr Sci, Interdept Grad Program Nutr Sci, Madison, WI 53706 USA. [Subar, Amy F.; Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Schoeller, DA (reprint author), Univ Wisconsin, Dept Nutr Sci, Interdept Grad Program Nutr Sci, 1415 Linden Dr, Madison, WI 53706 USA. EM dschoell@nutrisci.wisc.edu OI Troiano, Richard/0000-0002-6807-989X FU National Cancer Institute, Divisions of Cancer Control and Population Sciences and Cancer Epidemiology and Genetics FX Supported by the National Cancer Institute, Divisions of Cancer Control and Population Sciences and Cancer Epidemiology and Genetics. NR 19 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2012 VL 95 IS 3 BP 726 EP 731 DI 10.3945/ajcn.111.023036 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 897HK UT WOS:000300638700025 PM 22301936 ER PT J AU Cardozo, ER Clark, AD Banks, NK Henne, MB Stegmann, BJ Segars, JH AF Cardozo, Eden R. Clark, Andrew D. Banks, Nicole K. Henne, Melinda B. Stegmann, Barbara J. Segars, James H. TI The estimated annual cost of uterine leiomyomata in the United States SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cost; fibroid tumor; uterine leiomyomata ID HYSTERECTOMY RATES; PREGNANCY; FIBROIDS; WOMEN; COMPLICATIONS; INFERTILITY; POPULATION; MANAGEMENT; TRIMESTER; DELIVERY AB OBJECTIVE: The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications. STUDY DESIGN: A systematic review of the literature was conducted to estimate the number of women who seek treatment for symptomatic fibroid tumors annually, the costs of medical and surgical treatment, the amount of work time lost, and obstetric complications that are attributable to fibroid tumors. Total annual costs were converted to 2010 US dollars. A sensitivity analysis was performed. RESULTS: The estimated annual direct costs (surgery, hospital admissions, outpatient visits, and medications) were $ 4.1-9.4 billion. Estimated lost work-hour costs ranged from $ 1.55-17.2 billion annually. Obstetric outcomes that were attributed to fibroid tumors resulted in a cost of $ 238 million to $ 7.76 billion annually. Uterine fibroid tumors were estimated to cost the United States $ 5.9-34.4 billion annually. CONCLUSION: Obstetric complications that are associated with fibroid tumors contributed significantly to their economic burden. Lost work-hour costs may account for the largest proportion of societal costs because of fibroid tumors. C1 [Cardozo, Eden R.] Northwestern Univ, Dept Obstet & Gynecol, Feinberg Sch Med, Chicago, IL 60611 USA. [Clark, Andrew D.] Univ S Carolina, Sch Med, Greenville Hosp Syst Campus, Dept Obstet & Gynecol, Greenville, SC USA. [Banks, Nicole K.] NHGRI, NIH, Bethesda, MD 20892 USA. [Segars, James H.] Eunice Kennedy Shriver Natl Inst Child & Human De, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Henne, Melinda B.] Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Div Reprod Endocrinol, Washington, DC 20307 USA. [Stegmann, Barbara J.] Univ Iowa Hosp & Clin, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Iowa City, IA 52242 USA. RP Segars, JH (reprint author), Bldg 10,CRC,Room 1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU National Institute of Child Health and Human Development, National Institutes of Health; National Institutes of Health FX This study was supported, in part, by the Intramural Research Program of Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health.; We acknowledge the support and advice of Drs Alan H. DeCherney and Vivian Pinn (National Institutes of Health Intramural Funding; no compensation relative to the publication). The authors appreciated the suggestions and comments of Dr Alicia Armstrong (National Institutes of Health Intramural Funding; no compensation relative to the publication) and the technical expertise and assistance provided by Miriam Levy (PIRA Energy Group; no compensation relative to this publication). NR 39 TC 35 Z9 36 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2012 VL 206 IS 3 AR 211.e1 DI 10.1016/j.ajog.2011.12.002 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 900HW UT WOS:000300878600021 PM 22244472 ER PT J AU Tita, ATN Lai, YL Bloom, SL Spong, CY Varner, MW Ramin, SM Caritis, SN Grobman, WA Sorokin, Y Sciscione, A Carpenter, MW Mercer, BM Thorp, JM Malone, FD Harper, M Iams, JD AF Tita, Alan Thevenet N. Lai, Yinglei Bloom, Steven L. Spong, Catherine Y. Varner, Michael W. Ramin, Susan M. Caritis, Steve N. Grobman, William A. Sorokin, Yoram Sciscione, Anthony Carpenter, Marshall W. Mercer, Brian M. Thorp, John M., Jr. Malone, Fergal D. Harper, Margaret Iams, Jay D. TI Timing of delivery and pregnancy outcomes among laboring nulliparous women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cesarean delivery; labor; nulliparous; optimal timing of delivery; pregnancy outcomes ID NEONATAL RESPIRATORY MORBIDITY; REPEAT CESAREAN DELIVERY; EXPECTANT MANAGEMENT; ELECTIVE INDUCTION; GESTATIONAL-AGE; TERM PREGNANCY; INFANT-MORTALITY; UNITED-STATES; RISK; COMPLICATIONS AB OBJECTIVE: The objective of the study was to compare pregnancy outcomes by completed week of gestation after 39 weeks with outcomes at 39 weeks. STUDY DESIGN: Secondary analysis of a multicenter trial of fetal pulse oximetry in spontaneously laboring or induced nulliparous women at a gestation of 36 weeks or longer. Maternal outcomes included a composite (treated uterine atony, blood transfusion, and peripartum infections) and cesarean delivery. Neonatal outcomes included a composite of death, neonatal respiratory and other morbidities, and neonatal intensive care unit admission. RESULTS: Among the 4086 women studied, the risks of the composite maternal outcome (P value for trend < .001), cesarean delivery (P < .001), and composite neonatal outcome (P = .047) increased with increasing gestational age from 39 to 41 or more completed weeks. Adjusted odds ratios (95% confidence interval) for 40 and 41 or more weeks, respectively, compared with 39 weeks were 1.29 (1.03-1.64) and 2.05 (1.60-2.64) for composite maternal outcome, 1.28 (1.05-1.57) and 1.75 (1.41-2.16) for cesarean delivery, and 1.25 (0.86-1.83) and 1.37 (0.90-2.09) for composite neonatal outcome. CONCLUSION: Risks of maternal morbidity and cesarean delivery but not neonatal morbidity increased significantly beyond 39 weeks. C1 [Tita, Alan Thevenet N.] Univ Alabama, Sch Med, Dept Obstet, Birmingham, AL 35294 USA. [Tita, Alan Thevenet N.] Univ Alabama, Sch Med, Dept Gynecol, Birmingham, AL USA. [Bloom, Steven L.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Varner, Michael W.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Caritis, Steve N.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Grobman, William A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Sorokin, Yoram] Wayne State Univ, Sch Med, Detroit, MI USA. [Sciscione, Anthony] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Carpenter, Marshall W.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Mercer, Brian M.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Iams, Jay D.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Thorp, John M., Jr.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Harper, Margaret] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Malone, Fergal D.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Tita, ATN (reprint author), Univ Alabama, Sch Med, Dept Obstet, Birmingham, AL 35294 USA. RI Malone, Fergal/D-6233-2012; Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD36801] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, and HD36801). NR 37 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2012 VL 206 IS 3 AR 239.e1 DI 10.1016/j.ajog.2011.12.006 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 900HW UT WOS:000300878600033 PM 22244471 ER PT J AU Yi, L Liu, Q Orandle, MS Sadiq-Ali, S Koontz, SM Choi, U Torres-Velez, FJ Jackson, SH AF Yi, Liang Liu, Qi Orandle, Marlene S. Sadiq-Ali, Sara Koontz, Sherry M. Choi, Uimook Torres-Velez, Fernando J. Jackson, Sharon H. TI p47(Phox) Directs Murine Macrophage Cell Fate Decisions SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; LISTERIA-MONOCYTOGENES INFECTION; PHAGOCYTE NADPH OXIDASE; ALTERNATIVE ACTIVATION; DENDRITIC CELLS; MODEL; MICE; EXPRESSION; RESPONSES; SYSTEM AB Macrophage differentiation and function are pivotal for cell survival from infection and involve the processing of microenvironmental signals that determine macrophage cell fate decisions to establish appropriate inflammatory balance. NADPH oxidase 2 (Nox2)-deficient chronic granulomatous disease (CGD) mice that lack the gp91(Phox) (gp91P(hox-/-)) catalytic subunit show high mortality rates compared with wild-type mice when challenged by infection with Listeria monocylogenes (Lm), whereas p47(phox)-deficient (p47(phox-/-)) CGD mice show survival rates that are similar to those of wild-type mice. We demonstrate that such survival results from a skewed macrophage differentiation program in p47(phox-/-) mice that favors the production of higher levels of alternatively activated macrophages (AAMacs) compared with levels of either wild-type or gp91(phox-/-) mice. Furthermore, the adoptive transfer of AAMacs from p47(phox-/-) mice can rescue gp91(phox-/-) mice during primary Lm infection. Key features of the protective function provided by p47(phox-/-) AAMacs against Lin infection are enhanced production of IL-1 alpha and killing of Lm. Molecular analysis of this process indicates that p47(phox-/-) macrophages are hyperresponsive to EL-4 and show higher Stat6 phosphorylation levels and signaling coupled to downstream activation of AAMac transcripts in response to IL-4 stimulation. Notably, restoring p47(phox) protein expression levels reverts the p47(phox)-dependent AAMac phenotype. Our results indicate that p47(phox) is a previously unrecognized regulator for IL-4 signaling pathways that are important for macrophage cell fate choice. (Am J Pathol 2012, 180: 1049-1058; DOI: 10.1016/j.ajpath.2011.11.019) C1 [Choi, Uimook; Jackson, Sharon H.] NIAID, Genet Immunotherapy Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Yi, Liang; Liu, Qi; Sadiq-Ali, Sara; Koontz, Sherry M.; Jackson, Sharon H.] NIAID, Mol Trafficking Unit, NIH, Bethesda, MD 20892 USA. [Orandle, Marlene S.] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. [Torres-Velez, Fernando J.] USDA, Foreign Anim Dis Diagnost Lab, Phum Isl Anim Dis Ctr, Greenport, NY USA. RP Jackson, SH (reprint author), NIAID, Genet Immunotherapy Sect, Host Def Lab, NIH, CRC Bldg 5 W Labs,Room 5-3942,10 Ctr Dr MSC 1456, Bethesda, MD 20892 USA. EM sjackson@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; NIH; National Institute on Minority Health and Health Disparities, NIH FX Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH and in part by the National Institute on Minority Health and Health Disparities, NIH. NR 30 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2012 VL 180 IS 3 BP 1049 EP 1058 DI 10.1016/j.ajpath.2011.11.019 PG 10 WC Pathology SC Pathology GA 902EU UT WOS:000301022200018 PM 22222227 ER PT J AU Miller, EK Hernandez, JZ Wimmenauer, V Shepherd, BE Hijano, D Libster, R Serra, ME Bhat, N Batalle, JP Mohamed, Y Reynaldi, A Rodriguezs, A Otello, M Pisapia, N Bugna, J Bellabarba, M Kraft, D Coviello, S Ferolla, FM Chen, A London, SJ Siberry, GK Williams, JV Polack, FP AF Miller, E. Kathryn Zea Hernandez, Johanna Wimmenauer, Vera Shepherd, Bryan E. Hijano, Diego Libster, Romina Elina Serra, M. Bhat, Niranjan Batalle, Juan P. Mohamed, Yassir Reynaldi, Andrea Rodriguezs, Andrea Otello, Monica Pisapia, Nestor Bugna, Jimena Bellabarba, Miguel Kraft, David Coviello, Silvina Martin Ferolla, F. Chen, Aaron London, Stephanie J. Siberry, George K. Williams, John V. Polack, Fernando P. TI A Mechanistic Role for Type III IFN-lambda(1) in Asthma Exacerbations Mediated by Human Rhinoviruses SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE asthma; interferon-lambda; rhinovirus; children; asthma exacerbation ID VIRUS-INDUCED ASTHMA; INTERFERON-LAMBDA; NEUTROPHIL RECRUITMENT; RESPIRATORY-TRACT; ALLERGIC-ASTHMA; INDUCED SPUTUM; MESSENGER-RNA; CHILDREN; CELLS; AIRWAY AB Rationale: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. Objectives: To determine the role of H RV in pediatric asthma exacerbations and the mechanisms mediating wheezing. Methods: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. Measurements and Main Results: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-lambda(1) levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-lambda(1), children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66). Conclusions: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-lambda(1)., responses mediate exacerbations caused by HRV. Modulation of IFN-lambda(1) should be studied as a therapeutic target for exacerbations caused by HRV. C1 [Polack, Fernando P.] Vanderbilt Univ, Vanderbilt Vaccine Ctr, Dept Pediat, Nashville, TN 37232 USA. [Zea Hernandez, Johanna; Wimmenauer, Vera; Hijano, Diego; Libster, Romina; Elina Serra, M.; Batalle, Juan P.; Bugna, Jimena; Coviello, Silvina; Martin Ferolla, F.; Polack, Fernando P.] Fdn INFANT, Buenos Aires, DF, Argentina. [Bhat, Niranjan] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [Reynaldi, Andrea; Bellabarba, Miguel] Hosp Mi Pueblo, Buenos Aires, DF, Argentina. [Rodriguezs, Andrea] Hosp Evita Pueblo, Buenos Aires, DF, Argentina. [Otello, Monica] Hosp Iriarte, Buenos Aires, DF, Argentina. [Pisapia, Nestor] Hosp V Lopez & Planes, Buenos Aires, DF, Argentina. [Chen, Aaron] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Siberry, George K.] Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD USA. RP Polack, FP (reprint author), Vanderbilt Univ, Vanderbilt Vaccine Ctr, Dept Pediat, 221 Kirkland Hall, Nashville, TN 37232 USA. EM fernando.p.polack@vanderbilt.edu RI Williams, John/F-6962-2010; OI Williams, John/0000-0001-8377-5175; London, Stephanie/0000-0003-4911-5290 FU Thrasher Research Fund; [KL2 RR24977-03]; [1K23AI091691-01] FX Supported by the Thrasher Research Fund (to F.P.P.) and KL2 RR24977-03 and 1K23AI091691-01 (to E.K.M.). NR 48 TC 44 Z9 45 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 1 PY 2012 VL 185 IS 5 BP 508 EP 516 DI 10.1164/rccm.201108-1462OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 900AG UT WOS:000300858400011 PM 22135341 ER PT J AU Miettinen, M Wang, ZF AF Miettinen, Markku Wang, Zeng-Feng TI Prox1 Transcription Factor as a Marker for Vascular Tumors-Evaluation of 314 Vascular Endothelial and 1086 Nonvascular Tumors SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE hemangioma; hemangioendothelioma; lymphangioma; angiosarcoma; Prox1; podoplanin; CD34 ID GROWTH-FACTOR RECEPTOR-3; D2-40 IMMUNOHISTOCHEMISTRY; LYMPHATIC-ENDOTHELIUM; KAPOSIS-SARCOMA; CELLS; BLOOD; PHENOTYPE; HEMANGIOENDOTHELIOMA; DIFFERENTIATION; ANGIOSARCOMAS AB Prox 1, a transcription factor important in the regulation and maintenance of the lymphatic endothelial phenotype, is consistently expressed in lymphangiomas and Kaposi sarcoma and has also been reported in Kaposiform hemangioendothelioma. However, information on its distribution in vascular tumors, such as angiosarcoma, is limited. In this study, we examined selected normal tissues and 314 vascular endothelial and 1086 nonvascular tumors to get an insight into the biology of these tumors and on potential diagnostic use of Prox 1 as an immunohistochemical marker. In adult tissues, Prox 1 was essentially restricted to lymphatic endothelia, with expression in subsets of pancreatic and gastrointestinal epithelia. However, it was also detected in embryonic liver and heart. Prox 1 was consistently expressed in lymphangiomas, venous hemangiomas, Kaposi sarcoma, in endothelia of spindle cell hemangioma, Kaposiform hemangioendothelioma, and retiform hemangioendothelioma, and in half of epithelioid hemangioendotheliomas. It was present in most cutaneous angiosarcomas from different sites but was less commonly expressed in deep soft tissue and visceral angiosarcomas. In contrast, Prox 1 was generally absent in capillary and cavernous hemangiomas. In positive hemangiomas and angiosarcomas it was coexpressed with podoplanin, another marker of the lymphatic endothelial phenotype. There was an inverse correlation with CD34 expression. The expression in mesenchymal nonendothelial neoplasm was limited. Prox 1 was detected in 5 of 27 synovial sarcomas, specifically in the epithelia of biphasic tumors. Four of 16 Ewing sarcomas and 5 of 15 paragangliomas were also positive. All melanomas and undifferentiated sarcomas were negative. Among epithelial neoplasms, Prox 1 was detected in 18 of 38 colonic carcinomas and 10 of 15 cholangiocarcinomas and in a minority of pulmonary, prostatic, and endometrial adenocarcinomas. The common Prox 1 expression in angiosarcoma and its rare presence in nonvascular mesenchymal tumors make this marker suitable for the diagnosis of angiosarcoma and Kaposi sarcoma. However, the presence of Prox 1 in some malignant epithelial tumors necessitates caution in applying Prox 1 as a marker for vascular tumors. Common Prox 1 expression in angiosarcoma may reflect the lymphatic endothelial phenotype in these tumors. Its patterns of expression in hemangiomas and angiosarcoma may be diagnostically useful and offer a new parameter in the biological classification of vascular tumors. C1 [Miettinen, Markku; Wang, Zeng-Feng] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Miettinen, M (reprint author), NCI, Pathol Lab, 9000 Rockville Pike,Bldg 10,Rm 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU NCI FX This work was supported as a part of NCI's Intramural Research Program. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 31 TC 26 Z9 27 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2012 VL 36 IS 3 BP 351 EP 359 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 902KY UT WOS:000301038200004 PM 22067331 ER PT J AU Peprah, E AF Peprah, Emmanuel TI Fragile X Syndrome: The FMR1 CGG Repeat Distribution Among World Populations SO ANNALS OF HUMAN GENETICS LA English DT Review DE FMR1 gene; fragile X mutation; prevalence ID MENTALLY-RETARDED CHILDREN; PREMATURE OVARIAN FAILURE; SINGLE-NUCLEOTIDE-POLYMORPHISM; TREMOR/ATAXIA SYNDROME FXTAS; MESSENGER-RNA; PREMUTATION CARRIERS; FOUNDER CHROMOSOMES; GENETIC DIVERSITY; DXS548/FRAXAC1 HAPLOTYPES; INTELLECTUAL DISABILITY AB Fragile X syndrome (FXS) is characterized by moderate to severe intellectual disability, which is accompanied by macroorchidism and distinct facial morphology. FXS is caused by the expansion of the CGG trinucleotide repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. The syndrome has been studied in ethnically diverse populations around the world and has been extensively characterized in several populations. Similar to other trinucleotide expansion disorders, the gene-specific instability of FMR1 is not accompanied by genomic instability. Currently we do not have a comprehensive understanding of the molecular underpinnings of gene-specific instability associated with tandem repeats. Molecular evidence from in vitro experiments and animal models supports several pathways for gene-specific trinucleotide repeat expansion. However, whether the mechanisms reported from other systems contribute to trinucleotide repeat expansion in humans is not clear. To understand how repeat instability in humans could occur, the CGG repeat expansion is explored through molecular analysis and population studies which characterized CGG repeat alleles of FMR1. Finally, the review discusses the relevance of these studies in understanding the mechanism of trinucleotide repeat expansion in FXS. C1 [Peprah, Emmanuel] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Peprah, Emmanuel] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. RP Peprah, E (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bldg 12A,RM 4047,12 South Dr,MSC 5635, Bethesda, MD 20892 USA. EM peprahek@mail.nih.gov FU Emory University FX This project was supported by the Emory University Fellowships in Research and Science Teaching (FIRST) Program. Additional support from the Intramural Research Program of the NIH, National Human Genome Research Institute, Center on Genomics and Global Health is acknowledged. I would also like to acknowledge the kind editorial assistance of the NIH Fellows Editorial Board. NR 165 TC 24 Z9 26 U1 1 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD MAR PY 2012 VL 76 BP 178 EP 191 DI 10.1111/j.1469-1809.2011.00694.x PN 2 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 894SM UT WOS:000300447100008 PM 22188182 ER PT J AU Sionov, E Chang, YC Garraffo, HM Dolan, MA Ghannoum, MA Kwon-Chung, KJ AF Sionov, Edward Chang, Yun C. Garraffo, H. Martin Dolan, Michael A. Ghannoum, Mahmoud A. Kwon-Chung, Kyung J. TI Identification of a Cryptococcus neoformans Cytochrome P450 Lanosterol 14 alpha-Demethylase (Erg11) Residue Critical for Differential Susceptibility between Fluconazole/Voriconazole and Itraconazole/Posaconazole SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID FLUCONAZOLE RESISTANCE; AMINO-ACID; REDUCED SUSCEPTIBILITY; ASPERGILLUS-FUMIGATUS; MAINTENANCE THERAPY; INFECTED PATIENTS; AIDS; MENINGITIS; ITRACONAZOLE; HETERORESISTANCE AB Cryptococcus neoformans strains resistant to azoles due to mutations causing alterations in the ERG11 gene, encoding lanosterol 14 alpha-demethylase, have rarely been reported. In this study, we have characterized a C. neoformans serotype A strain that is resistant to high concentrations of fluconazole (FLC). This strain, which was isolated from an FLC-treated patient, contained five missense mutations in the ERG11 gene compared to the sequence of reference strain H99. Molecular manipulations of the ERG11 gene coupled with susceptibility to triazole revealed that a single missense mutation resulting in the replacement of tyrosine by phenylalanine at amino acid 145 was sufficient to cause the high FLC resistance of the strain. Importantly, this newly identified point mutation in the ERG11 gene of C. neoformans afforded resistance to voriconazole (VRC) but increased susceptibility to itraconazole (ITC) and posaconazole (PSC), which are structurally similar to each other but distinct from FLC/VRC. The in vitro susceptibility/resistance of the strains with or without the missense mutation was reflected in the therapeutic efficacy of FLC versus ITC in the animals infected with the strains. This study shows the importance of the Y145F alteration of Erg11 in C. neoformans for manifestation of differential susceptibility toward different triazoles. It underscores the necessity of in vitro susceptibility testing for each FLC-resistant C. neoformans clinical isolate against different groups of azoles in order to assist patient management. C1 [Sionov, Edward; Chang, Yun C.; Kwon-Chung, Kyung J.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Dolan, Michael A.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. [Garraffo, H. Martin] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Ghannoum, Mahmoud A.] Case Western Reserve Univ, Ctr Med Mycol, Cleveland, OH 44106 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM June_Kwon-Chung@nih.gov FU National Institute of Allergy and Infectious Diseases, NIH FX This study was supported by funds from the intramural program of the National Institute of Allergy and Infectious Diseases, NIH. NR 30 TC 27 Z9 28 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2012 VL 56 IS 3 BP 1162 EP 1169 DI 10.1128/AAC.05502-11 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 897DN UT WOS:000300623300003 PM 22155829 ER PT J AU Sohl, CD Singh, K Kasiviswanathan, R Copeland, WC Mitsuya, H Sarafianos, SG Anderson, KS AF Sohl, Christal D. Singh, Kamlendra Kasiviswanathan, Rajesh Copeland, William C. Mitsuya, Hiroaki Sarafianos, Stefan G. Anderson, Karen S. TI Mechanism of Interaction of Human Mitochondrial DNA Polymerase gamma with the Novel Nucleoside Reverse Transcriptase Inhibitor 4 '-Ethynyl-2-Fluoro-2 '-Deoxyadenosine Indicates a Low Potential for Host Toxicity SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL-THERAPY; LIPODYSTROPHY; RECOGNITION; VARIANTS; SUBUNIT; ANALOGS; DRUGS AB The potent antiretroviral 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a promising experimental agent for treating HIV infection. Pre-steady-state kinetics were used to characterize the interaction of EFdA-triphosphate (EFdA-TP) with human mitochondrial DNA polymerase gamma (Pol gamma) to assess the potential for toxicity. Pol gamma incorporated EFdA-TP 4,300-fold less efficiently than dATP, with an excision rate similar to ddATP. This strongly indicates EFdA is a poor Pol gamma substrate, suggesting minimal Pol gamma-mediated toxicity, although this should be examined under clinical settings. C1 [Sohl, Christal D.; Anderson, Karen S.] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. [Singh, Kamlendra; Sarafianos, Stefan G.] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA. [Kasiviswanathan, Rajesh; Copeland, William C.] Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC USA. [Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med Sci, Dept Infect Dis, Kumamoto, Japan. [Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med Sci, Dept Hematol, Kumamoto, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Anderson, KS (reprint author), Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. EM karen.anderson@yale.edu RI Kasiviswanathan, Rajesh/D-2744-2012 FU NIH [R01 GM049551, F32 GM099289, AI094715, AI076119, AI079801, AI074389]; NIH, NIEHS [ES 065080] FX This work was supported by NIH grants R01 GM049551 (to K.S.A.), F32 GM099289 (to C.D.S.), AI094715, AI076119, AI079801, and AI074389 (to S.G.S.) and by the Intramural Research Program of the NIH, NIEHS, ES 065080 (to W.C.C.). NR 29 TC 11 Z9 11 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2012 VL 56 IS 3 BP 1630 EP 1634 DI 10.1128/AAC.05729-11 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 897DN UT WOS:000300623300070 PM 22155823 ER PT J AU Lang, TF Sigurdsson, S Karlsdottir, G Oskarsdottir, D Sigmarsdottir, A Chengshi, J Kornak, J Harris, TB Sigurdsson, G Jonsson, BY Siggeirsdottir, K Eiriksdottir, G Gudnason, V Keyak, JH AF Lang, T. F. Sigurdsson, S. Karlsdottir, G. Oskarsdottir, D. Sigmarsdottir, A. Chengshi, J. Kornak, J. Harris, T. B. Sigurdsson, G. Jonsson, B. Y. Siggeirsdottir, K. Eiriksdottir, G. Gudnason, V. Keyak, J. H. TI Age-related loss of proximal femoral strength in elderly men and women: The Age Gene/Environment Susceptibility Study - Reykjavik SO BONE LA English DT Article DE Hip fracture; Osteoporosis; Bone strength; Finite element modeling; Computed tomography; Proximal femur ID HIP FRACTURE RISK; FINITE-ELEMENT MODELS; BONE LOSS; COMPUTED-TOMOGRAPHY; OLDER MEN; PREDICTION; FEMUR; GEOMETRY; DENSITY; WEIGHT AB The risk of hip fracture rises rapidly with age, and is particularly high in women. This increase in fracture risk reflects both the age-related change in the risk of falling and decrements in the strength of the proximal femur. To better understand the extent to which proximal femoral density, structure and strength change with age as a function of gender, we have carried out a longitudinal analysis of proximal femoral volumetric quantitative computed tomographic (vQCT) images in men and women, analyzing changes in trabecular and cortical bone properties, and using subject-specific finite element modeling (FEM) to estimate changes in bone strength. In the AGES-Reykjavik Study vQCT scans of the hip were performed at a baseline visit in 2002-2006 and at a second visit 5.05 +/- 0.25 years later. From these, 223 subjects (111 men, 112 women, aged 68-87 years) were randomly selected. The subjects were evaluated for longitudinal changes in three bone variables assessed in a region similar to the total femur region quantified by DXA: areal bone mineral density (aBMD), trabecular volumetric bone mineral density (tBMD) and the ratio of cortical to total tissue volume (cvol/ivol). They were also evaluated for changes in bone strength using FEM models of the left proximal femur. Models were analyzed under single-limb stance loading (F-Stance), which approximates normal physiologic loading of the hip, as well as a load approximating a fall onto the posterolateral aspect of the greater trochanter (F-Fall). We computed five-year absolute and percentage changes in aBmD, tBMD, cvol/ivol, F-Fall and F-Stance. The Mann-Whitney Test was employed to compare changes in bone variables between genders and the Wilcoxon Signed Rank Test was used to compare changes in bone strength between loading conditions. Multiple (linear) regression was employed to determine the association of changes in F-Fall and F-Stance with baseline age and five-year weight loss. Both men and women showed declines in indices of proximal femoral density and structure (aBMD: men -3.9 +/- 6.0%, women -6.1 +/- 6.2%; tBMD: men -14.8 +/- 20.3%, women -23.9 +/- 26.8%; cvol/ivol: men -2.6 +/- 4.6%, women -4.7 +/- 4.8%, gender difference: p<0.001). Both men and women lost bone strength in each loading condition (F-Stance: men -4.2 +/- 9.9%, women -8.3 +/- 8.5%; F-Fall: men -7.0 +/- 15.7%, women -12.8 +/- 13.2%; all changes from baseline p<0.0001). The gender difference in bone strength loss was statistically significant in both loading conditions (p<0.001 for F-Stance and P<0.01 for F-Fall) and F-Fall, was lost at a higher rate than F-Stance in men (p<0.01) and women (p<0.0001). The gender difference in strength loss was statistically significant after adjustment for baseline age and weight loss in both loading conditions (p<0.01). In these multi-linear models, men showed increasing rates of bone loss with increasing age (F-Fall: p=0.002; F-Stance; p=0.03), and women showed increasing bone strength loss with higher degrees of weight loss (F-Stance: p=0.003). The higher loss of F-Fall compared to F-Stance supports previous findings in animal and human studies that the sub-volumes of bone stressed under normal physiologic loading are relatively better protected in aging. The gender difference in hip bone strength loss is consistent with the higher incidence of hip fractureamong elderly women. (C) 2011 Elsevier Inc. All rights reserved. C1 [Lang, T. F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Sigurdsson, S.; Karlsdottir, G.; Oskarsdottir, D.; Sigmarsdottir, A.; Sigurdsson, G.; Siggeirsdottir, K.; Eiriksdottir, G.; Gudnason, V.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Chengshi, J.; Kornak, J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Sigurdsson, G.] Landspitalinn Univ Hosp, Reykjavik, Iceland. [Jonsson, B. Y.] Malmo Univ Hosp, Malmo, Sweden. [Oskarsdottir, D.; Sigurdsson, G.] Univ Iceland, Reykjavik, Iceland. [Keyak, J. H.] Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92717 USA. [Keyak, J. H.] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA USA. [Keyak, J. H.] Univ Calif Irvine, Dept Mech & Aerosp Engn, Irvine, CA 92717 USA. RP Lang, TF (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 185 Berry St,Suite 350, San Francisco, CA 94143 USA. EM thomas.lang@ucsf.edu RI Gudnason, Vilmundur/K-6885-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Lang, Thomas/0000-0002-3720-8038 FU NIH/NIA [R01-AG028832]; NIH [N01-AG-12100]; NIA; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This study was supported by NIH/NIA R01-AG028832. The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study was approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. NR 26 TC 21 Z9 21 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD MAR PY 2012 VL 50 IS 3 BP 743 EP 748 DI 10.1016/j.bone.2011.12.001 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 897KR UT WOS:000300650100021 PM 22178403 ER PT J AU Davis, MS Kovacic, BL Marini, JC Shih, AJ Kozloff, KM AF Davis, Mathieu S. Kovacic, Bethany L. Marini, Joan C. Shih, Albert J. Kozloff, Kenneth M. TI Increased susceptibility to microdamage in Brtl/+ mouse model for osteogenesis imperfecta SO BONE LA English DT Article DE Microdamage; Osteogenesis imperfecta; Mouse model; Fracture toughness; Collagen ID SUPPRESSED BONE TURNOVER; I COLLAGEN; BIOMECHANICAL PROPERTIES; DECREASED BONE; RAT ULNA; FATIGUE; TOUGHNESS; ACCUMULATION; FRACTURE; BISPHOSPHONATES AB Osteogenesis imperfecta (OI) is a genetic disease of collagen or collagen-related proteins that adversely impacts bone mass and fracture resistance. Little is known regarding the role that microdamage plays in OI and whether or not OI bone is more prone to damage accumulation than bone with unaffected collagen. The Brtl/+ mouse is a heterozygous model for OI which contains a Gly349Cys substitution in one COL1A1 allele, and demonstrates a low ductility phenotype. At 8 weeks of age. Brtl/+ demonstrates an increase in osteoclast number, which mimics the upregulated bone turnover often found in OI patients. We hypothesize that upregulated osteoclast activity in Brtl/+ is due, in part, to increased remodeling associated with microdamage repair. In the present study, we used Brtl/+ to investigate the susceptibility of OI bone to microdamage. The mouse ulnar loading model was used to induce microdamage and to test the hypothesis that Brtl/+ is more susceptible to damage accumulation than age-matched wild type (WT) counterparts. Linear elastic fracture mechanics (LEFM) was used to investigate the fracture toughness properties of both Brtl/+ and WT bones to determine if there is any correlation with toughness and the degree of microdamage. Results show that Brtl/+ ulnae subject to normal cage activity demonstrate an inherently larger amount of microdamage than WT controls. Following axial compressive loading, Brtl/+ ulnae are more prone to damage than WT counterparts despite demonstrating a greater resistance to whole-bone deformation. Fracture toughness results demonstrate that Brtl/+ specimens, despite not exhibiting a significant difference, display a trend toward lower fracture toughness values than their WT counterparts. Correlations show that microdamage levels tend to increase as fracture toughness decreases. Together, these findings may have strong clinical implications for explaining increased fragility and remodeling activity in OI patients. (C) 2011 Elsevier Inc. All rights reserved. C1 [Davis, Mathieu S.; Shih, Albert J.] Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA. [Kovacic, Bethany L.; Shih, Albert J.; Kozloff, Kenneth M.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Kozloff, Kenneth M.] Univ Michigan, Dept Orthopaed Surg, Ann Arbor, MI 48109 USA. [Marini, Joan C.] NICHHD, BEMB, NIH, Bethesda, MD 20892 USA. RP Kozloff, KM (reprint author), 2015 Biomed Sci Res Bldg,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM kenkoz@umich.edu FU American Society for Bone and Mineral Research FX Research was supported in part by the American Society for Bone and Mineral Research. NR 47 TC 10 Z9 10 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD MAR PY 2012 VL 50 IS 3 BP 784 EP 791 DI 10.1016/j.bone.2011.12.007 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 897KR UT WOS:000300650100027 PM 22207275 ER PT J AU Agurs-Collins, T Rohrmann, S Sutcliffe, C Bienstock, JL Monsegue, D Akereyeni, F Bradwin, G Rifai, N Pollak, MN Platz, EA AF Agurs-Collins, Tanya Rohrmann, Sabine Sutcliffe, Catherine Bienstock, Jessica L. Monsegue, Deborah Akereyeni, Folasade Bradwin, Gary Rifai, Nader Pollak, Michael N. Platz, Elizabeth A. TI Racial variation in umbilical cord blood sex steroid hormones and the insulin-like growth factor axis in African-American and white female neonates SO CANCER CAUSES & CONTROL LA English DT Article DE Umbilical cord blood; IGF axis; Sex steroid hormones; African-American ID BREAST-CANCER RISK; FACTOR BINDING-PROTEINS; I IGF-I; BIRTH-WEIGHT; UNITED-STATES; POSTMENOPAUSAL WOMEN; INTRAUTERINE GROWTH; TESTOSTERONE LEVELS; HEAD CIRCUMFERENCE; TERM NEWBORNS AB To evaluate whether there is racial variation in venous umbilical cord blood concentrations of sex steroid hormones and the insulin-like growth factor (IGF) axis between female African-American and white neonates. Maternal and birth characteristics and venous umbilical cord blood samples were collected from 77 African-American and 41 white full-term uncomplicated births at two urban hospitals in 2004 and 2005. Cord blood was measured for testosterone, dehydroespiandrosterone-sulfate, estradiol, and sex steroid hormone-binding globulin (SHBG) by immunoassay. IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP-3) were measured by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed for the hormones. African-American neonates weighed less at birth (3,228 g vs. 3,424 g, p < 0.004) than whites. Birth weight was positively correlated with IGF-1, IGFBP-3, and the molar ratio of IGF-1 to IGFBP-3, but inversely correlated with the molar ratio of IGF-2 to IGFBP-3. Adjusted models showed higher testosterone (1.82 ng/ml vs. 1.47 ng/ml, p = 0.006) and the molar ratio of testosterone to SHBG (0.42 vs. 0.30, p = 0.03) in African-American compared to white female neonates. IGF-1, IGF-2, and IGFBP-3 were lower in African-American compared to white female neonates, but only the difference for IGF-2 remained significant (496.5 ng/ml vs. 539.2 ng/ml, p = 0.04). We provide evidence of racial variation in cord blood testosterone and testosterone to SHBG in African-American compared to white female neonates, and higher IGF-2 in white compared to African-American female neonates. Findings suggest plausible explanations for a prenatal influence on subsequent breast cancer risk and mortality. Further work is needed to confirm these observations. C1 [Agurs-Collins, Tanya] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Rohrmann, Sabine] Univ Zurich, Inst Social & Prevent Med, Dept Canc Epidemiol & Prevent, CH-8006 Zurich, Switzerland. [Sutcliffe, Catherine; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Bienstock, Jessica L.] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. [Monsegue, Deborah] Howard Univ, Ctr Canc, Washington, DC 20059 USA. [Akereyeni, Folasade] Howard Univ, Howard Univ Human Genome Ctr, Washington, DC 20059 USA. [Bradwin, Gary; Rifai, Nader] Harvard Univ, Sch Med, Dept Lab Med, Boston, MA USA. [Bradwin, Gary; Rifai, Nader] Childrens Hosp, Boston, MA 02115 USA. [Pollak, Michael N.] McGill Univ, Jewish Gen Hosp, Dept Med & Oncol, Montreal, PQ H3T 1E2, Canada. [Platz, Elizabeth A.] Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Platz, Elizabeth A.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. RP Agurs-Collins, T (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM collinsta@mail.nih.gov RI Pollak, Michael/G-9094-2011; Rohrmann, Sabine/D-2113-2012 OI Pollak, Michael/0000-0003-3047-0604; FU National Cancer Institute [CA091431, CA091409] FX We thank Anna DeNooyer, MHS, research assistant, and Stacey Meyerer, laboratory manager, both at the Johns Hopkins Bloomberg School of Public Health, for their assistance in the conduct of this study, the delivery room nurses at the Prince George's Hospital Center and the Johns Hopkins Hospital for collecting the cord blood specimens, and Yuzhen Tao in the laboratory of Dr. Pollak for overseeing the laboratory assays. Authors received grant support from National Cancer Institute grant U54 (Howard CA091431) and U54 (Hopkins CA091409). NR 52 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2012 VL 23 IS 3 BP 445 EP 454 DI 10.1007/s10552-011-9893-6 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 900ML UT WOS:000300891100005 PM 22252677 ER PT J AU Kitahara, CM Platz, EA Freeman, LEB Black, A Hsing, AW Linet, MS Park, Y Schairer, C de Gonzalez, AB AF Kitahara, Cari M. Platz, Elizabeth A. Freeman, Laura E. Beane Black, Amanda Hsing, Ann W. Linet, Martha S. Park, Yikyung Schairer, Catherine de Gonzalez, Amy Berrington TI Physical activity, diabetes, and thyroid cancer risk: a pooled analysis of five prospective studies SO CANCER CAUSES & CONTROL LA English DT Article DE Physical activity; Energy expenditure; Type 2 diabetes; Insulin resistance; Thyroid neoplasms; Prospective study ID BODY-MASS INDEX; ANTHROPOMETRIC FACTORS; UNITED-STATES; COHORT; OBESITY; MEN; WEIGHT; ADULTS; CARCINOGENESIS; METAANALYSIS AB Although many studies have linked obesity with increased risk of thyroid cancer, few have investigated the role of obesity-related lifestyle characteristics and medical conditions in the etiology of this disease. We examined the associations of self-reported physical activity and diabetes history with thyroid cancer risk in a large pooled analysis of prospective cohort studies. Data from five prospective studies in the U.S. (n = 362,342 men, 312,149 women) were coded using standardized exposure, covariate, and outcome definitions. Hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer were estimated using age as the time metric and adjusting for sex, education, race, marital status, cigarette smoking, body mass index, alcohol intake, and cohort. Effect modification by other risk factors (e.g., age, sex, and body mass index) and differences by cancer subtype (e.g., papillary, follicular) were also examined. Over follow-up (median = 10.5 years), 308 men and 510 women were diagnosed with a first primary thyroid cancer. Overall, subjects reporting the greatest amount of physical activity had an increased risk of the disease (HR = 1.18, 95% CI:1.00-1.39); however, this association was restricted to participants who were overweight/obese (a parts per thousand yen25 kg/m(2); HR = 1.34, 95% CI:1.09-1.64) as opposed to normal-weight (< 25 kg/m(2); HR = 0.92, 95% CI:0.69-1.22; P-interaction = 0.03). We found no overall association between self-reported history of diabetes and thyroid cancer risk (HR = 1.08, 95% CI:0.83-1.40). Neither physical inactivity nor diabetes history was associated with increased risk of thyroid cancer. While it may have been a chance finding, the possible increased risk associated with greater physical activity warrants further investigation. C1 [Kitahara, Cari M.; Freeman, Laura E. Beane; Black, Amanda; Hsing, Ann W.; Linet, Martha S.; Park, Yikyung; Schairer, Catherine; de Gonzalez, Amy Berrington] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Kitahara, CM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, EPS 7056,6120 Execut Blvd, Rockville, MD 20852 USA. EM kitaharac@mail.nih.gov RI Kitahara, Cari/R-8267-2016; OI Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, National Institutes of Health; Florida Department of Health (FDOH) FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Specific to NIH-AARP: Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. In memory of Dr. Arthur Schatzkin, visionary investigator who founded the NIH-AARP Diet and Health Study. NR 28 TC 18 Z9 19 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2012 VL 23 IS 3 BP 463 EP 471 DI 10.1007/s10552-012-9896-y PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 900ML UT WOS:000300891100007 PM 22294499 ER PT J AU Brinton, LA Schwartz, L Spitz, MR Park, Y Hollenbeck, AR Gierach, GL AF Brinton, Louise A. Schwartz, Lauren Spitz, Margaret R. Park, Yikyung Hollenbeck, Albert R. Gierach, Gretchen L. TI Unopposed estrogen and estrogen plus progestin menopausal hormone therapy and lung cancer risk in the NIH-AARP Diet and Health Study Cohort SO CANCER CAUSES & CONTROL LA English DT Article DE Lung cancer; Menopausal hormone therapy; Risk; Histology ID REPLACEMENT THERAPY; REPRODUCTIVE FACTORS; POSTMENOPAUSAL WOMEN; RECEPTOR EXPRESSION; NURSES HEALTH; SMOKING; ASSOCIATION; ADENOCARCINOMA; PREGNANCY AB Previous studies have reported that lung cancer risk may be decreased, increased, or unaffected by prior use of menopausal hormone therapy (MHT). To assess this issue further, we examined relationships among 118,008 women, ages 50-71 years who were recruited during 1995-1996 for the NIH-AARP Diet and Health Study and in whom 2,097 incident lung carcinomas were identified during follow-up through 2006. Multivariable Cox proportional hazards models estimated relative risks (RR) and 95% confidence intervals (CIs) associated with various measures of self-reported MHT use. We found no evidence that either estrogen therapy (ET)-only or estrogen plus progestin therapy (EPT) use was substantially related to subsequent lung cancer risk (respective RRs and 95% CIs for ever use = 0.97, 0.86-1.09 and 1.03, 0.90-1.17). There were no significant variations according to currency or duration of use of either formulation, nor was there evidence that risks varied within subgroups defined by cigarette smoking or body size. The absence of effect was seen for nearly all lung cancer subtypes, with the exception of an increased risk of undifferentiated/large cell cancers associated with long-term ET-only use (p (trend) = 0.02), a relationship not observed among EPT users. Our results failed to support any substantial alterations in lung cancer risk associated with use of either unopposed estrogen or estrogen plus progestin MHT, even when detailed exposure measures and other risk predictors were considered. C1 [Brinton, Louise A.; Schwartz, Lauren; Park, Yikyung; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Hollenbeck, Albert R.] AARP, Org & Tracking Res Dept, Washington, DC 20049 USA. RP Brinton, LA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 5018,Suite 550, Rockville, MD 20852 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016; OI Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522; Park, Yikyung/0000-0002-6281-489X FU NIH FX This investigation was supported by the Intramural Research Program of the NIH. NR 40 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2012 VL 23 IS 3 BP 487 EP 496 DI 10.1007/s10552-012-9904-2 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 900ML UT WOS:000300891100009 PM 22367699 ER PT J AU Weir, SJ DeGennaro, LJ Austin, CP AF Weir, Scott J. DeGennaro, Louis J. Austin, Christopher P. TI Repurposing Approved and Abandoned Drugs for the Treatment and Prevention of Cancer through Public-Private Partnership SO CANCER RESEARCH LA English DT Article C1 [Weir, Scott J.] Univ Kansas Canc Ctr, Inst Advancing Med Innovat, Kansas City, KS USA. [DeGennaro, Louis J.] Leukemia & Lymphoma Soc, White Plains, NY USA. [Austin, Christopher P.] NIH Ctr Translat Therapeut, Rockville, MD USA. RP Weir, SJ (reprint author), Kansas Masonic Canc Res, 3901 Rainbow Blvd,Mailstop 1027, Kansas City, KS 66160 USA. EM sweir@kumc.edu FU Intramural NIH HHS [ZIB HG200319-08] NR 6 TC 29 Z9 29 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2012 VL 72 IS 5 BP 1055 EP 1058 DI 10.1158/0008-5472.CAN-11-3439 PG 4 WC Oncology SC Oncology GA 901TG UT WOS:000300989100004 PM 22246671 ER PT J AU White, KL Schildkraut, JM Palmieri, RT Iversen, ES Berchuck, A Vierkant, RA Rider, DN Charbonneau, B Cicek, MS Sutphen, R Birrer, MJ Pharoah, PPD Song, H Tyrer, J Gayther, SA Ramus, SJ Wentzensen, N Yang, HP Garcia-Closas, M Phelan, CM Cunningham, JM Fridley, BL Sellers, TA Goode, EL AF White, Kristin L. Schildkraut, Joellen M. Palmieri, Rachel T. Iversen, Edwin S., Jr. Berchuck, Andrew Vierkant, Robert A. Rider, David N. Charbonneau, Bridget Cicek, Mine S. Sutphen, Rebecca Birrer, Michael J. Pharoah, Paul P. D. Song, Honglin Tyrer, Jonathan Gayther, Simon A. Ramus, Susan J. Wentzensen, Nicolas Yang, Hannah P. Garcia-Closas, Montserrat Phelan, Catherine M. Cunningham, Julie M. Fridley, Brooke L. Sellers, Thomas A. Goode, Ellen L. CA Ovarian Canc Assoc Consortium TI Ovarian Cancer Risk Associated with Inherited Inflammation-Related Variants SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER; POLYMORPHISMS; GENES; SUSCEPTIBILITY; SNPS AB The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes and risk of ovarian cancer. In a multisite case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (P-heterogeneity = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis. Cancer Res; 72(5); 1064-9. (C) 2012 AACR. C1 [Goode, Ellen L.] Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Rochester, MN 55905 USA. [White, Kristin L.] Columbia Univ, New York, NY 10027 USA. [Schildkraut, Joellen M.; Berchuck, Andrew] Duke Univ, Duke Comprehens Canc Ctr, Durham, NC 27706 USA. [Palmieri, Rachel T.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 USA. [Iversen, Edwin S., Jr.] Duke Univ, Dept Stat Sci, Durham, NC 27706 USA. [Sutphen, Rebecca] Univ S Florida, Coll Med, Tampa, FL 33620 USA. [Birrer, Michael J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Pharoah, Paul P. D.; Song, Honglin; Tyrer, Jonathan] Univ Cambridge, Cambridge CB2 1TN, England. [Gayther, Simon A.; Ramus, Susan J.] Univ So Calif, Los Angeles, CA 90089 USA. [Wentzensen, Nicolas; Yang, Hannah P.] NCI, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Sutton, Surrey, England. [Phelan, Catherine M.; Sellers, Thomas A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. RP Goode, EL (reprint author), Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. EM egoode@mayo.edu RI Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; OI Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Vierkant, Robert/0000-0001-6242-5221; Ramus, Susan/0000-0003-0005-7798 FU National Cancer Institute U19 Post-GWAS Initiative [U19-CA148112]; Mayo Clinic Ovarian Cancer SPORE [P50-CA136393]; National Cancer Institute [R01-CA086888, R01-CA122443, R01-CA106414, R01-CA76016, R01-CA114343]; Cancer Research UK [A10119, A10124, A8339, A6187, A11306, A7058]; Medical Research Council [G0801875-89310]; Ovarian Cancer Research Fund; Mayo Foundation FX The scientific development and funding for this project were in part supported by the National Cancer Institute U19 Post-GWAS Initiative (U19-CA148112), the Mayo Clinic Ovarian Cancer SPORE (P50-CA136393), National Cancer Institute Research Project Grants (R01-CA086888, R01-CA122443, R01-CA106414, R01-CA76016, R01-CA114343), Cancer Research UK (A10119, A10124, A8339, A6187, A11306, A7058), the Medical Research Council (G0801875-89310), the Ovarian Cancer Research Fund, and the Mayo Foundation. NR 20 TC 23 Z9 24 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2012 VL 72 IS 5 BP 1064 EP 1069 DI 10.1158/0008-5472.CAN-11-3512 PG 6 WC Oncology SC Oncology GA 901TG UT WOS:000300989100006 PM 22282663 ER PT J AU Gasperini, P Espigol-Frigole, G McCormick, PJ Salvucci, O Maric, D Uldrick, TS Polizzotto, MN Yarchoan, R Tosato, G AF Gasperini, Paola Espigol-Frigole, Georgina McCormick, Peter J. Salvucci, Ombretta Maric, Dragan Uldrick, Thomas S. Polizzotto, Mark N. Yarchoan, Robert Tosato, Giovanna TI Kaposi Sarcoma Herpesvirus Promotes Endothelial-to-Mesenchymal Transition through Notch-Dependent Signaling SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; E-CADHERIN; DNA-SEQUENCES; CANCER-CELLS; PROTEIN; TRANSFORMATION; ACTIVATION; INFECTION; BETA; DIFFERENTIATION AB Endothelial-to-mesenchymal transition (EndMT) is now widely considered a pivotal contributor to cancer progression. In this study, we show that the Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a sufficient cause of EndMT, potentially helping to explain the aggressiveness of KS that occurs commonly in AIDS patients. Upon KSHV infection, primary dermal microvascular endothelial cells lost expression of endothelial markers and acquired expression of mesenchymal markers, displaying new invasive and migratory properties along with increased survival. KSHV activated Notch-induced transcription factors Slug and ZEB1, and canonical Notch signaling was required for KSHV-induced EndMT. In contrast, KSHV did not utilize the TGF beta signaling pathway, which has also been linked to EndMT. Within KS lesions, KSHV-infected spindle cells displayed features compatible with KSHV-induced EndMT including a complex phenotype of endothelial and mesenchymal properties, Notch activity, and nuclear ZEB1 expression. Our results show that KSHV engages the EndMT program to increase the invasiveness and survival of infected endothelial cells, traits that likely contribute to viral persistence and malignant progression. One important implication of our findings is that therapeutic approaches to disrupt the Notch pathway may offer novel approaches for KS treatment. Cancer Res; 72(5); 1157-69. (C) 2012 AACR. C1 [Uldrick, Thomas S.; Polizzotto, Mark N.; Yarchoan, Robert] NINDS, NIH, NCI,CCR, Cellular Oncol Lab,HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Neurophysiol Lab, Bethesda, MD 20892 USA. RP Espigol-Frigole, G (reprint author), NINDS, NIH, NCI,CCR, Cellular Oncol Lab,HIV & AIDS Malignancy Branch, Bldg 37,Room 4134, Bethesda, MD 20892 USA. EM Georgina.Frigole@mail.nih.gov RI McCormick, Peter/E-7387-2012 OI McCormick, Peter/0000-0002-2225-5181 FU CCR/NCI/NIH; NINDS/NIH FX The work was supported by Intramural research program of CCR/NCI/NIH and NINDS/NIH. NR 50 TC 27 Z9 27 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2012 VL 72 IS 5 BP 1157 EP 1169 DI 10.1158/0008-5472.CAN-11-3067 PG 13 WC Oncology SC Oncology GA 901TG UT WOS:000300989100015 PM 22237624 ER PT J AU Weinstein, SJ Stolzenberg-Solomon, RZ Kopp, W Rager, H Virtamo, J Albanes, D AF Weinstein, Stephanie J. Stolzenberg-Solomon, Rachael Z. Kopp, William Rager, Helen Virtamo, Jarmo Albanes, Demetrius TI Impact of Circulating Vitamin D Binding Protein Levels on the Association between 25-Hydroxyvitamin D and Pancreatic Cancer Risk: A Nested Case-Control Study SO CANCER RESEARCH LA English DT Article ID PROSTATE-CANCER; GC-GLOBULIN; PLASMA 1,25-DIHYDROXYVITAMIN-D; SCREENING TRIAL; D METABOLITES; SERUM; LUNG; COHORT AB High concentrations of circulating 25-hydroxyvitamin D [25(OH)D] have been associated with elevated pancreatic cancer risk. As this is contrary to an expected inverse association between vitamin D status and cancer, we examined whether vitamin D binding protein (DBP), the primary carrier of vitamin D compounds in circulation, plays a role in this relationship. Prediagnostic serum DBP and 25(OH)D were studied in relation to risk of pancreatic cancer in a nested case-control study of 234 cases and 234 controls in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. ORs and 95% CIs were estimated using logistic regression, and statistical tests were two-sided. We found that DBP and 25(OH)D were correlated (r = 0.27, P < 0.0001), and DBP was inversely associated with pancreatic cancer risk (OR = 0.66, 95% CI = 0.39-1.12, for the highest vs. lowest quartile; P-trend = 0.02). Importantly, this association seemed to have a threshold between quartiles 2 to 4 and quartile 1, and was primarily evident among men with concurrent high 25(OH)D concentrations (OR = 0.33, 95% CI = 0.16-0.70 for highest vs. lowest quartile; P-trend = 0.002), with no association in men with lower serum 25(OH) D (OR 1.28, 95% CI = 0.62-2.61 for highest vs. lowest quartile, P-trend 0.63, P-interaction = 0.01). Men with higher 25(OH) D concentrations and serum DBP below the median showed greatly elevated risk of pancreatic cancer (OR = 5.01, 95% CI 2.33-10.78, for highest vs. lowest quartile; P-trend < 0.0001), while risk was weakly inversely associated with serum 25(OH) D when DBP concentrations were higher (P-interaction = 0.001). Taken together, our findings indicate that higher DBP concentrations may sequester more 25(OH) D and reduce free 25(OH) D bioavailability. Simultaneous examination of DBP and 25(OH) D may be important in determining the association of vitamin D with cancer risk. Cancer Res; 72(5); 1190-8. (C) 2012 AACR. C1 [Weinstein, Stephanie J.; Stolzenberg-Solomon, Rachael Z.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20982 USA. [Kopp, William; Rager, Helen] SAIC Frederick Inc, NCI Frederick, Clin Support Lab, Frederick, MD USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Albanes, D (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Executive Blvd,Suite 320, Bethesda, MD 20982 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015 FU National Cancer Institute (NCI) at the NIH; U.S. Public Health Service, NCI, NIH [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, HHSN261200800001E] FX This work was supported by the Intramural Research Program of the National Cancer Institute (NCI) at the NIH. In addition, this research was supported by U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, and HHSN261200800001E) from the NCI, NIH. NR 35 TC 37 Z9 38 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2012 VL 72 IS 5 BP 1190 EP 1198 DI 10.1158/0008-5472.CAN-11-2950 PG 9 WC Oncology SC Oncology GA 901TG UT WOS:000300989100018 PM 22232734 ER PT J AU Rosenberger, A Bickeboller, H McCormack, V Brenner, DR Duell, EJ Tjonneland, A Friis, S Muscat, JE Yang, P Wichmann, HE Heinrich, J Szeszenia-Dabrowska, N Lissowska, J Zaridze, D Rudnai, P Fabianova, E Janout, V Bencko, V Brennan, P Mates, D Schwartz, AG Cote, ML Zhang, ZF Morgenstern, H Oh, SS Field, JK Raji, O McLaughlin, JR Wiencke, J LeMarchand, L Neri, M Bonassi, S Andrew, AS Lan, Q Hu, W Orlow, I Park, BJ Boffetta, P Hung, RJ AF Rosenberger, Albert Bickeboeller, Heike McCormack, Valerie Brenner, Darren R. Duell, Eric J. Tjonneland, Anne Friis, Soren Muscat, Joshua E. Yang, Ping Wichmann, H-Erich Heinrich, Joachim Szeszenia-Dabrowska, Neonila Lissowska, Jolanta Zaridze, David Rudnai, Peter Fabianova, Eleonora Janout, Vladimir Bencko, Vladimir Brennan, Paul Mates, Dana Schwartz, Ann G. Cote, Michele L. Zhang, Zuo-Feng Morgenstern, Hal Oh, Sam S. Field, John K. Raji, Olaide McLaughlin, John R. Wiencke, John LeMarchand, Loic Neri, Monica Bonassi, Stefano Andrew, Angeline S. Lan, Qing Hu, Wei Orlow, Irene Park, Bernard J. Boffetta, Paolo Hung, Rayjean J. TI Asthma and lung cancer risk: a systematic investigation by the International Lung Cancer Consortium SO CARCINOGENESIS LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; NONMALIGNANT RESPIRATORY CONDITIONS; UNITED-STATES; NEVER-SMOKERS; NONSMOKING WOMEN; FAMILY-HISTORY; PROSPECTIVE COHORT; RESIDENTIAL RADON; DISTINCT DISEASES; META-REGRESSION AB Asthma has been hypothesized to be associated with lung cancer (LC) risk. We conducted a pooled analysis of 16 studies in the International Lung Cancer Consortium (ILCCO) to quantitatively assess this association and compared the results with 36 previously published studies. In total, information from 585 444 individuals was used. Study-specific measures were combined using random effects models. A meta-regression and subgroup meta-analyses were performed to identify sources of heterogeneity. The overall LC relative risk (RR) associated with asthma was 1.28 [95% confidence intervals (CIs) = 1.16-1.41] but with large heterogeneity (I-2 = 73%, P < 0.001) between studies. Among ILCCO studies, an increased risk was found for squamous cell (RR = 1.69, 95%, CI = 1.26-2.26) and for small-cell carcinoma (RR = 1.71, 95% CI = 0.99-2.95) but was weaker for adenocarcinoma (RR = 1.09, 95% CI = 0.88-1.36). The increased LC risk was strongest in the 2 years after asthma diagnosis (RR = 2.13, 95% CI = 1.09-4.17) but subjects diagnosed with asthma over 10 years prior had no or little increased LC risk (RR = 1.10, 95% CI = 0.94-1.30). Because the increased incidence of LC was chiefly observed in small cell and squamous cell lung carcinomas, primarily within 2 years of asthma diagnosis and because the association was weak among never smokers, we conclude that the association may not reflect a causal effect of asthma on the risk of LC. C1 [Rosenberger, Albert; Bickeboeller, Heike] Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, D-37073 Gottingen, Germany. [McCormack, Valerie; McLaughlin, John R.] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Brenner, Darren R.; McLaughlin, John R.; Hung, Rayjean J.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Brenner, Darren R.; Hung, Rayjean J.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A1, Canada. [Duell, Eric J.] Catalan Inst Oncol, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona, Spain. [Tjonneland, Anne; Friis, Soren] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Yang, Ping] Mayo Clin, Rochester, MN USA. [Wichmann, H-Erich; Heinrich, Joachim] Helmholtz Ctr Munich, Inst Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Szeszenia-Dabrowska, Neonila] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Zaridze, David] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Rudnai, Peter] Fodor Jozsef Natl Ctr Publ Hlth, Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, Eleonora] Specialized State Hlth Inst, Dept Occupat Hlth, Banska Bystrica, Slovakia. [Janout, Vladimir] Palacky Univ, Dept Prevent Med, Fac Med, CR-77147 Olomouc, Czech Republic. