FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Madej, T Lanczycki, CJ Zhang, DC Thiessen, PA Geer, RC Marchler-Bauer, A Bryant, SH AF Madej, Thomas Lanczycki, Christopher J. Zhang, Dachuan Thiessen, Paul A. Geer, Renata C. Marchler-Bauer, Aron Bryant, Stephen H. TI MMDB and VAST+: tracking structural similarities between macromolecular complexes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID T-CELL-RECEPTOR; STRUCTURE ALIGNMENT; 3D STRUCTURES; PROTEINS; SEQUENCES; ACCURACY; DATABASE; PEPTIDE; TCR AB The computational detection of similarities between protein 3D structures has become an indispensable tool for the detection of homologous relationships, the classification of protein families and functional inference. Consequently, numerous algorithms have been developed that facilitate structure comparison, including rapid searches against a steadily growing collection of protein structures. To this end, NCBI's Molecular Modeling Database (MMDB), which is based on the Protein Data Bank (PDB), maintains a comprehensive and up-to-date archive of protein structure similarities computed with the Vector Alignment Search Tool (VAST). These similarities have been recorded on the level of single proteins and protein domains, comprising in excess of 1.5 billion pairwise alignments. Here we present VAST+, an extension to the existing VAST service, which summarizes and presents structural similarity on the level of biological assemblies or macromolecular complexes. VAST+ simplifies structure neighboring results and shows, for macromolecular complexes tracked in MMDB, lists of similar complexes ranked by the extent of similarity. VAST+ replaces the previous VAST service as the default presentation of structure neighboring data in NCBI's Entrez query and retrieval system. MMDB and VAST+ can be accessed via http://www.ncbi.nlm.nih.gov/Structure. C1 [Madej, Thomas; Lanczycki, Christopher J.; Zhang, Dachuan; Thiessen, Paul A.; Geer, Renata C.; Marchler-Bauer, Aron; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Madej, T (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38 A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. EM madej@ncbi.nlm.nih.gov OI Marchler-Bauer, Aron/0000-0003-1516-0712 FU Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS FX Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. Comments, suggestions and questions are welcome and should be directed to: info@ncbi.nlm.nih.gov. Funding for open access charge: Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS. NR 26 TC 33 Z9 35 U1 3 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN PY 2014 VL 42 IS D1 BP D297 EP D303 DI 10.1093/nar/gkt1208 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA5LF UT WOS:000331139800045 PM 24319143 ER PT J AU Pruitt, KD Brown, GR Hiatt, SM Thibaud-Nissen, F Astashyn, A Ermolaeva, O Farrell, CM Hart, J Landrum, MJ McGarvey, KM Murphy, MR O'Leary, NA Pujar, S Rajput, B Rangwala, SH Riddick, LD Shkeda, A Sun, HZ Tamez, P Tully, RE Wallin, C Webb, D Weber, J Wu, WD DiCuccio, M Kitts, P Maglott, DR Murphy, TD Ostell, JM AF Pruitt, Kim D. Brown, Garth R. Hiatt, Susan M. Thibaud-Nissen, Francoise Astashyn, Alexander Ermolaeva, Olga Farrell, Catherine M. Hart, Jennifer Landrum, Melissa J. McGarvey, Kelly M. Murphy, Michael R. O'Leary, Nuala A. Pujar, Shashikant Rajput, Bhanu Rangwala, Sanjida H. Riddick, Lillian D. Shkeda, Andrei Sun, Hanzhen Tamez, Pamela Tully, Raymond E. Wallin, Craig Webb, David Weber, Janet Wu, Wendy DiCuccio, Michael Kitts, Paul Maglott, Donna R. Murphy, Terence D. Ostell, James M. TI RefSeq: an update on mammalian reference sequences SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DATABASE; RESOURCES; DISEASE; NCBI; DNA AB The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database is a collection of annotated genomic, transcript and protein sequence records derived from data in public sequence archives and from computation, curation and collaboration (http://www.ncbi.nlm.nih.gov/refseq/). We report here on growth of the mammalian and human subsets, changes to NCBI's eukaryotic annotation pipeline and modifications affecting transcript and protein records. Recent changes to NCBI's eukaryotic genome annotation pipeline provide higher throughput, and the addition of RNAseq data to the pipeline results in a significant expansion of the number of transcripts and novel exons annotated on mammalian RefSeq genomes. Recent annotation changes include reporting supporting evidence for transcript records, modification of exon feature annotation and the addition of a structured report of gene and sequence attributes of biological interest. We also describe a revised protein annotation policy for alternatively spliced transcripts with more divergent predicted proteins and we summarize the current status of the RefSeqGene project. C1 [Pruitt, Kim D.; Brown, Garth R.; Hiatt, Susan M.; Thibaud-Nissen, Francoise; Astashyn, Alexander; Ermolaeva, Olga; Farrell, Catherine M.; Hart, Jennifer; Landrum, Melissa J.; McGarvey, Kelly M.; Murphy, Michael R.; O'Leary, Nuala A.; Pujar, Shashikant; Rajput, Bhanu; Rangwala, Sanjida H.; Riddick, Lillian D.; Shkeda, Andrei; Sun, Hanzhen; Tamez, Pamela; Tully, Raymond E.; Wallin, Craig; Webb, David; Weber, Janet; Wu, Wendy; DiCuccio, Michael; Kitts, Paul; Maglott, Donna R.; Murphy, Terence D.; Ostell, James M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Pruitt, KD (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM pruitt@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 24 TC 336 Z9 338 U1 2 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN PY 2014 VL 42 IS D1 BP D756 EP D763 DI 10.1093/nar/gkt1114 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA5LF UT WOS:000331139800112 PM 24259432 ER PT J AU Tatusova, T Ciufo, S Fedorov, B O'Neill, K Tolstoy, I AF Tatusova, Tatiana Ciufo, Stacy Fedorov, Boris O'Neill, Kathleen Tolstoy, Igor TI RefSeq microbial genomes database: new representation and annotation strategy SO NUCLEIC ACIDS RESEARCH LA English DT Article ID WHOLE-GENOME; SEQUENCE; COMMUNITY; TOOL AB The source of the microbial genomic sequences in the RefSeq collection is the set of primary sequence records submitted to the International Nucleotide Sequence Database public archives. These can be accessed through the Entrez search and retrieval system at http://www.ncbi.nlm.nih.gov/genome. Next-generation sequencing has enabled researchers to perform genomic sequencing at rates that were unimaginable in the past. Microbial genomes can now be sequenced in a matter of hours, which has led to a significant increase in the number of assembled genomes deposited in the public archives. This huge increase in DNA sequence data presents new challenges for the annotation, analysis and visualization bioinformatics tools. New strategies have been developed for the annotation and representation of reference genomes and sequence variations derived from population studies and clinical outbreaks. C1 [Tatusova, Tatiana; Ciufo, Stacy; Fedorov, Boris; O'Neill, Kathleen; Tolstoy, Igor] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Tatusova, T (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A 8600 Rockville Pike, Bethesda, MD 20894 USA. EM tatiana@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 20 TC 102 Z9 102 U1 3 U2 24 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN PY 2014 VL 42 IS D1 BP D553 EP D559 DI 10.1093/nar/gkt1274 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA5LF UT WOS:000331139800082 PM 24316578 ER PT J AU Tryka, KA Hao, LN Sturcke, A Jin, YM Wang, ZY Ziyabari, L Lee, M Popova, N Sharopova, N Kimura, M Feolo, M AF Tryka, Kimberly A. Hao, Luning Sturcke, Anne Jin, Yumi Wang, Zhen Y. Ziyabari, Lora Lee, Moira Popova, Natalia Sharopova, Nataliya Kimura, Masato Feolo, Michael TI NCBI's Database of Genotypes and Phenotypes: dbGaP SO NUCLEIC ACIDS RESEARCH LA English DT Article AB The Database of Genotypes and Phenotypes (dbGap, http://www.ncbi.nlm.nih.gov/gap) is a National Institutes of Health-sponsored repository charged to archive, curate and distribute information produced by studies investigating the interaction of genotype and phenotype. Information in dbGaP is organized as a hierarchical structure and includes the accessioned objects, phenotypes (as variables and datasets), various molecular assay data (SNP and Expression Array data, Sequence and Epigenomic marks), analyses and documents. Publicly accessible metadata about submitted studies, summary level data, and documents related to studies can be accessed freely on the dbGaP website. Individual-level data are accessible via Controlled Access application to scientists across the globe. C1 [Tryka, Kimberly A.; Hao, Luning; Sturcke, Anne; Jin, Yumi; Wang, Zhen Y.; Ziyabari, Lora; Lee, Moira; Popova, Natalia; Sharopova, Nataliya; Kimura, Masato; Feolo, Michael] Natl Lib Med, Natl Ctr Biotechnol Informat, Informat Engn Branch, Bethesda, MD 20894 USA. RP Feolo, M (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Informat Engn Branch, Bethesda, MD 20894 USA. EM trykak@ncbi.nlm.nih.gov; hao@ncbi.nlm.nih.gov; feolo@ncbi.nlm.nih.gov FU US National Institutes of Health, National Library of Medicine; National Institutes of Health, National Library of Medicine FX Intramural Research Program of the US National Institutes of Health, National Library of Medicine. Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 2 TC 66 Z9 66 U1 2 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN PY 2014 VL 42 IS D1 BP D975 EP D979 DI 10.1093/nar/gkt1211 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA5LF UT WOS:000331139800143 PM 24297256 ER PT J AU Wang, YL Suzek, T Zhang, J Wang, JY He, SQ Cheng, TJ Shoemaker, BA Gindulyte, A Bryant, SH AF Wang, Yanli Suzek, Tugba Zhang, Jian Wang, Jiyao He, Siqian Cheng, Tiejun Shoemaker, Benjamin A. Gindulyte, Asta Bryant, Stephen H. TI PubChem BioAssay: 2014 update SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA INTERFERENCE SCREEN; SIGNALING PATHWAY; SMALL MOLECULES; REGULATORS; DATABASE; GENES; CELLS AB PubChem's BioAssay database (http://pubchem.ncbi.nlm.nih.gov) is a public repository for archiving biological tests of small molecules generated through high-throughput screening experiments, medicinal chemistry studies, chemical biology research and drug discovery programs. In addition, the BioAssay database contains data from high-throughput RNA interference screening aimed at identifying critical genes responsible for a biological process or disease condition. The mission of PubChem is to serve the community by providing free and easy access to all deposited data. To this end, PubChem BioAssay is integrated into the National Center for Biotechnology Information retrieval system, making them searchable by Entrez queries and cross-linked to other biomedical information archived at National Center for Biotechnology Information. Moreover, PubChem BioAssay provides web-based and programmatic tools allowing users to search, access and analyze bioassay test results and metadata. In this work, we provide an update for the PubChem BioAssay resource, such as information content growth, new developments supporting data integration and search, and the recently deployed PubChem Upload to streamline chemical structure and bioassay submissions. C1 [Wang, Yanli; Suzek, Tugba; Zhang, Jian; Wang, Jiyao; He, Siqian; Cheng, Tiejun; Shoemaker, Benjamin A.; Gindulyte, Asta; 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, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Cheng, Tiejun/A-5344-2010; Suzek, Tugba/B-6943-2015; OI Cheng, Tiejun/0000-0002-4486-3356; Suzek, Tugba/0000-0002-3243-1759 FU NIH; National Insitutes of Health, USA FX The NIH Intramural Research program. Funding for open access charge: National Insitutes of Health, USA. NR 22 TC 94 Z9 95 U1 1 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN PY 2014 VL 42 IS D1 BP D1075 EP D1082 DI 10.1093/nar/gkt978 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA5LF UT WOS:000331139800158 PM 24198245 ER PT J AU Welter, D MacArthur, J Morales, J Burdett, T Hall, P Junkins, H Klemm, A Flicek, P Manolio, T Hindorff, L Parkinson, H AF Welter, Danielle MacArthur, Jacqueline Morales, Joannella Burdett, Tony Hall, Peggy Junkins, Heather Klemm, Alan Flicek, Paul Manolio, Teri Hindorff, Lucia Parkinson, Helen TI The NHGRI GWAS Catalog, a curated resource of SNP-trait associations SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SUSCEPTIBILITY LOCI; ONTOLOGY; DISEASE; INTEGRATION AB The National Human Genome Research Institute (NHGRI) Catalog of Published Genome-Wide Association Studies (GWAS) Catalog provides a publicly available manually curated collection of published GWAS assaying at least 100 000 single-nucleotide polymorphisms (SNPs) and all SNP-trait associations with P < 1 x 10(-5). The Catalog includes 1751 curated publications of 11 912 SNPs. In addition to the SNP-trait association data, the Catalog also publishes a quarterly diagram of all SNP-trait associations mapped to the SNPs' chromosomal locations. The Catalog can be accessed via a tabular web interface, via a dynamic visualization on the human karyotype, as a downloadable tab-delimited file and as an OWL knowledge base. This article presents a number of recent improvements to the Catalog, including novel ways for users to interact with the Catalog and changes to the curation infrastructure. C1 [Welter, Danielle; MacArthur, Jacqueline; Morales, Joannella; Burdett, Tony; Flicek, Paul; Parkinson, Helen] European Bioinformat Inst, European Mol Biol Lab, Hinxton CB10 1SD, Cambs, England. [Hall, Peggy; Junkins, Heather; Manolio, Teri; Hindorff, Lucia] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Klemm, Alan] NHGRI, Div Policy Commun & Educ, NIH, Bethesda, MD 20892 USA. RP Parkinson, H (reprint author), European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambs, England. EM hindorffl@mail.nih.gov; parkinson@ebi.ac.uk OI Welter, Danielle/0000-0003-1058-2668; Burdett, Anthony/0000-0002-2513-5396; Parkinson, Helen/0000-0003-3035-4195; Flicek, Paul/0000-0002-3897-7955 FU National Institutes of Health [3U41-HG006104]; EMBL; Health Thematic Area of the Cooperation Programme of the European Commission; NIH; [200754] FX The National Institutes of Health [3U41-HG006104 to D. W. and J.M-.A.] and EMBL core funds supporting (to P. F., H. P. and T. B.); EMBL Core Funds and by the Health Thematic Area of the Cooperation Programme of the European Commission within the VII Framework Programme for Research and Technological Development supported (to J.M.); Grant number [200754] Gen2Phen. conducted this work as employees of the NHGRI, NIH (by H.A.J., P. H., K. A. H., T. A. M. and L. A. H.). Funding for open access charge: NIH. NR 20 TC 735 Z9 750 U1 7 U2 44 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN PY 2014 VL 42 IS D1 BP D1001 EP D1006 DI 10.1093/nar/gkt1229 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA5LF UT WOS:000331139800147 PM 24316577 ER PT J AU Kobayashi, H Watanabe, R Choyke, PL AF Kobayashi, Hisataka Watanabe, Rira Choyke, Peter L. TI Improving Conventional Enhanced Permeability and Retention (EPR) Effects; What Is the Appropriate Target? SO THERANOSTICS LA English DT Review DE Cancer; Nano-delivery; Tumor physiology; Enhanced permeability and retention effects ID TRANSCAPILLARY PRESSURE-GRADIENT; HUMAN OSTEOSARCOMA XENOGRAFTS; MACROMOLECULAR DRUG-DELIVERY; INTERSTITIAL FLUID PRESSURE; GROWTH-FACTOR VEGF; TUMOR BLOOD-FLOW; SOLID TUMORS; LIPOSOMAL DOXORUBICIN; VASCULAR-PERMEABILITY; PHARMACO-ANGIOGRAPHY AB Nano-sized therapeutic agents have several advantages over low molecular weight agents such as a larger loading capacity, the ability to protect the payload until delivery, more specific targeting due to multivalency and the opportunity for controlled/sustained release. However, the delivery of nano-sized agents into cancer tissue is problematic because it mostly relies on the enhanced permeability and retention (EPR) effect that depends on the leaky nature of the tumor vasculature and the prolonged circulation of nano-sized agents, allowing slow but uneven accumulation in the tumor bed. Delivery of nano-sized agents is dependent on several factors that influence the EPR effect; 1. Regional blood flow to the tumor, 2. Permeability of the tumor vasculature, 3. Structural barriers imposed by perivascular tumor cells and extracellular matrix, 4. Intratumoral pressure. In this review, these factors will be described and methods to enhance nano-agent delivery will be reviewed. C1 [Kobayashi, Hisataka; Watanabe, Rira; Choyke, Peter L.] NCI, Ctr Canc Res, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Ctr Canc Res, Mol Imaging Program, NIH, Bldg 10,RoomB3B69,MSC1088, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural Research Program of the 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 84 TC 141 Z9 146 U1 29 U2 139 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2014 VL 4 IS 1 BP 81 EP 89 DI 10.7150/thno.7193 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AA9GP UT WOS:000331402100006 PM 24396516 ER PT J AU Kusumoto-Matsuo, R Ghosh, D Karmakar, P May, A Ramsden, D Bohr, VA AF Kusumoto-Matsuo, Rika Ghosh, Deblina Karmakar, Parimal May, Alfred Ramsden, Dale Bohr, Vilhelm A. TI Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks SO AGING-US LA English DT Article DE Werner; WRN; DNA-PK; serine phosphorylation; DSB; etoposide ID FUNCTIONAL INTERACTION; SYNDROME HELICASE; RECQ HELICASES; CATALYTIC SUBUNIT; HUMAN-CELLS; IV COMPLEX; IN-VITRO; S-PHASE; KINASE; DAMAGE AB WRN protein, defective in Werner syndrome (WS), a human segmental progeria, is a target of serine/threonine kinases involved in sensing DNA damage. DNA-PK phosphorylates WRN in response to DNA double strand breaks (DSBs). However, the main phosphorylation sites and functional importance of the phosphorylation of WRN has remained unclear. Here, we identify Ser-440 and -467 in WRN as major phosphorylation sites mediated by DNA-PK. In vitro, DNA-PK fails to phosphorylate a GST-WRN fragment with S440A and/or S467A substitution. In addition, full length WRN with the mutation expressed in 293T cells was not phosphorylated in response to DSBs produced by bleomycin. Accumulation of the mutant WRN at the site of laser-induced DSBs occurred with the same kinetics as wild type WRN in live HeLa cells. While the wild type WRN relocalized to the nucleoli after 24 hours recovery from etoposide-induced DSBs, the mutant WRN remained mostly in the nucleoplasm. Consistent with this, WS cells expressing the mutants exhibited less DNA repair efficiency and more sensitivity to etoposide, compared to those expressing wild type. Our findings indicate that phosphorylation of Ser-440 and -467 in WRN are important for relocalization of WRN to nucleoli, and that it is required for efficient DSB repair. C1 [Kusumoto-Matsuo, Rika; May, Alfred; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Ghosh, Deblina; Karmakar, Parimal] Jadavpur Univ, Dept Life Sci & Biotechnol, Kolkata 700032, India. [Ramsden, Dale] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Ramsden, Dale] Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. [Ramsden, Dale] Univ N Carolina, Chapel Hill, NC 27599 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Postdoctoral Fellowship for Research Abroad of Japan Society for the Promotion of Science (JSPS); Intramural Research Program of the National Institutes of Health [CA84442] FX This work was supported by the Postdoctoral Fellowship for Research Abroad of Japan Society for the Promotion of Science (JSPS) [to R.K.]; and the Intramural Research Program of the National Institutes of Health [CA84442 (to D.A.R)]. We thank Dr. Tomasz Kulikowicz for advice. We thank Drs. M. Rossi and M. Raamamorthy for their critical reading of this manuscript and Dr. T. Helleday for NU7026. NR 43 TC 9 Z9 10 U1 1 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD JAN PY 2014 VL 6 IS 1 BP 70 EP 81 PG 12 WC Cell Biology SC Cell Biology GA AA0ZT UT WOS:000330826600010 PM 24429382 ER PT J AU Chen, L Mizutani, A Kasai, T Yan, T Jin, GL Vaidyanath, A El-Aarag, BYA Liu, YX Kudoh, T Salomon, DS Fu, L Seno, M AF Chen, Ling Mizutani, Akifumi Kasai, Tomonari Yan, Ting Jin, Guoliang Vaidyanath, Arun El-Aarag, Bishoy Y. A. Liu, Yixin Kudoh, Takayuki Salomon, David S. Fu, Li Seno, Masaharu TI Mouse induced pluripotent stem cell microenvironment generates epithelial-mesenchymal transition in mouse Lewis lung cancer cells SO AMERICAN JOURNAL OF CANCER RESEARCH LA English DT Article DE Mouse induced pluripotent stem cell; stem cell microenvironment; epithelial-mesenchymal transition; lung Lewis cancer cell ID TUMOR-CELLS; DISEASE; DIFFERENTIATION; METASTASIS; PHENOTYPE; GROWTH; MODEL; LINE AB Induced pluripotent stem (iPS) cells may be a powerful tool in regenerative medicine, but their potential tumorigenicity is a significant challenge for the clinical use of iPS cells. Previously, we succeeded in converting miPS cells into cancer stem cells (CSCs) under the conditions of tumor microenvironment. Both stem cells and tumor cells are profoundly influenced by bi-directional communication with their respective microenvironment, which dictates cell fate determination and behavior. The microenvironment derived from iPS cells has not been well studied. In this paper, we have investigated the effects of secreted factors from Nanog-mouse iPS (miPS) cells on mouse Lewis lung cancer (LLC) cells that are found in the conditioned media. The results demonstrated that miPS cells secrete factors that can convert the epithelia phenotype of LLC cells to a mesenchymal phenotype, and that can promote tumorigenisity, migration and invasion. Furthermore, LLC cells that have been exposed to miPS conditioned medium became resistant to apoptosis. These various biological effects suggest that the miPS microenvironment contain factors that can promote an epithelial-mesenchymal transition (EMT) through an active Snail-MMP axis or by suppressing differentiation in LLC cells. C1 [Chen, Ling; Mizutani, Akifumi; Kasai, Tomonari; Yan, Ting; Jin, Guoliang; Vaidyanath, Arun; Kudoh, Takayuki; Seno, Masaharu] Okayama Univ, Grad Sch Nat Sci & Technol, Dept Med & Bioengn Sci, Okayama 7008530, Japan. [Chen, Ling] Tianjin Cent Hosp Gynecol Obstet, Dept Pathol, Tianjin 300100, Peoples R China. [Chen, Ling; Liu, Yixin] Japan Soc Promot Sci, Tokyo 1028472, Japan. [El-Aarag, Bishoy Y. A.] Menoufia Univ, Fac Sci, Dept Chem, Menoufia, Egypt. [Salomon, David S.] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Fu, Li] Tianjin Med Univ, Canc Hosp, Dept Breast Canc Pathol, Tianjin 300060, Peoples R China. [Fu, Li] Tianjin Med Univ, Canc Hosp, Res Lab, State Key Lab Breast Canc Res, Tianjin 300060, Peoples R China. RP Seno, M (reprint author), Okayama Univ, Grad Sch Nat Sci & Technol, Dept Med & Bioengn Sci, Kita Ku, 3-1-1 Tsushima Naka, Okayama 7008530, Japan. EM fulijyb@hotmail.com; mseno@cc.okayama-u.ac.jp RI SENO, Masaharu /B-2092-2011 OI SENO, Masaharu /0000-0001-8547-6259 FU Ministry of Education, Culture, Sports, Science and Technology in Japan [21300179] FX L. Chen was supported by Grant-in-Aid for JSPS Fellows. This work was partly supported by Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology (No. 21300179) in Japan. NR 31 TC 5 Z9 5 U1 1 U2 15 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 2156-6976 J9 AM J CANCER RES JI Am. J. Cancer Res. PY 2014 VL 4 IS 1 BP 80 EP U92 PG 12 WC Oncology SC Oncology GA AA4MM UT WOS:000331069800007 PM 24482741 ER PT S AU White, BH Ewer, J AF White, Benjamin H. Ewer, John BE Berenbaum, MR TI Neural and Hormonal Control of Postecdysial Behaviors in Insects SO ANNUAL REVIEW OF ENTOMOLOGY, VOL 59, 2014 SE Annual Review of Entomology LA English DT Review; Book Chapter DE ecdysis; bursicon; wing expansion; Drosophila; neuroendocrine; neuroethology ID HAWKMOTH MANDUCA-SEXTA; IMAGINAL ECDYSIS; WING EXPANSION; NEURONAL NETWORK; FRONTAL GANGLION; TELEOGRYLLUS-OCEANICUS; NEUROENDOCRINE CONTROL; SCHISTOCERCA-GREGARIA; PEPTIDERGIC ENSEMBLES; DECISION NETWORK AB The shedding of the old exoskeleton that occurs in insects at the end of a molt (a process called ecdysis) is typically followed by the expansion and tanning of a new one. At the adult molt, these postecdysial processes include expansion and hardening of the wings. Here we describe recent advances in understanding the neural and hormonal control of wing expansion and hardening, focusing on work using Drosophila melanogaster in which genetic manipulations have permitted detailed investigation of postecdysial processes and their modulation by sensory input. To place this work in context, we briefly review recent progress in understanding the neuroendocrine regulation of ecdysis, which appears to be largely conserved across insect species. Investigations into the neuroendocrine networks that regulate ecdysial and postecdysial behaviors provide insights into how stereotyped, yet environmentally responsive, sequences are generated and how they develop and evolve. C1 [White, Benjamin H.] NIMH, Sect Neural Funct, Mol Biol Lab, Bethesda, MD 20892 USA. [Ewer, John] Univ Valparaiso, Fac Ciencias, Ctr Interdisciplinario Neurociencia Valparaiso, Valparaiso, Chile. RP White, BH (reprint author), NIMH, Sect Neural Funct, Mol Biol Lab, Bethesda, MD 20892 USA. EM benjaminwhite@mail.nih.gov; john.ewer@uv.cl OI Ewer, John/0000-0002-6806-3628 FU Intramural NIH HHS [, ZIA MH002800-10]; NIMH NIH HHS [ZIA MH002800] NR 63 TC 11 Z9 11 U1 4 U2 28 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0066-4170 BN 978-0-8243-0159-0 J9 ANNU REV ENTOMOL JI Annu. Rev. Entomol. PY 2014 VL 59 BP 363 EP 381 DI 10.1146/annurev-ento-011613-162028 PG 19 WC Entomology SC Entomology GA BJQ17 UT WOS:000329608900020 PM 24160420 ER PT S AU Burge, CA Eakin, CM Friedman, CS Froelich, B Hershberger, PK Hofmann, EE Petes, LE Prager, KC Weil, E Willis, BL Ford, SE Harvell, CD AF Burge, Colleen A. Eakin, C. Mark Friedman, Carolyn S. Froelich, Brett Hershberger, Paul K. Hofmann, Eileen E. Petes, Laura E. Prager, Katherine C. Weil, Ernesto Willis, Bette L. Ford, Susan E. Harvell, C. Drew BE Carlson, CA Giovannoni, SJ TI Climate Change Influences on Marine Infectious Diseases: Implications for Management and Society SO ANNUAL REVIEW OF MARINE SCIENCE, VOL 6 SE Annual Review of Marine Science LA English DT Review; Book Chapter DE epizootics; mass mortalities; health; oceans; ocean warming ID OYSTER CRASSOSTREA-VIRGINICA; ABALONE HALIOTIS-RUFESCENS; HAPLOSPORIDIUM-NELSONI MSX; CANDIDATUS-XENOHALIOTIS-CALIFORNIENSIS; DOLPHINS STENELLA-COERULEOALBA; RICKETTSIALES-LIKE PROKARYOTE; CARIBBEAN ELKHORN CORAL; SEA-SURFACE TEMPERATURE; BLACK BAND DISEASE; GREAT-BARRIER-REEF AB Infectious diseases are common in marine environments, but the effects of a changing climate on marine pathogens are not well understood. Here we review current knowledge about how the climate drives host-pathogen interactions and infectious disease outbreaks. Climate-related impacts on marine diseases are being documented in corals, shellfish, finfish, and humans; these impacts are less clearly linked for other organisms. Oceans and people are inextricably linked, and marine diseases can both directly and indirectly affect human health, livelihoods, and well-being. We recommend an adaptive management approach to better increase the resilience of ocean systems vulnerable to marine diseases in a changing climate. Land-based management methods of quarantining, culling, and vaccinating are not successful in the ocean; therefore, forecasting conditions that lead to outbreaks and designing tools/approaches to influence these conditions may be the best way to manage marine disease. C1 [Burge, Colleen A.; Harvell, C. Drew] Cornell Univ, Dept Ecol & Evolutionary Biol, Ithaca, NY 14853 USA. [Eakin, C. Mark] NOAA, Coral Reef Watch, College Pk, MD 20740 USA. [Friedman, Carolyn S.] Univ Washington, Sch Aquat & Fishery Sci, Seattle, WA 98195 USA. [Froelich, Brett] Univ N Carolina, Inst Marine Sci, Morehead City, NC 28557 USA. [Hershberger, Paul K.] US Geol Survey, Marrowstone Marine Field Stn, Western Fisheries Res Ctr, Nordland, WA 98358 USA. [Hofmann, Eileen E.] Old Dominion Univ, Dept Ocean Earth & Atmospher Sci, Ctr Coastal Phys Oceanog, Norfolk, VA 23508 USA. [Petes, Laura E.] NOAA, Climate Program Off, Silver Spring, MD 20910 USA. [Prager, Katherine C.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Prager, Katherine C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Weil, Ernesto] Univ Puerto Rico, Dept Marine Sci, Mayaguez, PR 00680 USA. [Willis, Bette L.] James Cook Univ, Australian Res Council Ctr Excellence Coral Reef, Townsville, Qld 4811, Australia. [Willis, Bette L.] James Cook Univ, Sch Marine & Trop Biol, Townsville, Qld 4811, Australia. [Ford, Susan E.] Rutgers State Univ, Haskin Shellfish Res Lab, Port Norris, NJ 08349 USA. RP Burge, CA (reprint author), Cornell Univ, Dept Ecol & Evolutionary Biol, Ithaca, NY 14853 USA. EM cab433@cornell.edu; mark.eakin@noaa.gov; carolynf@uw.edu; bafroeli@unc.edu; phershberger@usgs.gov; hofmann@ccpo.odu.edu; laura.petes@noaa.gov; kcprager@ucla.edu; reefpal@gmail.com; bette.willis@jcu.edu.au; susan@hsrl.rutgers.edu; cdh5@cornell.edu RI Eakin, C. Mark/F-5585-2010 NR 198 TC 83 Z9 87 U1 25 U2 214 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1941-1405 BN 978-0-8243-4506-8 J9 ANNU REV MAR SCI JI Annu. Rev. Mar. Sci. PY 2014 VL 6 BP 249 EP 277 DI 10.1146/annurev-marine-010213-135029 PG 29 WC Geochemistry & Geophysics; Marine & Freshwater Biology; Oceanography SC Geochemistry & Geophysics; Marine & Freshwater Biology; Oceanography GA BJQ32 UT WOS:000329657800012 PM 23808894 ER PT S AU Niciu, MJ Henter, ID Luckenbaugh, DA Zarate, CA Charney, DS AF Niciu, Mark J. Henter, Ioline D. Luckenbaugh, David A. Zarate, Carlos A., Jr. Charney, Dennis S. BE Insel, PA TI Glutamate Receptor Antagonists as Fast-Acting Therapeutic Alternatives for the Treatment of Depression: Ketamine and Other Compounds SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 54 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE NMDA receptor antagonist; rapid-acting antidepressants; major depressive disorder; bipolar depression; preclinical models of depression; mammalian target of rapamycin; mTOR ID TREATMENT-RESISTANT DEPRESSION; D-ASPARTATE ANTAGONIST; RAPID ANTIDEPRESSANT RESPONSE; CLUB-DRUG-USE; MAGNETIC-RESONANCE-SPECTROSCOPY; NEW-YORK-CITY; OBSESSIVE-COMPULSIVE DISORDER; RANDOMIZED CONTROLLED-TRIAL; DELTA-SLEEP RATIO; LOW-DOSE KETAMINE AB The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine's antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine's antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine's adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine's antidepressant effects. C1 [Niciu, Mark J.; Henter, Ioline D.; Luckenbaugh, David A.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20814 USA. [Charney, Dennis S.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Niciu, MJ (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20814 USA. EM mark.niciu@nih.gov RI Niciu, Mark/J-1766-2014 OI Niciu, Mark/0000-0002-5612-3021 FU Intramural NIH HHS [ZIA MH002857-09] NR 132 TC 44 Z9 45 U1 5 U2 41 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0454-6 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2014 VL 54 BP 119 EP 139 DI 10.1146/annurev-pharmtox-011613-135950 PG 21 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BJR57 UT WOS:000329822200007 PM 24392693 ER PT J AU Xavier, CP Melikova, M Chuman, Y Uren, A Baljinnyam, B Rubin, JS AF Xavier, Charles P. Melikova, Maria Chuman, Yoshiro Ueren, Aykut Baljinnyam, Bolormaa Rubin, Jeffrey S. TI Secreted Frizzled-related protein potentiation versus inhibition of Wnt3a/beta-catenin signaling SO CELLULAR SIGNALLING LA English DT Article DE beta-Catenin; Cysteine-rich domain; Frizzled; sFRP; Wnt ID RENAL-CELL CARCINOMA; WNT/BETA-CATENIN; WNT ANTAGONIST; MYOCARDIAL-INFARCTION; COLORECTAL-CANCER; SPEMANN ORGANIZER; PROSTATE-CANCER; BETA-CATENIN; SFRP1; RECEPTOR AB Wnt signaling regulates a variety of cellular processes during embryonic development and in the adult. Many of these activities are mediated by the Frizzled family of seven-pass transmembrane receptors, which bind Wnts via a conserved cysteine-rich domain (CRD). Secreted Frizzled-related proteins (sFRPs) contain an amino-terminal, Frizzled-like CRD and a carboxyl-terminal, heparin-binding netrin-like domain. Previous studies identified sFRPs as soluble Wnt antagonists that bind directly to Wnts and prevent their interaction with Frizzleds. However, subsequent observations suggested that sFRPs and Frizzleds form homodimers and heterodimers via their respective CRDs, and that sFRPs can stimulate signal transduction. Here, we present evidence that sFRP1 either inhibits or enhances signaling in the Wnt3a/beta-catenin pathway, depending on its concentration and the cellular context. Nanomolar concentrations of sFRP1 increased Wnt3a signaling, while higher concentrations blocked it in HEK293 cells expressing a SuperTopFlash reporter. sFRP1 primarily augmented Wnt3a/beta-catenin signaling in C57MG cells, but it behaved as an antagonist in L929 fibroblasts. sFRP1 enhanced reporter activity in L cells that were engineered to stably express Frizzled 5, though not Frizzled 2. This implied that the Frizzled expression pattern could determine the response to sFRP1. Similar results were obtained with sFRP2 in HEK293, C57MG and L cell reporter assays. CRDsFRP1 mimicked the potentiating effect of sFRP1 in multiple settings, contradicting initial expectations that this domain would inhibit Wnt signaling. Moreover, CRDsFRP1 showed little avidity for Wnt3a compared to sFRP1, implying that the mechanism for potentiation by CRDsFRP1 probably does not require an interaction with Wnt protein. Together, these findings demonstrate that sFRPs can either promote or suppress Wnt/beta-catenin signaling, depending on cellular context, concentration and most likely the expression pattern of Fzd receptors. Published by Elsevier Inc. C1 [Xavier, Charles P.; Melikova, Maria; Chuman, Yoshiro; Baljinnyam, Bolormaa; Rubin, Jeffrey S.] Natl Canc Inst, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Ueren, Aykut] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Rubin, JS (reprint author), Bldg 37,Room 2042,37 Convent Dr,MSC 4256, Bethesda, MD 20892 USA. EM rubinj@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX We thank Drs. Xi He, Ray Habas and Randall Moon for providing us with plasmids, and Dr. Jeremy Nathans for sharing the HEK293/STF cell line. We also appreciate discussions with Dr. Sarangan Ravichandran (SAIC-Frederick, Inc.) about CRDsFRP1 and input from other members of the Rubin lab including Dr. Yoshimi Greer and Saad Saffo. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 56 TC 20 Z9 20 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD JAN PY 2014 VL 26 IS 1 BP 94 EP 101 DI 10.1016/j.cellsig.2013.09.016 PG 8 WC Cell Biology SC Cell Biology GA AA0WH UT WOS:000330817600010 PM 24080158 ER PT J AU Nguyen, AB Clark, TT Belgrave, FZ AF Nguyen, Anh B. Clark, Trenette T. Belgrave, Faye Z. TI Gender Roles and Acculturation: Relationships With Cancer Screening Among Vietnamese American Women SO CULTURAL DIVERSITY & ETHNIC MINORITY PSYCHOLOGY LA English DT Article DE Vietnamese American; women; breast cancer; cervical cancer; self-efficacy ID ASIAN-AMERICAN; BREAST-CANCER; UNITED-STATES; BEHAVIORAL-MODEL; ROLE TRAITS; HEALTH; ATTITUDES; CARE; PREDICTORS; SEX AB The aim of this study was to examine the influence of demographic variables and the interplay between gender roles and acculturation on breast and cervical cancer screening outcomes among Vietnamese American women. Convenience sampling was used to recruit 100 Vietnamese women from the Richmond, VA, metropolitan area. Women were recruited to participate in a larger cancer screening intervention. All participants completed measures on demographic variables, gender roles, acculturation, and cancer screening variables. Findings indicated that traditional masculine gender roles were associated with increased self-efficacy for breast and cervical cancer screening. Higher levels of acculturation were associated with higher probability of having had a Papanicolaou test. In addition, acculturation moderated the relationship between traditional female gender roles and cancer screening variables. For highly acculturated women, higher levels of feminine gender roles predicted higher probability of having had a previous clinical breast exam and higher levels of self-efficacy for cervical cancer screening, while the opposite was true for lower acculturated women. The findings of this study indicate the important roles that sociodemographic variables, gender roles, and acculturation play in affecting health attitudes and behaviors among Vietnamese women. These findings also help to identify a potentially high-risk subgroup and existing gaps that need to be targeted by preventive interventions. C1 [Nguyen, Anh B.] NCI, Canc Prevent Fellowship Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Clark, Trenette T.] Univ N Carolina, Sch Social Work, Chapel Hill, NC USA. [Belgrave, Faye Z.] Virginia Commonwealth Univ, Dept Psychol, Richmond, VA 23284 USA. RP Nguyen, AB (reprint author), NCI, Canc Prevent Fellowship Program, Rockville, MD 20850 USA. EM anh.nguyen3@nih.gov FU NCI NIH HHS [5F31CA136235]; NIDA NIH HHS [K01 DA035895] NR 59 TC 2 Z9 2 U1 0 U2 0 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1099-9809 EI 1939-0106 J9 CULT DIVERS ETHN MIN JI Cult. Divers. Ethn. Minor. Psychol. PD JAN PY 2014 VL 20 IS 1 BP 87 EP 97 DI 10.1037/a0033474 PG 11 WC Ethnic Studies; Psychology, Social SC Ethnic Studies; Psychology GA AA1SN UT WOS:000330876100011 PM 24491129 ER PT S AU Wall, VE Garvey, LA Mehalko, JL Procter, LV Esposito, D AF Wall, Vanessa E. Garvey, Leslie A. Mehalko, Jennifer L. Procter, Lauren V. Esposito, Dominic BE Valla, S Lale, R TI Combinatorial Assembly of Clone Libraries Using Site-Specific Recombination SO DNA CLONING AND ASSEMBLY METHODS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Cloning; Gateway; Site-specific recombination; Combinatorics ID PROTEIN EXPRESSION; MAMMALIAN-CELLS; DNA CLONING; GENES AB Generation of DNA clones for use in proteomic and genomic research often requires a significant level of parallel production, as the number of downstream options for these experiments increases. Where a single fluorescently tagged construct may have sufficed before, there is now the need for multiple types of labels for different readouts and different assays. Protein expression, which once utilized a very small set of vectors because of low throughput expression and purification, has now rapidly matured into a high throughput system in which dozens of conditions can be tested in parallel to identify the best candidate clones. This has returned the bottleneck in many of these technologies to the generation of DNA clones, and standard cloning techniques often dramatically limit the throughput and success of such processes. In order to overcome this bottleneck, higher-throughput and more parallel cloning processes need to be developed which would allow rapid, inexpensive production of final clones. In addition, there is a strong need to utilize standardized elements to avoid unnecessarily remaking fragments of clones that could be used in multiple constructs. The advent of recombinational cloning helped to increase the parallel processing of DNA clones, but was still limited by the need to generate different vector backbones for each specific need. The solution to this problem emerged with the introduction of combinatorial approaches to clone construction, based on either homologous or site-specific recombination processes. In particular, the Gateway Multisite system provides all of the necessary components for a highly parallel, inexpensive, rapid, and diverse platform for clone construction in many areas of proteomic and genomic research. Here we describe our optimized system for combinatorial cloning, including improvements in cloning protocols and construct design that permit users to easily generate libraries of clones which can be combined in parallel to create an unlimited number of final constructs. The system is capable of utilizing the tens of thousands of commercially available Gateway clones already in existence, and allows easy adaptation of most DNA vectors to the system. C1 [Wall, Vanessa E.; Garvey, Leslie A.; Mehalko, Jennifer L.; Procter, Lauren V.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Prot Express Lab, Frederick, MD 21702 USA. [Esposito, Dominic] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Wall, VE (reprint author), SAIC Frederick Inc, Frederick Natl Lab Canc Res, Prot Express Lab, Frederick, MD 21702 USA. FU PHS HHS [HHSN261200800001E] NR 9 TC 1 Z9 1 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-763-1; 978-1-62703-764-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1116 BP 193 EP 208 DI 10.1007/978-1-62703-764-8_14 D2 10.1007/978-1-62703-764-8 PG 16 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BJR28 UT WOS:000329761800015 PM 24395366 ER PT J AU Quick, VM Byrd-Bredbenner, C AF Quick, Virginia M. Byrd-Bredbenner, Carol TI Disordered eating, socio-cultural media influencers, body image, and psychological factors among a racially/ethnically diverse population of college women SO EATING BEHAVIORS LA English DT Article DE Disordered eating; Body image; Women; College ID UNIVERSITY-STUDENTS; DEPRESSIVE SYMPTOMS; ADOLESCENT GIRLS; COMMUNITY SAMPLE; AFRICAN-AMERICAN; DISSATISFACTION; WEIGHT; BLACK; BEHAVIORS; FEMALES AB This study examined disordered eating, socio-cultural media influencers, body image, and psychological factors among a large, racially/ethnically diverse sample of college women (n = 1445; 58% White, 21% Asian, 11% Hispanic, 11% Black) who completed an online survey. Black women were significantly more satisfied with their weight and shape and had lower eating concerns, disinhibited eating, and emotional eating than all other racial/ethnic groups. Black women tended to have significantly higher levels of self-esteem, were less likely to compare their body to those of people in the media, felt less pressured to attain the physical appearance standard set by the media, and had less awareness of the societal appearance norms set by the media than other racial groups. Findings suggest that Black college women, independent of weight status, may be protected from disordered eating, negative body image, and societal media pressures. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Quick, Virginia M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, DHHS, Bethesda, MD 20892 USA. [Byrd-Bredbenner, Carol] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08903 USA. RP Quick, VM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, DHHS, Bethesda, MD 20892 USA. EM gingermquick@gmail.com; bredbenner@aesop.rutgers.edu RI Byrd-Bredbenner, Carol/F-8064-2015; OI Byrd-Bredbenner, Carol/0000-0002-8010-3987; Quick, Virginia/0000-0002-4338-963X FU Intramural NIH HHS [Z99 HD999999] NR 39 TC 11 Z9 12 U1 3 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD JAN PY 2014 VL 15 IS 1 BP 37 EP 41 DI 10.1016/j.eatbeh.2013.10.005 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AA3WM UT WOS:000331025900008 PM 24411747 ER PT J AU Aggleton, JP Saunders, RC Wright, NF Vann, SD AF Aggleton, John P. Saunders, Richard C. Wright, Nicholas F. Vann, Seralynne D. TI The origin of projections from the posterior cingulate and retrosplenial cortices to the anterior, medial dorsal and laterodorsal thalamic nuclei of macaque monkeys SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE cingulate cortex; memory; primate; retrosplenial cortex; thalamus ID MILD COGNITIVE IMPAIRMENT; HEAD-DIRECTION CELLS; ALZHEIMERS-DISEASE; RHESUS-MONKEY; EFFERENT PROJECTIONS; MEDIODORSAL NUCLEUS; CORTEX; RAT; CONNECTIONS; LESIONS AB Interactions between the posterior cingulate cortex (areas 23 and 31) and the retrosplenial cortex (areas 29 and 30) with the anterior, laterodorsal and dorsal medial thalamic nuclei are thought to support various aspects of cognition, including memory and spatial processing. To detail these interactions better, the present study used retrograde tracers to reveal the origins of the corticothalamic projections in two closely related monkey species (Macaca mulatta, Macaca fascicularis). The medial dorsal thalamic nucleus received only light cortical inputs, which predominantly arose from area 23. Efferents to the anterior medial thalamic nucleus also arose principally from area 23, but these projections proved more numerous than those to the medial dorsal nucleus and also involved additional inputs from areas 29 and 30. The anterior ventral and laterodorsal thalamic nuclei had similar sources of inputs from the posterior cingulate and retrosplenial cortices. For both nuclei, the densest projections arose from areas 29 and 30, with numbers of thalamic inputs often decreasing when going dorsal from area 23a to 23c and to area 31. In all cases, the corticothalamic projections almost always arose from the deepest cortical layer. The different profiles of inputs to the anterior medial and anterior ventral thalamic nuclei reinforce other anatomical and electrophysiological findings suggesting that these adjacent thalamic nuclei serve different, but complementary, functions supporting memory. While the lack of retrosplenial connections singled out the medial dorsal nucleus, the very similar connection patterns shown by the anterior ventral and laterodorsal nuclei point to common roles in cognition. C1 [Aggleton, John P.; Wright, Nicholas F.; Vann, Seralynne D.] Cardiff Univ, Sch Psychol, Cardiff CF10 3AT, S Glam, Wales. [Saunders, Richard C.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Aggleton, JP (reprint author), Cardiff Univ, Sch Psychol, 70 Pk Pl, Cardiff CF10 3AT, S Glam, Wales. EM Aggleton@cf.ac.uk OI Vann, Seralynne/0000-0002-6709-8773; Aggleton, John/0000-0002-5573-1308 FU Wolfson Research Merit Award FX This research received support from a Wolfson Research Merit Award. NR 77 TC 5 Z9 5 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JAN PY 2014 VL 39 IS 1 BP 107 EP 123 DI 10.1111/ejn.12389 PG 17 WC Neurosciences SC Neurosciences & Neurology GA AA3DI UT WOS:000330972700011 PM 24134130 ER PT J AU Mansky, PJ Wallerstedt, DB Sannes, TS Stagl, J Johnson, LL Blackman, MR Grem, JL Swain, SM Monahan, BP AF Mansky, Patrick J. Wallerstedt, Dawn B. Sannes, Timothy S. Stagl, Jamie Johnson, Laura Lee Blackman, Marc R. Grem, Jean L. Swain, Sandra M. Monahan, Brian P. TI NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors (vol 2013, 964592, 2013) SO EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE LA English DT Correction C1 [Mansky, Patrick J.] Bellin Hlth, Canc Team, Green Bay, WI 54313 USA. [Mansky, Patrick J.; Johnson, Laura Lee] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Wallerstedt, Dawn B.] Samueli Inst, Alexandria, VA 22314 USA. [Sannes, Timothy S.] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL 32611 USA. [Stagl, Jamie] Univ Miami, Miami, FL 33124 USA. [Blackman, Marc R.] Georgetown Univ, Sch Med, Vet Affairs Med Ctr, Res Serv 151, Washington, DC 20422 USA. [Blackman, Marc R.] Georgetown Univ, Sch Med, Dept Med, Washington, DC 20422 USA. [Grem, Jean L.] Univ Nebraska Med Ctr, Omaha, NE 68198 USA. [Swain, Sandra M.] Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. [Monahan, Brian P.] Uniformed Serv Univ Hlth Sci, Dept Med, Hematol & Med Oncol Div, Bethesda, MD 20814 USA. RP Mansky, PJ (reprint author), Bellin Hlth, Canc Team, 1580 Commanche Ave, Green Bay, WI 54313 USA. EM manpaj@bellin.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1741-427X EI 1741-4288 J9 EVID-BASED COMPL ALT JI Evid.-based Complement Altern. Med. PY 2014 AR 606348 DI 10.1155/2014/606348 PG 2 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA AB4MX UT WOS:000331765100001 ER PT J AU Talavage, TM Gonzalez-Castillo, J Scott, SK AF Talavage, Thomas M. Gonzalez-Castillo, Javier Scott, Sophie K. TI Auditory neuroimaging with fMRI and PET SO HEARING RESEARCH LA English DT Review ID COCHLEAR IMPLANT PATIENTS; SCANNER ACOUSTIC NOISE; CEREBRAL-BLOOD-FLOW; HUMAN VISUAL-CORTEX; TONOTOPIC ORGANIZATION; FUNCTIONAL MRI; HUMAN BRAIN; NEURONAL-ACTIVITY; SENSORY STIMULATION; SPEECH-PERCEPTION AB For much of the past 30 years, investigations of auditory perception and language have been enhanced or even driven by the use of functional neuroimaging techniques that specialize in localization of central responses. Beginning with investigations using positron emission tomography (PET) and gradually shifting primarily to usage of functional magnetic resonance imaging (fMRI), auditory neuroimaging has greatly advanced our understanding of the organization and response properties of brain regions critical to the perception of and communication with the acoustic world in which we live. As the complexity of the questions being addressed has increased, the techniques, experiments and analyses applied have also become more nuanced and specialized. A brief review of the history of these investigations sets the stage for an overview and analysis of how these neuroimaging modalities are becoming ever more effective tools for understanding the auditory brain. We conclude with a brief discussion of open methodological issues as well as potential clinical applications for auditory neuroimaging. This article is part of a Special Issue entitled . (C) 2013 Elsevier B.V. All rights reserved. C1 [Talavage, Thomas M.] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. [Talavage, Thomas M.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. [Gonzalez-Castillo, Javier] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Scott, Sophie K.] UCL, Inst Cognit Neurosci, London, England. RP Talavage, TM (reprint author), 465 Northwestern Ave, W Lafayette, IN 47907 USA. EM tmt@purdue.edu RI Scott, Sophie/A-1843-2010; OI Scott, Sophie/0000-0001-7510-6297; Gonzalez-Castillo, Javier/0000-0002-6520-5125 FU NIBIB NIH HHS [R01 EB003990]; Wellcome Trust [090961] NR 155 TC 12 Z9 12 U1 4 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 EI 1878-5891 J9 HEARING RES JI Hear. Res. PD JAN PY 2014 VL 307 SI SI BP 4 EP 15 DI 10.1016/j.heares.2013.09.009 PG 12 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA AA8LU UT WOS:000331347800002 PM 24076424 ER PT J AU Parrish, JA Schachter, SC Carleton, PF Dempsey, M Spiliotis, D Collins, J AF Parrish, John A. Schachter, Steven C. Carleton, Penny Ford Dempsey, Mike Spiliotis, Diane Collins, John TI Accelerating the Innovation Cycle SO IEEE PULSE LA English DT Article C1 [Parrish, John A.; Schachter, Steven C.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Schachter, Steven C.; Spiliotis, Diane; Collins, John] CIMIT, Boston, MA USA. [Carleton, Penny Ford] NIBIB Point Of Care Technol Ctr Primary Care, CIMITs Clin Syst Innovat Program, Bethesda, MD USA. [Carleton, Penny Ford] CIMIT, Boston Simulat Consortium, Boston, MA USA. [Dempsey, Mike] CIMIT, Accelerator Program, Boston, MA USA. RP Parrish, JA (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. EM jparrish@partners.org; sschacht@bidmc.harvard.edu; pcarleton@partners.org; mdempsey1@partners.org; dspiliotis@partners.org; Jcollins11@partners.org NR 0 TC 1 Z9 1 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD JAN-FEB PY 2014 VL 5 IS 1 BP 46 EP 54 DI 10.1109/MPUL.2013.2289464 PG 9 WC Engineering, Biomedical SC Engineering GA AA2AU UT WOS:000330898300010 PM 25296373 ER PT J AU Tugarinov, V Venditti, V Clore, GM AF Tugarinov, Vitali Venditti, Vincenzo Clore, G. Marius TI A NMR experiment for simultaneous correlations of valine and leucine/isoleucine methyls with carbonyl chemical shifts in proteins SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Chemical shift assignments; Methyl labeling; Enzyme I; Methyl TROSY; Isotope shifts ID MOLECULAR-WEIGHT PROTEINS; BACTERIAL PHOSPHOTRANSFERASE SYSTEM; COLI ENZYME-I; SUGAR-TRANSPORT; TERMINAL DOMAIN; MONOMER/DIMER TRANSITION; SALMONELLA-TYPHIMURIUM; MULTIDIMENSIONAL NMR; LABELING STRATEGY; SPECTROSCOPY AB A methyl-detected 'out-and-back' NMR experiment for obtaining simultaneous correlations of methyl resonances of valine and isoleucine/leucine residues with backbone carbonyl chemical shifts, SIM-HMCM(CGCBCA)CO, is described. The developed pulse-scheme serves the purpose of convenience in recording a single data set for all Ile(delta 1), Leu(delta) and Val(gamma) (ILV) methyl positions instead of acquiring two separate spectra selective for valine or leucine/isoleucine residues. The SIM-HMCM(CGCBCA)CO experiment can be used for ILV methyl assignments in moderately sized protein systems (up to similar to 100 kDa) where the backbone chemical shifts of C-13(alpha), C-13(beta) and (CO)-C-13 are known from prior NMR studies and where some losses in sensitivity can be tolerated for the sake of an overall reduction in NMR acquisition time. C1 [Tugarinov, Vitali; Venditti, Vincenzo; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tugarinov, V (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM vitali.tugarinov@nih.gov; mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Program of the NIH; NIDDK; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX 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 59 TC 7 Z9 7 U1 2 U2 18 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD JAN PY 2014 VL 58 IS 1 BP 1 EP 8 DI 10.1007/s10858-013-9803-1 PG 8 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA AA1AA UT WOS:000330827300001 PM 24346684 ER PT J AU Huang, RSP Oleske, DA Tholpady, A Chang, BN Dasgupta, A Nguyen, A Wahed, A AF Huang, Richard Sheng Poe Oleske, Deanna Alicia Tholpady, Ashok Chang, Brian N. Dasgupta, Amitava Andy Nguyen Wahed, Amer TI High False-Positive Rate for Monoclonal Gammopathy Using Capillary Electrophoresis (CAPILLARYS 2) Alone SO JOURNAL OF CLINICAL LABORATORY ANALYSIS LA English DT Article DE monoclonal gammopathy; capillary zone electrophoresis; agarose gel electrophoresis; immunofixation electrophoresis ID SERUM-PROTEIN ELECTROPHORESIS; AGAROSE-GEL ELECTROPHORESIS; ZONE-ELECTROPHORESIS; PARAPROTEINS; PERFORMANCE; SEPARATION; SYSTEM; SEBIA AB BackgroundCapillary zone electrophoresis (CZE) is a newer method of performing serum protein electrophoresis and is considered to be faster and more efficient than agarose gel method. We decided to evaluate CZE as an efficient screening tool for monoclonal gammopathies, and we began recommending immunofixation studies in cases with such minor/subtle distortions to avoid missing monoclonal gammopathies. MethodsWe evaluated 163 serum protein agarose gel electrophoresis (SPAGE) samples between October and November 2011, and 447 serum protein CZE (SPCZE) samples between January 2012 to February 2012 and August 2012 to September 2012. ResultsImmunofixation studies were recommended in 51 of 163 cases (31.3%) performed by SPAGE, and in 274 of 447 cases (61.3%) performed by SPCZE. While using SPAGE, of the 51 cases recommended for immunofixation (24 were performed to date), six cases (25.0%) were positive for monoclonal gammopathy. In contrast, while using SPCZE, of the 274 cases recommended for immunofixation (118 were performed to date), 18 cases (15.2%) were positive for monoclonal gammopathy. Using the SPCZE method, of these 18 cases, five (27.8%) had minor/subtle distortions without obvious peaks. Our recommendation rate for immunofixation studies has thus almost doubled (61.3% vs. 31.3%) with the adoption of SPCZE. Yet, using SPCZE has not translated to detecting more cases of true monoclonal gammopathies. ConclusionTherefore, we conclude that there is a high false-positive rate for monoclonal gammopathy using CE alone. (C) 2013 Wiley Periodicals, Inc. C1 [Huang, Richard Sheng Poe; Oleske, Deanna Alicia; Chang, Brian N.; Dasgupta, Amitava; Andy Nguyen; Wahed, Amer] Univ Texas Hlth Sci Ctr Houston, Dept Pathol & Lab Med, Houston, TX 77030 USA. [Tholpady, Ashok] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Wahed, A (reprint author), Univ Texas Hlth Sci Ctr Houston, 6431 Fannin St,MSB 2-278, Houston, TX 77030 USA. EM Md.A.Wahed@uth.tmc.edu OI Tholpady, Ashok/0000-0003-3978-9574 NR 17 TC 1 Z9 1 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-8013 EI 1098-2825 J9 J CLIN LAB ANAL JI J. Clin. Lab. Anal. PD JAN PY 2014 VL 28 IS 1 BP 42 EP 46 DI 10.1002/jcla.21641 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AA0OF UT WOS:000330793800007 PM 24375896 ER PT J AU Baranowski, T Islam, N Douglass, D Dadabhoy, H Beltran, A Baranowski, J Thompson, D Cullen, KW Subar, AF AF Baranowski, T. Islam, N. Douglass, D. Dadabhoy, H. Beltran, A. Baranowski, J. Thompson, D. Cullen, K. W. Subar, A. F. TI Food Intake Recording Software System, version 4 (FIRSSt4): a self-completed 24-h dietary recall for children SO JOURNAL OF HUMAN NUTRITION AND DIETETICS LA English DT Review DE assessment; children; diet; recall; web-based ID 13-YEAR-OLD CHILDREN; MEASUREMENT ERROR; ACCURACY; RELIABILITY; 4TH-GRADE; VALIDITY; STUDENTS AB The Food Intake Recording Software System, version 4 (firsst4), is a web-based 24-h dietary recall (24hdr) self-administered by children based on the Automated Self-Administered 24-h recall (ASA24) (a self-administered 24hdr for adults). The food choices in firsst4 are abbreviated to include only those reported by children in US national surveys; and detailed food probe questions are simplified to exclude those that children could not be expected to answer (e.g. questions regarding food preparation and added fats). ASA24 and firsst4 incorporate 10000+ food images, with up to eight images per food, to assist in portion size estimation. We review the formative research conducted during the development of firsst4. When completed, firsst4 will be hosted and maintained for investigator use on the National Cancer Institute's ASA24 website. C1 [Baranowski, T.; Islam, N.; Douglass, D.; Dadabhoy, H.; Beltran, A.; Baranowski, J.; Thompson, D.; Cullen, K. W.] USDA ARS, Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Subar, A. F.] Natl Canc Inst, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch EPN 4005, Bethesda, MD USA. RP Baranowski, T (reprint author), USDA ARS, Baylor Coll Med, Childrens Nutr Res Ctr, 1100 Bates St, Houston, TX 77030 USA. EM tbaranow@bcm.edu OI Baranowski, Tom/0000-0002-0653-2222 FU National Cancer Institute [5 U01 CA130762-02]; USDA/ARS [58-6250-6001] FX The authors declare that they have no conflicts of interest. This research was primarily funded by a grant from the National Cancer Institute (5 U01 CA130762-02). This work is also a publication of the United States Department of Agriculture (USDA/ARS) Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, and had been funded in part with federal funds from the USDA/ARS under Cooperative Agreement No. 58-6250-6001. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organisations imply endorsement from the US government. NR 34 TC 12 Z9 12 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3871 EI 1365-277X J9 J HUM NUTR DIET JI J. Hum. Nutr. Diet. PD JAN PY 2014 VL 27 SU 1 SI SI BP 66 EP 71 DI 10.1111/j.1365-277X.2012.01251.x PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AA5JH UT WOS:000331131400009 PM 22616645 ER PT J AU Wei, L Shi, JF Afari, G Bhattacharyya, S AF Wei, Ling Shi, Jianfeng Afari, George Bhattacharyya, Sibaprasad TI Preparation of clinical-grade Zr-89-panitumumab as a positron emission tomography biomarker for evaluating epidermal growth factor receptor-targeted therapy SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE 89Zr-immuno-PET; Clinical production; Panitumumab; PET imaging ID MONOCLONAL-ANTIBODY; COLORECTAL-CANCER; PET; PANITUMUMAB; EGFR AB Panitumumab is a fully human monoclonal antibody approved for the treatment of epidermal growth factor receptor (EGFR) positive colorectal cancer. Recently, panitumumab has been radiolabeled with Zr-89 and evaluated for its potential to be used as immuno-positron emission tomography (PET) probe for EGFR positive cancers. Interesting preclinical results published by several groups of researchers have prompted us to develop a robust procedure for producing clinical-grade Zr-89-panitumumab as an immuno-PET probe to evaluate EGFR-targeted therapy. In this process, clinical-grade panitumumab is bio-conjugated with desferrioxamine chelate and subsequently radiolabeled with Zr-89 resulting in high radiochemical yield (>70%, n=3) and purity (>98%, n=3). All quality control (QC) tests were performed according to United States Pharmacopeia specifications. QC tests showed that Zr-89-panitumumab met all specifications for human injection. Herein, we describe a step-by-step method for the facile synthesis and QC tests of Zr-89-panitumumab for medical use. The entire process of bioconjugation, radiolabeling, and all QC tests will take about 5h. Because the synthesis is fully manual, two rapid, in-process QC tests have been introduced to make the procedure robust and error free. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Wei, Ling; Shi, Jianfeng; Afari, George; Bhattacharyya, Sibaprasad] ADRD, SAIC Frederick, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Bhattacharyya, S (reprint author), ADRD, SAIC Frederick, Frederick Natl Lab Canc Res, Frederick, MD USA. EM bhattacharyyas2@mail.nih.gov FU National Cancer Institute, National Institutes of Health [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 No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors are grateful to Dr. Lawrence Szajek of cyclotron facility at NIH Bethesda for providing 89Zr-oxalate. NR 25 TC 4 Z9 4 U1 3 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD JAN PY 2014 VL 57 IS 1 BP 25 EP 35 DI 10.1002/jlcr.3134 PG 11 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA AA4LZ UT WOS:000331068400004 PM 24448743 ER PT J AU Chen, YC Nawaz, AA Zhao, YH Huang, PH McCoy, JP Levine, SJ Wang, L Huang, TJ AF Chen, Yuchao Nawaz, Ahmad Ahsan Zhao, Yanhui Huang, Po-Hsun McCoy, J. Phillip Levine, Stewart J. Wang, Lin Huang, Tony Jun TI Standing surface acoustic wave (SSAW)-based microfluidic cytometer SO LAB ON A CHIP LA English DT Article ID ON-A-CHIP; POLYDIMETHYLSILOXANE PDMS MICROCHANNELS; FLOW-CYTOMETRY; HIGH-THROUGHPUT; CHANNEL; DEVICE; MICROPARTICLES; SHEATHLESS; PARTICLES; MICROCHIP AB The development of microfluidic chip-based cytometers has become an important area due to their advantages of compact size and low cost. Herein, we demonstrate a sheathless microfluidic cytometer which integrates a standing surface acoustic wave (SSAW)-based microdevice capable of 3D particle/cell focusing with a laser-induced fluorescence (LIF) detection system. Using SSAW, our microfluidic cytometer was able to continuously focus microparticles/cells at the pressure node inside a microchannel. Flow cytometry was successfully demonstrated using this system with a coefficient of variation (CV) of less than 10% at a throughput of similar to 1000 events s(-1) when calibration beads were used. We also demonstrated that fluorescently labeled human promyelocytic leukemia cells (HL-60) could be effectively focused and detected with our SSAW-based system. This SSAW-based microfluidic cytometer did not require any sheath flows or complex structures, and it allowed for simple operation over a wide range of sample flow rates. Moreover, with the gentle, bio-compatible nature of low-power surface acoustic waves, this technique is expected to be able to preserve the integrity of cells and other bioparticles. C1 [Chen, Yuchao; Nawaz, Ahmad Ahsan; Zhao, Yanhui; Huang, Po-Hsun; Huang, Tony Jun] Penn State Univ, Dept Engn Sci & Mech, University Pk, PA 16802 USA. [McCoy, J. Phillip; Levine, Stewart J.] NHLBI, Bethesda, MD 20810 USA. [Wang, Lin] Ascent Bionano Technol Inc, State Coll, PA 16801 USA. RP Huang, TJ (reprint author), Penn State Univ, Dept Engn Sci & Mech, 227 Hammond Bldg, University Pk, PA 16802 USA. EM junhuang@psu.edu RI Zhao, Yanhui/D-3926-2011; Chen, Yuchao/I-6237-2012; Huang, Po-Hsun/A-2713-2015; Huang, Tony/A-1546-2009 OI Zhao, Yanhui/0000-0003-1131-8527; Huang, Po-Hsun/0000-0001-9600-0141; FU National Institutes of Health [1DP2OD007209-01]; National Science Foundation [ECCS-0824183, ECCS-0801922]; Penn State Center for Nanoscale Science (MRSEC) [DMR-0820404]; NHLBI Division of Intramural Research FX We gratefully acknowledge financial support from National Institutes of Health (Director's New Innovator Award, 1DP2OD007209-01), National Science Foundation (ECCS-0824183 and ECCS-0801922), and the Penn State Center for Nanoscale Science (MRSEC) under grant DMR-0820404. J.P.M. and S.J.L. are supported by the NHLBI Division of Intramural Research. Components of this work were conducted at the Penn State node of the NSF-funded National Nanotechnology Infrastructure Network. NR 75 TC 43 Z9 43 U1 6 U2 72 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1473-0197 EI 1473-0189 J9 LAB CHIP JI Lab Chip PY 2014 VL 14 IS 5 BP 916 EP 923 DI 10.1039/c3lc51139a PG 8 WC Biochemical Research Methods; Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Chemistry; Science & Technology - Other Topics GA AA0KQ UT WOS:000330784400011 PM 24406848 ER PT J AU Chen, Y Li, S Gu, Y Li, P Ding, X Wang, L McCoy, JP Levine, SJ Huang, TJ AF Chen, Yuchao Li, Sixing Gu, Yeyi Li, Peng Ding, Xiaoyun Wang, Lin McCoy, J. Philip Levine, Stewart J. Huang, Tony Jun TI Continuous enrichment of low-abundance cell samples using standing surface acoustic waves (SSAW) SO LAB ON A CHIP LA English DT Article ID CIRCULATING TUMOR-CELLS; ON-A-CHIP; MICROFLUIDIC CHANNEL; OPTICAL MANIPULATION; MICROPARTICLES; SEPARATION; TRAP; CONCENTRATOR; PARTICLES; SYSTEMS AB Cell enrichment is a powerful tool in a variety of cellular studies, especially in applications with low-abundance cell types. In this work, we developed a standing surface acoustic wave (SSAW) based microfluidic device for non-contact, continuous cell enrichment. With a pair of parallel interdigital transducers (IDT) deposited on a piezoelectric substrate, a one-dimensional SSAW field was established along disposable micro-tubing channels, generating numerous pressure nodes (and thus numerous cell-enrichment regions). Our method is able to concentrate highly diluted blood cells by more than 100 fold with a recovery efficiency of up to 99%. Such highly effective cell enrichment was achieved without using sheath flow. The SSAW-based technique presented here is simple, bio-compatible, label-free, and sheath-flow-free. With these advantages, it could be valuable for many biomedical applications. C1 [Chen, Yuchao; Li, Sixing; Li, Peng; Ding, Xiaoyun; Huang, Tony Jun] Penn State Univ, Dept Engn Sci & Mech, University Pk, PA 16802 USA. [Li, Sixing; Huang, Tony Jun] Penn State Univ, Huck Inst Life Sci, Cell & Dev Biol CDB Grad Program, University Pk, PA 16802 USA. [Gu, Yeyi] Penn State Univ, Dept Food Sci, University Pk, PA 16802 USA. [Wang, Lin] Ascent Bionano Technol Inc, State Coll, PA 16802 USA. [McCoy, J. Philip; Levine, Stewart J.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Huang, TJ (reprint author), Penn State Univ, Dept Engn Sci & Mech, 227 Hammond Bldg, University Pk, PA 16802 USA. EM junhuang@psu.edu RI Chen, Yuchao/I-6237-2012; Li, Sixing/F-2383-2013; Ding, Xiaoyun/F-3695-2012; Li, Peng/B-3054-2013; Huang, Tony/A-1546-2009 OI Ding, Xiaoyun/0000-0003-4252-9335; Li, Peng/0000-0002-8332-7142; FU National Institutes of Health [1DP2OD007209-01]; American Asthma Foundation (AAF) Scholar Award; National Science Foundation; Penn State Center for Nanoscale Science (MRSEC) [DMR-0820404]; NHLBI Division of Intramural Research; NSF-funded National Nanotechnology Infrastructure Network FX We gratefully acknowledge financial support from National Institutes of Health (Director's New Innovator Award, 1DP2OD007209-01), American Asthma Foundation (AAF) Scholar Award, the National Science Foundation and the Penn State Center for Nanoscale Science (MRSEC) under grant DMR-0820404. J.P.M. and S.J.L. are supported by the NHLBI Division of Intramural Research. Components of this work were conducted at the Penn State node of the NSF-funded National Nanotechnology Infrastructure Network. NR 59 TC 35 Z9 35 U1 8 U2 61 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1473-0197 EI 1473-0189 J9 LAB CHIP JI Lab Chip PY 2014 VL 14 IS 5 BP 924 EP 930 DI 10.1039/c3lc51001h PG 7 WC Biochemical Research Methods; Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Chemistry; Science & Technology - Other Topics GA AA0KQ UT WOS:000330784400012 PM 24413889 ER PT J AU Parikh, S Goldstein, A Koenig, MK Scaglia, F Enns, GM Saneto, R Anselm, I Collins, A Cohen, BH DeBrosse, SD Dimmock, D Falk, MJ Ganesh, J Greene, C Gropman, AL Haas, R Kahler, SG Kamholz, J Kendall, F Korson, MS Mattman, A Milone, M Niyazov, D Pearl, PL Reimschisel, T Salvarinova-Zivkovic, R Sims, K Tarnopolsky, M Tsao, CY van Hove, J Walsh, L Wolfe, LA AF Parikh, Sumit Goldstein, Amy Koenig, Mary Kay Scaglia, Fernando Enns, Gregory M. Saneto, Russell Anselm, Irina Collins, Abigail Cohen, Bruce H. DeBrosse, Suzanne D. Dimmock, David Falk, Marni J. Ganesh, Jaya Greene, Carol Gropman, Andrea L. Haas, Richard Kahler, Stephen G. Kamholz, John Kendall, Fran Korson, Mark S. Mattman, Andre Milone, Margherita Niyazov, Dmitriy Pearl, Phillip L. Reimschisel, Tyler Salvarinova-Zivkovic, Ramona Sims, Katherine Tarnopolsky, Mark Tsao, Chang-Yong van Hove, Johan Walsh, Laurence Wolfe, Lynne A. CA Mitochondrial Med Soc Clinical Dir MMS Clinical Director's Work Grp TI Practice patterns of mitochondrial disease physicians in North America. Part 1: Diagnostic and clinical challenges SO MITOCHONDRION LA English DT Article DE Mitochondrial disease; Mitochondrial medicine; Clinical guidelines ID POLYACRYLAMIDE-GEL ELECTROPHORESIS; RESPIRATORY-CHAIN DEFICIENCIES; OXIDATIVE-PHOSPHORYLATION; DISORDERS; CRITERIA; CHILDREN; AUTISM; TOOL; DNA AB Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care. (C) 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 [Anselm, Irina] Boston Childrens Hosp, Boston, MA USA. [Collins, Abigail] Univ Colorado, Sch Med, Denver, CO USA. [Cohen, Bruce H.] Childrens Hosp, Med Ctr Akron, NeuroDev Sci Ctr, Akron, OH USA. [DeBrosse, Suzanne D.] Univ Hosp Case Med Ctr, Ctr Human Genet, Cleveland, OH USA. [DeBrosse, Suzanne D.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Dimmock, David] Med Coll Wisconsin, Dept Pediat, Div Genet, Milwaukee, WI 53226 USA. [Falk, Marni J.] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA. [Falk, Marni J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ganesh, Jaya] Childrens Hosp Philadelphia, Sect Metab Dis, Philadelphia, PA 19104 USA. [Greene, Carol] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Gropman, Andrea L.; Pearl, Phillip L.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Gropman, Andrea L.] George Washington Univ Hlth Sci, Washington, DC USA. [Haas, Richard] UCSD Med Ctr, La Jolla, CA USA. [Haas, Richard] Rady Childrens Hosp San Diego, La Jolla, CA USA. [Kahler, Stephen G.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Kahler, Stephen G.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Kamholz, John] Wayne State Univ, Detroit, MI USA. [Kendall, Fran] Virtual Med Practice LLC, Atlanta, GA USA. [Korson, Mark S.] Tufts Med Ctr, Boston, MA USA. [Mattman, Andre] Vancouver Gen Hosp, Adult Metab Dis Clin, Vancouver, BC, Canada. [Milone, Margherita] Mayo Med Ctr, Rochester, MN USA. [Niyazov, Dmitriy] Ochsner Clin Fdn, Dept Pediat, New Orleans, IA USA. [Reimschisel, Tyler] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Salvarinova-Zivkovic, Ramona] Univ British Columbia, BC Childrens Hosp, Dept Pediat, Div Biochem Dis, Vancouver, BC V5Z 1M9, Canada. [Sims, Katherine] Harvard Univ, Sch Med, Boston, MA USA. [Sims, Katherine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tarnopolsky, Mark] McMaster Univ, Hamilton, ON, Canada. [Tsao, Chang-Yong] Nationwide Childrens Hosp, Columbus, OH USA. [van Hove, Johan] Childrens Hosp Colorado, Denver, CO USA. [Walsh, Laurence] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Walsh, Laurence] James Whitcomb Riley Hosp Children, Indianapolis, IN 46202 USA. [Wolfe, Lynne A.] NIH, Bethesda, MD 20892 USA. [Parikh, Sumit] Cleveland Clin, Childrens Hosp, Ctr Child Neurol, Cleveland, OH 44195 USA. [Goldstein, Amy] Childrens Hosp Pittsburgh, Div Child Neurol, Pittsburgh, PA 15213 USA. [Koenig, Mary Kay] Univ Texas Houston, Sch Med, Div Child & Adolescent Neurol, Houston, TX USA. [Scaglia, Fernando] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Scaglia, Fernando] Texas Childrens Hosp, Houston, TX 77030 USA. [Enns, Gregory M.] Stanford Univ, Dept Pediat, Div Med Genet, Lucile Packard Childrens Hosp, Palo Alto, CA 94304 USA. [Saneto, Russell] Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA. RP Parikh, S (reprint author), Cleveland Clin, 9500 Euclid Ave,S60, Cleveland, OH 44195 USA. EM parikhs@ccf.org RI Falk, Marni/K-1997-2014; Dimmock, David/I-7913-2015 OI Dimmock, David/0000-0001-6690-2523 NR 21 TC 8 Z9 8 U1 2 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD JAN PY 2014 VL 14 BP 26 EP 33 DI 10.1016/j.mito.2013.07.116 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA AA2GD UT WOS:000330912200004 PM 23891656 ER PT J AU Tian, LJ Choi, SC Murakami, Y Allen, J Morse, HC Qi, CF Krzewski, K Coligan, JE AF Tian, Linjie Choi, Seung-Chul Murakami, Yousuke Allen, Joselyn Morse, Herbert C., III Qi, Chen-Feng Krzewski, Konrad Coligan, John E. TI p85 alpha recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression SO NATURE COMMUNICATIONS LA English DT Article ID INHIBITORY RECEPTOR; TYROSINE KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; CMRF-35-LIKE MOLECULE-1; PSEUDOPOD EXTENSION; CORPSE CLEARANCE; PHAGOCYTOSIS; ACTIVATION; DISEASE AB Apoptotic cell (AC) clearance is essential for immune homeostasis. Here we show that mouse CD300f (CLM-1) recognizes outer membrane-exposed phosphatidylserine, and regulates the phagocytosis of ACs. CD300f accumulates in phagocytic cups at AC contact sites. Phosphorylation within CD300f cytoplasmic tail tyrosine-based motifs initiates signals that positively or negatively regulate AC phagocytosis. Y276 phosphorylation is necessary for enhanced CD300f-mediated phagocytosis through the recruitment of the p85 alpha regulatory subunit of phosphatidylinositol-3-kinase (PI3K). CD300f-PI3K association leads to activation of downstream Rac/Cdc42 GTPase and mediates changes of F-actin that drive AC engulfment. Importantly, primary macrophages from CD300f-deficient mice have impaired phagocytosis of ACs. The biological consequence of CD300f deficiency is predisposition to autoimmune disease development, as FcgRIIB-deficient mice develop a systemic lupus erythematosus-like disease at a markedly accelerated rate if CD300f is absent. In this report we identify the mechanism and role of CD300f in AC phagocytosis and maintenance of immune homeostasis. C1 [Tian, Linjie; Choi, Seung-Chul; Murakami, Yousuke; Allen, Joselyn; Krzewski, Konrad; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Qi, Chen-Feng] NIAID, Pathol Core, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Krzewski, K (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM Konrad.Krzewski@nih.gov; jcoligan@niaid.nih.gov RI Tian, Linjie/E-6878-2014 FU National Institute of Allergy and Infectious Diseases FX We thank Dr Silvia Bolland for supplying Fcgr2b-/- mice. We thank Dr Joel A. Swanson and Dr Samuel Straight for the kind gift of the human p85-YFP, PLC delta 1-PH-FP and Btk-PH-YFP expression plasmids, Dr Klaus Hahn for PBD-EYFP plasmid, Dr Shigekazu Nagata for pMX-puro vector, Dr Debbie C. Thurmond for Cdc42 plasmid and Dr Joseph Brzostowski for the technical help with the microscopy. We thank Dr Francisco Borrego and Alexandra Gil-Krzewska for their critical comments. We also thank Mirna Pena for her work in handling our animal colony. This study was supported by the intramural programs of the National Institute of Allergy and Infectious Diseases. NR 60 TC 17 Z9 17 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN PY 2014 VL 5 AR 3146 DI 10.1038/ncomms4146 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA4WK UT WOS:000331097100010 PM 24477292 ER PT J AU Salafia, C Yampolsky, M Volk, D Stodgell, CJ Katzman, PJ Culhane, J Landrigan, P Szabo, S Thieux, N Swanson, J Dole, N Varner, MW Moye, J Miller, R AF Salafia, C. Yampolsky, M. Volk, D. Stodgell, C. J. Katzman, P. J. Culhane, J. Landrigan, P. Szabo, S. Thieux, N. Swanson, J. Dole, N. Varner, M. W. Moye, J. Miller, R. TI Mapping placental topology from 3D scans, the graphic display of variation in arborisation across gestation (vol 34, pg A73, 2013) SO PLACENTA LA English DT Correction C1 [Salafia, C.] Placental Analyt LLC, Larchmont, NY 10538 USA. [Salafia, C.] New York State Inst Basic Res Dev Disabil, Staten Isl, NY 10314 USA. [Yampolsky, M.] Univ Toronto, Toronto, ON, Canada. [Volk, D.] Royal Inst Technol, Stockholm, Sweden. [Stodgell, C. J.; Katzman, P. J.; Culhane, J.; Landrigan, P.; Szabo, S.; Thieux, N.; Swanson, J.; Dole, N.; Varner, M. W.; Moye, J.; Miller, R.] Natl Childrens Study Placenta Consortium, Bethesda, MD USA. [Stodgell, C. J.; Katzman, P. J.; Miller, R.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Culhane, J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Landrigan, P.] Mt Sinai Sch Med, New York, NY USA. [Szabo, S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Thieux, N.] S Dakota State Univ, Brookings, SD 57007 USA. [Swanson, J.] Univ Calif Irvine, Irvine, CA USA. [Dole, N.] Univ N Carolina, Chapel Hill, NC USA. [Varner, M. W.] Univ Utah, Salt Lake City, UT USA. [Moye, J.] NIH, Natl Childrens Study, Bethesda, MD 20892 USA. RP Salafia, C (reprint author), Placental Analyt LLC, Larchmont, NY 10538 USA. EM carolyn.salafia@gmail.com NR 1 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 EI 1532-3102 J9 PLACENTA JI Placenta PD JAN PY 2014 VL 35 IS 1 BP 75 EP 75 DI 10.1016/j.placenta.2013.11.004 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA AA2HU UT WOS:000330916500012 ER PT J AU Sioka, C Skarulis, MC Tulloch-Reid, MK Heiss, JD Reynolds, JC AF Sioka, C. Skarulis, M. C. Tulloch-Reid, M. K. Heiss, J. D. Reynolds, J. C. TI "Hidden" bone metastasis from thyroid carcinoma: A clinical note SO REVISTA ESPANOLA DE MEDICINA NUCLEAR E IMAGEN MOLECULAR LA English DT Article DE Follicular thyroid cancer; Metastatic disease; I-131-Iodide; SPECT; Radioiodine therapy ID DISTANT METASTASES; CANCER; I-131; DIAGNOSIS AB The I-131-iodide-(I-131) whole-body scan, for thyroid carcinoma is at times difficult to interpret. In a diagnostic whole body I-131 scan of a patient with follicular carcinoma, a posterior skull lesion was partially hidden by overlapping facial structures. On lateral head view, the abnormality was clearly evident. SPECT/CT and MRI showed the lesion originated in the occipital bone and had enlarged into the posterior fossa. The mass was surgically removed and the patient received 1311 therapy for residual tissue. The study demonstrates a pitfall in the reading of two dimensional radioiodine images which can be overcome by SPECS or lateral imaging. (C) 2013 Elsevier Espana, SI. and SEMNIM. All rights reserved. C1 [Sioka, C.; Reynolds, J. C.] Dept Radiol & Imaging Sci, Nucl Med Sect, Bethesda, MD 20892 USA. [Skarulis, M. C.] NIDDK, Diabet Obes & Endocrinol Branch, Bethesda, MD 20892 USA. [Tulloch-Reid, M. K.] Univ W Indies, Epidemiol Res Unit, Kingston 7, Jamaica. [Heiss, J. D.] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Reynolds, JC (reprint author), Dept Radiol & Imaging Sci, Nucl Med Sect, Bldg 10,Clin Ctr,10 Ctr Dr,Room 1C-461,MSC 1074, Bethesda, MD 20892 USA. EM jreynolds@mail.cc.nih.gov OI Heiss, John/0000-0002-3890-0165 FU NIDDK of the National Institutes of Health, Bethesda, MD [Z01-DK047053-06] FX This work was supported by the intramural research program of the NIDDK, project number Z01-DK047053-06 of the National Institutes of Health, Bethesda, MD. NR 10 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER DOYMA SL PI BARCELONA PA TRAVESERA DE GARCIA, 17-21, BARCELONA, 08021, SPAIN SN 2253-654X J9 REV ESP MED NUCL IMA JI Rev. Esp. Med. Nucl. Imagen Mol. PD JAN-FEB PY 2014 VL 33 IS 1 BP 36 EP 38 DI 10.1016/j.remn.2013.05.009 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AA2NB UT WOS:000330930200007 PM 23845451 ER PT J AU Olszewski, MB Chandris, P Park, BC Eisenberg, E Greene, LE AF Olszewski, Maciej B. Chandris, Panagiotis Park, Bum-Chan Eisenberg, Evan Greene, Lois E. TI Disruption of Clathrin-Mediated Trafficking Causes Centrosome Overduplication and Senescence SO TRAFFIC LA English DT Article DE centrosome; clathrin; DNA damage; endocytosis; overduplication; senescence; trafficking ID G-ASSOCIATED KINASE; INDUCED DNA-DAMAGE; LABILE IRON POOL; IN-VIVO; CELLULAR SENESCENCE; HUMAN-CELLS; ENDOCYTOSIS; DYNAMIN; REPLICATION; SPINDLE AB The Hsc70 cochaperone, G cyclin-associated kinase (GAK), has been shown to be essential for the chaperoning of clathrin by Hsc70 in the cell. In this study, we used conditional GAK knockout mouse embryonic fibroblasts (MEFs) to determine the effect of completely inhibiting clathrin-dependent trafficking on the cell cycle. After GAK was knocked out, the cells developed the unusual phenotype of having multiple centrosomes, but at the same time failed to divide and ultimately became senescent. To explain this phenotype, we examined the signaling profile and found that mitogenic stimulation of the GAK KO cells and the control cells were similar except for increased phosphorylation of Akt. In addition, the disruption of intracellular trafficking caused by knocking out GAK destabilized the lysosomal membranes, resulting in DNA damage due to iron leakage. Knocking down clathrin heavy chain or inhibiting dynamin largely reproduced the GAK KO phenotype, but inhibiting only clathrin-mediated endocytosis by knocking down adaptor protein (AP2) caused growth arrest and centrosome overduplication, but no DNA damage or senescence. We conclude that disruption of clathrin-dependent trafficking induces senescence accompanied by centrosome overduplication because of a combination of DNA damage and changes in mitogenic signaling that uncouples centrosomal duplication from DNA replication. C1 [Olszewski, Maciej B.; Chandris, Panagiotis; Park, Bum-Chan; Eisenberg, Evan; Greene, Lois E.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Olszewski, MB (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM molszewski@iimcb.gov.pl; greenel@helix.nih.gov RI Olszewski, Maciej/C-2021-2015 OI Olszewski, Maciej/0000-0003-0961-0801 FU Foundation for Polish Science grant 'Kolumb' FX M. B. O. was supported by Foundation for Polish Science grant 'Kolumb'. NR 48 TC 5 Z9 5 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 EI 1600-0854 J9 TRAFFIC JI Traffic PD JAN PY 2014 VL 15 IS 1 BP 60 EP 77 DI 10.1111/tra.12132 PG 18 WC Cell Biology SC Cell Biology GA AA7TR UT WOS:000331300300004 PM 24138026 ER PT J AU Szabon-Watola, MI Ulatowski, SV George, KM Hayes, CD Steiger, SA Natale, NR AF Szabon-Watola, Monika I. Ulatowski, Sarah V. George, Kathleen M. Hayes, Christina D. Steiger, Scott A. Natale, Nicholas R. TI Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Multidrug resistance transporter; Isoxazole; Dihydropyridine; Homology model ID MULTIDRUG-RESISTANCE MODIFIERS; P-GLYCOPROTEIN INHIBITORS; DRUG TRANSPORTER; IN-VITRO; 4-ISOXAZOLYL-1,4-DIHYDROPYRIDINES; MODULATORS; 1,4-DIHYDROPYRIDINES; DERIVATIVES; HOMODIMERS; DOCKING AB Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Ulatowski, Sarah V.; George, Kathleen M.; Hayes, Christina D.; Steiger, Scott A.; Natale, Nicholas R.] Univ Montana, NIH COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. [Szabon-Watola, Monika I.; Natale, Nicholas R.] Univ Idaho, Dept Chem, Moscow, ID 83843 USA. RP Natale, NR (reprint author), Univ Montana, NIH COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. EM nicholas.natale@umontana.edu FU NIH [NS038444, 5U01ES016102-02, P20RR015583]; NSF REU [0649306]; Malcolm and Carol Renfrew Scholarship; National Institute of Mental Health's Psychoactive Drug Screening Program (NIMH PDSP) [HHSN-271-2008-00025-C] FX The authors thank NIH for grants NS038444 (N.N., M. I. S.), 5U01ES016102-02 (K. M. G., S. V. U.), and P20RR015583 (N.N., S. S.). C. D. H. thanks the NSF REU Award Number 0649306. M. I. S. thanks the Malcolm and Carol Renfrew Scholarship. We thank Dr. Alex Blumenfeld for VT NMR and Dr. Gary Knerr for able assistance in FAB MS while at the University of Idaho. We thank Dr. Mike Braden and Dave Holley of the Core Facility for Molecular Computation (UM) for helpful discussions during pharmacophore modeling.; MDR1 data was generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program (NIMH PDSP), Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, Ph.D. at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. NR 49 TC 3 Z9 3 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 1 PY 2014 VL 24 IS 1 BP 117 EP 121 DI 10.1016/j.bmcl.2013.11.068 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 281PT UT WOS:000329114200019 PM 24342237 ER PT J AU Kim, MS Ki, Y Ahn, SY Yoon, S Kim, SE Park, HG Sun, W Son, K Cui, M Choi, S Pearce, LV Esch, TE DeAndrea-Lazarus, IA Blumberg, PM Lee, J AF Kim, Myeong Seop Ki, Yooran Ahn, Song Yeon Yoon, Suyoung Kim, Sung-Eun Park, Hyeung-Geun Sun, Wei Son, Karam Cui, Minghua Choi, Sun Pearce, Larry V. Esch, Timothy E. DeAndrea-Lazarus, Ian A. Blumberg, Peter M. Lee, Jeewoo TI Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonist; Capsaicin; Resiniferatoxin; Molecular modeling ID CAPSAICIN RECEPTORS; ANTAGONISTS; DERIVATIVES AB The chiral isomers of the two potent simplified RTX-based vanilloids, compounds 2 and 3, were synthesized employing highly enantioselective PTC alkylation and evaluated as hTRPV1 ligands. The analysis indicated that the R-isomer was the eutomer in binding affinity and functional activity. The agonism of compound 2R was comparable to that of RTX. Docking analysis of the chiral isomers of 3 suggested the basis for its stereospecific activity and the binding mode of 3R. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Kim, Myeong Seop; Ki, Yooran; Ahn, Song Yeon; Yoon, Suyoung; Kim, Sung-Eun; Park, Hyeung-Geun; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. [Sun, Wei] Shenyang Pharmaceut Univ, Shenyang 110016, Liaoning, Peoples R China. [Son, Karam; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 120750, South Korea. [Son, Karam; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Global Top Res Program 5, Seoul 120750, South Korea. [Pearce, Larry V.; Esch, Timothy E.; DeAndrea-Lazarus, Ian A.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU National Research Foundation of Korea (NRF) [2007-0056817]; NLRL program [2011-0028885]; Korea government MSIP; Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270] FX This research was supported by the National Research Foundation of Korea (NRF) Grant (2007-0056817) and NLRL program Grant (2011-0028885) funded by the Korea government MSIP, and was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Project Z1A BC 005270). NR 20 TC 5 Z9 5 U1 2 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 1 PY 2014 VL 24 IS 1 BP 382 EP 385 DI 10.1016/j.bmcl.2013.10.064 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 281PT UT WOS:000329114200075 PM 24321344 ER PT J AU Kleensang, A Maertens, A Rosenberg, M Fitzpatrick, S Lamb, J Auerbach, S Brennan, R Crofton, KM Gordon, B Fornace, AJ Gaido, K Gerhold, D Haw, R Henney, A Ma'ayan, A McBride, M Monti, S Ochs, MF Pandey, A Sharan, R Stierum, R Tugendreich, S Willett, C Wittwehr, C Xia, JG Patton, GW Arvidson, K Bouhifd, M Hogberg, HT Luechtefeld, T Smirnova, L Zhao, L Adeleye, Y Kanehisa, M Carmichael, P Andersen, ME Hartung, T AF Kleensang, Andre Maertens, Alexandra Rosenberg, Michael Fitzpatrick, Suzanne Lamb, Justin Auerbach, Scott Brennan, Richard Crofton, Kevin M. Gordon, Ben Fornace, Albert J., Jr. Gaido, Kevin Gerhold, David Haw, Robin Henney, Adrian Ma'ayan, Avi McBride, Mary Monti, Stefano Ochs, Michael F. Pandey, Akhilesh Sharan, Roded Stierum, Rob Tugendreich, Stuart Willett, Catherine Wittwehr, Clemens Xia, Jianguo Patton, Geoffrey W. Arvidson, Kirk Bouhifd, Mounir Hogberg, Helena T. Luechtefeld, Thomas Smirnova, Lena Zhao, Liang Adeleye, Yeyejide Kanehisa, Minoru Carmichael, Paul Andersen, Melvin E. Hartung, Thomas TI Pathways of Toxicity SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Article DE systems toxicology; pathways of toxicity; adverse outcome pathways; in vitro toxicology; human toxome ID BIOLOGICAL NETWORKS; SYSTEMS TOXICOLOGY; 21ST-CENTURY; THOUGHT; FOOD; VALIDATION; TOXICOGENOMICS; PERSPECTIVES; TECHNOLOGIES; INTEGRATION AB Despite wide-spread consensus on the need to transform toxicology and risk assessment in order to keep pace with technological and computational changes that have revolutionized the life sciences, there remains much work to be done to achieve the vision of toxicology based on a mechanistic foundation. A workshop was organized to explore one key aspect of this transformation the development of Pathways of Toxicity (PoT) as a key tool for hazard identification based on systems biology. Several issues were discussed in depth in the workshop: The first was the challenge of formally defining the concept of a PoT as distinct from, but complementary to, other toxicological pathway concepts such as mode of action (MoA). The workshop came up with a preliminary definition of PoT as "A molecular definition of cellular processes shown to mediate adverse outcomes of toxicants". It is further recognized that normal physiological pathways exist that maintain homeostasis and these, sufficiently perturbed, can become PoT. Second, the workshop sought to define the adequate public and commercial resources for PoT information, including data, visualization, analyses, tools, and use-cases, as well as the kinds of efforts that will be necessary to enable the creation of such a resource. Third, the workshop explored ways in which systems biology approaches could inform pathway annotation, and which resources are needed and available that can provide relevant PoT information to the diverse user communities. C1 [Kleensang, Andre; Maertens, Alexandra; Bouhifd, Mounir; Hogberg, Helena T.; Luechtefeld, Thomas; Smirnova, Lena; Zhao, Liang; Hartung, Thomas] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Alternat Anim Testing, Baltimore, MD USA. [Rosenberg, Michael; McBride, Mary] Agilent Technol, Santa Clara, CA USA. [Fitzpatrick, Suzanne; Gaido, Kevin] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Lamb, Justin] Genometry Inc, Cambridge, MA USA. [Auerbach, Scott] NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Brennan, Richard] Thomson Reuters Inc, Carlsbad, CA USA. [Crofton, Kevin M.] US EPA, Off Res & Dev, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA. [Gordon, Ben] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Fornace, Albert J., Jr.] Georgetown Univ, Dept Biochem & Mol & Cellular Biol, Washington, DC USA. [Fornace, Albert J., Jr.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Gerhold, David] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Haw, Robin] Ontario Inst Canc Res, Reactome, Toronto, ON, Canada. [Henney, Adrian] Heidelberg Univ, German Virtual Liver Network, Heidelberg, Germany. [Ma'ayan, Avi] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY USA. [Monti, Stefano] Boston Univ, Sch Med, Sect Computat Biomed, Boston, MA 02118 USA. [Ochs, Michael F.] Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21205 USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Sharan, Roded] Tel Aviv Univ, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Stierum, Rob] TNO Hlth Living Microbiol & Syst Biol, Zeist, Netherlands. [Tugendreich, Stuart] Ingenu Syst Inc, Redwood City, CA USA. [Willett, Catherine] Humane Soc United States, Washington, DC USA. [Wittwehr, Clemens] Commiss European Communities, Joint Res Ctr, Syst Toxicol Unit, I-21020 Ispra, Italy. [Xia, Jianguo] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V5Z 1M9, Canada. [Patton, Geoffrey W.; Arvidson, Kirk] US FDA, Ctr Food Safety & Appl Nutr, Off Food Addit Safety, College Pk, MD USA. [Adeleye, Yeyejide; Carmichael, Paul] Unilever, Safety & Environm Assurance Ctr, Sharnbrook, Beds, England. [Kanehisa, Minoru] Kyoto Univ, Inst Chem Res, Kyoto 606, Japan. [Andersen, Melvin E.] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Hartung, Thomas] Univ Konstanz, CAAT Europe, Constance, Germany. RP Hartung, T (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Alternat Anim Testing, 615 North Wolfe St,W7032, Baltimore, MD 21205 USA. EM thartung@jhsph.edu RI Crofton, Kevin/J-4798-2015; Zhao, Liang/I-4777-2015; OI Crofton, Kevin/0000-0003-1749-9971; Zhao, Liang/0000-0002-2126-6778; Kleensang, Andre/0000-0002-4564-7399 FU Unilever; NIH transformative research project on "Mapping the Human Toxome by Systems Toxicology" [R01ES020750]; FDA grant "DNTox-21c Identification of pathways of developmental neurotoxicity for high throughput testing by metabolomics" [U01FD004230] FX This CAAT workshop on Pathways of Toxicity was made possible by support from Unilever and the extensive discussions and experiences of the NIH transformative research project on "Mapping the Human Toxome by Systems Toxicology" (R01ES020750) and FDA grant "DNTox-21c Identification of pathways of developmental neurotoxicity for high throughput testing by metabolomics" (U01FD004230). NR 58 TC 38 Z9 39 U1 1 U2 14 PU SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH PI HEILDEBERG PA TIERGARTENSTRASSE 17, HEILDEBERG, 69121, GERMANY SN 1868-596X EI 1868-8551 J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2014 VL 31 IS 1 BP 53 EP 61 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 304MF UT WOS:000330750300007 PM 24127042 ER PT J AU Juberg, DR Borghoff, SJ Becker, RA Casey, W Hartung, T Holsapple, MP Marty, MS Mihaich, EM Van der Kraak, G Wade, MG Willett, CE Andersen, ME Borgert, CJ Coady, KK Dourson, ML Fowle, JR Gray, LE Lamb, JC Ortego, LS Schug, TT Toole, CM Zorrilla, LM Kroner, OL Patterson, J Rinckel, LA Jones, BR AF Juberg, Daland R. Borghoff, Susan J. Becker, Richard A. Casey, Warren Hartung, Thomas Holsapple, Michael P. Marty, M. Sue Mihaich, Ellen M. Van der Kraak, Glen Wade, Michael G. Willett, Catherine E. Andersen, Melvin E. Borgert, Christopher J. Coady, Katherine K. Dourson, Michael L. Fowle, John R., III Gray, L. Earl Lamb, James C. Ortego, Lisa S. Schug, Thaddeus T. Toole, Colleen M. Zorrilla, Leah M. Kroner, Oliver L. Patterson, Jacqueline Rinckel, Lori A. Jones, Brett R. TI Lessons Learned, Challenges, and Opportunities: The US Endocrine Disruptor Screening Program SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Article DE endocrine disruptors; Tier 1; screening; systematic review; Endocrine Disruptor Screening Program ID CHEMICALS; EXPOSURE; ASSAYS AB In 1996, the U.S. Congress passed the Food Quality Protection Act and amended the Safe Drinking Water Act (SDWA) requiring the U.S. Environmental Protection Agency (EPA) to implement a screening program to investigate the potential of pesticide chemicals and drinking water contaminants to adversely affect endocrine pathways. Consequently, the EPA launched the Endocrine Disruptor Screening Program (EDSP) to develop and validate estrogen, androgen, and thyroid (EAT) pathway screening assays and to produce standardized and harmonized test guidelines for regulatory application. In 2009, the EPA issued the first set of test orders for EDSP screening and a total of 50 pesticide actives and 2 inert ingredients have been evaluated using the battery of EDSP Tier 1 screening assays (i.e., five in vitro assays and six in vivo assays). To provide a framework for retrospective analysis of the data generated and to collect the insight of multiple stakeholders involved in the testing, more than 240 scientists from government, industry, academia, and non-profit organizations recently participated in a workshop titled "Lessons Learned, Challenges, Opportunities: The U.S. Endocrine Disruptor Screening Program." The workshop focused on the science and experience to date and was organized into three focal sessions: (a) Performance of the EDSP Tier 1 Screening Assays for Estrogen, Androgen, and Thyroid Pathways; (b) Practical Applications of Tier 1 Data; and (c) Indications and Opportunities for Future Endocrine Testing. A number of key findings and recommendations related to future EDSP evaluations emanated from the collective sessions. C1 [Juberg, Daland R.] Dow AgroSci LLC, Indianapolis, IN 46268 USA. [Borghoff, Susan J.] ToxStrategies Inc, Cary, NC USA. [Becker, Richard A.] Amer Chem Council, Washington, DC USA. [Casey, Warren; Schug, Thaddeus T.] NIEHS, Res Triangle Pk, NC 27709 USA. [Hartung, Thomas] Johns Hopkins Univ, Baltimore, MD USA. [Hartung, Thomas] Univ Konstanz, Constance, Germany. [Holsapple, Michael P.] Batelle, Columbus, OH USA. [Marty, M. Sue; Coady, Katherine K.] Dow Chem Co USA, Saginaw, MI USA. [Mihaich, Ellen M.] ER2 & Endocrine Policy Forum, Durham, NC USA. [Van der Kraak, Glen] Univ Guelph, Guelph, ON N1G 2W1, Canada. [Wade, Michael G.] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Willett, Catherine E.] Humane Soc United States, Washington, DC USA. [Andersen, Melvin E.] Hamner Inst Hlth Sci, Res Triangle Pk, NC USA. [Borgert, Christopher J.] Appl Pharmacol & Toxicol Inc, Gainesville, FL USA. [Dourson, Michael L.; Kroner, Oliver L.; Patterson, Jacqueline] Toxicol Excellence Risk Assessment, Cincinnati, OH USA. [Fowle, John R., III] Sci Inform, Pittsboro, NC USA. [Gray, L. Earl] US EPA, Res Triangle Pk, NC 27711 USA. [Lamb, James C.] Exponent, Alexandria, VA USA. [Ortego, Lisa S.] Bayer CropSci, Raleigh, NC USA. [Toole, Colleen M.] Ceetox, Kalamazoo, MI USA. [Zorrilla, Leah M.; Rinckel, Lori A.; Jones, Brett R.] Integrated Lab Syst Inc, Morrisville, NC USA. RP Juberg, DR (reprint author), Dow AgroSci LLC, 9330 Zionsville Rd, Indianapolis, IN 46268 USA. EM drjuberg@dow.com NR 23 TC 12 Z9 12 U1 6 U2 24 PU SPEKTRUM AKADEMISCHER VERLAG-SPRINGER-VERLAG GMBH PI HEILDEBERG PA TIERGARTENSTRASSE 17, HEILDEBERG, 69121, GERMANY SN 1868-596X EI 1868-8551 J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2014 VL 31 IS 1 BP 63 EP 78 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 304MF UT WOS:000330750300008 PM 24114257 ER PT J AU Crews, DC Kuczmarski, MF Grubbs, V Hedgeman, E Shahinian, VB Evans, MK Zonderman, AB Burrows, NR Williams, DE Saran, R Powe, NR AF Crews, Deidra C. Kuczmarski, Marie Fanelli Grubbs, Vanessa Hedgeman, Elizabeth Shahinian, Vahakn B. Evans, Michele K. Zonderman, Alan B. Burrows, Nilka Rios Williams, Desmond E. Saran, Rajiv Powe, Neil R. CA Ctr Disease Control & Preven TI Effect of Food Insecurity on Chronic Kidney Disease in Lower-Income Americans SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE Socioeconomic status; Disparity; Nutrition ID GLOMERULAR-FILTRATION-RATE; SOCIOECONOMIC-STATUS; NATIONAL-HEALTH; RACIAL DISPARITIES; SERUM CREATININE; UNITED-STATES; POVERTY; PREVALENCE; NUTRITION; ALBUMINURIA AB Background: The relation of food insecurity (inability to acquire nutritionally adequate and safe foods) and chronic kidney disease (CKD) is unknown. We examined whether food insecurity is associated with prevalent CKD among lower-income individuals in both the general US adult population and an urban population. Methods: We conducted cross-sectional analyses of lower-income participants of the National Health and Nutrition Examination Survey (NHANES) 2003-2008 (n = 9,126) and the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n = 1,239). Food insecurity was defined based on questionnaires and CKD was defined by reduced estimated glomerular filtration rate or albuminuria; adjustment was performed with multivariable logistic regression. Results: In NHANES, the age-adjusted prevalence of CKD was 20.3, 17.6, and 15.7% for the high, marginal, and no food insecurity groups, respectively. Analyses adjusting for sociodemographics and smoking status revealed high food insecurity to be associated with greater odds of CKD only among participants with either diabetes (OR = 1.67, 95% CI: 1.14-2.45 comparing high to no food insecurity groups) or hypertension (OR = 1.37, 95% CI: 1.03-1.82). In HANDLS, the age-adjusted CKD prevalence was 5.9 and 4.6% for those with and without food insecurity, respectively (p = 0.33). Food insecurity was associated with a trend towards greater odds of CKD (OR = 1.46, 95% CI: 0.98-2.18) with no evidence of effect modification across diabetes, hypertension, or obesity subgroups. Conclusion: Food insecurity may contribute to disparities in kidney disease, especially among persons with diabetes or hypertension, and is worthy of further study. (C) 2014 S. Karger AG, Basel C1 [Crews, Deidra C.] Johns Hopkins Med Inst, Dept Med, Div Nephrol, Baltimore, MD 21205 USA. [Crews, Deidra C.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Kuczmarski, Marie Fanelli] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. [Grubbs, Vanessa] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA USA. [Hedgeman, Elizabeth; Shahinian, Vahakn B.; Saran, Rajiv] Univ Michigan, Dept Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Evans, Michele K.; Zonderman, Alan B.] NIA, NIH, Baltimore, MD USA. [Burrows, Nilka Rios; Williams, Desmond E.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Powe, Neil R.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA USA. RP Crews, DC (reprint author), Johns Hopkins Univ, Sch Med, Div Nephrol, Johns Hopkins Bayview Med Ctr, 301 Mason F Lord Dr,Suite 2500, Baltimore, MD 21224 USA. EM dcrews1@jhmi.edu RI Nguyen, Giang/D-9027-2016 FU CDC [1U58DP003839-01]; Intramural Research Program of the NIA, National Institutes of Health; Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K23 DK093710]; NIDDK [R01 DK78124] FX This project was supported under a cooperative agreement from the CDC, grant 1U58DP003839-01. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.; This work was supported by the Intramural Research Program of the NIA, National Institutes of Health. Dr. Crews and Dr. Grubbs were supported by the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation.; Dr. Grubbs was also supported by grant K23 DK093710 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Powe was partially supported by grant R01 DK78124 from the NIDDK. NR 52 TC 7 Z9 7 U1 1 U2 10 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 EI 1421-9670 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2014 VL 39 IS 1 BP 27 EP 35 DI 10.1159/000357595 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 302VF UT WOS:000330632300005 PM 24434743 ER PT J AU Church, SE Jensen, SM Antony, PA Restifo, NP Fox, BA AF Church, Sarah E. Jensen, Shawn M. Antony, Paul A. Restifo, Nicholas P. Fox, Bernard A. TI Tumor-specific CD4(+) T cells maintain effector and memory tumor-specific CD8(+) T cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article ID LARGE ESTABLISHED MELANOMA; ADOPTIVE IMMUNOTHERAPY; IN-VIVO; CANCER REGRESSION; METASTATIC MELANOMA; LYMPHOPENIC HOSTS; INTERFERON-GAMMA; IFN-GAMMA; LYMPHOCYTES; HELP C1 [Church, Sarah E.; Jensen, Shawn M.; Fox, Bernard A.] Earle A Chiles Res Inst, Lab Mol & Tumor Immunol, Robert W Franz Canc Res Ctr, Providence Canc Ctr, Portland, OR 97213 USA. [Church, Sarah E.; Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Antony, Paul A.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Ctr Canc, Baltimore, MD 21201 USA. [Restifo, Nicholas P.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. RP Fox, BA (reprint author), Earle A Chiles Res Inst, Lab Mol & Tumor Immunol, 2N56 North Pavil,4805 NE Glisan St, Portland, OR 97213 USA. EM foxb@foxlab.org OI Restifo, Nicholas P./0000-0003-4229-4580 FU NCI [CA 80564]; NIH [T32 AI007472] FX We would like to thank Dan Haley for assistance with initial set-up of flow panels and sorting experiments, Tacy Brotherton and Amanda Lyon for breeding and caring for the mice, Dr. Dubay for initial help setting up polychromatic flow analysis, and Michael Afentoulis for help with experiments. We would like to additionally thank Dr. Urba, Dr. van de Ven, Dr. Twitty, Dr. Parker, Dr. Davey, and Dr. Weinberg for reviewing this manuscript and for thoughtful discussions throughout this work. Funding sources: NCI CA 80564, NIH T32 AI007472. NR 49 TC 34 Z9 35 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JAN PY 2014 VL 44 IS 1 BP 69 EP 79 PG 11 WC Immunology SC Immunology GA AA0RA UT WOS:000330803400009 PM 24114780 ER PT J AU Liu, BY Zhong, S Malecek, K Johnson, LA Rosenberg, SA Zhu, C Krogsgaard, M AF Liu, Baoyu Zhong, Shi Malecek, Karolina Johnson, Laura A. Rosenberg, Steven A. Zhu, Cheng Krogsgaard, Michelle TI 2D TCR-pMHC-CD8 kinetics determines T-cell responses in a self-antigen-specific TCR system SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; LIGAND BINDING-KINETICS; RECEPTOR AFFINITY; CD8 CORECEPTOR; ACTIVATION; IMPACT; SELECTION; MEMBRANE; RESPONSIVENESS; MICROTOPOLOGY C1 [Liu, Baoyu; Zhu, Cheng] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Zhu, Cheng] Georgia Inst Technol, Woodruff Sch Mech Engn, Atlanta, GA 30332 USA. [Zhu, Cheng] Georgia Inst Technol, Inst Bioengn & Biosci, Atlanta, GA 30332 USA. [Zhong, Shi; Malecek, Karolina; Krogsgaard, Michelle] NYU, Sch Med, NYU Canc Inst, New York, NY 10016 USA. [Malecek, Karolina; Krogsgaard, Michelle] NYU, Sch Med, Program Struct Biol, New York, NY 10016 USA. [Krogsgaard, Michelle] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Johnson, Laura A.; Rosenberg, Steven A.] NCI, Ctr Canc Res, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. RP Krogsgaard, M (reprint author), NYU, Sch Med, Dept Pathol, 522 First Ave,Smilow 1311, New York, NY 10016 USA. EM cheng.zhu@bme.gatech.edu; Michelle.Krogsgaard@nyumc.org RI Liu, Baoyu/C-4911-2009 OI Liu, Baoyu/0000-0002-0798-6314 FU Pew Trust; National Institute of Health [NCI 1U01CA137070, NIGMS 5R01GM085586, R01GM096187, R56AI038282]; American Cancer Society [RSG-09-070-01-LIB]; Cancer Research Investigator grant FX We thank New York University and Georgia Institute of Technology flow cytometry cores for technical assistance. We thank Dr. David Kranz and Dr. Michael Dustin for providing cell lines and plasmids, Katelyn McGary and Kevin Huang for assistance in soluble protein productions, and Dr. Jeffrey Donnell for critical reading of the manuscript. M.K. was a Pew Scholar in the Biomedical Sciences supported by the Pew Trust. This work was supported by the National Institute of Health grants NCI 1U01CA137070 and NIGMS 5R01GM085586 (to M.K.) and R01GM096187 and R56AI038282 (to C.Z.), an American Cancer Society Research Scholar grant RSG-09-070-01-LIB (to M.K), and a Cancer Research Investigator grant (to M.K.). NR 54 TC 13 Z9 13 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JAN PY 2014 VL 44 IS 1 BP 239 EP 250 PG 12 WC Immunology SC Immunology GA AA0RA UT WOS:000330803400024 PM 24114747 ER PT J AU Laughon, SK McLain, AC Sundaram, R Catov, JM Louis, GMB AF Laughon, S. Katherine McLain, Alexander C. Sundaram, Rajeshwari Catov, Janet M. Louis, Germaine M. Buck TI Maternal Lipid Change in Relation to Length of Gestation: A Prospective Cohort Study with Preconception Enrollment of Women SO GYNECOLOGIC AND OBSTETRIC INVESTIGATION LA English DT Article DE Cholesterol; Lipids; Miscarriage; Preterm birth; Triglycerides ID PRETERM BIRTH; PREGNANCY; SERUM; MORTALITY; WINDOWS; MOTHERS; RISK; LIFE AB Background/Aims:We sought to investigate the association between preconception serum lipids and their daily rate of change in relation to length of gestation. Methods: In a cohort of 70 women, 61(87%) became pregnant, resulting in 48 (69%) live births. Serum lipid measurements (in milligrams per deciliter) included total cholesterol, free cholesterol, triglycerides and phospholipids at preconception, upon human chorionic gonadotropin-confirmed pregnancy and following pregnancy loss (<14 weeks) or post partum. Pregnancy outcome (loss, preterm and term delivery) and gestational length were modeled relative to daily rate of change in lipids using multinomial regression and Cox proportional hazards models, respectively, adjusting for body mass index and smoking. Results: A rate of triglyceride change below the median was associated with an increased risk for pregnancy loss compared with term birth (adjusted odds ratio: 9.02; 95% CI: 1.62-50.30). A rate of triglyceride change of <= 3.01 mg/dl per day versus above the median was associated with a trend for increased risk of pregnancy loss or preterm (<37 weeks) birth (adjusted hazard ratio: 1.77; 95% CI: 0.94-3.33). Conclusion: A low rate of triglyceride change during early pregnancy may be a signal of risk of pregnancy loss or preterm birth. Lipids offer promise for identifying pregnancies at risk for adverse outcomes. (C) 2013 S. Karger AG, Basel C1 [Laughon, S. Katherine] Eunice Kennedy Shriyer Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Rockville, MD USA. [McLain, Alexander C.; Sundaram, Rajeshwari] Eunice Kennedy Shriyer Natl Inst Child Hlth & Hum, Biostat Branch, NIH, Rockville, MD USA. [Louis, Germaine M. Buck] Eunice Kennedy Shriyer Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Catov, Janet M.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Serv, Pittsburgh, PA USA. [Catov, Janet M.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. RP Laughon, SK (reprint author), NICHD, Epidemiol Branch, NIH, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM laughonsk@mail.nih.gov OI McLain, Alexander/0000-0002-5475-0670; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490; Grantz, Katherine/0000-0003-0276-8534 FU Great Lakes Protection Fund [RM791-3021]; Agency for Toxic Substances and Disease Registry [H751ATH298338]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported in part with funding from the Great Lakes Protection Fund (RM791-3021), the Agency for Toxic Substances and Disease Registry (H751ATH298338) and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 20 TC 4 Z9 4 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-7346 EI 1423-002X J9 GYNECOL OBSTET INVES JI Gynecol.Obstet.Invest. PY 2014 VL 77 IS 1 BP 6 EP 13 DI 10.1159/000355100 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 302LR UT WOS:000330606500002 PM 24334826 ER PT J AU Bergamaschi, MM Queiroz, RHC Chagas, MHN Linares, IMP Arrais, KC de Oliveira, DCG Queiroz, ME Nardi, AE Huestis, MA Hallak, JEC Zuardi, AW Moreira, FA Crippa, JAS AF Bergamaschi, Mateus M. Queiroz, Regina H. C. Chagas, Marcos H. N. Linares, Ila M. P. Arrais, Katia C. de Oliveira, Danielle C. G. Queiroz, Maria E. Nardi, Antonio E. Huestis, Marilyn A. Hallak, Jaime E. C. Zuardi, Antonio W. Moreira, Fabricio A. Crippa, Jose A. S. TI Rimonabant effects on anxiety induced by simulated public speaking in healthy humans: a preliminary report SO HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL LA English DT Article DE anxiety; public speaking test; rimonabant; SR141716; CB1 receptor ID ALCOHOL SCREENING-TEST; PSYCHOMETRIC PROPERTIES; CANNABINOID RECEPTORS; CLINICAL ANXIETY; INHIBITION; DEPRESSION; DISORDERS; INVENTORY; BLOCKADE; BEHAVIOR AB ObjectiveWe investigated the hypothesis that rimonabant, a cannabinoid antagonist/inverse agonist, would increase anxiety in healthy subjects during a simulation of the public speaking test. MethodsParticipants were randomly allocated to receive oral placebo or 90mg rimonabant in a double-blind design. Subjective effects were measured by Visual Analogue Mood Scale. Physiological parameters, namely arterial blood pressure and heart rate, also were monitored. ResultsTwelve participants received oral placebo and 12 received 90mg rimonabant. Rimonabant increased self-reported anxiety levels during the anticipatory speech and performance phase compared with placebo. Interestingly, rimonabant did not modulate anxiety prestress and was not associated with sedation, cognitive impairment, discomfort, or blood pressure changes. ConclusionsCannabinoid-1 antagonism magnifies the responses to an anxiogenic stimulus without interfering with the prestress phase. These data suggest that the endocannabinoid system may work on-demand to counteract the consequences of anxiogenic stimuli in healthy humans. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Bergamaschi, Mateus M.; Chagas, Marcos H. N.; Linares, Ila M. P.; Arrais, Katia C.; de Oliveira, Danielle C. G.; Hallak, Jaime E. C.; Zuardi, Antonio W.; Crippa, Jose A. S.] Univ Sao Paulo, Dept Neurosci & Behav, Ribeirao Preto Med Sch, BR-14048900 Ribeirao Preto, SP, Brazil. [Bergamaschi, Mateus M.; Queiroz, Regina H. C.] Univ Sao Paulo, Dept Clin Toxicol & Food Sci Anal, Sch Pharmaceut Sci Ribeirao Preto, BR-14048900 Ribeirao Preto, SP, Brazil. [Bergamaschi, Mateus M.; Queiroz, Regina H. C.; Chagas, Marcos H. N.; Linares, Ila M. P.; Arrais, Katia C.; de Oliveira, Danielle C. G.; Nardi, Antonio E.; Hallak, Jaime E. C.; Zuardi, Antonio W.; Moreira, Fabricio A.; Crippa, Jose A. S.] Natl Inst Translat Med INCT TM, CNPq, Rio De Janeiro, Brazil. [Queiroz, Maria E.] Univ Sao Paulo, Dept Quim, Fac Filosofia Ciencias & Letras Ribeirao Preto, BR-14048900 Ribeirao Preto, SP, Brazil. [Nardi, Antonio E.] Univ Fed Rio de Janeiro, Lab Pan & Respirat, Inst Psychiat, Rio De Janeiro, Brazil. [Huestis, Marilyn A.] NIDA, IRP, NIH, Baltimore, MD USA. [Moreira, Fabricio A.] Univ Fed Minas Gerais, Dept Pharmacol, Inst Biol Sci, Belo Horizonte, MG, Brazil. RP Bergamaschi, MM (reprint author), Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Neurociencias & Ciencias Comportamento, Av Bandeirantes,3900 Hosp Clin Terceiro Andar, BR-14048900 Ribeirao Preto, SP, Brazil. EM mateusbergamaschi@yahoo.com.br RI Chagas, Marcos Hortes N./D-9850-2012 OI Chagas, Marcos Hortes N./0000-0003-3752-7984 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2009/11805-4]; CNPq (Brazil) FX The authors acknowledge Sandra Bernardo and Selma Pontes for their clinical support. MMB was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (grant number 2009/11805-4). JASC (1B), AWZ (1C), JECH (1D) and AEN (1A) are the recipients of a CNPq (Brazil) fellowship award. NR 40 TC 7 Z9 7 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6222 EI 1099-1077 J9 HUM PSYCHOPHARM CLIN JI Hum. Psychopharmacol.-Clin. Exp. PD JAN PY 2014 VL 29 IS 1 BP 94 EP 99 DI 10.1002/hup.2374 PG 6 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology GA AA0OW UT WOS:000330795700014 PM 24424711 ER PT J AU Schneider, G Bowser, MJ Shin, DM Barr, FG Ratajczak, MZ AF Schneider, Gabriela Bowser, Mark J. Shin, Dong-Myung Barr, Frederic G. Ratajczak, Mariusz Z. TI The paternally imprinted DLK1-GTL2 locus is differentially methylated in embryonal and alveolar rhabdomyosarcomas SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE rhabdomyosarcoma; DLK1-GTL2 locus; genomic imprinting ID CHILDRENS ONCOLOGY GROUP; DNA METHYLATION; STEM-CELLS; REGION; EXPRESSION; GENE; DLK1; H19; MECHANISMS AB Parental imprinting of differentially methylated regions (DMRs) contributes to appropriate expression of several developmentally important genes from paternally or maternally derived chromosomes. Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and is associated with altered expression of certain parentally imprinted genes. As previously reported, RMS cells display loss of imprinting (LOI) of the DMR at the IGF2-H19 locus, resulting in insulin-like growth factor 2 (IGF2) transcription from both paternally and maternally inherited chromosomes, and overall IGF2 overexpression. As the DLK1-GTL2 locus is structurally similar to the IGF2-H19 locus, the status of parental imprinting of the DLK1-GTL2 locus was studied in RMS. We observed that while both embryonal and alveolar rhabdomyosarcomas (ERMS and ARMS, respectively) show LOI of the DMR at the IGF2-H19 locus, imprinting of the DMR at the DLK1-GTL2 locus varies in association with the histological subtype of RMS. We found that, while ERMS tumors consistently show LOI of the DMR at the DLK1-GTL2 locus, ARMS tumors have erasure of imprinting (EOI) at this locus. These changes in imprinting status of the DLK1-GTL2 locus result in a higher GTL2/DLK1 mRNA ratio in ARMS as compared to ERMS. This difference in imprinting elucidates a novel genetic difference between these two RMS subtypes and may provide a potential diagnostic tool to distinguish between these subtypes. C1 [Schneider, Gabriela; Shin, Dong-Myung; Ratajczak, Mariusz Z.] Univ Louisville, Stem Cell Inst, James Graham Brown Canc Ctr, Louisville, KY 40202 USA. [Bowser, Mark J.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Barr, Frederic G.] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Ratajczak, MZ (reprint author), Univ Louisville, Stem Cell Inst, James Graham Brown Canc Ctr, 500 S Floyd St,Rm 107, Louisville, KY 40202 USA. EM g0schn01@louisville.edu; mzrata01@louisville.edu RI Ratajczak, Mariusz Zdzislaw/N-1599-2014; OI Schneider, Gabriela/0000-0003-2088-8695 FU NIH [2R01 DK074720, R01HL112788]; Stella and Henry Endowment FX This study was supported by NIH grants 2R01 DK074720 and R01HL112788 and the Stella and Henry Endowment to M.Z.R. NR 25 TC 7 Z9 7 U1 0 U2 0 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD JAN PY 2014 VL 44 IS 1 BP 295 EP 300 DI 10.3892/ijo.2013.2153 PG 6 WC Oncology SC Oncology GA AA0LI UT WOS:000330786200032 PM 24173021 ER PT J AU Li, XL Yang, JH Rader, C AF Li, Xiuling Yang, Jiahui Rader, Christoph TI Antibody conjugation via one and two C-terminal selenocysteines SO METHODS LA English DT Article DE Antibody engineering; Antibody conjugation; Selenocysteine ID GENETIC-CODE; DRUG AB Conventional antibody conjugation methods generate antibody-drug conjugates that are heterogeneous mixtures with undefined stoichiometry and variable pharmacokinetic and pharmacodynamic properties. We have previously described a strategy to generate site-specific antibody conjugates by genetic engineering of an antibody with a single C-terminal selenocysteine, the 21st natural amino acid, which displays unique chemical reactivity allowing selective conjugation in the presence of all other natural amino acids. In the present work, we describe a method for expanding this technology to higher drug-to-antibody ratios by genetically engineering an antibody with two C-terminal selenocysteines. Both selenocysteines effectively conjugate to a fluorescent iodoacetamide derivative and the resulting conjugate fully retains its antigen binding capability. Our method provides a platform for creating stoichiometrically defined antibody-drug conjugates for therapeutic intervention. (C) 2013 Elsevier Inc. All rights reserved. C1 [Li, Xiuling; Rader, Christoph] Scripps Florida, Scripps Res Inst, Dept Canc Biol, Jupiter, FL 33458 USA. [Yang, Jiahui; Rader, Christoph] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rader, Christoph] Scripps Florida, Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. RP Rader, C (reprint author), Scripps Florida, Scripps Res Inst, Dept Canc Biol & Mol Therapeut, 130 Scripps Way 2C1, Jupiter, FL 33458 USA. EM crader@scripps.edu FU Intramural NIH HHS [ZIA BC010647-08, ZIA BC010648-08] NR 17 TC 19 Z9 20 U1 0 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD JAN 1 PY 2014 VL 65 IS 1 BP 133 EP 138 DI 10.1016/j.ymeth.2013.05.023 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302LM UT WOS:000330606000015 PM 23756202 ER PT J AU Galpern, WR Coffey, CS Albanese, A Cheung, K Comella, CL Ecklund, DJ Fahn, S Jankovic, J Kieburtz, K Lang, AE McDermott, MP Shefner, JM Teller, JK Thompson, JLP Yeatts, SD Jinnah, HA AF Galpern, Wendy R. Coffey, Christopher S. Albanese, Alberto Cheung, Ken Comella, Cynthia L. Ecklund, Dixie J. Fahn, Stanley Jankovic, Joseph Kieburtz, Karl Lang, Anthony E. McDermott, Michael P. Shefner, Jeremy M. Teller, Jan K. Thompson, John L. P. Yeatts, Sharon D. Jinnah, H. A. TI Designing Clinical Trials for Dystonia SO NEUROTHERAPEUTICS LA English DT Review DE Dystonia; Clinical trials; Exploratory trials; Confirmatory trials; Adaptive designs ID DEEP-BRAIN-STIMULATION; CONTINUAL REASSESSMENT METHOD; EARLY PARKINSON-DISEASE; CERVICAL DYSTONIA; BOTULINUM-TOXIN; DOUBLE-BLIND; MOVEMENT-DISORDERS; TORSION DYSTONIA; RATING-SCALES; ONSET AB With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs. C1 [Galpern, Wendy R.] NINDS, NIH, Bethesda, MD 20892 USA. [Coffey, Christopher S.; Ecklund, Dixie J.] Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA. [Albanese, Alberto] Catholic Univ, Dept Neurol, Milan, Italy. [Albanese, Alberto] Ist Nazl Neurol Carlo Besta, Milan, Italy. [Cheung, Ken; Thompson, John L. P.] Columbia Univ, Dept Biostat, New York, NY USA. [Comella, Cynthia L.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Fahn, Stanley] Columbia Univ, Neurol Inst, Movement Disorder Div, New York, NY USA. [Jankovic, Joseph] Baylor Coll Med, Parkinsons Dis Ctr, Houston, TX 77030 USA. [Jankovic, Joseph] Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA. [Kieburtz, Karl] Univ Rochester, Med Ctr, Ctr Human Expt Therapeut, Rochester, NY 14642 USA. [Lang, Anthony E.] Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Clin, Toronto, ON M5T 2S8, Canada. [Lang, Anthony E.] Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, ON M5T 2S8, Canada. [McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY USA. [McDermott, Michael P.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [Shefner, Jeremy M.] Upstate Med Univ, Dept Neurol, Syracuse, NY USA. [Teller, Jan K.] Dystonia Med Res Fdn, Chicago, IL USA. [Yeatts, Sharon D.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Jinnah, H. A.] Emory Univ, Dept Neurol Human Genet & Pediat, Atlanta, GA 30322 USA. RP Galpern, WR (reprint author), NINDS, NIH, 6001 Execut Blvd,Rm 2225, Bethesda, MD 20892 USA. EM galpernw@ninds.nih.gov FU Dystonia Medical Research Foundation; Dystonia Coalition from NINDS [U54 NS65701]; Office of Rare Diseases Research in NCATS at NIH; National Institute of Neurological Disorders and Stroke [U13NS079084] FX This article was based, in part, on a workshop that was held in May 2012 involving an international group of dystonia clinicians, clinical trialists, and statisticians, as well as representatives from industry and the US Food and Drug Administration. The workshop was sponsored by the Dystonia Medical Research Foundation, The Dystonia Coalition (U54 NS65701 from NINDS and the Office of Rare Diseases Research in NCATS at NIH), and the National Institute of Neurological Disorders and Stroke (U13NS079084). Full conflict of interest disclosures are available in the electronic supplementary material for this article. NR 64 TC 8 Z9 8 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JAN PY 2014 VL 11 IS 1 BP 117 EP 127 DI 10.1007/s13311-013-0221-6 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 302TC UT WOS:000330626800013 PM 24282121 ER PT J AU Roschewski, M Manasanch, EE Wilson, WH AF Roschewski, Mark Manasanch, Elisabet E. Wilson, Wyndham H. TI Management of Heavy Chain Diseases: The Challenges of Biologic Heterogeneity COMMENTARY ON THE BIANCHI ET AL ARTICLE: M. ROSCHEWSKI, EE MANASANCH, WH WILSON SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID MYD88; MUTATION; MACROGLOBULINEMIA; LYMPHOMAS; PROTEIN; CELLS C1 [Roschewski, Mark; Manasanch, Elisabet E.; Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Roschewski, M (reprint author), NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JAN PY 2014 VL 28 IS 1 BP 63 EP 65 PG 3 WC Oncology SC Oncology GA 301QQ UT WOS:000330547400008 PM 24683720 ER PT J AU Morris, SE Rumsey, JM Cuthbert, BN AF Morris, Sarah E. Rumsey, Judith M. Cuthbert, Bruce N. TI Rethinking mental disorders: The role of learning and brain plasticity SO RESTORATIVE NEUROLOGY AND NEUROSCIENCE LA English DT Article DE Psychiatric diagnosis; RDoC; neuroplasticity; psychiatric treatment ID TRANSCRANIAL MAGNETIC STIMULATION; OBSESSIVE-COMPULSIVE DISORDER; TREATMENT-RESISTANT DEPRESSION; ANTERIOR CINGULATE CORTEX; GLUCOSE METABOLIC-RATE; NEURAL STEM-CELL; REAL-TIME FMRI; PSYCHIATRIC-DISORDERS; AUDITORY HALLUCINATIONS; COGNITIVE REMEDIATION AB Recent research in neurodevelopment, neuroplasticity and genetics is providing new insights into the etiogenesis of psychopathology, but progress in treatment development has been hampered by reliance on diagnostic categories that are characterized by heterogeneity and based primarily on phenomenology. The NIMH Research Domain Criteria (RDoC) initiative seeks to provide a neuroscience-based nosological framework for future research on psychopathology, categorizing individuals for research purposes using a dimensional approach that capitalizes on advances in modern neuroscience. These scientific advances and new approaches to classification can inform the development of novel, circuit-based interventions and the personalization of treatment. In this paper, we review key advances areas in clinical neuroscience, describe the RDoC project and highlight some emerging treatment approaches that are consistent with these developments. C1 [Morris, Sarah E.; Rumsey, Judith M.; Cuthbert, Bruce N.] NIMH, Div Adult Translat Res, Bethesda, MD 20892 USA. RP Morris, SE (reprint author), NIMH, Div Adult Translat Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM sarah.morris@nih.gov NR 144 TC 10 Z9 10 U1 2 U2 16 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0922-6028 EI 1878-3627 J9 RESTOR NEUROL NEUROS JI Restor. Neurol. Neurosci. PY 2014 VL 32 IS 1 BP 5 EP 23 DI 10.3233/RNN-139015 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 302FQ UT WOS:000330588100002 PM 23902986 ER PT J AU Ahrens, K Silver, R Perkins, N Wong, LC Galai, N Lesher, L Faraggi, D Wactawski-Wende, J Townsend, J Lynch, A Mumford, S Schisterman, E AF Ahrens, Katherine Silver, Robert Perkins, Neil Wong, Luchin Galai, Noya Lesher, Laurie Faraggi, David Wactawski-Wende, Jean Townsend, Janet Lynch, Anne Mumford, Sunni Schisterman, Enrique TI Preconception low dose aspirin and preterm birth: findings from the EAGeR (Effects of Aspirin in Gestation and Reproduction) randomized trial SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Ahrens, Katherine; Perkins, Neil; Mumford, Sunni; Schisterman, Enrique] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Silver, Robert; Wong, Luchin; Lesher, Laurie] Univ Utah Hlth Serv, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Galai, Noya; Faraggi, David] Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Townsend, Janet] Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA USA. [Lynch, Anne] Univ Colorado, Dept Obstet & Gynecol, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S8 EP S8 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600013 ER PT J AU Bailit, J AF Bailit, Jennifer TI Induction for nonmedical indications compared with expectant management SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Bailit, Jennifer] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S280 EP S280 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600569 ER PT J AU Clark, EAS AF Clark, Erin A. S. TI Genetic predisposition to adverse neurodevelopmental outcome after early preterm birth: a validation analysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Clark, Erin A. S.] Eunice Kennedy Shriver NICHD, Maternal Fetal Med Units, Bethesda, MD USA. [Clark, Erin A. S.] Eunice Kennedy Shriver NICHD, Neonatal Res Networks, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S10 EP S10 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600018 ER PT J AU Clark-Ganheart, C Reddy, U Kominiarek, M Huang, CC Landy, H Laughon, SK AF Clark-Ganheart, Cecily Reddy, Uma Kominiarek, Michelle Huang, Chun-Chih Landy, Helain Laughon, S. Katherine TI The optimal delivery approach for obese women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Clark-Ganheart, Cecily] Medstar Washington Hosp Ctr, Washington, DC USA. [Reddy, Uma; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Kominiarek, Michelle] Univ Illinois, Chicago, IL USA. [Landy, Helain] Medstar Georgetown Univ Hosp, Washington, DC USA. [Huang, Chun-Chih] Medstar Hlth Res Inst, Hyattsville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S325 EP S325 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600663 ER PT J AU Costantine, M AF Costantine, Maged TI The effect of mode of delivery on childhood obesity SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Costantine, Maged] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, MFMU Network, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S73 EP S74 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600123 ER PT J AU Downes, K Hinkle, S Sjaarda, L Albert, P Laughon, SK AF Downes, Katheryne Hinkle, Stefanie Sjaarda, Lindsey Albert, Paul Laughon, S. Katherine TI Prelabor and intrapartum cesarean delivery and subsequent risk of placenta previa SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Downes, Katheryne; Hinkle, Stefanie; Sjaarda, Lindsey; Albert, Paul; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S263 EP S263 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600536 ER PT J AU Facco, F Reid, K Grobman, W Parker, C Zee, P AF Facco, Francesca Reid, Kathryn Grobman, William Parker, Corette Zee, Phyllis CA Natl Inst Child Hlth Human Dev TI Sleep duration and continuity in nulliparous women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Facco, Francesca] Univ Pittsburgh, Pittsburgh, PA USA. [Reid, Kathryn; Grobman, William; Zee, Phyllis] Northwestern Univ, Chicago, IL 60611 USA. [Parker, Corette] RTI Int, Res Triangle Pk, NC USA. [Natl Inst Child Hlth Human Dev] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S361 EP S362 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600738 ER PT J AU Frascoli, M MacKenzie, T Coniglio, L Gomez-Lopez, N Romero, R AF Frascoli, Michela MacKenzie, Tippi Coniglio, Lacy Gomez-Lopez, Nardhy Romero, Roberto TI Activation of the fetal but not maternal adaptive immune system in preterm premature rupture of membranes (PPROM) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Frascoli, Michela; MacKenzie, Tippi; Coniglio, Lacy] UCSF, Eli & Edythe Broad Ctr Regenerat Med, San Francisco, CA USA. [Frascoli, Michela; MacKenzie, Tippi; Coniglio, Lacy] UCSF, Fetal Treatment Ctr, San Francisco, CA USA. [Gomez-Lopez, Nardhy; Romero, Roberto] NICHD, Perinatol Res Branch, Intramural Div, NIH,DHHS, Detroit, MI USA. [Gomez-Lopez, Nardhy; Romero, Roberto] Hutzel Womens Hosp, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S361 EP S361 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600737 ER PT J AU Grobman, W AF Grobman, William TI Prediction of spontaneous preterm birth among nulliparous women with a short cervix SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Grobman, William] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S358 EP S358 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600732 ER PT J AU Landon, M AF Landon, Mark TI Mild gestational diabetes mellitus (GDM) treatment and long term child health SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Landon, Mark] Eunice Kennedy Shriver NICHD MFMU Networks, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S408 EP S409 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600836 ER PT J AU Lucas, JC Dugan, EK Aggarwal, V Bale, S Frayna, A Hussong, M Jobanputra, V Richard, G Vincent, L Williams, B Meck, J Wapner, R Levy, B AF Lucas, Jaclyn Coletta Dugan, Elizabeth Kramer Aggarwal, Vimla Bale, Sherri Frayna, Aileen Hussong, Melanie Jobanputra, Vaidehi Richard, Gabi Vincent, Lisa Williams, Bradley Meck, Jeanne Wapner, Ronald Levy, Brynn CA Prenatal Array Study Grp TI Increased nuchal translucency and normal karyotype: value of additional testing SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Lucas, Jaclyn Coletta; Aggarwal, Vimla; Jobanputra, Vaidehi; Wapner, Ronald; Levy, Brynn] Columbia Univ, Med Ctr, New York, NY USA. [Dugan, Elizabeth Kramer; Bale, Sherri; Frayna, Aileen; Hussong, Melanie; Richard, Gabi; Vincent, Lisa; Williams, Bradley; Meck, Jeanne] GeneDx, Prenatal Diagnost Serv, Gaithersburg, MD USA. [Prenatal Array Study Grp] NICHD, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S87 EP S87 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600151 ER PT J AU Romero, S Geiersbach, K Paxton, C Presson, A Schisterman, E Branch, DW Silver, R AF Romero, Stephanie Geiersbach, Katherine Paxton, Christian Presson, Angela Schisterman, Enrique Branch, D. Ware Silver, Robert TI Genetic abnormalities in early pregnancy loss SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Romero, Stephanie; Presson, Angela; Silver, Robert] Univ Utah, Salt Lake City, UT USA. [Branch, D. Ware] Intermt Med Ctr, Murray, UT USA. [Schisterman, Enrique] NICHD, Bethesda, MD USA. [Geiersbach, Katherine; Paxton, Christian] ARUP Labs, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S78 EP S79 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600133 ER PT J AU Romero, S Geiersbach, K Paxton, C Schisterman, E Presson, A Branch, DW Silver, R AF Romero, Stephanie Geiersbach, Katherine Paxton, Christian Schisterman, Enrique Presson, Angela Branch, D. Ware Silver, Robert TI Chromosomal microarray analysis (CMA) vs karyotype in the evaluation of early pregnancy loss SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Romero, Stephanie; Presson, Angela; Silver, Robert] Univ Utah, Salt Lake City, UT USA. [Branch, D. Ware] Intermt Med Ctr, Murray, UT USA. [Geiersbach, Katherine; Paxton, Christian] ARUP Labs, Salt Lake City, UT USA. [Schisterman, Enrique] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S79 EP S79 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600134 ER PT J AU Saade, G AF Saade, George TI Using pattern-recognition software to evaluate intrapartum fetal heart (FHR) tracings SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Saade, George] Eunice Kennedy Shriver NICHD MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S290 EP S290 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600589 ER PT J AU Saade, G AF Saade, George TI Intra-amniotic sludge and adverse pregnancy outcomes in nulliparous women with a short cervix SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Saade, George] Eunice Kennedy Shriver NICHD, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S54 EP S54 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600084 ER PT J AU Silver, R AF Silver, Robert CA Stillbirth Collaborative Res TI Exploration of microbial nucleic acids in stillbirth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Silver, Robert] Univ Utah, Salt Lake City, UT USA. [Stillbirth Collaborative Res] NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S201 EP S201 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600397 ER PT J AU Wong, LC Schliep, K Schisterman, E Wactawski-Wende, J Townsend, J Lynch, A Galai, N Faraggi, D Perkins, N Mumford, S Ye, AJ Silver, R AF Wong, Luchin Schliep, Karen Schisterman, Enrique Wactawski-Wende, Jean Townsend, Janet Lynch, Anne Galai, Noya Faraggi, David Perkins, Neil Mumford, Sunni Ye, Aijun Silver, Robert TI The effect of very short interpregnancy interval on pregnancy outcomes after previous pregnancy loss SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Wong, Luchin; Silver, Robert] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Schliep, Karen; Schisterman, Enrique; Perkins, Neil; Mumford, Sunni; Ye, Aijun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Townsend, Janet] Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA USA. [Lynch, Anne] Univ Colorado, Dept Obstet & Gynecol, Denver, CO 80202 USA. [Galai, Noya; Faraggi, David] Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S208 EP S209 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600413 ER PT J AU Yeung, E Liu, AY Mills, J Zhang, CL Mannisto, T Boghossian, N Robledo, C Mendola, P AF Yeung, Edwina Liu, Aiyi Mills, James Zhang, Cuilin Maennistoe, Tuija Boghossian, Nansi Robledo, Candace Mendola, Pauline TI Copeptin levels are elevated in women prior to diagnosis of clinical pre-eclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Yeung, Edwina; Liu, Aiyi; Mills, James; Zhang, Cuilin; Maennistoe, Tuija; Boghossian, Nansi; Robledo, Candace; Mendola, Pauline] NICHD, Div Intramural Populat Hlth Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S146 EP S146 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600277 ER PT J AU Zhang, CL Sundaram, R Maisog, J Barr, D Louis, GB AF Zhang, Cuilin Sundaram, Rajeshwari Maisog, Jose Barr, Dana Louis, Germaine Buck TI Pre-gravid serum concentrations of perfluorooctanoic acid and the risk of gestational diabetes: a prospective study in the LIFE study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Zhang, Cuilin; Sundaram, Rajeshwari; Maisog, Jose; Louis, Germaine Buck] NICHD, NIH, Div Intramural Populat Hlth Res, Rockville, MD USA. [Barr, Dana] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S145 EP S146 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600276 ER PT J AU Zhang, CL Martin, K Bowers, K Liu, AY Bao, W Vaag, A Yeung, E Sun, LP Boghossian, N Hu, F Olsen, S AF Zhang, Cuilin Martin, Kelly Bowers, Katherine Liu, Aiyi Bao, Wei Vaag, Allan Yeung, Edwina Sun, Liping Boghossian, Nansi Hu, Frank Olsen, Sjurdur TI Fasting glucose levels during pregnancy and long-term childhood growth in the offspring SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med C1 [Zhang, Cuilin; Martin, Kelly; Bowers, Katherine; Liu, Aiyi; Bao, Wei; Yeung, Edwina; Sun, Liping; Boghossian, Nansi] NICHD, NIH, Div Intramural Populat Hlth Res, Rockville, MD USA. [Vaag, Allan] Danish Natl State Hosp, Copenhagen, Denmark. [Olsen, Sjurdur] Statens Serum Inst, Ctr Fetal Programming, DK-2300 Copenhagen, Denmark. [Hu, Frank] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RI Bowers, Katherine/N-5226-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 SU S BP S44 EP S44 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 298KK UT WOS:000330322600070 ER PT J AU Desrosiers, NA Lee, D Scheidweiler, KB Concheiro-Guisan, M Gorelick, DA Huestis, MA AF Desrosiers, Nathalie A. Lee, Dayong Scheidweiler, Karl B. Concheiro-Guisan, Marta Gorelick, David A. Huestis, Marilyn A. TI In vitro stability of free and glucuronidated cannabinoids in urine following controlled smoked cannabis SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Cannabinoids; Urine; Stability; Glucuronide ID TANDEM MASS-SPECTROMETRY; ACID; DRUGS; TEMPERATURES; METABOLISM; SPECIMENS; THCCOOH; SAMPLES; PLASMA; BLOOD AB Analyte stability is an important factor in urine test interpretation, yet cannabinoid stability data are limited. A comprehensive study of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide stabilities in authentic urine was completed. Urine samples after ad libitum cannabis smoking were pooled to prepare low and high pools for each study participant; baseline concentrations were measured within 24 h at room temperature (RT), 4 A degrees C and -20 A degrees C. Stability at RT, 4 A degrees C and -20 A degrees C was evaluated by Friedman tests for up to 1 year. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were quantified in baseline pools. RT THCCOOH baseline concentrations were significantly higher than -20 A degrees C, but not 4 A degrees C baseline concentrations. After 1 week at RT, THCCOOH increased, THCCOOH-glucuronide decreased, but THC-glucuronide was unchanged. In RT low pool, total THCCOOH (THCCOOH + THCCOOH-glucuronide) was significantly lower after 1 week. At 4 A degrees C, THCCOOH was stable 2 weeks, THCCOOH-glucuronide 1 month and THC-glucuronide for at least 6 months. THCCOOH was stable frozen for 1 year, but 6 months high pool results were significantly higher than baseline; THC-glucuronide and THCCOOH-glucuronide were stable for 6 months. Total THCCOOH was stable 6 months at 4 A degrees C, and frozen 6 months (low) and 1 year (high). THC, cannabidiol and cannabinol were never detected in urine; although not detected initially, 11-OH-THC was detected in 2 low and 3 high pools after 1 week at RT. Substantial THCCOOH-glucuronide deconjugation was observed at RT and 4 A degrees C. Analysis should be conducted within 3 months if non-hydrolyzed THCCOOH or THCCOOH-glucuronide quantification is required. C1 [Desrosiers, Nathalie A.; Lee, Dayong; Scheidweiler, Karl B.; Concheiro-Guisan, Marta; Gorelick, David A.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Desrosiers, Nathalie A.; Lee, Dayong] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse, NIH FX We acknowledge the contributions of the clinical staffs of the National Institute on Drug Abuse, Intramural Research Program, and Behavioral Pharmacology Research Unit and Clinical Research Unit, Johns Hopkins Bayview Medical Center, as well as Dr. David M. Schwope for protocol assistance, Dan Nichols and the staff at the Forensic Toxicology Drug Testing Laboratory in Fort Meade who provided urine creatinine data, the Graduate Partnership Program, NIH and the "Fondation Baxter et Alma Ricard". This research was funded by the Intramural Research Program, National Institute on Drug Abuse, NIH. NR 29 TC 6 Z9 6 U1 2 U2 11 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JAN PY 2014 VL 406 IS 3 BP 785 EP 792 DI 10.1007/s00216-013-7524-7 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 288QD UT WOS:000329625800013 PM 24292435 ER PT J AU Fu, D Arias, IM AF Fu, Dong Arias, Irwin M. TI Intracellular trafficking of P-glycoprotein (vol 44, pg 461, 2012) SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Correction C1 [Fu, Dong; Arias, Irwin M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Cell Biol & Metab Program, Bethesda, MD 20892 USA. RP Fu, D (reprint author), NICHD, NIH, Bldg 18T,Room 101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM fudong@mail.nih.gov NR 1 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JAN PY 2014 VL 46 BP 161 EP 161 DI 10.1016/j.biocel.2013.10.011 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 301QI UT WOS:000330546600017 ER PT J AU Chen, MY Bandettini, WP Shanbhag, SM Vasu, S Booker, OJ Leung, SW Wilson, JR Kellman, P Hsu, LY Lederman, RJ Arai, AE AF Chen, Marcus Y. Bandettini, W. Patricia Shanbhag, Sujata M. Vasu, Sujethra Booker, Oscar J. Leung, Steve W. Wilson, Joel R. Kellman, Peter Hsu, Li-Yueh Lederman, Robert J. Arai, Andrew E. TI Concordance and diagnostic accuracy of vasodilator stress cardiac MRI and 320-detector row coronary CTA SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Coronary artery disease; Cardiac magnetic resonance imaging; Cardiac computed tomography; Myocardial perfusion imaging ID CARDIOVASCULAR MAGNETIC-RESONANCE; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; ARTERY-DISEASE; METAANALYSIS; RADIATION; INTERVENTION; ADENOSINE; OBESITY; TRIAL AB Vasodilator stress cardiac magnetic resonance (CMR) detects ischemia whereas coronary CT angiography (CTA) detects atherosclerosis. The purpose of this study was to determine concordance and accuracy of vasodilator stress CMR and coronary CTA in the same subjects. We studied 151 consecutive subjects referred to detect or exclude suspected obstructive coronary artery disease (CAD) in patients without known disease or recurrent stenosis or ischemia in patients with previously treated CAD. Vasodilator stress CMR was performed on a 1.5 T scanner. CTA was performed on a 320-detector row system. Subjects were followed for cardiovascular events and downstream diagnostic testing. Subjects averaged 56 +/- A 12 years (60 % male), and 62 % had intermediate pre-test probability for obstructive CAD. Follow-up averaged 450 +/- A 115 days and was 100 % complete. CMR and CTA agreed in 92 % of cases (kappa 0.81, p < 0.001). The event-free survival was 97 % for non-ischemic and 39 % for ischemic CMR (p < 0.0001). The event-free survival was 99 % for non-obstructive and 36 % for obstructive CTA (p < 0.0001). Using a reference standard including quantitative invasive angiography or major cardiovascular events, CMR and CTA had respective sensitivities of 93 and 98 %; specificities of 96 and 96 %; positive predictive values of 91 and 91 %; negative predictive values of 97 and 99 %; and accuracies of 95 and 97 %. Non-ischemic vasodilator stress CMR or non-obstructive coronary CTA were highly concordant and each confer an excellent prognosis. CMR and CTA are both accurate for assessment of obstructive CAD in a predominantly intermediate risk population. C1 [Chen, Marcus Y.; Bandettini, W. Patricia; Shanbhag, Sujata M.; Vasu, Sujethra; Booker, Oscar J.; Leung, Steve W.; Wilson, Joel R.; Kellman, Peter; Hsu, Li-Yueh; Lederman, Robert J.; Arai, Andrew E.] NHLBI, Adv Cardiovasc Imaging Lab, Div Intramural Res, US Dept HHS,Cardiovasc & Pulm Branch,NIH, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, Div Intramural Res, US Dept HHS,Cardiovasc & Pulm Branch,NIH, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM araia@nih.gov RI Leung, Steve/E-5624-2011; OI Leung, Steve/0000-0003-2832-2258; lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, USA [ZIA HL004607-15, ZIA HL006137-03, ZIA HL006138-03] FX This work was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, USA (ZIA HL004607-15, ZIA HL006137-03, ZIA HL006138-03). The authors thank Gregory Henderson RT, Dennis Johnson RT, Christine Mancini RT, Shirley Rollison RT, Pamela Vincent RT, Marsha Block RN, Kathie Bronson CRNP, Jennifer Henry RN, Tracy Lowrey RN and Luis Rosario for expert help with imaging, patient care, and follow-up of study participants. NR 29 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 EI 1573-0743 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD JAN PY 2014 VL 30 IS 1 BP 109 EP 119 DI 10.1007/s10554-013-0300-0 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 298RT UT WOS:000330342800012 PM 24122452 ER PT J AU Vickers, KC Remaley, AT AF Vickers, Kasey C. Remaley, Alan T. TI Thematic Review Series: High Density Lipoprotein Structure, Function, and Metabolism HDL and cholesterol: life after the divorce? SO JOURNAL OF LIPID RESEARCH LA English DT Review DE microRNA; extracellular miRNA; small RNA carrier ID APOLIPOPROTEIN-A-I; FATTY-ACID ESTERS; RECEPTOR CLASS-B; ACUTE CORONARY SYNDROME; ALPHA-TOCOPHEROL; SCAVENGER RECEPTOR; BILE-ACIDS; SPHINGOSINE 1-PHOSPHATE; CARDIOVASCULAR-DISEASE; ENDOTHELIAL-CELLS AB For decades, HDL and HDL-cholesterol (HDL-C) levels were viewed as synonymous, and modulation of HDL-C levels by drug therapy held great promise for the prevention and treatment of cardiovascular disease. Nevertheless, recent failures of drugs that raise HDL-C to reduce cardiovascular risk and the now greater understanding of the complexity of HDL composition and biology have prompted researchers in the field to redefine HDL. As such, the focus of HDL has now started to shift away from a cholesterol-centric view toward HDL particle number, subclasses, and other alternative metrics of HDL. Many of the recently discovered functions of HDL are, in fact, not strictly conferred by its ability to promote cholesterol flux but by the other molecules it transports, including a diverse set of proteins, small RNAs, hormones, carotenoids, vitamins, and bioactive lipids. Based on HDL's ability to interact with almost all cells and transport and deliver fat-soluble cargo, HDL has the remarkable capacity to affect a wide variety of endocrine-like systems. In this review, we characterize HDL's unique cargo and address the functional relevance and consequences of HDL transport and delivery of noncholesterol molecules to recipient cells and tissues. C1 [Vickers, Kasey C.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Vickers, KC (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. EM kasey.c.vickers@vanderbilt.edu FU National Institutes of Health [K22-HL-113039-01]; Intramural Research Program FX This work was supported by National Institutes of Health Grant K22-HL-113039-01 (K.C.V.) and the Intramural Research Program (A.T.R.). NR 95 TC 24 Z9 24 U1 0 U2 29 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD JAN PY 2014 VL 55 IS 1 BP 4 EP 12 DI 10.1194/jlr.R035964 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 301LZ UT WOS:000330535100002 PM 23515282 ER PT J AU Freeman, SR Jin, XT Anzinger, JJ Xu, Q Purushothaman, S Fessler, MB Addadi, L Kruth, HS AF Freeman, Sebastian R. Jin, Xueting Anzinger, Joshua J. Xu, Qing Purushothaman, Sonya Fessler, Michael B. Addadi, Lia Kruth, Howard S. TI ABCG1-mediated generation of extracellular cholesterol microdomains SO JOURNAL OF LIPID RESEARCH LA English DT Article DE atherosclerosis; apolipoprotein A-I; high density lipoprotein; probucol; macrophages ID LOW-DENSITY-LIPOPROTEIN; BINDING CASSETTE-TRANSPORTER; APOLIPOPROTEIN-A-I; MONOCYTE-DERIVED MACROPHAGES; MEMBRANE-LIPID DOMAINS; SCAVENGER RECEPTOR BI; NIEMANN-PICK-DISEASE; CELLULAR CHOLESTEROL; PLASMA-MEMBRANE; ANTIBODY RECOGNITION AB Previous studies have demonstrated that the ATP-binding cassette transporters (ABC)A1 and ABCG1 function in many aspects of cholesterol efflux from macrophages. In this current study, we continued our investigation of extracellular cholesterol microdomains that form during enrichment of macrophages with cholesterol. Human monocyte-derived macrophages and mouse bone marrow-derived macrophages, differentiated with macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulation factor (GM-CSF), were incubated with acetylated LDL (AcLDL) to allow for cholesterol enrichment and processing. We utilized an anti-cholesterol microdomain monoclonal antibody to reveal pools of unesterified cholesterol, which were found both in the extracellular matrix and associated with the cell surface, that we show function in reverse cholesterol transport. Coincubation of AcLDL with 50 mu g/ml apoA-I eliminated all extracellular and cell surface-associated cholesterol microdomains, while coincubation with the same concentration of HDL only removed extracellular matrix-associated cholesterol microdomains. Only at an HDL concentration of 200 mu g/ml did HDL eliminate the cholesterol microdomains that were cell-surface associated. The deposition of cholesterol microdomains was inhibited by probucol, but it was increased by the liver X receptor (LXR) agonist TO901317, which upregulates ABCA1 and ABCG1. Extracellular cholesterol microdomains did not develop when ABCG1-deficient mouse bone marrow-derived macrophages were enriched with cholesterol. Our findings show that generation of extracellular cholesterol microdomains is mediated by ABCG1 and that reverse cholesterol transport occurs not only at the cell surface but also within the extracellular space. C1 [Freeman, Sebastian R.; Jin, Xueting; Anzinger, Joshua J.; Xu, Qing; Purushothaman, Sonya; Kruth, Howard S.] NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. [Fessler, Michael B.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Addadi, Lia] Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel. RP Kruth, HS (reprint author), NHLBI, Sect Expt Atherosclerosis, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kruthh@nhlbi.nih.gov FU Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 57 TC 7 Z9 8 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD JAN PY 2014 VL 55 IS 1 BP 115 EP 127 DI 10.1194/jlr.M044552 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 301LZ UT WOS:000330535100012 PM 24212237 ER PT J AU Whitt, J Shipley, SM Newman, DJ Zuck, KM AF Whitt, James Shipley, Suzanne M. Newman, David J. Zuck, Karina M. TI Tetramic Acid Analogues Produced by Coculture of Saccharopolyspora erythraea with Fusarium pallidoroseum SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID TRICHODERMA-HARZIANUM; SECONDARY METABOLITES; EQUISETI NRRL-5537; FUNGAL METABOLITES; TOXIN EQUISETIN; GENOME SEQUENCE; INHIBITORS; DERIVATIVES; INTEGRASE; INDUCTION AB Coculture of the fungus Fusarium pallidoroseum with the bacterium Saccharopolyspora erythraea was found to produce three new decalin-type tetramic acid analogues related to equisetin. The structures were determined by spectroscopic methods. The absolute configurations were established by circular dichroism spectroscopy and comparing the data with those of equisetin. C1 [Whitt, James; Shipley, Suzanne M.; Zuck, Karina M.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Newman, David J.] NCI, Nat Prod Branch, Dev Therapeut Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Zuck, KM (reprint author), SAIC Frederick Inc, Frederick Natl Lab Canc Res, POB B, Frederick, MD 21702 USA. EM zuckk@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. We gratefully acknowledge T. DeLloyd for assistance with fermentations, Q. Van and A. Castro Ruiz for running NMR experiments, S. Tarasov and M. Dyba (Structural Biophysics Laboratory) for assistance with the CD determinations, and L. Cartner for help running the polarimeter. NR 37 TC 16 Z9 16 U1 1 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 EI 1520-6025 J9 J NAT PROD JI J. Nat. Prod. PD JAN PY 2014 VL 77 IS 1 BP 173 EP 177 DI 10.1021/np400761g PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 298PN UT WOS:000330336800027 PM 24422636 ER PT J AU Ziegler, A Wilson, AF Gagnon, F AF Ziegler, A. Wilson, A. F. Gagnon, F. TI Informatics and Genetic Epidemiology SO METHODS OF INFORMATION IN MEDICINE LA English DT Editorial Material C1 [Ziegler, A.] Med Univ Lubeck, Inst Med Biometry & Stat, Univ Med Ctr Schleswig Holstein, D-23562 Lubeck, Germany. [Ziegler, A.] Med Univ Lubeck, Ctr Clin Trials, D-23562 Lubeck, Germany. [Wilson, A. F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, Baltimore, MD USA. [Gagnon, F.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. RP Ziegler, A (reprint author), Med Univ Lubeck, Inst Med Biometry & Stat, Univ Med Ctr Schleswig Holstein, Campus Lubeck Ratzeburger Allee 160 House 24, D-23562 Lubeck, Germany. EM ziegler@imbs.uni-luebeck.de NR 4 TC 0 Z9 0 U1 0 U2 4 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0026-1270 J9 METHOD INFORM MED JI Methods Inf. Med. PY 2014 VL 53 IS 1 BP 1 EP 2 PG 2 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA 299SG UT WOS:000330415400001 PM 24407729 ER PT J AU Gaidamakov, S Maximova, OA Chon, H Blewett, NH Wang, HS Crawford, AK Day, A Tulchin, N Crouch, RJ Morse, HC Blitzer, RD Maraia, RJ AF Gaidamakov, Sergei Maximova, Olga A. Chon, Hyongi Blewett, Nathan H. Wang, Hongsheng Crawford, Amanda K. Day, Amanda Tulchin, Natalie Crouch, Robert J. Morse, Herbert C., III Blitzer, Robert D. Maraia, Richard J. TI Targeted Deletion of the Gene Encoding the La Autoantigen (Sjogren's Syndrome Antigen B) in B Cells or the Frontal Brain Causes Extensive Tissue Loss SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSFER-RNA MATURATION; POLYMERASE-III TRANSCRIPTS; PRECURSOR TRANSFER-RNAS; BINDING PROTEIN LA; NASCENT RNA; MOUSE-BRAIN; LEADER RNA; IN-VITRO; SCHIZOSACCHAROMYCES-POMBE; SMALL RIBONUCLEOPROTEINS AB La antigen (Sjogren's syndrome antigen B) is a phosphoprotein associated with nascent precursor tRNAs and other RNAs, and it is targeted by autoantibodies in patients with Sjogren's syndrome, systemic lupus erythematosus, and neonatal lupus. Increased levels of La are associated with leukemias and other cancers, and various viruses usurp La to promote their replication. Yeast cells (Saccharomyces cerevisiae and Schizosaccharomyces pombe) genetically depleted of La grow and proliferate, whereas deletion from mice causes early embryonic lethality, raising the question of whether La is required by mammalian cells generally or only to surpass a developmental stage. We developed a conditional La allele and used it in mice that express Cre recombinase in either B cell progenitors or the forebrain. B cell Mb1(Cre) La-deleted mice produce no B cells. Consistent with alpha CamKII Cre, which induces deletion in hippocampal CA1 cells in the third postnatal week and later throughout the neocortex, brains develop normally in La-deleted mice until similar to 5 weeks and then lose a large amount of forebrain cells and mass, with evidence of altered pretRNA processing. The data indicate that La is required not only in proliferating cells but also in nondividing postmitotic cells. Thus, La is essential in different cell types and required for normal development of various tissue types. C1 [Gaidamakov, Sergei; Chon, Hyongi; Blewett, Nathan H.; Crawford, Amanda K.; Day, Amanda; Crouch, Robert J.; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Programs, NIH, Bethesda, MD USA. [Maximova, Olga A.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wang, Hongsheng; Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Tulchin, Natalie] Mt Sinai Sch Med, Dept Pathol, New York, NY USA. [Blitzer, Robert D.] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Washington, DC USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Programs, NIH, Bethesda, MD USA. EM maraiar@mail.nih.gov OI Morse, Herbert/0000-0002-9331-3705 FU Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Allergy and Infectious Diseases. NR 63 TC 2 Z9 3 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN PY 2014 VL 34 IS 1 BP 123 EP 131 DI 10.1128/MCB.01010-13 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 302DK UT WOS:000330581600010 PM 24190965 ER PT J AU Blanco, FF Sanduja, S Deane, NG Blackshear, PJ Dixon, DA AF Blanco, Fernando F. Sanduja, Sandhya Deane, Natasha G. Blackshear, Perry J. Dixon, Dan A. TI Transforming Growth Factor beta Regulates P-Body Formation through Induction of the mRNA Decay Factor Tristetraprolin SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID N-TERMINAL KINASE; INTESTINAL EPITHELIAL-CELLS; AU-RICH ELEMENTS; TGF-BETA; PROCESSING BODIES; POSTTRANSCRIPTIONAL REGULATION; PROTEIN TRISTETRAPROLIN; MICRORNA MATURATION; COLORECTAL-CANCER; STRESS GRANULES AB Transforming growth factor beta (TGF-beta) is a potent growth regulator and tumor suppressor in normal intestinal epithelium. Likewise, epithelial cell growth is controlled by rapid decay of growth-related mRNAs mediated through 3= untranslated region (UTR) AU-rich element (ARE) motifs. We demonstrate that treatment of nontransformed intestinal epithelial cells with TGF-beta inhibited ARE-mRNA expression. This effect of TGF-beta was promoted through increased assembly of cytoplasmic RNA processing (P) bodies where ARE-mRNA localization was observed. P-body formation was dependent on TGF-beta /Smad signaling, as Smad3 deletion abrogated P-body formation. In concert with increased P-body formation, TGF-beta induced expression of the ARE-binding protein tristetraprolin (TTP), which colocalized to P bodies. TTP expression was necessary for TGF-beta -dependent P-body formation and promoted growth inhibition by TGF-beta. The significance of this was observed in vivo, where colonic epithelium deficient in TGF-beta /Smad signaling or TTP expression showed attenuated P-body levels. These results provide new insight into TGF-beta's antiproliferative properties and identify TGF-beta as a novel mRNA stability regulator in intestinal epithelium through its ability to promote TTP expression and subsequent P-body formation. C1 [Blanco, Fernando F.; Dixon, Dan A.] Univ Kansas, Med Ctr, Dept Canc Biol, Kansas City, KS 66103 USA. [Sanduja, Sandhya] Whitehead Inst Biomed Sci, Cambridge, MA USA. [Deane, Natasha G.] Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Dixon, DA (reprint author), Univ Kansas, Med Ctr, Dept Canc Biol, Kansas City, KS 66103 USA. EM ddixon3@kumc.edu FU National Institutes of Health [R01CA134609]; American Cancer Society [RSG-06-122-01-CNE] FX This work was supported by the National Institutes of Health (R01CA134609) and the American Cancer Society (RSG-06-122-01-CNE). NR 79 TC 13 Z9 13 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN PY 2014 VL 34 IS 2 BP 180 EP 195 DI 10.1128/MCB.01020-13 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 302DM UT WOS:000330581800003 PM 24190969 ER PT J AU Eccleston, JL Koh, C Markello, TC Gahl, WA Heller, T AF Eccleston, Jason L. Koh, Christopher Markello, Thomas C. Gahl, William A. Heller, Theo TI \ An apparent homozygous deletion in maltase-glucoamylase, a lesson in the evolution of SNP arrays (vol 107, pg 674, 2012) SO MOLECULAR GENETICS AND METABOLISM LA English DT Correction C1 [Eccleston, Jason L.; Koh, Christopher; Heller, Theo] Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD USA. [Markello, Thomas C.; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Markello, Thomas C.; Gahl, William A.] NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Gahl, WA (reprint author), NIH, Off Clin Director, Res Inst, Bldg 10,Room 10C103,10 Ctr,MSC 1851, Bethesda, MD 20892 USA. EM Bgahl@helix.nih.gov; TheoH@intra.niddk.nih.gov NR 1 TC 0 Z9 0 U1 1 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 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN PY 2014 VL 111 IS 1 BP 58 EP 59 DI 10.1016/j.ymgme.2013.11.008 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 296AS UT WOS:000330158100010 ER PT J AU Benazzi, C Al-Dissi, A Chau, CH Figg, WD Sarli, G de Oliveira, JT Gartner, F AF Benazzi, C. Al-Dissi, A. Chau, C. H. Figg, W. D. Sarli, G. de Oliveira, J. T. Gaertner, F. TI Angiogenesis in Spontaneous Tumors and Implications for Comparative Tumor Biology SO SCIENTIFIC WORLD JOURNAL LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; SQUAMOUS-CELL CARCINOMAS; VASCULAR-PERMEABILITY FACTOR; CANCER STEM-CELLS; INTUSSUSCEPTIVE MICROVASCULAR GROWTH; METASTATIC COLORECTAL-CANCER; MAMMARY-GLAND TUMORS; BREAST-CANCER; ANTIANGIOGENIC THERAPY; FACTOR EXPRESSION AB Blood supply is essential for development and growth of tumors and angiogenesis is the fundamental process of new blood vessel formation from preexisting ones. Angiogenesis is a prognostic indicator for a variety of tumors, and it coincides with increased shedding of neoplastic cells into the circulation and metastasis. Several molecules such as cell surface receptors, growth factors, and enzymes are involved in this process. While antiangiogenic therapy for cancer has been proposed over 20 years ago, it has garnered much controversy in recent years within the scientific community. The complex relationships between the angiogenic signaling cascade and antiangiogenic substances have indicated the angiogenic pathway as a valid target for anticancer drug development and VEGF has become the primary antiangiogenic drug target. This review discusses the basic and clinical perspectives of angiogenesis highlighting the importance of comparative biology in understanding tumor angiogenesis and the integration of these model systems for future drug development. C1 [Benazzi, C.; Sarli, G.] Univ Bologna, Dept Vet Med Sci, I-40064 Bologna, Italy. [Al-Dissi, A.] Univ Saskatchewan, Western Coll Vet Med, Dept Vet Pathol, Saskatoon, SK S7N 5B4, Canada. [Chau, C. H.; Figg, W. D.] NCI, Bethesda, MD 20892 USA. [de Oliveira, J. T.; Gaertner, F.] Univ Porto IPATIMUP, Inst Pathol & Mol Immunol, P-4200456 Oporto, Portugal. [de Oliveira, J. T.; Gaertner, F.] Univ Porto ICBAS UP, Abel Salazar Inst Biomed Sci, P-4200456 Oporto, Portugal. RP Sarli, G (reprint author), Univ Bologna, Dept Vet Med Sci, Via Tolara 50, I-40064 Bologna, Italy. EM giuseppe.sarli@unibo.it RI Figg Sr, William/M-2411-2016 NR 165 TC 6 Z9 9 U1 1 U2 14 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 1537-744X J9 SCI WORLD J JI Sci. World J. PY 2014 AR 919570 DI 10.1155/2014/919570 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA0CN UT WOS:000330762800001 ER PT J AU Minniti, CP Delaney, KMH Gorbach, AM Xu, DH Lee, CCR Malik, N Koroulakis, A Antalek, M Maivelett, J Peters-Lawrence, M Novelli, EM Lanzkron, SM Axelrod, KC Kato, GJ AF Minniti, Caterina P. Delaney, Kara-Marie H. Gorbach, Alexander M. Xu, Dihua Lee, Chyi-Chia Richard Malik, Nitin Koroulakis, Antony Antalek, Matthew Maivelett, Jordan Peters-Lawrence, Marlene Novelli, Enrico M. Lanzkron, Sophie M. Axelrod, Karen C. Kato, Gregory J. TI Vasculopathy, inflammation, and blood flow in leg ulcers of patients with sickle cell anemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID CHRONIC VENOUS INCOMPETENCE; PULMONARY-HYPERTENSION; LACTATE-DEHYDROGENASE; RISK-FACTOR; DISEASE; ULCERATION; SPHEROCYTOSIS; THALASSEMIA; WOUNDS; DEATH AB Chronic leg ulcers are frequent and debilitating complications of sickle cell anemia. Inadequate blood supply has been postulated to be an important factor in their occurrence and delayed healing. Little is known about their microcirculatory and histopathological changes. We evaluated the microcirculation of lower extremity ulcers with laser speckle contrast imaging and infrared thermography and obtained clinical and laboratory characteristics in 18 adults with sickle cell anemia and chronic leg ulcers. Skin biopsies were obtained in four subjects. Subjects had markers of severe disease, anemia, high degree of hemolysis, inflammation, and thrombophilia. The highest blood flow was present in the ulcer bed, progressively less in the immediate periwound area, and an unaffected control skin area in the same extremity. Microscopic examination showed evidence of venostasis, inflammation, and vasculopathy. Blood vessels were increased in number, had activated endothelium and evidence of thrombosis/recanalization. High blood flow may be due to chronic inflammation, cutaneous vasodilatation, venostasis, and in situ thrombosis. These changes in skin microcirculation are similar to chronic venous ulcers in the non-sickle cell disease (SCD) population, thus suggesting that leg ulcers may be another end-organ complication with endothelial dysfunction that appears in patients with SCD at a younger age and with higher frequency than in the general population. Am. J. Heamtol. 89:1-6, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Minniti, Caterina P.; Delaney, Kara-Marie H.; Peters-Lawrence, Marlene; Kato, Gregory J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Gorbach, Alexander M.; Malik, Nitin; Koroulakis, Antony; Antalek, Matthew; Maivelett, Jordan] NIBIB, Infrared Imaging & Thermometry Unit, NIH, Bethesda, MD USA. [Xu, Dihua] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Novelli, Enrico M.] Div Hematol Oncol, Pittsburgh, PA USA. [Lanzkron, Sophie M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. [Axelrod, Karen C.] NIH, Nursing & Patient Care Serv, Bethesda, MD 20892 USA. RP Minniti, CP (reprint author), NHLBI, Hematol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM minnitic@nhlbi.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Division of Intramural Research, National Heart, Lung and Blood Institute [1 ZIA HL006127-01, 1 ZIA HL006162-01] FX Contract grant sponsor: Division of Intramural Research, National Heart, Lung and Blood Institute; Contract grant numbers: 1 ZIA HL006127-01, 1 ZIA HL006162-01. NR 44 TC 11 Z9 11 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD JAN PY 2014 VL 89 IS 1 BP 1 EP 6 DI 10.1002/ajh.23571 PG 6 WC Hematology SC Hematology GA 295CJ UT WOS:000330093900001 PM 23963836 ER PT J AU Hudson, JL Kendall, PC Chu, BC Gosch, E Martin, E Taylor, A Knight, A AF Hudson, Jennifer L. Kendall, Philip C. Chu, Brian C. Gosch, Elizabeth Martin, Erin Taylor, Alan Knight, Ashleigh TI Child involvement, alliance, and therapist flexibility: Process variables in cognitive-behavioural therapy for anxiety disorders in childhood SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Therapy process; Alliance; Child involvement; Flexibility; Child anxiety ID RANDOMIZED CLINICAL-TRIAL; INTERVIEW SCHEDULE; ADOLESCENT THERAPY; WORKING ALLIANCE; MANIFEST ANXIETY; MISSING DATA; YOUTH; PREDICTION; SCALE; CARE AB Background: This study examined the relations between treatment process variables and child anxiety outcomes. Method: Independent raters watched/listened to taped therapy sessions of 151 anxiety-disordered (6-14 yr-old; M = 10.71) children (43% boys) and assessed process variables (child alliance, therapist alliance, child involvement, therapist flexibility and therapist functionality) within a manual-based cognitive-behavioural treatment. Latent growth modelling examined three latent variables (intercept, slope, and quadratic) for each process variable. Child age, gender, family income and ethnicity were examined as potential antecedents. Outcome was analyzed using factorially derived clinician, mother, father, child and teacher scores from questionnaire and structured diagnostic interviews at pretreatment, posttreatment and 12-month follow-up. Results: Latent growth models demonstrated a concave quadratic curve for child involvement and therapist flexibility over time. A predominantly linear, downward slope was observed for alliance, and functional flexibility remained consistent over time. Increased alliance, child involvement and therapist flexibility showed some albeit inconsistent, associations with positive treatment outcome. Conclusion: Findings support the notion that maintaining the initial high level of alliance or involvement is important for clinical improvement. There is some support that progressively increasing alliance/involvement also positively impacts on treatment outcome. These findings were not consistent across outcome measurement points or reporters. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Hudson, Jennifer L.; Taylor, Alan; Knight, Ashleigh] Macquarie Univ, Ctr Emot Hlth, Dept Psychol, N Ryde, NSW 2109, Australia. [Kendall, Philip C.] Temple Univ, Philadelphia, PA 19122 USA. [Chu, Brian C.] Rutgers State Univ, Piscataway, NJ 08855 USA. [Gosch, Elizabeth] Philadelphia Coll Osteopath Med, Philadelphia, PA USA. [Martin, Erin] NIMH, Bethesda, MD USA. RP Hudson, JL (reprint author), Macquarie Univ, Ctr Emot Hlth, Dept Psychol, N Ryde, NSW 2109, Australia. EM jennie.hudson@mq.edu.au OI Hudson, Jennie/0000-0001-5778-2670 FU NIMH NIH HHS [R01 MH064484] NR 41 TC 3 Z9 3 U1 0 U2 31 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 EI 1873-622X J9 BEHAV RES THER JI Behav. Res. Ther. PD JAN PY 2014 VL 52 BP 1 EP 8 DI 10.1016/j.brat.2013.09.011 PG 8 WC Psychology, Clinical SC Psychology GA 295YK UT WOS:000330152100001 PM 24246476 ER PT J AU Metzger, MB Pruneda, JN Klevit, RE Weissman, AM AF Metzger, Meredith B. Pruneda, Jonathan N. Klevit, Rachel E. Weissman, Allan M. TI RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Review DE RING finger; U-box; Ubiquitin ligase (E3); Ubiquitin-conjugating enzyme (E2); Protein degradation; Catalysis ID GROWTH-FACTOR RECEPTOR; RETICULUM-ASSOCIATED DEGRADATION; FANCONI-ANEMIA PATHWAY; MATRIX PROTEIN IMPORT; NUCLEAR-PORE COMPLEX; END RULE PATHWAY; ENDOPLASMIC-RETICULUM; STRUCTURAL BASIS; C-CBL; CHAIN FORMATION AB RING finger domain and RING finger-like ubiquitin ligases (E3s), such as U-box proteins, constitute the vast majority of known E3s. RING-type E3s function together with ubiquitin-conjugating enzymes (E2s) to mediate ubiquitination and are implicated in numerous cellular processes. In part because of their importance in human physiology and disease, these proteins and their cellular functions represent an intense area of study. Here we review recent advances in RING-type E3 recognition of substrates, their cellular regulation, and their varied architecture. Additionally, recent structural insights into RING-type E3 function, with a focus on important interactions with E2s and ubiquitin, are reviewed. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. Published by Elsevier B.V. C1 [Metzger, Meredith B.; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. [Pruneda, Jonathan N.; Klevit, Rachel E.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. RP Klevit, RE (reprint author), Univ Washington, Dept Biochem, Box 357350, Seattle, WA 98195 USA. EM klevit@uw.edu; weissmaa@mail.nih.gov FU National Institute of General Medical Sciences [R01 GM088055, R01 GM098503]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The study of RING-type E3s continues to grow extremely rapidly. We regret that it was possible to only cite a fraction of the outstanding primary publications in this field. This work was supported by the National Institute of General Medical Sciences grants R01 GM088055 and R01 GM098503 (R.E.K.) and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (A.M.W.). NR 170 TC 85 Z9 86 U1 10 U2 37 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JAN PY 2014 VL 1843 IS 1 SI SI BP 47 EP 60 DI 10.1016/j.bbamcr.2013.05.026 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 294AG UT WOS:000330014200006 PM 23747565 ER PT J AU Gao, R Das, BB Chatterjee, R Abaan, OD Agama, K Matuo, R Vinson, C Meltzer, PS Pommier, Y AF Gao, Rui Das, Benu Brata Chatterjee, Raghunath Abaan, Ogan D. Agama, Keli Matuo, Renata Vinson, Charles Meltzer, Paul S. Pommier, Yves TI Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel SO DNA REPAIR LA English DT Article DE TDP1; Topoisomerases; Topotecan; CellMiner; Promoter hypermethylation ID STRAND BREAK REPAIR; TOPOISOMERASE-I; SPINOCEREBELLAR ATAXIA; COVALENT COMPLEXES; CLEAVAGE COMPLEXES; AXONAL NEUROPATHY; DAMAGE; EXPRESSION; ENZYME; PHARMACOLOGY AB Tyrosyl-DNA-phosphodiesterase 1 (TDP1) repairs 3'-blocking DNA lesions by catalytically hydrolyzing the tyrosyl-DNA-phosphodiester bond of trapped topoisomerase I (Top1) cleavage complexes (Topl cc). It also removes 3'-blocking residues derived from oxidative damage or incorporation of chain terminating anticancer and antiviral nucleosides. Thus, TDP1 is regarded as a determinant of resistance to Top1 inhibitors and chain terminating nucleosides, and possibly of genomic stability. In the 60 cell lines of the NCI Developmental Therapeutic Anticancer Screen (the NCI-60), whose whole genome transcriptome and mutations have recently been characterized, we discovered two human lung cancer cell lines deficient for TDP1 (NCI_H522 and HOP_62). HOP_62 shows undetectable TDP1 mRNA and NCI_H522 bears a homozygous deleterious mutation of TDP1 at a highly conserved amino acid residue (K292E). Absence of TDP1 protein and lack of TDP1 catalytic activity were demonstrated in cell lysates from both cell lines. Lack of TDP1 expression in HOP_62 was shown to be due to TDP1 promoter hypermethylation. Our study provides insights into the possible inactivation of TDP1 in cancers and its relationship to cellular response to Top1-targeted drugs. It also reveals two TDP1 knockout lung cancer cell lines for further TDP1 functional analyses. Published by Elsevier B.V. C1 [Gao, Rui; Das, Benu Brata; Agama, Keli; Matuo, Renata; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Abaan, Ogan D.; Meltzer, Paul S.] NCI, Mol Genet Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chatterjee, Raghunath; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@mail.nih.gov FU Intramural NIH HHS [Z01 BC006150-26] NR 45 TC 6 Z9 6 U1 3 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JAN PY 2014 VL 13 BP 1 EP 9 DI 10.1016/j.dnarep.2013.09.001 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 298OU UT WOS:000330334700001 PM 24355542 ER PT J AU Sharma, NK Lebedeva, M Thomas, T Kovalenko, OA Stumpf, JD Shadel, GS Santos, JH AF Sharma, Nilesh K. Lebedeva, Maria Thomas, Terace Kovalenko, Olga A. Stumpf, Jeffrey D. Shadel, Gerald S. Santos, Janine H. TI Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia SO DNA REPAIR LA English DT Article DE ATM; Mitochondria; Mitochondrial DNA repair; DNA ligase 3; Ataxia Telangiectasia ID BASE EXCISION-REPAIR; OXIDATIVE STRESS; LIGASE-III; RIBONUCLEOTIDE REDUCTASE; PROTEIN-KINASE; STRAND BREAKS; ATM; CELLS; REPLICATION; DYSFUNCTION AB Ataxia Telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer. A-T is caused by mutations in the kinase ATM, a master regulator of the DNA double-strand break response. In addition to DNA-damage signaling defects, A-T cells display mitochondrial dysfunction that is thought to contribute to A-T pathogenesis. However, the molecular mechanism leading to mitochondrial dysfunction in A-T remains unclear. Here, we show that lack of ATM leads to reduced mitochondrial DNA (mtDNA) integrity and mitochondrial dysfunction, which are associated to defective mtDNA repair. While protein levels of mtDNA repair proteins are essentially normal, in the absence of ATM levels specifically of DNA ligase III (Lig3), the only DNA ligase working in mitochondria is reduced. The reduction of Lig3 is observed in different A-T patient cells, in brain and pre-B cells derived from ATM knockout mice as well as upon transient or stable knockdown of ATM. Furthermore, pharmacological inhibition of Lig3 in wild type cells phenocopies the mtDNA repair defects observed in A-T patient cells. As targeted deletion of LIG3 in the central nervous system causes debilitating ataxia in mice, reduced Lig3 protein levels and the consequent mtDNA repair defect may contribute to A-T neurodegeneration. A-T is thus the first disease characterized by diminished Lig3. Published by Elsevier B.V. C1 [Sharma, Nilesh K.; Thomas, Terace; Kovalenko, Olga A.; Santos, Janine H.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA. [Lebedeva, Maria; Shadel, Gerald S.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Shadel, Gerald S.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Stumpf, Jeffrey D.] NIEHS, Mol Genet Lab, Durham, NC 27709 USA. RP Santos, JH (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Durham, NC 27709 USA. EM Janine.santos@nih.gov OI Sharma, Nilesh Kumar/0000-0002-8774-3020 FU Department of Defense, Army Research Office [56027LS]; NIH [NS56206]; A-T Children's Project FX This work was partially funded by the Department of Defense, Army Research Office, Grant number 56027LS to J.H.S., and grants from the NIH (NS56206) and the A-T Children's Project to G.S.S. NR 45 TC 19 Z9 19 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JAN PY 2014 VL 13 BP 22 EP 31 DI 10.1016/j.dnarep.2013.11.002 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 298OU UT WOS:000330334700003 PM 24342190 ER PT J AU Kirklin, JK Naftel, DC Kormos, RL Pagani, FD Myers, SL Stevenson, LW Acker, MA Goldstein, DL Silvestry, SC Milano, CA Baldwin, JT Pinney, S Rame, JE Miller, MA AF Kirklin, James K. Naftel, David C. Kormos, Robert L. Pagani, Francis D. Myers, Susan L. Stevenson, Lynne W. Acker, Michael. A. Goldstein, Daniel. L. Silvestry, Scott C. Milano, Carmelo A. Baldwin, J. Timothy Pinney, Sean Rame, J. Eduardo Miller, Marissa A. TI Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the Heart Mate II left ventricular assist device SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE INTERMACS; pump thrombosis; LVAD; HeartMate II; heart failure ID DESTINATION THERAPY; DIAGNOSIS; ECHOCARDIOGRAPHY; FAILURE AB BACKGROUND: Pump thrombosis remains an uncommon but potentially catastrophic complication of durable continuous-flow left ventricular assist devices (LVAD). A perceived increase in the incidence of pump thrombosis in the HeartMate II (HMII) LVAD (Thoratec, Pleasanton, CA) by clinicians prompted this analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database. METHODS: Between 2006 and June 2013, 8,988 United States patients aged older than 18 years received a durable LVAD. Of these, 6,910 adult patients from 132 institutions who received a HMII LVAD were entered in the INTERMACS database and constitute the study group for this analysis. RESULTS: Overall survival (with censoring at transplant or explant for recovery) with the HMII LVAD was 80% at 1 year and 69% at 2 years and was not significantly different when stratified by era of implant. Freedom from device exchange or death due to thrombosis decreased from 99% at 6 months in 2009 to 94% in 2012 (p < 0.0001). Multivariable hazard function analysis showed risk factors for pump thrombosis included later implant year (p < 0.0001), younger age (p < 0.0001), higher creatinine (p = 0.002), larger body mass index (p = 0.004), white race (p = 0.0004), left ventricular ejection fraction above 20% (p = 0.02), and higher lactate dehydrogenase level at 1 month (p < 0.0001). Survival (p < 0.0001) and freedom from infection (p = 0.008) and cerebrovascular accident (p < 0.0001) were lower after pump exchange than after primary implant. CONCLUSIONS: Pump exchange or death due to pump thrombosis increased during 2011 and 2012, but the magnitude of the increase remained relatively small. Survival remains high (80% at 1 year) with the HVBI LVAD. Risk factor analysis suggests that a number of patient-related factors contribute to the risk of thrombosis. Markedly elevated lactate dehydrogenase in the first month is a predictor of pump thrombosis. This analysis could not examine the potential role of technical factors during implant, such as sub-optimal pump or graft positioning, changes in patient management paradigms with pump speed settings, improved recognition and change in the threshold for pump exchange, or design or production changes with the pump, as contributors to the risk of pump thrombosis. (C) 2014 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Kirklin, James K.; Naftel, David C.; Myers, Susan L.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Kormos, Robert L.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Pagani, Francis D.] Univ Michigan, Ann Arbor, MI 48109 USA. [Stevenson, Lynne W.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Acker, Michael. A.; Rame, J. Eduardo] Univ Penn, Philadelphia, PA 19104 USA. [Goldstein, Daniel. L.] Montefiore Med Ctr, Bronx, NY 10467 USA. [Silvestry, Scott C.] Washington Univ, Sch Med, St Louis, MO USA. [Milano, Carmelo A.] Duke Univ, Durham, NC USA. [Baldwin, J. Timothy; Miller, Marissa A.] NHLBI, Bethesda, MD 20892 USA. [Pinney, Sean] Mt Sinai Med Ctr, New York, NY 10029 USA. RP Kirklin, JK (reprint author), Univ Alabama Birmingham, 760 THT, Birmingham, AL 35294 USA. EM jkirklin@uab.edu FU NHLBI [HHSN268201100025C]; Heart Ware FX This analysis and the INTERMACS device database are funded by NHLBI contract HHSN268201100025C. James K. Kirklin is the principal investigator for INTERMACS.; David C. Naftel is a consultant for Heart Ware, and Francis D. Pagani does contract research with Heart Ware, managed by the University of Michigan. NR 22 TC 133 Z9 133 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD JAN PY 2014 VL 33 IS 1 BP 12 EP 22 DI 10.1016/j.healun.2013.11.001 PG 11 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 297LA UT WOS:000330255700002 PM 24418730 ER PT J AU Sirenko, S Maltsev, VA Maltseva, LA Yang, DM Lukyanenko, Y Vinogradova, TM Jones, LR Lakatta, EG AF Sirenko, Syevda Maltsev, Victor A. Maltseva, Larissa A. Yang, Dongmei Lukyanenko, Yevgeniya Vinogradova, Tatiana M. Jones, Larry R. Lakatta, Edward G. TI Sarcoplasmic reticulum Ca2+ cycling protein phosphorylation in a physiologic Ca2+ milieu unleashes a high-power, rhythmic Ca2+ clock in ventricular myocytes: Relevance to arrhythmias and bio-pacemaker design SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Cardiac ventricular myocytes; Calcium clock; Calcium cycling; Protein phosphorylation; Spontaneous local calcium releases ID CARDIAC RYANODINE RECEPTOR; PIG SINOATRIAL NODE; PKA PHOSPHORYLATION; CALCIUM-RELEASE; MUSCLE SERCA2A; KINASE-II; CELLS; PHOSPHOLAMBAN; OSCILLATIONS; CHANNEL AB Basal phosphorylation of sarcoplasmic reticulum (SR) Ca2+ proteins is high in sinoatrial nodal cells (SANC), which generate partially synchronized, spontaneous, rhythmic, diastolic local Ca2+ releases (LCRs), but low in ventricular myocytes (VM), which exhibit rare diastolic, stochastic SR-generated Ca2+ sparks. We tested the hypothesis that in a physiologic Ca2+ milieu, and independent of increased Ca2+ influx, an increase in basal phosphorylation of SR Ca2+ cycling proteins will convert stochastic Ca2+ sparks into periodic, high-power Ca2+ signals of the type that drives SANC normal automaticity. We measured phosphorylation of SR-associated proteins, phospholamban (PLB) and ryanodine receptors (RyR), and spontaneous local Ca2+ release characteristics (LCR) in permeabilized single, rabbit VM in physiologic [Ca2+], prior to and during inhibition of protein phosphatase (PP) and phosphodiesterase (POE), or addition of exogenous cAMP, or in the presence of an antibody (2012), that specifically inhibits binding of the PLB to SERCA-2. In the absence of the aforementioned perturbations, VM could only generate stochastic local Ca2+ releases of low power and low amplitude, as assessed by confocal Ca2+ imaging and spectral analysis. When the kinetics of Ca2+ pumping into the SR were increased by an increase in PLB phosphoiylation (via POE and PP inhibition or addition of cAMP) or by 2012, self-organized, "clock-like" local Ca2+ releases, partially synchronized in space and time (Ca2+ wavelets), emerged, and the ensemble of these rhythmic local Ca2+ wavelets generated a periodic high-amplitude Ca2+ signal. Thus, a Ca2+ clock is not specific to pacemaker cells, but can also be unleashed in VM when SR Ca2+ cycling increases and spontaneous local Ca2+ release becomes partially synchronized. This unleashed Ca2+ clock that emerges in a physiological Ca2+ milieu in VM has two faces, however: it can provoke ventricular arrhythmias; or if harnessed, can be an important feature of novel bio-pacemaker designs. Published by Elsevier Ltd. C1 [Sirenko, Syevda; Maltsev, Victor A.; Maltseva, Larissa A.; Yang, Dongmei; Lukyanenko, Yevgeniya; Vinogradova, Tatiana M.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Jones, Larry R.] Indiana Univ, Sch Med, Krannert Inst Cardiol, Dept Med, Indianapolis, IN 46202 USA. RP Lakatta, EG (reprint author), NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM LakattaE@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland; National Institutes of Health [HL49428] FX This work is supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland, and, in part, by National Institutes of Health Grant HL49428 (Larry Jones). NR 42 TC 6 Z9 6 U1 1 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JAN PY 2014 VL 66 BP 106 EP 115 DI 10.1016/j.yjmcc.2013.11.011 PG 10 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 294XH UT WOS:000330080700011 PM 24274954 ER PT J AU Li, KG Simons-Morton, BG Brooks-Russell, A Ehsani, J Hingson, R AF Li, Kaigang Simons-Morton, Bruce G. Brooks-Russell, Ashley Ehsani, Johnathon Hingson, Ralph TI Drinking and Parenting Practices as Predictors of Impaired Driving Behaviors Among US Adolescents SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID GROWTH CURVE ANALYSES; PROTECTIVE FACTORS; ABUSE PREVENTION; YOUNG ADULTHOOD; RISK BEHAVIORS; SUBSTANCE USE; ALCOHOL-USE; DRUG-USE; SMOKING; SCHOOL AB Objective: The purpose of this study was to identify the extent to which 10th-grade substance use and parenting practices predicted 11th-grade teenage driving while alcohol-/other drug impaired (DWI) and riding with alcohol-/other drug impaired drivers (RWI). Method: The data were from Waves 1 and 2 of the NEXT Generation study, with longitudinal assessment of a nationally representative sample of 10th graders starting in 2009-2010. Multivariate logistic regression analysis was used to examine the prospective associations between proposed predictors (heavy episodic drinking, illicit drug use, parental monitoring knowledge and control) in Wave 1 and DWI/RWI. Results: Heavy episodic drinking at Wave 1 predicted Wave 2 DWI (odds ratio [OR] = 3.73, p < .001) and RWI (OR = 3.92, p < .001) after controlling for parenting practices and selected covariates. Father's monitoring knowledge predicted lower DWI prevalence at Wave 2 when controlling for covariates and teenage substance use (OR = 0.66, p < .001). In contrast, mother's monitoring knowledge predicted lower RWI prevalence at Wave 2 when controlling for covariates only (OR = 0.67, p < .05), but the effect was reduced to nonsignificance when controlling for teen substance use. Conclusions: Heavy episodic drinking predicted DWI and RWI. In addition, parental monitoring knowledge, particularly by fathers, was protective against DWI, independent of the effect of substance use. This suggests that the enhancement of parenting practices could potentially discourage adolescent DWI. The findings suggest that the parenting practices of fathers and mothers may have differential effects on adolescent impaired-driving behaviors. C1 [Li, Kaigang; Simons-Morton, Bruce G.; Brooks-Russell, Ashley; Ehsani, Johnathon] NICHHD, Hlth Behav Branch, Bethesda, MD 20892 USA. [Hingson, Ralph] NIAAA, Epidemiol & Prevent Res Div, Rockville, MD 20852 USA. RP Li, KG (reprint author), NICHHD, Hlth Behav Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd 7B13B, Bethesda, MD 20892 USA. EM kaigang.li@nih.gov RI Brooks-Russell, Ashley/F-8364-2014; OI Brooks-Russell, Ashley/0000-0002-7728-8423; Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN267200800009C]; National Heart, Lung and Blood Institute; National Institute on Alcohol Abuse and Alcoholism; Maternal and Child Health Bureau of the Health Resources and Services Administration FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract no. HHSN267200800009C); the National Heart, Lung and Blood Institute; the National Institute on Alcohol Abuse and Alcoholism; and the Maternal and Child Health Bureau of the Health Resources and Services Administration, with supplemental support from the National Institute on Drug Abuse. NR 56 TC 9 Z9 10 U1 4 U2 17 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JAN PY 2014 VL 75 IS 1 BP 5 EP 15 PG 11 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 295UW UT WOS:000330142800001 PM 24411792 ER PT J AU Hingson, R White, A AF Hingson, Ralph White, Aaron TI New Research Findings Since the 2007 Surgeon General's Call to Action to Prevent and Reduce Underage Drinking: A Review SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Review ID ADOLESCENT ALCOHOL-USE; RANDOMIZED CONTROLLED-TRIAL; PARENT-BASED INTERVENTION; COLLEGE-STUDENT DRINKING; HIGH-RISK DRINKING; SUBSTANCE USE; DRUG-USE; OUTLET DENSITY; USE DISORDERS; YOUNG-ADULTS AB Objective: In 2007, the U.S. Department of Health and Human Services issued The Surgeon General's Call To Action To Prevent And Reduce Underage Drinking, a publication documenting a problem linked to nearly 5,000 injury deaths annually and poor academic performance, potential cognitive deficits, risky sexual behavior, physical and sexual assaults, and other substance use. This report reviews subsequent underage drinking and related traffic fatality trends and research on determinants, consequences, and prevention interventions. Method: New research reports, meta-analyses, and systematic literature reviews were examined. Results: Since the Call to Action, reductions in underage frequency of drinking, heavy drinking occasions, and alcohol-related traffic deaths that began in the 1980s when the drinking age nationally became 21 have continued. Knowledge regarding determinants and consequences, particularly the effects of early-onset drinking, parental alcohol provision, and cognitive effects, has expanded. Additional studies support associations between the legal drinking age of 21, zero tolerance laws, higher alcohol prices, and reduced drinking and related problems. New research suggests that use/lose laws, social host liability, internal possession laws, graduated licensing, and night driving restrictions reduce traffic deaths involving underage drinking drivers. Additional studies support the positive effects of individually oriented interventions, especially screening and brief motivational interventions, web and face-to-face social norms interventions, college web-based interventions, parental interventions, and multicomponent community interventions. Conclusions: Despite reductions in underage alcohol consumption and related traffic deaths, underage drinking remains an enduring problem. Continued research is warranted in minimally studied areas, such as prospective studies of alcohol and brain development, policy studies of use/lose laws, internal possession laws, social host liability, and parent family interventions. C1 [Hingson, Ralph; White, Aaron] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. RP Hingson, R (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM rhingson@mail.nih.gov NR 98 TC 27 Z9 27 U1 7 U2 34 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JAN PY 2014 VL 75 IS 1 BP 158 EP 169 PG 12 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 295UW UT WOS:000330142800017 PM 24411808 ER PT J AU Denlinger, CS Ligibel, J AF Denlinger, Crystal S. Ligibel, Jennifer TI A Work in Progress: Developing the New NCCN Guidelines for Survivorship SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material ID CANCER SURVIVORS; CARE C1 [Denlinger, Crystal S.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Ligibel, Jennifer] Dana Farber Canc Inst, Womens Canc Program, Boston, MA USA. [Ligibel, Jennifer] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Ligibel, Jennifer] NCI, Transdisciplinary Res Energet & Canc Initiat, Bethesda, MD 20892 USA. NR 15 TC 1 Z9 1 U1 0 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JAN PY 2014 VL 12 IS 1 BP 1 EP 4 PG 4 WC Oncology SC Oncology GA 298OG UT WOS:000330333200001 PM 24453287 ER PT J AU Gawel, D Fijalkowska, IJ Jonczyk, P Schaaper, RM AF Gawel, Damian Fijalkowska, Iwona J. Jonczyk, Piotr Schaaper, Roel M. TI Effect of dNTP pool alterations on fidelity of leading and lagging strand DNA replication in E. coli SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE DNA replication fidelity; Leading and lagging strands; Base.base mispairs; dNTP precursors; Base selection; Exonucleolytic proofreading ID NUCLEOSIDE DIPHOSPHATE KINASE; POLYMERASE III HOLOENZYME; ESCHERICHIA-COLI; BASE SUBSTITUTION; MISMATCH REPAIR; MUTATOR; GENE; MUTAGENESIS; CHROMOSOME; MUTATIONS AB The fidelity with which organisms replicate their chromosomal DNA is of considerable interest. Detailed studies in the bacterium Escherichia coli have indicated that the fidelity of leading- and lagging-strand DNA replication is not the same, based on experiments in which the orientation of certain mutational targets on the chromosome was inverted relative to the movement of the replication fork: different mutation rates for several base-pair substitutions were observed depending on this orientation. While these experiments are indicative of differential replication fidelity in the two strands, a conclusion whether leading or lagging strand is the more accurate depends on knowledge of the primary mispairing error responsible for the base substitutions in question. A broad analysis of in vitro base-pairing preferences of DNA polymerases led us to propose that lagging-strand is the more accurate strand. In the present work, we present more direct in vivo evidence in support of this proposal. We determine the orientation dependence of mutant frequencies in ndk and dcd strains, which carry defined dNTP pool alterations. As these pool alterations lead to predictable effects on the array of possible mispairing errors, they mark the strands in which the observed errors occur. The combined results support the proposed higher accuracy of lagging-strand replication in E. coli. Published by Elsevier B.V. C1 [Gawel, Damian; Fijalkowska, Iwona J.; Jonczyk, Piotr] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. [Gawel, Damian; Schaaper, Roel M.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Gawel, D (reprint author), Med Ctr Postgrad Educ, Dept Biochem & Mol Biol, Ul Marymoncka 99, PL-02813 Warsaw, Poland. EM gawel@cmkp.edu.pl RI Fijalkowska, Iwona/I-7796-2016 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES065086]; Foundation for Polish Science TEAM program [TEAM/2011-8/1] FX We thank Drs. Jordan Saint-Charles and Kasia Maslowska of the NIEHS for their careful reading of the manuscript for this paper. This work was supported by project number Z01 ES065086 of the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. IJ.F. acknowledges support from project TEAM/2011-8/1 (New players involved in the maintenance of genomic stability) from the Foundation for Polish Science TEAM program. 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 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JAN PY 2014 VL 759 BP 22 EP 28 DI 10.1016/j.mrfmmm.2013.11.003 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 297MM UT WOS:000330259600004 PM 24269257 ER PT J AU Nie, LM Chen, M Sun, XL Rong, PF Zheng, NF Chen, XY AF Nie, Liming Chen, Mei Sun, Xiaolian Rong, Pengfei Zheng, Nanfeng Chen, Xiaoyuan TI Palladium nanosheets as highly stable and effective contrast agents for in vivo photoacoustic molecular imaging SO NANOSCALE LA English DT Article ID GOLD NANOPARTICLES; TOMOGRAPHY; GENERATION; NANOCAGES; CANCER; SIZE; PD AB A stable and efficient contrast agent is highly desirable for photoacoustic (PA) imaging applications. Recently gold nanostructures have been widely reported and studied for PA imaging and photothermal therapy. However, the structures of the nonspherical gold nanoparticles are easily destroyed after laser irradiation and thus may fail to complete the intended tasks. In this study, we propose to apply palladium nanosheets (PNSs), with strong optical absorption in the near-infrared (NIR) region, as a new class of exogenous PA contrast agents. PA and ultrasound (US) images were acquired sequentially by a portable and fast photoacoustic tomography (PAT) system with a hand-held transducer. Significant and long-lasting imaging enhancement in SCC7 head and neck squamous cell carcinoma was successfully observed in mice by PAT over time after tail vein administration of PNSs. The morphology and functional perfusion of the tumors were delineated in PA images due to the nanoparticle accumulation. PAT of the main organs was also conducted ex vivo to trace the fate of PNSs, which was further validated by inductively coupled plasma atomic emission spectrometry (ICP-AES). No obvious toxic effect was observed by in vitro MTT assay and ex vivo histological examination 7 days after PNS administration. With the combination of a portable imaging instrument and signal specificity, PNSs might be applied as stable and effective agents for photoacoustic cancer detection, diagnosis and treatment guidance. C1 [Nie, Liming; Sun, Xiaolian; Rong, Pengfei; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Nie, Liming] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. [Chen, Mei; Zheng, Nanfeng] Xiamen Univ, Coll Chem & Chem Engn, State Key Lab Phys Chem Solid Surfaces, Xiamen 361005, Peoples R China. [Chen, Mei; Zheng, Nanfeng] Xiamen Univ, Coll Chem & Chem Engn, Dept Chem, Xiamen 361005, Peoples R China. RP Zheng, NF (reprint author), Xiamen Univ, Coll Chem & Chem Engn, State Key Lab Phys Chem Solid Surfaces, Xiamen 361005, Peoples R China. EM nfzheng@xmu.edu.cn; shawn.chen@nih.gov RI 陈, 美/E-6081-2013; Zheng, Nanfeng/G-4613-2010; Nie, Liming/F-7718-2016 OI Zheng, Nanfeng/0000-0001-9879-4790; FU National Science Foundation of China [81301257, 81371596]; National Basic Research Program of China (973 program) [2013CB733802, 2014CB744503]; intramural research program of the National Institute of Biomedical Imaging and Bioengineering FX This project is supported in part by the National Science Foundation of China (81301257, 81371596), the National Basic Research Program of China (973 program 2013CB733802, 2014CB744503), and by the intramural research program of the National Institute of Biomedical Imaging and Bioengineering. We also thank summer intern Mr. Eshwar Manoharan for the editorial assistance. NR 26 TC 41 Z9 41 U1 11 U2 127 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2014 VL 6 IS 3 BP 1271 EP 1276 DI 10.1039/c3nr05468c PG 6 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 294JK UT WOS:000330041400004 PM 24317132 ER PT J AU Seth, RK Das, S Kumar, A Chanda, A Kadiiska, MB Michelotti, G Manautou, J Diehl, AM Chatterjee, S AF Seth, Ratanesh Kumar Das, Suvarthi Kumar, Ashutosh Chanda, Anindya Kadiiska, Maria B. Michelotti, Gregory Manautou, Jose Diehl, Anna Mae Chatterjee, Saurabh TI CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8+T cells aid progression of environment-linked nonalcoholic steatohepatitis SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Bromodichloromethane; Lipid peroxidation; Apoptosis; CD3; Leptin; IL-2 ID FATTY LIVER-DISEASE; CD8(+) T-CELLS; EXTRACELLULAR-MATRIX; IMMUNE MODULATION; OXIDATIVE STRESS; STELLATE CELLS; KUPFFER CELLS; ACTIVATION; FIBROSIS; APOPTOSIS AB Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DID) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (1(0) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8 + CD57 + cytotoxic T cells but not CD4 + CD57 + cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1 beta, and IFN-gamma in bromodichloromethane exposed DID mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8 + CD57 + T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH. (C) 2013 Elsevier Inc. All rights reserved. C1 [Seth, Ratanesh Kumar; Das, Suvarthi; Chanda, Anindya; Chatterjee, Saurabh] Univ S Carolina, Arnold Sch Publ Hlth, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. [Kumar, Ashutosh; Kadiiska, Maria B.] NIEHS, Lab Toxicol & Pharmacol, Free Rad Metab Grp, Res Triangle Pk, NC 27709 USA. [Michelotti, Gregory; Diehl, Anna Mae] Duke Univ, Div Gastroenterol, Durham, NC 27707 USA. [Manautou, Jose] Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA. RP Chatterjee, S (reprint author), Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. EM schatt@mailbox.sc.edu RI Seth, Ratanesh/M-3700-2016; OI Seth, Ratanesh/0000-0002-7078-0052 FU NIH [4R00ES019875-02, R01DK053792]; Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX The authors gratefully acknowledge the technical services of Benny Davidson at the IRF, University of South Carolina, School of Medicine. We also thank Dr David C. Volz for the use of the BX51 fluorescence microscope and the Instrumentation Resource Facility (IRF) at the University of South Carolina School of Medicine for equipment usage and consulting services. This work has been supported by NIH pathway to Independence Award (4R00ES019875-02 to Saurabh Chatterjee), NIH R01 (R01DK053792 to Anna Mae Diehl) and the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 49 TC 11 Z9 12 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JAN 1 PY 2014 VL 274 IS 1 BP 42 EP 54 DI 10.1016/j.taap.2013.10.029 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 297LD UT WOS:000330256000006 PM 24211274 ER PT J AU Stanley, RE Ragusa, MJ Hurley, JH AF Stanley, Robin E. Ragusa, Michael J. Hurley, James H. TI The beginning of the end: how scaffolds nucleate autophagosome biogenesis SO TRENDS IN CELL BIOLOGY LA English DT Review DE SNAREs; Atg1; Atg9; Atg13; autophagy; ULK1; membrane bending; vesicle tethering ID PROTEIN-KINASE COMPLEX; SACCHAROMYCES-CEREVISIAE; ATG1 KINASE; PREAUTOPHAGOSOMAL STRUCTURE; SELECTIVE AUTOPHAGY; TRAPP COMPLEXES; MEMBRANE-FUSION; EARLY STEPS; TRS85; MACROAUTOPHAGY AB Autophagy is a conserved mechanism that is essential for cell survival in starvation. Moreover, autophagy maintains cellular health by clearing unneeded or harmful materials from cells. Autophagy proceeds by the engulfment of bulk cytosol and organelles by a cup-shaped double-membrane sheet known as the phagophore. The phagophore closes on itself to form the autophagosome, which delivers its contents to the vacuole or lysosome for degradation. A multiprotein complex comprising the protein kinase autophagy-related protein 1 (Atg1) together with Atg13, Atg17, Atg29, and Atg31 (ULK1, ATG13, FIP200, and ATG101 in humans) has a pivotal role in the earliest steps of this process. This review summarizes recent structural and ultrastructural analysis of the earliest step in autophagosome biogenesis and discusses a model in which the Atg1 complex clusters high-curvature vesicles containing the integral membrane protein Atg9, thereby initiating the phagophore. C1 [Stanley, Robin E.; Ragusa, Michael J.] Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Ragusa, Michael J.; Hurley, James H.] Univ Calif Berkeley, Dept Mol & Cell Biol, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA. RP Hurley, JH (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, Calif Inst Quantitat Biosci, 229 Stanley Hall, Berkeley, CA 94720 USA. EM jimhurley@berkeley.edu FU Damon Runyon Cancer Research Fellowship; Ruth Kirschtein NRSA fellowship [GM099319] FX Research in the Hurley laboratory was supported by the Intramural Program of the NIH, NIDDK (J.H.H.), a Damon Runyon Cancer Research Fellowship (R.E.S.), and Ruth Kirschtein NRSA fellowship GM099319 (M.J.R.). NR 57 TC 21 Z9 22 U1 0 U2 25 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD JAN PY 2014 VL 24 IS 1 SI SI BP 73 EP 81 DI 10.1016/j.tcb.2013.07.008 PG 9 WC Cell Biology SC Cell Biology GA 296AN UT WOS:000330157600010 PM 23999079 ER PT J AU Pletnev, S Subach, FV Verkhusha, VV Dauter, Z AF Pletnev, Sergei Subach, Fedor V. Verkhusha, Vladislav V. Dauter, Zbigniew TI The rotational order-disorder structure of the reversibly photoswitchable red fluorescent protein rsTagRFP SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID LATTICE-TRANSLOCATION DEFECTS; CO-CRYSTAL; ABSORBENCY; ANTIBODY AB The rotational order-disorder (OD) structure of the reversibly photoswitchable fluorescent protein rsTagRFP is discussed in detail. The structure is composed of tetramers of 222 symmetry incorporated into the lattice in two different orientations rotated 90 degrees with respect to each other around the crystal c axis and with tetramer axes coinciding with the crystallographic twofold axes. The random distribution of alternatively oriented tetramers in the crystal creates the rotational OD structure with statistically averaged I422 symmetry. Despite order-disorder pathology, the structure of rsTagRFP has electron-density maps of good quality for both non-overlapping and overlapping parts of the model. The crystal contacts, crystal internal architecture and a possible mechanism of rotational OD crystal formation are discussed. C1 [Pletnev, Sergei] Argonne Natl Lab, Basic Res Program, Leidos Biomed Res Inc, Argonne, IL 60439 USA. [Pletnev, Sergei; Dauter, Zbigniew] Argonne Natl Lab, Macromol Crystallog Lab, NCI, Argonne, IL 60439 USA. [Subach, Fedor V.; Verkhusha, Vladislav V.] Yeshiva Univ Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA. RP Pletnev, S (reprint author), Argonne Natl Lab, Basic Res Program, Leidos Biomed Res Inc, 9700 S Cass Ave, Argonne, IL 60439 USA. EM pletnevs@mail.nih.gov; dauter@anl.gov RI Subach, Fedor/K-7080-2014 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research; NIH [GM073913, CA164468] FX Diffraction data were collected on the SER-CAT 22BM beamline at the Advanced Photon Source, Argonne National Laboratory. 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. This work was supported in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH) contract No. HHSN261200800001E, the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research and by NIH grants GM073913 and CA164468 to VVV. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 31 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2014 VL 70 BP 31 EP 39 DI 10.1107/S1399004713024644 PN 1 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 293AD UT WOS:000329942900005 PM 24419376 ER PT J AU Litten, RZ Falk, D Ryan, M Fertig, J AF Litten, Raye Z. Falk, Daniel Ryan, Megan Fertig, Joanne TI Research Opportunities for Medications to Treat Alcohol Dependence: Addressing Stakeholders' Needs SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Medication Development; Alcohol Pharmacotherapy; Research Opportunities; Stakeholders' Needs ID UNITED-STATES; ADDICTION; NALTREXONE; PRESCRIPTION; DISORDERS; DRINKING; TRIALS; TRENDS; DRUG AB During the past decade, significant advances have been made in the development of medications to treat alcohol dependence. Four medications have been approved by the U.S. Food and Drug Administration for treating alcohol dependencenaltrexone, injectable naltrexone, acamprosate, and disulfiramand several others show promise. The fact remains, however, that because of the heterogeneity of alcohol dependence, these medications will not work for all people, in all circumstances. Moreover, clinicians are not routinely prescribing these medications for alcohol treatment. This commentary poses a number of issues that must be addressed in order to advance the alcohol research field and to make medications a mainstream treatment for problematic drinking. These issues are framed from the perspective of the various stakeholders involved, including clinicians, patients, regulatory agencies, the pharmaceutical industry, and third-party payers. Addressing these issues will not only help to improve treatment but, as further described, will also open up many new research opportunities for alcohol investigators in the coming decade. C1 [Litten, Raye Z.; Falk, Daniel; Ryan, Megan; Fertig, Joanne] NIAAA, NCIG, Div Treatment & Recovery Res, Bethesda, MD 20892 USA. RP Litten, RZ (reprint author), NIAAA, Div Treatment & Recovery Res, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM rlitten@mail.nih.gov NR 28 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2014 VL 38 IS 1 BP 27 EP 32 DI 10.1111/acer.12193 PG 6 WC Substance Abuse SC Substance Abuse GA 292EV UT WOS:000329885900003 PM 23889161 ER PT J AU Marshall, VJ Ramchandani, VA Kalu, N Kwagyan, J Scott, DM Ferguson, CL Taylor, RE AF Marshall, Vanessa J. Ramchandani, Vijay A. Kalu, Nnenna Kwagyan, John Scott, Denise M. Ferguson, Clifford L. Taylor, Robert E. TI Evaluation of the Influence of Alcohol Dehydrogenase Polymorphisms on Alcohol Elimination Rates in African Americans SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Dehydrogenase Polymorphisms; Breath Alcohol Clamping; Alcohol Elimination Rate; African Descent Population; Sib Pair Analysis ID FAMILY-HISTORY; ADH2-ASTERISK-3 ALLELE; YOUNG-ADULTS; NATIVE-AMERICANS; ACUTE RESPONSE; BODY-MASS; ASSOCIATION; PHARMACOKINETICS; METABOLISM; DEPENDENCE AB IntroductionThe relationship between alcohol dehydrogenase (ADH) polymorphisms and alcohol use disorders in populations of African descent has not been clearly established. This study examined the effect of ADH1B polymorphisms on alcohol metabolism and subjective response, following intravenous (IV) alcohol administration, and the influence of gender, recent drinking history, and family history of alcoholism (FHA), in nondependent African American drinkers. MaterialsThe sample included eighty-seven 21- to 35-year-old, light social drinkers of African descent. Participants included 39 sib pairs, 2 sibships with 3 siblings each, and 3 individuals who were not part of a sibship. Participants received infusions via the use of the clamp method that refers to the goal of controlling breath alcohol concentration in 2 randomized sessions at 0.06g% ethanol and 0mg% (placebo), and a battery of subjective scales at predefined time points. Dependent measures included alcohol elimination rates (AERs), alcohol disappearance rates (ADRs), subjective measures peak scores, and area under the curve. General linear model and mixed models were performed to examine the relationship between ADH1B genotype, dependent measures, and influence of covariates. ResultsParticipants with ADH1B1/1 genotypes showed higher number of drinks (p=0.023) and drinks per drinking day (p=0.009) compared with the persons with ADH1B1/3 genotype. AER (adjusted for body weight) was higher in ADH1B*1 homozygotes (p=0.045) compared with ADH1B1/3 heterozygotes. ADR differed significantly between males and females (p=0.002), regardless of body weight (p=0.004) and lean body mass (p<0.001) adjustments. Although a few subjective measures differed across genotype, all measures were higher in alcohol sessions compared with placebo sessions (p<0.001). These observations were mediated by drinks per drinking day, gender, and FHA. ConclusionsADH1B polymorphism had a marginal effect on alcohol pharmacokinetics following IV alcohol administration in nondependent drinkers of African descent. Session (alcohol vs. placebo) and ADH1B genotype did, however, influence subjective response to alcohol with some variation by gender, FHA, and drinks per drinking day. C1 [Marshall, Vanessa J.; Kalu, Nnenna; Kwagyan, John; Scott, Denise M.; Ferguson, Clifford L.; Taylor, Robert E.] Howard Univ, Alcohol Res Ctr, Washington, DC 20059 USA. [Ramchandani, Vijay A.] NIAAA, NIH, Bethesda, MD USA. RP Marshall, VJ (reprint author), Howard Univ, Coll Med, Alcohol Res Ctr, 520 W St,NW Suite 3408, Washington, DC 20059 USA. EM vjmarshall@howard.edu FU National Institute of Alcohol Abuse and Alcoholism (NIAAA) [AA-11898, AA-012553]; Howard University General Clinical Research Center (GCRC) [M01-RR10284] FX Dr. Tiebing Liang, Dr. Lucy Carr, and Tammy Graves from Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, IN, for assistance with DNA isolation and genotyping. This study was supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA), grant numbers AA-11898, AA-012553, Howard University General Clinical Research Center (GCRC) Grant M01-RR10284. NR 51 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2014 VL 38 IS 1 BP 51 EP 59 DI 10.1111/acer.12212 PG 9 WC Substance Abuse SC Substance Abuse GA 292EV UT WOS:000329885900008 PM 23915245 ER PT J AU Moon, KH Tajuddin, N Brown, J Neafsey, EJ Kim, HY Collins, MA AF Moon, Kwan-Hoon Tajuddin, Nuzhath Brown, James, III Neafsey, Edward J. Kim, Hee-Yong Collins, Michael A. TI Phospholipase A2, Oxidative Stress, and Neurodegeneration in Binge Ethanol-Treated Organotypic Slice Cultures of Developing Rat Brain SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol; Arachidonic Acid; Organotypic; Neuroinflammation; Endocannabinoid; Monoacylglycerol Lipase ID OXYGEN SPECIES CONTRIBUTE; ARACHIDONIC-ACID RELEASE; IN-VIVO; INDUCED NEUROINFLAMMATION; ALCOHOL-INTOXICATION; INDUCED APOPTOSIS; FATTY-ACIDS; A(2); ACTIVATION; DAMAGE AB BackgroundBrain neurodamage from chronic binge ethanol (EtOH) exposure is linked to neuroinflammation and associated oxidative stress. Using rat organotypic hippocampal-entorhinal cortical (HEC) slice cultures of developing brain age, we reported that binge EtOH promotes release of a neuroinflammatory instigator, arachidonic acid (AA), concomitant with neurodegeneration, and that mepacrine, a global inhibitor of phospholipase A2 (PLA2) enzymes mobilizing AA from phospholipids, is neuroprotective. Here, we sought with binge EtOH-treated HEC cultures to establish that PLA2 activity is responsible in part for significant oxidative stress and to ascertain the PLA2 families responsible for AA release and neurodegeneration. MethodsHEC slices, prepared from 1-week-old rats and cultured 2 to 2.5weeks, were exposed to 100mM EtOH over 6 successive days, with 4 daytime withdrawals (no EtOH). Brain 3-nitrotyrosinated (3-NT)- and 4-hydroxy-2-nonenal (4-HNE)-adducted proteins, oxidative stress footprints, were immunoassayed on days 3 through 6, and mepacrine's effect was determined on day 6. The effects of specific PLA2 inhibitors on neurodegeneration (propidium iodide staining) and AA release (ELISA levels in media) in the cultures were then determined. Also, the effect of JZL184, an inhibitor of monoacylglycerol lipase (MAGL) which is reported to mobilize AA from endocannabinoids during neuroinflammatory insults, was examined. Results3-NT- and 4-HNE-adducted proteins were significantly increased by the binge EtOH exposure, consistent with oxidative stress, and mepacrine prevented the increases. The PLA2 inhibitor results implicated secretory PLA2 (group II sPLA2) and to some extent Ca2+-independent cytosolic PLA2 (group VI iPLA2) in binge EtOH-induced neurotoxicity and in AA release, but surprisingly, Ca2+-dependent cytosolic PLA2 (group IV cPLA2) did not appear important. Furthermore, unlike PLA2 inhibition, MAGL inhibition failed to prevent the neurodegeneration. ConclusionsIn these developing HEC slice cultures, pro-oxidative signaling via sPLA2 and iPLA2, but not necessarily cPLA2 or MAGL, is involved in EtOH neurotoxicity. This study provides further insights into neuroinflammatory phospholipase signaling and oxidative stress underlying binge EtOH-induced neurodegeneration in developing (adolescent age) brain in vitro. C1 [Moon, Kwan-Hoon; Tajuddin, Nuzhath; Brown, James, III; Neafsey, Edward J.; Collins, Michael A.] Loyola Univ Chicago, Stritch Sch Med, Dept Mol Pharmacol & Therapeut, Maywood, IL 60153 USA. [Kim, Hee-Yong] NIAAA, Lab Mol Signaling, NIH, Bethesda, MD USA. RP Collins, MA (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Mol Pharmacol, Maywood, IL 60153 USA. EM mcollin@lumc.edu FU National Institutes of Health National Institute of Alcohol Abuse and Alcoholism [U01 AA018279, T32 AA13527, R21 AA011543]; Loyola University Potts Foundation FX This research was supported by the National Institutes of Health National Institute of Alcohol Abuse and Alcoholism (grants U01 AA018279, T32 AA13527, R21 AA011543) and the Loyola University Potts Foundation. NR 55 TC 8 Z9 8 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2014 VL 38 IS 1 BP 161 EP 169 DI 10.1111/acer.12221 PG 9 WC Substance Abuse SC Substance Abuse GA 292EV UT WOS:000329885900020 PM 23909864 ER PT J AU Moore, NM Nagahara, LA AF Moore, Nicole M. Nagahara, Larry A. TI Physical Biology in Cancer. 1. Cellular physics of cancer metastasis SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE physics of cancer; cell mechanics; microfluidics AB One of the major challenges in cancer research today is developing new therapeutic strategies to control metastatic disease, the spread of cancer cells from a primary tumor to seed in a distant site. Advances in diagnosis and treatment options have increased the survival rate for most patients with local tumors; however, less progress has been made in treatment of disseminated disease. According to the SEER Cancer Statistics Review, 19752010, in the case of breast and prostate cancers, only one in four patients diagnosed with distant metastatic disease will survive more than five years. Current research efforts largely focus on identifying biological targets, such as specific genes and signaling pathways that drive two key steps of metastasis, invasion from the primary tumor and growth in the secondary site. On the other hand, there are phenotypic traits and dynamics in the metastatic process that are not encoded by single genes or signaling pathways but, rather, a larger system of events and biophysical characteristics. Connecting genomic and pathway investigations with quantitative physical phenotypic characteristics of cells, the physical microenvironment, and the physical spatiotemporal interactions of the metastatic process provides a stronger complementary understanding of the disease. C1 [Moore, Nicole M.; Nagahara, Larry A.] NCI, Ctr Strateg Sci Initiat, Off Phys Sci Oncol, Bethesda, MD 20892 USA. RP Moore, NM (reprint author), NCI, Ctr Strateg Sci Initiat, Off Phys Sci Oncol, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM moorenm@mail.nih.gov NR 10 TC 2 Z9 2 U1 1 U2 21 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2014 VL 306 IS 2 BP C78 EP C79 DI 10.1152/ajpcell.00292.2013 PG 2 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 291WK UT WOS:000329862400002 PM 24153431 ER PT J AU Smith, JP Solomon, TE AF Smith, Jill P. Solomon, Travis E. TI Cholecystokinin and pancreatic cancer: the chicken or the egg? SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE receptor; G protein-coupled; gastrin; cholecystokinin; pancreas; cancer ID GASTRIN GENE-EXPRESSION; ACINAR-CELLS; FUNCTIONAL EXPRESSION; EXOCRINE SECRETION; CCK-B; ANTAGONIST RADIOLIGAND; STIMULATES GROWTH; MOLECULAR-CLONING; RECEPTOR FAMILY; TRANSGENIC MICE AB The gastrointestinal peptide cholecystokinin (CCK) causes the release of pancreatic digestive enzymes and growth of the normal pancreas. Exogenous CCK administration has been used in animal models to study pancreatitis and also as a promoter of carcinogen-induced or Kras-driven pancreatic cancer. Defining CCK receptors in normal human pancreas has been problematic because of its retroperitoneal location, high concentrations of pancreatic proteases, and endogenous RNase. Most studies indicate that the predominant receptor in human pancreas is the CCK-B type, and CCK-A is the predominant form in rodent pancreas. In pancreatic cancer cells and tumors, the role of CCK is better established because receptors are often overexpressed by these cancer cells and stimulation of such receptors promotes growth. Furthermore, in established cancer, endogenous production of CCK and/or gastrin occurs and their actions stimulate the synthesis of more receptors plus growth by an autocrine mechanism. Initially it was thought that the mechanism by which CCK served to potentiate carcinogenesis was by interplay with inflammation in the pancreatic microenvironment. But with the recent findings of CCK receptors on early PanIN (pancreatic intraepithelial neoplasia) lesions and on stellate cells, the question has been raised that perhaps CCK actions are not the result of cancer but an early driving promoter of cancer. This review will summarize what is known regarding CCK, its receptors, and pancreatic cancer, and also what is unknown and requires further investigation to determine which comes first, the chicken or the egg, "CCK or the cancer." C1 [Smith, Jill P.] NIDDK, NIH, Bethesda, MD 20892 USA. [Solomon, Travis E.] Univ Missouri, Dept Basic Med Sci, Kansas City, MO 64110 USA. RP Smith, JP (reprint author), NIDDK, NIH, 6707 Democracy Blvd,Rm 655, Bethesda, MD 20892 USA. EM jsmith2@psu.edu NR 106 TC 18 Z9 18 U1 1 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JAN PY 2014 VL 306 IS 2 BP G91 EP G101 DI 10.1152/ajpgi.00301.2013 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 293OR UT WOS:000329982700001 PM 24177032 ER PT J AU Balch, WE Sznajder, JI Budinger, S Finley, D Laposky, AD Cuervo, AM Benjamin, IJ Barreiro, E Morimoto, RI Postow, L Weissman, AM Gail, D Banks-Schlegel, S Croxton, T Gan, WN AF Balch, William E. Sznajder, Jacob I. Budinger, Scott Finley, Daniel Laposky, Aaron D. Cuervo, Ana Maria Benjamin, Ivor J. Barreiro, Esther Morimoto, Richard I. Postow, Lisa Weissman, Allan M. Gail, Dorothy Banks-Schlegel, Susan Croxton, Thomas Gan, Weiniu TI Malfolded Protein Structure and Proteostasis in Lung Diseases SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE protein misfolding; post-translational processing; proteosome; ubiquitination; pulmonary health ID OBSTRUCTIVE PULMONARY-DISEASE; ENDOPLASMIC-RETICULUM STRESS; OXIDATIVE STRESS; ALPHA(1)-ANTITRYPSIN DEFICIENCY; THERAPEUTIC PARADIGM; CYSTIC-FIBROSIS; PROTEASOME; AUTOPHAGY; UBIQUITIN; INJURY AB Recent discoveries indicate that disorders of protein folding and degradation play a particularly important role in the development of lung diseases and their associated complications. The overarching purpose of the National Heart, Lung, and Blood Institute workshop on "Malformed Protein Structure and Proteostasis in Lung Diseases" was to identify mechanistic and clinical research opportunities indicated by these recent discoveries in proteostasis science that will advance our molecular understanding of lung pathobiology and facilitate the development of new diagnostic and therapeutic strategies for the prevention and treatment of lung disease. The workshop's discussion focused on identifying gaps in scientific knowledge with respect to proteostasis and lung disease, discussing new research advances and opportunities in protein folding science, and highlighting novel technologies with potential therapeutic applications for diagnosis and treatment. C1 [Balch, William E.] Scripps Res Inst, Dept Cell Biol & Chem Physiol, La Jolla, CA 92037 USA. [Sznajder, Jacob I.; Budinger, Scott] Northwestern Univ, Div Pulm & Crit Care Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Morimoto, Richard I.] Northwestern Univ, Dept Mol Biosci, Chicago, IL 60611 USA. [Finley, Daniel] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Laposky, Aaron D.; Postow, Lisa; Gail, Dorothy; Banks-Schlegel, Susan; Croxton, Thomas; Gan, Weiniu] NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. [Cuervo, Ana Maria] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10467 USA. [Cuervo, Ana Maria] Albert Einstein Coll Med, Inst Aging Studies, Bronx, NY 10467 USA. [Benjamin, Ivor J.] Med Coll Wisconsin, Div Cardiovasc Med, Milwaukee, WI 53226 USA. [Barreiro, Esther] Hosp del Mar, Dept Resp Med, Lung Canc Res Grp, Inst Med Res Hosp del Mar IMIM,CIBERES, Barcelona, Spain. [Weissman, Allan M.] NCI, Lab Prot Dynam, Frederick, MD 21701 USA. [Weissman, Allan M.] NCI, Signaling Ctr Canc Res, Frederick, MD 21701 USA. RP Gan, WN (reprint author), NHLBI, NIH, 6701 Rockledge Dr,Suite 10042, Bethesda, MD 20892 USA. EM ganw2@nhlbi.nih.gov RI Barreiro, E/D-6919-2014 OI Barreiro, E/0000-0003-2708-3443 FU National Heart, Lung, and Blood Institute FX Supported by the National Heart, Lung, and Blood Institute. NR 65 TC 18 Z9 18 U1 2 U2 13 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JAN 1 PY 2014 VL 189 IS 1 BP 96 EP 103 DI 10.1164/rccm.201306-1164WS PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 290UW UT WOS:000329784800018 PM 24033344 ER PT S AU Adesunloye, BA Karzai, FH Dahut, WL AF Adesunloye, Bamidele A. Karzai, Fatima H. Dahut, William L. BE Marone, G Granata, F TI Angiogenesis Inhibitors in the Treatment of Prostate Cancer SO ANGIOGENESIS, LYMPHANGIOGENESIS AND CLINICAL IMPLICATIONS SE Chemical Immunology and Allergy LA English DT Article; Book Chapter ID ENDOTHELIAL GROWTH-FACTOR; PHASE-II TRIAL; 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID DMXAA; MITOXANTRONE PLUS PREDNISONE; MONOCLONAL-ANTIBODY J591; ADVANCED SOLID TUMORS; MEMBRANE ANTIGEN; DOUBLE-BLIND; IN-VITRO; HEPARANASE INHIBITOR AB Prostate cancer is the most common cancer in men in the United States and is the second most common cause of death. While treatment options in early stage disease are curative in intent, treatment of metastatic prostate cancer remains challenging. Although, several new and promising treatment options exploiting novel targets have permeated the therapeutic landscape in recent years, another viable target for therapy is tumor angiogenesis. Many antiangiogenic agents are under development and some are currently under investigation in clinical trials. Copyright (C) 2014 S. Karger AG, Basel C1 [Adesunloye, Bamidele A.; Karzai, Fatima H.; Dahut, William L.