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Mates, Dana] Univ Med & Pharm Carol Davila, Bucharest, Romania. [Schwartz, Ann G.; Cote, Michele L.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Oh, Sam S.] Univ Calif San Francisco, Ctr Tobacco Control Res & Educ, San Francisco, CA 94143 USA. [Field, John K.] Univ Liverpool, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool L69 3BX, Merseyside, England. [Raji, Olaide; Wiencke, John] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [LeMarchand, Loic] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Neri, Monica] IRCCS San Raffaele Pisana, Unit Clin & Mol Epidemiol, Rome, Italy. [Andrew, Angeline S.] Dartmouth Med Sch, Norris Cotton Canc Ctr, Unit Biostat & Epidemiol, Dept Community & Family Med, Lebanon, NH USA. [Lan, Qing] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hu, Wei] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Orlow, Irene; Park, Bernard J.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Transit Epidemiol, New York, NY USA. [Hung, Rayjean J.] Int Prevent Res Inst, Lyon, France. RP Rosenberger, A (reprint author), Univ Med Gottingen, Abt Genet Epidemiol, Humboldtallee 32, D-37073 Gottingen, Germany. EM arosenb@gwdg.de; rayjean.hung@lunenfeld.ca RI Hung, Rayjean/A-7439-2013; McLaughlin, John/E-4577-2013; Zaridze, David/K-5605-2013; Hu, Wei/M-3524-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Neri, Monica/J-6308-2012; OI Orlow, Irene/0000-0001-6234-6961; Neri, Monica/0000-0003-4796-3675; Duell, Eric J/0000-0001-5256-0163; mates, dana/0000-0002-6219-9807; Lissowska, Jolanta/0000-0003-2695-5799; Field, John/0000-0003-3951-6365; bonassi, stefano/0000-0003-3833-6717 FU National Institute of Health [1U19CA148127-01, HIN-CA77118, NIH-CA80127, R01CA060691, NIH R01CA87895, NIH N01-PC35145, NIH P30CA22453]; German Research Foundation [GRK1034]; Canadian Cancer Society [CCSRI 020214]; Cancer Care Ontario Research Chair Award; Mayo Clinic (MAYO): Mayo Foundation Fund; Roy Castle Lung Cancer Foundation UK; Memorial Sloan-Kettering Cancer Center (MSKCC); Labrecque Foundation; Society of MSKCC; World Cancer Research Fund; European Commission [IC15-CT96-0313]; Polish State Committee for Scientific Research [SPUB-M-COPERNICUS/P-05/DZ-30/99/2000]; Wayne State University; Karmanos Cancer Institute [WSU/KCI-1, WSU/KCI-2]; University of California, San Francisco (UCSF): National Institutes of Environmental Health Sciences [ES06717]; NCI [CA-113710]; Danish Diet Cancer and Health Study (DDCHS); Danish Cancer Society; Helmholtz lung cancer study: German Federal Ministry of Education, Science, Research and Technology, State of Bavaria, National Genome Research Network, German Research Foundation [BI 576/2-1, BI 576/2-2]; Helmholtz Association; Federal office for Radiation Protection [STSch4454] FX National Institute of Health (1U19CA148127-01); the German Research Foundation (GRK1034); the Canadian Cancer Society (CCSRI 020214); Cancer Care Ontario Research Chair Award. The individual studies were supported by the following sources:; Mayo Clinic (MAYO): Mayo Foundation Fund and National Institute of Health (HIN-CA77118, NIH-CA80127 to P.Y.]; Liverpool Lung Project (LLP): Roy Castle Lung Cancer Foundation UK; Study of the Memorial Sloan-Kettering Cancer Center (MSKCC): Steps for Breath, the Labrecque Foundation and the Society of MSKCC; Central Europe study (CE): World Cancer Research Fund and the European Commission's INCO-COPERNICUS Program (contract number IC15-CT96-0313); The Warsaw part of CE: The Polish State Committee for Scientific Research (SPUB-M-COPERNICUS/P-05/DZ-30/99/2000); Studies of the Wayne State University, Karmanos Cancer Institute (WSU/KCI-1, WSU/KCI-2): National Institute of Health (R01CA060691, NIH R01CA87895, NIH N01-PC35145, NIH P30CA22453); Study of the University of California, San Francisco (UCSF): National Institutes of Environmental Health Sciences (ES06717); NCI (CA-113710 to S.S.O); Danish Diet Cancer and Health Study (DDCHS): Danish Cancer Society; Helmholtz lung cancer study: German Federal Ministry of Education, Science, Research and Technology, State of Bavaria, National Genome Research Network, German Research Foundation (BI 576/2-1, BI 576/2-2); Helmholtz Association and the Federal office for Radiation Protection (STSch4454). NR 96 TC 24 Z9 24 U1 2 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2012 VL 33 IS 3 BP 587 EP 597 DI 10.1093/carcin/bgr307 PG 11 WC Oncology SC Oncology GA 901SW UT WOS:000300988100014 PM 22198214 ER PT J AU Wellems, TE Fairhurst, RM AF Wellems, Thomas E. Fairhurst, Rick M. TI An evolving picture of the interactions between malaria parasites and their host erythrocytes SO CELL RESEARCH LA English DT Editorial Material ID FALCIPARUM-INFECTED ERYTHROCYTES; PLASMODIUM-FALCIPARUM; INVASION; HEMOGLOBIN; BINDING; PROTEIN-1; MEMBRANE; PFRH5 AB In patients with malaria, Plasmodium falciparum parasites multiply to enormous numbers in the bloodstream, initiating processes of erythrocyte destruction, endothelial activation and microvascular inflammation that cause devastating pathological effects on host tissues and organs. Recent research casts new light on a mechanism by which hemoglobin mutations may protect against these effects, and on a critical receptor-ligand interaction that provides fresh opportunities for the development of vaccines against blood-stage infection. C1 [Wellems, Thomas E.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Wellems, TE (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. EM twellems@niaid.nih.gov NR 18 TC 1 Z9 1 U1 0 U2 7 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYAND ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD MAR PY 2012 VL 22 IS 3 BP 453 EP 456 DI 10.1038/cr.2012.14 PG 4 WC Cell Biology SC Cell Biology GA 901DR UT WOS:000300942400004 PM 22270182 ER PT J AU Chepelev, I Wei, G Wangsa, D Tang, QS Zhao, KJ AF Chepelev, Iouri Wei, Gang Wangsa, Dara Tang, Qingsong Zhao, Keji TI Characterization of genome-wide enhancer-promoter interactions reveals co-expression of interacting genes and modes of higher order chromatin organization SO CELL RESEARCH LA English DT Article DE chromatin interactions; enhancers; promoters; ChIA-PET; 3C; H3K4me2 ID CCCTC-BINDING FACTOR; BETA-GLOBIN LOCUS; CHIP-SEQ DATA; TRANSCRIPTION; CTCF; SITES; EXPRESSION; DOMAINS; CELLS; METHYLATIONS AB Recent epigenomic studies have predicted thousands of potential enhancers in the human genome. However, there has not been systematic characterization of target promoters for these potential enhancers. Using H3K4me2 as a mark for active enhancers, we identified genome-wide EP interactions in human CD4(+) T cells. Among the 6 520 long-distance chromatin interactions, we identify 2 067 enhancers that interact with 1 619 promoters and enhance their expression. These enhancers exist in accessible chromatin regions and are associated with various histone modifications and polymerase II binding. The promoters with interacting enhancers are expressed at higher levels than those without interacting enhancers, and their expression levels are positively correlated with the number of interacting enhancers. Interestingly, interacting promoters are co-expressed in a tissue-specific manner. We also find that chromosomes are organized into multiple levels of interacting domains. Our results define a global view of EP interactions and provide a data set to further understand mechanisms of enhancer targeting and long-range chromatin organization. The Gene Expression Omnibus accession number for the raw and analyzed chromatin interaction data is GSE32677. C1 [Chepelev, Iouri; Wei, Gang; Tang, Qingsong; Zhao, Keji] NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. [Wangsa, Dara] NCI, Sect Canc Genom, NIH, Bethesda, MD 20892 USA. RP Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov FU Division of Intramural Research, NHLBI, National Institutes of Health, USA FX We thank our colleagues Brian Abraham, Alika Maunakea and Daniel Kraushaar for critical reading of the manuscript and Thomas Ried for suggestions. The paired-end sequencing was performed by the DNA Sequencing Core Facility of National Heart, Lung and Blood Institute (NHLBI). This work was supported by the Division of Intramural Research, NHLBI, National Institutes of Health, USA. NR 48 TC 77 Z9 79 U1 5 U2 22 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD MAR PY 2012 VL 22 IS 3 BP 490 EP 503 DI 10.1038/cr.2012.15 PG 14 WC Cell Biology SC Cell Biology GA 901DR UT WOS:000300942400007 PM 22270183 ER PT J AU Leung, JYK Bennett, WR Herbert, RP West, AK Lee, PR Wake, H Fields, RD Chuah, MI Chung, RS AF Leung, Jacqueline Y. K. Bennett, William R. Herbert, Rosalind P. West, Adrian K. Lee, Philip R. Wake, Hiroaki Fields, R. Douglas Chuah, Meng Inn Chung, Roger S. TI Metallothionein promotes regenerative axonal sprouting of dorsal root ganglion neurons after physical axotomy SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE Metallothionein; Neuronal injury; Neurite sprouting; Megalin; Dorsal root ganglion neurons ID NEURITE GROWTH; MEGALIN; RECEPTORS; PROTEIN; INJURY; FAMILY; ROLES; BRAIN AB Prior studies have reported that metallothionein I/II (MT) promote regenerative axonal sprouting and neurite elongation of a variety of central nervous system neurons after injury. In this study, we evaluated whether MT is capable of modulating regenerative axon outgrowth of neurons from the peripheral nervous system. The effect of MT was firstly investigated in dorsal root ganglion (DRG) explants, where axons were scratch-injured in the presence or absence of exogenous MT. The application of MT led to a significant increase in regenerative sprouting of neurons 16 h after injury. We show that the pro-regenerative effect of MT involves an interaction with the low-density lipoprotein receptor megalin, which could be blocked using the competitive antagonist RAP. Pre-treatment with the mitogen-activated protein kinase (MAPK) inhibitor PD98059 also completely abrogated the effect of exogenous MT in promoting axonal outgrowth. Interestingly, we only observed megalin expression in neuronal soma and not axons in the DRG explants. To investigate this matter, an in vitro injury model was established using Campenot chambers, which allowed the application of MT selectively into either the axonal or cell body compartments after scratch injury was performed to axons. At 16 h after injury, regenerating axons were significantly longer only when exogenous MT was applied solely to the soma compartment, in accordance with the localized expression of megalin in neuronal cell bodies. This study provides a clear indication that MT promotes axonal regeneration of DRG neurons, via a megalin-and MAPK-dependent mechanism. C1 [Leung, Jacqueline Y. K.; Bennett, William R.; Herbert, Rosalind P.; West, Adrian K.; Chuah, Meng Inn; Chung, Roger S.] Univ Tasmania, Menzies Res Inst, Hobart, Tas 7001, Australia. [Lee, Philip R.; Wake, Hiroaki; Fields, R. Douglas] NICHHD, NIH, Bethesda, MD 20892 USA. RP Chung, RS (reprint author), Univ Tasmania, Menzies Res Inst, Private Bag 24, Hobart, Tas 7001, Australia. EM rschung@utas.edu.au RI Chuah, Meng Inn/J-7671-2014 FU Australian Research Council [DP0984673]; National Health and Medical Research Council of Australia [544913]; Motor Accident and Insurance Board of Tasmania; Australian Academy of Sciences FX This research was supported by research grants from the Australian Research Council (DP0984673), the National Health and Medical Research Council of Australia (ID#544913), and the Motor Accident and Insurance Board of Tasmania. JYKL also received a travel fellowship from the Australian Academy of Sciences to visit the NIH (USA) to undertake some of the experiments reported in this study. NR 14 TC 6 Z9 7 U1 0 U2 5 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD MAR PY 2012 VL 69 IS 5 BP 809 EP 817 DI 10.1007/s00018-011-0790-7 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 898IR UT WOS:000300736400010 PM 21833580 ER PT J AU Kim, WG Guigon, CJ Fozzatti, L Park, JW Lu, CX Willingham, MC Cheng, SY AF Kim, Won Gu Guigon, Celine J. Fozzatti, Laura Park, Jeong Won Lu, Changxue Willingham, Mark C. Cheng, Sheue-yann TI SKI-606, an Src Inhibitor, Reduces Tumor Growth, Invasion, and Distant Metastasis in a Mouse Model of Thyroid Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID FOCAL ADHESION KINASE; BREAST-CANCER; IN-VIVO; SOLID MALIGNANCIES; PROSTATE-CANCER; TARGETING SRC; CELL-ADHESION; E-CADHERIN; CARCINOMA; PROGRESSION AB Purpose: Src is overexpressed or hyperactivated in a variety of human cancers, including thyroid carcinoma. Src is a central mediator in multiple signaling pathways that are important in oncogenesis and cancer progression. In this study, we evaluated the effects of an Src inhibitor, SKI-606 (bosutinib), in a spontaneous metastatic thyroid cancer model with constitutively activated Src (Thrb(PV/PV) Pten(+/-) mice). Experimental Design: Thrb(PV/PV) Pten(+/-) mice were treated with SKI-606 or vehicle controls, beginning at 6 weeks of age until the mice succumbed to thyroid cancer. We assessed the effects of SKI-606 on thyroid cancer progression and analyzed the impact of SKI-606 on aberrant Src-mediated signaling. Results: SKI-606 effectively inhibited aberrant activation of Src and its downstream targets to markedly inhibit the growth of thyroid tumor, thereby prolonging the survival of treated mice. While Src inhibition did not induce cell apoptosis, it decreased cell proliferation by affecting the expression of key regulators of cell-cycle progression. Importantly, SKI-606 dramatically prevented dedifferentiation, vascular invasion, and lung metastasis of thyroid cancer cells. These responses were meditated by downregulation of mitogen-activated protein kinase pathways and inhibition of the epithelial-mesenchymal transition. Conclusions: Our findings suggest that Src is critical in the progression of thyroid cancer, making oral SKI-606 a promising treatment strategy for refractory thyroid cancer. Clin Cancer Res; 18(5); 1281-90. (C)2012 AACR. C1 [Cheng, Sheue-yann] NCI, Gene Regulat Sect, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Willingham, Mark C.] Wake Forest Univ, Dept Pathol, Winston Salem, NC 27109 USA. RP Cheng, SY (reprint author), NCI, Gene Regulat Sect, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov OI Kim, Won Gu/0000-0002-8404-7759 FU Center for Cancer Research; National Cancer Institute,; NIH FX The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, NIH. NR 38 TC 17 Z9 17 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2012 VL 18 IS 5 BP 1281 EP 1290 DI 10.1158/1078-0432.CCR-11-2892 PG 10 WC Oncology SC Oncology GA 902LW UT WOS:000301040700012 PM 22271876 ER PT J AU Kim, JW Madan, RA Gulley, JL AF Kim, Joseph W. Madan, Ravi A. Gulley, James L. TI Initial PSA Oscillations Precede Prolonged Stable Disease in a Patient Treated With a Therapeutic Cancer Vaccine SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Immunologic response; Prostate Cancer; PROSTVAC; PSA-TRICOM ID RESISTANT PROSTATE-CANCER; SURVIVAL; IMMUNOTHERAPY; MEN AB Clinical Practice Points center dot In the absence of symptomatic or radiographic evidence of disease progression, the decision to change treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) should not be based solely on changes in PSA values. This is especially true for immune-based therapies, such as Vaccines, In Which Short-term Changes In Progression Are Often Not seen. center dot Phase II Data Suggest That PSA-TRICOM, a Therapeutic Cancer Vaccine, Can Improve Long-term Clinical Outcomes With Minimal Toxicity In Patients With mCRPC. center dot PSA-TRICOM Will Be Prospectively Evaluated In a Phase III, Double-blind, Placebo-controlled Clinical Trial In 1200 Patients With mCRPC, With Overall Survival As the Primary Endpoint. C1 [Kim, Joseph W.; Madan, Ravi A.; Gulley, James L.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kim, Joseph W.; Madan, Ravi A.; Gulley, James L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Rm 13N208,MSC-1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010666-04] NR 15 TC 2 Z9 2 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD MAR PY 2012 VL 10 IS 1 BP 43 EP 46 DI 10.1016/j.clgc.2011.09.003 PG 4 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 902KG UT WOS:000301036400008 PM 22019260 ER PT J AU McEwing, R Kitchener, AC Holleley, C Kilshaw, K O'Donoghue, P AF McEwing, Ross Kitchener, Andrew C. Holleley, Clare Kilshaw, Kerry O'Donoghue, Paul TI An allelic discrimination SNP assay for distinguishing the mitochondrial lineages of European wildcats and domestic cats SO CONSERVATION GENETICS RESOURCES LA English DT Article DE Wildcat; SNP; Introgression; Felis silvestris ID SCOTTISH WILDCAT AB Here we present an allelic discrimination assay designed to distinguish European wildcat mtDNA lineages from those of the domestic cat. Introgression between the native wildcat and introduced domestic cat has the potential to limit and reduce the recent recovery of remnant populations. Applied conservation genetic techniques can aid current conservation decisions on lethal control and neutering measures in hybrid zones. This real-time PCR technique offers a rapid, inexpensive and reliable assay to assess mtDNA introgression in the wild and has already identified hybrid individuals in the Scottish wildcat captive breeding programme. C1 [McEwing, Ross] Royal Zool Soc Scotland, WildGenes Lab, Edinburgh EH12 6TS, Midlothian, Scotland. [Kitchener, Andrew C.] Natl Museum Scotland, Dept Nat Sci, Edinburgh EH1 1JF, Midlothian, Scotland. [Holleley, Clare] NCI, Lab Genom Div, Frederick, MD 21702 USA. [Kilshaw, Kerry] Univ Oxford, Wildlife Conservat Res Unit, Dept Zool, Oxford OX13 5QL, Oxon, England. [O'Donoghue, Paul] Univ Chester, Dept Biol Sci, Chester CH1 4BJ, Cheshire, England. RP McEwing, R (reprint author), Royal Zool Soc Scotland, WildGenes Lab, 134 Corstorphine Rd, Edinburgh EH12 6TS, Midlothian, Scotland. EM rmcewing@rzss.org.uk RI Holleley, Clare/C-4629-2011 OI Holleley, Clare/0000-0002-5257-0019 FU Royal Zoological Society of Scotland FX The authors are grateful to Neville Buck, Douglas Richardson, David Hetherington, Steve Piper and Rob Ogden. The work was funded by the Royal Zoological Society of Scotland. NR 6 TC 1 Z9 1 U1 1 U2 51 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1877-7252 J9 CONSERV GENET RESOUR JI Conserv. Genet. Resour. PD MAR PY 2012 VL 4 IS 1 BP 163 EP 165 DI 10.1007/s12686-011-9499-z PG 3 WC Biodiversity Conservation; Genetics & Heredity SC Biodiversity & Conservation; Genetics & Heredity GA 898WG UT WOS:000300772500039 ER PT J AU Nguyen, SA Walker, D Gillespie, MB Gutkind, JS Day, TA AF Nguyen, Shaun A. Walker, David Gillespie, M. Boyd Gutkind, J. Silvio Day, Terry A. TI mTOR Inhibitors and its Role in the Treatment of Head and Neck Squamous Cell Carcinoma SO CURRENT TREATMENT OPTIONS IN ONCOLOGY LA English DT Article DE mTOR inhibitors; temsirolimus; everolimus; deforolimus; head and neck squamous cell carcinomas ID PHASE-I TRIAL; MAMMALIAN TARGET; ADVANCED MALIGNANCIES; AKT/MAMMALIAN TARGET; SIROLIMUS RAPAMYCIN; CANCER-THERAPY; PATHWAY; EVEROLIMUS; PHOSPHORYLATION; ACTIVATION AB Head and neck squamous cell carcinomas (HNSCC) represent 6% of all cancers diagnosed each year in the United States, affecting approximately 43,000 new patients and resulting in approximately 12,000 deaths. Currently, three main rapalogs exist for the treatment of cancer: CCI-779 (temsirolimus), RAD001 (everolimus), and AP235373 (deforolimus). Clinicians managing HNSCC need to be aware of the three rapalogs. Extensive evidence has shown rapamycin-analogs to be effective agents in the treatment of a number of solid tumors. While extensive preclinical data suggests that HNSCC would be an appropriate tumor type to benefit from inhibition of the mTOR pathway, limited clinical data is yet available to support this. Numerous phase II trials evaluating mTOR inhibitors for use in HNSCC are currently recruiting patients. C1 [Nguyen, Shaun A.; Walker, David; Gillespie, M. Boyd; Day, Terry A.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. [Walker, David] Rush Med Coll, Chicago, IL 60612 USA. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Nguyen, SA (reprint author), Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. EM nguyensh@musc.edu NR 35 TC 26 Z9 26 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1527-2729 J9 CURR TREAT OPTION ON JI Curr. Treat. Options Oncol. PD MAR PY 2012 VL 13 IS 1 BP 71 EP 81 DI 10.1007/s11864-011-0180-2 PG 11 WC Oncology SC Oncology GA 898WK UT WOS:000300772900007 PM 22282394 ER PT J AU Yaguchi, J Angerer, LM Inaba, K Yaguchi, S AF Yaguchi, Junko Angerer, Lynne M. Inaba, Kazuo Yaguchi, Shunsuke TI Zinc finger homeobox is required for the differentiation of serotonergic neurons in the sea urchin embryo SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Neurogenesis; Serotonin; FoxQ2; Nodal; Delta; Notch; Lateral inhibition ID ORAL-ABORAL AXIS; NERVOUS-SYSTEM; STRONGYLOCENTROTUS-PURPURATUS; STEM-CELLS; C-ELEGANS; EXPRESSION PATTERNS; NEURAL INDUCTION; BETA-CATENIN; ANIMAL PLATE; GENE AB Serotonergic neurons differentiate in the neurogenic animal plate ectoderm of the sea urchin embryo. The regulatory mechanisms that control the specification or differentiation of these neurons in the sea urchin embryo are not yet understood, although, after the genome was sequenced, many genes encoding transcription factors expressed in this region were identified. Here, we report that zinc finger homeobox (zfhx1/z81) is expressed in serotonergic neural precursor cells, using double in situ hybridization screening with a serotonergic neural marker, tryptophan 5-hydroxylase (tph) encoding a serotonin synthase that is required for the differentiation of serotonergic neurons. zfhx1/z81 begins to be expressed at gastrula stage in individual cells in the anterior neuroectoderm, some of which also express delta. zfhx1/z81 expression gradually disappears as neural differentiation begins with tph expression. When the translation of Zfhx1/Z81 is blocked by morpholino injection, embryos express neither tph nor the neural marker synaptotagminB in cells of the animal plate, and serotonergic neurons do not differentiate. In contrast, Zfhx1/Z81 morphants do express fez, another neural precursor marker, which appears to function in the initial phase of specification/differentiation of serotonergic neurons. In addition, zfhx1/z81 is one of the targets suppressed in the animal plate by anti-neural signals such as Nodal as well as Delta-Notch. We conclude that Zfhx1/Z81 functions during the specification of individual anterior neural precursors and promotes the expression of tph and synaptotagminB, required for the differentiation of serotonergic neurons. (C) 2011 Elsevier Inc. All rights reserved. C1 [Yaguchi, Junko; Inaba, Kazuo; Yaguchi, Shunsuke] Univ Tsukuba, Shimoda Marine Res Ctr, Shizuoka 4150025, Japan. [Yaguchi, Junko; Yaguchi, Shunsuke] Univ Tsukuba, Initiat Promot Young Scientists Independent Res, Shizuoka 4150025, Japan. [Angerer, Lynne M.] Natl Inst Dent & Craniofacial Res, Dev Mech Sect, NIH, Bethesda, MD 20892 USA. RP Yaguchi, S (reprint author), Univ Tsukuba, Shimoda Marine Res Ctr, 5-10-1 Shimoda, Shizuoka 4150025, Japan. EM yag@kurofune.shimoda.tsukuba.ac.jp OI Yaguchi, Shunsuke/0000-0002-8326-5762 FU Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (MEXT) [22370023]; Takeda Science Foundation; MEXT [22370023]; National Institutes of Health, National Institute for Dental and Craniofacial Research; [21770227]; [23770241]; [23-3584] FX We thank Robert Angerer for fruitful comments on this manuscript and Robert Burke, Yoko Nakajima, and David McClay for essential reagents. We thank Masato Kiyomoto and Mamoru Yamaguchi for providing the adult sea urchins and Mrs. Y. Tsuchiya, T. Sato, H, Shinagawa, and Y. Yamada, Shimoda Marine Research Center, for collecting and keeping the adult sea urchins. This work was supported, in part, by Special Coordination Funds for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (MEXT), by Grant-in Aid for Young Scientists (B No. 21770227 and No. 23770241), and Takeda Science Foundation to S.Y., in part by MEXT (No. 22370023) to K.I., and in part by the Intramural Program of the National Institutes of Health, National Institute for Dental and Craniofacial Research, to L.M.A. J.Y. was a Predoctoral Fellow of JSPS with research grant (23-3584). NR 54 TC 9 Z9 9 U1 2 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAR 1 PY 2012 VL 363 IS 1 BP 74 EP 83 DI 10.1016/j.ydbio.2011.12.024 PG 10 WC Developmental Biology SC Developmental Biology GA 900AA UT WOS:000300857800007 PM 22210002 ER PT J AU Galanopoulou, AS Buckmaster, PS Staley, KJ Moshe, SL Perucca, E Engel, J Loscher, W Noebels, JL Pitkanen, A Stables, J White, HS O'Brien, TJ Simonato, M AF Galanopoulou, Aristea S. Buckmaster, Paul S. Staley, Kevin J. Moshe, Solomon L. Perucca, Emilio Engel, Jerome, Jr. Loescher, Wolfgang Noebels, Jeffrey L. Pitkanen, Asla Stables, James White, H. Steve O'Brien, Terence J. Simonato, Michele CA Amer Epilepsy Soc Basic Sci Comm Int League Epilepsy Working Grp TI Identification of new epilepsy treatments: Issues in preclinical methodology SO EPILEPSIA LA English DT Article DE Antiseizure drug; Antiepileptogenesis; Disease modification; Comorbidities; Biomarkers ID TEMPORAL-LOBE EPILEPSY; INFANTILE SPASMS; ANTIEPILEPTIC DRUGS; PERSISTENT SEIZURES; FUTURE-DIRECTIONS; FEBRILE SEIZURES; ANIMAL-MODEL; RODENT MODEL; MOUSE MODEL; EPILEPTOGENESIS AB Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities. C1 [Galanopoulou, Aristea S.; Moshe, Solomon L.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Saul R Korey Dept Neurol, Lab Dev Epilepsy,Montefiore Einstein Epilepsy Man, Bronx, NY 10461 USA. [Buckmaster, Paul S.] Stanford Univ, Dept Comparat Med & Neurol, Stanford, CA 94305 USA. [Buckmaster, Paul S.] Stanford Univ, Dept Neurol Sci, Stanford, CA 94305 USA. [Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Staley, Kevin J.] Harvard Univ, Sch Med, Boston, MA USA. [Moshe, Solomon L.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. [Perucca, Emilio] Univ Pavia, Dept Internal Med & Therapeut, Clin Pharmacol Unit, I-27100 Pavia, Italy. [Perucca, Emilio] IRCCS C Mondino Fdn, Natl Neurol Inst, Pavia, Italy. [Engel, Jerome, Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Engel, Jerome, Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Engel, Jerome, Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [Engel, Jerome, Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. [Loescher, Wolfgang] Univ Vet Med, Dept Pharmacol Toxicol & Pharm, Hannover, Germany. [Noebels, Jeffrey L.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Pitkanen, Asla] Univ Eastern Finland, AI Virtanen Inst Mol Sci, Epilepsy Res Lab, Kuopio, Finland. [Pitkanen, Asla] Kuopio Univ Hosp, Dept Neurol, SF-70210 Kuopio, Finland. [Stables, James] NINDS, ASP, NIH, Bethesda, MD 20892 USA. [White, H. Steve] Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84112 USA. [O'Brien, Terence J.] Univ Melbourne, Dept Med, Royal Melbourne Hosp, Parkville, Vic 3052, Australia. [O'Brien, Terence J.] Univ Melbourne, Royal Melbourne Hosp, Dept Neurol, Parkville, Vic, Australia. [Simonato, Michele] Univ Ferrara, Dept Clin & Expt Med, Pharmacol Sect, I-44100 Ferrara, Italy. [Simonato, Michele] Univ Ferrara, Ctr Neurosci, I-44100 Ferrara, Italy. [Simonato, Michele] Natl Inst Neurosci, Palermo, Italy. RP Galanopoulou, AS (reprint author), Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Saul R Korey Dept Neurol, Lab Dev Epilepsy,Montefiore Einstein Epilepsy Man, 1410 Pelham Pkwy S,Kennedy Ctr Rm 306, Bronx, NY 10461 USA. EM aristea.galanopoulou@einstein.yu.edu RI French, Jacqueline/G-6795-2013; O'Brien, Terence/L-8102-2013; OI Noebels, Jeffrey /0000-0002-2887-0839; French, Jacqueline/0000-0003-2242-8027; O'Brien, Terence/0000-0002-7198-8621 FU NIH NINDS/NICHD [NS62947]; Johnson Johnson; Novartis; NIH [R01 NS20253, R01-NS43209, 2UO1-NS45911, P01 NS02808, R01 NS33310, U01 NS42372]; Heffer Family Foundation; Eisai; GlaxoSmithKline; Bial; Pfizer; UCB Pharma; Upsher-Smith; Vertex; Italian Ministry of Health; Italian Ministry for University and Research; Italian Medicines Agency; European Commission of the EU; NeuroAdjuvants, Inc.; Janssen-Cilag; Sanofi-Synthelabo; Chiesi Pharmaceuticals (Italy); Schering-Plough FX ASG has received research support from NIH NINDS/NICHD grant NS62947 (PI) and recent research grant by Johnson & Johnson. ASG has also received consultancy fees from Novartis and royalties from Morgan and Claypool Life Sciences. PSB has nothing to disclose. KJS has nothing to disclose. SLM has received research support from NIH: R01 NS20253 (PI), R01-NS43209 (Investigator), 2UO1-NS45911 (Investigator), and the Heffer Family Foundation. SLM is serving on the Editorial Board of Neurobiology of Disease, Epileptic Disorders, Brain and Development, and Physiological Research and has received a consultancy fee from Eisai and speaker's fee and travel from GlaxoSmithKline. EP received speaker's or consultancy fees and/or research grants from Bial, Eisai, GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, Pfizer, UCB Pharma, Upsher-Smith, and Vertex. EP receives research support from the Italian Ministry of Health, the Italian Ministry for University and Research, the Italian Medicines Agency, and the European Commission of the EU. EP also serves on the editorial boards of Acta Neurologica Scandinavica, CNS Drugs, Epileptic Disorders, Epilepsy Research, Seizure, Lancet Neurology, Expert Reviews in Neurotherapeutics, Clinical Pharmacokinetics, Therapeutic Advances in Drug Safety, Frontiers in Clinical Trials and Pharmacotherapy, and Clinical Drug Investigation. JEJr has received research funding from NIH grants P01 NS02808, R01 NS33310, U01 NS42372, honoraria from Medtronic, Eisai, Johnson & Johnson, Lippincottand royalties from Medlink, Wolters-Kluwer, Blackwell, and Elsevier. WL has nothing to disclose. JLN has nothing to disclose. AP has nothing to disclose. JS has nothing to disclose. HSW has served as a paid consultant to Johnson & Johnson Pharmaceutical Research and Development, GlaxoSmithKline, Valeant Pharmaceuticals, Eli Lilly & Co., and Upsher-Smith Laboratories, Inc., is a member of the UCB Pharma Speakers Bureau, the NeuroTherapeutics Scientific Advisory Board, has received research funding from NeuroAdjuvants, Inc., and is one of two scientific cofounders of NeuroAdjuvants, Inc., Salt Lake City, UT. TJO'B has received unrestricted research grants from UCB Pharma Janssen-Cilag, Sanofi-Synthelabo, and Novartis. TJO'B has received speaking honorarium from UCB Pharma Janssen-Cilag, Sanofi-Synthelabo, and SciGen. MS has received research funding from GlaxoSmithKline, Chiesi Pharmaceuticals (Italy), Sanofi-Synthelabo, and Schering-Plough. We confirm that we have read the Journal's position on issues relating to ethical publication. This statement is consistent with these guidelines NR 61 TC 85 Z9 87 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD MAR PY 2012 VL 53 IS 3 BP 571 EP 582 DI 10.1111/j.1528-1167.2011.03391.x PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 899TF UT WOS:000300838400023 PM 22292566 ER PT J AU Hesdorffer, CS Malchinkhuu, E Biragyn, A Mabrouk, OS Kennedy, RT Madara, K Taub, DD Longo, DL Schwartz, JB Ferrucci, L Goetzl, EJ AF Hesdorffer, Charles S. Malchinkhuu, Enkhzol Biragyn, Arya Mabrouk, Omar S. Kennedy, Robert T. Madara, Karen Taub, Dennis D. Longo, Dan L. Schwartz, Janice B. Ferrucci, Luigi Goetzl, Edward J. TI Distinctive immunoregulatory effects of adenosine on T cells of older humans SO FASEB JOURNAL LA English DT Article DE cytokines; cellular antigens; chemotaxis; immunosenescence; immunodeficiency ID IMMUNE SUPPRESSION; LYMPHOCYTES; EXPRESSION; ACTIVATION; CD39; CD73; INTERLEUKIN-2 AB A role for adenosine in immunosenescence was investigated in T cells from older (>= 65 yr) and younger (24-45 yr) healthy humans. Adenosine concentrations in cultures of activated T cells were significantly higher (P<0.0001) for older (145 +/- 47 nM, mean +/- SD) than younger (58 +/- 5.5 nM) subjects. Expression of the activation coreceptor CD28 was suppressed significantly by 0.1 to 1 mu M exogenous adenosine, with greater effects of 1 mu M (P<0.01) on T cells of younger (mean suppression of 67 and 65% for CD4 and CD8 T cells, respectively) than older (means of 42 and 46%) subjects. T-cell chemotaxis to CCL21 was suppressed significantly by 0.3 and 1 mu M exogenous adenosine, with mean maximum decreases of 39 and 49%, respectively, for younger subjects and 28 and 31% for older subjects. Generation of IL-2 and IFN-gamma by T cells of younger and older subjects was suppressed substantially only at adenosine levels of 3 mu M or higher. Lower baseline expression of CD28 and chemotaxis to CCL21 and S1P for T cells from older subjects attributable to endogenous adenosine were reversed completely by two different A(2A) adenosine receptor antagonists without affecting T cells of younger subjects. Adenosine is an endogenous T-cell immunosuppressor in older humans, and A(2A) antagonists reverse adenosine-induced T-cell deficiencies of aging.-Hesdorffer, H. S., Malchinkhuu, E., Biragyn, A., Mabrouk, O. S., Kennedy, R. T., Madara, K., Taub, D. D., Longo, D. L., Schwartz, J. B., Ferrucci, L., Goetzl, E. J. Distinctive immunoregulatory effects of adenosine on T cells of older humans. FASEB J. 26, 1301-1310 (2012). www.fasebj.org C1 [Goetzl, Edward J.] JHSF, Geriatr Res Ctr, Geriatr Res Labs, San Francisco, CA 94112 USA. [Hesdorffer, Charles S.; Malchinkhuu, Enkhzol; Biragyn, Arya; Madara, Karen; Taub, Dennis D.; Longo, Dan L.; Ferrucci, Luigi; Goetzl, Edward J.] NIA, NIH, Baltimore, MD 21224 USA. [Mabrouk, Omar S.; Kennedy, Robert T.] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Schwartz, Janice B.; Goetzl, Edward J.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Goetzl, EJ (reprint author), JHSF, Geriatr Res Ctr, Geriatr Res Labs, 302 Silver Ave, San Francisco, CA 94112 USA. EM edward.goetzl@ucsf.edu RI Kennedy, Robert/G-9095-2016 OI Kennedy, Robert/0000-0003-2447-7471 FU U.S. National Institute on Aging; Jewish Home of San Francisco FX This research was supported by the intramural research program of the U.S. National Institute on Aging and endowment funds of the Jewish Home of San Francisco. The authors are grateful to Judith H. Goetzl for preparation of the figures and tables. C. S. H., E. M., A. B., O.S.M., R. T. K., J.B.S., and E.J.G. designed research; C. S. H., K. M., J.B.S., and L. F. evaluated and selected subjects; C. S. H., E. M., O.S.M., D. D. T., and E.J.G. performed laboratory research; C. S. H., E. M., O.S.M., D. L. L., L. F., and E.J.G. analyzed data and wrote the paper. NR 26 TC 5 Z9 5 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAR PY 2012 VL 26 IS 3 BP 1301 EP 1310 DI 10.1096/fj.11-197046 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 901FY UT WOS:000300949300032 PM 22121051 ER PT J AU Liao, LM Vaughan, TL Corley, DA Cook, MB Casson, AG Kamangar, F Abnet, CC Risch, HA Giffen, C Freedman, ND Chow, WH Sadeghi, S Pandeya, N Whiteman, DC Murray, LJ Bernstein, L Gammon, MD Wu, AH AF Liao, Linda M. Vaughan, Thomas L. Corley, Douglas A. Cook, Michael B. Casson, Alan G. Kamangar, Farin Abnet, Christian C. Risch, Harvey A. Giffen, Carol Freedman, Neal D. Chow, Wong-Ho Sadeghi, Shahram Pandeya, Nirmala Whiteman, David C. Murray, Liam J. Bernstein, Leslie Gammon, Marilie D. Wu, Anna H. TI Nonsteroidal Anti-inflammatory Drug Use Reduces Risk of Adenocarcinomas of the Esophagus and Esophagogastric Junction in a Pooled Analysis SO GASTROENTEROLOGY LA English DT Article DE BEACON; Esophageal Neoplasm; Stomach Cancer; Anti-Inflammatory Agent ID SELECTIVE CYCLOOXYGENASE-2 INHIBITION; BARRETTS-ESOPHAGUS; GASTRIC-CANCER; INCREASED EXPRESSION; RANDOMIZED-TRIAL; UNITED-STATES; ASPIRIN; METAANALYSIS; CHEMOPREVENTION; PREVENTION AB BACKGROUND & AIMS: Regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported to reduce risks of esophageal adenocarcinoma (EAC) and esophagogastric junctional adenocarcinoma (EGJA). However, individual studies have been too small to accurately assess the effects of medication type, frequency, or duration of use. We performed a pooled analysis to investigate these associations. METHODS: We performed a pooled analysis of 6 population-based studies within the Barrett's and Esophageal Adenocarcinoma Consortium to evaluate the association between NSAID use and the risk of EAC and EGJA, using uniform exposure definitions. We collected information from 6 studies (5 case-control and 1 cohort), with a total of 1226 EAC and 1140 EGJA cases, on aspirin and/or NSAID use. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate adjusted logistic regression models and then pooled using a random effects meta-analysis model. RESULTS: Compared with nonusers, individuals who have used NSAIDs had a statistically significant reduced risk of EAC (OR, 0.68; 95% CI, 0.56-0.83); they also appeared to have a reduced risk of EGJA (OR, 0.83; 95% CI, 0.66-1.03). Similar reductions in risk were observed among individuals who took aspirin or nonaspirin NSAIDs. The highest levels of frequency (daily or more frequently) and duration (>= 10 years) of NSAID use were associated with an approximately 40% reduction in risk of EAC, with ORs of 0.56 (95% CI, 0.43-0.73; P-trend < .001) and 0.63 (95% CI, 0.45-0.90; P-trend = .04), respectively. CONCLUSIONS: Although reverse causation could, in part, explain the inverse association observed between NSAID use and EAC risk, our pooled analysis suggests a possible role for NSAIDs in prevention of adenocarcinomas of the esophagus and esophagogastric junction. C1 [Liao, Linda M.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Corley, Douglas A.] Kaiser Permanente, Div Res, Oakland, CA USA. [Corley, Douglas A.] Kaiser Permanente, Oakland Med Ctr, Oakland, CA USA. [Casson, Alan G.] Univ Saskatchewan, Dept Surg, Saskatoon, SK, Canada. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Anal, Baltimore, MD 21239 USA. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD USA. [Sadeghi, Shahram; Pandeya, Nirmala; Whiteman, David C.] Queensland Inst Med Res, Div Genet & Populat Hlth, Brisbane, Qld 4006, Australia. [Murray, Liam J.] Queens Univ, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Dept Populat Sci, Duarte, CA USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Wu, Anna H.] USC Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. RP Liao, LM (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS Room 8003, Rockville, MD 20852 USA. EM liaolm@mail.nih.gov RI Liao, Linda/B-3960-2011; Cook, Michael/A-5641-2009; Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Whiteman, David/P-2728-2014; Pandeya, Nirmala/F-8054-2010 OI Cook, Michael/0000-0002-0533-7302; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Whiteman, David/0000-0003-2563-9559; Liao, Linda/0000-0002-1923-5294; Pandeya, Nirmala/0000-0003-1462-4968 FU National Institutes of Health (NIH); California Tobacco-Related Research Program [3RT-0122, 10RT-0251]; National Cancer Institute [CA59636]; Nova Scotia Health Research Foundation [N419]; Ireland-Northern Ireland Co-operation Research Project; Northern Ireland Research and Development Office; Health Research Board, Ireland; Queensland Cancer Fund; National Health and Medical Research Council of Australia [199600]; [U01-CA57949]; [U01-CA57983]; [U01-CA57923] FX Supported in part by the Intramural Program of the National Institutes of Health (NIH). The US Multicenter Study was funded by U01-CA57949 (to T. L. V.), U01-CA57983 (to M. D. G.), and U01-CA57923 (to H. A. R). The Los Angeles County Multi-ethnic Study was funded by 3RT-0122 ("Smoking and Risk of Proximal Vs. Distal Gastric Cancer," to A. H. W.) and 10RT-0251 ("Smoking, microsatellite instability & gastric cancers," to A. H. W.) from the California Tobacco-Related Research Program and CA59636 (to L. B.) from the National Cancer Institute. The Nova Scotia Barrett Esophagus Study was supported by the Nova Scotia Health Research Foundation ("Molecular mechanisms and lifestyle risk factor interactions in the pathogenesis of human esophageal adenocarcinoma," N419, to A. G. C.). The Factors Influencing the Barrett's Adenocarcinoma Relationship Study was funded by an Ireland-Northern Ireland Co-operation Research Project Grant sponsored by the Northern Ireland Research and Development Office, and the Health Research Board, Ireland (All-Ireland case-control study of Oesophageal Adenocarcinoma and Barrett's Oesophagus, to L.J.M. and Harry Comber). The Australian Study of Esophageal Cancer was supported by the Queensland Cancer Fund and the National Health and Medical Research Council of Australia (program no. 199600, to D. C. W., Adele C. Green, Nicholas K. Hayward, Peter G. Parsons, David M. Purdie, and Penelope M. Webb). The NIH-AARP Diet and Health Study was funded by the Intramural Program of the NIH. NR 45 TC 48 Z9 50 U1 0 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2012 VL 142 IS 3 BP 442 EP U85 DI 10.1053/j.gastro.2011.11.019 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 898XC UT WOS:000300774700022 PM 22108196 ER PT J AU Woo, DH Kim, SK Lim, HJ Heo, J Park, HS Kang, GY Kim, SE You, HJ Hoeppner, DJ Kim, Y Kwon, H Choi, TH Lee, JH Hong, SH Song, KW Ahn, EK Chenoweth, JG Tesar, PJ McKay, RDG Kim, JH AF Woo, Dong-Hun Kim, Suel-Kee Lim, Hee-Joung Heo, Jeonghoon Park, Hyung Soon Kang, Gum-Yong Kim, Sung-Eun You, Hyun-Ju Hoeppner, Daniel J. Kim, Youngchul Kwon, Heechung Choi, Tae Hyun Lee, Joo Hee Hong, Su Hee Song, Kang Won Ahn, Eun-Kyung Chenoweth, Josh G. Tesar, Paul J. McKay, Ronald D. G. Kim, Jong-Hoon TI Direct and Indirect Contribution of Human Embryonic Stem Cell-Derived Hepatocyte-Like Cells to Liver Repair in Mice SO GASTROENTEROLOGY LA English DT Article DE hES Cells; Hepatitis; Mouse Model; Stem Cell Therapy ID IN-VITRO; ANIMAL-MODELS; REGENERATION; DIFFERENTIATION; INJURY; EXPRESSION; MECHANISM; TRANSPLANTATION; NEOVASCULARIZATION; FIBROSIS AB BACKGROUND & AIMS: Many studies of embryonic stem cells have investigated direct cell replacement of damaged tissues, but little is known about how donor cell-derived signals affect host tissue regeneration. We investigated the direct and indirect roles of human embryonic stem cell-derived cells in liver repair in mice. METHODS: To promote the initial differentiation of human embryonic stem cells into mesendoderm, we activated the beta-catenin signaling pathway with lithium; cells were then further differentiated into hepatocyte-like cells. The differentiated cells were purified by indocyanine green staining and laser microdissection and characterized by immunostaining, polymerase chain reaction, biochemical function, electron microscopy, and transplantation analyses. To investigate indirect effects of these cells, secreted proteins (secretomes) were analyzed by a label-free quantitative mass spectrometry. Carbon tetrachloride was used to induce acute liver injury in mice; cells or secreted proteins were administered by intrasplenic or intraperitoneal injection, respectively. RESULTS: The differentiated hepatocyte-like cells had multiple features of normal hepatocytes, engrafted efficiently into mice, and continued to have hepatic features; they promoted proliferation of host hepatocytes and revascularization of injured host liver tissues. Proteomic analysis identified proteins secreted from these cells that might promote host tissue repair. Injection of the secreted proteins into injured livers of mice promoted significant amounts of tissue regeneration without cell grafts. CONCLUSIONS: Hepatocyte-like cells derived from human embryonic stem cells contribute to recovery of injured liver tissues in mice, not only by cell replacement but also by delivering trophic factors that support endogenous liver regeneration. C1 [Woo, Dong-Hun; Kim, Suel-Kee; Lim, Hee-Joung; Kim, Sung-Eun; You, Hyun-Ju; Kim, Jong-Hoon] Korea Univ, Coll Life Sci & Biotechnol, Div Biotechnol, Lab Stem Cell Biol, Seoul 136713, South Korea. [Kim, Youngchul] Korea Univ, Coll Med, Dept Surg, Seoul 136713, South Korea. [Kim, Suel-Kee; Hoeppner, Daniel J.; Chenoweth, Josh G.; Tesar, Paul J.; McKay, Ronald D. G.] Natl Inst Neurol Disorders & Stroke, Mol Biol Lab, NIH, Bethesda, MD USA. [Heo, Jeonghoon; Ahn, Eun-Kyung] Kosin Univ, Coll Med, Dept Mol Biol & Immunol, Pusan, South Korea. [Park, Hyung Soon; Kang, Gum-Yong] Diatech Korea Co Ltd, Seoul, South Korea. [Kwon, Heechung; Lee, Joo Hee] Korea Inst Radiol & Med Sci, Div Radiat Canc Res, Seoul, South Korea. [Choi, Tae Hyun; Hong, Su Hee] Korea Inst Radiol & Med Sci, Radiopharmaceut & Lab Nucl Med, Seoul, South Korea. [Song, Kang Won] Natl Canc Ctr, Dept Pathol, Gyeonggi Do, South Korea. RP Kim, JH (reprint author), Korea Univ, Coll Life Sci & Biotechnol, Div Biotechnol, Lab Stem Cell Biol, West Bldg,Room 304,Sci Campus,1 Anam Dong 5 Ga, Seoul 136713, South Korea. EM jhkim@korea.ac.kr RI Kim, Jong-Hoon/F-2504-2013; Tesar, Paul/C-9848-2014; Kim, Jong-Hoon/H-1476-2015 OI Tesar, Paul/0000-0003-1532-3155; FU Stem Cell Research Center [SC-3130]; Korea Research Foundation [KRF-313-2008-2-C00737]; Ministry of Education, Science and Technology, Republic of Korea FX Supported by a grant (SC-3130) from Stem Cell Research Center of the 21st Century Frontier Research Program and a grant (KRF-313-2008-2-C00737) from the Korea Research Foundation funded by the Ministry of Education, Science and Technology, Republic of Korea. NR 47 TC 48 Z9 54 U1 2 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2012 VL 142 IS 3 BP 602 EP 611 DI 10.1053/j.gastro.2011.11.030 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 898XC UT WOS:000300774700039 PM 22138358 ER PT J AU Belal, C Ameli, NJ El Kommos, A Bezalel, S Al'Khafaji, AM Mughal, MR Mattson, MP Kyriazis, GA Tyrberg, B Chan, SL AF Belal, Cherine Ameli, Neema J. El Kommos, Adam Bezalel, Spencer Al'Khafaji, Aziz M. Mughal, Mohamed R. Mattson, Mark P. Kyriazis, George A. Tyrberg, Bjoern Chan, Sic L. TI The homocysteine-inducible endoplasmic reticulum (ER) stress protein Herp counteracts mutant -synuclein-induced ER stress via the homeostatic regulation of ER-resident calcium release channel proteins SO HUMAN MOLECULAR GENETICS LA English DT Article ID ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; DOPAMINERGIC-NEURONS; RYANODINE RECEPTOR; SUBSTANTIA-NIGRA; CORTICAL-NEURONS; NEUROTOXIN MODEL; DEGRADATION; APOPTOSIS; DEATH AB Endoplasmic reticulum (ER) stress has been implicated as an initiator or contributing factor in neurodegenerative diseases. The mechanisms that lead to ER stress and whereby ER stress contributes to the degenerative cascades remain unclear but their understanding is critical to devising effective therapies. Here we show that knockdown of Herp (Homocysteine-inducible ER stress protein), an ER stress-inducible protein with an ubiquitin-like (UBL) domain, aggravates ER stress-mediated cell death induced by mutant -synuclein (Syn) that causes an inherited form of Parkinsons disease (PD). Functionally, Herp plays a role in maintaining ER homeostasis by facilitating proteasome-mediated degradation of ER-resident Ca-2 release channels. Deletion of the UBL domain or pharmacological inhibition of proteasomes abolishes the Herp-mediated stabilization of ER Ca-2 homeostasis. Furthermore, knockdown or pharmacological inhibition of ER Ca-2 release channels ameliorates ER stress, suggesting that impaired homeostatic regulation of Ca-2 channels promotes a protracted ER stress with the consequent activation of ER stress-associated apoptotic pathways. Interestingly, sustained upregulation of ER stress markers and aberrant accumulation of ER Ca-2 release channels were detected in transgenic mutant A53T-Syn mice. Collectively, these data establish a causative link between impaired ER Ca-2 homeostasis and chronic ER stress in the degenerative cascades induced by mutant Syn and suggest that Herp is essential for the resolution of ER stress through maintenance of ER Ca-2 homeostasis. Our findings suggest a therapeutic potential in PD for agents that increase Herp levels or its ER Ca-2-stabilizing action. C1 [Belal, Cherine; Ameli, Neema J.; El Kommos, Adam; Bezalel, Spencer; Al'Khafaji, Aziz M.; Chan, Sic L.] Univ Cent Florida, Burnett Sch Biomed Sci, Coll Med, Orlando, FL 32816 USA. [Mughal, Mohamed R.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Kyriazis, George A.; Tyrberg, Bjoern] Sanford Burnham Med Res Inst, Diabet & Obes Res Ctr, Orlando, FL USA. RP Chan, SL (reprint author), 4000 Cent Florida Blvd, Orlando, FL 32816 USA. EM schan@mail.ucf.edu RI Mattson, Mark/F-6038-2012 FU American Federation on Aging Research; National Institutes of Health (NIH) [1R21NS066265-01]; National Institute on Aging of the National Institute of Health FX This work was supported by the American Federation on Aging Research (to S. L. C.); National Institutes of Health (NIH 1R21NS066265-01 to S. L. C.); and the National Institute on Aging Intramural Research Program of the National Institute of Health (to M.P.M.). NR 43 TC 20 Z9 22 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 1 PY 2012 VL 21 IS 5 BP 963 EP 977 DI 10.1093/hmg/ddr502 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 891UL UT WOS:000300242000001 PM 22045699 ER PT J AU Sterky, FH Hoffman, AF Milenkovic, D Bao, B Paganelli, A Edgar, D Wibom, R Lupica, CR Olson, L Larsson, NG AF Sterky, Fredrik H. Hoffman, Alexander F. Milenkovic, Dusanka Bao, Betty Paganelli, Arianna Edgar, Daniel Wibom, Rolf Lupica, Carl R. Olson, Lars Larsson, Nils-Goeran TI Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons SO HUMAN MOLECULAR GENETICS LA English DT Article ID PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; DNA DELETIONS; PARS COMPACTA; HUMAN BRAIN; CHAIN; MODEL; MOUSE; TRANSPORT; TOXICITY AB A variety of observations support the hypothesis that deficiency of complex I [reduced nicotinamide-adenine dinucleotide (NADH):ubiquinone oxidoreductase] of the mitochondrial respiratory chain plays a role in the pathophysiology of Parkinsons disease (PD). However, recent data from a study using mice with knockout of the complex I subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4) has challenged this concept as these mice show degeneration of non-dopamine neurons. In addition, primary dopamine (DA) neurons derived from such mice, reported to lack complex I activity, remain sensitive to toxins believed to act through inhibition of complex I. We tissue-specifically disrupted the Ndufs4 gene in mouse heart and found an apparent severe deficiency of complex I activity in disrupted mitochondria, whereas oxidation of substrates that result in entry of electrons at the level of complex I was only mildly reduced in intact isolated heart mitochondria. Further analyses of detergent-solubilized mitochondria showed the mutant complex I to be unstable but capable of forming supercomplexes with complex I enzyme activity. The loss of Ndufs4 thus causes only a mild complex I deficiency in vivo. We proceeded to disrupt Ndufs4 in midbrain DA neurons and found no overt neurodegeneration, no loss of striatal innervation and no symptoms of Parkinsonism in tissue-specific knockout animals. However, DA homeostasis was abnormal with impaired DA release and increased levels of DA metabolites. Furthermore, Ndufs4 DA neuron knockouts were more vulnerable to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Taken together, these findings lend in vivo support to the hypothesis that complex I deficiency can contribute to the pathophysiology of PD. C1 [Milenkovic, Dusanka; Larsson, Nils-Goeran] Max Planck Inst Biol Ageing, D-50931 Cologne, Germany. [Sterky, Fredrik H.; Paganelli, Arianna; Edgar, Daniel; Wibom, Rolf; Larsson, Nils-Goeran] Karolinska Inst, Dept Lab Med, SE-17177 Stockholm, Sweden. [Sterky, Fredrik H.; Olson, Lars] Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden. [Hoffman, Alexander F.; Bao, Betty; Lupica, Carl R.] NIDA, Electrophysiol Res Sect, Baltimore, MD 21224 USA. RP Larsson, NG (reprint author), Max Planck Inst Biol Ageing, Robert Koch Str 21, D-50931 Cologne, Germany. EM larsson@age.mpg.de RI Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU National Institutes of Health-Karolinska Institute; Swedish Research Council [K2011-62X-21870-01-6, K2009-61X-03185-39-3]; Swedish Brain Power; Parkinson Foundation; Karolinska Institutet; US Public Health Service, National Institute on Drug Abuse FX This work was supported by the National Institutes of Health-Karolinska Institute Graduate Partnership Program for the Neurosciences (F. H. S.), The Swedish Research Council (grant numbers K2011-62X-21870-01-6, K2009-61X-03185-39-3), Swedish Brain Power, The Parkinson Foundation, The Karolinska Institutet and US Public Health Service, National Institute on Drug Abuse, Intramural Research Program. NR 41 TC 35 Z9 38 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 1 PY 2012 VL 21 IS 5 BP 1078 EP 1089 DI 10.1093/hmg/ddr537 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 891UL UT WOS:000300242000010 PM 22090423 ER PT J AU Han, SS Yeager, M Moore, LE Wei, MH Pfeiffer, R Toure, O Purdue, MP Johansson, M Scelo, G Chung, CC Gaborieau, V Zaridze, D Schwartz, K Szeszenia-Dabrowska, N Davis, F Bencko, V Colt, JS Janout, V Matveev, V Foretova, L Mates, D Navratilova, M Boffetta, P Berg, CD Grubb, RL Stevens, VL Thun, MJ Diver, WR Gapstur, SM Albanes, D Weinstein, SJ Virtamo, J Burdett, L Brisuda, A McKay, JD Fraumeni, JF Chatterjee, N Rosenberg, PS Rothman, N Brennan, P Chow, WH Tucker, MA Chanock, SJ Toro, JR AF Han, Summer S. Yeager, Meredith Moore, Lee E. Wei, Ming-Hui Pfeiffer, Ruth Toure, Ousmane Purdue, Mark P. Johansson, Mattias Scelo, Ghislaine Chung, Charles C. Gaborieau, Valerie Zaridze, David Schwartz, Kendra Szeszenia-Dabrowska, Neonilia Davis, Faith Bencko, Vladimir Colt, Joanne S. Janout, Vladimir Matveev, Vsevolod Foretova, Lenka Mates, Dana Navratilova, M. Boffetta, Paolo Berg, Christine D. Grubb, Robert L., III Stevens, Victoria L. Thun, Michael J. Diver, W. Ryan Gapstur, Susan M. Albanes, Demetrius Weinstein, Stephanie J. Virtamo, Jarmo Burdett, Laurie Brisuda, Antonin McKay, James D. Fraumeni, Joseph F., Jr. Chatterjee, Nilanjan Rosenberg, Philip S. Rothman, Nathaniel Brennan, Paul Chow, Wong-Ho Tucker, Margaret A. Chanock, Stephen J. Toro, Jorge R. TI The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; KIDNEY CANCER; FAMILY-HISTORY; MUTATIONS; SEQUENCES; RESOURCE; OBESITY; DESIGN; COMMON; TRIAL AB In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P 5.75 10(8), per-allele odds ratio (OR) 1.27, 95 confidence interval (CI): 1.171.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P 4.09 10(14)) and rs12617313 (P 7.48 10(12)), both highly correlated with rs9679290 (r(2) 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r(2) 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P 1.72 10(9), per-allele OR 1.28, 95 CI: 1.181.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants. C1 [Han, Summer S.; Yeager, Meredith; Moore, Lee E.; Wei, Ming-Hui; Pfeiffer, Ruth; Toure, Ousmane; Purdue, Mark P.; Chung, Charles C.; Colt, Joanne S.; Albanes, Demetrius; Weinstein, Stephanie J.; Burdett, Laurie; Fraumeni, Joseph F., Jr.; Chatterjee, Nilanjan; Rosenberg, Philip S.; Rothman, Nathaniel; Chow, Wong-Ho; Tucker, Margaret A.; Chanock, Stephen J.; Toro, Jorge R.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Berg, Christine D.] NCI, Canc Prevent Div, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Yeager, Meredith] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,SAIC Frederick Inc, Frederick, MD 21701 USA. [Johansson, Mattias; Scelo, Ghislaine; Gaborieau, Valerie; McKay, James D.; Brennan, Paul] IARC, Lyon, France. [Zaridze, David; Matveev, Vsevolod] NN Blokhin Canc Res Ctr, Moscow, Russia. [Schwartz, Kendra] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Zaridze, David] Wayne State Univ, Dept Family Med, Detroit, MI USA. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Davis, Faith] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL USA. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Janout, Vladimir] Palacky Univ, CR-77147 Olomouc, Czech Republic. [Foretova, Lenka; Navratilova, M.] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Grubb, Robert L., III] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Stevens, Victoria L.; Thun, Michael J.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Brisuda, Antonin] Univ Hosp Motol, Dept Urol, Prague, Czech Republic. [Toro, Jorge R.] DC VAMC, Washington, DC USA. RP Toro, JR (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,Room 7012, Rockville, MD 20892 USA. EM toroj@mail.nih.gov RI Zaridze, David/K-5605-2013; Berg , Christine/K-1047-2014; Janout, Vladimir/M-5133-2014; Tucker, Margaret/B-4297-2015; Albanes, Demetrius/B-9749-2015; Szeszenia-Dabrowska, Neonila/F-7190-2010; Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; mates, dana/0000-0002-6219-9807 FU Division of Cancer Epidemiology and Genetics; National Cancer Institute; NIH; DHHS; Bethesda, MD, USA; European Commission [IC15-CT96-0313] FX This research was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA, and by European Commission INCOCOPERNICUS grant IC15-CT96-0313. NR 44 TC 15 Z9 16 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 1 PY 2012 VL 21 IS 5 BP 1190 EP 1200 DI 10.1093/hmg/ddr551 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 891UL UT WOS:000300242000020 PM 22113997 ER PT J AU Bower, M Salomon, R Allanson, J Antignac, C Benedicenti, F Benetti, E Binenbaum, G Jensen, UB Cochat, P DeCramer, S Dixon, J Drouin, R Falk, MJ Feret, H Gise, R Hunter, A Johnson, K Kumar, R Lavocat, MP Martin, L Moriniere, V Mowat, D Murer, L Nguyen, HT Peretz-Amit, G Pierce, E Place, E Rodig, N Salerno, A Sastry, S Sato, T Sayer, JA Schaafsma, GCP Shoemaker, L Stockton, DW Tan, WH Tenconi, R Vanhille, P Vats, A Wang, XJ Warman, B Weleber, RG White, SM Wilson-Brackett, C Zand, DJ Eccles, M Schimmenti, LA Heidet, L AF Bower, Matthew Salomon, Remi Allanson, Judith Antignac, Corinne Benedicenti, Francesco Benetti, Elisa Binenbaum, Gil Jensen, Uffe B. Cochat, Pierre DeCramer, Stephane Dixon, Joanne Drouin, Regen Falk, Marni J. Feret, Holly Gise, Robert Hunter, Alasdair Johnson, Kisha Kumar, Rajiv Lavocat, Marie Pierre Martin, Laura Moriniere, Vincent Mowat, David Murer, Luisa Nguyen, Hiep T. Peretz-Amit, Gabriela Pierce, Eric Place, Emily Rodig, Nancy Salerno, Ann Sastry, Sujatha Sato, Tadashi Sayer, John A. Schaafsma, Gerard C. P. Shoemaker, Lawrence Stockton, David W. Tan, Wen-Hann Tenconi, Romano Vanhille, Philippe Vats, Abhay Wang, Xinjing Warman, Berta Weleber, Richard G. White, Susan M. Wilson-Brackett, Carolyn Zand, Dina J. Eccles, Michael Schimmenti, Lisa A. Heidet, Laurence TI Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database SO HUMAN MUTATION LA English DT Article DE PAX2; renal coloboma syndrome; papillorenal syndrome ID URETERAL BUD APOPTOSIS; MORNING GLORY SYNDROME; MISSENSE MUTATION; VARIABLE PHENOTYPE; GENE MUTATION; MUTANT MICE; FAMILY; DISEASE; KIDNEY; HYPOPLASIA AB Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. Hum Mutat 33:457466, 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Bower, Matthew] Univ Minnesota Med Ctr, Div Genet & Metab, Minneapolis, MN USA. [Salomon, Remi; Antignac, Corinne] Hop Necker Enfants Malad, INSERM, U983, Paris, France. [Salomon, Remi; Moriniere, Vincent; Heidet, Laurence] APHP, Ctr Reference Malad Renales Hereditaires Enfant &, Paris, France. [Salomon, Remi; Heidet, Laurence] Hop Necker Enfants Malad, APHP, Serv Nephrol Pediat, Paris, France. [Allanson, Judith; Hunter, Alasdair] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada. [Allanson, Judith; Hunter, Alasdair] Univ Ottawa, Ottawa, ON, Canada. [Antignac, Corinne; Moriniere, Vincent] Hop Necker Enfants Malad, APHP, Dept Genet, Paris, France. [Salomon, Remi; Antignac, Corinne] Univ Paris 05, Paris, France. [Benedicenti, Francesco] Reg Hosp Bolzano, Dept Pediat, Genet Counseling Serv S Tyrol, Bolzano, Italy. [Benetti, Elisa; Murer, Luisa] Univ Padua, Nephrol Dialysis & Transplant Unit, Padua, Italy. [Murer, Luisa; Tenconi, Romano] Univ Padua, Dept Pediat, Padua, Italy. [Binenbaum, Gil; Pierce, Eric] Childrens Hosp Philadelphia, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Falk, Marni J.; Feret, Holly; Pierce, Eric; Place, Emily] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Falk, Marni J.; Feret, Holly; Place, Emily] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Jensen, Uffe B.] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Cochat, Pierre] Hosp Civils Lyon, Ctr Reference Malad Renales Rares, Lyon, France. [DeCramer, Stephane] CHU Toulouse, Hop Enfants, Serv Nephrol Med Interne Hypertens Pediat, F-31059 Toulouse, France. [DeCramer, Stephane] Fac Med Toulouse, INSERM, Inst Cardiovasc & Metab Dis, U1048, F-31073 Toulouse, France. [Dixon, Joanne] Wellington Hosp, Cent & So Reg Genet Serv, Wellington, New Zealand. [Drouin, Regen] Univ Sherbrooke, Div Genet, Dept Pediat, Sherbrooke, PQ J1K 2R1, Canada. [Gise, Robert] UMASS Mem Childrens Med Ctr, Dept Ophthalmol, Worcester, MA USA. [Salerno, Ann] UMASS Mem Childrens Med Ctr, Dept Pediat, Worcester, MA USA. [Johnson, Kisha] Rush Univ Med Ctr, Dept Pediat, Chicago, IL USA. [Kumar, Rajiv] Auckland City Hosp, Reg Blood & Canc Serv, Auckland, New Zealand. [Lavocat, Marie Pierre] CHU St Etienne, Hop Nord, Dept Paediat, St Etienne, France. [Martin, Laura] Nemours Childrens Clin, Div Genet, Jacksonville, FL USA. [Mowat, David] Sydney Childrens Hosp, Dept Med Genet, Sydney, NSW, Australia. [Nguyen, Hiep T.] Childrens Hosp Boston, Dept Urol, Boston, MA USA. [Rodig, Nancy] Childrens Hosp Boston, Div Nephrol, Boston, MA USA. [Tan, Wen-Hann] Childrens Hosp Boston, Div Genet, Boston, MA USA. [Peretz-Amit, Gabriela] Rabin Med Ctr, Dept Med Genet, Petah Tiqwa, Israel. [Sastry, Sujatha; Stockton, David W.] Childrens Hosp Michigan, Div Genet & Metab Disorders, Detroit, MI 48201 USA. [Sato, Tadashi] Saga Med Sch, Dept Pediat, Saga, Japan. [Sayer, John A.] Newcastle Univ, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Schaafsma, Gerard C. P.] Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands. [Shoemaker, Lawrence] Univ Louisville, Div Pediat Nephrol, Louisville, KY 40292 USA. [Stockton, David W.] Wayne State Sch Med, Div Genet & Metab Disorders, Detroit, MI USA. [Vanhille, Philippe] Ctr Hosp Valenciennes, Serv Nephrol & Med Interne, Valenciennes, France. [Vats, Abhay] Univ Pittsburgh, Dept Pediat, Div Pediat Nephrol, Pittsburgh, PA 15260 USA. [Wang, Xinjing] NEI, NIH, Bethesda, MD 20892 USA. [Warman, Berta] Newborn Screening Program, Minneapolis, MN USA. [Weleber, Richard G.] Oregon Hlth & Sci Univ, Casey Eye Inst, Dept Ophthalmol & Mol & Med Genet, Portland, OR 97201 USA. [White, Susan M.] Royal Childrens Hosp, Genet Hlth Serv Victoria, Parkville, Vic 3052, Australia. [White, Susan M.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Wilson-Brackett, Carolyn] Fullerton Genet Ctr, Dept Genet, Asheville, NC USA. [Zand, Dina J.] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. [Eccles, Michael] Univ Otago, Dunedin Sch Med, Dev Genet Grp, Dunedin, New Zealand. [Schimmenti, Lisa A.] Univ Minnesota, Inst Human Genet, Ctr Dev Biol, Dept Pediat, Minneapolis, MN 55455 USA. [Schimmenti, Lisa A.] Univ Minnesota, Inst Human Genet, Ctr Dev Biol, Dept Ophthalmol, Minneapolis, MN 55455 USA. [Schimmenti, Lisa A.] Univ Minnesota, Inst Human Genet, Ctr Dev Biol, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. RP Bower, M (reprint author), Univ Minnesota Med Ctr, Div Genet & Metab, 420 Delaware St SE,MMC 485, Minneapolis, MN USA. EM mbower1@fairview.org RI Falk, Marni/K-1997-2014; Schaafsma, Gerard/F-6138-2014 OI Sayer, John/0000-0003-1881-3782; Kumar, Rajiv/0000-0002-6093-0395; Murer, Luisa/0000-0002-3010-2337; Schaafsma, Gerard/0000-0001-6351-7486 FU European Community's Seventh Framework Programme [FP7/2007-2013]; GEN2PHEN [200754] FX The authors would like to thank the patients and families who have contributed to this work. In addition, the authors wish to thank the many professionals who are not formally recognized, but have made significant contributions to this work including the staff of the molecular diagnostics laboratory at the University of Minnesota Medical Center, Fairview. Construction of the LOVD database has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 200754: The GEN2PHEN project. NR 61 TC 27 Z9 28 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAR PY 2012 VL 33 IS 3 BP 457 EP 466 DI 10.1002/humu.22020 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 898AB UT WOS:000300706000003 PM 22213154 ER PT J AU Kanaan, Z Rai, SN Eichenberger, MR Barnes, C Dworkin, AM Weller, C Cohen, E Roberts, H Keskey, B Petras, RE Crawford, NPS Galandiuk, S AF Kanaan, Ziad Rai, Shesh N. Eichenberger, M. Robert Barnes, Christopher Dworkin, Amy M. Weller, Clayton Cohen, Eric Roberts, Henry Keskey, Bobby Petras, Robert E. Crawford, Nigel P. S. Galandiuk, Susan TI Differential MicroRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer SO HUMAN MUTATION LA English DT Article DE IBD; Crohn disease; ulcerative colitis; cancer; dysplasia; microRNA ID ULCERATIVE-COLITIS; CROHNS-DISEASE; COLON-CANCER; SAMPLE-SIZE; DNA-CONTENT; P53; RISK; DYSPLASIA; EPIDEMIOLOGY; SUPPRESSOR AB One of the most serious complications faced by patients with inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small nonprotein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were upregulated from non-neoplastic tissue to dysplasia, but downregulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (P < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (P < 0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was downregulated in both cell lines transfected with let-7e (P < 0.05) as well as in HCT-116 cells transfected with miR-17 (P < 0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was downregulated in both cell lines (P < 0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines. Hum Mutat 33:551560, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Kanaan, Ziad; Eichenberger, M. Robert; Weller, Clayton; Cohen, Eric; Roberts, Henry; Keskey, Bobby; Galandiuk, Susan] Univ Louisville, Sch Med, Dept Surg, Price Inst Surg Res, Louisville, KY 40292 USA. [Kanaan, Ziad; Eichenberger, M. Robert; Weller, Clayton; Cohen, Eric; Roberts, Henry; Keskey, Bobby; Galandiuk, Susan] Univ Louisville, Sch Med, Sect Colorectal Surg, Louisville, KY 40292 USA. [Rai, Shesh N.; Barnes, Christopher] Univ Louisville, Sch Publ Hlth & Informat Sci, Dept Bioinformat & Biostat, Louisville, KY 40292 USA. [Dworkin, Amy M.; Crawford, Nigel P. S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Petras, Robert E.] Ameripath, Oakwood Village, OH USA. RP Galandiuk, S (reprint author), Univ Louisville, Sch Med, Dept Surg, Price Inst Surg Res, Louisville, KY 40292 USA. EM s0gala01@louisville.edu OI Kanaan, Ziad/0000-0001-5376-562X FU Center for Environmental Genomics and Integrative Biology (CEGIB) [1P30ES014443-01A1]; Wendell Cherry Chair-James Graham Brown Cancer Center, University of Louisville FX This publication is made possible in part by the John W. and Caroline Price Family Trust, a gift from Ms. Sara Shallenberger Brown, and NIH/NIEHS grant 1P30ES014443-01A1) to The Center for Environmental Genomics and Integrative Biology (CEGIB). Dr. Shesh Rai was partly supported by the Wendell Cherry Chair-James Graham Brown Cancer Center, University of Louisville. NR 42 TC 47 Z9 48 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAR PY 2012 VL 33 IS 3 BP 551 EP 560 DI 10.1002/humu.22021 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 898AB UT WOS:000300706000016 PM 22241525 ER PT J AU Sayres, MAW Brookes, AJ Chanock, SJ Cheung, VG Goldstein, DB Jin, L Kwok, PY AF Sayres, Melissa A. Wilson Brookes, Anthony J. Chanock, Stephen J. Cheung, Vivian G. Goldstein, David B. Jin, Li Kwok, Pui-Yan TI HGV2011: Personalized genomic medicine meets the incidentalome SO HUMAN MUTATION LA English DT Editorial Material DE human variation; GWAS; SNP; medical genomics AB The 12th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2011: Berkeley, California, USA, 8th10th September 2011) was a stimulating workshop where researchers from academia and industry explored the latest progress, challenges, and opportunities in genome variation research. Key themes included progress beyond GWAS, variation in human populations, use of sequence data in medical settings, large-scale sequencing data analysis, and bioinformatics approaches to large datasets. Hum Mutat 33:582585, 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Sayres, Melissa A. Wilson] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Sayres, Melissa A. Wilson] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Brookes, Anthony J.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chanock, Stephen J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Cheung, Vivian G.] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. [Goldstein, David B.] Hosp Sick Children, Res Inst, Ctr Appl Genom, Program Genet & Genom Biol, Toronto, ON M5G 1X8, Canada. [Jin, Li] Fudan Univ, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Jin, Li] Fudan Univ, MOE Key Lab Contemporary Anthropol, Sch Life Sci, Shanghai 200433, Peoples R China. [Jin, Li] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. [Kwok, Pui-Yan] Univ Calif San Francisco, Dept Dermatol, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. RP Sayres, MAW (reprint author), 1005 VLSB,MC 3140, Berkeley, CA 94720 USA. EM mwilsonsayres@berkeley.edu; Pui.Kwok@ucsf.edu RI Kwok, Pui-Yan/F-7725-2014; Jin, Li/C-1468-2009; OI Kwok, Pui-Yan/0000-0002-5087-3059; Jin, Li/0000-0002-4546-2415; Wilson Sayres, Melissa/0000-0002-2614-0285 FU National Human Genome Research Institute (NHGRI) [R13 HG003953]; The National Cancer Institute (NCI); The McLaughlin Centre at the University of Toronto; Gen2Phen FX National Human Genome Research Institute (NHGRI, R13 HG003953); The National Cancer Institute (NCI); The McLaughlin Centre at the University of Toronto; Gen2Phen. NR 0 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD MAR PY 2012 VL 33 IS 3 BP 582 EP 585 DI 10.1002/humu.22008 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 898AB UT WOS:000300706000019 ER PT J AU Leach, RE Jessmon, P Coutifaris, C Kruger, M Myers, ER Ali-Fehmi, R Carson, S Legro, RS Schlaff, WD Carr, BR Steinkampf, MP Silva, S Leppert, PC Giudice, L Diamond, MP Armant, DR AF Leach, Richard E. Jessmon, Philip Coutifaris, Christos Kruger, Michael Myers, Evan R. Ali-Fehmi, Rouba Carson, SandraA. Legro, Richard S. Schlaff, William D. Carr, Bruce R. Steinkampf, Michael P. Silva, Susan Leppert, Phyllis C. Giudice, Linda Diamond, Michael P. Armant, D. Randall CA Reproductive Med Network TI High throughput, cell type-specific analysis of key proteins in human endometrial biopsies of women from fertile and infertile couples SO HUMAN REPRODUCTION LA English DT Article DE endometrium; idiopathic infertility; protein expression; developmental regulation; immunohistochemistry ID LEUKEMIA INHIBITORY FACTOR; GENE-EXPRESSION PROFILES; PROGESTERONE-RECEPTOR-B; DNA MICROARRAY ANALYSIS; GROWTH-FACTOR; MENSTRUAL-CYCLE; GLYCODELIN-A; IMPLANTATION FAILURE; BLASTOCYST IMPLANTATION; UNEXPLAINED INFERTILITY AB Although histological dating of endometrial biopsies provides little help for prediction or diagnosis of infertility, analysis of individual endometrial proteins, proteomic profiling and transcriptome analysis have suggested several biomarkers with altered expression arising from intrinsic abnormalities, inadequate stimulation by or in response to gonadal steroids or altered function due to systemic disorders. The objective of this study was to delineate the developmental dynamics of potentially important proteins in the secretory phase of the menstrual cycle, utilizing a collection of endometrial biopsies from women of fertile (n 89) and infertile (n 89) couples. Progesterone receptor-B (PGR-B), leukemia inhibitory factor, glycodelin/progestagen-associated endometrial protein (PAEP), homeobox A10, heparin-binding EGF-like growth factor, calcitonin and chemokine ligand 14 (CXCL14) were measured using a high-throughput, quantitative immunohistochemical method. Significant cyclic and tissue-specific regulation was documented for each protein, as well as their dysregulation in women of infertile couples. Infertile patients demonstrated a delay early in the secretory phase in the decline of PGR-B (P 0.05) and premature mid-secretory increases in PAEP (P 0.05) and CXCL14 (P 0.05), suggesting that the implantation interval could be closing early. Correlation analysis identified potential interactions among certain proteins that were disrupted by infertility. This approach overcomes the limitations of a small sample number. Protein expression and localization provided important insights into the potential roles of these proteins in normal and pathological development of the endometrium that is not attainable from transcriptome analysis, establishing a basis for biomarker, diagnostic and targeted drug development for women with infertility. C1 [Jessmon, Philip; Kruger, Michael; Ali-Fehmi, Rouba; Diamond, Michael P.; Armant, D. Randall] Wayne State Univ, CS Mott Ctr Human Growth & Dev, Sch Med, Detroit, MI 48201 USA. [Leach, Richard E.] Michigan State Univ, Spectrum Hlth Med Grp, Grand Rapids, MI USA. [Jessmon, Philip; Armant, D. Randall] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Coutifaris, Christos] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Silva, Susan] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Carson, SandraA.] Brown Univ, Providence, RI 02912 USA. [Legro, Richard S.] Penn State Univ, Hershey, PA USA. [Schlaff, William D.] Univ Colorado, Denver, CO 80202 USA. [Carr, Bruce R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Steinkampf, Michael P.] Univ Alabama, Birmingham, AL USA. [Giudice, Linda] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Armant, DR (reprint author), Wayne State Univ, CS Mott Ctr Human Growth & Dev, Sch Med, 275 E Hancock Ave, Detroit, MI 48201 USA. EM d.armant@wayne.edu OI Diamond, Michael/0000-0001-6353-4489; Armant, D. Randall/0000-0001-5904-9325 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH [U54HD40093, HD040093]; NICHD National Cooperative Reproductive Medicine Network [HD045966, HD27049, HD38997, HD39005, HD27011, HD33172, HD38988, HD38992, HD38998]; NICHD, NIH, DHHS FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH through Cooperative Agreement (U54HD40093) as part of the Specialized Cooperative Center Program in Reproduction and Infertility Research to R. E. L., grants to R. E. L. (HD040093) and D. R. A. (HD045966), grants from the NICHD National Cooperative Reproductive Medicine Network to C. C. (HD27049), E. R. M. (HD38997), M. P. D. (HD39005), S. A. C. (HD27011), M. P. S. (HD33172), B. R. C. (HD38988), R. S. L. (HD38992) and W. D. S. (HD38998) and the Intramural Research Program of the NICHD, NIH, DHHS (D.R.A.). NR 105 TC 17 Z9 18 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD MAR PY 2012 VL 27 IS 3 BP 814 EP 828 DI 10.1093/humrep/der436 PG 15 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 895QA UT WOS:000300510100024 PM 22215622 ER PT J AU Bairagi, S Gopal, J Nathan, AA Babu, SS Kumar, NP Dixit, M AF Bairagi, Soumi Gopal, Jayashree Nathan, Abel A. Babu, Subash S. Kumar, N. Pavan Dixit, Madhulika TI Glucose-induced increase in circulating progenitor cells is blunted in polycystic amenorrhoeic subjects SO HUMAN REPRODUCTION LA English DT Article DE amenorrhea; polycystic ovaries; bone marrow-derived stem cells; insulin resistance; OGTT ID OVARY-SYNDROME; BONE-MARROW; PERIPHERAL-BLOOD; STEM-CELLS; INSULIN-RESISTANCE; CARDIOVASCULAR RISK; METABOLIC SYNDROME; HUMAN ENDOMETRIUM; MENSTRUAL-CYCLE; EXPRESSION AB Glucose-induced kinetics of bone marrow-derived stem cells in healthy females is presently unknown. The objectives of this study were to determine whether circulating levels of CD133, CD34 and CD133CD34 cells increase in response to glucose load in healthy females and whether the kinetics is altered in amenorrhoeic women. The other objective of the work was to compare the endothelial differentiation potential of peripheral blood-derived endothelial progenitor cells(EPCs) from healthy versus amenorrhoeic women. In this casecontrol study, 44 amenorrhoeic subjects and 36 age-matched females with no menstrual disturbance were recruited at Apollo Hospitals, a Tertiary health care center in Chennai, India. Circulating bone marrow-derived stem cells were measured by two color direct flow cytometry. Cultured progenitor cells were characterized at Day 7 and 14 for expression of endothelial markers and production of nitric oxide (NO) via immunofluoroscence. The amenorrhoeic subjects were insulin resistant with homeostatic model of assessment of insulin resistance values of 3.33 0.3 versus 1.75 0.148 observed for controls (P 0.0001). Among the amenorrhoeic subjects, 38 subjects had polycystic ovaries with no signs of hyperandrogenism. Fasting levels of CD133, CD34 and CD133CD34 cells were reduced in amenorrhoeic subjects (P 0.001). There was a 1.5 to 2-fold increase in the circulating levels of these cells in response to 75 g oral glucose challenge at 1 and 2 h post-load conditions in controls, which was significantly blunted for CD133 (P 0.001) and CD133CD34 (P 0.001) cells in amenorrhoeic subjects. A positive correlation was observed between estrogen and fasting CD133 (r 0.205, P 0.070), CD34 (r 0.249, P 0.027) and CD133CD34 (r 0.217, P 0.055) cell counts. Additionally, fasting counts for CD34 and CD133CD34 cells positively correlated with FSH and inversely correlated with LH and C-peptide in the polycystic group. Cultured cells from polycystic subjects exhibited reduced adherence to fibronectin and expressed lower levels of endothelial nitric-oxide synthase and NO. Oral glucose-induced increase in circulating numbers of CD133 and CD133CD34 cells and endothelial differentiation potential of peripheral blood-derived EPCs is attenuated in insulin resistant amenorrhoeic subjects. C1 [Bairagi, Soumi; Nathan, Abel A.; Dixit, Madhulika] IIT Madras, Lab Vasc Biol, Dept Biotechnol, Madras 600036, Tamil Nadu, India. [Gopal, Jayashree] Apollo Hosp, Dept Diabetol, Madras 600006, Tamil Nadu, India. [Babu, Subash S.; Kumar, N. Pavan] Natl Inst Hlth Int Ctr Excellence Res, Madras 600031, Tamil Nadu, India. [Babu, Subash S.; Kumar, N. Pavan] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Dixit, M (reprint author), IIT Madras, Lab Vasc Biol, Dept Biotechnol, BT 415, Madras 600036, Tamil Nadu, India. EM mdixit@iitm.ac.in FU Council of Scientific and Industrial Research (CSIR), Govt. of India; Department of Biotechnology (DBT), Govt. of India; Apollo Hospitals Education and Research Foundation (AHERF), India FX Ms Soumi Bairagi acknowledges Council of Scientific and Industrial Research (CSIR), Govt. of India for Senior Research Fellowship and Dr Madhulika Dixit acknowledges Department of Biotechnology (DBT), Govt. of India for Innovative Young Biotechnologist Award fellowship. Help rendered by Spectra team of AHERF is also acknowledged.; This work was funded by Apollo Hospitals Education and Research Foundation (AHERF), India. NR 55 TC 1 Z9 1 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 MAR PY 2012 VL 27 IS 3 BP 844 EP 853 DI 10.1093/humrep/der457 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 895QA UT WOS:000300510100026 PM 22252083 ER PT J AU Akinbami, LJ Sullivan, SD Campbell, JD Grundmeier, RW Hartert, TV Lee, TA Smith, RA AF Akinbami, Lara J. Sullivan, Sean D. Campbell, Jonathan D. Grundmeier, Robert W. Hartert, Tina V. Lee, Todd A. Smith, Robert A. TI Asthma outcomes: Healthcare utilization and costs SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma hospital admissions; asthma emergency department visits; asthma outpatient visits; asthma medication use; asthma intervention resource use; asthma study perspective ID INNER-CITY CHILDREN; QUALITY-OF-CARE; TO-TREAT ASTHMA; ACTIVITY IMPAIRMENT; WORK PRODUCTIVITY; CHILDHOOD ASTHMA; TIME; INTERVENTION; MOTION; IMPACT AB Background: Measures of healthcare utilization and indirect impact of asthma morbidity are used to assess clinical interventions and estimate cost. Objective: National Institutes of Health institutes and other federal agencies convened an expert group to propose standardized measurement, collection, analysis, and reporting of healthcare utilization and cost outcomes in future asthma studies. Methods: We used comprehensive literature reviews and expert opinion to compile a list of asthma healthcare utilization outcomes that we classified as core (required in future studies), supplemental (used according to study aims and standardized), and emerging (requiring validation and standardization). We also have identified methodology to assign cost to these outcomes. This work was discussed at an National Institutes of Health-organized workshop in March 2010 and finalized in September 2011. Results: We identified 3 ways to promote comparability across clinical trials for measures of healthcare utilization, resource use, and cost: (1) specify the study perspective (patient, clinician, payer, and society); (2) standardize the measurement period (ideally 12 months); and (3) use standard units to measure healthcare utilization and other asthma-related events. Conclusions: Large clinical trials and observational studies should collect and report detailed information on healthcare utilization, intervention resources, and indirect impact of asthma, so that costs can be calculated and cost-effectiveness analyses can be conducted across several studies. Additional research is needed to develop standard, validated survey instruments for collection of provider-reported and participant-reported data regarding asthma-related health care. (J Allergy Clin Immunol 2012; 129: S49-64.) C1 [Smith, Robert A.] NHLBI, DLD, NIH, Bethesda, MD 20892 USA. [Akinbami, Lara J.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Sullivan, Sean D.] Univ Washington, Seattle, WA 98195 USA. [Campbell, Jonathan D.] Univ Colorado, Aurora, CO USA. [Grundmeier, Robert W.] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Hartert, Tina V.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Lee, Todd A.] Univ Illinois, Chicago, IL USA. RP Smith, RA (reprint author), NHLBI, DLD, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM smithra3@nhlbi.nih.gov RI Campbell, Jonathan/C-1279-2015 FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency; Merck; AHRQ; NIH; MCHB FX The Asthma Outcomes work shop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.; Disclosure of potential conflict of interest: S. D. Sullivan has received research support from Merck. J. D. Campbell is a consultant for VeriTech Corp and has received research support from the Agency for Healthcare Research and Quality. R. W. Grundmeier has received research support from AHRQ, the NIH, and MCHB. T. V. Hartert has received research support from the NIH and AHRQ; is an Associate Editor for the ATS; and is a consultant for Merck. The rest of the authors declare that they have no relevant conflicts of interest. NR 67 TC 33 Z9 33 U1 2 U2 8 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 MAR PY 2012 VL 129 IS 3 SU S BP S49 EP S64 DI 10.1016/j.jaci.2011.12.984 PG 16 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600005 PM 22386509 ER PT J AU Busse, WW Morgan, WJ Taggart, V Togias, A AF Busse, William W. Morgan, Wayne J. Taggart, Virginia Togias, Alkis TI Asthma outcomes workshop: Overview SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma clinical research; National Institutes of Health asthma initiatives; standardizing outcomes AB Background: Asthma clinical research will highly benefit from standardization of major outcomes in terms of definition and assessment methodology. This will permit useful comparisons across interventional or observational studies and will allow more effective data sharing. Objective: National Institutes of Health (NIH) institutes and the Agency for Healthcare Research and Quality convened a workshop involving 7 expert subcommittees to propose which asthma outcomes should be assessed with standardized methodology in future asthma clinical research studies. Methods: Each subcommittee utilized comprehensive literature reviews and expert opinion to compile a list of asthma outcomes and classified them as either core (required in future studies), supplemental (to be used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. Results: Outcomes for study participant characterization, as well as for prospective clinical trial intervention and observational studies, were proposed for adults and children, and methodologies for outcome collection and reporting were determined. Furthermore, the workshop identified areas in which new outcomes or instruments for their measurement need to be developed and validated. Conclusions: Standardized outcomes for clinical research in asthma have been proposed. Participating NIH institutes and other federal agencies will consider these recommendations in future clinical research initiatives in asthma. (J Allergy Clin Immunol 2012; 129: S1-8.) C1 [Togias, Alkis] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Busse, William W.] Univ Wisconsin, Madison, WI 53706 USA. [Morgan, Wayne J.] Univ Arizona, Phoenix, AZ USA. [Taggart, Virginia] NHLBI, Bethesda, MD 20892 USA. RP Togias, A (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM togiasa@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency; National Institutes of Health (NIAID); National Institutes of Health (NHLBI); NIH-NHLBI CARE Network; Cystic Fibrosis Network FX The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.; Disclosure of potential conflict of interest: W. W. Busse is on the Advisory Board for Centocor and Merck; is a consultant for Amgen, AstraZeneca, Novartis, GlaxoSmithKline, MedImmune, Genentech, and Boehringer Ingelheim; is on the Actelion Date Safety Monitoring Board; and has received research support from the National Institutes of Health (NIAID and NHLBI). W. J. Morgan is a consultant for Genentech, Novartis, and the Cystic Fibrosis Foundation; has received research support from the NIH-NHLBI CARE Network and the Cystic Fibrosis Network; and is a speaker for Phadia. The rest of the authors declare that they have no relevant conflicts of interest. NR 3 TC 47 Z9 47 U1 0 U2 4 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 MAR PY 2012 VL 129 IS 3 SU S BP S1 EP S8 DI 10.1016/j.jaci.2011.12.985 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600001 PM 22386504 ER PT J AU Cloutier, MM Schatz, M Castro, M Clark, N Kelly, HW Mangione-Smith, R Sheller, J Sorkness, C Stoloff, S Gergen, P AF Cloutier, Michelle M. Schatz, Michael Castro, Mario Clark, Noreen Kelly, H. William Mangione-Smith, Rita Sheller, James Sorkness, Christine Stoloff, Stuart Gergen, Peter TI Asthma outcomes: Composite scores of asthma control SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma Control Questionnaire; Asthma Control Test; Asthma Therapy Assessment Questionnaire; Childhood Asthma Control Test ID QUALITY-OF-LIFE; HEALTH-CARE UTILIZATION; PATIENT-REPORTED OUTCOMES; EXHALED NITRIC-OXIDE; CONTROL QUESTIONNAIRE; SPANISH VERSION; REAL-LIFE; UNCONTROLLED DISEASE; ADULT ASTHMATICS; CLINICAL SCORES AB Background: Current asthma guidelines recommend assessing the level of a patient's asthma control. Consequently, there is increasing use of asthma control as an outcome measure in clinical research studies. Several composite assessment instruments have been developed to measure asthma control. Objective: National Institutes of Health institutes and federal agencies convened an expert group to propose the most appropriate standardized composite score of asthma control instruments to be used in future asthma studies. Methods: We conducted a comprehensive search of PubMed using both the National Library of Medicine's Medical Subject Headings and key terms to identify studies that attempted to develop and/or test composite score instruments for asthma control. We classified instruments as core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health-organized workshop convened in March 2010 and finalized in September 2011. Results: We identified 17 composite score instruments with published validation information; all had comparable content. Eight instruments demonstrated responsiveness over time; 3 demonstrated responsiveness to treatment. A minimal clinically important difference has been established for 3 instruments. The instruments have demographic limitations; some are proprietary, and their use could be limited by cost. Conclusion: Two asthma composite score instruments are sufficiently validated for use in adult populations, but additional research is necessary to validate their use in nonwhite populations. Gaps also exist in validating instruments for pediatric populations. (J Allergy Clin Immunol 2012; 129: S24-33.) C1 [Gergen, Peter] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Cloutier, Michelle M.] Univ Connecticut, Farmington, CT USA. [Castro, Mario] Washington Univ, St Louis, MO 63130 USA. [Schatz, Michael] Kaiser Permanente, San Diego, CA USA. [Clark, Noreen] Univ Michigan, Ann Arbor, MI 48109 USA. [Kelly, H. William] Univ New Mexico, Albuquerque, NM 87131 USA. [Mangione-Smith, Rita] Univ Washington, Seattle, WA 98195 USA. [Sheller, James] Vanderbilt Univ, Nashville, TN USA. [Sorkness, Christine] Univ Wisconsin, Madison, WI 53706 USA. RP Gergen, P (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM pgergen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency; Aerocrine; GlaxoSmithKline; Merck; Genentech; Asthmatx; Elsevier; Amgen; Ception/Cephalon; MedImmune; Novartis; NIH; Actelion Pharmaceuticals FX The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences, and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.; Disclosure of potential conflict of interest: M. Schatz has consulted for Amgen and has received research support from Aerocrine, GlaxoSmithKline, Merck, and Genentech. M. Castro has received consulting and speaker fees from Asthmatx; is a speaker and is on the advisory board for Genentech; is a speaker for AstraZeneca, Merck, and GlaxoSmithKline; has received royalties from Elsevier; and has received research support from Asthmatx, Amgen, Ception/Cephalon, Genentech, MedImmune, Merck, Novartis, the NIH, and GlaxoSmithKline. J. R. Sheller has received research support from Actelion Pharmaceuticals. S. W. Stoloff is Chairman of the Allergy and Asthma Network Mothers of Asthmatics Board. The rest of the authors declare that they have no relevant conflicts of interest. NR 89 TC 72 Z9 73 U1 1 U2 10 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 MAR PY 2012 VL 129 IS 3 SU S BP S24 EP S33 DI 10.1016/j.jaci.2011.12.980 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600003 PM 22386507 ER PT J AU Fuhlbrigge, A Peden, D Apter, AJ Boushey, HA Camargo, CA Gern, J Heymann, PW Martinez, FD Mauger, D Teague, WG Blaisdell, C AF Fuhlbrigge, Anne Peden, David Apter, Andrea J. Boushey, Homer A. Camargo, Carlos A., Jr. Gern, James Heymann, Peter W. Martinez, Fernando D. Mauger, David Teague, William G. Blaisdell, Carol TI Asthma outcomes: Exacerbations SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma exacerbations; severity of acute asthma; systemic steroids in asthma; urgent asthma care ID RANDOMIZED CONTROLLED-TRIAL; METERED-DOSE INHALER; MILD PERSISTENT ASTHMA; EXHALED NITRIC-OXIDE; INNER-CITY CHILDREN; BUDESONIDE/FORMOTEROL COMBINATION THERAPY; POORLY CONTROLLED ASTHMA; BROMIDE PLUS FENOTEROL; AMBIENT AIR-POLLUTION; DRY POWDER INHALER AB Background: The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining "exacerbation" or about how to characterize an episode's severity. Objective: National Institutes of Health institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies. Methods: We used comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health-organized workshop in March 2010 and finalized in September 2011. Results: No dominant definition of "exacerbation" was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalizations, and (3) use of short-acting beta-agonists as quick-relief (sometimes referred to as "rescue" or "reliever") medications. Conclusions: The working group participants propose that the definition of "asthma exacerbation" be "a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome." As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Furthermore, they propose the development of a standardized, component-based definition of "exacerbation" with clear thresholds of severity for each component. (J Allergy Clin Immunol 2012; 129: S34-48.) C1 [Blaisdell, Carol] NHLBI, DLD, NIH, Bethesda, MD 20892 USA. [Fuhlbrigge, Anne] Brigham & Womens Hosp, Boston, MA 02115 USA. [Peden, David] Univ N Carolina, Chapel Hill, NC USA. [Apter, Andrea J.] Univ Penn, Philadelphia, PA 19104 USA. [Boushey, Homer A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gern, James] Univ Wisconsin, Madison, WI 53706 USA. [Heymann, Peter W.; Teague, William G.] Univ Virginia, Charlottesville, VA USA. [Martinez, Fernando D.] Univ Arizona, Tucson, AZ USA. [Mauger, David] Penn State Univ, Hershey, PA USA. RP Blaisdell, C (reprint author), NHLBI, DLD, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM blaisdellcj@nhlbi.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency; NIH/NIAID; MedImmune; Aquinox Pharmaceuticals; GlaxoSmithKline; Genentech; Sanofi-Aventis; Centocor; Boehringer Ingelheim; Biota; Theraclone; NIH; Novartis; NIH/NHLBI; American Lung Association FX The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.; Disclosure of potential conflict of interest: A. Fuhlbrigge is on the Merck Respiratory Advisory Board and is a consultant for the Lovelace Respiratory and Research Institute. D. Peden has received research support from the NIH/NIAID, MedImmune, the US Environmental Protection Agency, and Aquinox Pharmaceuticals. A. J. Apter has received research support from the NHLBI and is on the AAAAI Board of Directors. H. A. Boushey has provided ad-hoc consultation for Kalobics; is on the Pharmaxis advisory committee; is on the ad-hoc advisory committee for Merck and GlaxoSmithKline; has provided consultation for Genentech and Johnson & Johnson; and has received research support from GlaxoSmithKline and Genentech. C. A. Camargo, Jr, is a consultant for Dey, Genentech, Merck, Novartis, and Pfizer; and has received research support from GlaxoSmithKline and Sanofi-Aventis. J. Gern is on the Scientific Advisory Board and has stock options in 3V Biosciences, and has received consulting fees from Centocor, Boehringer Ingelheim, GlaxoSmithKline, Biota, MedImmune, and Theraclone. P. W. Heymann has received research support from the NIH and Novartis. F. D. Martinez has consulted for MedImmune and received lecture honorarium from Abbott. W. G. Teague is a speaker for Merck and Genentech, and has received research support from the NIH/NHLBI and the American Lung Association. C. Blaisdell is on the American Academy of Pediatrics Executive Board and is an abstract reviewer for the Pediatric Academic Society. The rest of the authors declare that they have no relevant conflicts of interest. NR 138 TC 66 Z9 67 U1 2 U2 14 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 MAR PY 2012 VL 129 IS 3 SU S BP S34 EP S48 DI 10.1016/j.jaci.2011.12.983 PG 15 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600004 PM 22386508 ER PT J AU Krishnan, JA Lemanske, RF Canino, GJ Elward, KS Kattan, M Matsui, EC Mitchell, H Sutherland, ER Minnicozzi, M AF Krishnan, Jerry A. Lemanske, Robert F., Jr. Canino, Glorisa J. Elward, Kurtis S. Kattan, Meyer Matsui, Elizabeth C. Mitchell, Herman Sutherland, E. Rand Minnicozzi, Michael TI Asthma outcomes: Symptoms SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma Symptom Utility Index; Asthma Symptom Diary Scales; Pediatric Asthma Caregiver Diary ID LEUKOTRIENE RECEPTOR ANTAGONIST; POORLY CONTROLLED ASTHMA; MILD PERSISTENT ASTHMA; PRESCHOOL-CHILDREN; INDUCED BRONCHOCONSTRICTION; PATIENT PREFERENCES; ALLERGIC RHINITIS; CHILDHOOD ASTHMA; CLINICAL-TRIALS; UTILITY INDEX AB Background: Respiratory symptoms are commonly used to assess the impact of patient-centered interventions. Objective: At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to propose which measurements of asthma symptoms should be used as a standardized measure in future clinical research studies. Methods: Asthma symptom instruments were classified as daily diaries (prospectively recording symptoms between research visits) or retrospective questionnaires (completed at research visits). We conducted a systematic search in PubMed and a search for articles that cited key studies describing development of instruments. We classified outcome instruments as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. Results: Four instruments (3 daily diaries, 1 for adults and 2 for children; and 1 retrospective questionnaire for adults) were identified. Minimal clinically important differences have not been established for these instruments, and validation studies were only conducted in a limited number of patient populations. Validity of existing instruments may not be generalizable across racial-ethnic or other subgroups. Conclusions: An evaluation of symptoms should be a core asthma outcome measure in clinical research. However, available instruments have limitations that preclude selection of a core instrument. The working group participants propose validation studies in diverse populations, comparisons of diaries versus retrospective questionnaires, and evaluations of symptom assessment alone versus composite scores of asthma control. (J Allergy Clin Immunol 2012; 129: S124-35.) C1 [Minnicozzi, Michael] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Krishnan, Jerry A.] Univ Illinois, Chicago, IL USA. [Lemanske, Robert F., Jr.] Univ Wisconsin, Madison, WI 53706 USA. [Canino, Glorisa J.] Univ Puerto Rico, San Juan, PR 00936 USA. [Elward, Kurtis S.] Family Med Albermarle, Charlottesville, VA USA. [Kattan, Meyer] Columbia Univ, Med Ctr, New York, NY USA. [Matsui, Elizabeth C.] Johns Hopkins Univ, Baltimore, MD USA. [Mitchell, Herman] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Sutherland, E. Rand] Natl Jewish Hlth, Denver, CO USA. RP Minnicozzi, M (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM minnicozzmi@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency; National Asthma Control Initiative; NIH-NIAID FX The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences, and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.; Disclosure of potential conflict of interest: R. F. Lemanske, Jr, is a speaker for Merck and AstraZeneca and has consulted for AstraZeneca, Map Pharmaceuticals, Gray Consulting, Smith Research Inc, Merck Childhood Asthma Network, Novartis, Quintiles/Innovax, RC Horowitz & Co Inc. Scienomics, Scientific Therapeutics, Cognimed Inc, SA Boney and Associates, GlaxoSmithKline, and Double Helix Development Inc. K. S. Elward is a speaker on guidelines implementation for Merck; has received research support from the National Asthma Control Initiative; is a member of the Virginia Asthma Coalition; and is a member of the National Asthma Education and Prevention Program Coordination Committee. M. Kattan has received research support from the NIH-NIAID. The rest of the authors declare that they have no relevant conflicts of interest. NR 54 TC 31 Z9 31 U1 1 U2 5 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 MAR PY 2012 VL 129 IS 3 SU S BP S124 EP S135 DI 10.1016/j.jaci.2011.12.981 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600008 PM 22386505 ER PT J AU Rand, CS Wright, RJ Cabana, MD Foggs, MB Halterman, JS Olson, L Vollmer, WM Wilson, SR Taggart, V AF Rand, Cynthia S. Wright, Rosalind J. Cabana, Michael D. Foggs, Michael B. Halterman, Jill S. Olson, Lynn Vollmer, William M. Wilson, Sandra R. Taggart, Virginia TI Mediators of asthma outcomes SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Adherence; self-management skills; asthma patient education; stress ID SELF-MANAGEMENT PROGRAM; POSTNATAL DEPRESSION SCALE; STRESSFUL LIFE EVENTS; MEDICATION ADHERENCE; INHALED CORTICOSTEROIDS; PREDICTIVE-VALIDITY; PERCEIVED STRESS; CHRONIC DISEASE; CHILDREN; VALIDATION AB Background: Patient adherence, the level of asthma self-management skills, exposure to stress, and depression can have considerable influence on a wide range of asthma outcomes and thus are considered asthma outcome mediators. Objective: National Institutes of Health institutes and other federal agencies convened an expert group to recommend standardized measures for 7 domains of asthma clinical research outcomes measures. Although the review of mediators of these outcomes was not within the scope of any specific outcome topic, a brief summary is presented so that researchers might consider potential mediators. Methods: We prepared a summary of key mediators of asthma outcomes based on expertise and knowledge of the literature. Results: The rationale for including measures of adherence, self-management skills, and exposures to stress in asthma clinical research is presented, along with a brief review of instruments for collecting this information from clinical research participants. Conclusions: Appropriate measurement of adherence, self-management skills, and exposures to stress will enhance characterization of study participants and provide information about the potential impact these factors can have on mediating the effects of treatment interventions. (J Allergy Clin Immunol 2012; 129: S136-41.) C1 [Taggart, Virginia] NHLBI, DLD, NIH, Bethesda, MD 20892 USA. [Rand, Cynthia S.] Johns Hopkins Univ, Baltimore, MD USA. [Wright, Rosalind J.] Harvard Univ, Sch Med, Boston, MA USA. [Cabana, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Foggs, Michael B.] Advocate Hlth Care, Oak Brook, IL USA. [Halterman, Jill S.] Univ Rochester, Rochester, NY 14627 USA. [Olson, Lynn] Amer Acad Pediat, Elk Grove Village, IL USA. [Vollmer, William M.] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Wilson, Sandra R.] Palo Alto Med Fdn, Res Inst, Palo Alto, CA 94301 USA. RP Taggart, V (reprint author), NHLBI, DLD, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM taggartv@nih.gov RI Osborne, Nicholas/N-4915-2015 OI Osborne, Nicholas/0000-0002-6700-2284 FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency FX The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and for all other articles in this supplement. NR 79 TC 28 Z9 28 U1 5 U2 11 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 MAR PY 2012 VL 129 IS 3 SU S BP S136 EP S141 DI 10.1016/j.jaci.2011.12.987 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600009 PM 22386506 ER PT J AU Szefler, SJ Wenzel, S Brown, R Erzurum, SC Fahy, JV Hamilton, RG Hunt, JF Kita, H Liu, AH Panettieri, RA Schleimer, RP Minnicozzi, M AF Szefler, Stanley J. Wenzel, Sally Brown, Robert Erzurum, Serpil C. Fahy, John V. Hamilton, Robert G. Hunt, John F. Kita, Hirohito Liu, Andrew H. Panettieri, Reynold A., Jr. Schleimer, Robert P. Minnicozzi, Michael TI Asthma outcomes: Biomarkers SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Multiallergen screen; fractional exhaled nitric oxide; sputum eosinophils; total eosinophils; IgE; urinary leukotriene E-4 ID EXHALED NITRIC-OXIDE; SKIN-TEST REACTIVITY; EOSINOPHILIC AIRWAY INFLAMMATION; URINARY LEUKOTRIENE E-4; SPUTUM CELL COUNTS; HEALTHY-SUBJECTS; CHILDHOOD ASTHMA; REFERENCE VALUES; INHALED CORTICOSTEROIDS; PERSISTENT ASTHMA AB Background: Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects. Objective: National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies. Methods: We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health-organized workshop convened in March 2010 and finalized in September 2011. Results: Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (FENO), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures. Conclusion: The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories. (J Allergy Clin Immunol 2012; 129:S9-23.) C1 [Minnicozzi, Michael] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Szefler, Stanley J.; Liu, Andrew H.] Natl Jewish Hlth, Denver, CO USA. [Wenzel, Sally] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Brown, Robert; Hamilton, Robert G.] Johns Hopkins Univ, Baltimore, MD USA. [Erzurum, Serpil C.] Cleveland Clin Fdn, Cleveland, OH USA. [Fahy, John V.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hunt, John F.] Univ Virginia, Charlottesville, VA USA. [Kita, Hirohito] Mayo Clin Rochester, Rochester, MN USA. [Panettieri, Reynold A., Jr.] Univ Penn, Philadelphia, PA 19104 USA. [Schleimer, Robert P.] Northwestern Univ, Chicago, IL 60611 USA. RP Minnicozzi, M (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM minnicozzim@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency; NIH (NHLBI, NIAID, NIEHS); Environmental Protection Agency; NIH (NHLBI); NIH (NIAID); Genentech; NIH-NIAID; Altrea; AstraZeneca; Johnson Johnson; Merck; Roche FX The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.; Disclosure of potential conflict of interest: S. J. Szefler is a consultant for GlaxoSmithKline, Genentech, Merck, Boehringer-Ingelheim, Novartis, and Schering-Plough; and has received research support from the NIH (NHLBI, NIAID, NIEHS) and the Environmental Protection Agency. J. V. Fahy is on the Cytokinetics Scientific advisory board; has received consulting fees from Amgen, Gilcad, Five Prime Therapeutics, Merck, Regeneron Pharmaceuticals, Portola Pharmaceuticals; and has received research support from the NIH (NHLBI and NIAID) and Genentech. J. F. Hunt is on the Pulse Health LLC advisory board; is founder of Respiratory Research, Inc; has received research support from the NIH-NIAID and Altrea; and is Chair of the AAAAI Asthma Diagnosis and Pharmacotherapeutics Committee and Cough Committee. A. H. Liu has received speaker honoraria from Merck; is on the Data Safety Monitoring Board for GlaxoSmithKline; and is a consultant for DBV. R. A. Panettieri, Jr, is a consultant for Johnson & Johnson, Forest Pharmaceuticals, Genentech, and Merck; and has received research support from AstraZeneca, Johnson & Johnson, Merck, and Roche. R. P. Schleimer is a consultant for GlaxoSmithKline and Intersect ENT. The rest of the authors declare that they have no relevant conflicts of interest. NR 178 TC 128 Z9 130 U1 3 U2 26 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 MAR PY 2012 VL 129 IS 3 SU S BP S9 EP S23 DI 10.1016/j.jaci.2011.12.979 PG 15 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600002 PM 22386512 ER PT J AU Tepper, RS Wise, RS Covar, R Irvin, CG Kercsmar, CM Kraft, M Liu, MC O'Connor, GT Peters, SP Sorkness, R Togias, A AF Tepper, Robert S. Wise, Robert S. Covar, Ronina Irvin, Charles G. Kercsmar, Carolyn M. Kraft, Monica Liu, Mark C. O'Connor, George T. Peters, Stephen P. Sorkness, Ronald Togias, Alkis TI Asthma outcomes: Pulmonary physiology SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Spirometry; airway responsiveness; peak expiratory flow monitoring; lung volumes; gas exchange ID PEAK EXPIRATORY FLOW; EXERCISE-INDUCED BRONCHOCONSTRICTION; COLD-AIR CHALLENGE; EXHALED NITRIC-OXIDE; METHACHOLINE-INDUCED BRONCHOCONSTRICTION; NONSPECIFIC BRONCHIAL RESPONSIVENESS; LEUKOTRIENE-RECEPTOR ANTAGONIST; NASAL INSPIRATORY FLOW; LUNG-FUNCTION; BRONCHODILATOR RESPONSIVENESS AB Background: Outcomes of pulmonary physiology have a central place in asthma clinical research. Objective: At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons. Methods: Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. Results: A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (FEV1, forced vital capacity, and FEV1/forced vital capacity ratio) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and prebronchodilator and postbronchodilator FEV1 also are core outcomes for study population characterization and observational studies. Conclusions: The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research. (J Allergy Clin Immunol 2012; 129: S65-87.) C1 [Togias, Alkis] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Tepper, Robert S.] Indiana Univ, Indianapolis, IN 46204 USA. [Wise, Robert S.; Liu, Mark C.] Johns Hopkins Univ, Baltimore, MD USA. [Covar, Ronina] Natl Jewish Hlth, Denver, CO USA. [Irvin, Charles G.] Univ Vermont, Burlington, VT 05405 USA. [Kercsmar, Carolyn M.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Kraft, Monica] Duke Univ, Durham, NC 27706 USA. [O'Connor, George T.] Boston Univ, Boston, MA 02215 USA. [Peters, Stephen P.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Sorkness, Ronald] Univ Wisconsin, Madison, WI 53706 USA. RP Togias, A (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM togiasa@niaid.nih.gov OI O'Connor, George/0000-0002-6476-3926; Wise, Robert/0000-0002-8353-2349 FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency; GlaxoSmithKline; Boehringer-Ingelheim; Merck; Forest; NIH; American Lung Association; Asthmatx; Eumedics; Novartis; Genentech; MedImmune; Sanofi-Aventis; Amgen FX The Asthma Outcomes work shop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.; Disclosure of potential conflict of interest: R. S. Tepper has received research support from the NHLBI. R. S. Wise is a consultant for GlaxoSmithKline, AstraZeneca, Novartis, Boehringer-Ingelheim, Merck, and Sunovion; and has received research support from GlaxoSmithKline, Boehringer-Ingelheim, Merck, and Forest. R. Covar has received research support from the NHLBI. C. G. Irvin has received research support from the NIH and the American Lung Association. M. Kraft has received research support from GlaxoSmithKline, Merck, Asthmatx, Eumedics, Novartis, and Genentech. M. C. Liu has received research support from GlaxoSmithKline, MedImmune, Sanofi-Aventis, and Amgen. G. T. O'Connor is a consultant for Sunovion Inc and has received research support from Novartis. R. Sorkness has received research support from the NIH. The rest of the authors declare that they have no relevant conflicts of interest. NR 225 TC 31 Z9 33 U1 2 U2 13 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 MAR PY 2012 VL 129 IS 3 SU S BP S65 EP S87 DI 10.1016/j.jaci.2011.12.986 PG 23 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600006 PM 22386510 ER PT J AU Wilson, SR Rand, CS Cabana, MD Foggs, MB Halterman, JS Olson, L Vollmer, WM Wright, RJ Taggart, V AF Wilson, Sandra R. Rand, Cynthia S. Cabana, Michael D. Foggs, Michael B. Halterman, Jill S. Olson, Lynn Vollmer, William M. Wright, Rosalind J. Taggart, Virginia TI Asthma outcomes: Quality of life SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma burden; asthma-related well-being; health perceptions; health status; patient-reported outcomes ID GEORGES-RESPIRATORY-QUESTIONNAIRE; CHILDRENS HEALTH SURVEY; GENERIC CORE SCALES; PEDIATRIC-ASTHMA; ADULT ASTHMA; CHILDHOOD ASTHMA; YOUNG-ADULTS; SELF-MANAGEMENT; DISEASE-CONTROL; LONGITUDINAL CHANGES AB Background: "Asthma-related quality of life" (QOL) refers to the perceived impact that asthma has on the patient's QOL. Objective: National Institutes of Health institutes and other federal agencies convened an expert group to recommend standardized measures of the impact of asthma on QOL for use in future asthma clinical research. Methods: We reviewed published documentation regarding the development and psychometric evaluation; clinical research use since 2000; and extent to which the content of each existing QOL instrument provides a unique, reliable, and valid assessment of the intended construct. We classified instruments as core (required in future studies), supplemental (used according to the study's aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health-organized workshop convened in March 2010 and finalized in September 2011. Results: Eleven instruments for adults and 6 for children were identified for review. None qualified as core instruments because they predominantly measured indicators of asthma control (symptoms and/or functional status); failed to provide a distinct, reliable score measuring all key dimensions of the intended construct; and/or lacked adequate psychometric data. Conclusions: In the absence of existing instruments that meet the stated criteria, currently available instruments are classified as either supplemental or emerging. Research is strongly recommended to develop and evaluate instruments that provide a distinct, reliable measure of the patient's perception of the impact of asthma on all of the key dimensions of QOL, an important outcome that is not captured in other outcome measures. (J Allergy Clin Immunol 2012; 129: S88-123.) C1 [Taggart, Virginia] NHLBI, DLD, NIH, Bethesda, MD 20892 USA. [Wilson, Sandra R.] Palo Alto Med Fdn, Res Inst, Palo Alto, CA 94301 USA. [Rand, Cynthia S.] Johns Hopkins Univ, Baltimore, MD USA. [Cabana, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Foggs, Michael B.] Advocate Hlth Care, Oak Brook, IL USA. [Halterman, Jill S.] Univ Rochester, Rochester, NY 14627 USA. [Olson, Lynn] Amer Acad Pediat, Elk Grove Village, IL USA. [Vollmer, William M.] Kaiser Permanente, Portland, OR USA. [Wright, Rosalind J.] Harvard Univ, Sch Med, Boston, MA USA. RP Taggart, V (reprint author), NHLBI, DLD, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM taggartv@nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency FX The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement. NR 146 TC 45 Z9 45 U1 1 U2 14 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 MAR PY 2012 VL 129 IS 3 SU S BP S88 EP S123 DI 10.1016/j.jaci.2011.12.988 PG 36 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600007 PM 22386511 ER PT J AU Neunuebel, MR Mohammadi, S Jarnik, M Machner, MP AF Neunuebel, M. Ramona Mohammadi, Sina Jarnik, Michal Machner, Matthias P. TI Legionella pneumophila LidA Affects Nucleotide Binding and Activity of the Host GTPase Rab1 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID EFFECTOR PROTEIN DRRA; ENDOPLASMIC-RETICULUM; INTRACELLULAR SURVIVAL; TRANSLOCATED SUBSTRATE; GUANINE-NUCLEOTIDES; VESICULAR TRANSPORT; GOLGI COMPARTMENTS; PLASMA-MEMBRANE; HUMAN-MONOCYTES; EXCHANGE FACTOR AB Legionella pneumophila, the causative agent of a severe pneumonia known as Legionnaires' disease, intercepts material from host cell membrane transport pathways to create a specialized vacuolar compartment that supports bacterial replication. Delivery of bacterial effector proteins into the host cell requires the Dot/Icm type IV secretion system. Several effectors, including SidM, SidD, and LepB, were shown to target the early secretory pathway by manipulating the activity of the host GTPase Rab1. While the function of these effectors has been well characterized, the role of another Rab1-interacting protein from L. pneumophila, the effector protein LidA, is poorly understood. Here, we show that LidA binding to Rab1 stabilized the Rab1-guanosine nucleotide complex, protecting it from inactivation by GTPase-activating proteins (GAPs) and from nucleotide extraction. The protective effect of LidA on the Rab1-guanine nucleotide complex was concentration dependent, consistent with a 1:1 stoichiometry of the LidA-Rab1 complex. The central coiled-coil region of LidA was sufficient for Rab1 binding and to prevent GAP-mediated inactivation or nucleotide extraction from Rab1. In addition, the central region mediated binding to phosphatidylinositol 3-phosphate and other phosphoinositides. When bound to Rab1, LidA interfered with the covalent modification of Rab1 by phosphocholination or AMPylation, and it also blocked de-AMPylation of Rab1 by SidD and dephosphocholination by Lem3. Based on these findings, we propose a role for LidA in bridging the membrane of the Legionella-containing vacuole (LCV) with that of secretory transport vesicles surrounding the LCV. C1 [Neunuebel, M. Ramona; Jarnik, Michal; Machner, Matthias P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. [Mohammadi, Sina] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Machner, MP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. EM machnerm@mail.nih.gov RI Machner, Matthias/G-2758-2015; OI Machner, Matthias/0000-0002-6971-7451 FU NIH FX This work was supported by the Intramural Research Program of the NIH. NR 52 TC 27 Z9 30 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD MAR PY 2012 VL 194 IS 6 BP 1389 EP 1400 DI 10.1128/JB.06306-11 PG 12 WC Microbiology SC Microbiology GA 899WI UT WOS:000300846900012 PM 22228731 ER PT J AU Nguyen, HT Torian, U Faulk, K Mather, K Engle, RE Thompson, E Bonkovsky, HL Emerson, SU AF Nguyen, H. T. Torian, U. Faulk, K. Mather, K. Engle, R. E. Thompson, E. Bonkovsky, H. L. Emerson, S. U. TI A naturally occurring human/hepatitis E recombinant virus predominates in serum but not in faeces of a chronic hepatitis E patient and has a growth advantage in cell culture SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID ENZYME-IMMUNOASSAY; EFFICIENT; ANTIBODIES; INFECTION; THERAPY; STRAINS; SYSTEM; BLOOD; HEV AB Hepatitis E virus is the aetiological agent of acute hepatitis E, a self-limiting disease prevalent in developing countries. Molecular analysis of viral genomic RNA from a chronically infected patient confirmed the recent discovery that chronic infection correlated with extensive diversification of the virus quasispecies: the hypervariable region of some virus genomes in this USA patient contained large continuous deletions and a minor proportion of genomes in faeces and serum had acquired a mammalian sequence that encoded 39 aa of S19 ribosomal protein fused to the virus non-structural protein. Genomes with this insert were selected during virus passage in cultured cells to become the predominant species, suggesting that the inserted sequence promoted virus growth. The results demonstrated that hepatitis E virus can mutate dramatically during a prolonged infection and suggests it may be important to prevent or cure chronic infections before new variants with unpredictable properties arise. C1 [Nguyen, H. T.; Torian, U.; Faulk, K.; Mather, K.; Engle, R. E.; Emerson, S. U.] NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Thompson, E.] Carolinas Digest Hlth Associates, Charlotte, NC 28211 USA. [Bonkovsky, H. L.] Carolinas Hlth Care Syst, Ctr Liver, Charlotte, NC 28203 USA. [Bonkovsky, H. L.] Univ N Carolina, Charlotte, NC 28203 USA. [Bonkovsky, H. L.] Univ Connecticut, Farmington, CT 06030 USA. RP Emerson, SU (reprint author), NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM semerson@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. This work was carried out under an approved protocol of the Carolinas Medical Center, IRB 10-0709B, with the informed consent of the patient. NR 20 TC 22 Z9 23 U1 1 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2012 VL 93 BP 526 EP 530 DI 10.1099/vir.0.037259-0 PN 3 PG 5 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 902JE UT WOS:000301033600007 PM 22113007 ER PT J AU Marshall, LJ Moore, LD Mirsky, MM Major, EO AF Marshall, Leslie J. Moore, Lisa D. Mirsky, Matthew M. Major, Eugene O. TI JC virus promoter/enhancers contain TATA box-associated Spi-B-binding sites that support early viral gene expression in primary astrocytes SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; LARGE T-ANTIGEN; TRANSCRIPTIONAL CONTROL REGION; HUMAN NEUROTROPIC VIRUS; LARGE TUMOR-ANTIGEN; GLIAL-CELLS; REGULATORY REGION; MULTIPLE-SCLEROSIS; ENHANCER ACTIVITY; PROMOTER ACTIVITY AB JC virus (JCV) is the aetiological agent of the demyelinating disease progressive multifocal leukoencephalopathy, an AIDS defining illness and serious complication of mAb therapies. Initial infection probably occurs in childhood. In the working model of dissemination, virus persists in the kidney and lymphoid tissues until immune suppression/modulation causes reactivation and trafficking to the brain where JCV replicates in oligodendrocytes. JCV infection is regulated through binding of host factors such as Spi-B to, and sequence variation in the non-coding control region (NCCR). Although NCCR sequences differ between sites of persistence and pathogenesis, evidence suggests that the virus that initiates infection in the brain disseminates via B-cells derived from latently infected haematopoietic precursors in the bone marrow. Spi-B binds adjacent to TATA boxes in the promoter/enhancer of the PML-associated JCV Mad-1 and Mad-4 viruses but not the non-pathogenic, kidney-associated archetype. The Spi-B-binding site of Mad-1/Mad-4 differs from that of archetype by a single nucleotide, AAAAGGGAAGGGA to AAAAGGGAAGGTA. Point mutation of the Mad-1 Spi-B site reduced early viral protein large T-antigen expression by up to fourfold. Strikingly, the reverse mutation in the archetype NCCR increased large T-antigen expression by 10-fold. Interestingly, Spi-B protein binds the NCCR sequence flanking the viral promoter/enhancer, but these sites are not essential for early viral gene expression. The effect of mutating Spi-B-binding sites within the JCV promoter/enhancer on early viral gene expression strongly suggests a role for Spi-B binding to the viral promoter/enhancer in the activation of early viral gene expression. C1 [Marshall, Leslie J.; Moore, Lisa D.; Mirsky, Matthew M.; Major, Eugene O.] Natl Inst Neurol Disorders & Stroke, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov FU Laboratory of Molecular Medicine and Neuroscience at the NINDS; NINDS FX We thank Francoise Moreau-Gachelin of the Institut Curie (Paris, France) for generously providing polyclonal rabbit Spi-B antiserum and human Spi-B plasmid. We thank the DNA sequencing facility at the National Institute of Neurological Disorders and Stroke (NINDS) for aid in sequencing of mutant viral plasmids. We thank all of the members of the Laboratory of Molecular Medicine and Neuroscience at the NINDS for their hard work, support, and valuable input. The intramural program at the NINDS provided support for this work. NR 65 TC 16 Z9 17 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2012 VL 93 BP 651 EP 661 DI 10.1099/vir.0.035832-0 PN 3 PG 11 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 902JE UT WOS:000301033600023 PM 22071512 ER PT J AU Srinivasalu, H Barnes, MG Layh-Schmitt, G Ward, MM Colbert, RA AF Srinivasalu, Hemalatha Barnes, Michael G. Layh-Schmitt, Gerlinde Ward, Michael M. Colbert, Robert A. TI EARLY DISEASE CHARACTERISTICS OF ENTHESITIS-RELATED ARTHRITIS REVEALS ELEVATED TRANSFORMING GROWTH FACTOR-BETA SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Srinivasalu, Hemalatha; Layh-Schmitt, Gerlinde; Ward, Michael M.; Colbert, Robert A.] NIAMS, NIH, Bethesda, MD USA. [Srinivasalu, Hemalatha] Nemours Alfred I duPont Hosp Children, Wilmington, DE USA. [Barnes, Michael G.] Cincinnati Childrens Hosp, Cincinnati BioBank, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2012 VL 60 IS 3 BP 621 EP 621 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 898YL UT WOS:000300778200024 ER PT J AU Estrada-Veras, JI Gahl, WA Gochuico, B AF Estrada-Veras, Juvianee I. Gahl, William A. Gochuico, Bernadette TI ERDHEIM-CHESTER DISEASE (ECD): NATURAL HISTORY SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Estrada-Veras, Juvianee I.; Gahl, William A.; Gochuico, Bernadette] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2012 VL 60 IS 3 BP 626 EP 626 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 898YL UT WOS:000300778200041 ER PT J AU Zhang, JH Chen, ZL Fritz, JH Rochman, Y Leonard, WJ Gommerman, JL Plumb, AW Abraham, N Croy, BA AF Zhang, Jianhong Chen, Zhilin Fritz, Joerg H. Rochman, Yrina Leonard, Warren J. Gommerman, Jennifer L. Plumb, Adam W. Abraham, Ninan Croy, B. Anne TI Unusual timing of CD127 expression by mouse uterine natural killer cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE decidua; interleukin 7; stromal factor; thymic stromal lymphopoietin ID THYMIC STROMAL LYMPHOPOIETIN; METRIAL GLAND-CELLS; NK CELLS; MATERNAL/FETAL INTERFACE; INTERFERON-GAMMA; BONE-MARROW; PREGNANCY; DIFFERENTIATION; MATURATION; AIRE AB Decidualization, a progesterone-dependent process that alters endometrial stromal cells at implantation sites in humans and rodents, is accompanied by a highly regulated, NK cell-dominated leukocyte influx into decidual basalis (DB). Whether uNK cells differentiate from uterine progenitor cells is unknown, as are the mechanisms restricting leukocytes to DB. We asked if cells expressing the early NK lineage marker CD127 (IL-7R alpha)occurred in mouse decidua. CD127 was absent from gd6.5 decidual lymphoid cells but became expressed by a mature uNK cell subset in gd10.5 DB. DB and transient myometrial structures (MLAp) that ring maternal blood vessels supplying placentae expressed IL-7 and TSLP, the CD127 ligands, but with differing temporal and spatial patterns. UNK cells expressed TSLPR, and study of gd10.5 implantation sites from mice deleted for IL-7, CD127, or TSLPR suggested that IL-7 and its receptor have physiological roles in limiting expansion of immature uNK cells within MLAp, while the TSLP signaling pathway is used in DB to sustain IFN-gamma production from a subset of mature uNK cells. Regionalized, dynamic expression of the additional lymphoid organ stromal markers gp38/podoplanin and ER-TR7, but not CD157, were seen by immunohistochemistry in implantation sites, and DB and MLAp contained transcripts for Aire, a tolerance-promoting factor. These observations suggest that CD127(+) NK lineage progenitors are not present in the early postimplantation period of mouse uterus and that decidualized endometrial stroma has key immunoregulatory properties. J. Leukoc. Biol. 91: 417-426; 2012. C1 [Zhang, Jianhong; Chen, Zhilin; Croy, B. Anne] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada. [Fritz, Joerg H.] McGill Univ, Dept Microbiol & Immunol, Complex Traits Grp, Montreal, PQ, Canada. [Rochman, Yrina; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Gommerman, Jennifer L.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A1, Canada. [Plumb, Adam W.; Abraham, Ninan] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V5Z 1M9, Canada. [Abraham, Ninan] Univ British Columbia, Dept Zool, Cell Biol Grp, Vancouver, BC, Canada. RP Zhang, JH (reprint author), Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Room 6-1025,25 Orde St, Toronto, ON M5T 3H7, Canada. EM jhz.zhang@utoronto.ca OI Abraham, Ninan/0000-0002-2747-1246 FU Natural Sciences and Engineering Research Council, Canada; Canadian Institutes of Health Research; Canada and Canadian Institutes of Health Research Canada [67157]; Canada Research Chairs Program; Province of Ontario/Queen; National Heart, Lung, and Blood Institute, National Institutes of Health FX This study was supported by the Natural Sciences and Engineering Research Council, Canada and Canadian Institutes of Health Research (B.A.C.), the Canada and Canadian Institutes of Health Research Canada (MOP#67157; J.H.F and J.L.G), the Canada Research Chairs Program (B.A.C.), Province of Ontario/Queen's Postdoctoral Fellowship (J.Z.), and the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health (Y.R. and W.J.L). We thank Mr. K. Hatta and Drs. G. N. Smith and C. Tayade (Queen's University) for helpful discussions and Dr. C. Paige and Mr. S. Corfe (University of Toronto) for provision of pregnant Il7-/- uteri. NR 49 TC 12 Z9 12 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2012 VL 91 IS 3 BP 417 EP 426 DI 10.1189/jlb.1011501 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 901BT UT WOS:000300937400008 PM 22227963 ER PT J AU Zhao, G Wang, JN Xu, XZ Jing, YY Tu, L Li, XG Chen, C Cianflone, K Wang, PH Dackor, RT Zeldin, DC Wang, DW AF Zhao, Gang Wang, Jianing Xu, Xizhen Jing, Yanyan Tu, Ling Li, Xuguang Chen, Chen Cianflone, Katherine Wang, Peihua Dackor, Ryan T. Zeldin, Darryl C. Wang, Dao Wen TI Epoxyeicosatrienoic acids protect rat hearts against tumor necrosis factor-alpha-induced injury SO JOURNAL OF LIPID RESEARCH LA English DT Article DE apoptosis; cytochrome P450; eicosanoids; heart; peroxisome proliferator-activated receptors ID EPOXYGENASE-DERIVED EICOSANOIDS; EPIDERMAL-GROWTH-FACTOR; NITRIC-OXIDE SYNTHASE; ARACHIDONIC-ACID; ENDOTHELIAL-CELLS; SIGNALING PATHWAYS; CARDIAC MYOCYTES; HYPERTENSIVE-RATS; INDUCED APOPTOSIS; K+ CHANNELS AB Epoxyeicosatrienoic acids (EET), the primary arachidonic acid metabolites of cytochrome P450 2J (CYP2J) epoxygenases, possess potent vasodilatory, anti-inflammatory, antiapoptotic, and mitogenic effects. To date, little is known about the role of CYP2J2 and EETs in tumor necrosis factor (TNF)-alpha-induced cardiac injury. We utilized cell culture and in vivo models to examine the effects of exogenously applied EETs or CYP2J2 overexpression on TNF-alpha-induced cardiac apoptosis and cardiac dysfunction. In neonatal rat cardiomyocytes, TNF-alpha-induced apoptosis was markedly attenuated by EETs or CYP2J2 overexpression, leading to significantly improved cell survival. Further studies showed that TNF-alpha decreased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL, decreased I kappa B alpha and PPAR gamma, and also inhibited PI3K-dependent Akt and EGFR signaling. Both EETs and CYP2J2 overexpression reversed the effects of TNF-alpha on these pathways. Furthermore, overexpression of CYP2J2 in rats prevented the decline in cardiac function that is normally observed in TNF-alpha challenged animals. These results demonstrate that EETs or CYP2J2 overexpression can prevent TNF-alpha-induced cardiac cell injury and cardiac dysfunction by inhibiting apoptosis, reducing inflammation, and enhancing PPAR gamma expression. Targeting the CYP2J2 epoxygenase pathway may represent a novel approach to mitigate cardiac injury in diseases such as heart failure, where increased TNF-alpha levels are known to occur.-Zhao, G., J. Wang, X. Xu, Y. Jing, L. Tu, X. Li, C. Chen, K. Cianflone, P. Wang, R. T. Dackor, D. C. Zeldin, and D. W. Wang. Epoxyeicosatrienoic acids protect rat hearts against tumor necrosis factor-alpha-induced injury. J. Lipid Res. 2012. 53: 456-466. C1 [Zhao, Gang; Wang, Jianing; Xu, Xizhen; Jing, Yanyan; Tu, Ling; Li, Xuguang; Chen, Chen; Wang, Peihua; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Internal Med, Wuhan 430030, Peoples R China. [Zhao, Gang; Wang, Jianing; Xu, Xizhen; Jing, Yanyan; Tu, Ling; Li, Xuguang; Chen, Chen; Wang, Peihua; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Gene Therapy Ctr, Wuhan 430030, Peoples R China. [Cianflone, Katherine; Wang, Dao Wen] Univ Laval, Ctr Rech, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ G1V 4G5, Canada. [Dackor, Ryan T.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Tu, L (reprint author), Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Internal Med, Wuhan 430030, Peoples R China. EM proftu@tom.com; dwwang@tjh.tjmu.edu.cn FU National Natural Science Foundation of China [31130031, 30770882, 81070236, 3113031]; National Basic Research Program of China (973 Program) [2007CB512004]; National Institute of Environmental Health Sciences, National Institutes of Health FX This work was supported by National Natural Science Foundation of China Grant Nos. 31130031, 30770882, 81070236 and 3113031; by National Basic Research Program of China (973 Program) Grant No. 2007CB512004; and by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 46 TC 24 Z9 25 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD MAR PY 2012 VL 53 IS 3 BP 456 EP 466 DI 10.1194/jlr.M017319 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 900IK UT WOS:000300880200014 PM 22223859 ER PT J AU Vyas, NS Shamsi, SA Malhotra, AK Aitchison, KJ Kumari, V AF Vyas, Nora S. Shamsi, Syed A. Malhotra, Anil K. Aitchison, Katherine J. Kumari, Veena TI Can genetics inform the management of cognitive deficits in schizophrenia? SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Review DE Schizophrenia; BDNF; copy number variation; cognition; dopamine; glutamate receptors; pharmacology; serotonin ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; EARLY-ONSET SCHIZOPHRENIA; CARDIO-FACIAL SYNDROME; DONEPEZIL ADJUNCTIVE TREATMENT; POSITRON-EMISSION-TOMOGRAPHY; BDNF VAL66MET POLYMORPHISM; ANTERIOR CINGULATE CORTEX; VAL(108/158) MET GENOTYPE; RARE STRUCTURAL VARIANTS AB There is no doubt that schizophrenia has a significant genetic component and a number of candidate genes have been identified for this debilitating disorder. Of note, several of these are implicated in cognition. Cognitive deficits constitute core symptoms of schizophrenia, and while current antipsychotic treatment strategies aim to help psychosis-related symptomatology, the cognitive symptom domain is largely inadequately treated. A number of other pharmacological approaches (e.g. using drugs that target specific neurotransmitter systems) have also been attempted for the amelioration of cognitive deficits in this population; however, these too have had limited success so far. Psychological interventions appear promising, though there has been speculation regarding whether or not these produce long-term functional improvements. Pharmacogenetic studies of the cognitive effects of currently available antipsychotics, although in relatively early stages, suggest that the treatment of cognitive deficits in schizophrenia may be advanced by focusing on genetic variants associated with specific cognitive dysfunctions in the general population and using this to match the most relevant pharmacological and/or psychological interventions with the genetic and cognitive profiles of the target population. Such a strategy would encourage bottom-up advances in drug development and provide a platform for individualised treatment of cognitive deficits in schizophrenia. C1 [Vyas, Nora S.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Vyas, Nora S.; Aitchison, Katherine J.] Kings Coll London, Inst Psychiat, MRC SGDP Ctr, London WC2R 2LS, England. [Shamsi, Syed A.; Malhotra, Anil K.] Zucker Hillside Hosp, Div Psychiat Res, N Shore Long Isl Jewish Hlth Syst, Glen Oaks, NY USA. [Aitchison, Katherine J.] Univ Alberta, Dept Psychiat, Edmonton, AB, Canada. [Kumari, Veena] Kings Coll London, Inst Psychiat, Dept Psychol, London WC2R 2LS, England. [Kumari, Veena] S London & Maudsley NHS Fdn Trust, NIHR Biomed Res Ctr Mental Hlth, London, England. RP Vyas, NS (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. EM nora.vyas@nih.gov RI Aitchison, Katherine/G-4476-2013 OI Aitchison, Katherine/0000-0002-1107-3024 FU Fulbright Distinguished Scholar Award; US-UK Fulbright Commission FX Dr Nora S Vyas is supported by the Fulbright Distinguished Scholar Award by the US-UK Fulbright Commission. NR 279 TC 6 Z9 6 U1 3 U2 13 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 MAR PY 2012 VL 26 IS 3 SI SI BP 334 EP 348 DI 10.1177/0269881111434623 PG 15 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 900HE UT WOS:000300876800002 PM 22328662 ER PT J AU Cutler, JA Rush, AJ McMahon, FJ Laje, G AF Cutler, Jessica A. Rush, A. John McMahon, Francis J. Laje, Gonzalo TI Common genetic variation in the indoleamine-2,3-dioxygenase genes and antidepressant treatment outcome in major depressive disorder SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Pharmacogenetics; depressive disorder; treatment outcome; indoleamine-pyrrole 2, 3-dioxygenase; ID0; ID01; ID02 ID STAR-ASTERISK-D; ALPHA-INDUCED DEPRESSION; REPORT QIDS-SR; PSYCHOMETRIC EVALUATION; QUICK INVENTORY; TRYPTOPHAN; ASSOCIATION; RECEPTOR; SYMPTOMATOLOGY; NEUROTOXICITY AB The essential amino acid tryptophan is the precursor to serotonin, but it can also be metabolized into kynurenine through indoleamine-2,3-dioxygenase (ID0). Increased immune activation has long been associated with symptoms of depression and has been shown to upregulate the expression of ID0. The presence of additional ID0 directs more tryptophan down the kynurenine pathway, leaving less available for synthesis of serotonin and its metabolites. Kynurenine can be metabolized through a series of enzymes to quinolinic acid, a potent N-methyl-D-aspartate receptor agonist with demonstrated neurotoxic effects. We tested the hypothesis that ID0 plays a role in outcome of treatment with the selective serotonin reuptake inhibitor, citalopram. Patients consisted of 1953 participants enrolled in the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D). Genotypes corresponding to 94 single nucleotide polymorphisms (SNPs) in the genes ID01 and ID02, which encode ID0 and ID02, were extracted from a larger genome-wide set and analyzed using single marker tests to look for association with previously defined response, remission and QIDS-C score change phenotypes, with adequate correction for racial stratification and multiple testing. One SNP, rs2929115, showed evidence of association with citalopram response (OR = 0.64, p = 0.0005) after experiment-wide correction for multiple testing. Another closely associated marker, rs2929116 (OR = 0.64, p = 0.0006) had an experiment-wide significant result. Both implicated SNPs are located between 26 kb and 28 kb downstream of ID02. We conclude that common genetic variation in ID01 and ID02 may play a role in antidepressant treatment outcome. These results are modest in a genome-wide context and need to be replicated in an independent sample. C1 [Cutler, Jessica A.; McMahon, Francis J.; Laje, Gonzalo] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Bethesda, MD 20892 USA. [Rush, A. John] Duke Natl Univ, Singapore, Singapore. RP Laje, G (reprint author), NIMH, Genet Basis Mood & Anxiety Disorders Sect, 35 Convent Dr,Rm 1A207, Bethesda, MD 20892 USA. EM gonzalo.laje@nih.gov RI Laje, Gonzalo/L-2654-2014; OI Laje, Gonzalo/0000-0003-2763-3329; McMahon, Francis/0000-0002-9469-305X; Rush, Augustus/0000-0003-2004-2382 FU National Institute of Mental Health, NIH [N01MH90003]; NARSAD; Advanced Neuromodulation Systems, Inc.; AstraZenica; Best Practice Project Management, Inc.; Cyberonics Inc.; Eli Lilly Company; Forest Pharmaceuticals Inc.; Gerson Lehman Group; GlaxoSmithKline; Healthcare Technology Systems Inc.; Jazz Pharmaceuticals; Magellan Health Services; Merck Co. Inc.; National Institute of Mental Health; Neuronetics; Ono Pharmaceutical; Organon USA Inc.; Otsuka; Pamlab; Personality Disorder Research Corporation; Pfizer Inc.; Robert Wood Johnson Foundation; Stanley Medical Research Institute; Urban Institute; Wyeth-Ayerst Laboratories Inc.; Guilford Publications and Healthcare Technology Systems Inc.; UT Southwestern Medical Center; [K99MH085098-01] FX This study was funded by the Intramural Research Program of the National Institute of Mental Health, NIH, by a NARSAD Independent Investigator Award to Francis McMahon and by K99MH085098-01 to Gonzalo Laje. The authors thank the STAR*D research team for acquisition of clinical data and DNA samples. Data and sample collection were funded with federal funds from the NIMH, NIH, under contract N01MH90003 to University of Texas Southwestern Medical Center at Dallas (Principal investigator, A John Rush).; Ms Cutler, Dr Laje and Dr McMahon report no competing interests. Dr Rush has served as an advisor, consultant, or speaker for or received research support from Advanced Neuromodulation Systems, Inc.; AstraZenica; Best Practice Project Management, Inc.; Bristol-Meyers Squibb Company; Cyberonics Inc.; Eli Lilly & Company; Forest Pharmaceuticals Inc.; Gerson Lehman Group; GlaxoSmithKline; Healthcare Technology Systems Inc.; Jazz Pharmaceuticals; Magellan Health Services; Merck & Co. Inc.; the National Institute of Mental Health; Neuronetics; Ono Pharmaceutical; Organon USA Inc.; Otsuka; Pamlab; Personality Disorder Research Corporation; Pfizer Inc.; the Robert Wood Johnson Foundation; the Stanley Medical Research Institute; the Urban Institute; and Wyeth-Ayerst Laboratories Inc. Dr Rush has equity holdings in Pfizer Inc., and receives royalty/patent income from Guilford Publications and Healthcare Technology Systems Inc., and UT Southwestern Medical Center. NR 27 TC 19 Z9 19 U1 1 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 MAR PY 2012 VL 26 IS 3 SI SI BP 360 EP 367 DI 10.1177/0269881111434622 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 900HE UT WOS:000300876800004 PM 22282879 ER PT J AU Morgan, AA Pyrgos, VJ Nadeau, KC Williamson, PR Butte, AJ AF Morgan, Alexander A. Pyrgos, Vasilios J. Nadeau, Kari C. Williamson, Peter R. Butte, Atul Janardhan TI Multiplex meta-analysis of RNA expression to identify genes with variants associated with immune dysfunction SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID CD8(+) T-CELLS; MISSING HERITABILITY; COMPLEX DISEASES; WINNERS CURSE; GENOME; TRANSCRIPTION; IDENTIFICATION; MUTATIONS; RESPONSES; PROFILES AB Objective We demonstrate a genome-wide method for the integration of many studies of gene expression of phenotypically similar disease processes, a method of multiplex meta-analysis. We use immune dysfunction as an example disease process. Design We use a heterogeneous collection of datasets across human and mice samples from a range of tissues and different forms of immunodeficiency. We developed a method integrating Tibshirani's modified t-test (SAM) is used to interrogate differential expression within a study and Fisher's method for omnibus meta-analysis to identify differentially expressed genes across studies. The ability of this overall gene expression profile to prioritize disease associated genes is evaluated by comparing against the results of a recent genome wide association study for common variable immunodeficiency (CVID). Results Our approach is able to prioritize genes associated with immunodeficiency in general (area under the ROC curve = 0.713) and CVID in particular (area under the ROC curve - 0.643). Conclusions This approach may be used to investigate a larger range of failures of the immune system. Our method may be extended to other disease processes, using RNA levels to prioritize genes likely to contain disease associated DNA variants. C1 [Morgan, Alexander A.; Butte, Atul Janardhan] Stanford Univ, Dept Pediat, Div Syst Med, Stanford, CA 94305 USA. [Morgan, Alexander A.; Butte, Atul Janardhan] Stanford Univ, Biomed Informat Grad Training Program, Stanford, CA 94305 USA. [Pyrgos, Vasilios J.; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Nadeau, Kari C.] Stanford Univ, Div Immunol, Dept Pediat, Stanford, CA 94305 USA. RP Butte, AJ (reprint author), Stanford Univ, Dept Pediat, Div Syst Med, 1265 Welch Rd X-163,MS-5415, Stanford, CA 94305 USA. EM abutte@stanford.edu FU March of Dimes; Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; National Library of Medicine [R01 LM009719]; Biomedical Informatics training grant [T15 LM007033]; NIH, NIAID FX This work was supported in part by the March of Dimes, the Lucile Packard Foundation for Children's Health, the Hewlett Packard Foundation, and the National Library of Medicine through direct research funding (R01 LM009719) and a Biomedical Informatics training grant (T15 LM007033). This research was also supported, in part, by the Intramural Research Program of the NIH, NIAID. NR 49 TC 2 Z9 2 U1 0 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR PY 2012 VL 19 IS 2 BP 284 EP 288 DI 10.1136/amiajnl-2011-000657 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 898UP UT WOS:000300768100023 PM 22319178 ER PT J AU Gipson, C Brown, P AF Gipson, Chester Brown, Patricia TI A word from USDA and OLAW SO LAB ANIMAL LA English DT Editorial Material C1 [Gipson, Chester] USDA, APHIS, AC, Washington, DC 20250 USA. [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. RP Gipson, C (reprint author), USDA, APHIS, AC, Washington, DC 20250 USA. NR 3 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 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2012 VL 41 IS 3 BP 64 EP 64 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 902BW UT WOS:000301014600015 PM 22343456 ER PT J AU Yi, J Wu, XFS Crites, T Hammer, JA AF Yi, Jason Wu, Xufeng S. Crites, Travis Hammer, John A., III TI Actin retrograde flow and actomyosin II arc contraction drive receptor cluster dynamics at the immunological synapse in Jurkat T cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SUPRAMOLECULAR ACTIVATION CLUSTER; NEURONAL GROWTH CONES; MYOSIN-II; ADHESION MOLECULES; FUSION PROTEIN; FISSION YEAST; MICROCLUSTERS; CYTOSKELETON; RECRUITMENT; MIGRATION AB Actin retrograde flow and actomyosin II contraction have both been implicated in the inward movement of T cell receptor (TCR) microclusters and immunological synapse formation, but no study has integrated and quantified their relative contributions. Using Jurkat T cells expressing fluorescent myosin IIA heavy chain and F-tractin-a novel reporter for F-actin-we now provide direct evidence that the distal supramolecular activation cluster (dSMAC) and peripheral supramolecular activation cluster (pSMAC) correspond to lamellipodial (LP) and lamellar (LM) actin networks, respectively, as hypothesized previously. Our images reveal concentric and contracting actomyosin II arcs/rings at the LM/pSMAC. Moreover, the speeds of centripetally moving TCR microclusters correspond very closely to the rates of actin retrograde flow in the LP/dSMAC and actomyosin II arc contraction in the LM/pSMAC. Using cytochalasin D and jasplakinolide to selectively inhibit actin retrograde flow in the LP/dSMAC and b.lebbistatin to selectively inhibit actomyosin II arc contraction in the LM/pSMAC, we demonstrate that both forces are required for centripetal TCR microcluster transport. Finally, we show that leukocyte function-associated antigen 1 clusters accumulate over time at the inner aspect of the LM/pSMAC and that this accumulation depends on actomyosin II contraction. Thus actin retrograde flow and actomyosin II arc contraction coordinately drive receptor cluster dynamics at the immunological synapse. C1 [Yi, Jason; Wu, Xufeng S.; Hammer, John A., III] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Yi, Jason] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Crites, Travis] NIAID, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov NR 52 TC 76 Z9 76 U1 1 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 1 PY 2012 VL 23 IS 5 BP 834 EP 852 DI 10.1091/mbc.E11-08-0731 PG 19 WC Cell Biology SC Cell Biology GA 901BN UT WOS:000300936800010 PM 22219382 ER PT J AU Wu, TL Topfer, K Lin, SW Li, H Bian, A Zhou, XY High, KA Ertl, HCJ AF Wu, TeLang Toepfer, Katrin Lin, Shih-Wen Li, Hua Bian, Ang Zhou, Xiang Y. High, Katherine A. Ertl, Hildegund C. J. TI Self-complementary AAVs Induce More Potent Transgene Product-specific Immune Responses Compared to a Single-stranded Genome SO MOLECULAR THERAPY LA English DT Article ID ADENOASSOCIATED VIRUS VECTORS; EFFICIENT TRANSDUCTION; GENE-THERAPY; MUSCULAR-DYSTROPHY; FACTOR-IX; EXPRESSION; LIVER; HEMOPHILIA; CELLS; ACTIVATION AB Using a mouse model we show that self-complementary (sc) adeno-associated virus (AAV) vectors pseudotyped with capsids of serotypes 2, 7 or 8 induce more potent transgene product-specific CD8(+) T cell and antibody responses compared to corresponding single-stranded (ss) AAV vectors. These data suggest that the higher and more rapidly appearing amounts of transgene product achieved with scAAV vectors may increase detrimental immune responses in gene transfer recipients. Received 22 March 2011; accepted 21 November 2011; published online 20 December 2011. doi:10.1038/mt.2011.280 C1 [Wu, TeLang; Toepfer, Katrin; Lin, Shih-Wen; Li, Hua; Bian, Ang; Zhou, Xiang Y.; Ertl, Hildegund C. J.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Wu, TeLang] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Toepfer, Katrin] German Primate Ctr, Unit Infect Models, Gottingen, Germany. [Lin, Shih-Wen] NCI, NIH, Bethesda, MD 20892 USA. [High, Katherine A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [High, Katherine A.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Ertl, HCJ (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM ertl@wistar.upenn.edu FU NHLBL [P01 HL078810] FX This work was supported by a grant from NHLBL (P01 HL078810). We wish to thank Ms Cole for assistance in preparing the figures and the manuscript. The authors declared no conflict of interest. NR 31 TC 13 Z9 14 U1 0 U2 3 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 MAR PY 2012 VL 20 IS 3 BP 572 EP 579 DI 10.1038/mt.2011.280 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 901EE UT WOS:000300943700011 PM 22186792 ER PT J AU Bish, LT Sleeper, MM Forbes, SC Wang, BJ Reynolds, C Singletary, GE Trafny, D Morine, KJ Sanmiguel, J Cecchini, S Virag, T Vulin, A Beley, C Bogan, J Wilson, JM Vandenborne, K Kornegay, JN Walter, GA Kotin, RM Garcia, L Sweeney, HL AF Bish, Lawrence T. Sleeper, Meg M. Forbes, Sean C. Wang, Bingjing Reynolds, Caryn Singletary, Gretchen E. Trafny, Dennis Morine, Kevin J. Sanmiguel, Julio Cecchini, Sylvain Virag, Tamas Vulin, Adeline Beley, Cyriaque Bogan, Janet Wilson, James M. Vandenborne, Krista Kornegay, Joe N. Walter, Glenn A. Kotin, Robert M. Garcia, Luis Sweeney, H. Lee TI Long-term Restoration of Cardiac Dystrophin Expression in Golden Retriever Muscular Dystrophy Following rAAV6-mediated Exon Skipping SO MOLECULAR THERAPY LA English DT Article ID PERCUTANEOUS TRANSENDOCARDIAL DELIVERY; CONJUGATED MORPHOLINO OLIGOMERS; ADENOASSOCIATED VIRUS 6; GENE-THERAPY; DUCHENNES CARDIOMYOPATHY; SKELETAL-MUSCLES; CANINE MODEL; MDX MICE; DMD; STRAIN AB Although restoration of dystrophin expression via exon skipping in both cardiac and skeletal muscle has been successfully demonstrated in the mdx mouse, restoration of cardiac dystrophin expression in large animal models of Duchenne muscular dystrophy (DMD) has proven to be a challenge. In large animals, investigators have focused on using intravenous injection of antisense oligonucleotides (AO) to mediate exon skipping. In this study, we sought to optimize restoration of cardiac dystrophin expression in the golden retriever muscular dystrophy (GRMD) model using percutaneous transendocardial delivery of recombinant AAV6 (rAAV6) to deliver a modified U7 small nuclear RNA (snRNA) carrying antisense sequence to target the exon splicing enhancers of exons 6 and 8 and correct the disrupted reading frame. We demonstrate restoration of cardiac dystrophin expression at 13 months confirmed by reverse transcription-PCR (RT-PCR) and immunoblot as well as membrane localization by immunohistochemistry. This was accompanied by improved cardiac function as assessed by cardiac magnetic resonance imaging (MRI). Percutaneous transendocardial delivery of rAAV6 expressing a modified U7 exon skipping construct is a safe, effective method for restoration of dystrophin expression and improvement of cardiac function in the GRMD canine and may be easily translatable to human DMD patients. Received 24 May 2011; accepted 9 November 2011; published online 6 December 2011. doi:10.1038/mt.2011.264 C1 [Bish, Lawrence T.; Wang, Bingjing; Morine, Kevin J.; Sweeney, H. Lee] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Sleeper, Meg M.; Reynolds, Caryn; Singletary, Gretchen E.; Trafny, Dennis] Univ Penn, Cardiol Sect, Dept Clin Studies, Vet Hosp, Philadelphia, PA 19104 USA. [Forbes, Sean C.; Vandenborne, Krista] Univ Florida, Dept Phys Therapy, Gainesville, FL USA. [Sanmiguel, Julio; Wilson, James M.] Univ Penn, Sch Med, Div Med Genet, Gene Therapy Program, Philadelphia, PA 19104 USA. [Cecchini, Sylvain; Virag, Tamas; Kotin, Robert M.] NHLBI, Mol Virol & Gene Delivery Sect, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. [Vulin, Adeline; Beley, Cyriaque; Garcia, Luis] CNRS UMR7215, Inst Myol, UPMC Um76, Inserm U974, Paris, France. [Bogan, Janet; Kornegay, Joe N.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Bogan, Janet; Kornegay, Joe N.] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. [Bogan, Janet; Kornegay, Joe N.] Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC USA. [Walter, Glenn A.] Univ Florida, Dept Physiol & Funct Genom, Gainesville, FL USA. RP Bish, LT (reprint author), B400 Richards Bldg,3700 Hamilton Walk, Philadelphia, PA 19104 USA. EM bish@mail.med.upenn.edu RI Wilson, James/F-9220-2011 OI Wilson, James/0000-0002-9630-3131 FU NHLBI [P01-HL059407]; Parent Project Muscular Dystrophy; Wellstone Muscular Dystrophy Cooperative Center [U54-AR052646]; NIH [T32-HL-007748, RR02512]; International Collaborative Effort (ICE) for DMD; Division of Intramural Research of National Heart, Lung, and Blood Institute (NIH); University of Pennsylvania FX This work was supported by a grant from the NHLBI (P01-HL059407) (to H. L. S. and J. M. W.), from the Parent Project Muscular Dystrophy (to H. L. S.), by a Wellstone Muscular Dystrophy Cooperative Center Grant (U54-AR052646) (to H. L. S.), by NIH (T32-HL-007748) (to L. T. B.) and (RR02512) (to Mark Haskins), and by the International Collaborative Effort (ICE) for DMD (to H. L. S., R. M. K., and L. G.). Support was also provided by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NIH) (R. M. K.). We thank the Vector Core of the Children's Hospital of Philadelphia and Katherine High, MD for vector production. We thank Mark Haskins, VMD, PhD (University of Pennsylvania) for support of the canine colony. J. M. W. is an inventor on patents that have been licensed to various biopharmaceutical companies. Portions of the technology described in this report are covered by United States and European patents assigned to the Secretary of the Department of Health and Human Services. A fraction of the licensing fees and royalty payments made to the NIH are distributed to the inventors in accordance with US Government and NIH policy. NR 49 TC 35 Z9 35 U1 1 U2 11 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 MAR PY 2012 VL 20 IS 3 BP 580 EP 589 DI 10.1038/mt.2011.264 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 901EE UT WOS:000300943700012 PM 22146342 ER PT J AU Savage, SA AF Savage, Sharon A. TI Connecting complex disorders through biology SO NATURE GENETICS LA English DT Editorial Material ID DYSKERATOSIS-CONGENITA; TELOMERE BIOLOGY; COMPONENT; MICROANGIOPATHY; CALCIFICATIONS; MUTATIONS; DISEASE; LENGTH; CYSTS AB Mutations in CTC1, which encodes a key telomere component, have been identified as the cause of Coats plus syndrome. This discovery provides an important pathophysiological link between Coats plus and the clinically related telomere disorders dyskeratosis congenita, Revesz syndrome and Hoyeraal-Hreidarsson syndrome. C1 NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 NR 16 TC 12 Z9 13 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2012 VL 44 IS 3 BP 238 EP 240 DI 10.1038/ng.2206 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 899VC UT WOS:000300843600004 PM 22366859 ER PT J AU Stolk, L Perry, JRB Chasman, DI He, CY Mangino, M Sulem, P Barbalic, M Broer, L Byrne, EM Ernst, F Esko, T Franceschini, N Gudbjartsson, DF Hottenga, JJ Kraft, P McArdle, PF Porcu, E Shin, SY Smith, AV van Wingerden, S Zhai, G Zhuang, WV Albrecht, E Alizadeh, BZ Aspelund, T Bandinelli, S Lauc, LB Beckmann, JS Boban, M Boerwinkle, E Broekmans, FJ Burri, A Campbell, H Chanock, SJ Chen, C Cornelis, MC Corre, T Coviello, AD d'Adamo, P Davies, G de Faire, U de Geus, EJC Deary, IJ Dedoussis, GVZ Deloukas, P Ebrahim, S Eiriksdottir, G Emilsson, V Eriksson, JG Fauser, BCJM Ferreli, L Ferrucci, L Fischer, K Folsom, AR Garcia, ME Gasparini, P Gieger, C Glazer, N Grobbee, DE Hall, P Haller, T Hankinson, SE Hass, M Hayward, C Heath, AC Hofman, A Ingelsson, E Janssens, ACJW Johnson, AD Karasik, D Kardia, SLR Keyzer, J Kiel, DP Kolcic, I Kutalik, Z Lahti, J Lai, S Laisk, T Laven, JSE Lawlor, DA Liu, JJ Lopez, LM Louwers, YV Magnusson, PKE Marongiu, M Martin, NG Klaric, IM Masciullo, C McKnight, B Medland, SE Melzer, D Mooser, V Navarro, P Newman, AB Nyholt, DR Onland-Moret, NC Palotie, A Pare, G Parker, AN Pedersen, NL Peeters, PHM Pistis, G Plump, AS Polasek, O Pop, VJM Psaty, BM Raikkonen, K Rehnberg, E Rotter, JI Rudan, I Sala, C Salumets, A Scuteri, A Singleton, A Smith, JA Snieder, H Soranzo, N Stacey, SN Starr, JM Stathopoulou, MG Stirrups, K Stolk, RP Styrkarsdottir, U Sun, YV Tenesa, A Thorand, B Toniolo, D Tryggvadottir, L Tsui, K Ulivi, S van Dam, RM van der Schouw, YT van Gils, CH van Nierop, P Vink, JM Visscher, PM Voorhuis, M Waeber, G Wallaschofski, H Wichmann, HE Widen, E Wijnands-van Gent, CJM Willemsen, G Wilson, JF Wolffenbuttel, BHR Wright, AF Yerges-Armstrong, LM Zemunik, T Zgaga, L Zillikens, MC Zygmunt, M Arnold, AM Boomsma, DI Buring, JE Crisponi, L Demerath, EW Gudnason, V Harris, TB Hu, FB Hunter, DJ Launer, LJ Metspalu, A Montgomery, GW Oostra, BA Ridker, PM Sanna, S Schlessinger, D Spector, TD Stefansson, K Streeten, EA Thorsteinsdottir, U Uda, M Uitterlinden, AG van Duijn, CM Volzke, H Murray, A Murabito, JM Visser, JA Lunetta, KL AF Stolk, Lisette Perry, John R. B. Chasman, Daniel I. He, Chunyan Mangino, Massimo Sulem, Patrick Barbalic, Maja Broer, Linda Byrne, Enda M. Ernst, Florian Esko, Tonu Franceschini, Nora Gudbjartsson, Daniel F. Hottenga, Jouke-Jan Kraft, Peter McArdle, Patrick F. Porcu, Eleonora Shin, So-Youn Smith, Albert V. van Wingerden, Sophie Zhai, Guangju Zhuang, Wei V. Albrecht, Eva Alizadeh, Behrooz Z. Aspelund, Thor Bandinelli, Stefania Lauc, Lovorka Barac Beckmann, Jacques S. Boban, Mladen Boerwinkle, Eric Broekmans, Frank J. Burri, Andrea Campbell, Harry Chanock, Stephen J. Chen, Constance Cornelis, Marilyn C. Corre, Tanguy Coviello, Andrea D. d'Adamo, Pio Davies, Gail de Faire, Ulf de Geus, Eco J. C. Deary, Ian J. Dedoussis, George V. Z. Deloukas, Panagiotis Ebrahim, Shah Eiriksdottir, Gudny Emilsson, Valur Eriksson, Johan G. Fauser, Bart C. J. M. Ferreli, Liana Ferrucci, Luigi Fischer, Krista Folsom, Aaron R. Garcia, Melissa E. Gasparini, Paolo Gieger, Christian Glazer, Nicole Grobbee, Diederick E. Hall, Per Haller, Toomas Hankinson, Susan E. Hass, Merli Hayward, Caroline Heath, Andrew C. Hofman, Albert Ingelsson, Erik Janssens, A. Cecile J. W. Johnson, Andrew D. Karasik, David Kardia, Sharon L. R. Keyzer, Jules Kiel, Douglas P. Kolcic, Ivana Kutalik, Zoltan Lahti, Jari Lai, Sandra Laisk, Triin Laven, Joop S. E. Lawlor, Debbie A. Liu, Jianjun Lopez, Lorna M. Louwers, Yvonne V. Magnusson, Patrik K. E. Marongiu, Mara Martin, Nicholas G. Klaric, Irena Martinovic Masciullo, Corrado McKnight, Barbara Medland, Sarah E. Melzer, David Mooser, Vincent Navarro, Pau Newman, Anne B. Nyholt, Dale R. Onland-Moret, N. Charlotte Palotie, Aarno Pare, Guillaume Parker, Alex N. Pedersen, Nancy L. Peeters, Petra H. M. Pistis, Giorgio Plump, Andrew S. Polasek, Ozren Pop, Victor J. M. Psaty, Bruce M. Raikkonen, Katri Rehnberg, Emil Rotter, Jerome I. Rudan, Igor Sala, Cinzia Salumets, Andres Scuteri, Angelo Singleton, Andrew Smith, Jennifer A. Snieder, Harold Soranzo, Nicole Stacey, Simon N. Starr, John M. Stathopoulou, Maria G. Stirrups, Kathleen Stolk, Ronald P. Styrkarsdottir, Unnur Sun, Yan V. Tenesa, Albert Thorand, Barbara Toniolo, Daniela Tryggvadottir, Laufey Tsui, Kim Ulivi, Sheila van Dam, Rob M. van der Schouw, Yvonne T. van Gils, Carla H. van Nierop, Peter Vink, Jacqueline M. Visscher, Peter M. Voorhuis, Marlies Waeber, Gerard Wallaschofski, Henri Wichmann, H. Erich Widen, Elisabeth Wijnands-van Gent, Colette J. M. Willemsen, Gonneke Wilson, James F. Wolffenbuttel, Bruce H. R. Wright, Alan F. Yerges-Armstrong, Laura M. Zemunik, Tatijana Zgaga, Lina Zillikens, M. Carola Zygmunt, Marek Arnold, Alice M. Boomsma, Dorret I. Buring, Julie E. Crisponi, Laura Demerath, Ellen W. Gudnason, Vilmundur Harris, Tamara B. Hu, Frank B. Hunter, David J. Launer, Lenore J. Metspalu, Andres Montgomery, Grant W. Oostra, Ben A. Ridker, Paul M. Sanna, Serena Schlessinger, David Spector, Tim D. Stefansson, Kari Streeten, Elizabeth A. Thorsteinsdottir, Unnur Uda, Manuela Uitterlinden, Andre G. van Duijn, Cornelia M. Voelzke, Henry Murray, Anna Murabito, Joanne M. Visser, Jenny A. Lunetta, Kathryn L. CA LifeLines Cohort Study TI Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways SO NATURE GENETICS LA English DT Article ID PREMATURE OVARIAN FAILURE; FOLLICLE-STIMULATING-HORMONE; GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; NATURAL MENOPAUSE; PROTEIN; DISEASE; POLYMORPHISMS; ONSET; MUTATION AB To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 x 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-kappa B signaling and mitochondrial dysfunction as biological processes related to timing of menopause. C1 [Perry, John R. B.; Melzer, David; Murray, Anna] Univ Exeter, Peninsula Med Sch, Exeter, Devon, England. [Stolk, Lisette; Zillikens, M. Carola; Uitterlinden, Andre G.; Visser, Jenny A.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Stolk, Lisette; Uitterlinden, Andre G.; van Duijn, Cornelia M.] Netherlands Consortium Hlth Aging, Rotterdam, Netherlands. [Perry, John R. B.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Chasman, Daniel I.; Pare, Guillaume; Buring, Julie E.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Chasman, Daniel I.; Pare, Guillaume; Buring, Julie E.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [He, Chunyan] Indiana Univ Sch Med, Dept Publ Hlth, Indianapolis, IN USA. [He, Chunyan] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Mangino, Massimo; Zhai, Guangju; Burri, Andrea; Soranzo, Nicole; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Sulem, Patrick; Gudbjartsson, Daniel F.; Stacey, Simon N.; Styrkarsdottir, Unnur; Stefansson, Kari; Thorsteinsdottir, Unnur] deCODE Genet, Reykjavik, Iceland. [Barbalic, Maja; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX USA. [Broer, Linda; van Wingerden, Sophie; Hofman, Albert; Janssens, A. Cecile J. W.; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Visscher, Peter M.] Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4006, Australia. [Ernst, Florian] Ernst Moritz Arndt Univ Greifswald, Interfakultares Inst Genomforsch, Greifswald, Germany. [Esko, Tonu; Fischer, Krista; Haller, Toomas; Hass, Merli; Salumets, Andres; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu; Metspalu, Andres] Estonian Bioctr, Tartu, Estonia. [Esko, Tonu; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Hottenga, Jouke-Jan; de Geus, Eco J. C.; Vink, Jacqueline M.; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Kraft, Peter; Chen, Constance; Hankinson, Susan E.; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter; Hofman, Albert; Hunter, David J.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Kraft, Peter; Hofman, Albert; Hunter, David J.] MIT, Cambridge, MA 02139 USA. [McArdle, Patrick F.; Yerges-Armstrong, Laura M.; Streeten, Elizabeth A.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Porcu, Eleonora; Ferreli, Liana; Lai, Sandra; Marongiu, Mara; Crisponi, Laura; Sanna, Serena; Uda, Manuela] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Shin, So-Youn; Deloukas, Panagiotis; Palotie, Aarno; Soranzo, Nicole; Stirrups, Kathleen] Wellcome Trust Sanger Inst, Hinxton, England. [Smith, Albert V.; Aspelund, Thor; Eiriksdottir, Gudny; Emilsson, Valur; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Aspelund, Thor; Tryggvadottir, Laufey; Gudnason, Vilmundur; Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Zhai, Guangju] Mem Univ Newfoundland, Fac Med, Discipline Genet, St John, NF, Canada. [Zhuang, Wei V.; Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Albrecht, Eva; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Alizadeh, Behrooz Z.; Snieder, Harold; Stolk, Ronald P.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 AB Groningen, Netherlands. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Lauc, Lovorka Barac] Croatian Sci Fdn, Zagreb, Croatia. [Beckmann, Jacques S.; Kutalik, Zoltan] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Beckmann, Jacques S.] Univ Lausanne Hosp, CHU Vaudois, Serv Med Genet, Lausanne, Switzerland. [Boban, Mladen; Kolcic, Ivana; Polasek, Ozren; Rudan, Igor; Zemunik, Tatijana] Univ Split, Fac Med, Split, Croatia. [Broekmans, Frank J.; Fauser, Bart C. J. M.; Voorhuis, Marlies] Univ Med Ctr Utrecht, Dept Reprod Med & Gynaecol, Utrecht, Netherlands. [Campbell, Harry; Rudan, Igor; Wilson, James F.; Zgaga, Lina] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Chen, Constance; Cornelis, Marilyn C.; van Dam, Rob M.; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Corre, Tanguy; Masciullo, Corrado; Navarro, Pau; Pistis, Giorgio; Sala, Cinzia; Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Coviello, Andrea D.; Glazer, Nicole; Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med Prevent Med & Epidemiol, Boston, MA 02118 USA. [Coviello, Andrea D.; Johnson, Andrew D.; Karasik, David; Kiel, Douglas P.; Murabito, Joanne M.; Lunetta, Kathryn L.] NHLBI, Framingham Heart Study, Framingham, MA USA. [d'Adamo, Pio; Gasparini, Paolo; Ulivi, Sheila] Ist Ricovero & Cura Carattere Sci Materno Infanti, Inst Maternal & Child Hlth, Trieste, Italy. [d'Adamo, Pio; Gasparini, Paolo] Univ Trieste, Trieste, Italy. [Davies, Gail; Deary, Ian J.; Lopez, Lorna M.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [de Faire, Ulf] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [de Geus, Eco J. C.; Boomsma, Dorret I.] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Deary, Ian J.; Lopez, Lorna M.; Starr, John M.; Visscher, Peter M.] Univ Edinburgh, Ctr Cognit Aging & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Dedoussis, George V. Z.; Stathopoulou, Maria G.] Harokopio Univ, Dept Nutr & Dietet, Athens, Greece. [Ebrahim, Shah] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Eriksson, Johan G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Folsom, Aaron R.; Demerath, Ellen W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Garcia, Melissa E.; Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Grobbee, Diederick E.; Onland-Moret, N. Charlotte; Peeters, Petra H. M.; van der Schouw, Yvonne T.; van Gils, Carla H.; Voorhuis, Marlies] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Hall, Per; Ingelsson, Erik; Magnusson, Patrik K. E.; Pedersen, Nancy L.; Rehnberg, Emil] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hankinson, Susan E.; Hu, Frank B.; Hunter, David J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Hayward, Caroline; Tenesa, Albert; Wright, Alan F.] Univ Edinburgh, Western Gen Hosp, MRC Inst Genet & Mol Med, Med Res Council MRC,Human Genet Unit, Edinburgh, Midlothian, Scotland. [Heath, Andrew C.] Washington Univ, St Louis, MO USA. [Karasik, David; Kiel, Douglas P.] Harvard Univ, Sch Med, Hebrew Senior Life Inst Aging Res, Boston, MA USA. [Kardia, Sharon L. R.; Smith, Jennifer A.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Keyzer, Jules] Diagnost GP Lab Eindhoven, Eindhoven, Netherlands. [Kutalik, Zoltan] Swiss Inst Bioinformat, Lausanne, Switzerland. [Lahti, Jari; Raikkonen, Katri] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Laisk, Triin; Salumets, Andres] Univ Tartu, Dept Obstet & Gynecol, EE-50090 Tartu, Estonia. [Laven, Joop S. E.; Louwers, Yvonne V.] Erasmus MC, Dept Obstet & Gynaecol, Div Reprod Med, Rotterdam, Netherlands. [Lawlor, Debbie A.] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England. [Liu, Jianjun] Genome Inst Singapore, Singapore, Singapore. [Klaric, Irena Martinovic] Inst Migrat & Ethn Studies, Zagreb, Croatia. [McKnight, Barbara; Arnold, Alice M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Mooser, Vincent] GlaxoSmithKline, Div Genet, King Of Prussia, PA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Palotie, Aarno; Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Cent Hosp, Helsinki, Finland. [Pare, Guillaume] McMaster Univ, Genet & Mol Epidemiol Lab, Hamilton, ON, Canada. [Parker, Alex N.; Tsui, Kim] Amgen Inc, Cambridge, MA USA. [Parker, Alex N.] Fdn Med, Cambridge, MA USA. [Peeters, Petra H. M.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Fac Med, Dept Epidemiol & Biostat, London, England. [Plump, Andrew S.] Merck Res Lab, Rahway, NJ USA. [Pop, Victor J. M.] Tilburg Univ, Dept Clin Hlth Psychol, NL-5000 LE Tilburg, Netherlands. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Salumets, Andres; Metspalu, Andres] Competence Ctr Reprod Med & Biol, Tartu, Estonia. [Scuteri, Angelo] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Snieder, Harold; Stolk, Ronald P.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, Groningen, Netherlands. [Snieder, Harold; Stolk, Ronald P.; Wolffenbuttel, Bruce H. R.; LifeLines Cohort Study] Univ Groningen, Univ Med Ctr Groningen, Biobank, Groningen, Netherlands. [Starr, John M.] Univ Edinburgh, Geriatr Med Unit, Edinburgh, Midlothian, Scotland. [Stathopoulou, Maria G.] Univ Henri Poincare, Cardiovasc Genet Res Unit, Nancy, France. [Sun, Yan V.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Tenesa, Albert] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin Inst, Roslin, Midlothian, Scotland. [Thorand, Barbara] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Toniolo, Daniela] CNR, Inst Mol Genet, Pavia, Italy. [Tryggvadottir, Laufey] Iceland Canc Registry, Reykjavik, Iceland. [van Dam, Rob M.] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [van Dam, Rob M.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117595, Singapore. [van Nierop, Peter] Municipal Hlth Serv Brabant Zuidoost, Helmond, Netherlands. [Waeber, Gerard] Univ Lausanne Hosp, CHUV, Dept Internal Med, Lausanne, Switzerland. [Wallaschofski, Henri] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Wichmann, H. Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Wichmann, H. Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Wijnands-van Gent, Colette J. M.] POZOB Veldhoven, Veldhoven, Netherlands. [Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 AB Groningen, Netherlands. [Zgaga, Lina] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia. [Zygmunt, Marek] Ernst Moritz Arndt Univ Greifswald, Klin Gynakol & Geburtshilfe, Greifswald, Germany. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Schlessinger, David] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. RP Murray, A (reprint author), Univ Exeter, Peninsula Med Sch, Exeter, Devon, England. EM anna.murray@pms.ac.uk; klunetta@bu.edu RI Polasek, Ozren/B-6002-2011; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Smith, Albert/K-5150-2015; Stathopoulou, Maria/H-7324-2016; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Magnusson, Patrik/C-4458-2017; Boban, Mladen/E-2777-2017; Kolcic, Ivana/E-2713-2017; Byrne, Enda/J-6068-2014; Johnson, Andrew/G-6520-2013; Ulivi, Sheila/H-3700-2013; Aspelund, Thor/C-5983-2008; Grobbee, Diederick/C-7651-2014; Newman, Anne/C-6408-2013; Thorand, Barbara/B-5349-2014; Colaus, PsyColaus/K-6607-2013; Laisk, Triin/J-2290-2015; Salumets, Andres/J-2278-2015; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Beckmann, Jacques S /A-9772-2008; Singleton, Andrew/C-3010-2009; Stolk, Ronald/B-2341-2013; Deloukas, Panos/B-2922-2013; Wolffenbuttel, Bruce/A-8419-2011; d'Adamo, Adamo Pio/G-4064-2011; Medland, Sarah/C-7630-2013; Deary, Ian/C-6297-2009; van Dam, Rob/F-9674-2010; Visser, Jenny /F-8156-2011; Rudan, Igor/I-1467-2012; Lopez, Lorna/F-7265-2010; Nyholt, Dale/C-8384-2013 OI Martin, Nicholas/0000-0003-4069-8020; Ziad Alizadeh, Behrooz/0000-0002-1415-8007; Visscher, Peter/0000-0002-2143-8760; Eriksson, Johan/0000-0002-2516-2060; Smith, Jennifer/0000-0002-3575-5468; Lahti, Jari/0000-0002-4310-5297; Lawlor, Debbie A/0000-0002-6793-2262; Raikkonen, Katri/0000-0003-3124-3470; Esko, Tonu/0000-0003-1982-6569; Tryggvadottir, Laufey/0000-0001-8067-9030; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Kiel, Douglas/0000-0001-8474-0310; Melzer, David/0000-0002-0170-3838; Karasik, David/0000-0002-8826-0530; MARONGIU, MARA/0000-0002-7321-2384; Zgaga, Lina/0000-0003-4089-9703; Murray, Anna/0000-0002-2351-2522; sanna, serena/0000-0002-3768-1749; Gudbjartsson, Daniel/0000-0002-5222-9857; Janssens, A Cecile/0000-0002-6153-4976; Polasek, Ozren/0000-0002-5765-1862; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Smith, Albert/0000-0003-1942-5845; Stathopoulou, Maria/0000-0003-4376-2083; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Kolcic, Ivana/0000-0001-7918-6052; Byrne, Enda/0000-0002-9491-7797; Murabito, Joanne/0000-0002-0192-7516; Lunetta, Kathryn/0000-0002-9268-810X; Ulivi, Sheila/0000-0003-3606-835X; Aspelund, Thor/0000-0002-7998-5433; Grobbee, Diederick/0000-0003-4472-4468; Newman, Anne/0000-0002-0106-1150; Thorand, Barbara/0000-0002-8416-6440; Salumets, Andres/0000-0002-1251-8160; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Beckmann, Jacques S /0000-0002-9741-1900; Stolk, Ronald/0000-0002-0518-1205; Deloukas, Panos/0000-0001-9251-070X; Wolffenbuttel, Bruce/0000-0001-9262-6921; d'Adamo, Adamo Pio/0000-0001-9367-4909; Medland, Sarah/0000-0003-1382-380X; van Dam, Rob/0000-0002-7354-8734; Rudan, Igor/0000-0001-6993-6884; FU Biotechnology and Biological Sciences Research Council [BB/F019394/1]; Chief Scientist Office [CZB/4/710]; Medical Research Council [G0600705, G0700704, MC_PC_U127561128, MC_PC_U127592696, MC_U127561128, MC_U127592696]; NCATS NIH HHS [UL1 TR000124]; NCI NIH HHS [P01 CA087969, P01 CA087969-12, R01 CA040356-15, R01 CA047988, R01 CA047988-09, U01 CA098233, U01 CA098233-01]; NHGRI NIH HHS [U01 HG004402, U01 HG004402-01]; NHLBI NIH HHS [N01 HC025195, N01 HC035129, N01 HC055015, N01 HC085086, N02 HL64278, R01 HL043851, R01 HL043851-09, R01 HL087660, R01 HL087660-01, R01 HL105756, R01 HL105756-01, U01 HL072515, U01 HL072515-01, U01 HL084756, U01 HL084756-01]; NIA NIH HHS [N01 AG012100, N01 AG012109, N01 AG050002, R21 AG032598, R21 AG032598-01]; NIAAA NIH HHS [K05 AA017688]; NIAMS NIH HHS [R01 AR041398, R01 AR041398-09]; NIDDK NIH HHS [P30 DK063491, P30 DK072488]; NIMHD NIH HHS [263 MD821336, 263 MD9164 13]; The Dunhill Medical Trust [R69/0208] NR 81 TC 120 Z9 123 U1 8 U2 62 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2012 VL 44 IS 3 BP 260 EP U55 DI 10.1038/ng.1051 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 899VC UT WOS:000300843600010 PM 22267201 ER PT J AU Ghoussaini, M Fletcher, O Michailidou, K Turnbull, C Schmidt, MK Dicks, E Dennis, J Wang, Q Humphreys, MK Luccarini, C Baynes, C Conroy, D Maranian, M Ahmed, S Driver, K Johnson, N Orr, N Silva, ID Waisfisz, Q Meijers-Heijboer, H Uitterlinden, AG Rivadeneira, F Hall, P Czene, K Irwanto, A Liu, JJ Nevanlinna, H Aittomaki, K Blomqvist, C Meindl, A Schmutzler, RK Muller-Myhsok, B Lichtner, P Chang-Claude, J Hein, R Nickels, S Flesch-Janys, D Tsimiklis, H Makalic, E Schmidt, D Bui, M Hopper, JL Apicella, C Park, DJ Southey, M Hunter, DJ Chanock, SJ Broeks, A Verhoef, S Hogervorst, FBL Fasching, PA Lux, MP Beckmann, MW Ekici, AB Sawyer, E Tomlinson, I Kerin, M Marme, F Schneeweiss, A Sohn, C Burwinkel, B Guenel, P Truong, T Cordina-Duverger, E Menegaux, F Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Milne, RL Alonso, MR Gonzalez-Neira, A Benitez, J Anton-Culver, H Ziogas, A Bernstein, L Dur, CC Brenner, H Muller, H Arndt, V Stegmaier, C Justenhoven, C Brauch, H Bruning, T Wang-Gohrke, S Eilber, U Dork, T Schurmann, P Bremer, M Hillemanns, P Bogdanova, NV Antonenkova, NN Rogov, YI Karstens, JH Bermisheva, M Prokofieva, D Khusnutdinova, E Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Lambrechts, D Yesilyurt, BT Floris, G Leunen, K Manoukian, S Bonanni, B Fortuzzi, S Peterlongo, P Couch, FJ Wang, XS Stevens, K Lee, A Giles, GG Baglietto, L Severi, G McLean, C Alnaes, GG Kristensen, V Borrensen-Dale, AL John, EM Miron, A Winqvist, R Pylkas, K Jukkola-Vuorinen, A Kauppila, S Andrulis, IL Glendon, G Mulligan, AM Devilee, P van Asperen, CJ Tollenaar, RAEM Seynaeve, C Figueroa, JD Garcia-Closas, M Brinton, L Lissowska, J Hooning, MJ Hollestelle, A Oldenburg, RA van den Ouweland, AMW Cox, A Reed, MWR Shah, M Jakubowska, A Lubinski, J Jaworska, K Durda, K Jones, M Schoemaker, M Ashworth, A Swerdlow, A Beesley, J Chen, XQ Muir, KR Lophatananon, A Rattanamongkongul, S Chaiwerawattana, A Kang, D Yoo, KY Noh, DY Shen, CY Yu, JC Wu, PE Hsiung, CN Perkins, A Swann, R Velentzis, L Eccles, DM Tapper, WJ Gerty, SM Graham, NJ Ponder, BAJ Chenevix-Trench, G Pharoah, PDP Lathrop, M Dunning, AM Rahman, N Peto, J Easton, DF AF Ghoussaini, Maya Fletcher, Olivia Michailidou, Kyriaki Turnbull, Clare Schmidt, Marjanka K. Dicks, Ed Dennis, Joe Wang, Qin Humphreys, Manjeet K. Luccarini, Craig Baynes, Caroline Conroy, Don Maranian, Melanie Ahmed, Shahana Driver, Kristy Johnson, Nichola Orr, Nicholas Silva, Isabel dos Santos Waisfisz, Quinten Meijers-Heijboer, Hanne Uitterlinden, Andre G. Rivadeneira, Fernando Hall, Per Czene, Kamila Irwanto, Astrid Liu, Jianjun Nevanlinna, Heli Aittomaki, Kristiina Blomqvist, Carl Meindl, Alfons Schmutzler, Rita K. Mueller-Myhsok, Bertram Lichtner, Peter Chang-Claude, Jenny Hein, Rebecca Nickels, Stefan Flesch-Janys, Dieter Tsimiklis, Helen Makalic, Enes Schmidt, Daniel Bui, Minh Hopper, John L. Apicella, Carmel Park, Daniel J. Southey, Melissa Hunter, David J. Chanock, Stephen J. Broeks, Annegien Verhoef, Senno Hogervorst, Frans B. L. Fasching, Peter A. Lux, Michael P. Beckmann, Matthias W. Ekici, Arif B. Sawyer, Elinor Tomlinson, Ian Kerin, Michael Marme, Frederik Schneeweiss, Andreas Sohn, Christof Burwinkel, Barbara Guenel, Pascal Truong, Therese Cordina-Duverger, Emilie Menegaux, Florence Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Milne, Roger L. Rosario Alonso, M. Gonzalez-Neira, Anna Benitez, Javier Anton-Culver, Hoda Ziogas, Argyrios Bernstein, Leslie Dur, Christina Clarke Brenner, Hermann Mueller, Heiko Arndt, Volker Stegmaier, Christa Justenhoven, Christina Brauch, Hiltrud Bruening, Thomas Wang-Gohrke, Shan Eilber, Ursula Doerk, Thilo Schuermann, Peter Bremer, Michael Hillemanns, Peter Bogdanova, Natalia V. Antonenkova, Natalia N. Rogov, Yuri I. Karstens, Johann H. Bermisheva, Marina Prokofieva, Darya Khusnutdinova, Elza Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Lambrechts, Diether Yesilyurt, Betul T. Floris, Giuseppe Leunen, Karin Manoukian, Siranoush Bonanni, Bernardo Fortuzzi, Stefano Peterlongo, Paolo Couch, Fergus J. Wang, Xianshu Stevens, Kristen Lee, Adam Giles, Graham G. Baglietto, Laura Severi, Gianluca McLean, Catriona Alnaes, Grethe Grenaker Kristensen, Vessela Borrensen-Dale, Anne-Lise John, Esther M. Miron, Alexander Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Andrulis, Irene L. Glendon, Gord Mulligan, Anna Marie Devilee, Peter van Asperen, Christie J. Tollenaar, Rob A. E. M. Seynaeve, Caroline Figueroa, Jonine D. Garcia-Closas, Montserrat Brinton, Louise Lissowska, Jolanta Hooning, Maartje J. Hollestelle, Antoinette Oldenburg, Rogier A. van den Ouweland, Ans M. W. Cox, Angela Reed, Malcolm W. R. Shah, Mitul Jakubowska, Ania Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Jones, Michael Schoemaker, Minouk Ashworth, Alan Swerdlow, Anthony Beesley, Jonathan Chen, Xiaoqing Muir, Kenneth R. Lophatananon, Artitaya Rattanamongkongul, Suthee Chaiwerawattana, Arkom Kang, Daehee Yoo, Keun-Young Noh, Dong-Young Shen, Chen-Yang Yu, Jyh-Cherng Wu, Pei-Ei Hsiung, Chia-Ni Perkins, Annie Swann, Ruth Velentzis, Louiza Eccles, Diana M. Tapper, Will J. Gerty, Susan M. Graham, Nikki J. Ponder, Bruce A. J. Chenevix-Trench, Georgia Pharoah, Paul D. P. Lathrop, Mark Dunning, Alison M. Rahman, Nazneen Peto, Julian Easton, Douglas F. CA Netherlands Collaborative Grp Here FBCS Gene Environm Interaction Breast C kConFab Investigators Australian Ovarian Canc Study Grp TI Genome-wide association analysis identifies three new breast cancer susceptibility loci SO NATURE GENETICS LA English DT Article ID HORMONE-RELATED PROTEIN; DEVELOPMENTAL REGULATORY MOLECULE; ULNAR-MAMMARY SYNDROME; PARATHYROID-HORMONE; NEGATIVE-FEEDBACK; COMMON VARIANTS; CONFER SUSCEPTIBILITY; GENE-EXPRESSION; CELL CARCINOMA; RETINOIC ACID AB Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for similar to 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in similar to 70,000 cases and similar to 68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 x 10(-35)), 12q24 (rs1292011; P = 4.3 x 10(-19)) and 21q21 (rs2823093; P = 1.1 x 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth. C1 [Ghoussaini, Maya; Dicks, Ed; Luccarini, Craig; Baynes, Caroline; Conroy, Don; Maranian, Melanie; Ahmed, Shahana; Driver, Kristy; Shah, Mitul; Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Fletcher, Olivia; Johnson, Nichola; Orr, Nicholas; Ashworth, Alan] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Michailidou, Kyriaki; Dennis, Joe; Wang, Qin; Humphreys, Manjeet K.