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Dahut, WL (reprint author), NCI, Bldg 10,Room 12N226 10 Ctr Dr, Bethesda, MD 20892 USA. EM dahutw@mail.nih.gov NR 114 TC 0 Z9 0 U1 0 U2 1 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 1660-2242 BN 978-3-318-02480-7; 978-3-318-02481-4 J9 CHEM IMMUNOL ALLERGY JI Chem. Immunol. Allergy PY 2014 VL 99 BP 197 EP 215 DI 10.1159/000353255 PG 19 WC Cell Biology; Immunology SC Cell Biology; Immunology GA BJM05 UT WOS:000329030400013 PM 24217611 ER PT J AU Milling, TJ Brown, J AF Milling, Truman J. TJ, Jr. Brown, Jeremy TI Annals Q&A With Dr. Jeremy Brown SO ANNALS OF EMERGENCY MEDICINE LA English DT Editorial Material C1 [Brown, Jeremy] NIH, OECR, Bethesda, MD USA. [Brown, Jeremy] George Washington Univ GW, Dept Emergency Med, Washington, DC USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD JAN PY 2014 VL 63 IS 1 BP 13A EP 15A DI 10.1016/j.annemergmed.2013.11.004 PG 3 WC Emergency Medicine SC Emergency Medicine GA 292GN UT WOS:000329890300001 PM 24498646 ER PT J AU Zeng, WQ Chen, XZ Ma, Y Huang, ZX Qin, Y Wu, FP Wu, LL Liang, XH Qin, YF Zhou, J Lu, DC Kuang, XC Li, QQ Luo, ZJ AF Zeng, Wenqing Chen, Xiaozhou Ma, Yan Huang, Zhenxing Qin, Yuan Wu, Fengping Wu, Lili Liang, Xinghuan Qin, Yingfen Zhou, Jia Lu, Decheng Kuang, Xiaocong Li, Qingdi Quentin Luo, Zuojie TI A Novel Approach for Enriching Cancer Stem Cells from the Human SW-13 Adrenocortical Carcinoma Cell Line SO ANTICANCER RESEARCH LA English DT Article DE Adrenocortical carcinoma; cancer stem cell; chemotherapy; CXCR4; ABCG2; cyclophosphamide ID CHEMOKINE RECEPTOR CXCR4; LUNG-CANCER; CHEMOTHERAPY; METASTASIS; GROWTH; EXPRESSION; RESISTANCE; CISPLATIN; FEATURES; TUMORS AB The present study was undertaken to develop a new method for enriching cancer stem cells (CSCs) from the human adrenal cortical carcinoma (ACC) cell line SW-13. Given that the existence of CSCs in ACC causes resistance to conventional chemotherapies, treatment with cyclophosphamide was used for in vivo selection of CSCs in a BALB/c nude mouse tumor xenograft model established using the ACC cell line SW-13. The characteristics of CSCs in three generations of tumor xenografts were assessed for single-cell colony formation, flat colony formation, and cell sphere formation in serum-free suspension culture. The formation rates of single-cell colonies, flat colonies, and cell spheres were significantly higher for tumor xenograft cells treated with cyclophosphamide than for untreated engrafted tumor cells. Flow cytometry to examine expression of the CSC markers C-X-C chemokine receptor type-4 (CXCR4; CD184) and ATP-binding cassette sub-family G member-2 (ABCG2; CDw338) revealed markedly higher levels of CXCR4 and ABCG2 in cyclophosphamide-treated xenograft tumor cells compared to untreated tumor cells. Together, these results indicate that cyclophosphamide treatment of tumor xeno graft cells caused enrichment of CSCs with a strong capability for self-renewal and proliferation. In this method, the administration of cyclophosphamide selectively kills cancer cells without toxicity to CSCs and thereby provides a practical approach for achieving the enrichment of CSCs in ACC. C1 [Zeng, Wenqing; Chen, Xiaozhou; Huang, Zhenxing; Qin, Yuan; Wu, Fengping; Wu, Lili; Liang, Xinghuan; Qin, Yingfen; Zhou, Jia; Lu, Decheng; Luo, Zuojie] Guangxi Med Univ, Affiliated Hosp 1, Dept Endocrinol, Nanning 530021, Peoples R China. [Ma, Yan] Guangxi Med Univ, Affiliated Hosp 1, Dept Ultrason Diag, Nanning 530021, Peoples R China. [Kuang, Xiaocong] Guangxi Med Univ, Dept Pathophysiol, Nanning 530021, Peoples R China. [Li, Qingdi Quentin] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Li, QQ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov; zluo888@163.com FU National Natural Science Foundation of China [81060220]; Natural Science Foundation of Guangxi [2011GXNSFA018172] FX This work was supported by grants from the National Natural Science Foundation of China (no. 81060220) and the Natural Science Foundation of Guangxi (no. 2011GXNSFA018172). NR 26 TC 3 Z9 3 U1 0 U2 5 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD JAN PY 2014 VL 34 IS 1A BP 117 EP 123 PG 7 WC Oncology SC Oncology GA 290NJ UT WOS:000329765300012 PM 24403451 ER PT J AU Jakopovic, M Thomas, A Lopez-Chavez, A AF Jakopovic, Marko Thomas, Anish Lopez-Chavez, Ariel TI From Platinum Compounds to Targeted Therapies in Advanced Thoracic Malignancies SO ANTICANCER RESEARCH LA English DT Review DE Platinum-based chemotherapy; advanced thoracic malignancies; targeted therapy; review ID CELL LUNG-CANCER; THYMIC EPITHELIAL TUMORS; EML4-ALK FUSION GENE; PHASE-II; 1ST-LINE TREATMENT; INTERGROUP TRIAL; OPEN-LABEL; COMBINATION CHEMOTHERAPY; ACTIVATING MUTATIONS; RECURRENT THYMOMA AB Improved understanding of the molecular mechanisms involved in development, growth and spread of cancer have led to develpment of targeted therapies for many cancers. Based on their superior tolerability and efficacy, targeted therapies with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) or crizotinib are preferred first-line treatments over platinum-based chemotherapies in patients whose tumours harbour EGFR-activating mutations and anaplastic lymphoma kinase (ALK) translocations, respectively. Active areas of research in EGFR-mutant and ALK-translocated NSCLC include identification of mechanisms of resistance and overcoming them. Therapeutic targeting of several other targets including ROS, RET and discoidin domain receptor 2 (DDR2) tyrosine kinases are in early phases of clinical evaluation. Despite the advances in tumour genomic sequencing, a substantial fraction of patients with non-small cell lung cancer (NSCLC) do not have any targetable genetic alteration. Ongoing research is focused on identifying mechanisms of carcinogenesis in these patients. Targeted therapies in small cell lung cancer (SCLC) and thymic malignancies have not yielded meaningful clinical benefits, and platinum-based therapies remain the cornerstone of treating patients with advanced disease. C1 [Jakopovic, Marko] Univ Zagreb, Sch Med, Dept Resp Dis, Univ Hosp Ctr Zagreb, Zagreb 41001, Croatia. [Thomas, Anish] NCI, Thorac & GI Oncol Branch, Bethesda, MD 20892 USA. [Lopez-Chavez, Ariel] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Lopez-Chavez, A (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. EM lopezcha@ohsu.edu OI Thomas, Anish/0000-0003-3293-3115 NR 55 TC 3 Z9 3 U1 0 U2 2 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD JAN PY 2014 VL 34 IS 1B BP 477 EP 482 PG 6 WC Oncology SC Oncology GA 290NK UT WOS:000329765400009 PM 24403504 ER PT J AU Doherty, B Lawlor, D Gillet, JP Gottesman, M O'Leary, JJ Stordal, B AF Doherty, Ben Lawlor, Denise Gillet, Jean-Pierre Gottesman, Michael O'Leary, John J. Stordal, Britta TI Collateral Sensitivity to Cisplatin in KB-8-5-11 Drug-resistant Cancer Cells SO ANTICANCER RESEARCH LA English DT Article DE Cisplatin; paclitaxel; drug resistance; collateral sensitivity; cervical cancer; KB-8-5-11 cells ID GLUTATHIONE-S-TRANSFERASE; HUMAN OVARIAN-CARCINOMA; TRANSPORTER ATP7A; EXPRESSION; PLATINUM; LINES; CYTOTOXICITY; GENE AB Background: KB-8-5-11 cells are a drug-resistant cervical cell model that overexpresses ABCB1 (P-glycoprotein). KB-8-5-11 has become sensitive to non-ABCB1 substrate cisplatin. Understanding the mechanism of collateral sensitivity to cisplatin may lead to biomarker discovery for platinum sensitivity in patients with cancer. Materials and Methods: A Taqman low-density array was used to characterize the expression of 380 genes previously associated with chemoresistance. Identified pathways were further analyzed using cytotoxicity assays, metabolomics and western blots. Results: KB-8-5-11 cells were sensitive to CuSO4 and the glutathione inhibitor buthionine sulphoximine. Expression of ATPase, Cu2+ transporting alpha (ATP7A) and ATP7B were decreased at the protein and gene levels respectively in KB-8-5-11. KB-8-5-11 had decreased gene expression of glutathione S-transferase pi 1 (GSTP1), GSTA4 and GSTK1. Cisplatin treatment significantly lowered total cellular glutathione in parental KB-3-1 cells. Glutathione also tended to be lower in KB-8-5-11 cells compared to KB-3-1 cells. Conclusion: KB-8-5-11 cells have alterations in their copper transporters and glutathione metabolism, contributing to their cisplatin-sensitive phenotype. C1 [Doherty, Ben; Lawlor, Denise; O'Leary, John J.; Stordal, Britta] St James Hosp, Dept Histopathol, Dublin 8, Ireland. [Doherty, Ben; Lawlor, Denise; O'Leary, John J.; Stordal, Britta] Trinity Coll Dublin, Dublin, Ireland. [Gillet, Jean-Pierre; Gottesman, Michael] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Stordal, B (reprint author), St James Hosp, Dept Histopathol, Trinity Coll Dublin, Sir Patrick Dun Res Lab 1 18, Cent Pathol Bldg, Dublin 8, Ireland. EM stordalb@tcd.ie FU Irish Cancer Society Postdoctoral Fellowship; Marie Curie Reintegration Grant from the European Union FP7 programme; European Association of Cancer Research Travel Fellowship FX This research was funded by the following grants: Irish Cancer Society Postdoctoral Fellowship (BS), Marie Curie Reintegration Grant from the European Union FP7 programme (BS) and a European Association of Cancer Research Travel Fellowship (BS). NR 18 TC 1 Z9 1 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD JAN PY 2014 VL 34 IS 1B BP 503 EP 507 PG 5 WC Oncology SC Oncology GA 290NK UT WOS:000329765400013 PM 24403508 ER PT J AU Lee, J Armstrong, DT Ssengooba, W Park, JA Yu, Y Mumbowa, F Namaganda, C Mboowa, G Nakayita, G Armakovitch, S Chien, G Cho, SN Via, LE Barry, CE Ellner, JJ Alland, D Dorman, SE Joloba, ML AF Lee, Jongseok Armstrong, Derek T. Ssengooba, Willy Park, Jeong-Ae Yu, Yeuni Mumbowa, Francis Namaganda, Carolyn Mboowa, Gerald Nakayita, Germine Armakovitch, Sandra Chien, Gina Cho, Sang-Nae Via, Laura E. Barry, Clifton E., III Ellner, Jerrold J. Alland, David Dorman, Susan E. Joloba, Moses L. TI Sensititre MYCOTB MIC Plate for Testing Mycobacterium tuberculosis Susceptibility to First- and Second-Line Drugs SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID RESISTANT TUBERCULOSIS; AGAR PROPORTION; MUTATIONS; DIAGNOSIS AB For Mycobacterium tuberculosis, phenotypic methods for drug susceptibility testing of second-line drugs are poorly standardized and technically challenging. The Sensititre MYCOTB MIC plate (MYCOTB) is a microtiter plate containing lyophilized antibiotics and configured for determination of MICs to first- and second-line antituberculosis drugs. To evaluate the performance of MYCOTB for M. tuberculosis drug susceptibility testing using the Middlebrook 7H10 agar proportion method (APM) as the comparator, we conducted a two-site study using archived M. tuberculosis isolates from Uganda and the Republic of Korea. Thawed isolates were subcultured, and dilutions were inoculated into MYCOTB wells and onto 7H10 agar. MYCOTB results were read at days 7, 10, 14, and 21; APM results were read at 21 days. A total of 222 isolates provided results on both platforms. By APM, 106/222 (47.7%) of isolates were resistant to at least isoniazid and rifampin. Agreement between MYCOTB and APM with respect to susceptibility or resistance was >= 92% for 7 of 12 drugs when a strict definition was used and >= 96% for 10 of 12 drugs when agreement was defined by allowing a +/- one-well range of dilutions around the APM critical concentration. For ethambutol, agreement was 80% to 81%. For moxifloxacin, agreement was 83% to 85%; incorporating existing DNA sequencing information for discrepant analysis raised agreement to 91% to 96%. For MYCOTB, the median time to plate interpretation was 10 days and interreader agreement was >= 95% for all drugs. MYCOTB provided reliable results for M. tuberculosis susceptibility testing of first-and second-line drugs except ethambutol, and results were available sooner than those determined by APM. C1 [Lee, Jongseok; Park, Jeong-Ae; Yu, Yeuni; Cho, Sang-Nae] Int TB Res Ctr, Masan, South Korea. [Armstrong, Derek T.; Dorman, Susan E.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Ssengooba, Willy; Mumbowa, Francis; Namaganda, Carolyn; Mboowa, Gerald; Nakayita, Germine; Joloba, Moses L.] Makerere Univ, Mycobacteriol Lab, Kampala, Uganda. [Armakovitch, Sandra; Chien, Gina; Ellner, Jerrold J.] Boston Univ, Med Ctr, Boston, MA USA. [Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Alland, David] Rutgers State Univ, New Jersey Med Sch, Newark, NJ 07102 USA. RP Dorman, SE (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. EM DSUSAN1@JHMI.EDU RI Barry, III, Clifton/H-3839-2012; OI Mboowa, Gerald/0000-0001-8445-9414; Via, Laura/0000-0001-6074-9521; Ssengooba, Willy/0000-0002-1643-110X; Joloba, Moses/0000-0002-0334-9983 FU National Institute of Allergy and Infectious Diseases (NIAID) [HHSN2722000900050C]; U.S. Intramural Research Program of NIAID, National Institutes of Health, Department of Health and Human Services FX This work was funded by contract HHSN2722000900050C from the National Institute of Allergy and Infectious Diseases (NIAID) and in part by the U.S. Intramural Research Program of NIAID, National Institutes of Health, Department of Health and Human Services. NR 24 TC 16 Z9 18 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2014 VL 58 IS 1 BP 11 EP 18 DI 10.1128/AAC.01209-13 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 287ZL UT WOS:000329581100002 PM 24100497 ER PT J AU Barton, C Kouokam, JC Lasnik, AB Foreman, O Cambon, A Brock, G Montefiori, DC Vojdani, F McCormick, AA O'Keefe, BR Palmer, KE AF Barton, Christopher Kouokam, J. Calvin Lasnik, Amanda B. Foreman, Oded Cambon, Alexander Brock, Guy Montefiori, David C. Vojdani, Fakhrieh McCormick, Alison A. O'Keefe, Barry R. Palmer, Kenneth E. TI Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HEPATITIS-C VIRUS; ENTRY INHIBITOR GRIFFITHSIN; N-LINKED GLYCANS; CYANOVIRIN-N; CARBOHYDRATE-BINDING; PROTEIN GRIFFITHSIN; TYPE-1 STRAINS; IN-VITRO; GP120; RESISTANCE AB Griffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections. C1 [Barton, Christopher; Kouokam, J. Calvin; Lasnik, Amanda B.; Palmer, Kenneth E.] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Barton, Christopher; Kouokam, J. Calvin; Lasnik, Amanda B.; Palmer, Kenneth E.] Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. [Kouokam, J. Calvin; Palmer, Kenneth E.] Owensboro Canc Res Program, Owensboro, KY USA. [Foreman, Oded] Jackson Lab, Bar Harbor, ME 04609 USA. [Cambon, Alexander; Brock, Guy] Univ Louisville, Dept Bioinformat & Biostat, Louisville, KY 40292 USA. [Montefiori, David C.] Duke Univ, Sch Med, Dept Surg, Durham, NC USA. [Vojdani, Fakhrieh; Palmer, Kenneth E.] Intrucept Biomed LLC, Owensboro, KY USA. [McCormick, Alison A.] Touro Coll Pharm, Vallejo, CA USA. [O'Keefe, Barry R.] NCI, Frederick, MD 21701 USA. RP Palmer, KE (reprint author), Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. EM kenneth.palmer@louisville.edu OI Palmer, Kenneth/0000-0002-2811-1111 FU NIH [AI076169, T32-ES011564, HHSN27201100016C]; DOD [USAMRMC W81XWH-10-2-CLIN 1]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by NIH grant AI076169 to K.E.P. and NIH grant T32-ES011564, DOD grant USAMRMC W81XWH-10-2-CLIN 1, and NIH contract HHSN27201100016C. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 42 TC 26 Z9 26 U1 4 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2014 VL 58 IS 1 BP 120 EP 127 DI 10.1128/AAC.01407-13 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 287ZL UT WOS:000329581100015 PM 24145548 ER PT J AU Debing, Y Emerson, SU Wang, YJ Pan, QW Balzarini, J Dallmeier, K Neyts, J AF Debing, Yannick Emerson, Suzanne U. Wang, Yijin Pan, Qiuwei Balzarini, Jan Dallmeier, Kai Neyts, Johan TI Ribavirin Inhibits In Vitro Hepatitis E Virus Replication through Depletion of Cellular GTP Pools and Is Moderately Synergistic with Alpha Interferon SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID FAMILY HEPEVIRIDAE; ANTIVIRAL ACTIVITY; MYCOPHENOLIC-ACID; INFECTION; DEHYDROGENASE; THERAPY; BIOSYNTHESIS; FLAVIVIRUSES; MECHANISM; GENOTYPE AB Hepatitis E virus (HEV) is a common cause of acute hepatitis that results in high mortality in pregnant women and may establish chronic infections in immunocompromised patients. We demonstrate for the first time that alpha interferon (IFN-alpha) and ribavirin inhibit in vitro HEV replication in both a subgenomic replicon and an infectious culture system based on a genotype 3 strain. IFN-alpha showed a moderate but significant synergism with ribavirin. These findings corroborate the reported clinical effectiveness of both drugs. In addition, the antiviral activity of ribavirin against wild-type genotype 1, 2, and 3 strains was confirmed by immunofluorescence staining. Furthermore, the in vitro activity of ribavirin depends on depletion of intracellular GTP pools, which is evident from the facts that (i) other GTP-depleting agents (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide [EICAR] and mycophenolic acid) inhibit viral replication, (ii) exogenously added guanosine reverses the antiviral effects, and (iii) a strong correlation (R-2 = 0.9998) exists between the antiviral activity and GTP depletion of ribavirin and other GTP-depleting agents. C1 [Debing, Yannick; Pan, Qiuwei; Balzarini, Jan; Dallmeier, Kai; Neyts, Johan] Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, Louvain, Belgium. [Emerson, Suzanne U.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wang, Yijin; Pan, Qiuwei] Erasmus MC Univ Med Ctr, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands. RP Neyts, J (reprint author), Katholieke Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, Louvain, Belgium. EM johan.neyts@rega.kuleuven.be OI Debing, Yannick/0000-0001-6566-9408 FU European Association; KU Leuven Geconcerteerde Onderzoeksacties [GOA/10/014]; EU FP7 project SILVER [260644]; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX Y.D. is a fellow of the Research Foundation-Flanders (FWO). Q.P. is supported by a Sheila Sherlock Fellowship from the European Association for the Study of the Liver (EASL). This work was supported by KU Leuven Geconcerteerde Onderzoeksacties (GOA/10/014) and by EU FP7 project SILVER (260644) and in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (S.U.E.). NR 43 TC 37 Z9 38 U1 2 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2014 VL 58 IS 1 BP 267 EP 273 DI 10.1128/AAC.01795-13 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 287ZL UT WOS:000329581100033 PM 24145541 ER PT J AU Gupta, S Cohen, KA Winglee, K Maiga, M Diarra, B Bishai, WR AF Gupta, Shashank Cohen, Keira A. Winglee, Kathryn Maiga, Mamoudou Diarra, Bassirou Bishai, William R. TI Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium tuberculosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MULTIDRUG-RESISTANT TUBERCULOSIS; DRUG-RESISTANCE; DIARYLQUINOLINE TMC207; REVERSAL AB Drug efflux is an important resistance mechanism in Mycobacterium tuberculosis. We found that verapamil, an efflux inhibitor, profoundly decreases the MIC of bedaquiline and clofazimine to M. tuberculosis by 8- to 16-fold. This exquisite susceptibility was noted among drug-susceptible and drug-resistant clinical isolates. Thus, efflux inhibition is an important sensitizer of bedaquiline and clofazimine, and efflux may emerge as a resistance mechanism to these drugs. C1 [Gupta, Shashank; Winglee, Kathryn; Maiga, Mamoudou; Bishai, William R.] JHU, Dept Med, Ctr TB Res, Baltimore, MD USA. [Gupta, Shashank; Bishai, William R.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Cohen, Keira A.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Cohen, Keira A.; Bishai, William R.] KwaZulu Natal Res Inst TB & HIV, Durban, South Africa. [Maiga, Mamoudou; Diarra, Bassirou] Univ Bamako Res Collaborat HIV TB, Project SEREFO NIAID, Bamako, Mali. RP Bishai, WR (reprint author), JHU, Dept Med, Ctr TB Res, Baltimore, MD USA. EM wbishai@jhmi.edu RI Gupta, Shashank/E-7382-2016 OI Gupta, Shashank/0000-0003-0445-5195 FU NIAID [AI 079590, AI 037856, AI 036973]; NHLBI [T32HL007633]; Howard Hughes Medical Institute FX This work was supported by grants AI 079590, AI 037856, and AI 036973 from NIAID, T32HL007633 from the NHLBI, and the Howard Hughes Medical Institute. NR 18 TC 44 Z9 45 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2014 VL 58 IS 1 BP 574 EP 576 DI 10.1128/AAC.01462-13 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 287ZL UT WOS:000329581100073 PM 24126586 ER PT J AU Komatsu, TE Pikis, A Naeger, LK Harrington, PR AF Komatsu, Takashi E. Pikis, Andreas Naeger, Lisa K. Harrington, Patrick R. TI Resistance of human cytomegalovirus to ganciclovir/valganciclovir: A comprehensive review of putative resistance pathways SO ANTIVIRAL RESEARCH LA English DT Review DE Cytomegalovirus; Ganciclovir; Valganciclovir; Resistance; Cidofovir; Foscarnet ID DNA-POLYMERASE MUTATIONS; ORGAN TRANSPLANT RECIPIENTS; STEM-CELL TRANSPLANTATION; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; OPEN READING FRAME; ANTICYTOMEGALOVIRUS COMPOUND AIC246; CONFERRING FOSCARNET RESISTANCE; PLAQUE REDUCTION ASSAY; GANCICLOVIR-RESISTANT; DRUG-RESISTANCE AB Human cytomegalovirus (HCMV) is a pathogen that can be life-threatening in immunocompromised individuals. Valganciclovir and its parent drug ganciclovir are currently the principle drugs used for the treatment or prevention of HCMV disease. The development of HCMV resistance to ganciclovir/valganciclovir has been documented in treated patients and is associated with the emergence of amino acid substitutions in the viral proteins pUL97, pUL54 or both. Generally, single amino acid substitutions associated with clinical resistance that alone do not confer decreased ganciclovir susceptibility in cell culture have been disregarded as causative or clinically significant. This review focuses on the analysis and mechanisms of antiviral drug resistance to HCMV. We also conducted a review of publicly available clinical and nonclinical data to construct a comprehensive list of pUL97 and pUL54 amino acid substitutions that are associated with a poor clinical response to the first line therapies ganciclovir and valganciclovir, or associated with reduced HCMV ganciclovir susceptibility in cell culture. Over 40 putative ganciclovir/valganciclovir resistance-associated substitutions were identified in this analysis. These include the commonly reported substitutions M460I/V and C592G in pUL97. There were additional substitutions that are not widely considered as ganciclovir/valganciclovir resistance-associated substitutions, including V466M in pUL97 and E315D in pUL54. Some of these ganciclovir/valganciclovir resistance-associated substitutions may confer cross-resistance to other HCMV therapies, such as cidofovir and foscarnet. Based on this review, we propose that there are more potential HCMV ganciclovir/valganciclovir resistance pathways than generally appreciated. The resulting comprehensive list of putative ganciclovir/valganciclovir resistance-associated substitutions provides a foundation for future investigations to characterize the role of specific substitutions or combinations of substitutions, which will enhance our understanding of HCMV mechanisms of ganciclovir/valganciclovir resistance and also provide insight regarding the potential for cross-resistance to other HCMV therapies. Published by Elsevier B.V. C1 [Komatsu, Takashi E.; Pikis, Andreas; Naeger, Lisa K.; Harrington, Patrick R.] US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Pikis, Andreas] NIDCR, Microbial Biochem & Genet Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Komatsu, TE (reprint author), US FDA, Div Antiviral Prod, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 22 Room 6323, Silver Spring, MD 20993 USA. EM Takashi.Komatsu@fda.hhs.gov FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland FX We thank Debra Birnkrant, Mike Bray, Edward Cox, Jeffrey Murray, Jules O'Rear, and Kuate Seraphin for helpful manuscript suggestions and discussion. A.P. is supported in part by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. NR 191 TC 21 Z9 23 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD JAN PY 2014 VL 101 BP 12 EP 25 DI 10.1016/j.antiviral.2013.10.011 PG 14 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 290QF UT WOS:000329772700002 PM 24184129 ER PT J AU Beidas, RS Lindhiem, O Brodman, DM Swan, A Carper, M Cummings, C Kendall, PC Albano, AM Rynn, M Piacentini, J McCracken, J Compton, SN March, J Walkup, J Ginsburg, G Keeton, CP Birmaher, B Sakolsky, D Sherrill, J AF Beidas, Rinad S. Lindhiem, Oliver Brodman, Douglas M. Swan, Anna Carper, Matthew Cummings, Colleen Kendall, Philip C. Albano, Anne Marie Rynn, Moira Piacentini, John McCracken, James Compton, Scott N. March, John Walkup, John Ginsburg, Golda Keeton, Courtney P. Birmaher, Boris Sakolsky, Dara Sherrill, Joel TI A Probabilistic and Individualized Approach for Predicting Treatment Gains: An Extension and Application to Anxiety Disordered Youth SO BEHAVIOR THERAPY LA English DT Article DE child/adolescent anxiety; evidence-based treatment; individualized treatment benefit; patient-centered decision-making; treatment response and outcome ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CLINICAL-TRIAL; CHILDHOOD ANXIETY; PSYCHOTHERAPY-RESEARCH; TREATMENT RESPONSE; CHILDREN; ADOLESCENTS; VARIABILITY; COMORBIDITY; REMISSION AB The objective of this study was to extend the probability of treatment benefit method by adding treatment condition as a stratifying variable, and illustrate this extension of the methodology using the Child and Adolescent Anxiety Multimodal Study data. The probability of treatment benefit method produces a simple and practical way to predict individualized treatment benefit based on pretreatment patient characteristics. Two pretreatment patient characteristics were selected in the production of the probability of treatment benefit charts: baseline anxiety severity, measured by the Pediatric Anxiety Rating Scale, and treatment condition (cognitive-behavioral therapy, sertraline, their combination, and placebo). We produced two charts as exemplars which provide individualized and probabilistic information for treatment response and outcome to treatments for child anxiety. We discuss the implications of the use of the probability of treatment benefit method, particularly with regard to patient-centered outcomes and individualized decision-making in psychology and psychiatry. C1 [Beidas, Rinad S.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Lindhiem, Oliver; Birmaher, Boris; Sakolsky, Dara] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Brodman, Douglas M.; Swan, Anna; Carper, Matthew; Cummings, Colleen; Kendall, Philip C.] Temple Univ, Philadelphia, PA 19122 USA. [Albano, Anne Marie; Rynn, Moira] Columbia Univ, New York, NY 10027 USA. [Piacentini, John; McCracken, James] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Compton, Scott N.; March, John] Duke Child & Family Study Ctr, Durham, NC USA. [Walkup, John] Cornell Univ, Ithaca, NY 14853 USA. [Ginsburg, Golda; Keeton, Courtney P.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Sherrill, Joel] NIMH, Bethesda, MD USA. RP Beidas, RS (reprint author), Univ Penn, 3535 Market St,3015, Philadelphia, PA 19104 USA. EM rbeidas@upenn.edu FU NIMH NIH HHS [U01 MH064088, U01 MH064107, U01 MH64088, U01 MH64107, K01 MH93508, K01 MH093508, K23 MH099179, K23 MH99179, K24 MH096760, R25 MH080916, U01 MH063747, U01 MH064003, U01 MH064089, U01 MH064092, U01 MH64003, U01 MH64092, U01MH63747, U01MH64003] NR 48 TC 6 Z9 6 U1 1 U2 8 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 EI 1878-1888 J9 BEHAV THER JI Behav. Therapy PD JAN PY 2014 VL 45 IS 1 BP 126 EP 136 PG 11 WC Psychology, Clinical SC Psychology GA 294XG UT WOS:000330080600013 PM 24411120 ER PT J AU Qi, RX Luo, Y Ma, BY Nussinov, R Wei, GH AF Qi, Ruxi Luo, Yin Ma, Buyong Nussinov, Ruth Wei, Guanghong TI Conformational Distribution and alpha-Helix to beta-Sheet Transition of Human Amylin Fragment Dimer SO BIOMACROMOLECULES LA English DT Article ID ISLET AMYLOID POLYPEPTIDE; MOLECULAR-DYNAMICS SIMULATIONS; NMR-SPECTROSCOPY; MEMBRANE ENVIRONMENT; FIBER FORMATION; PI-STACKING; PEPTIDE; PROTEIN; IAPP; OLIGOMERS AB Experiments suggested that the fibrillation of the 11-25 fragment (hIAPP(11-25)) of human islet amyloid polypeptide (hIAPP or amylin) involves the formation of transient alpha-helical intermediates, followed by conversion to beta-sheet-rich structure. However, atomic details of alpha-helical intermediates and the transition mechanism are mostly unknown. We investigated the structural properties of the monomer and dimer in atomistic detail by replica exchange molecular dynamics (REMD) simulations. Transient alpha-helical monomers and dimers were both observed in the REMD trajectories. Our calculated H-alpha chemical shifts based on the monomer REMD run are in agreement with the solution-state NMR experimental observations. Multiple 300 ns MD simulations at 310 K show that alpha-helix-to-beta-sheet transition follows two mechanisms: the first involved direct transition of the random coil part of the helical conformation into antiparallel beta-sheet, and in the second, the alpha-helical conformation unfolded and converted into antiparallel beta-sheet. In both mechanisms, the alpha-helix-to-beta-sheet transition occurred via random coil, and the transition was accompanied by an increase of interpeptide contacts. In addition, our REMD simulations revealed different temperature dependencies of helical and beta-structures. Comparison with experimental data suggests that the propensity for hIAPP(11-25) to form alpha-helices and amyloid structures is concentration- and temperature-dependent. C1 [Qi, Ruxi; Luo, Yin; Wei, Guanghong] Fudan Univ, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai 200433, Peoples R China. [Qi, Ruxi; Luo, Yin; Wei, Guanghong] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [Ma, Buyong; Nussinov, Ruth] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NSF of China [91227102, 11074047, 11274075]; Research Fund for the Doctoral Program of Higher Education of China; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX G.W. acknowledges the financial support from the NSF of China (Grant Nos. 91227102, 11074047, and 11274075) and the Research Fund for the Doctoral Program of Higher Education of China. Simulations were performed at the Shanghai Supercomputing Center and the National High Performance Computing Center of Fudan University. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 87 TC 23 Z9 23 U1 4 U2 50 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 EI 1526-4602 J9 BIOMACROMOLECULES JI Biomacromolecules PD JAN PY 2014 VL 15 IS 1 BP 122 EP 131 DI 10.1021/bm401406e PG 10 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 292CO UT WOS:000329879800014 PM 24313776 ER PT J AU Speer, AM Wassermann, EM Benson, BE Herscovitch, P Post, RM AF Speer, Andrew M. Wassermann, Eric M. Benson, Brenda E. Herscovitch, Peter Post, Robert M. TI Antidepressant Efficacy of High and Low Frequency rTMS at 110% of Motor Threshold versus Sham Stimulation over Left Prefrontal Cortex SO BRAIN STIMULATION LA English DT Article DE Left prefrontal cortex; Major depression; Motor threshold; rTMS; Sham ID TRANSCRANIAL MAGNETIC STIMULATION; MAJOR DEPRESSIVE DISORDER; CEREBRAL GLUCOSE-METABOLISM; ELECTROCONVULSIVE-THERAPY; RANDOMIZED-TRIAL; RESISTANT DEPRESSION; DURATION; NUMBER; TMS AB Background: While the efficacy of repetitive transcranial magnetic stimulation (rTMS) at 10 Hz over the left prefrontal cortex has been repeatedly demonstrated, it is not clear that the optimal parameters for the treatment of depression have been adequately elucidated. Objectives: We sought to assess the antidepressant effectiveness of high and low frequency at a higher intensity rTMS compared to sham in patients with moderately treatment resistant depression. Method: The authors conducted a three-week, double-blind, randomized, sham-controlled study of 24 acutely depressed patients given either active 20 Hz (n = 8) or 1 Hz (n = 8) rTMS (at 110% of motor threshold [MT]) or sham treatments (n = 8) over the left prefrontal cortex. Hamilton Depression ratings were analyzed by ANOVA. Results: Patients on both frequencies showed greater improvement than on sham, which was associated with minor increases in depression. During open continuation to allow 7 weeks of active treatment in all individuals, additional improvement was observed. Conclusions: The results seen here using 110% of MT for 3 weeks were more robust than those of previous studies of 1-Hz or 20-Hz rTMS for 2 weeks (at 80% and 100% of MT). The results also raise the possibility that both high and low frequency rTMS over left prefrontal cortex (and not just low frequency over the right prefrontal cortex) exert antidepressant effects, but further work is required to assess what parameters may be most effective in general and for a given individual. (C) 2014 Elsevier Inc. All rights reserved. C1 [Speer, Andrew M.] Lab Brain & Cognit, Bethesda, MD 20814 USA. [Wassermann, Eric M.] NINDS, Behav Neurol Unit, NIH, DHHS, Bethesda, MD 20892 USA. [Benson, Brenda E.] NIMH, Mood & Anxiety Disorder Branch, NIH, DHHS, Bethesda, MD USA. [Herscovitch, Peter] NIH, PET Dept, Ctr Clin, DHHS, Bethesda, MD USA. [Post, Robert M.] Bipolar Collaborat Network, Bethesda, MD 20814 USA. RP Post, RM (reprint author), Bipolar Collaborat Network, 5415 W Cedar Lane,Suite 201-B, Bethesda, MD 20814 USA. EM robert.post@speakeasy.net NR 35 TC 6 Z9 9 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X EI 1876-4754 J9 BRAIN STIMUL JI Brain Stimul. PD JAN-FEB PY 2014 VL 7 IS 1 BP 36 EP 41 DI 10.1016/j.brs.2013.07.004 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 293BV UT WOS:000329947300006 PM 23928104 ER PT J AU Rogers, T Ratnayaka, K Lederman, RJ AF Rogers, Toby Ratnayaka, Kanishka Lederman, Robert J. TI MRI Catheterization in Cardiopulmonary Disease SO CHEST LA English DT Article ID CARDIOVASCULAR-MAGNETIC-RESONANCE; PULMONARY ARTERIAL-HYPERTENSION; VENTRICULAR SYSTOLIC FUNCTION; CONGENITAL HEART-DISEASE; CARDIAC-CATHETERIZATION; TRICUSPID REGURGITATION; NONINVASIVE ESTIMATION; EXERCISE CAPACITY; EJECTION FRACTION; PROGNOSTIC VALUE AB Diagnosis and prognostication in patients with complex cardiopulmonary disease can be a clinical challenge. A new procedure, MRI catheterization, involves invasive right-sided heart catheterization performed inside the MRI scanner using MRI instead of traditional radiographic fluoroscopic guidance. MRI catheterization combines simultaneous invasive hemodynamic and MRI functional assessment in a single radiation-free procedure. By combining both modalities, the many individual limitations of invasive catheterization and noninvasive imaging can be overcome, and additional clinical questions can be addressed. Today, MRI catheterization is a clinical reality in specialist centers in the United States and Europe. Advances in medical device design for the MRI environment will enable not only diagnostic but also interventional MRI procedures to be performed within the next few years. C1 [Rogers, Toby; Ratnayaka, Kanishka; Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Ratnayaka, Kanishka] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC 1538, Bethesda, MD 20892 USA. EM lederman@nih.gov OI Rogers, Toby/0000-0002-6043-3137; lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS; NHLBI NIH HHS [Z01 HL005062] NR 48 TC 7 Z9 7 U1 0 U2 2 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JAN PY 2014 VL 145 IS 1 BP 30 EP 36 DI 10.1378/chest.13-1759 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 293JD UT WOS:000329966300014 PM 24394821 ER PT J AU Cai, X Pacheco-Rodriguez, G Haughey, M Samsel, L Xu, SW Wu, HP McCoy, JP Stylianou, M Darling, TN Moss, J AF Cai, Xiong Pacheco-Rodriguez, Gustavo Haughey, Mary Samsel, Leigh Xu, Suowen Wu, Hai-Ping McCoy, J. Philip Stylianou, Mario Darling, Thomas N. Moss, Joel TI Sirolimus Decreases Circulating Lymphangioleiomyomatosis Cells in Patients With Lymphangioleiomyomatosis SO CHEST LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; TSC2 LOSS; GROWTH; METASTASIS; GENE; SURVIVAL; DISEASE AB Background: Lymphangioleiomyomatosis (LAM), sporadic or in women with tuberous sclerosis complex (TSC), is characterized by cystic lung destruction, lymphatic involvement (eg, chylous pleural effusions, lymphangioleiomyomas), and renal angiomyolipomas (AMLs). The multisystem manifestations of LAM appear to result from metastatic dissemination of LAM cells bearing inactivating mutations or having loss of heterozygosity (LOH) of the tumor suppressor genes TSC1 or TSC2, which leads to hyperactivation of the mammalian target of rapamycin. Sirolimus slows the decline of lung function, reduces chylous effusions, and shrinks the size of AMLs. The purpose of this study was to determine the effect of sirolimus on circulating LAM cells. Methods: Cells from blood were isolated by a density-gradient fractionation system and from urine and chylous effusions by centrifugation. Blood cells were incubated with anti-CD45-fluorescein isothiocyanate (FITC) and anti-CD235a-R-phycoerythrin (PE) antibodies, and urine and chylous effusion cells were incubated with anti-CD44v6-FITC and anti-CD9-R-PE antibodies. Cells were sorted and analyzed for TSC2 LOH. Results: LAM cells with TSC2 LOH were identified in 100% of blood specimens and 75% of urine samples from patients before therapy. Over a mean duration of 2.2 +/- 0.4 years of sirolimus therapy, detection rates of LAM cells were significantly decreased to 25% in blood (P < .001) and 8% in urine (P = .003). Following therapy, a greater loss of circulating LAM cells was seen in postmenopausal patients (P = .025). Conclusions: Patients receiving sirolimus had a progressive loss of circulating LAM cells that depended on time of treatment and menopausal status. C1 [Cai, Xiong; Pacheco-Rodriguez, Gustavo; Haughey, Mary; Xu, Suowen; Wu, Hai-Ping; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Samsel, Leigh; McCoy, J. Philip] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Stylianou, Mario] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Darling, Thomas N.] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. RP Moss, J (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D05,MSC 1590,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov OI Darling, Thomas/0000-0002-5161-1974 FU Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute; [R01-AR062080] FX This study was funded in part by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute [to Dr Moss], and R01-AR062080 [to Dr Darling]. NR 19 TC 15 Z9 15 U1 0 U2 6 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JAN PY 2014 VL 145 IS 1 BP 108 EP + DI 10.1378/chest.13-1071 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 293JD UT WOS:000329966300025 PM 24051985 ER PT J AU Shah, AM Cheng, SS Skali, H Wu, J Mangion, JR Kitzman, D Matsushita, K Konety, S Butler, KR Fox, ER Cook, N Ni, HY Coresh, J Mosley, TH Heiss, G Folsom, AR Solomon, SD AF Shah, Amil M. Cheng, Susan Skali, Hicham Wu, Justina Mangion, Judy R. Kitzman, Dalane Matsushita, Kunihiro Konety, Suma Butler, Kenneth R. Fox, Ervin R. Cook, Nakela Ni, Hanyu Coresh, Josef Mosley, Thomas H. Heiss, Gerardo Folsom, Aaron R. Solomon, Scott D. TI Rationale and Design of a Multicenter Echocardiographic Study to Assess the Relationship Between Cardiac Structure and Function and Heart Failure Risk in a Biracial Cohort of Community-Dwelling Elderly Persons The Atherosclerosis Risk in Communities Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE aging; echocardiography; epidemiology ID LEFT-VENTRICULAR MASS; PRESERVED EJECTION FRACTION; WHITE ADULT MEN; GENERAL-POPULATION; EUROPEAN-ASSOCIATION; DIASTOLIC FUNCTION; AMERICAN-SOCIETY; PREVALENCE; DYSFUNCTION; WOMEN AB Background Heart failure is an important public health concern, particularly among persons >65 years of age. Women and blacks are critically understudied populations that carry a sizeable portion of the heart failure burden. Limited normative and prognostic data exist on measures of cardiac structure, diastolic function, and novel measures of systolic deformation in older adults living in the community. Methods and Results The Atherosclerosis Risk in Communities (ARIC) study is a large, predominantly biracial, National Heart, Lung, and Blood Institute-sponsored epidemiological cohort study. Between 2011 and 2013, approximate to 6000 surviving participants, now in their seventh to ninth decade of life, are expected to return for a fifth study visit during which comprehensive 2-dimensional, Doppler, tissue Doppler, and speckle-tracking echocardiography will be performed uniformly in all cohort clinic visit participants. The following objectives will be addressed: (1) to characterize cardiac structural and functional abnormalities among the elderly and to determine how they differ by sex and race/ethnicity, (2) to determine the relationship between ventricular and vascular abnormalities, and (3) to prospectively examine the extent to which these noninvasive measures associate with incident heart failure. Conclusions We describe the design, imaging acquisition and analysis methods, and quality assurance metrics for echocardiography in visit 5 of the ARIC cohort. A better understanding of the differences in cardiac structure and function through the spectrum of heart failure stages in elderly persons generally, and between sexes and racial/ethnic groups specifically, will deepen our understanding of the pathophysiology driving heart failure progression in these at-risk populations and may inform novel prevention or therapeutic strategies. C1 [Shah, Amil M.; Cheng, Susan; Skali, Hicham; Wu, Justina; Mangion, Judy R.; Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Kitzman, Dalane] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Matsushita, Kunihiro; Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Konety, Suma] Univ Minnesota, Sch Med, Div Cardiol, Minneapolis, MN 55455 USA. [Butler, Kenneth R.; Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med Geriatr Gerontol, Jackson, MS USA. [Fox, Ervin R.] Univ Mississippi, Med Ctr, Div Cardiovasc Dis, Jackson, MS USA. [Cook, Nakela; Ni, Hanyu] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Heiss, Gerardo] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. RP Shah, AM (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boson, MA 02445 USA. EM ashah11@partners.org FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100 009C, HHSN268201100010C, HHSN268201100011C, HHSN26 8201100012C, NHLBI-HC-11-08, 1K08HL116792-01A1] FX The ARIC study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100 009C, HHSN268201100010C, HHSN268201100011C, and HHSN26 8201100012C). This work was also supported by NHLBI cooperative agreement NHLBI-HC-11-08 (Brigham and Women's Hospital) and grant 1K08HL116792-01A1 (to Dr Shah). NR 33 TC 21 Z9 21 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD JAN PY 2014 VL 7 IS 1 BP 173 EP 181 DI 10.1161/CIRCIMAGING.113.000736 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 293BF UT WOS:000329945700023 PM 24214885 ER PT J AU Stetler-Stevenson, WG Gavil, NV AF Stetler-Stevenson, William G. Gavil, Noah Veis TI Normalization of the tumor microenvironment: evidence for tissue inhibitor of metalloproteinase-2 as a cancer therapeutic SO CONNECTIVE TISSUE RESEARCH LA English DT Article DE Angiogenesis; extracellular matrix; homeostasis; metalloproteinases; progression ID SINGLE NUCLEOTIDE POLYMORPHISMS; MATRIX-METALLOPROTEINASE; ANGIOGENESIS INHIBITOR; EXTRACELLULAR-MATRIX; COMBINATION THERAPY; ENDOTHELIAL-CELLS; GROWTH; TIMP-2; GENE; INVASION AB Matrix metalloproteinases (MMPs) are members of the Metzincin family of proteases responsible for degrading the extracellular matrix (ECM). In early studies, MMP degradation of the sub-epithelial basement membrane was thought to be tumor cell autonomous and contribute to the invasive behavior of malignant cells. It is now recognized that MMPs have multiple roles that can either promote or inhibit tumor progression and metastasis. The endogenous inhibitors of the MMPs are the tissue inhibitors of metalloproteinases (TIMPs). Early studies on the tumor microenvironment revealed TIMP function to be principally through the inhibition of MMPs, thereby blocking tumor cell migration and invasion. However, data from a number of laboratories are now reporting that TIMPs have direct cellular functions, independent of their MMP inhibitory activity. The TIMPs can modulate normal tissue physiology and development, as well as pathology and progression in a variety of acute and chronic disease states. In this review, we briefly describe the role of MMPs and TIMPs in ECM turnover and formation of the tumor microenvironment. Based on the evidence presented, we postulate that TIMP-2 and other soluble components of the normal ECM may provide a novel therapeutic approach to cancer treatment through "normalization" of the tumor microenvironment. C1 [Stetler-Stevenson, William G.] NIH, Senior Biomed Res Serv, Bethesda, MD 20892 USA. [Stetler-Stevenson, William G.] NCI, Extracellular Matrix Pathol Sect, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Gavil, Noah Veis] Bowdoin Coll, Brunswick, ME 04011 USA. [Gavil, Noah Veis] NCI, Canc Res Summer Interns Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Stetler-Stevenson, WG (reprint author), Adv Technol Ctr, Radiat Oncol Branch, 8717 Grovemont Circle,Room 115, Gaithersburg, MD 20877 USA. EM sstevenw@mail.nih.gov RI Stetler-Stevenson, William/H-6956-2012; OI Stetler-Stevenson, William/0000-0002-5500-5808; Gavil, Noah/0000-0003-4686-4181 FU NCI FX The authors thank D. Sandra Jensen-Taubman for helpful discussions and assistance in editing the manuscript. The authors are honored and pleased to contribute to this issue of Connective Tissue Research dedicated to Dr Arthur Veis, former and founding Editor-in-Chief of this journal. WGSS - Arthur Veis, PhD, was my advisor and mentor during my PhD studies in the Medical Scientist Training Program from 1975 through 1983 at the Northwestern University Feinberg School of Medicine. I am very grateful to Arthur for his encouragement and support both during my time at Northwestern, as well as my tenure at NCI for the last 26 years. Arthur continues to teach his students and post-doctoral fellows as a Professor Emeritus through a masterly balance of guidance and creative freedom as he has for over 50 years. During this time, he has nurtured many scientific careers, and his students and fellows have gone on to establish their own exceptional careers in academia and biotechnology. What impresses me the most over the many years that I have known Arthur is his compassion and generosity. I will always remember my time as a graduate student in his laboratory as the best years of my career, as it was not only productive, but also fun. NVG-Arthur Veis, PhD, is my grandfather, and his encouragement, support, and clear love of his vocation have inspired me to pursue a degree in biochemistry at Bowdoin College. My sincerest thanks go to Dr. Stetler-Stevenson, who graciously welcomed me into his lab during the summer of 2012 as a young undergraduate and invited me to join him in this tribute. Dr. Stetler-Stevenson has further inspired me with his wonderful mentorship, and I am especially grateful for the stories he tells that convey his nostalgia and admiration for the days he spent in the Veis Lab. NR 50 TC 10 Z9 11 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0300-8207 EI 1607-8438 J9 CONNECT TISSUE RES JI Connect. Tissue Res. PD JAN-FEB PY 2014 VL 55 IS 1 BP 13 EP 19 DI 10.3109/03008207.2013.867339 PG 7 WC Cell Biology; Orthopedics SC Cell Biology; Orthopedics GA 291ZG UT WOS:000329870800004 PM 24437600 ER PT J AU Liu, Y Litiere, S de Vries, EGE Sargent, D Shankar, L Bogaerts, J Seymour, L AF Liu, Yan Litiere, Saskia de Vries, Elisabeth G. E. Sargent, Daniel Shankar, Lalitha Bogaerts, Jan Seymour, Lesley CA RECIST Comm TI The role of response evaluation criteria in solid tumour in anticancer treatment evaluation: Results of a survey in the oncology community SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE RECIST; Tumour assessment criteria; Targeted agents; FDG-PET; Advanced MR techniques ID POSITRON-EMISSION-TOMOGRAPHY; IMATINIB MESYLATE; RECIST GUIDELINE; CLINICAL-TRIALS; WORKING GROUP; CANCER; RECOMMENDATIONS; PET AB Purpose: With the increasing use of novel targeted agents and the development of high imaging techniques, response evaluation criteria in solid tumour (RECIST) 1.1 developed primarily for cytotoxic agents and anatomic imaging, has demonstrated limitations. A survey was conducted of RECIST users to identify concerns and their suggestions for future RECIST criteria. Methods: 140 key partners of the RECIST collaboration were asked to complete a questionnaire. The 49 questions concerned (a) satisfaction and concerns with RECIST 1.1; (b) use of modified RECIST criteria and (c) suggestions for the next RECIST Version. Results: Sixty-five replies were received. 52.3% responders were satisfied with RECIST 1.1, while 10.8% indicated dissatisfaction. Areas of potential weakness included: (a) lack of incorporation of potential early indicators of response such as functional imaging, (b) lack of validation in rarer tumour types and (c) lack of validation for novel (targeted) agents. Suggestions were multiple, with highest numbers on two points: developing sub-criteria for certain disease types and including advanced imaging techniques for the evaluation. Conclusions: Constructive suggestions were received for optimising the next version. Ongoing data collection will make it possible to investigate the possible utilisation of fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging in tumour assessment, to verify whether RECIST is/can still be applicable in novel targeted therapy and to consider the need for criteria for specific disease types. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Liu, Yan; Litiere, Saskia; Bogaerts, Jan] EORTC, B-1200 Brussels, Belgium. [de Vries, Elisabeth G. E.] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, Groningen, Netherlands. [Seymour, Lesley] Queens Univ, Natl Canc Inst, Canada Clin Trials Grp, Kingston, ON, Canada. [Sargent, Daniel] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Shankar, Lalitha] NCI, Canc Imaging Program, Bethesda, MD 20892 USA. RP Liu, Y (reprint author), EORTC, Translat Res Radiotherapy & Imaging Dept, Ave E Mounier 83-11, B-1200 Brussels, Belgium. EM yan.liu@eortc.be OI Sargent, Daniel/0000-0002-2684-4741 FU EORTC Charitable Trust FX This publication was supported by the EORTC Charitable Trust. The authors wish to thank the members of the RECIST Working Group for their generous participation: Janet Dancey, Robert Ford, Steve Gwyther, Wendy Hayes, Otto Hoekstra, Eric Huang, Sumithra Mandrekar, Margaret Mooney, Larry Rubinstein, Larry Schwartz, Patrick Therasse and Helen Young. NR 27 TC 10 Z9 10 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JAN PY 2014 VL 50 IS 2 BP 260 EP 266 DI 10.1016/j.ejca.2013.10.011 PG 7 WC Oncology SC Oncology GA 293PV UT WOS:000329986500002 PM 24239447 ER PT J AU Bulliard, JL Garcia, M Blom, J Senore, C Mai, V Klabunde, C AF Bulliard, Jean-Luc Garcia, Montse Blom, Johannes Senore, Carlo Mai, Verna Klabunde, Carrie TI Sorting out measures and definitions of screening participation to improve comparability: The example of colorectal cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Review DE Participation; Definition; Colorectal cancer; Screening; Programme ID OCCULT BLOOD-TEST; RANDOMIZED CONTROLLED-TRIAL; FECAL IMMUNOCHEMICAL TEST; LONGITUDINAL ADHERENCE; QUALITY-ASSURANCE; PILOT PROGRAM; POPULATION; COLONOSCOPY; MAMMOGRAPHY; SIGMOIDOSCOPY AB Participation is a key indicator of the potential effectiveness of any population-based intervention. Defining, measuring and reporting participation in cancer screening programmes has become more heterogeneous as the number and diversity of interventions have increased, and the purposes of this benchmarking parameter have broadened. This study, centred on colorectal cancer, addresses current issues that affect the increasingly complex task of comparing screening participation across settings. Reports from programmes with a defined target population and active invitation scheme, published between 2005 and 2012, were reviewed. Differences in defining and measuring participation were identified and quantified, and participation indicators were grouped by aims of measure and temporal dimensions. We found that consistent terminology, clear and complete reporting of participation definition and systematic documentation of coverage by invitation were lacking. Further, adherence to definitions proposed in the 2010 European Guidelines for Quality Assurance in Colorectal Cancer Screening was suboptimal. Ineligible individuals represented 1% to 15% of invitations, and variable criteria for ineligibility yielded differences in participation estimates that could obscure the interpretation of colorectal cancer screening participation internationally. Excluding ineligible individuals from the reference population enhances comparability of participation measures. Standardised measures of cumulative participation to compare screening protocols with different intervals and inclusion of time since invitation in definitions are urgently needed to improve international comparability of colorectal cancer screening participation. Recommendations to improve comparability of participation indicators in cancer screening interventions are made. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Bulliard, Jean-Luc] Univ Inst Social & Prevent Med, Canc Epidemiol Unit, Lausanne, Switzerland. [Garcia, Montse] Catalan Inst Oncol, Canc Prevent & Control Program, IDIBELL, Lhospitalet De Llobregat, Spain. [Blom, Johannes] Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden. [Senore, Carlo] CPO Piemonte, AO Citta Salute & Sci, Turin, Italy. [Mai, Verna] Canadian Partnership Canc, Toronto, ON, Canada. [Klabunde, Carrie] NCI, Bethesda, MD 20892 USA. RP Bulliard, JL (reprint author), Inst Univ Med Sociale & Prevent, Unite Epidemiol Canc, Biopole 2,Rte Corniche 10, CH-1010 Lausanne, Switzerland. EM Jean-Luc.Bulliard@chuv.ch RI Garcia, Montse/B-8832-2014; OI Garcia, Montse/0000-0002-3437-3185; Senore, Carlo/0000-0003-1023-7477 FU Carlos III Health Institute [RD/12/0036/0053] FX The International Cancer Screening Network (ICSN) is acknowledged for their leadership. The authors are indebted to Gregory Doyle (Canada), Lea Hagoel-Salomon (Israel), Iben Holten (Denmark), Julietta Patnick (UK) and Sven Tornberg (Sweden) for their collaboration in the ICSN Screening Participation Rates working group. M. G. acknowledges the support from the Carlos III Health Institute (RD/12/0036/0053). NR 68 TC 9 Z9 10 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JAN PY 2014 VL 50 IS 2 BP 434 EP 446 DI 10.1016/j.ejca.2013.09.015 PG 13 WC Oncology SC Oncology GA 293PV UT WOS:000329986500021 PM 24144735 ER PT J AU Nath, A Steiner, J AF Nath, Avindra Steiner, Joseph TI Synaptodendritic injury with HIV-Tat protein: What is the therapeutic target? SO EXPERIMENTAL NEUROLOGY LA English DT Editorial Material ID MEMORY DEFICITS; IMMUNODEFICIENCY; RECEPTOR; ACTIVATION; EXPRESSION; BRAIN; MOUSE C1 [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Nath, Avindra; Steiner, Joseph] NINDS, Translat Neurosci Ctr, NIH, Bethesda, MD 20892 USA. RP Nath, A (reprint author), Room 7C-103,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003130-06] NR 26 TC 7 Z9 8 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 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JAN PY 2014 VL 251 BP 112 EP 114 DI 10.1016/j.expneurol.2013.11.004 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 293DI UT WOS:000329951200012 PM 24246278 ER PT J AU Dutta, A Chatterjee, R Chaudhuri, K AF Dutta, Avirup Chatterjee, Raghunath Chaudhuri, Keya TI Identification of C. elegans & C-briggsae miRNAs by modified miRsearch SO FRONTIERS IN BIOSCIENCE-LANDMARK LA English DT Article DE miRNA; C. elegans and C. briggasae miRNA; Modified Mirsearch ID MICRORNA GENES; SMALL RNAS; BIOGENESIS; DROSOPHILA; TARGETS; ENCODES AB In this study, a modified miRsearch program was developed in C++ for the detection of miRNAs. All the mature miRNA sequences of Caenorhabditis elegans, Caenorhabditis briggsae, Caenorhabditis remanei, Drosophila melanogaster, Homo sapiens and Rattus norvegicus available in miRbase was searched by this program for homologous sequences with a maximum of 3mismatches in the chromosomes of C. elegans excluding the miRNAs of C. elegans. The same strategy was repeated for C. briggsae excluding C. briggsae miRNAs. The probable pre-miRNA sequences with stem loop secondary structures were assessed by implementation of longest-common- subsequence (LCS) algorithm with appropriate scoring system. As miRNA genes could be on either strand, each sequence was searched in both forward and reverse strands. The putative miRNAs were viewed through Mapviewer to identify their intronic or intergenic location in C. elegans and C. briggsae genomes. Further, the quality of stem-loop formation of the remaining pre-miRNA sequences was assessed through RNAFOLD. This algorithm will be helpful in detection of potential miRNAs in future sequencing data, making this an invaluable tool for miRNA prediction. C1 [Dutta, Avirup; Chaudhuri, Keya] Indian Inst Chem Biol, Mol & Human Genet Div, Kolkata 700032, India. [Chatterjee, Raghunath] NCI, NIH, Bethesda, MD 20892 USA. [Chatterjee, Raghunath] ISI, Div Biol Sci, Human Genet Unit, Kolkata 700108, India. RP Chaudhuri, K (reprint author), CSIR Indian Inst Chem Biol, Mol & Human Genet Div, 4,Raja SC Mullick Rd, Kolkata 700032, India. EM keya.chaudhuri@gmail.com FU Council of Scientific and Industrial Research (CSIR), Govt. of India; CSIR Senior Research Fellowship FX Avirup Dutta and Raghunath Chatterjee have equally contributed to this manuscript. The study was supported by the Council of Scientific and Industrial Research (CSIR), Govt. of India. A.D. is the recipient of the CSIR Senior Research Fellowship. NR 30 TC 1 Z9 1 U1 0 U2 2 PU FRONTIERS IN BIOSCIENCE INC PI IRVINE PA 16471 SCIENTIFIC WAY, IRVINE, CA 92618 USA SN 1093-9946 EI 1093-4715 J9 FRONT BIOSCI-LANDMRK JI Front. Biosci. PD JAN 1 PY 2014 VL 19 BP 504 EP 514 DI 10.2741/4221 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 294FQ UT WOS:000330029100008 PM 24389198 ER PT J AU Wivel, NA AF Wivel, Nelson A. TI Historical Perspectives Pertaining to the NIH Recombinant DNA Advisory Committee SO HUMAN GENE THERAPY LA English DT Editorial Material AB Science is host to a constantly emerging series of new paradigms, and it is this characteristic that makes science both interesting and dynamic. As a part of this continuum, it became possible to create recombinant DNA molecules. Immediately it was recognized that there was a potential for serious adverse events associated with this new technology. Following two scientific conferences at Asilomar, California, the National Institutes of Health moved quickly to create the Recombinant DNA Advisory Committee (RAC). For approximately 38 years the RAC has served as an open forum for review of various recombinant DNA experiments, and for the last 23 years it has played a pivotal role in the oversight of human gene therapy. The RAC's existence obviated the need for more restrictive governmental legislation and has supported the development of genetic interventions that are leading to actual human therapies. C1 [Wivel, Nelson A.] NIH, NIH Off Recombinant DNA Act, Bethesda, MD 20892 USA. [Wivel, Nelson A.] NIH, RAC, Bethesda, MD 20892 USA. [Wivel, Nelson A.] Univ Penn, Sch Med, Inst Human Gene Therapy, Philadelphia, PA 19104 USA. RP Wivel, NA (reprint author), NIH, NIH Off Recombinant DNA Act, Bldg 10, Bethesda, MD 20892 USA. EM nawdoc@msn.com NR 12 TC 2 Z9 2 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD JAN 1 PY 2014 VL 25 IS 1 BP 19 EP 24 DI 10.1089/hum.2013.2524 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 291SC UT WOS:000329848600005 PM 24444182 ER PT J AU Singh, UP Singh, NP Guan, HB Busbee, B Price, RL Taub, DD Mishra, MK Fayad, R Nagarkatti, M Nagarkatti, PS AF Singh, Udai P. Singh, Narendra P. Guan, Hongbing Busbee, Brandon Price, Robert L. Taub, Dennis D. Mishra, Manoj K. Fayad, Raja Nagarkatti, Mitzi Nagarkatti, Prakash S. TI The Emerging Role of Leptin Antagonist as Potential Therapeutic Option for Inflammatory Bowel Disease SO INTERNATIONAL REVIEWS OF IMMUNOLOGY LA English DT Review DE Crohn's disease (CD); inflammation; inflammatory bowel disease (IBD); leptin antagonist; pegylated leptin; ulcerative colitis (UC) ID REGULATORY T-CELLS; NECROSIS-FACTOR-ALPHA; PLASMA LEPTIN; INTESTINAL INFLAMMATION; CROHNS-DISEASE; ADIPOSE-TISSUE; SERUM LEPTIN; AUTOIMMUNE ENCEPHALOMYELITIS; PROINFLAMMATORY CYTOKINES; ULCERATIVE-COLITIS AB Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disorder that affects millions of people around the world. Leptin is a satiety hormone produced primarily by adipose tissue and acts both centrally and peripherally. Leptin has been shown to play a major role in regulating metabolism, which increases during IBD progression. Leptin mediates several physiological functions including elevated blood pressure, tumorogenesis, cardiovascular pathologies and enhanced immune response in many autoimmune diseases. Recent development of a leptin mutant antagonist that blocks leptin activity raises great hope and opens up new possibilities for therapy in many autoimmune diseases including IBD. To this end, preliminary data from an ongoing study in our laboratory on pegylated leptin antagonist mutant L39A/D40A/F41A (PEG-MLA) treatment shows an inhibition of chronic colitis in IL-10(-/-) mice. PEG-MLA effectively attenuates the overall clinical scores, reverses colitis-associated pathogenesis including a decrease in body weight, and decreases systemic leptin level. PEG-MLA induces both central and peripheral leptin deficiency by mediating the cellular immune response. In summary, after blocking leptin activity, the correlative outcome between leptin-mediated cellular immune response, systemic leptin levels, and amount of adipose tissue together may provide new strategies for therapeutic intervention in autoimmune diseases, especially for intestinal inflammation. C1 [Singh, Udai P.; Singh, Narendra P.; Guan, Hongbing; Busbee, Brandon; Nagarkatti, Mitzi; Nagarkatti, Prakash S.] Univ S Carolina, Dept Pathol Microbiol & Immunol, Sch Med, Columbia, SC 29208 USA. [Price, Robert L.] Univ S Carolina, Dept Cell & Dev Biol, Columbia, SC 29208 USA. [Taub, Dennis D.] NIA, Lab Mol Biol & Immunol, IRP, NIH, Baltimore, MD 21224 USA. [Mishra, Manoj K.] Alabama State Univ, Dept Math & Sci, Montgomery, AL 36101 USA. [Fayad, Raja] Univ S Carolina, Arnold Sch Publ Hlth, Dept Exercise Sci, Columbia, SC 29208 USA. RP Singh, UP (reprint author), Univ S Carolina, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA. EM Udai.singh@uscmed.sc.edu OI Nagarkatti, Mitzi/0000-0002-5977-5615 FU NIH [R56 DK087836, P01 AT003961]; Research and Development Funds from the University of South Carolina School of Medicine; Intramural Program of the National Institute on Aging, NIH FX This work was supported, in part by NIH grants R56 DK087836 and P01 AT003961, Research and Development Funds from the University of South Carolina School of Medicine, and the Intramural Program of the National Institute on Aging, NIH. NR 92 TC 6 Z9 6 U1 1 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0883-0185 EI 1563-5244 J9 INT REV IMMUNOL JI Int. Rev. Immunol. PD JAN PY 2014 VL 33 IS 1 BP 23 EP 33 DI 10.3109/08830185.2013.809071 PG 11 WC Immunology SC Immunology GA 291MV UT WOS:000329833700004 PM 23841494 ER PT J AU Mordini, FE Haddad, T Hsu, LY Kellrnan, P Lowrey, TB Aletras, AH Bandettini, P Arai, AE AF Mordini, Federico E. Haddad, Tariq Hsu, Li-Yueh Kellrnan, Peter Lowrey, Tracy B. Aletras, Anthony H. Bandettini, Patricia Arai, Andrew E. TI Diagnostic Accuracy of Stress Perfusion CMR in Comparison With Quantitative Coronary Angiography SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE cardiac magnetic resonance; myocardial ischemia; myocardial perfusion; quantitative perfusion; stress testing ID CARDIAC MAGNETIC-RESONANCE; POSITRON-EMISSION-TOMOGRAPHY; ABSOLUTE MYOCARDIAL-PERFUSION; FRACTIONAL FLOW RESERVE; ARTERY-DISEASE; COMPUTED-TOMOGRAPHY; NONINVASIVE DETECTION; STENOSIS SEVERITY; TRANSIT-TIME; N-13 AMMONIA AB OBJECTIVES This study's primary objective was to determine the sensitivity, specificity, and accuracy of fully quantitative stress perfusion cardiac magnetic resonance (CMR) versus a reference standard of quantitative coronary angiography. We hypothesized that fully quantitative analysis of stress perfusion CMR would have high diagnostic accuracy for identifying significant coronary artery stenosis and exceed the accuracy of semiquantitative measures of perfusion and qualitative interpretation. BACKGROUND Relatively few studies apply fully quantitative CMR perfusion measures to patients with coronary disease and comparisons to semiquantitative and qualitative methods are limited. METHODS Dual bolus dipyridamole stress perfusion CMR exams were performed in 67 patients with clinical indications for assessment of myocardial ischemia. Stress perfusion images alone were analyzed with a fully quantitative perfusion (QP) method and 3 semiquantitative methods including contrast enhancement ratio, upslope index, and upslope integral. Comprehensive exams (cine imaging, stress/rest perfusion, late gadolinium enhancement) were analyzed qualitatively with 2 methods including the Duke algorithm and standard clinical interpretation. A 70% or greater stenosis by quantitative coronary angiography was considered abnormal. RESULTS The optimum diagnostic threshold for QP determined by receiver-operating characteristic curve occurred when endocardial flow decreased to <50% of mean epicardial flow, which yielded a sensitivity of 87% and specificity of 93%. The area under the curve for QP was 92%, which was superior to semiquantitative methods: contrast enhancement ratio: 78%; upslope index: 82%; and upslope integral: 75% (p = 0.011, p = 0.019, p = 0.004 vs. QP, respectively). Area under the curve for QP was also superior to qualitative methods: Duke algorithm: 70%; and clinical interpretation: 78% (p < 0.001 and p < 0.001 vs. QP, respectively). CONCLUSIONS Fully quantitative stress perfusion CMR has high diagnostic accuracy for detecting obstructive coronary artery disease. QP outperforms semiquantitative measures of perfusion and qualitative methods that incorporate a combination of cine, perfusion, and late gadolinium enhancement imaging. These findings suggest a potential clinical role for quantitative stress perfusion CMR. (C) 2014 by the American College of Cardiology Foundation C1 [Mordini, Federico E.; Haddad, Tariq; Hsu, Li-Yueh; Kellrnan, Peter; Lowrey, Tracy B.; Aletras, Anthony H.; Bandettini, Patricia; Arai, Andrew E.] Natl Heart Lung & Blood Inst, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mordini, Federico E.] Vet Affairs Med Ctr, Dept Cardiol, Washington, DC 20422 USA. [Aletras, Anthony H.] Univ Cent Greece, Dept Biomed Informat, Lamia, Greece. RP Arai, AE (reprint author), Natl Heart Lung & Blood Inst, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room BID 416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov FU Division of Intramural Research; National Heart, Lung, and Blood Institute; National Institutes of Health; Siemens Medical Imaging (United States Government Cooperative Research and Development Award) FX From the *Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; dagger Department of Cardiology, Veterans Affairs Medical Center, Washington, DC; and the double dagger Department of Biomedical Informatics, University of Central Greece, Lamia, Greece. This study was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. Dr. Arai receives research support from Siemens Medical Imaging (United States Government Cooperative Research and Development Award). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 44 TC 16 Z9 16 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JAN PY 2014 VL 7 IS 1 BP 14 EP 22 DI 10.1016/j.jcmg.2013.08.014 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 293EF UT WOS:000329953500003 PM 24433707 ER PT J AU Hruby, A O'Donnell, CJ Jacques, PF Meigs, JB Hoffmann, U McKeown, NM AF Hruby, Adela O'Donnell, Christopher J. Jacques, Paul F. Meigs, James B. Hoffmann, Udo McKeown, Nicola M. TI Magnesium Intake Is Inversely Associated With Coronary Artery Calcification SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE abdominal aortic calcification; computed tomography; coronary artery calcification; diet; Framingham Heart Study; magnesium ID DIETARY MAGNESIUM; CARDIOVASCULAR-DISEASE; ATHEROSCLEROTIC PLAQUE; RISK-FACTORS; HEART; CALCIUM; SERUM; CONSUMPTION; MORTALITY; INSULIN AB OBJECTIVES The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC). BACKGROUND Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying cardiovascular disease. Little is known about the association of magnesium intake and atherosclerotic calcification in humans. METHODS We examined cross-sectional associations of self-reported total (dietary and supplemental) magnesium intake estimated by food frequency questionnaire with CAC and AAC in participants of the Framingham Heart Study who were free of cardiovascular disease and underwent Multi-Detector Computed Tomography (MDCT) of the heart and abdomen (n = 2,695; age: 53 11 years), using multivariate-adjusted Tobit regression. CAC and AAC were quantified using modified Agatston scores (AS). Models were adjusted for age, sex, body mass index, smoking status, systolic blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy (women only), menopausal status (women only), treatment for hyperlipidemia, hypertension, cardiovascular disease prevention, or diabetes, as well as self-reported intake of calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy. Secondary analyses included logistic regressions of CAC and AAC outcomes as cut-points (AS >0 and AS >= 90th percentile for age and sex), as well as sex-stratified analyses. RESULTS In fully adjusted models, a 50-mg/day increment in self-reported total magnesium intake was associated with 22% lower CAC (p < 0.001) and 12% lower AAC (p = 0.07). Consistent with these observations, the odds of having any CAC were 58% lower (p trend: <0.001) and any AAC were 34% lower (p trend: 0.01), in those with the highest compared to those with the lowest magnesium intake. Stronger inverse associations were observed in women than in men. CONCLUSIONS In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium's protective associations in stroke and fatal coronary heart disease. (C) 2014 by the American College of Cardiology Foundation C1 [Hruby, Adela; Jacques, Paul F.; McKeown, Nicola M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr Epidemiol Program, Boston, MA 02111 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBIs Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiovasc, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Meigs, James B.; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP McKeown, NM (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr Epidemiol Program, 711 Washington St,9th Floor, Boston, MA 02111 USA. EM nicola.mckeown@tufts.edu FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Heart Association Predoctoral Fellowship; United States Department of Agriculture (USDA) [58-1950-0-014]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K24 DK080140] FX From the *Nutritional Epidemiology Program, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; dagger National Heart, Lung, and Blood Institute (NHLBI) Division of Intramural Research, and NHLBI's Framingham Heart Study, Framingham, Massachusetts; double dagger Cardiovascular Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; (General Medicine Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and the Massachusetts General Hospital Cardiac MR PET CT Program and the Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. At the time of writing, Dr. Hruby was supported by an American Heart Association Predoctoral Fellowship. This work was also supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195) and the United States Department of Agriculture (USDA agreement no. 58-1950-0-014). Dr. Jacques has been a member of the Bay State Milling Nutrition Science Advisory Council and of the Dannon Yogurt Advisory Board. Dr. Meigs is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (K24 DK080140). All authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 49 TC 28 Z9 30 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JAN PY 2014 VL 7 IS 1 BP 59 EP 69 DI 10.1016/j.jcmg.2013.10.006 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 293EF UT WOS:000329953500009 PM 24290571 ER PT J AU Yuan, A Xu, JF Zheng, G AF Yuan, Ao Xu, Jinfeng Zheng, Gang TI On empirical likelihood statistical functions SO JOURNAL OF ECONOMETRICS LA English DT Article DE Empirical likelihood; Quantile estimation; Uniform SLLN; Uniform CLT ID KERNEL DENSITY-ESTIMATION; AUXILIARY INFORMATION; CONFIDENCE-INTERVALS; MOMENT RESTRICTIONS; BANACH-SPACE; LINEAR-MODELS; INFERENCE; QUANTILES AB We consider the empirical likelihood method for estimation of distribution and quantile functions where side information is incorporated through moment conditions. We systematically study the asymptotic properties of the estimators, such as the uniform strong laws of large numbers and weak convergence over classes of functions. Two Monte Carlo examples are also given to illustrate the practical utility of the method. (C) 2013 Elsevier B.V. All rights reserved. C1 Georgetown Univ, Washington, DC 20057 USA. NYU, New York, NY 10016 USA. NHLBI, Bethesda, MD 20892 USA. RP Yuan, A (reprint author), 2216 6th St NW,Suite 206, Washington, DC 20059 USA. EM yuanao@hotmail.com FU National Center for Research Resources at NIH [2G12RR003048] FX We are grateful to the editor, associate editor and two referees for their helpful comments, which have greatly improved the manuscript. This work is supported in part by the National Center for Research Resources at NIH grant 2G12RR003048. NR 42 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0304-4076 EI 1872-6895 J9 J ECONOMETRICS JI J. Econom. PD JAN PY 2014 VL 178 BP 613 EP 623 DI 10.1016/j.jeconom.2013.08.037 PN 3 PG 11 WC Economics; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Business & Economics; Mathematics; Mathematical Methods In Social Sciences GA 293HC UT WOS:000329961000017 ER PT J AU Zebrack, B Kent, EE Keegan, THM Kato, I Smith, AW AF Zebrack, Brad Kent, Erin E. Keegan, Theresa H. M. Kato, Ikuko Smith, Ashley Wilder CA AYA HOPE Study Collaborative Grp TI "Cancer Sucks," and Other Ponderings by Adolescent and Young Adult Cancer Survivors SO JOURNAL OF PSYCHOSOCIAL ONCOLOGY LA English DT Article DE adolescent; young adult; medical care; qualitative research; psychosocial ID PSYCHOSOCIAL IMPACT; SERVICE NEEDS; HEALTH; OLDER; INFORMATION; DIAGNOSIS; FAMILIES AB As part of the National Cancer Institute's AYA HOPE study, 296 adolescent and young adults (AYAs) completed an open-ended survey item asking them to describe their medical care or experience with cancer. Patient, provider, and system-level characteristics all appear to influence AYAs' perceptions of their medical care. Participants attributed levels of satisfaction with care to the availability and communication of information, the management of side-effects, and the expediency and flexibility of treatments. Struggles with health insurance and finances were evident. Findings contribute to a better understanding of AYAs' cancer treatment experiences and will inform improvements to oncology care for this population. C1 [Zebrack, Brad] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Kent, Erin E.] NCI, Off Canc Survivorship, NIH, Bethesda, MD 20892 USA. [Keegan, Theresa H. M.] Canc Prevent Inst Calif, Fremont, CA USA. [Keegan, Theresa H. M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Kato, Ikuko] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA. [Kato, Ikuko] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Smith, Ashley Wilder] NCI, Outcomes Res Branch, Bethesda, MD 20892 USA. RP Zebrack, B (reprint author), Univ Michigan, Sch Social Work, 1080 S Univ, Ann Arbor, MI 48109 USA. EM zebrack@umich.edu FU NCI NIH HHS [N01 PC035139, N01 PC035142, N01 PC035136, N01-PC-35136, N01-PC-35139, N01-PC-35142, N01-PC-35143, N01-PC-35145, N01-PC-54402, N01-PC-54404, N01PC35136, N01PC35139, N01PC35142, N01PC35143, N01PC35145, N01PC54402, N01PC54404] NR 30 TC 11 Z9 11 U1 0 U2 9 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0734-7332 EI 1540-7586 J9 J PSYCHOSOC ONCOL JI J. Psychosoc. Oncol. PD JAN 1 PY 2014 VL 32 IS 1 BP 1 EP + DI 10.1080/07347332.2013.855959 PG 13 WC Psychology, Social SC Psychology GA 289NI UT WOS:000329688800007 PM 24428248 ER PT J AU Rebok, GW Ball, K Guey, LT Jones, RN Kim, HY King, JW Marsiske, M Morris, JN Tennstedt, SL Unverzagt, FW Willis, SL AF Rebok, George W. Ball, Karlene Guey, Lin T. Jones, Richard N. Kim, Hae-Young King, Jonathan W. Marsiske, Michael Morris, John N. Tennstedt, Sharon L. Unverzagt, Frederick W. Willis, Sherry L. CA ACTIVE Study Grp TI Ten-Year Effects of the Advanced Cognitive Training for Independent and Vital Elderly Cognitive Training Trial on Cognition and Everyday Functioning in Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE cognitive training; elderly; cognitive abilities; everyday function; training maintenance ID INSTRUMENTAL ACTIVITIES; HOME-CARE; FOLLOW-UP; MDS-HC; MEMORY; INTERVENTIONS; COMMUNITY; OUTCOMES; PROGRAM; DECLINE AB ObjectivesTo determine the effects of cognitive training on cognitive abilities and everyday function over 10years. DesignTen-year follow-up of a randomized, controlled single-blind trial (Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)) with three intervention groups and a no-contact control group. SettingSix U.S. cities. ParticipantsA volunteer sample of 2,832 persons (mean baseline age 73.6; 26% African American) living independently. InterventionTen training sessions for memory, reasoning, or speed of processing; four sessions of booster training 11 and 35months after initial training. MeasurementsObjectively measured cognitive abilities and self-reported and performance-based measures of everyday function. ResultsParticipants in each intervention group reported less difficulty with instrumental activities of daily living (IADLs) (memory: effect size=0.48, 99% confidence interval (CI)=0.12-0.84; reasoning: effect size=0.38, 99% CI=0.02-0.74; speed of processing: effect size=0.36, 99% CI=0.01-0.72). At a mean age of 82, approximately 60% of trained participants, versus 50% of controls (P<.05), were at or above their baseline level of self-reported IADL function at 10years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10years (reasoning: effect size=0.23, 99% CI=0.09-0.38; speed of processing: effect size=0.66, 99% CI=0.43-0.88). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size=0.21, 99% CI=0.01-0.41) and the speed-of-processing intervention for speed-of-processing performance (effect size = 0.62, 99% CI=0.31-0.93). ConclusionEach Advanced Cognitive Training for Independent and Vital Elderly cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years. C1 [Rebok, George W.] Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD 21205 USA. [Rebok, George W.] Johns Hopkins Univ, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Ball, Karlene] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Guey, Lin T.; Kim, Hae-Young; Tennstedt, Sharon L.] New England Res Inst, Watertown, MA 02172 USA. [Jones, Richard N.; Morris, John N.] Hebrew SeniorLife, Social & Hlth Policy Res, Boston, MA USA. [King, Jonathan W.] NIA, Div Behav & Social Res, Bethesda, MD 20892 USA. [Marsiske, Michael] Univ Florida, Inst Aging, Gainesville, FL USA. [Marsiske, Michael] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL USA. [Unverzagt, Frederick W.] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Willis, Sherry L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Rebok, GW (reprint author), Johns Hopkins Univ, Dept Mental Hlth, Hampton House 891,624 North Broadway, Baltimore, MD 21205 USA. EM grebok@jhsph.edu RI Jones, Richard/J-3488-2013; OI Jones, Richard/0000-0002-1049-218X; Marsiske, Michael/0000-0001-5973-2116 FU National Institute on Aging; National Institute of Nursing Research to Hebrew Senior Life [U01 NR04507]; Indiana University School of Medicine [U01NR04508]; Johns Hopkins University [U01AG14260]; New England Research Institute [U01 AG14282]; Pennsylvania State University [U01 AG14263]; University of Alabama at Birmingham [U01 AG14289]; University of Florida [U01AG14276]; Posit Science, Inc.; Robert Wood Johnson Foundation; McKnight Brain Research Foundation; National Academy of Neuropsychology FX ACTIVE is supported by grants from the National Institute on Aging and the National Institute of Nursing Research to Hebrew Senior Life (U01 NR04507), Indiana University School of Medicine (U01NR04508), Johns Hopkins University (U01AG14260), New England Research Institute (U01 AG14282), Pennsylvania State University (U01 AG14263), University of Alabama at Birmingham (U01 AG14289), and University of Florida (U01AG14276). Drs. Unverzagt and Marsiske have received research support from Posit Science, Inc., in the form of site licenses for cognitive training programs for investigator-initiated research projects. Dr. Marsiske has received research support from Robert Wood Johnson Foundation and McKnight Brain Research Foundation and payment for development of education presentations from the National Academy of Neuropsychology and the International Neuropsychological Society for workshops on cognitive interventions and from the National Institute on Aging and American Society on Aging for overview presentation on cognitive interventions. Dr. Ball is a consultant and owns stock in the Visual Awareness Research Group and Posit Science, Inc., the companies that market the UFOV Test and speed-ofprocessing training software, now called Insight (the Visual Awareness Research Group invented Insight and the UFOV). Dr. Ball serves as a member of the Posit Science Scientific Advisory Board. Posit Science paid royalties to the Visual Awareness Research Group (unrelated to the study described). The Visual Awareness Research Group is an S Corp; all profits and losses flow to stockholders. Dr. Rebok is an investigator with Compact Disc Incorporated for the development of an electronic version of the ACTIVE memory intervention. Drs. Morris and Jones received support from the Edward Fein Foundation and Vicki and Arthur Loring for research activities. The views expressed in this article are those of the authors and not to be ascribed to the National Institute on Aging, National Institute of Nursing Research or the Department of Health and Human Services. NR 48 TC 114 Z9 119 U1 8 U2 88 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2014 VL 62 IS 1 BP 16 EP 24 DI 10.1111/jgs.12607 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 292AS UT WOS:000329874600003 PM 24417410 ER PT J AU Ceresini, G Ceda, GP Lauretani, F Maggio, M Usberti, E Marina, M Bandinelli, S Guralnik, JM Valenti, G Ferrucci, L AF Ceresini, Graziano Ceda, Gian P. Lauretani, Fulvio Maggio, Marcello Usberti, Elisa Marina, Michela Bandinelli, Stefania Guralnik, Jack M. Valenti, Giorgio Ferrucci, Luigi TI LOW THYROTROPIN FROM NONTHYROIDAL ILLNESS? RESPONSE SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter ID CHIANTI C1 [Ceresini, Graziano; Ceda, Gian P.; Maggio, Marcello; Usberti, Elisa; Marina, Michela; Valenti, Giorgio] Univ Hosp Parma, Dept Clin & Expt Med, Geriatr Endocrine Unit, Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Unit, Parma, Italy. [Bandinelli, Stefania] ASF Toscana, Geriatr Unit, Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Ceresini, G (reprint author), Univ Hosp Parma, Dept Clin & Expt Med, Geriatr Endocrine Unit, Parma, Italy. NR 5 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2014 VL 62 IS 1 BP 208 EP 209 DI 10.1111/jgs.12616 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 292AS UT WOS:000329874600041 PM 25180397 ER PT J AU Shen, QF Yamano, K Head, BP Kawajiri, S Cheung, JTM Wang, CX Cho, JH Hattori, N Youle, RJ van der Bliek, AM AF Shen, Qinfang Yamano, Koji Head, Brian P. Kawajiri, Sumihiro Cheung, Jesmine T. M. Wang, Chunxin Cho, Jeong-Hoon Hattori, Nobutaka Youle, Richard J. van der Bliek, Alexander M. TI Mutations in Fis1 disrupt orderly disposal of defective mitochondria SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID DYNAMIN-RELATED GTPASE; MAMMALIAN-CELLS; C-ELEGANS; FISSION MACHINERY; PEROXISOMAL FISSION; PROTEIN DRP1; PARKIN; MEMBRANE; MITOPHAGY; AUTOPHAGY AB Mitochondrial fission is mediated by the dynamin-related protein Drp1 in metazoans. Drp1 is recruited from the cytosol to mitochondria by the mitochondrial outer membrane protein Mff. A second mitochondrial outer membrane protein, named Fis1, was previously proposed as recruitment factor, but Fis1(-/-) cells have mild or no mitochondrial fission defects. Here we show that Fis1 is nevertheless part of the mitochondrial fission complex in metazoan cells. During the fission cycle, Drp1 first binds to Mff on the surface of mitochondria, followed by entry into a complex that includes Fis1 and endoplasmic reticulum (ER) proteins at the ER-mitochondrial interface. Mutations in Fis1 do not normally affect fission, but they can disrupt downstream degradation events when specific mitochondrial toxins are used to induce fission. The disruptions caused by mutations in Fis1 lead to an accumulation of large LC3 aggregates. We conclude that Fis1 can act in sequence with Mff at the ER-mitochondrial interface to couple stress-induced mitochondrial fission with downstream degradation processes. C1 [Shen, Qinfang; Head, Brian P.; Kawajiri, Sumihiro; Cheung, Jesmine T. M.; Cho, Jeong-Hoon; van der Bliek, Alexander M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. [Yamano, Koji; Wang, Chunxin; van der Bliek, Alexander M.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Kawajiri, Sumihiro; Hattori, Nobutaka] Juntendo Univ, Dept Neurol, Sch Med, Tokyo 1138421, Japan. RP van der Bliek, AM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. EM avan@mednet.ucla.edu RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 FU National Institutes of Health [GM051866, T32-GM07104]; National Science Foundation [0552271]; Naito Foundation; Nakatomi Foundation; Japan Society for the Promotion of Science; Japan Society for the Promotion of Science Fellowship for Research Abroad FX We thank other members of the van der Bliek and Youle labs for helpful discussions. Strains were provided by the Caenorhabditis Genetics Center and S. Mitani. Technical support for electron microscopy was provided by the National Institute of Neurological Disorders and Stroke EM Facility. This work was supported by grants from the National Institutes of Health (GM051866) and the National Science Foundation (0552271) to A.M.V.D.B. B.P.H. received a National Institutes of Health Training Grant (T32-GM07104). S.K. was supported by a fellowship from the Naito Foundation and the Nakatomi Foundation. N.H. was supported by the Japan Society for the Promotion of Science, and K.Y. was supported by a Japan Society for the Promotion of Science Fellowship for Research Abroad. NR 61 TC 42 Z9 44 U1 2 U2 11 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JAN 1 PY 2014 VL 25 IS 1 BP 145 EP 159 DI 10.1091/mbc.E13-09-0525 PG 15 WC Cell Biology SC Cell Biology GA 294DL UT WOS:000330022500013 PM 24196833 ER PT J AU Chow, KH Elgort, S Dasso, M Powers, MA Ullman, KS AF Chow, Kin-Hoe Elgort, Suzanne Dasso, Mary Powers, Maureen A. Ullman, Katharine S. TI The SUMO proteases SENP1 and SENP2 play a critical role in nucleoporin homeostasis and nuclear pore complex function SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID AXIN-BINDING PROTEIN; CELL-CYCLE; SUMOYLATION; PATHWAY; POM121; ISOPEPTIDASE; TRANSPORT; UBIQUITIN; MEMBRANE; PHOSPHORYLATION AB Nuclear pore complexes are composed of similar to 30 different proteins, each present at the pore in multiple copies. Together these proteins create specialized channels that convey cargo between the cytoplasm and the nuclear interior. With the building blocks of nuclear pores identified, one challenge is to decipher how these proteins are coordinately produced and assembled into macromolecular pore structures with each cell division. Specific individual pore proteins and protein cofactors have been probed for their role in the assembly process, as well as certain kinases that add a layer of regulation via the phosphorylation status of nucleoporins. Other posttranslational modifications are candidates for coordinating events of pore assembly as well. In this study of two pore-associated small ubiquitin-like modifier (SUMO) proteases, sentrin/SUMO-specific protease 1 (SENP1) and SENP2, we observe that many nucleoporins are mislocalized and, in some cases, reduced in level when SENP1 and SENP2 are codepleted. The pore complexes present under these conditions are still capable of transport, although the kinetics of specific cargo is altered. These results reveal a new role for the pore-associated SENPs in nucleoporin homeostasis and in achieving proper configuration of the nuclear pore complex. C1 [Chow, Kin-Hoe; Elgort, Suzanne; Ullman, Katharine S.] Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. [Dasso, Mary] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Powers, Maureen A.] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA. RP Ullman, KS (reprint author), Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. EM katharine.ullman@hci.utah.edu OI Dasso, Mary/0000-0002-5410-1371 FU National Institutes of Health [R01 GM61275, RO1 GM059975]; National Institute of Child Health and Human Development intramural funds [Z01 HD001902, Z01 HD008816]; [P30 CA042014] FX We thank Douglass Forbes for providing antibodies. This work was supported by National Institutes of Health Grants R01 GM61275 (K.U.) and RO1 GM059975 (M.P.) and National Institute of Child Health and Human Development intramural funds (Projects Z01 HD001902 and Z01 HD008816 to M.D.). Shared resources used in this project are supported in part by P30 CA042014 awarded to the Huntsman Cancer Institute. NR 67 TC 3 Z9 4 U1 1 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JAN 1 PY 2014 VL 25 IS 1 BP 160 EP 168 DI 10.1091/mbc.E13-05-0256 PG 9 WC Cell Biology SC Cell Biology GA 294DL UT WOS:000330022500014 PM 24196834 ER PT J AU Parkhitko, AA Priolo, C Coloff, JL Yun, J Wu, JJ Mizumura, K Xu, WP Malinowska, IA Yu, J Kwiatkowski, DJ Locasale, JW Asara, JM Choi, AMK Finkel, T Henske, EP AF Parkhitko, Andrey A. Priolo, Carmen Coloff, Jonathan L. Yun, Jihye Wu, Julia J. Mizumura, Kenji Xu, Wenping Malinowska, Izabela A. Yu, Jane Kwiatkowski, David J. Locasale, Jason W. Asara, John M. Choi, Augustine M. K. Finkel, Toren Henske, Elizabeth P. TI Autophagy-Dependent Metabolic Reprogramming Sensitizes TSC2-Deficient Cells to the Antimetabolite 6-Aminonicotinamide SO MOLECULAR CANCER RESEARCH LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; ANTITUMOR-ACTIVITY; CANCER; ACTIVATION AB The mammalian target of rapamycin complex 1 (mTORC1) is hyperactive in many human cancers and in tuberous sclerosis complex (TSC). Autophagy, a key mTORC1-targeted process, is a critical determinant of metabolic homeostasis. Metabolomic profiling was performed to elucidate the cellular consequences of autophagy dysregulation under conditions of hyperactive mTORC1. It was discovered that TSC2-null cells have distinctive autophagy-dependent pentose phosphate pathway (PPP) alterations. This was accompanied by enhanced glucose uptake and utilization, decreased mitochondrial oxygen consumption, and increased mitochondrial reactive oxygen species (ROS) production. Importantly, these findings revealed that the PPP is a key autophagy-dependent compensatory metabolic mechanism. Furthermore, PPP inhibition with 6-aminonicotinamide (6-AN) in combination with autophagy inhibition suppressed proliferation and prompted the activation of NF-kappa B and CASP1 in TSC2-deficient, but not TSC2-proficient cells. These data demonstrate that TSC2-deficient cells can be therapeutically targeted, without mTORC1 inhibitors, by focusing on their metabolic vulnerabilities. C1 [Parkhitko, Andrey A.; Priolo, Carmen; Mizumura, Kenji; Xu, Wenping; Yu, Jane; Choi, Augustine M. K.; Henske, Elizabeth P.] Harvard Univ, Sch Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Malinowska, Izabela A.; Kwiatkowski, David J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Translat Med, Boston, MA 02115 USA. [Coloff, Jonathan L.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Parkhitko, Andrey A.; Priolo, Carmen; Coloff, Jonathan L.; Yun, Jihye; Mizumura, Kenji; Xu, Wenping; Malinowska, Izabela A.; Yu, Jane; Kwiatkowski, David J.; Asara, John M.; Choi, Augustine M. K.; Henske, Elizabeth P.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Yun, Jihye; Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA. [Wu, Julia J.; Finkel, Toren] NHLBI, Bethesda, MD USA. [Parkhitko, Andrey A.] Russian State Med Univ, Moscow 117437, Russia. [Locasale, Jason W.] Cornell Univ, Div Nutr Sci, New York, NY 10021 USA. RP Priolo, C (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, 1 Blackfan Circle, Boston, MA 02115 USA. EM ehenske@partners.org OI Locasale, Jason/0000-0002-7766-3502 FU LAM Foundation; Adler Foundation; Tuberous Sclerosis Alliance; National Institute of Diabetes and Digestive and Kidney Diseases; NIH [5P01CA120964-04]; NIH DF/HCC; Cancer Center [P30CA006516-46]; National Heart, Lung, and Blood Institute; National Cancer Institute FX This work was supported by the LAM Foundation, the Adler Foundation, the Tuberous Sclerosis Alliance, the National Institute of Diabetes and Digestive and Kidney Diseases (to E.P. Henske); grants NIH 5P01CA120964-04 and NIH DF/HCC, Cancer Center Support Grant P30CA006516-46 (to J.M. Asara); the National Heart, Lung, and Blood Institute (to J.J. Yu); and the National Cancer Institute (to D.J. Kwiatkowski). NR 22 TC 11 Z9 11 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD JAN PY 2014 VL 12 IS 1 BP 48 EP 57 DI 10.1158/1541-7786.MCR-13-0258-T PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 292RL UT WOS:000329919800006 PM 24296756 ER PT J AU Postnikov, YV Furusawa, T Haines, DC Factor, VM Bustin, M AF Postnikov, Yuri V. Furusawa, Takashi Haines, Diana C. Factor, Valentina M. Bustin, Michael TI Loss of the Nucleosome-Binding Protein HMGN1 Affects the Rate of N-Nitrosodiethylamine-Induced Hepatocarcinogenesis in Mice SO MOLECULAR CANCER RESEARCH LA English DT Article ID FATTY LIVER-DISEASE; HEPATOCELLULAR-CARCINOMA; HEPATIC CARCINOGENESIS; DNA-REPAIR; CHROMATIN; CANCER; PHOSPHORYLATION; INFLAMMATION; EPIGENOMICS; ACTIVATION AB We report that HMGN1, a nucleosome-binding protein that affects chromatin structure and function, affects the growth of N-nitrosodiethylamine (DEN)-induced liver tumors. Following a single DENinjection at 2 weeks of age, Hmgn1(tm1/tm1) mice, lacking the nucleosome-binding domain of HMGN1, had earlier signs of liver tumorigenesis than their Hmgn1(+/+) littermates. Detailed gene expression profiling revealed significant differences between DEN-injected and control saline-injected mice, but only minor differences between the injected Hmgn1(tm1/tm1) mice and their Hmgn1(+/+) littermates. Pathway analysis revealed that the most significant process affected by loss of HMGN1 involves the lipid/sterol metabolic pathway. Our study indicates that in mice, loss of HMGN1 leads to transcription changes that accelerate the progression of DEN-induced hepatocarcinogenesis, without affecting the type of tumors or the final total tumor burden of these mice. C1 [Postnikov, Yuri V.; Furusawa, Takashi; Bustin, Michael] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Factor, Valentina M.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Haines, Diana C.] NCI, Sci Applicat Int Corp, NIH, Bethesda, MD 20892 USA. RP Postnikov, YV (reprint author), NIH, 37 Convent Dr 3122, Bethesda, MD 20892 USA. EM postniky@mail.nih.gov RI Bustin, Michael/G-6155-2015 FU Center for Cancer Research; Intramural Research Program at the NIH, National Cancer Institute; National Cancer Institute, NIH [HHSN261200800001E] FX The research was supported by the Center for Cancer Research, The Intramural Research Program at the NIH, National Cancer Institute, and with funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. NR 31 TC 3 Z9 3 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD JAN PY 2014 VL 12 IS 1 BP 82 EP 90 DI 10.1158/1541-7786.MCR-13-0392 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 292RL UT WOS:000329919800009 PM 24296759 ER PT S AU Thurin, M Marincola, FM AF Thurin, Magdalena Marincola, Francesco M. BE Thurin, M Marincola, FM TI Molecular Diagnostics for Melanoma Methods and Protocols Preface SO MOLECULAR DIAGNOSTICS FOR MELANOMA: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Editorial Material; Book Chapter AB A new taxonomy of cancers defined by molecular signatures with prognostic and therapeutic implications is emerging. Pathological assessment of melanoma that is the current standard method to determine diagnosis is improving due to additional criteria evolving from understanding of biology of melanoma. Genomics, epigenomics, and proteomics approaches have already led to molecular reclassification of melanoma in the context with pathological findings. Moreover, discovery of genetic alterations that drive melanoma progression provide the basis for the development of targeted therapies for patients with metastatic disease. Following these discoveries, the U.S. Food and Drug Administration (FDA) approved in 2011 and 2013 small molecular compounds vemurafenib and dabrafenib, respectively, that provide novel treatment options for melanoma patients. Vemurafenib and dabrafenib target mutated V600 codon of BRAF signaling molecule that is a key effector of RAS/RAF/MEK/ERK pathway. Mutations in this gene occur in over half of melanoma tumors and BRAF V600E mutations are the most common. Additional agent targeting downstream MAPK kinases including MEK1/2 inhibitor, trametinib was also approved by the FDA in 2013. Concomitantly with these drugs, companion diagnostic tests for detection of BRAF V600 mutations were also approved. These tests can identify specific subpopulations of melanoma patients with BRAF V600 codon mutations who most likely will benefit from the therapy. These examples are a prototype of a broad category of personalized treatment that uses a companion test to select patients for specifi c treatment. Recent, promising approaches to improve responses in melanoma by blocking negative regulators of T cell activity, i.e., cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) receptors were demonstrated and anti-CTLA drug ipilimumab was approved by the FDA in 2011. While there are no approved diagnostics for immunotherapy, promising markers associated with response to ipilimumab and anti-PD1 therapy were identified. Given that the majority of patients do not respond to these drugs and drugs are highly toxic, predictive markers could potentially improve therapeutic ratio of these drugs. The primary purpose of this volume is to provide updated information on well-characterized diagnostic and prognostic assays and assays predicting response to treatment for routine testing. The focus is also on a few emerging biomarkers categories with potential clinical validity rather than on early discovery stage. Most of chapters provide detailed protocols for markers' detection and novel technologies with potential for clinical application. Several review chapters provide an overview of the current status in diagnosis and therapy of melanoma and discuss the need to incorporate biomarkers to impact patient care. Important issues related to marker development and validation such as statistical approaches and specimen requirements are also discussed. C1 [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. [Marincola, Francesco M.] Qatar Fdn, Sidra Med & Res Ctr, Doha, Qatar. RP Thurin, M (reprint author), NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-726-6; 978-1-62703-727-3 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1102 BP V EP XIV D2 10.1007/978-1-62703-727-3 PG 10 WC Oncology SC Oncology GA BJM68 UT WOS:000329172000001 ER PT S AU Lau, C Killian, KJ Samuels, Y Rudloff, U AF Lau, Christopher Killian, Keith J. Samuels, Yardena Rudloff, Udo BE Thurin, M Marincola, FM TI ERBB4 Mutation Analysis: Emerging Molecular Target for Melanoma Treatment SO MOLECULAR DIAGNOSTICS FOR MELANOMA: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Metastatic melanoma; Genomic landscape; Somatic mutations; DNA isolation; Sanger sequencing; ERBB4 gene; Marker predictive for treatment; Mutation validation; Treatment target ID EPIDERMAL-GROWTH-FACTOR; IMPROVED SURVIVAL; CRYSTAL-STRUCTURE; FAMILY REVEALS; CANCER; GENOME; METALLOPROTEINASE; INHIBITION; CELLS; TRIAL AB Recent sequencing efforts in melanoma have elucidated many previously unknown molecular pathways and biological mechanisms involved in melanoma development and progression and have yielded a number of promising targets for molecular therapy. As sequencing technologies have become more sophisticated and have revealed an ever-increasing complexity of the genetic landscape of melanoma, it has become clear that sequencing methods applied to clinical specimens have to reliably capture not only recurrent "hotspot" mutations like BRAFV600 and NRASQ61 or "mini-hotspot" mutations like exon 11 and 13 c-KIT but also heterogeneous somatic mutations dispersed across multiple functionally conserved regions of genes or entire genes. One such example in melanoma is the ERBB4 receptor, or HER4, a member of the Erb receptor family, which has recently been shown to be a major oncogenic "driver" in melanoma. Mutated ERBB4 signaling activates both aberrant ERBB4 and PI3K-AKT signal transduction, mediates sensitivity to small-molecule inhibition with the dual-tyrosine kinase inhibitor lapatinib, and has recently also been implied in oncogenic glutamatergic signaling in melanoma. Mutations involving the ERBB4 gene act as "gain-of-function" mutations and predominantly involve the extracellular domains of the receptor. Additional sequencing efforts have recently identified recurrent mutations ("mini-hotspots") or mutation clusters which affect the regulation of, e. g., ligand binding, arrangement of extracellular domain alignment, or intramolecular tether formation. In this chapter, we describe the methods used to determine the mutation status of all exons of the ERBB4 gene in clinical specimens obtained from patients afflicted by metastatic melanoma. Upon slight modifications, this protocol can also be used for mutational analysis of other oncogenes affected by "non-hotspot" mutations dispersed across multiple exons. This sequencing technique has successfully been applied within a clinical trial selecting patients with ERBB4-mutant melanoma for lapatinib treatment. With the increasing emergence of low-frequency oncogenes affected by heterogeneous activating mutations located in different exons and regions this method will provide a mean to translate the promise of recently obtained genetic knowledge into clinical genotype-directed targeted therapy trials. C1 [Lau, Christopher; Killian, Keith J.] NCI, Clin Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Rudloff, Udo] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lau, C (reprint author), NCI, Clin Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. FU European Research Council [335377] NR 37 TC 3 Z9 3 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-726-6; 978-1-62703-727-3 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1102 BP 461 EP 480 DI 10.1007/978-1-62703-727-3_24 D2 10.1007/978-1-62703-727-3 PG 20 WC Oncology SC Oncology GA BJM68 UT WOS:000329172000025 PM 24258993 ER PT S AU Quackenbush, JF Cassidy, PB Pfeffer, LM Boucher, KM Hawkes, JE Pfeffer, SR Kopelovich, L Leachman, SA AF Quackenbush, John F. Cassidy, Pamela B. Pfeffer, Lawrence M. Boucher, Kenneth M. Hawkes, Jason E. Pfeffer, Susan R. Kopelovich, Levy Leachman, Sancy A. BE Thurin, M Marincola, FM TI Isolation of Circulating MicroRNAs from Microvesicles Found in Human Plasma SO MOLECULAR DIAGNOSTICS FOR MELANOMA: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE MicroRNA; Microvesicles; Plasma; Serum; ExoQuick ID FAMILIAL MELANOMA; GENE-EXPRESSION; RNA AB Intact miRNAs can be isolated from the circulation in significant quantities despite the presence of extremely high levels of RNase activity. The remarkable stability of circulating miRNAs makes them excellent candidates for biomarkers in diagnostic applications as well as therapeutic targets in a variety of disease states including melanoma. Circulating RNA molecules are resistant to degradation by RNases because they are encapsulated in membrane-bound microvesicles. We describe a convenient method for the use of ExoQuick, a proprietary resin developed by Systems Biosciences (Mountain View, CA), whereby microvesicles can be purified under gentle conditions using readily available laboratory equipment. This protocol allows for isolation all microvesicles, regardless of their origin, and provides a convenient method for identifying potential cancer-specific biomarkers from biological fluids including serum and plasma. C1 [Quackenbush, John F.; Boucher, Kenneth M.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Cassidy, Pamela B.; Leachman, Sancy A.] Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97201 USA. [Pfeffer, Lawrence M.; Pfeffer, Susan R.] Univ Tennessee Hlth Sci Ctr, Dept Pathol, Memphis, TN USA. [Hawkes, Jason E.] Univ Utah, Dept Dermatol, Salt Lake City, UT USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Rockville, MD USA. RP Quackenbush, JF (reprint author), Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. OI Boucher, Kenneth/0000-0003-2833-0127; Hawkes, Jason E./0000-0001-5870-181X FU NCI NIH HHS [5P30CA042014-23]; PHS HHS [N201143] NR 23 TC 17 Z9 17 U1 1 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-726-6; 978-1-62703-727-3 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1102 BP 641 EP 653 DI 10.1007/978-1-62703-727-3_34 D2 10.1007/978-1-62703-727-3 PG 13 WC Oncology SC Oncology GA BJM68 UT WOS:000329172000035 PM 24259003 ER PT J AU Taylor, TN Alter, SP Wang, MZ Goldstein, DS Miller, GW AF Taylor, Tonya N. Alter, Shawn P. Wang, Minzheng Goldstein, David S. Miller, Gary W. TI Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus SO NEUROPHARMACOLOGY LA English DT Article DE VMAT2; Norepinephrine; Parkinson's disease; Locus ceruleus ID PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; POLYCHLORINATED-BIPHENYLS; IMMUNOCHEMICAL ANALYSIS; CYTOSOLIC DOPAMINE; STRIATAL DOPAMINE; SUBSTANTIA-NIGRA; KNOCKOUT MICE; MOUSE MODEL; CELL LOSS AB Parkinson's disease (PD) is the most common neurodegenerative motor disease. Pathologically, PD is characterized by Lewy body deposition and subsequent death of dopamine neurons in the substantia nigra pars compacta. PD also consistently features degeneration of the locus ceruleus, the main source of norepinephrine in the central nervous system. We have previously reported a mouse model of dopaminergic neurodegeneration based on reduced expression of the vesicular monoamine transporter (VMAT2 LO). To determine if reduced vesicular storage can also cause noradrenergic degeneration, we examined indices of damage to the catecholaminergic systems in brain and cardiac tissue of VMAT2 LO mice. At two months of age, neurochemical analyses revealed substantial reductions in striatal dopamine (94%), cortical dopamine (57%) and norepinephrine (54%), as well as cardiac norepinephrine (97%). These losses were accompanied by increased conversion of dopamine and norepinephrine to their deaminated metabolites. VMAT2 LO mice exhibited loss of noradrenergic innervation in the cortex, as determined by norepinephrine transporter immunoreactivity and H-3-nisoxetine binding. Using unbiased stereological techniques, we observed progressive degeneration in the locus ceruleus that preceded degeneration of the substantia nigra pars compacta. In contrast, the ventral tegmental area, which is spared in human PD, remained unaffected. The coordinate loss of dopamine and norepinephrine neurons in VMAT2 LO mice parallels the pattern of neurodegeneration that occurs in human PD, and demonstrates that insufficient catecholamine storage can cause spontaneous degeneration in susceptible neurons, underscoring cytosolic catecholamine catabolism as a determinant of neuronal susceptibility in PD. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Taylor, Tonya N.; Alter, Shawn P.; Wang, Minzheng; Miller, Gary W.] Ctr Neurodegenerat Dis, Atlanta, GA USA. [Taylor, Tonya N.; Alter, Shawn P.; Wang, Minzheng; Miller, Gary W.] Emory Univ, Dept Environm Hlth, Atlanta, GA 30322 USA. [Goldstein, David S.] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Miller, GW (reprint author), Emory Univ, Dept Environm Hlth, 1518 Clifton Rd,Claudia Nance Rollins 8007, Atlanta, GA 30322 USA. EM gary.miller@emory.edu OI Miller, Gary/0000-0001-8984-1284 FU [F31 ES017247]; [T32 ES012870]; [T32 GM008602]; [P50 NS071669]; [P01 ES01673] FX This work was supported by funding from F31 ES017247 (Taylor), T32 ES012870, T32 GM008602 (Alter), P50 NS071669 and P01 ES01673 (Miller). The authors are grateful for the technical assistance provided by Patricia Sullivan in acquisition of HPLC data. We would like to thank Dr. Alison Bernstein for generating and characterizing the VMAT2 antibody. NR 61 TC 18 Z9 18 U1 0 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2014 VL 76 SI SI BP 97 EP 105 DI 10.1016/j.neuropharm.2013.08.033 PN A PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 294YI UT WOS:000330083400010 PM 24025942 ER PT J AU Hall, FS Itokawa, K Schmitt, A Moessner, R Sora, I Lesch, KP Uhl, GR AF Hall, F. S. Itokawa, K. Schmitt, A. Moessner, R. Sora, I. Lesch, K. P. Uhl, G. R. TI Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems SO NEUROPHARMACOLOGY LA English DT Article DE Transgenic mice; Gene knockout; Dopamine; Aging; Amphetamine; Cocaine ID AGE-RELATED DECLINE; PARKINSONISM-INDUCING NEUROTOXIN; POSITRON-EMISSION-TOMOGRAPHY; VESICLE AMINE TRANSPORTER; LONG-EVANS RATS; STRIATAL DOPAMINE; SUBSTANTIA-NIGRA; IN-VIVO; OXIDATIVE STRESS; COCAINE REWARD AB Dopamine (DA) is accumulated and compartmentalized by the dopamine transporter (DAT; SLOA6) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2). These transporters work at the plasma and vesicular membranes of dopaminergic neurons, respectively, and thus regulate levels of DA in neuronal compartments that include the extravesicular cytoplasmic compartment. DA in this compartment has been hypothesized to contribute to oxidative damage that can reduce the function of dopaminergic neurons in aging brains and may contribute to reductions in dopaminergic neurochemical markers, locomotor behavior and responses to dopaminergic drugs that are found in aged animals. The studies reported here examined aged mice with heterozygous deletions of VMAT2 or of DAT, which each reduce transporter expression to about 50% of levels found in wild-type (WT) mice. Aged mice displayed reduced locomotor responses under a variety of circumstances, including in response to locomotor stimulants, as well as changes in monoamine levels and metabolites in a regionally dependent manner. Several effects of aging were more pronounced in heterozygous VMAT2 knockout (KO) mice, including aging induced reductions in locomotion and reduced locomotor responses to cocaine. By contrast, some effects of aging were reduced or not observed in heterozygous DAT KO mice. These findings support the idea that altered DAT and VMAT2 expression affect age-related changes in dopaminergic function. These effects are most likely mediated by alterations in DA compartmentalization, and might be hypothesized to be exacerbated by other factors that affect the metabolism of cytosolic DA. (C) Published by Elsevier Ltd. C1 [Hall, F. S.; Uhl, G. R.] NIDA, NIH, DHHS, Mol Neurobiol Branch,Intramural Res Program, Baltimore, MD 21224 USA. [Itokawa, K.] Saitama Med Sch, Dept Neurol, Saitama, Japan. [Schmitt, A.; Moessner, R.; Lesch, K. P.] Univ Wurzburg, Dept Psychiat, Wurzburg, Germany. [Sora, I.] Tohoku Univ, Grad Sch Med, Dept Neurosci, Div Psychobiol, Sendai, Miyagi 980, Japan. RP Hall, FS (reprint author), NIDA, IRP, Mol Neurobiol Branch, 333 Cassell Dr, Baltimore, MD 21224 USA. EM shall@intra.nida.nih.gov RI Lesch, Klaus-Peter/J-4906-2013; Hall, Frank/C-3036-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X; Hall, Frank/0000-0002-0822-4063 FU Intramural Research Program of the National Institute on Drug Abuse (NIH/DHHS); Deutsche Forschungsgemeinschaft [SFB 581, KFO 125/1-2]; European Commission [NEWMOOD LSHM-CT-2003-503474] FX The authors are grateful for the expert technical assistance of T. Heinemann and R. Burger, and the financial support of the Intramural Research Program of the National Institute on Drug Abuse (NIH/DHHS), the Deutsche Forschungsgemeinschaft (SFB 581, KFO 125/1-2) and the European Commission (NEWMOOD LSHM-CT-2003-503474). The authors declare that there exist no conflicts of interest with regard to the publication of this work. NR 115 TC 7 Z9 7 U1 2 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2014 VL 76 SI SI BP 146 EP 155 DI 10.1016/j.neuropharm.2013.07.031 PN A PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 294YI UT WOS:000330083400015 PM 23978383 ER PT J AU Shurtleff, D Sasek, C Kautz, M AF Shurtleff, David Sasek, Cathrine Kautz, Mary TI Sponsor's foreword: NIDA at forty Foreword SO NEUROPHARMACOLOGY LA English DT Editorial Material ID DRUG-ADDICTION; NEUROBIOLOGICAL MECHANISMS; SMOKING-CESSATION; COCAINE ADDICTION; REWARD; VULNERABILITY; RECEPTOR; FUTURE; ABUSE; MODEL C1 [Shurtleff, David; Sasek, Cathrine; Kautz, Mary] NIDA, NIH, Bethesda, MD 20892 USA. RP Sasek, C (reprint author), NIDA, Off Sci Policy & Commun, 6001 Execut Blvd,Rm 5230,MSC 9991, Bethesda, MD 20892 USA. EM csasek@nih.gov NR 37 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 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2014 VL 76 SI SI BP 195 EP 197 DI 10.1016/j.neuropharm.2013.08.020 PN B PG 3 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 294YK UT WOS:000330083600001 PM 23994442 ER PT J AU Volkow, ND Baler, RD AF Volkow, N. D. Baler, R. D. TI Addiction science: Uncovering neurobiological complexity SO NEUROPHARMACOLOGY LA English DT Review DE Addiction; SUD; Dopamine; Nucleus accumbens; Brain imaging; Reward ID VENTRAL TEGMENTAL AREA; CATECHOL-O-METHYLTRANSFERASE; COCAINE-SEEKING BEHAVIOR; GENOME-WIDE ASSOCIATION; NICOTINE REPLACEMENT THERAPY; SUCCESSFUL SMOKING-CESSATION; ALCOHOL-DEPENDENT PATIENTS; MEDIAL PREFRONTAL CORTEX; INDUCED DOPAMINE RELEASE; PITUITARY-ADRENAL AXIS AB Until very recently addiction-research was limited by existing tools and strategies that were inadequate for studying the inherent complexity at each of the different phenomenological levels. However, powerful new tools (e.g., optogenetics and designer drug receptors) and high throughput protocols are starting to give researchers the potential to systematically interrogate "all" genes, epigenetic marks, and neuronal circuits. These advances, combined with imaging technologies (both for preclinical and clinical studies) and a paradigm shift toward open access have spurred an unlimited growth of datasets transforming the way we investigate the neurobiology of substance use disorders (SUD) and the factors that modulate risk and resilience. Published by Elsevier Ltd. C1 [Volkow, N. D.; Baler, R. D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, NIH, 6001 Execut Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvokow1@nida.nih.gov FU Intramural NIH HHS [ZIA AA000550-09] NR 245 TC 53 Z9 57 U1 5 U2 65 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2014 VL 76 SI SI BP 235 EP 249 DI 10.1016/j.neuropharm.2013.05.007 PN B PG 15 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 294YK UT WOS:000330083600006 PM 23688927 ER PT J AU Ikemoto, S Bonci, A AF Ikemoto, Satoshi Bonci, Antonello TI Neurocircuitry of drug reward SO NEUROPHARMACOLOGY LA English DT Review DE Drug reward; Motivation; Emotion; Dopamine; Ventral tegmental area; Ventral striatum; Supramammillary nucleus; Median raphe nucleus ID VENTRAL TEGMENTAL AREA; MEDIAN RAPHE NUCLEUS; CONDITIONED PLACE PREFERENCE; MESOLIMBIC DOPAMINE SYSTEM; FREELY MOVING RATS; C-FOS EXPRESSION; OLFACTORY TUBERCLE; SUPRAMAMMILLARY NUCLEUS; LOCOMOTOR-ACTIVITY; SELF-STIMULATION AB In recent years, neuroscientists have produced profound conceptual and mechanistic advances on the neurocircuitry of reward and substance use disorders. Here, we will provide a brief review of intracranial drug self-administration and optogenetic self-stimulation studies that identified brain regions and neurotransmitter systems involved in drug- and reward-related behaviors. Also discussed is a theoretical framework that helps to understand the functional properties of the circuitry involved in these behaviors. The circuitry appears to be homeostatically regulated and mediate anticipatory processes that regulate behavioral interaction with the environment in response to salient stimuli. That is, abused drugs or, at least, some may act on basic motivation and mood processes, regulating behavior-environment interaction. Optogenetics and related technologies have begun to uncover detailed circuit mechanisms linking key brain regions in which abused drugs act for rewarding effects. Published by Elsevier Ltd. C1 [Ikemoto, Satoshi; Bonci, Antonello] NIDA, Intramural Res Program, NIH, US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Bonci, Antonello] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94110 USA. [Bonci, Antonello] Johns Hopkins Sch Med, Solomon H Snyder Neurosci Inst, Baltimore, MD 21205 USA. RP Ikemoto, S (reprint author), NIDA, Intramural Res Program, NIH, US Dept Hlth & Human Serv, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM satoshi.ikemoto@nih.gov; antonello.bonci@nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU intramural Research Program of National Institute of Drug Abuse, National Institutes of Health FX The present work is supported by the intramural Research Program of National Institute of Drug Abuse, National Institutes of Health. NR 141 TC 34 Z9 35 U1 3 U2 33 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2014 VL 76 SI SI BP 329 EP 341 DI 10.1016/j.neuropharm.2013.04.031 PN B PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 294YK UT WOS:000330083600014 PM 23664810 ER PT J AU Calu, DJ Chen, YW Kawa, AB Nair, SG Shaham, Y AF Calu, Donna J. Chen, Yu-Wei Kawa, Alex B. Nair, Sunila G. Shaham, Yavin TI The use of the reinstatement model to study relapse to palatable food seeking during dieting SO NEUROPHARMACOLOGY LA English DT Review DE Food; Relapse; Stress; Priming; cue; Reinstatement; Dieting; Self-administration ID MELANIN-CONCENTRATING HORMONE; STRESS-INDUCED REINSTATEMENT; CORTICOTROPIN-RELEASING-FACTOR; COCAINE-INDUCED REINSTATEMENT; ANXIOGENIC DRUG YOHIMBINE; CUE-INDUCED REINSTATEMENT; CONDITIONED PLACE PREFERENCE; ANTAGONIST SNAP 94847; RECEPTOR ANTAGONIST; PREFRONTAL CORTEX AB Excessive consumption of unhealthy foods is a major public health problem. While many people attempt to control their food intake through dieting, many relapse to unhealthy eating habits within a few months. We have begun to study this clinical condition in rats by adapting the reinstatement model, which has been used extensively to study relapse to drug seeking. In our adaptation of the relapse model, reinstatement of palatable food seeking by exposure to food-pellet priming, food-associated cues, or stress is assessed in food-restricted (to mimic dieting) rats after operant food-pellet self-administration training and subsequent extinction of the food-reinforced responding. In this review, we first outline the clinical problem and discuss a recent study in which we assessed the predictive validity of the reinstatement model for studying relapse to food seeking during dieting by using the anorexigenic drug fenfluramine. Next, we summarize results from our initial studies on the role of several stress- and feeding-related peptides (corticotropin-releasing factor, hypocretin, melanin-concentrating hormone, peptide YY3-36) in reinstatement of palatable food seeking. We then present results from our studies on the role of dopamine and medial prefrontal cortex in stress-induced reinstatement of food seeking. We conclude by discussing potential clinical implications. We offer two main conclusions: (1) the food reinstatement model is a simple, reliable, and valid model to study mechanisms of relapse to palatable food seeking during dieting, and to identify medications to prevent this relapse; (2) mechanisms of relapse to food seeking are often dissociable from mechanisms of ongoing food intake. Published by Elsevier Ltd. C1 [Calu, Donna J.; Chen, Yu-Wei; Kawa, Alex B.; Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Nair, Sunila G.] Univ Washington, Harborview Med Ctr, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. RP Calu, DJ (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM yshaham@intra.nida.nih.gov; yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; OI Calu, Donna/0000-0003-2377-9494 FU National Institute on Drug Abuse, Intramural Research Program FX Preparation of this review was supported by the National Institute on Drug Abuse, Intramural Research Program. The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript. NR 152 TC 22 Z9 22 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2014 VL 76 SI SI BP 395 EP 406 DI 10.1016/j.neuropharm.2013.04.030 PN B PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 294YK UT WOS:000330083600020 PM 23660229 ER PT J AU Lucantonio, F Caprioli, D Schoenbaum, G AF Lucantonio, Federica Caprioli, Daniele Schoenbaum, Geoffrey TI Transition from 'model-based' to 'model-free' behavioral control in addiction: Involvement of the orbitofrontal cortex and dorsolateral striatum SO NEUROPHARMACOLOGY LA English DT Review DE Addiction; Orbitofrontal cortex; Striatum ID VENTROMEDIAL PREFRONTAL CORTEX; TEMPORAL DIFFERENCE MODELS; BASOLATERAL AMYGDALA; DECISION-MAKING; DORSAL STRIATUM; AMPHETAMINE EXPOSURE; DRUG-ADDICTION; HUMAN BRAIN; REPEATED PRETREATMENT; COCAINE EXPOSURE AB Cocaine addiction is a complex and multidimensional process involving a number of behavioral and neural forms of plasticity. The behavioral transition from voluntary drug use to compulsive drug taking may be explained at the neural level by drug-induced changes in function or interaction between a flexible planning system, associated with prefrontal cortical regions, and a rigid habit system, associated with the striatum. The dichotomy between these two systems is operationalized in computational theory by positing model-based and model-free learning mechanisms, the former relying on an "internal model" of the environment and the latter on pre-computed or cached values to control behavior. In this review, we will suggest that model-free and model-based learning mechanisms appear to be differentially affected, at least in the case of psychostimulants such as cocaine, with the former being enhanced while the latter are disrupted. As a result, the behavior of long-term drug users becomes less flexible and responsive to the desirability of expected outcomes and more habitual, based on the long history of reinforcement. To support our specific proposal, we will review recent neural and behavioral evidence on the effect of psychostimulant exposure on orbitofrontal and dorsolateral striatum structure and function. Published by Elsevier Ltd. C1 [Lucantonio, Federica] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Lucantonio, Federica; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Caprioli, Daniele] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Caprioli, Daniele] Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. RP Schoenbaum, G (reprint author), NIDA, Intramural Res Program, Baltimore, MD 21224 USA. EM geoffrey.schoenbaum@nih.gov FU NIDA FX The work of writing it was supported by funding from the intramural programs of NIDA. Correspondence should be addressed to G.S. (schoenbaumgm@nida.nih.gov). NR 94 TC 18 Z9 19 U1 2 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2014 VL 76 SI SI BP 407 EP 415 DI 10.1016/j.neuropharm.2013.05.033 PN B PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 294YK UT WOS:000330083600021 PM 23752095 ER PT S AU Wang, YJ Chan, CC AF Wang, Yujuan Chan, Chi-Chao BE Singh, AD TI Ocular and Adnexal T-Cell Lymphoma SO OCULAR AND ADNEXAL LYMPHOMA SE Essentials in Ophthalmology LA English DT Article; Book Chapter ID EPSTEIN-BARR-VIRUS; PRIMARY INTRAOCULAR LYMPHOMA; PRIMARY VITREORETINAL LYMPHOMA; NERVOUS-SYSTEM LYMPHOMA; NON-HODGKINS-LYMPHOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; OF-THE-LITERATURE; PERIPHERAL T; CLINICOPATHOLOGICAL FEATURES; INTRAVITREAL METHOTREXATE C1 [Wang, Yujuan; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Yujuan] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM yujuan.wang@nih.gov; chanc@nei.nih.gov NR 117 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 1612-3212 BN 978-3-642-38498-1; 978-3-642-38499-8 J9 ESSENT OPHTHALMOL PY 2014 BP 103 EP 115 DI 10.1007/978-3-642-38499-8_10 D2 10.1007/978-3-642-38499-8 PG 13 WC Oncology; Ophthalmology SC Oncology; Ophthalmology GA BJM43 UT WOS:000329099500011 ER PT J AU LoBiondo-Wood, G Brown, CG Knobf, MT Lyon, D Mallory, G Mitchell, SA Von Ah, D Wesmiller, S Fellman, B AF LoBiondo-Wood, Geri Brown, Carlton G. Knobf, M. Tish Lyon, Debra Mallory, Gail Mitchell, Sandra A. Von Ah, Diane Wesmiller, Susan Fellman, Bryan TI Priorities for Oncology Nursing Research: The 2013 National Survey SO ONCOLOGY NURSING FORUM LA English DT Article DE evidence-based practice; clinical practice ID BREAST-CANCER SURVIVORS; COGNITIVE IMPAIRMENT; CLINICAL ONCOLOGY; AMERICAN SOCIETY; CARE; CHEMOTHERAPY; PREVENTION; STATEMENT; CHOICES; IMPACT AB Purpose/Objectives: To advance the goals of evidence-based care and prioritize the knowledge generation that addresses contemporary challenges in oncology nursing. Results are used to inform the development of the Oncology Nursing Society (ONS) Research Agenda and by the ONS Foundation to develop strategic research initiatives. Design: Descriptive, cross-sectional survey. Setting: Web-based survey. Sample: 8,554 ONS members from all levels of education. All doctorally prepared members were invited to participate. A random stratified sample was obtained from the remainder of the membership. Methods: The ONS Research Priorities Survey project team created the survey and analyzed and interpreted the results. Members received an email invitation and follow-up reminders for survey completion. Main Research Variables: Oncology nursing research and evidence-based practice topic questions. Findings: The response rate was 11%, which is comparable to previous surveys. Topics ranked included descriptive research on patient adherence; intervention studies to optimize adherence, achieve concordance with cancer screening guidelines in minority populations, manage neurologic and cardiovascular late effects, and manage symptoms and symptom clusters; and studies to identify optimal delivery models for survivorship care. These findings have direct implications for translating existing evidence into practice and underscore the need for intervention research focused on improving patient-centered outcomes. Conclusions: Results provide a broad assessment of member views regarding oncology research priorities. Given the response rate, additional strategies to encourage member participation will be considered. Implications for Nursing: The results, together with the updates of the ONS Research Agenda, can guide ONS and ONS Foundation research and evidence-based practice initiatives. C1 [LoBiondo-Wood, Geri] Univ Texas Hlth Sci Ctr Houston, Sch Nursing, PhD Nursing Program, Houston, TX 77030 USA. [Brown, Carlton G.] NYU, New York, NY USA. [Knobf, M. Tish] Yale Univ, Sch Nursing, Acute Care & Hlth Syst Div, New Haven, CT 06536 USA. [Lyon, Debra] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Mallory, Gail] Oncol Nursing Soc, Pittsburgh, PA USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Von Ah, Diane] Indiana Univ, Sch Nursing, Dept Sci Nursing Care, Indianapolis, IN 46204 USA. [Wesmiller, Susan] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15260 USA. [Fellman, Bryan] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. RP LoBiondo-Wood, G (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Nursing, PhD Nursing Program, Houston, TX 77030 USA. EM geri.l.wood@uth.tmc.edu FU NCI NIH HHS [P30 CA016672]; NINR NIH HHS [T32 NR011972] NR 44 TC 9 Z9 9 U1 1 U2 7 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD JAN PY 2014 VL 41 IS 1 BP 67 EP 76 DI 10.1188/14.ONF.67-76 PG 10 WC Oncology; Nursing SC Oncology; Nursing GA 292DK UT WOS:000329882200013 PM 24368240 ER PT S AU Nielsen, PE Appella, DH AF Nielsen, Peter E. Appella, Daniel H. BE Nielsen, PE Appella, DH TI Peptide Nucleic Acids Methods and Protocols Second Edition Preface SO PEPTIDE NUCLEIC ACIDS: METHODS AND PROTOCOLS, 2ND EDITION SE Methods in Molecular Biology LA English DT Editorial Material; Book Chapter C1 [Nielsen, Peter E.] Univ Copenhagen, Fac Hlth Sci, Dept Cellular & Mol Med, Copenhagen, Denmark. [Appella, Daniel H.] NIDDK, Sect Synthet Bioact Mol, Bioorgan Chem Lab, NIH,DHHS, Bethesda, MD 20892 USA. RP Nielsen, PE (reprint author), Univ Copenhagen, Fac Hlth Sci, Dept Cellular & Mol Med, Copenhagen, Denmark. NR 0 TC 0 Z9 0 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-552-1; 978-1-62703-553-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1050 BP V EP V D2 10.1007/978-1-62703-553-8 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BJM59 UT WOS:000329161900001 ER PT S AU Englund, EA Zhang, N Appella, DH AF Englund, Ethan A. Zhang, Ning Appella, Daniel H. BE Nielsen, PE Appella, DH TI Cyclopentane Peptide Nucleic Acids SO PEPTIDE NUCLEIC ACIDS: METHODS AND PROTOCOLS, 2ND EDITION SE Methods in Molecular Biology LA English DT Article; Book Chapter DE PNA; Cyclopentane; Nucleic acid ID BACKBONE MODIFICATION; DNA DUPLEXES AB Incorporating a cyclopentane ring into the two-carbon unit of a peptide nucleic acid backbone increases its binding affinity to complementary nucleic acid sequences. This approach is a general method to improve binding and can be applied at either purine or pyrimidine bases. C1 [Englund, Ethan A.; Zhang, Ning; Appella, Daniel H.] NIDDK, Sect Synthet Bioact Mol, Bioorgan Chem Lab, NIH,DHHS, Bethesda, MD 20892 USA. RP Englund, EA (reprint author), NIDDK, Sect Synthet Bioact Mol, Bioorgan Chem Lab, NIH,DHHS, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-552-1; 978-1-62703-553-8 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1050 BP 13 EP 18 DI 10.1007/978-1-62703-553-8_2 D2 10.1007/978-1-62703-553-8 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BJM59 UT WOS:000329161900003 PM 24297347 ER PT J AU Cotugna, N Fanelli-Kuczmarski, M Clymer, J Hotchkiss, L Zonderman, AB Evans, MK AF Cotugna, Nancy Fanelli-Kuczmarski, Marie Clymer, Julie Hotchkiss, Lawrence Zonderman, Alan B. Evans, Michele K. TI Sodium intake of special populations in the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study (vol 57, pg 334, 2013) SO PREVENTIVE MEDICINE LA English DT Correction C1 [Cotugna, Nancy; Fanelli-Kuczmarski, Marie; Hotchkiss, Lawrence] Univ Delaware, Dept Behav Hlth &Nutr, Newark, DE 19701 USA. [Clymer, Julie] Wilmington VA Med Hosp, Wilmington, DE USA. [Zonderman, Alan B.] NIA, Res Resources Branch, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. RP Cotugna, N (reprint author), Univ Delaware, Dept Behav Hlth &Nutr, 26 N Coll Ave, Newark, DE 19701 USA. EM ncotugna@udel.edu NR 1 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 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD JAN PY 2014 VL 58 BP 87 EP 87 DI 10.1016/j.ypmed.2013.10.016 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 295AL UT WOS:000330088900016 ER PT J AU Pichu, S Ribeiro, JMC Mather, TN Francischetti, IMB AF Pichu, Sivakamasundari Ribeiro, Jose M. C. Mather, Thomas N. Francischetti, Ivo M. B. TI Purification of a serine protease and evidence for a protein C activator from the saliva of the tick, Ixodes scapularis SO TOXICON LA English DT Article DE Serine protease; Saliva; Ixodes scapularis; Protease activated receptors (PAR); Activated protein C (APC) ID HAEMAPHYSALIS-LONGICORNIS; EXPRESSION PROFILE; GLAND; INFLAMMATION; INHIBITOR; TRYPSIN; MECHANISMS; DISEASES; SIALOME; CLONING AB The saliva of ticks is critical to their survival as parasites and hematophagous animals. In this study, we have purified an enzyme with trypsin-like activity from the saliva of the tick vector of Lyme Disease, Ixodes scapularis. This enzyme, named as IXOSP (I. scapularis salivary serine protease), is a 29.9 kDa molecule with N-terminus FPxMVxLRIKxR. A BLAST search identified IXOSP as a secreted serine protease (AAY66740) with a conserved catalytic triad His, Asp, and Set. In vitro studies demonstrated that IXOSP cleaves chromogenic substrates with arginine in the P-1 position, by a mechanism inhibited by PMSF or aprotinin. Gene expression studies revealed that IXOSP is expressed at different tick developmental stages, including eggs, and unfed or fed adult tick salivary glands, but not in nymphs or in the midgut While the physiological substrate for IXOSP remains to be identified, we demonstrated that I. scapularis saliva activate protein C (PC) resulting in the production of activated PC, a potent anticoagulant that also regulates a myriad of inflammatory responses through protease activated receptors. In contrast, the salivary glands of Anopheles gambiae, Anopheles stephensi, Anopheles albimanus, Aedes aegypti, Lutzomyia longipalpis, and Phlebotomus ariasi did not activate protein C. These discoveries are discussed in the context of blood coagulation, inflammation and vector-host interactions. Published by Elsevier Ltd. C1 [Pichu, Sivakamasundari; Mather, Thomas N.] Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. [Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Pichu, S (reprint author), Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. EM au_sudha@yahoo.com; ifrancischetti@niaid.nih.gov RI Ribeiro, Jose/J-7011-2015; OI Ribeiro, Jose/0000-0002-9107-0818 FU National Institute of Health [AI 37230, 1U19 AI 082642, P20 RR16457]; Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; URI Proteomics Core facility; [2006-34438-17306] FX This work was supported by National Institute of Health Grant AI 37230 (TNM) and 1U19 AI 082642 (TNM), a subcontract to USDA Special Grant 2006-34438-17306 (TNM), and by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Experiments were supported by the URI Proteomics Core facility, made available by the RI-BRIN and RI-INBRE (NIH award P20 RR16457). We are grateful to Nathan Miller for helpful technical discussions. We also thank NIAID intramural editor Brenda Rae Marshall for assistance. Because IMBF and JMCR are government employee and this is a government work, the work is in the public domain of the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. NR 39 TC 3 Z9 3 U1 2 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD JAN PY 2014 VL 77 BP 32 EP 39 DI 10.1015/j.toxicon.2013.10.025 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 293CK UT WOS:000329948800005 PM 24184517 ER PT J AU Love, PE Warzecha, C Li, LQ AF Love, Paul E. Warzecha, Claude Li, LiQi TI Ldb1 complexes: the new master regulators of erythroid gene transcription SO TRENDS IN GENETICS LA English DT Review DE erythropoiesis; Gata1; Tal1; Klf1; Ldb1 complexes; transcriptional regulation; ChIP-Seq ID KRUPPEL-LIKE FACTOR; BETA-GLOBIN LOCUS; HEMATOPOIETIC STEM-CELLS; GENOME-WIDE ANALYSIS; FACTOR EKLF GENE; FACTOR GATA-1; CHROMATIN OCCUPANCY; LEUKEMIA GENE; PROTEIN LMO2; MICE LACKING AB Elucidation of the genetic pathways that control red blood cell development has been a central goal of erythropoiesis research over the past decade. Notably, data from several recent studies have provided new insights into the regulation of erythroid gene transcription. Transcription profiling demonstrates that erythropoiesis is mainly controlled by a small group of lineage-restricted transcription factors [Gata binding protein 1 (Gata1), T cell acute lymphocytic leukemia 1 protein (Tal1), and Erythroid Kruppel-like factor (EKLF; henceforth referred to as Klf1)]. Binding-site mapping using ChIP-Seq indicates that most DNA-bound Gata1 and Tal1 proteins are contained within higher order complexes (Ldb1 complexes) that include the nuclear adapters Ldb1 and Lmo2. Ldb1 complexes regulate Klf1, and Ldb1 complex-binding sites frequently colocalize with Klf1 at erythroid genes and cis-regulatory elements, indicating strong functional synergy between Gata1, Tal1, and Klf1. Together with new data demonstrating that Ldb1 can mediate long-range promoter-enhancer interactions, these findings provide a foundation for the first comprehensive models of the global regulation of erythroid gene transcription. C1 [Love, Paul E.; Warzecha, Claude; Li, LiQi] NICHHD, NIH, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM lovep@mail.nih.gov FU Intramural Research Programs of Eunice Kennedy Shriver NICBD [1ZIAHD001803-19] FX This work was supported by the Intramural Research Programs of Eunice Kennedy Shriver NICBD [Project number1ZIAHD001803-19 (to P.E.L.)]. The authors thank Karl Pfeifer for critical review of the manuscript. NR 75 TC 29 Z9 29 U1 1 U2 15 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JAN PY 2014 VL 30 IS 1 BP 1 EP 9 DI 10.1016/j.tig.2013.10.001 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 293ZW UT WOS:000330013200001 PM 24290192 ER PT J AU Niciu, MJ Henter, ID Sanacora, G Zarate, CA AF Niciu, Mark J. Henter, Ioline D. Sanacora, Gerard Zarate, Carlos A., Jr. TI Glial abnormalities in substance use disorders and depression: Does shared glutamatergic dysfunction contribute to comorbidity? SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Review DE Glia; depression; glutamate; alcohol use disorders; drug use disorders ID D-ASPARTATE ANTAGONIST; FIBRILLARY ACIDIC PROTEIN; DORSOLATERAL PREFRONTAL CORTEX; NECROSIS-FACTOR-ALPHA; LATE-LIFE DEPRESSION; CONDITIONED PLACE PREFERENCE; ANTERIOR CINGULATE CORTEX; INDUCED SICKNESS BEHAVIOR; ABSTINENT COCAINE USERS; CLOCK GENE PER2 AB Objectives. Preclinical and clinical research in neuropsychiatric disorders, particularly mood and substance use disorders, have historically focused on neurons; however, glial cells - astrocytes, microglia, and oligodendrocytes - also play key roles in these disorders. Methods. Peer-reviewed PubMed/Medline articles published through December 2012 were identified using the following keyword combinations: glia, astrocytes, oligodendrocytes/glia, microglia, substance use, substance abuse, substance dependence, alcohol, opiate, opioid, cocaine, psychostimulants, stimulants, and glutamate. Results. Depressive and substance use disorders are highly comorbid, suggesting a common or overlapping aetiology and pathophysiology. Reduced astrocyte cell number occurs in both disorders. Altered glutamate neurotransmission and metabolism - specifically changes in the levels/activity of transporters, receptors, and synaptic proteins potentially related to synaptic physiology - appear to be salient features of both disorders. Glial cell pathology may also underlie the pathophysiology of both disorders via impaired astrocytic production of neurotrophic factors. Microglial/neuroinflammatory pathology is also evident in both depressive and substance use disorders. Finally, oligodendrocyte impairment decreases myelination and impairs expression of myelin-related genes in both substance use and depressive disorders. Conclusions. Glial-mediated glutamatergic dysfunction is a common neuropathological pathway in both substance use and depression. Therefore, glutamatergic neuromodulation is a rational drug target in this comorbidity. C1 [Niciu, Mark J.; Sanacora, Gerard] Yale Univ, Dept Psychiat, CMHC, CNRU, New Haven, CT 06520 USA. [Niciu, Mark J.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, Bethesda, MD 20814 USA. [Henter, Ioline D.] NIMH, Mol Imaging Branch, Bethesda, MD 20814 USA. RP Niciu, MJ (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 7-5545, Bethesda, MD 20814 USA. EM mark.niciu@nih.gov RI Niciu, Mark/J-1766-2014 OI Niciu, Mark/0000-0002-5612-3021 FU AstraZeneca; Avanier Pharmaceuticals; Bristol-Myers Squibb; Evotec; Eli Lilly Co.; Hoffman La-Roche; Naurex; Novartis; Novum Pharmaceuticals; Eli Lilly; Merck Co.; Severier; Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); Department of Veterans Affairs; VA National Center for PTSD; National Alliance for Research on Schizophrenia and Depression (NARSAD); NIMH [R01 MH071676-05, R01 MH081211-3, T32 MH19961, R25 MH071584]; State of Connecticut Department of Mental Health and Addiction Services; NARSAD Independent Investigator Award; Brain and Behavior Foundation Bipolar Research Award FX Dr Niciu and Ms Henter have no potential conflicts of interest to disclose, financial or otherwise. Dr Sanacora has received consulting fees from AstraZeneca, Avanier Pharmaceuticals, Bristol-Myers Squibb, Evotec, Eli Lilly & Co., Hoffman La-Roche, Naurex, Novartis and Novum Pharmaceuticals over the last 24 months. He has also received additional grant support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Hoffman La-Roche, Merck & Co., Naurex, and Severier over the last 24 months. In addition, he is a co-inventor on a filed patent application by Yale University (PCTWO06108055A1) concerning the use of glutamate-modulating drugs as antidepressants and anxiolytics. Dr Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr Zarate has assigned his rights in the patent to the US Government but will share a percentage of any royalties that may be received.; This work was supported in part by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); by the Department of Veterans Affairs, via its funding of the VA National Center for PTSD (GS); by the National Alliance for Research on Schizophrenia and Depression (NARSAD) (GS); by NIMH grants R01 MH071676-05 and R01 MH081211-3 (GS); by the State of Connecticut Department of Mental Health and Addiction Services (through its support of clinical research services at the Connecticut Mental Health Center and Clinical Neuroscience Research Unit) (GS); by salary support from NIMH T32 MH19961 and R25 MH071584 (MJN); and by a NARSAD Independent Investigator Award and Brain and Behavior Foundation Bipolar Research Award (CAZ). NR 187 TC 6 Z9 6 U1 1 U2 15 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 EI 1814-1412 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD JAN PY 2014 VL 15 IS 1 BP 2 EP 16 DI 10.3109/15622975.2013.829585 PG 15 WC Psychiatry SC Psychiatry GA 291KT UT WOS:000329828300002 PM 24024876 ER PT J AU Feero, WG Guttmacher, AE AF Feero, William Gregory Guttmacher, Alan E. TI Genomics, Personalized Medicine, and Pediatrics SO ACADEMIC PEDIATRICS LA English DT Article DE genetics; genomics; genotyping; pediatrics; personalized medicine; sequencing ID HUMAN MICROBIOME; GENOMEWIDE ASSOCIATION; WIDE ASSOCIATION; LARGE-SCALE; DISEASE; OUTBREAK; CANCER; OBESITY; HEALTH; METHYLATION AB Genomic discoveries are advancing biomedicine at an ever-increasing pace. Pediatrics is near the epicenter of these discoveries, which are revising our understanding of the genome and its function. Since the completion of the Human Genome Project in 2003, dramatic reductions in the cost of genotyping, and more recently sequencing, have permitted the study of the genomes of a great number of species as well as humans. These studies have led to insights on gene regulation and the complex interplay of factors responsible for normal development and biology. Study of single-gene disorders has greatly benefited from the genomics revolution and tests are now available for well over 2000 Mendelian conditions; availability of these tests are changing screening and diagnosis paradigms for rare conditions. Genomics is also yielding an increased understanding of common conditions such as diabetes, obesity, asthma, cancers, and mental health conditions. Personalized medicine, an approach to care in which an individual's genomic information is used to help tailor interventions to maximize health outcomes, is rapidly becoming a reality for a variety of conditions. Though challenges remain in translating new genomic insights into improved patient health, today's pediatricians and their patients will increasingly benefit from this watershed moment in the biological sciences. C1 [Feero, William Gregory] MaineDartmouth Family Med Residency Program, Augusta, ME USA. [Guttmacher, Alan E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Feero, WG (reprint author), 4 Sheridan Dr,Suite 2, Fairfield, ME 04937 USA. EM wfeero@mainegeneral.org FU Intramural NIH HHS [Z99 CA999999] NR 58 TC 9 Z9 10 U1 5 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1876-2859 EI 1876-2867 J9 ACAD PEDIATR JI Acad. Pediatr. PD JAN-FEB PY 2014 VL 14 IS 1 BP 14 EP 22 PG 9 WC Pediatrics SC Pediatrics GA 287SS UT WOS:000329563100005 PM 24369865 ER PT J AU Brimacombe, KR Walsh, MJ Liu, L Vasquez-Valdivieso, MG Morgan, HP McNae, I Fothergill-Gilmore, LA Michels, PAM Auld, DS Simeonov, A Walkinshaw, MD Shen, M Boxer, MB AF Brimacombe, Kyle R. Walsh, Martin J. Liu, Li Vasquez-Valdivieso, Montserrat G. Morgan, Hugh P. McNae, Iain Fothergill-Gilmore, Linda A. Michels, Paul A. M. Auld, Douglas S. Simeonov, Anton Walkinshaw, Malcolm D. Shen, Min Boxer, Matthew B. TI Identification of ML251, a Potent Inhibitor of T. brucei and T. cruzi Phosphofructokinase SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Trypanosoma brucei; Trypanosoma cruzi; phosphofructokinase; inhibitors; glycolysis; high-throughput screening ID TRYPANOSOMA-BRUCEI; DRUG DISCOVERY; GLYCOLYSIS; PARASITE; DESIGN; TARGET AB Human African Trypanosomiasis (HAT) is a severe, often fatal disease caused by the parasitic protist Trypanosoma brucei. The glycolytic pathway has been identified as the sole mechanism for ATP generation in the infective stage of these organisms, and several glycolytic enzymes, phosphofructokinase (PFK) in particular, have shown promise as potential drug targets. Herein, we describe the discovery of ML251, a novel nanomolar inhibitor of T. brucei PFK, and the structure-activity relationships within the series. C1 [Brimacombe, Kyle R.; Walsh, Martin J.; Liu, Li; Auld, Douglas S.; Simeonov, Anton; Shen, Min; Boxer, Matthew B.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Vasquez-Valdivieso, Montserrat G.; Morgan, Hugh P.; McNae, Iain; Fothergill-Gilmore, Linda A.; Walkinshaw, Malcolm D.] Univ Edinburgh, Sch Biol Sci, Ctr Translat & Chem Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [Michels, Paul A. M.] Catholic Univ Louvain, Trop Dis Res Unit, de Duve Inst, B-1200 Brussels, Belgium. [Michels, Paul A. M.] Catholic Univ Louvain, Biochem Lab, B-1200 Brussels, Belgium. RP Boxer, MB (reprint author), NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM boxerm@mail.nih.gov RI Michels, Paul/A-5637-2009; OI walkinshaw, malcolm/0000-0001-5955-9325 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research [R03MH092153-01, U54MH084681] FX This research was supported in part by Award No. R03MH092153-01 from the Molecular Libraries Initiative of the NIH Roadmap for Medical Research (grant U54MH084681). NR 16 TC 6 Z9 7 U1 2 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD JAN PY 2014 VL 5 IS 1 BP 12 EP 17 DI 10.1021/ml400259d PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 289JI UT WOS:000329677900005 PM 24900769 ER PT J AU Bhambhani, V Muenke, M AF Bhambhani, Vikas Muenke, Maximilian TI Noonan Syndrome SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID MANAGEMENT; DIAGNOSIS; FEATURES; PTPN11 AB Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of potential health conditions. Most affected individuals have characteristic facial features that evolve with age; a broad, webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism, developmental or behavioral problems, vision problems, hearing loss, and lymphedema. Familial recurrence is consistent with an autosomal dominant mode of inheritance, but most cases are due to de novo mutations. Diagnosis can be made on the basis of clinical features, but may be missed in mildly affected patients. Molecular genetic testing can confirm diagnosis in 70% of cases and has important implications for genetic counseling and management. Most patients with Noonan syndrome are intellectually normal as adults, but some may require multidisciplinary evaluation and regular follow-up care. Age-based Noonan syndrome specific growth charts and treatment guidelines are available. Copyright (C) 2014 American Academy of Family Physicians. C1 [Bhambhani, Vikas] NHGRI, NIH, Bethesda, MD 20892 USA. [Bhambhani, Vikas; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 17 TC 6 Z9 6 U1 1 U2 5 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X EI 1532-0650 J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD JAN 1 PY 2014 VL 89 IS 1 BP 37 EP 43 PG 7 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 289KV UT WOS:000329682300007 PM 24444506 ER PT J AU Coleman, HG Kitahara, CM Murray, LJ Dodd, KW Black, A Stolzenberg-Solomon, RZ Cantwell, MM AF Coleman, Helen G. Kitahara, Cari M. Murray, Liam J. Dodd, Kevin W. Black, Amanda Stolzenberg-Solomon, Rachael Z. Cantwell, Marie M. TI Dietary Carbohydrate Intake, Glycemic Index, and Glycemic Load and Endometrial Cancer Risk: A Prospective Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE carbohydrate; dietary fiber; endometrial cancer; glycemic index; glycemic load ID FOOD FREQUENCY QUESTIONNAIRES; UNITED-STATES; ENERGY-INTAKE; NUTRITIONAL FACTORS; PHYSICAL-ACTIVITY; SCREENING TRIAL; METAANALYSIS; FIBER; ASSOCIATION; INSTITUTE AB Endometrial cancer risk has been directly associated with glycemic load. However, few studies have investigated this link, and the etiological role of specific dietary carbohydrate components remains unclear. Our aim was to investigate associations of carbohydrate intake, glycemic index, and glycemic load with endometrial cancer risk in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Recruitment took place in 19932001. Over a median of 9.0 years of follow-up through 2009, 386 women developed endometrial cancer among 36,115 considered in the analysis. Dietary intakes were assessed using a 124-item diet history questionnaire. Cox proportional hazards models were applied to calculate hazard ratios and 95 confidence intervals. Significant inverse associations were detected between endometrial cancer risk and total available carbohydrate intake (hazard ratio (HR) 0.66, 95 confidence interval (CI): 0.49, 0.90), total sugars intake (HR 0.71, 95 CI: 0.52, 0.96), and glycemic load (HR 0.63, 95 CI: 0.46, 0.84) when women in the highest quartile of intake were compared with those in the lowest. These inverse associations were strongest among overweight and obese women. No associations with endometrial cancer risk were observed for glycemic index or dietary fiber. Our findings contrast with previous evidence and suggest that high carbohydrate intakes and glycemic loads are protective against endometrial cancer development. Further clarification of these associations is warranted. C1 [Coleman, Helen G.; Murray, Liam J.; Cantwell, Marie M.] Queens Univ Belfast, Ctr Publ Hlth, Canc Epidemiol & Hlth Serv Res Grp, Belfast BT12 6BJ, Antrim, North Ireland. [Kitahara, Cari M.; Black, Amanda; Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Dodd, Kevin W.] NCI, Canc Prevent Div, Rockville, MD USA. RP Coleman, HG (reprint author), Queens Univ Belfast, Royal Victoria Hosp, Ctr Publ Hlth, ICS B Bldg,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM h.coleman@qub.ac.uk RI Kitahara, Cari/R-8267-2016; OI Coleman, Helen/0000-0003-4872-7877 FU Medical Research Council [MR/K023241/1] NR 46 TC 5 Z9 6 U1 0 U2 12 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 JAN 1 PY 2014 VL 179 IS 1 BP 75 EP 84 DI 10.1093/aje/kwt222 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 280WI UT WOS:000329061100011 PM 24091889 ER PT J AU Wirdefeldt, K Weibull, CE Chen, HL Kamel, F Lundholm, C Fang, F Ye, WM AF Wirdefeldt, Karin Weibull, Caroline E. Chen, Honglei Kamel, Freya Lundholm, Cecilia Fang, Fang Ye, Weimin TI Parkinson's Disease and Cancer: A Register-based Family Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cancer; cohort studies; hazard ratio; Parkinson's disease; siblings ID MALIGNANT-MELANOMA; RISK AB We wanted to compare cancer incidence rates between Parkinson's disease (PD) patients and persons without PD, as well as between siblings of these groups. We conducted a family-based matched cohort study based on nationwide Swedish health registries and the Swedish Multi-Generation Register. We assessed risk of incident cancer in PD patients (n = 11,786) during 1964-2009 versus a matched cohort of PD-free individuals (n = 58,930) and in siblings of PD patients (n = 16,841) versus siblings of PD-free individuals (n = 84,205). Hazard ratios with 95% confidence intervals were estimated using Cox proportional hazards regression. Cancer occurrence was slightly higher in PD patients than in PD-free individuals (hazard ratio (HR) = 1.05, 95% confidence interval (CI): 1.00, 1.10), largely because of cancers arising within 1 year before or after the index date for PD, but risk of smoking-related cancers was lower (HR = 0.87, 95% CI: 0.79, 0.96). PD patients had a higher risk of melanoma both up to 1 year before the PD index date (HR = 1.53, 95% CI: 1.23, 1.91) and from 1 year after the index date onward (HR = 1.46, 95% CI: 1.01, 2.10). In the sibling comparison, cancer occurrence was largely similar. These results indicate that melanoma risk is higher among PD patients and that mechanisms other than familial ones explain the association. C1 [Wirdefeldt, Karin; Weibull, Caroline E.; Lundholm, Cecilia; Fang, Fang; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Wirdefeldt, Karin] Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden. [Chen, Honglei; Kamel, Freya] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Wirdefeldt, K (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, SE-17177 Stockholm, Sweden. EM karin.wirdefeldt@ki.se OI Fang, Fang/0000-0002-3310-6456; Kamel, Freya/0000-0001-5052-6615; Lundholm, Cecilia/0000-0002-6546-3650; Chen, Honglei/0000-0003-3446-7779 FU Swedish Research Council (SIMSAM) [80748301]; Swedish Parkinson Foundation; Swedish Medical Society; Swedish Society for Medical Research; Swedish Brain Foundation; Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES-101986] FX This work was supported by grants from the Swedish Research Council (SIMSAM grant 80748301), the Swedish Parkinson Foundation, the Swedish Medical Society, the Swedish Society for Medical Research, and the Swedish Brain Foundation. The study was also partially supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences (grant Z01ES-101986). NR 20 TC 18 Z9 18 U1 1 U2 6 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 JAN 1 PY 2014 VL 179 IS 1 BP 85 EP 94 DI 10.1093/aje/kwt232 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 280WI UT WOS:000329061100012 PM 24142916 ER PT J AU Zablotska, LB Little, MP Cornett, RJ AF Zablotska, Lydia B. Little, Mark P. Cornett, R. Jack TI Potential Increased Risk of Ischemic Heart Disease Mortality With Significant Dose Fractionation in the Canadian Fluoroscopy Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cardiovascular disease; dose fractionation; ionizing radiation; ischemic heart disease; noncancer diseases; radiation dose-response relationship ID ATOMIC-BOMB SURVIVORS; INDUCED CARDIOVASCULAR-DISEASE; CHILDHOOD-CANCER SURVIVOR; RATE IONIZING-RADIATION; LONG-TERM SURVIVORS; BREAST-CANCER; CIRCULATORY DISEASE; TUBERCULOSIS PATIENTS; LUNG-CANCER; EXPOSURE AB Risks of noncancer causes of death, particularly cardiovascular disease, associated with exposures to high-dose ionizing radiation, are well known. Recent studies have reported excess risk in workers who are occupationally exposed to low doses at a low dose rate, but the risks of moderately fractionated exposures, such as occur during diagnostic radiation procedures, remain unclear. The Canadian Fluoroscopy Cohort Study includes 63,707 tuberculosis patients exposed to multiple fluoroscopic procedures in 19301952 and followed-up for death from noncancer causes in 19501987. We used a Poisson regression to estimate excess relative risk (ERR) per Gy of cumulative radiation dose to the lung (mean dose 0.79 Gy; range, 011.60). The risk of death from noncancer causes was significantly lower in these subjects compared with the Canadian general population (P 0.001). We estimated small, nonsignificant increases in the risk of death from noncancer causes with dose. We estimated an ERR/Gy of 0.176 (95 confidence interval: 0.011, 0.393) (n 5,818 deaths) for ischemic heart disease (IHD) after adjustment for dose fractionation. A significant (P 0.022) inverse dose fractionation effect in dose trends of IHD was observed, with the highest estimate of ERR/Gy for those with the fewest fluoroscopic procedures per year. Radiation-related risks of IHD decreased significantly with increasing time since first exposure and age at first exposure (both P 0.05). This is the largest study of patients exposed to moderately fractionated low-to-moderate doses of radiation, and it provides additional evidence of increased radiation-associated risks of death from IHD, in particular, significantly increased radiation risks from doses similar to those from diagnostic radiation procedures. The novel finding of a significant inverse dose-fractionation association in IHD mortality requires further investigation. C1 [Zablotska, Lydia B.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Little, Mark P.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Cornett, R. Jack] Hlth Canada, Radiat Protect Bur, Ottawa, ON K1A 0L2, Canada. RP Zablotska, LB (reprint author), 3333 Calif St,Suite 280, San Francisco, CA 94118 USA. EM lydia.zablotska@ucsf.edu OI Little, Mark/0000-0003-0980-7567 FU National Institutes of Health; National Cancer Institute [CA132918]; National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics FX L.B.Z. was supported by the National Institutes of Health, the National Cancer Institute (grant CA132918). M. P. L. was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 44 TC 6 Z9 9 U1 0 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 JAN 1 PY 2014 VL 179 IS 1 BP 120 EP 131 DI 10.1093/aje/kwt244 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 280WI UT WOS:000329061100015 PM 24145888 ER PT J AU Rada, B Boudreau, HE Park, JJ Leto, TL AF Rada, Balazs Boudreau, Howard E. Park, Jonathan J. Leto, Thomas L. TI Histamine Stimulates Hydrogen Peroxide Production by Bronchial Epithelial Cells via Histamine H1 Receptor and Dual Oxidase SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE Duox; NADPH oxidase; asthma; airway epithelium; oxidative stress ID GROWTH-FACTOR RECEPTOR; ATP-MEDIATED ACTIVATION; NADPH OXIDASE; PSEUDOMONAS-AERUGINOSA; BREATH CONDENSATE; MUCIN EXPRESSION; OXIDATIVE STRESS; HOST-DEFENSE; KAPPA-B; ASTHMA AB Oxidative stress has been implicated in the pathogenesis of bronchial asthma. Besides granulocytes, the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma-related oxidative stress. Histamine is a major inflammatory mediator present in large quantities in asthmatic airways. Whether histamine triggers epithelium-derived oxidative stress is unknown. We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine. We found that air-liquid interface cultures of primary human bronchial epithelial cells (BECs) and an immortalized BEC model (Cdk4/hTERT HBEC) produce H2O2 in response to histamine. The main source of airway epithelial H2O2 is an NADPH dual oxidase, Duox1. Out of the four histamine receptors (H1R-H4R), H1R has the highest expression in BECs and mediates the H2O2-producing effects of histamine. IL-4 induces Duoxl gene and protein expression levels and enhances histamine-induced H2O2 production by epithelial cells. Using HEK-293 cells expressing Duox1 or Duox2 and endogenous H1R, histamine triggers an immediate intracellular calcium signal and H2O2 release. Overexpression of H1R further increases the oxidative output of Duox-expressing HEK-293 cells. Our observations show that BECs respond to histamine with Duox-mediated H2O2 production. These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways, suggesting novel therapeutic targets for treating asthmatic airway disease. C1 [Rada, Balazs] Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA USA. [Rada, Balazs; Boudreau, Howard E.; Park, Jonathan J.; Leto, Thomas L.] NIAID, Lab Host Defenses, NIH, Rockville, MD 20852 USA. RP Leto, TL (reprint author), NIAID, Lab Host Defenses, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM tleto@niaid.nih.gov FU National Institutes of Health; National Institute of Allergy and Infectious Diseases FX Supported by funds from the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 53 TC 11 Z9 11 U1 0 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JAN PY 2014 VL 50 IS 1 BP 125 EP 134 DI 10.1165/rcmb.2013-0254OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 291IF UT WOS:000329820900013 PM 23962049 ER PT J AU James, S Takken, W Collins, FH Gottlieb, M AF James, Stephanie Takken, Willem Collins, Frank H. Gottlieb, Michael TI Perspective Piece: Needs for Monitoring Mosquito Transmission of Malaria in a Pre-Elimination World SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID ANOPHELES-GAMBIAE MOSQUITOS; VECTOR CONTROL; AGE; IDENTIFICATION; EXPOSURE; AFRICA AB As global efforts to eliminate malaria intensify, accurate information on vector populations and transmission dynamics is critical for directing control efforts, developing new control tools, and predicting the effects of these interventions under various conditions. Currently available sampling tools for mosquito population monitoring suffer from well-recognized limitations. As reported in this workshop summary, a recent gathering of medical entomologists, modelers, and malaria experts reviewed these issues and agreed that efforts are needed to improve methods to monitor key transmission parameters. Identified needs include standardized methods for sampling of both mosquito adults and larvae, improved tools for mosquito species identification and age-grading, and a better means for determining the entomological inoculation rate. C1 [James, Stephanie; Gottlieb, Michael] Fdn Natl Inst Hlth, Div Sci, Bethesda, MD 20814 USA. [Takken, Willem] Univ Wageningen & Res Ctr, Entomol Lab, Wageningen, Netherlands. [Collins, Frank H.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. RP James, S (reprint author), Fdn Natl Inst Hlth, Div Sci, 9650 Rockville Pike, Bethesda, MD 20814 USA. EM sjames@fnih.org; willem.takken@wur.nl; frank@nd.edu; mgottlieb@fnih.org FU Foundation for the National Institutes of Health through the Vector-Based Control of Transmission: Discovery Research Program of the Grand Challenges in Global Health Initiative FX Support was provided by the Foundation for the National Institutes of Health through the Vector-Based Control of Transmission: Discovery Research Program of the Grand Challenges in Global Health Initiative. NR 35 TC 8 Z9 8 U1 0 U2 13 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2014 VL 90 IS 1 BP 6 EP 10 DI 10.4269/ajtmh.13-0175 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 288BO UT WOS:000329587200004 PM 24277786 ER PT J AU Mo, AX Agosti, JM Watson, JL Hall, BF Gordon, L AF Mo, Annie X. Agosti, Jan M. Watson, Judd L. Hall, B. Fenton Gordon, Lance TI Schistosomiasis Elimination Strategies and Potential Role of a Vaccine in Achieving Global Health Goals SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article AB In March 2013, the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation co-sponsored a meeting entitled "Schistosomiasis Elimination Strategy and Potential Role of a Vaccine in Achieving Global Health Goals" to discuss the potential role of schistosomiasis vaccines and other tools in the context of schistosomiasis control and elimination strategies. It was concluded that although schistosomiasis elimination in some focal areas may be achievable through current mass drug administration programs, global control and elimination will face several significant scientific and operational challenges, and will require an integrated approach with other, additional interventions. These challenges include vector (snail) control; environmental modification; water, sanitation, and hygiene; and other future innovative tools such as vaccines. Defining a clear product development plan that reflects a vaccine strategy as complementary to the existing control programs to combat different forms of schistosomiasis will be important to develop a vaccine effectively. C1 [Mo, Annie X.; Hall, B. Fenton] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Agosti, Jan M.; Gordon, Lance] Bill & Melinda Gates Fdn, Seattle, WA USA. [Watson, Judd L.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Watson, Judd L.] Univ Washington, Dept Med, Seattle, WA USA. [Watson, Judd L.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. RP Mo, AX (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM annie.mo@nih.gov; jan.agosti@gatesfoundation.org; walson@uw.edu; lhall@niaid.nih.gov; lance.gordon@gatesfoundation.org NR 0 TC 17 Z9 18 U1 0 U2 12 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2014 VL 90 IS 1 BP 54 EP 60 DI 10.4269/ajtmh.13-0467 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 288BO UT WOS:000329587200011 PM 24402703 ER PT J AU Treger, RS Otchere, J Keil, MF Quagraine, JE Rai, G Mott, BT Humphries, DL Wilson, M Cappello, M Vermeire, JJ AF Treger, Rebecca S. Otchere, Joseph Keil, Martin F. Quagraine, Josephine E. Rai, Ganesha Mott, Bryan T. Humphries, Debbie L. Wilson, Michael Cappello, Michael Vermeire, Jon J. TI Short Report: In vitro Screening of Compounds against Laboratory and Field Isolates of Human Hookworm Reveals Quantitative Differences in Anthelmintic Susceptibility SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID EGG-HATCH ASSAY; NECATOR-AMERICANUS; ANCYLOSTOMA-CEYLANICUM; VETERINARY IMPORTANCE; HELMINTH INFECTIONS; DRUG-SENSITIVITY; VIVO EFFICACY; RESISTANCE; IVERMECTIN; NEMATODES AB A panel of 80 compounds was screened for anthelmintic activity against a laboratory strain of Ancylostoma ceylanicum and field isolates of hookworm obtained from school children in the Kintampo North District of the Brong Ahafo Region of Ghana. Although the laboratory strain of A. ceylanicum was more susceptible to the compounds tested than the field isolates of hookworm, a twofold increase in compound concentration resulted in comparable egg hatch percent inhibition for select compounds. These data provide evidence that the efficacy of anthelmintic compounds may be species-dependent and that field and laboratory strains of hookworm differ in their sensitivities to the anthelmintics tested. These data also suggest that both compound concentration and hookworm species must be considered when screening to identify novel anthelmintic compounds. C1 [Treger, Rebecca S.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Treger, Rebecca S.] Yale Univ, Sch Med, Program Int Child Hlth, New Haven, CT USA. [Otchere, Joseph; Quagraine, Josephine E.; Wilson, Michael] Univ Ghana, Noguchi Mem Inst Med Res, Legon, Ghana. NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Keil, Martin F.; Humphries, Debbie L.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. [Rai, Ganesha; Mott, Bryan T.] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Cappello, Michael; Vermeire, Jon J.] Yale Univ, Yale Child Hlth Res Ctr, New Haven, CT USA. RP Vermeire, JJ (reprint author), Univ Calif San Francisco, Dept Pathol, QB3 Room 501e,Box 2550,1700 4th St, San Francisco, CA 94143 USA. EM rebecca.treger@yale.edu; jotchere@noguchi.mimcom.org; martin.keil@yale.edu; jquagraine@noguchi.mimcom.org; bantukallug@mail.nih.gov; bryan.mott@nih.gov; debbie.humphries@yale.edu; mwilson@noguchi.mimcom.org; michael.cappello@yale.edu; jon.vermeire@yale.edu FU National Institutes of Health Chemical Genomics Center [HHSN268201000217P]; National Institutes of Health [K22 A08476]; Noguchi Memorial Institute for Medical Research; Yale-Ghana Partnership in Global Health FX This work was supported by National Institutes of Health Chemical Genomics Center Contract HHSN268201000217P (to M.C. and J.J.V.), National Institutes of Health Career Development Award K22 A08476 (to J.J.V.), the Noguchi Memorial Institute for Medical Research, and the Yale-Ghana Partnership in Global Health. NR 40 TC 3 Z9 3 U1 0 U2 3 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2014 VL 90 IS 1 BP 71 EP 74 DI 10.4269/ajtmh.12-0547 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 288BO UT WOS:000329587200013 PM 24297811 ER PT J AU Platts-Mills, JA Gratz, J Mduma, E Svensen, E Amour, C Liu, J Maro, A Saidi, Q Swai, N Kumburu, H McCormick, BJJ Kibiki, G Houpt, ER AF Platts-Mills, James A. Gratz, Jean Mduma, Esto Svensen, Erling Amour, Caroline Liu, Jie Maro, Athanasia Saidi, Queen Swai, Ndealilia Kumburu, Happiness McCormick, Benjamin J. J. Kibiki, Gibson Houpt, Eric R. TI Association Between Stool Enteropathogen Quantity and Disease in Tanzanian Children Using TaqMan Array Cards: A Nested Case-Control Study SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID REAL-TIME PCR; INFECTIOUS INTESTINAL DISEASE; POLYMERASE-CHAIN-REACTION; GROUP-A ROTAVIRUS; DEVELOPING-COUNTRIES; ENTERIC PATHOGENS; DIARRHEAL DISEASE; FECAL SAMPLES; BANGLADESH; CRYPTOSPORIDIUM AB Etiologic studies of diarrhea are limited by uneven diagnostic methods and frequent asymptomatic detection of enteropathogens. Polymerase chain reaction-based stool, pathogen quantification may help distinguish clinically significant infections. We performed a nested case-control study of diarrhea in infants from a community-based birth cohort in Tanzania. We tested 71 diarrheal samples and pre-diarrheal matched controls with a laboratory-developed TaqMan Array Card for 19 enteropathogens. With qualitative detection, no pathogens were significantly associated with diarrhea. When pathogen quantity was considered, rotavirus (odds ratio [OR] = 2.70 per log(10) increase, P < 0.001), astrovirus (OR = 1.49, P = 0.01), and Shigella/enteroinvasive Escherichia coli (OR = 1.47, P = 0.04) were associated with diarrhea. Enterotoxigenic E. coli (0.15 SD decline in length-for-age z score after 3 months per log(10) increase, P < 0.001) and Campylobacter jejuni/C. coli (0.11 SD decline, P = 0.003) in pre-diarrheal stools were associated with poor linear growth. Quantitative analysis can help refine the association between enteropathogens and disease in endemic settings. C1 [Platts-Mills, James A.; Gratz, Jean; Liu, Jie; Houpt, Eric R.] Univ Virginia, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. [Mduma, Esto; Svensen, Erling; Amour, Caroline] Haydom Lutheran Hosp, Haydom, Tanzania. [Maro, Athanasia; Saidi, Queen; Swai, Ndealilia; Kumburu, Happiness; Kibiki, Gibson] Kilimanjaro Clin Res Inst, Moshi, Tanzania. [McCormick, Benjamin J. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Houpt, ER (reprint author), Univ Virginia, Dept Med, Div Infect Dis & Int Hlth, Mr4,2144, Charlottesville, VA 22908 USA. EM jp5t@virginia.edu; jean.gratz@gmail.com; estomih.mduma@haydom.co.tz; erling.svensen@cih.uib.no; lyneamour@gmail.com; jl5yj@virginia.edu; athanasia.maro@gmail.com; queensaidi@gmail.com; lilia2005tz@yahoo.co.uk; hk9s@virginia.edu; ben.mccormick@gmail.com; g.kibiki@kcri.ac.tz; erh6k@virginia.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [U01 AI075396]; Bill & Melinda Gates Foundation Global Health [OPP1019093] FX This work was supported by National Institute of Allergy and Infectious Diseases, National Institutes of Health Grant U01 AI075396 and Bill & Melinda Gates Foundation Global Health Grant OPP1019093 (to E.R.H.). NR 28 TC 23 Z9 23 U1 1 U2 12 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2014 VL 90 IS 1 BP 133 EP 138 DI 10.4269/ajtmh.13-0439 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 288BO UT WOS:000329587200023 PM 24189366 ER PT J AU Carothers, CL Heimburger, DC Schlachter, S Gardner, P Primack, A Warner, TL Vermund, SH AF Carothers, Catherine L. Heimburger, Douglas C. Schlachter, Sarah Gardner, Pierce Primack, Aron Warner, Tokesha L. Vermund, Sten H. TI Review Article: Training Programs Within Global Networks: Lessons Learned in the Fogarty International Clinical Research Scholars and Fellows Program SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID MEDICAL-STUDENTS; HEALTH; ELECTIVES; PARTNERSHIPS; INSTITUTIONS; WORKFORCE AB The Fogarty International Clinical Research Scholars and Fellows Support Center at Vanderbilt describes administrative lessons learned from the management of 436 scholars (American students or host country junior trainees) and 122 post-doctoral fellows (Americans or host country nationals). Trainees spent 10-11 months working on mentored research projects at 61 well-vetted sites in 27 low- or middle-income host countries (LMICs) with strong US partners. Economies of scale, strong centralized information exchange, and effective standardized operations linking US institutions with LMIC field sites were achieved in a program that minimized administrative overhead. Advantages and drawbacks of this approach are presented and discussed. Training of a new generation of global research leaders is greatly facilitated by an overseas mentored research experience that is administratively streamlined to optimize the use of resources for training, research, and capacity building. C1 [Carothers, Catherine L.; Heimburger, Douglas C.; Vermund, Sten H.] Vanderbilt Univ, Inst Global Hlth, Nashville, TN 37203 USA. Vanderbilt Univ, Fogarty Int Clin Res Scholars & Fellows Support C, Nashville, TN 37203 USA. SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Warner, Tokesha L.] Univ Georgia, Athens, GA 30602 USA. [Schlachter, Sarah] Univ Kansas, Med Ctr, Frontiers, Fairway, KS USA. [Gardner, Pierce] SUNY Stony Brook, Sch Med, Off Dean, Stony Brook, NY 11794 USA. RP Carothers, CL (reprint author), Vanderbilt Univ, Inst Global Hlth, 2525 West End Ave,Suite 750, Nashville, TN 37203 USA. EM catherine.lem@vanderbilt.edu; douglas.heimburger@vanderbilt.edu; sschlachter@kumc.edu; pgardner@stonybrookmedicine.edu; aprimack@rcn.com; gsmart@uga.edu; sten.vermund@vanderbilt.edu FU NIH Office of the Director; Fogarty International Center; Office of AIDS Research; National Cancer Institute; National Eye Institute; National Heart, Blood, and Lung Institute; National Institute of Dental and Craniofacial Research; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Allergy and Infectious Diseases Health through Fogarty International Clinical Research Fellows Program at Vanderbilt-Association of American Medical Colleges [R24 TW007988]; American Recovery and Reinvestment Act (ARRA) funds FX We thank Drs. Roger Glass, Kenneth Bridbord, and Myat Htoo Razak, Ms. Yolanda Thomas, and the staff of the Fogarty International Center for their support; the FICRS-F site principal investigators and field mentors; and participating National Institutes of Health (NIH) institute and center directors and staff. This work was supported by the NIH Office of the Director, Fogarty International Center, Office of AIDS Research, National Cancer Institute, National Eye Institute, National Heart, Blood, and Lung Institute, National Institute of Dental and Craniofacial Research, National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Allergy and Infectious Diseases Health through Fogarty International Clinical Research Fellows Program R24 TW007988 at Vanderbilt-Association of American Medical Colleges. Additional support in 2010 and 2011 was received from American Recovery and Reinvestment Act (ARRA) funds (http://recovery.nih.gov/). NR 25 TC 8 Z9 8 U1 1 U2 6 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2014 VL 90 IS 1 BP 173 EP 179 DI 10.4269/ajtmh.12-0512 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 288BO UT WOS:000329587200031 PM 24297815 ER PT J AU Hartman, RL Desrosiers, NA Barnes, AJ Yun, K Scheidweiler, KB Kolbrich-Spargo, EA Gorelick, DA Goodwin, RS Huestis, MA AF Hartman, Rebecca L. Desrosiers, Nathalie A. Barnes, Allan J. Yun, Keming Scheidweiler, Karl B. Kolbrich-Spargo, Erin A. Gorelick, David A. Goodwin, Robert S. Huestis, Marilyn A. TI 3,4-Methylenedioxymethamphetamine (MDMA) and metabolites disposition in blood and plasma following controlled oral administration SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE MDMA; Ecstasy; Pharmacokinetics; Metabolites; Blood; Plasma ID WHOLE-BLOOD; FLUORESCENCE DETECTION; HUMAN PHARMACOLOGY; MASS-SPECTROMETRY; ECSTASY; URINE; DRUG; MDA; HUMANS; HPLC AB 3,4-Methylenedioxymethamphetamine (MDMA) is an illicit phenethylamine ingested for entactogenic and euphoric effects. Although blood is more commonly submitted for forensic analysis, previous human MDMA pharmacokinetics research focused on plasma data; no direct blood-plasma comparisons were drawn. Blood and plasma specimens from 50 healthy adult volunteers (33 males, 17 females, 36 African-American) who ingested recreational 1.0 and 1.6 mg/kg MDMA doses were quantified for MDMA and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) by two-dimensional gas chromatography-mass spectrometry. Specimens were collected up to 3 h post-dose and evaluated for maximum concentration (C-max), first detection time (t(first)), time of C-max (t(max)), and 3-h area under the curve (AUC(0-3 h)); as well as blood metabolite ratios and blood/plasma ratios. Median blood MDMA and MDA C-max were significantly greater (p < 0.0005) than in plasma, but HMMA was significantly less (p < 0.0005). HMA was detected in few blood specimens, at low concentrations. Nonlinear pharmacokinetics were not observed for MDMA or MDA in this absorptive phase, but HMMA C-max and AUC(0-3 h) were similar for both doses despite the 1.6-fold dose difference. Blood MDA/MDMA and MDA/HMMA significantly increased (p < 0.0001) over the 3-h time course, and HMMA/MDMA significantly decreased (p < 0.0001). Blood MDMA C-max was significantly greater in females (p = 0.010) after the low dose only. Low-dose HMMA AUC(0-3 h) was significantly decreased in females' blood and plasma (p = 0.027) and in African-Americans' plasma (p = 0.035). These data provide valuable insight into MDMA blood-plasma relationships for forensic interpretation and evidence of sex-and race-based differential metabolism and risk profiles. C1 [Hartman, Rebecca L.; Desrosiers, Nathalie A.; Barnes, Allan J.; Yun, Keming; Scheidweiler, Karl B.; Gorelick, David A.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Hartman, Rebecca L.; Desrosiers, Nathalie A.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Yun, Keming] Shanxi Med Univ, Sch Forens Med, Taiyuan 030001, Peoples R China. [Kolbrich-Spargo, Erin A.] Southwestern Inst Forens Sci, Dallas, TX 75207 USA. [Gorelick, David A.] Univ Maryland, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, 251 Bayview Blvd,Suite 200 Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse, NIH FX We thank the National Institute on Drug Abuse Intramural Research Program and Johns Hopkins Bayview Medical Center Behavioral Pharmacology Research Unit clinical staff. We further acknowledge the Graduate Partnership Program, National Institutes of Health. This research was funded by the Intramural Research Program, National Institute on Drug Abuse, NIH. NR 36 TC 2 Z9 2 U1 3 U2 18 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JAN PY 2014 VL 406 IS 2 BP 587 EP 599 DI 10.1007/s00216-013-7468-y PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 288QK UT WOS:000329626600022 PM 24232751 ER PT J AU de Lima, M Porter, DL Battiwalla, M Bishop, MR Giralt, SA Hardy, NM Kroger, N Wayne, AS Schmid, C AF de Lima, Marcos Porter, David L. Battiwalla, Minoo Bishop, Michael R. Giralt, Sergio A. Hardy, Nancy M. Kroeger, Nicolaus Wayne, Alan S. Schmid, Christoph TI Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part III. Prevention and Treatment of Relapse after Allogeneic Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Relapse; Stem cell transplantation; Prevention; Treatment; Allogeneic ID ACUTE MYELOID-LEUKEMIA; DONOR LYMPHOCYTE INFUSIONS; ACUTE LYMPHOBLASTIC-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; MINIMAL RESIDUAL DISEASE; VERSUS-HOST-DISEASE; T-CELLS; EX-VIVO; LEUKOCYTE INFUSIONS; ENGAGING ANTIBODY AB In the Second Annual National Cancer Institute's Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Prevention and Treatment of Relapse after Allogeneic Transplantation highlighted progress in developing new therapeutic approaches since the first relapse workshop. Recent insights that might provide a basis for the development of novel, practical clinical trials were emphasized, including utilization of newer agents, optimization of donor lymphocyte infusion (DLI), and investigation of novel cellular therapies. Dr. de Lima discussed pre-emptive and maintenance strategies to prevent relapse after transplantation, for example, recent promising results suggestive of enhanced graft-versus-tumor activity with hypomethylating agents. Dr. Schmid provided an overview of adjunctive strategies to improve cell therapy for relapse, including cytoreduction before DLI, combination of targeted agents with DLI, and considerations in use of second transplantations. Dr. Porter addressed strategies to enhance T cell function, including ex vivo activated T cells and T cell engineering, and immunomodulatory approaches to enhance T cell function in vivo, including exogenous cytokines and modulation of costimulatory pathways. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [de Lima, Marcos] Case Western Reserve Univ, Univ Hosp Seidman Canc Ctr, Hematol Malignancies & Stem Cell Transplant Progr, Cleveland, OH 44106 USA. [Porter, David L.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Bishop, Michael R.] Univ Chicago Med, Hematol Oncol Sect, Chicago, IL USA. [Giralt, Sergio A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Hardy, Nancy M.] NCI, Expt Transplantat Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Kroeger, Nicolaus] Univ Med Ctr Hamburg Eppendorf, Dept Stem Cell Transplantat, Hamburg, Germany. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Schmid, Christoph] Univ Munich, Klinikum Augsburg, Munich, Germany. RP Hardy, NM (reprint author), NCI, Expt Transplantat Immunol Branch, Ctr Canc Res, Hatfield Clin Res Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. EM hardyn@mail.nih.gov FU National Institutes of Health: the National Cancer Institute/Center for Cancer Research; National Heart, Lung and Blood Institute; Novartis FX Financial disclosure: Supported in part by the Intramural Research Programs of the National Institutes of Health: the National Cancer Institute/Center for Cancer Research and the National Heart, Lung and Blood Institute.; Conflict of interest statement: The authors declare the following financial relationships: M.L. has received consultancy honoraria from Celgene. D.L.P. receives research support and has potential future IP rights from patents and licensure to Novartis. Conflict of interest was managed in accordance with University of Pennsylvania policy and oversight. NR 61 TC 26 Z9 26 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JAN PY 2014 VL 20 IS 1 BP 4 EP 13 DI 10.1016/j.bbmt.2013.08.012 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 289LG UT WOS:000329683400003 PM 24018392 ER PT J AU Shand, JC Qin, HY Nasholm, N Capitini, CM Fry, TJ AF Shand, Jessica C. Qin, Haiying Nasholm, Nicole Capitini, Christian M. Fry, Terry J. TI Minor Antigen Distribution Predicts Site-Specific Graft-versus-Tumor Activity of Adoptively Transferred, Minor Antigen-Specific CD8 T Cells SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic transplantation; Minor histocompatibility antigens; Adoptive T cell therapy; CD8 T cell function; Acute lymphoblastic leukemia ID BONE-MARROW-TRANSPLANTATION; CHRONIC VIRAL-INFECTION; HISTOCOMPATIBILITY ANTIGENS; HOST-DISEASE; MOUSE MODELS; SOLID TUMORS; LEUKEMIA; EXHAUSTION; SURVIVAL; PROLIFERATION AB The clinical success of allogeneic T cell therapy for cancer relies on the selection of antigens that can effectively elicit antitumor responses with minimal toxicity toward nonmalignant tissues. Although minor histocompatibility antigens (MiHA) represent promising targets, broad expression of these antigens has been associated with poor responses and T cell dysfunction that may not be prevented by targeting MiHA with limited expression. In this study, we hypothesized that antitumor activity of MiHA-specific CD8 T cells after allogeneic bone marrow transplantation (BMT) is determined by the distribution of antigen relative to the site of tumor growth. To test this hypothesis, we utilized the clinically relevant male-specific antigen HY and studied the fate of adoptively transferred, HY-CD8(+) T cells (HY-CD8) against a HY-expressing epithelial tumor (MB49) and pre-B cell leukemia (HY-E2APBX ALL) in BMT recipients. Transplants were designed to produce broad HY expression in nonhematopoietic tissues (female -> male BMT, [F -> M]), restricted HY expression in hematopoietic tissues (male -> female BMT, [M -> F]) tissues, and no HY tissue expression (female -> female BMT, [F -> F]). Broad HY expression induced poor responses to MB49 despite sublethal graft-versus-host disease and accumulation of HY-CD8 in secondary lymphoid tissues. Antileukemia responses, however, were preserved. In contrast, restriction of HY expression to hematopoietic tissues restored MB49 responses but resulted in a loss of antileukemia responses. We concluded that target alloantigen expression in the same compartment of tumor growth impairs CD8 responses to both solid and hematologic tumors. (C) 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Shand, Jessica C.; Qin, Haiying; Nasholm, Nicole; Fry, Terry J.] NCI, Blood & Marrow Transplant Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Capitini, Christian M.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI USA. [Capitini, Christian M.] Univ Wisconsin, Sch Med & Publ Hlth, UW Carbone Canc Ctr, Madison, WI USA. RP Shand, JC (reprint author), Univ Rochester, Med Ctr, Div Pediat Hematol Oncol, 601 Elmwood Ave,Box 777, Rochester, NY 14642 USA. EM Jessica_Shand@URMC.Rocnester.edu OI Capitini, Christian/0000-0002-2276-6731 FU NIH FX The authors thank Crystal Mackall and Daniel Fowler for their critical review of the data and manuscript drafts. The GFP-conjugated male E2APBX-ALL cell line was generously provided by Janet Bijil, Centre de Recherche de l'Hopital Maisonneuve-Rosemont, Montreal, Quebec, Canada. This work was supported by the NIH-T32 Training Grant "Laboratory Training in Pediatric Hematology-Oncology", Principal Investigator Donald Small, Johns Hopkins University. NR 41 TC 6 Z9 6 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JAN PY 2014 VL 20 IS 1 BP 26 EP 36 DI 10.1016/j.bbmt.2013.10.009 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 289LG UT WOS:000329683400006 PM 24141010 ER PT J AU Switzer, GE Bruce, JG Harrington, D Haagenson, M Drexler, R Foley, A Confer, D Bishop, M Anderlini, P Rowley, S Leitman, SF Anasetti, C Wingard, JR AF Switzer, Galen E. Bruce, Jessica G. Harrington, Donna Haagenson, Michael Drexler, Rebecca Foley, Amy Confer, Dennis Bishop, Michelle Anderlini, Paolo Rowley, Scott Leitman, Susan F. Anasetti, Claudio Wingard, John R. TI Health-related Quality of Life of Bone Marrow versus Peripheral Blood Stem Cell Donors: A Prespecified Subgroup Analysis from a Phase III RCT-BMTCTN Protocol 0201 SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Marrow versus peripheral blood stem cell donation; Unrelated hematopoietic stem cell donation; Randomized trial ID UNRELATED DONORS; PROSPECTIVE TRIAL; MOOD STATES; DONATION; EXPERIENCE; PROGRAM; TRANSPLANTATION; SAFETY; PRODUCT; PROFILE AB Hematopoietic stem cells can be procured from unrelated donors via either the bone marrow (BM) aspiration or peripheral blood stem cell (PBSC) collection methods. There is no evidence from prospective randomized trials in the unrelated donor setting about the relative health-related quality-of-life (HRQoL) benefits/costs to donors. The goals of this prospective longitudinal investigation were to describe and compare the donation-related HRQoL experiences of 332 BM and PBSC donors. Donors were interviewed before donation, 48 hours after donation, weekly until fully recovered, and at 6 and 12 months after donation. Before donation, BM donors had lower confusion, fewer concerns, and were more prepared for donation. Shortly after donation, BM donors reported more physical side effects. BM donors also reported more donation-related impact on their social activities. However, BM donors reported somewhat better psychological status and were more likely to indicate that the donation made their lives more meaningful. There were virtually no longer term differences in the experiences of the 2 donor groups, including no recovery time difference beginning 3 weeks after donation. Although BM donors may experience the process as more physically stressful and more psychologically beneficial in the short term, the longer term HRQoL consequences of BM and PBSC donors are similar. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Switzer, Galen E.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Switzer, Galen E.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Switzer, Galen E.; Bruce, Jessica G.; Harrington, Donna] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Switzer, Galen E.] Univ Pittsburgh, Dept Clin & Translat Sci, Pittsburgh, PA 15213 USA. [Haagenson, Michael; Drexler, Rebecca; Foley, Amy; Confer, Dennis] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Haagenson, Michael] Natl Marrow Donor Program, Minneapolis, MN USA. [Bishop, Michelle; Wingard, John R.] Univ Florida, Coll Med, Gainesville, FL USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Rowley, Scott] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Leitman, Susan F.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Anasetti, Claudio] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. RP Switzer, GE (reprint author), Univ Pittsburgh, 3501 Forbes Ave,Oxford Bld Suite 410, Pittsburgh, PA 15213 USA. EM SwitzerGE@upmc.edu FU National Heart, Lung, and Blood Institute; National Cancer Institute [U10HL069294]; Office of Naval Research; National Marrow Donor program FX Financial disclosure: Supported by a grant from the National Heart, Lung, and Blood Institute and the National Cancer Institute (U10HL069294), by the Office of Naval Research, and by the National Marrow Donor program. NR 24 TC 9 Z9 9 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JAN PY 2014 VL 20 IS 1 BP 118 EP 127 DI 10.1016/j.bbmt.2013.10.024 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 289LG UT WOS:000329683400018 PM 24184336 ER PT J AU Yu, MD Tatalovich, Z Gibson, JT Cronin, KA AF Yu, Mandi Tatalovich, Zaria Gibson, James T. Cronin, Kathleen A. TI Using a composite index of socioeconomic status to investigate health disparities while protecting the confidentiality of cancer registry data SO CANCER CAUSES & CONTROL LA English DT Article DE SEER; Socioeconomic index; Health disparity; Census tract; Cancer incidence; Cancer survival ID PROSTATE-CANCER; MORTALITY AB The lack of individual socioeconomic status (SES) information in cancer registry data necessitates the use of area-based measures to investigate health disparities. Concerns about confidentiality, however, prohibit publishing patients' residential locations at the subcounty level. We developed a census tract-based composite SES index to be released in place of individual census tracts to minimize the risk of disclosure. Two SES indices based on the measures identified in the literature were constructed using factor analysis. The analyses were repeated using the data from the 2000 decennial census and 2005-2009 American Community Survey to create the indices at two time points, which were linked to 2000-2009 Surveillance, Epidemiology, and End Results registry data to estimate incidence and survival rates. The two indices performed similarly in stratifying census tracts and detecting socioeconomic gradients in cancer incidence and survival. The gradient in the incidence is positive for breast and prostate, and negative for lung cancers, in all races, although the level varies. The positive gradient in survival is more salient for regional-staged breast, colorectal, and lung cancers. The census tract-based SES index provides a valuable tool for monitoring the disparities in cancer burdens while avoiding potential identity disclosure. This index, divided into tertiles and quintiles, is now available to the researchers on request. C1 [Yu, Mandi; Tatalovich, Zaria; Cronin, Kathleen A.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. [Gibson, James T.] Informat Management Serv Inc, Silver Spring, MD USA. RP Yu, MD (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD USA. EM yum3@mail.nih.gov NR 21 TC 9 Z9 10 U1 2 U2 9 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 JAN PY 2014 VL 25 IS 1 BP 81 EP 92 DI 10.1007/s10552-013-0310-1 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 284WG UT WOS:000329351700008 PM 24178398 ER PT J AU Tanimoto, K Muranski, P Miner, S Fujiwara, H Kajigaya, S Keyvanfar, K Hensel, N Barrett, AJ Melenhorst, JJ AF Tanimoto, Kazushi Muranski, Pawel Miner, Samantha Fujiwara, Hiroshi Kajigaya, Sachiko Keyvanfar, Keyvan Hensel, Nancy Barrett, A. John Melenhorst, J. Joseph TI Genetically engineered fixed K562 cells: potent "off-the-shelf" antigen-presenting cells for generating virus-specific T cells SO CYTOTHERAPY LA English DT Article DE artificial APC; cytomegalovirus; cytotoxic T cell; fixation ID ACUTE MYELOID-LEUKEMIA; ADOPTIVE IMMUNOTHERAPY; DENDRITIC CELLS; BK VIRUS; LYMPHOCYTES; RESPONSES; EXPRESSION; EXPANSION; THERAPY; 4-1BB AB Background aims. The human leukemia cell line K562 represents an attractive platform for creating artificial antigen-presenting cells (aAPC). It is readily expandable, does not express human leukocyte antigen (HLA) class I and II and can be stably transduced with various genes. Methods. In order to generate cytomegalovirus (CMV) antigen-specific T cells for adoptive immunotherapy, we transduced K562 with HLA-A*0201 in combination with co-stimulatory molecules. Results. In preliminary experiments, irradiated K562 expressing HLA-A*0201 and 4-1BBL pulsed with CMV pp65 and IE-1 peptide libraries failed to elicit antigen-specific CD8(+) T cells in HLA-A*0201(+) peripheral blood mononuclear cells (PBMC) or isolated T cells. Both wild-type K62 and aAPC strongly inhibited T cell proliferation to the bacterial superantigen staphylococcal enterotoxin B (SEB) and OKT3 and in mixed lymphocyte reaction (MLR). Transwell experiments suggested that suppression was mediated by a soluble factor; however, MLR inhibition was not reversed using transforming growth factor-beta blocking antibody or prostaglandin E-2 inhibitors. Full abrogation of the suppressive activity of K562 on MLR, SEB and OKT3 stimulation was only achieved by brief fixation with 0.1% formaldehyde. Fixed, pp65 and IE-1 peptide-loaded aAPC induced robust expansion of CMV-specific T cells. Conclusions. Fixed gene-modified K562 can serve as effective aAPC to expand CMV-specific cytotoxic T lymphocytes for therapeutic use in patients after stem cell transplantation. Our findings have implications for broader understanding of the immune evasion mechanisms used by leukemia and other tumors. C1 [Tanimoto, Kazushi; Muranski, Pawel; Miner, Samantha; Kajigaya, Sachiko; Keyvanfar, Keyvan; Hensel, Nancy; Barrett, A. John; Melenhorst, J. Joseph] NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Fujiwara, Hiroshi] Ehime Univ, Grad Sch Med, Dept Bioregulatory Med, Matsuyama, Ehime 790, Japan. [Melenhorst, J. Joseph] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Tanimoto, K (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM kazshi.tanimoto@gmail.com NR 42 TC 2 Z9 2 U1 1 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JAN PY 2014 VL 16 IS 1 BP 135 EP 146 DI 10.1016/j.jcyt.2013.08.008 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 288DS UT WOS:000329592800014 PM 24176543 ER PT J AU Miller, DS AF Miller, David S. TI REGULATION OF ABC TRANSPORTERS AT THE BLOOD-BRAIN AND BLOOD-SPINAL CORD BARRIERS SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 10th International Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY SEP 29-OCT 03, 2013 CL Toronto, CANADA SP Int Soc Study Xenobiot C1 [Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PD JAN PY 2014 VL 45 SU 1 BP 7 EP 7 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 286DO UT WOS:000329445700016 ER PT J AU Gonzalez, FJ AF Gonzalez, Frank J. TI PREGNANE X RECEPTOR AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR alpha HUMANIZED MICE SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 10th International Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY SEP 29-OCT 03, 2013 CL Toronto, CANADA SP Int Soc Study Xenobiot C1 [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PD JAN PY 2014 VL 45 SU 1 BP 20 EP 20 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 286DO UT WOS:000329445700048 ER PT J AU Gotoh, S Negishi, M AF Gotoh, Saki Negishi, Masahiko TI PXR IS A LIGAND-ACTIVATED SIGNAL SCAFFOLD THAT FACILITATES PP2C DEPHOSPHORYLATING SGK2 TO REGULATE HEPATIC GLUCONEOGENESIS SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 10th International Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) CY SEP 29-OCT 03, 2013 CL Toronto, CANADA SP Int Soc Study Xenobiot C1 [Gotoh, Saki; Negishi, Masahiko] Natl Inst Environm Hlth Sci, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PD JAN PY 2014 VL 45 SU 1 BP 145 EP 145 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 286DO UT WOS:000329445700292 ER PT J AU Lee, D Huestis, MA AF Lee, Dayong Huestis, Marilyn A. TI Current knowledge on cannabinoids in oral fluid SO DRUG TESTING AND ANALYSIS LA English DT Review DE oral fluid; cannabis; delta-9-tetrahydrocannabinol; marijuana; saliva; cannabinoid ID TANDEM MASS-SPECTROMETRY; ILLICIT DRUG-USE; PERFORMANCE LIQUID-CHROMATOGRAPHY; CONTROLLED SMOKED CANNABIS; SOLID-PHASE EXTRACTION; EXTERNAL QUALITY ASSESSMENT; POSITIVE PREVALENCE RATES; RANDOMLY SELECTED DRIVERS; MOTOR-VEHICLE CRASHES; CHRONIC PAIN PATIENTS AB Oral fluid (OF) is a new biological matrix for clinical and forensic drug testing, offering non-invasive and directly observable sample collection reducing adulteration potential, ease of multiple sample collections, lower biohazard risk during collection, recent exposure identification, and stronger correlation with blood than urine concentrations. Because cannabinoids are usually the most prevalent analytes in illicit drug testing, application of OF drug testing requires sufficient scientific data to support sensitive and specific OF cannabinoid detection. This review presents current knowledge of OF cannabinoids, evaluating pharmacokinetic properties, detection windows, and correlation with other biological matrices and impairment from field applications and controlled drug administration studies. In addition, onsite screening technologies, confirmatory analytical methods, drug stability, and effects of sample collection procedure, adulterants, and passive environmental exposure are reviewed. Delta-9-tetrahydrocannabinol OF concentrations could be >1000 mu g/L shortly after smoking, whereas minor cannabinoids are detected at 10-fold and metabolites at 1000-fold lower concentrations. OF research over the past decade demonstrated that appropriate interpretation of test results requires a comprehensive understanding of distinct elimination profiles and detection windows for different cannabinoids, which are influenced by administration route, dose, and drug use history. Thus, each drug testing program should establish cut-off criteria, collection/analysis procedures, and storage conditions tailored to its purposes. Building a scientific basis for OF testing is ongoing, with continuing OF cannabinoids research on passive environmental exposure, drug use history, donor physiological conditions, and oral cavity metabolism needed to better understand mechanisms of cannabinoid OF disposition and expand OF drug testing applicability. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. C1 [Lee, Dayong; Huestis, Marilyn A.] Natl Inst Drug Abuse, Natl Inst Hlth, Chem & Drug Metab Intramural Res Program, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, IRP, NIH, Biomed Res Ctr, 251 Bayview Blvd Suite 200,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse, NIH FX This research was funded by Intramural Research Program, National Institute on Drug Abuse, NIH. NR 246 TC 16 Z9 16 U1 6 U2 52 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JAN PY 2014 VL 6 IS 1-2 SI SI BP 88 EP 111 DI 10.1002/dta.1514 PG 24 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA 287QE UT WOS:000329556500012 PM 23983217 ER PT J AU Armstrong, AC Gjesdal, O Almeida, A Nacif, M Wu, C Bluemke, DA Brumback, L Lima, JAC AF Armstrong, Anderson C. Gjesdal, Ola Almeida, Andre Nacif, Marcelo Wu, Colin Bluemke, David A. Brumback, Lyndia Lima, Joao A. C. TI Left Ventricular Mass and Hypertrophy by Echocardiography and Cardiac Magnetic Resonance: The Multi-Ethnic Study of Atherosclerosis SO ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES LA English DT Article DE left ventricular mass; left ventricular hypertrophy; echocardiography; image quality ID SOCIETY-OF-CARDIOLOGY; CARDIOVASCULAR RISK; BODY-SIZE; HYPERTENSION; REGRESSION; AGE; QUANTIFICATION; POPULATION; GUIDELINES; DISEASE AB BackgroundLeft ventricular mass (LVM) and hypertrophy (LVH) are important parameters, but their use is surrounded by controversies. We compare LVM by echocardiography and cardiac magnetic resonance (CMR), investigating reproducibility aspects and the effect of echocardiography image quality. We also compare indexing methods within and between imaging modalities for classification of LVH and cardiovascular risk. MethodsMulti-Ethnic Study of Atherosclerosis enrolled 880 participants in Baltimore city, 146 had echocardiograms and CMR on the same day. LVM was then assessed using standard techniques. Echocardiography image quality was rated (good/limited) according to the parasternal view. LVH was defined after indexing LVM to body surface area, height(1.7), height(2.7), or by the predicted LVM from a reference group. Participants were classified for cardiovascular risk according to Framingham score. Pearson's correlation, Bland-Altman plots, percent agreement, and kappa coefficient assessed agreement within and between modalities. ResultsLeft ventricular mass by echocardiography (14040g) and by CMR were correlated (r=0.8, P<0.001) regardless of the echocardiography image quality. The reproducibility profile had strong correlations and agreement for both modalities. Image quality groups had similar characteristics; those with good images compared to CMR slightly superiorly. The prevalence of LVH tended to be higher with higher cardiovascular risk. The agreement for LVH between imaging modalities ranged from 77% to 98% and the kappa coefficient from 0.10 to 0.76. ConclusionsEchocardiography has a reliable performance for LVM assessment and classification of LVH, with limited influence of image quality. Echocardiography and CMR differ in the assessment of LVH, and additional differences rise from the indexing methods. C1 [Armstrong, Anderson C.; Gjesdal, Ola; Almeida, Andre; Lima, Joao A. C.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21287 USA. [Armstrong, Anderson C.] Univ Sao Francisco Valley, Sch Med, Petrolina, PE, Brazil. [Nacif, Marcelo; Bluemke, David A.] NIH, Bethesda, MD 20892 USA. [Wu, Colin] NHLBI, NIH, Bethesda, MD 20892 USA. [Brumback, Lyndia] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Div Cardiol, 600 N Wolfe St,Blalock 524D1, Baltimore, MD 21287 USA. EM jlima@jhmi.edu RI Armstrong, Anderson/G-8407-2012; Gjesdal, Ola/C-1941-2015; OI Armstrong, Anderson/0000-0003-3161-8922; Gjesdal, Ola/0000-0003-1913-6445; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute NHLBI; MESA [RO1-HL-66075, NO1-HC-9808, N01-HC-95162, NO1-HC-95168, NO1-HC-95169]; Universidade Federal do Vale do Sao Francisco UNIVASF, Petrolina, PE, Brazil FX The study was funded by the National Heart, Lung, and Blood Institute NHLBI supported by the MESA study contracts RO1-HL-66075, NO1-HC-9808, N01-HC-95162, NO1-HC-95168, and NO1-HC-95169. Dr. Armstrong was funded by Universidade Federal do Vale do Sao Francisco UNIVASF, Petrolina, PE, Brazil. NR 28 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-2822 EI 1540-8175 J9 ECHOCARDIOGR-J CARD JI Echocardiography-J. Cardiovasc. Ultrasound Allied Tech. PD JAN PY 2014 VL 31 IS 1 BP 12 EP 20 DI 10.1111/echo.12303 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282TS UT WOS:000329197100015 PM 23930739 ER PT J AU Lendvai, N Pawlosky, R Bullova, P Eisenhofer, G Patocs, A Veech, RL Pacak, K AF Lendvai, Nikoletta Pawlosky, Robert Bullova, Petra Eisenhofer, Graeme Patocs, Attila Veech, Richard L. Pacak, Karel TI Succinate-to-Fumarate Ratio as a New Metabolic Marker to Detect the Presence of SDHB/D-related Paraganglioma: Initial Experimental and Ex Vivo Findings SO ENDOCRINOLOGY LA English DT Article ID HEREDITARY PARAGANGLIOMA; TUMOR SUPPRESSORS; GENE-MUTATIONS; PHEOCHROMOCYTOMA; DEHYDROGENASE; HYPOXIA; SUBUNIT; SDHC; TUMORIGENESIS; ACTIVATION AB Pheochromocytomas (PHEOs) and paragangliomas (PGLs; extra-adrenal tumors) are rare neuroendocrine chromaffin cell tumors with a hereditary background in about 30%-35%. Those caused by succinate dehydrogenase subunit B (SDHB) germline mutations are associated with a high metastatic potential and ultimately higher patient mortality. Succinate dehydrogenase converts succinate to fumarate, uniquely linking the Krebs cycle and oxidative phosphorylation. SDH mutations result in the accumulation of succinate associated with various metabolic disturbances and the shift to aerobic glycolysis in tumor tissue. In the present study, we measured succinate and fumarate levels in mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells and in 10 apparently sporadic, 10 SDHB-, 5 SDHD-, and 2 neurofibromatosis 1-related PHEOs/PGLs and plasma samples using mass spectrometry. We found that the succinate-to-fumarate ratio was significantly higher in the SDHB- and SDHD-related PGLs than in apparently sporadic and neurofibromatosis 1-related PHEOs/PGLs (P = .0376). To further support our data, we silenced SDHB expression in MPC and MTT cells and evaluated the succinate and fumarate levels. Compared with control samples, SDHB-silenced MTT cells also showed an increase in the succinate-to-fumarate ratio (MTT cells: 2.45 vs 7.53), similar to the findings in SDHB-related PGLs. The present findings for the first time demonstrate a significantly increased succinate-to-fumarate ratio in SDHB/D-related PGLs and thus suggest this ratio may be used as a new metabolic marker for the detection of SDHB/D-related PHEOs/PGLs. C1 [Lendvai, Nikoletta; Bullova, Petra; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Lendvai, Nikoletta] Semmelweis Univ, Dept Med 2, H-1088 Budapest, Hungary. [Pawlosky, Robert; Veech, Richard L.] NIAAA, Sect Metab Control Anal, NIH, Rockville, MD 20852 USA. [Bullova, Petra] Slovak Acad Sci, Inst Virol, Dept Mol Med, Bratislava 84505, Slovakia. [Eisenhofer, Graeme] Univ Hosp Carl Gustav Carus TU Dresden, Inst Clin Chem & Lab Med, Dresden, Germany. [Eisenhofer, Graeme] Univ Hosp Carl Gustav Carus TU Dresden, Dept Med 3, D-01307 Dresden, Germany. [Patocs, Attila] Hungarian Acad Sci, Mol Med Res Grp, Budapest, Hungary. [Patocs, Attila] Semmelweis Univ, H-1085 Budapest, Hungary. [Patocs, Attila] Semmelweis Univ, Cent Isotope Lab, Dept Lab, Inst Med, H-1088 Budapest, Hungary. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, Bldg 10 CRC,1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov NR 27 TC 20 Z9 21 U1 0 U2 13 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 JAN PY 2014 VL 155 IS 1 BP 27 EP 32 DI 10.1210/en.2013-1549 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 279NU UT WOS:000328967500007 PM 24189137 ER PT J AU Neumann, S Nir, EA Eliseeva, E Huang, WW Marugan, J Xiao, JB Dulcey, AE Gershengorn, MC AF Neumann, Susanne Nir, Eshel A. Eliseeva, Elena Huang, Wenwei Marugan, Juan Xiao, Jingbo Dulcey, Andres E. Gershengorn, Marvin C. TI A Selective TSH Receptor Antagonist Inhibits Stimulation of Thyroid Function in Female Mice SO ENDOCRINOLOGY LA English DT Article ID THYROTROPIN RECEPTOR; INVERSE AGONIST; GRAVES OPHTHALMOPATHY; ORBITAL FIBROBLASTS; HORMONE-RECEPTOR; CAMP PRODUCTION; DISEASE; SUPPRESSION; MECHANISMS; ANTIBODY AB Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of cAMP production stimulated by TSH, LH, or FSH. We tested the in vivo activity of ANTAG3 by measuring its effects to lower serum free T-4 and thyroid gene expression in female BALB/c mice continuously treated with ANTAG3 for 3 days and given low doses of TRH continuously or stimulated by a single administration of a monoclonal thyroid-stimulating antibody M22. ANTAG3 was selective for TSHR inhibition; half-maximal inhibitory doses were 2.1 mu M for TSHR and greater than 30 mu M for LH and FSH receptors. In mice treated with TRH, ANTAG3 lowered serum free T-4 by 44% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 75% and 83%, respectively. In mice given M22, ANTAG3 lowered serum free T-4 by 38% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 73% and 40%, respectively. In conclusion, we developed a selective TSHR antagonist that is effective in vivo in mice. This is the first report of a small-molecule TSHR antagonist active in vivo and may lead to a drug to treat Graves' disease. C1 [Neumann, Susanne; Nir, Eshel A.; Eliseeva, Elena; Gershengorn, Marvin C.] Natl Inst Diabet & Digest & Kidney Dis, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Huang, Wenwei; Marugan, Juan; Xiao, Jingbo; Dulcey, Andres E.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), Natl Inst Diabet & Digest & Kidney Dis, NIH, Lab Endocrinol & Receptor Biol, 50 South Dr, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov FU Intramural Research Program of the National Institutes of Health [1 Z01 DK047044] FX This work was supported by the Intramural Research Program of the National Institutes of Health (Grant 1 Z01 DK047044). NR 18 TC 19 Z9 23 U1 0 U2 4 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 JAN PY 2014 VL 155 IS 1 BP 310 EP 314 DI 10.1210/en.2013-1835 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 279NU UT WOS:000328967500034 PM 24169564 ER PT J AU Quick, V Lipsky, LM Laffel, LMB Mehta, SN Quinn, H Nansel, TR AF Quick, V. Lipsky, L. M. Laffel, L. M. B. Mehta, S. N. Quinn, H. Nansel, T. R. TI Relationships of neophobia and pickiness with dietary variety, dietary quality and diabetes management adherence in youth with type 1 diabetes SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary variety; dietary quality; neophobia; pickiness; type 1 diabetes; youth ID CHILDRENS FOOD PREFERENCES; CORONARY-HEART-DISEASE; BODY-MASS INDEX; CHILDHOOD; ADOLESCENTS; ACCEPTANCE; CONSUMPTION; VALIDATION; ADULTS; PREDICTORS AB BACKGROUND/OBJECTIVES: Neophobia, pickiness and diet variety are associated with diet quality and health outcomes in young children. Limited research has examined these associations among youth with type 1 diabetes (T1D), a population at risk for poor health outcomes when dietary quality is inadequate. SUBJECTS/METHODS: Youth (n = 252, age 13.2 +/- 2.8 years, 92% white, diabetes duration 6.3 +/- 3.4 years) with T1D and their parents completed 3-day youth diet records; parents completed questionnaires regarding youth neophobia, pickiness and diabetes management adherence. Medical records provided biomedical data. Dietary quality indicators included Nutrient-Rich Foods Index 9.3 (NRF9.3), Healthy Eating Index-2005 (HEI-2005), Whole Plant Food Density (WPFD) and key single nutrients. Dietary variety was operationalized as a count of 20 recommended food groups consumed. Relationships of dietary quality and diabetes management adherence with neophobia, pickiness and dietary variety as independent variables were examined using multiple linear regression analyses adjusted for total energy intake, age, height and weight. RESULTS: In multiple linear regression analyses, NRF9.3 and HEI-2005 were each inversely associated with neophobia and pickiness, and positively associated with dietary variety. WPF and potassium were each positively associated and saturated fat was inversely associated with dietary variety. However, in models simultaneously including neophobia, pickiness and dietary variety as independent correlates of dietary quality, only relationships with dietary variety remained significant. Diabetes management adherence was negatively associated with both neophobia and pickiness and positively associated with dietary variety. CONCLUSIONS: Findings suggest that increasing dietary variety may contribute toward improved dietary quality among youth with T1D, despite potentially adverse influences of neophobia and pickiness. C1 [Quick, V.; Lipsky, L. M.; Nansel, T. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Laffel, L. M. B.; Mehta, S. N.; Quinn, H.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Genet & Epidemiol Sect,Pediat Adolescent & Young, Boston, MA 02115 USA. RP Quick, V (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, US Dept HHS, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM gingermquick@gmail.com OI Quick, Virginia/0000-0002-4338-963X; Nansel, Tonja/0000-0002-8298-7595; Lipsky, Leah/0000-0003-2645-4388 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN267200703434C] FX This research was supported by the intramural research program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Contract Number HHSN267200703434C. NR 49 TC 5 Z9 5 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JAN PY 2014 VL 68 IS 1 BP 131 EP 136 DI 10.1038/ejcn.2013.239 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 285ZL UT WOS:000329433900024 PM 24253761 ER PT B AU Martin, WJ Hollingsworth, JW Ramanathan, V AF Martin, William J., II Hollingsworth, John W. Ramanathan, Veerabhadran BE Pinkerton, KE Rom, WN TI Household Air Pollution from Cookstoves: Impacts on Health and Climate SO GLOBAL CLIMATE CHANGE AND PUBLIC HEALTH SE Respiratory Medicine Series LA English DT Article; Book Chapter DE Biomass; Household air pollution; Climate change; Poverty and climate change ID ATMOSPHERIC BROWN CLOUDS; BLACK CARBON; DNA METHYLATION; BIOMASS COOKSTOVES; GLOBAL BURDEN; RISK-FACTORS; LUNG-CANCER; EXPOSURE; INDIA; DISEASE AB Household air pollution (HAP) is an exposure of poverty. The success in having a sustainable reduction in HAP requires an understanding of the traditions and culture of the family as well as the causes of poverty that place the family at the bottom of the energy ladder. An integrated approach to reducing HAP with efforts also aimed at correcting other poverty-related issues is challenging but offers the hope for addressing root causes of poverty in a community setting that provides a more comprehensive and sustainable approach to improving health, the environment, and, ultimately, the global climate. From one perspective, research that provides detailed exposure-responses to HAP may seem superfluous to the obvious need for poor families to breathe cleaner air at home. One can argue that we already have decades of information on the health risks from outdoor air pollution or the products of incomplete combustion from tobacco smoke and so further research is not needed. However, there is a compelling need to know how clean a stove or fuel must be to significantly reduce health risks, so that with proper use, major implementation of such new technology may reasonably provide the intended benefits for improved health, the regional environment, and the global climate. The alternative of providing electrification or use of clean fuels such as LPG may not be realistic for the world's poor for decades to come, if ever. Addressing the key scientific gaps related to HAP and its reduction will provide critical new information that can inform large scale implementation programs to provide sufficiently clean household air for families living in poverty, such that diseases are prevented, a healthier lifestyle is promoted, and a reduction in global warming trends buys more time for a planet in peril from climate change. C1 [Martin, William J., II] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Hollingsworth, John W.] Duke Univ Med Ctr, Dept Med & Immunol, Durham, NC 27710 USA. [Ramanathan, Veerabhadran] Scripps Inst Oceanog, Ctr Atmospher Sci, La Jolla, CA 92037 USA. [Ramanathan, Veerabhadran] Univ Calif San Diego, La Jolla, CA 92093 USA. RP Martin, WJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 31 Ctr Dr,Bldg 31,Room 2A32,MSC 2425, Bethesda, MD 20892 USA. EM wjmartin@mail.nih.gov NR 65 TC 4 Z9 4 U1 2 U2 9 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-4614-8417-2; 978-1-4614-8416-5 J9 RESPIR MED SER PY 2014 VL 7 BP 237 EP 255 DI 10.1007/978-1-4614-8417-2_13 D2 10.1007/978-1-4614-8417-2 PG 19 WC Environmental Sciences; Public, Environmental & Occupational Health; Respiratory System SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Respiratory System GA BJJ05 UT WOS:000328380700014 ER PT B AU Levine, M Balbus, J AF Levine, Maya Balbus, John BE Pinkerton, KE Rom, WN TI Federal Programs in Climate Change and Health Research SO GLOBAL CLIMATE CHANGE AND PUBLIC HEALTH SE Respiratory Medicine Series LA English DT Article; Book Chapter DE Federal programs in climate change and health research; Health research and climate change; Climate change and federal programs; Research in climate change; Global Change Research Program AB The federal government plays an integral role in supporting climate change science and health research in the USA. Federally funded climate change research initially focused on science to understand climate and earth systems change during the 1970s and 1980s. Today, federally supported climate change research involves numerous agencies pursuing a wide range of climate change science topics and applications, including research exploring the connections between human health and climate change. Because each federal agency has a different mandate and range of scientific expertise, the focus and goals of various agencies' climate change and human health research vary. For example, the National Oceanic and Atmospheric Administration (NOAA) emphasizes the use of weather and climate forecasts and oceanographic data for public health applications, while the National Aeronautics and Space Administration (NASA) emphasizes health applications of remotely sensed data from its satellites. This chapter provides a brief history of federally funded climate research and includes a survey of the relevant agencies, programs, tools, and datasets to illustrate the diversity of health and climate change research supported by the federal government. C1 [Levine, Maya; Balbus, John] NIEHS, Bethesda, MD 20892 USA. RP Balbus, J (reprint author), NIEHS, 31 Ctr Dr,Room B1C02, Bethesda, MD 20892 USA. EM balbusjm@niehs.nih.gov NR 31 TC 0 Z9 0 U1 1 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-4614-8417-2; 978-1-4614-8416-5 J9 RESPIR MED SER PY 2014 VL 7 BP 319 EP 340 DI 10.1007/978-1-4614-8417-2_19 D2 10.1007/978-1-4614-8417-2 PG 22 WC Environmental Sciences; Public, Environmental & Occupational Health; Respiratory System SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Respiratory System GA BJJ05 UT WOS:000328380700020 ER PT J AU Opletalova, K Bourillon, A Yang, W Pouvelle, C Armier, J Despras, E Martin, L Mateus, C Robert, C Kannouche, P Soufir, N Sarasin, A AF Opletalova, Kristina Bourillon, Agnes Yang, Wei Pouvelle, Caroline Armier, Jacques Despras, Emmanuelle Martin, Ludovic Mateus, Christine Robert, Caroline Kannouche, Patricia Soufir, Nadem Sarasin, Alain TI Correlation of Phenotype/Genotype in a Cohort of 23 Xeroderma Pigmentosum-Variant Patients Reveals 12 New Disease-Causing POLH Mutations SO HUMAN MUTATION LA English DT Article DE DNA repair; UV; trans-lesion polymerases; skin cancers; melanomas; POLH ID DNA-POLYMERASE-ETA; TRANSLESION SYNTHESIS; MOLECULAR ANALYSIS; JAPANESE PATIENTS; HUMAN-CELLS; GENE; REPAIR; HYPERMUTATION; REPLICATION; MECHANISM AB Xeroderma pigmentosum variant (XP-V) is a rare genetic disease, characterized by some sunlight sensitivity and predisposition to cutaneous malignancies. We described clinical and genetic features of the largest collection ever published of 23 XP-V patients (ages between 21 and 86) from 20 unrelated families. Primary fibroblasts from patients showed normal nucleotide excision repair but UV-hypersensitivity in the presence of caffeine, a signature of the XP-V syndrome. 