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Turnbull, Clare; Garcia-Closas, Montserrat; Rahman, Nazneen; FBCS] Inst Canc Res, Sect Canc Genet, Sutton, Surrey, England. [Schmidt, Marjanka K.; Broeks, Annegien] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Expt Therapy, Amsterdam, Netherlands. [Schmidt, Marjanka K.] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Silva, Isabel dos Santos; Peto, Julian] London Sch Hyg & Trop Med, Noncommunicable Dis Epidemiol Dept, London WC1, England. [Waisfisz, Quinten; Meijers-Heijboer, Hanne] Vrije Univ Amsterdam Med Ctr, Sect Oncogenet, Dept Clin Genet, Amsterdam, Netherlands. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands. [Hall, Per; Czene, Kamila] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Irwanto, Astrid; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Irwanto, Astrid; Nevanlinna, Heli; Aittomaki, Kristiina; Blomqvist, Carl] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Liu, Jianjun] Genome Inst Singapore, Human Genet Div, Singapore, Singapore. [Aittomaki, Kristiina] Univ Helsinki, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol Tumor Genet, Clin Gynaecol & Obstet, Munich, Germany. [Schmutzler, Rita K.] Univ Cologne, Dept Obstet & Gynaecol, Div Mol Gynaecooncol, D-50931 Cologne, Germany. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Lichtner, Peter] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Eilber, Ursula] Deutsch Krebsforschungszentrum, Div Canc Epidemiol, D-6900 Heidelberg, Germany. [Hein, Rebecca] Univ Cologne, Dept Child & Adolescent Psychiat & Psychotherapy, Primar Med Versorgung PMV Res Grp, D-50931 Cologne, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Tsimiklis, Helen; Park, Daniel J.; Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Makalic, Enes; Schmidt, Daniel; Bui, Minh; Hopper, John L.; Apicella, Carmel; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Chanock, Stephen J.; Figueroa, Jonine D.; Brinton, Louise] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Verhoef, Senno] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Dept Clin Genet, Amsterdam, Netherlands. [Hogervorst, Frans B. L.] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Dept Mol Pathol, Amsterdam, Netherlands. [Fasching, Peter A.; Lux, Michael P.; Beckmann, Matthias W.] Univ Hosp Erlangen, Univ Breast Ctr, Dept Gynecol & Obstet, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Sawyer, Elinor] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Div Canc Studies, Natl Inst Hlth Res NIHR Comprehens Biomed Res Ctr, London, England. [Sawyer, Elinor] Kings Coll London, Div Canc Studies, London WC2R 2LS, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Kerin, Michael] Univ Hosp Galway, Inst Clin Sci, Galway, Ireland. [Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Marme, Frederik; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Unit, Heidelberg, Germany. [Guenel, Pascal; Truong, Therese; Cordina-Duverger, Emilie; Menegaux, Florence] Ctr Rech Epidemiol & Populat Hlth CESP, INSERM, U1018, Villejuif, France. [Guenel, Pascal; Truong, Therese; Cordina-Duverger, Emilie; Menegaux, Florence] Univ Paris 11, Unite Mixte Rech Sante UMRS 1018, Villejuif, France. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Milne, Roger L.] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Genet & Mol Epidemiol Grp, Madrid, Spain. [Rosario Alonso, M.; Gonzalez-Neira, Anna] CNIO, Human Canc Genet Programme, Human Genotyping Unit, Madrid, Spain. [Benitez, Javier] CNIO, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Bernstein, Leslie] City Hope Canc Ctr, Duarte, CA USA. [Dur, Christina Clarke; John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Brenner, Hermann; Mueller, Heiko; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Justenhoven, Christina; Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany. [Justenhoven, Christina; Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Bruening, Thomas] German Social Accid Insurance IPA, Inst Prevent & Occupat Med, Bochum, Germany. DKFZ, Heidelberg, Germany. [Gene Environm Interaction Breast C] Johanniter Krankenhaus, Evangel Kliniken Bonn, Dept Internal Med, Bonn, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Doerk, Thilo; Schuermann, Peter; Bremer, Michael; Hillemanns, Peter] Hannover Med Sch, Dept Obstet & Gynaecol, D-3000 Hannover, Germany. [Bogdanova, Natalia V.; Karstens, Johann H.] Hannover Med Sch, Dept Radiat Oncol, D-3000 Hannover, Germany. [Antonenkova, Natalia N.; Rogov, Yuri I.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Bermisheva, Marina; Prokofieva, Darya; Khusnutdinova, Elza] Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa 450001, Russia. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med, Sch Med, Dept Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Lee, Adam] Univ Eastern Finland, Bioctr Kuopio, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, SF-70210 Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Inst Clin Med, Sch Med, Dept Oncol, Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Dept Oncol, SF-70210 Kuopio, Finland. [Lambrechts, Diether; Yesilyurt, Betul T.] VIB, VRC, Louvain, Belgium. [Floris, Giuseppe; Leunen, Karin] Univ Hosp Gasthuisberg, Multidisciplinary Breast Ctr, B-3000 Louvain, Belgium. [Manoukian, Siranoush] Ist Nazl Tumori, Unit Med Genet, Dept Prevent & Predict Med, Fdn Ist Ricovero & Cura Carattere Sci IRCCS, I-20133 Milan, Italy. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, Milan, Italy. [Fortuzzi, Stefano; Peterlongo, Paolo] Ist FIRC Fdn Italiana Ric Canc Oncol Mol IFOM, Milan, Italy. [Peterlongo, Paolo] Fdn IRCCS INT, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predict Med, Milan, Italy. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Couch, Fergus J.; Stevens, Kristen] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Lee, Adam] Mayo Clin, Dept Pharmacol, Rochester, MN USA. [Giles, Graham G.; Baglietto, Laura; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [McLean, Catriona] Alfred Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [Alnaes, Grethe Grenaker; Kristensen, Vessela; Borrensen-Dale, Anne-Lise] Radiumhosp, Dept Genet, Inst Canc Res, Oslo Univ Hosp, Oslo, Norway. [Kristensen, Vessela; Borrensen-Dale, Anne-Lise] Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway. [John, Esther M.] Stanford Univ, Dept Hlth Res Policy, Div Epidemiol, Sch Med, Stanford, CA 94305 USA. [Miron, Alexander] Dana Farber Canc Ctr, Boston, MA USA. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Oulu Univ Hosp, Dept Clin Genet, Lab Canc Genet, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Kauppila, Saila] Univ Oulu, Dept Pathol, Oulu Univ Hosp, Oulu, Finland. [Andrulis, Irene L.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Glendon, Gord] Canc Care Ontario, Ontario Canc Genet Network, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Mulligan, Anna Marie] St Michaels Hosp, Li Ka Shing Knowledge Inst, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [Mulligan, Anna Marie] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [van Asperen, Christie J.] Leiden Univ, Dept Clin Genet, Med Ctr, Leiden, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Dept Surg, Med Ctr, Leiden, Netherlands. [Seynaeve, Caroline] Erasmus MC Daniel den Hoed Canc Ctr, Rotterdam Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Garcia-Closas, Montserrat; Jones, Michael; Schoemaker, Minouk; Swerdlow, Anthony] Inst Canc Res, Epidemiol Sect, Sutton, Surrey, England. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Hooning, Maartje J.] Erasmus Univ, Dept Med Oncol, Family Canc Clin, Med Ctr, Rotterdam, Netherlands. [Hollestelle, Antoinette] Erasmus Univ, Dept Med Oncol, Josephine Nefkens Inst, Med Ctr, Rotterdam, Netherlands. [Oldenburg, Rogier A.; van den Ouweland, Ans M. W.] Erasmus Univ, Dept Clin Genet, Family Canc Clin, Med Ctr, Rotterdam, Netherlands. [Cox, Angela] Univ Sheffield, Dept Oncol, Inst Canc Studies, Sheffield, S Yorkshire, England. [Reed, Malcolm W. R.] Univ Sheffield, Acad Unit Surg Oncol, Dept Oncol, Sheffield, S Yorkshire, England. [Jakubowska, Ania; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Beesley, Jonathan; Chen, Xiaoqing; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Muir, Kenneth R.; Lophatananon, Artitaya] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Rattanamongkongul, Suthee] Srinakharainwirot Univ, Dept Prevent Med, Ongkharak, Thailand. [Chaiwerawattana, Arkom] Minist Publ Hlth, Natl Canc Inst Thailand, Dept Acad Support, Bangkok, Thailand. [Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Shen, Chen-Yang; Wu, Pei-Ei; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Perkins, Annie; Swann, Ruth; Velentzis, Louiza] Univ Westminster, Breast Canc Res Grp, Dept Mol & Appl Biosci, London W1R 8AL, England. [Eccles, Diana M.; Tapper, Will J.; Gerty, Susan M.; Graham, Nikki J.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Ponder, Bruce A. J.] Univ Cambridge, Dept Oncol, Cambridge, England. [Ponder, Bruce A. J.] Canc Res UK CRUK Cambridge Res Inst, Cambridge, England. [Lathrop, Mark] Ctr Natl Genotypage, Evry, France. [Lathrop, Mark] CEPH, Fdn Jean Dausset, Paris, France. RP Easton, DF (reprint author), Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. EM douglas@srl.cam.ac.uk RI Rahman, Nazneen/D-2802-2013; Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Hartikainen, Jaana/E-6256-2015; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Khusnutdinova, Elza/A-4810-2013; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Dzhemileva, Lilya/K-8636-2013; Dork, Thilo/J-8620-2012; Jakubowska, Anna/O-8050-2014; Shen, CY/F-6271-2010; Verdrengh, Evelien/H-4571-2012; Noh, Dong-Young/G-5531-2011; Kang, Dae Hee/E-8631-2012; Yoo, Keun-Young/J-5548-2012; truong, therese/A-2837-2013; Muller-Myhsok, Bertram/A-3289-2013; Kerin, Michael/D-6748-2013; Ekici, Arif/C-3971-2013; Andrulis, Irene/E-7267-2013 OI Giles, Graham/0000-0003-4946-9099; Arndt, Volker/0000-0001-9320-8684; Rahman, Nazneen/0000-0003-4376-0440; Schoemaker, Minouk/0000-0001-8403-2234; Lux, Michael Patrick/0000-0002-2781-2178; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Rivadeneira, Fernando/0000-0001-9435-9441; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Bui, Minh/0000-0002-9099-6870; Park, Daniel/0000-0002-6354-0931; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Fortuzzi, Stefano/0000-0002-5662-3800; Hollestelle, Antoinette/0000-0003-1166-1966; Dennis, Joe/0000-0003-4591-1214; Czene, Kamila/0000-0002-3233-5695; Dzhemileva, Lilya/0000-0003-3315-4746; FU Cancer Research UK [A10710, 10118, 10124]; Medical Research Council [G0700491]; NCI NIH HHS [R25 CA092049]; Wellcome Trust [090532] NR 67 TC 135 Z9 139 U1 4 U2 65 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2012 VL 44 IS 3 BP 312 EP U120 DI 10.1038/ng.1049 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 899VC UT WOS:000300843600018 PM 22267197 ER PT J AU Postel-Vinay, S Veron, AS Tirode, F Pierron, G Reynaud, S Kovar, H Oberlin, O Lapouble, E Ballet, S Lucchesi, C Kontny, U Gonzalez-Neira, A Picci, P Alonso, J Patino-Garcia, A de Paillerets, BB Laud, K Dina, C Froguel, P Clavel-Chapelon, F Doz, F Michon, J Chanock, SJ Thomas, G Cox, DG Delattre, O AF Postel-Vinay, Sophie Veron, Amelie S. Tirode, Franck Pierron, Gaelle Reynaud, Stephanie Kovar, Heinrich Oberlin, Odile Lapouble, Eve Ballet, Stelly Lucchesi, Carlo Kontny, Udo Gonzalez-Neira, Anna Picci, Piero Alonso, Javier Patino-Garcia, Ana de Paillerets, Brigitte Bressac Laud, Karine Dina, Christian Froguel, Philippe Clavel-Chapelon, Francoise Doz, Francois Michon, Jean Chanock, Stephen J. Thomas, Gilles Cox, David G. Delattre, Olivier TI Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; TUMORS; RISK; DISEASE; CANCER; TRANSLOCATION; PATHOGENESIS; EXPRESSION; SIBLINGS; FUSION AB Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 x 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 x 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 x 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2. C1 [Postel-Vinay, Sophie; Tirode, Franck; Lucchesi, Carlo; Laud, Karine; Delattre, Olivier] Inst Curie, INSERM, Genet & Biol Canc U830, Paris, France. [Postel-Vinay, Sophie; Tirode, Franck; Lucchesi, Carlo; Laud, Karine; Delattre, Olivier] Inst Curie, Ctr Rech, Paris, France. [Veron, Amelie S.; Thomas, Gilles; Cox, David G.] Canc Res Ctr Lyon, INSERM, U1052, Leon Berard Canc Ctr, Lyon, France. [Pierron, Gaelle; Reynaud, Stephanie; Lapouble, Eve; Ballet, Stelly; Delattre, Olivier] Ctr Hosp, Inst Curie, Unite Genet Somat, Paris, France. [Kovar, Heinrich] St Anna Childrens Hosp, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Oberlin, Odile] Inst Gustave Roussy, Serv Pediat, Villejuif, France. [Kontny, Udo] Univ Freiburg Klinikum, Zentrum Kinder & Jugendmed, Freiburg, Germany. [Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr, Human Genotyping Unit CeGen, Human Canc Genet Programme, Madrid, Spain. [Picci, Piero] Ist Ortoped Rizzoli Bologna, Lab Oncol Sperimentale, Bologna, Italy. [Alonso, Javier] Inst Salud Carlos III, Unidad Tumores Solidos Infantiles, Majadahonda, Spain. [Patino-Garcia, Ana] Univ Navarra, Univ Clin, Lab Pediat, E-31080 Pamplona, Spain. [de Paillerets, Brigitte Bressac] Inst Gustave Roussy, Serv Genet, Villejuif, France. [Dina, Christian] IRI UN, INSERM, U915, Inst Thorax, Nantes, France. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Clavel-Chapelon, Francoise] Inst Gustave Roussy, Ctr Natl Rech Sci, Unite Mixtre Rech 1018, Villejuif, France. [Doz, Francois] Univ Paris 05, Paris, France. [Doz, Francois; Michon, Jean] Ctr Hosp, Dept Pediat, Inst Curie, Paris, France. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Thomas, Gilles] Synergie Lyon Canc, Lyon, France. RP Delattre, O (reprint author), Inst Curie, INSERM, Genet & Biol Canc U830, Paris, France. EM olivier.delattre@curie.fr RI Cox, David/A-2023-2009; Tirode, Franck/B-4586-2009; Patino-Garcia, Ana/I-4299-2012; Doz, Francois/K-8616-2012; Clavel-Chapelon, Francoise/G-6733-2014; Gonzalez-Neira, Anna/C-5791-2015; Dina, Christian/D-3535-2015; Alonso, Javier/B-6012-2013; Picci, Piero/J-5979-2016 OI Cox, David/0000-0002-2152-9259; Tirode, Franck/0000-0003-4731-7817; Dina, Christian/0000-0002-7722-7348; Alonso, Javier/0000-0002-6287-8391; Kovar, Heinrich/0000-0001-6873-9109; Picci, Piero/0000-0002-8519-4101 FU Institut Curie; Inserm; Ligue Nationale Contre le Cancer; Region Ile de France; Institut National du Cancer [2008-044, 0627, ZP09-027-EPI]; Synergie Lyon Cancer foundation; KCK; European Embryonal Tumor (EET) pipeline programs; Societe Francaise des Cancers de l'Enfant; Spanish Ministry of Science and Technology [SAF2009-10158]; Fundacion de la Asociacion Espanola Contra el Cancer; Fundacion Maria Francisca de Roviralta; Sociedad Espanola de Hematologia y Oncologia Pediatricas; Courir pour Mathieu; Dans les pas du Geant; Olivier Chape; Les Bagouzamanon; Enfants et Sante; les Amis de Claire FX We thank E. Thomas from Synergie Lyon Cancer for advice on statistical methods. We thank the staff from the Integragen Company for excellent service and V. Chene for outstanding assistance. We thank the following clinicians for providing samples used in this work: C. Alenda, F. Almazan, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Belendez, C. Berger, C. Bergeron, P. Biron, J. Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D. Chauveaux, C. Calvo, A. Carbone, C. Clement, T. Contra, N. Corradini, A. S. Defachelles, V. Gendemer-Delignieres, A. Deville, A. Echevarria, J. Fayette, M. Fraga, D. Frappaz, J. L. Fuster, P. Garcia-Miguel, J. C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O. Lejars, R. Lopez-Almaraz, B. Lopez-Ibor, P. Lutz, J. F. Mallet, L. Mansuy, P. Marec Berard, G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G. Margueritte, C. Mata, M. E. Mateos, M. Melo, C. Moscardo, M. Munzer, B. Narciso, A. Navajas, D. Orbach, C. Oudot, H. Pacquement, C. Paillard, Y. Perel, T. Philip, C. Piguet, M. I. Pintor, D. Plantaz, E. Plouvier, S. Ramirez-Del-Villar, I. Ray-Coquard, Y. Reguerre, M. Rios, P. Rohrlich, H. Rubie, A. Sastre, G. Schleiermacher, C. Schmitt, P. Schneider, L. Sierrasesumaga, C. Soler, N. Sirvent, S. Taque, E. Thebaud, A. Thyss, R. Tichit, J. J. Uriz, J. P. Vannier, F. Watelle-Pichon. We also thank the European Prospective Investigation into Cancer and Nutrition (EPIC) Steering Committee (E. Riboli, Principal Investigator) for access to genotype data from the EPIC cohorts and the Children's Cancer and Leukaemia Group (CCLG) Tissue Bank (funded by Cancer Research UK) for access to specimens. This work was supported by grants from the Institut Curie, the Inserm, the Ligue Nationale Contre le Cancer (Equipe labellisee, Carte d'Identite des Tumeurs program and Recherche Epidemiologique 2009 program), the Region Ile de France, the Institut National du Cancer (2008-044, 0627 and ZP09-027-EPI), the Synergie Lyon Cancer foundation, the KCK and European Embryonal Tumor (EET) pipeline programs, the Societe Francaise des Cancers de l'Enfant, the Spanish Ministry of Science and Technology (SAF2009-10158), the Fundacion de la Asociacion Espanola Contra el Cancer, the Fundacion Maria Francisca de Roviralta and the Sociedad Espanola de Hematologia y Oncologia Pediatricas and the following associations: Courir pour Mathieu, Dans les pas du Geant, Olivier Chape, Les Bagouzamanon, Enfants et Sante and les Amis de Claire. NR 35 TC 43 Z9 43 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2012 VL 44 IS 3 BP 323 EP U133 DI 10.1038/ng.1085 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 899VC UT WOS:000300843600020 PM 22327514 ER PT J AU Bellenguez, C Bevan, S Gschwendtner, A Spencer, CCA Burgess, AI Pirinen, M Jackson, CA Traylor, M Strange, A Su, Z Band, G Syme, PD Malik, R Pera, J Norrving, B Lemmens, R Freeman, C Schanz, R James, T Poole, D Murphy, L Segal, H Cortellini, L Cheng, YC Woo, D Nalls, MA Muller-Myhsok, B Meisinger, C Seedorf, U Ross-Adams, H Boonen, S Wloch-Kopec, D Valant, V Slark, J Furie, K Delavaran, H Langford, C Deloukas, P Edkins, S Hunt, S Gray, E Dronov, S Peltonen, L Gretarsdottir, S Thorleifsson, G Thorsteinsdottir, U Stefansson, K Boncoraglio, GB Parati, EA Attia, J Holliday, E Levi, C Franzosi, MG Goel, A Helgadottir, A Blackwell, JM Bramon, E Brown, MA Casas, JP Corvin, A Duncanson, A Jankowski, J Mathew, CG Palmer, CNA Plomin, R Rautanen, A Sawcer, SJ Trembath, RC Viswanathan, AC Wood, NW Worrall, BB Kittner, SJ Mitchell, BD Kissela, B Meschia, JF Thijs, V Lindgren, A Macleod, MJ Slowik, A Walters, M Rosand, J Sharma, P Farrall, M Sudlow, CLM Rothwell, PM Dichgans, M Donnelly, P Markus, HS AF Bellenguez, Celine Bevan, Steve Gschwendtner, Andreas Spencer, Chris C. A. Burgess, Annette I. Pirinen, Matti Jackson, Caroline A. Traylor, Matthew Strange, Amy Su, Zhan Band, Gavin Syme, Paul D. Malik, Rainer Pera, Joanna Norrving, Bo Lemmens, Robin Freeman, Colin Schanz, Renata James, Tom Poole, Deborah Murphy, Lee Segal, Helen Cortellini, Lynelle Cheng, Yu-Ching Woo, Daniel Nalls, Michael A. Mueller-Myhsok, Bertram Meisinger, Christa Seedorf, Udo Ross-Adams, Helen Boonen, Steven Wloch-Kopec, Dorota Valant, Valerie Slark, Julia Furie, Karen Delavaran, Hossein Langford, Cordelia Deloukas, Panos Edkins, Sarah Hunt, Sarah Gray, Emma Dronov, Serge Peltonen, Leena Gretarsdottir, Solveig Thorleifsson, Gudmar Thorsteinsdottir, Unnur Stefansson, Kari Boncoraglio, Giorgio B. Parati, Eugenio A. Attia, John Holliday, Elizabeth Levi, Chris Franzosi, Maria-Grazia Goel, Anuj Helgadottir, Anna Blackwell, Jenefer M. Bramon, Elvira Brown, Matthew A. Casas, Juan P. Corvin, Aiden Duncanson, Audrey Jankowski, Janusz Mathew, Christopher G. Palmer, Colin N. A. Plomin, Robert Rautanen, Anna Sawcer, Stephen J. Trembath, Richard C. Viswanathan, Ananth C. Wood, Nicholas W. Worrall, Bradford B. Kittner, Steven J. Mitchell, Braxton D. Kissela, Brett Meschia, James F. Thijs, Vincent Lindgren, Arne Macleod, Mary Joan Slowik, Agnieszka Walters, Matthew Rosand, Jonathan Sharma, Pankaj Farrall, Martin Sudlow, Cathie L. M. Rothwell, Peter M. Dichgans, Martin Donnelly, Peter Markus, Hugh S. CA ISGC WTCCC2 TI Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke SO NATURE GENETICS LA English DT Article ID ATRIAL-FIBRILLATION; HISTONE DEACETYLASES; SUSCEPTIBILITY LOCI; ALGORITHM; GENETICS; DISEASE; SIGNALS; ROLES; RISK AB Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes. C1 [Bellenguez, Celine; Spencer, Chris C. A.; Pirinen, Matti; Strange, Amy; Su, Zhan; Band, Gavin; Freeman, Colin; Goel, Anuj; Helgadottir, Anna; Rautanen, Anna; Farrall, Martin; Donnelly, Peter] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Bevan, Steve; Traylor, Matthew; James, Tom; Markus, Hugh S.] St Georges Univ London, Stroke & Dementia Res Grp, London, England. [Gschwendtner, Andreas; Malik, Rainer; Dichgans, Martin] Univ Munich, Univ Munchen Klinikum, Inst Stroke & Dementia Res, Munich, Germany. [Burgess, Annette I.; Poole, Deborah; Segal, Helen; Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford, England. [Jackson, Caroline A.; Sudlow, Cathie L. M.] Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. [Syme, Paul D.; Macleod, Mary Joan] Univ Aberdeen, Div Appl Med, Aberdeen, Scotland. [Pera, Joanna; Ross-Adams, Helen; Wloch-Kopec, Dorota; Slowik, Agnieszka] Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland. [Norrving, Bo; Delavaran, Hossein; Lindgren, Arne] Lund Univ, Dept Clin Sci, Lund, Sweden. [Norrving, Bo; Delavaran, Hossein; Lindgren, Arne] Skane Univ Hosp, Dept Neurol, Lund, Sweden. [Lemmens, Robin; Thijs, Vincent] Univ Hosp Leuven, Dept Neurol, Louvain, Belgium. [Lemmens, Robin; Thijs, Vincent] VIB, Vesalius Res Ctr, Louvain, Belgium. [Schanz, Renata; Slark, Julia; Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England. [Murphy, Lee] Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil Genet Core Lab, Edinburgh, Midlothian, Scotland. [Cortellini, Lynelle; Valant, Valerie; Furie, Karen; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Cortellini, Lynelle; Valant, Valerie; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Woo, Daniel; Kissela, Brett] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Meisinger, Christa] German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany. [Boonen, Steven] Univ Hosp Leuven, Div Geriatr Med, Louvain, Belgium. [Langford, Cordelia; Deloukas, Panos; Edkins, Sarah; Hunt, Sarah; Gray, Emma; Dronov, Serge; Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge, England. [Gretarsdottir, Solveig; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari; Helgadottir, Anna] deCODE Genet, Reykjavik, Iceland. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Boncoraglio, Giorgio B.; Parati, Eugenio A.] Fdn Ist Ricovero & Cura Carattere Sci IRCCS, Ist Neurol Carlo Besta, Milan, Italy. [Attia, John; Holliday, Elizabeth; Levi, Chris] Univ Newcastle, Hunter Med Res Inst, Ctr Brain & Mental Hlth Res, Newcastle, NSW 2300, Australia. [Franzosi, Maria-Grazia] Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Goel, Anuj; Helgadottir, Anna; Farrall, Martin] Univ Oxford, Dept Cardiovasc Med, Oxford, England. [Blackwell, Jenefer M.] Univ Western Australia, Ctr Child Hlth Res, Perth, WA, Australia. [Blackwell, Jenefer M.] Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Cambridge, England. [Bramon, Elvira] Kings Coll London, Inst Psychiat, Biomed Res Ctr Mental Hlth, Div Psychol Med & Psychiat, London WC2R 2LS, England. [Brown, Matthew A.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia. [Casas, Juan P.] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Casas, Juan P.] UCL, Dept Epidemiol & Publ Hlth, London, England. [Corvin, Aiden] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Duncanson, Audrey] Wellcome Trust Res Labs, London, England. [Jankowski, Janusz] Barts & London Queen Marys Sch Med & Dent, Ctr Gastroenterol, London, England. [Jankowski, Janusz] Univ Oxford, Div Clin Pharmacol, Oxford, England. [Mathew, Christopher G.; Trembath, Richard C.] Kings Coll London, Guys Hosp, Sch Med, Dept Med & Mol Genet, London WC2R 2LS, England. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland. [Plomin, Robert] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Sawcer, Stephen J.] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England. [Viswanathan, Ananth C.] Natl Hlth Serv NHS Fdn Trust, Moorfields Eye Hosp, Biomed Res Ctr Ophthalmol, Natl Inst Hlth Res NIHR, London, England. [Viswanathan, Ananth C.] UCL, Inst Ophthalmol, London, England. [Wood, Nicholas W.] UCL, Inst Neurol, Dept Mol Neuroscience, London, England. [Worrall, Bradford B.] Univ Virginia, Sch Med, Dept Neurol, Charlottesville, VA 22908 USA. [Worrall, Bradford B.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Kittner, Steven J.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Kittner, Steven J.] Baltimore Vet Affairs Med Ctr, Baltimore Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Walters, Matthew] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Donnelly, Peter] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. RP Donnelly, P (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM peter.donnelly@well.ox.ac.uk; hmarkus@sgul.ac.uk RI Muller-Myhsok, Bertram/A-3289-2013; Deloukas, Panos/B-2922-2013; Attia, John/F-5376-2013; Jackson, Caroline/B-5954-2012; Meisinger, Christine/B-5358-2014; Wood, Nicholas/C-2505-2009; Jankowski, Janusz/H-2706-2012; Blackwell, Jenefer/H-3015-2015; Mathew, Christopher/G-3434-2015; Study, GoDARTS/K-9448-2016; Boncoraglio, Giorgio/B-8647-2011; Palmer, Colin/C-7053-2008; Thijs, Vincent/C-3647-2009 OI Macleod, Mary Joan/0000-0003-2115-8184; Pirinen, Matti/0000-0002-1664-1350; Plomin, Robert/0000-0002-0756-3629; Bevan, Steve/0000-0003-0490-6830; Trembath, Richard/0000-0003-0550-3400; Meisinger, Christa/0000-0002-9026-6544; Mitchell, Braxton/0000-0003-4920-4744; Kissela, Brett/0000-0002-9773-4013; Seedorf, Udo/0000-0003-4652-5358; Murphy, Lee/0000-0001-6467-7449; Corvin, Aiden/0000-0001-6717-4089; Norrving, Bo/0000-0002-8024-5096; Hunt, Sarah/0000-0002-8350-1235; Brown, Matthew A/0000-0003-0538-8211; Traylor, Matthew/0000-0001-6624-8621; Deloukas, Panos/0000-0001-9251-070X; Attia, John/0000-0001-9800-1308; Jackson, Caroline/0000-0002-2067-2811; Wood, Nicholas/0000-0002-9500-3348; Jankowski, Janusz/0000-0003-2130-9181; Mathew, Christopher/0000-0003-4178-1838; Palmer, Colin/0000-0002-6415-6560; Thijs, Vincent/0000-0002-6614-8417 FU Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 085475/B/08/Z, 085475/Z/08/Z, WT084724MA, WTCCC2] FX We thank S. Bertrand, J. Bryant, S. L. Clark, J. S. Conquer, T. Dibling, J. C. Eldred, S. Gamble, C. Hind, M. L. Perez, C. R. Stribling, S. Taylor and A. Wilk of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We acknowledge use of the British 1958 Birth Cohort DNA collection, which is funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls funded by the Wellcome Trust. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank the following individuals who contributed to collection, phenotyping, sample processing and data management for the different cohorts: A. Burgess, A. Syed and N. Paul (Oxford Vascular Study); M. Dennis, P. Sandercock, C. Warlow, S. Hart, S. Keir, J. Wardlaw, A. Farrall, G. Potter, A. Hutchison and M. McDowall (Edinburgh Stroke Study); A. Pasdar and H. Clinkscale (Aberdeen); P. Higgins (Glasgow); T. G. Brott, R. D. Brown, S. Silliman, M. Frankel, D. Case, S. Rich, J. Hardy, A. Singleton (ISGS); M. J. Sparks, K. Ryan, J. Cole, M. Wozniak, B. Stern, R. Wityk, C. Johnson and D. Buchholz (GEOS); and J. Maguire, S. Koblar, J. Golledge, J. Surm, G. Hankey, J. Jannes, M. Lewis, R. Scott, L. Lincz; P. Moscato and R. Baker (Australian Stroke Genetics Collaborative membership). The principal funding for this study was provided by the Wellcome Trust as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). For details of other funding support, see the Supplementary Note. NR 30 TC 153 Z9 155 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2012 VL 44 IS 3 BP 328 EP U141 DI 10.1038/ng.1081 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 899VC UT WOS:000300843600021 ER PT J AU Angermann, BR Klauschen, F Garcia, AD Prustel, T Zhang, FK Germain, RN Meier-Schellersheim, M AF Angermann, Bastian R. Klauschen, Frederick Garcia, Alex D. Prustel, Thorsten Zhang, Fengkai Germain, Ronald N. Meier-Schellersheim, Martin TI Computational modeling of cellular signaling processes embedded into dynamic spatial contexts SO NATURE METHODS LA English DT Article ID FUS3 MAP KINASE; MATING PATHWAY; ADHESION; YEAST; PROTEIN; DIFFUSION; TRANSDUCTION; ACTIVATION; NETWORKS; BIOLOGY AB Cellular signaling processes depend on spatiotemporal distributions of molecular components. Multicolor, high-resolution microscopy permits detailed assessment of such distributions, providing input for fine-grained computational models that explore mechanisms governing dynamic assembly of multimolecular complexes and their role in shaping cellular behavior. However, it is challenging to incorporate into such models both complex molecular reaction cascades and the spatial localization of signaling components in dynamic cellular morphologies. Here we introduce an approach to address these challenges by automatically generating computational representations of complex reaction networks based on simple bimolecular interaction rules embedded into detailed, adaptive models of cellular morphology. Using examples of receptor-mediated cellular adhesion and signal-induced localized mitogen-activated protein kinase (MAPK) activation in yeast, we illustrate the capacity of this simulation technique to provide insights into cell biological processes. The modeling algorithms, implemented in a new version of the Simmune toolset, are accessible through intuitive graphical interfaces and programming libraries. C1 [Angermann, Bastian R.; Klauschen, Frederick; Garcia, Alex D.; Prustel, Thorsten; Zhang, Fengkai; Germain, Ronald N.; Meier-Schellersheim, Martin] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Klauschen, Frederick] Charite, Inst Pathol, D-13353 Berlin, Germany. RP Angermann, BR (reprint author), NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bastian.angermann@nih.gov; mms@niaid.nih.gov RI Klauschen, Frederick/C-5637-2015 FU US National Institute of Allergy and Infectious Diseases of the National Institutes of Health FX We thank R. Schwartz, R. Varma, A. Nita-Lazar, I. Fraser, J. Tsang and D. Cioffi for helpful comments, members of the Laboratory for Systems Biology at the US National Institute of Allergy and Infectious Diseases for insightful discussions, G. Mack for advice during the early stages of Simmune development and A. Meier-Schellersheim for creating Figure 2 and Supplementary Figure 1. This work was supported by the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases of the National Institutes of Health. NR 35 TC 43 Z9 43 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD MAR PY 2012 VL 9 IS 3 BP 283 EP U95 DI 10.1038/NMETH.1861 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 900ME UT WOS:000300890400026 PM 22286385 ER PT J AU Sims, JJ Scavone, F Cooper, EM Kane, LA Youle, RJ Boeke, JD Cohen, RE AF Sims, Joshua J. Scavone, Francesco Cooper, Eric M. Kane, Lesley A. Youle, Richard J. Boeke, Jef D. Cohen, Robert E. TI Polyubiquitin-sensor proteins reveal localization and linkage-type dependence of cellular ubiquitin signaling SO NATURE METHODS LA English DT Article ID K11-LINKED POLYUBIQUITINATION; DNA-REPAIR; BINDING; CHAINS; TNF; DEGRADATION; CELLS; MULTIUBIQUITINATION; P62/SQSTM1; ACTIVATION AB Polyubiquitin chain topology is thought to direct modified substrates to specific fates, but this function-topology relationship is poorly understood, as are the dynamics and subcellular locations of specific polyubiquitin signals. Experimental access to these questions has been limited because linkage-specific inhibitors and in vivo sensors have been unavailable. Here we present a general strategy to track linkage-specific polyubiquitin signals in yeast and mammalian cells, and to probe their functions. We designed several high-affinity Lys63 polyubiquitin-binding proteins and demonstrate their specificity in vitro and in cells. We apply these tools as competitive inhibitors to dissect the polyubiquitin-linkage dependence of NF-kappa B activation in several cell types, inferring the essential role of Lys63 polyubiquitin for signaling via the IL-1 beta and TNF-related weak inducer of apoptosis (TWEAK) but not TNF-alpha receptors. We anticipate live-cell imaging, proteomic and biochemical applications for these tools and extension of the design strategy to other polymeric ubiquitin-like protein modifications. C1 [Sims, Joshua J.; Cohen, Robert E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD USA. [Scavone, Francesco; Cohen, Robert E.] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Cooper, Eric M.; Boeke, Jef D.] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Cooper, Eric M.; Boeke, Jef D.] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA. [Kane, Lesley A.; Youle, Richard J.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, US Natl Inst Hlth, Bethesda, MD USA. RP Cohen, RE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD USA. EM joshua_sims@hms.harvard.edu; bob.cohen@colostate.edu OI Boeke, Jef/0000-0001-5322-4946 FU Damon Runyon Cancer Research Foundation (DRG) [2073-11]; US National Institutes of Health (NIH) [RR020839]; NIH [P01 CA139980, RC1 GM091424, 1R01 GM097452]; US National Institute of Neurologial Disorders and Stroke FX We thank S. Beese-Sims for constructing the leucine-auxotrophic version of the single-ubiquitin yeast strains, P. Sorger and B. Millard for helpful discussions about the manuscript and technical assistance on NF-kappa B activation experiments, A. Sliva for assistance with yeast experiments, B. Schmitt for assistance with binding experiments, A. Hess for help with statistical analyses and T. Yao for many helpful discussions. J.J.S. is supported by a fellowship from the Damon Runyon Cancer Research Foundation (DRG#2073-11). This work was supported, in part, by US National Institutes of Health (NIH) Common Fund grant RR020839 (J.D.B.), NIH grant P01 CA139980 (P. Sorger), US National Institute of Neurologial Disorders and Stroke Intramural Program (R.J.Y.), and NIH grants RC1 GM091424 (R. E. C.) and 1R01 GM097452 (R.E.C.). NR 36 TC 45 Z9 45 U1 1 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD MAR PY 2012 VL 9 IS 3 BP 303 EP U122 DI 10.1038/NMETH.1888 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 900ME UT WOS:000300890400029 PM 22306808 ER PT J AU Lucantonio, F Stalnaker, TA Shaham, Y Niv, Y Schoenbaum, G AF Lucantonio, Federica Stalnaker, Thomas A. Shaham, Yavin Niv, Yael Schoenbaum, Geoffrey TI The impact of orbitofrontal dysfunction on cocaine addiction SO NATURE NEUROSCIENCE LA English DT Review ID ORBITAL PREFRONTAL CORTEX; DECISION-MAKING; DRUG-ADDICTION; BASOLATERAL AMYGDALA; NEURONAL-ACTIVITY; METHAMPHETAMINE ABUSERS; AMPHETAMINE EXPOSURE; BEHAVIORAL-CONTROL; REWARD PREFERENCE; EXPERIENCED RATS AB Cocaine addiction is characterized by poor judgment and maladaptive decision-making. Here we review evidence implicating the orbitofrontal cortex in such behavior. This evidence suggests that cocaine-induced changes in orbitofrontal cortex disrupt the representation of states and transition functions that form the basis of flexible and adaptive 'model-based' behavioral control. By impairing this function, cocaine exposure leads to an overemphasis on less flexible, maladaptive 'model-free' control systems. We propose that such an effect accounts for the complex pattern of maladaptive behaviors associated with cocaine addiction. C1 [Lucantonio, Federica; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Stalnaker, Thomas A.; Shaham, Yavin; Schoenbaum, Geoffrey] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. [Niv, Yael] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. [Niv, Yael] Princeton Univ, Inst Neurosci, Princeton, NJ 08544 USA. RP Schoenbaum, G (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. EM schoenbg@schoenbaumlab.org RI shaham, yavin/G-1306-2014 FU US National Institute on Drug Abuse FX This review is dedicated to the family of Jacob Peter Waletzky. The work of writing it was supported by funding from the intramural and extramural programs of the US National Institute on Drug Abuse, including time while G. S. and T. A. S. were employed at the University of Maryland, Baltimore. The opinions expressed in this article are the author's own and do not reflect the view of the US National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 100 TC 78 Z9 79 U1 2 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAR PY 2012 VL 15 IS 3 BP 358 EP 366 DI 10.1038/nn.3014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 899CY UT WOS:000300793100007 PM 22267164 ER PT J AU Schmitz, A Grillon, C AF Schmitz, Anja Grillon, Christian TI Assessing fear and anxiety in humans using the threat of predictable and unpredictable aversive events (the NPU-threat test) SO NATURE PROTOCOLS LA English DT Article ID COMMON MENTAL-DISORDERS; POTENTIATED STARTLE; BED NUCLEUS; ANXIOUS RESPONSES; UNCERTAIN THREAT; CONTEXTUAL FEAR; CUED FEAR; STIMULI; STRESS; LESIONS AB The threat of predictable and unpredictable aversive events was developed to assess short-duration (fear) and long-duration (anxiety) aversive states in humans. A typical experiment consists of three conditions: a safe condition (neutral (N)), during which participants are safe from aversive stimuli, and two threat conditions-one in which aversive events are administered predictably (P) (i.e., signaled by a threat cue), and one in which aversive stimuli are administered unpredictably (U). During the so-called NPU-threat test, ongoing change in aversive states is measured with the startle reflex. The NPU-threat test has been validated in pharmacological and clinical studies and can be implemented in children and adults. Similar procedures have been applied in animal models, making the NPU-threat test an ideal tool for translational research. The procedure is relatively short (35 min), simple to implement and generates consistent results with large effect sizes. C1 [Schmitz, Anja] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA. RP Schmitz, A (reprint author), NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. EM schmitza2@mail.nih.gov FU NIMH [MH002798, MH002804-09] FX This research was supported by the Intramural Research Program of the NIMH (MH002798 and MH002804-09). NR 36 TC 65 Z9 65 U1 3 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 J9 NAT PROTOC JI Nat. Protoc. PD MAR PY 2012 VL 7 IS 3 BP 527 EP 532 DI 10.1038/nprot.2012.001 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 901FQ UT WOS:000300948500010 PM 22362158 ER PT J AU Peters, JM Shah, YM Gonzalez, FJ AF Peters, Jeffrey M. Shah, Yatrik M. Gonzalez, Frank J. TI The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention SO NATURE REVIEWS CANCER LA English DT Review ID BETA/DELTA PPAR-BETA/DELTA; BREAST-CANCER CELLS; ENDOTHELIAL GROWTH-FACTOR; RETINOID-X-RECEPTOR; PHASE-II TRIAL; DIFFERENTIATED THYROID-CANCER; GAMMA AGONIST TROGLITAZONE; HUMAN HACAT KERATINOCYTES; TRAIL-INDUCED APOPTOSIS; HUMAN PANCREATIC-CANCER AB Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs that are used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists. C1 [Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Shah, Yatrik M.] Univ Michigan, Dept Mol & Integrat Physiol, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu FU US National Institutes of Health [CA124533, CA126826, CA141029, CA140369, AA018863, R01CA148828]; National Cancer Institute [ZIABC005561, ZIABC005562, ZIABC005708] FX The authors gratefully acknowledge J. Corell for technical assistance with the figures and P. Devchand for critical review and suggestions for the manuscript. The authors' research is supported by the US National Institutes of Health (CA124533, CA126826, CA141029, CA140369 and AA018863) to J. M. P., (R01CA148828) to Y.M.S. and the National Cancer Institute Intramural Research Program (ZIABC005561, ZIABC005562 and ZIABC005708) to F.J.G. NR 232 TC 135 Z9 141 U1 0 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD MAR PY 2012 VL 12 IS 3 BP 181 EP 195 DI 10.1038/nrc3214 PG 15 WC Oncology SC Oncology GA 899RK UT WOS:000300833600011 PM 22318237 ER PT J AU Blagoev, KB Wilkerson, J Fojo, T AF Blagoev, Krastan B. Wilkerson, Julia Fojo, Tito TI Hazard ratios in cancer clinical trials-a primer SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Article ID PANCREATIC NEUROENDOCRINE TUMORS; RENAL-CELL CARCINOMA; SUNITINIB; MODEL AB The increase and diversity of clinical trial data has resulted in a greater reliance on statistical analyses to discern value. Assessing differences between two similar survival curves can pose a challenge for those without formal training in statistical interpretation; therefore, there has been an increased reliance on hazard ratios often to the exclusion of more-traditional survival measures. However, because a hazard ratio lacks dimensions it can only inform the reader about the reliability and uniformity of the data. It does not provide practitioners with quantitative values they can use, nor does it provide information they can discuss with patients. Motivated by a non-scientific poll of oncologists in training and those with board certification that suggested only a limited understanding of the derivation of hazard ratios we undertook this presentation of hazard ratios: a measure of treatment efficacy that is increasingly used and often misused. C1 [Wilkerson, Julia; Fojo, Tito] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Blagoev, Krastan B.] Natl Sci Fdn, Div Phys, Arlington, VA 22230 USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov OI Wilkerson, Julia/0000-0002-6965-0867 FU National Science Foundation FX K. B. Blagoev would like to acknowledge that this work was supported in part by the National Science Foundation. Any opinion, finding, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. NR 18 TC 3 Z9 3 U1 0 U2 6 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 MAR PY 2012 VL 9 IS 3 BP 178 EP 183 DI 10.1038/nrclinonc.2011.217 PG 6 WC Oncology SC Oncology GA 901DX UT WOS:000300943000008 PM 22290283 ER PT J AU Zumla, A Hafner, R Lienhardt, C Hoelscher, M Nunn, A AF Zumla, Alimuddin Hafner, Richard Lienhardt, Christian Hoelscher, Michael Nunn, Andrew TI Advancing the development of tuberculosis therapy SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 [Zumla, Alimuddin] UCL, Div Infect & Immun, London NW3 2PF, England. [Hafner, Richard] NIAID, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Lienhardt, Christian] WHO, Stop TB Partnership, CH-1211 Geneva, Switzerland. [Hoelscher, Michael] Univ Munich, Div Infect Dis & Trop Med, D-80802 Munich, Germany. [Nunn, Andrew] MRC, London NW1 2DA, England. RP Zumla, A (reprint author), UCL, Div Infect & Immun, London NW3 2PF, England. EM a.zumla@ucl.ac.uk RI Hoelscher, Michael/D-3436-2012; OI Zumla, Alimuddin/0000-0002-5111-5735 FU Medical Research Council [MC_U122888469] NR 5 TC 34 Z9 35 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD MAR PY 2012 VL 11 IS 3 BP 170 EP 171 DI 10.1038/nrd3694 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 901CV UT WOS:000300940200001 PM 22378254 ER PT J AU Kelloff, GJ Sigman, CC AF Kelloff, Gary J. Sigman, Caroline C. TI Cancer biomarkers: selecting the right drug for the right patient SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID CELL LUNG-CANCER; POSITRON-EMISSION-TOMOGRAPHY; CLINICAL-TRIAL DESIGN; SURROGATE END-POINTS; ADAPTIVE SIGNATURE DESIGN; CIRCULATING TUMOR-CELLS; BREAST-CANCER; INTRAEPITHELIAL NEOPLASIA; MONOCLONAL-ANTIBODY; GENETIC ALTERATIONS AB This Perspective highlights biomarkers that are expressed as a consequence of cancer development and progression. We focus on those biomarkers that are most relevant for identifying patients who are likely to respond to a given therapy, as well as those biomarkers that are most effective for measuring patient response to therapy. These two measures are necessary for selecting the right drug for the right patient, regardless of whether the setting is in drug development or in the post-approval use of the drug for patients with cancer. We also discuss the innovative designs of clinical trials and methodologies that are used to validate and qualify biomarkers for use in specific contexts. Furthermore, we look ahead to the promises and challenges in the field of cancer biomarkers. C1 [Kelloff, Gary J.] NCI, Canc Imaging Program, Bethesda, MD 20852 USA. [Sigman, Caroline C.] CCS Associates, Mountain View, CA 94043 USA. RP Kelloff, GJ (reprint author), NCI, Canc Imaging Program, EPN Rm 6058,6130 Execut Blvd, Bethesda, MD 20852 USA. EM kelloffg@mail.nih.gov; csigman@ccsainc.com NR 117 TC 105 Z9 110 U1 3 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD MAR PY 2012 VL 11 IS 3 BP 201 EP 214 DI 10.1038/nrd3651 PG 14 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 901CV UT WOS:000300940200022 PM 22322254 ER PT J AU Balow, JE AF Balow, James E. TI Perspectives on maintenance therapy in lupus nephritis SO NATURE REVIEWS NEPHROLOGY LA English DT News Item ID MYCOPHENOLATE-MOFETIL; CONTROLLED-TRIAL; CYCLOPHOSPHAMIDE; AZATHIOPRINE; PREDNISONE AB Maintenance immunosuppressive drug therapy is necessary to counter the propensity of lupus nephritis to relapse. Claims that mycophenolate mofetil might be the magic bullet for both induction and maintenance therapies merit critical reappraisal due to inconsistent evidence of the superiority of mycophenolate mofetil over azathioprine, as well as its inordinately greater cost. C1 Natl Inst Diabet & Digest & Kidney Dis, Kidney Dis Sect, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. RP Balow, JE (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Kidney Dis Sect, NIH, Clin Res Ctr, Room 5-2551, Bethesda, MD 20892 USA. EM james.e.balow@nih.gov FU Intramural NIH HHS [Z99 DK999999, ZIA DK043414-07] NR 10 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD MAR PY 2012 VL 8 IS 3 BP 136 EP 138 DI 10.1038/nrneph.2012.17 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 900KW UT WOS:000300886900003 PM 22310950 ER PT J AU Spencer, R AF Spencer, Richard TI Magnetic resonance in tissue engineering SO NMR IN BIOMEDICINE LA English DT Editorial Material C1 NIA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Spencer, R (reprint author), NIA, NIH, Intramural Res Program, GRC 4D-08,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov FU Intramural NIH HHS [ZIA AG000923-05] NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD MAR PY 2012 VL 25 IS 3 SI SI BP 401 EP 401 DI 10.1002/nbm.1806 PG 1 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 897QX UT WOS:000300670600002 PM 22134896 ER PT J AU Reiter, DA Irrechukwu, O Lin, PC Moghadam, S Von Thaer, S Pleshko, N Spencer, RG AF Reiter, David A. Irrechukwu, Onyi Lin, Ping-Chang Moghadam, Somaieh Von Thaer, Sarah Pleshko, Nancy Spencer, Richard G. TI Improved MR-based characterization of engineered cartilage using multiexponential T-2 relaxation and multivariate analysis SO NMR IN BIOMEDICINE LA English DT Article DE cartilage MRI; multiexponential T-2; support vector machine; proteoglycan; tissue engineering ID MAGNETIC-RESONANCE MICROSCOPY; SUPPORT VECTOR MACHINES; ARTICULAR-CARTILAGE; BIOMECHANICAL PROPERTIES; TISSUE CLASSIFICATION; COLLAGEN DYNAMICS; SOLID-STATE; MODEL; BRAIN; BONE AB Noninvasive monitoring of tissue quality would be of substantial use in the development of cartilage tissue engineering strategies. Conventional MR parameters provide noninvasive measures of biophysical tissue properties and are sensitive to changes in matrix development, but do not clearly distinguish between groups with different levels of matrix development. Furthermore, MR outcomes are nonspecific, with particular changes in matrix components resulting in changes in multiple MR parameters. To address these limitations, we present two new approaches for the evaluation of tissue engineered constructs using MR, and apply them to immature and mature engineered cartilage after 1 and 5 weeks of development, respectively. First, we applied multiexponential T-2 analysis for the quantification of matrix macromolecule-associated water compartments. Second, we applied multivariate support vector machine analysis using multiple MR parameters to improve detection of degree of matrix development. Monoexponential T-2 values decreased with maturation, but without further specificity. Much more specific information was provided by multiexponential analysis. The T-2 distribution in both immature and mature constructs was qualitatively comparable to that of native cartilage. The analysis showed that proteoglycan-bound water increased significantly during maturation, from a fraction of 0.05 +/- 0.01 to 0.07 +/- 0.01. Classification of samples based on individual MR parameters, T-1, T-2, km or apparent diffusion coefficient, showed that the best classifiers were T-1 and km, with classification accuracies of 85% and 84%, respectively. Support vector machine analysis improved the accuracy to 98% using the combination (km, apparent diffusion coefficient). These approaches were validated using biochemical and Fourier transform infrared imaging spectroscopic analyses, which showed increased proteoglycan and collagen with maturation. In summary, multiexponential T2 and multivariate support vector machine analyses provide improved sensitivity to changes in matrix development and specificity to matrix composition in tissue engineered cartilage. These approaches show substantial potential for the evaluation of engineered cartilage tissue and for extension to other tissue engineering constructs. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Reiter, David A.] NIA, Clin Res Branch, NIH, Baltimore, MD 21225 USA. [Irrechukwu, Onyi; Lin, Ping-Chang; Von Thaer, Sarah; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21225 USA. [Moghadam, Somaieh; Pleshko, Nancy] Temple Univ, Dept Mech Engn, Philadelphia, PA 19122 USA. RP Reiter, DA (reprint author), NIA, Clin Res Branch, NIH, 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. EM reiterda@mail.nih.gov OI Lin, Ping-Chang/0000-0003-0918-4072 FU National Institutes of Health (NIH); National Institute on Aging; NIH [R01 EB000744, NIH AR056145] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging, and by NIH R01 EB000744 (NP) and NIH AR056145 (NP). NR 63 TC 15 Z9 17 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD MAR PY 2012 VL 25 IS 3 SI SI BP 476 EP 488 DI 10.1002/nbm.1804 PG 13 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 897QX UT WOS:000300670600010 PM 22287335 ER PT J AU Inamoto, Y Chai, XY Kurland, BF Cutler, C Flowers, MED Palmer, JM Carpenter, PA Heffernan, MJ Jacobsohn, D Jagasia, MH Pidala, J Khera, N Vogelsang, GB Weisdorf, D Martin, PJ Pavletic, SZ Lee, SJ AF Inamoto, Yoshihiro Chai, Xiaoyu Kurland, Brenda F. Cutler, Corey Flowers, Mary E. D. Palmer, Jeanne M. Carpenter, Paul A. Heffernan, Mary J. Jacobsohn, David Jagasia, Madan H. Pidala, Joseph Khera, Nandita Vogelsang, Georgia B. Weisdorf, Daniel Martin, Paul J. Pavletic, Steven Z. Lee, Stephanie J. CA Chronic GVHD Consortium TI Validation of Measurement Scales in Ocular Graft-versus-Host Disease SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT BMT Tandem Meeting CY FEB, 2011 CL Honolulu, HI ID QUALITY-OF-LIFE; CONSENSUS DEVELOPMENT PROJECT; BONE-MARROW-TRANSPLANTATION; WORKING GROUP-REPORT; STEM-CELL TRANSPLANTATION; DRY EYE SYNDROME; TERM-FOLLOW-UP; CLINICAL-TRIALS; THERAPEUTIC RESPONSE; HEALTH-STATUS AB Purpose: To validate measurement scales for rating ocular chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. Candidate scales were recommended for use in clinical trials by the National Institutes of Health (NIH) Chronic GVHD Consensus Conference or have been previously validated in dry eye syndromes. Design: Prospective follow-up study. Participants: Between August 2007 and June 2010, the study enrolled 387 patients with chronic GVHD in a multicenter, prospective, observational cohort. Methods: Using anchor-based methods, we compared clinician or patient-reported changes in eye symptoms (8-point scale) with calculated changes in 5 candidate scales: The NIH eye score, patient-reported global rating of eye symptoms, Lee eye subscale, Ocular Surface Disease Index, and Schirmer test. Change was examined for 333 follow-up visits where both clinician and patient reported eye involvement at the previous visit. Linear mixed models were used to account for within-patient correlation. Main Outcome Measures: An 8-point scale of clinician or patient-reported symptom change was used as an anchor to measure symptom changes at the follow-up visits. Results: In serial evaluations, agreement regarding improvement, stability, or worsening between the clinician and patient was fair (weighted kappa = 0.34). Despite only fair agreement between evaluators, all scales except the Schirmer test correlated with both clinician-reported and patient-reported changes in ocular GVHD activity. Among all scales, changes in the NIH eye scores showed the greatest sensitivity to symptom change reported by clinicians or patients. Conclusions: Our results support the use of the NIH eye score as a sensitive measure of eye symptom changes in clinical trials assessing treatment of chronic GVHD. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;119:487-493 (C) 2012 by the American Academy of Ophthalmology. C1 [Inamoto, Yoshihiro; Chai, Xiaoyu; Kurland, Brenda F.; Flowers, Mary E. D.; Carpenter, Paul A.; Heffernan, Mary J.; Khera, Nandita; Martin, Paul J.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Palmer, Jeanne M.] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Jacobsohn, David] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. [Jagasia, Madan H.] Vanderbilt Univ, Med Ctr, Hematol & Stem Cell Transplant Program, Nashville, TN USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Vogelsang, Georgia B.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Weisdorf, Daniel] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Pavletic, Steven Z.] NCI, Bethesda, MD 20892 USA. RP Lee, SJ (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-290, Seattle, WA 98109 USA. EM sjlee@fhcrc.org OI Kurland, Brenda/0000-0002-5669-0595 FU NCI NIH HHS [U01 CA118953, CA118953, CA18029, P01 CA018029, P30 CA015704, R01 CA118953, U01 CA118953-05, U54 CA163438] NR 37 TC 30 Z9 30 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2012 VL 119 IS 3 BP 487 EP 493 DI 10.1016/j.ophtha.2011.08.040 PG 7 WC Ophthalmology SC Ophthalmology GA 901ID UT WOS:000300957200009 PM 22153706 ER PT J AU Momynaliev, KT Gorbatenko, EV Shevtsov, AB Gribanov, OG Babenko, NN Kaabak, MM AF Momynaliev, K. T. Gorbatenko, E. V. Shevtsov, A. B. Gribanov, O. G. Babenko, N. N. Kaabak, M. M. TI Prevalence and subtypes of BK virus in pediatric renal transplant recipients in Russia SO PEDIATRIC TRANSPLANTATION LA English DT Article DE transplantation; kidney; BK virus; qualitative PCR ID POLYOMAVIRUS-ASSOCIATED NEPHROPATHY; SEQUENCE ALIGNMENT; HUMAN-POPULATIONS; DNA-SEQUENCES; JC VIRUS; MARKER; CYCLOSPORINE; PERSISTENCE; INFECTION; IMPACT AB BKV reactivation is associated with impaired graft function in kidney transplant patients. The objective of our study was to determine the prevalence of BKV infection in consecutive pediatric kidney transplant recipients at our center. Fifty-eight pediatric kidney transplant recipients were studied. The mean age at screening was 9.4 +/- 2.8 yr, and samples were obtained at a median of 2.4 +/- 1.4 yr after transplantation. BKV-DNA was analyzed in urine and plasma by quantitative PCR. Occurrences of BK-DNAuria and BK-DNAemia did not change in the first two yr after transplantation in children and amounted to 21-23% and 7-8%, respectively (p > 0.05). In the third year, the occurrences of BK-DNAuria and BK-DNAemia increased insignificantly to 27% and 9% in the pediatric patients. We also determined the subtypes and subgroups of BK virus isolated from Russian renal transplant recipients and found that BKV isolates were composed of subtypes Ib-2 and IV/c2. The data we obtained indicate that although only 5% of BKVAN cases occurred between years two and five post-transplantation, it seems necessary to regularly monitor pediatric patients for BKV infection through the third year after transplantation. C1 [Momynaliev, K. T.; Gribanov, O. G.] Fed Agcy Biol & Med, Res Inst Physicochem Med, Moscow 119992, Russia. [Momynaliev, K. T.; Shevtsov, A. B.] Natl Biotechnol Ctr, Astana, Kazakhstan. [Gorbatenko, E. V.] Lytech Ltd, Moscow, Russia. [Babenko, N. N.; Kaabak, M. M.] Russian Acad Med Sci, Russian Natl Res Ctr Surg, Moscow, Russia. RP Momynaliev, KT (reprint author), Fed Agcy Biol & Med, Res Inst Physicochem Med, 1A Malaya Pirogovskaya St, Moscow 119992, Russia. EM dhoroshun@gmail.com OI Shevtsov, Alexandr/0000-0002-7576-2750; Kaabak, Michael/0000-0001-7566-2330; Babenko, Nadezda/0000-0002-4651-4061 NR 33 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1397-3142 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD MAR PY 2012 VL 16 IS 2 BP 151 EP 159 DI 10.1111/j.1399-3046.2011.01640.x PG 9 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA 898BF UT WOS:000300709600014 PM 22300090 ER PT J AU Vollrath-Smith, FR Shin, R Ikemoto, S AF Vollrath-Smith, Fiori R. Shin, Rick Ikemoto, Satoshi TI Synergistic interaction between baclofen administration into the median raphe nucleus and inconsequential visual stimuli on investigatory behavior of rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Median and dorsal raphe nuclei; GABA(B) receptors; Baclofen; Serotonin; Dopamine; Visual stimuli; Incentive motivation; Sensation seeking ID GABA-B RECEPTORS; D-AMPHETAMINE; CONDITIONED REWARD; STRIATAL SUBREGIONS; SEROTONIN NEURONS; DOPAMINE; REINFORCEMENT; ACCUMBENS; NICOTINE; MICROINJECTIONS AB Rationale Noncontingent administration of amphetamine into the ventral striatum or systemic nicotine increases responses rewarded by inconsequential visual stimuli. When these drugs are contingently administered, rats learn to self-administer them. We recently found that rats self-administer the GABA(B) receptor agonist baclofen into the median (MR) or dorsal (DR) raphe nuclei. Objectives We examined whether noncontingent administration of baclofen into the MR or DR increases rats' investigatory behavior rewarded by a flash of light. Results Contingent presentations of a flash of light slightly increased lever presses. Whereas noncontingent administration of baclofen into the MR or DR did not reliably increase lever presses in the absence of visual stimulus reward, the same manipulation markedly increased lever presses rewarded by the visual stimulus. Heightened locomotor activity induced by intraperitoneal injections of amphetamine (3 mg/kg) failed to concur with increased lever pressing for the visual stimulus. These results indicate that the observed enhancement of visual stimulus seeking is distinct from an enhancement of general locomotor activity. Visual stimulus seeking decreased when baclofen was co-administered with the GABA(B) receptor antagonist, SCH 50911, confirming the involvement of local GABA(B) receptors. Seeking for visual stimulus also abated when baclofen administration was preceded by intraperitoneal injections of the dopamine antagonist, SCH 23390 (0.025 mg/kg), suggesting enhanced visual stimulus seeking depends on intact dopamine signals. Conclusions Baclofen administration into the MR or DR increased investigatory behavior induced by visual stimuli. Stimulation of GABA(B) receptors in the MR and DR appears to disinhibit the motivational process involving stimulus-approach responses. C1 [Vollrath-Smith, Fiori R.; Shin, Rick; Ikemoto, Satoshi] NIDA, Behav Neurosci Branch, NIH, US Dept HHS, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, NIH, US Dept HHS, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM sikemoto@intra.nida.nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU National Institute on Drug Abuse, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. The authors thank the NIH Fellows Editorial Board for editorial assistance. We declare that we do not have any financial conflict of interest and that the experiments comply with the current laws of the USA in which they were performed. NR 39 TC 4 Z9 4 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2012 VL 220 IS 1 BP 15 EP 25 DI 10.1007/s00213-011-2450-x PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 898ZH UT WOS:000300780400002 PM 21904820 ER PT J AU Robinson, JE Fish, EW Krouse, MC Thorsell, A Heilig, M Malanga, CJ AF Robinson, J. E. Fish, E. W. Krouse, M. C. Thorsell, A. Heilig, M. Malanga, C. J. TI Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism SO PSYCHOPHARMACOLOGY LA English DT Article DE Morphine; Opioid; Neurokinin; Substance P; Dopamine; Reward; Reinforcement ID INTRACRANIAL SELF-STIMULATION; VENTRAL TEGMENTAL AREA; CONDITIONED PLACE PREFERENCE; MEDIAL FOREBRAIN-BUNDLE; MU-OPIOID RECEPTORS; SUBSTANCE-P; NUCLEUS-ACCUMBENS; DOPAMINE RELEASE; NK1 RECEPTOR; MICE LACKING AB Rationale The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists. Objective This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method. Methods Adult male C57BL/6J mice (n=15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (theta(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline. Results Morphine dose-dependently decreased theta(0) (maximum effect=62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered theta(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect theta(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect theta(0) or MAX. Conclusions The decrease in theta(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids. C1 [Robinson, J. E.; Fish, E. W.; Krouse, M. C.; Malanga, C. J.] Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. [Robinson, J. E.; Fish, E. W.; Krouse, M. C.; Malanga, C. J.] Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. [Thorsell, A.; Heilig, M.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Malanga, CJ (reprint author), Univ N Carolina, Dept Neurol, 170 Manning Dr,CB 7025, Chapel Hill, NC 27599 USA. EM malangacj@neurology.unc.edu OI Malanga, C.J./0000-0003-4808-3995; Robinson, J. Elliott/0000-0001-9417-3938; Thorsell, Annika/0000-0003-3535-3845 FU NIAAA; [R01-AA 018335] FX This research was supported by R01-AA 018335 (CJM) and the NIAAA intramural research budget (MH). NR 91 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2012 VL 220 IS 1 BP 215 EP 224 DI 10.1007/s00213-011-2469-z PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 898ZH UT WOS:000300780400020 PM 21909635 ER PT J AU Cappellacci, L Petrelli, R Vita, P Torquati, I Jacobson, KA Barrett, MO Franklin, D Harden, KT Franchetti, P Grifantini, M AF Cappellacci, Loredana Petrelli, Riccardo Vita, Patrizia Torquati, Ilaria Jacobson, Kenneth A. Barrett, Matthew O. Franklin, Derek Harden, Kendall T. Franchetti, Palmarisa Grifantini, Mario TI ADP- and ATP-mimetics derived from 2 '(3 ')-C-methyladenosine as human P2Y(1) and P2Y(2) receptor ligands SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Cappellacci, Loredana; Petrelli, Riccardo; Vita, Patrizia; Torquati, Ilaria; Franchetti, Palmarisa; Grifantini, Mario] Univ Camerino, Med Chem Unit, Sch Pharm, I-62032 Camerino, MC, Italy. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Barrett, Matthew O.; Franklin, Derek; Harden, Kendall T.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 2 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAR PY 2012 VL 8 IS 1 BP 143 EP 143 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 898YO UT WOS:000300778500068 ER PT J AU Bonaventura, J Brugarolas, M Navarro, G Mallol, J Canela, EI Lluis, C Franco, R Meana, J Salles, J Cortes, A Casado, V Ferre, S AF Bonaventura, Jordi Brugarolas, Marc Navarro, Gemma Mallol, Josefa Canela, Enric I. Lluis, Carme Franco, Rafael Meana, Javier Salles, Joan Cortes, Antoni Casado, Vicent Ferre, Sergi TI Caffeine and other A(2A) ligands modulate the binding of raclopride to D2 receptors SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Bonaventura, Jordi; Brugarolas, Marc; Navarro, Gemma; Mallol, Josefa; Canela, Enric I.; Lluis, Carme; Franco, Rafael; Cortes, Antoni; Casado, Vicent] Univ Barcelona, Fac Biol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-08028 Barcelona, Spain. [Bonaventura, Jordi; Brugarolas, Marc; Navarro, Gemma; Mallol, Josefa; Canela, Enric I.; Lluis, Carme; Franco, Rafael; Cortes, Antoni; Casado, Vicent] Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. [Franco, Rafael] Univ Navarra, CIMA, Pamplona 31008, Spain. [Meana, Javier] Univ Basque Country, Dept Pharmacol, Leioa, Bizkaia, Spain. [Meana, Javier; Salles, Joan] CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain. [Salles, Joan] Univ Basque Country, Fac Farm, Dept Pharmacol, Vitoria, Spain. [Ferre, Sergi] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RI Franco, Rafael/C-3694-2015; Salles, Joan/A-7141-2015 OI Franco, Rafael/0000-0003-2549-4919; Salles, Joan/0000-0001-6727-2674 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAR PY 2012 VL 8 IS 1 BP 172 EP 172 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 898YO UT WOS:000300778500127 ER PT J AU Stoddard, J Takarae, Y Simon, TJ AF Stoddard, Joel Takarae, Yukari Simon, Tony J. TI A second look: No effect of the COMT Val158Met polymorphism on conflict adaptation in youth with chromosome 22q11.2 deletion syndrome SO SCHIZOPHRENIA RESEARCH LA English DT Letter ID SCHIZOPHRENIA; ADULTS; GENOTYPE; CHILDREN C1 [Stoddard, Joel; Simon, Tony J.] Univ Calif Davis Hlth Syst, Med Investigat Neurodev Disorders MIND Inst, Dept Psychiat & Behav Sci, Davis, CA USA. [Stoddard, Joel] NIMH, Mood & Anxiety Disorders Branch, Bethesda, MD USA. [Takarae, Yukari] Univ Calif Davis, Ctr Mind & Brain, Davis, CA 95616 USA. RP Stoddard, J (reprint author), Bldg 10,B1D43B2, Bethesda, MD 20892 USA. EM joel.stoddard@nih.gov OI Stoddard, Joel/0000-0003-4070-4566 FU NICHD NIH HHS [R01 HD042974] NR 10 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2012 VL 135 IS 1-3 BP 202 EP 203 DI 10.1016/j.schres.2011.12.011 PG 2 WC Psychiatry SC Psychiatry GA 901CT UT WOS:000300940000039 PM 22245443 ER PT J AU Arnaoutova, I George, J Kleinman, HK Benton, G AF Arnaoutova, Irina George, Jay Kleinman, Hynda K. Benton, Gabriel TI Basement Membrane Matrix (BME) has Multiple Uses with Stem Cells SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE Matrigel; Basement membrane; Stem cells; Differentiation; Culture; Proliferation; BME ID ENDOTHELIAL PROGENITOR CELLS; EXTRACELLULAR-MATRIX; DIFFERENTIATION; CULTURE; GROWTH; IDENTIFICATION; TISSUE; LINE; EFFICIENCY; PROTEINS AB The utilization of basement membrane matrix has helped to overcome many of the obstacles associated with stem cell research. Initially, there were several problems with investigating stem cells, including difficult extraction from tissues, the need for feeder layers, poor survival, minimal proliferation, limited differentiation in vitro, and inadequate survival when injected or transplanted in vivo. Given that the basement membrane is the first extracellular matrix that is produced by the developing embryo, it was quickly identified as an important factor for modulating stem cell behavior, and since then, basement membrane extract (BME) has been successfully employed in numerous methods as a substratum in vitro and as a bioactive support in vivo to overcome many of these problems. A thin BME coating is sufficient to maintain an undifferentiated phenotype during embryonic stem cell expansion, while a thick BME hydrogel may be employed to induce stem cell differentiation. BME also promotes stem cell survival for in vivo applications and provides a physiological environment for evaluating stem cell co-culture with other cell types. The present article provides a concise review of current methodologies utilizing BME for stem cell research. C1 [Arnaoutova, Irina; George, Jay; Benton, Gabriel] Trevigen Inc, Gaithersburg, MD 20877 USA. [Kleinman, Hynda K.] NIDCR, NIH, Bethesda, MD USA. RP Benton, G (reprint author), Trevigen Inc, 8405 Helgerman Ct, Gaithersburg, MD 20877 USA. EM gbenton@trevigen.com OI Benton, Gabriel/0000-0003-4244-5764 NR 53 TC 8 Z9 9 U1 2 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD MAR PY 2012 VL 8 IS 1 BP 163 EP 169 DI 10.1007/s12015-011-9278-y PG 7 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 898YT UT WOS:000300779000015 PM 21655946 ER PT J AU Hernandez, DA Bokkers, RPH Mirasol, RV Luby, M Henning, EC Merino, JG Warach, S Latour, LL AF Hernandez, Daymara A. Bokkers, Reinoud P. H. Mirasol, Raymond V. Luby, Marie Henning, Erica C. Merino, Jose G. Warach, Steven Latour, Lawrence L. TI Pseudocontinuous Arterial Spin Labeling Quantifies Relative Cerebral Blood Flow in Acute Stroke SO STROKE LA English DT Article DE acute stroke; cerebral blood flow; perfusion quantification ID ACUTE ISCHEMIC-STROKE; REPERFUSION; INVERSION; THERAPY; DISEASE; TIME; MRI AB Background and Purpose-The aim of this study was to test whether arterial spin labeling (ASL) can detect significant differences in relative cerebral blood flow (rCBF) in the core, mismatch, and reverse-mismatch regions, and whether rCBF values measured by ASL in those areas differ from values obtained using dynamic susceptibility contrast (DSC) MRI. Methods-Acute stroke patients were imaged with diffusion-weighted imaging (DWI) and perfusion-weighted imaging (ASL and DSC) MRI. An expert reader segmented the ischemic lesion on DWI and the DSC time-to-peak (TTP) maps. Three regions were defined: core (DWI+, TTP+), mismatch (DWI+, TTP+), and reverse-mismatch (DWI+, TTP+). For both ASL and DSC, rCBF maps were created with commercially available software, and the ratio was calculated as the mean signal intensity measured on the side of the lesion to that of the homologous region in the contralateral hemisphere. Values obtained from core, mismatch, and reverse-mismatch were used for paired comparison. Results-Twenty-eight patients were included in the study. The mean age was 65.6 (16.9) years, with a median baseline National Institutes of Health Stroke Scale score of 10 (interquartile range, 4-17). Median time from last known normal to MRI was 5.7 hours (interquartile range, 2.9-22.6). Mean rCBF ratios were significantly higher in the mismatch 0.53 (0.23) versus the core 0.39 (0.33) and reverse-mismatch 0.68 (0.49) versus the core 0.38 (0.35). Differences in rCBF measured with DSC and ASL were not significant. Conclusions-ASL allows for the measurement of rCBF in the core and mismatch regions. Values in the mismatch were significantly higher than in the core, suggesting there is potential salvageable tissue. (Stroke. 2012;43:753-758.) C1 [Hernandez, Daymara A.; Mirasol, Raymond V.; Luby, Marie; Henning, Erica C.; Merino, Jose G.; Warach, Steven; Latour, Lawrence L.] NINDS, NIH, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. [Bokkers, Reinoud P. H.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [Merino, Jose G.] Johns Hopkins Community Phys, Bethesda, MD USA. [Mirasol, Raymond V.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Latour, LL (reprint author), NINDS, NIH, Sect Stroke Diagnost & Therapeut, 10 Ctr Dr,MSC 1063,Bldg 10,Room B1D733, Bethesda, MD 20892 USA. EM latourl@ninds.nih.gov OI Merino, Jose/0000-0002-6676-0008 FU Washington Hospital Center Stroke Center; Division of Intramural Research of the National Institute of Neurological Disorders and Stroke; National Institutes of Health FX The authors thank the National Institutes of Health Stroke Program at the Washington Hospital Center Stroke Center for their support of the study.; This research was supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 28 TC 19 Z9 21 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2012 VL 43 IS 3 BP 753 EP 758 DI 10.1161/STROKEAHA.111.635979 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 897HQ UT WOS:000300639400031 PM 22343640 ER PT J AU Jette, AM Ni, PS Rasch, EK Appelman, J Sandel, ME Terdiman, J Chan, LT AF Jette, Alan M. Ni, Pengsheng Rasch, Elizabeth K. Appelman, Jed Sandel, M. Elizabeth Terdiman, Joseph Chan, Leighton TI Evaluation of Patient and Proxy Responses on the Activity Measure for Postacute Care SO STROKE LA English DT Article DE disability evaluation; rehabilitation; stroke assessment; stroke outcome ID QUALITY-OF-LIFE; STROKE IMPACT SCALE; PATIENTS PERCEPTIONS; FUNCTIONAL STATUS; AGREEMENT; ASSESSMENTS; APHASIA; INDEX; EQ-5D AB Background and Purpose-Our objective was to examine the agreement between adult patients with stroke and family member or clinician proxies in activity measure for postacute care (AM-PAC) summary scores for daily activity, basic mobility, and applied cognitive function. Methods-This study involved 67 patients with stroke admitted to a hospital within the Kaiser Permanente of Northern California system and were participants in a parent study on stroke outcomes. Each participant and proxy respondent completed the AM-PAC by personal or telephone interview at the point of hospital discharge or during >= 1 transitions to different postacute care settings. Results-The results suggest that for patients with a stroke proxy, AM-PAC data are robust for family or clinician proxy assessment of basic mobility function and clinician proxy assessment of daily activity function, but less robust for family proxy assessment of daily activity function and for all proxy groups' assessments of applied cognitive function. The pattern of disagreement between patient and proxy was, on average, relatively small and random. There was little evidence of systematic bias between proxy and patient reports of their functional status. The degree of concordance between patient and proxy was similar for those with moderate to severe strokes compared with mild strokes. Conclusions-Patient and proxy ratings on the AM-PAC achieved adequate agreement for use in stroke research when using proxy respondents could reduce sample selection bias. The AM-PAC data can be implemented across institutional as well as community care settings while achieving precision and reducing respondent burden. (Stroke. 2012;43:824-829.) C1 [Jette, Alan M.; Ni, Pengsheng] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [Rasch, Elizabeth K.; Chan, Leighton] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Sandel, M. Elizabeth] Kaiser Fdn, Rehabil Ctr, Napa Solano Serv Area, Vallejo, CA USA. [Terdiman, Joseph] Kaiser Permanente, Div Res, Oakland, CA USA. RP Jette, AM (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Med Campus,715 Albany St,T5W, Boston, MA 02118 USA. EM Ajette@bu.edu OI Jette, Alan/0000-0002-2117-9973; Ni, Pengsheng/0000-0003-1774-2185 FU National Institutes of Health; American Recovery and Reinvestment Act grant [1RC1NS068397] FX This research was supported, in part, by the National Institutes of Health Intramural Research Program. It was also supported by an American Recovery and Reinvestment Act grant to Kaiser Permanente, number 1RC1NS068397. NR 35 TC 11 Z9 11 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2012 VL 43 IS 3 BP 824 EP 829 DI 10.1161/STROKEAHA.111.619643 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 897HQ UT WOS:000300639400042 PM 22343646 ER PT J AU Kitano, M Rahbari, R Patterson, EE Steinberg, SM Prasad, NB Wang, YC Zeiger, MA Kebebew, E AF Kitano, Mio Rahbari, Reza Patterson, Erin E. Steinberg, Seth M. Prasad, Nijaguna B. Wang, Yongchun Zeiger, Martha A. Kebebew, Electron TI Evaluation of Candidate Diagnostic MicroRNAs in Thyroid Fine-Needle Aspiration Biopsy Samples SO THYROID LA English DT Article ID GROWTH-FACTOR RECEPTOR; EXPRESSION PROFILES; CANCER; CARCINOMA; NODULES; AGGRESSIVENESS; TUMORIGENESIS; MANAGEMENT; PATHWAY; TARGETS AB Background: Thyroid cancer diagnosis in the United States has increased by 2.3-folds in the last three decades. Up to 30% of thyroid fine-needle aspiration biopsy (FNAB) results are inconclusive. Several differentially expressed microRNAs (miRNAs) have been identified as candidate diagnostic markers for thyroid nodules. We hypothesized that these differentially expressed miRNAs may improve the accuracy of FNAB in difficult to diagnose thyroid nodules. Methods: Expression levels of four miRNAs (miR-7, -126, -374a, and let-7g) were analyzed using quantitative real-time reverse transcription-polymerase chain reaction in 95 FNAB samples as the training set. A predictor model was formulated based on the most differentially expressed miRNA (miR-7) Delta Ct value and the model was applied on a separate cohort of 59 FNAB samples as the validation set. Results: miR-7 was the best predictor to distinguish benign from malignant thyroid FNAB samples. The other three miRNAs were co-expressed and did not significantly contribute to the predictor model. miR-7 had a sensitivity of 100%, specificity of 29%, positive predictive value (PPV) of 36%, negative predictive value (NPV) of 100%, and overall accuracy of 76% when applied to the validation set. In subgroup analysis of preoperative nondiagnostic, indeterminate, or suspicious FNAB samples, the predictor model had an overall accuracy of 37% with sensitivity of 100%, specificity of 20%, PPV of 25%, and NPV of 100%. Conclusions: miR-7 may be a helpful adjunct marker to thyroid FNAB in tumor types which are inconclusive. Given the high NPV of miR-7, a patient with a benign result based on the predictor model may be followed as opposed to performing an immediate diagnostic thyroidectomy. Future prospective clinical trials evaluating its accuracy in a larger cohort are warranted to determine its clinical utility. C1 [Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, NIH,CRC, Bethesda, MD 20892 USA. [Prasad, Nijaguna B.; Wang, Yongchun; Zeiger, Martha A.] Johns Hopkins Univ, Sch Med, Dept Surg, Endocrine Surg Sect, Baltimore, MD 21205 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Sect, Surg Branch, NIH,CRC, 10 Ctr Dr, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 42 TC 38 Z9 39 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD MAR PY 2012 VL 22 IS 3 BP 285 EP 291 DI 10.1089/thy.2011.0313 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 902MF UT WOS:000301041700008 PM 22304369 ER PT J AU Cheng, TJ Li, QL Zhou, ZG Wang, YL Bryant, SH AF Cheng, Tiejun Li, Qingliang Zhou, Zhigang Wang, Yanli Bryant, Stephen H. TI Structure-Based Virtual Screening for Drug Discovery: a Problem-Centric Review SO AAPS JOURNAL LA English DT Review DE docking; machine learning; structure-based virtual scoring; target-biased scoring function ID PROTEIN-LIGAND INTERACTIONS; BINDING-AFFINITY PREDICTION; EMPIRICAL SCORING FUNCTIONS; HIGH-THROUGHPUT DOCKING; MOLECULAR DOCKING; FLEXIBLE DOCKING; KINASE INHIBITORS; AUTOMATED DOCKING; GENETIC ALGORITHM; WATER-MOLECULES AB Structure-based virtual screening (SBVS) has been widely applied in early-stage drug discovery. From a problem-centric perspective, we reviewed the recent advances and applications in SBVS with a special focus on docking-based virtual screening. We emphasized the researchers' practical efforts in real projects by understanding the ligand-target binding interactions as a premise. We also highlighted the recent progress in developing target-biased scoring functions by optimizing current generic scoring functions toward certain target classes, as well as in developing novel ones by means of machine learning techniques. C1 [Cheng, Tiejun; Li, Qingliang; Zhou, Zhigang; 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 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. NR 97 TC 127 Z9 130 U1 9 U2 96 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAR PY 2012 VL 14 IS 1 BP 133 EP 141 DI 10.1208/s12248-012-9322-0 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 896GP UT WOS:000300554000015 PM 22281989 ER PT J AU Song, R Yang, RF Wu, N Su, RB Li, J Peng, XQ Li, X Gaal, J Xi, ZX Gardner, EL AF Song, Rui Yang, Ri-Fang Wu, Ning Su, Rui-Bin Li, Jin Peng, Xiao-Qing Li, Xia Gaal, Jozsef Xi, Zheng-Xiong Gardner, Eliot L. TI YQA14: a novel dopamine D-3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D-3 receptor-knockout mice SO ADDICTION BIOLOGY LA English DT Article DE Cocaine; D-3 receptor; dopamine; SB-277011A; self-administration; YQA14 ID DRUG-SEEKING BEHAVIOR; CONDITIONED PLACE PREFERENCE; ENHANCED BRAIN REWARD; PROGRESSIVE-RATIO; INDUCED REINSTATEMENT; HIGH-AFFINITY; PHARMACOLOGICAL ACTIONS; SELECTIVE ANTAGONISM; REINFORCING EFFICACY; TRIGGERED RELAPSE AB The dopamine (DA) D3 receptor is posited to be importantly involved in drug reward and addiction, and D3 receptor antagonists have shown extraordinary promise as potential anti-addiction pharmacotherapeutic agents in animal models of drug addiction. SB-277011A is the best characterized D3 receptor antagonist in such models. However, the potential use of SB-277011A in humans is precluded by pharmacokinetic and toxicity problems. We here report a novel D3 receptor antagonist YQA14 that shows similar pharmacological properties as SB-277011A. In vitro receptor binding assays suggest that YQA14 has two binding sites on human cloned D3 receptors with Ki-High (0.68 x 10(4) nM) and Ki-Low (2.11 nM), and displays > 150-fold selectivity for D3 over D2 receptors and > 1000-fold selectivity for D3 over other DA receptors. Systemic administration of YQA14 (6.25-25 mg/kg) or SB-277011A (12.5-25 mg/kg) significantly and dose-dependently reduced intravenous cocaine self-administration under both low fixed-ratio and progressive-ratio reinforcement conditions in rats, while failing to alter oral sucrose self-administration and locomotor activity, suggesting a selective inhibition of drug reward. However, when the drug dose was increased to 50 mg/kg, YQA14 and SB-277011A significantly inhibited basal and cocaine-enhanced locomotion in rats. Finally, both D3 antagonists dose-dependently inhibited intravenous cocaine self-administration in wild-type mice, but not in D3 receptor-knockout mice, suggesting that their action is mediated by D3 receptor blockade. These findings suggest that YQA14 has a similar anti-addiction profile as SB-277011A, and deserves further study and development. C1 [Song, Rui; Peng, Xiao-Qing; Li, Xia; Xi, Zheng-Xiong; Gardner, Eliot L.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. [Song, Rui; Yang, Ri-Fang; Wu, Ning; Su, Rui-Bin; Li, Jin] Beijing Inst Pharmacol & Toxicol, Beijing, Peoples R China. RP Xi, ZX (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. EM lijin@nic.bmi.ac.cn; zxi@intra.nida.nih.gov OI Yang, Rifang/0000-0001-8087-9614; PENG, XIAOQING/0000-0002-7272-5428 FU US National Institute on Drug Abuse Intramural Research Program; National Basic Research Program of China [2009CB522008]; National Key Technology Research and Development Program of China [2007BAI07B02] FX This work was supported by the US National Institute on Drug Abuse Intramural Research Program (for the in vivo behavioral studies) and the National Basic Research Program of China (No. 2009CB522008) and the National Key Technology Research and Development Program of China (No. 2007BAI07B02) (for the in vitro binding assays). We thank Dr Xue- Chu Zhen for providing us with DA D1-, D2- and D5-transfected cells we used in these experiments. NR 62 TC 44 Z9 46 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2012 VL 17 IS 2 BP 259 EP 273 DI 10.1111/j.1369-1600.2011.00317.x PG 15 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 896LT UT WOS:000300568500005 PM 21507153 ER PT J AU Gilman, JM Smith, AR Ramchandani, VA Momenan, R Hommer, DW AF Gilman, Jodi M. Smith, Ashley R. Ramchandani, Vijay A. Momenan, Reza Hommer, Daniel W. TI The effect of intravenous alcohol on the neural correlates of risky decision making in healthy social drinkers SO ADDICTION BIOLOGY LA English DT Article DE Alcohol; imaging; impulsivity; nucleus accumbens; reward; risk taking ID NUCLEUS-ACCUMBENS; FAMILY HISTORY; PREFRONTAL CORTEX; BINGE DRINKING; MG-PERCENT; ETHANOL; MODEL; IMPAIRMENT; BEHAVIOR; IMPULSIVITY AB Alcohol is thought to contribute to an increase in risk-taking behavior, but the neural correlates underlying this effect are not well understood. In this study, participants were given intravenous alcohol or placebo while undergoing functional magnetic resonance imaging (fMRI) and playing a risk-taking game. The game allowed us to examine the neural response to choosing a safe or risky option, anticipating outcome and receiving feedback. We found that alcohol increased risk-taking behavior, particularly among participants who experienced more stimulating effects of alcohol. fMRI scans demonstrated that alcohol increased activation in the striatum to risky compared with safe choices and dampened the neural response to notification of both winning and losing throughout the caudate, thalamus and insula. This study suggests that alcohol may increase risk-taking behavior by both activating brain regions involved in reward when a decision is made, and dampening the response to negative and positive feedback. C1 [Gilman, Jodi M.; Smith, Ashley R.; Ramchandani, Vijay A.; Momenan, Reza; Hommer, Daniel W.] NIAAA, Sect Brain Electrophysiol & Imaging, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Gilman, JM (reprint author), 10 Ctr Dr,Bldg 10 CRC Hatfield Clinical Res Ctr,R, Bethesda, MD 20892 USA. EM gilmanj@mail.nih.gov FU Intramural NIH HHS [ZIA AA000466-06] NR 61 TC 18 Z9 19 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2012 VL 17 IS 2 BP 465 EP 478 DI 10.1111/j.1369-1600.2011.00383.x PG 14 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 896LT UT WOS:000300568500021 PM 21995446 ER PT J AU Hirsch, CH Buzkova, P Robbins, JA Patel, KV Newman, AB AF Hirsch, Calvin Hayes Buzkova, Petra Robbins, John A. Patel, Kushang V. Newman, Anne B. TI Predicting late-life disability and death by the rate of decline in physical performance measures(dagger) SO AGE AND AGEING LA English DT Article DE ageing; motor skills; activities of daily living; disabled persons; mortality; elderly ID WHITE-MATTER ABNORMALITIES; FUNCTIONING OLDER-ADULTS; LOWER-EXTREMITY FUNCTION; INCIDENT DISABILITY; MOTOR FUNCTION; WALKING SPEED; GAIT SPEED; MORTALITY; RISK; ASSOCIATION AB Background: the rate of performance decline may influence the risk of disability or death. Methods: for 4,182 Cardiovascular Health Study participants, we used multinomial Poisson log-linear models to assess the contribution of physical performance in 1998-99, and the rate of performance change between 1992-93 and 1998-99, to the risk of death or disability in 2005-06 in three domains: mobility, upper-extremity function (UEF) and activities of daily living (ADL). We evaluated performance in finger-tapping, grip strength, stride length, gait speed and chair stands separately and together for each outcome, adjusting for age, gender, race and years of disability in that outcome between 1992-93 and 1998-99. Results: participants' age averaged 79.4 in 1998-99; 1,901 died over 7 years. Compared with the lowest change quintile in stride length, the highest quintile had a 1.32 relative risk (RR) of ADL disability (95% CI: 1.16 -1.96) and a 1.27 RR of death (95% CI: 1.07 -1.51). The highest change quintile for grip strength increased the risk of ADL disability by 35% (95% CI: 1.13 -1.61) and death by 31% (95% CI: 1.16 -1.49), compared with the lowest quintile. The annual change in stride length and grip strength also predicted disability in mobility and UEF. Conclusion: performance trajectories independently predict death and disability. C1 [Hirsch, Calvin Hayes; Robbins, John A.] Univ Calif Davis, Davis Med Ctr, Div Gen Med, Sacramento, CA 95817 USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Patel, Kushang V.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Piottsburgh, PA USA. RP Hirsch, CH (reprint author), Univ Calif Davis, Davis Med Ctr, Div Gen Med, 4150 V St,PSSB Suite 2400, Sacramento, CA 95817 USA. EM chhirsch@ucdavis.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging [AG-023629, R01 AG-15928, R01 AG-20098, AG-027058]; National Institute on Aging, National Institutes of Health; National Heart, Lung, and Blood Institute [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL-075366]; University of Pittsburgh Claude. D. Pepper Older Americans Independence Center [P30-AG-024827] FX The research reported in this article was supported in part by the National Institute on Aging AG-023629 and in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. CHS was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant number U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01 AG-15928, R01 AG-20098, and AG-027058 from the National Institute on Aging, R01 HL-075366 from the National Heart, Lung and Blood Institute, and the University of Pittsburgh Claude. D. Pepper Older Americans Independence Center P30-AG-024827. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. NR 27 TC 17 Z9 17 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD MAR PY 2012 VL 41 IS 2 BP 155 EP 161 DI 10.1093/ageing/afr151 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 895HS UT WOS:000300487600004 PM 22156556 ER PT J AU Choi, S McAleer, JP Zheng, M Deleo, FR Ouyang, W Hooper, LV Qin, S Reinhart, TA Kolls, JK AF Choi, S. McAleer, J. P. Zheng, M. DeLeo, F. R. Ouyang, W. Hooper, L. V. Qin, S. Reinhart, T. A. Kolls, J. K. TI Acute alcohol inhibits STAT3 induction of Reg3 gamma in MRSA Pneumonia SO ALCOHOL LA English DT Meeting Abstract CT Meeting of the Alcohol-and-Immunology-Research-Interest-Group on Alcohol and Epigenetic Changes (AIRIG) CY NOV 18, 2011 CL Loyola Univ Med Ctr, Maywood, IL SP Alcohol & Immunol Res Interest Grp (AIRIG) HO Loyola Univ Med Ctr C1 [Choi, S.; McAleer, J. P.; Kolls, J. K.] LSUHSC, New Orleans, LA USA. [DeLeo, F. R.] NIAID, Rocky Mt, MT USA. [Ouyang, W.] Genentech San Francisco, San Francisco, CA USA. [Hooper, L. V.] UT SW Dallas, Dallas, TX USA. [Qin, S.; Reinhart, T. A.] U Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 J9 ALCOHOL JI Alcohol PD MAR PY 2012 VL 46 IS 2 MA 5 BP 175 EP 175 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 898RW UT WOS:000300760500013 ER PT J AU O'Seaghdha, CM Lyass, A Massaro, JM Meigs, JB Coresh, J D'Agostino, RB Astor, BC Fox, CS AF O'Seaghdha, Conall M. Lyass, Asya Massaro, Joseph M. Meigs, James B. Coresh, Josef D'Agostino, Ralph B., Sr. Astor, Brad C. Fox, Caroline S. TI A Risk Score for Chronic Kidney Disease in the General Population SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Chronic kidney disease; CKD; Risk score ID GLOMERULAR-FILTRATION-RATE; CORONARY-HEART-DISEASE; IMPROVING GLOBAL OUTCOMES; ATHEROSCLEROSIS RISK; POSITION STATEMENT; SERUM CREATININE; RENAL-DISEASE; PREDICTION; COMMUNITIES; PROGRESSION AB BACKGROUND: Stratification of individuals at risk for chronic kidney disease may allow optimization of preventive measures to reduce disease incidence and complications. We sought to develop a risk score that estimates an individual's absolute risk of incident chronic kidney disease. METHODS: Framingham Heart Study participants free of baseline chronic kidney disease, who attended a baseline examination in 1995-1998 and follow-up in 2005-2008, were included in the analysis (n = 2490). Chronic kidney disease was defined as an estimated glomerular filtration rate <60 mL/min/1.73m(2) using the Modification of Diet in Renal Disease equation. Participants were assessed for the development of chronic kidney disease at 10 years follow-up. Stepwise logistic regression was used to identify chronic kidney disease risk factors, and these were used to construct a risk score predicting 10-year chronic kidney disease risk. Performance characteristics were assessed using calibration and discrimination measures. The final model was externally validated in the bi-ethnic Atherosclerosis Risk in Communities Study (n = 1777). RESULTS: There were 1171 men and 1319 women at baseline, and the mean age was 57.1 years. At follow-up, 9.2% (n = 229) had developed chronic kidney disease. Age, diabetes, hypertension, baseline estimated glomerular filtration rate, and albuminuria were independently associated with incident chronic kidney disease (P < .05), and these covariates were incorporated into a risk function (c-statistic 0.813). In external validation in the ARIC study, the c-statistic was 0.74 in whites (n = 1353) and 0.75 in blacks (n = 424). CONCLUSION: Risk stratification for chronic kidney disease is achievable using a risk score derived from clinical factors that are readily accessible in primary care. The utility of this score in identifying individuals in the community at high risk of chronic kidney disease warrants further investigation. Published by Elsevier Inc. . The American Journal of Medicine (2012) 125, 270-277 C1 [O'Seaghdha, Conall M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Renal, Brigham & Womens Hosp, Boston, MA 02114 USA. [O'Seaghdha, Conall M.; Meigs, James B.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Lyass, Asya; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Coresh, Josef; Astor, Brad C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Coresh, Josef; Astor, Brad C.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Coresh, Josef; Astor, Brad C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute [N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; National Institute of Diabetes and Digestive and Kidney Diseases [1 R01 DK076770-01]; [U01HL075572-01] FX The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195); urinary albumin excretion assay reagents were donated by Roche Diagnostics Inc. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022, with the ARIC Carotid MRI Study funded by U01HL075572-01. Drs Astor and Coresh are supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1 R01 DK076770-01). NR 39 TC 16 Z9 16 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAR PY 2012 VL 125 IS 3 BP 270 EP 277 DI 10.1016/j.amjmed.2011.09.009 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 897BI UT WOS:000300615400020 PM 22340925 ER PT J AU Scliar, MO Soares-Souza, GB Chevitarese, J Lemos, L Magalhaes, WCS Fagundes, NJ Bonatto, SL Yeager, M Chanock, SJ Tarazona-Santos, E AF Scliar, Marilia O. Soares-Souza, Giordano B. Chevitarese, Juliana Lemos, Livia Magalhaes, Wagner C. S. Fagundes, Nelson J. Bonatto, Sandro L. Yeager, Meredith Chanock, Stephen J. Tarazona-Santos, Eduardo TI The population genetics of quechuas, the largest native south american group: Autosomal sequences, SNPs, and microsatellites evidence high level of diversity SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Article DE native American; Andes; microsatellites; autosomal noncoding sequence; HGDP-CEPH ID MITOCHONDRIAL-DNA DIVERSITY; MULTILOCUS GENOTYPE DATA; GENOME-WIDE PATTERNS; AMERINDIAN POPULATIONS; CENTRAL ANDES; ADMIXTURE; POLYMORPHISM; FREQUENCIES; MARKERS; MODELS AB Elucidating the pattern of genetic diversity for non-European populations is necessary to make the benefits of human genetics research available to individuals from these groups. In the era of large human genomic initiatives, Native American populations have been neglected, in particular, the Quechua, the largest South Amerindian group settled along the Andes. We characterized the genetic diversity of a Quechua population in a global setting, using autosomal noncoding sequences (nine unlinked loci for a total of 16 kb), 351 unlinked SNPs and 678 microsatellites and tested predictions of the model of the evolution of Native Americans proposed by (Tarazona-Santos et al.: Am J Hum Genet 68 (2001) 14851496). European admixture is <5% and African ancestry is barely detectable in the studied population. The largest genetic distances were between African versus Quechua or Melanesian populations, which is concordant with the African origin of modern humans and the fact that South America was the last part of the world to be peopled. The diversity in the Quechua population is comparable with that of Eurasian populations, and the allele frequency spectrum based on resequencing data does not reflect a reduction in the proportion of rare alleles. Thus, the Quechua population is a large reservoir of common and rare genetic variants of South Amerindians. These results are consistent with and complement our evolutionary model of South Amerindians (Tarazona-Santos et al.: Am J Hum Genet 68 (2001) 14851496), proposed based on Y-chromosome data, which predicts high genomic diversity due to the high level of gene flow between Andean populations and their long-term effective population size. Am J Phys Anthropol 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Scliar, Marilia O.; Soares-Souza, Giordano B.; Chevitarese, Juliana; Lemos, Livia; Magalhaes, Wagner C. S.; Tarazona-Santos, Eduardo] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, BR-31270910 Belo Horizonte, MG, Brazil. [Fagundes, Nelson J.] Univ Fed Rio Grande do Sul, Inst Biociencias, Dept Genet, BR-91501970 Porto Alegre, RS, Brazil. [Bonatto, Sandro L.] Pontificia Univ Catolica Rio Grande do Sul, Fac Biociencias, BR-90619900 Porto Alegre, RS, Brazil. [Yeager, Meredith] NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21702 USA. [Yeager, Meredith] NCI, Core Genotype Facil, NIH, Gaithersburg, MD 20877 USA. [Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD 20877 USA. RP Tarazona-Santos, E (reprint author), Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, Av Antonio Carlos 6627,Pampulha Caixa Postal 486, BR-31270910 Belo Horizonte, MG, Brazil. EM edutars@icb.ufmg.br RI Magalhaes, Wagner/D-8822-2015; Bonatto, Sandro/A-1240-2010 OI Bonatto, Sandro/0000-0002-0064-467X FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Brazil); Fundacao de Amparo a Pesquisa de Minas Gerais (Brazil); Brazilian Ministry of Education (Agency for the Development of Graduate Education-CAPES); National Cancer Institute FX Grant sponsors: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Brazil), Fundacao de Amparo a Pesquisa de Minas Gerais (Brazil), Brazilian Ministry of Education (Agency for the Development of Graduate Education-CAPES) and National Cancer Institute. NR 72 TC 7 Z9 7 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAR PY 2012 VL 147 IS 3 BP 443 EP 451 DI 10.1002/ajpa.22013 PG 9 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 894TH UT WOS:000300449300011 PM 22282032 ER PT J AU Molica, F Matter, CM Burger, F Pelli, G Lenglet, S Zimmer, A Pacher, P Steffens, S AF Molica, Filippo Matter, Christian M. Burger, Fabienne Pelli, Graziano Lenglet, Sebastien Zimmer, Andreas Pacher, Pal Steffens, Sabine TI Cannabinoid receptor CB2 protects against balloon-induced neointima formation SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE restenosis; smooth muscle cells; macrophages ID HEPATIC ISCHEMIA/REPERFUSION INJURY; CORONARY STENT THROMBOSIS; DRUG-ELUTING STENTS; APOE-KNOCKOUT MICE; ENDOCANNABINOID SYSTEM; MULTIPLE-SCLEROSIS; ATHEROSCLEROSIS; MIGRATION; INFLAMMATION; ACTIVATION AB Molica F, Matter CM, Burger F, Pelli G, Lenglet S, Zimmer A, Pacher P, Steffens S. Cannabinoid receptor CB2 protects against balloon-induced neointima formation. Am J Physiol Heart Circ Physiol 302: H1064-H1074, 2012. First published January 6, 2012; doi:10.1152/ajpheart.00444.2011.-Cannabinoid receptor CB2 activation inhibits inflammatory proliferation and migration of vascular smooth muscle cells in vitro. The potential in vivo relevance of these findings is unclear. We performed carotid balloon distension injury in hypercholesterolemic apolipoprotein E knockout (ApoE(-/-)) mice receiving daily intraperitoneal injection of the CB2 agonist JWH133 (5 mg/kg) or vehicle, with the first injection given 30 min before injury. Alternatively, we subjected CB2-/- and wild-type (WT) mice to balloon injury. We determined CB2 mRNA and protein expression in dilated arteries of ApoE(-/-) mice. Neointima formation was assessed histologically. We used bone marrow-derived murine CB2-/- and WT macrophages to study adhesion to plastic, fibronectin, or collagen, and migration was assayed by modified Boyden chamber. Aortic smooth muscle cells were isolated to determine in vitro proliferation rates. We found increased vascular CB2 expression in ApoE(-/-) mice in response to balloon injury. Seven to twenty-one days after dilatation, injured vessels of JWH133-treated mice had less intimal nuclei numbers as well as intimal and medial areas, associated with less staining for proliferating cells, smooth muscle cells, and macrophages. Complete endothelial repair was observed after 14 days in both JWH133- and vehicle-treated mice. CB2 deficiency resulted in increased intima formation compared with WT, whereas JWH133 did not affect intimal formation in CB2-/- mice. Apoptosis rates assessed by in situ terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining 1 h postballooning were significantly higher in the CB2 knockouts. In vitro, bone marrow-derived CB2-/- macrophages showed enhanced adherence and migration compared with WT cells and elevated mRNA levels of adhesion molecules, chemokine receptors CCR1 and 5, and chemokine CCL2. Proliferation rates were significantly increased in CB2-/- smooth muscle cells compared with WT. In conclusion, pharmacological activation or genetic deletion of CB2 receptors modulate neointima formation via protective effects in macrophages and smooth muscle cells. C1 [Molica, Filippo; Burger, Fabienne; Pelli, Graziano; Lenglet, Sebastien; Steffens, Sabine] Univ Hosp Geneva, Dept Internal Med, Div Cardiol, Geneva, Switzerland. [Matter, Christian M.] Univ Zurich, Inst Physiol, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. [Matter, Christian M.] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Zimmer, Andreas] Univ Bonn, Inst Mol Psychiat, Bonn, Germany. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, Bethesda, MD USA. RP Steffens, S (reprint author), Fdn Med Res, Univ Hosp, Dept Med, Div Cardiol, 64 Ave Roseraie, CH-1211 Geneva, Switzerland. EM sabine.steffens@unige.ch RI Pacher, Pal/B-6378-2008; Zimmer, Andreas/B-8357-2009; LENGLET, Sebastien/N-8923-2013; Filippo, Molica/A-6315-2013 OI Pacher, Pal/0000-0001-7036-8108; LENGLET, Sebastien/0000-0002-4853-8163; FU Swiss National Science Foundation [310030-116324, 310030-130732]; Swiss Life; OPO Foundation; Prevot FX This work was supported by Swiss National Science Foundation Grants 310030-116324 and 310030-130732, Swiss Life, Prevot, and OPO Foundation (to S. Steffens). NR 41 TC 11 Z9 11 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD MAR PY 2012 VL 302 IS 5 BP H1064 EP H1074 DI 10.1152/ajpheart.00444.2011 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 898EX UT WOS:000300720500004 PM 22227125 ER PT J AU Glasgow, RE AF Glasgow, Russell E. TI Estimating Population Impact SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Letter C1 NCI, Implementat Sci Div Canc Control & Populat Sci, Rockville, MD USA. RP Glasgow, RE (reprint author), NCI, Implementat Sci Div Canc Control & Populat Sci, Rockville, MD USA. EM glasgowre@mail.nih.gov NR 5 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 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2012 VL 42 IS 3 BP E30 EP E31 DI 10.1016/j.amepre.2011.12.004 PG 3 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 897CI UT WOS:000300618600003 PM 22341177 ER PT J AU Balansky, R D'Agostini, F Micale, RT La Maestra, S Steele, VE De Flora, S AF Balansky, Roumen D'Agostini, Francesco Micale, Rosanna T. La Maestra, Sebastiano Steele, Vernon E. De Flora, Silvio TI Dose-related cytogenetic damage in pulmonary alveolar macrophages from mice exposed to cigarette smoke early in life SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Cigarette smoke; Neonatal mice; Pulmonary alveolar macrophages; Cytogenetic damage; Micronucleus test ID GLUTATHIONE-S-TRANSFERASE; VITRO MICRONUCLEUS TEST; N-ACETYLCYSTEINE; TOBACCO-SMOKE; NEONATAL MICE; LUNG-CANCER; HUMAN-CELLS; MOUSE LUNG; MODULATION; RISK AB The micronucleus test detects both structural and numerical chromosomal aberrations caused by environmental agents. However, this test is poorly sensitive to detect the clastogenicity of cigarette smoke (CS) in human peripheral blood lymphocytes. At variance with peripheral blood lymphocytes and other cells outside the lower respiratory tract, pulmonary alveolar macrophages (PAM) are selectively affected by inhalable carcinogens and have been used to evaluate the modulation of CS-related cytogenetic alterations in vivo. The present study was aimed at evaluating (1) the cytogenetic response in PAM isolated from the lung of mice exposed to CS during the first 4 weeks of life and (2) the dose dependence of MN and polynucleated (PN) PAM formation in CS-exposed mice. To this purpose, ICR(CD-1) mice were exposed whole body to mainstream CS for 4 weeks, starting immediately after birth. Bronchoalveolar lavage (BAL) was performed to evaluate the cellularity of this fluid and the frequency of PN and MN PAM. At the doses of 119, 292, and 438 mg/m(3) total particulate matter, CS significantly increased both the proportion of PAM in the BAL fluid and the frequencies of PN and MN PAM. The cytogenetic effects were significantly correlated with the CS dose. In conclusion, PAM are suitable to detect induction by CS of clastogenic and aneugenic effects in mice during a developmental period corresponding to infancy, childhood, and early adolescence in humans. These surrogate cells, providing an important defense mechanism of the respiratory tract, are proposed as indicators of CS-related DNA damage in youngsters. C1 [D'Agostini, Francesco; Micale, Rosanna T.; La Maestra, Sebastiano; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Balansky, Roumen] Natl Oncol Ctr, Sofia 1756, Bulgaria. [Steele, Vernon E.] NCI, Rockville, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM rubalansky@sbaloncology.bg; steelev@mail.nih.gov; sdf@unige.it FU U.S. National Cancer Institute [NO1-CN53301]; Bulgarian Ministry of Education, Youth and Science; Hasumi International Research Foundation (Bulgaria) FX We thank Dr. Ilaria Righi for her skillful assistance in preparation of the manuscript. This study was supported by the U.S. National Cancer Institute (grant NO1-CN53301), the Bulgarian Ministry of Education, Youth and Science (National Science Fund), and the Hasumi International Research Foundation (Bulgaria). NR 54 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD MAR PY 2012 VL 86 IS 3 BP 509 EP 516 DI 10.1007/s00204-011-0765-3 PG 8 WC Toxicology SC Toxicology GA 896NX UT WOS:000300575900016 PM 21989788 ER PT J AU Francischetti, IMB Oliveira, CJ Ostera, GR Yager, SB Debierre-Grockiego, F Carregaro, V Jaramillo-Gutierrez, G Hume, JCC Jiang, LB Moretz, SE Lin, CK Ribeiro, JMC Long, CA Vickers, BK Schwarz, RT Seydel, KB Iacobelli, M Ackerman, HC Srinivasan, P Gomes, RB Wang, XD Monteiro, RQ Kotsyfakis, M Sa-Nunes, A Waisberg, M AF Francischetti, Ivo M. B. Oliveira, Carlo J. Ostera, Graciela R. Yager, Stephanie B. Debierre-Grockiego, Francoise Carregaro, Vanessa Jaramillo-Gutierrez, Giovanna Hume, Jen C. C. Jiang, Lubin Moretz, Samuel E. Lin, Christina K. Ribeiro, Jose M. C. Long, Carole A. Vickers, Brandi K. Schwarz, Ralph T. Seydel, Karl B. Iacobelli, Massimo Ackerman, Hans C. Srinivasan, Prakash Gomes, Regis B. Wang, Xunde Monteiro, Robson Q. Kotsyfakis, Michail Sa-Nunes, Anderson Waisberg, Michael TI Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE anticoagulants; blood coagulation; endothelium; microcirculation; vascular biology ID FALCIPARUM-INFECTED ERYTHROCYTES; FACTOR PATHWAY INHIBITOR; INNATE IMMUNE-RESPONSE; DENDRITIC CELLS; VENOOCCLUSIVE DISEASE; ADENOSINE RECEPTORS; BLOOD-COAGULATION; ENDOTHELIAL-CELLS; IXODES-SCAPULARIS; CEREBRAL MALARIA AB Objective-The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria. Methods and Results-DF blocks tissue factor expression by ECs incubated with parasitized red blood cells and attenuates prothrombinase activity, platelet aggregation, and complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol (Pf-GPI) induces tissue factor expression in ECs and cytokine production by dendritic cells. Notably, dendritic cells, known to modulate coagulation and inflammation systemically, were identified as a novel target for DF. Accordingly, DF inhibits Toll-like receptor ligand-dependent dendritic cells activation by a mechanism that is blocked by adenosine receptor antagonist (8-p-sulfophenyltheophylline) but not reproduced by synthetic poly-A, -C, -T, and -G. These results imply that aptameric sequences and adenosine receptor mediate dendritic cells responses to the drug. DF also prevents rosetting formation, red blood cells invasion by P. falciparum and abolishes oocysts development in Anopheles gambiae. In a murine model of cerebral malaria, DF affected parasitemia, decreased IFN-gamma levels, and ameliorated clinical score (day 5) with a trend for increased survival. Conclusion-Therapeutic use of DF in malaria is proposed. (Arterioscler Thromb Vasc Biol. 2012; 32:786-798.) C1 [Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Oliveira, Carlo J.] Univ Fed Triangulo Mineiro, Inst Ciencias Biol & Nat, Uberaba, Brazil. [Yager, Stephanie B.; Lin, Christina K.; Vickers, Brandi K.; Waisberg, Michael] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Debierre-Grockiego, Francoise; Schwarz, Ralph T.] Univ Marburg, Parasitol Lab, Inst Virol, Marburg, Germany. [Debierre-Grockiego, Francoise] Parasite Immunol Vaccinol & Antiinfect Biotherapy, Tours, France. [Carregaro, Vanessa] Univ Sao Paulo, Dept Farmacol, BR-14049 Ribeirao Preto, Brazil. [Carregaro, Vanessa] Univ Sao Paulo, Dept Imunol, BR-14049 Ribeirao Preto, Brazil. [Hume, Jen C. C.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Schwarz, Ralph T.] Univ Lille Nord France, Unit Struct & Funct Glycobiol, Lille, France. [Seydel, Karl B.] Michigan State Univ, Coll Osteopath Med, Dept Med, E Lansing, MI 48824 USA. [Iacobelli, Massimo] Gentium SpA, Como, Italy. [Wang, Xunde] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Monteiro, Robson Q.] Univ Fed Rio de Janeiro, Inst Bioquim Med, Rio De Janeiro, Brazil. [Kotsyfakis, Michail] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, CR-37005 Ceske Budejovice, Czech Republic. [Sa-Nunes, Anderson] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, BR-05508 Sao Paulo, Brazil. RP Francischetti, IMB (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ifrancischetti@niaid.nih.gov RI Carregaro, Vanessa/D-2913-2012; Sa-Nunes, Anderson/D-8667-2012; Inbeb, Inct/K-2317-2013; Kotsyfakis, Michail/G-9525-2014; Monteiro, Robson/B-8007-2014; Ribeiro, Jose/J-7011-2015; OI Sa-Nunes, Anderson/0000-0002-1859-4973; Kotsyfakis, Michail/0000-0002-7526-1876; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; DFG, Bonn, Germany [SCHW 296/18-2]; Brazilian Malaria Network [MCT/CNPq/MS/SCTIE/DECIT/PRONEX 555648/2009-5]; National Academy of Sciences of the Czech Republic [Z60220518] 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. Ralph T. Schwarz received a grant (SCHW 296/18-2) from DFG, Bonn, Germany. Anderson Sa-Nunes is recipient of grant MCT/CNPq/MS/SCTIE/DECIT/PRONEX 555648/2009-5 from the Brazilian Malaria Network. Michail Kotsyfakis received support from grant number Z60220518 and from a Jan Evangelista Purkyne fellowship of the National Academy of Sciences of the Czech Republic. NR 58 TC 13 Z9 13 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAR PY 2012 VL 32 IS 3 BP 786 EP U575 DI 10.1161/ATVBAHA.111.240291 PG 30 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 897HP UT WOS:000300639300035 PM 22116094 ER PT J AU Scuteri, A Orru', M Morrell, CH Tarasov, K Schlessinger, D Uda, M Lakatta, EG AF Scuteri, Angelo Orru', Marco Morrell, Christopher H. Tarasov, Kirill Schlessinger, David Uda, Manuela Lakatta, Edward G. TI Associations of large artery structure and function with adiposity: Effects of age, gender, and hypertension. The SardiNIA Study SO ATHEROSCLEROSIS LA English DT Article DE Arteries; Arterial stiffness; Carotid intima-media thickness; Obesity; Waist circumference; Population study ID BODY-MASS-INDEX; INTIMA-MEDIA THICKNESS; PULSE-WAVE VELOCITY; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; ABDOMINAL ADIPOSITY; CAROTID-ARTERY; RISK-FACTOR; MYOCARDIAL-INFARCTION; INDEPENDENT PREDICTOR AB In the context of obesity epidemic, no large population study has extensively investigated the relationships between total and abdominal adiposity and large artery structure and function nor have such relationships been examined by gender, by age, by hypertensive status. We investigated these potential relationships in a large cohort of community dwelling volunteers participating the SardiNIA Study. Methods and results: Total and visceral adiposity and arterial properties were assessed in 6148 subjects, aged 14-102 in a cluster of 4 towns in Sardinia, Italy. Arterial stiffness was measured as aortic pulse wave velocity (PWV), arterial thickness and lumen as common carotid artery (CCA) intima-media thickness (IMT) and diameter, respectively. We reported a nonlinear relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter. The association between adiposity and arterial properties was steeper in women than in men, in younger than in older subjects. Waist correlated with arterial properties better than BMI. Within each BMI quartile, increasing waist circumference was associated with further significant changes in arterial structure and function. Conclusion: The relationship between total or abdominal adiposity and arterial aging (PWV and CCA IMT) is not linear as described in the current study. Therefore, BMI- and/or waist-specific reference values for arterial measurements might need to be defined. Published by Elsevier Ireland Ltd. C1 [Scuteri, Angelo; Morrell, Christopher H.; Tarasov, Kirill; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Orru', Marco; Uda, Manuela] Cittadella Univ Monserrato, CNR, INN, I-09042 Cagliari, Italy. [Schlessinger, David] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Morrell, Christopher H.] Loyola Univ Maryland, Baltimore, MD USA. RP Scuteri, A (reprint author), INRCA IRCCS, UOC Geriatria, Via Cassia 1167, I-00189 Rome, Italy. EM angeloelefante@interfree.it FU NIA [NO1-AG-1-2109]; NIH, National Institute on Aging (USA) FX The SardiNIA team was supported by Contract NO1-AG-1-2109 from the NIA.; This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (USA). NR 51 TC 26 Z9 27 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAR PY 2012 VL 221 IS 1 BP 189 EP 197 DI 10.1016/j.atherosclerosis.2011.11.045 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 897EV UT WOS:000300629500028 PM 22222417 ER PT J AU Veeraragavan, S Graham, D Bui, N Yuva-Paylor, LA Wess, J Paylor, R AF Veeraragavan, Surabi Graham, Deanna Bui, Nghiem Yuva-Paylor, Lisa A. Wess, Juergen Paylor, Richard TI Genetic reduction of muscarinic M-4 receptor modulates analgesic response and acoustic startle response in a mouse model of fragile X syndrome (FXS) SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Fragile X syndrome; Muscarinic; M-4 receptors; Analgesic response; Behavior; Sensorimotor gating ID FMR1 KNOCKOUT MICE; SENSORIMOTOR GATING ABNORMALITIES; SERTOLI-CELL PROLIFERATION; BEHAVIORAL-TEST BATTERIES; SELF-INJURIOUS-BEHAVIOR; ACETYLCHOLINE-RECEPTOR; MENTAL-RETARDATION; PREPULSE INHIBITION; TEGMENTAL NUCLEUS; M4 AB Introduction: The G-protein coupled muscarinic acetylcholine receptors, widely expressed in the CNS, have been implicated in fragile X syndrome (FXS). Recent studies have reported an overactive signaling through the muscarinic receptors in the Fmr1KO mouse model. Hence, it was hypothesized that reducing muscarinic signaling might modulate behavioral phenotypes in the Fmr1KO mice. Pharmacological studies from our lab have provided evidence for this hypothesis, with subtype-preferring muscarinic M-1 and M-4 receptor antagonists modulating select behaviors in the Fmr1KO mice. Since the pharmacological antagonists were not highly specific, we investigated the specific role of M-4 receptors in the Fmr1KO mouse model, using a genetic approach. Methods: We created a double mutant heterozygous for the M-4 receptor gene and hemizygous for the Fmr1 gene and examined the mutants on various behaviors. Each animal was tested on a behavior battery comprising of open-field activity (activity), light-dark (anxiety), marble burying (perseverative behavior), prepulse inhibition (sensorimotor gating), rotarod (motor coordination), passive avoidance (learning and memory) and hotplate (analgesia). Animals were also tested on the audiogenic seizure protocol and testis weights were measured. Results: Reduction of M-4 receptor expression in the heterozygotes completely rescued the analgesic response and partly rescued the acoustic startle response phenotype in the Fmr1KO mice. However, no modulation was observed in a number of behaviors including learning and memory, activity, perseverative behavior and audiogenic seizures. Conclusion: Reducing M-4 receptor signaling altered only select behavioral phenotypes in the Fmr1KO mouse model, suggesting that other targets are involved in the modulation of fragile X behaviors. (C) 2011 Elsevier B.V. All rights reserved. C1 [Veeraragavan, Surabi; Graham, Deanna; Bui, Nghiem; Yuva-Paylor, Lisa A.; Paylor, Richard] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Paylor, Richard] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Wess, Juergen] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Paylor, R (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM veerarag@bcm.edu; deannag@bcm.edu; nbui@bcm.edu; lisay@bcm.edu; jwess@helix.nih.gov; rpaylor@bcm.edu FU Baylor Fragile X Center; Baylor College of Medicine Intellectual and Developmental Disabilities Research Center FX This research was supported by the Baylor Fragile X Center and the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center NR 59 TC 20 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 1 PY 2012 VL 228 IS 1 BP 1 EP 8 DI 10.1016/j.bbr.2011.11.018 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 895CA UT WOS:000300472600001 PM 22123412 ER PT J AU Zhou, ZL Yu, PP Geller, HM Ober, CK AF Zhou, Zhaoli Yu, Panpan Geller, Herbert M. Ober, Christopher K. TI The role of hydrogels with tethered acetylcholine functionality on the adhesion and viability of hippocampal neurons and glial cells SO BIOMATERIALS LA English DT Article DE PEG-based hydrogels; Neurotransmitters; Acetylcholine functionality; Concentration-dependent manner ID MEMBRANE-RECEPTORS; NEURITE OUTGROWTH; STEM-CELLS; POLYMER; DIFFERENTIATION; REGENERATION; ATTACHMENT; BEHAVIOR; SCAFFOLD; MODULUS AB In neural tissue engineering, designing materials with the right chemical cues is crucial in providing a permissive microenvironment to encourage and guide neuronal cell attachment and differentiation. Modifying synthetic hydrogels with biologically active molecules has become an increasingly important route in this field to provide a successful biomaterial and cell interaction. This study presents a strategy of using the monomer 2-methacryloxyethyl trimethylammonium chloride (MAETAC) to provide tethered neurotransmitter acetylcholine-like functionality with a complete 2-acetoxy-N,N,N-trimethylethanaminium segment, thereby modifying the properties of commonly used, non-adhesive PEG-based hydrogels. The effect of the functional monomer concentration on the physical properties of the hydrogels was systematically studied, and the resulting hydrogels were also evaluated for mice hippocampal neural cell attachment and growth. Results from this study showed that MAETAC in the hydrogels promotes neuronal cell attachment and differentiation in a concentration-dependent manner, different proportions of MAETAC monomer in the reaction mixture produce hydrogels with different porous structures, swollen states, and mechanical strengths. Growth of mice hippocampal cells cultured on the hydrogels showed differences in number, length of processes and exhibited different survival rates. Our results indicate that chemical composition of the biomaterials is a key factor in neural cell attachment and growth, and integration of the appropriate amount of tethered neurotransmitter functionalities can be a simple and effective way to optimize existing biomaterials for neuronal tissue engineering applications. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Zhou, Zhaoli; Ober, Christopher K.] Cornell Univ, Dept Mat Sci & Engn, Ithaca, NY 14853 USA. [Zhou, Zhaoli; Ober, Christopher K.] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA. [Yu, Panpan; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Ober, CK (reprint author), Cornell Univ, Dept Mat Sci & Engn, Ithaca, NY 14853 USA. EM cko3@cornell.edu RI Yu, Panpan/A-4962-2013; OI Geller, Herbert/0000-0002-7048-6144 FU National Science Foundation Materials Research Science and Engineering Center [DMR-0520404]; NIH [NSR01-044287]; Nanobiotechnology Centre (NBTC); STC of the National Science Foundation [ECS-9876771]; NHLBI Division of Intramural Research FX We would like to acknowledge Dr. Ray Molloy and Professor Manfred Lindau for the initial cell studies. We would also like to acknowledge the use of the Microscopy and Imaging Facility at Cornell University and its facility manager, Carol Bayles, and the use of the electron microscope and the dynamic mechanical analyzer housed in the Cornell Center for Materials Research (CCMR), Shared Experimental Facilities, supported through the National Science Foundation Materials Research Science and Engineering Center Program (DMR-0520404) and the facility managers, John Hunt and Yuanming Zhang. We also acknowledge the assistance of the NHLBI DIR Light Microscopy Core Facility. This work was partially supported by NIH NSR01-044287 and by the Nanobiotechnology Centre (NBTC), an STC program of the National Science Foundation under agreement no. ECS-9876771, as well as the NHLBI Division of Intramural Research (P.Y. and H.M.G). NR 37 TC 14 Z9 14 U1 1 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD MAR PY 2012 VL 33 IS 8 BP 2473 EP 2481 DI 10.1016/j.biomaterials.2011.12.005 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 895AY UT WOS:000300469800007 PM 22196899 ER PT J AU Huang, CY Qin, J Follmann, DA AF Huang, Chiung-Yu Qin, Jing Follmann, Dean A. TI A maximum pseudo-profile likelihood estimator for the Cox model under length-biased sampling SO BIOMETRIKA LA English DT Article DE Approximate likelihood; Cross-sectional sampling; Product-limit estimator; Random truncation; Screening trials ID REGRESSION-MODELS; SURVIVAL-DATA; DURATION; UNEMPLOYMENT; TIMES; AIDS AB This paper considers semiparametric estimation of the Cox proportional hazards model for right-censored and length-biased data arising from prevalent sampling. To exploit the special structure of length-biased sampling, we propose a maximum pseudo-profile likelihood estimator, which can handle time-dependent covariates and is consistent under covariate-dependent censoring. Simulation studies show that the proposed estimator is more efficient than its competitors. A data analysis illustrates the methods and theory. C1 [Huang, Chiung-Yu; Qin, Jing; Follmann, Dean A.] NIAID, Biostatist Res Branch, NIH, Bethesda, MD 20892 USA. RP Huang, CY (reprint author), NIAID, Biostatist Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huangchi@niaid.nih.gov; jingqin@niaid.nih.gov; dfollmann@niaid.nih.gov FU National Health Research and Development Program, Canada; Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada; Bayer Incorporated; British Columbia Health Research Foundation FX The authors thank Professors Ian McDowell, Masoud Asgharian and Christina Wolfson for kindly sharing the Canadian Study of Health and Aging data. The core study was funded by the National Health Research and Development Program, Canada. Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, Bayer Incorporated and the British Columbia Health Research Foundation. The authors also thank the referees, associate editor and editor for their comments which improved the presentation of this article. NR 22 TC 10 Z9 10 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3444 J9 BIOMETRIKA JI Biometrika PD MAR PY 2012 VL 99 IS 1 BP 199 EP 210 DI 10.1093/biomet/asr072 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 898IC UT WOS:000300734400015 ER PT J AU Liu, AY Liu, CL Zhang, ZW Albert, PS AF Liu, Aiyi Liu, Chunling Zhang, Zhiwei Albert, Paul S. TI Optimality of group testing in the presence of misclassification SO BIOMETRIKA LA English DT Article DE Binary outcome; Maximum likelihood estimation; Pooling; Prevalence; Sensitivity; Specificity ID ESTIMATING PREVALENCE; RARE DISEASE; TEST ERROR; PROPORTIONS; HIV; SPECIFICITY; SENSITIVITY; ANTIBODIES; SERA AB Several optimality properties of Dorfman's (1943) group testing procedure are derived for estimation of the prevalence of a rare disease whose status is classified with error. Exact ranges of disease prevalence are obtained for which group testing provides more efficient estimation when group size increases. C1 [Liu, Aiyi; Zhang, Zhiwei; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. [Liu, Chunling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. EM liua@mail.nih.gov; Catherine.Chunling.Liu@inet.polyu.edu.hk; zhangz7@mail.nih.gov; albertp@mail.nih.gov RI Ghartouchent, malek/B-9088-2012; Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. The authors thank the editor, associate editor and two referees for their constructive comments, and Dr Yaakov Malinovsky for helpful discussions. NR 28 TC 11 Z9 11 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3444 EI 1464-3510 J9 BIOMETRIKA JI Biometrika PD MAR PY 2012 VL 99 IS 1 BP 245 EP 251 DI 10.1093/biomet/asr064 PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 898IC UT WOS:000300734400020 ER PT J AU Kim, YS Kumar, V Lee, S Iwai, A Neckers, L Malhotra, SV Trepel, JB AF Kim, Yeong Sang Kumar, Vineet Lee, Sunmin Iwai, Aki Neckers, Len Malhotra, Sanjay V. Trepel, Jane B. TI Methoxychalcone inhibitors of androgen receptor translocation and function SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Chalcone; Antiandrogen; Androgen receptor translocation; Prostate cancer; Hsp90 ID RESISTANT PROSTATE-CANCER; CHALCONES; THERAPIES AB Androgen receptor activity drives incurable castrate-resistant prostate cancer. All approved antiandrogens inhibit androgen receptor-driven transcription, and in addition the second-generation antiandrogen MDV3100 inhibits ligand-activated androgen receptor nuclear translocation, via an unknown mechanism. Here, we report methoxychalcones that lock the heat shock protein 90-androgen receptor complex in the cytoplasm in an androgen-non-responsive state, thus demonstrating a novel chemical scaffold for antiandrogen development and a unique mechanism of antiandrogen activity. Published by Elsevier Ltd. C1 [Kumar, Vineet; Malhotra, Sanjay V.] Natl Canc Inst Frederick, Lab Synthet Chem, Dev Therapeut Program Support, SAIC Frederick, Frederick, MD 21702 USA. [Kim, Yeong Sang; Lee, Sunmin; Trepel, Jane B.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Iwai, Aki; Neckers, Len] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Malhotra, SV (reprint author), Natl Canc Inst Frederick, Lab Synthet Chem, Dev Therapeut Program Support, SAIC Frederick, 1050 Boyles St, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov; trepelj@mail.nih.gov FU NCI, National Institutes of Health; DTP NCI-Frederick SAIC [HSN261200800001E] FX V.K. and S. V. M. would like to thank the National Cancer Institute (NCI) Developmental Therapeutics Program. This project has been funded in whole or in part with federal funds from the NCI, National Institutes of Health, to the Intramural Research Program (Y.S.K., A. I., S. L., L.N., and J.B.T.), and to DTP NCI-Frederick SAIC, under Contract No. HSN261200800001E. 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 25 TC 7 Z9 7 U1 0 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 MAR 1 PY 2012 VL 22 IS 5 BP 2105 EP 2109 DI 10.1016/j.bmcl.2011.12.141 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 894UA UT WOS:000300451200053 PM 22310230 ER PT J AU Yu, BB Tiwari, RC AF Yu, Binbing Tiwari, Ram C. TI A Bayesian approach to mixture cure models with spatial frailties for population-based cancer relative survival data SO CANADIAN JOURNAL OF STATISTICS-REVUE CANADIENNE DE STATISTIQUE LA English DT Article DE Colon cancer; cure fraction; finite mixture models; random effects; relative survival; SEER ID FAILURE TIME MODEL; REGRESSION-MODELS; FRACTION; CHILDHOOD; DEATHS AB As the treatments of cancer progress, a certain number of cancers are curable if diagnosed early. In population-based cancer survival studies, cure is said to occur when mortality rate of the cancer patients returns to the same level as that expected for the general cancer-free population. The estimates of cure fraction are of interest to both cancer patients and health policy makers. Mixture cure models have been widely used because the model is easy to interpret by separating the patients into two distinct groups. Usually parametric models are assumed for the latent distribution for the uncured patients. The estimation of cure fraction from the mixture cure model may be sensitive to misspecification of latent distribution. We propose a Bayesian approach to mixture cure model for population-based cancer survival data, which can be extended to county-level cancer survival data. Instead of modeling the latent distribution by a fixed parametric distribution, we use a finite mixture of the union of the lognormal, loglogistic, and Weibull distributions. The parameters are estimated using the Markov chain Monte Carlo method. Simulation study shows that the Bayesian method using a finite mixture latent distribution provides robust inference of parameter estimates. The proposed Bayesian method is applied to relative survival data for colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the cure fractions. The Canadian Journal of Statistics 40: 4054; 2012 (C) 2012 Statistical Society of Canada C1 [Yu, Binbing] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Tiwari, Ram C.] US FDA, Off Biostat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Yu, BB (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM yubi@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX The authors wish to thank two anonymous reviewers and the Associate Editor for their helpful comments. The views expressed in this article by the author, Dr. Tiwari, are solely his own and do necessarily reflect that of the FDA. Dr. Yu was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. This research utilised the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, Maryland, USA (http://biowulf.nih.gov). NR 36 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0319-5724 J9 CAN J STAT JI Can. J. Stat.-Rev. Can. Stat. PD MAR PY 2012 VL 40 IS 1 BP 40 EP 54 DI 10.1002/cjs.10135 PG 15 WC Statistics & Probability SC Mathematics GA 897PY UT WOS:000300667000003 ER PT J AU Rahma, OE Ashtar, E Czystowska, M Szajnik, ME Wieckowski, E Bernstein, S Herrin, VE Shams, MA Steinberg, SM Merino, M Gooding, W Visus, C DeLeo, AB Wolf, JK Bell, JG Berzofsky, JA Whiteside, TL Khleif, SN AF Rahma, Osama E. Ashtar, Ed Czystowska, Malgorzata Szajnik, Marta E. Wieckowski, Eva Bernstein, Sarah Herrin, Vincent E. Shams, Mortada A. Steinberg, Seth M. Merino, Maria Gooding, William Visus, Carmen DeLeo, Albert B. Wolf, Judith K. Bell, Jeffrey G. Berzofsky, Jay A. Whiteside, Theresa L. Khleif, Samir N. TI A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE p53; IL-2; Ovarian cancer; Cancer vaccine ID COLONY-STIMULATING FACTOR; REGULATORY T-CELLS; ANTITUMOR IMMUNE-RESPONSES; METASTATIC RENAL-CANCER; ADVANCED BREAST-CANCER; MELANOMA PATIENTS; INTRANODAL INJECTION; ANTIGEN PRESENTATION; CTL RESPONSES; IMMUNIZATION AB Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine. Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles. Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively. We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials. C1 [Rahma, Osama E.; Ashtar, Ed; Bernstein, Sarah; Shams, Mortada A.; Berzofsky, Jay A.; Khleif, Samir N.] NCI, Vaccine Branch, CCR, Bethesda, MD 20892 USA. [Czystowska, Malgorzata; Szajnik, Marta E.; Wieckowski, Eva; Gooding, William; Visus, Carmen; DeLeo, Albert B.; Whiteside, Theresa L.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Szajnik, Marta E.] Univ Med Sci, Dept Gynecol Oncol, PL-61107 Poznan, Poland. [Herrin, Vincent E.] Univ Mississippi, Jackson, MS 39216 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, CCR, Rockville, MD USA. [Merino, Maria] NIH, Ctr Clin, Dept Pathol, Bethesda, MD 20892 USA. [Wolf, Judith K.] Univ Texas MD Anderson Canc Ctr, Dept GYN Oncol, Houston, TX 77030 USA. [Bell, Jeffrey G.] Riverside Methodist Hosp, Columbus Canc Council, Div Gynecol Oncol, Columbus, OH 43214 USA. RP Khleif, SN (reprint author), NCI, Vaccine Branch, CCR, 41 Medlars Dr,Bldg 41,Room B624, Bethesda, MD 20892 USA. EM khleif@nih.gov FU National Institute of Health (NIH), National Cancer Institute, Center for Cancer Research; NCI/NIH [P01 CA109688, R01 DE13918]; National Institute [CA27469, CA37517]; NHLBI [HB-37-165] FX Supported in part by the intramural research program of the National Institute of Health (NIH), National Cancer Institute, Center for Cancer Research and by of the NCI/NIH grants P01 CA109688 (TLW) and R01 DE13918 (TLW) as well as National Institute grants to the Gynecologic Oncology Group Administrative Office (CA27469) and the Gynecologic Oncology Group Statistical Office (CA37517). Dr. M. Szajnik is a postdoctoral fellow supported by the NHLBI contract HB-37-165 (TLW). The following member institutions participated in this study: Tacoma General Hospital; MD Anderson Cancer Center; Columbus Cancer Council and the Cleveland Clinic Foundation. NR 47 TC 42 Z9 45 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAR PY 2012 VL 61 IS 3 BP 373 EP 384 DI 10.1007/s00262-011-1100-9 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA 897OC UT WOS:000300659900008 PM 21927947 ER PT J AU Tejeda, HA Shippenberg, TS Henriksson, R AF Tejeda, H. A. Shippenberg, T. S. Henriksson, R. TI The dynorphin/kappa-opioid receptor system and its role in psychiatric disorders SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Dynorphin; kappa-Opioid receptor; Psychiatric disorder; Pharmacology; Neuroanatomy ID MESSENGER-RNA EXPRESSION; CENTRAL-NERVOUS-SYSTEM; RAT NUCLEUS-ACCUMBENS; PRODYNORPHIN GENE-EXPRESSION; CONDITIONED PLACE-PREFERENCE; ELEMENT-BINDING PROTEIN; VENTRAL TEGMENTAL AREA; IN-VIVO MICRODIALYSIS; SPRAGUE-DAWLEY RATS; AMINO-ACID-SEQUENCE AB The dynorphin/kappa-opioid receptor system has been implicated in the pathogenesis and pathophysiology of several psychiatric disorders. In the present review, we present evidence indicating a key role for this system in modulating neurotransmission in brain circuits that subserve mood, motivation, and cognitive function. We overview the pharmacology, signaling, post-translational, post-transcriptional, transcriptional, epigenetic and cis regulation of the dynorphin/kappa-opioid receptor system, and critically review functional neuroanatomical, neurochemical, and pharmacological evidence, suggesting that alterations in this system may contribute to affective disorders, drug addiction, and schizophrenia. We also overview the dynorphin/kappa-opioid receptor system in the genetics of psychiatric disorders and discuss implications of the reviewed material for therapeutics development. C1 [Tejeda, H. A.; Shippenberg, T. S.; Henriksson, R.] NIDA, Integrat Neurosci Sect, Integrat Neurosci Res Branch, IRP,NIH, Baltimore, MD 21224 USA. [Tejeda, H. A.] Univ Maryland, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Henriksson, R.] Karolinska Inst, Dept Clin Neurosci, S-17176 Stockholm, Sweden. RP Shippenberg, TS (reprint author), NIDA, Integrat Neurosci Sect, Integrat Neurosci Res Branch, IRP,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM tshippen@intra.nida.nih.gov FU National Institute on Drug Abuse; National Institute of Mental Health [R01MH083928]; National Science Foundation; Ford Foundation; Meyerhoff Fellowship; Department of Clinical Neuroscience, Karolinska Institutet FX This review was supported by the: (1) Intramural Research Program, National Institute on Drug Abuse; (2) National Institute of Mental Health (R01MH083928); (3) National Science Foundation Graduate Research Fellowship (HAT); (4) Ford Foundation Predoctoral Fellowship (HAT); (5) Meyerhoff Fellowship (HAT); and (6) Department of Clinical Neuroscience, Karolinska Institutet(RH). Special thanks to Dr. Vladimir Chefer for his thoughtful comments on the manuscript. NR 467 TC 52 Z9 54 U1 4 U2 23 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD MAR PY 2012 VL 69 IS 6 BP 857 EP 896 DI 10.1007/s00018-011-0844-x PG 40 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 898IY UT WOS:000300737200002 PM 22002579 ER PT J AU Lee, HK Park, DW Bae, JH Kim, HJ Shin, DG Park, JS Lee, JG Lee, SJ Bae, YS Baek, SH AF Lee, Hyung-Kyoung Park, Dae-Weon Bae, Jun Ho Kim, Hyung Jun Shin, Dong-Gu Park, Jong-Seon Lee, Jin-Gu Lee, Sung Joong Bae, Yoe-Sik Baek, Suk-Hwan TI RGS2 is a negative regulator of STAT3-mediated Nox1 expression SO CELLULAR SIGNALLING LA English DT Article DE RGS2; STAT3; PLD2; PKC-eta; Nox1 ID OXIDASE 1 EXPRESSION; FOAM CELL-FORMATION; TOLL-LIKE RECEPTORS; BLOOD-PRESSURE; ANGIOTENSIN-II; HYPERTENSIVE PATIENTS; NADPH OXIDASES; PROTEINS; LIPOPOLYSACCHARIDE; INFECTION AB NADPH oxidase 1 (Nox1) is essential for reactive oxygen species production in the innate immune responses mediated by toll-like receptor (TLR), but the mechanism regulating its expression remains uncertain. Here, we find that Nox1 induction is TLR2-dependent, but independent of myeloid differentiation primary response gene 88 (MyD88). We demonstrate the capacity of signal transducer and activator of transcription 3 (STAT3) to activate Nox1's transcription, as well as cooperative regulation by Janus kinase 1 and 3 (JAK1 and JAK3). We find that regulator of G-protein signaling 2 (RGS2) inhibits STAT3-mediated Nox1 transcription, and can itself be repressed by TLR2; Nox1 induction upon RGS2 down-regulation is controlled by protein kinase C-eta (PKC-eta) and phospholipase D2 (PLD2). A GFP-tagged version of RGS2 concentrates in the nucleus; RGS2 additionally directly binds STAT3 to regulate its transcriptional activity through TLR2 stimulation. Cumulatively, these results suggest that TLR2 signaling enhances Nox1 expression through the JAK1/3-STAT3 pathway, and that RGS2, through its regulation by the PKC-eta/PLD2 pathway, represses STAT3's transcriptional activation of Nox1. (C) 2011 Published by Elsevier Inc. C1 [Lee, Hyung-Kyoung; Park, Dae-Weon; Baek, Suk-Hwan] Yeungnam Univ, Dept Biochem & Mol Biol, Coll Med, Aging Associated Vasc Dis Res Ctr, Taegu 705802, South Korea. [Bae, Jun Ho; Kim, Hyung Jun; Shin, Dong-Gu; Park, Jong-Seon] Yeungnam Univ, Coll Med, Dept Internal Med, Taegu 705802, South Korea. [Lee, Jin-Gu] NIDDK, Dept Lab Mol Biol, NIH, Bethesda, MD USA. [Lee, Sung Joong] Seoul Natl Univ, Sch Dent, Dept Neurosci, Dent Res Inst, Seoul, South Korea. [Bae, Yoe-Sik] Sungkyunkwan Univ, Dept Biol Sci, Suwon, South Korea. RP Baek, SH (reprint author), Yeungnam Univ, Dept Biochem & Mol Biol, Coll Med, Aging Associated Vasc Dis Res Ctr, 210 Main Bldg,317-1 Daemyung 5 Dong, Taegu 705802, South Korea. EM sbaek@med.yu.ac.kr FU Korean Science and Engineering Foundation (KOSEF); Korea government (MEST) [2011-0006181] FX This work was supported by the Korean Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (2011-0006181). NR 39 TC 7 Z9 7 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD MAR PY 2012 VL 24 IS 3 BP 803 EP 809 DI 10.1016/j.cellsig.2011.11.015 PG 7 WC Cell Biology SC Cell Biology GA 895EG UT WOS:000300478400024 PM 22120521 ER PT J AU Fessler, MB AF Fessler, M. B. TI Next stop for HDL: the lung SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Editorial Material ID ASTHMA; CHOLESTEROL; HYPERRESPONSIVENESS; LIPOPROTEINS; CHILDREN; CELLS C1 Natl Inst Environm Hlth Sci, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Fessler, MB (reprint author), Natl Inst Environm Hlth Sci, Lab Resp Biol, NIH, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102005-06]; NIEHS NIH HHS [Z01 ES102005] NR 22 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD MAR PY 2012 VL 42 IS 3 BP 340 EP 342 DI 10.1111/j.1365-2222.2011.03942.x PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 897TX UT WOS:000300681600001 PM 22356140 ER PT J AU Baggott, MJ Li, L Galloway, GP Scheidweiler, KB Barnes, AJ Huestis, MA Mendelson, J AF Baggott, M. J. Li, L. Galloway, G. P. Scheidweiler, K. B. Barnes, A. J. Huestis, M. A. Mendelson, J. TI PHARMACOKINETICS OF ORAL 3,4-METHYLENEDIOXYAMPHETAMINE IN HUMANS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Baggott, M. J.; Li, L.; Galloway, G. P.; Mendelson, J.] CPMCRI, San Francisco, CA USA. [Scheidweiler, K. B.; Barnes, A. J.; Huestis, M. A.] NIDA Intramural, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S135 EP S135 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900361 ER PT J AU Cheang, KI Xu, X Veenstra, TD Nestler, JE AF Cheang, K. I. Xu, X. Veenstra, T. D. Nestler, J. E. TI ESTRADIOL METABOLITES AND CHANGES IN INSULIN SENSITIVITY DURING ORAL CONTRACEPTIVE USE SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Cheang, K. I.; Nestler, J. E.] Virginia Commonwealth Univ, Richmond, VA USA. [Xu, X.; Veenstra, T. D.] NCI, Frederick, MD 21701 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S25 EP S25 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900064 ER PT J AU Gong, SL Tai, W Tsunoda, SM Greenberg, HE Gorski, JC Penzak, SR Stoch, SA Ma, JD AF Gong, S. L. Tai, W. Tsunoda, S. M. Greenberg, H. E. Gorski, J. C. Penzak, S. R. Stoch, S. A. Ma, J. D. TI ORAL MIDAZOLAM (MDZ) PARTIAL AREA-UNDER CURVE (AUC) DOES NOT RELIABLY PREDICT CYTOCHROME P450 (CYP) 3A BASELINE ACTIVITY IN HEALTHY SUBJECTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Gong, S. L.; Tai, W.; Tsunoda, S. M.; Ma, J. D.] UCSD, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA USA. [Greenberg, H. E.] Thomas Jefferson Univ, Dept Pharmacol & Expt Therapeut, Philadelphia, PA 19107 USA. [Gorski, J. C.] Mylan Pharmaceut, Morgantown, WV USA. [Penzak, S. R.] NIH, Dept Pharm, Bethesda, MD 20892 USA. [Stoch, S. A.] Merck, Rahway, NJ 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S42 EP S43 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900110 ER PT J AU Iyer, LV Ramamoorthy, A Furimsky, AM Tang, L Catz, P Green, CE Wainer, IW AF Iyer, L. V. Ramamoorthy, A. Furimsky, A. M. Tang, L. Catz, P. Green, C. E. Wainer, I. W. TI STEREOSELECTIVE CONJUGATION OF 4 '-METHOXYFENOTEROL STEREOISOMERS BY SULFOTRANSFERASES. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Iyer, L. V.; Furimsky, A. M.; Tang, L.; Catz, P.; Green, C. E.] SRI Int, Menlo Pk, CA USA. [Ramamoorthy, A.; Wainer, I. W.] NIA, Baltimore, MD 21224 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S19 EP S19 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900049 ER PT J AU Moaddel, R Rosenberg, A Abdrakhmanova, G Jozwiak, K Ramamoorthy, A Wainer, IW AF Moaddel, R. Rosenberg, A. Abdrakhmanova, G. Jozwiak, K. Ramamoorthy, A. Wainer, I. W. TI KETAMINE AND METABOLITES SUBTYPE SELECTIVITY IN THE NICOTINIC RECEPTOR FAMILY. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Moaddel, R.; Rosenberg, A.; Ramamoorthy, A.; Wainer, I. W.] NIA, NIH, Baltimore, MD 21224 USA. [Abdrakhmanova, G.] Virginia Commonwealth Univ, Richmond, VA USA. [Jozwiak, K.] Med Univ Lublin, Lublin, Poland. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S15 EP S16 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900038 ER PT J AU Momary, KM Jann, M Spratlin, V Zhang, H Turner, D Penzak, S Wright, A VanDenBerg, C AF Momary, K. M. Jann, M. Spratlin, V. Zhang, H. Turner, D. Penzak, S. Wright, A. VanDenBerg, C. TI LACK OF EFFECT OF ABCB1 GENOTYPE ON THE DRUG-DRUG INTERACTIONS BETWEEN INDINAVIR AND VENLAFAXINE EXTENDED-RELEASE OR DESVENLAFAXINE EXTENDED-RELEASE. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Momary, K. M.; Jann, M.; Spratlin, V.; Zhang, H.; Turner, D.; Wright, A.; VanDenBerg, C.] Mercer Univ, Coll Pharm & Hlth Sci, Atlanta, GA USA. [Penzak, S.] NIH, Clin Pharmacokinet Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S120 EP S121 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900320 ER PT J AU Ramamoorthy, A Van Wart, S de Cabo, R Mager, D Wainer, I AF Ramamoorthy, A. Van Wart, S. de Cabo, R. Mager, D. Wainer, I. TI POPULATION PHARMACOKINETIC ANALYSIS OF (R)- AND (S)-KETAMINE AND NORKETAMINE IN RATS ON AD LIB AND CALORIE RESTRICTED DIETS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Ramamoorthy, A.; de Cabo, R.; Wainer, I.] NIA, NIH, Baltimore, MD 21224 USA. [Van Wart, S.; Mager, D.] SUNY Buffalo, Buffalo, NY 14260 USA. RI de Cabo, Rafael/J-5230-2016 OI de Cabo, Rafael/0000-0002-3354-2442 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S26 EP S27 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900068 ER PT J AU Sanghvi, M Moaddel, R OLoughlin, K Green, C Ramamoorthy, A Wainer, I AF Sanghvi, M. Moaddel, R. OLoughlin, K. Green, C. Ramamoorthy, A. Wainer, I. TI DETERMINATION OF KETAMINE AND ITS DOWNSTREAM METABOLITES IN PLASMA AND BRAIN OF WISTAR RATS SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Sanghvi, M.; Moaddel, R.; Ramamoorthy, A.; Wainer, I.] NIA, NIH, Baltimore, MD 21224 USA. [OLoughlin, K.; Green, C.] SRI Int, Menlo Pk, CA 94025 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S27 EP S27 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900069 ER PT J AU Singh, NS Paul, RK Sichler, M Moaddel, R Bernier, M Wainer, IW Ramamoorthy, A AF Singh, N. S. Paul, R. K. Sichler, M. Moaddel, R. Bernier, M. Wainer, I. W. Ramamoorthy, A. TI CAPILLARY ELECTROPHORESIS-LASER INDUCED FLUORESCENCE (CE-LIF) ASSAY FOR MEASUREMENT OF INTRA-CELLULAR D-SERINE AND SERINE RACEMASE ACTIVITY. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Singh, N. S.; Paul, R. K.; Sichler, M.; Moaddel, R.; Bernier, M.; Wainer, I. W.; Ramamoorthy, A.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S15 EP S15 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900037 ER PT J AU Stangl, BL Zametkin, M Vatsalya, V Ramchandani, VA AF Stangl, B. L. Zametkin, M. Vatsalya, V. Ramchandani, V. A. TI CHARACTERIZATION OF OPERANT INTRAVENOUS (IV) ETHANOL SELF-ADMINISTRATION IN HUMANS: OPEN-BAR AND PROGRESSIVE-RATIO PARADIGMS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Stangl, B. L.; Zametkin, M.; Vatsalya, V.; Ramchandani, V. A.] NIAAA, 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S56 EP S56 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900146 ER PT J AU Tai, W Gong, SL Tsunoda, SM Greenberg, HE Gorski, JC Penzak, SR Stoch, SA Ma, JD AF Tai, W. Gong, S. L. Tsunoda, S. M. Greenberg, H. E. Gorski, J. C. Penzak, S. R. Stoch, S. A. Ma, J. D. TI ORAL MIDAZOLAM (MDZ) PARTIAL AREA-UNDER CURVE (AUC) DOES NOT RELIABLY PREDICT CYTOCHROME P450 (CYP) 3A BASELINE ACTIVITY IN HEALTHY SUBJECTS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Tai, W.; Gong, S. L.; Tsunoda, S. M.; Ma, J. D.] UCSD, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA USA. [Greenberg, H. E.] Thomas Jefferson Univ, Dept Pharmacol & Expt Therapeut, Philadelphia, PA 19107 USA. [Gorski, J. C.] Mylan Pharmaceut, Morgantown, WV USA. [Penzak, S. R.] NIH, Dept Pharm, Bethesda, MD 20892 USA. [Stoch, S. A.] Merck, Rahway, NJ 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S42 EP S42 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900109 ER PT J AU Vatsalya, V Stangl, B Zametkin, M Ramchandani, VA AF Vatsalya, V. Stangl, B. Zametkin, M. Ramchandani, V. A. TI SKIN BLOOD FLOW (SBF) RESPONSE FOLLOWING ACUTE INTRAVENOUS (IV) ETHANOL AND ASSOCIATION WITH SUBJECTIVE RESPONSES IN SOCIAL DRINKERS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 113th Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 14-17, 2012 CL Natl Harbor, MD SP Amer Soc Clin Pharmacol & Therapeut (ASCPT) C1 [Vatsalya, V.; Stangl, B.; Zametkin, M.; Ramchandani, V. A.] NIAAA, NIH, 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2012 VL 91 SU 1 BP S128 EP S128 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 895VN UT WOS:000300524900340 ER PT J AU Li Bassi, G Saucedo, L Marti, JD Rigol, M Esperatti, M Luque, N Ferrer, M Gabarrus, A Fernandez, L Kolobow, T Torres, A AF Li Bassi, Gianluigi Saucedo, Lina Marti, Joan-Daniel Rigol, Montserrat Esperatti, Mariano Luque, Nestor Ferrer, Miguel Gabarrus, Albert Fernandez, Laia Kolobow, Theodor Torres, Antoni TI Effects of duty cycle and positive end-expiratory pressure on mucus clearance during mechanical ventilation SO CRITICAL CARE MEDICINE LA English DT Article DE intensive care; intrinsic positive end-expiratory pressure; mechanical ventilation; mucociliary clearance; peak expiratory flow rate; positive end-expiratory pressure ID LIQUID FLOW MECHANISM; RESPIRATORY MECHANICS; CHEST PHYSIOTHERAPY; CYSTIC-FIBROSIS; TRANSPORT; AIRWAYS; MODEL AB Objectives: During mechanical ventilation, air flows may play a role in mucus transport via two-phase gas liquid flow. The aim of this study was to evaluate effects of duty cycles and positive end-expiratory pressure on mucus clearance in pigs using mechanical ventilation, and to assess their safety. Design: Prospective randomized animal study. Setting: Animal research facility, University of Barcelona, Spain. Subjects: Eight healthy pigs. Interventions: Pigs were intubated and on volume-control mechanical ventilation for up to 84 hrs. After 4, 24, 48, and 72 hrs of mechanical ventilation, six levels of duty cycle (0.26, 0.33, 0.41, 0.50, 0.60, and 0.75) with no associated positive end-expiratory pressure or 5 cm H2O of positive end-expiratory pressure were randomly applied. Surgical bed was oriented 30 degrees in the reverse Trendelenburg position, as in the semirecumbent position. Measurement and Main Results: Inspiratory and expiratory flows and hemodynamics were measured after each 30-min ventilation period. Mucus movement was assessed through fluoroscopy tracking of radio-opaque markers. Mucus velocity was described by a positive vector (toward the glottis) or negative vector (toward the lungs). No effect of positive end-expiratory pressure was found; however, as duty cycle was increasingly prolonged, a trend toward reduced velocity of mucus moving toward the lungs and increased outward mucus velocity was found (p = .064). Two clusters of mucus velocities were identified as duty cycle was prolonged beyond 0.41. Thus, duty cycle >0.41 increased mean expiratory inspiratory flow bias from -4.1 +/- 4.6 to 7.9 +/- 5.9 L/min (p < .0001) and promoted outward mucus velocity from -0.22 +/- 1.71 mm/min (range, -5.78 to 2.42) to 0.53 +/- 1.06 mm/min (-1.91 to 3.88; p = .0048). Duty cycle of 0.75 resulted in intrinsic positive end-expiratory pressure (2.1 +/- 1.1 cm H2O [p < .0001] vs. duty cycle 0.26-0.5), with no hemodynamic compromise. Conclusions: In the semirecumbent position, mucus clearance is improved with prolongation of the duty cycle. However, in clinical practice, positive findings must be balanced against the potentially adverse hemodynamic and respiratory effects. (Crit Care Med 2012; 40:895-902) C1 [Gabarrus, Albert; Torres, Antoni] Hosp Clin Barcelona, Thorax Inst, Dept Pneumol, Off Biostat, Barcelona, Spain. [Li Bassi, Gianluigi; Rigol, Montserrat; Ferrer, Miguel; Fernandez, Laia; Torres, Antoni] Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain. [Li Bassi, Gianluigi; Rigol, Montserrat; Esperatti, Mariano; Ferrer, Miguel; Gabarrus, Albert; Fernandez, Laia; Torres, Antoni] Ctr Invest Biomed Red Enfermedades Resp, Barcelona, Spain. [Rigol, Montserrat] Hosp Clin Barcelona, Thorax Inst, Dept Cardiol, Barcelona, Spain. [Kolobow, Theodor] NHLBI, Pulm & Crit Care Med Branch, Sect Pulm & Cardiac Assist Devices, NIH, Bethesda, MD 20892 USA. [Torres, Antoni] Univ Barcelona, Barcelona, Spain. RP Torres, A (reprint author), Hosp Clin Barcelona, Thorax Inst, Dept Pneumol, Off Biostat, Barcelona, Spain. EM atorres@clinic.ub.es FU Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Ministerio de Ciencia e Innovacion [PS09/01249]; European Society of Intensive Care Medicine- ESICM; Fundacio Catalana de Pneumologia (FUCAP); Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR); Centro de Investigacion Biomedica En Red- Enfermedades Respiratorias, (CIBERES); HERACLES [RD06/0009/0008] FX Supported, in part, by the Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Ministerio de Ciencia e Innovacion (PS09/01249); European Society of Intensive Care Medicine- ESICM (2009 Alain Hart Award on Applied Respiratory Physiology); Fundacio Catalana de Pneumologia (FUCAP); Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR); and Centro de Investigacion Biomedica En Red- Enfermedades Respiratorias, (CIBERES); and HERACLES, RD06/0009/0008. NR 20 TC 11 Z9 11 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2012 VL 40 IS 3 BP 895 EP 902 DI 10.1097/CCM.00013e318236efb5 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 895YO UT WOS:000300532800025 PM 22080638 ER PT J AU Ackerman, HC Carroll, RW Casals-Pascual, C AF Ackerman, Hans C. Carroll, Ryan W. Casals-Pascual, Climent TI A better biomarker for cerebral malaria: In the eye of the beheld? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE angiopoietin; biomarker; cerebral malaria; endothelium; malaria; nitric oxide; retinopathy; sensitivity; specificity ID FALCIPARUM-MALARIA; AFRICAN CHILDREN; NITRIC-OXIDE; ANGIOPOIETIN-2; INDICATORS; LIGAND; TIE2 C1 [Ackerman, Hans C.] NIAID, Lab Malaria & Vector Res, Rockville, MD 20892 USA. [Carroll, Ryan W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pediat Crit Care Med, Boston, MA USA. [Carroll, Ryan W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Anesthesiol Ctr Crit Care Res, Boston, MA USA. [Casals-Pascual, Climent] Wellcome Trust Ctr Human Genet, Oxford, England. RP Ackerman, HC (reprint author), NIAID, Lab Malaria & Vector Res, Rockville, MD 20892 USA. FU Intramural NIH HHS [ZIA AI001150-02]; Medical Research Council [G0701885] NR 18 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2012 VL 40 IS 3 BP 1018 EP 1020 DI 10.1097/CCM.0b013e31823d7810 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 895YO UT WOS:000300532800063 PM 22343865 ER PT J AU Beigel, JH Luke, TC AF Beigel, John H. Luke, Thomas C. TI A study in scarlet-convalescent plasma for severe influenza SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE convalescent; H1N1; H5N1; influenza; passive immunotherapy; plasma; treatment ID H1N1 VIRUS-INFECTION; OSELTAMIVIR; RESISTANT; THERAPY; CANADA C1 [Beigel, John H.] NIAID, Div Intramural Res, SAIC Frederick Inc, NCI Frederick, Frederick, MD 21701 USA. [Luke, Thomas C.] USN, Med Res Ctr, Henry Jackson Fdn, Virol & Rickettsial Dis Div, Silver Spring, MD USA. RP Beigel, JH (reprint author), NIAID, Div Intramural Res, SAIC Frederick Inc, NCI Frederick, Frederick, MD 21701 USA. FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [Z99 AI999999]; NCI NIH HHS [HHSN261200800001E] NR 14 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2012 VL 40 IS 3 BP 1027 EP 1028 DI 10.1097/CCM.0b013e31823d77c3 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 895YO UT WOS:000300532800069 PM 22343871 ER PT J AU Degheidy, HA Venzon, DJ Farooqui, MZH Abbasi, F Arthur, DC Wilson, WH Wiestner, A Stetler-Stevenson, MA Marti, GE AF Degheidy, Heba A. Venzon, David J. Farooqui, Mohammed Z. H. Abbasi, Fatima Arthur, Diane C. Wilson, Wyndham H. Wiestner, Adrian Stetler-Stevenson, M. A. Marti, Gerald E. TI Combined normal donor and CLL: Single tube ZAP-70 analysis SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE chronic lymphocytic leukemia; ZAP-70; flow cytometry; one tube assay; IGHV; cytogenetics ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GENE MUTATION STATUS; GENOMIC ABERRATIONS; PROGNOSTIC-FACTORS; CD38 EXPRESSION; DIAGNOSIS; SURVIVAL; RATIO AB Introduction: Zeta-chain-associated protein kinase 70 (ZAP-70) has been identified as an independent prognostic marker in chronic lymphocytic leukemia (CLL). Based on our previous studies, we have developed a combined one-tube technology with multiple internal controls to optimize ZAP-70 assessment. Methods: Forty-eight untreated CLL cases were examined for ZAP-70 expression using a modified 7-color one-tube assay. Normal donor (ND) whole blood is stained with CD3 APC-Cy7 and CD19 APC. In a second tube, patient whole blood is stained with CD5 PE-Cy7, CD19 PerCP-Cy5.5, and CD20 eFluor450. After surface staining and fixation, these two tubes are combined. After saponin permeabilization, the cells were stained with two anti-ZAP-70 clones (1E7.2/AF488 and SBZAP/PE). The results obtained from this modified tube were compared with those obtained concurrently using the non-mixed single sample tubes. Five different methods of ZAP-70 expression analysis were evaluated: percentage positive cells using ND T-cells as a reference; the internal patient T-cell/clone ratio; ND T-cell/clone ratio; clone/ND B-cell ratio; and modified Z-index. Result: Overall, the combined patient and ND mix tube performed better than the non-mixed single sample tube. The strongest correlations between ZAP-70 expression and immunoglobulin heavy chain variable (IGHV) mutational status were seen with percentage positive ND T-cell, ND T-cell/clone ratio, and clone/ND B-cell ratio for both 1E7.2 and SBZAP clone (P < 0.0001). Conclusion: The modified one tube method combining the ND and patient sample provides highly reliable results that correlate with the IGHV mutational status. This method should be considered as part of the next step in standardization of the ZAP-70 assay in CLL. Published 2011 Wiley Periodicals, Inc.(dagger) C1 [Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. [Arthur, Diane C.; Stetler-Stevenson, M. A.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Degheidy, Heba A.; Abbasi, Fatima; Marti, Gerald E.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Marti, GE (reprint author), OIVD DIHD CDRH, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM gemarti@mac.com FU NHLBI; NIH; CBER/FDA FX Grant sponsor: Intramural Research Program of the NHLBI, NIH and CBER/FDA. NR 21 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2012 VL 82B IS 2 BP 67 EP 77 DI 10.1002/cyto.b.20622 PG 11 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 897WT UT WOS:000300692000003 PM 22031337 ER PT J AU Chitnis, AB Nogare, DD Matsuda, M AF Chitnis, Ajay B. Nogare, Damian Dalle Matsuda, Miho TI Building the posterior lateral line system in zebrafish SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Review DE lateral line; zebrafish; pattern formation; self-organization; neuromasts ID COLLECTIVE CELL-MIGRATION; CHEMOKINE RECEPTOR CXCR4; HAIR-CELLS; DANIO-RERIO; POSTEMBRYONIC DEVELOPMENT; APICAL CONSTRICTION; WNT/BETA-CATENIN; TISSUE MIGRATION; LARVAL ZEBRAFISH; BETA-ARRESTIN AB The posterior lateral line (pLL) in zebrafish has emerged as an excellent system to study how a sensory organ system develops. Here we review recent studies that illustrate how interactions between multiple signaling pathways coordinate cell fate, morphogenesis, and collective migration of cells in the posterior lateral line primordium. These studies also illustrate how the pLL system is contributing much more broadly to our understanding of mechanisms operating during the growth, regeneration, and self-organization of other organ systems during development and disease. (c) 2011 Wiley Periodicals, Inc. Develop Neurobiol 72: 234255, 2012 C1 [Chitnis, Ajay B.; Nogare, Damian Dalle; Matsuda, Miho] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Dev, NIH, Bethesda, MD USA. RP Chitnis, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Dev, NIH, Bethesda, MD USA. EM chitnisa@mail.nih.gov FU Intramural NIH HHS [ZIA HD001012-14]; NICHD NIH HHS [R00 HD062561] NR 97 TC 35 Z9 35 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1932-8451 J9 DEV NEUROBIOL JI Dev. Neurobiol. PD MAR PY 2012 VL 72 IS 3 SI SI BP 234 EP 255 DI 10.1002/dneu.20962 PG 22 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 894MA UT WOS:000300429600003 PM 21818862 ER PT J AU Rosell, M Hondares, E Iwamoto, S Gonzalez, FJ Wabitsch, M Staels, B Olmos, Y Monsalve, M Giralt, M Iglesias, R Villarroya, F AF Rosell, Meritxell Hondares, Elayne Iwamoto, Sadahiko Gonzalez, Frank J. Wabitsch, Martin Staels, Bart Olmos, Yolanda Monsalve, Maria Giralt, Marta Iglesias, Roser Villarroya, Francesc TI Peroxisome Proliferator-Activated Receptors-alpha and -gamma, and cAMP-Mediated Pathways, Control Retinol-Binding Protein-4 Gene Expression in Brown Adipose Tissue SO ENDOCRINOLOGY LA English DT Article ID INSULIN-RESISTANCE; PPAR-ALPHA; RETINOL-BINDING-PROTEIN-4 PRODUCTION; SERUM RETINOL-BINDING-PROTEIN-4; DIABETIC SUBJECTS; ACID; TRANSCRIPTION; FAT; DIFFERENTIATION; CELL AB Retinol binding protein-4 (RBP4) is a serum protein involved in the transport of vitamin A. It is known to be produced by the liver and white adipose tissue. RBP4 release by white fat has been proposed to induce insulin resistance. We analyzed the regulation and production of RBP4 in brown adipose tissue. RBP4 gene expression is induced in brown fat from mice exposed to cold or treated with peroxisome proliferator-activated receptor(PPAR) agonists. In brown adipocytes in culture, norepinephrine, cAMP, and activators of PPAR gamma and PPAR alpha induced RBP4 gene expression and RBP4 protein release. The induction of RBP4 gene expression by norepinephrine required intact PPAR-dependent pathways, as evidenced by impaired response of the RBP4 gene expression to norepinephrine in PPAR alpha-null brown adipocytes or in the presence of inhibitors of PPAR gamma and PPAR alpha. PPAR gamma and norepinephrine can also induce the RBP4 gene in white adipocytes, and over expression of PPAR alpha confers regulation by this PPAR subtype to white adipocytes. The RBP4 gene promoter transcription is activated by cAMP, PPAR alpha, and PPAR gamma. This is mediated by a PPAR-responsive element capable of binding PPAR alpha and PPAR gamma and required also for activation by cAMP. The induction of the RBP4 gene expression by norepinephrine in brown adipocytes is protein synthesis dependent and requires PPAR gamma-coactivator-1-alpha, which acts as a norepinephine-induced coactivator of PPAR on the RBP4 gene. We conclude that PPAR gamma- and PPAR alpha-mediated signaling controls RBP4 gene expression and releases in brown adipose tissue, and thermogenic activation induces RBP4 gene expression in brown fat through mechanisms involving PPAR gamma-coactivator-1-alpha coactivation of PPAR signaling. (Endocrinology 153: 1162-1173, 2012) C1 [Rosell, Meritxell; Hondares, Elayne; Giralt, Marta; Iglesias, Roser; Villarroya, Francesc] Univ Barcelona, Dept Bioquim & Biol Mol, Inst Biomed, E-08028 Barcelona, Spain. Ctr Invest Biomed Red Fisiopatol Obesidad & Nutr, E-08028 Barcelona, Spain. [Iwamoto, Sadahiko] Jichi Med Univ, Div Human Genet, Shimotsuke, Tochigi 3290498, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. [Wabitsch, Martin] Univ Ulm, Dept Pediat & Adolescent Med, D-89075 Ulm, Germany. [Staels, Bart] Univ Lille Nord France, INSERM, U1011, Inst Pasteur Lille, F-59019 Lille, France. [Olmos, Yolanda; Monsalve, Maria] Inst Salud Carlos III, Ctr Nacl Invest Cardiovasc, Madrid 28029, Spain. Consejo Super Invest Cient, Inst Invest Biomed Alberto Sols, Madrid 28029, Spain. RP Villarroya, F (reprint author), Univ Barcelona, Dept Bioquim & Biol Mol, Inst Biomed, Avinguda Diagonal 643, E-08028 Barcelona, Spain. EM fvillarroya@ub.edu RI Giralt, Marta/A-4756-2013; Villarroya, Francesc/K-4357-2014; OI Giralt, Marta/0000-0001-7968-4190; Staels, Bart/0000-0002-3784-1503 FU Ministerio de Ciencia e Innovacion [SAF2008-01896, SAF2011-23636]; Fondo de Investigaciones Sanitarias, Spain [PI081715]; European Union [HEALTH-F2-2011-277713] FX This work was supported by the Ministerio de Ciencia e Innovacion Grant SAF2008-01896, SAF2011-23636 and Fondo de Investigaciones Sanitarias Grant PI081715, Spain. Centro de Investigacion Biomedica en Red Fisiopatologia de la Obesidad y Nutricion is an initiative of Instituto de Salud Carlos III Spain, and Grant HEALTH-F2-2011-277713 by the European Union. NR 45 TC 15 Z9 15 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2012 VL 153 IS 3 BP 1162 EP 1173 DI 10.1210/en.2011-1367 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 897JG UT WOS:000300645600022 PM 22253419 ER PT J AU Pang, XY Cheng, J Kim, JH Matsubara, T Krausz, KW Gonzalez, FJ AF Pang, Xiao-Yan Cheng, Jie Kim, Jung-Hwan Matsubara, Tsutomu Krausz, Kristopher W. Gonzalez, Frank J. TI Expression and Regulation of Human Fetal-Specific CYP3A7 in Mice SO ENDOCRINOLOGY LA English DT Article ID PREGNANE X-RECEPTOR; ADULT HUMAN LIVER; DEHYDROEPIANDROSTERONE-SULFATE; CYTOCHROMES P450; PRIMARY CULTURE; GENE; HEPATOCYTES; INDUCTION; ELEMENT; MOUSE AB CYP3A7 is the predominant cytochrome P450 (CYP) expressed in human fetal liver, accounting for 30-50% of the total CYP in fetal liver and 87-100% of total fetal hepatic CYP3A content. However, the lack of a rodent model limits the investigation of CYP3A7 regulation and function. Hence, double-transgenic mice expressing human pregnane X receptor (PXR) and CYP3A4/7 (Tg3A4/7-hPXR) were used to investigate the regulation and function of CYP3A7. Expression of CYP3A7 was monitored in mice that ranged in age from 14.5-d-old embryos to 8.5-d-old newborns; expression of CYP3A7 mRNA was increased before birth in the embryos and decreased after birth in the newborns. This is consistent with the observed developmental regulation of CYP3A7 protein levels and CYP3A7-mediated dehydroepiandrosterone 16 alpha-hydroxylase activities. This developmental flux is also in agreement with previous studies that have investigated the expression of CYP3A7 in developing human liver. The regulation of CYP3A7 was further studied using hepatoblasts from the Tg3A4/7-hPXR mice. Glucocorticoids, including dexamethasone, cortisol, corticosterone, and cortisone all induced the expression of CYP3A7 mRNA, whereas rifampicin, an activator of PXR and an inducer of CYP3A4 in adult liver, had no effect on CYP3A7 expression. Cell-based promoter luciferase and chromatin immunoprecipitation assays further confirmed glucocorticoid receptor-mediated control of the CYP3A7 promoter. These findings indicate that CYP3A7 is developmentally regulated in mouse liver primarily by glucocorticoids through the glucocorticoid receptor. The Tg3A4/7-hPXR mouse model could therefore potentially serve as a tool for investigating CYP3A7 regulation and function. (Endocrinology 153: 1453-1463, 2012) C1 [Pang, Xiao-Yan; Cheng, Jie; Kim, Jung-Hwan; Matsubara, Tsutomu; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov FU National Cancer Institute; China Scholarship Council FX This work was supported by the National Cancer Institute Intramural Research Program. X.-Y.P. was partially supported by a fellowship from China Scholarship Council. We thank Caroline H. Johnson for careful review of the manuscript, and John Buckley and Linda G Byrd for assistance with the mouse studies. NR 41 TC 10 Z9 11 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2012 VL 153 IS 3 BP 1453 EP 1463 DI 10.1210/en.2011-1020 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 897JG UT WOS:000300645600048 PM 22253426 ER PT J AU Cordas, EA Ng, L Hernandez, A Kaneshige, M Cheng, SY Forrest, D AF Cordas, Emily A. Ng, Lily Hernandez, Arturo Kaneshige, Masahiro Cheng, Sheue-Yann Forrest, Douglas TI Thyroid Hormone Receptors Control Developmental Maturation of the Middle Ear and the Size of the Ossicular Bones SO ENDOCRINOLOGY LA English DT Article ID CONDUCTIVE HEARING-LOSS; OTITIS-MEDIA; CONGENITAL HYPOTHYROIDISM; STRUCTURAL MATURATION; EARLY HYPOPHYSECTOMY; TEMPORAL BONES; NULL MICE; MESENCHYME; MUTATION; RESISTANCE AB Thyroid hormone is critical for auditory development and has well-known actions in the inner ear. However, less is known of thyroid hormone functions in the middle ear, which contains the ossicles (malleus, incus, stapes) that relay mechanical sound vibrations from the outer ear to the inner ear. During the later stages of middle ear development, prior to the onset of hearing, middle ear cavitation occurs, involving clearance of mesenchyme from the middle ear cavity while the immature cartilaginous ossicles attain appropriate size and ossify. Using in situ hybridization, we detected expression of Thra and Thrb genes encoding thyroid hormone receptors alpha 1 and beta (TR alpha 1 and TR beta, respectively) in the immature ossicles, surrounding mesenchyme and tympanic membrane in the mouse. Thra(+/PV) mice that express a dominant-negative TR alpha 1 protein exhibited deafness with elevated auditory thresholds and a range of middle ear abnormalities including chronic persistence of mesenchyme in the middle ear into adulthood, markedly enlarged ossicles, and delayed ossification of the ossicles. Congenitally hypothyroid Tshr(-/-) mice and TR-deficient Thra1(-/-); Thrb(-/-) mice displayed similar abnormalities. These findings demonstrate that middle ear maturation is TR dependent and suggest that the middle ear is a sensitive target for thyroid hormone in development. (Endocrinology 153: 1548-1560, 2012) C1 [Forrest, Douglas] NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Kaneshige, Masahiro; Cheng, Sheue-Yann] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Hernandez, Arturo] Dartmouth Med Sch, Dept Physiol, Lebanon, NH 03756 USA. RP Forrest, D (reprint author), NIDDKD, Lab Endocrinol & Receptor Biol, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU National Institutes of Health at the National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute FX This work was supported by the intramural research program of the National Institutes of Health at the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. NR 60 TC 12 Z9 12 U1 0 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2012 VL 153 IS 3 BP 1548 EP 1560 DI 10.1210/en.2011-1834 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 897JG UT WOS:000300645600057 PM 22253431 ER PT J AU Chambers, SK Girgis, A Occhipinti, S Hutchison, S Turner, J Morris, B Dunn, J AF Chambers, S. K. Girgis, A. Occhipinti, S. Hutchison, S. Turner, J. Morris, B. Dunn, J. TI Psychological distress and unmet supportive care needs in cancer patients and carers who contact cancer helplines SO EUROPEAN JOURNAL OF CANCER CARE LA English DT Article DE psychological distress; cancer; supportive care needs; intervention; telephone information service ID INFORMATION-SERVICE; BREAST-CANCER; TELEPHONE HELPLINE; THERMOMETER; INTERVENTION; VALIDATION; IMPACT; MODEL; EXPERIENCE; SYMPTOMS AB Cancer information services are a highly accessible source of support for people affected by cancer. To date the nature and extent of distress experienced by such callers and their unmet support needs have not been well described. A cross-sectional survey of 354 cancer patients and 336 carers who reported elevated distress on contact with a cancer information service assessed socio-demographic variables; anxiety, depression and somatization; unmet supportive care needs; cancer-specific distress; presenting problems; post-traumatic growth. Adjustment to cancer was most commonly reported; followed by anxiety. In all, 53.4% of patients and 45.2% of carers reached caseness in anxiety, depression or somatization. Carers had higher distress ratings and intrusive thinking compared to patients; whereas patients had higher somatization. For patients, most unmet supportive care needs were psychological; for carers unmet needs were related to health care services and information related to the person diagnosed with cancer. Being single, unemployed, in treatment, having higher initial distress scores, higher intrusion and avoidance predicted poorer outcomes. Information service frameworks should include distress screening and clear triage and referral processes for psychological care. C1 [Chambers, S. K.; Occhipinti, S.; Dunn, J.] Griffith Univ, Griffith Hlth Inst, Gold Coast, Qld, Australia. [Chambers, S. K.; Hutchison, S.; Morris, B.; Dunn, J.] Canc Council Queensland, Viertel Ctr Res Canc Control, Brisbane, Qld, Australia. [Chambers, S. K.] Univ Queensland, Clin Res Ctr, Brisbane, Qld, Australia. [Girgis, A.] Univ Newcastle, Newcastle, NSW 2300, Australia. [Turner, J.] Univ Queensland, Sch Med, Brisbane, Qld, Australia. [Morris, B.] NIH, Bethesda, MD 20892 USA. [Dunn, J.] Univ Queensland, Sch Social Sci, Brisbane, Qld, Australia. RP Chambers, SK (reprint author), Griffith Hlth Inst, POB 201, Spring Hill, Qld 4004, Australia. EM suzanne.chambers@griffith.edu.au RI Chambers, Suzanne/H-5957-2012; Dunn, Jeff/H-6002-2012; Turner, Jane/F-4838-2010; Occhipinti, Stefano/G-3361-2015 OI Turner, Jane/0000-0003-1438-217X; Occhipinti, Stefano/0000-0002-2558-0609 FU beyondblue, Cancer Australia [APP561701]; Cancer Council Queensland and New South Wales FX This project was funded by beyondblue, Cancer Australia (APP561701), Cancer Council Queensland and New South Wales. We thank Barbara Haddon for research management support, Samantha Clutton and Brigid Hanley for clinical input, Megan Ferguson for manuscript preparation support and Paula Vallentine for project support in New South Wales. NR 59 TC 28 Z9 30 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-5423 J9 EUR J CANCER CARE JI Eur. J. Cancer Care PD MAR PY 2012 VL 21 IS 2 BP 213 EP 223 DI 10.1111/j.1365-2354.2011.01288.x PG 11 WC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation SC Oncology; Health Care Sciences & Services; Nursing; Rehabilitation GA 895LY UT WOS:000300498900009 PM 21895814 ER PT J AU Gaskins, AJ Mumford, SL Wactawski-Wende, J Schisterman, EF AF Gaskins, Audrey J. Mumford, Sunni L. Wactawski-Wende, Jean Schisterman, Enrique F. TI Effect of daily fiber intake on luteinizing hormone levels in reproductive-aged women SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE Dietary fiber; Luteinizing hormone; Estradiol; Women ID MENSTRUAL-CYCLE; DIETARY FIBER; BIOCYCLE; LEPTIN AB To evaluate whether the association between fiber intake and LH levels is driven by the association between fiber and estradiol, or whether there is an independent association. A prospective cohort of 259 premenopausal women were followed for up to 2 menstrual cycles. Estrogen and LH were measured a parts per thousand currency sign8 times per cycle at visits scheduled using fertility monitors. Diet was assessed a parts per thousand currency sign4 times per cycle by 24-h recall. Linear mixed models on the log scale of hormones were utilized to evaluate the total effects of fiber intake. Inverse probability weights were utilized to estimate the independent effect of fiber on LH levels. In unweighted analyses, we observed a significant, inverse association between fiber intake (in 5 g/day increments) and log LH levels (beta, -0.051, 95% confidence interval (CI), -0.100, -0.002). No association was observed in the weighted analyses, after estradiol levels were taken into account (beta, -0.016, 95% CI, -0.060, 0.027). The decreased levels of LH associated with high fiber intake were attenuated after taking estradiol levels into account, suggesting that the association between fiber and LH is most likely a consequence of fiber's impact on estradiol and not due to an independent mechanism. C1 [Gaskins, Audrey J.; Mumford, Sunni L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Preventat Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,7B03M, 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 (NICHD) FX Funding: The BioCycle study and their researchers were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Contributors: The authors thank all the investigators and staff at the University at Buffalo and NICHD for their respective roles in the study, specifically Cuilin Zhang, Kathleen M. Hovey, Brian W. Whitcomb, Penelope P. Howards, Neil J. Perkins, and Edwina Yeung. NR 12 TC 2 Z9 2 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1436-6207 J9 EUR J NUTR JI Eur. J. Nutr. PD MAR PY 2012 VL 51 IS 2 BP 249 EP 253 DI 10.1007/s00394-011-0207-2 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 896EW UT WOS:000300549200014 PM 21667182 ER PT J AU Zhang, Y Crous, PW Schoch, CL Hyde, KD AF Zhang, Ying Crous, Pedro W. Schoch, Conrad L. Hyde, Kevin D. TI Pleosporales SO FUNGAL DIVERSITY LA English DT Article DE Generic type; Massarineae; Molecular phylogeny; Morphology; Pleosporales; Taxonomy ID RIBOSOMAL DNA-SEQUENCES; AUSTRALIAN FRESH-WATER; INTERTIDAL MANGROVE WOOD; SP-NOV; NORTH-AMERICA; MARINE FUNGI; MOLECULAR PHYLOGENY; TREMATOSPHAERIA-CIRCINANS; SHIRAIA-BAMBUSICOLA; MULTIGENE PHYLOGENY AB One hundred and five generic types of Pleosporales are described and illustrated. A brief introduction and detailed history with short notes on morphology, molecular phylogeny as well as a general conclusion of each genus are provided. For those genera where the type or a representative specimen is unavailable, a brief note is given. Altogether 174 genera of Pleosporales are treated. Phaeotrichaceae as well as Kriegeriella, Zeuctomorpha and Muroia are excluded from Pleosporales. Based on the multigene phylogenetic analysis, the suborder Massarineae is emended to accommodate five families, viz. Lentitheciaceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae and Trematosphaeriaceae. C1 [Hyde, Kevin D.] King Saud Univ, Coll Sci, Dept Bot & Microbiol, Riyadh 11442, Saudi Arabia. [Zhang, Ying] Univ Hong Kong, Sch Biol Sci, Div Microbiol, Hong Kong, Hong Kong, Peoples R China. [Crous, Pedro W.] CBS KNAW Fungal Biodivers Ctr, NL-3508 AD Utrecht, Netherlands. [Schoch, Conrad L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Hyde, Kevin D.] Mae Fah Luang Univ, Sch Sci, Muang 57100, Chiang Rai, Thailand. RP Hyde, KD (reprint author), King Saud Univ, Coll Sci, Dept Bot & Microbiol, Riyadh 11442, Saudi Arabia. EM kdhyde3@gmail.com RI Crous, Pedro/H-1489-2012; Schoch, Conrad/J-4825-2012 OI Crous, Pedro/0000-0001-9085-8825; FU Global Research Network; King Saud University FX We are grateful to the Directors and Curators of the following herbaria for loan of specimens in their keeping: BAFC, BISH, BPI, BR, BRIP, CBS, E, ETH, FFE, FH, G, H, Herb. J. Kohlmeyer, HHUF, IFRD, ILLS, IMI, K(M), L, LPS, M, MA, NY, PAD, PC, PH, RO, S, TNS, TRTC, UB, UBC, UPS and ZT; to Dr. L. Cai, Dr. A. J. L. Phillips, Dr. C. Shearer and some other mycologists for their permission to use or refer to their published figures, to J. K. Liu, H. Zhang, Y.L. Yang and J. Fournier for helping me loan or collect specimens, to H. Leung for technical help. The third coauthor acknowledges the Intramural Research Program of the NIH, National Library of Medicine. The Global Research Network and King Saud University are also thanked for support. NR 429 TC 252 Z9 259 U1 2 U2 50 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1560-2745 J9 FUNGAL DIVERS JI Fungal Divers. PD MAR PY 2012 VL 53 IS 1 BP 1 EP 221 DI 10.1007/s13225-011-0117-x PG 221 WC Mycology SC Mycology GA 896QB UT WOS:000300583500001 PM 23097638 ER PT J AU Lakatta, EG Maltsev, VA AF Lakatta, Edward G. Maltsev, Victor A. TI Rebuttal: What I-f the shoe doesn't fit? "The funny current has a major pacemaking role in the sinus node" SO HEART RHYTHM LA English DT Editorial Material C1 [Lakatta, Edward G.; Maltsev, Victor A.