87% of patients developed skin tumors with a median age of 21 for the first occurrence. The median numbers of basal-cell carcinoma was 13 per patient, six for squamous-cell carcinoma, and five for melanoma. XP-V is due to defects in the translesion-synthesis DNA polymerase Pol coded by the POLH gene. DNA sequencing of POLH revealed 29 mutations, where 12 have not been previously identified, leading to truncated polymerases in 69% of patients. Four missense mutations are correlated with the protein stability by structural modeling of the Pol polymerase domain. There is a clear relationship between the types of missense mutations and clinical severity. For truncating mutations, which lead to an absence of or to inactive proteins, the life-cumulated UV exposure is probably the best predictor of cancer incidence, reinforcing the necessity to protect XP-Vs from sun exposure. (C) 2013 Wiley Periodicals, Inc. C1 [Opletalova, Kristina; Pouvelle, Caroline; Armier, Jacques; Despras, Emmanuelle; Kannouche, Patricia; Sarasin, Alain] Univ Paris 11, CNRS, UMR8200, Lab Genet Stabil & Oncogenesis, Villejuif, France. [Opletalova, Kristina; Pouvelle, Caroline; Armier, Jacques; Despras, Emmanuelle; Kannouche, Patricia; Sarasin, Alain] Inst Gustave Roussy, F-94805 Villejuif, France. [Opletalova, Kristina; Mateus, Christine; Robert, Caroline] Inst Gustave Roussy, Dept Dermatol, F-94805 Villejuif, France. [Bourillon, Agnes; Soufir, Nadem] Hop Bichat Claude Bernard, APHP, Genet Lab, F-75877 Paris, France. [Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Pouvelle, Caroline; Despras, Emmanuelle; Kannouche, Patricia] Univ Paris 11, Equipe Labellisee Ligue Canc TLS Polymerases & Ca, Villejuif, France. [Pouvelle, Caroline; Despras, Emmanuelle; Kannouche, Patricia] Inst Cancerol Gustave Roussy, Villejuif, France. [Martin, Ludovic] CHU Angers, Serv Dermatol, Angers, France. [Soufir, Nadem] Hop St Louis, APHP, INSERM, U976,Ctr Rech Peau, Paris, France. [Soufir, Nadem] Univ Paris, F-75252 Paris, France. [Sarasin, Alain] Inst Gustave Roussy, Dept Genet, F-94805 Villejuif, France. RP Sarasin, A (reprint author), Inst Gustave Roussy, CNRS, UMR8200, PR2,114,Rue Edouard Vaillant, F-94805 Villejuif, France. EM alain.sarasin@gustaveroussy.fr RI Yang, Wei/D-4926-2011; Martin, Ludovic/K-2674-2015 OI Yang, Wei/0000-0002-3591-2195; FU Centre National de la Recherche Scientifique (Paris, France); Agence Nationale pour la Recherche (Paris); Association des Enfants de la Lune (Tercis, France); La Ligue Nationale contre le Cancer ("Equipe labellisee"), Paris, France; Institut National du Cancer (INCa), Paris; Agence Nationale de la Recherche, Paris [ANR-09-PIRI-001] FX Contract grant sponsors: Centre National de la Recherche Scientifique (Paris, France); the Agence Nationale pour la Recherche (Paris); the Association des Enfants de la Lune (Tercis, France); La Ligue Nationale contre le Cancer ("Equipe labellisee"), Paris, France; the Institut National du Cancer (INCa, PLBio-2010), Paris; the Agence Nationale de la Recherche (No ANR-09-PIRI-001), Paris. NR 31 TC 7 Z9 8 U1 2 U2 10 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 JAN PY 2014 VL 35 IS 1 BP 117 EP 128 DI 10.1002/humu.22462 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 289JP UT WOS:000329678600016 PM 24130121 ER PT J AU Lokanga, RA Zhao, XN Usdin, K AF Lokanga, Rachel Adihe Zhao, Xiao-Nan Usdin, Karen TI The Mismatch Repair Protein MSH2 is Rate Limiting for Repeat Expansion in a Fragile X Premutation Mouse Model SO HUMAN MUTATION LA English DT Article DE fragile X-related disorders; FXTAS; FXPOI; triplet repeat expansion; mismatch repair; MMR; MSH2 ID DM1 TRANSGENIC MICE; MUTS HOMOLOG 2; KNOCK-IN MICE; FMR1 GENE; TRINUCLEOTIDE REPEAT; FULL MUTATION; SOMATIC EXPANSION; TRIPLET REPEAT; DEFICIENT MICE; CAG REPEAT AB Fragile X-associated tremor and ataxia syndrome, Fragile X-associated primary ovarian insufficiency, and Fragile X syndrome are Repeat Expansion Diseases caused by expansion of a CGG center dot CCG-repeat microsatellite in the 5 UTR of the FMR1 gene. To help understand the expansion mechanism responsible for these disorders, we have crossed mice containing approximate to 147 CGG center dot CCG repeats in the endogenous murine Fmr1 gene with mice containing a null mutation in the gene encoding the mismatch repair protein MSH2. MSH2 mutations are associated with elevated levels of generalized microsatellite instability. However, we show here for the first time that in the FX mouse model, all maternally and paternally transmitted expansions require Msh2. Even the loss of one Msh2 allele reduced the intergenerational expansion frequency significantly. Msh2 is also required for all somatic expansions and loss of even one functional Msh2 allele reduced the extent of somatic expansion in some organs. Tissues with lower levels of MSH2 were more sensitive to the loss of a single Msh2 allele. This suggests that MSH2 is rate limiting for expansion in this mouse model and that MSH2 levels may be a key factor that accounts for tissue-specific differences in expansion risk. Published 2013 Wiley Periodicals, Inc. C1 [Lokanga, Rachel Adihe; Zhao, Xiao-Nan; Usdin, Karen] NIDDK, Sect Genom Struct & Funct, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Lokanga, Rachel Adihe] Univ Cape Town, Div Med Biochem, ZA-7925 Cape Town, South Africa. RP Usdin, K (reprint author), NIH, Bldg 8,Room 2A19,8 Ctr DR MSC 0830, Bethesda, MD 20892 USA. EM ku@helix.nih.gov RI Zhao, Xiaonan/S-3139-2016 FU Intramural Program of NIH (NIDDK) [DK057808-05] FX Contract grant sponsor: Intramural Program of NIH (NIDDK) (DK057808-05). NR 50 TC 24 Z9 24 U1 2 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 JAN PY 2014 VL 35 IS 1 BP 129 EP 136 DI 10.1002/humu.22464 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 289JP UT WOS:000329678600017 PM 24130133 ER PT J AU Ribeiro, JMC Chagas, AC Pham, VM Lounibos, LP Calvo, E AF Ribeiro, Jose M. C. Chagas, Andrezza C. Pham, Van M. Lounibos, L. P. Calvo, Eric TI An insight into the sialome of the frog biting fly, Corethrella appendiculata SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Evolution; Culicomorpha; Corethrellidae; Salivary gland; Hematophagy; Medical entomology ID MOSQUITO AEDES-AEGYPTI; SEQUENCE ALIGNMENT; ANOPHELES-GAMBIAE; RANA-CATESBEIANA; SALIVARY-GLANDS; O-GLYCOSYLATION; YELLOW-FEVER; DIPTERA; THROMBOCYTES; PROTEIN AB The Nematocera infraorder Culicomorpha is believed to have descended from bloodfeeding ancestors over 200 million years ago, generating bloodfeeding and non-bloodfeeding flies in two superfamilies, the Culicoidea-containing the mosquitoes, the frog-feeding midges, the Chaoboridae, and the Dixidae-and the Chironomoidea-containing the black flies, the ceratopogonids, the Chironomidae, and the Thaumaleidae. Bloodfeeding requires many adaptations, including development of a sophisticated salivary potion that disarms host hemostasis, the physiologic mechanism comprising platelet aggregation, vasoconstriction, and blood clotting. The composition of the sialome (from the Greek sialo = saliva) from bloodfeeding animals can be inferred from analysis of their salivary gland transcriptome. While members of the mosquitoes, black flies, and biting midges have provided sialotranscriptome descriptions, no species of the frog-biting midges has been thus analyzed. We describe in this work the sialotranscriptome of Corethrella appendiculata, revealing a complex potion of enzymes, classical nematoceran protein families involved in bloodfeeding, and novel protein families unique to this species of frog-feeding fly. Bacterial (Wolbachia) and novel viral sequences were also discovered. Published by Elsevier Ltd. C1 [Ribeiro, Jose M. C.; Chagas, Andrezza C.; Pham, Van M.; Calvo, Eric] NIAID, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Lounibos, L. P.] Univ Florida, Florida Med Entomol Lab, Vero Beach, FL 32962 USA. RP Ribeiro, JMC (reprint author), NIAID, Vector Biol Sect, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy,Room 2E-32D, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov RI Ribeiro, Jose/J-7011-2015; OI Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA; NIH [R01 AI044793, R21 AI095780] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA, and by NIH grants R01 AI044793 and R21 AI095780 to L.P.L. We thank B. R. Marshall, DPSS, NIAID, for editing. NR 83 TC 10 Z9 10 U1 0 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 EI 1879-0240 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD JAN PY 2014 VL 44 BP 23 EP 32 DI 10.1016/j.ibmb.2013.10.006 PG 10 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 290QB UT WOS:000329772300003 ER PT J AU Inge, TH Zeller, MH Jenkins, TM Helmrath, M Brandt, ML Michalsky, MP Harmon, CM Courcoulas, A Horlick, M Xanthakos, SA Dolan, L Mitsnefes, M Barnett, SJ Buncher, R AF Inge, Thomas H. Zeller, Meg H. Jenkins, Todd M. Helmrath, Michael Brandt, Mary L. Michalsky, Marc P. Harmon, Carroll M. Courcoulas, Anita Horlick, Mary Xanthakos, Stavra A. Dolan, Larry Mitsnefes, Mark Barnett, Sean J. Buncher, Ralph CA Teen-LABS Consortium TI Perioperative Outcomes of Adolescents Undergoing Bariatric Surgery The Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Study SO JAMA PEDIATRICS LA English DT Article ID SEVERELY OBESE ADOLESCENTS; ACADEMIC MEDICAL-CENTERS; DISEASE RISK-FACTORS; NATIONAL TRENDS; PREVALENCE; CHILDREN; SAFETY; COHORT AB IMPORTANCE Severe obesity in childhood is a major health problem with few effective treatments. Weight-loss surgery (WLS) is being used to treat severely obese adolescents, although with very limited data regarding surgical safety for currently used, minimally invasive procedures. OBJECTIVE To assess the preoperative clinical characteristics and perioperative safety outcomes of severely obese adolescents undergoing WLS. DESIGN, SETTING, AND PARTICIPANTS This prospective, multisite observational study enrolled patients from February 28, 2007, through December 30, 2011. Consecutive patients aged 19 years or younger who were approved to undergo WLS (n = 277) were offered enrollment into the study at 5 academic referral centers in the United States; 13 declined participation and 22 did not undergo surgery after enrollment, thus the final analysis cohort consisted of 242 individuals. There were no withdrawals. MAIN OUTCOMES AND MEASURES This analysis examined preoperative anthropometrics, comorbid conditions, and major and minor complications occurring within 30 days of operation. All data were collected in a standardized fashion. Reoperations and hospital readmissions were adjudicated by independent reviewers to assess relatedness to the WLS procedure. RESULTS The mean (SD) age of participants was 17.1 (1.6) years and the median body mass index (calculated as weight in kilograms divided by height in meters squared) was 50.5. Fifty-one percent demonstrated 4 or more major comorbid conditions. Laparoscopic Roux-en-Y gastric bypass, vertical sleeve gastrectomy, and adjustable gastric banding were performed in 66%, 28%, and 6% of patients, respectively. There were no deaths during the initial hospitalization or within 30 days of operation; major complications (eg, reoperation) were seen in 19 patients (8%). Minor complications (eg, readmission for dehydration) were noted in 36 patients (15%). All reoperations and 85% of readmissions were related to WLS. CONCLUSIONS AND RELEVANCE In this series, adolescents with severe obesity presented with abundant comorbid conditions. We observed a favorable short-term complication profile, supporting the early postoperative safety of WLS in select adolescents. Further longitudinal study of this cohort will permit accurate assessment of long-term outcomes for adolescents undergoing bariatric surgery. C1 [Inge, Thomas H.; Zeller, Meg H.; Jenkins, Todd M.; Helmrath, Michael; Xanthakos, Stavra A.; Dolan, Larry; Mitsnefes, Mark; Barnett, Sean J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Brandt, Mary L.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Michalsky, Marc P.] Nationwide Childrens Hosp, Columbus, OH USA. [Harmon, Carroll M.] Univ Alabama Birmingham, Birmingham, AL USA. [Courcoulas, Anita] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Horlick, Mary] NIDDK, NIH, Bethesda, MD 20892 USA. [Buncher, Ralph] Univ Cincinnati, Cincinnati, OH USA. RP Inge, TH (reprint author), Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. RI Michalsky, Marc/E-3674-2011; OI michalsky, marc/0000-0002-7119-3634 FU National Institute of Diabetes and Digestive and Kidney Diseases (Cincinnati Children's Hospital Medical Center) [U01DK072493, UM1DK072493]; National Institute of Diabetes and Digestive and Kidney Diseases (University of Cincinnati) [UM1DK095710]; National Institutes of Health (Cincinnati Children's Hospital Medical Center) [UL1 TR000077-04]; National Institutes of Health (Nationwide Children's Hospital) [UL1RR025755]; National Institutes of Health (Texas Children's Hospital/Baylor College of Medicine) [M01-RR00188]; National Institutes of Health (University of Pittsburgh) [UL1 RR024153, UL1TR000005]; National Institutes of Health (University of Alabama, Birmingham) [UL1 TR000165] FX The Teen-LABS Consortium was funded by cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases through grants U01DK072493 (Cincinnati Children's Hospital Medical Center), UM1DK072493 (Cincinnati Children's Hospital Medical Center), and UM1DK095710 (University of Cincinnati). The study was also supported by National Institutes of Health grants UL1 TR000077-04 (Cincinnati Children's Hospital Medical Center), UL1RR025755 (Nationwide Children's Hospital), M01-RR00188 (Texas Children's Hospital/Baylor College of Medicine), UL1 RR024153 and UL1TR000005 (University of Pittsburgh), and UL1 TR000165 (University of Alabama, Birmingham). NR 28 TC 64 Z9 66 U1 1 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD JAN PY 2014 VL 168 IS 1 BP 47 EP 53 DI 10.1001/jamapediatrics.2013.4296 PG 7 WC Pediatrics SC Pediatrics GA 291RK UT WOS:000329846600012 PM 24189578 ER PT J AU Chiles, NS Phillips, CL Volpato, S Bandinelli, S Ferrucci, L Guralnik, JM Patel, KV AF Chiles, Nancy S. Phillips, Caroline L. Volpato, Stefano Bandinelli, Stefania Ferrucci, Luigi Guralnik, Jack M. Patel, Kushang V. TI Diabetes, peripheral neuropathy, and lower-extremity function SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article DE Gerontology; Geriatrics; Peripheral neuropathy; Lower extremity function ID PHYSICAL PERFORMANCE; BODY-COMPOSITION; WOMENS HEALTH; NERVE DYSFUNCTION; OLDER-ADULTS; AGE; DISABILITY; DECLINE; COMPLICATIONS; EPIDEMIOLOGY AB Objective: Diabetes among older adults causes many complications, including decreased lower-extremity function and physical disability. Diabetes can cause peripheral nerve dysfunction, which might be one pathway through which diabetes leads to decreased physical function. The study aims were to determine the following: (1) whether diabetes and impaired fasting glucose are associated with objective measures of physical function in older adults, (2) which peripheral nerve function (PNF) tests are associated with diabetes, and (3) whether PNF mediates the diabetes-physical function relationship. Research Design and Methods: This study included 983 participants, age 65 years and older from the InCHIANTI study. Diabetes was diagnosed by clinical guidelines. Physical performance was assessed using the Short Physical Performance Battery (SPPB), scored from 0 to 12 (higher values, better physical function) and usual walking speed (m/s). PNF was assessed via standard surface electroneurographic study of right peroneal nerve conduction velocity, vibration and touch sensitivity. Clinical cutpoints of PNF tests were used to create a neuropathy score from 0 to 5 (higher values, greater neuropathy). Multiple linear regression models were used to test associations. Results and Conclusion: One hundred twenty-six (12.8%) participants had diabetes. Adjusting for age, sex, education, and other confounders, diabetic participants had decreased SPPB (beta = -0.99; p < 0.01), decreased walking speed (beta = -0.1 m/s; p < 0.01), decreased nerve conduction velocity (beta = -1.7 m/s; p < 0.01), and increased neuropathy (beta = 0.25; p < 0.01) compared to non-diabetic participants. Adjusting for nerve conduction velocity and neuropathy score decreased the effect of diabetes on SPPB by 20%, suggesting partial mediation through decreased PNF. (C) 2014 Elsevier Inc. All rights reserved. C1 [Chiles, Nancy S.] Univ Maryland, Doctoral Program Gerontol, Baltimore, MD 21201 USA. [Chiles, Nancy S.] Univ Maryland Baltimore Cty, Doctoral Program Gerontol, Baltimore, MD 21201 USA. [Chiles, Nancy S.; Guralnik, Jack M.] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Phillips, Caroline L.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Volpato, Stefano] Univ Ferrara, Dept Med Sci, I-44100 Ferrara, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Chiles, NS (reprint author), 660 W Redwood St,Suite 200, Baltimore, MD 21201 USA. EM nchiles@epiumaryland.edu RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 FU Italian Ministry of Health [ICS 110.1\RS97.71]; Intramural Research Program of the National Institute on Aging, NIH [N01-AG-916413, N01-AG-821336, N01-AG-5-0002] FX The InCHIANTI study was supported as a targeted project (ICS 110.1\RS97.71) by the Italian Ministry of Health and, in part, by the Intramural Research Program of the National Institute on Aging, NIH (Contracts N01-AG-916413, N01-AG-821336, and N01-AG-5-0002). NR 25 TC 16 Z9 16 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD JAN-FEB PY 2014 VL 28 IS 1 BP 91 EP 95 DI 10.1016/j.jdiacomp.2013.08.007 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 288DL UT WOS:000329592100019 PM 24120281 ER PT J AU Pecoraro, A Ewen, E Horton, T Mooney, R Kolm, P McGraw, P Woody, G AF Pecoraro, Anna Ewen, Edward Horton, Terry Mooney, Ruth Kolm, Paul McGraw, Patty Woody, George TI Using the AUDIT-PC to Predict Alcohol Withdrawal in Hospitalized Patients SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE alcoholism; addictive behavior; screening; risk assessment; hospital medicine ID DISORDERS IDENTIFICATION TEST; OPERATING CHARACTERISTIC CURVES; PRIMARY-CARE; ROC ANALYSIS; CONSUMPTION; DETOXIFICATION; POPULATION; PRINCIPLES; SCIENCE; TESTS AB Alcohol withdrawal syndrome (AWS) occurs when alcohol-dependent individuals abruptly reduce or stop drinking. Hospitalized alcohol-dependent patients are at risk. Hospitals need a validated screening tool to assess withdrawal risk, but no validated tools are currently available. To examine the admission Alcohol Use Disorders Identification Test-(Piccinelli) Consumption (AUDIT-PC) ability to predict the subsequent development of AWS among hospitalized medical-surgical patients admitted to a non-intensive care setting. Retrospective case-control study of patients discharged from the hospital with a diagnosis of AWS. All patients with AWS were classified as presenting with AWS or developing AWS later during admission. Patients admitted to an intensive care setting and those missing AUDIT-PC scores were excluded from analysis. A hierarchical (by hospital unit) logistic regression was performed and receiver-operating characteristics were examined on those developing AWS after admission and randomly selected controls. Because those diagnosing AWS were not blinded to the AUDIT-PC scores, a sensitivity analysis was performed. The study cohort included all patients age a parts per thousand yen18 years admitted to any medical or surgical units in a single health care system from 6 October 2009 to 7 October 2010. After exclusions, 414 patients were identified with AWS. The 223 (53.9 %) who developed AWS after admission were compared to 466 randomly selected controls without AWS. An AUDIT-PC score a parts per thousand yen4 at admission provides 91.0 % sensitivity and 89.7 % specificity (AUC = 0.95; 95 % CI, 0.94-0.97) for AWS, and maximizes the correct classification while resulting in 17 false positives for every true positive identified. Performance remained excellent on sensitivity analysis (AUC = 0.92; 95 % CI, 0.90-0.93). Increasing AUDIT-PC scores were associated with an increased risk of AWS (OR = 1.68, 95 % CI 1.55-1.82, p < 0.001). The admission AUDIT-PC score is an excellent discriminator of AWS and could be an important component of future clinical prediction rules. Calibration and further validation on a large prospective cohort is indicated. C1 [Pecoraro, Anna; Woody, George] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Pecoraro, Anna; Horton, Terry; Woody, George] Delaware Valley Node, NIDA Clin Trials Network, Philadelphia, PA USA. [Ewen, Edward; Horton, Terry; McGraw, Patty] Christiana Care Hlth Syst, Dept Med, Newark, DE 19718 USA. [Mooney, Ruth] Christiana Care Hlth Syst, Dept Nursing, Newark, DE 19718 USA. [Kolm, Paul] Christiana Care Hlth Syst, Ctr Outcomes Res, Newark, DE 19718 USA. RP Ewen, E (reprint author), Christiana Care Hlth Syst, John H Ammon Med Educ Ctr, Dept Med, Suite 2E70, Newark, DE 19718 USA. EM eewen@christianacare.org RI Ewen, Edward/O-1904-2013 OI Ewen, Edward/0000-0003-4838-8182 FU National Institute on Drug Abuse (NIDA): Clinical Trials Network (CTN) [U10 DA-13043, KO5 DA-17009] FX This work was not funded by any external sources. Drs. Pecoraro and Woody receive salary support through the National Institute on Drug Abuse (NIDA): Clinical Trials Network (CTN) U10 DA-13043 (Pecoraro and Woody) and KO5 DA-17009 (Woody). NR 29 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JAN PY 2014 VL 29 IS 1 BP 34 EP 40 DI 10.1007/s11606-013-2551-9 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 284WR UT WOS:000329352900014 PM 23959745 ER PT J AU Danis, M Sommers, R Logan, J Weidmer, B Chen, S Goold, S Pearson, S McGlynn, E AF Danis, Marion Sommers, Roseanna Logan, Jean Weidmer, Beverly Chen, Shirley Goold, Susan Pearson, Steven McGlynn, Elizabeth TI Exploring Public Attitudes Towards Approaches to Discussing Costs in the Clinical Encounter SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE communication; decision making; health care costs; patient engagement ID OUT-OF-POCKET; EMPATHIC COMMUNICATION; CARE; BARRIERS; SEEKING; END AB Patients' willingness to discuss costs of treatment alternatives with their physicians is uncertain. To explore public attitudes toward doctor-patient discussions of insurer and out-of-pocket costs and to examine whether several possible communication strategies might enhance patient receptivity to discussing costs with their physicians. Focus group discussions and pre-discussion and post-discussion questionnaires. Two hundred and eleven insured individuals with mean age of 48 years, 51 % female, 34 % African American, 27 % Latino, and 50 % with incomes below 300 % of the federal poverty threshold, participated in 22 focus groups in Santa Monica, CA and in the Washington, DC metro area. Attitudes toward discussing out-of-pocket and insurer costs with physicians, and towards physicians' role in controlling costs; receptivity toward recommended communication strategies regarding costs. Participants expressed more willingness to talk to doctors about personal costs than insurer costs. Older participants and sicker participants were more willing to talk to the doctor about all costs than younger and healthier participants (OR = 1.8, p = 0.004; OR = 1.6, p = 0.027 respectively). Participants who face cost-related barriers to accessing health care were in greater agreement than others that doctors should play a role in reducing out-of-pocket costs (OR = 2.4, p = 0.011). Participants did not endorse recommended communication strategies for discussing costs in the clinical encounter. In contrast, participants stated that trust in one's physician would enhance their willingness to discuss costs. Perceived impediments to discussing costs included rushed, impersonal visits, and clinicians who are insufficiently informed about costs. This study suggests that trusting relationships may be more conducive than any particular discussion strategy to facilitating doctor-patient discussions of health care costs. Better public understanding of how medical decisions affect insurer costs and how such costs ultimately affect patients personally will be necessary if discussions about insurer costs are to occur in the clinical encounter. C1 [Danis, Marion; Sommers, Roseanna; Logan, Jean; Pearson, Steven] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Weidmer, Beverly] RAND Corp, Santa Monica, CA USA. [Chen, Shirley; Goold, Susan] Univ Michigan, Ann Arbor, MI 48109 USA. [McGlynn, Elizabeth] Kaiser Permanente, Oakland, CA USA. RP Danis, M (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM mdanis@nih.gov OI Goold, Susan Dorr/0000-0002-0258-9774 FU Intramural Research Program of the NIH, The Office of the Director of the NIH; Department of Bioethics at the NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH, The Office of the Director of the NIH and the Department of Bioethics at the NIH Clinical Center. NR 28 TC 13 Z9 13 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JAN PY 2014 VL 29 IS 1 BP 223 EP 229 DI 10.1007/s11606-013-2543-9 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 284WR UT WOS:000329352900048 PM 23881272 ER PT J AU Lehmann, T Dao, A Yaro, AS Diallo, M Timbine, S Huestis, DL Adamou, A Kassogue, Y Traore, AI AF Lehmann, Tovi Dao, A. Yaro, A. S. Diallo, M. Timbine, S. Huestis, D. L. Adamou, A. Kassogue, Y. Traore, A. I. TI Seasonal Variation in Spatial Distributions of Anopheles gambiae in a Sahelian Village: Evidence for Aestivation SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE spatial aggregation; dry-season diapause; hotspot; malaria; long-distance migration ID WESTERN KENYA HIGHLANDS; MALARIA TRANSMISSION; DRY SEASON; MOLECULAR-FORMS; VECTOR CONTROL; METABOLIC-RATE; SUDAN SAVANNA; HIGH-ALTITUDE; S FORMS; COMPLEX AB Changes in spatial distribution of mosquitoes over time in a Sahelian village were studied to understand the sources of the mosquitoes during the dry season when no larval sites are found. At that time, the sources of Anopheles gambiae Giles may be local shelters used by aestivating mosquitoes or migrants from distant populations. The mosquito distribution was more aggregated during the dry season, when few houses had densities 7- to 24-fold higher than expected. The high-density houses during the dry season differed from those of the wet season. Most high-density houses during the dry season changed between years, yet their vicinity was rather stable. Scan statistics confirmed the presence of one or two adjacent hotspots in the dry season, usually found on one edge of the village. These hotspots shifted between the early and late dry season. During the wet season, the hotspots were relatively stable near the main larval site. The locations of the hotspots in the wet season and early and late dry season were similar between years. Season-specific, stable, and focal hotspots are inconsistent with the predictions based on the arrival of migrants from distant localities during the dry season, but are consistent with the predictions based on local shelters used by aestivating mosquitoes. Targeting hotspots in Sahelian villages for vector control may not be effective because the degree of aggregation is moderate, the hotspots are not easily predicted, and they are not the sources of the population. However, targeting the dry-season shelters may be highly cost-effective, once they can be identified and predicted. C1 [Lehmann, Tovi; Huestis, D. L.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Dao, A.; Yaro, A. S.; Diallo, M.; Timbine, S.; Adamou, A.; Kassogue, Y.; Traore, A. I.] Univ Sci Tech & Technol, Mali Int Ctr Excellence Res ICER, Bamako, Mali. RP Lehmann, T (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM tlehmann@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank the villagers in Thierola for their hospitality and assistance with mosquito collections; Dia Elnaiem, Jose Ribeiro, Nafo Sogoba, Zhijian (Jake) Tu, and Mike Levy for their helpful comments on previous versions of this manuscript; and Cheick Traore, Richard Sakai, Robert Gwadz, and Thomas Wellems for logistical support. This study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 53 TC 8 Z9 8 U1 2 U2 11 PU ENTOMOLOGICAL SOC AMER PI LANHAM PA 10001 DEREKWOOD LANE, STE 100, LANHAM, MD 20706-4876 USA SN 0022-2585 EI 1938-2928 J9 J MED ENTOMOL JI J. Med. Entomol. PD JAN PY 2014 VL 51 IS 1 BP 27 EP 38 DI 10.1603/ME13094 PG 12 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 291CF UT WOS:000329804600003 PM 24605449 ER PT J AU Sandoz, KM Sturdevant, DE Hansen, B Heinzen, RA AF Sandoz, Kelsi M. Sturdevant, Daniel E. Hansen, Bryan Heinzen, Robert A. TI Developmental transitions of Coxiella bumetii grown in axenic media SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE Q fever; Coxiella; Differentiation; Axenic growth; Development; Viability ID Q-FEVER; LEGIONELLA-PNEUMOPHILA; BORDETELLA-PERTUSSIS; HYDROGEN-PEROXIDE; FATTY-ACIDS; BURNETII; CYCLODEXTRINS; CYCLE; BACTERIA; ENZYMES AB Coxiella burnetii undergoes a biphasic developmental cycle within its host cell that generates morphologically and physiologically distinct large cell variants (LCV) and small cell variants (SCV). During the lag phase of the C. burnetii growth cycle, non-replicating SCV differentiate into replicating LCV that in turn differentiate back into SCV during stationary phase. Nearly homogeneous SCV are observed in infected Vero cells after extended incubation (21 to 28 days). In the current study, we sought to establish whether C burnetii developmental transitions in host cells are recapitulated during host cell-free (axenic) growth in first and second generation acidified citrate cysteine media (ACCM-1 and ACCM-2, respectively). We show that ACCM-2 supported developmental transitions and viability. Although ACCM-1 also supported SCV to LCV transition, LCV to SCV transition did not occur after extended incubation (21 days). Instead, C burnetii exhibited a ghost-like appearance with bacteria containing condensed chromatin but otherwise devoid of cytoplasmic content. This phenotype correlated with a near total loss in viability between 14 and 21 days of cultivation. Transcriptional profiling of C burnetii following 14 days of incubation revealed elevated expression of oxidative stress genes in ACCM-1 cultivated bacteria. ACCM-2 differs from ACCM-1 by the substitution of methyl-beta-cyclodextrin (M beta-CD) for fetal bovine serum. Addition of M beta-CD to ACCM-1 at 7 days post-inoculation rescued C burnetii viability and lowered expression of oxidative stress genes. Thus, M beta-CD appears to alleviate oxidative stress in ACCM-2 to result in C burnetii developmental transitions and viability that mimic host cell-cultivated organisms. Axenic cultivation of C burnetii in ACCM-2 and new methods of genetic manipulation now allow investigation of the molecular basis of C burnetii biphasic development. Published by Elsevier B.V. C1 [Sandoz, Kelsi M.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Lab Intracellular Parasites, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Sturdevant, Daniel E.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Hansen, Bryan] NIAID, Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Heinzen, RA (reprint author), Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank Anders Omsland for critical review of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 38 TC 6 Z9 8 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 EI 1872-8359 J9 J MICROBIOL METH JI J. Microbiol. Methods PD JAN PY 2014 VL 96 BP 104 EP 110 DI 10.1016/j.mimet.2013.11.010 PG 7 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 290PO UT WOS:000329771000020 PM 24286928 ER PT J AU Steffen-Smith, EA Baker, EH Venzon, D Shandilya, S Bent, RS Warren, KE AF Steffen-Smith, Emilie A. Baker, Eva H. Venzon, David Shandilya, Shaefali Bent, Robyn S. Warren, Katherine E. TI Measurements of the pons as a biomarker of progression for pediatric DIPG SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Pediatric brain tumors; Diffuse intrinsic pontine glioma; Magnetic resonance imaging; Measurements; Prognosis ID INTRINSIC PONTINE GLIOMAS; BRAIN-STEM GLIOMAS; CLINICAL-TRIALS; DIFFUSE; CHILDREN; MRI; SPECTROSCOPY; SURVIVAL AB Treatment of pediatric diffuse intrinsic pontine glioma (DIPG) remains challenging, and reliable biomarkers of response are lacking. Radiographic response is a primary endpoint in many investigational studies of brain tumors, but there is no standard method of tumor measurement for DIPG, significant inter-observer variability exists given the invasive nature of these tumors, and tumor measurements are not predictive of outcome. Because DIPGs involve a significant portion of the pons, we evaluated the reliability and prognostic value of one-dimensional (1D) and two-dimensional (2D) pons measurements using anatomical landmarks rather than tumor boundaries. Patients with DIPG (n = 75) were evaluated longitudinally at our institution using MRI. Four readers independently performed 1D and 2D measurements of the pons using FLAIR images. Agreement and inter-reader variability were evaluated using differences among the six reader pairs and the coefficient of variation (CV). Prognostic value of pons measurements was calculated using Cox proportional hazards models, where relative hazard (RH) represents risk of death. Readers evaluated 384 exams. Agreement of readers' 1D and 2D measurements was strong (median difference between reader pairs 3.1 and 5.4 %, respectively), with low inter-reader variability (median CV = 3.1 % and median CV = 4.8 %, respectively). Increases in 1D and 2D pons measurements over time indicated poorer prognosis (RH = 2.29, p = 0.0025 and RH = 1.13, p = 0.0016, respectively), with shorter overall survival. Pons measurements had low inter-reader variability compared to previously reported tumor measurement techniques and correlated with outcome in children with DIPG. Measurements of the pons (as opposed to direct measurements of tumor) are a viable in vivo biomarker for DIPG. C1 [Steffen-Smith, Emilie A.; Shandilya, Shaefali; Bent, Robyn S.; Warren, Katherine E.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Baker, Eva H.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Steffen-Smith, EA (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10 Room 1-5750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM steffene@mail.nih.gov; warrenk@mail.nih.gov OI Steffen-Smith, Emilie/0000-0002-4966-3046 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was presented in part at the 2012 International Society of Pediatric Neuro-Oncology meeting in Toronto, Ontario Canada. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The views expressed do not necessarily represent the views of the National Institutes of Health or the United States Government. NR 21 TC 3 Z9 4 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JAN PY 2014 VL 116 IS 1 BP 127 EP 133 DI 10.1007/s11060-013-1266-4 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 288OU UT WOS:000329622100016 PM 24113877 ER PT J AU Nash, SH Kristal, AR Hopkins, SE Boyer, BB O'Brien, DM AF Nash, Sarah H. Kristal, Alan R. Hopkins, Scarlett E. Boyer, Bert B. O'Brien, Diane M. TI Stable Isotope Models of Sugar Intake Using Hair, Red Blood Cells, and Plasma, but Not Fasting Plasma Glucose, Predict Sugar Intake in a Yup'ik Study Population SO JOURNAL OF NUTRITION LA English DT Article ID SWEETENED BEVERAGE INTAKE; ASSESSING DIETARY-INTAKE; LIFE-SPAN; C-13 ABUNDANCE; CARBON; DELTA-C-13; BIOMARKER; NITROGEN; DELTA-N-15; FRUCTOSE AB Objectively measured biomarkers will help to resolve the controversial role of sugar intake in the etiology of obesity and related chronic diseases. We recently validated a dual-isotope model based on RBC carbon (delta C-13) and nitrogen (delta N-15) isotope ratios that explained a large percentage of the variation in self-reported sugar intake in a Yup'ik study population..Stable isotope ratios can easily be measured from many tissues, including RBCs, plasma, and hair; however, it is not known how isotopic models of sugar intake compare among these tissues. Here, we compared self-reported sugar intake with models based on RBCs, plasma, and hair delta C-13 and delta N-15 in Yup'ik people. We also evaluated associations of sugar intake with fasting plasma glucose delta C-13. Finally, we evaluated relations between delta C-13 and delta N-15 values in hair, plasma, RBCs, and fasting plasma glucose to allow comparison of isotope ratios across tissue types. Models using RBCs, plasma, or hair isotope ratios explained similar amounts of variance in total sugar, added sugar, and sugar-sweetened beverage intake (similar to 53%, 48%, and 34%, respectively); however, the association with delta C-13 was strongest for models based on RBCs and hair. There were no associations with fasting plasma glucose delta C-13 (R-2 = 0.03). The delta C-13 and delta N-15 values of RBCs, plasma, and hair showed strong, positive correlations; the slopes of these relations did not differ from 1. This study demonstrates that RBC, plasma, and hair isotope ratios predict sugar intake and provides data that will allow comparison of studies using different sample types. C1 [Nash, Sarah H.; Hopkins, Scarlett E.; Boyer, Bert B.; O'Brien, Diane M.] Univ Alaska Fairbanks, Inst Arctic Biol, Ctr Alaska Native Hlth Res, Fairbanks, AK USA. [Nash, Sarah H.; Boyer, Bert B.; O'Brien, Diane M.] Univ Alaska Fairbanks, Dept Biol & Wildlife, Fairbanks, AK USA. [Kristal, Alan R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Nash, SH (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. EM sarahhnash@gmail.com RI O'Brien, Diane/B-2919-2010; OI O'Brien, Diane/0000-0001-5807-9661; Kristal, Alan/0000-0002-7329-1617 FU National Center for Research Resources; National Institute of General Medical Sciences of the NIH [P20RR016430]; NIH National Institute of Diabetes and Digestive and Kidney Diseases [R01DK07442] FX Supported by the National Center for Research Resources and the National Institute of General Medical Sciences of the NIH through grant no. P20RR016430 and NIH National Institute of Diabetes and Digestive and Kidney Diseases through grant no. R01DK07442. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Research Resources or the NIH. NR 30 TC 6 Z9 6 U1 0 U2 8 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JAN PY 2014 VL 144 IS 1 BP 75 EP 80 DI 10.3945/jn.113.182113 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 287GU UT WOS:000329530800013 PM 24198311 ER PT J AU Ravillah, D Mohammed, A Qian, L Brewer, M Zhang, YT Biddick, L Steele, VE Rao, CV AF Ravillah, Durgadevi Mohammed, Altaf Qian, Li Brewer, Misty Zhang, Yuting Biddick, Laura Steele, Vernon E. Rao, Chinthalapally V. TI Chemopreventive Effects of an HDAC2-Selective Inhibitor on Rat Colon Carcinogenesis and APC(min/+) Mouse Intestinal Tumorigenesis SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; COLORECTAL-CANCER; CELL-CYCLE; PHASE-I; CHROMATIN-STRUCTURE; MOLECULAR-ORIGINS; HDAC2 EXPRESSION; APC GENE; APOPTOSIS AB Epigenetic modulators, particularly histone deacetylases (HDACs), are valid targets for cancer prevention and therapy. Recent studies report that HDAC2 overexpression is associated with colon tumor progression and is a potential target for colon cancer prevention. This study tested chemopreventive and dose-response effects of Ohio State University HDAC42 (OSU-HDAC42), a selective HDAC2 inhibitor, using a rat colon carcinogenesis model to assess aberrant crypt foci inhibition and a familial adenomatous polyposis model to assess intestinal tumor inhibition. Colonic aberrant crypt foci were induced by azoxymethane (AOM) (15 mg/kg body weight, once-weekly subcutaneous injections at 8 and 9 weeks age). One week after AOM treatment, groups of rats were fed an AIN-76A diet containing 0, 75, 150, and 300 ppm OSU-HDAC42 for 8 weeks, and colonic aberrant crypt foci were evaluated. To assess the inhibitory effect of OSU-HDAC42 on small-intestinal polyps and colon tumor growth, 6-week-old male C57Bl/6J-APC(min/+)mice were fed an AIN-76A diet containing 150 ppm OSU-HADC42 or 300 ppm pan-HDAC inhibitor suberoylanilide hydroxyamic acid (SAHA) for 80 days. Our results demonstrate that dietary OSU-HDAC42 produced dose-dependent inhibition of AOM-induced colonic aberrant crypt foci formation (13-50%; P, 0.01 to, 0.0001) and reduced multiple crypts with >= 4 crypts per focus (25-57%; P, 0.01 to, 0.0001) in F344 rats. Our findings show that 150 ppm OSU-HDAC42 significantly inhibited small-intestinal polyps (. 46%; P, 0.001), with polyp size measuring.1 mm (P, 0.001), and colon tumors (. 26%) in APCmin/1mice, whereas 300 ppm SAHA showed nonsignificant inhibition. Mice fed 150 ppm OSU-HDAC42 had significantly decreased HDAC2, proliferating cell nuclear antigen, B cell lymphoma 2, cyclin-dependent kinase 2, and cell division cycle homolog 25C expression levels and increased p53 expression levels. These observations demonstrate the chemopreventive efficacy of OSU-HDAC42 against chemically induced and polyposis models of intestinal tumorigenesis. C1 [Ravillah, Durgadevi; Mohammed, Altaf; Qian, Li; Brewer, Misty; Zhang, Yuting; Biddick, Laura; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, Hematol Oncol Sect,Dept Med,PCS Oklahoma Canc Ctr, Oklahoma City, OK 73104 USA. [Steele, Vernon E.] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, NIH, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, 975 NE 10th St,BRC Bldg 2,Room 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU NCI NIH HHS [N01CN53300, N01-CN53300] NR 49 TC 4 Z9 5 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JAN PY 2014 VL 348 IS 1 BP 59 EP 68 DI 10.1124/jpet.113.208645 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 292OI UT WOS:000329911200006 PM 24218540 ER PT J AU Desai, RI Grandy, DK Lupica, CR Katz, JL AF Desai, Rajeev I. Grandy, David K. Lupica, Carl R. Katz, Jonathan L. TI Pharmacological Characterization of a Dopamine Transporter Ligand That Functions as a Cocaine Antagonist SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID UPTAKE INHIBITORS; IN-VIVO; BENZTROPINE ANALOGS; 3-ALPHA-DIPHENYLMETHOXYTROPANE ANALOGS; H-3 WIN-35,428; RATS; RECEPTOR; BINDING; DRUGS; MICE AB An N-butyl analog of benztropine, JHW007 [N-(n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane], binds to dopamine transporters (DAT) but has reduced cocaine-like behavioral effects and antagonizes various effects of cocaine. The present study further examined mechanisms underlying these effects. Cocaine dose-dependently increased locomotion, whereas JHW007 was minimally effective but increased activity 24 hours after injection. JHW007 (3-10 mg/kg) dose-dependently and fully antagonized the locomotor-stimulant effects of cocaine (5-60 mg/kg), whereas N-methyl and N-allyl analogs and the dopamine (DA) uptake inhibitor GBR12909 [1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl) piperazine dihydrochloride] stimulated activity and failed to antagonize effects of cocaine. JHW007 also blocked the locomotor-stimulant effects of the DAT inhibitor GBR12909 but not stimulation produced by the delta-opioid agonist SNC 80 [4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide], which increases activity through nondopaminergic mechanisms. JHW007 blocked locomotor-stimulant effects of cocaine in both DA D2- and CB1-receptor knockout and wild-type mice, indicating a lack of involvement of these targets. Furthermore, JHW007 blocked effects of cocaine on stereotyped rearing but enhanced stereotyped sniffing, suggesting that interference with locomotion by enhanced stereotypies is not responsible for the cocaine-antagonist effects of JHW007. Time-course data indicate that administration of JHW007 antagonized the locomotor-stimulant effects of cocaine within 10 minutes of injection, whereas occupancy at the DAT, as determined in vivo, did not reach a maximum until 4.5 hours after injection. The sigma(1)-receptor antagonist BD 1008 [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide] blocked the locomotor-stimulant effects of cocaine. Overall, these findings suggest that JHW007 has cocaine-antagonist effects that are deviate from its DAT occupancy and that some other mechanism, possibly sigma-receptor antagonist activity, may contribute to the cocaineantagonist effect of JHW007 and like drugs. C1 [Desai, Rajeev I.; Katz, Jonathan L.] NIDA, Psychobiol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Lupica, Carl R.] NIDA, Electrophysiol Res Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Grandy, David K.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 FU Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse] FX This work was supported by the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse]. NR 33 TC 5 Z9 7 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JAN PY 2014 VL 348 IS 1 BP 106 EP 115 DI 10.1124/jpet.113.208538 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 292OI UT WOS:000329911200011 PM 24194528 ER PT J AU Gotoh, S Negishi, M AF Gotoh, Saki Negishi, Masahiko TI Serum- and Glucocorticoid-Regulated Kinase 2 Determines Drug-Activated Pregnane X Receptor to Induce Gluconeogenesis in Human Liver Cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CROSS-TALK; PROTEIN-KINASE; GLUCOSE; RIFAMPIN; MOUSE; PHARMACODYNAMICS; PHARMACOKINETICS; METABOLISM; TRANSPORT; AGONISTS AB Drug activation of the human nuclear pregnane X receptor (PXR) induced gluconeogenic genes and increased glucose production. In this study, we have determined that serum-and glucocorticoid-regulated kinase 2 (SGK2) is an essential factor that mediates this PXR-regulated glucose 6-phosphatase (G6Pase) induction and glucose production. Both SGK2 and G6Pase mRNAs were increased in rifampicin-treated HepG2 cells stably expressing human PXR. Reporter and chromatin immunoprecipitation assays delineated PXR activation of the SGK2 gene to a distal and proximal DNA sequence within its promoter: distal PXR response element (-2587/-2209) and proximal PXR response element (-115/-75), respectively. Small interfering RNA (siRNA) knockdown of SGK2 severely attenuated PXR-regulated induction of G6Pase as well as glucose production. SGK2 constitutes an insulin-independent signal pathway to regulate gluconeogenesis because siRNA knockdown of the insulin-responsive transcription factor forkhead box protein O1 did not affect rifampicin induction of G6Pase. Rifampicin treatment of two different samples of human primary hepatocytes revealed that PXR induces G6Pase in the presence of high levels of SGK2, whereas PXR represses G6Pase in its absence. Mediating PXR activation of the G6Pase gene is the first biological role found for hepatic SGK2 and might have therapeutic implications for side effects, such as diabetes, caused by drugs that activate PXR. C1 [Gotoh, Saki; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Intramural Research Program of National Institutes of Health National Institute of Environmental Health Sciences [Z01ES1005-01] FX This work was supported by the Intramural Research Program of National Institutes of Health National Institute of Environmental Health Sciences [Grant Z01ES1005-01]. NR 22 TC 6 Z9 6 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JAN PY 2014 VL 348 IS 1 BP 131 EP 140 DI 10.1124/jpet.113.209379 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 292OI UT WOS:000329911200014 PM 24204015 ER PT J AU Hiranita, T Kohut, SJ Soto, PL Tanda, G Kopajtic, TA Katz, JL AF Hiranita, Takato Kohut, Stephen J. Soto, Paul L. Tanda, Gianluigi Kopajtic, Theresa A. Katz, Jonathan L. TI Preclinical Efficacy of N-Substituted Benztropine Analogs as Antagonists of Methamphetamine Self-Administration in Rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DOPAMINE UPTAKE INHIBITORS; RHESUS-MONKEYS; MESOLIMBIC DOPAMINE; BINDING AFFINITIES; COCAINE DEPENDENCE; RECEPTOR-BINDING; HEROIN ADDICTION; SIGMA-RECEPTOR; AGONIST-LIKE; JHW 007 AB Atypical dopamine-uptake inhibitors have low abuse potential and may serve as leads for development of cocaine-abuse treatments. Among them, the benztropine (BZT) derivatives, N-butyl (JHW007), N-allyl (AHN2-005), and N-methyl (AHN1-055) analogs of 3 alpha-[bis(4'-fluorophenyl) methoxy]-tropane dose-dependently decreased cocaine self-administration without effects on food-maintained responding. Our study examined selectivity by assessing their effects on self-administration of other drugs. As with cocaine, each BZT analog (1.0-10.0 mg/kg i. p.) dose-dependently decreased maximal self-administration of d-methamphetamine (0.01-0.32 mg/kg/infusion) but was inactive against heroin (1.0-32.0 mu g/kg/infusion) and ketamine (0.032-1.0 mg/kg/infusion) self-administration. Further, standard dopamine indirect-agonists [WIN35,428 ((2)-3 beta-(4-fluorophenyl)- tropan-2-beta-carboxylic acid methyl ester tartrate), damphetamine (0.1-1.0 mg/kg i.p., each)] dose-dependently left-shifted self-administration dose-effect curves for d-methamphetamine, heroin, and ketamine. Noncompetitive NMDAglutamate receptor/channel antagonists [(+)-MK-801 (0.01-0.1 mg/kg i.p.), memantine (1.0-10.0 mg/kg i.p.)] also left-shifted dose-effect curves for d-methamphetamine and ketamine (but not heroin) self-administration. The mu-agonists [dl-methadone and morphine (1.0-10.0 mg/kg i. p., each)] dose-dependently decreased maximal self-administration of m-agonists (heroin, remifentanil) but not d-methamphetamine or ketamine self-administration. The mu-agonist-induced decreases were similar to the effects of BZT analogs on stimulant self-administration and effects of food prefeeding on responding maintained by food reinforcement. Radioligand-binding and behavioral studies suggested that inhibition of dopamine transporters and sigma receptors were critical for blocking stimulant self-administration by BZT-analogs. Thus, the present results suggest that the effects of BZT analogs on stimulant self-administration are similar to effects of mu-agonists on mu-agonist self-administration and food prefeeding on food-reinforced responding, which implicates behavioral mechanisms for these effects and further supports development of atypical dopamine uptake inhibitors as medications for stimulant abuse. C1 [Hiranita, Takato; Kohut, Stephen J.; Tanda, Gianluigi; Kopajtic, Theresa A.; Katz, Jonathan L.] NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Soto, Paul L.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Behav Biol, Baltimore, MD 21205 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov RI Tanda, Gianluigi/B-3318-2009; OI Tanda, Gianluigi/0000-0001-9526-9878; Katz, Jonathan/0000-0002-1068-1159 FU Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse. NR 52 TC 10 Z9 11 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JAN PY 2014 VL 348 IS 1 BP 174 EP 191 DI 10.1124/jpet.113.208264 PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 292OI UT WOS:000329911200018 PM 24194527 ER PT J AU Ganmaa, D Holick, MF Rich-Edwards, JW Frazier, LA Davaalkham, D Ninjin, B Janes, C Hoover, RN Troisi, R AF Ganmaa, Davaasambuu Holick, Michael F. Rich-Edwards, Janet W. Frazier, Lindsay A. Davaalkham, Dambadarjaa Ninjin, Boldbaatar Janes, Craig Hoover, Robert N. Troisi, Rebecca TI Vitamin D deficiency in reproductive age Mongolian women: A cross sectional study SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE 25-Hydroxyvitamin D; Vitamin D; Vitamin D deficiency; Healthy women; Reproductive age ID 25-HYDROXYVITAMIN D CONCENTRATIONS; BODY-MASS INDEX; LIVER-CIRRHOSIS; BINDING-PROTEIN; D INSUFFICIENCY; D METABOLITES; RISK; PREVALENCE; PREGNANCY; DISEASE AB Vitamin D production is critical not only for rickets prevention but for its role in several chronic diseases of adulthood. Maternal vitamin D status also has consequences for the developing fetus. This study assessed the prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] < 20 ng/ml) and insufficiency [25(OH)D = 20-29 ng/ml] in spring, among reproductive age Mongolian women. Blood was drawn in March and April, 2009 from 420 Mongolian women, 18-44 years of age. Serum 25(OH)D concentrations were measured, anthropometric measurements were performed and information was collected by interview on lifestyle, dietary and reproductive factors. Logarithm-transformed 25(OH)D levels were compared across risk factor categories by analysis of variance. Linear regression analysis was used to assess the independent associations of factors with vitamin D status. Cutaneous vitamin D-3 synthesis was assessed between December and July using a standard 7-dehydrocholesterol ampoule model. The vast majority of women 415 (98.8%) had serum 25(OH)D < 20 ng/ml (50 nmol/l) with an additional 4 women (<1%) in the insufficient range (20-29 ng/ml); only one women (0.2%) had sufficient levels (>30 ng/ml or 75 nmol/l). 25(OH)D concentrations were positively and independently associated with educational status and use of vitamin D supplements, but not with other demographic, lifestyle, reproductive, or anthropometric factors. 25(OH)D levels were not associated with dietary factors in this population, as there is little access to foods containing vitamin D in Mongolia. No production of previtamin D-3 was observed until March and was maximally effective in April and was sustained through July. These data suggest that the prevalence of vitamin D deficiency in spring among reproductive age women in Mongolia is high. Given the lack of naturally vitamin D-rich food in the diet and limited use of vitamin D supplements, food fortification and/or supplementation with vitamin D should be considered among these women. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Ganmaa, Davaasambuu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Rich-Edwards, Janet W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ganmaa, Davaasambuu] Harvard Univ, Sch Med, Dept Med, Channing Lab, Cambridge, MA 02138 USA. [Rich-Edwards, Janet W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Connors Ctr Womens Hlth & Gender Biol, Cambridge, MA 02138 USA. [Holick, Michael F.] Boston Univ, Med Ctr, Dept Med, Boston, MA 02215 USA. [Holick, Michael F.] Boston Univ, Med Ctr, Dept Physiol & Biophys, Vitamin Skin & Bone Res Lab D, Boston, MA 02215 USA. [Holick, Michael F.] Boston Univ, Med Ctr, Biol Effects Light Res Ctr, Boston, MA 02215 USA. [Frazier, Lindsay A.] Dana Farber Childrens Canc Ctr, Dept Pediat Oncol, Boston, MA USA. [Davaalkham, Dambadarjaa; Ninjin, Boldbaatar] Hlth Sci Univ Mongolia, Ulaanbaatar, Mongol Peo Rep. [Janes, Craig] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Hoover, Robert N.; Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. EM gdavaasa@hsph.harvard.edu FU National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This research was supported by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 40 TC 7 Z9 7 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD JAN PY 2014 VL 139 BP 1 EP 6 DI 10.1016/j.jsbmb.2013.09.011 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 288GF UT WOS:000329599300001 PM 24076033 ER PT J AU Deye, GA Magill, AJ AF Deye, Gregory A. Magill, Alan J. TI Primaquine for Prophylaxis of Malaria: Has the CYP Sailed? SO JOURNAL OF TRAVEL MEDICINE LA English DT Editorial Material ID NONIMMUNE COLOMBIAN SOLDIERS; PLASMODIUM-VIVAX MALARIA; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; DOXYCYCLINE; CHLOROQUINE; FALCIPARUM; MEFLOQUINE; TRAVELERS; 2D6 C1 [Deye, Gregory A.] NIH, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. [Magill, Alan J.] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Deye, GA (reprint author), NIAID, NIH, DMID, 6610 Rockledge Dr, North Bethesda, MD 20817 USA. EM gregory.deye@nih.gov NR 14 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1195-1982 EI 1708-8305 J9 J TRAVEL MED JI J. Travel Med. PD JAN PY 2014 VL 21 IS 1 BP 67 EP 69 DI 10.1111/jtm.12080 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 285DC UT WOS:000329372400014 PM 24251618 ER PT J AU Liu, XF Xiang, LM FitzGerald, DJ Pastan, I AF Liu, Xiu-Fen Xiang, Laiman FitzGerald, David J. Pastan, Ira TI Antitumor Effects of Immunotoxins Are Enhanced by Lowering HCK or Treatment with Src Kinase Inhibitors SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PSEUDOMONAS EXOTOXIN; FAMILY KINASES; MEDIATED APOPTOSIS; PHASE-I; MESOTHELIOMA; ACTIVATION; LEUKEMIA; GROWTH; TOXIN; CELLS AB Recombinant immunotoxins (RIT) are agents being developed for cancer treatment. They are composed of an Fv that binds to a cancer cell, fused to a 38-kDa fragment of Pseudomonas exotoxin A. SS1P is a RIT that targets mesothelin, a protein expressed on mesothelioma as well as pancreatic, ovarian, lung, and other cancers. Because the protein tyrosine kinase family regulates a variety of cellular processes and pathways, we hypothesized that tyrosine kinases might regulate susceptibility to immunotoxin killing. To investigate their role, we used siRNAs to lower the level of expression of the 88 known tyrosine kinases. We identified five tyrosine kinases, INSR, HCK, SRC, PDGFR beta, and BMX that enhance the activity of SS1P when their level of expression is lowered by siRNAs. We further investigated the Src family member HCK in this study. Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P. We investigated the mechanism of enhancement and found that HCK knockdown enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax. We then found that Src inhibitors mimic the stimulatory effect of HCK knockdown; both SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22-expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models. Our data suggest that the combination of immunotoxin with tyrosine kinase inhibitors may be an effective way to treat some cancers. C1 [Liu, Xiu-Fen; Xiang, Laiman; FitzGerald, David J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural Research Program of the 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 32 TC 9 Z9 9 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JAN PY 2014 VL 13 IS 1 BP 82 EP 89 DI 10.1158/1535-7163.MCT-13-0726 PG 8 WC Oncology SC Oncology GA 291GE UT WOS:000329815200009 PM 24145282 ER PT J AU Maede, Y Shimizu, H Fukushima, T Kogame, T Nakamura, T Miki, T Takeda, S Pommier, Y Murai, J AF Maede, Yuko Shimizu, Hiroyasu Fukushima, Toru Kogame, Toshiaki Nakamura, Terukazu Miki, Tsuneharu Takeda, Shunichi Pommier, Yves Murai, Junko TI Differential and Common DNA Repair Pathways for Topoisomerase I- and II-Targeted Drugs in a Genetic DT40 Repair Cell Screen Panel SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ANTITUMOR DRUGS; DAMAGE; COMPLEXES; PHOSPHODIESTERASE; INHIBITORS; CLEAVAGE; YEAST; ENZYME; TDP1; ANTICANCER AB Clinical topoisomerase I (Top1) and II (Top2) inhibitors trap topoisomerases on DNA, thereby inducing protein-linked DNA breaks. Cancer cells resist the drugs by removing topoisomerase-DNA complexes, and repairing the drug-induced DNA double-strand breaks (DSB) by homologous recombination and nonhomologous end joining (NHEJ). Because numerous enzymes and cofactors are involved in the removal of the topoisomerase-DNA complexes and DSB repair, it has been challenging to comprehensively analyze the relative contribution of multiple genetic pathways in vertebrate cells. Comprehending the relative contribution of individual repair factors would give insights into the lesions induced by the inhibitors and genetic determinants of response. Ultimately, this information would be useful to target specific pathways to augment the therapeutic activity of topoisomerase inhibitors. To this end, we put together 48 isogenic DT40 mutant cells deficient in DNA repair and generated one cell line deficient in autophagy (ATG5). Sensitivity profiles were established for three clinically relevant Top1 inhibitors (camptothecin and the indenoisoquinolines LMP400 and LMP776) and three Top2 inhibitors (etoposide, doxorubicin, and ICRF-193). Highly significant correlations were found among Top1 inhibitors as well as Top2 inhibitors, whereas the profiles of Top1 inhibitors were different from those of Top2 inhibitors. Most distinct repair pathways between Top1 and Top2 inhibitors include NHEJ, TDP1, TDP2, PARP1, and Fanconi Anemia genes, whereas homologous recombination seems relevant especially for Top1 and, to a lesser extent, for Top2 inhibitors. We also found and discuss differential pathways among Top1 inhibitors and Top2 inhibitors. (C)2013 AACR. C1 [Maede, Yuko; Kogame, Toshiaki; Takeda, Shunichi; Murai, Junko] Kyoto Univ, Dept Radiat Genet, Grad Sch Med, Kyoto, Japan. [Fukushima, Toru] Kyoto Univ, Grad Sch Med, Dept Diabet & Clin Nutr, Kyoto, Japan. [Nakamura, Terukazu] Kyoto Prefectural Univ, Dept Urol, Grad Sch Med, Kyoto 606, Japan. [Shimizu, Hiroyasu; Miki, Tsuneharu] Osaka Med Coll, Dept Hyg & Publ Hlth, Osaka, Japan. [Pommier, Yves; Murai, Junko] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM pommier@nih.gov; murai@rg.med.kyoto-u.ac.jp FU Japan Society for the Promotion of Science (JSPS); Kyoto University Foundation; Intramural Program of the National Cancer Institute, Center for Cancer Research [Z01 BC 006150]; JSPS Core-to-Core Program FX J. Murai is a recipient of a fellowship from the Japan Society for the Promotion of Science (JSPS) and the Kyoto University Foundation. Y. Pommier and J. Murai were supported by the Intramural Program of the National Cancer Institute, Center for Cancer Research (Z01 BC 006150). Y. Maede, H. Shimizu, and S. Takeda were supported by the JSPS Core-to-Core Program. NR 40 TC 36 Z9 37 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JAN PY 2014 VL 13 IS 1 BP 214 EP 220 DI 10.1158/1535-7163.MCT-13-0551 PG 7 WC Oncology SC Oncology GA 291GE UT WOS:000329815200021 PM 24130054 ER PT J AU Pan, J Zhang, Q Xiong, DH Vedell, P Yan, Y Jiang, H Cui, P Ding, F Tichelaar, JW Wang, Y Lubet, RA You, M AF Pan, Jing Zhang, Qi Xiong, Donghai Vedell, Peter Yan, Ying Jiang, Hui Cui, Peng Ding, Feng Tichelaar, Jay W. Wang, Yian Lubet, Ronald A. You, Ming TI Transcriptomic Analysis by RNA-Seq Reveals AP-1 Pathway as Key Regulator that Green Tea May Rely on to Inhibit Lung Tumorigenesis SO MOLECULAR CARCINOGENESIS LA English DT Article DE lung cancer; green tea; AP-1 ID C-JUN; (-)-EPIGALLOCATECHIN GALLATE; INDUCED TRANSFORMATION; TUMOR PROMOTION; POLYPHENON-E; A/J MICE; CANCER; EXPRESSION; CARCINOGENESIS; GROWTH AB Green tea is a promising chemopreventive agent for lung cancer. Multiple signaling events have been reported, however, the relative importance of these mechanisms in mediating the chemopreventive function of green tea is unclear. In the present study, to examine the involvement of AP-1 in green tea polyphenols induced tumor inhibition, human NSCLC cell line H1299 and mouse SPON 10 cells were identified as AP-1 dependent, as these two lines exhibit high constitutive AP-1 activity, and when TAM67 expression was induced with doxycycline, cell growth was inhibited and correlated with suppressed AP-1 activity. RNA-seq was used to determine the global transcriptional effects of AP-1 inhibition and also uncover the possible involvement of AP-1 in tea polyphenols induced chemoprevention. TAM67 mediated changes in gene expression were identified, and within down-regulated genes, AP-1 was identified as a key transcription regulator. RNA-seq analysis revealed that Polyphenon E-treated cells shared 293 commonly down-regulated genes within TAM67 expressing H1299 cells, and by analysis of limited Chip-seq data, over 10% of the down-regulated genes contain a direct AP-1 binding site, indicating that Polyphenon E elicits chemopreventive activity by regulating AP-1 target genes. Conditional TAM67 expressing transgenic mice and NSCLC cell lines were used to further confirm that the chemopreventive activity of green tea is AP-1 dependent. Polyphenon E lost its chempreventive function both in vitro and in vivo when AP-1 was inhibited, indicating that AP-1 inhibition is a major pathway through which green tea exhibits chemopreventive effects. (c) 2013 Wiley Periodicals, Inc. C1 [Pan, Jing; Yan, Ying; Wang, Yian; You, Ming] Washington Univ, Sch Med, Dept Surg, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Pan, Jing; Zhang, Qi; Xiong, Donghai; Vedell, Peter; Jiang, Hui; Cui, Peng; Ding, Feng; Tichelaar, Jay W.; You, Ming] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Ctr Canc, Milwaukee, WI 53226 USA. [Lubet, Ronald A.] NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Med Coll Wisconsin, Dept Pharmacol & Toxicol, Ctr Canc, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. NR 34 TC 1 Z9 2 U1 1 U2 41 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JAN PY 2014 VL 53 IS 1 BP 19 EP 29 DI 10.1002/mc.21941 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 271CP UT WOS:000328368400003 PM 24343902 ER PT J AU Wendell, CR Waldstein, SR Zonderman, AB AF Wendell, Carrington R. Waldstein, Shari R. Zonderman, Alan B. TI Nonlinear Longitudinal Trajectories of Cholesterol and Neuropsychological Function SO NEUROPSYCHOLOGY LA English DT Article DE cholesterol; neuropsychology; cognitive decline; longitudinal ID COGNITIVE DECLINE; LATE-LIFE; SERUM-CHOLESTEROL; ALZHEIMERS-DISEASE; PERFORMANCE; POPULATION; DEMENTIA; ASSOCIATIONS; IMPAIRMENT; STATINS AB Objective: Prior literature has identified inconsistent longitudinal associations between total cholesterol and cognitive decline. The authors examined prospective nonlinear relations of coincident trajectories of total cholesterol and cognitive function among persons free of stroke, dementia, and other neurological disease. Method: Up to 1,601 participants from the Baltimore Longitudinal Study of Aging (aged 19-93, 51% male, 75% White) underwent fasting cholesterol measurement and neuropsychological assessment on up to 12 occasions (M = 3.2, SD = 2.1) over up to 19 years (M = 6.4, SD = 5.3) of follow-up. Mixed-effects regression analyses were adjusted for age, sex, race, education, systolic blood pressure, body mass index, cardiovascular disease, lipid-lowering medication use, smoking, alcohol use, and depressive symptoms. Results: Analyses revealed significant longitudinal associations between quadratic total cholesterol and performance on measures of global mental status, verbal learning, executive function, and language (all ps < .05). In general, higher total cholesterol was associated with poorer middle-aged or young-old (60-69 years) cognitive performance, but better old-old (80-89 years) cognitive performance. Linear models also revealed an association between lower total cholesterol and accelerated decline in visual memory performance. Conclusions: Overall, results indicate nonlinear longitudinal relations of total cholesterol to cognitive decline. Whereas higher cholesterol levels were associated with cognitive decline in the middle-aged or young-old, lower cholesterol levels were related to cognitive decline among old-old participants. C1 [Wendell, Carrington R.; Zonderman, Alan B.] NIH, Bethesda, MD USA. [Wendell, Carrington R.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21218 USA. [Wendell, Carrington R.; Waldstein, Shari R.] Univ Maryland, College Pk, MD 20742 USA. [Waldstein, Shari R.] Univ Maryland, Sch Med, College Pk, MD 20742 USA. [Waldstein, Shari R.] Baltimore VA Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. RP Wendell, CR (reprint author), NIA, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM cwendell@jhmi.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 35 TC 5 Z9 5 U1 0 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 EI 1931-1559 J9 NEUROPSYCHOLOGY JI Neuropsychology PD JAN PY 2014 VL 28 IS 1 BP 106 EP 112 DI 10.1037/neu0000002 PG 7 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 281RO UT WOS:000329118900012 PM 24188111 ER PT J AU McPherson, CA Merrick, BA Harry, GJ AF McPherson, C. A. Merrick, B. A. Harry, G. J. TI In Vivo Molecular Markers for Pro-inflammatory Cytokine M1 Stage and Resident Microglia in Trimethyltin-Induced Hippocampal Injury SO NEUROTOXICITY RESEARCH LA English DT Article DE M1 microglia; Neuroinflammation; Trimethyltin; Tumor necrosis factor; Microglia polarization ID NECROSIS-FACTOR-ALPHA; NICOTINIC ACETYLCHOLINE-RECEPTORS; QUANTITATIVE NUCLEASE PROTECTION; B-CELL LYMPHOMA; GENE-EXPRESSION; MESSENGER-RNA; DENTATE GYRUS; ALTERNATIVE ACTIVATION; INDUCED APOPTOSIS; GRANULE NEURONS AB Microglia polarization to the classical M1 activation state is characterized by elevated pro-inflammatory cytokines; however, a full profile has not been generated in the early stages of a sterile inflammatory response recruiting only resident microglia. We characterized the initial M1 state in a hippocampal injury model dependent upon tumor necrosis factor (TNF) receptor signaling for dentate granule cell death. Twenty-one-day-old CD1 male mice were injected with trimethyltin (TMT 2.3 mg/kg, i.p.) and the hippocampus was examined at an early stage (24-h post-dosing) of neuronal death. Glia activation was assessed using a custom quantitative nuclease protection assay. We report elevated mRNA levels for glia response such as ionizing calcium-binding adapter molecule-1 and glial fibrillary acidic protein (Gfap); Fas, hypoxia inducible factor alpha, complement component 1qb, TNF-related genes (Tnf, Tnfaip3, Tnfrsfla); interleukin-1 alpha, Cd44, chemokine (C-C motif) ligand (Ccl)2, Cc14, integrin alpha M, lipocalin (Lcn2), and secreted phosphoprotein 1 (Spp1). These changes occurred in the absence of changes in matrix metalloproteinase 9 and 12, neural cell adhesion molecule, metabotropic glutamate receptor (Grm)3, and Ly6/neurotoxin 1 (Lynx1), as well as, a decrease in neurotrophin 3, glutamate receptor subunit epsilon (Grin)-2b, and neurotrophic tyrosine kinase receptor, type 3. The M2 anti-inflammatory marker, transforming growth factor beta-1 (Tgfb1) was elevated. mRNAs associated with early stage of injury-induced neurogenesis including fibroblast growth factor 21 and Mki67 were elevated. In the "non-injured" temporal cortex receiving projections from the hippocampus, Lynx1, Grm3, and Grin2b were decreased and Gfap increased. Formalin fixed-paraffin-embedded tissue did not generate a comparable profile. C1 [McPherson, C. A.; Harry, G. J.] NIEHS, Neurotoxicol Grp, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Merrick, B. A.] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), NIEHS, Neurotoxicol Grp, Div Natl Toxicol Program, NIH, POB 12233,MD E1-07, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU Division of Intramural Research and the Division National Toxicology Program, NIEHS/NIH [1Z01ES101623] FX The authors thank the NIEHS Microarray Core for their expert assistant with the initial microarray analysis used for selection of qNPA probes, Dr. Grace Kissling for statistical expertise, and Drs. Stephanie L. Smith-Roe and Chad Blystone of NIEHS for reviewing the final manuscript. This study was funded by the Division of Intramural Research and the Division National Toxicology Program, NIEHS/NIH (1Z01ES101623). The qNPA was conducted at HTG under an NTP contract with technical expertise from Dr John Luecke. The statements, opinions, or conclusions contained within this manuscript do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the United States Government. NR 73 TC 11 Z9 11 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 EI 1476-3524 J9 NEUROTOX RES JI Neurotox. Res. PD JAN PY 2014 VL 25 IS 1 BP 45 EP 56 DI 10.1007/s12640-013-9422-3 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 284NR UT WOS:000329326600005 PM 24002884 ER PT J AU Svetkey, LP Clark, JM Funk, K Corsino, L Batch, BC Hollis, JF Appel, LJ Brantley, PJ Loria, CM Champagne, CM Vollmer, WM Stevens, VJ AF Svetkey, Laura P. Clark, Jeanne M. Funk, Kristine Corsino, Leonor Batch, Bryan C. Hollis, Jack F. Appel, Lawrence J. Brantley, Phillip J. Loria, Catherine M. Champagne, Catherine M. Vollmer, William M. Stevens, Victor J. TI Greater weight loss with increasing age in the weight loss maintenance trial SO OBESITY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; TYPE-2 DIABETES-MELLITUS; LIFE-STYLE INTERVENTION; DISEASE RISK-FACTORS; ALL-CAUSE MORTALITY; BODY-MASS INDEX; BLOOD-PRESSURE; HYPERTENSION PREVENTION; OLDER PERSONS; OBESITY AB Objective To determine the effect of age on weight loss and weight loss maintenance in participants in the Weight Loss Maintenance trial (WLM). Design and Methods Secondary analysis of a randomized controlled trial of overweight/obese adults with CVD risk factors was conducted. Participants were 1685 adults with baseline BMI 25-45 kg m2 with hypertension and/or dyslipidemia. Those who lost at least 4kg in an initial 6-month behavioral weight loss intervention (N = 1,032) were randomly assigned to a 30-month maintenance phase of self-directed control (SD), monthly personal counseling (PC), or unlimited access to an internet-based intervention (IT). Age groups were defined post-hoc and weight change was compared among age groups. Results Participants 60 years old initially lost more weight than younger individuals, and sustained greater weight loss in IT and PC but not in SD (P value for trend 0.024, 0.002, and 0.36, respectively). Conclusions In WLM, adults age 60 years had greater initial weight loss and greater sustained weight loss over 3 years, compared to younger adults. Older adults had greater weight loss maintenance with either personal counseling or internet-based intervention. Future research should determine optimal implementation strategies and effects of weight loss on health outcomes in older adults. C1 [Svetkey, Laura P.] Duke Univ, Med Ctr, Dept Med, Div Nephrol, Durham, NC 27710 USA. [Svetkey, Laura P.] Duke Univ, Med Ctr, Duke Hypertens Ctr, Durham, NC 27710 USA. [Svetkey, Laura P.] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27710 USA. [Clark, Jeanne M.; Appel, Lawrence J.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Funk, Kristine; Hollis, Jack F.; Vollmer, William M.; Stevens, Victor J.] Kaiser Permanente Northwest, Ctr Hlth Res, Hlth Sci Programs, Portland, OR USA. [Corsino, Leonor; Batch, Bryan C.] Duke Univ, Med Ctr, Dept Med, Div Endocrinol, Durham, NC 27710 USA. [Brantley, Phillip J.; Champagne, Catherine M.] Louisiana State Univ, Pennington Biomed Res Ctr, Behav Med Lab, Baton Rouge, LA 70808 USA. [Loria, Catherine M.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Svetkey, LP (reprint author), Duke Univ, Med Ctr, Dept Med, Div Nephrol, Durham, NC 27710 USA. FU National Heart, Lung, Blood Institute [5-U01 HL68734, 5-U01 HL68676, 5-U01 HL68790, 5-U01 HL68920, 5-HL68955] FX National Heart, Lung, Blood Institute grants 5-U01 HL68734, 5-U01 HL68676, 5-U01 HL68790, 5-U01 HL68920, and 5-HL68955. NR 39 TC 6 Z9 6 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JAN PY 2014 VL 22 IS 1 BP 39 EP 44 DI 10.1002/oby.20506 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 288LN UT WOS:000329613600010 PM 23640912 ER PT J AU Xiao, Q Hsing, AW Park, Y Moore, SC Matthews, CE de Gonzalez, AB Kitahara, CM AF Xiao, Qian Hsing, Ann W. Park, Yikyung Moore, Steven C. Matthews, Charles E. de Gonzalez, Amy Berrington Kitahara, Cari M. TI Body mass index and mortality among blacks and whites adults in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial SO OBESITY LA English DT Article ID ALL-CAUSE MORTALITY; US ADULTS; WAIST CIRCUMFERENCE; PROSPECTIVE COHORT; ABDOMINAL OBESITY; WOMEN; RISK; WEIGHT; BMI; FAT AB Objective In a large prospective cohort, we examined the relationship of body mass index (BMI) with mortality among blacks and compared the results to those among whites in this population. Design and Methods The study population consisted of 7,446 non-Hispanic black and 130,598 white participants, ages 49-78 at enrollment, in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. BMI at baseline, BMI at age 20, and BMI change were calculated using self-reported and recalled height and weight. Relative risks were stratified by race and sex and adjusted for age, education, marital status, and smoking. Results During follow-up, 1,495 black and 18,236 white participants died (mean = 13 years). Clear J-shaped associations between BMI and mortality were observed among white men and women. Among black men and women, the bottoms of these curves were flatter, and increasing risks of death with greater BMI were observed only at higher BMI levels (35.0). Associations for BMI at age 20 and BMI change also appeared to be stronger in magnitude in whites versus blacks, and these racial differences appeared to be more pronounced among women. Conclusion Our results suggest that BMI may be more weakly associated with mortality in blacks, particularly black women, than in whites. C1 [Xiao, Qian; Park, Yikyung; Moore, Steven C.; Matthews, Charles E.; de Gonzalez, Amy Berrington; Kitahara, Cari M.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hsing, Ann W.] Stanford Canc Inst, Canc Prevent Inst Calif, Fremont, CA USA. RP Xiao, Q (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM qian.xiao@nih.gov RI matthews, Charles/E-8073-2015; Moore, Steven/D-8760-2016; Kitahara, Cari/R-8267-2016; OI matthews, Charles/0000-0001-8037-3103; Moore, Steven/0000-0002-8169-1661; Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health, National Cancer Institute, National Institutes of Health, 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, National Institutes of Health, Department of Health and Human Services. NR 38 TC 4 Z9 4 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JAN PY 2014 VL 22 IS 1 BP 260 EP 268 DI 10.1002/oby.20412 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 288LN UT WOS:000329613600038 PM 23512729 ER PT J AU Srinivasan, S Williams, SD AF Srinivasan, Shobha Williams, Shanita D. TI Transitioning from Health Disparities to a Health Equity Research Agenda: The Time Is Now SO PUBLIC HEALTH REPORTS LA English DT Article ID ASTHMA AB Health disparities are real. The evidence base is large and irrefutable. As such, the time is now to shift the research emphasis away from solely documenting the pervasiveness of the health disparities problem and begin focusing on health equity, the highest level of health possible. The focus on health equity research will require investigators to propose projects that develop and evaluate evidence-based solutions to health differences that are driven largely by social, economic, and environmental factors. This article highlights ongoing research and programmatic efforts underway at the National Institutes of Health that hold promise for advancing population health and improving health equity. C1 [Srinivasan, Shobha] NCI, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Williams, Shanita D.] Bur Hlth Profess, US Dept HHS, US Hlth Resources & Serv Adm, Div Nursing, Rockville, MD USA. RP Srinivasan, S (reprint author), NCI, US Dept HHS, NIH, 9609 Med Ctr Dr,Room 4E432,MSC 9764, Bethesda, MD 20892 USA. EM ss688k@nih.gov NR 23 TC 5 Z9 5 U1 0 U2 3 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1900 M ST NW, STE 710, WASHINGTON, DC 20036 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD JAN-FEB PY 2014 VL 129 SU 2 BP 71 EP 76 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 288BN UT WOS:000329587100013 PM 24385668 ER PT J AU Koola, MM Gorelick, DA McMahon, RP Liu, F Huestis, MA Linthicum, J Feldman, SM Warren, KR Wehring, HJ Kelly, DL AF Koola, Maju Mathew Gorelick, David A. McMahon, Robert P. Liu, Fang Huestis, Marilyn A. Linthicum, Jared Feldman, Stephanie M. Warren, Kimberly R. Wehring, Heidi J. Kelly, Deanna L. TI Psychiatric symptom differences in people with schizophrenia associated with substantial lifetime substance use but no current substance use disorder SO SCHIZOPHRENIA RESEARCH LA English DT Letter ID DOUBLE-BLIND; RIMONABANT C1 [Koola, Maju Mathew; Gorelick, David A.; McMahon, Robert P.; Liu, Fang; Linthicum, Jared; Feldman, Stephanie M.; Warren, Kimberly R.; Wehring, Heidi J.; Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Koola, Maju Mathew] Sheppard Pratt Hlth Syst, Baltimore, MD 21204 USA. [Gorelick, David A.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Warren, Kimberly R.] Morgan State Univ, Dept Psychol, Baltimore, MD 21239 USA. RP Koola, MM (reprint author), Sheppard Pratt Hlth Syst, Clin Res Program, Baltimore, MD 21204 USA. EM majujuju@yahoo.com FU Intramural NIH HHS [Z99 DA999999]; NIMH NIH HHS [R34 MH077839, R34 MH 077839]; PHS HHS [P30 068580, HSN271200599091CADB] NR 6 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN PY 2014 VL 152 IS 1 BP 315 EP 316 DI 10.1016/j.schres.2013.11.035 PG 2 WC Psychiatry SC Psychiatry GA 283AR UT WOS:000329217000052 PM 24333005 ER PT J AU Agnihothri, RV Courville, AB Linderman, JD Smith, S Brychta, R Remaley, A Chen, KY Simchowitz, L Celi, FS AF Agnihothri, Ritesh V. Courville, Amber B. Linderman, Joyce D. Smith, Sheila Brychta, Robert Remaley, Alan Chen, Kong Y. Simchowitz, Louis Celi, Francesco S. TI Moderate Weight Loss Is Sufficient to Affect Thyroid Hormone Homeostasis and Inhibit Its Peripheral Conversion SO THYROID LA English DT Article ID BODY-MASS INDEX; RESTING METABOLIC-RATE; ENERGY-EXPENDITURE; EUTHYROID SUBJECTS; LOSS MAINTENANCE; MAJOR SOURCE; US ADULTS; FREE T4; OBESITY; TRIIODOTHYRONINE AB Background: Thyroid hormones are important determinants of energy expenditure, and in rodents, adipose tissue affects thyroid hormone homeostasis via leptin signaling. The relationship between thyroid hormones and nutritional status in humans has been assessed primarily in drastic dietary or bariatric surgery interventions, while limited information is available on serial assessment of this axis during moderate, prolonged dietary restriction. Methods: To evaluate the effects of moderate dietary restriction on thyroid hormone homeostasis, 47 subjects with a body mass index (BMI) of 25-45kg/m(2) were enrolled in a longitudinal intervention study; 30 nonoverweight volunteers were also enrolled as controls. Overweight and obese subjects underwent a 12-month individualized dietary intervention aimed at achieving a 5-10% weight loss. Results: The intervention resulted in a 6.30.9kg (6.5 +/- 1.0%) weight loss. At baseline, thyrotropin (TSH) and T3 concentrations correlated significantly with fat mass (R=0.257, p=0.024 and R=0.318, p=0.005, respectively). After weight loss, T3 decreased significantly (from 112.7 +/- 3.1 to 101.8 +/- 2.6ng/dL, p<0.001) in the absence of significant changes in TSH or free T4 (fT4). The decrease in serum T3 correlated with the decrease in weight (R=0.294, p<0.001). The T3:fT4 ratio decreased significantly (p=0.02) in individuals who lost >5% body weight. Conclusions: T3 concentration closely correlates with individual nutritional status, and moderate weight loss results in a decrease in T3 with minimal changes in other thyroid hormone homeostasis parameters. The data suggest that a decrease in peripheral conversion of the prohormone T4 into its hormonally active metabolite T3 is at least in part responsible for the observed changes in thyroid hormone homeostasis. C1 [Agnihothri, Ritesh V.; Linderman, Joyce D.; Smith, Sheila; Brychta, Robert; Chen, Kong Y.; Simchowitz, Louis; Celi, Francesco S.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. [Simchowitz, Louis] Natl Inst Diabet & Digest & Kidney Dis, Off Director, Bethesda, MD 20892 USA. [Courville, Amber B.] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Remaley, Alan] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Celi, FS (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, CRC, Bldg 10,RM 6-3940 10 Ctr Dr,MSC 1613, Bethesda, MD 20892 USA. EM fsceli@vcu.edu OI Chen, Kong/0000-0002-0306-1904 FU Intramural Research Program of the NIDDK program [Z01-DK047057-02]; Clinical Center, NIH FX The authors gratefully acknowledge the help and professionalism of the nursing, Nutrition Department, laboratory, and ancillary personnel of the NIH Metabolic Unit. The technical help of Mary Walter and Xiongce Zhao and the constructive criticism of Paul Lee are gratefully acknowledged. This research could not have been accomplished without the selfless participation of the study volunteers. This work was supported by the Intramural Research Program of the NIDDK program Z01-DK047057-02, and the Clinical Center, NIH. NR 46 TC 13 Z9 13 U1 2 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 JAN 1 PY 2014 VL 24 IS 1 BP 19 EP 26 DI 10.1089/thy.2013.0055 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 285YM UT WOS:000329431000004 PM 23902316 ER PT J AU McLeod, DSA Cooper, DS Ladenson, PW Ain, KB Brierley, JD Fein, HG Haugen, BR Jonklaas, J Magner, J Ross, DS Skarulis, MC Steward, DL Maxon, HR Sherman, SI AF McLeod, Donald S. A. Cooper, David S. Ladenson, Paul W. Ain, Kenneth B. Brierley, James D. Fein, Henry G. Haugen, Bryan R. Jonklaas, Jacqueline Magner, James Ross, Douglas S. Skarulis, Monica C. Steward, David L. Maxon, Harry R. Sherman, Steven I. CA Natl Thyroid Canc Treatment Cooper TI Prognosis of Differentiated Thyroid Cancer in Relation to Serum Thyrotropin and Thyroglobulin Antibody Status at Time of Diagnosis SO THYROID LA English DT Article ID CHRONIC LYMPHOCYTIC THYROIDITIS; STAGING SYSTEMS; PAPILLARY; CARCINOMA; RISK; DISEASE; TSH; SUPPRESSION; PROGRESSION; RECURRENCE AB Background: Serum thyrotropin (TSH) concentration and thyroid autoimmunity may be of prognostic importance in differentiated thyroid cancer (DTC). Preoperative serum TSH level has been associated with higher DTC stage in cross-sectional studies; data are contradictory on the significance of thyroid autoimmunity at the time of diagnosis. Objective: We sought to assess whether preoperative serum TSH and perioperative antithyroglobulin antibodies (TgAb) were associated with thyroid cancer stage and outcome in DTC patients followed by the National Thyroid Cancer Treatment Cooperative Study, a large multicenter thyroid cancer registry. Methods: Patients registered after 1996 with available preoperative serum TSH (n=617; the TSH cohort) or perioperative TgAb status (n=1770; the TgAb cohort) were analyzed for tumor stage, persistent disease, recurrence, and overall survival (OS; median follow-up, 5.5 years). Parametric tests assessed log-transformed TSH, and categorical variables were tested with chi square. Disease-free survival (DFS) and OS was assessed with Cox models. Results: Geometric mean serum TSH levels were higher in patients with higher-stage disease (Stage III/IV=1.48 vs. 1.02mU/L for Stages I/II; p=0.006). The relationship persisted in those aged 45 years after adjusting for sex (p=0.01). Gross extrathyroidal extension (p=0.03) and presence of cervical lymph node metastases (p=0.003) were also significantly associated with higher serum TSH. Disease recurrence and all-cause mortality occurred in 37 and 38 TSH cohort patients respectively, which limited the power for survival analysis. Positive TgAb was associated with lower stage on univariate analysis (positive TgAb in 23.4% vs. 17.8% of Stage I/II vs. III/IV patients, respectively; p=0.01), although the relationship lost significance when adjusting for age and sex (p=0.34). Perioperative TgAb was not an independent predictor of DFS (hazard ratio=1.12 [95% confidence interval=0.74-1.69]) or OS (hazard ratio=0.98 [95% confidence interval=0.56-1.72]). Conclusions: Preoperative serum TSH level is associated with higher DTC stage, gross extrathyroidal extension, and neck node metastases. Perioperative TgAb is not an independent predictor of DTC prognosis. A larger cohort is required to assess whether preoperative serum TSH level predicts recurrence or mortality. C1 [McLeod, Donald S. A.] Royal Brisbane & Womens Hosp, Dept Internal Med & Aged Care, Herston, Qld 4029, Australia. [McLeod, Donald S. A.] Royal Brisbane & Womens Hosp, Dept Endocrinol, Herston, Qld 4029, Australia. [McLeod, Donald S. A.] Queensland Inst Med Res, Canc Control Grp, Herston, Qld 4006, Australia. [Cooper, David S.; Ladenson, Paul W.] Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Baltimore, MD USA. [Ain, Kenneth B.] Vet Affairs Med Ctr, Dept Internal Med, Lexington, KY USA. [Ain, Kenneth B.] Univ Kentucky, Lexington, KY USA. [Brierley, James D.] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Fein, Henry G.] Sinai Hosp, Div Endocrinol & Metab, Baltimore, MD 21215 USA. [Haugen, Bryan R.] Univ Colorado, Sch Med, Div Endocrinol Metab & Diabet, Aurora, CO USA. [Jonklaas, Jacqueline] Georgetown Univ, Med Ctr, Dept Med, Div Endocrinol, Washington, DC 20007 USA. [Magner, James] Genzyme Corp, Cambridge, MA USA. [Ross, Douglas S.] Massachusetts Gen Hosp, Thyroid Unit, Boston, MA 02114 USA. [Skarulis, Monica C.] NIH, Diabet Endocrinol Obes Branch, Bethesda, MD 20892 USA. [Steward, David L.] Univ Cincinnati, Med Ctr, Dept Head & Neck Surg, Cincinnati, OH 45267 USA. [Maxon, Harry R.] Univ Cincinnati, Med Ctr, Dept Nucl Med, Cincinnati, OH 45267 USA. [Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. RP McLeod, DSA (reprint author), Royal Brisbane & Womens Hosp, Dept Internal Med & Aged Care, Herston, Qld 4029, Australia. EM donald.mcleod@qimr.edu.au RI Jonklaas, Jacqueline/G-2807-2010; McLeod, Donald/C-4242-2014; OI Jonklaas, Jacqueline/0000-0002-2238-2666; McLeod, Donald/0000-0003-1131-020X; Sherman, Steven/0000-0002-3079-5153 FU Genzyme Corporation; Pfizer; University of Texas M.D. Anderson Cancer Center Support Grant (NCI Grant) [P30 CA016672]; Royal Australasian College of Physicians IMS Traveling Fellowship; Cancer Council Queensland PhD scholarship FX The NTCTCSG is supported in part by research grants from Genzyme Corporation and Pfizer, and by the University of Texas M.D. Anderson Cancer Center Support Grant (NCI Grant P30 CA016672). A Royal Australasian College of Physicians IMS Traveling Fellowship and a Cancer Council Queensland PhD scholarship supported D. S. A. M. We, as principal investigators at each NTCTCSG institution, thank the physicians and staff members who participated in the management and follow-up of these patients. We acknowledge the substantial contributions of the institutional research staff that collected and submitted the data, including Shehnaz Bana, Marge E. Ewertz, RN, and Beverly McLaughlin, RMA. We also appreciate the considerable assistance provided by Jeffrey Cui for the management of NTCTCSG's databases. Finally, we acknowledge the efforts of the numerous physicians and scientists whose contributions were critical in the early years of the registry. NR 37 TC 25 Z9 25 U1 0 U2 8 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 JAN 1 PY 2014 VL 24 IS 1 BP 35 EP 42 DI 10.1089/thy.2013.0062 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 285YM UT WOS:000329431000006 PM 23731273 ER PT J AU Bianco, AC Anderson, G Forrest, D Galton, VA Gereben, B Kim, BW Kopp, PA Liao, XH Obregon, MJ Peeters, RP Refetoff, S Sharlin, DS Simonides, WS Weiss, RE Williams, GR AF Bianco, Antonio C. Anderson, Grant Forrest, Douglas Galton, Valerie Anne Gereben, Balazs Kim, Brian W. Kopp, Peter A. Liao, Xiao Hui Obregon, Maria Jesus Peeters, Robin P. Refetoff, Samuel Sharlin, David S. Simonides, Warner S. Weiss, Roy E. Williams, Graham R. TI American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models SO THYROID LA English DT Article ID TYPE-2 IODOTHYRONINE DEIODINASE; BROWN ADIPOSE-TISSUE; THYROTROPIN-RELEASING-HORMONE; MYOSIN HEAVY-CHAIN; MESSENGER-RIBONUCLEIC-ACID; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; SARCOPLASMIC-RETICULUM CA2+-ATPASE; RAT SKELETAL-MUSCLE; ANTERIOR-PITUITARY-CELLS; SODIUM-IODIDE SYMPORTER AB Background: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment approaches for patients with thyroid disease. Summary: Important clinical practices in use today for the treatment of patients with hypothyroidism, hyperthyroidism, or thyroid cancer are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a series of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. Conclusions: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes. C1 [Bianco, Antonio C.; Kim, Brian W.] Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA. [Anderson, Grant] Univ Minnesota, Coll Pharm, Dept Pharm Practice & Pharmaceut Sci, Duluth, MN 55812 USA. [Forrest, Douglas] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Galton, Valerie Anne] Dartmouth Med Sch, Dept Physiol & Neurobiol, Lebanon, NH USA. [Gereben, Balazs] Hungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, Budapest, Hungary. [Kopp, Peter A.] Northwestern Univ, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Kopp, Peter A.] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA. [Liao, Xiao Hui; Refetoff, Samuel; Weiss, Roy E.] Univ Chicago, Sect Adult & Pediat Endocrinol Diabet & Metab, Chicago, IL 60637 USA. [Obregon, Maria Jesus] CSIC, Inst Invest Biomed, Spanish Natl Res Council, Madrid, Spain. [Obregon, Maria Jesus] Autonomous Univ Madrid, E-28049 Madrid, Spain. [Peeters, Robin P.] Erasmus MC, Dept Internal Med, Div Endocrinol, Rotterdam, Netherlands. [Sharlin, David S.] Minnesota State Univ, Dept Biol Sci, Mankato, MN USA. [Simonides, Warner S.] Vrije Univ Amsterdam Med Ctr, Inst Cardiovasc Res, Physiol Lab, Amsterdam, Netherlands. [Williams, Graham R.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. RP Bianco, AC (reprint author), Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Suite 816 Dominion Towers,1400 NW 10th Ave, Miami, FL 33136 USA. EM abianco@deiodinase.org RI Peeters, Robin/P-3603-2014 FU NIDDK at the National Institutes of Health; NIDDK [2R01-DK58538-08, 1R01-DK065055-02, R01-DK77148, R37DK015070, R21 HD 072526-02]; NICHD [R03 HD061901]; MINECO [SAF2012-32491]; CAM [S2010/BMD-2423]; U.S.-Israel Binational Science Foundation; National Science Foundation of Hungary [OTKA K81226]; European Community [259772]; ZonMw Clinical Fellowship Grant [90700412]; ZonMW TOP Grant [91212044] FX This work was supported in part by the intramural research program of NIDDK at the National Institutes of Health (to D.F.), NIDDK grants 2R01-DK58538-08, 1R01-DK065055-02, R01-DK77148 (to A. C. B.), R37DK015070 (to X. H. L. and S. R.) and R21 HD 072526-02 (to V. A. G.), NICHD grant R03 HD061901 (to P. A. K.), SAF2012-32491 from MINECO and S2010/BMD-2423 from CAM (to M.J.O.), U.S.-Israel Binational Science Foundation (to G. A.), National Science Foundation of Hungary (OTKA K81226) and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259772 (to B. G.), and the ZonMw Clinical Fellowship Grant (90700412) and a ZonMW TOP Grant (91212044) (to R.P.P.). NR 725 TC 39 Z9 40 U1 3 U2 27 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 JAN 1 PY 2014 VL 24 IS 1 BP 88 EP 168 DI 10.1089/thy.2013.0109 PG 81 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 285YM UT WOS:000329431000013 PM 24001133 ER PT J AU Danilenko, DM Nambiar, PR Cesta, MF AF Danilenko, Dimitry M. Nambiar, Prashant R. Cesta, Mark F. TI A Brief Overview of the 32nd Annual STP Symposium on the Toxicologic Pathology of the Digestive Tract and Pancreas SO TOXICOLOGIC PATHOLOGY LA English DT Article DE digestive system; pancreas; toxicologic pathology; pathobiology C1 [Danilenko, Dimitry M.] Genentech Inc, San Francisco, CA 94080 USA. [Nambiar, Prashant R.] Pfizer Inc, Groton, CT 06340 USA. [Cesta, Mark F.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Danilenko, DM (reprint author), Genentech Inc, 1 DNA Way MS-59, San Francisco, CA 94080 USA. EM ddanilen@gene.com NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JAN PY 2014 VL 42 IS 1 BP 45 EP 48 DI 10.1177/0192623313502402 PG 4 WC Pathology; Toxicology SC Pathology; Toxicology GA 289MS UT WOS:000329687200001 PM 24002990 ER PT J AU Lee, EB Mattson, MP AF Lee, Edward B. Mattson, Mark P. TI The neuropathology of obesity: insights from human disease SO ACTA NEUROPATHOLOGICA LA English DT Review ID BARDET-BIEDL-SYNDROME; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; BODY-MASS INDEX; PRADER-WILLI-SYNDROME; CONGENITAL LEPTIN DEFICIENCY; INDUCED STATUS EPILEPTICUS; EARLY-ONSET OBESITY; Y GASTRIC BYPASS; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; PENTYLENETETRAZOLE-INDUCED SEIZURES AB Obesity, a pathologic state defined by excess adipose tissue, is a significant public health problem as it affects a large proportion of individuals and is linked with increased risk for numerous chronic diseases. Obesity is the result of fundamental changes associated with modern society including overnutrition and sedentary lifestyles. Proper energy homeostasis is dependent on normal brain function as the master metabolic regulator, which integrates peripheral signals, modulates autonomic outflow and controls feeding behavior. Therefore, many human brain diseases are associated with obesity. This review explores the neuropathology of obesity by examining brain diseases which either cause or are influenced by obesity. First, several genetic and acquired brain diseases are discussed as a means to understand the central regulation of peripheral metabolism. These diseases range from monogenetic causes of obesity (leptin deficiency, MC4R deficiency, Bardet-Biedl syndrome and others) to complex neurodevelopmental disorders (Prader-Willi syndrome and Sim1 deficiency) and neurodegenerative conditions (frontotemporal dementia and Gourmand's syndrome) and serve to highlight the central regulatory mechanisms which have evolved to maintain energy homeostasis. Next, to examine the effect of obesity on the brain, chronic neuropathologic conditions (epilepsy, multiple sclerosis and Alzheimer's disease) are discussed as examples of obesity leading to maladaptive processes which exacerbate chronic disease. Thus, obesity is associated with multiple pathways including abnormal metabolism, altered hormonal signaling and increased inflammation which act in concert to promote downstream neuropathology. Finally, the effect of anti-obesity interventions is discussed in terms of brain structure and function. Together, understanding human diseases and anti-obesity interventions leads to insights into the bidirectional interaction between peripheral metabolism and central brain function, highlighting the need for continued clinicopathologic and mechanistic studies of the neuropathology of obesity. C1 [Lee, Edward B.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Translat Neuropathol Res Lab,Div Neuropathol, Philadelphia, PA 19104 USA. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Lee, EB (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Translat Neuropathol Res Lab,Div Neuropathol, 605B Stellar Chance Labs,422 Curie Blvd, Philadelphia, PA 19104 USA. EM edward.lee@uphs.upenn.edu FU National Institutes of Health [AG039510, DK19525, AG010124]; Intramural Research Program of the National Institute on Aging FX EBL is funded in part by grants from the National Institutes of Health (AG039510, DK19525, AG010124) and MPM is funded in part by the Intramural Research Program of the National Institute on Aging. EBL thanks Dr. Rexford Ahima for useful discussions in developing this review. NR 269 TC 11 Z9 13 U1 4 U2 31 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JAN PY 2014 VL 127 IS 1 BP 3 EP 28 DI 10.1007/s00401-013-1190-x PG 26 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 283DL UT WOS:000329225300002 PM 24096619 ER PT J AU Cadet, JL Bisagno, V Milroy, CM AF Cadet, Jean Lud Bisagno, Veronica Milroy, Christopher Mark TI Neuropathology of substance use disorders SO ACTA NEUROPATHOLOGICA LA English DT Review DE Cannabis; Cocaine; Methamphetamine; MDMA; Heroin; Cathinones; Bath salts; Dopamine; Toxicity; Frontal cortex; Hippocampus; Nucleus accumbens; Striatum; Reward mechanisms ID ABSTINENT METHAMPHETAMINE ABUSERS; VOXEL-BASED MORPHOMETRY; WHITE-MATTER INTEGRITY; CENTRAL-NERVOUS-SYSTEM; COCAINE-DEPENDENT INDIVIDUALS; POSITRON-EMISSION-TOMOGRAPHY; PSYCHOACTIVE BATH SALTS; HEAVY MARIJUANA USERS; MDMA ECSTASY USERS; CANNABIS USE AB Addictions to licit and illicit drugs are chronic relapsing brain disorders that affect circuits that regulate reward, motivation, memory, and decision-making. Drug-induced pathological changes in these brain regions are associated with characteristic enduring behaviors that continue despite adverse biopsychosocial consequences. Repeated exposure to these substances leads to egocentric behaviors that focus on obtaining the drug by any means and on taking the drug under adverse psychosocial and medical conditions. Addiction also includes craving for the substances and, in some cases, involvement in risky behaviors that can cause death. These patterns of behaviors are associated with specific cognitive disturbances and neuroimaging evidence for brain dysfunctions in a diverse population of drug addicts. Postmortem studies have also revealed significant biochemical and/or structural abnormalities in some addicted individuals. The present review provides a summary of the evidence that has accumulated over the past few years to implicate brain dysfunctions in the varied manifestations of drug addiction. We thus review data on cerebrovascular alterations, brain structural abnormalities, and postmortem studies of patients who abuse cannabis, cocaine, amphetamines, heroin, and "bath salts". We also discuss potential molecular, biochemical, and cellular bases for the varied clinical presentations of these patients. Elucidation of the biological bases of addiction will help to develop better therapeutic approaches to these patient populations. C1 [Cadet, Jean Lud] NIDA NIH DHHS, NIDA Intramural Res Program, Mol Neuropsychiatry Res Branch, Baltimore, MD 21224 USA. [Bisagno, Veronica] Inst Invest Farmacol ININFA UBA CONICET, Buenos Aires, DF, Argentina. [Milroy, Christopher Mark] Ottawa Hosp, Div Anat Pathol, Eastern Ontario Forens Pathol, Unit Ontario Forens Pathol Serv, Ottawa, ON K2A 2L4, Canada. RP Cadet, JL (reprint author), NIDA NIH DHHS, NIDA Intramural Res Program, Mol Neuropsychiatry Res Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA), NIH; United States Department of State, Argentina [PIP11420100100072, PICT 2012-0924]; DHHS FX This paper is supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), NIH, and DHHS. V. Bisagno is a Fulbright Fellow, United States Department of State and is also supported by grants PIP11420100100072 and PICT 2012-0924, Argentina. NR 209 TC 29 Z9 29 U1 12 U2 70 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JAN PY 2014 VL 127 IS 1 BP 91 EP 107 DI 10.1007/s00401-013-1221-7 PG 17 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 283DL UT WOS:000329225300006 PM 24292887 ER PT J AU Velagaleti, RS Gona, P Pencina, MJ Aragam, J Wang, TJ Levy, D D'Agostino, RB Lee, DS Kannel, WB Benjamin, EJ Vasan, RS AF Velagaleti, Raghava S. Gona, Philimon Pencina, Michael J. Aragam, Jayashri Wang, Thomas J. Levy, Daniel D'Agostino, Ralph B. Lee, Douglas S. Kannel, William B. Benjamin, Eme Lia J. Vasan, Ramachandran S. TI Left Ventricular Hypertrophy Patterns and Incidence of Heart Failure With Preserved Versus Reduced Ejection Fraction SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID MYOCARDIAL-INFARCTION; DILATED CARDIOMYOPATHY; LONGITUDINAL TRACKING; CARDIOVASCULAR HEALTH; HYPERTENSIVE PATIENTS; GEOMETRIC PATTERNS; WALL STRESS; FRAMINGHAM; MASS; DISEASE AB Higher left ventricular (LV) mass, wall thickness, and internal dimension are associated with increased heart failure (HF) risk. Whether different LV hypertrophy patterns vary with respect to rates and types of HF incidence is unclear. In this study, 4,768 Framingham Heart Study participants (mean age 50 years, 56% women) were classified into 4 mutually exclusive LV hypertrophy pattern groups (normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy) using American Society of Echocardiography recommended thresholds of echocardiographic LV mass indexed to body surface area and relative wall thickness, and these groups were related to HF incidence. Whether risk for HF types (HF with reduced ejection fraction [<45%] vs preserved ejection fraction [>= 45%]) varied by hypertrophy pattern was then evaluated. On follow-up (mean 21 years), 458 participants (9.6%, 250 women) developed new-onset HF. The age- and gender-adjusted 20-year HF incidence increased from 6.96% in the normal left ventricle group to 8.67%, 13.38%, and 15.27% in the concentric remodeling, concentric hypertrophy, and eccentric hypertrophy groups, respectively. After adjustment for co-morbidities and incident myocardial infarction, LV hypertrophy patterns were associated with higher HF incidence relative to the normal left ventricle group (p = 0.0002); eccentric hypertrophy carried the greatest risk (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.41 to 2.54), followed by concentric hypertrophy (HR 1.40, 95% CI 1.04 to 1.87). Participants with eccentric hypertrophy had a higher propensity for HF with reduced ejection fraction (HR 2.23, 95% CI 1.48 to 3.37), whereas those with concentric hypertrophy were more prone to HF with preserved ejection fraction (HR 1.66, 95% CI 1.09 to 2.51). In conclusion, in this large community-based sample, HF risk varied by LV hypertrophy pattern, with eccentric and concentric hypertrophy predisposing to HF with reduced and preserved ejection fraction, respectively. (C) 2014 Elsevier Inc. All rights reserved. C1 [Velagaleti, Raghava S.; Gona, Philimon; Pencina, Michael J.; Levy, Daniel; D'Agostino, Ralph B.; Kannel, William B.; Benjamin, Eme Lia J.; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Velagaleti, Raghava S.] Univ Massachusetts, Sch Med, Div Cardiol, Worcester, MA USA. [Gona, Philimon] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Pencina, Michael J.; D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Aragam, Jayashri] Vet Adm Hosp, West Roxbury, MA USA. [Aragam, Jayashri; Wang, Thomas J.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Lee, Douglas S.] Univ Toronto, Inst Clin Evaluat Sci, Toronto, ON, Canada. [Lee, Douglas S.] Univ Toronto, Toronto Gen Hosp, Toronto, ON M5G 1L7, Canada. [Benjamin, Eme Lia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Eme Lia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, Framingham, MA USA. EM vasan@bu.edu RI Lee, Douglas/J-4315-2014; OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-25195]; National Institutes of Health, Bethesda, Maryland [RO1 HL67288] FX This work was supported by the Contract N01-HC-25195 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and Grant RO1 HL67288 from the National Institutes of Health, Bethesda, Maryland. NR 30 TC 25 Z9 25 U1 0 U2 8 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 1 PY 2014 VL 113 IS 1 BP 117 EP 122 DI 10.1016/j.amjcard.2013.09.028 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 284QA UT WOS:000329333800020 PM 24210333 ER PT J AU Roseman, DA Hwang, SJ Manders, ES O'Donnell, CJ Upadhyay, A Hoffmann, U Fox, CS AF Roseman, Daniel A. Hwang, Shih-Jen Manders, Emily S. O'Donnell, Christopher J. Upadhyay, Ashish Hoffmann, Udo Fox, Caroline S. TI Renal Artery Calcium, Cardiovascular Risk Factors, and Indexes of Renal Function SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ANGIOTENSIN-ALDOSTERONE SYSTEM; VASCULAR CALCIFICATIONS; COMPUTED-TOMOGRAPHY; KIDNEY-DISEASE; MICROALBUMINURIA; FRAMINGHAM; STIFFNESS; ATHEROSCLEROSIS; RACE; MEN AB Vascular calcium is well studied in the coronary and peripheral arteries, although there are limited data focusing on calcium deposits specific to renal arteries. The associations among renal artery calcium (RAC), cardiovascular disease risk factors, and indexes of renal function are unknown. We examined 2,699 Framingham Heart Study participants who were part of a multidetector computed tomography substudy from 2008 to 2011. RAC was measured as a calcified plaque of >130 HU and an area of >3 contiguous pixels. Detectable RAC was defined as an Agatston score >0. Chronic kidney disease was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m(2). Microalbuminuria was defined as an albumin/creatinine ratio of >= 17 mg/g for men and >= 25 mg/g for women. Multivariable adjusted logistic regression models were used to evaluate the associations between RAC, cardiovascular disease risk factors, and renal function. The associations were secondarily adjusted for coronary artery calcium (CAC) that was used as a marker of nonrenal systemic vascular calcium. The prevalence of RAC was 28.2%; this was similar in women (28.8%) and men (27.5%). Patients with RAC had a higher odds of microalbuminuria (Odds ratio [OR] 1.79, 95% confidence interval [CI] 1.22 to 2.61, p = 0.003), hypertension (OR 2.11, 95% CI 1.69 to 2.64, p<0.001), and diabetes (OR 1.60, 95% CI 1.14 to 2.24, p = 0.01) but not chronic kidney disease (OR 0.87, 95% CI 0.58 to 1.32). After adjustment for CAC, the association with microalbuminuria and hypertension persisted, but the association with diabetes became nonsignificant. In conclusion, RAC is common and independently associated with microalbuminuria and hypertension after adjustment for nonrenal vascular calcium. RAC may be uniquely associated with these markers of renal end-organ damage. Published by Elsevier Inc. C1 [Roseman, Daniel A.; Upadhyay, Ashish] Boston Univ, Med Ctr, Renal Sect, Boston, MA USA. [Hwang, Shih-Jen; Manders, Emily S.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hwang, Shih-Jen; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM foxca@nhlbi.nih.gov OI Upadhyay, Ashish/0000-0002-0536-5776 FU Boston University from the National Heart, Lung, and Blood Institute [N01-HC-25195]; National Institutes of Health (Bethesda, Maryland) [T32-DK-007053] FX The Framingham Heart Study is conducted and supported in collaboration with Boston University by contract N01-HC-25195 from the National Heart, Lung, and Blood Institute; Dr. Roseman received funding from grant T32-DK-007053, National Institutes of Health (Bethesda, Maryland). NR 25 TC 6 Z9 9 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 1 PY 2014 VL 113 IS 1 BP 156 EP 161 DI 10.1016/j.amjcard.2013.09.036 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 284QA UT WOS:000329333800027 PM 24210678 ER PT J AU Al-Mallah, MH Nasir, K Katz, R Lima, JA Bluemke, DA Blumenthal, RS Mao, SS Hundley, WG Budoff, MJ AF Al-Mallah, Mouaz H. Nasir, Khurram Katz, Ronit Lima, Joao A. Bluemke, David A. Blumenthal, Roger S. Mao, Songshou Hundley, W. Gregory Budoff, Matthew J. TI Relation of Thoracic Aortic Distensibility to Left Ventricular Area (from the Multi-Ethnic Study of Atherosclerosis [MESA]) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PROGNOSTIC VALUE; CARDIOVASCULAR MORTALITY; ESSENTIAL-HYPERTENSION; INDEPENDENT PREDICTOR; COMPUTED-TOMOGRAPHY; ARTERIAL STIFFNESS; SCANNER TYPE; ALL-CAUSE; HYPERTROPHY; CALCIFICATION AB Decreased arterial compliance is an early manifestation of adverse structural and functional changes within the vessel wall. Its correlation with left ventricular (LV) area on computed tomography, a marker of LV remodeling, has not been well demonstrated. The aim of this study was to test the hypothesis that decreasing aortic compliance and increasing arterial stiffness are independently associated. with increased LV area. The study population consisted of 3,540 patients (mean age 61 +/- 10 years, 46% men) from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent aortic distensibility (AD) assessment on magnetic resonance imaging and LV area measurement on computed tomography (adjusted to body surface area). Multivariate logistic regression was performed to assess the association between body surface area-normalized LV area >75th percentile and AD after adjusting for baseline clinical, historical, and imaging covariates. Mean LV area index was 2,153 cm, and mean AD was 1.84 x 10(3) mm Hg-1. Subjects in the lowest AD quartile were older, with higher prevalence rates of hypertension, diabetes, and hypercholesterolemia (p<0.05 for all comparisons). Using multivariate linear regression adjusting for demographics, traditional risk factors, coronary artery calcium, and C-reactive protein, each SD decrease was associated with an 18-cm(2) increase in LV area. In addition, decreasing AD quartiles were independently associated with increasing LV area index, defined as >75th percentile. In conclusion, in this multiethnic cohort, reduced AD was associated with increased LV area. Longitudinal studies are needed to determine if decreased distensibility precedes and directly influences increased LV area. (C) 2014 Elsevier Inc. All rights reserved. C1 [Al-Mallah, Mouaz H.] Wayne State Univ, Henry Ford Hosp, Div Cardiol, Detroit, MI 48202 USA. [Al-Mallah, Mouaz H.] King Abdulaziz Cardiac Ctr, Div Cardiac Imaging, Riyadh, Saudi Arabia. [Nasir, Khurram] Baptist Hlth Med Grp, Ctr Prevent & Wellness Res, Miami Beach, FL USA. [Katz, Ronit] Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Lima, Joao A.; Blumenthal, Roger S.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Dept Radiol & Imaging Sci, NIH, Bethesda, MD USA. [Mao, Songshou; Budoff, Matthew J.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Div Cardiol, Torrance, CA 90509 USA. [Hundley, W. Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Cardiol Sect, Winston Salem, NC 27103 USA. RP Al-Mallah, MH (reprint author), Wayne State Univ, Henry Ford Hosp, Div Cardiol, Detroit, MI 48202 USA. EM mouaz74@gmail.com OI Bluemke, David/0000-0002-8323-8086; Al-Mallah, Mouaz/0000-0003-2348-0484 FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [R01 HL071739, N01-HC-95159, N01-HC-95165, N01-HC-95169] FX This research was supported by Grant R01 HL071739 and Contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. NR 30 TC 2 Z9 2 U1 1 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 1 PY 2014 VL 113 IS 1 BP 178 EP 182 DI 10.1016/j.amjcard.2013.09.039 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 284QA UT WOS:000329333800031 PM 24210674 ER PT J AU Hughey, CC James, FD Ma, LL Bracy, DP Wang, ZZ Wasserman, DH Rottman, JN Shearer, J AF Hughey, Curtis C. James, Freyja D. Ma, Lianli Bracy, Deanna P. Wang, Zhizhang Wasserman, David H. Rottman, Jeffrey N. Shearer, Jane TI Diminishing impairments in glucose uptake, mitochondrial content, and ADP-stimulated oxygen flux by mesenchymal stem cell therapy in the infarcted heart SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE mitochondria; glucose uptake; myocardial infarction; stem cells ID ACID-BINDING PROTEIN; FATTY-ACID; COACTIVATOR PGC-1-ALPHA; MYOCARDIAL-INFARCTION; INSULIN-RESISTANCE; 3T3-L1 ADIPOCYTES; ENERGY-METABOLISM; MECHANISMS; TRANSPLANTATION; DISEASE AB A constant provision of ATP is of necessity for cardiac contraction. As the heart progresses toward failure following a myocardial infarction (MI), it undergoes metabolic alterations that have the potential to compromise the ability to meet energetic demands. This study evaluated the efficacy of mesenchymal stem cell (MSC) transplantation into the infarcted heart to minimize impairments in the metabolic processes that contribute to energy provision. Seven and twenty-eight days following the MI and MSC transplantation, MSC administration minimized cardiac systolic dysfunction. Hyperinsulinemic-euglycemic clamps, coupled with 2-[C-14] deoxyglucose administration, were employed to assess systemic insulin sensitivity and tissue-specific, insulin-mediated glucose uptake 36 days following the MI in the conscious, unrestrained, C57BL/6 mouse. The improved systolic performance in MSC-treated mice was associated with a preservation of in vivo insulin-stimulated cardiac glucose uptake. Conserved glucose uptake in the heart was linked to the ability of the MSC treatment to diminish the decline in insulin signaling as assessed by Akt phosphorylation. The MSC treatment also sustained mitochondrial content, ADP-stimulated oxygen flux, and mitochondrial oxidative phosphorylation efficiency in the heart. Maintenance of mitochondrial function and density was accompanied by preserved peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, a master regulator of mitochondrial biogenesis. These studies provide insight into mechanisms of action that lead to an enhanced energetic state in the infarcted heart following MSC transplantation that may assist in energy provision and dampen cardiac dysfunction. C1 [Hughey, Curtis C.; Shearer, Jane] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 1N4, Canada. [James, Freyja D.; Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Ma, Lianli; Wang, Zhizhang; Wasserman, David H.; Rottman, Jeffrey N.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. [Rottman, Jeffrey N.] Vanderbilt Univ, Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37212 USA. [Shearer, Jane] Univ Calgary, Fac Kinesiol, Calgary, AB T2N 1N4, Canada. RP Hughey, CC (reprint author), Univ Calgary, KNB Rm 218,2500 Univ Dr NW, Calgary, AB T2N 1N4, Canada. EM cchughey@ucalgary.ca FU Canadian Institutes of Health Research; Killam Trusts; MitoCanada; National Institute of Diabetes and Digestive and Kidney Diseases [DK-054902, DK-59637] FX This work was supported by Canadian Institutes of Health Research (C. C. Hughey, J. Shearer), the Killam Trusts (C. C. Hughey), MitoCanada (J. Shearer), and National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-054902 (D. H. Wasserman) and DK-59637 (Vanderbilt University Mouse Metabolic Phenotyping Center). NR 48 TC 2 Z9 2 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2014 VL 306 IS 1 BP C19 EP C27 DI 10.1152/ajpcell.00156.2013 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 282SO UT WOS:000329193700003 PM 24196528 ER PT J AU Cai, Y Winn, ME Zehmer, JK Gillette, WK Lubkowski, JT Pilon, AL Kimura, S AF Cai, Yan Winn, Melissa E. Zehmer, John K. Gillette, William K. Lubkowski, Jacek T. Pilon, Aprile L. Kimura, Shioko TI Preclinical evaluation of human secretoglobin 3A2 in mouse models of lung development and fibrosis SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE SCGB; embryonic lung ex vivo organ culture; bleomycin-induced pulmonary fibrosis; phospholipase A(2) inhibitory activity; drug candidate treating lung diseases ID RESPIRATORY-DISTRESS-SYNDROME; CELL 10-KDA PROTEIN; PULMONARY-FIBROSIS; GROWTH-FACTOR; GENE-EXPRESSION; UTEROGLOBIN; MICE; BINDING; INFLAMMATION; SUPERFAMILY AB Secretoglobin (SCGB) 3A2 is a member of the SCGB gene superfamily of small secreted proteins, predominantly expressed in lung airways. We hypothesize that human SCGB3A2 may exhibit anti-inflammatory, growth factor, and antifibrotic activities and be of clinical utility. Recombinant human SCGB3A2 was expressed, purified, and biochemically characterized as a first step to its development as a therapeutic agent in clinical settings. Human SCGB3A2, as well as mouse SCGB3A2, readily formed a dimer in solution and exhibited novel phospholipase A2 inhibitory activity. This is the first demonstration of any quantitative biochemical measurement for the evaluation of SCGB3A2 protein. In the mouse as an experimental animal, human SCGB3A2 exhibited growth factor activity by promoting embryonic lung development in both ex vivo and in vivo systems and antifibrotic activity in the bleomycin-induced lung fibrosis model. The results suggested that human SCGB3A2 can function as a growth factor and an antifibrotic agent in humans. When SCGB3A2 was administered to pregnant female mice through the tail vein, the protein was detected in the dam's serum and lung, as well as the placenta, amniotic fluids, and embryonic lungs at 10 min postadministration, suggesting that SCGB3A2 readily crosses the placenta. The results warrant further development of recombinant SCGB3A2 as a therapeutic agent in treating patients suffering from lung diseases or preterm infants with respiratory distress. C1 [Cai, Yan; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Winn, Melissa E.; Zehmer, John K.; Pilon, Aprile L.] Clarassance Inc, Rockville, MD USA. [Gillette, William K.] Leidos Biomed Res Inc, Prot Express Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Lubkowski, Jacek T.] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Kimura, S (reprint author), NIH, Bldg 37,Rm 3106,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov RI Cai, Yan/P-4383-2015 FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research [ZIABC010449] FX This study was carried out under the CRADA (Corporate Research and Development Agreement) between National Cancer Institute and Clarassance, Inc. and funded in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (ZIABC010449). NR 33 TC 5 Z9 5 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD JAN PY 2014 VL 306 IS 1 BP L10 EP L22 DI 10.1152/ajplung.00037.2013 PG 13 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 282SE UT WOS:000329192400002 PM 24213919 ER PT J AU Sakamoto, K Ueno, T Kobayashi, N Hara, S Takashima, Y Pastan, I Matsusaka, T Nagata, M AF Sakamoto, Kazuo Ueno, Toshiharu Kobayashi, Namiko Hara, Satoshi Takashima, Yasutoshi Pastan, Ira Matsusaka, Taiji Nagata, Michio TI The direction and role of phenotypic transition between podocytes and parietal epithelial cells in focal segmental glomerulosclerosis SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE focal segmental glomerulosclerosis; cellular FSGS; podocyte; parietal epithelial cell; phenotypic transition ID DE-NOVO EXPRESSION; GLOMERULAR PODOCYTES; NEPHROPATHY; SCLEROSIS; PROTEINS; STRESS; INJURY; RATS; PAX2 AB Focal segmental glomerulosclerosis (FSGS) is a podocyte disease. Among the various histologies of FSGS, active epithelial changes, hyperplasia, as typically seen in the collapsing variant, indicates disease progression. Using a podocyte-specific injury model of FSGS carrying a genetic podocyte tag combined with double immunostaining by different sets of podocytes and parietal epithelial cell (PEC) markers [nestin/Pax8, Wilms' tumor- 1 (WT1)/claudin1, and podocalyxin/Pax2], we investigated the direction of epithelial phenotypic transition and its role in FSGS. FSGS mice showed progressive proteinuria and renal dysfunction often accompanied by epithelial hyperplasia, wherein 5-bromo-4-chloro- 3-indoyl beta-D-galactoside (X-gal)-positive podocyte-tagged cells were markedly decreased. The average numbers of double-positive cells in all sets of markers were significantly increased in the FSGS mice compared with the controls. In addition, the average numbers of double-positive cells for X-gal/Pax8, nestin/Pax8 and podocalyxin/Pax2 staining in the FSGS mice were comparable, whereas those of WT1/claudin1 were significantly increased. When we divided glomeruli from FSGS mice into those with FSGS lesions and those without, double-positive cells tended to be more closely associated with glomeruli without FSGS lesions compared with those with FSGS lesions. Moreover, the majority of double-positive cells appeared to be isolated and very rarely associated with FSGS lesions (1/1,997 glomeruli). This study is the first to show the incidence and localization of epithelial cells with phenotypical changes in FSGS using a genetic tag. The results suggest that the major direction of epithelial phenotypic transition in cellular FSGS is from podocytes to PECs and that these cells were less represented in the active lesions of FSGS. C1 [Sakamoto, Kazuo; Ueno, Toshiharu; Kobayashi, Namiko; Hara, Satoshi; Takashima, Yasutoshi; Nagata, Michio] Univ Tsukuba, Fac Med, Ibaraki, Japan. [Sakamoto, Kazuo] Iizuka Hosp, Dept Nephrol, Fukuoka, Japan. [Matsusaka, Taiji] Tokai Univ, Sch Med, Inst Med Sci, Dept Internal Med, Isehara City, Kanagawa 2591100, Japan. [Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Nagata, M (reprint author), Univ Tsukuba, Fac Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058577, Japan. EM nagatam@md.tsukuba.ac.jp FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center of Cancer Research; basic research support program of the Japanese Society of Nephrology; Japan Society for the Promotion of Science (KAKEN) [22590877]; Ministry of Health, Labor, and Welfare of Japan FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center of Cancer Research, and was also supported by the basic research support program of the Japanese Society of Nephrology and by Grants-in-Aid for Scientific Research of the Japan Society for the Promotion of Science (KAKEN; research project no. 22590877) and Progressive Renal Disease Research of the Ministry of Health, Labor, and Welfare of Japan. NR 23 TC 23 Z9 23 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN PY 2014 VL 306 IS 1 BP F98 EP F104 DI 10.1152/ajprenal.00228.2013 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 282SL UT WOS:000329193300012 PM 24154691 ER PT J AU Dickinson, D AF Dickinson, Dwight TI Zeroing In on Early Cognitive Development in Schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID INTELLIGENCE; IMPAIRMENT; CHILDHOOD; FLUID C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Dickinson, D (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. EM dwight.dickinson@nih.gov FU Intramural NIH HHS [Z99 MH999999, ZIA MH002712-19] NR 19 TC 4 Z9 5 U1 1 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2014 VL 171 IS 1 BP 9 EP 12 DI 10.1176/appi.ajp.2013.13101303 PG 4 WC Psychiatry SC Psychiatry GA 286OO UT WOS:000329478800003 PM 24399421 ER PT J AU Gorsi, B Liu, F Ma, X Chico, TJA Shrinivasan, A Kramer, KL Bridges, E Monteiro, R Harris, AL Patient, R Stringer, SE AF Gorsi, Bushra Liu, Feng Ma, Xing Chico, Timothy J. A. Shrinivasan, Ashok Kramer, Kenneth L. Bridges, Esther Monteiro, Rui Harris, Adrian L. Patient, Roger Stringer, Sally E. TI The heparan sulfate editing enzyme Sulf1 plays a novel role in zebrafish VegfA mediated arterial venous identity SO ANGIOGENESIS LA English DT Article DE Angiogenesis; Arteries; VEGF; Glycocalyx; Sulf1 ID EMBRYONIC VASCULAR DEVELOPMENT; ENDOTHELIAL-GROWTH-FACTOR; IN-VIVO; BRANCHING MORPHOGENESIS; REDUNDANT ROLES; ANGIOGENESIS; SOX18; 6-O-ENDOSULFATASES; DIFFERENTIATION; QSULF1 AB Arterial and venous specification is critical for establishing and maintaining a functioning vascular system, and defects in key arteriovenous signaling pathways including VEGF (vascular endothelial growth factor) lead to congenital arteriopathies. The activities of VEGF, are in part controlled by heparan sulfate (HS) proteoglycans, significant components of the endothelial glycocalyx. The level of 6-O sulfation on HS polysaccharide chains, that mediate the interaction between HS and VEGFA, is edited at the cell surface by the enzyme SULF1. We investigated the role of sulf1 in vascular development. In zebrafish sulf1 is expressed in the head and tail vasculature, corresponding spatially and temporally with vascular development. Targeted knockdown of sulf1 by antisense morpholinos resulted in severe vascular patterning and maturation defects. 93 % of sulf1 morphants show dysmorphogenesis in arterial development leading to occlusion of the distal aorta and lack of axial and cranial circulation. Co-injection of vegfa (165) mRNA rescued circulatory defects. While the genes affecting haematopoiesis are unchanged, expression of several arterial markers downstream of VegfA signalling such as notch and ephrinB2 are severely reduced in the dorsal aorta, with a concomitant increase in expression of the venous markers flt4 in the dorsal aorta of the morphants. Furthermore, in vitro, lack of SULF1 expression downregulates VEGFA-mediated arterial marker expression, confirming that Sulf1 mediates arterial specification by regulating VegfA(165) activity. This study provides the first in vivo evidence for the integral role of the endothelial glycocalyx in specifying arterial-venous identity, vascular patterning and arterial integrity, and will help to better understand congenital arteriopathies. C1 [Gorsi, Bushra] Univ Manchester, Fac Med & Human Sci, Manchester M13 9NT, Lancs, England. [Liu, Feng] Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100101, Peoples R China. [Ma, Xing] Univ Sheffield, MRC Ctr Dev & Biomed Genet, Sheffield, S Yorkshire, England. [Chico, Timothy J. A.] Univ Sheffield, MRC Ctr Dev & Biomed Genet, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. [Shrinivasan, Ashok; Kramer, Kenneth L.] NHLBI, NIH, Bethesda, MD 20892 USA. [Bridges, Esther; Monteiro, Rui; Harris, Adrian L.; Patient, Roger] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [Stringer, Sally E.] Univ Manchester, Fac Med & Human Sci, Inst Cardiovasc Sci, Manchester M13 9NT, Lancs, England. RP Gorsi, B (reprint author), Univ Utah, Program Mol Med, Eccles Inst Human Genet, Dept Neurobiol & Anat, Bldg 533,Room 3160,15 North 2030 East, Salt Lake City, UT 84112 USA. EM bgorsi@genetics.utah.edu; sally.stringer@manchester.ac.uk RI Monteiro, Rui/J-2544-2013; OI Monteiro, Rui/0000-0002-4223-8506; Harris, Adrian/0000-0003-1376-8409 FU University of Manchester Medical School strategic studentship; British Heart Foundation; Diabetes UK; Medical Research Council; Cancer Research UK FX We would like to thank the BSU staff at the Universities of Manchester and Oxford for taking care of the aquarium and the staff at the confocal microscope core facilities. This work was funded by University of Manchester Medical School strategic studentship, British Heart Foundation, Diabetes UK, Medical Research Council and Cancer Research UK. Conceived and designed the experiments: BG and SS. Performed the experiments: BG, FL, EB, RM Analyzed the data: BG, FL, EB, SS. Contributed reagents/materials/analysis tools: FL, AS, KLK, RP, AH, TC, XM. Wrote the paper: BG and SS with input from RP and AH authors. NR 50 TC 4 Z9 4 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 EI 1573-7209 J9 ANGIOGENESIS JI Angiogenesis PD JAN PY 2014 VL 17 IS 1 BP 77 EP 91 DI 10.1007/s10456-013-9379-0 PG 15 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 283EJ UT WOS:000329228000007 PM 23959107 ER PT J AU Davis, GE Kim, DJ Stratman, AN Bowers, SLK AF Davis, George E. Kim, Dae Joong Stratman, Amber N. Bowers, Stephanie L. K. TI Molecular control of capillary tube regression in 3D extracellular matrices SO ANGIOGENESIS LA English DT Meeting Abstract C1 [Davis, George E.; Kim, Dae Joong; Bowers, Stephanie L. K.] Univ Missouri, Sch Med, Columbia, MO USA. [Stratman, Amber N.] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 EI 1573-7209 J9 ANGIOGENESIS JI Angiogenesis PD JAN PY 2014 VL 17 IS 1 BP 281 EP 281 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 283EJ UT WOS:000329228000044 ER PT J AU Xie, ZH Ghosh, C Awaki, S Wisch, L Nelson, C Young, M Parikh, S Druey, KM AF Xie Zhihui Ghosh, Chandra Awaki, Shoko Wisch, Laura Nelson, Celeste Young, Michael Parikh, Samir Druey, Kirk M. TI Phenotypic diversity of the systemic capillary leak syndrome (clarkson disease) SO ANGIOGENESIS LA English DT Meeting Abstract C1 [Xie Zhihui; Awaki, Shoko; Wisch, Laura; Nelson, Celeste; Young, Michael; Druey, Kirk M.] NIH, Bethesda, MD 20892 USA. [Ghosh, Chandra; Parikh, Samir] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ghosh, Chandra; Parikh, Samir] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 EI 1573-7209 J9 ANGIOGENESIS JI Angiogenesis PD JAN PY 2014 VL 17 IS 1 BP 302 EP 303 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 283EJ UT WOS:000329228000124 ER PT J AU Sek, AC Xie, ZH Terai, K Dudek, A Druey, K AF Sek, Albert C. Xie Zhihui Terai, Koaru Dudek, Arkadiusz Druey, Kirk TI Role of endothelin receptor a in the systemic capillary leak syndrome (SCLS) SO ANGIOGENESIS LA English DT Meeting Abstract C1 [Sek, Albert C.; Xie Zhihui; Druey, Kirk] NIH, Bethesda, MD 20892 USA. [Terai, Koaru; Dudek, Arkadiusz] Univ Minnesota, Minneapolis, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 EI 1573-7209 J9 ANGIOGENESIS JI Angiogenesis PD JAN PY 2014 VL 17 IS 1 BP 310 EP 310 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 283EJ UT WOS:000329228000152 ER PT J AU Mukouyama, YS James, J Nalbandian, A AF Mukouyama, Yoh-suke James, Jennifer Nalbandian, Ani TI Regulation of TGF beta signaling by peripheral nerves influences skin lymphangiogenesis SO ANGIOGENESIS LA English DT Meeting Abstract C1 [Mukouyama, Yoh-suke; James, Jennifer; Nalbandian, Ani] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 EI 1573-7209 J9 ANGIOGENESIS JI Angiogenesis PD JAN PY 2014 VL 17 IS 1 BP 312 EP 312 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 283EJ UT WOS:000329228000159 ER PT J AU Outeda, P Germino, GG Watnick, TJ AF Outeda, Patricia Germino, Gregory G. Watnick, Terry J. TI Polycystin signaling is required for directed endothelial cell migration and lymphatic development SO ANGIOGENESIS LA English DT Meeting Abstract C1 [Outeda, Patricia; Watnick, Terry J.] Univ Maryland, Baltimore, MD 21201 USA. [Germino, Gregory G.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 EI 1573-7209 J9 ANGIOGENESIS JI Angiogenesis PD JAN PY 2014 VL 17 IS 1 BP 315 EP 315 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 283EJ UT WOS:000329228000169 ER PT J AU Kulkarni, SR Donepudi, AC Xu, JL Wei, W Cheng, QQC Driscoll, MV Johnson, DA Johnson, JA Li, XL Slitt, AL AF Kulkarni, Supriya R. Donepudi, Ajay C. Xu, Jialin Wei, Wei Cheng, Qiuqiong C. Driscoll, Maureen V. Johnson, Delinda A. Johnson, Jeffrey A. Li, Xiaoling Slitt, Angela L. TI Fasting Induces Nuclear Factor E2-Related Factor 2 and ATP-Binding Cassette Transporters via Protein Kinase A and Sirtuin-1 in Mouse and Human SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID ANTIOXIDANT RESPONSE ELEMENT; BILE-ACID; MOLECULAR-MECHANISMS; CYCLIC-NUCLEOTIDES; LIVER; RESISTANCE; EXPRESSION; PATHWAY; SIRT1; INDUCTION AB Aims: The purpose of this study was to determine whether 3-5-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Sirtuin-1 (SIRT1) dependent mechanisms modulate ATP-binding Cassette (ABC) transport protein expression. ABC transport proteins (ABCC2-4) are essential for chemical elimination from hepatocytes and biliary excretion. Nuclear factor-E2 related-factor 2 (NRF2) is a transcription factor that mediates ABCC induction in response to chemical inducers and liver injury. However, a role for NRF2 in the regulation of transporter expression in nonchemical models of liver perturbation is largely undescribed. Results: Here we show that fasting increased NRF2 target gene expression through NRF2- and SIRT1-dependent mechanisms. In intact mouse liver, fasting induces NRF2 target gene expression by at least 1.5 to 5-fold. In mouse and human hepatocytes, treatment with 8-Bromoadenosine-cAMP, a cAMP analogue, increased NRF2 target gene expression and antioxidant response element activity, which was decreased by the PKA inhibitor, H-89. Moreover, fasting induced NRF2 target gene expression was decreased in liver and hepatocytes of SIRT1 liver-specific null mice and NRF2-null mice. Lastly, NRF2 and SIRT1 were recruited to MAREs and Antioxidant Response Elements (AREs) in the human ABCC2 promoter. Innovation: Oxidative stress mediated NRF2 activation is well described, yet the influence of basic metabolic processes on NRF2 activation is just emerging. Conclusion: The current data point toward a novel role of nutrient status in regulation of NRF2 activity and the antioxidant response, and indicates that cAMP/PKA and SIRT1 are upstream regulators for fasting-induced activation of the NRF2-ARE pathway. Antioxid. Redox Signal. 20, 15-30. C1 [Kulkarni, Supriya R.; Donepudi, Ajay C.; Xu, Jialin; Wei, Wei; Cheng, Qiuqiong C.; Driscoll, Maureen V.; Slitt, Angela L.] Univ Rhode Isl, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA. [Johnson, Delinda A.; Johnson, Jeffrey A.] Univ Wisconsin, Sch Pharm, Madison, WI 53706 USA. [Li, Xiaoling] NIEHS, Lab Signal Transduct, Mammalian Aging Grp, Res Triangle Pk, NC 27709 USA. RP Slitt, AL (reprint author), Univ Rhode Isl, Dept Biomed & Pharmaceut Sci, 7 Greenhouse Rd, Kingston, RI 02881 USA. EM aslitt@uri.edu OI Kulkarni, Supriya/0000-0002-3146-0582 FU National Institutes of Health [5R01ES016042, 5K22ES013782]; Rhode Island IDeA Network of Biomedical Research Excellence from the National Center for Research Resources, National Institutes of Health [P20RR016457-10]; Rhode Island Foundation FX The authors thank Drs. Joseph T. Rodgers and Pere Puigserver (Dana-Farber Cancer Institute, Harvard Medical School) for sharing liver tissue, Dr. Curtis D. Klaassen (University of Kansas Medical School) and Dr. Jeff Chan (UC-Irvine) for sharing NRF2-null mice. We thank Dr. Michael Goedken for histopathology consultation, as well as, Laura Armstrong, Vijay More, Prajakta Shimpi, and Maneesha Paranjpe for technical assistance. This work was supported by National Institutes of Health [5R01ES016042], and, in part, by Rhode Island IDeA Network of Biomedical Research Excellence [Award # P20RR016457-10] from the National Center for Research Resources, National Institutes of Health, National Institutes of Health [5K22ES013782], and the Rhode Island Foundation. NR 53 TC 19 Z9 21 U1 2 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JAN 1 PY 2014 VL 20 IS 1 BP 15 EP 30 DI 10.1089/ars.2012.5082 PG 16 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 284XU UT WOS:000329356300002 PM 23725046 ER PT J AU Franco, R Bortner, CD Schmitz, I Cidlowski, JA AF Franco, Rodrigo Bortner, Carl D. Schmitz, Ingo Cidlowski, John A. TI Glutathione depletion regulates both extrinsic and intrinsic apoptotic signaling cascades independent from multidrug resistance protein 1 SO APOPTOSIS LA English DT Article DE Glutathione; Extrinsic; Intrinsic; MRP1; Multidrug resistance; MK571 ID MITOCHONDRIAL PERMEABILITY TRANSITION; REDUCED GLUTATHIONE; CASPASE-8 ACTIVATION; OXIDATIVE STRESS; LEUKEMIA-CELLS; IONIC HOMEOSTASIS; GSH EXTRUSION; EFFLUX; TRANSPORT; FAS AB Glutathione (GSH) depletion is an important hallmark of apoptosis. We previously demonstrated that GSH depletion, by its efflux, regulates apoptosis by modulation of executioner caspase activity. However, both the molecular identity of the GSH transporter(s) involved and the signaling cascades regulating GSH loss remain obscure. We sought to determine the role of multidrug resistance protein 1 (MRP1) in GSH depletion and its regulatory role on extrinsic and intrinsic pathways of apoptosis. In human lymphoma cells, GSH depletion was stimulated rather than inhibited by pharmacological blockage of MRP1 with MK571. GSH loss was dependent on initiator caspases 8 and 9 activity. Genetic knock-down (> 60 %) of MRP1 by stable transfection with short hairpin small interfering RNA significantly reduced MRP1 protein levels, which correlated directly with the loss of MRP1-mediated anion transport. However, GSH depletion and apoptosis induced by both extrinsic and intrinsic pathways were not affected by MRP1 knock-down. Interestingly, stimulation of GSH loss by MK571 also enhanced the initiator phase of apoptosis by stimulating initiator caspase 8 and 9 activity and pro-apoptotic BCL-2 interacting domain cleavage. Our results clearly show that caspase-dependent GSH loss and apoptosis are not mediated by MRP1 proteins and that GSH depletion stimulates the initiation phase of apoptosis in lymphoid cells. C1 [Franco, Rodrigo] Univ Nebraska, Redox Biol Ctr, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA. [Bortner, Carl D.; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Schmitz, Ingo] Univ Magdeburg, Lab Syst Oriented Immunol & Inflammat Res, Inst Mol & Clin Immunol, D-39106 Magdeburg, Germany. [Schmitz, Ingo] Helmholtz Ctr Infect Res, Div Immune Control, D-38124 Braunschweig, Germany. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov RI Franco, Rodrigo/D-9470-2013 OI Franco, Rodrigo/0000-0003-3241-8615 FU Intramural Research Program of the NIH/National Institute of Environmental Health Sciences [1Z01ES090079]; Centers of Biomedical Research Excellence (COBRE) Grant (Franco) [P20RR17675] FX This work was supported by the Intramural Research Program of the NIH/National Institute of Environmental Health Sciences 1Z01ES090079 (Cidlowski and Bortner), the P20RR17675 Centers of Biomedical Research Excellence (COBRE) Grant (Franco). NR 77 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1360-8185 EI 1573-675X J9 APOPTOSIS JI Apoptosis PD JAN PY 2014 VL 19 IS 1 BP 117 EP 134 DI 10.1007/s10495-013-0900-0 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 284CP UT WOS:000329294000009 PM 24146141 ER PT J AU Duarte, RF Greinix, H Rabin, B Mitchell, SA Basak, G Wolff, D Madrigal, JA Pavletic, SZ Lee, SJ AF Duarte, R. F. Greinix, H. Rabin, B. Mitchell, S. A. Basak, G. Wolff, D. Madrigal, J. A. Pavletic, S. Z. Lee, S. J. TI Uptake and use of recommendations for the diagnosis, severity scoring and management of chronic GVHD: an international survey of the EBMT-NCI Chronic GVHD Task Force SO BONE MARROW TRANSPLANTATION LA English DT Article DE chronic GVHD; allogeneic hematopoietic cell transplantation; survey; uptake; implementation; recommendations ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; CLINICAL-TRIALS; CELL TRANSPLANTATION; CRITERIA; ORGAN AB In 2005, the National Institutes of Health (NIH) consensus conference published a series of papers recommending methods to improve the conduct of clinical trials in chronic GVHD. Although the NIH recommendations were primarily aimed at strengthening research, several papers addressed issues relevant for clinical practice, particularly diagnosis, severity scoring, and ancillary and supportive care practices. We conducted an international survey to assess the uptake of these recommendations, identify barriers to greater use and document the use and perceived effectiveness of available treatments. The response rate for the American survey of 1387 practitioners was 21.8%, and it was 24.6% for 407 centers surveyed in Europe, Asia, Australia and Africa. Most respondents were familiar with the NIH consensus recommendations (94-96%) and used them in practice. Multiple barriers to greater use were reported. Besides lack of time (55-62%), unfamiliarity with the recommendations, scarcity of evidence supporting the impact of recommendations on outcomes, insufficient training/experience in chronic GVHD management and inaccessibility of subspecialists were also endorsed. Systemic corticosteroids were reported to be the most effective treatment for chronic GVHD, but many others were perceived to have moderate or great success. Therapeutic management of steroid-refractory chronic GVHD was identified as the highest priority for research. C1 [Duarte, R. F.] Hosp Duran I Reynals, Catalan Inst Oncol, Dept Hematol, Barcelona, Spain. [Greinix, H.] Med Univ Vienna, Dept Internal Med 1, Vienna, Austria. [Rabin, B.] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [Mitchell, S. A.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Basak, G.] Med Univ Warsaw, Dept Hematol Oncol & Internal Med, Warsaw, Poland. [Wolff, D.] Univ Regensburg, Dept Internal Med 3, D-93053 Regensburg, Germany. [Madrigal, J. A.] Royal Free Hosp, Anthony Nolan Res Inst, London NW3 2QG, England. [Pavletic, S. Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lee, S. J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. RP Lee, SJ (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave North,D5-290, Seattle, WA 98109 USA. EM sjlee@fhcrc.org FU The Center for Global Health; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX We thank all the participating practitioners and centers, CIBMTR for providing contact information for the American survey and the EBMT administrative office for their help with survey distribution to EBMT centers. The Center for Global Health provided support for the initial meeting of the EBMT-NCI Chronic GVHD Task Force. This work was in part supported by the Center for Cancer Research, the intramural program of the National Cancer Institute, National Institutes of Health. The Chronic GVHD Consortium (U54 CA163438) is a part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 20 TC 19 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JAN PY 2014 VL 49 IS 1 BP 49 EP 54 DI 10.1038/bmt.2013.129 PG 6 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 286CN UT WOS:000329442200009 PM 23955633 ER PT J AU Bassim, CW Fassil, H Mays, JW Edwards, D Baird, K Steinberg, SM Williams, KM Cowen, EW Mitchell, SA Cole, K Taylor, T Avila, D Zhang, D Pulanic, D Grkovic, L Fowler, D Gress, RE Pavletic, SZ AF Bassim, C. W. Fassil, H. Mays, J. W. Edwards, D. Baird, K. Steinberg, S. M. Williams, K. M. Cowen, E. W. Mitchell, S. A. Cole, K. Taylor, T. Avila, D. Zhang, D. Pulanic, D. Grkovic, L. Fowler, D. Gress, R. E. Pavletic, S. Z. TI Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures SO BONE MARROW TRANSPLANTATION LA English DT Article DE oral cGVHD; chronic graft-versus-host disease; validation ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; STEM-CELL TRANSPLANTATION; WORKING GROUP-REPORT; THERAPEUTIC RESPONSE; CLINICAL-TRIALS; CANCER; SCALE; CGVHD; CRITERIA AB Oral chronic GVHD (cGVHD) is a common, late complication of alloSCT that is associated with significant patient morbidity. The NIH Oral Mucosal Score (NIH OMS) was developed to assess oral cGVHD therapeutic response, but has not been fully validated. This study's purpose was to conduct a rigorous construct validity and internal consistency analysis of this score and its components (erythema, lichenoid, ulcers, mucoceles) using established measures of oral pain, oral function, oral-related quality-of-life, nutrition and laboratory parameters in 198 patients with cGVHD. The construct validity of the NIH OMS was supported: a moderate correlation was observed between NIH OMS and mouth pain (rho = 0.43), while a weaker correlation was observed with low albumin (rho = -0.26). Total NIH OMS, erythema and lichenoid components were associated with malnutrition, oral pain and impaired oral QOL, while ulcers were only associated with oral pain. No associations were found between mucoceles and any indicator evaluated, including salivary function or xerostomia. Kappa determined between scale components was low overall (all <= 0.35), supporting a conclusion that each component measures a distinct manifestation of oral cGVHD. This study supports the use of the NIH OMS and its components (erythema, lichenoid and ulcerations) to measure clinician-reported severity of oral cGVHD. C1 [Bassim, C. W.; Mays, J. W.; Edwards, D.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Fassil, H.; Williams, K. M.; Cole, K.; Taylor, T.; Avila, D.; Pulanic, D.; Grkovic, L.; Fowler, D.; Gress, R. E.; Pavletic, S. Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Fassil, H.] Tufts Univ, Sch Dent Med, Boston, MA 02111 USA. [Baird, K.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, S. M.; Zhang, D.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Cowen, E. W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Mitchell, S. A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Pulanic, D.; Grkovic, L.] Clin Hosp Ctr Zagreb, Dept Internal Med, Div Hematol, Zagreb, Croatia. RP Bassim, CW (reprint author), Natl Inst Dent & Craniofacial Res, Clin Res Ctr, NIH, Bldg 10,Room 1N-117, Bethesda, MD 20892 USA. EM carol.bassim@nih.gov FU NIH; Pfizer Inc.; National Cancer Institute, Center for Cancer Research, National Institute of Health FX H Fassil's research year was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc., and by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institute of Health. NR 29 TC 6 Z9 6 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JAN PY 2014 VL 49 IS 1 BP 116 EP 121 DI 10.1038/bmt.2013.137 PG 6 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 286CN UT WOS:000329442200019 PM 23995099 ER PT J AU Dan, T Hewitt, SM Ohri, N Ly, D Soule, BP Smith, SL Matsuda, K Council, C Shankavaram, U Lippman, ME Mitchell, JB Camphausen, K Simone, NL AF Dan, T. Hewitt, S. M. Ohri, N. Ly, D. Soule, B. P. Smith, S. L. Matsuda, K. Council, C. Shankavaram, U. Lippman, M. E. Mitchell, J. B. Camphausen, K. Simone, N. L. TI CD44 is prognostic for overall survival in the NCI randomized trial on breast conservation with 25 year follow-up SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Breast conservation; CD44; Biomarker; Randomized trial ID NEOADJUVANT CHEMOTHERAPY RESPONSE; CANCER STEM-CELLS; NODE METASTASIS; TUMOR-MARKERS; EXPRESSION; HYALURONAN; CARCINOMA; CD44(+)/CD24(-/LOW); PHARMACOKINETICS; DIFFERENTIATION AB CD44 is a transmembrane glycoprotein involved in numerous cellular functions, including cell adhesion and extracellular matrix interactions. It is known to be functionally diverse, with alternative splice variants increasingly implicated as a marker for tumor-initiating stem cells associated with poor prognosis. Here, we evaluate CD44 as a potential marker of long-term breast cancer outcomes. Tissue specimens from patients treated on the National Cancer Institute 79-C-0111 randomized trial of breast conservation versus mastectomy between 1979 and 1987 were collected, and immunohistochemistry was performed using the standard isoform of CD44. Specimens were correlated with patient characteristics and outcomes. Survival analysis was performed using the log rank test. Fifty-one patients had evaluable tumor sections and available long-term clinical follow up data at a median follow up of 25.7 years. Significant predictors of OS were tumor size (median OFS 25.4 years for a parts per thousand currency sign2 cm vs. 7.5 years for > 2 cm, p = 0.001), nodal status (median OS 17.2 years for node-negative patients vs. 6.7 years for node positive patients, p = 0.017), and CD44 expression (median OS 18.9 years for CD44 positive patients vs. 8.6 years for CD44 negative patients, p = 0.049). There was a trend toward increased PFS for patients with CD44 positive tumors (median PFS 17.9 vs. 4.3 years, p = 0.17), but this did not reach statistical significance. These findings illustrate the potential utility of CD44 as a prognostic marker for early stage breast cancer. Subgroup analysis in patients with lymph node involvement revealed CD44 positivity to be most strongly associated with increased survival, suggesting a potential role of CD44 in decision making for axillary management. As there is increasing interest in CD44 as a therapeutic target in ongoing clinical trials, the results of this study suggest additional investigation regarding the role CD44 in breast cancer is warranted. C1 [Dan, T.; Ohri, N.; Simone, N. L.] Thomas Jefferson Univ, Dept Radiat Oncol, Bodine Ctr Canc Treatment, Kimmel Canc Ctr,Jefferson Med Coll, Philadelphia, PA 19107 USA. [Hewitt, S. M.; Matsuda, K.] NCI, Pathol Branch, Bethesda, MD 20892 USA. [Ly, D.; Smith, S. L.; Council, C.; Shankavaram, U.; Camphausen, K.; Simone, N. L.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Soule, B. P.; Mitchell, J. B.] NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. [Lippman, M. E.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. RP Simone, NL (reprint author), Thomas Jefferson Univ, Dept Radiat Oncol, Bodine Ctr Canc Treatment, Kimmel Canc Ctr,Jefferson Med Coll, 111 S 11th St G-301G, Philadelphia, PA 19107 USA. EM nicole.simone@jeffersonhospital.org OI Dan, Tu/0000-0003-1154-0507; Hewitt, Stephen/0000-0001-8283-1788 FU NIH; Kimmel Cancer Center's NCI Cancer Center [P30 CA56036] FX Research support was in part through the Intramural Research Program of the NIH and also in part by the Kimmel Cancer Center's NCI Cancer Center Support Grant P30 CA56036. NR 55 TC 7 Z9 7 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JAN PY 2014 VL 143 IS 1 BP 11 EP 18 DI 10.1007/s10549-013-2758-9 PG 8 WC Oncology SC Oncology GA 284DE UT WOS:000329295500002 PM 24276281 ER PT J AU Horne, HN Sherman, ME Garcia-Closas, M Pharoah, PD Blows, FM Yang, XHR Hewitt, SM Conway, CM Lissowska, J Brinton, LA Prokunina-Olsson, L Dawson, SJ Caldas, C Easton, DF Chanock, SJ Figueroa, JD AF Horne, Hisani N. Sherman, Mark E. Garcia-Closas, Montserrat Pharoah, Paul D. Blows, Fiona M. Yang, Xiaohong R. Hewitt, Stephen M. Conway, Catherine M. Lissowska, Jolanta Brinton, Louise A. Prokunina-Olsson, Ludmila Dawson, Sarah-Jane Caldas, Carlos Easton, Douglas F. Chanock, Stephen J. Figueroa, Jonine D. TI Breast cancer susceptibility risk associations and heterogeneity by E-cadherin tumor tissue expression SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE E-cadherin; Single nucleotide polymorphism (SNP); Genetics of risk ID GENOME-WIDE ASSOCIATION; PROGNOSTIC-SIGNIFICANCE; LOBULAR CARCINOMA; 14Q24.1 RAD51L1; VARIANTS; MARKERS; TRANSITION; CONSORTIUM; SUBTYPES; 1P11.2 AB E-cadherin is involved in cell-cell adhesion and epithelial-to-mesenchymal transitions. In cancers, loss or inactivation of E-cadherin is associated with epithelial cell proliferation and invasion. Here, we sought to determine, if risk associations for 18 breast cancer susceptibility single nucleotide polymorphisms (SNPs) differed by E-cadherin tumor tissue expression in the Polish Breast Cancer Study (PBCS), using data on 1,347 invasive breast cancer cases and 2,366 controls. E-cadherin expression (low/high) was assessed using immunohistochemical staining of tumor tissue microarrays. Replication data on 2,006 cases and 6,714 controls from the Study of Epidemiology and Risk Factors in Cancer Heredity was used to follow-up promising findings from PBCS. In PBCS, we found the rs11249433 SNP at the 1p11.2 locus to be more strongly associated with risk of E-cadherin low tumors (OR = 1.30, 95 % CI = 1.08-1.56) than with E-cadherin high tumors [OR = 1.06, 95 % CI = 0.95-1.18; case-only p-heterogeneity (p-het) = 0.05]. Findings in PBCS for rs11249433 were replicated in SEARCH. Combined analyses of the two datasets for SNP rs11249433 revealed significant heterogeneity by E-cadherin expression (combined case-only p-het = 0.004). Further, among carriers of rs11249433, the highest risk was seen for E-cadherin low tumors that were ER-positive and of lobular histology. Our results in two independent data sets suggest that rs11249433, which is located between the NOTCH2 and FCGR1B genes within the 1p11.2 locus, is more strongly associated with risk of breast tumors with low or absent E-cadherin expression, and suggest that evaluation of E-cadherin tumor tissue expression may be useful in clarifying breast cancer risk factor associations. C1 [Horne, Hisani N.; Yang, Xiaohong R.; Brinton, Louise A.; Prokunina-Olsson, Ludmila; Chanock, Stephen J.; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Horne, Hisani N.] NCI, NIH, DCEG, HREB, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, NIH, Rockville, MD USA. [Garcia-Closas, Montserrat] Breast Canc Breakthrough Ctr, London, England. [Garcia-Closas, Montserrat] Inst Canc Res, Sect Epidemiol & Genet, Sutton, Surrey, England. [Pharoah, Paul D.; Blows, Fiona M.; Dawson, Sarah-Jane; Caldas, Carlos; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D.; Blows, Fiona M.; Dawson, Sarah-Jane; Caldas, Carlos; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Hewitt, Stephen M.; Conway, Catherine M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. RP Horne, HN (reprint author), NCI, NIH, DCEG, HREB, 9609 Med Ctr Dr,Rm 7E234 MSC 7234, Bethesda, MD 20892 USA. EM hisani.horne@nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Dawson, Sarah-Jane/0000-0002-8276-0374; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Hewitt, Stephen/0000-0001-8283-1788; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural Research Programs of the Division of Cancer Epidemiology and Genetics; Center for Cancer Research of the National Cancer Institute; Breakthrough Breast Cancer Centre; Institute of Cancer Research, London, UK; NHS FX This research was supported by the Intramural Research Programs of the Division of Cancer Epidemiology and Genetics and Center for Cancer Research of the National Cancer Institute. M. Garcias-Closas is funded by the Breakthrough Breast Cancer Centre and the Institute of Cancer Research, London, UK. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. NR 28 TC 7 Z9 7 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JAN PY 2014 VL 143 IS 1 BP 181 EP 187 DI 10.1007/s10549-013-2771-z PG 7 WC Oncology SC Oncology GA 284DE UT WOS:000329295500018 PM 24292867 ER PT J AU Larkin, KL Saboo, US Comer, GM Forooghian, F Mackensen, F Merrill, P Sen, HN Singh, A Essex, RW Lake, S Lim, LL Vasconcelos-Santos, DV Foster, CS Wilson, DJ Smith, JR AF Larkin, Kelly L. Saboo, Ujwala S. Comer, Grant M. Forooghian, Farzin Mackensen, Friederike Merrill, Pauline Sen, H. Nida Singh, Arun Essex, Rohan W. Lake, Stewart Lim, Lyndell L. Vasconcelos-Santos, Daniel V. Foster, C. Stephen Wilson, David J. Smith, Justine R. TI Use of intravitreal rituximab for treatment of vitreoretinal lymphoma SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID PRIMARY INTRAOCULAR LYMPHOMA; NERVOUS-SYSTEM LYMPHOMA; PRIMARY CNS LYMPHOMA; COLLABORATIVE GROUP-REPORT; B-CELLS; METHOTREXATE; OUTCOMES; INVOLVEMENT; INJECTIONS; FEATURES AB Aim Vitreoretinal lymphoma is a diffuse large B cell non-Hodgkin lymphoma. Targeting malignant cells with rituximab is being used increasingly as local chemotherapy, but information on this treatment is scant. We aimed to describe current therapeutic approaches, as well as responses to and complications of, intravitreal rituximab in patients with vitreoretinal lymphoma. Methods Clinical data were collected in a standardised manner retrospectively on patients with vitreoretinal lymphoma treated with intravitreal rituximab. Results 48 eyes (34 patients) with vitreoretinal lymphoma were treated with a median of 3.5 intravitreal injections of rituximab (1 mg/0.1 mL) for new diagnosis (68.8%), progressive disease (29.9%) and maintenance therapy (2.1%). Intravitreal rituximab +/- methotrexate was the sole treatment in 19 eyes (39.6%). 31 eyes (64.6%) eyes achieved complete remission, after a median of 3 injections; 7 of these eyes developed recurrent disease. 11 eyes (22.9%) achieved partial remission. Although rituximab may have contributed to complications reported in 12 eyes (25.0%), a 2-line loss of Snellen visual acuity occurred in only 2 of those eyes (4.2%). Conclusions Approaches in rituximab-based intravitreal chemotherapy vary widely, but our findings suggest that this treatment may be safe and effective in inducing remission in a majority of eyes with vitreoretinal lymphoma. C1 [Larkin, Kelly L.; Wilson, David J.; Smith, Justine R.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Saboo, Ujwala S.; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Saboo, Ujwala S.; Foster, C. Stephen] Ocular Immunol & Uveitis Fdn, Cambridge, MA USA. [Comer, Grant M.] Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Forooghian, Farzin] Univ British Columbia, Dept Ophthalmol & Visual Sci, Vancouver, BC V5Z 1M9, Canada. [Mackensen, Friederike] Univ Klinikum Heidelberg, Dept Ophthalmol, Interdisciplinary Uveitis Ctr, Heidelberg, Germany. [Merrill, Pauline] Rush Univ, Dept Ophthalmol, Chicago, IL 60612 USA. [Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. [Singh, Arun] Cleveland Clin, Cleveland, OH 44106 USA. [Essex, Rohan W.] Australian Natl Univ, Dept Ophthalmol, Canberra, ACT, Australia. [Lake, Stewart; Smith, Justine R.] Flinders Univ S Australia, Adelaide, SA 5001, Australia. [Lim, Lyndell L.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Vasconcelos-Santos, Daniel V.] Univ Fed Minas Gerais, Dept Uveitis & Ophthalm Pathol, Belo Horizonte, MG, Brazil. [Foster, C. Stephen] Harvard Univ, Dept Ophthalmol, Cambridge, MA 02138 USA. RP Smith, JR (reprint author), Flinders Univ S Australia, Sch Med, Flinders Med Ctr, Room 4E-431,Flinders Dr, Bedford Pk, SA 5042, Australia. EM justine.smith@flinders.edu.au OI Lim, Lyndell/0000-0003-2491-685X FU Research to Prevent Blindness FX This work was supported in part by Research to Prevent Blindness (Unrestricted Grant to: Casey Eye Institute, Oregon Health & Science University). NR 30 TC 10 Z9 11 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD JAN PY 2014 VL 98 IS 1 BP 99 EP 103 DI 10.1136/bjophthalmol-2013-304043 PG 5 WC Ophthalmology SC Ophthalmology GA 269MX UT WOS:000328246500020 PM 24158837 ER PT J AU Hecht, SS Szabo, E AF Hecht, Stephen S. Szabo, Eva TI Fifty Years of Tobacco Carcinogenesis Research: From Mechanisms to Early Detection and Prevention of Lung Cancer SO CANCER PREVENTION RESEARCH LA English DT Article ID NICOTINE METABOLITE RATIO; RISK PREDICTION MODEL; SUSCEPTIBILITY LOCUS; CIGARETTE-SMOKING; POLICY STATEMENT; GENE-EXPRESSION; SCREENING CT; SMOKERS; TRIAL; BIOMARKERS AB The recognition of the link between cigarette smoking and lung cancer in the 1964 Surgeon General's Report initiated definitive and comprehensive research on the identification of carcinogens in tobacco products and the relevant mechanisms of carcinogenesis. The resultant comprehensive data clearly illustrate established pathways of cancer induction involving carcinogen exposure, metabolic activation, DNA adduct formation, and consequent mutation of critical genes along with the exacerbating influences of inflammation, cocarcinogenesis, and tumor promotion. This mechanistic understanding has provided a framework for the regulation of tobacco products and for the development of relevant tobacco carcinogen and toxicant biomarkers that can be applied in cancer prevention. Simultaneously, the recognition of the link between smoking and lung cancer paved the way for two additional critical approaches to cancer prevention that are discussed here: detection of lung cancer at an early, curable stage, and chemoprevention of lung cancer. Recent successes in more precisely identifying at-risk populations and in decreasing lung cancer mortality with helical computed tomography screening are notable, and progress in chemoprevention continues, although challenges with respect to bringing these approaches to the general population exist. Collectively, research performed since the 1964 Report demonstrates unequivocally that the majority of deaths from lung cancer are preventable. C1 [Hecht, Stephen S.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN 55455 USA. [Szabo, Eva] NCI, Lung & Upper Aerodigest Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Hecht, SS (reprint author), Univ Minnesota, Mason Canc Ctr, 2231 6th St Southeast,Room 2-148 CCRB, Minneapolis, MN 55455 USA. EM hecht002@umn.edu; szaboe@mail.nih.gov OI Hecht, Stephen/0000-0001-7228-1356 FU [CA-81301]; [CA-92025] FX This work was supported by CA-81301 and CA-92025 (to S.S. Hecht). NR 52 TC 13 Z9 13 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JAN PY 2014 VL 7 IS 1 BP 1 EP 8 DI 10.1158/1940-6207.CAPR-13-0371 PG 8 WC Oncology SC Oncology GA 285YR UT WOS:000329431500001 PM 24403288 ER PT J AU Klepin, HD Geiger, AM Bandos, H Costantino, JP Rapp, SR Sink, KM Lawrence, JA Atkinson, HH Espeland, MA AF Klepin, Heidi D. Geiger, Ann M. Bandos, Hanna Costantino, Joseph P. Rapp, Stephen R. Sink, Kaycee M. Lawrence, Julia A. Atkinson, Hal H. Espeland, Mark A. TI Cognitive Factors Associated with Adherence to Oral Antiestrogen Therapy: Results from the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) Study SO CANCER PREVENTION RESEARCH LA English DT Article ID POSITIVE BREAST-CANCER; MEDICATION ADHERENCE; HORMONAL-THERAPY; OLDER WOMEN; ALZHEIMERS-DISEASE; ADJUVANT TAMOXIFEN; UNITED-STATES; NONADHERENCE; DISCONTINUATION; IMPAIRMENT AB Little is known about the cognitive factors associated with adherence to antiestrogen therapy. Our objective was to investigate the association between domain-specific cognitive function and adherence among women in a clinical prevention trial of oral antiestrogen therapies. We performed a secondary analysis of Co-STAR, an ancillary study of the STAR breast cancer prevention trial in which postmenopausal women at increased breast cancer risk were randomized to tamoxifen or raloxifene. Co-STAR enrolled nondemented participants >= 65 years old to compare treatment effects on cognition. The cognitive battery assessed global cognitive function (Modified Mini-Mental State Exam), and specific cognitive domains of verbal knowledge, verbal fluency, figural memory, verbal memory, attention and working memory, spatial ability, and fine motor speed. Adherence was defined by a ratio of actual time taking therapy per protocol >= 80% of expected time. Logistic regression was used to evaluate the association between cognitive test scores and adherence to therapy. The mean age of the 1,331 Co-STAR participants was 67.2 +/- 4.3 years. Mean 3MS score was 95.1 (4.7) and 14% were nonadherent. In adjusted analyses, the odds of nonadherence were lower for those with better scores on verbal memory [OR (95% confidence interval): 0.75 (0.62-0.92)]. Larger relative deficits in verbal memory compared with verbal fluency were also associated with nonadherence [1.28 (1.08-1.51)]. Among nondemented older women, subtle differences in memory performance were associated with medication adherence. Differential performance across cognitive domains may help identify persons at greater risk for poor adherence. C1 [Klepin, Heidi D.; Rapp, Stephen R.; Sink, Kaycee M.; Lawrence, Julia A.; Atkinson, Hal H.; Espeland, Mark A.] Wake Forest Sch Med, Winston Salem, NC USA. [Geiger, Ann M.] NCI, Rockville, MD USA. [Bandos, Hanna; Costantino, Joseph P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Bandos, Hanna; Costantino, Joseph P.] Natl Surg Adjuvant Breast & Bowel Project NSABP B, Pittsburgh, PA USA. RP Klepin, HD (reprint author), Wake Forest Baptist Hlth, Sect Hematol & Oncol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM hklepin@wakehealth.edu FU Public Health Service grants from the National Cancer Institute, NIH [U10-CA-37377, U10-CA-69974, U10CA-12027, U10CA-69651]; Department of Health and Human Services; AstraZeneca Pharmaceuticals; Eli Lilly and Co; National Institute on Aging [NO1-AG-2106]; Intramural Research Program, NIA, NIH; NIA, NIH; Wake Forest University Claude D. Pepper Older Americans Independence Center [P30 AG-021332]; Atlantic Philanthropies; American Society of Hematology; John A. Hartford Foundation; Association of Specialty Professors; Paul Beeson Career Development Award in Aging Research [K23AG038361]; NIA; AFAR; Gabrielle's Angel Foundation for Cancer Research FX STAR was supported by Public Health Service grants U10-CA-37377, U10-CA-69974, U10CA-12027, and U10CA-69651 from the National Cancer Institute, NIH, Department of Health and Human Services, AstraZeneca Pharmaceuticals, and Eli Lilly and Co (to J. Costantino). Co-STAR was supported by the National Institute on Aging, NO1-AG-2106, and in part by the Intramural Research Program, NIA, NIH (M. Espeland, H. Klepin). Dr. Klepin was also funded in part by the Intramural Research Program, NIA, NIH, the Wake Forest University Claude D. Pepper Older Americans Independence Center (P30 AG-021332), Atlantic Philanthropies, American Society of Hematology, John A. Hartford Foundation and Association of Specialty Professors. Current support includes a Paul Beeson Career Development Award in Aging Research (K23AG038361; supported by NIA, AFAR, The John A. Hartford Foundation, and The Atlantic Philanthropies) and The Gabrielle's Angel Foundation for Cancer Research (H. Klepin). NR 35 TC 9 Z9 9 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JAN PY 2014 VL 7 IS 1 BP 161 EP 168 DI 10.1158/1940-6207.CAPR-13-0165 PG 8 WC Oncology SC Oncology GA 285YR UT WOS:000329431500017 PM 24253314 ER PT J AU Kitahara, CM Gamborg, M de Gonzalez, AB Sorensen, TIA Baker, JL AF Kitahara, Cari M. Gamborg, Michael de Gonzalez, Amy Berrington Sorensen, Thorkild I. A. Baker, Jennifer L. TI Childhood Height and Body Mass Index Were Associated with Risk of Adult Thyroid Cancer in a Large Cohort Study SO CANCER RESEARCH LA English DT Article ID ANTHROPOMETRIC FACTORS; INCREASING INCIDENCE; PHYSICAL-ACTIVITY; POOLED ANALYSIS; SECULAR TRENDS; OBESITY; GROWTH; POPULATION; OVERWEIGHT; PATTERNS AB Taller stature and obesity in adulthood have been consistently associated with an increased risk of thyroid cancer, but few studies have investigated the role of childhood body size. Using data from a large prospective cohort, we examined associations for height and body mass index (BMI) at ages 7 to 13 years with risk of thyroid cancer in later life. The study population included 321,085 children from the Copenhagen School Health Records Register, born between 1930 and 1989 in Copenhagen, Denmark, with measurements of height and weight from 7 to 13 years of age. These data were linked with the Danish Cancer Registry to identify incident thyroid cancer cases (1968-2010). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for age- and sex-specific height and BMI SD scores (SDS) using proportional hazards models stratified by birth cohort and sex. During follow-up (median = 38.6 years), 171 women and 64 men were diagnosed with thyroid cancer. Both height and BMI were positively associated with thyroid cancer risk, and these associations were similar by age at measurement. Using age 10 as an example, HRs per 1 unit increase in SDS for height (similar to 6-7 cm) and BMI (similar to 1.5-2 kg/m(2)) were 1.22 (95% CI, 1.07-1.40) and 1.15 (95% CI, 1.00-1.34), respectively. These results, together with the relatively young ages at which thyroid cancers are diagnosed compared with other malignancies, suggest a potential link between early-life factors related to growth and body weight and thyroid carcinogenesis. (C)2013 AACR. C1 [Kitahara, Cari M.; de Gonzalez, Amy Berrington] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Gamborg, Michael; Sorensen, Thorkild I. A.; Baker, Jennifer L.] Inst Prevent Med, Frederiksberg, Denmark. [Gamborg, Michael; Sorensen, Thorkild I. A.; Baker, Jennifer L.] Bispebjerg Hosp, DK-2400 Copenhagen, Denmark. [Gamborg, Michael; Sorensen, Thorkild I. A.; Baker, Jennifer L.] Frederiksberg Univ Hosp, Copenhagen, Denmark. [Sorensen, Thorkild I. A.; Baker, Jennifer L.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark. RP Baker, JL (reprint author), Inst Prevent Med, Nordre Fasanvej 57, Frederiksberg, Denmark. EM jennifer.lyn.baker@regionh.dk RI Baker, Jennifer/F-1917-2010; Kitahara, Cari/R-8267-2016 OI Baker, Jennifer/0000-0002-9649-6615; FU Intramural Research Program of the National Cancer Institute; European Research Council under European Union; ERC [281418]; NIH FX This research was supported in part by the Intramural Research Program of the National Cancer Institute, NIH and by funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013), ERC Grant Agreement no. 281418, childgrowth2-cancer (J.L. Baker). NR 42 TC 17 Z9 19 U1 0 U2 7 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 JAN 1 PY 2014 VL 74 IS 1 BP 235 EP 242 DI 10.1158/0008-5472.CAN-13-2228 PG 8 WC Oncology SC Oncology GA 284DZ UT WOS:000329297600023 PM 24247722 ER PT J AU Li, HT Zhu, F Chen, HY Cheng, KW Zykova, T Oi, N Lubet, RA Bode, AM Wang, MF Dong, ZG AF Li, Haitao Zhu, Feng Chen, Hanyong Cheng, Ka Wing Zykova, Tatyana Oi, Naomi Lubet, Ronald A. Bode, Ann M. Wang, Mingfu Dong, Zigang TI 6-C-(E-phenylethenyl)-Naringenin Suppresses Colorectal Cancer Growth by Inhibiting Cyclooxygenase-1 SO CANCER RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ADENOMATOUS POLYPOSIS; INTESTINAL POLYPOSIS; RANDOMIZED-TRIAL; ASPIRIN; CHEMOPREVENTION; PREVENTION; MOUSE; COX-2; EXPRESSION AB Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors and cyclooxygenase-1 (COX-1) is now being reconsidered as a target for chemoprevention. Our aims were to determine whether selective COX-1 inhibition could delay or prevent cancer development and also clarify the underlying mechanisms. Data clearly showed that COX-1 was required for maintenance of malignant characteristics of colon cancer cells or tumor promoter-induced transformation of preneoplastic cells. We also successfully applied a ligand-docking computational method to identify a novel selective COX-1 inhibitor, 6-C-(E-phenylethenyl)-naringenin (designated herein as 6CEPN). 6CEPN could bind to COX-1 and specifically inhibited its activity both in vitro and ex vivo. In colorectal cancer cells, it potently suppressed anchorage-independent growth by inhibiting COX-1 activity. 6CEPN also effectively suppressed tumor growth in a 28-day colon cancer xenograft model without any obvious systemic toxicity. Taken together, COX-1 plays a critical role in human colorectal carcinogenesis, and this specific COX-1 inhibitor merits further investigation as a potential preventive agent against colorectal cancer. (C)2013 AACR. C1 [Li, Haitao; Zhu, Feng; Chen, Hanyong; Zykova, Tatyana; Oi, Naomi; Bode, Ann M.; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55009 USA. [Lubet, Ronald A.] NCI, NIH, Bethesda, MD 20892 USA. [Cheng, Ka Wing; Wang, Mingfu] Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China. RP Dong, ZG (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55009 USA. EM zgdong@hi.umn.edu RI Wang, Mingfu/D-3136-2009 FU Hormel Foundation; National Institutes of Health [R37 CA081064, ES016548]; NCI [HHSN-261200533001C-NO1-CN-53301, N01-CN-43309-18018-01WA 13B] FX This work was supported by The Hormel Foundation and National Institutes of Health grants R37 CA081064 and ES016548 and NCI contract numbers HHSN-261200533001C-NO1-CN-53301 and N01-CN-43309-18018-01WA 13B. NR 35 TC 9 Z9 9 U1 2 U2 22 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 JAN 1 PY 2014 VL 74 IS 1 BP 243 EP 252 DI 10.1158/0008-5472.CAN-13-2245 PG 10 WC Oncology SC Oncology GA 284DZ UT WOS:000329297600024 PM 24220240 ER PT J AU Hayman, TJ Wahba, A Rath, BH Bae, H Kramp, T Shankavaram, UT Camphausen, K Tofilon, PJ AF Hayman, Thomas J. Wahba, Amy Rath, Barbara H. Bae, Heekyong Kramp, Tamalee Shankavaram, Uma T. Camphausen, Kevin Tofilon, Philip J. TI The ATP-Competitive mTOR Inhibitor INK128 Enhances In Vitro and In Vivo Radiosensitivity of Pancreatic Carcinoma Cells SO CLINICAL CANCER RESEARCH LA English DT Article ID TRANSLATIONAL CONTROL; MESSENGER-RNAS; CANCER CELLS; INITIATION; EIF4E; GAMMA-H2AX; THERAPY; TARGET AB Purpose: Radiotherapy remains a primary treatment modality for pancreatic carcinoma, a tumor characterized by aberrant mTOR activity. Given the regulatory role of mTOR in gene translation, in this study, we defined the effects of the clinically relevant, ATP-competitive mTOR inhibitor, INK128 on the radiosensitivity of pancreatic carcinoma cell lines. Experimental Design: Clonogenic survival was used to determine the effects of INK128 on in vitro radiosensitivity of three pancreatic carcinoma cell lines and a normal fibroblast cell line with mTOR activity defined using immunoblots. DNA double-strand breaks were evaluated according to gamma H2AX foci. The influence of INK128 on radiation-induced gene translation was determined by microarray analysis of polysome-bound mRNA. Leg tumor xenografts grown from pancreatic carcinoma cells were evaluated for mTOR activity, eIF4F cap complex formation, and tumor growth delay. Results: INK128, while inhibiting mTOR activity in each of the cell lines, enhanced the in vitro radiosensitivity of the pancreatic carcinoma cells but had no effect on normal fibroblasts. The dispersal of radiation-induced gamma H2AX foci was inhibited in pancreatic carcinoma cells by INK128 as were radiation-induced changes in gene translation. Treatment of mice with INK128 resulted in an inhibition of mTOR activity as well as cap complex formation in tumor xenografts. Whereas INK128 alone had no effect of tumor growth rate, it enhanced the tumor growth delay induced by single and fractionated doses of radiation. Conclusion: These results indicate that mTOR inhibition induced by INK128 enhances the radiosensitivity of pancreatic carcinoma cells and suggest that this effect involves the inhibition of DNA repair. (C)2013 AACR. C1 [Hayman, Thomas J.] Univ S Florida, Morsani Coll Med, Tampa, FL USA. [Hayman, Thomas J.; Wahba, Amy; Rath, Barbara H.; Bae, Heekyong; Kramp, Tamalee; Shankavaram, Uma T.; Camphausen, Kevin; Tofilon, Philip J.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Tofilon, PJ (reprint author), NCI, 10 Ctr Dr MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. EM tofilonp@mail.nih.gov FU Intramural NIH HHS [ZIA BC011373-03] NR 29 TC 12 Z9 12 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 1 PY 2014 VL 20 IS 1 BP 110 EP 119 DI 10.1158/1078-0432.CCR-13-2136 PG 10 WC Oncology SC Oncology GA 284GC UT WOS:000329303100014 PM 24198241 ER PT J AU Laurie, SA Goss, GD Shepherd, FA Reaume, MN Nicholas, G Philip, L Wang, L Schwock, J Hirsh, V Oza, A Tsao, MS Wright, JJ Leighl, NB AF Laurie, Scott A. Goss, Glenwood D. Shepherd, Frances A. Reaume, M. Neil Nicholas, Garth Philip, Lindsay Wang, Lisa Schwock, Joerg Hirsh, Vera Oza, Amit Tsao, Ming-Sound Wright, John J. Leighl, Natasha B. TI A Phase II Trial of Saracatinib, an Inhibitor of src Kinases, in Previously-Treated Advanced Non-Small-Cell Lung Cancer: The Princess Margaret Hospital Phase II Consortium SO CLINICAL LUNG CANCER LA English DT Article DE Biomarker; Non-small cell; Src inhibitor; Systemic therapy ID FAMILY KINASES; SOLID TUMORS; AZD0530; CHEMOTHERAPY; DASATINIB; DOCETAXEL; ERLOTINIB AB Treatment options for advanced non-small-cell lung cancer (NSCLC) after failure of platinum-based chemotherapy are limited. Dysregulated src kinases may play a role in the malignant phenotype. This 2-stage phase II study evaluated saracatinib, an inhibitor of src kinases in this patient population, and responses were observed, including in a patient with an activating epidermal growth factor receptor (EGFR) mutation. Future studies of this class of agents in molecular subtypes of NSCLC are warranted. Background: The src family of kinases may play a role in the malignant phenotype through effects on migration, motility, adhesion and proliferation. The activity of saracatinib, an orally available inhibitor of src kinases, was evaluated in patients with advanced, platinum-pretreated NSCLC. Patients and Methods: Eligible patients with advanced NSCLC of any histologic subtype and who had obtained a best response to prior platinum-based chemotherapy of at least stable disease received saracatanib 175 mg orally daily in a 28 day cycle. The primary end point was the proportion of patients progression-free after 4 cycles (16 weeks) of therapy; 8 such patients of 32 evaluable were required to deem the therapy active. Immunohistochemistry for src expression was performed on archival tissue from enrolled patients. Results: Thirty-seven patients received a median of 2 cycles (range, 1-14) each. Six of 31 evaluable patients were progression-free at 16 weeks. Two partial responses were observed, lasting 3.7 and 14.6 months; 1 responder had an EGFR exon 19 deletion. An additional 4 patients had stable disease for at least 4 cycles. The median progression-free and overall survival times were 1.8 and 7.6 months. No correlation between src protein expression and outcome was observed. Conclusions: There may be a subset of saracatinib-responsive NSCLC that is currently molecularly undefined. Further studies of this agent in a population preselected for target mutations that potentially relevant to src pathways, such as EGFR, should be considered. (C) 2014 Elsevier Inc. All rights reserved. C1 [Laurie, Scott A.; Goss, Glenwood D.; Reaume, M. Neil; Nicholas, Garth] Univ Ottawa, Ottawa Hosp, Ctr Canc, Ottawa, ON K1H 8L6, Canada. [Shepherd, Frances A.; Philip, Lindsay; Wang, Lisa; Schwock, Joerg; Oza, Amit; Tsao, Ming-Sound; Leighl, Natasha B.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Hirsh, Vera] McGill Univ, Montreal Gen Hosp, Montreal, PQ H3G 1A4, Canada. [Wright, John J.] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Laurie, SA (reprint author), Univ Ottawa, Ottawa Hosp, Ctr Canc, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada. EM slaurie@toh.on.ca FU [HHSN261201100032C/NO1-CM-2011-00032] FX Supported by contracts HHSN261201100032C/NO1-CM-2011-00032. NR 22 TC 9 Z9 10 U1 3 U2 5 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1525-7304 EI 1938-0690 J9 CLIN LUNG CANCER JI Clin. Lung Cancer PD JAN PY 2014 VL 15 IS 1 BP 52 EP 57 DI 10.1016/j.cllc.2013.08.001 PG 6 WC Oncology SC Oncology GA 281TZ UT WOS:000329125200005 PM 24169259 ER PT J AU Goey, AKL Meijerman, I Rosing, H Marchetti, S Mergui-Roelvink, M Keessen, M Burgers, JA Beijnen, JH Schellens, JHM AF Goey, Andrew K. L. Meijerman, Irma Rosing, Hilde Marchetti, Serena Mergui-Roelvink, Marja Keessen, Marianne Burgers, Jacobus A. Beijnen, Jos H. Schellens, Jan H. M. TI The Effect of St John's Wort on the Pharmacokinetics of Docetaxel SO CLINICAL PHARMACOKINETICS LA English DT Article ID HUMAN HEPATOCYTE CULTURES; P-GLYCOPROTEIN INHIBITOR; HYPERICUM-PERFORATUM; CONSTITUENT HYPERFORIN; IMATINIB MESYLATE; DRUG-INTERACTIONS; CANCER-PATIENTS; INDUCTION; METABOLISM; IRINOTECAN AB St John's wort (SJW), a herbal antidepressant, is commonly used by cancer patients, and its component hyperforin is a known inducer of the cytochrome P450 (CYP) isoenzyme 3A4. Here, the potential pharmacokinetic interaction between SJW and the sensitive CYP3A4 substrate docetaxel was investigated. In ten evaluable cancer patients, the pharmacokinetics of docetaxel (135 mg administered intravenously over 60 min) were compared before and after 14 days of supplementation with SJW (300 mg extract [Hyperiplant(A (R))] three times daily). SJW supplementation resulted in a statistically significant decrease in the mean area under the docetaxel plasma concentration-time curve extrapolated to infinity (AUC(a)) from 3,035 +/- A 756 to 2,682 +/- A 717 ng center dot A h/mL (P = 0.045). Furthermore, docetaxel clearance significantly increased from 47.2 to 53.7 L/h (P = 0.045) after SJW intake. The maximum plasma concentration and elimination half-life of docetaxel were (non-significantly) decreased after SJW supplementation. In addition, the incidence of docetaxel-related toxicities was lower after SJW supplementation. These results suggest that concomitant use of docetaxel and the applied SJW product should be avoided to prevent potential undertreatment of cancer patients. C1 [Goey, Andrew K. L.; Beijnen, Jos H.; Schellens, Jan H. M.] Univ Utrecht, Dept Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands. [Meijerman, Irma] Univ Utrecht, Div Pharmacol, Dept Pharmaceut Sci, Utrecht, Netherlands. [Rosing, Hilde; Beijnen, Jos H.] Netherlands Canc Inst, Dept Pharm & Pharmacol, Slotervaart Hosp, Amsterdam, Netherlands. [Marchetti, Serena; Mergui-Roelvink, Marja; Keessen, Marianne; Schellens, Jan H. M.] Netherlands Canc Inst, Dept Clin Pharmacol, Amsterdam, Netherlands. [Burgers, Jacobus A.] Netherlands Canc Inst, Dept Thorac Oncol, Amsterdam, Netherlands. RP Goey, AKL (reprint author), NCI, Clin Pharmacol Program, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM andrew.goey@nih.gov FU Dutch Cancer Society [UU 2007-3795] FX This work was supported by the Dutch Cancer Society [UU 2007-3795]. NR 43 TC 15 Z9 16 U1 1 U2 11 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 0312-5963 EI 1179-1926 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD JAN PY 2014 VL 53 IS 1 BP 103 EP 110 DI 10.1007/s40262-013-0102-5 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 283EZ UT WOS:000329229900007 PM 24068654 ER PT J AU Sandler, NG Sereti, I AF Sandler, Netanya G. Sereti, Irini TI Can early therapy reduce inflammation? SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE biomarkers; HIV; inflammation; monocyte activation; morbidity; T-cell activation ID HIV-INFECTED PATIENTS; T-CELL-ACTIVATION; SUPPRESSIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS TYPE-1; BOOSTED PROTEASE INHIBITORS; IMMUNE ACTIVATION; RALTEGRAVIR INTENSIFICATION; MICROBIAL TRANSLOCATION; HIV-1-INFECTED PATIENTS; MYOCARDIAL-INFARCTION AB Purpose of reviewSerious non-AIDS events or noninfectious complications of HIV infection far outnumber AIDS events in the current combination antiretroviral therapy (ART) era and are attributed to chronic inflammation. Thus, a better understanding of why inflammation persists on ART will assist in developing better therapeutic strategies, including optimal timing of ART initiation.Recent findingsMarkers of inflammation and coagulation, such as D-dimer, interleukin-6, C-reactive protein, soluble CD14, and soluble CD163, predict end-organ disease and mortality, whereas markers of T-cell activation appear more predictive of CD4 T-cell decline, AIDS events, or response to therapy. Initiating ART at high CD4 T-cell counts can result in less inflammation as supported by studies in acute and early HIV infection, but antiretroviral drugs may differentially affect inflammatory pathways. Decreasing inflammation in HIV-uninfected individuals may decrease morbidity, but long-term outcomes studies in HIV-infected individuals are lacking.SummaryCirculating biomarkers of inflammation are among the strongest predictors of non-AIDS outcomes in treated HIV infection. With additional investigation, they may serve in the future as specific end-organ disease surrogate endpoints and may help identify those patients at highest risk of non-AIDS events who may benefit from either early ART and/or potential adjuvant anti-inflammatory therapies. C1 [Sandler, Netanya G.] Univ Texas Med Branch, Dept Internal Med, Infect Dis Div, Galveston, TX 77555 USA. [Sereti, Irini] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Sandler, NG (reprint author), Univ Texas Med Branch, 301 Univ Blvd,Route 0435, Galveston, TX 77555 USA. EM neutay@utmb.edu OI Utay, Netanya/0000-0002-6407-8670 FU University of Texas Medical Branch at Galveston; Intramural Research Program of NIAID FX The work of N.S. was supported by the University of Texas Medical Branch at Galveston. The work of I. S. was supported by the Intramural Research Program of NIAID. The authors have no conflicts of interest to declare. NR 99 TC 12 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JAN PY 2014 VL 9 IS 1 BP 72 EP 79 DI 10.1097/COH.0000000000000020 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 282PW UT WOS:000329185500011 PM 24247669 ER PT J AU Prasad, B Evers, R Gupta, A Hop, CECA Salphati, L Shukla, S Ambudkar, SV Unadkat, JD AF Prasad, Bhagwat Evers, Raymond Gupta, Anshul Hop, Cornelis E. C. A. Salphati, Laurent Shukla, Suneet Ambudkar, Suresh V. Unadkat, Jashvant D. TI Interindividual Variability in Hepatic Organic Anion-Transporting Polypeptides and P-Glycoprotein (ABCB1) Protein Expression: Quantification by Liquid Chromatography Tandem Mass Spectroscopy and Influence of Genotype, Age, and Sex SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID RESISTANCE-ASSOCIATED PROTEIN-2; DRUG-DRUG INTERACTIONS; OATP-C; HUMAN LIVER; UDP-GLUCURONOSYLTRANSFERASES; SLCO1B1 POLYMORPHISMS; PLASMA-CONCENTRATIONS; HUMAN HEPATOCYTES; GEMFIBROZIL; CERIVASTATIN AB Interindividual variability in protein expression of organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, OATP2B1, and multidrug resistance-linked P-glycoprotein (P-gp) or ABCB1 was quantified in frozen human livers (n = 64) and cryopreserved human hepatocytes (n = 12) by a validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. Membrane isolation, sample workup, and LC-MS/MS analyses were as described before by our laboratory. Briefly, total native membrane proteins, isolated from the liver tissue and cryopreserved hepatocytes, were trypsin digested and quantified by LC-MS/MS using signature peptide(s) unique to each transporter. The mean 6 S. D. (maximum/minimum range in parentheses) protein expression (fmol/mu g of membrane protein) in human liver tissue was OATP1B1-2.0 +/- 0.9 (7), OATP1B3-1.1 +/- 0.5 (8), OATP2B1-1 1.7 +/- 0.6 (5), and P-gp- 0.4 +/- 0.2 (8). Transporter expression in the liver tissue was comparable to that in the cryopreserved hepatocytes. Most important is that livers with SLCO1B1 (encoding OATP1B1) haplotypes *14/*14 and *14/*1a [i.e., representing single nucleotide polymorphisms (SNPs), c.388A > G, and c.463C > A] had significantly higher (P < 0.0001) protein expression than the reference haplotype (*1a/*1a). Based on these genotype-dependent protein expression data, we predicted (using Simcyp) an up to similar to 40% decrease in the mean area under the curve of rosuvastatin or repaglinide in subjects harboring these variant alleles compared with those harboring the reference alleles. SLCO1B3 (encoding OATP1B3) SNPs did not significantly affect protein expression. Age and sex were not associated with transporter protein expression. These data will facilitate the prediction of population-based human transporter-mediated drug disposition, drug-drug interactions, and interindividual variability through physiologically based pharmacokinetic modeling. C1 [Prasad, Bhagwat; Unadkat, Jashvant D.] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. [Evers, Raymond] Merck & Co Inc, Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ 07065 USA. [Gupta, Anshul] AstraZeneca Pharmaceut LLP, Infect DMPK, Drug Metab & Pharmacokinet, Waltham, MA USA. [Hop, Cornelis E. C. A.; Salphati, Laurent] Genentech Inc, Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Unadkat, JD (reprint author), Univ Washington, Dept Pharmaceut, POB 357610, Seattle, WA 98195 USA. EM jash@u.washington.edu FU University of Washington Research Affiliate Program on Transporters; AstraZeneca; Genentech; Merck Co., Inc.; Merck Research Laboratories New Technologies Review and Licensing Committee; Intramural Research Program of the National Institutes of Health National Cancer Institute Center for Cancer Research [ZIA BC010030-13] FX This study was supported by the University of Washington Research Affiliate Program on Transporters sponsored by AstraZeneca, Genentech, and Merck & Co., Inc. (http://sop.washington.edu/uwrapt). R.E. thanks the Merck Research Laboratories New Technologies Review and Licensing Committee for funding. A. G. thanks the AstraZeneca External Science Committee and licensing group for their support. S. S. and S. V. A were supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute Center for Cancer Research (grant number ZIA BC010030-13). NR 44 TC 54 Z9 54 U1 0 U2 12 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JAN PY 2014 VL 42 IS 1 BP 78 EP 88 DI 10.1124/dmd.113.053819 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 286XI UT WOS:000329502200010 PM 24122874 ER PT J AU Concheiro, M Baumann, MH Scheidweiler, KB Rothman, RB Marrone, GF Huestis, MA AF Concheiro, Marta Baumann, Michael H. Scheidweiler, Karl B. Rothman, Richard B. Marrone, Gina F. Huestis, Marilyn A. TI Nonlinear Pharmacokinetics of (+/-)3, 4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; MAIN METABOLITES; ECSTASY; HUMANS; NEUROTOXICITY; PLASMA; AMPHETAMINE; DISPOSITION; METHYLENEDIOXYMETHAMPHETAMINE; (+/-)-3,4-METHYLENEDIOXYMETHAMPHETAMINE AB 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMA's safety are needed. We evaluated MDMA's pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (+/-)-3,4-dihydroxymethamphetamine (HHMA), (+/-)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (6)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA C-max was 164 +/- 47.1 ng/ml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5- and 10-mg/ kg doses, MDMA areas under the curve (AUCs) were 3- and 10-fold greater than those after 2.5 mg/kg; HHMA and HMMA AUC values were relatively constant across doses; and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r = 0.8083; P < 0.0001) and core temperature correlated with MDA concentrations (r = 0.7595; P < 0.0001), suggesting that MDMA's behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses. C1 [Concheiro, Marta; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, NIH, Baltimore, MD 21224 USA. [Baumann, Michael H.; Rothman, Richard B.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Marrone, Gina F.] Weill Cornell Med Coll, Dept Neurosci, New York, NY USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Biomed Res Ctr, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse. NR 45 TC 10 Z9 10 U1 1 U2 16 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JAN PY 2014 VL 42 IS 1 BP 119 EP 125 DI 10.1124/dmd.113.053678 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 286XI UT WOS:000329502200015 PM 24141857 ER PT J AU Torre, P Hoffman, HJ Springer, G Cox, C Young, M Margolick, JB Plankey, M AF Torre, Peter, III Hoffman, Howard J. Springer, Gayle Cox, Christopher Young, Mary Margolick, Joseph B. Plankey, Michael TI Cochlear Function Among HIV-Seropositive and HIV-Seronegative Men and Women SO EAR AND HEARING LA English DT Article DE Cochlear function; Multicenter AIDS Cohort Study; Women's Interagency HIV Study ID MULTICENTER AIDS COHORT; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; DIABETES-MELLITUS; INTERAGENCY HIV; EMISSIONS; HEARING; ADULTS AB Objectives: There is limited research about cochlear function in adults who are human immunodeficiency virus (HIV) positive (+). The aim of the present study was to collect measures of cochlear function in a large sample of adults with, or at risk for, HIV infection, to evaluate associations between HIV status, HIV treatment, and cochlear function. Design: Distortion product otoacoustic emissions (DPOAEs) were used to evaluate cochlear function in 506 participants; 329 men, 150 of whom were HIV+, and 177 women, 136 of whom were HIV+. DPOAEs were measured at frequencies 1000, 2000, 3000, 4000, and 6000 Hz. A DPOAE nonresponse (NR) was defined as an absolute DPOAE level less than -15 dB SPL or a difference between the absolute DPOAE level and the background noise level less than 6 dB. The total number of NRs was calculated for each ear. The associations of demographic variables, HIV status, and HIV treatment with number of NRs were evaluated with univariate and multivariate ordinal regression models. Results: There was a statistically significant increase in the odds of higher numbers of NRs with age, being male, and being non-Black, but not with HIV status. Among HIV+ participants, there were no statistically significant associations of the HIV disease status or treatment variables with higher number of NRs. Conclusion: The authors found no evidence of impaired cochlear function by HIV disease status or highly active antiretroviral therapy-treated HIV infection in this cross-sectional study. C1 [Torre, Peter, III] San Diego State Univ, Sch Speech Language & Hearing Sci, San Diego, CA 92182 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders NIDCD, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Springer, Gayle; Cox, Christopher] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Young, Mary; Plankey, Michael] Georgetown Univ, Med Ctr, Dept Med, Div Infect Dis, Wa, DC USA. [Margolick, Joseph B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Torre, P (reprint author), San Diego State Univ, Sch Speech Language & Hearing Sci, 5500 Campanile Dr,SLHS 244, San Diego, CA 92182 USA. EM ptorre@mail.sdsu.edu FU National Institute on Deafness and Other Communication Disorders, National Institutes of Health via interagency agreement; National Institute of Allergy and Infectious Diseases for Cooperative Agreements [U01 AI-035042-18, U01 AI-034994-17] FX Supported by the National Institute on Deafness and Other Communication Disorders, National Institutes of Health via interagency agreement with National Institute of Allergy and Infectious Diseases for Cooperative Agreements U01 AI-035042-18 (Multicenter AIDS Cohort Study) and U01 AI-034994-17 (Women's Interagency HIV Study). Support of the Baltimore-Washington, DC Multicenter AIDS Cohort Study site was provided by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (U01-AI-35042, UL1-RR025005 [General Clinic Research Center]). Support of the Metropolitan Washington, DC Women's Interagency HIV Study site, was provided by the National Institute of Allergy and Infectious Diseases (U01-AI-34994) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01-HD-32632). NR 26 TC 4 Z9 4 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JAN-FEB PY 2014 VL 35 IS 1 BP 56 EP 62 DI 10.1097/AUD.0b013e3182a021c8 PG 7 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 285CE UT WOS:000329370000009 PM 24080949 ER PT J AU King, KA Gordon-Salant, S Yanjanin, N Zalewski, C Houser, A Porter, FD Brewer, CC AF King, Kelly A. Gordon-Salant, Sandra Yanjanin, Nicole Zalewski, Christopher Houser, Ari Porter, Forbes D. Brewer, Carmen C. TI Auditory Phenotype of Niemann-Pick Disease, Type C1 SO EAR AND HEARING LA English DT Article DE Niemann-Pick Type C; NPC; Hearing; Auditory phenotype ID CHOLESTEROL; RESPONSES; FIBROBLASTS; HEARING; GENE AB Objectives: The aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ss-cyclodextrin) may be more appropriately monitored and understood. Design: Fifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients. Results: Over half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function. Conclusions: This is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype. C1 [King, Kelly A.; Zalewski, Christopher; Brewer, Carmen C.] Natl Inst Deafness & Other Commun Disorders, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Gordon-Salant, Sandra] Univ Maryland, Dept Hearing & Speech Sci, College Pk, MD 20742 USA. [Yanjanin, Nicole; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US Dept HHS, NIH, Bethesda, MD USA. [Houser, Ari] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD 20742 USA. RP Brewer, CC (reprint author), Natl Inst Deafness & Other Commun Disorders, US Dept HHS, NIH, 10 Ctr Dr,Bldg 10-5C306, Bethesda, MD 20892 USA. EM brewerc@nidcd.nih.gov FU National Institutes of Health (NIH) training grant [T32DC000046]; National Institute on Deafness and Other Communication Disorders; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH Office of Rare diseases; NIH Clinical Research Center; Ara Parseghian Medical Research Foundation; Dana's Angels Research Trust FX This work was supported, in part, by a National Institutes of Health (NIH) training grant (T32DC000046) to Kelly A. King, and by the intramural divisions of the National Institute on Deafness and Other Communication Disorders and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Further support came from a Bench-to-Bedside award from the NIH Office of Rare diseases and the NIH Clinical Research Center, and from both the Ara Parseghian Medical Research Foundation and Dana's Angels Research Trust. NR 28 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JAN-FEB PY 2014 VL 35 IS 1 BP 110 EP 117 DI 10.1097/AUD.0b013e3182a362b8 PG 8 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 285CE UT WOS:000329370000014 PM 24225652 ER PT J AU Liu, WX Shang, YL Zeng, Y Liu, C Li, YC Zhai, LH Wang, P Lou, JZ Xu, P Ye, YH Li, W AF Liu, Weixiao Shang, Yongliang Zeng, Yan Liu, Chao Li, Yanchang Zhai, Linhui Wang, Pan Lou, Jizhong Xu, Ping Ye, Yihong Li, Wei TI Dimeric Ube2g2 simultaneously engages donor and acceptor ubiquitins to form Lys48-linked ubiquitin chains SO EMBO JOURNAL LA English DT Article DE E2 dimerization; ER-associated degradation/ERAD; K48-linked ubiquitin chain; linkage specificity; ubiquitination mechanism ID HMG-COA REDUCTASE; CONJUGATING ENZYME; ENDOPLASMIC-RETICULUM; POLYUBIQUITIN CHAINS; CRYSTAL-STRUCTURE; E1 ENZYMES; E2; LIGASE; COMPLEX; GP78 AB Cellular adaptation to proteotoxic stress at the endoplasmic reticulum (ER) depends on Lys48-linked polyubiquitination by ER-associated ubiquitin ligases (E3s) and subsequent elimination of ubiquitinated retrotranslocation products by the proteasome. The ER-associated E3 gp78 ubiquitinates misfolded proteins by transferring preformed Lys48-linked ubiquitin chains from the cognate E2 Ube2g2 to substrates. Here we demonstrate that Ube2g2 synthesizes linkage specific ubiquitin chains by forming an unprecedented homodimer: The dimerization of Ube2g2, mediated primarily by electrostatic interactions between two Ube2g2s, is also facilitated by the charged ubiquitin molecules. Mutagenesis studies show that Ube2g2 dimerization is required for ER-associated degradation (ERAD). In addition to E2 dimerization, we show that a highly conserved arginine residue in the donor Ube2g2 senses the presence of an aspartate in the acceptor ubiquitin to position only Lys48 of ubiquitin in proximity to the donor E2 active site. These results reveal an unanticipated mode of E2 self-association that allows the E2 to effectively engage two ubiquitins to specifically synthesize Lys48-linked ubiquitin chains. C1 [Liu, Weixiao; Shang, Yongliang; Liu, Chao; Wang, Pan; Li, Wei] Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Beijing, Peoples R China. [Zeng, Yan; Lou, Jizhong] Chinese Acad Sci, Inst Biophys, Lab Noncoding RNAs, Beijing 100080, Peoples R China. [Li, Yanchang; Zhai, Linhui; Xu, Ping] Beijing Inst Radiat Med, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing, Peoples R China. [Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Li, W (reprint author), Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Beijing, Peoples R China. EM yihongy@mail.nih.gov; leways@ioz.ac.cn FU National Natural Science Foundation of China [30970603]; Major Basic Research Program [2012CB944404]; Knowledge Innovation Program [KSCX2-YW-N-071]; One Hundred Talents Program of Chinese Academy of Sciences; intramural research program at NIDDK of the National Institutes of Health, USA FX We thank Xinhua Lin and Jun Tang for critical reading of the manuscript, Huimin Wang and Jianwu Wang for their assistance in the Biolayer Interferometry study. This work is supported by a National Natural Science Foundation of China (Grant No. 30970603), the Major Basic Research Program (Grant No. 2012CB944404), the Knowledge Innovation Program (Grant No. KSCX2-YW-N-071), the One Hundred Talents Program of Chinese Academy of Sciences, and the intramural research program at NIDDK of the National Institutes of Health, USA. NR 50 TC 18 Z9 18 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD JAN PY 2014 VL 33 IS 1 BP 46 EP 61 DI 10.1002/embj.201385315 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 284UL UT WOS:000329346500007 PM 24366945 ER PT J AU Starling, AP Engel, SM Whitworth, KW Richardson, DB Stuebe, AM Daniels, JL Haug, LS Eggesbo, M Becher, G Sabaredzovic, A Thomsen, C Wilson, RE Travlos, GS Hoppin, JA Baird, DD Longnecker, MP AF Starling, Anne P. Engel, Stephanie M. Whitworth, Kristina W. Richardson, David B. Stuebe, Alison M. Daniels, Julie L. Haug, Line Smastuen Eggesbo, Merete Becher, Georg Sabaredzovic, Azemira Thomsen, Cathrine Wilson, Ralph E. Travlos, Gregory S. Hoppin, Jane A. Baird, Donna D. Longnecker, Matthew P. TI Perfluoroalkyl substances and lipid concentrations in plasma during pregnancy among women in the Norwegian Mother and Child Cohort Study SO ENVIRONMENT INTERNATIONAL LA English DT Article DE The Norwegian Mother and Child Cohort Study MoBa; Perfluoroalkyl substances; Perfluorooctanoic acid; Perfluorooctane sulfonate ID ACTIVATED RECEPTOR-ALPHA; PERFLUOROOCTANOIC ACID; PERFLUORINATED COMPOUNDS; SERUM-LIPIDS; DENSITY-LIPOPROTEIN; HDL CHOLESTEROL; PREECLAMPSIA; EXPOSURE; RISK; APOLIPOPROTEINS AB Background: Perfluoroalkyl substances (PFASs) are widespread and persistent environmental pollutants. Previous studies, primarily among non-pregnant individuals, suggest positive associations between PFAS levels and certain blood lipids. If there is a causal link between PFAS concentrations and elevated lipids during pregnancy, this may suggest a mechanism by which PFAS exposure leads to certain adverse pregnancy outcomes, including preeclampsia. Methods: This cross-sectional analysis included 891 pregnant women enrolled in the Norwegian Mother and Child (MoBa) Cohort Study in 2003-2004. Non-fasting plasma samples were obtained at mid-pregnancy and analyzed for nineteen PFASs. Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured in plasma. Linear regression was used to quantify associations between each PFAS exposure and each lipid outcome. A multiple PFAS model was also fitted. Results: Seven PFASs were quantifiable in >50% of samples. Perfluorooctane sulfonate (PFOS) concentration was associated with total cholesterol, which increased 4.2 mg/dL per inter-quartile shift (95% CI=0.8, 7.7) in adjusted models. Five of the seven PFASs studied were positively associated with HDL cholesterol; and all seven had elevated HDL associated with the highest quartile of exposure. Perfluoroundecanoic acid showed the strongest association with HDL: HDL increased 3.7 mg/dL per inter-quartile shift (95% CI = 2.5, 4.9). Conclusion: Plasma concentrations of PFASs were positively associated with HDL cholesterol, and PFOS was positively associated with total cholesterol in this sample of pregnant Norwegian women. While elevated HDL is not an adverse outcome per se, elevated total cholesterol associated with PFASs during pregnancy could be of concern if causal. Published by Elsevier Ltd. C1 [Starling, Anne P.; Hoppin, Jane A.; Baird, Donna D.; Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Starling, Anne P.; Engel, Stephanie M.; Richardson, David B.; Daniels, Julie L.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Whitworth, Kristina W.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, San Antonio, TX USA. [Stuebe, Alison M.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Stuebe, Alison M.] Univ N Carolina, Dept Maternal & Child Hlth, Chapel Hill, NC USA. [Haug, Line Smastuen; Eggesbo, Merete; Becher, Georg; Sabaredzovic, Azemira; Thomsen, Cathrine] Norwegian Inst Publ Hlth, Oslo, Norway. [Wilson, Ralph E.; Travlos, Gregory S.] NIEHS, Cellular & Mol Pathol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Longnecker, MP (reprint author), NIEHS, Epidemiol Branch, Mail Drop A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM longnec1@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; National Institute of Environmental Health Sciences [1-F30-ES022126-01]; Norwegian Ministry of Health; Ministry of Education and Research; NIH/NIEHS [N01-ES-75558]; NIH/NINDS [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Norwegian Research Council/FUGE [151918/S10] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. A.P. Starling was supported by an extramural award (1-F30-ES022126-01) from the National Institute of Environmental Health Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537-01, grant no.2 UO1 NS 047537-06A1), and the Norwegian Research Council/FUGE (grant no. 151918/S10). We are grateful to all the participating families in Norway who take part in this ongoing cohort study. NR 64 TC 21 Z9 22 U1 4 U2 36 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD JAN PY 2014 VL 62 BP 104 EP 112 DI 10.1016/j.envint.2013.10.004 PG 9 WC Environmental Sciences SC Environmental Sciences & Ecology GA 280BF UT WOS:000329003000012 PM 24189199 ER PT J AU Schisterman, EF Mumford, SL Sjaarda, LA AF Schisterman, Enrique F. Mumford, Sunni L. Sjaarda, Lindsey A. TI Failure to Consider the Menstrual Cycle Phase May Cause Misinterpretation of Clinical and Research Findings of Cardiometabolic Biomarkers in Premenopausal Women SO EPIDEMIOLOGIC REVIEWS LA English DT Article DE biomarkers, cardiometabolic; inflammation; menstrual cycle; variability ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; ENDOGENOUS REPRODUCTIVE HORMONES; HEALTHY-YOUNG WOMEN; ESTROGEN PLUS PROGESTIN; LOW-DENSITY-LIPOPROTEIN; SERUM URIC-ACID; CARDIOVASCULAR-DISEASE; SEX-HORMONES; INSULIN SENSITIVITY AB Biomarker assessment plays a critical role in the study and prevention of disease. However, variation in biomarkers attributable to the menstrual cycle in premenopausal women may impair understanding the role of certain biomarkers in disease development and progression. Thus, in light of the recently increasing evidence of menstrual cycle variability in multiple cardiometabolic biomarkers, a reexamination of approaches for appropriately studying and diagnosing cardiovascular disease in premenopausal women is warranted. We reviewed studies (from 1934 through 2012) evaluating changes in cardiometabolic biomarkers across phases of the menstrual cycle, including markers of oxidative stress, lipids, insulin sensitivity, and systemic inflammation. Each was observed to vary significantly during the menstrual cycle. For example, nearly twice as many women had elevated cholesterol levels warranting therapy (>= 200 mg/dL) during the follicular phase compared with the luteal phase (14.3% vs. 7.9%), with only 3% having consistently high levels during all phases of the cycle. Similarly, nearly twice as many women were classified as being at an elevated risk of cardiovascular disease (high sensitivity C-reactive protein >3 mg/L) during menses compared with other phases (12.3% vs. 7.4%). Menstrual cycle-associated variability in cardiometabolic biomarkers is an important source of variability that should be accounted for in both research and clinical settings. C1 [Schisterman, Enrique F.; Mumford, Sunni L.; Sjaarda, Lindsey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Suite 7B03N, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health [HHSN275200403394C] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (contract HHSN275200403394C). NR 89 TC 15 Z9 16 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0193-936X EI 1478-6729 J9 EPIDEMIOL REV JI Epidemiol. Rev. PY 2014 VL 36 IS 1 SI SI BP 71 EP 82 DI 10.1093/epirev/mxt007 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 281WK UT WOS:000329131500007 PM 24042431 ER PT J AU Lynge, E Ponti, A James, T Majek, O von Euler-Chelpin, M Anttila, A Fitzpatrick, P Frigerio, A Kawai, M Scharpantgen, A Broeders, M Hofvind, S Vidal, C Ederra, M Salas, D Bulliard, JL Tomatis, M Kerlikowske, K Taplin, S AF Lynge, Elsebeth Ponti, Antonio James, Ted Majek, Ondrej von Euler-Chelpin, My Anttila, Ahti Fitzpatrick, Patricia Frigerio, Alfonso Kawai, Masaaki Scharpantgen, Astrid Broeders, Mireille Hofvind, Solveig Vidal, Carmen Ederra, Maria Salas, Dolores Bulliard, Jean-Luc Tomatis, Mariano Kerlikowske, Karla Taplin, Stephen CA ICSN DCIS Working Grp TI Variation in detection of ductal carcinoma in situ during screening mammography: A survey within the International Cancer Screening Network SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Breast cancer; Ductal carcinoma in situ (DCIS); Screening mammography; Cancer registration ID BREAST-CANCER; PROGRAM; WOMEN; MORTALITY; DIAGNOSIS; OUTCOMES; SCIENCE; TRENDS; IMPACT; STATE AB Background: There is concern about detection of ductal carcinoma in situ (DCIS) in screening mammography. DCIS accounts for a substantial proportion of screen-detected lesions but its effect on breast cancer mortality is debated. The International Cancer Screening Network conducted a comparative analysis to determine variation in DCIS detection. Patients and Methods: Data were collected during 2004-2008 on number of screening examinations, detected breast cancers, DCIS cases and Globocan 2008 breast cancer incidence rates derived from national or regional cancer registers. We calculated screen-detection rates for breast cancers and DCIS. Results: Data were obtained from 15 screening settings in 12 countries; 7,176,050 screening examinations; 29,605 breast cancers and 5324 DCIS cases. The ratio between highest and lowest breast cancer incidence was 2.88 (95% confidence interval (CI) 2.76-3.00); 2.97 (95% CI 2.51-3.51) for detection of breast cancer; and 3.49 (95% CI 2.70-4.51) for detection of DCIS. Conclusions: Considerable international variation was found in DCIS detection. This variation could not be fully explained by variation in incidence nor in breast cancer detection rates. It suggests the potential for wide discrepancies in management of DCIS resulting in overtreatment of indolent DCIS or undertreatment of potentially curable disease. Comprehensive cancer registration is needed to monitor DCIS detection. Efforts to understand discrepancies and standardise management may improve care. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved. C1 [Lynge, Elsebeth; von Euler-Chelpin, My] Univ Copenhagen, Dept Publ Hlth, DK-1014 Copenhagen K, Denmark. [Ponti, Antonio; Tomatis, Mariano] AOU San Giovanni Battista, CPO Piemonte, Turin, Italy. [James, Ted] Univ Vermont, Dept Surg, Burlington, VT 05405 USA. [Majek, Ondrej] Masaryk Univ, Inst Biostat & Anal, Brno, Czech Republic. [Anttila, Ahti] Finnish Canc Registry, Mass Screening Registry, FIN-00170 Helsinki, Finland. [Fitzpatrick, Patricia] Natl Canc Screening Serv, Dublin, Ireland. [Frigerio, Alfonso] Reg Reference Ctr Breast Canc Screening, Turin, Italy. [Kawai, Masaaki] Tohoku Univ, Grad Sch Med, Dept Surg Oncol, Sendai, Miyagi 980, Japan. [Scharpantgen, Astrid] Direct Sante, Programme Mammog, Luxembourg, Luxembourg. [Broeders, Mireille] Natl Expert & Training Ctr Breast Canc Screening, Nijmegen, Netherlands. [Hofvind, Solveig] Canc Registry Norway, Oslo, Norway. [Vidal, Carmen] Catalan Inst Oncol, Canc & Prevent Control Program, Barcelona, Spain. [Ederra, Maria] Inst Salud Publ, Breast Canc Screening Program, Navarra, Spain. [Salas, Dolores] Gen Directorate Res & Publ Hlth, Valencia, Spain. [Salas, Dolores] Ctr Publ Hlth Res, Valencia, Spain. [Bulliard, Jean-Luc] Univ Lausanne Hosp, Epalinges, Switzerland. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Med & Epidemiol & Biostatist, San Francisco, CA 94143 USA. [Taplin, Stephen] Natl Canc Inst, Div Canc Control & Populat Sci, Behav Res Program, Bethesda, MD USA. RP Lynge, E (reprint author), Univ Copenhagen, Dept Publ Hlth, Ostre Farimagsgade 5, DK-1014 Copenhagen K, Denmark. EM elsebeth@sund.ku.dk RI Garcia, Montse/B-8832-2014; Broeders, Mireille/C-8820-2015; OI Garcia, Montse/0000-0002-3437-3185; Fitzpatrick, Patricia/0000-0003-2524-3677; Lynge, Elsebeth/0000-0003-4785-5236; Vidal, Carmen/0000-0003-2768-2710 FU National Cancer Institute [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA 70013, U01CA69976, U01CA63731, U01CA70040] FX The collection of US data was supported by the National Cancer Institute-funded Breast Cancer Surveillance Consortium co-operative agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA 70013, U01CA69976, U01CA63731, U01CA70040). A list of the BCSC investigators and procedures for requesting BCSC data for research purposes are provided at: http://breastscreening.cancer.gov/. The collection of cancer data used in this study was supported in part by several state public health departments and cancer registries throughout the U.S. For a full description of these sources, please see: http://breastscreening.cancer.gov/work/acknowledgement.html. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. We thank Weiwei Zhu at the Statistical Coordinating Center for preparing the BCSC data for the manuscript. Coordination for this study was provided by the U.S. National Cancer Institute, Bethesda, Maryland. Data management and analysis were provided by CPO Piemonte, Torino, Italy. We thank the participating women, mammography facilities and radiologists for the data they have provided for this study. NR 21 TC 12 Z9 12 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JAN PY 2014 VL 50 IS 1 BP 185 EP 192 DI 10.1016/j.ejca.2013.08.013 PG 8 WC Oncology SC Oncology GA 282KO UT WOS:000329170300020 PM 24041876 ER PT J AU Moore, KR Smith, JS Laughlin-Tommaso, SK Baird, DD AF Moore, Kristen R. Smith, Jennifer S. Laughlin-Tommaso, Shannon K. Baird, Donna D. TI Cervical neoplasia-related factors and decreased prevalence of uterine fibroids among a cohort of African American women SO FERTILITY AND STERILITY LA English DT Article DE Uterine fibroids; cervical neoplasia; cervical treatment; abnormal Pap smear; colposcopy ID HUMAN-PAPILLOMAVIRUS; DNA METHYLATION; REPRODUCTIVE FACTORS; CANCER-SOCIETY; RISK; LEIOMYOMATA; ABNORMALITIES; INFECTION; FREQUENCY; GENETICS AB Objective: To investigate whether the previously reported inverse association between cervical neoplasia and uterine fibroids is corroborated. Design: Cross-sectional analysis of enrollment data from an ongoing prospective study of fibroid development. Setting: Not applicable. Patient(s): Self-reported data on abnormal Pap smear, colposcopy, and cervical treatment were obtained from 1,008 African American women ages 23-34 with no previous fibroid diagnosis and no reported history of human papillomavirus vaccination. Presence of fibroids was assessed at a standardized ultrasound examination. Intervention(s): None. Main Outcome Measure(s): The association between the three cervical neoplasia-related variables and the presence of fibroids was evaluated with logistic regression to estimate age-adjusted and multivariable-adjusted odds ratios (aORs). Result(s): Of the analysis sample, 46%, 29%, and 14% reported a prior abnormal Pap smear, colposcopy, and cervical treatment, respectively. Twenty-five percent had fibroids at ultrasound. Those reporting cervical treatment had a 39% (aOR, 0.61; 95% confidence interval [CI] [0.38-0.96]) reduction in fibroid risk. Weak nonsignificant associations were found for abnormal Pap smear and colposcopy. Conclusion(s): Although a protective-type association of cervical neoplasia with uterine fibroids seems counterintuitive, a causal pathway is possible, and the findings are consistent with two prior studies. Further investigation is needed on the relationship between fibroids and cervical neoplasia and human papillomavirus-related mechanisms. (Fertil Steril (R) 2014; 101: 208-14. (C) 2014 by American Society for Reproductive Medicine.) C1 [Moore, Kristen R.; Smith, Jennifer S.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Moore, Kristen R.; Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Laughlin-Tommaso, Shannon K.] Mayo Clin, Dept Obstet & Gynecol, Ctr Uterine Fibroids, Rochester, MN USA. RP Baird, DD (reprint author), NIEHS, Epidemiol Branch, A3-05, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Moore, Kristen/C-2303-2017; Baird, Donna/D-5214-2017 OI Moore, Kristen/0000-0001-9993-3270; Baird, Donna/0000-0002-5544-2653 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [10-E-N044] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (10-E-N044). NR 34 TC 7 Z9 7 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD JAN PY 2014 VL 101 IS 1 BP 208 EP 214 DI 10.1016/j.fertnstert.2013.09.021 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 281VJ UT WOS:000329128800040 PM 24268705 ER PT J AU Legro, RS Brzyski, RG Diamond, MP Coutifaris, C Schlaff, WD Alvero, R Casson, P Christman, GM Huang, H Yan, QY Haisenleder, DJ Barnhart, KT Bates, GW Usadi, R Lucidi, R Baker, V Trussell, JC Krawetz, SA Snyder, P Ohl, D Santoro, N Eisenberg, E Zhang, HP AF Legro, Richard S. Brzyski, Robert G. Diamond, Michael P. Coutifaris, Christos Schlaff, William D. Alvero, Ruben Casson, Peter Christman, Gregory M. Huang, Hao Yan, Qingshang Haisenleder, Daniel J. Barnhart, Kurt T. Bates, G. Wright Usadi, Rebecca Lucidi, Richard Baker, Valerie Trussell, J. C. Krawetz, Stephen A. Snyder, Peter Ohl, Dana Santoro, Nanette Eisenberg, Esther Zhang, Heping CA Natl Inst Child Hlth Human Dev Rep TI The Pregnancy in Polycystic Ovary Syndrome II study: baseline characteristics and effects of obesity from a multicenter randomized clinical trial SO FERTILITY AND STERILITY LA English DT Article DE Insulin resistance; hirsutism; infertility; ovulation induction; metabolic syndrome ID QUALITY-OF-LIFE; FEMALE SEXUAL FUNCTION; GENERAL PSYCHOMETRIC PROPERTIES; BIOLOGIC SPECIMENS REPOSITORY; FERTIQOL TOOL DEVELOPMENT; FUNCTION INDEX FSFI; SYNDROME PCOS; METABOLIC SYNDROME; DOUBLE-BLIND; INTERCOURSE COMPLIANCE AB Objective: To summarize baseline characteristics from a large multicenter infertility clinical trial. Design: Cross-sectional baseline data from a double-blind randomized trial of two treatment regimens (letrozole vs. clomiphene). Setting: Academic Health Centers throughout the United States. Patient(s): Seven hundred fifty women with polycystic ovary syndrome (PCOS) and their male partners took part in the study. Intervention(s): None. Main Outcome Measure(s): Historic, biometric, biochemical, and questionnaire parameters. Result(s): Females averaged 30 years and were obese (body mass index [BMI] 35) with 20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). Most of the women had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH-to-FSH ratio (2), and antimullerian hormone levels (8.0 ng/mL). In addition, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH-to-FSH levels, antimullerian hormone levels, and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Men were obese (BMI 30) and had normal mean semen parameters. Conclusion(s): The treatment groups were well matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators. C1 [Legro, Richard S.] Penn State Univ, Dept Gynecol & Obstet, Hershey, PA USA. [Brzyski, Robert G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX USA. [Schlaff, William D.; Alvero, Ruben; Santoro, Nanette] Univ Colorado, Dept Obstet & Gynecol, Denver, CO 80202 USA. [Christman, Gregory M.; Ohl, Dana] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Coutifaris, Christos; Barnhart, Kurt T.; Snyder, Peter] Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Diamond, Michael P.; Krawetz, Stephen A.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Casson, Peter] Univ Vermont, Dept Obstet & Gynecol, Burlington, VT USA. [Haisenleder, Daniel J.] Univ Virginia, Ctr Res Reprod, Ligand Core Lab, Charlottesville, VA USA. [Lucidi, Richard] Virginia Commonwealth Univ, Dept Obstet & Gynecol, Richmond, VA USA. [Baker, Valerie] Stanford Hosp, Dept Obstet & Gynecol, Palo Alto, CA USA. [Usadi, Rebecca] Carolinas HealthCare Ctr Reprod Med, Dept Obstet & Gynecol, Charlotte, NC USA. [Bates, G. Wright] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Trussell, J. C.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Eisenberg, Esther] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Fertil & Infertil Branch, Rockville, MD USA. [Huang, Hao; Yan, Qingshang; Zhang, Heping] Yale Univ, Sch Med, Dept Biostat, New Haven, CT USA. RP Legro, RS (reprint author), Penn State Coll Med, Milton S Hershey Med Ctr, Dept Obstet & Gynecol, 500 Univ Dr,H103, Hershey, PA 17033 USA. EM RSL1@PSU.EDU OI Diamond, Michael/0000-0001-6353-4489 FU Ohio State University; Yale University; University of Michigan; NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD33172, U10 HD38998, U10 HD055936, U10 HD055942, U10 HD055944, U54-HD29834]; General Clinical Research Center [MO1RR10732, C06 RR016499] FX R.S.L. reports honorarium from Ferring, Germany for lecture. R. G. B. has nothing to disclose. M. P. D. reports ASRM Board Membership, consultancy with Halt Medical, Genzyme, and grants with Abbvie, Novartis, Boeringher Ingelheim, Ferring, EMD Serono, Biosante. C. C. reports NOVA Therapeutics Medical Advisory Board, pending grants with National Institutes of Health (NIH), payment for lectures from Ohio State University, Yale University, University of Michigan, and reimbursement for attending Executive Board meetings from ASRM. W. D. S. has nothing to disclose. R. A. has nothing to disclose. P. C. has nothing to disclose. G. M. C. has nothing to disclose. H. H. has nothing to disclose. Q.Y. has nothing to disclose. D.J.H. reports employment with NIH and pending grants with NIH. K. T. B. has nothing to disclose. G. W. B. has nothing to disclose. R. U. has nothing to disclose. R. L. has nothing to disclose. V. B. has nothing to disclose. J.C.T. reports ownership of equities in Pfizer, Merck, Astellas, J and J. S. A. K. has nothing to disclose. P. S. has nothing to disclose. D.O. has nothing to disclose. N.S. has nothing to disclose. E. E. has nothing to disclose. H.Z. has nothing to disclose.; Supported by NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grants U10 HD27049 (to C. C.), U10 HD38992 (to R. S. L.), U10HD055925 (to H.Z.), U10 HD39005 (to M. P. D.), U10 HD33172 (to M. P. S.), U10 HD38998 (to W. D. S), U10 HD055936 (to G. M. C.), U10 HD055942 (to R. G. B.), and U10 HD055944 (to P. R. C.); U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research); General Clinical Research Center grants MO1RR10732 and construction grant C06 RR016499 (to Pennsylvania State University). NR 53 TC 13 Z9 13 U1 2 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD JAN PY 2014 VL 101 IS 1 BP 258 EP + DI 10.1016/j.fertnstert.2013.08.056 PG 20 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 281VJ UT WOS:000329128800049 PM 24156957 ER PT S AU Biesso, A Xu, JH Knutson, JR AF Biesso, Arianna Xu, Jianhua Knutson, Jay R. BE Engelborghs, Y Visser, AJWG TI Upconversion Spectrophotofluorometry SO FLUORESCENCE SPECTROSCOPY AND MICROSCOPY: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Time-resolved fluorescence; Upconversion; Tryptophan; Protein dynamics and photo-damage ID TIME-RESOLVED FLUORESCENCE; TRYPTOPHAN FLUORESCENCE; FEMTOSECOND DYNAMICS; SOLVATION DYNAMICS; BIOLOGICAL WATER; PROTEIN SURFACE; ENERGY-TRANSFER; PEPTIDE-BOND; PICOSECOND; HYDRATION AB As the other chapters attest, sensitivity of fluorescent molecules to their local environment has created powerful tools in the study of molecular biology, particularly in the study of protein, DNA, and lipid dynamics. Surprisingly, even events faster than the nanosecond lifetimes of fluorophores are important in protein function, and in particular, events lasting just a few ps reflect on water motion and the coupled dynamics of proteins. These ultrafast phenomena can best be studied by using the same laser that excites fluorescence to also "strobe" the emission, providing sub-picosecond time slices of the action. We explain the strobing "upconversion" technique and some limits on its execution. C1 [Biesso, Arianna] NIDDK, NIH, Bethesda, MD 20892 USA. [Xu, Jianhua; Knutson, Jay R.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Biesso, A (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA HL001452-30] NR 55 TC 0 Z9 0 U1 2 U2 11 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-648-1 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1076 BP 303 EP 319 DI 10.1007/978-1-62703-649-8_12 D2 10.1007/978-1-62703-649-8 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Microscopy; Spectroscopy SC Biochemistry & Molecular Biology; Microscopy; Spectroscopy GA BJJ01 UT WOS:000328374800013 PM 24108631 ER PT J AU Youngren, B Nielsen, HJ Jun, S Austin, S AF Youngren, Brenda Nielsen, Henrik Joerk Jun, Suckjoon Austin, Stuart TI The multifork Escherichia coli chromosome is a self-duplicating and self-segregating thermodynamic ring polymer SO GENES & DEVELOPMENT LA English DT Article DE bacterial cell cycle; bacterial chromosome; chromosome organization; chromosome segregation multifork replication ID SEPARATE CELL HALVES; DIVISION CYCLE; E. COLI; BACTERIAL CHROMOSOME; REPLICATION; LOCALIZATION; DYNAMICS; FTSK; TERMINUS; PROTEIN AB At all but the slowest growth rates, Escherichia coli cell cycles overlap, and its nucleoid is segregated to daughter cells as a forked DNA circle with replication ongoing-a state fundamentally different from eukaryotes. We have solved the chromosome organization, structural dynamics, and segregation of this constantly replicating chromosome. It is locally condensed to form a branched donut, compressed so that the least replicated DNA spans the cell center and the newest DNA extends toward the cell poles. Three narrow zones at the cell center and quarters contain both the replication forks and nascent DNA and serve to segregate the duplicated chromosomal information as it flows outward. The overall pattern is smoothly self-replicating, except when the duplicated terminus region is released from the septum and recoils to the center of a sister nucleoid. In circular cross-section of the cell, the left and right arms of the chromosome form separate, parallel structures that lie in each cell half along the radial cell axis. In contrast, replication forks and origin and terminus regions are found mostly at the center of the cross section, balanced by the parallel chromosome arms. The structure is consistent with the model in which the nucleoid is a constrained ring polymer that develops by spontaneous thermodynamics. The ring polymer pattern extrapolates to higher growth rates and also provides a structural basis for the form of the chromosome during very slow growth. C1 [Youngren, Brenda; Nielsen, Henrik Joerk; Austin, Stuart] NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Jun, Suckjoon] Univ Calif San Diego, Div Biol Sci, Mol Biol Sect, La Jolla, CA 92093 USA. [Jun, Suckjoon] Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA. RP Austin, S (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. EM stuart.austin66@gmail.com RI Jun, Suckjoon/K-9008-2015 OI Jun, Suckjoon/0000-0002-0139-4297 FU Intramural Program of the National Cancer Institute; Paul G. Allen Family Foundation; Pew Charitable Trusts; National Science Foundation CAREER award FX We thank Youngkyun Jung and Bae-Yeun Ha for supercomputer simulations data, Sattar Taheri-Araghi for help with time-lapse experiments, and A. Wright for helpful discussions. This research was supported in part by the Intramural Program of the National Cancer Institute (S.J.A.), the Paul G. Allen Family Foundation, the Pew Charitable Trusts, and the National Science Foundation CAREER award (S.J.). NR 41 TC 36 Z9 36 U1 2 U2 12 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JAN 1 PY 2014 VL 28 IS 1 BP 71 EP 84 DI 10.1101/gad.231050.113 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 284CK UT WOS:000329293500008 PM 24395248 ER PT J AU Prakash, S Guo, DC Maslen, CL Silberbach, M Milewicz, D Bondy, CA AF Prakash, Siddharth Guo, Dongchuan Maslen, Cheryl L. Silberbach, Michael Milewicz, Dianna Bondy, Carolyn A. CA GenTAC Investigators TI Single-nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome SO GENETICS IN MEDICINE LA English DT Article DE array; cytogenetics; diagnosis; karyotype; sex chromosomes; Turner syndrome ID PERIPHERAL-BLOOD LYMPHOCYTES; IDIOPATHIC SHORT STATURE; COPY NUMBER VARIATION; CHROMOSOME INSTABILITY; MOSAICISM; MECHANISMS; GUIDELINE; CELLS; RISK AB Purpose: Turner syndrome is a developmental disorder caused by partial or complete monosomy for the X chromosome in 1 in 2,500 females. We hypothesized that single-nucleotide polymorphism (SNP) array genotyping could provide superior resolution in comparison to metaphase karyotype analysis to facilitate genotype-phenotype correlations. Methods: We genotyped 187 Turner syndrome patients with 733,000 SNP marker arrays. All cases met diagnostic criteria for Turner syndrome based on karyotypes (60%) or characteristic physical features. The SNP array results confirmed the diagnosis of Turner syndrome in 100% of cases. Results: We identified a single X chromosome (45, X) in 113 cases. In 58 additional cases (31%), other mosaic cell lines were present, including isochromosomes (16%), rings (5%), and Xp deletions (8%). The remaining cases were mosaic for monosomy X and normal male or female cell lines. Array-based models of X chromosome structure were compatible with karyotypes in 104 of 116 comparable cases (90%). We found that the SNP array data did not detect X-autosome translocations (three cases) but did identify two derivative Y chromosomes and 13 large copy-number variants that were not detected by karyotyping. Conclusion: Our study is the first systematic comparison between the two methods and supports the utility of SNP array genotyping to address clinical and research questions in Turner syndrome. C1 [Prakash, Siddharth; Guo, Dongchuan; Milewicz, Dianna] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Houston, TX 77030 USA. [Maslen, Cheryl L.] Oregon Hlth & Sci Univ, Div Cardiovasc Med, Portland, OR 97201 USA. [Maslen, Cheryl L.] Oregon Hlth & Sci Univ, Heart Res Ctr, Portland, OR 97201 USA. [Silberbach, Michael] Oregon Hlth & Sci Univ, Div Pediat Cardiol, Portland, OR 97201 USA. [Bondy, Carolyn A.