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, IRP, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000260-01]; NIA NIH HHS [Z01 AG000260-01] NR 5 TC 6 Z9 6 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD MAR PY 2012 VL 9 IS 3 BP 459 EP 460 DI 10.1016/j.hrthm.2011.09.024 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 898CJ UT WOS:000300712700031 PM 21925131 ER PT J AU Zarember, KA Marshall-Batty, KR Cruz, AR Chu, J Fenster, ME Shoffner, AR Rogge, LS Whitney, AR Czapiga, M Song, HH Shaw, PA Nagashima, K Malech, HL Deleo, FR Holland, SM Gallin, JI Greenberg, DE AF Zarember, Kol A. Marshall-Batty, Kimberly R. Cruz, Anna R. Chu, Jessica Fenster, Michael E. Shoffner, Adam R. Rogge, Larissa S. Whitney, Adeline R. Czapiga, Meggan Song, Helen H. Shaw, Pamela A. Nagashima, Kunio Malech, Harry L. Deleo, Frank R. Holland, Steven M. Gallin, John I. Greenberg, David E. TI Innate Immunity against Granulibacter bethesdensis, an Emerging Gram-Negative Bacterial Pathogen SO INFECTION AND IMMUNITY LA English DT Article ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; CHRONIC GRANULOMATOUS-DISEASE; HUMAN NEUTROPHILS; PERITONEAL-DIALYSIS; SEQUENCE-ANALYSIS; ASAIA-BOGORENSIS; APOPTOSIS; PATIENT; PHAGOCYTOSIS; BACTEREMIA AB Acetic acid bacteria were previously considered nonpathogenic in humans. However, over the past decade, five genera of Acetobacteraceae have been isolated from patients with inborn or iatrogenic immunodeficiencies. Here, we describe the first studies of the interactions of the human innate immune system with a member of this bacterial family, Granulibacter bethesdensis, an emerging pathogen in patients with chronic granulomatous disease (CGD). Efficient phagocytosis of G. bethesdensis by normal and CGD polymorphonuclear leukocytes (CGD PMN) required heat-labile serum components (e.g., C3), and binding of C3 and C9 to G. bethesdensis was detected by immunoblotting. However, this organism survived in human serum concentrations of >= 90%, indicating a high degree of serum resistance. Consistent with the clinical host tropism of G. bethesdensis, CGD PMN were unable to kill this organism, while normal PMN, in the presence of serum, reduced the number of CFU by about 50% after a 24-h coculture. This finding, together with the observations that G. bethesdensis was sensitive to H2O2 but resistant to LL-37, a human cationic antimicrobial peptide, suggests an inherent resistance to O-2-independent killing. Interestingly, 10 to 100 times greater numbers of G. bethesdensis were required to achieve the same level of reactive oxygen species (ROS) production induced by Escherichia coli in normal PMN. In addition to the relative inability of the organism to elicit production of PMN ROS, G. bethesdensis inhibited both constitutive and FAS-induced PMN apoptosis. These properties of reduced PMN activation and resistance to nonoxidative killing mechanisms likely play an important role in G. bethesdensis pathogenesis. C1 [Zarember, Kol A.; Cruz, Anna R.; Chu, Jessica; Rogge, Larissa S.; Song, Helen H.; Malech, Harry L.; Gallin, John I.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Marshall-Batty, Kimberly R.; Fenster, Michael E.; Shoffner, Adam R.; Holland, Steven M.; Greenberg, David E.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Marshall-Batty, Kimberly R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Whitney, Adeline R.; Deleo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT USA. [Czapiga, Meggan; Greenberg, David E.] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Shaw, Pamela A.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Nagashima, Kunio] SAIC Frederick Inc, Frederick, MD USA. RP Zarember, KA (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kzarember@niaid.nih.gov; david.greenberg@utsouthwestern.edu OI Malech, Harry/0000-0001-5874-5775; DeLeo, Frank/0000-0003-3150-2516; Chu, Jessica/0000-0002-5763-873X FU National Institute of Allergy and Infectious Diseases; NIH Clinical Center; [HHSN26120080001E] FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases as well as the NIH Clinical Center. K.N. is supported through contract HHSN26120080001E. NR 32 TC 8 Z9 8 U1 0 U2 2 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 MAR PY 2012 VL 80 IS 3 BP 975 EP 981 DI 10.1128/IAI.05557-11 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 897DA UT WOS:000300621600010 PM 22184421 ER PT J AU Copeland-Linder, N Johnson, SB Haynie, DL Chung, SE Cheng, TL AF Copeland-Linder, Nikeea Johnson, Sara B. Haynie, Denise L. Chung, Shang-en Cheng, Tina L. TI Retaliatory Attitudes and Violent Behaviors Among Assault-Injured Youth SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Youth violence; Assault injury; Adolescents; Violent behavior ID AFRICAN-AMERICAN ADOLESCENTS; AGGRESSIVE-BEHAVIOR; ANTISOCIAL-BEHAVIOR; PREVENTION; VICTIMIZATION; STUDENTS AB Objectives: To examine the effect of retaliatory attitudes on subsequent violent behavior and fight-related injuries among youth who presented to the emergency department with assault injuries. Design: Assault-injured youth were interviewed at baseline, 6 months, and 18 months to assess fighting behavior, retaliatory attitudes, weapon carrying, and injury history as part of a larger randomized control trial. Setting: Two emergency departments in urban areas were selected for the study. Participants: A total of 129 adolescents aged 10-15 years were included in the study. Outcome measures: Fighting behavior, assault injury, weapon carrying, and aggressive behavior. Results: Higher retaliatory attitudes at baseline were associated with more aggression and a higher frequency of fighting over time. Conclusions: Retaliatory attitudes may fuel cycles of violence among youth. Medical professionals in acute care settings have an opportunity to identify youths at risk of future assault injury by assessing retaliation, providing anticipatory guidance, and referring to intervention programs. (C) 2012 Society for Adolescent Health and Medicine. All rights reserved. C1 [Copeland-Linder, Nikeea; Johnson, Sara B.; Chung, Shang-en; Cheng, Tina L.] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21231 USA. [Johnson, Sara B.; Cheng, Tina L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. [Haynie, Denise L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent, Bethesda, MD USA. RP Copeland-Linder, N (reprint author), Johns Hopkins Univ, Dept Pediat, 1750 E Fairmount Ave, Baltimore, MD 21231 USA. EM nlinder@ssw.umaryland.edu OI Haynie, Denise/0000-0002-8270-6079 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [1K24HD052559]; Maternal and Child Health Bureau, Health Resources and Services Administration, Department of Health and Human Services [R40MC00174, 4H34MC00025]; DC-Baltimore Research Center on Child Health Disparities from the National Center on Minority Health and Health Disparities [P20 MD00165, 00198] FX This project was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (to D. L. H.), 1K24HD052559 (T. L. C.), the Maternal and Child Health Bureau (Title V Social Security Act), Health Resources and Services Administration, Department of Health and Human Services, R40MC00174, 4H34MC00025 (T. L. C.), the DC-Baltimore Research Center on Child Health Disparities grant number P20 MD00165 and 00198 from the National Center on Minority Health and Health Disparities (T. L. C., N. L.). NR 31 TC 11 Z9 12 U1 3 U2 6 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 MAR PY 2012 VL 50 IS 3 BP 215 EP 220 DI 10.1016/j.jadohealth.2011.04.005 PG 6 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 897AK UT WOS:000300612800002 PM 22325125 ER PT J AU Dempsey, AG MacDonell, KE Naar-King, S Lau, CY AF Dempsey, Allison G. MacDonell, Karen E. Naar-King, Sylvie Lau, Chuen-Yen CA Adolescent Med Trials Network HIV TI Patterns of Disclosure Among Youth Who Are HIV-Positive: A Multisite Study SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Serostatus disclosure; HIV/AIDS; Public health; Prevention/control ID TRANSMISSION RISK; SEXUAL-BEHAVIOR; SELF-EFFICACY; ADOLESCENTS AB Purpose: Disclosure of serostatus is critical in preventing the transmission of HIV among youth. The purpose of this exploratory study was to describe serostatus disclosure in a multisite study of youth living with HIV. Methods: This study investigated serostatus disclosure and its relationship to unprotected sex among 146 youth participating in a multisite study of young people living with HIV who were sexually active within the past 3 months. Results: Forty percent of participants reported a sexual relationship with a partner to whom they had not disclosed their serostatus. Participants with multiple sexual partners were less likely to disclose their serostatus than those with one partner. Disclosure was more frequent when the serostatus of the sexual partner was known. Disclosure was not associated with unprotected sex. Conclusions: Prevention initiatives should focus on both disclosure and condom use in this high-risk population, particularly for youth with multiple sexual partners. (C) 2012 Society for Adolescent Health and Medicine. All rights reserved. C1 [Dempsey, Allison G.] Univ Houston, Dept Educ Psychol, Houston, TX 77204 USA. [MacDonell, Karen E.; Naar-King, Sylvie] Wayne State Univ, Dept Pediat, Pediat Prevent Res Ctr, Detroit, MI 48202 USA. [Lau, Chuen-Yen] NIAID, Collaborat Clin Res Branch, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Dempsey, AG (reprint author), Univ Houston, Dept Educ Psychol, 491 Farish Hall, Houston, TX 77204 USA. EM agdempsey@uh.edu RI Ghartouchent, malek/B-9088-2012 FU NICHD NIH HHS [5 U01 HD 40474, 5 U01-HD040533, U01 HD040474, U01 HD040533, U01 HD040533-01, U01 HD040533-10] NR 9 TC 13 Z9 13 U1 1 U2 4 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 MAR PY 2012 VL 50 IS 3 BP 315 EP 317 DI 10.1016/j.jadohealth.2011.06.003 PG 3 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 897AK UT WOS:000300612800017 PM 22325140 ER PT J AU Takeuchi, N Wolf, YI Makarova, KS Koonin, EV AF Takeuchi, Nobuto Wolf, Yuri I. Makarova, Kira S. Koonin, Eugene V. TI Nature and Intensity of Selection Pressure on CRISPR-Associated Genes SO JOURNAL OF BACTERIOLOGY LA English DT Article ID IMMUNE-SYSTEM; ANTAGONISTIC COEVOLUTION; RECOMBINANT SEQUENCES; PROKARYOTIC GENOMES; ACQUIRED-RESISTANCE; HORIZONTAL TRANSFER; MAXIMUM-LIKELIHOOD; ANTIVIRAL DEFENSE; PROTEIN FAMILIES; MOSAIC STRUCTURE AB The recently discovered CRISPR-Cas adaptive immune system is present in almost all archaea and many bacteria. It consists of cassettes of CRISPR repeats that incorporate spacers homologous to fragments of viral or plasmid genomes that are employed as guide RNAs in the immune response, along with numerous CRISPR-associated (cas) genes that encode proteins possessing diverse, only partially characterized activities required for the action of the system. Here, we investigate the evolution of the cas genes and show that they evolve under purifying selection that is typically much weaker than the median strength of purifying selection affecting genes in the respective genomes. The exceptions are the cas1 and cas2 genes that typically evolve at levels of purifying selection close to the genomic median. Thus, although these genes are implicated in the acquisition of spacers from alien genomes, they do not appear to be directly involved in an arms race between bacterial and archaeal hosts and infectious agents. These genes might possess functions distinct from and additional to their role in the CRISPR-Cas-mediated immune response. Taken together with evidence of the frequent horizontal transfer of cas genes reported previously and with the wide-spread microscale recombination within these genes detected in this work, these findings reveal the highly dynamic evolution of cas genes. This conclusion is in line with the involvement of CRISPR-Cas in antiviral immunity that is likely to entail a coevolutionary arms race with rapidly evolving viruses. However, we failed to detect evidence of strong positive selection in any of the cas genes. C1 [Takeuchi, Nobuto; Wolf, Yuri I.; Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 68 TC 31 Z9 31 U1 2 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAR PY 2012 VL 194 IS 5 BP 1216 EP 1225 DI 10.1128/JB.06521-11 PG 10 WC Microbiology SC Microbiology GA 895XU UT WOS:000300530800033 PM 22178975 ER PT J AU Prado, MAM Baron, G AF Prado, Marco A. M. Baron, Gerald TI Seeding plaques in Alzheimer's disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Editorial Material ID AMYLOID PRECURSOR PROTEIN; CEREBRAL BETA-AMYLOIDOSIS; DEPOSITION; INDUCTION; MODEL C1 [Prado, Marco A. M.] Univ Western Ontario, Schulich Sch Med & Dent, Dept Anat & Cell Biol, Robarts Res Inst,Dept Physiol & Pharmacol, London, ON, Canada. [Baron, Gerald] NIAID, NIH, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT USA. RP Prado, MAM (reprint author), Univ Western Ontario, Schulich Sch Med & Dent, Dept Anat & Cell Biol, Robarts Res Inst,Dept Physiol & Pharmacol, London, ON, Canada. EM mprado@robarts.ca RI Prado, Marco/K-7638-2013 OI Prado, Marco/0000-0002-3028-5778 FU Canadian Institutes of Health Research; Intramural NIH HHS [ZIA AI000982-07] NR 18 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2012 VL 120 IS 5 BP 641 EP 643 DI 10.1111/j.1471-4159.2011.07574.x PG 3 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 895NQ UT WOS:000300503400001 PM 22050472 ER PT J AU McBryde, KD AF McBryde, Kevin D. TI Blood Pressure in Pediatric Chronic Kidney Disease-It's in the Ears of the Beholder SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID CHILDREN; AGREEMENT C1 NIDDK, Off Minor Hlth Res Coordinat, NIH, Bethesda, MD 20892 USA. RP McBryde, KD (reprint author), NIDDK, Off Minor Hlth Res Coordinat, NIH, 6707 Democracy Blvd,2 Democracy Plaza,Room 906B, Bethesda, MD 20892 USA. EM kevin.mcbryde@nih.gov NR 15 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2012 VL 160 IS 3 BP 363 EP 365 DI 10.1016/j.jpeds.2011.10.004 PG 3 WC Pediatrics SC Pediatrics GA 897AT UT WOS:000300613700004 PM 22082951 ER PT J AU O'Shea, TM Allred, EN Kuban, KCK Dammann, O Paneth, N Fichorova, R Hirtz, D Leviton, A AF O'Shea, T. Michael Allred, Elizabeth N. Kuban, Karl C. K. Dammann, Olaf Paneth, Nigel Fichorova, Raina Hirtz, Deborah Leviton, Alan CA Extremely Low Gestational Age TI Elevated Concentrations of Inflammation-Related Proteins in Postnatal Blood Predict Severe Developmental Delay at 2 Years of Age in Extremely Preterm Infants SO JOURNAL OF PEDIATRICS LA English DT Article ID WHITE-MATTER ABNORMALITIES; NECROTIZING ENTEROCOLITIS; CEREBRAL-PALSY; BRAIN-DAMAGE; CHILDREN; CHORIOAMNIONITIS; NEWBORNS; OUTCOMES; MARKERS; BIRTH AB Objective To evaluate the hypothesis that elevated levels of inflammation-related proteins in early postnatal blood predict impaired mental and motor development in extremely preterm infants. Study design We measured concentrations of 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14 from 939 infants born before 28 weeks gestation. An elevated level was defined as a concentration in the highest quartile for gestational age and day of blood collection. We identified impaired development at age 24 months using the Bayley Scales of Infant Development, Second Edition. The primary outcomes were scores on the Mental Scale or the Motor Scale of <55 (more than 3 SDs below the mean). Results For 17 of the 25 inflammation-related proteins, 1 or more statistically significant associations (P < .01) was found between an elevated blood level of the protein and a developmental impairment. Elevations on multiple days were more often associated with developmental impairment than were elevations present for only 1 day. The highest number of predictive elevations was found in day-14 blood. Conclusion In extremely preterm infants, elevated levels of inflammation-related proteins in blood collected on postnatal days 7 and 14, especially when sustained, are associated with impaired mental and motor development at age 2 years. (J Pediatr 2012; 160:395-401). C1 [O'Shea, T. Michael] Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, Winston Salem, NC 27157 USA. [Allred, Elizabeth N.; Fichorova, Raina; Leviton, Alan] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Allred, Elizabeth N.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Kuban, Karl C. K.] Boston Med Ctr, Dept Pediat, Boston, MA USA. [Paneth, Nigel] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Fichorova, Raina] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Hirtz, Deborah] NINDS, Bethesda, MD 20892 USA. RP O'Shea, TM (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. EM moshea@wfubmc.edu RI Fichorova, Raina/G-9969-2014; OI Kuban, Karl/0000-0001-5299-3567 FU National Institute of Neurological Disorders and Stroke [NS 40069] FX Supported by the National Institute of Neurological Disorders and Stroke (Grant NS 40069). This study was completed as a cooperative agreement with the National Institute of Neurological Disorders and Stroke. The study sponsor participated in the study design, but not in the data collection or data analysis. The authors declare no conflicts of interest. NR 29 TC 35 Z9 38 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2012 VL 160 IS 3 BP 395 EP 401 DI 10.1016/j.jpeds.2011.08.069 PG 7 WC Pediatrics SC Pediatrics GA 897AT UT WOS:000300613700011 PM 22000304 ER PT J AU Higgins, RD Devaskar, S Hay, WW Ehrenkranz, RA Greer, FR Kennedy, K Meier, P Papile, L Sherman, MP AF Higgins, Rosemary D. Devaskar, Sherin Hay, William W., Jr. Ehrenkranz, Richard A. Greer, Frank R. Kennedy, Kathleen Meier, Paula Papile, LuAnn Sherman, Michael P. TI Executive Summary of the Workshop "Nutritional Challenges in the High Risk Infant" SO JOURNAL OF PEDIATRICS LA English DT Article ID BIRTH-WEIGHT INFANTS; EPIDERMAL-GROWTH-FACTOR; INTENSIVE-CARE-UNIT; PREVENT NECROTIZING ENTEROCOLITIS; BREAST-MILK; PRETERM INFANTS; DEVELOPMENTAL ORIGINS; GESTATIONAL-AGE; NEONATAL-RATS; ADULT DISEASE C1 [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. [Devaskar, Sherin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Hay, William W., Jr.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Greer, Frank R.] Univ Wisconsin, Dept Pediat, Madison, WI USA. [Kennedy, Kathleen] Univ Texas Houston, Sch Med, Div Neonatal Perinatal Med, Houston, TX USA. [Meier, Paula] Rush Univ, Med Ctr, Dept Women Children & Family Nursing, Chicago, IL 60612 USA. [Meier, Paula] Rush Univ, Med Ctr, Dept Pediat, Chicago, IL 60612 USA. [Papile, LuAnn] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Sherman, Michael P.] Univ Missouri, Dept Child Hlth, Columbia, MO 65201 USA. RP Higgins, RD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov FU Office of Rare Disease and National Institutes of Health FX This workshop was co-funded by the Office of Rare Disease and National Institutes of Health. The authors declare no conflicts of interest. NR 40 TC 5 Z9 5 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2012 VL 160 IS 3 BP 511 EP 516 DI 10.1016/j.jpeds.2011.12.024 PG 6 WC Pediatrics SC Pediatrics GA 897AT UT WOS:000300613700033 PM 22240111 ER PT J AU Arabshahi, B Silverman, RA Jones, OY Rider, LG AF Arabshahi, Bita Silverman, Robert A. Jones, Olcay Y. Rider, Lisa G. TI Abatacept and Sodium Thiosulfate for Treatment of Recalcitrant Juvenile Dermatomyositis Complicated by Ulceration and Calcinosis SO JOURNAL OF PEDIATRICS LA English DT Article ID RHEUMATOID-ARTHRITIS AB We report the successful use of abatacept and sodium thiosulfate in a patient with severe recalcitrant juvenile dermatomyositis complicated by ulcerative skin disease and progressive calcinosis. This combination therapy resulted in significant reductions in muscle and skin inflammation, decreased corticosteroid dependence, and halted the progression of calcinosis. (J Pediatr 2012;160:520-2) C1 [Arabshahi, Bita] Inova Fairfax Hosp Children, Div Pediat Rheumatol, Dept Pediat, Fairfax, VA USA. [Silverman, Robert A.] Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. [Jones, Olcay Y.] Walter Reed Army Med Ctr, Dept Pediat, Div Pediat Rheumatol, Washington, DC 20307 USA. [Jones, Olcay Y.; Rider, Lisa G.] George Washington Univ, Dept Med, Ctr Myositis, Washington, DC USA. [Rider, Lisa G.] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Program Clin Res, NIH,US Dept HHS, Bethesda, MD USA. RP Arabshahi, B (reprint author), Inova Fairfax Pediat Subspecialty Ctr, 8505 Arlington Blvd,Suite 100, Fairfax, VA 22031 USA. EM bita.arabshahi@inova.org OI Rider, Lisa/0000-0002-6912-2458 FU National Institute of Environmental Health Sciences, National Institutes of Health; Cure JM Foundation; Inova Fairfax Hospital for Children, Inova Health System Foundation FX Supported by the intramural research program of the National Institute of Environmental Health Sciences, National Institutes of Health; the Cure JM Foundation; and the Mohsen Ziai, MD Pediatric Endowment at Inova Fairfax Hospital for Children, Inova Health System Foundation. 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 Defense or the US Government. The authors declare no conflicts of interest. NR 11 TC 30 Z9 32 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2012 VL 160 IS 3 BP 520 EP 522 DI 10.1016/j.jpeds.2011.11.057 PG 3 WC Pediatrics SC Pediatrics GA 897AT UT WOS:000300613700035 PM 22244459 ER PT J AU Negus, SS O'Connell, R Morrissey, E Cheng, KJ Rice, KC AF Negus, S. Stevens O'Connell, Robert Morrissey, Ember Cheng, Kejun Rice, Kenner C. TI Effects of Peripherally Restricted kappa Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID IRRITABLE-BOWEL-SYNDROME; SALVINORIN-A; ANALGESIC EFFICACY; PRECLINICAL ASSAYS; SALVIA-DIVINORUM; SELF-STIMULATION; ASIMADOLINE; MICE; ICI-204448; ENADOLINE AB kappa Opioid receptor agonists that do not readily cross the blood-brain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted kappa agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral kappa receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central kappa receptors. The present study used assays of pain-related stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted kappa agonists [the tetrapeptide D-Phe-D-Phe-D-Ile-D-Arg-NH2 (ffir) and the nonpeptidic compound ((R, S)-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride (ICI204448)], 2) a centrally penetrating kappa agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal anti-inflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted kappa agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted kappa agonists had little effect, and salvinorin A exacerbated acid-induced depression of ICSS. These results suggest that peripherally restricted kappa agonists may be safer than centrally penetrating kappa agonists but less efficacious than NSAIDS or kappa opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with kappa agonists capable of greater peripheral selectivity are warranted. C1 [Negus, S. Stevens; O'Connell, Robert; Morrissey, Ember] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23220 USA. [Cheng, Kejun; Rice, Kenner C.] Natl Inst Drug Abuse, Biol Res Branch, Bethesda, MD USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, Bethesda, MD USA. RP Negus, SS (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 N 12th St, Richmond, VA 23220 USA. EM ssnegus@vcu.edu FU National Institutes of Health National Institute on Drug Abuse [R01-DA11460]; National Institutes of Health National Institute of Neurological Disorders and Stroke [R01-NS070715]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA11460]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS070715]; and the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. NR 41 TC 23 Z9 23 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 MAR PY 2012 VL 340 IS 3 BP 501 EP 509 DI 10.1124/jpet.111.186783 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 897CL UT WOS:000300619000002 PM 22128346 ER PT J AU Hogg, ME Vavra, AK Banerjee, MN Martinez, J Jiang, Q Keefer, LK Chambon, P Kibbe, MR AF Hogg, Melissa E. Vavra, Ashley K. Banerjee, Monisha N. Martinez, Janet Jiang, Qun Keefer, Larry K. Chambon, Pierre Kibbe, Melina R. TI The Role of Estrogen Receptor alpha and beta in Regulating Vascular Smooth Muscle Cell Proliferation is Based on Sex SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE neointimal hyperplasia; vascular smooth muscle; nitric oxide; hormones; estrogen receptors ID NITRIC-OXIDE SYNTHASE; PRECURSOR L-ARGININE; RAT CAROTID-ARTERY; INTIMAL HYPERPLASIA; NEOINTIMA FORMATION; INJURY RESPONSE; PERIVASCULAR DELIVERY; DEFICIENT MICE; KNOCKOUT MICE; GENE-TRANSFER AB Background. We previously demonstrated that vascular smooth muscle cells (VSMC) proliferation and development of neointimal hyperplasia as well as the ability of nitric oxide (NO) to inhibit these processes is dependent on sex and hormone status. The aim of this study was to evaluate the role of estrogen receptor (ER) in mediating proliferation in male and female VSMC. Materials and Methods. Proliferation was assessed in primary rat aortic male and female VSMC using 3 H-thymidine incorporation in the presence or absence of ER alpha (alpha) inhibitor methyl-piperidinopyrazole, the ER beta (beta) inhibitor (R, R)-5,11-Diethyl-5,6,11,12- tetrahydro-2,8-chrysenediol, the combined ER alpha beta inhibitor ICI 182,780, and/or the NO donor DETA/NO. Proliferation was also assessed in primary aortic mouse VSMC harvested from wildtype (WT), ER alpha knockout (ER alpha KO), and ER beta knockout (ER beta KO) mice in the presence or absence of DETA/NO and the ER alpha, ER beta, and ER alpha beta inhibitors. Protein levels were assessed using Western blot analysis. Results. Protein expression of ER alpha and ER beta was present and equal in male and female VSMC, and did not change after exposure to NO. Inhibition of either ER alpha or ER beta had no effect on VSMC proliferation in the presence or absence of NO in either sex. However, inhibition of ER alpha beta in rat VSMC mitigated NO-mediated inhibition in female but not male VSMC (P<0.05). Evaluation of proliferation in the knockout mice revealed distinct patterns. Male ER alpha KO and ER beta KO VSMC proliferated faster than male WT VSMC (P < 0.05). Female ER beta KO proliferated faster than female WT VSMC (P < 0.05), but female ER alpha KO VSMC proliferated slower than female WT VSMC (P<0.05). Last, we evaluated the effect of combined inhibition of ER alpha and ER beta in these knockout strains. Combined ER alpha beta inhibition abrogated NO-mediated inhibition of VSMC proliferation in female WT and knockout VSMC (P<0.05), but not in male VSMC. Conclusions. These data clearly demonstrate a role for the ER in mediating VSMC proliferation in both sexes. However, these data suggest that the antiproliferative effects of NO may be regulated by the ER in females but not males. Published by Elsevier Inc. C1 [Kibbe, Melina R.] Northwestern Univ, Div Vasc Surg, Inst BioNanotechnol Med, Chicago, IL 60611 USA. [Hogg, Melissa E.; Vavra, Ashley K.; Banerjee, Monisha N.; Martinez, Janet; Jiang, Qun; Kibbe, Melina R.] Northwestern Univ, Feinberg Sch Med, Div Vasc Surg, Chicago, IL 60611 USA. [Keefer, Larry K.] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. [Chambon, Pierre] CU, Inst Genet & Biol Mol & Cellulaire, Illkirch Graffenstaden, De Strasbourg, France. RP Kibbe, MR (reprint author), Northwestern Univ, Div Vasc Surg, Inst BioNanotechnol Med, 676 N St Clair St,650, Chicago, IL 60611 USA. EM mkibbe@nmh.org RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU Intramural NIH HHS; NCI NIH HHS [N01CO12400]; NCRR NIH HHS [UL1 RR025741]; NHLBI NIH HHS [K08 HL084203-05, K08HL084203, K08 HL084203] NR 42 TC 7 Z9 8 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 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD MAR PY 2012 VL 173 IS 1 BP E1 EP E10 DI 10.1016/j.jss.2011.09.021 PG 10 WC Surgery SC Surgery GA 897AH UT WOS:000300612500001 PM 22099601 ER PT J AU Oh, JK Pellikka, PA Panza, JA Biernat, J Attisano, T Manahan, BG Wiste, HJ Lin, G Lee, K Miller, FA Stevens, S Sopko, G She, LL Velazquez, EJ AF Oh, Jae K. Pellikka, Patricia A. Panza, Julio A. Biernat, Jolanta Attisano, Tiziana Manahan, Barbara G. Wiste, Heather J. Lin, Grace Lee, Kerry Miller, Fletcher A. Stevens, Susanna Sopko, George She, Lilin Velazquez, Eric J. CA STICH Trial Investigators TI Core Lab Analysis of Baseline Echocardiographic Studies in the STICH Trial and Recommendation for Use of Echocardiography in Future Clinical Trials SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Ischemic; Cardiomyopathy; Echocardiography ID VENTRICULAR DIASTOLIC DYSFUNCTION; FUNCTIONAL MITRAL REGURGITATION; INFERIOR VENA-CAVA; HEART-FAILURE; AMERICAN-SOCIETY; DILATED CARDIOMYOPATHY; MYOCARDIAL-INFARCTION; STANDARDS COMMITTEE; OF-ECHOCARDIOGRAPHY; MAJOR DETERMINANT AB Background: The Surgical Treatment for Ischemic Heart Failure (STICH) randomized trial was designed to identify an optimal management strategy for patients with ischemic cardiomyopathy. Baseline echocardiographic examinations were required for all patients. The primary aim of this report is to describe the baseline STICH Echocardiography Core Laboratory data. The secondary aim is to provide recommendations regarding how echocardiography should be used in clinical practice and research on the basis of the experience gained from echocardiography in STICH. Methods: Between September 2002 and January 2006, 2,136 patients with ejection fractions (EFs)<= 35% and coronary artery disease amenable to coronary artery bypass grafting were enrolled. Echocardiography was acquired by 122 clinical enrolling sites, and measurements were performed by the Echocardiography Core Laboratory after a certification process for all clinical sites. Results: Echocardiography was available for analysis in 2,006 patients (93.9%); 1,734 (86.4%) were men, and the mean age was 60.9 +/- 9.5 years. The mean left ventricular end-systolic volume index, measureable in 72.8%, was 84.0 +/- 30.9 mL/m(2), and the mean EF was 28.9 +/- 8.3%, with 18.5% of patients having EFs > 35%. Single-plane measurements of left ventricular and left atrial volumes were similar to their volumes by biplane measurement (r = 0.97 and r = 0.92, respectively). Mitral regurgitation severity by visual assessment was associated with a wide range of effective regurgitant orifice area, while effective regurgitant orifice area >= 0.2 cm(2) indicated at least moderate mitral regurgitation by visual assessment. Deceleration time of mitral inflow velocity had a weak correlation with EF (r = 0.25) but was inversely related to estimated pulmonary artery systolic pressure (r = -0.49). Conclusions: In STICH patients with ischemic cardiomyopathy, Echocardiography Core Laboratory analysis of baseline echocardiographic findings demonstrated a wide spectrum of left ventricular shape, function, and hemodynamics, as well as the feasibility and limitations of obtaining essential echocardiographic measurements. It is critical that the use of echocardiographic parameters in clinical practice and research balance the strengths and weaknesses of the technique. (J Am Soc Echocardiogr 2012;25:327-36.) C1 [Oh, Jae K.; Pellikka, Patricia A.; Manahan, Barbara G.; Wiste, Heather J.; Lin, Grace; Miller, Fletcher A.] Mayo Clin, Div Cardiovasc Dis, Echocardiog Core Lab, Rochester, MN 55905 USA. [Panza, Julio A.] Washington Hosp Ctr, Dept Med Cardiovasc Dis, Washington, DC 20010 USA. [Biernat, Jolanta] Med Univ Silesia, Katowich, Poland. [Attisano, Tiziana] DAragona Hosp, Salemo, Italy. [Lee, Kerry; Stevens, Susanna; She, Lilin] Data Coordinating Ctr STICH, Duke Clin Res Inst, Durham, NC USA. [Sopko, George] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Velazquez, Eric J.] Duke Univ, Div Cardiovasc Med, Duke Clin Res Inst, Durham, NC USA. RP Oh, JK (reprint author), Mayo Clin, Div Cardiovasc Dis, Echocardiog Core Lab, 200 1st St SW, Rochester, MN 55905 USA. EM oh.jae@mayo.edu FU National Institutes of Health (Bethesda, MD) [UO5-HL-69010] FX This study was supported by grant UO5-HL-69010 from the National Institutes of Health (Bethesda, MD). NR 38 TC 25 Z9 26 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD MAR PY 2012 VL 25 IS 3 BP 327 EP 336 DI 10.1016/j.echo.2011.12.002 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 897FW UT WOS:000300633200015 PM 22227341 ER PT J AU Majeed, F Kamal, AK AF Majeed, Farzin Kamal, Ayeesha Kamran TI Can community based interventions control hypertension in developing countries? What is the evidence from Pakistan? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material ID BLOOD-PRESSURE C1 [Majeed, Farzin] Aga Khan Univ Hosp, Stroke Serv, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. Aga Khan Univ Hosp, Int Cerebrovasc Translat Clin Res Training Progra, Vasc Fellowship Program, Fogarty Int Ctr, Karachi, Pakistan. RP Majeed, F (reprint author), Aga Khan Univ Hosp, Stroke Serv, Karachi, Pakistan. FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 3 TC 0 Z9 0 U1 0 U2 1 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD MAR PY 2012 VL 62 IS 3 BP 301 EP 302 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 892HJ UT WOS:000300277000030 PM 22764475 ER PT J AU Mazurov, D Ilinskaya, A Heidecker, G Filatov, A AF Mazurov, Dmitriy Ilinskaya, Anna Heidecker, Gisela Filatov, Alexander TI Role of O-Glycosylation and Expression of CD43 and CD45 on the Surfaces of Effector T Cells in Human T Cell Leukemia Virus Type 1 Cell-to-Cell Infection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIROLOGICAL SYNAPSES; GAG PROTEIN; B-CELLS; HTLV-I; TRANSMISSION; ANTIGEN; LYMPHOCYTES; MEMBRANE; ADHESION AB We used replication-dependent retroviral vectors to identify cell surface antigens involved in the cell-to-cell transmission of human T cell leukemia virus type 1 (HTLV-1). We generated monoclonal antibodies (MAbs) against Jurkat T cells and selected several IgM MAbs that strongly inhibited HTLV-1 but not human immune deficiency virus type 1 (HIV-1) cell-to-cell infection. These MAbs recognized the so-called Tn antigen (GalNAc alpha 1-O-Ser/Thr) that arises on Jurkat cells from a mutation in the T-synthase-specific chaperone Cosmc and the consequent loss of O-glycan elongation. Anti-Tn MAbs precipitated two major O-glycan carrier proteins, CD43 and CD45, and caused a strong aggregation of Jurkat cells. The restoration of O-glycosylation in Jurkat cells by stably transducing the wild-type Cosmc gene resulted in a 3- to 4-fold increase in the level of surface expression of CD43 and enhanced HTLV-1 transmission 10-fold in comparison to that of parental cells. The short hairpin RNA (shRNA) knockdown of CD43 or CD45 expression in Jurkat-Cosmc, HBP-ALL, and CEM T cells decreased HTLV-1 infection severalfold. The knockdown of CD45 in Jurkat cells severely reduced both HTLV-1 and HIV-1 infections, but Cosmc coexpression partially rescued infection. HTLV-1 proteins, which assembled in small patches on Jurkat cells, formed large clusters on the surface of Jurkat-Cosmc cells. These data indicate that large aggregates of HTLV-1 assemblies are more infectious than multiple clustered virions. We suggest that heavily O-glycosylated CD43 and CD45 molecules render cells less adhesive, prevent inappropriate cell-cell contacts, and favor the assembly of HTLV-1 particles into large, highly infectious structures on the surface of T cells. C1 [Mazurov, Dmitriy; Filatov, Alexander] Inst Immunol, Lab Immunochem, Moscow, Russia. [Ilinskaya, Anna; Heidecker, Gisela] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Mazurov, D (reprint author), Inst Immunol, Lab Immunochem, Moscow, Russia. EM dvmazurov@yandex.ru RI Ghartouchent, malek/B-9088-2012 FU Russian Foundation for Basic Research [RFBR 09-04-00426-a]; National Institutes of Health; National Cancer Institute Center for Cancer Research FX This work has been supported by the Russian Foundation for Basic Research, (grant RFBR 09-04-00426-a [D.M. and A.F.]) and the Intramural Research Program of the National Institutes of Health and the National Cancer Institute Center for Cancer Research (A.I. and G.H.). NR 53 TC 12 Z9 12 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2012 VL 86 IS 5 BP 2447 EP 2458 DI 10.1128/JVI.06993-11 PG 12 WC Virology SC Virology GA 896AC UT WOS:000300536800006 PM 22171268 ER PT J AU Samal, S Khattar, SK Kumar, S Collins, PL Samal, SK AF Samal, Sweety Khattar, Sunil K. Kumar, Sachin Collins, Peter L. Samal, Siba K. TI Coordinate Deletion of N-Glycans from the Heptad Repeats of the Fusion F Protein of Newcastle Disease Virus Yields a Hyperfusogenic Virus with Increased Replication, Virulence, and Immunogenicity SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RESPIRATORY SYNCYTIAL VIRUS; PARAMYXOVIRUS FUSION; MEMBRANE-FUSION; LINKED GLYCOSYLATION; NUCLEOTIDE-SEQUENCE; ENVELOPE GLYCOPROTEINS; INFLUENZA-VIRUSES; STRUCTURAL BASIS; GENOME SEQUENCE AB The role of N-linked glycosylation of the Newcastle disease virus (NDV) fusion (F) protein in viral replication and pathogenesis was examined by eliminating potential acceptor sites using a reverse genetics system for the moderately pathogenic strain Beaudette C (BC). The NDV-BC F protein contains six potential acceptor sites for N-linked glycosylation at residues 85, 191, 366, 447, 471, and 541 (sites Ng1 to Ng6, respectively). The sites at Ng2 and Ng5 are present in heptad repeat (HR) domains HR1 and HR2, respectively, and thus might affect fusion. Each N-glycosylation site was eliminated individually by replacing asparagine (N) with glutamine (Q), and a double mutant (Ng2 + 5) involving the two HR domains was also made. Each mutant was successfully recovered by reverse genetics except for the one involving Ng6, which is present in the cytoplasmic domain. All of the F proteins expressed by the recovered mutant viruses were efficiently cleaved and transported to the infected-cell surface. None of the individual mutations affected viral fusogenicity, but the double mutation at Ng2 and Ng5 in HR1 and HR2 increased fusogenicity >12-fold. The single mutations at sites Ng1, Ng2, and Ng5 resulted in modestly reduced multicycle growth in vitro. These three single mutations were also the most attenuating in eggs and 1-day-old chicks and were associated with decreased replication and spread in 2-week-old chickens. In contrast, the combination of the mutations at Ng2 and Ng5 yielded a virus that, compared to the BC parent, replicated >100-fold more efficiently in vitro, was more virulent in eggs and chicks, replicated more efficiently in chickens with enhanced tropism for the brain and gut, and elicited stronger humoral cell responses. These results illustrate the effects of N-glycosylation of the F protein on NDV pathobiology and suggest that the N-glycans in HR1 and HR2 coordinately downregulate viral fusion and virulence. C1 [Samal, Sweety; Khattar, Sunil K.; Kumar, Sachin; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU NIAID [N01A060009]; NIAID, NIH FX This research was supported by NIAID contract no. N01A060009 (85% support) and NIAID, NIH Intramural Research Program (15% support). NR 52 TC 12 Z9 14 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2012 VL 86 IS 5 BP 2501 EP 2511 DI 10.1128/JVI.06380-11 PG 11 WC Virology SC Virology GA 896AC UT WOS:000300536800010 PM 22205748 ER PT J AU Suguitan, AL Matsuoka, Y Lau, YF Santos, CP Vogel, L Cheng, LI Orandle, M Subbarao, K AF Suguitan, Amorsolo L., Jr. Matsuoka, Yumiko Lau, Yuk-Fai Santos, Celia P. Vogel, Leatrice Cheng, Lily I. Orandle, Marlene Subbarao, Kanta TI The Multibasic Cleavage Site of the Hemagglutinin of Highly Pathogenic A/Vietnam/1203/2004 (H5N1) Avian Influenza Virus Acts as a Virulence Factor in a Host-Specific Manner in Mammals SO JOURNAL OF VIROLOGY LA English DT Article ID LOWER RESPIRATORY-TRACT; A H5N1; PROCESSING ENDOPROTEASES; CONNECTING PEPTIDE; FERRETS; HUMANS; CLEAVABILITY; INFECTION; MICE; DETERMINANT AB Highly pathogenic avian influenza (HPAI) viruses of the H5 and H7 subtypes typically possess multiple basic amino acids around the cleavage site (MBS) of their hemagglutinin (HA) protein, a recognized virulence motif in poultry. To determine the importance of the H5 HA MBS as a virulence factor in mammals, recombinant wild-type HPAI A/Vietnam/1203/2004 (H5N1) viruses that possessed (H5N1) or lacked (Delta H5N1) the H5 HA MBS were generated and evaluated for their virulence in BALB/c mice, ferrets, and African green monkeys (AGMs) (Chlorocebus aethiops). The presence of the H5 HA MBS was associated with lethality, significantly higher virus titers in the respiratory tract, virus dissemination to extrapulmonary organs, lymphopenia, significantly elevated levels of proinflammatory cytokines and chemokines, and inflammation in the lungs of mice and ferrets. In AGMs, neither H5N1 nor Delta H5N1 virus was lethal and neither caused clinical symptoms. The H5 HA MBS was associated with mild enhancement of replication and delayed virus clearance. Thus, the contribution of H5 HA MBS to the virulence of the HPAI H5N1 virus varies among mammalian hosts and is most significant in mice and ferrets and less remarkable in nonhuman primates. C1 [Suguitan, Amorsolo L., Jr.; Matsuoka, Yumiko; Lau, Yuk-Fai; Santos, Celia P.; Vogel, Leatrice; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Cheng, Lily I.; Orandle, Marlene] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU MedImmune FX We thank Chris O'Donnell, Kobporn Boonnak, Elaine Lamirande of LID, Jadon Jackson, and the staff of the Comparative Medicine Branch, NIAID, for superior technical support for the animal studies conducted at the NIH and Brad Finneyfrock for excellent assistance in performing the studies in ferrets and AGMs at Bioqual. We are grateful to Hong Jin and George Kemble of MedImmune and Li-Mei Chen and Ruben Donis from the CDC for the reverse genetics plasmids and to Le Quynh Mai, National Institute of Hygiene and Epidemiology (NI HE), Vietnam, for providing the A/Vietnam/1203/2004 (H5N1) virus used in this study, which was made available to us by Nancy Cox and Alexander Klimov, Influenza Division, Centers for Disease Control and Prevention (CDC), Atlanta, GA. We also thank David Tabor, Kathy Wang, and Xiamou Chen of MedImmune for their assistance and support in conducting the qPCR assays for ferret cytokine and chemokine genes. NR 55 TC 36 Z9 37 U1 0 U2 7 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 MAR PY 2012 VL 86 IS 5 BP 2706 EP 2714 DI 10.1128/JVI.05546-11 PG 9 WC Virology SC Virology GA 896AC UT WOS:000300536800028 PM 22205751 ER PT J AU Ochsenbauer, C Edmonds, TG Ding, HT Keele, BF Decker, J Salazar, MG Salazar-Gonzalez, JF Shattock, R Haynes, BF Shaw, GM Hahn, BH Kappes, JC AF Ochsenbauer, Christina Edmonds, Tara G. Ding, Haitao Keele, Brandon F. Decker, Julie Salazar, Maria G. Salazar-Gonzalez, Jesus F. Shattock, Robin Haynes, Barton F. Shaw, George M. Hahn, Beatrice H. Kappes, John C. TI Generation of Transmitted/Founder HIV-1 Infectious Molecular Clones and Characterization of Their Replication Capacity in CD4 T Lymphocytes and Monocyte-Derived Macrophages SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 R5 ENVELOPES; CENTRAL-NERVOUS-SYSTEM; ANTIBODY NEUTRALIZATION; BIOLOGICAL PHENOTYPE; SEXUAL TRANSMISSION; VIRAL DETERMINANTS; LYMPHOID-TISSUES; FUSION INHIBITOR; TROPISM AB Genome sequences of transmitted/founder (T/F) HIV-1 have been inferred by analyzing single genome amplicons of acute infection plasma viral RNA in the context of a mathematical model of random virus evolution; however, few of these T/F sequences have been molecularly cloned and biologically characterized. Here, we describe the derivation and biological analysis of ten infectious molecular clones, each representing a T/F genome responsible for productive HIV-1 clade B clinical infection. Each of the T/F viruses primarily utilized the CCR5 coreceptor for entry and replicated efficiently in primary human CD4(+) T lymphocytes. This result supports the conclusion that single genome amplification-derived sequences from acute infection allow for the inference of T/F viral genomes that are consistently replication competent. Studies with monocyte-derived macrophages (MDM) demonstrated various levels of replication among the T/F viruses. Although all T/F viruses replicated in MDM, the overall replication efficiency was significantly lower compared to prototypic "highly macrophage-tropic" virus strains. This phenotype was transferable by expressing the env genes in an isogenic proviral DNA backbone, indicating that T/F virus macrophage tropism mapped to Env. Furthermore, significantly higher concentrations of soluble CD4 were required to inhibit T/F virus infection compared to prototypic macrophage-tropic virus strains. Our findings suggest that the acquisition of clinical HIV-1 subtype B infection occurs by mucosal exposure to virus that is not highly macrophage tropic and that the generation and initial biological characterization of 10 clade B T/F infectious molecular clones provides new opportunities to probe virus-host interactions involved in HIV-1 transmission. C1 [Ochsenbauer, Christina; Ding, Haitao; Decker, Julie; Salazar, Maria G.; Salazar-Gonzalez, Jesus F.; Kappes, John C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Edmonds, Tara G.; Kappes, John C.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL USA. [Kappes, John C.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL USA. [Keele, Brandon F.] NCI Frederick, SAIC Frederick Inc, Frederick, MD USA. [Shattock, Robin] Univ London Imperial Coll Sci Technol & Med, London, England. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Duke Human Vaccine Inst, Durham, NC 27706 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Duke Human Vaccine Inst, Durham, NC USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Kappes, John C.] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL USA. RP Kappes, JC (reprint author), Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. EM kappesjc@uab.edu RI Ghartouchent, malek/B-9088-2012 FU NIH Center for HIV/AIDS Vaccine Immunology (CHAVI) [UO1-AI067854]; Bill and Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody Vaccine Immune Monitoring Consortium [38619]; Bill and Melinda Gates Foundation [37874]; facilities of the Virology, Biostatistics, and Genetic Sequencing cores of the UAB Center for AIDS Research [P30-AI-27767]; Genetically Defined Microbe and Expression Core of the UAB Mucosal HIV and Immunobiology Center [R24 DK-64400]; Department of Veterans Affairs Medical Center, Research Services; NIH [AI007439] FX This study was supported by the NIH Center for HIV/AIDS Vaccine Immunology (CHAVI; UO1-AI067854); the Bill and Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody Vaccine Immune Monitoring Consortium (grant 38619); a Bill and Melinda Gates Foundation Grand Challenges grant (grant 37874); the facilities of the Virology, Biostatistics, and Genetic Sequencing cores of the UAB Center for AIDS Research (P30-AI-27767); and the Genetically Defined Microbe and Expression Core of the UAB Mucosal HIV and Immunobiology Center (R24 DK-64400). Research was also supported by a Merit Review Award (J.C.K.) and a Research Career Scientist Award (J.C.K.) from the Department of Veterans Affairs Medical Center, Research Services. T.G.E. is supported by NIH training grant AI007439. NR 71 TC 123 Z9 123 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 MAR PY 2012 VL 86 IS 5 BP 2715 EP 2728 DI 10.1128/JVI.06157-11 PG 14 WC Virology SC Virology GA 896AC UT WOS:000300536800029 PM 22190722 ER PT J AU Dobrikova, EY Goetz, C Walters, RW Lawson, SK Peggins, JO Muszynski, K Ruppel, S Poole, K Giardina, SL Vela, EM Estep, JE Gromeier, M AF Dobrikova, Elena Y. Goetz, Christian Walters, Robert W. Lawson, Sarah K. Peggins, James O. Muszynski, Karen Ruppel, Sheryl Poole, Karyol Giardina, Steven L. Vela, Eric M. Estep, James E. Gromeier, Matthias TI Attenuation of Neurovirulence, Biodistribution, and Shedding of a Poliovirus:Rhinovirus Chimera after Intrathalamic Inoculation in Macaca fascicularis SO JOURNAL OF VIROLOGY LA English DT Article ID RIBOSOME ENTRY SITE; INTERGENERIC POLIOVIRUS RECOMBINANTS; TRANSLATION INITIATION; ONCOLYTIC POLIOVIRUS; GENETIC ADAPTATION; NONCODING REGION; MESSENGER-RNA; BINDING; GLIOMA; PHOSPHORYLATION AB A dependence of poliovirus on an unorthodox translation initiation mode can be targeted selectively to drive viral protein synthesis and cytotoxicity in malignant cells. Transformed cells are naturally susceptible to poliovirus, due to widespread ectopic upregulation of the poliovirus receptor, Necl-5, in ectodermal/neuroectodermal cancers. Viral tumor cell killing and the host immunologic response it engenders produce potent, lasting antineoplastic effects in animal tumor models. Clinical application of this principle depends on unequivocal demonstration of safety in primate models for paralytic poliomyelitis. We conducted extensive dose-range-finding, toxicity, biodistribution, shedding, and neutralizing antibody studies of the prototype oncolytic poliovirus recombinant, PVS-RIPO, after intrathalamic inoculation in Macaca fascicularis. These studies suggest that intracerebral PVS-RIPO inoculation does not lead to viral propagation in the central nervous system (CNS), does not cause histopathological CNS lesions or neurological symptoms that can be attributed to the virus, is not associated with extraneural virus dissemination or replication and does not induce shedding of virus with stool. Intrathalamic PVS-RIPO inoculation induced neutralizing antibody responses against poliovirus serotype 1 in all animals studied. C1 [Dobrikova, Elena Y.; Goetz, Christian; Walters, Robert W.; Lawson, Sarah K.; Gromeier, Matthias] Duke Univ, Med Ctr, Dept Surg, Div Neurosurg, Durham, NC 27710 USA. [Peggins, James O.] NCI, Toxicol & Pharmacol Branch, Frederick, MD 21701 USA. [Muszynski, Karen] NCI, Biol Res Branch, Frederick, MD 21701 USA. [Ruppel, Sheryl; Poole, Karyol; Giardina, Steven L.] NCI Frederick, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD USA. [Vela, Eric M.; Estep, James E.] Battelle Mem Inst, Columbus, OH USA. RP Gromeier, M (reprint author), Duke Univ, Med Ctr, Dept Surg, Div Neurosurg, Durham, NC 27710 USA. EM grome001@mc.duke.edu FU National Cancer Institute, National Institutes of Health [NO1-CO-12400]; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health; PHS [CA124756, CA140510] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract NO1-CO-12400 and also supported in part through the NCI-RAID Program of the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health.; This study was partly supported by PHS grants CA124756 and CA140510 (M.G.). 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 48 TC 10 Z9 10 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2012 VL 86 IS 5 BP 2750 EP 2759 DI 10.1128/JVI.06427-11 PG 10 WC Virology SC Virology GA 896AC UT WOS:000300536800032 PM 22171271 ER PT J AU Elleder, D Kim, O Padhi, A Bankert, JG Simeonov, I Schuster, SC Wittekindt, NE Motameny, S Poss, M AF Elleder, Daniel Kim, Oekyung Padhi, Abinash Bankert, Jason G. Simeonov, Ivan Schuster, Stephan C. Wittekindt, Nicola E. Motameny, Susanne Poss, Mary TI Polymorphic Integrations of an Endogenous Gammaretrovirus in the Mule Deer Genome SO JOURNAL OF VIROLOGY LA English DT Article ID FELINE LEUKEMIA VIRUSES; INSERTIONAL POLYMORPHISMS; RETROVIRAL ELEMENTS; IDENTIFICATION; PHYLOGENIES; SEQUENCES; SHEEP; MITOCHONDRIAL; ORIGIN; GENES AB Endogenous retroviruses constitute a significant genomic fraction in all mammalian species. Typically they are evolutionarily old and fixed in the host species population. Here we report on a novel endogenous gammaretrovirus (CrERV gamma; for cervid endogenous gammaretrovirus) in the mule deer (Odocoileus hemionus) that is insertionally polymorphic among individuals from the same geographical location, suggesting that it has a more recent evolutionary origin. Using PCR-based methods, we identified seven CrERV gamma proviruses and demonstrated that they show various levels of insertional polymorphism in mule deer individuals. One CrERV gamma provirus was detected in all mule deer sampled but was absent from white-tailed deer, indicating that this virus originally integrated after the split of the two species, which occurred approximately one million years ago. There are, on average, 100 CrERV gamma copies in the mule deer genome based on quantitative PCR analysis. A CrERV gamma provirus was sequenced and contained intact open reading frames (ORFs) for three virus genes. Transcripts were identified covering the entire provirus. CrERV gamma forms a distinct branch of the gammaretrovirus phylogeny, with the closest relatives of CrERV gamma being endogenous gammaretroviruses from sheep and pig. We demonstrated that white-tailed deer (Odocoileus virginianus) and elk (Cervus canadensis) DNA contain proviruses that are closely related to mule deer CrERV gamma in a conserved region of pol; more distantly related sequences can be identified in the genome of another member of the Cervidae, the muntjac (Muntiacus muntjak). The discovery of a novel transcriptionally active and insertionally polymorphic retrovirus in mammals could provide a useful model system to study the dynamic interaction between the host genome and an invading retrovirus. C1 [Elleder, Daniel; Kim, Oekyung; Padhi, Abinash; Bankert, Jason G.; Poss, Mary] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Simeonov, Ivan] Penn State Univ, Dept Stat, University Pk, PA 16802 USA. [Schuster, Stephan C.; Wittekindt, Nicola E.] Penn State Univ, Dept Biochem Microbiol & Mol Biol, University Pk, PA 16802 USA. [Motameny, Susanne] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany. [Poss, Mary] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Poss, M (reprint author), Penn State Univ, Dept Biol, University Pk, PA 16802 USA. EM mposs@bx.psu.edu RI Wittekindt, Nicola/G-3469-2013; Elleder, Daniel/G-3551-2014 OI Wittekindt, Nicola/0000-0002-3310-0919; FU USGS [06HQAG0131] FX This work was supported by USGS grant 06HQAG0131. NR 53 TC 10 Z9 10 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2012 VL 86 IS 5 BP 2787 EP 2796 DI 10.1128/JVI.06859-11 PG 10 WC Virology SC Virology GA 896AC UT WOS:000300536800036 PM 22190723 ER PT J AU Fontana, J Cardone, G Heymann, JB Winkler, DC Steven, AC AF Fontana, Juan Cardone, Giovanni Heymann, J. Bernard Winkler, Dennis C. Steven, Alasdair C. TI Structural Changes in Influenza Virus at Low pH Characterized by Cryo-Electron Tomography SO JOURNAL OF VIROLOGY LA English DT Article ID VIRAL MEMBRANE-FUSION; MATRIX PROTEIN M1; A VIRUS; 3-DIMENSIONAL STRUCTURE; CONFORMATIONAL CHANGE; ELECTRON-MICROSCOPY; DISULFIDE BONDS; HEMAGGLUTININ; ANTIBODY; M2 AB Influenza virus enters host cells by endocytosis. The low pH of endosomes triggers conformational changes in hemagglutinin (HA) that mediate fusion of the viral and endosomal membranes. We have used cryo-electron tomography to visualize influenza A virus at pH 4.9, a condition known to induce fusogenicity. After 30 min, when all virions are in the postfusion state, dramatic changes in morphology are apparent: elongated particles are no longer observed, larger particles representing fused virions appear, the HA spikes become conspicuously disorganized, a layer of M1 matrix protein is no longer resolved on most virions, and the ribonucleoprotein complexes (RNPs) coagulate on the interior surface of the virion. To probe for intermediate states, preparations were imaged after 5 min at pH 4.9. These virions could be classified according to their glycoprotein arrays (organized or disorganized) and whether or not they have a resolved M1 layer. Employing subtomogram averaging, we found, in addition to the neutral-pH state of HA, two intermediate conformations that appear to reflect an outwards movement of the fusion peptide and rearrangement of the HA1 subunits, respectively. These changes are reversible. The tomograms also document pH-induced changes affecting the M1 layer that appear to render the envelope more pliable and hence conducive to fusion. However, it appears desirable for productive infection that fusion should proceed before the RNPs become coagulated with matrix protein, as eventually happens at low pH. C1 [Fontana, Juan; Cardone, Giovanni; Heymann, J. Bernard; Winkler, Dennis C.; Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Fontana, Juan/A-9138-2009; OI Fontana, Juan/0000-0002-9084-2927; Heymann, Bernard/0000-0002-8872-5326 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 47 TC 53 Z9 55 U1 1 U2 13 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 MAR PY 2012 VL 86 IS 6 BP 2919 EP 2929 DI 10.1128/JVI.06698-11 PG 11 WC Virology SC Virology GA 897GC UT WOS:000300634100003 PM 22258245 ER PT J AU Liu, XQ Li, QX Dowdell, K Fischer, ER Cohen, JI AF Liu, XueQiao Li, Qingxue Dowdell, Kennichi Fischer, Elizabeth R. Cohen, Jeffrey I. TI Varicella-Zoster Virus ORF12 Protein Triggers Phosphorylation of ERK1/2 and Inhibits Apoptosis SO JOURNAL OF VIROLOGY LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; LATENCY-ASSOCIATED PROTEIN; KINASE PATHWAYS; SIGNALING PATHWAY; MAPK PATHWAY; ACTIVATION; REPLICATION; INFECTION; NEURONS; VZV AB Mitogen-activated protein kinases (MAPKs) are a family of serine-threonine protein kinases involved in many cellular processes, including cell proliferation, differentiation, inflammation, and cell death. Activation of several MAPKs, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK), results in stimulation of activator protein 1 (AP-1), which promotes gene transcription. Previous studies have demonstrated that varicella-zoster virus (VZV) infection activates ERK1/2, p38, and JNK to promote viral replication, but the underlying mechanism(s) is unclear. To identify viral proteins responsible for the activation of MAPK, we used a proteomic approach to screen viral proteins for AP-1 promoter activation by an AP-1-luciferase reporter assay. We found that VZV ORF12 protein, located in the tegument of virions, enhances AP-1 reporter activity. This effect of ORF12 protein was markedly inhibited by a MAPK/ERK kinase 1 and 2 (MEK1/2) inhibitor (U0126), partially blocked by a p38 inhibitor (SB202190), but not inhibited by a JNK inhibitor (SP600125). Expression of VZV ORF12 protein in cells resulted in phosphorylation of ERK1/2 and p38 but not JNK. Infection of cells with a VZV ORF12 deletion mutant resulted in reduced levels of phosphorylated ERK1/2 (p-ERK1/2) compared to infection with wild-type VZV. Furthermore, deletion of ORF12 rendered VZV-infected cells more susceptible to staurosporine-induced apoptosis. In conclusion, VZV ORF12 protein activates the AP-1 pathway by selectively triggering the phosphorylation of ERK1/2 and p38. Cells infected with a VZV ORF12 deletion mutant have reduced levels of p-ERK1/2 and are more susceptible to apoptosis than cells infected with wild-type VZV. C1 [Liu, XueQiao; Li, Qingxue; Dowdell, Kennichi; Cohen, Jeffrey I.] NIH, Med Virol Sect, Infect Dis Lab, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.] NIH, Res Technol Sect, Res Technol Branch, Rocky Mt Labs, Hamilton, MT USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Infect Dis Lab, Bldg 10, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 35 TC 26 Z9 29 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 MAR PY 2012 VL 86 IS 6 BP 3143 EP 3151 DI 10.1128/JVI.06923-11 PG 9 WC Virology SC Virology GA 897GC UT WOS:000300634100023 PM 22238304 ER PT J AU Del Prete, GQ Kearney, MF Spindler, J Wiegand, A Chertova, E Roser, JD Estes, JD Hao, XP Trubey, CM Lara, A Lee, K Chaipan, C