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Prakash, S (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Houston, TX 77030 USA. EM Siddharth.K.Prakash@uth.tmc.edu FU Vivian L. Smith Foundation [RO1 HL62594, P50HL083794-01]; Richard T. Pisani Funds; TexGen Foundation; National Institutes of Health [UL1 RR024148 (CTSA)]; US federal government [HHSN268200648199C, HHSN268201000048C]; National Heart Lung and Blood Institute (Bethesda, MD); RTI International (Research Triangle Park, NC); National Institute of Arthritis and Musculoskeletal and Skin Diseases; Oregon Clinical and Translational Research Institute (Portland, OR) [UL1 RR024140]; National Center for Research Resources (Bethesda, MD); Weill Cornell Medical College Clinical Translational Science Center (New York, NY) [UL1RR024996] FX The authors are extremely grateful to patients for providing clinical data and samples for this study. The following sources provided funding to D.M.M. for these studies: RO1 HL62594 (D.M.M.), P50HL083794-01 (D.M.M.), Vivian L. Smith Foundation, Richard T. Pisani Funds, and TexGen Foundation. The National Institutes of Health UL1 RR024148 (CTSA) grant also provided funds for these studies. The GenTAC Registry has been supported by US federal government contracts HHSN268200648199C and HHSN268201000048C from the National Heart Lung and Blood Institute (Bethesda, MD) with RTI International (Research Triangle Park, NC). Additional support was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Oregon Clinical and Translational Research Institute (Portland, OR), grant UL1 RR024140 from the National Center for Research Resources (Bethesda, MD), and the Weill Cornell Medical College Clinical Translational Science Center (New York, NY), grant UL1RR024996. NR 24 TC 10 Z9 10 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JAN PY 2014 VL 16 IS 1 BP 53 EP 59 DI 10.1038/gim.2013.77 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 284GO UT WOS:000329304300008 PM 23743550 ER PT J AU Rudolph, KE Wand, GS Stuart, EA Glass, TA Marques, AH Duncko, R Merikangas, KR AF Rudolph, Kara E. Wand, Gary S. Stuart, Elizabeth A. Glass, Thomas A. Marques, Andrea H. Duncko, Roman Merikangas, Kathleen R. TI The association between cortisol and neighborhood disadvantage in a US population-based sample of adolescents SO HEALTH & PLACE LA English DT Article DE Neighborhood; Adolescents; Cortisol; Propensity; Score ID SUPPLEMENT NCS-A; PITUITARY-ADRENAL RESPONSES; SALIVARY CORTISOL; SOCIOECONOMIC-STATUS; PROPENSITY SCORE; SOCIAL STRESS; YOUNG-ADULTS; LIFE STRESS; HEALTH; CHILDREN AB The association between neighborhood conditions and corrisol is rarely studied in children or adolescents and has been hampered by small sample size and racial/ethnic and geographic homogeneity. Our objective was to estimate the association between neighborhood disadvantage and salivary cortisol levels in a large, geographically and racially/ethnically diverse sample of adolescents from the National Comorbidity Survey Replication Adolescent Supplement. Salivary cortisol was collected before and after an interview administered in the adolescent's home. We used a propensity score approach to match adolescents living in disadvantaged neighborhoods with those in non-disadvantaged neighborhoods to create two similar groups based on the time and day of cortisol collection as well as demographic characteristics. Adolescents living in disadvantaged neighborhoods had higher pre-interview cortisol levels and steeper rates of decline in cortisol levels over the course of the interview than similar adolescents in non-disadvantaged neighborhoods. This bolsters the evidence base suggesting that place may influence the stress response system. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Rudolph, Kara E.; Glass, Thomas A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Rudolph, Kara E.; Stuart, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Wand, Gary S.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21287 USA. [Stuart, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Marques, Andrea H.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Marques, Andrea H.; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Duncko, Roman] South London & Maudsley NHS Fdn Trust, London, England. RP Rudolph, KE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,E6144, Baltimore, MD 21205 USA. EM krudolph@jhsph.edu; gwand@jhmi.edu; estuart@jhsph.edu; tglass@jhsph.edu; andreahorvathmarques@gmail.com; roman.duncko@gmail.com; merikank@mail.nih.gov OI Stuart, Elizabeth/0000-0002-9042-8611; Glass, Thomas/0000-0003-4399-612X FU Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health (NIH) [Z01 MH-002808-08]; NIH [K05AA02034]; National Institute of Mental Health [U01-MH60220]; National Institute of Drug Abuse at the NIH [R01 DA016558] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health (NIH) [Z01 MH-002808-08]. GSW's time was supported by NIH grant K05AA02034. The National Comorbidity Survey Replication Adolescent Supplement (NCS-A) and the larger program of related National Comorbidity Surveys are supported by the National Institute of Mental Health [U01-MH60220] and the National Institute of Drug Abuse [R01 DA016558] at the NIH. The NCS-A was carried out in conjunction with the World Health Organization World Mental Health Survey Initiative. The authors wish to thank Vanya Aggarwal for help with Census data abstraction. NR 71 TC 10 Z9 10 U1 6 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 EI 1873-2054 J9 HEALTH PLACE JI Health Place PD JAN PY 2014 VL 25 BP 68 EP 77 DI 10.1016/j.healthplace.2013.11.001 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 280WB UT WOS:000329060400009 PM 24367996 ER PT J AU Alter, HJ AF Alter, Harvey J. TI The Road Not Taken or How I Learned to Love the Liver: A Personal Perspective on Hepatitis History SO HEPATOLOGY LA English DT Editorial Material ID NON-B-HEPATITIS; TRANSFUSION-TRANSMITTED VIRUSES; NON-A-HEPATITIS; POSTTRANSFUSION HEPATITIS; BLOOD-DONORS; C VIRUS; ANTIGEN; RECIPIENTS; ANTIBODY; TRANSMISSION C1 [Alter, Harvey J.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Alter, HJ (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bldg 10,Room 1C-711,10 Ctr Dr, Bethesda, MD 20892 USA. EM HAlter@cc.nih.gov NR 21 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JAN PY 2014 VL 59 IS 1 BP 4 EP 12 DI 10.1002/hep.26787 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 276GZ UT WOS:000328738400001 PM 24123147 ER PT J AU Cinar, R Godlewski, G Liu, J Tam, J Jourdan, T Mukhopadhyay, B Harvey-White, J Kunos, G AF Cinar, Resat Godlewski, Grzegorz Liu, Jie Tam, Joseph Jourdan, Tony Mukhopadhyay, Bani Harvey-White, Judith Kunos, George TI Hepatic Cannabinoid-1 Receptors Mediate Diet-Induced Insulin Resistance by Increasing De Novo Synthesis of Long-Chain Ceramides SO HEPATOLOGY LA English DT Article ID SKELETAL-MUSCLE CELLS; KINASE-C-ZETA; SERINE-PALMITOYLTRANSFERASE; SPHINGOLIPID METABOLISM; PROTEIN PHOSPHATASE-2A; LEPTIN RESISTANCE; OBESE SUBJECTS; CB1 RECEPTORS; RISK-FACTORS; INHIBITION AB Obesity is associated with increased activity of two lipid signaling systems (endocannabinoids [ECs] and ceramides), with both being implicated in insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reverse obesity and insulin resistance, but have psychiatric side effects. Here we analyzed the role of ceramide in CB1R-mediated insulin resistance in C57Bl6/J mice with high-fat diet-induced obesity (DIO), using JD5037, a peripherally restricted CB1R inverse agonist. Chronic JD5037 treatment of DIO mice reduced body weight and steatosis and improved glucose tolerance and insulin sensitivity. Peripheral CB1R blockade also attenuated the diet-induced increase in C14:0, C16:0, C18:0, and C20:0 ceramide species with either C16 or C18 sphingosine-base in the liver. Decreased ceramide levels reflected their reduced de novo synthesis, due to inhibition of the activity of serine-palmitoyl transferase (SPT) and the expression of its SPTLC3 catalytic subunit, as well as reduced ceramide synthase (CerS) activity related to reduced expression of CerS1 and CerS6. JD5037 treatment also increased ceramide degradation due to increased expression of ceramidases. In primary cultured mouse hepatocytes and HepG2 cells, the EC anandamide increased ceramide synthesis in an eIF2-dependent manner, and inhibited insulin-induced akt phosphorylation by increased serine phosphorylation of IRS1 and increased expression of the serine/threonine phosphatase Phlpp1. These effects were abrogated by JD5037 or the SPT inhibitor myriocin. Chronic treatment of DIO mice with myriocin or JD5037 similarly reversed hepatic insulin resistance, as verified using a euglycemic/hyperinsulinemic clamp. Conclusion: ECs induce CB1R-mediated, endoplasmic reticulum stress-dependent synthesis of specific ceramide subspecies in the liver, which plays a key role in obesity-related hepatic insulin resistance. (Hepatology 2014;58:143-153) C1 [Cinar, Resat; Godlewski, Grzegorz; Liu, Jie; Tam, Joseph; Jourdan, Tony; Mukhopadhyay, Bani; Harvey-White, Judith; Kunos, George] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. EM cinarr@mail.nih.gov; George.Kunos@nih.gov OI CINAR, RESAT/0000-0002-8597-7253 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX Supported by Intramural funds from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 47 TC 34 Z9 37 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JAN PY 2014 VL 59 IS 1 BP 143 EP 153 DI 10.1002/hep.26606 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 276GZ UT WOS:000328738400018 PM 23832510 ER PT J AU Ozel, AB Moroi, SE Reed, DM Nika, M Schmidt, CM Akbari, S Scott, K Rozsa, F Pawar, H Musch, DC Lichter, PR Gaasterland, D Branham, K Gilbert, J Garnai, SJ Chen, W Othman, M Heckenlively, J Swaroop, A Abecasis, G Friedman, DS Zack, D Ashley-Koch, A Ulmer, M Kang, JH Liu, YT Yaspan, BL Haines, J Allingham, RR Hauser, MA Pasquale, L Wiggs, J Richards, JE Li, JZ AF Ozel, A. Bilge Moroi, Sayoko E. Reed, David M. Nika, Melisa Schmidt, Caroline M. Akbari, Sara Scott, Kathleen Rozsa, Frank Pawar, Hemant Musch, David C. Lichter, Paul R. Gaasterland, Doug Branham, Kari Gilbert, Jesse Garnai, Sarah J. Chen, Wei Othman, Mohammad Heckenlively, John Swaroop, Anand Abecasis, Goncalo Friedman, David S. Zack, Don Ashley-Koch, Allison Ulmer, Megan Kang, Jae H. Liu, Yutao Yaspan, Brian L. Haines, Jonathan Allingham, R. Rand Hauser, Michael A. Pasquale, Louis Wiggs, Janey Richards, Julia E. Li, Jun Z. CA NEIGHBOR Consortium TI Genome-wide association study and meta-analysis of intraocular pressure SO HUMAN GENETICS LA English DT Article ID OPEN-ANGLE GLAUCOMA; CENTRAL CORNEAL THICKNESS; TO-DISC RATIO; MACULAR DEGENERATION; MOLECULAR-BIOLOGY; GENETIC-VARIANTS; RISK-FACTORS; HERITABILITY; EYE; POPULATION AB Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in > 6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 x 10(-8)). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk. C1 [Ozel, A. Bilge; Li, Jun Z.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Moroi, Sayoko E.; Reed, David M.; Nika, Melisa; Schmidt, Caroline M.; Akbari, Sara; Scott, Kathleen; Rozsa, Frank; Pawar, Hemant; Musch, David C.; Lichter, Paul R.; Branham, Kari; Gilbert, Jesse; Garnai, Sarah J.; Othman, Mohammad; Heckenlively, John; Richards, Julia E.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Musch, David C.; Richards, Julia E.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Gaasterland, Doug] Eye Doctors Washington DC, Washington, DC USA. [Chen, Wei] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Div Pulm Med Allergy & Immunol, Pittsburgh, PA USA. [Chen, Wei] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Chen, Wei] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Swaroop, Anand] NEI, NIH, Bethesda, MD 20892 USA. [Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Friedman, David S.; Zack, Don] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Ashley-Koch, Allison; Ulmer, Megan; Liu, Yutao; Allingham, R. Rand; Hauser, Michael A.] Duke Univ, Sch Med, Ctr Human Genet, Durham, NC USA. [Kang, Jae H.; Pasquale, Louis] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Yaspan, Brian L.; Haines, Jonathan] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. [Pasquale, Louis; Wiggs, Janey] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Li, JZ (reprint author), Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. EM smoroi@med.umich.edu; junzli@med.umich.edu OI Rozsa, Frank/0000-0002-1378-7020; Reed, David/0000-0002-4772-6138; Carnes, Megan/0000-0002-7270-132X; Zack, Don/0000-0002-7966-1973; Swaroop, Anand/0000-0002-1975-1141; Ashley-Koch, Allison/0000-0001-5409-9155 FU University of Michigan Glaucoma Research Center; Ellison Medical Foundation; Harvard Glaucoma Center for Excellence; Margolis Fund; Research to Prevent Blindness; Glaucoma Research Foundation; Glaucoma Foundation; American Health Assistance Foundation; Elmer and Silvia Sramek Foundation; Foundation Fighting Blindness; Macula Vision Research Foundation; Pew Charitable Trusts; Casey Macular Degeneration Center Fund; Marion W. and Edward F. Knight AMD Fund; Harold and Pauline Price Foundation; National Genotyping Centre of Spain FX Other supports included funding from University of Michigan Glaucoma Research Center (S. E. M., J.E.R., J.Z.L.); Ellison Medical Foundation (J.Z.L.); Harvard Glaucoma Center for Excellence, and the Margolis Fund (J.W. and L. P.); Research to Prevent Blindness (A. S., D. C. M., J.W., L. P., J.R.H., and J.E.R.); the Glaucoma Research Foundation (S. E. M., Y.L.); the Glaucoma Foundation (Y.L.); American Health Assistance Foundation (Y.L., J.E.R., J.R.H., A. S.); Elmer and Silvia Sramek Foundation (J.R.H., A. S.); Foundation Fighting Blindness (J.R.H., A. S.); the Macula Vision Research Foundation (J.R.H., A. S.); the Pew Charitable Trusts (J.R.H., A. S.); the Casey Macular Degeneration Center Fund (J.R.H., A. S.); the Marion W. and Edward F. Knight AMD Fund (J.R.H., A. S.); the Harold and Pauline Price Foundation, National Genotyping Centre of Spain (J.R.H., A.S.). NR 50 TC 30 Z9 30 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JAN PY 2014 VL 133 IS 1 BP 41 EP 57 DI 10.1007/s00439-013-1349-5 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 283KH UT WOS:000329244500004 PM 24002674 ER PT J AU Shameer, K Denny, JC Ding, KY Jouni, H Crosslin, DR de Andrade, M Chute, CG Peissig, P Pacheco, JA Li, RL Bastarache, L Kho, AN Ritchie, MD Masys, DR Chisholm, RL Larson, EB McCarty, CA Roden, DM Jarvik, GP Kullo, IJ AF Shameer, Khader Denny, Joshua C. Ding, Keyue Jouni, Hayan Crosslin, David R. de Andrade, Mariza Chute, Christopher G. Peissig, Peggy Pacheco, Jennifer A. Li, Rongling Bastarache, Lisa Kho, Abel N. Ritchie, Marylyn D. Masys, Daniel R. Chisholm, Rex L. Larson, Eric B. McCarty, Catherine A. Roden, Dan M. Jarvik, Gail P. Kullo, Iftikhar J. TI A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects SO HUMAN GENETICS LA English DT Article ID ELECTRONIC MEDICAL-RECORDS; BLOOD-PRESSURE; ANKYLOSING-SPONDYLITIS; MYOCARDIAL-INFARCTION; DISEASE ASSOCIATIONS; METASTASIS; PATHWAYS; RISK; PHEWAS; HUMANS AB Platelets are enucleated cell fragments derived from megakaryocytes that play key roles in hemostasis and in the pathogenesis of atherothrombosis and cancer. Platelet traits are highly heritable and identification of genetic variants associated with platelet traits and assessing their pleiotropic effects may help to understand the role of underlying biological pathways. We conducted an electronic medical record (EMR)-based study to identify common variants that influence inter-individual variation in the number of circulating platelets (PLT) and mean platelet volume (MPV), by performing a genome-wide association study (GWAS). We characterized genetic variants associated with MPV and PLT using functional, pathway and disease enrichment analyses; we assessed pleiotropic effects of such variants by performing a phenome-wide association study (PheWAS) with a wide range of EMR-derived phenotypes. A total of 13,582 participants in the electronic MEdical Records and GEnomic network had data for PLT and 6,291 participants had data for MPV. We identified five chromosomal regions associated with PLT and eight associated with MPV at genome-wide significance (P < 5E-8). In addition, we replicated 20 SNPs [out of 56 SNPs (alpha: 0.05/56 = 9E-4)] influencing PLT and 22 SNPs [out of 29 SNPs (alpha: 0.05/29 = 2E-3)] influencing MPV in a published meta-analysis of GWAS of PLT and MPV. While our GWAS did not find any new associations, our functional analyses revealed that genes in these regions influence thrombopoiesis and encode kinases, membrane proteins, proteins involved in cellular trafficking, transcription factors, proteasome complex subunits, proteins of signal transduction pathways, proteins involved in megakaryocyte development, and platelet production and hemostasis. PheWAS using a single-SNP Bonferroni correction for 1,368 diagnoses (0.05/1368 = 3.6E-5) revealed that several variants in these genes have pleiotropic associations with myocardial infarction, autoimmune, and hematologic disorders. We conclude that multiple genetic loci influence interindividual variation in platelet traits and also have significant pleiotropic effects; the related genes are in multiple functional pathways including those relevant to thrombopoiesis. C1 [Shameer, Khader; Ding, Keyue; Jouni, Hayan; Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Denny, Joshua C.; Bastarache, Lisa] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Denny, Joshua C.; Bastarache, Lisa] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA. [Crosslin, David R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [de Andrade, Mariza; Chute, Christopher G.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Peissig, Peggy] Marshfield Clin Fdn Med Res & Educ, Biomed Informat Res Ctr, Marshfield, WI 54449 USA. [Pacheco, Jennifer A.; Chisholm, Rex L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Li, Rongling] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Kho, Abel N.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Ritchie, Marylyn D.] Penn State Univ, Eberly Coll Sci, Huck Inst Life Sci, Ctr Syst Genom, University Pk, PA 16802 USA. [Masys, Daniel R.] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37232 USA. [Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN 55805 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Kullo, IJ (reprint author), Mayo Clin, Div Cardiovasc Dis, 200 1st St SW, Rochester, MN 55905 USA. EM kullo.iftikhar@mayo.edu RI Jarvik, Gail/N-6476-2014; Khader, Shameer/J-2564-2016; OI Jarvik, Gail/0000-0002-6710-8708; Pacheco, Jennifer/0000-0001-8021-5818 FU National Human Genome Research Institute (NHGRI); National Institute of General Medical Sciences (NIGMS) [U01-HG-04599, U01-HG-004610, UO1-AG-06781, U01-HG-004608, U01HG004609, U01-HG-04603]; Washington State Life Sciences Discovery Fund award; [R01-LM-010685] FX The eMERGE network was initiated and funded by the National Human Genome Research Institute (NHGRI), with additional funding from National Institute of General Medical Sciences (NIGMS) through the following grants: U01-HG-04599 (Mayo Clinic); U01-HG-004610 and UO1-AG-06781 (Group Health Cooperative); U01-HG-004608 (Marshfield Clinic); U01HG004609 (Northwestern University); and U01-HG-04603 (Vanderbilt University, also serving as the Administrative Coordinating Center). We also acknowledge the genotyping centers U01-HG-004424 (Broad Institute) and U01-HG-004438 (Johns Hopkins University, Center for Inherited Disease Research). Additional genotyping support was provided by a Washington State Life Sciences Discovery Fund award to the Northwest Institute of Genetic Medicine (G.P.J). Additional support for PheWAS was provided through R01-LM-010685. NR 84 TC 38 Z9 40 U1 1 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD JAN PY 2014 VL 133 IS 1 BP 95 EP 109 DI 10.1007/s00439-013-1355-7 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 283KH UT WOS:000329244500008 PM 24026423 ER PT J AU Gearhart, PJ Kelsoe, G AF Gearhart, Patricia J. Kelsoe, Garnett TI A tribute to Michael S. Neuberger Obituary SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Biographical-Item C1 [Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Kelsoe, Garnett] Duke Univ, Dept Immunol, Durham, NC USA. [Kelsoe, Garnett] Duke Univ, Human Vaccine Inst, Durham, NC USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM gearhartp@mail.nih.gov NR 1 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2014 VL 124 IS 1 BP 3 EP 5 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 284PX UT WOS:000329333500002 PM 24382382 ER PT J AU El Touny, LH Vieira, A Mendoza, A Khanna, C Hoenerhoff, MJ Green, JE AF El Touny, Lara H. Vieira, Anthony Mendoza, Arnulfo Khanna, Chand Hoenerhoff, Mark J. Green, Jeffrey E. TI Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BREAST-CANCER CELLS; MOUSE MAMMARY-TUMOR; PHASE-II TRIAL; C-SRC; 3-DIMENSIONAL CULTURE; EXTRACELLULAR-MATRIX; BONE METASTASIS; KINASE-ACTIVITY; DOWN-REGULATION; POOR-PROGNOSIS AB Breast cancer (BC) can recur as metastatic disease many years after primary tumor removal, suggesting that disseminated tumor cells survive for extended periods in a dormant state that is refractory to conventional therapies. We have previously shown that altering the tumor microenvironment through fibrosis with collagen and fibronectin deposition can trigger tumor cells to switch from a dormant to a proliferative state. Here, we used an in vivo preclinical model and a 3D in vitro model of dormancy to evaluate the role of Src family kinase (SFK) in regulating this dormant-to-proliferative switch. We found that pharmacological inhibition of SFK signaling or Src knockdown results in the nuclear localization of cyclin-dependent kinase inhibitor p27 and prevents the proliferative outbreak of dormant BC cells and metastatic lesion formation; however, SFK inhibition did not kill dormant cells. Dormant cell proliferation also required ERK1/2 activation. Combination treatment of cells undergoing the dormant-to-proliferative switch with the Src inhibitor (AZD0530) and MEK1/2 inhibitor (AZD6244) induced apoptosis in a large fraction of the dormant cells and delayed metastatic outgrowth, neither of which was observed with either inhibitor alone. Thus, targeting Src prevents the proliferative response of dormant cells to external stimuli, but requires MEK1/2 inhibition to suppress their survival. These data indicate that treatments targeting Src in combination with MEK1/2 may prevent BC recurrence. C1 [El Touny, Lara H.; Vieira, Anthony; Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Mendoza, Arnulfo; Khanna, Chand] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Hoenerhoff, Mark J.] NIEHS, Natl Toxicol Program, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. RP Green, JE (reprint author), NCI, Lab Canc Biol & Genet, Bldg 37,Room 4054,37 Convent Dr, Bethesda, MD 20892 USA. EM jegreen@nih.gov FU NIH; CCR; NCI FX This work was supported by the Intramural Research Program of the NIH, CCR, and NCI. We thank Glenn Merlino, Stuart Yuspa, Peter Blumberg, and Olga Aprelikova for useful discussions; Julie Foley and Norris Flagler for the collagen image analysis; and the Laboratory Animal Science Program and the FACS core facility at the NCI for excellent technical assistance. NR 51 TC 23 Z9 24 U1 1 U2 22 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2014 VL 124 IS 1 BP 156 EP 168 DI 10.1172/JCI70259 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 284PX UT WOS:000329333500025 PM 24316974 ER PT J AU Terunuma, A Putluri, N Mishra, P Mathe, EA Dorsey, TH Yi, M Wallace, TA Issaq, HJ Zhou, M Killian, JK Stevenson, HS Karoly, ED Chan, K Samanta, S Prieto, D Hsu, TYT Kurley, SJ Putluri, V Sonavane, R Edelman, DC Wulff, J Starks, AM Yang, YM Kittles, RA Yfantis, HG Lee, DH Loffe, OB Schiff, R Stephens, RM Meltzer, PS Veenstra, TD Westbrook, TF Sreekumar, A Ambs, S AF Terunuma, Atsushi Putluri, Nagireddy Mishra, Prachi Mathe, Ewy A. Dorsey, Tiffany H. Yi, Ming Wallace, Tiffany A. Issaq, Haleem J. Zhou, Ming Killian, J. Keith Stevenson, Holly S. Karoly, Edward D. Chan, King Samanta, Susmita Prieto, DaRue Hsu, Tiffany Y. T. Kurley, Sarah J. Putluri, Vasanta Sonavane, Rajni Edelman, Daniel C. Wulff, Jacob Starks, Adrienne M. Yang, Yinmeng Kittles, Rick A. Yfantis, Harry G. Lee, Dong H. Loffe, Olga B. Schiff, Rachel Stephens, Robert M. Meltzer, Paul S. Veenstra, Timothy D. Westbrook, Thomas F. Sreekumar, Arun Ambs, Stefan TI MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GENE-EXPRESSION SIGNATURE; HYDROXYACID-OXOACID TRANSHYDROGENASE; GLUTAMINE-METABOLISM; MOLECULAR PORTRAITS; ALPHA-KETOGLUTARATE; MASS-SPECTROMETRY; C-MYC; IDH1; METHYLATION; PROGRESSION AB Metabolic profiling of cancer cells has recently been established as a promising tool for the development of therapies and identification of cancer biomarkers. Here we characterized the metabolomic profile of human breast tumors and uncovered intrinsic metabolite signatures in these tumors using an untargeted discovery approach and validation of key metabolites. The oncometabolite 2-hydroxyglutarate (2HG) accumulated at high levels in a subset of tumors and human breast cancer cell lines. We discovered an association between increased 2HG levels and MYC pathway activation in breast cancer, and further corroborated this relationship using MYC overexpression and knockdown in human mammary epithelial and breast cancer cells. Further analyses revealed globally increased DNA methylation in 2HG-high tumors and identified a tumor subtype with high tissue 2HG and a distinct DNA methylation pattern that was associated with poor prognosis and occurred with higher frequency in African-American patients. Tumors of this subtype had a stem cell-like transcriptional signature and tended to overexpress glutaminase, suggestive of a functional relationship between glutamine and 2HG metabolism in breast cancer. Accordingly, 13C-labeled glutamine was incorporated into 2HG in cells with aberrant 2HG accumulation, whereas pharmacologic and siRNA-mediated glutaminase inhibition reduced 2HG levels. Our findings implicate 2HG as a candidate breast cancer oncometabolite associated with MYC activation and poor prognosis. C1 [Terunuma, Atsushi; Mishra, Prachi; Mathe, Ewy A.; Dorsey, Tiffany H.; Wallace, Tiffany A.; Starks, Adrienne M.; Yang, Yinmeng; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Putluri, Nagireddy; Samanta, Susmita; Hsu, Tiffany Y. T.; Kurley, Sarah J.; Putluri, Vasanta; Sonavane, Rajni; Westbrook, Thomas F.; Sreekumar, Arun] Baylor Coll Med, Alkek Ctr Mol Discovery, Verna & Marrs Mclean Dept Biochem, Dept Mol & Cell Biol, Houston, TX 77030 USA. [Yi, Ming; Stephens, Robert M.] SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD USA. [Issaq, Haleem J.; Zhou, Ming; Chan, King; Prieto, DaRue; Veenstra, Timothy D.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Lab Prote & Analyt Technol, Frederick, MD USA. [Killian, J. Keith; Stevenson, Holly S.; Edelman, Daniel C.; Meltzer, Paul S.] NCI, Genet Branch, CCR, NIH, Bethesda, MD 20892 USA. [Karoly, Edward D.; Wulff, Jacob] Metabolon Inc, Durham, NC USA. [Kittles, Rick A.] Univ Illinois, Coll Med, Chicago, IL USA. [Yfantis, Harry G.; Lee, Dong H.] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Loffe, Olga B.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Schiff, Rachel] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Schiff, Rachel] Baylor Coll Med, Dept Mol & Cell Biol, Houston, TX 77030 USA. [Killian, J. Keith; Stevenson, Holly S.; Edelman, Daniel C.; Meltzer, Paul S.] NCI, Clin Mol Profiling Core, NIH, Bethesda, MD 20892 USA. RP Ambs, S (reprint author), NCI, Bldg 37,Room 3050B, Bethesda, MD 20892 USA. EM Arun.Sreekumar@bcm.edu; ambss@mail.nih.gov FU Intramural Research Program of the NIH; NCI; CCR; NCI Director's Innovation Award; NIH SPORE [CA58183]; Susan Komen Foundation [KG110818, U01 CA167234, DMS-1161759, RP120092]; Alkek,Center for Molecular Discovery; [1RO1CA133458-01] FX This research was supported by the Intramural Research Program of the NIH, NCI, CCR and by a NCI Director's Innovation Award to S. Ambs. A. Sreekumar acknowledges the following grant support: 1RO1CA133458-01, NIH SPORE CA58183, Susan Komen Foundation grant KG110818, U01 CA167234, DMS-1161759, RP120092, and funds from the Alkek,Center for Molecular Discovery (ASK). The authors thank Raymond Jones, Audrey Salabes, Leoni Leondaridis, Glennwood Trivers, Elise Bowman, and personnel at the University of Maryland and the Baltimore Veterans Administration and the Surgery and Pathology Departments at the University of Maryland Medical Center, Baltimore Veterans Affairs Medical Center, Union Memorial Hospital, Mercy Medical Center, and Sinai Hospital for their contributions in patient recruitment. NR 70 TC 81 Z9 81 U1 1 U2 21 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN PY 2014 VL 124 IS 1 BP 398 EP 412 DI 10.1172/JCI71180 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 284PX UT WOS:000329333500045 PM 24316975 ER PT J AU Cousins, MM Konikoff, J Laeyendecker, O Celum, C Buchbinder, SP Seage, GR Kirk, GD Moore, RD Mehta, SH Margolick, JB Brown, J Mayer, KH Koblin, BA Wheeler, D Justman, JE Hodder, SL Quinn, TC Brookmeyer, R Eshleman, SH AF Cousins, Matthew M. Konikoff, Jacob Laeyendecker, Oliver Celum, Connie Buchbinder, Susan P. Seage, George R., III Kirk, Gregory D. Moore, Richard D. Mehta, Shruti H. Margolick, Joseph B. Brown, Joelle Mayer, Kenneth H. Koblin, Beryl A. Wheeler, Darrell Justman, Jessica E. Hodder, Sally L. Quinn, Thomas C. Brookmeyer, Ron Eshleman, Susan H. TI HIV Diversity as a Biomarker for HIV Incidence Estimation: Including a High-Resolution Melting Diversity Assay in a Multiassay Algorithm SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID UNITED-STATES; VACCINE PREPAREDNESS; INCIDENCE RATES; COHORT; INFECTION; TRIALS; SEROCONVERSION; IMMUNOASSAY; NETWORK; PLASMA AB Multiassay algorithms (MAAs) can be used to estimate cross-sectional HIV incidence. We previously identified a robust MAA that includes the BED capture enzyme immunoassay (BED-CEIA), the Bio-Rad Avidity assay, viral load, and CD4 cell count. In this report, we evaluated MAAs that include a high-resolution melting (HRM) diversity assay that does not require sequencing. HRM scores were determined for eight regions of the HIV genome (2 in gag, 1 in pol, and 5 in env). The MAAs that were evaluated included the BED-CEIA, the Bio-Rad Avidity assay, viral load, and the HRM diversity assay, using HRM scores from different regions and a range of region-specific HRM diversity assay cutoffs. The performance characteristics based on the proportion of samples that were classified as MAA positive by duration of infection were determined for each MAA, including the mean window period. The cross-sectional incidence estimates obtained using optimized MAAs were compared to longitudinal incidence estimates for three cohorts in the United States. The performance of the HRM-based MAA was nearly identical to that of the MAA that included CD4 cell count. The HRM-based MAA had a mean window period of 154 days and provided cross-sectional incidence estimates that were similar to those based on cohort follow-up. HIV diversity is a useful biomarker for estimating HIV incidence. MAAs that include the HRM diversity assay can provide accurate HIV incidence estimates using stored blood plasma or serum samples without a requirement for CD4 cell count data. C1 [Cousins, Matthew M.; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Konikoff, Jacob; Brookmeyer, Ron] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Moore, Richard D.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Celum, Connie] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Celum, Connie] Univ Washington, Dept Med, Seattle, WA USA. [Buchbinder, Susan P.] San Francisco Dept Hlth, Bridge HIV, San Francisco, CA USA. [Buchbinder, Susan P.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Buchbinder, Susan P.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Seage, George R., III] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kirk, Gregory D.; Mehta, Shruti H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Margolick, Joseph B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Brown, Joelle] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Mayer, Kenneth H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Fenway Inst, Boston, MA 02215 USA. [Koblin, Beryl A.] New York Blood Ctr, Lab Infect Dis Prevent, New York, NY 10021 USA. [Wheeler, Darrell] Loyola Univ Chicago, Grad Sch Social Work, Chicago, IL USA. [Justman, Jessica E.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Justman, Jessica E.] Columbia Univ, Dept Med, New York, NY USA. [Hodder, Sally L.] Rutgers State Univ, Dept Med, Div Infect Dis, Newark, NJ 07102 USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 FU HIV Prevention Trials Network (HPTN); National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Drug Abuse (NIDA); National Institute of Mental Health; Office of AIDS Research of the National Institutes of Health (NIH), Department of Health and Human Services [UM1-AI068613]; Division of Intramural Research, NIAID, NIH; HIVNET 001/001.1 [N01-AI35176, N01-AI-45200, AI-45202]; ALIVE [R01-DA-04334, R01-DA12568]; MACS [U01-AI35042, U01-AI35043, U01-AI35039, U01-AI35040, U01-AI35041, UL1-RR025005]; JHHCC [R01-DA011602, R01-AA016893]; [R01-AI095068]; [UM1-AI068619]; [UM1-AI068617] FX We thank the study teams and participants who provided the samples and data for this work. We also thank the laboratory staff at Johns Hopkins University for their technical support and Deborah Donnell for her helpful discussions. This work was supported by: the HIV Prevention Trials Network (HPTN), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health, and the Office of AIDS Research of the National Institutes of Health (NIH), Department of Health and Human Services (grant no. UM1-AI068613 to S. H. E.). Additional funding was provided by grant no. R01-AI095068 (to S. H. E. and R. B.) and the Division of Intramural Research, NIAID, NIH. Support for the studies that provided samples for this project are as follows: from HIVNET 001/001.1, grant no. N01-AI35176, N01-AI-45200, and AI-45202; from ALIVE, grant no. R01-DA-04334 and R01-DA12568; from MACS, grant no. U01-AI35042, U01-AI35043, U01-AI35039, U01-AI35040, U01-AI35041, and UL1-RR025005; from JHHCC, grant no. R01-DA011602 and R01-AA016893 to R. D. M.; and from HPTN 061 and HPTN 064, grant no. UM1-AI068619, UM1-AI068617, and UM1-AI068613. The funders had no role in the design or conduct of the study, data collection or analysis, preparation of the manuscript, or the decision to publish. NR 36 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 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JAN PY 2014 VL 52 IS 1 BP 115 EP 121 DI 10.1128/JCM.02040-13 PG 7 WC Microbiology SC Microbiology GA 283CM UT WOS:000329222400019 PM 24153134 ER PT J AU Sahasrabuddhe, VV Gravitt, PE Dunn, ST Brown, D Allen, RA Eby, YJ Smith, K Zuna, RE Zhang, RR Gold, MA Schiffman, M Walker, JL Castle, PE Wentzensen, N AF Sahasrabuddhe, Vikrant V. Gravitt, Patti E. Dunn, S. Terence Brown, David Allen, Richard A. Eby, Yolanda J. Smith, Katie Zuna, Rosemary E. Zhang, Roy R. Gold, Michael A. Schiffman, Mark Walker, Joan L. Castle, Philip E. Wentzensen, Nicolas TI Comparison of Human Papillomavirus Detections in Urine, Vulvar, and Cervical Samples from Women Attending a Colposcopy Clinic SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID VAGINAL HUMAN-PAPILLOMAVIRUS; HPV-DNA DETECTION; PAIRED URINE; CANCER; PCR; POPULATION; PREVALENCE; PREVENTION; INFECTION; SPECIMENS AB While urine-based sampling for human papillomavirus (HPV) is being explored as a simple and noninvasive approach for cervical cancer screening, data comparing HPV genotyping in urine and those in cellular sampling of the cervix and vulva, and their correlation with rigorously confirmed cervical disease status, are sparse. We performed HPV genotyping on voided-urine and clinician-collected vulvar and cervical samples from 72 women undergoing colposcopy. Although urine-based HPV carcinogenic HPV detection was lower (58.3%) than cervical (73.6%) and vulvar (72.1%) detection (P = 0.05 and 0.07, respectively), the agreement of urine HPV with cervical and vulvar HPV was moderate (kappa = 0.55) and substantial (kappa = 0.62), respectively. Urine-based carcinogenic HPV detection had a clinical sensitivity of 80.8% (95% confidence interval [CI] = 60.7 to 93.5) and a specificity of 53.3% (95% CI = 37.9 to 68.3) for diagnosing cervical intraepithelial neoplasia grades 2/3 (CIN2/3) on histology; 90.0% of CIN3 was positive for urine HPV. The corresponding sensitivity and specificity values for vulvar sampling were 92% (95% CI = 74 to 99) and 40.5% (95% CI = 25.6 to 56.7), and those for cervical sampling were 96.2% (95% CI = 80.4 to 99.9) and 40% (95% CI = 25.7 to 55.7), respectively. HPV16 was the most common carcinogenic genotype detectable in 25% of urine, 33.8% of vulvar, and 31.9% of cervical samples overall, with prevalence increasing with cervical disease grade, regardless of the sampling method. Stronger cervical HPV PCR signal strengths were associated with increased frequency of urine HPV detection. In summary, the relatively lower detection rates but comparable clinical performance of urine-based HPV sampling underscore the need for larger studies to evaluate urine-based sampling for cervical cancer screening, epidemiologic studies, and postvaccination HPV disease surveillance. C1 [Sahasrabuddhe, Vikrant V.; Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Sahasrabuddhe, Vikrant V.] Vanderbilt Univ, Nashville, TN 37235 USA. [Gravitt, Patti E.; Eby, Yolanda J.; Walker, Joan L.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Dunn, S. Terence; Brown, David; Allen, Richard A.; Smith, Katie; Zuna, Rosemary E.; Zhang, Roy R.; Gold, Michael A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Castle, Philip E.] Global Canc Initiat, Chestertown, MD USA. RP Sahasrabuddhe, VV (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. EM vikrant.sahasrabuddhe@nih.gov FU National Cancer Institute at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 30 TC 7 Z9 7 U1 0 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JAN PY 2014 VL 52 IS 1 BP 187 EP 192 DI 10.1128/JCM.01623-13 PG 6 WC Microbiology SC Microbiology GA 283CM UT WOS:000329222400028 PM 24197879 ER PT J AU Gupta, GN Benson, JS Ross, MJ Sundaram, VS Lin, KY Pinto, PA Linehan, WM Bratslavsky, G AF Gupta, Gopal N. Benson, Jonas S. Ross, Michael J. Sundaram, Vani S. Lin, Kelly Y. Pinto, Peter A. Linehan, W. Marston Bratslavsky, Gennady TI Perioperative, Functional, and Oncologic Outcomes of Partial Adrenalectomy for Multiple Ipsilateral Pheochromocytomas SO JOURNAL OF ENDOUROLOGY LA English DT Article ID FOLLOW-UP; HISTORY AB Objective: Managing patients with multiple adrenal masses is technically challenging. We present our experience with minimally invasive partial adrenalectomy (PA) performed for synchronous multiple ipsilateral pheochromocytomas in a single setting. Materials and Methods: We reviewed records of patients undergoing PA for pheochromocytoma at the National Cancer Institute between 1994 and 2010. Patients were included if multiple tumors were excised from the ipsilateral adrenal gland in the same operative setting. Perioperative, functional, and oncologic outcomes of PA for multiple pheochromocytomas are shown. Results: Of 121 partial adrenalectomies performed, 10 procedures performed in eight patients for synchronous multiple ipsilateral pheochromocytomas were identified. All eight patients were symptomatic at presentation. The mean patient age was 30.6 years, median follow up was 12 months. The average surgical time was 228 minutes, average blood loss of 125mL, and average number of tumors removed was 2.6 per adrenal. In total, 26 tumors were removed, 24 were pathologically confirmed pheochromocytomas, while two were adrenal cortical hyperplasia. After surgery, all patients had resolution of their symptoms, one patient required steroid replacement postoperatively. On postoperative imaging, one patient had evidence of ipsilateral adrenal nodule at the prior resection site 2 months postoperatively, which was consistent with incomplete resection. Conclusions: Minimally invasive surgical resection of synchronous multiple pheochromocytomas is feasible with acceptable perioperative, functional, and short-term oncologic outcomes. C1 [Gupta, Gopal N.; Benson, Jonas S.; Ross, Michael J.; Sundaram, Vani S.] Loyola Univ, Med Ctr, Dept Urol, Maywood, IL 60153 USA. [Lin, Kelly Y.; Pinto, Peter A.; Linehan, W. Marston; Bratslavsky, Gennady] NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Gupta, GN (reprint author), Loyola Univ, Med Ctr, Stritch Sch Med, Dept Urol, Maywood, IL 60153 USA. EM gogupta@lumc.edu FU National Institute of Health (NIH) FX This research was funded by the National Institute of Health (NIH) intramural research program. NR 16 TC 2 Z9 3 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 EI 1557-900X J9 J ENDOUROL JI J. Endourol. PD JAN 1 PY 2014 VL 28 IS 1 BP 112 EP 116 DI 10.1089/end.2013.0298 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 284ZM UT WOS:000329361400020 PM 23998199 ER PT J AU Glass, RI Parashar, U Patel, M Gentsch, J Jiang, BM AF Glass, Roger I. Parashar, Umesh Patel, Manish Gentsch, Jon Jiang, Baoming TI Rotavirus vaccines: Successes and challenges SO JOURNAL OF INFECTION LA English DT Article DE Rotavirus; Vaccines; Childhood diarrhea ID CHILDHOOD DIARRHEA; UNITED-STATES; ACUTE GASTROENTERITIS; VACCINATION PROGRAMS; GLOBAL SEASONALITY; YOUNG-CHILDREN; INFECTION; INFANTS; EFFICACY; ANTIBODY AB Since 2006, the availability of two new rotavirus vaccines has raised enthusiasm to consider the eventual control and elimination of severe rotavirus diarrhea through the global use of vaccines. Rotavirus remains the most severe cause of acute diarrhea in children worldwide responsible for several hundred thousands of deaths in low income countries and up to half of hospital admissions for diarrhea around the world. The new vaccines have been recommended by WHO for all infants and in more than 47 countries, their introduction into routine childhood immunization programs has led to a remarkable decline in hospital admissions and even deaths within 3 years of introduction. Challenges remain with issues of vaccine finance globally and the problem that these live oral vaccines perform less well in low income settings where they are needed most. Ongoing research that will accompany vaccine introduction might help address these issues of efficacy and new vaccines and novel financing schemes may both help make these vaccines universally available and affordable in the decade. Published by Elsevier Ltd on behalf of The British Infection Association. C1 [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Parashar, Umesh; Patel, Manish; Gentsch, Jon; Jiang, Baoming] Ctr Dis Control & Prevent, Viral Gastroenteritis Team, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. RP Glass, RI (reprint author), NIH, Fogarty Int Ctr, 31 Ctr Dr,Mailstop 2220, Bethesda, MD 20892 USA. EM glassr@mail.nih.gov; uap2@CDC.GOV; aul3@CDC.GOV; jrg4@CDC.GOV; bxj4@CDC.GOV FU CDC; U.S. Government FX All of this work has been funded through the CDC and the U.S. Government. NR 59 TC 28 Z9 30 U1 3 U2 10 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 EI 1532-2742 J9 J INFECTION JI J. Infect. PD JAN PY 2014 VL 68 SU 1 BP S9 EP S18 DI 10.1016/j.jinf.2013.09.010 PG 10 WC Infectious Diseases SC Infectious Diseases GA 283CN UT WOS:000329222500003 PM 24156947 ER PT J AU Hara, K Rivera, MM Koh, C DeMino, M Page, S Nagabhyru, PR Rehermann, B Liang, TJ Hoofnagle, JH Heller, T AF Hara, Koji Rivera, Maria M. Koh, Christopher DeMino, Mary Page, Sandra Nagabhyru, Pothu Raju Rehermann, Barbara Liang, T. Jake Hoofnagle, Jay H. Heller, Theo TI Sequence Analysis of Hepatitis C Virus From Patients With Relapse After a Sustained Virological Response: Relapse or Reinfection? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Hepatitis C virus; late relapse; sequence; liver ID TERM-FOLLOW-UP; INTERFERON; RIBAVIRIN; THERAPY; INFECTION AB Background. A sustained virological response (SVR) is the major end point of therapy for chronic hepatitis C virus (ICV) infection. Late relapse of infection is rare and poorly characterized. Three of 103 patients with a SVR treated at the National Institutes of Health had late relapse. We evaluated fICV RNA sequences in serum and liver tissue to distinguish relapse from reinfection. Methods. Per patient, 10-22 clones of amplified 5' untranslated region were evaluated in pretreatment and relapse serum specimens and in liver biopsy specimens obtained during SVR. Genotypes and sequence diversity were evaluated. Four patients whose infection relapsed before they reached a SVR (ie, the early relapse group) were used as a comparison. Results. Results of tests for detection of serum IICV RNA in all patients with late relapse were repeatedly negative during the first 24 weeks after therapy but became positive 8, 75, and 78 months after SVR. Reinfection risk factors were absent in 2 of 3 patients. In all patients with early or late relapse, apart from minor variations, the original IICV sequence was present before treatment and after relapse. All liver biopsy specimens from patients with late relapse were IICV RNA positive at SVR, with sequences nearly identical to those of specimens obtained at other time points. Conclusions. Sequence comparisons suggest that reappearance of fICV RNA years after a SVR can be from relapse of the initial viral infection rather than reinfection from a different virus. C1 [Hara, Koji; Rivera, Maria M.; Koh, Christopher; DeMino, Mary; Page, Sandra; Nagabhyru, Pothu Raju; Rehermann, Barbara; Liang, T. Jake; Hoofnagle, Jay H.; Heller, Theo] NIDDK, Translat Hepatol Unit, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Heller, T (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Rm 9B16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM theller@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 18 TC 18 Z9 18 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2014 VL 209 IS 1 BP 38 EP 45 DI 10.1093/infdis/jit541 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 282FY UT WOS:000329157000008 PM 24127561 ER PT J AU Ng, OT Laeyendecker, O Redd, AD Munshaw, S Grabowski, MK Paquet, AC Evans, MC Haddad, M Huang, W Robb, ML Reynolds, SJ Gray, RH Wawer, MJ Serwadda, D Eshleman, SH Quinn, TC AF Ng, Oon Tek Laeyendecker, Oliver Redd, Andrew D. Munshaw, Supriya Grabowski, Mary K. Paquet, Agnes C. Evans, Mark C. Haddad, Mojgan Huang, Wei Robb, Merlin L. Reynolds, Steven J. Gray, Ronald H. Wawer, Maria J. Serwadda, David Eshleman, Susan H. Quinn, Thomas C. TI HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV-1 Subtype; subtype A; subtype D; disease progression; polymerase; replication capacity; amino acid polymorphisms ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL DECLINE; DRUG-SUSCEPTIBILITY; CATALYTIC EFFICIENCY; VIRAL SUBTYPE; NAIVE ADULTS; INFECTION; UGANDA; RAKAI; IMPACT AB Background. Determinants of intersubtype differences in human immunodeficiency virus type 1 (HIV-1) clinical disease progression remain unknown. Methods. HIV-1 subtype was independently determined for 5 separate genomic regions in 396 HIV-1 seroconverters from Rakai, Uganda, using a multiregion hybridization assay. Replication capacities (RC) in samples from a subset of 145 of these subjects were determined. HIV-1 genomic regions and poi RC were examined for association with disease progression. Amino acid polymorphisms were examined for association with pot RC. Results. In multivariate analyses, the hazard for progression to the composite end point (defined as a CD4+ Tcell count <250 cells/mm(3), antiretroviral therapy initiation, or death) among patients with subtype D pot infection was 2.4 times the hazard for those infected with subtype A pol infection (P =.001). Compared with subtype A pol (the reference group), the hazard for progression to the composite end point for subtype D pol infection with a pol RC >67% (ie, the median pot RC) was significantly greater (HR, 4.6; 95% confidence interval [CI], 1.9-11.0; P =.001), whereas the hazard for progression to the composite end point for subtype D pol infection with a pol RC <= 67% was not significantly different (HR, 2.2; 959/0 CI, 1.0-4.9; P =.051). Amino acid substitutions at protease positions 62 and 64 and at reverse transcriptase position 272 were associated with significant differences in pot RC. Conclusion. HIV-1 pol gene intersubtype and RC differences are associated with disease progression and may be influenced by amino acid polymorphisms. C1 [Ng, Oon Tek; Laeyendecker, Oliver; Munshaw, Supriya; Reynolds, Steven J.; Quinn, Thomas C.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Eshleman, Susan H.] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Grabowski, Mary K.; Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Laeyendecker, Oliver; Redd, Andrew D.; Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Robb, Merlin L.] US Mil HIV Res Program, Henry M Jackson Fdn, Rockville, MD USA. [Paquet, Agnes C.; Evans, Mark C.; Haddad, Mojgan; Huang, Wei] Monogram Biosci, San Francisco, CA USA. [Ng, Oon Tek] Tan Tock Seng Hosp, Dept Infect Dis, Singapore, Singapore. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Quinn, TC (reprint author), Johns Hopkins Univ, Sch Med, John Rangos Sr Bldg,Rm 530,855 N Wolfe St, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Singapore National Medical Research Training Fellowship Grant [EDG10nov070]; National Institutes of Health (NIH) [NIDA R01 DA024565]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by a Singapore National Medical Research Training Fellowship Grant (EDG10nov070 to O. T. N.), the National Institutes of Health (NIH; NIDA R01 DA024565 to S. M.), and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 25 TC 3 Z9 3 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 1 PY 2014 VL 209 IS 1 BP 66 EP 73 DI 10.1093/infdis/jit425 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 282FY UT WOS:000329157000011 PM 23922373 ER PT J AU Evangelou, IE Oh, U Massoud, R Jacobson, S AF Evangelou, Iordanis E. Oh, Unsong Massoud, Raya Jacobson, Steven TI HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis: Semiautomatic Quantification of Spinal Cord Atrophy from 3-Dimensional MR Images SO JOURNAL OF NEUROIMAGING LA English DT Article DE Spinal cord; HTLV-I; HAM; TSP; MRI; atrophy ID MAGNETIC-RESONANCE IMAGES; CLINICAL-FEATURES; HAM/TSP; INFECTION; CARRIERS AB BACKGROUNDHuman T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a disabling neurological disorder characterized by inflammatory changes in the spinal cord. We used a semiautomatic technique to quantify spinal cord volume from 3-dimensional MR images of patients with HAM/TSP. METHODSFive patients and 5 matched healthy volunteers (HVs) underwent MRI of the cervical and thoracic spinal cord at 1.5 T. Quantification of the spinal cord volume was obtained from 3-dimensional MR images using a semiautomatic technique based on level sets. An unpaired t-test was used to assess statistical significance. RESULTSSignificant differences were found between mean spinal cord volume of HVs and HAM/TSP patients. The thoracic spinal cord volume was 14,050 981 mm(3) for HVs and 8,774 +/- 2,218 mm(3) for HAM/TSP patients (P = .0079), a reduction of 38%. The cervical spinal cord volume was 9,721 +/- 797 mm(3) for HVs and 6,589 +/- 897 mm(3) for HAM/TSP patients (P = .0079), a reduction of 32%. These results suggest that atrophy is evident throughout the spinal cord not routinely quantified. CONCLUSIONSSemiautomatic spinal cord volume quantification is a sensitive technique for quantifying the extent of spinal cord involvement in HAM/TSP. C1 [Evangelou, Iordanis E.; Oh, Unsong; Massoud, Raya; Jacobson, Steven] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Evangelou, IE (reprint author), NINDS, Neuroimmunol Branch, NIH, 10 Ctr Dr,Bldg 10-5C103, Bethesda, MD 20892 USA. EM iordanis_evangelou@yahoo.com FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This study was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 12 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD JAN PY 2014 VL 24 IS 1 BP 74 EP 78 DI 10.1111/j.1552-6569.2011.00648.x PG 5 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 286ZZ UT WOS:000329509100012 PM 22303896 ER PT J AU Corcoran, AE Commons, KG Wu, YM Smith, JC Harris, MB Richerson, GB AF Corcoran, Andrea E. Commons, Kathryn G. Wu, Yuanming Smith, Jeffrey C. Harris, Michael B. Richerson, George B. TI Dual Effects of 5-HT1a Receptor Activation on Breathing in Neonatal Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE 8-OH-DPAT; Lmx1b; serotonin ID CENTRAL SEROTONIN NEURONS; BROWN ADIPOSE-TISSUE; THERMOREGULATORY CONTROL; RESPIRATORY RHYTHM; TRANSGENIC MICE; CONSCIOUS RATS; RAPHE NEURONS; IN-VITRO; 8-OH-DPAT; AGONIST AB Inhibitory 5-HT1a receptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT1a agonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), could either be due to decreased firing of 5-HT neurons or direct effects on the respiratory network. Mice in which the transcription factor LMX1B is genetically deleted selectively in Pet1-1-expressing cells (Lmx1b(f/f/p)) essentially have complete absence of central 5-HT neurons, providing a unique opportunity to separate the effect of activation of downstream 5-HT1a heteroreceptors from that of autoreceptors. We used rhythmically active medullary slices from wild-type (WT) and Lmx1b(f/f/p) neonatal mice to differentiate autoreceptor versus heteroreceptor effects of 8-OH-DPAT on hypoglossal nerve respiratory output. 8-OH-DPAT transiently increased respiratory burst frequency in Lmx1b(f/f/p) preparations, but not inWTslices. This excitation was abolished when synaptic inhibition was blocked by GABAergic/glycinergic receptor antagonists. Conversely, after 10 min of application, frequency in Lmx1b(f/f/p) slices was not different from baseline, whereas it was significantly depressed in WT slices. In WT mice in vivo, subcutaneous injection of 8-OH-DPAT produced similar biphasic respiratory effects as in Lmx1b(f/f/p) mice. We conclude that 5-HT1a receptor agonists have two competing effects: rapid stimulation of breathing due to excitation of the respiratory network, and delayed inhibition of breathing due to autoreceptor inhibition of 5-HT neurons. The former effect is presumably due to inhibition of inhibitory interneurons embedded in the respiratory network. C1 [Corcoran, Andrea E.; Harris, Michael B.] Univ Alaska Fairbanks, Dept Biol & Wildlife, Fairbanks, AK 99775 USA. [Corcoran, Andrea E.; Richerson, George B.] Yale Univ, Dept Neurol, New Haven, CT 06520 USA. [Corcoran, Andrea E.; Richerson, George B.] Yale Univ, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. [Corcoran, Andrea E.] Geisel Sch Med Dartmouth, Dept Physiol & Neurobiol, Lebanon, NH 03756 USA. [Commons, Kathryn G.] Boston Childrens Hosp, Dept Anesthesia Perioperat & Pain Med, Boston, MA 02115 USA. [Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Richerson, George B.] Vet Affairs Med Ctr, Iowa City, IA 52242 USA. [Wu, Yuanming; Richerson, George B.] Univ Iowa, Dept Neurol, Iowa City, IA 52242 USA. [Wu, Yuanming; Richerson, George B.] Univ Iowa, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. RP Corcoran, AE (reprint author), Geisel Sch Med Dartmouth, Dept Physiol & Neurobiol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM andrea.e.corcoran@dartmouth.edu RI Harris, Michael/A-3809-2010 FU Intramural Research Program of the NIH; NINDS; NIH [2U54NS041069]; NIH/NICHD [P01HD36379, R01HD052772] FX This work was supported in part by the Intramural Research Program of the NIH, NINDS, and from the NIH Grants 2U54NS041069, NIH/NICHD, P01HD36379, and R01HD052772. NR 52 TC 8 Z9 9 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 1 PY 2014 VL 34 IS 1 BP 51 EP 59 DI 10.1523/JNEUROSCI.0864-13.2014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 282NE UT WOS:000329177800005 PM 24381267 ER PT J AU Cheng, Q Yakel, JL AF Cheng, Qing Yakel, Jerrel L. TI Presynaptic alpha 7 Nicotinic Acetylcholine Receptors Enhance Hippocampal Mossy Fiber Glutamatergic Transmission via PKA Activation SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; PROTEIN-KINASE-A; EXCITATORY SYNAPTIC-TRANSMISSION; PREFRONTAL CORTEX; NERVE-TERMINALS; RAT HIPPOCAMPUS; COGNITIVE PERFORMANCE; ALLOSTERIC MODULATOR; TRANSMITTER RELEASE; KAINATE RECEPTORS AB Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory. However, the mechanism of nicotine's action on cognitive function remains elusive. We performed patch-clamp recordings from hippocampal CA3 pyramidal neurons to determine the effect of nicotine on mossy fiber glutamatergic synaptic transmission. We found that nicotine in combination with NS1738, an alpha 7 nAChR-positive allosteric modulator, strongly potentiated the amplitude of evoked EPSCs (eEPSCs), and reduced the EPSC paired-pulse ratio. The action of nicotine and NS1738 was mimicked by PNU-282987 (an alpha 7 nAChR agonist), and was absent in alpha 7 nAChR knock-out mice. These data indicate that activation of alpha 7 nAChRs was both necessary and sufficient to enhance the amplitude of eEPSCs. BAPTA applied postsynaptically failed to block the action of nicotine and NS1738, suggesting again a presynaptic action of the alpha 7 nAChRs. We also observed alpha 7 nAChR-mediated calcium rises at mossy fiber giant terminals, indicating the presence of functional alpha 7 nAChRs at presynaptic terminals. Furthermore, the addition of PNU-282987 enhanced action potential-dependent calcium transient at these terminals. Last, the potentiating effect of PNU-282987 on eEPSCs was abolished by inhibition of protein kinase A (PKA). Our findings indicate that activation of alpha 7 nAChRs at presynaptic sites, via a mechanism involving PKA, plays a critical role in enhancing synaptic efficiency of hippocampal mossy fiber transmission. C1 [Cheng, Qing; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, 111 TW Alexander Dr, Durham, NC 27709 USA. EM yakel@niehs.nih.gov FU National Institute of Environmental Health Sciences Intramural Research Program/National Institutes of Health FX This research was funded by the National Institute of Environmental Health Sciences Intramural Research Program/National Institutes of Health. We thank Pattie Lamb for genotyping and mouse colony management, and Jeff Tucker for technical support of confocal microscopy. We appreciate Drs. Georgia Alexander, Serena Dudek, and Christian Erxleben for the helpful reading and suggestions on this manuscript. NR 85 TC 19 Z9 20 U1 1 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 1 PY 2014 VL 34 IS 1 BP 124 EP 133 DI 10.1523/JNEUROSCI.2973-13.2014 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 282NE UT WOS:000329177800011 PM 24381273 ER PT J AU Nduom, EK Zhuang, ZP Lonser, RR AF Nduom, Edjah K. Zhuang, Zhengping Lonser, Russell R. TI Blood-brain barrier RESPONSE SO JOURNAL OF NEUROSURGERY LA English DT Letter C1 [Nduom, Edjah K.] Emory Univ, Atlanta, GA 30322 USA. [Nduom, Edjah K.; Zhuang, Zhengping; Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Lonser, Russell R.] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA. RP Nduom, EK (reprint author), Emory Univ, Atlanta, GA 30322 USA. FU Intramural NIH HHS [Z99 NS999999] NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD JAN PY 2014 VL 120 IS 1 BP 291 EP 291 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 281GL UT WOS:000329087900050 PM 24520575 ER PT J AU Shrestha, SS Liow, JS Lu, SY Jenko, K Gladding, RL Svenningsson, P Morse, CL Zoghbi, SS Pike, VW Innis, RB AF Shrestha, Stal Saurav Liow, Jeih-San Lu, Shuiyu Jenko, Kimberly Gladding, Robert L. Svenningsson, Per Morse, Cheryl L. Zoghbi, Sami S. Pike, Victor W. Innis, Robert B. TI C-11-CUMI-101, a PET Radioligand, Behaves as a Serotonin 1A Receptor Antagonist and Also Binds to alpha(1) Adrenoceptors in Brain SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE CUMI-101; 5-HT1A receptor; alpha(1) adrenoceptor; cross-reactivity; positron emission tomography (PET); S-35-GTP gamma S; homogenate binding ID IN-VIVO; 5-HT1A RECEPTORS; AGONIST; RADIOTRACER; ALPHA(1)-ADRENOCEPTOR; QUANTIFICATION; CONFOUNDS; AFFINITY; MONKEY AB The PET radioligand C-11-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT(1)A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.75 nM) for alpha(1) adrenoceptors measured in vitro. The current study examined the functional properties and selectivity of CUMI-101, both in vitro and in vivo. Methods: The functional assay was performed using S-35-GTP gamma S (GTP is guanosine triphosphate) in primate brains. The cross-reactivity of CUMI-101 with alpha(1) adrenoceptors was performed using in vitro radioligand binding studies in rat, monkey, and human brains as well as in vivo PET imaging in mouse, rat, and monkey brains. Results: CUMI-101 did not stimulate S-35-GTP gamma S binding in primate brain, in contrast to 8-OH-DPAT, a potent 5-HT1A receptor agonist. Instead, CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT-stimulated S-35-GTP gamma S binding. Both in vitro and in vivo studies showed that CUMI-101 had significant a1 adrenoceptor cross-reactivity. On average, across all 3 species examined, cross-reactivity was highest in the thalamus (>45%) and lowest in the neocortex and cerebellum (<10%). PET imaging further confirmed that only preblocking with WAY-100635 plus prazosin decreased C-11-CUMI-101 brain uptake to that of self-block. Conclusion: CUMI-101 behaves as a 5-HT1A receptor antagonist in primate brain, with significant, regional-dependent alpha(1) adrenoceptor cross-reactivity, limiting its potential use as a PET radioligand in humans. C1 [Shrestha, Stal Saurav; Liow, Jeih-San; Lu, Shuiyu; Jenko, Kimberly; Gladding, Robert L.; Morse, Cheryl L.; Zoghbi, Sami S.; Pike, Victor W.; Innis, Robert B.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Shrestha, Stal Saurav; Svenningsson, Per] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. RP Shrestha, SS (reprint author), NIH, 10 Ctr Dr B1D43, Bethesda, MD 20892 USA. EM saurav.shrestha@nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX We gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). PMOD Technologies (Zurich, Switzerland) graciously provided image analysis and modeling software. We thank Dr. Ramin Parsey and Dr. Victoria Arango for providing human brain tissues, Ioline Henter for excellent editorial assistance, Kacey Anderson for assisting with PET imaging, and the joint National Institutes of Health-Karolinska Institutet Doctoral Program in Neuroscience. NR 24 TC 6 Z9 7 U1 0 U2 4 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD JAN 1 PY 2014 VL 55 IS 1 BP 141 EP 146 DI 10.2967/jnumed.113.125831 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 282PG UT WOS:000329183600029 PM 24385311 ER PT J AU Guo, JX Guo, N Lang, LX Kiesewetter, DO Xie, QG Li, QZ Eden, HS Niu, G Chen, XY AF Guo, Jinxia Guo, Ning Lang, Lixin Kiesewetter, Dale O. Xie, Qingguo Li, Quanzheng Eden, Henry S. Niu, Gang Chen, Xiaoyuan TI F-18-Alfatide II and F-18-FDG Dual-Tracer Dynamic PET for Parametric, Early Prediction of Tumor Response to Therapy SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE dual-tracer dynamic PET; parametric imaging; F-18-alfatide II; F-18-FDG; therapy response ID POSITRON-EMISSION-TOMOGRAPHY; BLOOD-FLOW; INPUT FUNCTIONS; FDG-PET; CHEMOTHERAPY; FEASIBILITY; MICROPET; HYPOXIA; CANCER AB A single dynamic PET acquisition using multiple tracers administered closely in time could provide valuable complementary information about a tumor's status under quasiconstant conditions. This study aimed to investigate the utility of dual-tracer dynamic PET imaging with F-18-alfatide II (F-18-AlF-NOTA-E[PEG(4)-c(RGDfk)](2)) and F-18-FDG for parametric monitoring of tumor responses to therapy. Methods: We administered doxorubicin to one group of athymic nude mice with U87MG tumors and paclitaxel protein-bound particles to another group of mice with MDA-MB-435 tumors. To monitor therapeutic responses, we performed dual-tracer dynamic imaging, in sessions that lasted 90 min, starting with injection via the tail vein catheters with F-18-alfatide II, followed 40 min later by F-18-FDG. To achieve signal separation of the 2 tracers, we fit a 3-compartment reversible model to the time-activity curve of F-18-alfatide II for the 40 min before F-18-FDG injection and then extrapolated to 90 min. The F-18-FDG tumor time-activity curve was isolated from the 90min dual-tracer tumor time-activity curve by subtracting the fitted F-18-alfatide II tumor time-activity curve. With separated tumor time-activity curves, the F-18-alfatide II binding potential (Bp = k(3)/k(4)) and volume of distribution (VD) and F-18-FDG influx rate ((K-1 x k(3))/(k(2) + k(3))) based on the Patlak method were calculated to validate the signal recovery in a comparison with 60-min single-tracer imaging and to monitor therapeutic response. Results: The transport and binding rate parameters K-1-k(3) of F-18-alfatide II, calculated from the first 40 min of the dual-tracer dynamic scan, as well as Bp and VD correlated well with the parameters from the 60-min single-tracer scan (R-2 > 0.95). Compared with the results of single-tracer PET imaging, F-18-FDG tumor uptake and influx were recovered well from dualtracer imaging. On doxorubicin treatment, whereas no significant changes in static tracer uptake values of F-18-alfatide II or F-18-FDG were observed, both F-18-alfatide II Bp and F-18-FDG influx from kinetic analysis in tumors showed significant decreases. For therapy of MDA-MB-435 tumors with paclitaxel protein-bound particles, a significant decrease was observed only with F-18-alfatide II Bp value from kinetic analysis but not F-18-FDG influx. Conclusion: The parameters fitted with compartmental modeling from the dual-tracer dynamic imaging are consistent with those from single-tracer imaging, substantiating the feasibility of this methodology. Even though no significant differences in tumor size were found until 5 d after doxorubicin treatment started, at day 3 there were already substantial differences in F-18-alfatide II Bp and F-18-FDG influx rate. Dual-tracer imaging can measure F-18-alfatide II Bp value and F-18-FDG influx simultaneously to evaluate tumor angiogenesis and metabolism. Such changes are known to precede anatomic changes, and thus parametric imaging may offer the promise of early prediction of therapy response. C1 [Guo, Jinxia; Xie, Qingguo] Huazhong Univ Sci & Technol, Dept Biomed Engn, Wuhan 430074, Hubei, Peoples R China. [Guo, Jinxia; Xie, Qingguo] Huazhong Univ Sci & Technol, Wuhan Natl Lab Optoelect, Wuhan 430074, Hubei, Peoples R China. [Guo, Jinxia; Guo, Ning; Lang, Lixin; Kiesewetter, Dale O.; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, Natl Inst Hlth NIBIB, Bethesda, MD USA. [Guo, Jinxia; Guo, Ning] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen, Peoples R China. [Li, Quanzheng] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA 02138 USA. [Eden, Henry S.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, Natl Inst Hlth NIBIB, Bethesda, MD USA. RP Chen, XY (reprint author), NIH, 31 Ctr Dr,Suite 1C14, Bethesda, MD 20892 USA. EM niug@mail.nih.gov; shawn.chen@nih.gov FU National Key Basic Research Program (973 Project) [2013CB733802]; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported in part by National Key Basic Research Program (973 Project; 2013CB733802) and by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). No other potential conflict of interest relevant to this article was reported. NR 36 TC 12 Z9 13 U1 2 U2 19 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD JAN 1 PY 2014 VL 55 IS 1 BP 154 EP 160 DI 10.2967/jnumed.113.122069 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 282PG UT WOS:000329183600031 PM 24232871 ER PT J AU Shechner, T Rimon-Chakir, A Britton, JC Lotan, D Apter, A Bliese, PD Pine, DS Bar-Haim, Y AF Shechner, Tomer Rimon-Chakir, Adi Britton, Jennifer C. Lotan, Danny Apter, Alan Bliese, Paul D. Pine, Daniel S. Bar-Haim, Yair TI Attention Bias Modification Treatment Augmenting Effects on Cognitive Behavioral Therapy in Children With Anxiety: Randomized Controlled Trial SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE anxiety; attention bias; attention bias modification treatment (ABMT); cognitive behavioral therapy (CBT) ID EMOTIONAL DISORDERS; PEDIATRIC ANXIETY; ANXIOUS CHILDREN; CLINICAL-TRIAL; FOLLOW-UP; YOUTH; AUGMENTATION; INDIVIDUALS AB Objective: Attention bias modification treatment (ABMT) is a promising novel treatment for anxiety disorders, but clinical trials have focused largely on stand-alone formats among adults. This randomized controlled trial examined the augmenting effects of threat-based ABMT on cognitive behavioral therapy (CBT) in clinically anxious youth. Method: Sixty-three treatment-seeking children with anxiety disorder were randomly assigned to 1 of the following 3 treatment groups: ABMT + CBT; ABMT placebo + CBT; and CBT-alone. Participants in the 2 ABMT conditions received repeated training on dot-probe tasks either designed to shift attention away from threats (active) or designed to induce no changes in attention patterns (placebo). Primary outcome measures were frequency and severity of anxiety symptoms as determined by a clinician using a semi-structured interview. Self- and parent-rated anxiety measures and threat-related attention bias scores were also measured before and after treatment. Results: Both the active and placebo ABMT groups showed greater reductions in clinician-rated anxiety symptoms than the CBT-alone group. Furthermore, only the active ABMT group showed significant reduction in self- or parent-rated anxiety symptoms. Finally, all groups showed a shift in attention patterns across the study, starting with a bias toward threat at baseline and shifting attention away from threat after treatment. Conclusions: Active and placebo ABMT might augment the clinical response to CBT for anxiety. This effect could arise from benefits associated with performing computer-based paradigms such as the dot-probe task. Given the absence of group differences in attention-bias changes during treatment, possible mechanisms and methodological issues underlying the observed findings are discussed. Clinical trial registration information Augmenting Effects of ABMT on CBT in Anxious Children: A Randomized Clinical Trial; http://clinicaltrials.gov/; NCT01730625. C1 [Shechner, Tomer] Univ Haifa, IL-3498838 Haifa, Israel. [Rimon-Chakir, Adi; Bar-Haim, Yair] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Britton, Jennifer C.] Univ Miami, Coral Gables, FL 33124 USA. [Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. RP Shechner, T (reprint author), Univ Haifa, Psychol Dept, IL-3498838 Haifa, Israel. FU Adler Center for Research in Child Development and Psychopathology; National Institutes of Health FX This study was partially supported by a grant from the Adler Center for Research in Child Development and Psychopathology to Dr. Bar-Haim and by the National Institutes of Health intramural research program. NR 29 TC 35 Z9 36 U1 1 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JAN PY 2014 VL 53 IS 1 BP 61 EP 71 DI 10.1016/j.jaac.2013.09.016 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 280GG UT WOS:000329016100008 PM 24342386 ER PT J AU Scahill, L Dimitropoulos, A McDougle, CJ Aman, MG Feurer, ID McCracken, JT Tierney, E Pu, J White, S Lecavalier, L Hallett, V Bearss, K King, B Arnold, LE Vitiello, B AF Scahill, Lawrence Dimitropoulos, Anastasia McDougle, Christopher J. Aman, Michael G. Feurer, Irene D. McCracken, James T. Tierney, Elaine Pu, Jie White, Susan Lecavalier, Luc Hallett, Victoria Bearss, Karen King, Bryan Arnold, L. Eugene Vitiello, Benedetto TI Children's Yale-Brown Obsessive Compulsive Scale in Autism Spectrum Disorder: Component Structure and Correlates of Symptom Checklist SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE autism spectrum disorder; clinical trials; outcome measures; repetitive behavior ID PERVASIVE DEVELOPMENTAL DISORDERS; SERIOUS BEHAVIORAL-PROBLEMS; REPETITIVE BEHAVIOR; RISPERIDONE; QUESTIONNAIRE; RELIABILITY; VALIDATION; INTERVIEW; TRIAL; SELF AB Objective: Repetitive behaviors in autism spectrum disorders (ASD) range from motor stereotypy to immersion in restricted interests. The modified Children's Yale Brown Obsessive Compulsive Scale for children with autism spectrum disorder (CYBOCS-ASD) includes a Symptom Checklist (behavior present or absent) and 5 severity scales (Time Spent, Interference, Distress, Resistance and Control). Method: We assembled CYBOCS-ASD data from 3 Research Units on Pediatric Psychopharmacology Autism Network trials to explore the component structure of repetitive behaviors in children with ASD. Raters trained to reliability conducted the CYBOCS-ASD in 272 medication-free subjects. Fifteen Symptom Checklist items were endorsed for less than 5% of the sample and were dropped. Principal component analysis was used to explore the clustering of 23 checklist items. Component scores computed for each subject were correlated with other measures. We also examined the distribution of severity scales. Results: The subjects (229 boys and 43 girls; mean age = 7.8 +/- 2.6 years) met criteria for an ASD; half were intellectually disabled. The PCA resulted in a 5-component solution to classify repetitive behaviors (34.4% of the variance): hoarding and ritualistic behavior; sensory and arranging behavior; sameness and self-injurious behavior; stereotypy; restricted interests. Sensory and arranging and stereotypy components were associated with lower adaptive functioning (Pearson r = 0.2-0.3; p < .003). The resistance scale showed little variation, with more than 60% of the sample with the highest score. Conclusions: Rarely endorsed items can be dropped from the Checklist. The resistance item does not appear to be relevant for children with ASD. C1 [Scahill, Lawrence; Bearss, Karen] Emory Univ, Atlanta, GA 30322 USA. [Dimitropoulos, Anastasia] Case Western Reserve Univ, Cleveland, OH 44106 USA. [McDougle, Christopher J.] Harvard Univ, Cambridge, MA 02138 USA. [Aman, Michael G.; Lecavalier, Luc; Arnold, L. Eugene] Ohio State Univ, Columbus, OH 43210 USA. [Feurer, Irene D.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [McCracken, James T.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Tierney, Elaine] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Pu, Jie] Univ Arizona, Tucson, AZ 85721 USA. [White, Susan] Virginia Polytech Univ, Blacksburg, VA 24061 USA. [Hallett, Victoria] Kings Coll London, London WC2R 2LS, England. [King, Bryan] Univ Washington, Seattle, WA 98195 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD USA. RP Scahill, L (reprint author), Marcus Ctr, 1920 Briarcliff Rd, Atlanta, GA 30329 USA. EM lawrence.scahill@emory.edu OI Scahill, Lawrence/0000-0001-5073-1707 FU NIMH by Research Unit on Pediatric Psychopharmacology (RUPP), Yale [U10MH66764]; NIMH by Research Unit on Pediatric Psychopharmacology (RUPP), Indiana University [U10MH66766]; NIMH by Research Unit on Pediatric Psychopharmacology (RUPP), Ohio, State University [U10MH66768]; Yale CTSA from the National Center for Research Resources (NCRR) [UL1 RR024139]; IU CTSA from the National Center for Research Resources (NCRR) [UL1 RR025761]; OSU CTSA from the National Center for Research Resources (NCRR) [UL1 RR025755] FX This work was funded by NIMH by the following Research Units on Pediatric Psychopharmacology (RUPP) grants: Yale, U10MH66764; Indiana University, U10MH66766, and Ohio, State University, U10MH66768. This publication was also supported by the Yale CTSA, UL1 RR024139, IU CTSA UL1 RR025761, OSU CTSA UL1 RR025755 from the National Center for Research Resources (NCRR). NR 35 TC 6 Z9 7 U1 2 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JAN PY 2014 VL 53 IS 1 BP 97 EP 107 DI 10.1016/j.jaac.2013.09.018 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 280GG UT WOS:000329016100011 PM 24342389 ER PT J AU Karlsson, EM Pearson, LM Kuzma, KM Burkholder, TH AF Karlsson, Eleanor M. Pearson, Laura M. Kuzma, Kristen M. Burkholder, Tanya H. TI Combined Evaluation of Commonly Used Techniques, Including PCR, for Diagnosis of Mouse Fur Mites SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID MYOBIA-MUSCULI; MYOCOPTES-MUSCULINUS; MURINE ACARIASIS; INFECTIOUS AGENTS; PARASITIC ECOLOGY; RODENT MITE; MICE; INFESTATION; MOXIDECTIN; IVERMECTIN AB Our study evaluated and compared the false-negative rates (FNR) of a wide array of fur-mite diagnostic tests, including 2 postmortem tests (pelt exam and sticky paper) and 3 antemortem tests (adhesive tape, fur pluck, and PCR). Past publications examining fur-mite diagnostic techniques primarily used paired comparisons, evaluating tests by their level of agreement with only one other test. However, different combinations or pairs of diagnostics are used in the different studies, making the results of these comparisons difficult to interpret across all available diagnostics. In the current study, mice from a conventionally maintained colony endemic for Myobia musculi were identified as positive based on at least one positive diagnostic test. From this pool of positive animals, the FNR of all tests were quantified. The PCR assay and the pelt exam performed the best, with 0% and 2% FNR respectively, whereas tape, fur-pluck, and sticky-paper tests showed 24%, 26%, and 36% FNR, respectively. Our study shows that for mice in a colony naturally infested with Myobia musculi, PCR testing can be used for reliable antemortem detection, and pelt exam performed by experienced examiners is reliable for postmortem detection. C1 [Karlsson, Eleanor M.; Pearson, Laura M.; Kuzma, Kristen M.; Burkholder, Tanya H.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Karlsson, EM (reprint author), NIH, Div Vet Resources, Off Res Serv, Bldg 10, Bethesda, MD 20892 USA. EM ellie.m.karlsson@gmail.com FU Division of Veterinary Resources; Office of Research Services; NIH FX This study was supported by the Division of Veterinary Resources, Office of Research Services, and NIH. NR 38 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD JAN PY 2014 VL 53 IS 1 BP 69 EP 73 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 283UO UT WOS:000329272700010 PM 24411782 ER PT J AU Shaikh, Q Kamal, AK AF Shaikh, Quratulain Kamal, Ayeesha Kamran TI Can prophylactic antibiotics for aspiration improve stroke outcomes? The PANTHERIS trial SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv & Vasc Fellowship Program, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stroke Serv & Vasc Fellowship Program, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43 TW008660] NR 1 TC 0 Z9 0 U1 0 U2 1 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD JAN PY 2014 VL 64 IS 1 BP 98 EP 98 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 283OZ UT WOS:000329257900027 PM 24605726 ER PT J AU Liu, SW Wyatt, LS Orandle, MS Minai, M Moss, B AF Liu, Shin-Wu Wyatt, Linda S. Orandle, Marlene S. Minai, Mahnaz Moss, Bernard TI The D10 Decapping Enzyme of Vaccinia Virus Contributes to Decay of Cellular and Viral mRNAs and to Virulence in Mice SO JOURNAL OF VIROLOGY LA English DT Article ID HOST SHUTOFF PROTEIN; GENE-EXPRESSION; MICROARRAY ANALYSIS; DENDRITIC CELLS; WILD-TYPE; IN-VIVO; INFECTION; REVEALS; REPLICATION; DEGRADATION AB Posttranscriptional mechanisms are important for regulation of cellular and viral gene expression. The presence of the 5' cap structure m(7)G(5') ppp(5') Nm is a general feature of mRNAs that provides protection from exoribonuclease digestion and enhances translation. Vaccinia virus and other poxviruses encode enzymes for both cap synthesis and decapping. Decapping is mediated by two related enzymes, D9 and D10, which are synthesized before and after viral DNA replication, respectively. The timing of D10 synthesis correlates better with the shutdown of host gene expression, and deletion of this gene has been shown to cause persistence of host and viral mRNAs in infected cells. Here, we constructed specific mutant viruses in which translation of D10 was prevented by stop codons or activity of D10 was abrogated by catalytic site mutations, without other genomic alterations. Both mutants formed plaques of normal size and replicated to similar extents as the parental virus in monkey epithelial cells and mouse embryonic fibroblasts. The synthesis of viral proteins was slightly delayed, and cellular and viral mRNAs persisted longer in cells infected with the mutants compared to either the parental virus or clonal revertant. Despite the mild effects in vitro, both mutants were more attenuated than the revertants in intranasal and intraperitoneal mouse models, and less infectious virus was recovered from organs. In addition, there was less lung histopathology following intranasal infection with mutant viruses. These data suggest that the D10 decapping enzyme may help restrict antiviral responses by accelerating host mRNA degradation during poxvirus infection. C1 [Liu, Shin-Wu; Wyatt, Linda S.; Moss, Bernard] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Orandle, Marlene S.; Minai, Mahnaz] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Rockville, MD USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX The research was supported by the Division of Intramural Research, NIAID, NIH. NR 55 TC 12 Z9 12 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2014 VL 88 IS 1 BP 202 EP 211 DI 10.1128/JVI.02426-13 PG 10 WC Virology SC Virology GA 282SW UT WOS:000329194600018 PM 24155373 ER PT J AU Fenizia, C Fiocchi, M Jones, K Parks, RW Ceribelli, M Chevalier, SA Edwards, D Ruscetti, F Pise-Masison, CA Franchini, G AF Fenizia, Claudio Fiocchi, Martina Jones, Kathryn Parks, Robyn Washington Ceribelli, Michele Chevalier, Sebastien A. Edwards, Dustin Ruscetti, Francis Pise-Masison, Cynthia A. Franchini, Genoveffa TI Human T-Cell Leukemia/Lymphoma Virus Type 1 p30, but Not p12/p8, Counteracts Toll-Like Receptor 3 (TLR3) and TLR4 Signaling in Human Monocytes and Dendritic Cells SO JOURNAL OF VIROLOGY LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; INTERFERON REGULATORY FACTOR-3; LEUKEMIA-VIRUS; HTLV-I; GENE-EXPRESSION; HUMAN MACROPHAGES; ALPHA/BETA INTERFERON; INFECTION; ACTIVATION; PROTEIN AB The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) p30 protein, essential for virus infectivity in vivo, is required for efficient infection of human dendritic cells (DCs) but not B and T cells in vitro. We used a human monocytic cell line, THP-1, and dendritic cells to study the mechanism of p30 and p12/p8 requirements in these cell types. p30 inhibited the expression of interferon (IFN)-responsive genes (ISG) following stimulation by lipopolysaccharide (LPS) of Toll-like receptor 4 (TLR4) and by poly(I.C) of TLR3 but not of TLR7/8 with imiquimod. Results with THP-1 mirrored those for ex vivo human primary monocytes and monocyte-derived dendritic cells (Mo-mDC). The effect of p30 on TLR signaling was also demonstrated by ablating its expression within a molecular clone of HTLV-1. HTLV-1 infection of monocytes inhibited TLR3- and TLR4-induced ISG expression by 50 to 90% depending on the genes, whereas the isogenic clone p30 knockout virus was less effective at inhibiting TLR3 and TRL4 signaling and displayed lower infectivity. Viral expression and inhibition of ISG transcription was, however, rescued by restoration of p30 expression. A chromatin immunoprecipitation assay demonstrated that p30 inhibits initiation and elongation of PU.1-dependent transcription of IFN-alpha 1, IFN-beta, and TLR4 genes upon TLR stimulation. In contrast, experiments conducted with p12/p8 did not demonstrate an effect on ISG expression. These results provide a mechanistic explanation of the requirement of p30 for HTLV-1 infectivity in vivo, suggest that dampening interferon responses in monocytes and DCs is specific for p30, and represent an essential early step for permissive HTLV-1 infection and persistence. C1 [Fenizia, Claudio; Parks, Robyn Washington; Edwards, Dustin; Pise-Masison, Cynthia A.; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20892 USA. [Fiocchi, Martina] UNIMI, LITA Vialba, Immunol Lab, Milan, Italy. [Jones, Kathryn] NCI, Basic Res Program, SAIC Frederick Inc, NIH, Frederick, MD 21701 USA. [Chevalier, Sebastien A.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ruscetti, Francis] NCI, Expt Immunol Lab, CCR, Frederick, MD 21701 USA. [Ceribelli, Michele] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, NIH, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov NR 55 TC 6 Z9 6 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2014 VL 88 IS 1 BP 393 EP 402 DI 10.1128/JVI.01788-13 PG 10 WC Virology SC Virology GA 282SW UT WOS:000329194600035 PM 24155397 ER PT J AU Koganti, S de la Paz, A Freeman, AF Bhaduri-McIntosh, S AF Koganti, Siva de la Paz, Amanda Freeman, Alexandra F. Bhaduri-McIntosh, Sumita TI B Lymphocytes from Patients with a Hypomorphic Mutation in STAT3 Resist Epstein-Barr Virus-Driven Cell Proliferation SO JOURNAL OF VIROLOGY LA English DT Article ID HYPER-IGE SYNDROME; ELEMENT-BINDING PROTEIN; SIGNAL TRANSDUCER; GENE-EXPRESSION; VIRAL GENOME; EARLY EVENTS; TRANSCRIPTION; ACTIVATION; INFECTION; DIFFERENTIATION AB Epstein-Barr virus (EBV) oncogenes exert potent B cell proliferative effects. EBV infection gives rise to B cell lines that readily proliferate in culture. This ability of EBV represents a powerful tool to study cell proliferation. In efforts to delineate the contribution of signal transducer and activator of transcription 3 (STAT3) toward EBV-driven cell proliferation, we have discovered that B cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES) resist such EBV oncogene-driven outgrowth of cells. Patients with AD-HIES have a dominant negative mutation in their STAT3 gene which renders most of the protein nonfunctional. Exposure of healthy subject-derived B cells to EBV resulted in early activation of STAT3, rapidly followed by increased expression of its mRNA and protein. STAT3 upregulation preceded the expression of EBNA2, temporally one of the first viral oncogenes to be expressed. We found that STAT3 was necessary for subsequent survival and for proliferation of EBV-infected cells past the S phase of the cell cycle. Consequently, B cells from AD-HIES patients were prone to dying and accumulated in the S phase, thereby accounting for impaired cell outgrowth. Of importance, we have now identified a cohort of patients with a primary immunodeficiency disorder whose B cells oppose EBV-driven proliferative signals. These findings simultaneously reveal how EBV manipulates host STAT3 even before expression of viral oncogenes to facilitate cell survival and proliferation, processes fundamental to EBV lymphomagenesis. C1 [Koganti, Siva; Bhaduri-McIntosh, Sumita] SUNY Stony Brook, Sch Med, Dept Pediat, Stony Brook, NY 11794 USA. [Koganti, Siva; Bhaduri-McIntosh, Sumita] SUNY Stony Brook, Sch Med, Stony Brook Childrens Hosp, Stony Brook, NY 11794 USA. [de la Paz, Amanda] Thomas Jefferson Univ, Dept Family & Community Med, Philadelphia, PA 19107 USA. [Freeman, Alexandra F.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Bhaduri-McIntosh, Sumita] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. RP Bhaduri-McIntosh, S (reprint author), SUNY Stony Brook, Sch Med, Dept Pediat, Stony Brook, NY 11794 USA. EM sumita.bhaduri-mcintosh@stonybrookmedicine.edu FU The Research Foundation for The State University of New York; [K08 AI062732]; [K12 HD001401]; [1UL1RR024139-02] FX This study was supported by K08 AI062732, K12 HD001401, 1UL1RR024139-02, and funds from The Research Foundation for The State University of New York to S. B.-M. NR 47 TC 8 Z9 9 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2014 VL 88 IS 1 BP 516 EP 524 DI 10.1128/JVI.02601-13 PG 9 WC Virology SC Virology GA 282SW UT WOS:000329194600047 PM 24173212 ER PT J AU Nguyen, HT Shukla, P Torian, U Faulk, K Emerson, SU AF Nguyen, H. T. Shukla, P. Torian, U. Faulk, K. Emerson, S. U. TI Hepatitis E Virus Genotype 1 Infection of Swine Kidney Cells In Vitro Is Inhibited at Multiple Levels SO JOURNAL OF VIROLOGY LA English DT Article ID RECEPTOR-BINDING; CULTURE-SYSTEM; ORF3 PROTEIN; REPLICATION; RECOMBINANT; DISCOVERY; PRIMATES; HEPATOMA; RELEASE; DEPENDS AB Genotype 1 hepatitis E viruses (HEVs) are restricted to primate hosts, whereas genotype 3 HEVs predominantly infect swine, in addition to primates. In order to identify possible determinants of the host range, infectious recombinant viruses and chimeras of a genotype 1 isolate and a genotype 3 isolate were compared for their ability to infect versus transfect cultured human HepG2/C3A cells and swine LLC-PK cells. The patterns of luciferase expression from virus replicons containing the Gaussia luciferase gene in place of the viral ORF2 or ORF3 genes demonstrated that translation of the ORF2 capsid gene of genotype 1 virus is severely inhibited in swine kidney cells compared to its translation in rhesus macaque kidney or human liver cells. Therefore, this virus may produce insufficient capsid protein for optimal assembly in swine cells. Infectivity assays with a virus containing a chimeric capsid protein confirmed that amino acids 456 to 605 of the virus capsid protein comprised the virus receptor-binding region and suggested that genotype 1 viruses may be prevented from infecting swine because genotype 1 viruses are unable to enter swine cells. Rhesus macaque cells appeared to be better than human cells for growing the genotype 1 virus. These cell and virus combinations may serve as a useful in vitro model with which to study determinants of the natural host range of this virus. C1 [Nguyen, H. T.; Shukla, P.; Torian, U.; Emerson, S. U.] NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Faulk, K.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 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 Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 30 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2014 VL 88 IS 2 BP 868 EP 877 DI 10.1128/JVI.02205-13 PG 10 WC Virology SC Virology GA 282SY UT WOS:000329194900011 PM 24198420 ER PT J AU Chen, WZ Feng, Y Prabakaran, P Ying, TL Wang, YP Sun, JP Macedo, CDS Zhu, ZY He, YX Polonis, VR Dimitrov, DS AF Chen, Weizao Feng, Yang Prabakaran, Ponraj Ying, Tianlei Wang, Yanping Sun, Jianping Macedo, Camila D. S. Zhu, Zhongyu He, Yuxian Polonis, Victoria R. Dimitrov, Dimiter S. TI Exceptionally Potent and Broadly Cross-Reactive, Bispecific Multivalent HIV-1 Inhibitors Based on Single Human CD4 and Antibody Domains SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; IMMUNODEFICIENCY-VIRUS TYPE-1; GP120 ENVELOPE GLYCOPROTEIN; AIDS-RELATED COMPLEX; HUMAN SOLUBLE CD4; CRYSTAL-STRUCTURE; T-CELLS; PHASE-I; NEUTRALIZING ANTIBODIES; HYDROPHOBIC CORE AB Soluble forms of the human immunodeficiency virus type 1 (HIV-1) primary receptor CD4 (soluble CD4 [sCD4]) have been extensively characterized for a quarter of a century as promising HIV-1 inhibitors, but they have not been clinically successful. By combining a protein cavity-filling strategy and the power of library technology, we identified an engineered cavity-altered single-domain sCD4 (mD1.22) with a unique combination of excellent properties, including broad and potent neutralizing activity, high specificity, stability, solubility, and affinity for the HIV-1 envelope glycoprotein gp120, and small molecular size. To further improve its neutralizing potency and breadth, we generated bispecific multivalent fusion proteins of mD1.22 with another potent HIV-1 inhibitor, an antibody domain (m36.4) that targets the coreceptor-binding site on gp120. The fusion proteins neutralized all HIV-1 isolates tested, with potencies about 10-, 50-, and 200-fold higher than those of the broadly neutralizing antibody VRC01, the U. S. FDA-approved peptide inhibitor T20, and the clinically tested sCD4-Fc fusion protein CD4-Ig, respectively. In addition, they exhibited higher stability and specificity and a lower aggregation propensity than CD4-Ig. Therefore, mD1.22 and related fusion proteins could be useful for HIV-1 prevention and therapy, including eradication of the virus. C1 [Chen, Weizao; Feng, Yang; Prabakaran, Ponraj; Ying, Tianlei; Wang, Yanping; Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Prabakaran, Ponraj; Wang, Yanping] NCI, Basic Res Program, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc,NIH, Frederick, MD 21701 USA. [Sun, Jianping; He, Yuxian] Chinese Acad Med Sci, Inst Pathogen Biol, MOH Key Lab Syst Biol Pathogens, Beijing 100730, Peoples R China. [Sun, Jianping; He, Yuxian] Chinese Acad Med Sci, Inst Pathogen Biol, AIDS Res Ctr, Beijing 100730, Peoples R China. [Sun, Jianping; He, Yuxian] Peking Union Med Coll, Beijing 100021, Peoples R China. [Macedo, Camila D. S.] Henry M Jackson Fdn, Bethesda, MD USA. [Macedo, Camila D. S.; Polonis, Victoria R.] Walter Reed Army Inst Res, Mil HIV Res Program, Silver Spring, MD USA. RP Chen, WZ (reprint author), NCI, Prot Interact Grp, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM chenw3@mail.nih.gov; dimiter.dimitrov@nih.gov FU Intramural AIDS Targeted Antiviral Program (IATAP) of the National Institutes of Health (NIH); Intramural Research Program of the NIH; National Cancer Institute (NCI), Center for Cancer Research; NIH NCI [NO1-CO-12400]; U.S.-China Program for Biomedical Research Cooperation; Natural Science Foundation of China [81025009, 81271830] FX This project was supported by the Intramural AIDS Targeted Antiviral Program (IATAP) of the National Institutes of Health (NIH), the Intramural Research Program of the NIH, National Cancer Institute (NCI), Center for Cancer Research, federal funds from the NIH NCI under contract number NO1-CO-12400, the U.S.-China Program for Biomedical Research Cooperation, and grants to Y.H. (81025009 and 81271830) from the Natural Science Foundation of China. NR 71 TC 11 Z9 11 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2014 VL 88 IS 2 BP 1125 EP 1139 DI 10.1128/JVI.02566-13 PG 15 WC Virology SC Virology GA 282SY UT WOS:000329194900034 PM 24198429 ER PT J AU Sun, M Grigsby, IF Gorelick, RJ Mansky, LM Musier-Forsyth, K AF Sun, Meng Grigsby, Iwen F. Gorelick, Robert J. Mansky, Louis M. Musier-Forsyth, Karin TI Retrovirus-Specific Differences in Matrix and Nucleocapsid Protein-Nucleic Acid Interactions: Implications for Genomic RNA Packaging SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GAG MEMBRANE-BINDING; HIV-1 GAG; IN-VITRO; FLUORESCENCE POLARIZATION; ENCAPSIDATION SIGNAL; CHAPERONE ACTIVITY; PLASMA-MEMBRANE; ZINC-FINGER; AMINO-ACIDS AB Retroviral RNA encapsidation involves a recognition event between genomic RNA (gRNA) and one or more domains in Gag. In HIV-1, the nucleocapsid (NC) domain is involved in gRNA packaging and displays robust nucleic acid (NA) binding and chaperone functions. In comparison, NC of human T-cell leukemia virus type 1 (HTLV-1), a deltaretrovirus, displays weaker NA binding and chaperone activity. Mutation of conserved charged residues in the deltaretrovirus bovine leukemia virus (BLV) matrix (MA) and NC domains affects virus replication and gRNA packaging efficiency. Based on these observations, we hypothesized that the MA domain may generally contribute to NA binding and genome encapsidation in deltaretroviruses. Here, we examined the interaction between HTLV-2 and HIV-1 MA proteins and various NAs in vitro. HTLV-2 MA displays higher NA binding affinity and better chaperone activity than HIV-1 MA. HTLV-2 MA also binds NAs with higher affinity than HTLV-2 NC and displays more robust chaperone function. Mutation of two basic residues in HTLV-2 MA alpha-helix II, previously implicated in BLV gRNA packaging, reduces NA binding affinity. HTLV-2 MA binds with high affinity and specificity to RNA derived from the putative packaging signal of HTLV-2 relative to nonspecific NA. Furthermore, an HIV-1 MA triple mutant designed to mimic the basic character of HTLV-2 MA alpha-helix II dramatically improves binding affinity and chaperone activity of HIV-1 MA in vitro and restores RNA packaging to a Delta NC HIV-1 variant in cell-based assays. Taken together, these results are consistent with a role for deltaretrovirus MA proteins in viral RNA packaging. C1 [Sun, Meng; Musier-Forsyth, Karin] Ohio State Univ, Ctr Retroviral Res, Dept Chem & Biochem, Columbus, OH 43210 USA. [Sun, Meng; Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. [Grigsby, Iwen F.; Mansky, Louis M.] Univ Minnesota, Sch Dent & Med Sch, Inst Mol Virol, Dept Diagnost, Minneapolis, MN USA. [Grigsby, Iwen F.; Mansky, Louis M.] Univ Minnesota, Sch Dent & Med Sch, Dept Biol Sci & Microbiol, Minneapolis, MN USA. [Gorelick, Robert J.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Leidos Biomed Res Inc, Frederick, MD USA. RP Musier-Forsyth, K (reprint author), Ohio State Univ, Ctr Retroviral Res, Dept Chem & Biochem, Columbus, OH 43210 USA. EM musier@chemistry.ohio-state.edu FU NIH, National Cancer Institute; Center for Cancer Research; NIH [GM065056, GM098500]; National Cancer Institute, National Institutes of Health, [HHSN261200800001E]; Leidos Biomedical Research, Inc. FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by NIH grants GM065056 (to K.M.-F.) and GM098500 (to L.M.M.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with Leidos Biomedical Research, Inc. (R.J.G.). NR 60 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 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2014 VL 88 IS 2 BP 1271 EP 1280 DI 10.1128/JVI.02151-13 PG 10 WC Virology SC Virology GA 282SY UT WOS:000329194900044 PM 24227839 ER PT J AU Sunshine, J Kim, M Carlson, JM Heckerman, D Czartoski, J Migueles, SA Maenza, J McElrath, MJ Mullins, JI Frahm, N AF Sunshine, Justine Kim, Moon Carlson, Jonathan M. Heckerman, David Czartoski, Julie Migueles, Stephen A. Maenza, Janine McElrath, M. Juliana Mullins, James I. Frahm, Nicole TI Increased Sequence Coverage through Combined Targeting of Variant and Conserved Epitopes Correlates with Control of HIV Replication SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; IMMUNE-RESPONSES; LYMPHOCYTE RESPONSE; DISEASE PROGRESSION; PRIMARY INFECTION; TYPE-1 INFECTION; RHESUS-MONKEYS; VIRAL LOAD; ESCAPE AB A major challenge in the development of an HIV vaccine is that of contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions and induction of HIV-specific T-cell responses recognizing a high number of epitope variants have both been proposed as strategies to overcome this challenge. We addressed the ability of cytotoxic T lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1,300 peptides) using gamma interferon and interleukin-2 (IFN-gamma/IL-2) FluoroSpot analysis. While targeting of conserved regions was similar in the two groups (P = 0.47), we found that subjects with control of virus replication demonstrated marginally lower recognition of Gag epitope variants than subjects with normal progression (P = 0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (r = 0.62, P = 0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (r = -0.38, P = 0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (r = 0.50, P = 0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure by which to evaluate the protective potential of future vaccination strategies. C1 [Sunshine, Justine; McElrath, M. Juliana; Frahm, Nicole] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Kim, Moon; Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Maenza, Janine; McElrath, M. Juliana; Mullins, James I.] Univ Washington, Dept Med, Seattle, WA USA. [McElrath, M. Juliana; Mullins, James I.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Carlson, Jonathan M.; Heckerman, David] Microsoft Res, eSci Grp, Los Angeles, CA USA. [Czartoski, Julie; McElrath, M. Juliana; Frahm, Nicole] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Migueles, Stephen A.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Frahm, N (reprint author), Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. EM nfrahm@fhcrc.org FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R21AI078809, T32AI007140, P01AI057005, R01AI047086, UM1AI068618] FX Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R21AI078809, T32AI007140, P01AI057005, R01AI047086, and UM1AI068618. NR 68 TC 5 Z9 5 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2014 VL 88 IS 2 BP 1354 EP 1365 DI 10.1128/JVI.02361-13 PG 12 WC Virology SC Virology GA 282SY UT WOS:000329194900051 PM 24227851 ER PT J AU Liu, XQ Cohen, JI AF Liu, XueQiao Cohen, Jeffrey I. TI Inhibition of Bim Enhances Replication of Varicella-Zoster Virus and Delays Plaque Formation in Virus-Infected Cells SO JOURNAL OF VIROLOGY LA English DT Article ID PROTEIN-KINASE; BLOCKS APOPTOSIS; GLYCOPROTEIN-D; BAD; PHOSPHORYLATION; SURVIVAL; ERK; PATHWAY; ACTIVATION; RESISTANCE AB Programmed cell death (apoptosis) is an important host defense mechanism against intracellular pathogens, such as viruses. Accordingly, viruses have evolved multiple mechanisms to modulate apoptosis to enhance replication. Varicella-zoster virus (VZV) induces apoptosis in human fibroblasts and melanoma cells. We found that VZV triggered the phosphorylation of the proapoptotic proteins Bim and BAD but had little or no effect on other Bcl-2 family members. Since phosphorylation of Bim and BAD reduces their proapoptotic activity, this may prevent or delay apoptosis in VZV-infected cells. Phosphorylation of Bim but not BAD in VZV-infected cells was dependent on activation of the MEK/extracellular signal-regulated kinase (ERK) pathway. Cells knocked down for Bim showed delayed VZV plaque formation, resulting in longer survival of VZV-infected cells and increased replication of virus, compared with wild-type cells infected with virus. Conversely, overexpression of Bim resulted in earlier plaque formation, smaller plaques, reduced virus replication, and increased caspase 3 activity. Inhibition of caspase activity in VZV-infected cells overexpressing Bim restored levels of virus production similar to those seen with virus-infected wildtype cells. Previously we showed that VZV ORF12 activates ERK and inhibits apoptosis in virus-infected cells. Here we found that VZV ORF12 contributes to Bim and BAD phosphorylation. In summary, VZV triggers Bim phosphorylation; reduction of Bim levels results in longer survival of VZV-infected cells and increased VZV replication. C1 [Liu, XueQiao; Cohen, Jeffrey I.] NIH, Infect Dis Lab, Med Virol Sect, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Infect Dis Lab, Med Virol Sect, 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 61 TC 2 Z9 3 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN PY 2014 VL 88 IS 2 BP 1381 EP 1388 DI 10.1128/JVI.01695-13 PG 8 WC Virology SC Virology GA 282SY UT WOS:000329194900053 PM 24227856 ER PT J AU Hillengass, J Weber, MA Kilk, K Listl, K Wagner-Gund, B Hillengass, M Hielscher, T Farid, A Neben, K Delorme, S Landgren, O Goldschmidt, H AF Hillengass, J. Weber, M-A Kilk, K. Listl, K. Wagner-Gund, B. Hillengass, M. Hielscher, T. Farid, A. Neben, K. Delorme, S. Landgren, O. Goldschmidt, H. TI Prognostic significance of whole-body MRI in patients with monoclonal gammopathy of undetermined significance SO LEUKEMIA LA English DT Article DE monoclonal gammopathy of undetermined significance; whole body magnetic resonance imaging; prognosis; focal lesions ID ASYMPTOMATIC MULTIPLE-MYELOMA; BONE-MARROW; SIGNIFICANCE MGUS; COMPETING RISK; PROGRESSION; DISEASE; INFILTRATION; ENHANCEMENT; POPULATION; PATTERNS AB Radiological skeletal survey or computed tomography are currently applied to assess bone diseases in patients with monoclonal plasma cell disorders. Whole-body magnetic resonance imaging (whole-body MRI) allows detecting the infiltration of clonal cells in nearly the whole bone marrow compartment even before bone destruction has occurred. Those MRI results (i.e., patterns of bone marrow infiltration) have been demonstrated to be of prognostic significance in patients with symptomatic as well as asymptomatic multiple myeloma. We have therefore analyzed the findings of whole-body MRI in 137 consecutive individuals with monoclonal gammopathy of undetermined significance (MGUS). A focal infiltration pattern was detected in 23.4% of patients. Presence and number of focal lesions as well as value of M-Protein were of independent prognostic significance for progression into a symptomatic disease requiring systemic treatment (P = 0.02; P<0.0001 and P = 0.0005, respectively). Lower homogeneous signal intensities in T1-weighted images were related to a physiologically higher bone marrow cellularity in younger individuals (P = 0.002). We conclude that whole-body MRI identifies patients with focal accumulations of presumably monoclonal cells in bone marrow with prognostic impact concerning the risk of progression into symptomatic disease. C1 [Hillengass, J.; Wagner-Gund, B.; Hillengass, M.; Farid, A.; Neben, K.; Goldschmidt, H.] Heidelberg Univ, Dept Hematol & Oncol, D-69120 Heidelberg, Germany. [Hillengass, J.; Delorme, S.] German Canc Res Ctr, Dept Radiol, Heidelberg, Germany. [Weber, M-A; Kilk, K.; Listl, K.] Heidelberg Univ, Dept Diagnost & Intervent Radiol, D-69120 Heidelberg, Germany. [Hielscher, T.] German Canc Res Ctr, Dept Biostat, Heidelberg, Germany. [Landgren, O.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Goldschmidt, H.] Natl Ctr Tumor Dis, Heidelberg, Germany. RP Hillengass, J (reprint author), Heidelberg Univ, Dept Hematol & Oncol, Neuenheimer Feld 410, D-69120 Heidelberg, Germany. EM Jens.hillengass@med.uni-heidelberg.de RI Weber, Marc-Andre/C-4452-2016; OI Delorme, Stefan/0000-0002-1000-2582 FU International Myeloma Foundation; Dietmar Hopp Stiftung; German Research Foundation [SFB Transregio 79] FX Parts of this study were supported by grants from the International Myeloma Foundation, the Dietmar Hopp Stiftung and the German Research Foundation (SFB Transregio 79). NR 33 TC 23 Z9 23 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JAN PY 2014 VL 28 IS 1 BP 174 EP 178 DI 10.1038/leu.2013.244 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 286CD UT WOS:000329441200018 PM 23958921 ER PT J AU Miettinen, M AF Miettinen, Markku TI Smooth muscle tumors of soft tissue and non-uterine viscera: biology and prognosis SO MODERN PATHOLOGY LA English DT Article DE bone and soft tissue; leiomyoma; leiomyosarcoma ID INFERIOR VENA-CAVA; EPSTEIN-BARR-VIRUS; GASTROINTESTINAL STROMAL TUMORS; OF-THE-LITERATURE; LEIOMYOMATOSIS PERITONEALIS DISSEMINATA; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; BENIGN METASTASIZING LEIOMYOMA; EPITHELIAL MEMBRANE ANTIGEN; CLINICOPATHOLOGICAL ANALYSIS; RETROPERITONEAL LEIOMYOSARCOMAS AB Smooth muscle tumors are here considered an essentially dichotomous group composed of benign leiomyomas and malignant leiomyosarcomas. Soft tissue smooth muscle tumors with both atypia and mitotic activity are generally diagnosed lelomyosarcomas acknowledging potential for metastasis. However, lesions exist that cannot be comfortably placed in either category, and in such cases the designation 'smooth muscle tumor of uncertain biologic potential' is appropriate. The use of this category is often necessary with limited sampling, such as needle core biopsies. Benign smooth muscle tumors include smooth muscle hamartoma and angioleiomyoma. A specific category of leiomyomas are estrogen-receptor positive ones in women. These are similar to uterine leiomyomas and can occur anywhere in the abdomen and abdominal wall. Leiomyosarcomas can occur at any site, although are more frequent in the retroperitoneum and proximal extremities. They are recognized by likeness to smooth muscle cells but can undergo pleomorphic evolution ('dedifferentiation'). Presence of smooth muscle actin is nearly uniform and desmin-positivity usual. This and the lack of KIT expression separate leiomyosarcoma from GIST, an important problem in abdominal soft tissues. EBV-associated smooth muscle tumors are a specific subcategory occurring in AIDS or post-transplant patients. These tumors can have incomplete smooth muscle differentiation but show nuclear EBER as a diagnostic feature. In contrast to many other soft tissue tumors, genetics of smooth muscle tumors are poorly understood and such diagnostic testing is not yet generally applicable in this histogenetic group. Leiomyosarcomas are known to be genetically complex, often showing 'chaotic' karyotypes including aneuploidy or polyploidy, and no recurrent tumor-specific translocations have been detected. C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Miettinen, M (reprint author), NCI, Pathol Lab, 9000 Rockville Pike,Bldg 10,Room 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov FU NCI FX This work has been supported as a part of NCI's intramural research program. NR 85 TC 13 Z9 13 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD JAN PY 2014 VL 27 SU 1 BP S17 EP S29 DI 10.1038/modpathol.2013.178 PG 13 WC Pathology SC Pathology GA 285TW UT WOS:000329418900002 PM 24384850 ER PT J AU Rees, E Kirov, G Sanders, A Walters, JTR Chambert, KD Shi, J Szatkiewicz, J O'Dushlaine, C Richards, AL Green, EK Jones, I Davies, G Legge, SE Moran, JL Pato, C Pato, M Genovese, G Levinson, D Duan, J Moy, W Goring, HHH Morris, D Cormican, P Kendler, KS O'Neill, FA Riley, B Gill, M Corvin, A Craddock, N Sklar, P Hultman, C Sullivan, PF Gejman, PV McCarroll, SA O'Donovan, MC Owen, MJ AF Rees, E. Kirov, G. Sanders, A. Walters, J. T. R. Chambert, K. D. Shi, J. Szatkiewicz, J. O'Dushlaine, C. Richards, A. L. Green, E. K. Jones, I. Davies, G. Legge, S. E. Moran, J. L. Pato, C. Pato, M. Genovese, G. Levinson, D. Duan, J. Moy, W. Goering, H. H. H. Morris, D. Cormican, P. Kendler, K. S. O'Neill, F. A. Riley, B. Gill, M. Corvin, A. Craddock, N. Sklar, P. Hultman, C. Sullivan, P. F. Gejman, P. V. McCarroll, S. A. O'Donovan, M. C. Owen, M. J. CA Wellcome Trust Case Control Consor TI Evidence that duplications of 22q11.2 protect against schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE 22q11.2; CNV; duplication; protective; schizophrenia ID CARDIO-FACIAL SYNDROME; COPY NUMBER VARIATION; MICRODUPLICATION 22Q11.2; DELETION SYNDROME; VARIANTS; ADULTS; COMMON; RISK AB A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2-the reciprocal of the well-known, risk-inducing deletion of this locus-are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR = 0.17, P - 0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia. C1 [Rees, E.; Kirov, G.; Walters, J. T. R.; Richards, A. L.; Green, E. K.; Jones, I.; Davies, G.; Legge, S. E.; Craddock, N.; O'Donovan, M. C.; Owen, M. J.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Inst Psychol Med & Clin Neurosci, Cardiff CF24 4HQ, S Glam, Wales. [Sanders, A.; Duan, J.; Moy, W.; Gejman, P. V.] NorthShore Univ HealthSyst, Dept Psychiat & Behav Sci, Evanston, IL USA. [Sanders, A.; Duan, J.; Gejman, P. V.] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Chambert, K. D.; O'Dushlaine, C.; Moran, J. L.; Genovese, G.; McCarroll, S. A.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. [Shi, J.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. [Szatkiewicz, J.; Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Green, E. K.] Univ Plymouth, Sch Biomed & Biol Sci, Plymouth PL4 8AA, Devon, England. [Pato, C.; Pato, M.] Univ So Calif, Zilkha Neurogenet Inst, Dept Psychiat & Behav Sci, Los Angeles, CA USA. [Levinson, D.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Goering, H. H. H.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Morris, D.; Cormican, P.; Gill, M.; Corvin, A.] Univ Dublin Trinity Coll, Inst Mol Med, Dept Psychiat, Dublin 2, Ireland. [Morris, D.; Cormican, P.; Gill, M.; Corvin, A.] Univ Dublin Trinity Coll, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin 2, Ireland. [Kendler, K. S.; Riley, B.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat & Human Genet, Richmond, VA USA. [O'Neill, F. A.] Queens Univ, Dept Psychiat, Belfast, Antrim, North Ireland. [Sklar, P.] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA. [Hultman, C.; Sullivan, P. F.] Karolinska Inst, Dept Med Epidemiol & Biostat, Karolinska, Sweden. [Sullivan, P. F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Owen, MJ (reprint author), Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Hadyn Ellis Bldg Maindy Rd, Cardiff CF24 4HQ, S Glam, Wales. EM ODonovanMC@cf.ac.uk; OwenMJ@cf.ac.uk OI Gill, Michael/0000-0003-0206-5337; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Morris, Derek/0000-0002-3413-570X; Moran, Jennifer/0000-0002-5664-4716; Walters, James/0000-0002-6980-4053; O'Neill, Francis Anthony/0000-0002-7531-7657 FU Stanley Center for Psychiatric Research; MRC/Welsh Assembly Government; British Medical Association; Medical Research Council (MRC) Centre [G0800509, G0801418]; European Community [HEALTH-F2-2010-241909]; NIMH [R01 MH077139, R01 MH095034, MH 41953, MH083094]; Karolinska Institutet; Karolinska University Hospital; Swedish Research Council; Swedish County Council; Soderstrom Konigska Foundation; Netherlands Scientific Organization [NWO 645-000-003]; Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z, 085475/Z/08/Z]; Wellcome Trust [072894/Z/03/Z, 090532/Z/09/Z, 075491/Z/04/B]; Science Foundation Ireland [08/IN.1/B1916]; National Institutes of Health [HHSN268200782096C]; Gene Environment Association Studies (GENEVA) Coordinating Center [U01 HG004446]; Collaborative Genetic Study of Nicotine Dependence (COGEND) [P01 CA089392]; University of Wisconsin Transdisciplinary Tobacco Use Research Center [P50 DA019706, P50 CA084724]; National Institutes of Health, Bethesda, MD, USA [R01 EY020483]; [RC2MH090030]; [R01MH094091]; [1 x 01 HG005274-01]; [3P50CA093459]; [5P50CA097007]; [5R01ES011740]; [5R01CA133996] FX The 6882 schizophrenia cases from the discovery sample were genotyped at the Broad Institute and funded by a philanthropic gift to the Stanley Center for Psychiatric Research. We thank the participants and clinicians who took part in the Cardiff COGS study. This work was supported by a clinical research fellowship to JW from the MRC/Welsh Assembly Government and the Margaret Temple Award from the British Medical Association. We acknowledge Andrew Iles, David Parslow, Carissa Philipart and Sophie Canton for their work in recruitment, interviewing and rating. For the CLOZUK sample, we thank Novartis for their guidance and co-operation. We also thank staff at The Doctor's Laboratory, in particular Lisa Levett and Andrew Levett, for help and advice regarding sample acquisition. We acknowledge Kiran Mantripragada, Lesley Bates, Catherine Bresner and Lucinda Hopkins for laboratory sample management. The work at Cardiff University was funded by the Medical Research Council (MRC) Centre (G0800509) and Program Grants (G0801418), the European Community's Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI) and a PhD to ER. Funding support for the Swedish study was provided by NIMH R01 MH077139 (P Sullivan), NIMH R01 MH095034 (P Sklar), the Stanley Center for Psychiatric Research, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, an ALF grant from Swedish County Council, the Soderstrom Konigska Foundation and the Netherlands Scientific Organization (NWO 645-000-003). For Irish/WTCCC2 study, funding was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). The LCL expression data was generated with grant support from RC2MH090030 and R01MH094091. The authors acknowledge the contribution of data from outside sources: (1) Genetic Architecture of Smoking and Smoking Cessation accessed through dbGAP: Study Accession: phs000404.v1.p1. Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by 1 x 01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of data sets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). (2) High Density SNP Association Analysis of Melanoma: Case-Control and Outcomes Investigation, dbGaP Study Accession: phs000187.v1.p1: Research support to collect data and develop an application to support this project was provided by 3P50CA093459, 5P50CA097007, 5R01ES011740 and 5R01CA133996. (3) Genetic Epidemiology of Refractive Error in the KORA (Kooperative Gesundheitsforschung in der Region Augsburg) Study, dbGaP Study Accession: phs000303.v1.p1. Principal Investigators: Dwight Stambolian, University of Pennsylvania, Philadelphia, PA, USA; H Erich Wichmann, Institut fur Humangenetik, Helmholtz-Zentrum Munchen, Germany, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.; Funded by R01 EY020483, National Institutes of Health, Bethesda, MD, USA. (4) WTCCC2 project samples from National Blood Doners (NBS) Cohort, EGAD00000000024. WTCCC2 project samples from 1958 British Birth Cohort, EGAD00000000022. NR 22 TC 30 Z9 31 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JAN PY 2014 VL 19 IS 1 BP 37 EP 40 DI 10.1038/mp.2013.156 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 279MS UT WOS:000328964700010 PM 24217254 ER PT J AU Uhl, GR Walther, D Musci, R Fisher, C Anthony, JC Storr, CL Behm, FM Eaton, WW Ialongo, N Rose, JE AF Uhl, G. R. Walther, D. Musci, R. Fisher, C. Anthony, J. C. Storr, C. L. Behm, F. M. Eaton, W. W. Ialongo, N. Rose, J. E. TI Smoking quit success genotype score predicts quit success and distinct patterns of developmental involvement with common addictive substances SO MOLECULAR PSYCHIATRY LA English DT Article DE cannabis; complex genetics; development; genetic scores; predictive validity; smoking ID GENOME-WIDE ASSOCIATION; SAMPLE-SIZE CALCULATIONS; CESSATION SUCCESS; POLYSUBSTANCE ABUSERS; NICOTINE REPLACEMENT; CANCER RISK; DISEASE; POLYMORPHISMS; GENES; TRIAL AB Genotype scores that predict relevant clinical outcomes may detect other disease features and help direct prevention efforts. We report data that validate a previously established v1.0 smoking cessation quit success genotype score and describe striking differences in the score in individuals who display differing developmental trajectories of use of common addictive substances. In a cessation study, v1.0 genotype scores predicted ability to quit with P = 0.00056 and area under receiver-operating characteristic curve 0.66. About 43% vs 13% quit in the upper vs lower genotype score terciles. Latent class growth analyses of a developmentally assessed sample identified three latent classes based on substance use. Higher v1.0 scores were associated with (a) higher probabilities of participant membership in a latent class that displayed low use of common addictive substances during adolescence (P = 0.0004) and (b) lower probabilities of membership in a class that reported escalating use (P = 0.001). These results indicate that: (a) we have identified genetic predictors of smoking cessation success, (b) genetic influences on quit success overlap with those that influence the rate at which addictive substance use is taken up during adolescence and (c) individuals at genetic risk for both escalating use of addictive substances and poor abilities to quit may provide especially urgent focus for prevention efforts. C1 [Uhl, G. R.; Walther, D.; Fisher, C.] NIDA, NIH IRP, Mol Neurobiol Branch, Baltimore, MD 21224 USA. [Musci, R.; Eaton, W. W.; Ialongo, N.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Anthony, J. C.] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Storr, C. L.] Univ Maryland, Sch Nursing, Dept Family & Community Hlth, Baltimore, MD 21201 USA. [Storr, C. L.; Behm, F. M.; Rose, J. E.] Duke Univ, Dept Psychiat, Durham, NC 27706 USA. [Storr, C. L.; Behm, F. M.; Rose, J. E.] Duke Univ, Ctr Nicotine & Smoking Cessat Res, Durham, NC 27706 USA. RP Uhl, GR (reprint author), NIDA, NIH IRP, Mol Neurobiol Branch, Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov FU National Institutes of Health (NIH)-Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services; Philip Morris, USA; NIDA [R01-DA009897, 4R37DA011796-11] FX This study was supported by the National Institutes of Health (NIH)-Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services (Dr Uhl); a grant to Duke University (PI, Dr Rose) from Philip Morris, USA for the work performed before January 2012; NIDA grants R01-DA009897 (WE) and 4R37DA011796-11 (NI). The funders had no role in the planning or execution of the study, data analysis or publication of results. We are grateful to TGEN investigators for generous access to Alzheimer's disease GWAS genotype data and D Sisto for its analysis, to E Westman for assistance with the smoking cessation clinical trial, for each of the prevention study investigators, especially S Kellam, for the sustained cooperation of the study participants and for help and thoughtful advice from C Johnson, J Schroder, P Zandi and K Masyn. The underlying smoking cessation clinical trial was registered with clinicaltrials.gov (NCT00894166). NR 32 TC 14 Z9 14 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JAN PY 2014 VL 19 IS 1 BP 50 EP 54 DI 10.1038/mp.2012.155 PG 5 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 279MS UT WOS:000328964700012 PM 23128154 ER PT J AU Lohoff, FW Hodge, R Narasimhan, S Nall, A Ferraro, TN Mickey, BJ Heitzeg, MM Langenecker, SA Zubieta, JK Bogdan, R Nikolova, YS Drabant, E Hariri, AR Bevilacqua, L Goldman, D Doyle, GA AF Lohoff, F. W. Hodge, R. Narasimhan, S. Nall, A. Ferraro, T. N. Mickey, B. J. Heitzeg, M. M. Langenecker, S. A. Zubieta, J-K Bogdan, R. Nikolova, Y. S. Drabant, E. Hariri, A. R. Bevilacqua, L. Goldman, D. Doyle, G. A. TI Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing SO MOLECULAR PSYCHIATRY LA English DT Article DE amygdala; bipolar disorder; medial PFC; schizophrenia; SLC18A1 ID AMYGDALA ACTIVATION; AMINE TRANSPORTER; MAJOR DEPRESSION; BIPOLAR DISORDER; CHROMOSOME 8P; SCHIZOPHRENIA; ASSOCIATION; BRAIN; AMPHETAMINE; RESERPINE AB Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology. C1 [Lohoff, F. W.; Hodge, R.; Narasimhan, S.; Nall, A.; Ferraro, T. N.; Doyle, G. A.] Univ Penn, Sch Med, Ctr Neurobiol & Behav, Translat Res Labs,Dept Psychiat, Philadelphia, PA 19104 USA. [Mickey, B. J.; Heitzeg, M. M.; Langenecker, S. A.; Zubieta, J-K] Univ Michigan, Dept Psychiat, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Bogdan, R.; Nikolova, Y. S.; Hariri, A. R.] Duke Univ, Inst Genome Sci & Policy, Dept Psychol & Neurosci, Durham, NC USA. [Bogdan, R.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Drabant, E.] 23andMe, Mountain View, CA USA. [Bevilacqua, L.; Goldman, D.] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Lohoff, FW (reprint author), Univ Penn, Sch Med, Ctr Neurobiol & Behav, Translat Res Labs,Dept Psychiat, 125 South 31st St,Room 2213, Philadelphia, PA 19104 USA. EM lohoff@mail.med.upenn.edu RI Mickey, Brian/J-1756-2014; Goldman, David/F-9772-2010; Lohoff, Falk/M-7951-2016; OI Mickey, Brian/0000-0002-7847-7680; Goldman, David/0000-0002-1724-5405; Bogdan, Ryan/0000-0002-1430-1045; Narasimhan, Sneha/0000-0002-1665-9681 FU National Institutes of Health [NIH K08MH080372]; NCRR [UL1 RR 024986]; NIMH [P01 MH 42251, R25 MH 6374, K23 MH 074459]; NIDA [R01 DA 016423, R01 DA 022520, R01 DA 026222, R01 DA 031579]; Phil F Jenkins Research Fund FX This work was supported by the Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania. Financial support is gratefully acknowledged from National Institutes of Health Grants (NIH K08MH080372 to FWL), NCRR (UL1 RR 024986), NIMH (P01 MH 42251, R25 MH 6374 and K23 MH 074459), NIDA (R01 DA 016423 and R01 DA 022520, and 026222 and 031579) and the Phil F Jenkins Research Fund. NR 59 TC 5 Z9 5 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JAN PY 2014 VL 19 IS 1 BP 129 EP 139 DI 10.1038/mp.2012.193 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 279MS UT WOS:000328964700022 PM 23337945 ER PT J AU Sellers, SE Dumitriu, B Morgan, MJ Hughes, WM Wu, CO Raghavarchari, N Yang, YQ Uchida, N Tisdale, JF An, DS Chen, IS Hematti, P Donahue, RE LaRochelle, A Young, NS Calado, RT Dunbar, CE AF Sellers, Stephanie E. Dumitriu, Bogdan Morgan, Mary J. Hughes, William M. Wu, Colin O. Raghavarchari, Nalini Yang, Yanqin Uchida, Naoya Tisdale, John F. An, Dong S. Chen, Irvin S. Hematti, Peiman Donahue, Robert E. LaRochelle, Andre Young, Neal S. Calado, Rodrigo T. Dunbar, Cynthia E. TI No Impact of Lentiviral Transduction on Hematopoietic Stem/Progenitor Cell Telomere Length or Gene Expression in the Rhesus Macaque Model SO MOLECULAR THERAPY LA English DT Article ID RETROVIRAL VECTOR INTEGRATION; STEM-CELLS; BLOOD-CELLS; TRANSGENE EXPRESSION; REPOPULATING CELLS; NONHUMAN-PRIMATES; SITE SELECTION; IN-VIVO; THERAPY; SCID-X1 AB The occurrence of clonal perturbations and leukemia in patients transplanted with gamma-retroviral (RV) vector-transduced autologous hematopoietic stem and progenitor cells (HSPCs) has stimulated extensive investigation, demonstrating that proviral insertions may perturb adjacent proto-oncogene expression. Although enhancer-deleted lentiviruses are less likely to result in insertional oncogenesis, there is evidence that they may perturb transcript splicing, and one patient with a benign clonal expansion of lentivirally transduced HPSC has been reported. The rhesus macaque model provides an opportunity for informative long-term analysis to ask whether transduction impacts on long-term HSPC properties. We used two techniques to examine whether lentivirally transduced HSPCs from eight rhesus macaques transplanted 1-13.5 years previously are perturbed at a population level, comparing telomere length as a measure of replicative history and gene expression profile of vector positive versus vector negative cells. There were no differences in telomere lengths between sorted GFP(+) and GFP(-) blood cells, suggesting that lentiviral (LV) transduction did not globally disrupt replicative patterns. Bone marrow GFP(+) and GFP(-) CD34(+) cells showed no differences in gene expression using unsupervised and principal component analysis. These studies did not uncover any global long-term perturbation of proliferation, differentiation, or other important functional parameters of transduced HSPCs in the rhesus macaque model. C1 [Sellers, Stephanie E.; Dumitriu, Bogdan; Morgan, Mary J.; Hughes, William M.; Donahue, Robert E.; LaRochelle, Andre; Young, Neal S.; Calado, Rodrigo T.; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Raghavarchari, Nalini; Yang, Yanqin] NHLBI, DNA Sequencing & Genom Core, NIH, Bethesda, MD 20892 USA. [Uchida, Naoya; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [An, Dong S.; Chen, Irvin S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Hematti, Peiman] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 CRC,Room 4E-5232,10 Ctr Dr, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011 FU intramural research program of the NHLBI FX The authors thank Keyvan Kevanfar for flow cytometric sorting, and Mark Metzger, Alan Krouse, Barrington Thompson, and Sandra Price for excellent animal care. Funding for these studies was provided by the intramural research program of the NHLBI. The authors declared no conflict of interest. NR 49 TC 2 Z9 2 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JAN PY 2014 VL 22 IS 1 BP 52 EP 58 DI 10.1038/mt.2013.168 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 282ZI UT WOS:000329213500008 PM 23863881 ER PT J AU Johnson, TR Rangel, D Graham, BS Brough, DE Gall, JG AF Johnson, Teresa R. Rangel, David Graham, Barney S. Brough, Douglas E. Gall, Jason G. TI Genetic Vaccine for Respiratory Syncytial Virus Provides Protection Without Disease Potentiation SO MOLECULAR THERAPY LA English DT Article ID COTTON RATS; NEUTRALIZING ANTIBODIES; INTRANASAL IMMUNIZATION; CANDIDATE VACCINE; YOUNG-CHILDREN; BALB/C MICE; SUBGROUP-B; F-PROTEIN; IN-VITRO; T-CELLS AB Respiratory syncytial virus (RSV) is a major cause of infectious lower respiratory disease in infants and the elderly. As there is no vaccine for RSV, we developed a genetic vaccine approach that induced protection of the entire respiratory tract from a single parenteral administration. The approach was based on adenovirus vectors derived from newly isolated nonhuman primate viruses with low seroprevalence. We show for the first time that a single intramuscular (IM) injection of the replication-deficient adenovirus vectors expressing the RSV fusion (F0) glycoprotein induced immune responses that protected both the lungs and noses of cotton rats and mice even at low doses and for several months postimmunization. The immune response included high titers of neutralizing antibody that were maintained >= 24 weeks and RSV-specific CD8(+) and CD4(+) T cells. The vectors were as potently immunogenic as a human adenovirus 5 vector in these two key respiratory pathogen animal models. Importantly, there was minimal alveolitis and granulocytic infiltrates in the lung, and type 2 cytokines were not produced after RSV challenge even under conditions of partial protection. Overall, this genetic vaccine is highly effective without potentiating immunopathology, and the results support development of the vaccine candidate for human testing. C1 [Johnson, Teresa R.; Rangel, David; Brough, Douglas E.; Gall, Jason G.] GenVec Inc, Gaithersburg, MD 20878 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Gall, JG (reprint author), GenVec Inc, 65 West Watkins Mill Rd, Gaithersburg, MD 20878 USA. EM jgall@genvec.com FU NIH [R43AI075686-01]; GenVec; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank Grant Liao, Emmanuella Eastman, Grace Lee, Karen Tressler, Valerie Moore, and Damador EttyReddy for excellent technical assistance as well as Jorge Blanco and Kevin Yim (Sigmovir) for expert advice and histopathology review. The work was funded by NIH grant R43AI075686-01 and GenVec. T.R.J, D.R., D.E.B., and J.G.G. were employees of GenVec, a for-profit corporation, and hold stock interests in the company. B.S.G. and T.R.J. are named on a patent application for the F antigen construct expressed by the rAd vectors, and B. S. G. is supported by intramural funding from the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The authors declared no conflict of interest. NR 45 TC 14 Z9 14 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JAN PY 2014 VL 22 IS 1 BP 196 EP 205 DI 10.1038/mt.2013.142 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 282ZI UT WOS:000329213500023 PM 23752342 ER PT J AU McGray, AJR Hallett, R Bernard, D Swift, SL Zhu, ZQ Teoderascu, F VanSeggelen, H Hassell, JA Hurwitz, AA Wan, YH Bramson, JL AF McGray, A. J. Robert Hallett, Robin Bernard, Dannie Swift, Stephanie L. Zhu, Ziqiang Teoderascu, Florentina VanSeggelen, Heather Hassell, John A. Hurwitz, Arthur A. Wan, Yonghong Bramson, Jonathan L. TI Immunotherapy-induced CD8(+) T Cells Instigate Immune Suppression in the Tumor SO MOLECULAR THERAPY LA English DT Article ID RESISTANT PROSTATE-CANCER; MELANOMA PATIENTS; OVARIAN-CANCER; ANTIGEN; VACCINATION; VARIANTS; VACCINES; TRIAL; LYMPHOCYTES; RECRUITMENT AB Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8(+) T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies. C1 [McGray, A. J. Robert; Hallett, Robin; Bernard, Dannie; Swift, Stephanie L.; Teoderascu, Florentina; VanSeggelen, Heather; Hassell, John A.; Wan, Yonghong; Bramson, Jonathan L.] McMaster Univ, McMaster Immunol Res Ctr, Hamilton, ON L8N 3Z5, Canada. [Zhu, Ziqiang; Hurwitz, Arthur A.] NCI, Canc & Inflammat Program, FCRF, CCR,NIH, Frederick, MD 21701 USA. RP Bramson, JL (reprint author), McMaster Univ, McMaster Immunol Res Ctr, 1200 Main St West, Hamilton, ON L8N 3Z5, Canada. EM bramsonj@mcmaster.ca FU Terry Fox Foundation; Canadian Institutes for Health Research FX This work was supported by funds from the Terry Fox Foundation. D.B. was supported by a scholarship from the Canadian Institutes for Health Research. The authors declared no conflict of interest. NR 45 TC 26 Z9 26 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JAN PY 2014 VL 22 IS 1 BP 206 EP 218 DI 10.1038/mt.2013.255 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 282ZI UT WOS:000329213500024 PM 24196579 ER PT S AU Iantorno, S Gori, K Goldman, N Gil, M Dessimoz, C AF Iantorno, Stefano Gori, Kevin Goldman, Nick Gil, Manuel Dessimoz, Christophe BE Russell, DJ TI Who Watches the Watchmen? An Appraisal of Benchmarks for Multiple Sequence Alignment SO MULTIPLE SEQUENCE ALIGNMENT METHODS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Multiple sequence alignment; Benchmarking; Phylogenetic; Protein structure; Sequence evolution; Consistency; Homology ID HIGH-THROUGHPUT; EVOLUTION; PROGRAMS; SIMULATION; CHALLENGES; ACCURACY; DATABASE; QUALITY; GAPS; TECHNOLOGY AB Multiple sequence alignment (MSA) is a fundamental and ubiquitous technique in bioinformatics used to infer related residues among biological sequences. Thus alignment accuracy is crucial to a vast range of analyses, often in ways difficult to assess in those analyses. To compare the performance of different aligners and help detect systematic errors in alignments, a number of benchmarking strategies have been pursued. Here we present an overview of the main strategies-based on simulation, consistency, protein structure, and phylogeny-and discuss their different advantages and associated risks. We outline a set of desirable characteristics for effective benchmarking, and evaluate each strategy in light of them. We conclude that there is currently no universally applicable means of benchmarking MSA, and that developers and users of alignment tools should base their choice of benchmark depending on the context of application-with a keen awareness of the assumptions underlying each benchmarking strategy. C1 [Iantorno, Stefano] Wellcome Trust Sanger Inst, Cambridge, England. [Iantorno, Stefano] NIAID, NIH, Bethesda, MD 20892 USA. [Gori, Kevin; Goldman, Nick; Dessimoz, Christophe] EMBL European Bioinformat Inst, Cambridge, England. [Gil, Manuel] Univ Vienna, Med Univ Vienna, Max F Perutz Labs, Ctr Integrat Bioinformat Vienna, Vienna, Austria. RP Iantorno, S (reprint author), Wellcome Trust Sanger Inst, Cambridge, England. OI Gori, Kevin/0000-0001-7975-4275; Goldman, Nick/0000-0001-8486-2211; Dessimoz, Christophe/0000-0002-2170-853X NR 50 TC 14 Z9 14 U1 1 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-645-0; 978-1-62703-646-7 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1079 BP 59 EP 73 DI 10.1007/978-1-62703-646-7_4 D2 10.1007/978-1-62703-646-7 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA BJJ02 UT WOS:000328376500005 PM 24170395 ER PT J AU Anderson, KG Mayer-Barber, K Sung, H Beura, L James, BR Taylor, JJ Qunaj, L Griffith, TS Vezys, V Barber, DL Masopust, D AF Anderson, Kristin G. Mayer-Barber, Katrin Sung, Heungsup Beura, Lalit James, Britnie R. Taylor, Justin J. Qunaj, Lindor Griffith, Thomas S. Vezys, Vaiva Barber, Daniel L. Masopust, David TI Intravascular staining for discrimination of vascular and tissue leukocytes SO NATURE PROTOCOLS LA English DT Article ID MEMORY T-CELLS; DENDRITIC CELLS; NONLYMPHOID TISSUE; LYMPHOID-TISSUES; LOCAL IMMUNITY; B-CELLS; LUNG; MIGRATION; INFECTION; SUBSETS AB Characterization of the cellular participants in tissue immune responses is crucial to understanding infection, cancer, autoimmunity, allergy, graft rejection and other immunological processes. Previous reports indicate that leukocytes in lung vasculature fail to be completely removed by perfusion. Several studies suggest that intravascular staining may discriminate between tissue-localized and blood-borne cells in the mouse lung. Here we outline a protocol for the validation and use of intravascular staining to define innate and adaptive immune cells in mice. We demonstrate application of this protocol to leukocyte analyses in many tissues and we describe its use in the contexts of lymphocytic choriomeningitis virus and Mycobacterium tuberculosis infections or solid tumors. Intravascular staining and organ isolation usually takes 5-30 min per mouse, with additional time required for any subsequent leukocyte isolation, staining and analysis. In summary, this simple protocol should help enable interpretable analyses of tissue immune responses. C1 [Anderson, Kristin G.; Sung, Heungsup; Beura, Lalit; Taylor, Justin J.; Qunaj, Lindor; Vezys, Vaiva; Masopust, David] Univ Minnesota, Dept Microbiol, Ctr Immunol, Minneapolis, MN 55455 USA. [Mayer-Barber, Katrin] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [James, Britnie R.; Griffith, Thomas S.] Univ Minnesota, Masonic Canc Ctr, Ctr Immunol, Dept Urol, Minneapolis, MN 55455 USA. [Barber, Daniel L.] NIAID, T Lymphocyte Biol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Masopust, D (reprint author), Univ Minnesota, Dept Microbiol, Ctr Immunol, Minneapolis, MN 55455 USA. EM masopust@umn.edu OI Vezys, Vaiva/0000-0002-2520-809X; Qunaj, Lindor/0000-0001-8461-8374 FU US NIH grant [AI084913-01, DP2 OD006467, CA109446]; Arnold and Mabel Beckman Foundation; National Institute of Dental and Craniofacial Research [T90DE022732]; National Institute of Allergy and Infectious Diseases Intramural Program FX This study was supported by US NIH grant nos. AI084913-01 and DP2 OD006467 (D.M.), the Arnold and Mabel Beckman Foundation (D.M.), grant no. T90DE022732 from the National Institute of Dental and Craniofacial Research (K.G.A.), the National Institute of Allergy and Infectious Diseases Intramural Program (K.M.-B. and D.L.B.) and US NIH grant no. CA109446 (T.S.G.). We thank the University of Minnesota Center for Immunology Imaging Core, the University of Minnesota Imaging Center and the Flow Cytometry Core. NR 61 TC 76 Z9 76 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD JAN PY 2014 VL 9 IS 1 BP 209 EP 222 DI 10.1038/nprot.2014.005 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 282QD UT WOS:000329186400019 PM 24385150 ER PT J AU Walkiewicz, MP Dimitriadis, EK Dalal, Y AF Walkiewicz, Marcin P. Dimitriadis, Emilios K. Dalal, Yamini TI CENP-A octamers do not confer a reduction in nucleosome height by AFM SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Letter ID CENTROMERIC NUCLEOSOMES; HISTONE H3; IN-VITRO; KINETOCHORE; CHROMATIN; RECONSTITUTION; MECHANISM C1 [Walkiewicz, Marcin P.; Dalal, Yamini] NCI, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] Natl Inst BioImaging & BioEngn, NIH, Bethesda, MD USA. RP Dalal, Y (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM dalaly@mail.nih.gov FU Intramural NIH HHS [ZIA BC011207-01, ZIA BC011207-03, ZIA BC011207-05, ZIA BC011209-01, ZIA BC011209-03, ZIA BC011209-05, ZIA BC011209-06, ZIA BC011207-02, ZIA BC011207-04, ZIA BC011207-06, ZIA BC011209-02, ZIA BC011209-04] NR 24 TC 12 Z9 12 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JAN PY 2014 VL 21 IS 1 BP 2 EP 3 DI 10.1038/nsmb.2742 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 284BJ UT WOS:000329290700002 PM 24389541 ER PT J AU Morris, SA Baek, S Sung, MH John, S Wiench, M Johnson, TA Schiltz, RL Hager, GL AF Morris, Stephanie A. Baek, Songjoon Sung, Myong-Hee John, Sam Wiench, Malgorzata Johnson, Thomas A. Schiltz, R. Louis Hager, Gordon L. TI Overlapping chromatin-remodeling systems collaborate genome wide at dynamic chromatin transitions SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID GLUCOCORTICOID-RECEPTOR BINDING; MAMMALIAN SWI/SNF COMPLEXES; IN-VIVO; DNA-SEQUENCE; PROMOTER NUCLEOSOMES; TRANSCRIPTION; ENZYMES; BRG1; ISWI; ACCESSIBILITY AB ATP-dependent chromatin remodeling is an essential process required for the dynamic organization of chromatin structure. Here we describe the genome-wide location and activity of three remodeler proteins with diverse physiological functions in the mouse genome: Brg1, Chd4 and Snf2h. The localization patterns of all three proteins substantially overlap with one another and with regions of accessible chromatin. Furthermore, using inducible mutant variants, we demonstrate that the catalytic activity of these proteins contributes to the remodeling of chromatin genome wide and that each of these remodelers can independently regulate chromatin reorganization at distinct sites. Many regions require the activity of more than one remodeler to regulate accessibility. These findings provide a dynamic view of chromatin organization and highlight the differential contributions of remodelers to chromatin maintenance in higher eukaryotes. C1 [Morris, Stephanie A.; Baek, Songjoon; Sung, Myong-Hee; John, Sam; Wiench, Malgorzata; Johnson, Thomas A.; Schiltz, R. Louis; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov FU Intramural Research Program of the US National Institutes of Health, National Cancer Institute Center for Cancer Research; UNCF/Merck Postdoctoral Science Research Fellowship FX The authors thank D. Picketts (University of Ottawa) and J. Svaren (University of Wisconsin) for the kind gift of remodeler cDNA constructs (hSNF2H and mChd4, respectively), A. Indrawan for technical assistance, the US National Cancer Institute Advanced Technology Program Sequencing Facility for sequencing services and Epitomics, Inc. for generation of the monoclonal rabbit antibody to BRG1. This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute Center for Cancer Research and by a UNCF/Merck Postdoctoral Science Research Fellowship to S.A.M. NR 62 TC 44 Z9 44 U1 5 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JAN PY 2014 VL 21 IS 1 BP 73 EP + DI 10.1038/nsmb.2718 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 284BJ UT WOS:000329290700017 PM 24317492 ER PT J AU Kahn, J Hayman, TJ Jamal, M Rath, BH Kramp, T Camphausen, K Tofilon, PJ AF Kahn, Jenna Hayman, Thomas J. Jamal, Muhammad Rath, Barbara H. Kramp, Tamalee Camphausen, Kevin Tofilon, Philip J. TI The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells SO NEURO-ONCOLOGY LA English DT Article DE AZD2014; glioblastoma; mTOR; orthotopic xenograft; Radiation; tumor stem cell ID TUMOR-INITIATING CELLS; TRANSLATION INITIATION; ANTITUMOR-ACTIVITY; IONIZING IRRADIATION; DNA-DAMAGE; FACTOR 4E; IN-VITRO; CANCER; MTOR; RAPAMYCIN AB The mammalian target of rapamycin (mTOR) has been suggested as a target for radiosensitization. Given that radiotherapy is a primary treatment modality for glioblastoma (GBM) and that mTOR is often dysregulated in GBM, the goal of this study was to determine the effects of AZD2014, a dual mTORC1/2 inhibitor, on the radiosensitivity of GBM stem-like cells (GSCs). mTORC1 and mTORC2 activities were defined by immunoblot analysis. The effects of this mTOR inhibitor on the in vitro radiosensitivity of GSCs were determined using a clonogenic assay. DNA double strand breaks were evaluated according to H2AX foci. Orthotopic xenografts initiated from GSCs were used to define the in vivo response to AZD2014 and radiation. Exposure of GSCs to AZD2014 resulted in the inhibition of mTORC1 and 2 activities. Based on clonogenic survival analysis, addition of AZD2014 to culture media 1 hour before irradiation enhanced the radiosensitivity of CD133 and CD15 GSC cell lines. Whereas AZD2014 treatment had no effect on the initial level of H2AX foci, the dispersal of radiation-induced H2AX foci was significantly delayed. Finally, the combination of AZD2014 and radiation delivered to mice bearing GSC-initiated orthotopic xenografts significantly prolonged survival as compared with the individual treatments. These data indicate that AZD2014 enhances the radiosensitivity of GSCs both in vitro and under orthotopic in vivo conditions and suggest that this effect involves an inhibition of DNA repair. Moreover, these results suggest that this dual mTORC1/2 inhibitor may be a radiosensitizer applicable to GBM therapy. C1 [Kahn, Jenna; Hayman, Thomas J.; Jamal, Muhammad; Rath, Barbara H.; Kramp, Tamalee; Camphausen, Kevin; Tofilon, Philip J.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kahn, Jenna] Brown Univ, Warren Alpert Sch Med, Providence, RI 02912 USA. [Hayman, Thomas J.] Univ S Florida, Morsani Coll Med, Tampa, FL USA. RP Tofilon, PJ (reprint author), NCI, 10 Ctr Dr MSC 1002,Bldg 10,B3B69B, Bethesda, MD 20892 USA. EM tofilonp@mail.nih.gov FU Division of Basic Sciences, National Cancer Institute [Z1A BC011372, Z1A BC011373] FX Division of Basic Sciences, National Cancer Institute (Z1A BC011372, Z1A BC011373). NR 44 TC 19 Z9 21 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JAN PY 2014 VL 16 IS 1 BP 29 EP 37 DI 10.1093/neuonc/not139 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 281YC UT WOS:000329135900006 PM 24311635 ER PT J AU He, MG Abdou, A Ellwein, LB Naidoo, KS Sapkota, YD Thulasiraj, RD Varma, R Zhao, JL Kocur, I Congdon, NG AF He, Mingguang Abdou, Amza Ellwein, Leon B. Naidoo, Kovin S. Sapkota, Yuddha D. Thulasiraj, R. D. Varma, Rohit Zhao, Jialiang Kocur, Ivo Congdon, Nathan G. TI Age-related Prevalence and Met Need for Correctable and Uncorrectable Near Vision Impairment in a Multi-country Study SO OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; FUNCTIONAL PRESBYOPIA; POPULATION; INDIA; EYE AB Purpose: To estimate the prevalence, potential determinants, and proportion of met need for near vision impairment (NVI) correctable with refraction approximately 2 years after initial examination of a multi-country cohort. Design: Population-based, prospective cohort study. Participants: People aged 35 years examined at baseline in semi-rural (Shunyi) and urban (Guangzhou) sites in China; rural sites in Nepal (Kaski), India (Madurai), and Niger (Dosso); a semi-urban site (Durban) in South Africa; and an urban site (Los Angeles) in the United States. Methods: Near visual acuity (NVA) with and without current near correction was measured at 40 cm using a logarithm of the minimum angle of resolution near vision tumbling E chart. Participants with uncorrected binocular NVA 20/ 40 were tested with plus sphere lenses to obtain best-corrected binocular NVA. Main Outcome Measures: Prevalence of total NVI (defined as uncorrected NVA 20/ 40) and NVI correctable and uncorrectable to > 20/ 40, and current spectacle wearing among those with bilateral NVA 20/ 63 improving to > 20/ 40 with near correction (met need). Results: Among 13 671 baseline participants, 10 533 (77.2%) attended the follow-up examination. The prevalence of correctable NVI increased with age from 35 to 50e60 years and then decreased at all sites. Multiple logistic regression modeling suggested that correctable NVI was not associated with gender at any site, whereas more educated persons aged > 54 years were associated with a higher prevalence of correctable NVI in Nepal and India. Although near vision spectacles were provided free at baseline, wear among those who could benefit was < 40% at all but 2 centers (Guangzhou and Los Angeles). Conclusions: Prevalence of correctable NVI is greatest among persons of working age, and rates of correction are low in many settings, suggesting that strategies targeting the workplace may be needed. Ophthalmology 2014; 121: 417-422 (C) 2014 by the American Academy of Ophthalmology. C1 [He, Mingguang; Congdon, Nathan G.] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China. [Abdou, Amza] Minist Sante Publ, Programme Natl Lutte Cecite, Niamey, Niger. [Ellwein, Leon B.] NEI, Bethesda, MD 20892 USA. [Naidoo, Kovin S.] Univ KwaZulu Natal, Brien Holden Vis Inst, Durban, South Africa. [Naidoo, Kovin S.] Univ KwaZulu Natal, AVRI, Durban, South Africa. [Sapkota, Yuddha D.] Nepal Netra Jyoti Sangh, Kathmandu, Nepal. [Thulasiraj, R. D.] Aravind Eye Care Syst, Lions Aravind Inst Community Ophthalmol, Madurai, Tamil Nadu, India. [Varma, Rohit] Univ So Calif, Doheny Eye Inst, Los Angeles, CA USA. [Zhao, Jialiang] Chinese Acad Med Sci, Beijing 100730, Peoples R China. [Zhao, Jialiang] Beijing Union Med Coll Hosp, Beijing, Peoples R China. [Kocur, Ivo] WHO, CH-1211 Geneva, Switzerland. [Congdon, Nathan G.] ORBIS Int, New York, NY USA. RP He, MG (reprint author), Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab, 54 Xianlie Rd, Guangzhou 510060, Guangdong, Peoples R China. EM mingguang_he@yahoo.com FU World Health Organization, Geneva, Switzerland [N01-EY-2103)] FX Funding: Supported by the World Health Organization, Geneva, Switzerland (under National Institutes of Health, Bethesda, MD, contract No. N01-EY-2103). NR 14 TC 2 Z9 2 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JAN PY 2014 VL 121 IS 1 BP 417 EP 422 DI 10.1016/j.ophtha.2013.06.051 PG 6 WC Ophthalmology SC Ophthalmology GA 282KG UT WOS:000329169500064 PM 23993359 ER PT J AU Ramos-Alvarez, I Moreno-Villegas, Z Martin-Duce, A Sanz, R Aparicio, C Portal-Nunez, S Mantey, SA Jensen, RT Gonzalez, N AF Ramos-Alvarez, I. Moreno-Villegas, Z. Martin-Duce, A. Sanz, R. Aparicio, C. Portal-Nunez, S. Mantey, S. A. Jensen, R. T. Gonzalez, N. TI Human BRS-3 receptor: Functions/role in cell signaling pathways and glucose metabolism in obese or diabetic myocytes SO PEPTIDES LA English DT Article DE BRS-3 human muscle; Signaling; Glucose metabolism; Diabetes; Obesity ID GASTRIN-RELEASING-PEPTIDE; MAMMALIAN BOMBESIN RECEPTORS; HUMAN ORPHAN RECEPTOR; LUNG-CANCER CELLS; SUBTYPE-3 BRS-3; SUBTYPE-3-DEFICIENT MICE; SKELETAL-MUSCLE; MOLECULAR-BASIS; AGONIST; RAT AB Several studies showed that the orphan Bombesin Receptor Subtype-3 (BRS-3) - member of the bombesin receptor family - has an important role in glucose homeostasis (v.g.: BRS-3-KO mice developed mild obesity, and decreased levels of BRS-3 mRNA/protein have been described in muscle from obese ( OB) and type 2 diabetic (T2D) patients). In this work, to gain insight into BRS-3 receptor cell signaling pathways, and its implication on glucose metabolism, primary cultured myocytes from normal subjects, OB or T2D patients were tested using high affinity ligand - [D-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]bombesin(6-14). In muscle cells from all metabolic conditions, the compound significantly increased not only MAPKs, p90RSK1, PKB and p7056K phosphorylation levels, but also PI3K activity; moreover, it produced a dose-response stimulation of glycogen synthase a activity and glycogen synthesis. Myocytes from OB and T2D patients were more sensitive to the ligand than normal, and T2D cells even more than obese myocytes. These results widen the knowledge of human BRS-3 cell signaling pathways induced by a BRS-3 agonist, described its insulin-mimetic effects on glucose metabolism, showed the role of BRS-3 receptor in glucose homeostasis, and also propose the employing of BRS-3/ligand system, as participant in the obese and diabetic therapies. (C) 2013 Elsevier Inc. All rights reserved. C1 [Ramos-Alvarez, I.; Moreno-Villegas, Z.; Gonzalez, N.] CIBERDEM, IIS Fdn Jimenez Diaz, Dept Metab Nutr & Hormones, Madrid, Spain. [Martin-Duce, A.] Univ Alcala de Henares, Surg Unit, Dept Nursery, Madrid, Spain. [Sanz, R.] IIS Fdn Jimenez Diaz, Dept Neurol, Madrid 28040, Spain. [Aparicio, C.] Fdn Jimenez Diaz, Dept Vasc Surg, Madrid, Spain. [Portal-Nunez, S.] IIS Fdn Jimenez Diaz, Dept Bone Mineral Metab, Madrid 28040, Spain. [Mantey, S. A.; Jensen, R. T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Gonzalez, N (reprint author), IIS Fdn Jimenez Diaz, Dpt Metab Nutr & Hormonas, Avda Reyes Catolicos 2, Madrid 28040, Spain. EM ngonzalezg@fjd.es RI Portal-Nunez, Sergio/L-7391-2014; Gonzalez, Nieves/N-2199-2014 OI Portal-Nunez, Sergio/0000-0003-0659-1545; Gonzalez, Nieves/0000-0002-1551-2872 FU Institute of Health Carlos III [CP08/00158]; Fundacion Rodriguez Pascual, Spain FX This study was supported by a grant from the Institute of Health Carlos III (CP08/00158) and Fundacion Rodriguez Pascual, Spain. IRA was Research Fellow from the Fundacion Conchita Rabago de Jimenez Diaz. NR 36 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 EI 1873-5169 J9 PEPTIDES JI Peptides PD JAN PY 2014 VL 51 BP 91 EP 99 DI 10.1016/j.peptides.2013.11.002 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 282XO UT WOS:000329208100015 PM 24220502 ER PT J AU Zhou, YJ Boudreau, DM Freedman, AN AF Zhou, Yingjun Boudreau, Denise M. Freedman, Andrew N. TI Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general US population SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE aspirin; NSAIDs; NHIS; prevalence; pharmacoepidemiology ID SERVICES-TASK-FORCE; RANDOMIZED CONTROLLED-TRIALS; COLLEGE-OF-CARDIOLOGY; LUNG-CANCER RISK; COLORECTAL-CANCER; CARDIOVASCULAR-DISEASE; PRIMARY PREVENTION; PANCREATIC-CANCER; REGULAR ASPIRIN; CYCLOOXYGENASE-2 INHIBITORS AB PurposeThe objective of this study was to describe trends in the prevalence of regular aspirin and nonsteroidal anti-inflammatory drug (NSAID) use among adults in the United States during 2005 and 2010, and to identify characteristics of regular users. MethodsData from the 2005 and 2010 National Health Interview Survey (NHIS) were analyzed to estimate the prevalence of regular use of aspirin and NSAIDs among U.S. adults aged 18years and older. Results were stratified by demographics and self-reported medical conditions and extrapolated to provide U.S. population estimates. ResultsIn 2010, around 43 million adults (19.0%) took aspirin at least three times per week for more than 3months (i.e. regular users), and more than 29 million adults (12.1%) were regular users of NSAIDs. Compared with 2005, this was an overall increase of 57% in aspirin use and 41% in NSAID use. These increases were consistent across the strata of age, sex, race, and selected medical conditions, including cardiovascular disease (CVD), arthritis, peptic ulcers, cancer, and severe headache, except for Asian Americans. ConclusionLarge increases in the use of both aspirin and NSAIDs were observed over a 5year period. The increase may be the result of increasing media attention reporting that regular aspirin use lowers the risk of CVD and related deaths, and may also prevent cancer. Moreover, safety concerns related to alternative medications such as acetaminophen and selective COX-2 inhibitors may influence users of these drugs to switch to aspirin and NSAIDs. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Zhou, Yingjun; Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Boudreau, Denise M.] Grp Hlth Res Inst, Seattle, WA USA. [Boudreau, Denise M.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. RP Freedman, AN (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 5128, Bethesda, MD 20892 USA. EM Andrew_Freedman@nih.gov NR 62 TC 45 Z9 46 U1 6 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2014 VL 23 IS 1 BP 43 EP 50 DI 10.1002/pds.3463 PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 282ND UT WOS:000329177700007 PM 23723142 ER PT J AU Simpson, RM Bastian, BC Michael, HT Webster, JD Prasad, ML Conway, CM Prieto, VM Gary, JM Goldschmidt, MH Esplin, DG Smedley, RC Piris, A Meuten, DJ Kiupel, M Lee, CCR Ward, JM Dwyer, JE Davis, BJ Anver, MR Molinolo, AA Hoover, SB Rodriguez-Canales, J Hewitt, SM AF Simpson, R. Mark Bastian, Boris C. Michael, Helen T. Webster, Joshua D. Prasad, Manju L. Conway, Catherine M. Prieto, Victor M. Gary, Joy M. Goldschmidt, Michael H. Esplin, D. Glen Smedley, Rebecca C. Piris, Adriano Meuten, Donald J. Kiupel, Matti Lee, Chyi-Chia R. Ward, Jerrold M. Dwyer, Jennifer E. Davis, Barbara J. Anver, Miriam R. Molinolo, Alfredo A. Hoover, Shelley B. Rodriguez-Canales, Jaime Hewitt, Stephen M. TI Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanoma; animal model; comparative study; clinical trial design; image analysis; digital telepathology; signal transduction ID ORAL MALIGNANT MELANOMAS; MUCOSAL MELANOMA; MELANOCYTIC NEOPLASMS; METASTATIC MELANOMA; DISTINCT SUBTYPES; CLINICAL-EFFICACY; BRAF MUTATIONS; ACTIVATED AKT; CELL-LINES; KIT AB Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. C1 [Simpson, R. Mark; Michael, Helen T.; Webster, Joshua D.; Gary, Joy M.; Dwyer, Jennifer E.; Hoover, Shelley B.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Bastian, Boris C.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Bastian, Boris C.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Bastian, Boris C.] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Prasad, Manju L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Conway, Catherine M.; Lee, Chyi-Chia R.; Rodriguez-Canales, Jaime; Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Prieto, Victor M.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Prieto, Victor M.] Univ Texas MD Anderson Canc Ctr, Dept Dermatol, Houston, TX 77030 USA. [Goldschmidt, Michael H.] Univ Penn, Sch Vet Med, Lab Pathol & Toxicol, Philadelphia, PA 19104 USA. [Esplin, D. Glen] ARUP Labs, Anim Reference Pathol Div, Salt Lake City, UT USA. [Smedley, Rebecca C.; Kiupel, Matti] Michigan State Univ, Diagnost Ctr Populat & Anim Hlth, E Lansing, MI 48824 USA. [Piris, Adriano] Massachusetts Gen Hosp, Dermatopathol Unit, Pathol Serv, Boston, MA 02114 USA. [Piris, Adriano] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Meuten, Donald J.] N Carolina State Univ, Coll Vet Med, Dept Populat Hlth & Pathobiol, Raleigh, NC USA. [Kiupel, Matti] Michigan State Univ, Dept Pathobiol & Diagnost Invest, Lansing, MI USA. [Ward, Jerrold M.] Global Vet Pathol Inc, Montgomery Village, MD USA. [Ward, Jerrold M.] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, Bethesda, MD 20892 USA. [Davis, Barbara J.] Davis Toxicol Pathol Consulting, Harvard, MA USA. [Anver, Miriam R.] Sci Applicat Int Corp Frederick Inc, Pathol Histotechnol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Molinolo, Alfredo A.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. RP Simpson, RM (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. EM ms43b@nih.gov; genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Goldschmidt, Michael/0000-0001-9515-0535 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; [R01- CA131524]; [P01 CA025874] FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Additional funding support was provided by The Animal Cancer Foundation, Norwalk, Connecticut [www.acfoundation.org/], and The Canine Comparative Oncology and Genomics Consortium, Inc., Rockville, Maryland [http://www.ccogc.net/]. NCI Comparative Melanoma Tumor Board meeting support was provided by the NCI Center for Cancer Research and The Animal Cancer Foundation. Dr. B. C. Bastian is supported by awards R01- CA131524, and P01 CA025874. Drs. J. M. Gary and H. T. Michael are currently molecular pathology fellows in the NIH Comparative Biomedical Scientist Training Program supported by the National Cancer Institute, in partnership with Michigan State University, East Lansing (Gary) and University of Maryland, College Park (Michael). Dr. M. R. Anver receives support through the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The authors thank Christina Mazcko, NCI, for assistance with study specimens and patient data, and John Hickerson, Kelly Government Solutions, for logistical support of tumor board study meetings. The views of the authors and tumor board members are their own, and no commercial endorsement is attributable to them or their affiliations. NR 55 TC 21 Z9 21 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD JAN PY 2014 VL 27 IS 1 DI 10.1111/pcmr.12185 PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 274UG UT WOS:000328631100010 PM 24128326 ER PT J AU Zhang, YL Helke, KL Coelho, SG Valencia, JC Hearing, VJ Sun, SL Liu, B Li, ZH AF Zhang, Yongliang Helke, Kristi L. Coelho, Sergio G. Valencia, Julio C. Hearing, Vincent J. Sun, Shaoli Liu, Bei Li, Zihai TI Essential role of the molecular chaperone gp96 in regulating melanogenesis SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE Gp96; melanogenesis; tyrosinase; melanosome ID SHOCK-PROTEIN GP96; B16 MELANOMA-CELLS; ENDOPLASMIC-RETICULUM; OCULOCUTANEOUS ALBINISM; QUALITY-CONTROL; MOUSE MELANOMA; TYROSINASE; MELANOCYTES; INHIBITION; MELANOSOMES AB Through a process known as melanogenesis, melanocyte produces melanin in specialized organelles termed melanosomes, which regulates pigmentation of the skin, eyes, and hair. Gp96 is a constitutively expressed heat shock protein in the endoplasmic reticulum whose expression is further upregulated upon ultraviolet irradiation. However, the roles and mechanisms of this chaperone in pigmentation biology are unknown. In this study, we found that knockdown of gp96 by RNA interference significantly perturbed melanin synthesis and blocked late melanosome maturation. Gp96 knockdown did not impair the expression of tyrosinase, an essential enzyme in melanin synthesis, but compromised its catalytic activity and melanosome translocation. Further, mice with melanocyte-specific deletion of gp96 displayed decreased pigmentation. A mechanistic study revealed that the defect in melanogenesis can be rescued by activation of the canonical Wnt pathway, consistent with the critical roles of gp96 in chaperoning Wnt-coreceptor LRP6. Thus, this work uncovered the essential role of gp96 in regulating melanogenesis. C1 [Zhang, Yongliang; Liu, Bei; Li, Zihai] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Helke, Kristi L.] Med Univ S Carolina, Dept Comparat Med, Charleston, SC 29425 USA. [Helke, Kristi L.; Sun, Shaoli] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Coelho, Sergio G.; Valencia, Julio C.; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Li, ZH (reprint author), Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. EM zihai@musc.edu RI zhang, yongliang/N-8326-2013; OI Helke, Kris/0000-0001-9746-0764 FU Intramural Research Program of the National Cancer Institute at NIH; NIH extramural Grants [AI070603, AI077283] FX This work was supported in part by the Intramural Research Program of the National Cancer Institute at NIH (to V.H.) and by NIH extramural Grants AI070603 and AI077283 to Z.L. NR 38 TC 3 Z9 3 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD JAN PY 2014 VL 27 IS 1 DI 10.1111/pcmr.12165 PG 9 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 274UG UT WOS:000328631100014 PM 24024552 ER PT J AU Phillips, SM McAuley, E AF Phillips, Siobhan M. McAuley, Edward TI Physical activity and quality of life in breast cancer survivors: the role of self-efficacy and health status SO PSYCHO-ONCOLOGY LA English DT Article DE breast cancer survivors; physical activity; quality of life; self-efficacy; health status ID MAXIMUM-LIKELIHOOD-ESTIMATION; STRUCTURAL EQUATION MODELS; OLDER-ADULTS; CLINICAL-TRIALS; MISSING DATA; METAANALYSIS; EXERCISE; PARTICIPATION; POPULATION; THERAPY AB ObjectiveMechanisms underlying the relationship between physical activity and quality of life (QOL) in breast cancer survivors are not well understood. The purpose of the present study was to longitudinally test a model examining self-efficacy and health status as potential mediators of this relationship. MethodsAt baseline and 6months, breast cancer survivors (n=1527) completed physical activity, self-efficacy, health status, and QOL measures, and a subsample (n=370) wore an accelerometer. Panel analysis within a covariance modeling framework was used to test the hypothesis that physical activity indirectly influences QOL across time. ResultsThe hypothesized model provided a good fit in the full sample ((2)=409.06; d.f.=91, p<0.001; comparative fit index (CFI)=0.98; standardized root mean residual (SRMR)=0.04) and the accelerometer subsample ((2)=320.96, d.f.=134, p<0.001; CFI=0.95; SRMR=0.05), indicating that physical activity indirectly, via self-efficacy and health status indicators, influences QOL across time. ConclusionsPhysical activity may influence QOL in breast cancer survivors through more proximal, modifiable factors. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Phillips, Siobhan M.; McAuley, Edward] Univ Illinois, Dept Kinesiol & Community Hlth, Urbana, IL USA. RP Phillips, SM (reprint author), NCI, Div Canc Control & Populat Sci, Off Canc Survivorship, 9609 Med Ctr Dr,Off 4E516, Rockville, MD 20850 USA. EM siobhan.phillips@mail.nih.gov FU National Institute on Aging at the National Institutes of Health [F31AG034025, AG020118]; Shahid and Ann Carlson Khan endowed professorship FX This work was supported by the National Institute on Aging at the National Institutes of Health through award numbers F31AG034025 and AG020118, and the Shahid and Ann Carlson Khan endowed professorship. NR 43 TC 7 Z9 7 U1 2 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD JAN PY 2014 VL 23 IS 1 BP 27 EP 34 DI 10.1002/pon.3366 PG 8 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 281ZW UT WOS:000329140800004 PM 24003002 ER PT J AU Fu, Y Mi, LX Sanda, M Silverstein, S Aggarwal, M Wang, DY Gupta, P Goldman, R Appella, DH Chung, FL AF Fu, Ying Mi, Lixin Sanda, Miloslav Silverstein, Shana Aggarwal, Monika Wang, Deyun Gupta, Pankaj Goldman, Radoslav Appella, Daniel H. Chung, Fung-Lung TI A click chemistry approach to identify protein targets of cancer chemopreventive phenethyl isothiocyanate SO RSC ADVANCES LA English DT Article ID APOPTOSIS; IDENTIFICATION; SULFORAPHANE; BINDING; CELLS; PROTEOMICS; MECHANISM; PRODUCTS; PLASMA; ARREST AB Here we report the identification of protein targets of chemopreventive phenethyl isothiocyanate (PEITC) via "click" chemistry in the A549 human lung cancer cell line, using a novel alkyne-tagged PEITC which was also found to show potent in vitro anticancer activity. C1 [Fu, Ying; Mi, Lixin; Sanda, Miloslav; Silverstein, Shana; Aggarwal, Monika; Goldman, Radoslav; Chung, Fung-Lung] Georgetown Univ, Lombardi Canc Res Ctr, Washington, DC 20007 USA. [Wang, Deyun; Gupta, Pankaj; Appella, Daniel H.] NIDDK, NIH, Bethesda, MD 20814 USA. RP Chung, FL (reprint author), Georgetown Univ, Lombardi Canc Res Ctr, Washington, DC 20007 USA. EM appellad@niddk.nih.gov; flc6@georgetown.edu FU NCI [CA100853, RO1-CA-100083-7]; National Institutes of Health [RO1CA135069]; Lombardi Cancer Center [P30 CA51008] FX This work is supported by NCI (grant CA100853 and RO1-CA-100083-7), National Institutes of Health grant RO1CA135069 and Lombardi Cancer Center Support Grant P30 CA51008. We thank Dr Lawrence Marnett (Vanderbilt University) and Dr Qiang Zhang (University of Warwick) for the suggestions on "click" chemistry, Mr Jishen Pan and Dr Marcin Dyba for the help of HPLC purification, Drs Ercheng Li, Amrita Cheema and Georgetown Lombardi Shared Resources for NMR and MS analysis, Dr Karen Creswell and Ms Marcy Chen (both are from core facilities of Lombardi Comprehensive Cancer Centre at Georgetown University) for flow cytometry analysis. NR 25 TC 1 Z9 1 U1 1 U2 13 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2046-2069 J9 RSC ADV JI RSC Adv. PY 2014 VL 4 IS 8 BP 3920 EP 3923 DI 10.1039/c3ra46849f PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 280ON UT WOS:000329040500032 ER PT J AU Aagaard, KM Segars, JH AF Aagaard, Kjersti M. Segars, James H. TI What Is the Microbiome and How Do We Study It? Preface SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Editorial Material C1 [Aagaard, Kjersti M.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Aagaard, KM (reprint author), HGSC, Dept Obstet & Gynecol, Div Maternal Fetal Med, 1 Baylor Plaza, Houston, TX 77030 USA. EM aagaardt@bcm.edu FU Intramural NIH HHS [ZIE HD008737-13]; NIDDK NIH HHS [P30 DK056338] NR 0 TC 1 Z9 1 U1 2 U2 8 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 EI 1526-4564 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JAN PY 2014 VL 32 IS 1 BP 3 EP 4 DI 10.1055/s-0033-1361816 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 285AQ UT WOS:000329365200002 PM 24390914 ER PT J AU Sirota, I Zarek, SM Segars, JH AF Sirota, Ido Zarek, Shvetha M. Segars, James H. TI Potential Influence of the Microbiome on Infertility and Assisted Reproductive Technology SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE microbiome; in vitro fertilization; Lactobacillus; progesterone ID IN-VITRO FERTILIZATION; COLONY-STIMULATING FACTOR; UTERINE EPITHELIAL-CELLS; CULTIVATION-INDEPENDENT METHODS; GRADIENT GEL-ELECTROPHORESIS; POLYMERASE-CHAIN-REACTION; BACTERIAL VAGINOSIS; HUMAN-ENDOMETRIUM; EMBRYO-TRANSFER; PROGESTERONE RESISTANCE AB Although an altered vaginal microbiota has been demonstrated to affect parturition, its role in assisted reproductive technologies is uncertain. Nevertheless, the effect of known pathogens such as Mycoplasma tuberculosis, Chlamydia trachomatis, and Neisseria gonorrhoeae is clear, causing subclinical changes thought to be risk factors in subfertility. The Human Microbiome Project (HMP) has allowed for metagenomic studies to aid in characterizing normal vaginal flora. Recent findings from the HMP demonstrate that many different species of Lactobacillus are present in the vaginal tract, with a few that predominate. Studies that characterize the vaginal microbiome in assisted reproductive technology support the hypothesis that colonizing the transfer-catheter tip with Lactobacillus crispatus at the time of embryo transfer may increase the rates of implantation and live birth rate while decreasing the rate of infection. In addition, there is some evidence that a progesterone-resistant endometrium might increase the risk of an abnormal vaginal microbiome. C1 [Sirota, Ido] St Lukes Roosevelt Hosp, Dept Obstet & Gynecol, New York, NY USA. [Zarek, Shvetha M.; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 CRC Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU Intramural research program of the Program in Reproductive and Adult Endocrinology, NICHD, NIH FX This research was supported, in part, by Intramural research program of the Program in Reproductive and Adult Endocrinology, NICHD, NIH. NR 106 TC 9 Z9 10 U1 3 U2 25 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 EI 1526-4564 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JAN PY 2014 VL 32 IS 1 BP 35 EP 42 DI 10.1055/s-0033-1361821 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 285AQ UT WOS:000329365200007 PM 24390919 ER PT J AU Sharma, H Tal, R Clark, NA Segars, JH AF Sharma, Harsha Tal, Reshef Clark, Natalie A. Segars, James H. TI Microbiota and Pelvic Inflammatory Disease SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE vaginal microbiota; bacterial vaginosis; pelvic inflammatory disease ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHLAMYDIA-TRACHOMATIS INFECTION; REPRODUCTIVE-AGE WOMEN; FEMALE GENITAL-TRACT; VAGINAL BACTERIAL COMMUNITIES; TUBO-OVARIAN ABSCESS; TRICHOMONAS-VAGINALIS; MYCOPLASMA-GENITALIUM; TUBOOVARIAN ABSCESS; ATOPOBIUM-VAGINAE AB Female genital tract microbiota play a crucial role in maintaining health. Disequilibrium of the microbiota has been associated with increased risk of pelvic infections. In recent years, culture-independent molecular techniques have expanded understanding of the composition of genital microbiota and the dynamic nature of the microbiota. There is evidence that upper genital tract may not be sterile and may harbor microflora in the physiologic state. The isolation of bacterial vaginosis-associated organisms in women with genital infections establishes a link between pelvic infections and abnormal vaginal flora. With the understanding of the composition of the microbiota in healthy and diseased states, the next logical step is to identify the function of the newly identified microbes. This knowledge will further expand our understanding of the causation of pelvic infections, which may lead to more effective prevention and treatment strategies. C1 [Sharma, Harsha] Queens Hosp Ctr, Mt Sinai Sch Med, Jamaica Program, Dept Obstet & Gynecol, Queens, NY USA. [Tal, Reshef] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Clark, Natalie A.] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Segars, JH (reprint author), NIH, CRC, Bldg 10,Room 1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov OI Tal, Reshef/0000-0002-2500-9904 FU NIH Intramural Research Program in Reproductive and Adult Endocrinology FX This research was supported in part by the NIH Intramural Research Program in Reproductive and Adult Endocrinology. NR 102 TC 12 Z9 14 U1 3 U2 13 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 EI 1526-4564 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JAN PY 2014 VL 32 IS 1 BP 43 EP 49 DI 10.1055/s-0033-1361822 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 285AQ UT WOS:000329365200008 PM 24390920 ER PT S AU Domagalski, MJ Zheng, HP Zimmerman, MD Dauter, Z Wlodawer, A Minor, W AF Domagalski, Marcin J. Zheng, Heping Zimmerman, Matthew D. Dauter, Zbigniew Wlodawer, Alexander Minor, Wladek BE Chen, YW TI The Quality and Validation of Structures from Structural Genomics SO STRUCTURAL GENOMICS: GENERAL APPLICATIONS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Structure quality; Structure validation; Drug discovery; Data mining; Structural genomics ID PROTEIN DATA-BANK; CRYSTAL-STRUCTURES; WATER-MOLECULES; STRUCTURE REFINEMENT; DENSITY MODIFICATION; MODEL; CRYSTALLOGRAPHY; REPLACEMENT; DIFFRACTION; RESOLUTION AB Quality control of three-dimensional structures of macromolecules is a critical step to ensure the integrity of structural biology data, especially those produced by structural genomics centers. Whereas the Protein Data Bank (PDB) has proven to be a remarkable success overall, the inconsistent quality of structures reveals a lack of universal standards for structure/deposit validation. Here, we review the state-of-the-art methods used in macromolecular structure validation, focusing on validation of structures determined by X-ray crystallography. We describe some general protocols used in the rebuilding and re-refinement of problematic structural models. We also briefly discuss some frontier areas of structure validation, including refinement of protein-ligand complexes, automation of structure redetermination, and the use of NMR structures and computational models to solve X-ray crystal structures by molecular replacement. C1 [Domagalski, Marcin J.; Zheng, Heping; Zimmerman, Matthew D.; Minor, Wladek] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22903 USA. [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Argonne Natl Lab, Argonne, IL USA. [Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Domagalski, MJ (reprint author), Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22903 USA. RI Minor, Wladek/F-3096-2014; Zimmerman, Matthew/N-9489-2013; OI Zimmerman, Matthew/0000-0002-6274-9493; Minor, Wladek/0000-0001-7075-7090 FU Intramural NIH HHS; NCI NIH HHS [P30 CA044579]; NIAID NIH HHS [HHSN272201200026C]; NIGMS NIH HHS [R01 GM053163, U54 GM094585, U54 GM094662]; PHS HHS [HHSN272201200026C] NR 42 TC 6 Z9 6 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-62703-691-7; 978-1-62703-690-0 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2014 VL 1091 BP 297 EP 314 DI 10.1007/978-1-62703-691-7_21 D2 10.1007/978-1-62703-691-7 PG 18 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA BJJ06 UT WOS:000328383200022 PM 24203341 ER PT J AU Beratarrechea, A Lee, AG Willner, JM Jahangir, E Ciapponi, A Rubinstein, A AF Beratarrechea, Andrea Lee, Allison G. Willner, Jonathan M. Jahangir, Eiman Ciapponi, Agustin Rubinstein, Adolfo TI The Impact of Mobile Health Interventions on Chronic Disease Outcomes in Developing Countries: A Systematic Review SO TELEMEDICINE AND E-HEALTH LA English DT Article DE chronic disease; mobile health; short message service; cellular phone; developing countries; systematic review ID RANDOMIZED CONTROLLED-TRIAL; SHORT-MESSAGE SERVICE; IMPROVE ATTENDANCE; BEHAVIOR-CHANGE; ASTHMA CONTROL; CARE; TELEPHONE; REMINDERS; MANAGEMENT; PHONES AB Introduction:Rates of chronic diseases will continue to rise in developing countries unless effective and cost-effective interventions are implemented. This review aims to discuss the impact of mobile health (m-health) on chronic disease outcomes in low- and middle-income countries (LMIC).Materials and Methods:Systematic literature searches were performed using CENTRAL, MEDLINE, EMBASE, and LILACS databases and gray literature. Scientific literature was searched to identify controlled studies evaluating cell phone voice and text message interventions to address chronic diseases in adults in low- or middle-income countries. Outcomes measured included morbidity, mortality, hospitalization rates, behavioral or lifestyle changes, process of care improvements, clinical outcomes, costs, patient-provider satisfaction, compliance, and health-related quality of life (HRQoL).Results:From the 1,709 abstracts retrieved, 163 articles were selected for full text review, including 9 randomized controlled trials with 4,604 participants. Most of the studies addressed more than one outcome. Of the articles selected, six studied clinical outcomes, six studied processes of care, three examined healthcare costs, and two examined HRQoL. M-health positively impacted on chronic disease outcomes, improving attendance rates, clinical outcomes, and HRQoL, and was cost-effective.Conclusions:M-health is emerging as a promising tool to address access, coverage, and equity gaps in developing countries and low-resource settings. The results for m-health interventions showed a positive impact on chronic diseases in LMIC. However, a limiting factor of this review was the relatively small number of studies and patients enrolled, highlighting the need for more rigorous research in this area in developing countries. C1 [Beratarrechea, Andrea; Ciapponi, Agustin; Rubinstein, Adolfo] South Amer Ctr Excellence Cardiovasc Hlth, Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Lee, Allison G.; Willner, Jonathan M.; Jahangir, Eiman] Fogarty Int Ctr, Bethesda, MD USA. RP Beratarrechea, A (reprint author), South Amer Ctr Excellence Cardiovasc Hlth, Inst Clin Effectiveness & Hlth Policy, Emilio Ravignani 2024,C1414CPV, Buenos Aires, DF, Argentina. EM aberatarrechea@iecs.org.ar RI Jahangir, Eiman/P-1053-2015; Emchi, Karma/Q-1952-2016 OI Jahangir, Eiman/0000-0001-6944-5321; FU National Institutes of Health; Office of the Director; Fogarty International Center; Office of AIDS Research; National Cancer Center; National Eye Institute; National Heart, Blood, and Lung Institute; National Institute of Dental and Craniofacial Research; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Allergy and Infectious Diseases; National Institutes of Health Office of Women's Health and Research through the Vanderbilt University [R24 TW007988]; American Relief and Recovery Act FX A.G.L., J.M.W., and E.J. received funding as a Fogarty International Clinical Research Fellow, a program that is supported by the National Institutes of Health, Office of the Director, Fogarty International Center, Office of AIDS Research, National Cancer Center, National Eye Institute, National Heart, Blood, and Lung Institute, National Institute of Dental and Craniofacial Research, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, and National Institutes of Health Office of Women's Health and Research through the International Clinical Research Scholars and Fellows Program at Vanderbilt University (R24 TW007988) and the American Relief and Recovery Act. NR 52 TC 48 Z9 49 U1 1 U2 33 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD JAN 1 PY 2014 VL 20 IS 1 BP 75 EP 82 DI 10.1089/tmj.2012.0328 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 282HV UT WOS:000329162700011 PM 24205809 ER PT J AU Ward, JM Rehg, JE AF Ward, J. M. Rehg, J. E. TI Rodent Immunohistochemistry: Pitfalls and Troubleshooting SO VETERINARY PATHOLOGY LA English DT Article DE immunohistochemistry; IHC; antibodies; background staining; artifacts; mice; mouse pathology ID NORMAL-TISSUES; MICE; ANTIBODIES; REACTIVITY; DIAGNOSIS; PATHOLOGY; UTILITY; LESIONS; IMMUNE; SYSTEM AB Immunohistochemistry (IHC) is a common adjunct in pathology for morphologic diagnosis, research pathology, and studying the pathogenesis of the disease. Proper technique and interpretation of an immunohistochemistry assay is of utmost importance. A variety of problems, including the presence of artifacts (nonspecific background or other staining problems) and the differentiation between nonspecific and specific staining, commonly occur. It is essential that antibody quality and IHC technique be optimized. We review the histologic patterns of specific and nonspecific staining after using IHC techniques, as well as basic troubleshooting procedures, and provide some examples of nonspecific staining and other artifacts especially in formalin-fixed, paraffin-embedded tissues (FFPE) of mice. C1 [Ward, J. M.] Global VetPathol, Montgomery Village, MD USA. [Ward, J. M.] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Rehg, J. E.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. RP Ward, JM (reprint author), NIAID, VCIS, LIG, NIH, MS 8152,Twinbrook 1,Room 1518, Bethesda, MD 20892 USA. EM veterinarypathology@gmail.com FU National Cancer Institute [P30C CA 21765]; American Lebanese Syrian Associated Charities (ALSAC) FX The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This publication was supported, in part, by grant P30C CA 21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). Its contents are solely the responsibility of the authors and do not necessary represent the official view of the National Cancer Institute. NR 22 TC 5 Z9 5 U1 0 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD JAN PY 2014 VL 51 IS 1 BP 88 EP 101 DI 10.1177/0300985813503571 PG 14 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 284UY UT WOS:000329347900006 PM 24078006 ER PT J AU Ramos-Vara, JA Webster, JD DuSold, D Miller, MA AF Ramos-Vara, J. A. Webster, J. D. DuSold, D. Miller, M. A. TI Immunohistochemical Evaluation of the Effects of Paraffin Section Storage on Biomarker Stability SO VETERINARY PATHOLOGY LA English DT Article DE cell markers; immunohistochemistry; infectious diseases; paraffin section storage; photo-oxidation; antigen decay; tissue-based biomarkers ID MARKER-IMMUNOSTAINING INTENSITY; EMBEDDED TISSUE-SECTIONS; P53 ANTIGEN LOSS; STORED PARAFFIN; BREAST-CANCER; DIAGNOSTIC IMMUNOHISTOCHEMISTRY; EXPRESSION ANALYSIS; FORMALIN FIXATION; MOLECULAR-BIOLOGY; ARCHIVAL TISSUE AB Environmental stresses can alter immunoreactivity of biomarkers in stored tissue sections. The effect of temperature and lighting on 49 cellular or microbial antigens was evaluated in 4 serial paraffin sections, cut 12 months, 10 months, 8 months, 5 months, 3 months, 1month, 3 days, and 1day before immunohistochemistry. Slides were stored at room temperature (RT) in the dark, at 4 degrees C in the dark, at RT under fluorescent light, or at RT with windowpane exposure to sunlight. Immunohistochemistry was performed simultaneously in an automated immunostainer. Immunoreactivity was compared with that in the corresponding 1-day-old section and scored as 4 (<10% reduction), 3 (10%-25% reduction), 2 (26%-60% reduction), 1(>60% reduction), or 0 (no reactivity). Any loss of immunoreactivity was proportional to the tissue section age and was least in sections stored in the dark. Immunoreactivity was only completely lost in light-exposed sections and as early as 1month for CD45. Other markers with complete loss of immunoreactivity were bovine viral diarrhea virus, CD18 (only with fluorescent light), CD31, CD68, canine parvovirus, chromogranins, and thyroid transcription factor-1. Markers with complete loss after light exposure also had reduced immunoreactivity when stored in the dark, as early as day 3. Eight markers (Bartonella spp, CD11d, high molecular weight cytokeratins, feline coronavirus, GATA-4, insulin, p63, progesterone receptor) had minimal decrease in immunoreactivity, regardless of treatment. In conclusion, light-induced antigen decay (tissue section aging) is antigen dependent and could explain unexpectedly weak or negative immunohistochemical reactions in stored paraffin sections. C1 [Ramos-Vara, J. A.; DuSold, D.; Miller, M. A.] Purdue Univ, Anim Dis Diagnost Lab, W Lafayette, IN 47907 USA. [Ramos-Vara, J. A.; DuSold, D.; Miller, M. A.] Purdue Univ, Dept Comparat Pathobiol, W Lafayette, IN 47907 USA. [Webster, J. D.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Ramos-Vara, JA (reprint author), Purdue Univ, Anim Dis Diagnost Lab, 406 South Univ, W Lafayette, IN 47907 USA. EM ramosja@purdue.edu NR 59 TC 5 Z9 5 U1 2 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD JAN PY 2014 VL 51 IS 1 BP 102 EP 109 DI 10.1177/0300985813476067 PG 8 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 284UY UT WOS:000329347900007 PM 23435571 ER PT J AU Tabe, Y Jin, LH Konopleva, M Shikami, M Kimura, S Andreeff, M Raffeld, M Miida, T AF Tabe, Yoko Jin, Linhua Konopleva, Marina Shikami, Masato Kimura, Shinya Andreeff, Michael Raffeld, Mark Miida, Takashi TI Class IA Phosphatidylinositol 3-Kinase Inhibition Inhibits Cell Growth and Proliferation in Mantle Cell Lymphoma SO ACTA HAEMATOLOGICA LA English DT Article DE Akt; BCR signaling; Class IA phosphatidylinositol 3-kinase; Mantle cell lymphoma ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CYCLIN D1; PHOSPHOINOSITIDE 3-KINASE; P110-DELTA; GENE; KINASE; PI3K; PATHOGENESIS; ACTIVATION; EXPRESSION AB Background/Aims: Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway preferentially occurs in aggressive blastoid variants of mantle cell lymphoma (MCL) and is implicated in the pathogenesis of this disease. In this study, we investigated the role of PI3K isoforms on proliferation of aggressive MCL cells. Methods:The changes in cell viability, cell cycle distribution and apoptosis induction by the PI3K isoform-selective inhibitors were evaluated. The molecular basis underlying the effects of the specific inhibition of PI3K isoforms was investigated by Western blot analysis. Results: Our results demonstrated that a class IA PI3K isoform is most commonly involved in the constitutive activation of Akt in aggressive MCL. Treatment with a p110 alpha isoform-specific inhibitor induced prominent cell cycle arrest followed by a poptosis through complete abolishment of phosphorylated (p)-Akt and its downstream targets. An inhibitor of isoform p110 delta induced moderate cell cycle arrest with down-regulation of p-Akt and p-S6K. A dual inhibitor of p110 alpha and p110 delta GDC-0941 caused more prominent cell growth inhibition compared to selective p110 alpha or p110 delta inhibitors. Inhibition of the class IB PI3K isoform p110 gamma did not cause cell cycle arrest or induce apoptosis in MCL cells. Conclusion: These findings suggest that the therapeutic ablation of class IA PI3K may be a promising strategy for the treatment of refractory, aggressive MCL. Copyright (C) 2013 S. Karger AG, Basel C1 [Tabe, Yoko; Jin, Linhua; Miida, Takashi] Juntendo Univ, Sch Med, Dept Clin Lab Med, Tokyo, Japan. [Kimura, Shinya] Saga Univ, Fac Med, Dept Internal Med, Div Hematol Resp Med & Oncol, Honjo, Japan. [Konopleva, Marina; Andreeff, Michael] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Raffeld, Mark] NCI, Mol Diagnost Sect, Pathol Lab, Bethesda, MD 20892 USA. RP Tabe, Y (reprint author), Juntendo Univ, Sch Med, Dept Clin Lab Med, 2-1-1 Bunkyo Ku, Hongo, Tokyo, Japan. EM tabe@juntendo.ac.jp RI Miida, Takashi/A-5589-2012 OI Miida, Takashi/0000-0002-4294-8030 FU Institute for Environmental and Gender-specific Medicine, Juntendo University; Project Research Program of the Juntendo University School of Medicine FX This work was supported in part by the Institute for Environmental and Gender-specific Medicine, Juntendo University, and by the Project Research Program of the Juntendo University School of Medicine (to Y.T.). NR 35 TC 6 Z9 8 U1 0 U2 14 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0001-5792 EI 1421-9662 J9 ACTA HAEMATOL-BASEL JI Acta Haematol. PY 2014 VL 131 IS 1 BP 59 EP 69 DI 10.1159/000353164 PG 11 WC Hematology SC Hematology GA 278UN UT WOS:000328915500010 PM 24052005 ER PT J AU Chaves, LF Scott, TW Morrison, AC Takada, T AF Chaves, Luis Fernando Scott, Thomas W. Morrison, Amy C. Takada, Takenori TI Hot temperatures can force delayed mosquito outbreaks via sequential changes in Aedes aegypti demographic parameters in autocorrelated environments SO ACTA TROPICA LA English DT Article DE Population delay; Density dependence; Climate change; Trade-offs; Lefkovitch matrix ID YELLOW-FEVER MOSQUITO; POPULATION-DYNAMICS; DIPTERA-CULICIDAE; DENSITY-DEPENDENCE; SEASONAL ABUNDANCE; LIFE-HISTORY; INTRASPECIFIC COMPETITION; VARIABLE ENVIRONMENTS; INSECT METABOLISM; STEGOMYIA AEGYPTI AB Aedes aegypti L (Diptera: Culicidae) is a common pantropical urban mosquito, vector of dengue, Yellow Fever and chikungunya viruses. Studies have shown Ae. aegypti abundance to be associated with environmental fluctuations, revealing patterns such as the occurrence of delayed mosquito outbreaks, i.e., sudden extraordinary increases in mosquito abundance following transient extreme high temperatures. Here, we use a two-stage (larvae and adults) matrix model to propose a mechanism for environmental signal canalization into demographic parameters of Ae. aegypti that could explain delayed high temperature induced mosquito outbreaks. We performed model simulations using parameters estimated from a weekly time series from Thailand, assuming either independent or autocorrelated environments. For autocorrelated environments, we found that long delays in the association between the onset of "hot" environments and mosquito outbreaks (10 weeks, as observed in Thailand) can be generated when "hot" environments sequentially trigger a larval survival decrease and over-compensatory fecundity increase, which lasts for the whole "hot" period, in conjunction with a larval survival increase followed by a fecundity decrease when the environment returns to "normal". This result was not observed for independent environments. Finally, we discuss our results implications for prospective entomological research and vector management under changing environments. (C) 2013 Elsevier B.V. All rights reserved. C1 [Chaves, Luis Fernando] Nagasaki Univ, Inst Trop Med NEKKEN, Nagasaki 8528523, Japan. [Chaves, Luis Fernando] Univ Nacl, Escuela Medicina Veterinaria, Programa Invest Enfermedades Trop, Heredia, Costa Rica. [Chaves, Luis Fernando; Takada, Takenori] Hokkaido Univ, Grad Sch Environm Sci, Sapporo, Hokkaido 0600810, Japan. [Scott, Thomas W.; Morrison, Amy C.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Chaves, LF (reprint author), Nagasaki Univ, Inst Trop Med NEKKEN, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. EM lchaves@nagasaki-u.ac.jp RI Chaves, Luis Fernando/F-3448-2010 OI Chaves, Luis Fernando/0000-0002-5301-2764 FU Nagasaki University; Japan Society for the Promotion of Science FX This research was funded by Nagasaki University (Program for Nurturing Global Leaders in Tropical and Emerging Communicable Diseases and Cooperative Grant) and Japan Society for the Promotion of Science. This work also 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 Center, National Institutes of Health, USA. LFC and TT wish to dedicate this article to the memory of their friend Shoichi Yamada, who left too early. NR 89 TC 12 Z9 13 U1 5 U2 45 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X EI 1873-6254 J9 ACTA TROP JI Acta Trop. PD JAN PY 2014 VL 129 SI SI BP 15 EP 24 DI 10.1016/j.actatropica.2013.02.025 PG 10 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 278FJ UT WOS:000328874300002 PM 23537497 ER PT J AU O'Seaghdha, CM Tin, A Yang, Q Katz, R Liu, YM Harris, T Astor, B Coresh, J Fox, CS Kao, WHL Shlipak, MG AF O'Seaghdha, Conall M. Tin, Adrienne Yang, Qiong Katz, Ronit Liu, YongMei Harris, Tamara Astor, Brad Coresh, Josef Fox, Caroline S. Kao, W. H. Linda Shlipak, Michael G. TI Association of a Cystatin C Gene Variant With Cystatin C Levels, CKD, and Risk of Incident Cardiovascular Disease and Mortality SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Cystatin C; chronic kidney disease; genetics; single-nucleotide polymorphism; net reclassification improvement ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; GENOME-WIDE ASSOCIATION; SERUM CREATININE; ELDERLY PERSONS; POOLED ANALYSIS; RENAL-DISEASE; EQUATION; RECLASSIFICATION; PREDICTION AB Background: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFR(cys)). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality. Study Design: Observational. Setting&Population: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies. Predictors: We estimated the association of rs13038305 with eGFR(cys) and serum creatinine-based eGFR (eGFR(cr)) and performed longitudinal analyses of the associations of eGFR(cys) with mortality and cardiovascular events following adjustment for rs13038305. Outcomes: We assessed reclassification by genotype-adjusted eGFR(cys) across CKD categories:, 45, 45-59, 60-89, and >= 90mL/min/1.73m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFR(cys) category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis. Results: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73m(2) higher eGFR(cys), and 36%[95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73m(2) lower eGFR(cys) were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, 20.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD. Limitations: rs13038305 explains only a small proportion of cystatin C variation. Conclusions: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [O'Seaghdha, Conall M.; Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Renal, Boston, MA 02114 USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Tin, Adrienne; Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Katz, Ronit; Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94143 USA. [Katz, Ronit; Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Liu, YongMei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Harris, Tamara] Natl Inst Aging, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. [Astor, Brad] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA. [Coresh, Josef] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. RP Shlipak, MG (reprint author), Univ Calif San Francisco, 4150 Clement St 111A1, San Francisco, CA 94121 USA. EM michael.shlipak@ucsf.edu RI Yang, Qiong/G-5438-2014 FU National Institute on Aging (NIA) [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health (NIH) [HHSN268200782096C]; Intramural Research Program of the NIH, NIA FX Support: This research was supported by National Institute on Aging (NIA) contracts N01AG62101, N01AG62103, and N01AG62106. The GWAS was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA. NR 24 TC 6 Z9 6 U1 1 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JAN PY 2014 VL 63 IS 1 BP 16 EP 22 DI 10.1053/j.ajkd.2013.06.015 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 281PA UT WOS:000329112300007 PM 23932088 ER PT J AU Dember, LM Imrey, PB Beck, GJ Cheung, AK Himmelfarb, J Huber, TS Kusek, JW Roy-Chaudhury, P Vazquez, MA Alpers, CE Robbin, ML Vita, JA Greene, T Gassman, JJ Feldman, HI AF Dember, Laura M. Imrey, Peter B. Beck, Gerald J. Cheung, Alfred K. Himmelfarb, Jonathan Huber, Thomas S. Kusek, John W. Roy-Chaudhury, Prabir Vazquez, Miguel A. Alpers, Charles E. Robbin, Michelle L. Vita, Joseph A. Greene, Tom Gassman, Jennifer J. Feldman, Harold I. CA Hemodialysis Fistula Maturation St TI Objectives and Design of the Hemodialysis Fistula Maturation Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Vascular access; arteriovenous fistula; observational ID PULSE-WAVE VELOCITY; FLOW-MEDIATED VASODILATION; STAGE RENAL-DISEASE; ARTERIOVENOUS-FISTULA; INTIMAL HYPERPLASIA; BRACHIAL-ARTERY; GENE-EXPRESSION; ACCESS OUTCOMES; FAILURE; MODEL AB Background: A large proportion of newly created arteriovenous fistulas cannot be used for dialysis because they fail to mature adequately to support the hemodialysis blood circuit. The Hemodialysis Fistula Maturation (HFM) Studywasdesigned to elucidate clinical and biological factors associated with fistula maturation outcomes. Study Design: Multicenter prospective cohort study. Setting & Participants: Approximately 600 patients undergoing creation of a new hemodialysis fistula will be enrolled at 7 centers in the United States and followed up for as long as 4 years. Predictors: Clinical, anatomical, biological, and process-of-care attributes identified pre-, intra-, or postoperatively. Outcomes: The primary outcome is unassisted clinical maturation, defined as successful use of the fistula for dialysis for 4 weeks without maturation-enhancing procedures. Secondary outcomes include assisted clinical maturation, ultrasound-based anatomical maturation, fistula procedures, fistula abandonment, and central venous catheter use. Measurements: Preoperative ultrasound arterial and venous mapping, flow-mediated and nitroglycerin-mediated brachial artery dilation, arterial pulse wave velocity, and venous distensibility; intraoperative vein tissue collection for histopathologic and molecular analyses; postoperative ultrasounds at 1 day, 2 weeks, 6 weeks, and prior to fistula intervention and initial cannulation. Results: Assuming complete data, no covariate adjustment, and unassisted clinical maturation of 50%, there will be 80% power to detect ORs of 1.83 and 1.61 for dichotomous predictor variables with exposure prevalences of 20% and 50%, respectively. Limitations: Exclusion of 2-stage transposition fistulas limits generalizability. The requirement for study visits may result in a cohort that is healthier than the overall population of patients undergoing fistula creation. Conclusions: The HFM Study will be of sufficient size and scope to: (1) evaluate a broad range of mechanistic hypotheses, (2) identify clinical practices associated with maturation outcomes, (3) assess the predictive utility of early indicators of fistula outcome, and (4) establish targets for novel therapeutic interventions to improve fistula maturation. (C) 2013 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Dember, Laura M.; Feldman, Harold I.] Univ Penn, Perelman Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Imrey, Peter B.; Beck, Gerald J.; Gassman, Jennifer J.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Cheung, Alfred K.] Univ Utah, Sch Med, Nephrol & Hypertens Div, Salt Lake City, UT USA. [Himmelfarb, Jonathan] Univ Washington, Kidney Res Inst, Div Nephrol, Seattle, WA 98195 USA. [Huber, Thomas S.] Univ Florida, Coll Med, Div Vasc Surg & Endovasc Therapy, Gainesville, FL USA. [Kusek, John W.] NIDDK, NIH, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Roy-Chaudhury, Prabir] Univ Cincinnati, Coll Med, Div Nephrol & Hypertens, Cincinnati, OH USA. [Vazquez, Miguel A.] Univ Texas Southwestern, Div Nephrol, Dallas, TX USA. [Alpers, Charles E.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Robbin, Michelle L.] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL USA. [Vita, Joseph A.] Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. [Vita, Joseph A.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Greene, Tom] Univ Utah, Sch Med, Div Epidemiol, Salt Lake City, UT USA. [Feldman, Harold I.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Dember, LM (reprint author), Univ Penn, Perelman Sch Med, Renal Electrolyte & Hypertens Div, 1 Founders,3400 Spruce St, Philadelphia, PA 19104 USA. EM ldember@upenn.edu OI Imrey, Peter/0000-0002-0533-4603 FU NIDDK [U01DK066597, U01DK082179, U01DK082189, U01DK082218, U01DK082222, U01DK082236, U01DK082240] FX Support: The HFM Study is funded by the following grants from the NIDDK: U01DK066597, U01DK082179, U01DK082189, U01DK082218, U01DK082222, U01DK082236, and U01DK082240. NR 45 TC 26 Z9 28 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JAN PY 2014 VL 63 IS 1 BP 104 EP 112 DI 10.1053/j.ajkd.2013.06.024 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 281PA UT WOS:000329112300017 PM 23992885 ER PT J AU Johnston, JJ Sapp, JC Curry, C Horton, M Leon, E Cusmano-Ozog, K Dobyns, WB Hudgins, L Zackai, E Biesecker, LG AF Johnston, Jennifer J. Sapp, Julie C. Curry, Cynthia Horton, Margaret Leon, Eyby Cusmano-Ozog, Kristina Dobyns, William B. Hudgins, Louanne Zackai, Elaine Biesecker, Leslie G. TI Expansion of the TARP Syndrome Phenotype Associated With De Novo Mutations and Mosaicism SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE TARP; RBM10 ID RBM10; EXONS; GENE AB The TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) is an X-linked disorder that was determined to be caused by mutations in RBM10 in two families, and confirmed in a subsequent case report. The first two original families were quite similar in phenotype, with uniform early lethality although a confirmatory case report showed survival into childhood. Here we report on five affecteds from three newly recognized families, including patients with atypical manifestations. None of the five patients had talipes and others also lacked cardinal TARP features of Robin sequence and atrial septal defect. All three families demonstrated de novo mutations, and one of the families had two recurrences, with demonstrable maternal mosaicism. (c) 2013 Wiley Periodicals, Inc. C1 [Johnston, Jennifer J.; Sapp, Julie C.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Curry, Cynthia] Fresno Calif State Univ Fresno, Fresno, CA USA. [Horton, Margaret; Zackai, Elaine] Childrens Hosp Philadelphia, Dept Pediat, Div Genet, Philadelphia, PA 19104 USA. [Leon, Eyby] Univ Utah, Dept Pediat, Div Genet, Salt Lake City, UT USA. [Cusmano-Ozog, Kristina; Hudgins, Louanne] Stanford Univ, Dept Pediat, Div Genet, Palo Alto, CA 94304 USA. [Dobyns, William B.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Dobyns, William B.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Dobyns, William B.] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA USA. RP Johnston, JJ (reprint author), 49 Convent Dr,Room 4C64, Bethesda, MD 20892 USA. EM jjohnsto@mail.nih.gov OI Dobyns, William/0000-0002-7681-2844 FU National Human Genome Research Institute, National Institutes of Health FX Grant sponsor: National Human Genome Research Institute, National Institutes of Health. NR 11 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2014 VL 164 IS 1 BP 120 EP 128 DI 10.1002/ajmg.a.36212 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 276FV UT WOS:000328734900017 PM 24259342 ER PT J AU Ahmed, A Bourge, RC Fonarow, GC Patel, K Morgan, CJ Fleg, JL Aban, IB Love, TE Yancy, CW Deedwania, P van Veldhuisen, DJ Filippatos, GS Anker, SD Allman, RM AF Ahmed, Ali Bourge, Robert C. Fonarow, Gregg C. Patel, Kanan Morgan, Charity J. Fleg, Jerome L. Aban, Inmaculada B. Love, Thomas E. Yancy, Clyde W. Deedwania, Prakash van Veldhuisen, Dirk J. Filippatos, Gerasimos S. Anker, Stefan D. Allman, Richard M. TI Digoxin Use and Lower 30-day All-cause Readmission for Medicare Beneficiaries Hospitalized for Heart Failure SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Digoxin; Heart failure; Hospital readmission ID CONVERTING ENZYME-INHIBITORS; PRESERVED EJECTION FRACTION; INVESTIGATION GROUP TRIAL; RENIN-ANGIOTENSIN INHIBITION; CHRONIC KIDNEY-DISEASE; PROPENSITY-SCORE; CLINICAL EFFECTIVENESS; OLDER PATIENTS; DIG TRIAL; MORTALITY AB BACKGROUND: Heart failure is the leading cause for hospital readmission, the reduction of which is a priority under the Affordable Care Act. Digoxin reduces 30-day all-cause hospital admission in chronic systolic heart failure. Whether digoxin is effective in reducing readmission after hospitalization for acute decompensation remains unknown. METHODS: Of the 5153 Medicare beneficiaries hospitalized for acute heart failure and not receiving digoxin, 1054 (20%) received new discharge prescriptions for digoxin. Propensity scores for digoxin use, estimated for each of the 5153 patients, were used to assemble a matched cohort of 1842 (921 pairs) patients (mean age, 76 years; 56% women; 25% African American) receiving and not receiving digoxin, who were balanced on 55 baseline characteristics. RESULTS: Thirty-day all-cause readmission occurred in 17% and 22% of matched patients receiving and not receiving digoxin, respectively (hazard ratio [HR] for digoxin, 0.77; 95% confidence interval [CI], 0.63-0.95). This beneficial association was observed only in those with ejection fraction < 45% (HR 0.63; 95% CI, 0.47-0.83), but not in those with ejection fraction >= 45% (HR 0.91; 95% CI, 0.60-1.37; P for interaction,.145), a difference that persisted throughout the first 12 months postdischarge (P for interaction, .019). HRs (95% CIs) for 12-month heart failure readmission and all-cause mortality were 0.72 (0.61-0.86) and 0.83 (0.70-0.98), respectively. CONCLUSIONS: In Medicare beneficiaries with systolic heart failure, a discharge prescription of digoxin was associated with lower 30-day all-cause hospital readmission, which was maintained at 12 months, and was not at the expense of higher mortality. Future randomized controlled trials are needed to confirm these findings. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ahmed, Ali; Bourge, Robert C.; Patel, Kanan; Morgan, Charity J.; Aban, Inmaculada B.; Allman, Richard M.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Ahmed, Ali; Allman, Richard M.] Vet Affairs Med Ctr, Birmingham, AL USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Los Angeles, CA USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Love, Thomas E.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Yancy, Clyde W.] Northwestern Univ, Chicago, IL 60611 USA. [Deedwania, Prakash] Univ Calif San Francisco, Fresno, CA USA. [van Veldhuisen, Dirk J.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Filippatos, Gerasimos S.] Attikon Univ Hosp, Athens, Greece. [Anker, Stefan D.] Campus Virchow Klinikum, Charite, Berlin, Germany. RP Ahmed, A (reprint author), Univ Alabama Birmingham, 1720 2nd Ave South,CH19,Ste 219, Birmingham, AL 35294 USA. EM aahmed@uab.edu RI van Veldhuisen, Dirk Jan/E-8967-2014; Lainscak, Mitja/F-3237-2015 FU National Institutes of Health (NIH) through National Heart, Lung, and Blood Institute [R01-HL085561, R01-HL085561-S, R01-HL097047]; NIH [UL1 TR000165] FX AA was in part supported by the National Institutes of Health (NIH) through grants (R01-HL085561, R01-HL085561-S, and R01-HL097047) from the National Heart, Lung, and Blood Institute and a generous gift from Ms. Jean B. Morris of Birmingham, AL. RMA is supported in part by grant number UL1 TR000165 from NIH. NR 51 TC 18 Z9 19 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD JAN PY 2014 VL 127 IS 1 BP 61 EP 70 DI 10.1016/j.amjmed.2013.08.027 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 281UA UT WOS:000329125300023 PM 24257326 ER PT J AU Nygaard, IE Romero, R AF Nygaard, Ingrid E. Romero, Roberto TI In appreciation of the leadership and stewardship of Drs Thomas J. Garite and Moon H. Kim SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID PRETERM PREMATURE RUPTURE; FETAL PULSE OXIMETRY; HEART-RATE PATTERNS; EARLY EMBRYO DEVELOPMENT; JOURNAL-OF-OBSTETRICS; INTRAPARTUM MANAGEMENT; GROWTH RESTRICTION; CONTROLLED TRIAL; CLINICAL-TRIAL; MEMBRANES C1 [Nygaard, Ingrid E.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT 84108 USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Nygaard, IE (reprint author), Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT 84108 USA. NR 50 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 BP 1 EP 2 DI 10.1016/j.ajog.2013.10.878 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 281XL UT WOS:000329134200003 PM 24359865 ER PT J AU Romero, R Badr, MS AF Romero, Roberto Badr, M. Safwan TI A role for sleep disorders in pregnancy complications: challenges and opportunities SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID PREECLAMPSIA PROSPECTIVE COHORT; GESTATIONAL DIABETES-MELLITUS; POSITIVE AIRWAY PRESSURE; FETAL-GROWTH RESTRICTION; NEURODEGENERATIVE DISEASES; INDUCED-HYPERTENSION; BLOOD-PRESSURE; NASAL CPAP; INSULIN SENSITIVITY; DAYTIME SLEEPINESS C1 [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Badr, M. Safwan] Wayne State Univ, Dept Med, Div Pulm Crit Care & Sleep Med, Detroit, MI 48202 USA. RP Romero, R (reprint author), 3990 John R Rd, Detroit, MI 48201 USA. EM romeror@mail.nih.gov FU Intramural NIH HHS NR 125 TC 4 Z9 5 U1 2 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 BP 3 EP 11 DI 10.1016/j.ajog.2013.11.020 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 281XL UT WOS:000329134200004 PM 24359866 ER PT J AU Sjaarda, LA Albert, PS Mumford, SL Hinkle, SN Mendola, P Laughon, SK AF Sjaarda, Lindsey A. Albert, Paul S. Mumford, Sunni L. Hinkle, Stefanie N. Mendola, Pauline Laughon, S. Katherine TI Customized large-for-gestational-age birthweight at term and the association with adverse perinatal outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE customized birthweight; delivery complications; large for gestational age; macrosomia; neonatal morbidity; neonatal mortality ID FETAL-GROWTH; INCREASING PREVALENCE; PREGNANCY OUTCOMES; DIABETES-MELLITUS; RISK; INFANTS; PERCENTILES; POPULATION; MACROSOMIA; STANDARDS AB OBJECTIVE: Using a cohort of 110,447 singleton, term pregnancies, we aimed to validate the previously proposed customized standard of large-for-gestational-age (LGA) birthweight, derive an additional customized LGA model excluding maternal weight, and evaluate the association between differing definitions of customized LGA and perinatal morbidities. STUDY DESIGN: Three customized LGA classifications, in addition to a population-based 90th percentile, were made according to the principals described by Gardosi: (1) customized LGA using Gardosi's previously published coefficients (LGA-Gardosi), (2) customized LGA using coefficients derived by a similar method but from our larger cohort, and (3) derived without customization for maternal weight. Associations between the LGA classifications and various perinatal morbidity outcomes were evaluated. RESULTS: Coefficients derived here for physiologic and pathologic effects on birthweight were similar to those previously reported by Gardosi. Customized LGA (any method) generally identified more births to younger, nonwhite, nulliparous mothers with female neonates of lower birthweight compared with population-based LGA. Rates of maternal and neonatal morbidity were greatest in births classified by both population-based LGA and customized LGA (any method). However, the model that excluded customization for maternal weight, revealed a greater proportion of women previously unidentified by population-based LGA who were more frequently black (40% vs 25%) and obese (30% vs 5.1%), along with greater rates of shoulder dystocia, neonatal intensive care unit admission and neonatal respiratory complications, than with LGA-Gardosi. CONCLUSION: The use of customized methods of defining LGA was not decisively superior compared with population-based LGA, but custom LGA may be improved by modification of the parameters included in customization. C1 [Sjaarda, Lindsey A.; Albert, Paul S.; Mumford, Sunni L.; Hinkle, Stefanie N.; Mendola, Pauline; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. RP Laughon, SK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. EM laughonsk@mail.nih.gov RI Hinkle, Stefanie/F-8253-2013; OI Hinkle, Stefanie/0000-0003-4312-708X; Sjaarda, Lindsey/0000-0003-0539-8110; Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] 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 (contract number HHSN267200603425C). NR 35 TC 2 Z9 2 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2014 VL 210 IS 1 AR 63.e1 DI 10.1016/j.ajog.2013.09.006 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 281XL UT WOS:000329134200021 PM 24035985 ER PT J AU Wei, ZS Yao, JH Wang, SJ Liu, JM Dwyer, AJ Pickhardt, PJ Nowinski, WL Summers, RM AF Wei, Zhuoshi Yao, Jianhua Wang, Shijun Liu, Jiamin Dwyer, Andrew J. Pickhardt, Perry J. Nowinski, Wieslaw L. Summers, Ronald M. TI Feasibility of Using the Marginal Blood Vessels as Reference Landmarks for CT Colonography SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE colon; colonic polyps; CT; CT colonography; mesentery; virtual imaging ID TOMOGRAPHIC VIRTUAL COLONOSCOPY; OPTICAL COLONOSCOPY; FALSE POSITIVES; POLYP DETECTION; COLONIC POLYPS; SUPINE; PRONE; REGISTRATION; POPULATION; REDUCTION AB OBJECTIVE. The purpose of this study was to show the spatial relationship of the colonic marginal blood vessels and the teniae coli on CT colonography (CTC) and the use of the marginal blood vessels for supine-prone registration of polyps and for determination of proper connectivity of collapsed colonic segments. MATERIALS AND METHODS. We manually labeled the marginal blood vessels on 15 CTC examinations. Colon segmentation, centerline extraction, teniae detection, and teniae identification were automatically performed. For assessment of their spatial relationships, the distances from the marginal blood vessels to the three teniae coli and to the colon were measured. Student t tests (paired, two-tailed) were performed to evaluate the differences among these distances. To evaluate the reliability of the marginal vessels as reference points for polyp correlation, we analyzed 20 polyps from 20 additional patients who underwent supine and prone CTC. The average difference of the circumferential polyp position on the supine and prone scans was computed. Student t tests (paired, two-tailed) were performed to evaluate the supine-prone differences of the distance. We performed a study on 10 CTC studies from 10 patients with collapsed colonic segments by manually tracing the marginal blood vessels near the collapsed regions to resolve the ambiguity of the colon path. RESULTS. The average distances (+/- SD) from the marginal blood vessels to the tenia mesocolica, tenia omentalis, and tenia libera were 20.1 +/- 3.1 mm (95% CI, 18.5-21.6 mm), 39.5 +/- 4.8 mm (37.1-42.0 mm), and 36.9 +/- 4.2 mm (34.8-39.1 mm), respectively. Pairwise comparison showed that these distances to the tenia libera and tenia omentalis were significantly different from the distance to the tenia mesocolica (p < 0.001). The average distance from the marginal blood vessels to the colon wall was 15.3 +/- 2.0 mm (14.2-16.3 mm). For polyp localization, the average difference of the circumferential polyp position on the supine and prone scans was 9.6 +/- 9.4 mm (5.5-13.7 mm) (p = 0.15) and expressed as a percentage of the colon circumference was 3.1% +/- 2.0% (2.3-4.0%) (p = 0.83). We were able to trace the marginal blood vessels for 10 collapsed colonic segments and determine the paths of the colon in these regions. CONCLUSION. The marginal blood vessels run parallel to the colon in proximity to the tenia mesocolica and enable accurate supine-prone registration of polyps and localization of the colon path in areas of collapse. Thus, the marginal blood vessels may be used as reference landmarks complementary to the colon centerline and teniae coli. C1 [Wei, Zhuoshi; Yao, Jianhua; Wang, Shijun; Liu, Jiamin; Dwyer, Andrew J.; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Pickhardt, Perry J.] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Nowinski, Wieslaw L.] Agcy Sci Technol & Res, Singapore Bioimaging Consortium, Biomed Imaging Lab, Singapore, Singapore. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10,Rm 1C224D,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU National Institutes of Health Clinical Center; iCAD FX This research was supported by the Intramural Research Program of the National Institutes of Health Clinical Center.; R. M. Summers and J. Yao have patents (pending or awarded) for related automated analyses for CT colonography. R. M. Summers and J. Yao receive royalty income for a patent license from iCAD. R. M. Summers's laboratory receives research support from iCAD and received research software from Viatronix. P. J. Pickhardt is a consultant for Viatronix, Bracco, iCAD, and Check-Cap and cofounder of VirtuoCTC. NR 45 TC 2 Z9 2 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JAN PY 2014 VL 202 IS 1 BP W50 EP W58 DI 10.2214/AJR.12.10463 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 281PH UT WOS:000329113000007 PM 24370165 ER PT J AU Mbulaiteye, SM Pullarkat, ST Nathwani, BN Weiss, LM Rao, N Emmanuel, B Lynch, CF Hernandez, B Neppalli, V Hawes, D Cockburn, MG Kim, A Williams, M Altekruse, S Bhatia, K Goodman, MT Cozen, W AF Mbulaiteye, Sam M. Pullarkat, Sheeja T. Nathwani, Bharat N. Weiss, Lawrence M. Rao, Nagesh Emmanuel, Benjamin Lynch, Charles F. Hernandez, Brenda Neppalli, Vishala Hawes, Debra Cockburn, Myles G. Kim, Andre Williams, Makeda Altekruse, Sean Bhatia, Kishor Goodman, Marc T. Cozen, Wendy TI Epstein-Barr virus patterns in US Burkitt lymphoma tumors from the SEER residual tissue repository during 1979-2009 SO APMIS LA English DT Article DE Non-hodgkin lymphoma; burkitt lymphoma; epstein-barr virus; MYC; HIV; AIDS; Africa ID NON-HODGKIN LYMPHOMAS; UNITED-STATES; EPIDEMIOLOGIC EVIDENCE; DISEASE; MYC; CELLS; APOPTOSIS; DIAGNOSIS; GENOMICS; ETIOLOGY AB Burkitt lymphoma (BL) occurs at all ages, but the patterns of Epstein-Barr virus (EBV) positivity in relation to human immunodeficiency virus (HIV), immunoprofiles and age have not been fully explored. BL tissues from residual tissue repositories, and two academic centers in the United States were examined by expert hematopathologists for morphology, immunohistochemistry, MYC rearrangement, EBV-encoded RNA (EBER), and diagnosed according to the 2008 WHO lymphoma classification. Analysis was done using frequency tables, Chi-squared statistics, and Student's t-test. Of 117 cases examined, 91 were confirmed as BL. The age distribution was 26%, 15%, 19%, and 29% for 0-19, 20-34, 35-59, 60+ years, and missing in 11%. MYC rearrangement was found in 89% and EBER positivity in 29% of 82 cases with results. EBER positivity varied with age (from 13% in age group 0-19 to 55% in age group 20-34, and fell to 25% in age group 60+ years, p=0.08); with race (56% in Blacks/Hispanics vs 21% in Whites/Asians/Pacific Islanders, p=0.006); and by HIV status (64% in HIV positive vs 22% in HIV negative cases, p=0.03). EBER positivity was demonstrated in about one-third of tumors and it was strongly associated with race and HIV status, and marginally with age-group. C1 [Mbulaiteye, Sam M.; Emmanuel, Benjamin; Bhatia, Kishor] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. [Pullarkat, Sheeja T.; Rao, Nagesh] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Nathwani, Bharat N.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Weiss, Lawrence M.] Clarient Inc, Aliso Viejo, CA USA. [Lynch, Charles F.; Neppalli, Vishala] Univ Iowa, Iowa City, IA USA. [Hernandez, Brenda; Goodman, Marc T.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Hawes, Debra; Cockburn, Myles G.; Kim, Andre; Cozen, Wendy] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Williams, Makeda] NCI, Dept Hlth & Human Serv, Ctr Global Hlth, NIH, Rockville, MD 20852 USA. [Altekruse, Sean] NCI, Div Canc Control & Populat Sci, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. RP Mbulaiteye, SM (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,Execut Plaza South,Rm 7080 MSC 7, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services by NCI [HHSN261200900444P, HHSN26120090058 6P, NO1-PC-35143, NO1-PC-35137, N01-PC-35139 N01-PC-2010-00035]; California Department of Health Services as part of the statewide cancer reporting program; Centers for Disease Control and Prevention [1U58D P000807-3] FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services (HHSN261200900444P and HHSN26120090058 6P) by NCI grants to the participating SEER Registries (NO1-PC-35143 for Iowa, NO1-PC-35137 for Hawaii, and N01-PC-35139 N01-PC-2010-00035 for Los Angeles), and by a grant from the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885 and from the Centers for Disease Control and Prevention (1U58D P000807-3). NR 35 TC 7 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0903-4641 EI 1600-0463 J9 APMIS JI APMIS PD JAN PY 2014 VL 122 IS 1 BP 5 EP 15 DI 10.1111/apm.12078 PG 11 WC Immunology; Microbiology; Pathology SC Immunology; Microbiology; Pathology GA 278SD UT WOS:000328909100002 PM 23607450 ER PT J AU Plazinska, A Pajak, K Rutkowska, E Jimenez, L Kozocas, J Koolpe, G Tanga, M Toll, L Wainer, IW Jozwiak, K AF Plazinska, Anita Pajak, Karolina Rutkowska, Ewelina Jimenez, Lucita Kozocas, Joseph Koolpe, Gary Tanga, Mary Toll, Lawrence Wainer, Irving W. Jozwiak, Krzysztof TI Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the beta(2)-adrenergic receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE beta(2)-Adrenoceptor selective agonist; beta(2)-Adrenoceptor conformations; Agonist-stabilized conformations; Antagonist-stabilized conformations; [H-3]-(R,R ')-4 '-methoxyfenoterol ID DOCKING AB The beta(2)-adrenergic receptor (beta(2)-AR) agonist [H-3]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (K-i values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at alpha' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [H-3]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC50 values, were determined in HEK293 cells expressing the beta(2)-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the alpha' position. The results also indicate that the K-i values obtained using [H-3]-(R,R')methoxyfenoterol as the marker ligand modeled the EC50 values obtained from cAMP stimulation better than the data obtained using [H-3]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the beta(2)-AR conformation probed by [H-3]-(R,R')-4'-methoxyfenoterol. The CoMFA model of the agonist-stabilized beta(2)-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the beta(2)-AR is governed to a greater extend by steric effects than binding to the [H-3]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Plazinska, Anita; Pajak, Karolina; Rutkowska, Ewelina; Jozwiak, Krzysztof] Med Univ Lublin, Lublin, Poland. [Jimenez, Lucita; Kozocas, Joseph; Koolpe, Gary; Tanga, Mary] SRI Int, Menlo Pk, CA 94025 USA. [Toll, Lawrence] Torrey Pines Inst Mol Studies, Port St Lucie, FL USA. [Wainer, Irving W.] NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Jozwiak, K (reprint author), Med Univ Lublin, Lublin, Poland. EM krzysztof.jozwiak@umlub.pl RI Pajak, Karolina/B-7811-2014; OI Pajak, Karolina/0000-0001-7725-5392; Plazinska, Anita/0000-0002-3698-2574 FU National Institutes of Health National Institute on Aging [N01-AG31009]; NIA/NIH; Foundation for Polish Science (TEAM Programme) FX This research was supported by the National Institutes of Health National Institute on Aging [Contract N01-AG31009] by the Intramural Research Program of the NIA/NIH; and by the Foundation for Polish Science (TEAM Programme). The article was developed using the equipment purchased within the Project 'The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases' within the Operational Program Development of Eastern Poland 2007-2013, Priority Axis I Modern Economy, Operations I.3 Innovation Promotion. NR 16 TC 6 Z9 6 U1 1 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JAN 1 PY 2014 VL 22 IS 1 BP 234 EP 246 DI 10.1016/j.bmc.2013.11.030 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 280ZD UT WOS:000329068400019 PM 24326276 ER PT J AU Slobounov, S Bazarian, J Bigler, E Cantu, R Hallett, M Harbaugh, R Hovda, D Mayer, AR Nuwer, MR Kou, Z Lazzarino, G Papa, L Vagnozzi, R AF Slobounov, Semyon Bazarian, Jeff Bigler, Erin Cantu, Robert Hallett, Mark Harbaugh, Robert Hovda, David Mayer, Andrew R. Nuwer, Marc R. Kou, Zhifeng Lazzarino, Giuseppe Papa, Linda Vagnozzi, Roberto TI Sports-related concussion: ongoing debate SO BRITISH JOURNAL OF SPORTS MEDICINE LA English DT Editorial Material DE Concussion C1 [Slobounov, Semyon] Penn State Univ, Dept Kinesiol & Neurosurg, Penn State Ctr Sports Concuss, Penn State Hershey Med Ctr, University Pk, PA 16802 USA. [Bazarian, Jeff] Univ Rochester Sch Med & Dent, Dept Emergency Med, Rochester, NY USA. [Bigler, Erin] Brigham Young Univ, Dept Psychol & Neurosci, Provo, UT 84602 USA. [Cantu, Robert] Bo